摘要:

5. GENERAL METHODS By R. Brettle (Department of Chemistry The University Sheffield S37Hfl Reduction.-Catalytic hydrogenation. Interest in the use of homogeneous hydrogenation catalysts has continued. Naphtha-1,4-quinone is hydrogenated to the 2,3-dihydro-derivative in the presence of chlorotris(tripheny1phos-phine)rhodium a transformation previously only accomplished in low yield.’ The non-conjugated double bond in eremophiline (1) is reduced2 by this catalyst but it is the conjugated double bond in (2) which is red~ced,~ in agreement with earlier reports that di- but not tri-substituted olefins are selectively reduced. ap-Olefinic aldehydes can be reduced to their saturated O (1) analogues despite the fact that chlorotris(tripheny1phosphine) rhodium is a powerful decarbonylation ~atalyst.~ This catalyst is poisoned by thiols but it reduces ally1 phenyl sulphide to phenyl propyl sulphide in high yield.’ Trihydrotris(triphenylphosphine)iridium(rrI)catalyses the homogeneous hydro- genation of saturated aldehydes but not simple olefins in the presence of acetic acid.6 Only terminal olefins are reduced when the catalyst is hydrido- chlorotris(tripheny1phosphine)ruthenium (11)’ A stereoselective reduction of the unsaturated proline derivative (3) has been achieved’ using a heterogeneous platinum catalyst deposited on a basic ion- exchange resin.With this catalyst much greater amounts of the trans-isomer (4) are obtained than with conventional catalysts. It is presumed that the carboxyl face of the molecule is preferentially absorbed on the basic catalyst A.J. Birch and K. A. M. Walker Tetrahedron Letters 1967,3457. M. Brown and L. W. Piskzkiewicz J. Org. Chem. 1967,32,2013. R. D. Hoffsommer D. Taub and N. L. Wendler J. Org.Chem. 1967,32,3074. F. H. Jardine and G. Wilkinson J. Chem. SOC.(C) 1967,270. ’ A. J. Birch and K. A. M. Walker Tetrahedron Letters 1967 1935. ‘R. S. Coffey Chem. Comm. 1967,923. ’ P. S. Hallman D. Evans J. A. Osborn and G. Wilkinson Chem. Comm. 1967 305. * B. J. Magerlein R. D. Birkenmeyer R. R. Herr and F. Kagan J. Amer. Chem. SOC. 1967 89,2459. 200 R. Brettle Et -CH Et-CH HN-CO-OCH Ph HQ-c0-0cH2ph G C02H C02H (3) (4) resin. Earlier work on catalysts based on ion-exchange resins had shown the effect of polarity at the catalyst surface on the steric course of the reduction of steroidal 3-0xo-4-enes.~ Such catalysts merit further attention.The semi-hydrogenation of allenes has been investigated using a palladium catalyst. In certain cases this method may prove a useful stereospecific synthesis for a trisubstituted olefin.'' MeO2G MeO2C,-Me /c=c=c /H -c Me 'H M~-H The reduction of cyclohexanones using a pre-reduced palladium hydroxide catalyst in an alcohol gives the cyclohexyl ether in high yield.' Further work aimed at an understanding of the mechanism of the hydro- genolysis of benzyl alcohols and their derivatives has appeared.' The results are essentially in agreement with the earlier generali~ation'~ that chiral benzyl alcohols undergo hydrogenolysis with retention at a Raney nickel catalyst but with inversion at a palladium catalyst.The stereochemical consequences of the hydrogenolysis of the secondary allylic ester 0-P-phenylpropionyl- taxicin-1 at a palladium catalyst can best be interpreted in terms of an in- version at the hydrogenolysis centre. l4 Aluminium hydrides. Sodium aluminium hydride which can be prepared directly from the elements reacts with alcohols to give modified reagents one of which sodium tri-t-butoxyaluminium hydride reduces certain acyl halides to aldehydes in better yield than the corresponding lithium salt." Addition of ethanol to the complex of lithium aluminium hydride with 3-0-benzyl-1,2-0- cyclohexylidene-a-D-glucofuranoseleads to a new reducing species which reduces methyl ketones asymmetrically to give predominantly the R-alcohols whereas the unmodified complex gives a smaller excess of the S-alcohols.16 Some acylhydrazones are reduced by two equivalents of lithium aluminium hydride to I-acyl-2-alkylhydrazines." R '-CO-NH-N=CHR~ -+ R'-CO-NH-NH-CH ,R~ F.J. McQuillin W. 0.Ord and P. L. Simpson J. Chem. SOC.,1963 5996. lo L. Crombie P. A. Jenkins D. A. Mitchard and J. C. Williams Tetrahedron Letters 1967,4297. S. Nishimura T. Itaya and M. Shiota Chem. Comm. 1967,422. l2 A. M. Khan F. J. McQuillin and I. Jardine J. Chem. SOC.(C),1967 136; E. W. Garbisch jun. L. Schreader and J. J. Frankel .I. Amer. Chem. SOC.,1967,89,4233. S. Mitsui and Y. Kudo Chem. and Id., 1965,381.I4 M. Dukes and B. Lythgoe J. Chem. SOC.(C) 1967,2144. Is L. I. Zakharkin D. N. Mash and V. V. Gavrilenko,J. Org. Chem. (U.S.S.R.),1966 2,2153. l6 S. R. Landor B. J. Miller and A. R. Tatchell,J. Chem. SOC.(C),1967 197. l7 B. T. Gillis and R. E. Kadunce,J. Org. Chem. 1967,32,91. General Methods 20 1 Boron hydrides. The synthetic possibilities of vinylalanes and vinylboranes have been explored ;the results are discussed below in the section dealing with olefins. Pure 1,l-diboroalkanes uncontaminated with the 1,2-isomers can be obtained by treating alk- 1-ynes with reagents like dicyclohexylborane. On treatment with aqueous alkaline peroxide they give alkan-1-ols but oxidation in the absence of water (e.g. by rn-chloroperbenzoic acid) gives high yields of alkanoic acids.’* The hydroboronation of some ally1 derivatives has been investigated. Allylic alcohols can give either diols or olefins (by elimination); the yield of diols is enhanced by using the tetrahydropyranol ethers and the theoretical amount of diborane. l9 The hydroboronation of each of the diastereoisomers of (1R)-isopulegol (e.g. 5) is unexpectedly stereospecific for the formation of the new chiral centre; this effect is not observed in limonene (6)which lacks the hydroxyl group.20 y” Me The action of diborane on benzofulvenes causes hydrogenation not hydro- boronation at the semicyclic double bond.2 ‘ The use of norbornene or dec-1-ene to regenerate an olefin from an organo- borane provides a useful means of olefin isomerization when used in con- junction with a hydroboronation-thermal isomerisation sequence,22 as illustrated in Scheme 1.CH2Me CH2Me CH2CH,B< CH=CH -b*-Ie: B,H -0RCH=CH2 0 SCHEME 1 Selective protonolysis of a primary carbon-boron bond in a mixed trialkyl- borane can be accomplished. This is used in the conversion of limonene (6) into the saturated alcohol (7) via the cyclic organoborane produced by the action of 2,3-dimethylbut-2-ylborane (thexylborane) in dilute solution.23 G. Zweifel and H. Arzoumanian J. Amer. Chem. SOC. 1967,89 291. R. M. Gailivan jun. Diss. Abs. 1966,27B 751. 2o K. H. Schulte-Elte and G. Ohloff; Helv. Chim. Acta 1967,50 153. 21 M. Rabinovitz G. Salemnik and E. D. Bergmann Tetrahedron Letters 1967 3271. ” H.C. Brown and G. Zweifel J. Amer. Chem. SOC.,1967,89 561; H. C. Brown M. V. Bhatt T. Munekata and G. Zweifel ibid. p. 567. 23 H. C. Brown and C. D. Pfaffenberger J. Amer. Chem. SOC.,1967,89,5475. 202 R. Bwttle HO-__c (6)-H202 The reduction of oxime ethers24 or esters2’ with diborane gives primary amines ; oximes give hydroxylamines.26 The reducing power of diborane is modified by the addition of 10% of ethyl acetate.27 Side chain aliphatic-type esters in the pyrr01e~~” series are not reduced though they are and ind01e~~’ readily reduced by the unmodified reagent so that for example selective reduction of pyrroketones carrying propionic ester residues to the corres- ponding dipyrromethanes can be effected ; aromatic-type ester groups are not reduced by either system.Diborane rapidly reduces 3,3-disubstituted indolenines to in do line^.^^' Hydrogenolysis of cyclopropyl ketones and carbinols occurs with diborane in the presence of boron trifluoride.’* Certain variations in behaviour observed with externally generated diborane may be due to en- trainment of boron trifluoride in the gas stream.28 The anomalous reduction of a cyanide to a primary amine by sodium borohydride has been observed for 2- and 4- (but not 3-) cyanopyridine,” and the cleavage of a highly hindered diterpene methyl ester to the corresponding acid by the action of sodium borohydride in refluxing propan-2-01 has been rep~rted.~’ The hydrogenolysis of thymine dimer by sodium borohydride can be accomplished in aqueous solution at room temperature; the reaction is reported to be general for cyclic imide~.~’ The reduction of a 14-alkenyl-codeinone (an ap-olefinic ketone) by sodium borohydride in pyridine at room temperature gives a mixture of the 7,8-dihydro-derivative (the saturated ketone) and the 14-alkenylcodeine (the allylic alcohol) ;only the latter product is formed when the solvent is 2-etho~yethanol.~~ 24 H.Feuer and D. M. Braunstein Abstracts 154th Amer. Chem. SOC. Meeting 1967 568. ’’ A. Hassner and P. Catsoulacos Chem. Comm. 1967 59 26 H. Feuer B. F. Vincent jun. and R. S. Bartlett J. Org. Chem. 1965,30 2877. 2’ (a)A. H. Jackson G. W. Kenner and G. S. Sach J. Chem. SOC. (C),1967,2045; (b)A. H. Jackson and P. Smith Chem. Comm. 1967,264. 28 E.Breuer Tetrahedron Letters 1967 1849. ’’ S. Yamada and Y. Kikugawa Chem. and Ind. 1967,1325. 30 D. M. S. Wheeler M. M. Wheeler M. Fetizon and W. H. Castine Tetrahedron 1967,23,3909. 31 T. Kumieda and B. Witkop J. Amer. Chem.SOC.,1967,89,4233. 32 K. W. Bentley D. G. Hardy and B. Meek,J. Amer. Chem. SOC.,1967,89,3293. General Methods 203 Other methods. Previous had shown that heterocyclic compounds in their excited states were amenable to reduction in a selective fashion which is often not possible by catalytic hydrogenation. A further example is the photoreduction of kynurenic acid (8) which can be accomplished with sodium borohydride or more advantageously by sodium ~ulphite.~~ Catalytic hydro- genation affects the benzene ring.(8) The photoreduction of a phenol 3J7P-oestradiol (9) has also been ~tudied.~' Sodium sulphite gives twice the yield obtained with borohydride. The nature of the products depends on the reducing agent and (for borohydride) on the solvent. Identified products are shown in Scheme 2. SCHEME 2 The reduction of phenols to homoallylic alcohols can be effected by a large excess of lithium in liquid ammonia. 36 Steroidal 3-hydroxy- 1,4-dienes with lithium in liquid ammonia-1-methoxypropan-2-01give the 1,4-dienes by protonation of the intermediate U-shaped pentadienyl anion at the central po~ition.~' The presence of excess alcohol during the lithium in liquid ammonia reduction of certain 5-methoxy-indoles3* and -benzfurans3' alters the nature of the products and causes reduction to occur in the benzene ring.33 cj. Ann. Reports 1966 339. 34 T. Tokuyama S. Senoh T. Sakan K. S. Brown jun. and B. Witkop J. Amer. Chem. SOC. 1967,89 1017. 35 J. A. Waters and B. Witkop J. Amer. Chem. SOC.,1967,89 1022. 36 J. Fried N. A. Abraham and T. S. Santhanakrishnan J. Amer. Chem. SOC.,1967,89,1044. ''I T. J. Foell R.W. Rees,R.E. Bright and H. Smith Chem. and Ind. 1967,1452. W. A. Remers G. J. Gibs C. Pidocks and M. J. Weiss J. Amer. Chem. SOC. 1967,89,5513. 39 S. D. Darling and K. D. Wills J. Org. Chem. 1967,32 2794. 204 R. BEttle The advantages of reducing tertiary halides homolytically using organo- stannanes especially those containing hydrogen isotopes have been ~tressed.~’ The use of organosilanes may prove to be a useful alternative; the results on the selective dehalogenation of geminal polyhalides are pr~mising.~’ Olefins which on protonation give a stable carbonium ion can be reduced at room temperature by triethylsilane in excess trifluoracetic acid.42 Some representa- tive organic compounds are reduced by ‘precipitated nickel’ in boiling water (e.g.mesityl oxide to methyl isobutyl ketone).43 The method requires a fuller evaluation. The synthetic possibilities of electrolytic hydrodimerization have been appraised44 and full details of electrochemical hydrocyclisation have a~peared.~’ The conversion [CO -+ CDz] can be effected electrochemically in very high yield ; thioacetal desulphurisation frequently results in isotopic ~crarnbling.~~ Oxidation.-Reviews have appeared on 2,3-dichloro-5,6-dicyanobenzo-quinone (DDQ) and its reaction^?^ dimethyl sulphoxide oxidation^,^^ and the organic chemistry of period ate^.^^ Albright and Goldman have published full details of their use of dimethyl sulphoxide-acetic anhydride in oxidation.This system oxidises all inositols to penta-acetoxybenzene,’ 3,4-dihydr0-3,4-dihydroxy-9,1 O-dimethyl-1,7-benzanthracene to the corresponding quinone (when many other oxidants failed),” and converts an indole alkaloid cyclic hemi-acetal into the corres- ponding la~tone.’~ Substitution of diethylcarbodi-imide for dicyclohexyl- carbodi-imide in the Pfitzner-Moffat dimethyl sulphoxide reagent may facilitate the isolation of the oxidation product since the resulting urea is water-~oluble.’~Another useful oxidising system allowing easy product isolation is dimethyl sulphoxide-sulphur trioxide (as the pryidine complex)- triethylamine ; it is particularly useful for allylic alcohols and gives few by- products of the methyl thiomethyl ether type so frequently encountered in 40 F.D. Greene and N. N. Lowry J. Org. Chem. 1967,32,882. 41 Y. Nagai K. Yamazaki and I. Shiojima,Bull. Chem. SOC.Japan 1967,40,2210. 42 D. N. Kursanov Z. N. Pares G. I. Bussova N. M. Loim and V. I. Zdanovich Tetrahedron 1967,23,2235. 43 K. Sakai and K. Watanabe Bull. Chem. SOC.Japan 1967,40 1548. 44 M. M. Baizer J. D. Anderson J. H. Wagenknecht M. R. Ort and J. P. Petrovich Electrochim. Acta 1967 12 1377. 45 J. D. Anderson M.M. Baizer and J. P. Petrovich,J. Org. Chem. 1966,31 3890. 46 L. Throop and L. TBkts J. Amer. Chem. SOC. 1967,89,4789. ” D. Walker and J. D. Hiebert Chem.Rev. 1967,67,153. W. W. Epstein and F. W. Sweat Chem. Rev. 1967,67,247. 49 B. Sklarz Quart. Rev. 1967.21 3. ” J. D. Albright and L. Goldman J. Arner. Chem. SOC.,1967,89,2416. 51 A. J. Fatiadi Chem. Comm.,1967,441. s2 M. S. Newman and C. C. Davis J. Org. Chem. 1967,32,66. ’’ C. W. L. Bevan M. B. Patel A. H. Rees and A. G. Loudon Tetrahedron 1967,23,3809. 54 G. H. Jones and J. G. Moffatt quoted by A. F. Cook and J. G. Moffatt J. Amer. Chem. SOC. 1967,89,2697. General Methods 205 oxidations with dimethyl ~ulphoxide.~~ Acids catalyse the oxidation of isocyanides to isocyanates by dimethyl sulphoxide.The widely-used Lemieux-von Rudloff periodate-permanganate oxidation has been adapted for large scale preparative use.57 Permanganate oxidation in acetone of the phthalimidine derivative (10) caused dehydrogenation to the styrene derivative (11).58 Earlier examples of this type of behaviour on the oxidation of tertiary centres are known.59 Me Me (10) (11) Amines in which the alkyl groups have an a-hydrogen atom are degraded to carbonyl compounds under very mild conditions by the action of buffered permanganate in warm aqueous t-butyl alcohol.60 This process represents an interesting alternative to amine degradations based on p-eliminations. R~RZCH-N’\+ R~R~c-/\ A $3-olefinic ester has been converted into the afky6-diolefinic ester by DDQ.6 Chromic acid oxidation OF secondary-tertiary glycols leads to carbon- carbon bond fission with the production of a ketone function at the tertiary site but in the presence of manganous ions the reaction takes a different course and the secondary alcohol function is oxidised normally.62 FH,OAc CH,OAc I Certain prop-2-ynyl alcohols are oxidised in good yields to the corresponding aldehydes with nickel peroxide but manganese dioxide gives low yields.63 a Synthetic routes to 4-phenyl-l,2,4-triazoline-3,5-dione very powerful oxidising agent,64 have been described.65 55 J.R. Parikh and W. von E. Doering J. Amer. Chem. SOC.,1967,89,5505. 56 D. Martin and A. Weise Angew. Chem. Internat. Edn. 1967,6 168. 5’ C. G. Overberger and H. Kaye J.Amer. Chem. SOC. 1967,89,5640. 58 D. C. Aldridge J. J. Armstrong R. N. Speake and W. B. Turner J. Chem. SOC.(C),1967 1667. 59 B. E. Cross J. F. Grove J. MacMillan and T. P. C. Mulholland J. Chem. SOC.,1958 2520; J. F. Grove and T. P. C. Mulholland ibid. 1960 3007. 6o S. S. Rawalay and H. Schechter J. Org. Chem. 1967,32 3129. 61 T. R. Kasturi G. R. Pettit and K. A. Jaeggi Chem. Comm. 1967,644. B. H. Walker J. Org. Chem. 1967,32 1098. R. E. Atkinson R. F. Curtis D. M. Jones and J. A. Taylor Chem. Comm. 1967 718. 64 cf Ann. Reports 1966 342. R. C. Cookson S. S. H. Gilani and I. D. R. Stevens,J. Chem. SOC.(C),1967 1905. 206 R. Brettte A variation on intramolecular oxidation via alkyl hypoiodides has been discovered.66 One of the products from the action of lead tetra-acetate and iodine on the alcohol (12) is the iodo-ether (13).The genesis of (1 3) involves a 'billiard' reaction in which generation of a radical centre at oxygen for the second time causes generation of a radical centre at the axial C-4 methyl H H (1 2) (13) group via formation of a carbon radical at the C-10 substituent. This variation can occur whenever two consecutive 1,5-hydrogen-atom shifts are possible and both linear and angled 'shots' have been discovered. An alternative to the Wurtz-Fittig coupling reaction involves the oxidation of copper(1)ate complexes and works for primary and secondary alkyl aryl and vinyl halides.67 0lefins.-An excellent new route to mono- di tri- or tetra-substituted olefins has advantages over the Wittig synthesis.68 Lithiophosphon-bis-NN- dialkylamides (14) which unlike Wittig ylids can be alkylated (14; R3 R4 = H to R3,R4 = alkyl) condense with aldehydes and ketones to give P-hydroxy- phosphon-bis-NN-dialkylamides (1 5) which decompose thermally in benzene to give olefins as shown in Scheme 3.Diastereoisomeric P-hydroxyphosphon- amides decompose stereospecifically each giving a single olefin. The reaction R4 0 0-~3o R' '/ C=O + R3-kL8-NR52+ R'J-t!-j-NR52 R2 Li LRs2 b2 b4 kRS2 (14) 1 OHR~o R'R2C=CR3R3 silica gel SCHEME (15) 3 giving the trans-olefm is the faster so that partial decomposition of a mixture of the diastereoisomers gives pure trans-olefin. Uusually both pure diastereo- isomers can be obtained either by fractionation of the mixtures or by the reduction of P-ketophosphonamides which can be carried out with equili- 66 E.Wenkert and B. L. Mylari J. Amer. Chem. Soc. 1967,89 174. 67 G. M. Whitesides J. San Filippo Jr. C. P. Casey and E. J. Panek J. Amer. Chem. SOC.,1967 89 5302. 68 E. 3. Corey and G. T. Kwiatkowski J. Am. Chem. SOC.,1966,88,5652. General Methods 207 brati~n.~’ The P-ketophosphonamides are available by acylation of lithio- phosphonamides (14) or by oxidation of P-hydroxyphosphonamides (1 5 ;R or R2= H). Predictable stereochemical control in this olefin synthesis should soon be achieved. Other less generally useful syntheses involving phosphono- thioate esters7’ and ~ulphinamides~ have also been investigated. Russian7’ and German73 groups have-given full details of earlier work on the stereochemical control of the Wittig synthesis.Sodium 2-methylbutan-2- oxide is better than other bases for the preparation of non-stabilized phos- phonium ylid~.~~ New syntheses employing phosphonium ylids include those of 1-alkenyl alkyl ethers (an alternative route using formate ester^),^' y-keto-esters and P-acylacrylic cis-py-unsaturated aliphatic nit rile^,^ and a-halogenoacrylic esters and nit rile^.^^ A new synthesis of cyclic phosphonium ylids from am-dihalides has been rep~rted.~’ A new type of transylidation has been discovered.80 CH,-LH-CN + Ph3P = CHCO,Etc* Ph,P-LH-CN + CH2-LH-C02Et A useful olefi? synthesis stems from the crossed coupling of a x-allylnickel(Z) bromide conveniently prepared from an allylic bromide and excess nickel carbonyl in benzene with an alkyl aryl vinyl or benzyl halide; the presence of hydroxy carbonyl ester or less reactive halide functions is tolerated.* ’ Partial isomerisat ion of the double bond occurs.aa-Dimethylallyl bromide couples at the y-position providing a route to isoprenoid compounds. The n-allylnickel bromides also react with carbonyl compounds and epoxides to give hydroxy-olefins. The nickel-catalysed reactions of ally1 halides have been reviewed.82 The electrochemical bisdecarboxylation of 1,Zdicarboxylic acids in bridged systems is a very mild olefin synthesis;83 the best route to ‘Dewar benzene’ involves such a step.84 Further works5 has established that excess of an alkyl-lithium (like sodium 69 E.J. Corey and G. T. Kwiatkowski J. Amer. Chem. SOC. 1966.88 5653. ’O E. J. Corey and G. T. Kwiatkowski J. Amer. Chem. SOC. 1967,88 5654. E. J. Corey and T. Durst J. Amer. Chern. SOC.,1966,88 5656. 72 L. D. Bergelson L. I. Barsukov and M. M. Shemyakin Tetrahedron 1967.23 2709. 73 M. Schlosser and K. F. Christmann Annalen 1967 708 1. 74 J. M. Conia and J-C1 Limasset Bull. SOC. chim. France 1967 1936. ’’ S. P. Ivashchenko I. K. Sarycheva and N. A. Preobrazhenskii J. Org. Chem. (U.S.S.R.),1966 2 2139. 76 H-J. Bestmann G. Graf and H. Hartung Annalen 1967,706,68. ” J. D. McClure Tetrahedron Letters 1967 2401. D. J. Burton and J. R. Greenwald Tetrahedron Letters 1967 1535. 79 H-J. Bestmann and E. Kranz Angew.Chem. Internat. Edn. 1967,6 81. 8o J. D. McClure Tetrahedron Letters 1967 240 . E. J. Corey and M. F. Semmelhack J. Amer. Chem. SOC. 1967,89 2755. G. P. Chiusoli and L. Cassar Angew. Chem. Internat. Edn. 1967,6 124. 83 H. Plieninger and W. Lehnert Chem. Ber. 1967 100,2427. 84 T. Whitesides quoted by E. E. van Tamelen and D. Corty J. Amer. Chem. SOC. 1967,89,3922. ’’ R. H. Shapiro and M. J. Heath J. Amer. Chem. SOC. 1967,89 5734; G. Kaufman F. Cook H. Shechter J. Bayless and L. Friedman ibid. p. 5736. 208 R. Brettle hydride)86 promotes Hofmann rather than Saytzev orientation in the base- catalysed decomposition of N-toluene-p-sulphonylhydrazones and that rearrangements and cyclopropane formation resulting from carbonium ion and carbenoid pathways do not occur.An improved synthesis of NN‘-thiocarbonyldi-imidazole the reagent used to prepare thionocarbonates for the Corey-Winter olefin synthesis has been described.87 A synthesis of thionocarbonates by the disproportionation of ad-dihydroxy-bis(0-thiocarbony1)disulphides has found application in the synthesis of carbohydrate olefins.88 Thionocarbonates can be converted into olefins at room temperature by the diazophospholidines (16)?’ I Me Much interest has been shown in the synthesis of olefins from acetylenes through vinyl-alanes and -boranes. Hydroalumination of acetylenes with reagents like di-isobutylaluminium hydride proceeds via cis-addition to give cis-vinylalanes from disubstituted acetylenes and the equivalent trans-vinylalanes from terminal acetylene^.^' H H Trans-hydroalumination can be achieved with lithium di-isobutylmethyl- aluminium hydride ; the reagent is obtained from methyl-lithium and di- isobutylaluminium hydride.” The ate complexes of vinylalanes react with carbon dioxide to give up-olefinic acids and with formaldehyde and acet- aldehyde to give ally1 alcohols; the configuration of the double bond is retained.’ 86 c& Ann.Reports 1966 346. T. J. Pullukat and G. Urry Tetrahedron Letters 1967 1953. W. B. Doane B. S. Shasha C. R. Russell and C. E. Rist J. Org. Chem. 1965 30 162; B. S. Shasha W. M. Doane C. R. Russell and C. E. Rist Carbohydrate Res. 1966 3 121; E. I. Stout W. M. Doane B. S. Shasha C. R. Russell and C. E. Rist ibid. 1967,3 354. 89 E.J. Corey Pure Appl. Chem. 1967 14 19. 90 G. Wilke and H. Muller Annalen 1960,629,222. 91 G. Zweifel and C. C. Witney J. Amer. Chem. SOC. 1967,89,2753. 92 G. Zweifel and R. B. Steele J. Amer. Chem. SOC.,1967,89 2754. General Methods 209 Protonolysis of the trans-hydroalumination product leads to tr~ns-olefins,’~ a reaction already known in the cis-series; the method complements that reported last year,94 based on hydroalumination with lithium aluminium hydride which has since been experimentally simplified.” Halogenation of vinylalanes proceeds with retention of configuration to give vinyl halides ;” this is particularly useful for 1-iodoalk-1-enes since hydrogen iodide does not add to alk-1-ynes under peroxide conditions. The orientation in the hydro- alumination of a prop-2-ynyl alcohol can be controlled leading to either of two products which on iodination give isomeric vinyl iodides of definite configuration.Methylation of these with lithium dimethylcopperg6 then leads to specific trisubstituted 01efins.~’ The overall process is shown in Scheme 4. R-C-C-CH,OH (i) LiAIH,/AlCI / \ (i)LiAlH,/NaOMe (ii) I (ii) I R I R .H >C=C \/ ‘/ c=c H I CH,OH I I CH,OH I I Me zcuLi R .Me R H ‘C4’ H / \,CHZOH Me-CH,OH SCHEME 4 The reactions of vinylboranes do not exactly parallel those of vinylalanes. An alk-1 -yne with bis(3-methyl-2-butyI)boranegives a trans-vinylborane. Treatment of this with bromine gives an intermediate which decomposes in refluxing carbon tetrachloride to give the trans-vinyl bromide but which on alkaline hydrolysis gives the ~is-bromide.’~ Treatment of a vinylborane with iodine in the presence of alkali gives a cis-olefin with the stereospecific migration of a group from boron to carbon.” A similar migration occurs in the hydro- H H H H Bu CY Bu boronation of vinyl halides since alkaline peroxide converts the product into a secondary 93 G.Zweifel and R. B. Steele J. Amer. Chem. SOC.,1967,89 5085. 94 cJ Ann. Reports. 1966 338. 95 E.F.Magoon and L. H. Slaugh Tetrahedron 1967,23,4509. 96 E.J. Corey and G. H. Posner J. Amer. Chem. Soc. 1967,89,3911. 97 E.J. Corey J. A. Katzenellenbogen and G. H. Posner J. Amer. Chem. SOC. 1967,89 4245. 98 H.C. Brown D. H. Bowman S.Misumi and M. K. Unni J. Amer. Chem. SOC. 1967,89,4531. 99 G.Zweifel H. Arzoumanian and C. C. Whitney J. Amer. Chem. SOC.,1967,89 3652. loo G.Zweifel and H. Arzoumanian J. Amer. Chem. Soc. 1967,89 5086. 210 R. BIlettZe (i)RZ2BH R'CH-rH1 (ii)oH; H2G2 R'CH2CH( OH)RZ Trans-a-halogenovinylboranescan be prepared from l-halogenoacetyl- enes.'" With acetic acid they give cis-vinyl halides. On treatment with sodium methoxide they undergo the boron-carbon migration. OMe R' Br B' \/ NaOMe "\ / \ ,c=c \ -,C=C RZ H B-R~ H RZ The new vinylboranes on treatment with acid give trans-olefins and with alkaline hydrogen peroxide give (uia the enol) ketones. looThese last syntheses are governed by the availability of the appropriate dialkylboranes.Oxymercuration-demercuration reported last year as a route to ethers33 has now been thoroughly investigated as a mild procedure for the Markovnikov hydration of olefins.'" Very high yields can be obtained by this convenient and rapid method. Allylic chlorination can be effected by N-chloro-N-cyclohexylbenzene-sulp honamide. lo Carbonyl Compounds.-The Dickmann condensation with the Thorpe- Ziegler rea~tion,''~ and the Knoevenagel reaction' O4 have been reviewed. Two new aldehyde syntheses allow the conversion of acids or nitriles into the corresponding aldehydes via heterocyclic intermediates in such a way that deuterium can be incorporated at C-1.'05 New and superior methods for the synthesis of y6-olefinic aldehydes and ketones and py-allenic ketones (which can be isomerised by base to CtpyG-diolefinic ketones) have been fully described.lo6 They are based on the acid-catalysed condensations of enol- ethers with tertiary allylic or prop-2-ynyl alcohols.Several extremely valuable synthetic procedures involving the migration of alkyl groups from boron to carbon (see the previous section) have been developed. Aldehydes and ketones (and hence acids oia the haloform reaction) can be prepared by the addition of trialkylboranes to acrolein and methyl vinyl ketone in the presence of water."' R1,B + CH2==€H-COR2~R1CH,CH2COR2 lo' H. C. Brown and P. Geoghegan jun. J. Amer. Chem. SOC. 1967,89 1522; H. C. Brown and W. J. Hammar ibid. p. 1524; H. C. Brown J. H. Kawakami and S. Ikegami ibid. p. 1525. lo2 W.Theilacker and H. Wessel Annalen 1967,703 34. J. P. Schaefer and J. J. Bloomfield Organic Reactions 1967 15 1. lo4 G. Jones Org. Reactions 1967 15 204. 1. C. Nordin J. Heterocyclic Chem. 1966 3 531 ;A. I. Meyers and A. Nabeya Chem. Comm. 1967,1163. lo6 G. Saucy and R. Marbet Helv. Chim. Acta 1967 50 1158 2091; R. Marbet and G. Saucy ibid. p. 2095. lo' H. C. Brown M. M. RogiC M. W. Rathke and G. W. Kabalka J. Amer. Chem. Soc. 1967 89,5709; A. Suzuki A. Arase H. Matsumoto M. Itoh H. C. Brown M. M. RogiC and M. W. Rathke ibid. p. 5708. General Methods 21 1 Secondary groups show a large preference for migration over primary groups so that for example although hydroboronation of styrene gives only 18% attack at the secondary site reaction of the mixture of organoboranes with methyl vinyl ketone gives 43 % of 5-methyl-Sphenylpentanone.Carbonylation of trialkylboranes following earlier work under pressure has now been effected at atmospheric pressure. In the absence of moisture migration of all three alkyl groups occurs and oxidative hydrolysis leads to a tertiary alcohol in very high yield."* UH,H o R3B + CO L2R3COH However water inhibits the migration of the third group so that an inter- mediate organoborane results which on oxidative hydrolysis leads to a ketone. lo' HO R3B + CO-RB-CR~S OH R2C4 II OH OH It should be added that in the presence of sodium borohydride only one alkyl group is transferred providing a synthesis of primary alcohols.' lo These three methods provide alternative routes more tolerant of functional groups to NaBH, R3B + CO KOK RCH,OH products otherwise accessible through Grignard syntheses.Application of the second method to mixed organoboranes gives unsymmetrical ketones. For example hydroboronation of an olefin with dicyclohexylborane gives a new organoborane which by this method can be converted into a mixture of ketones containing in many cases a high proportion of the alkyl cyclohexyl ketone.'' Since Baeyer-Villiger oxidation of alkyl cyclohexyl ketones gives cyclohexyl alkanoates a useful route from olefins to acids with one more carbon atom has become available.112 The 2,3-dimethylbut-2-~1 (thexyl) group has a very low migratory aptitude in these carbonylation reactions. Stepwise hydroboronation of two olefins by thexylborane leads to a trialkyl- borane which by the second method (though the carbonylation now has to be carried out under pressure) gives a ketone not containing the thexyl group ;'l3 symmetrical or unsymmetrical ketones can be obtained in high yield.Use of a diene leads to cyclic ketones. In this way 1-vinylcyclohex-1-ene gives a 60% yield of trans-hydrindanone.''4 The synthetic potentialities of 0-ketosulphoxides have been further em-phasised."' Compounds available in this way include ketones a-ketols Io8 H. C. Brown and M.W. Rathke J. Amer. Chem. SOC. 1967,89,2737. Io9 H. C. Brown and M.W. Rathke J. Amer. Chem. SOC.,1967,89,2738. M. W. Rathke and H. C. Brown J. Amer. Chem. SOC.,1967,89,2740. H. C. Brown and M.W. Rathke J. Amer. Chem. SOC.,1967,89,4528. H. C. Brown G. W. Kabalka and M.W. Rathke J. Amer. Chem. SOC. 1967,89,4530. 113 H. C. Brown and E. Negishi J. Amer. Chem. SOC. 1967,89 5285. H. C. Brown and E. Negishi J. Amer. Chem. SOC. 1967,89 5477. 'I5 G. A. Russell and G. J. Mikol J. Amer. Chem. SOC. 1966,88 5498. 212 R. Brettle glyoxals,' ' a-keto-acids glycols and a-hydroxy-acids having one carbon atom more than the acyl group. Whereas P-ketosulphon-NN-dialkylamides can be converted into ketones by reduction with aluminium amalgam,' ' P-ketosulphinyl-N-monoalkylamidesgive ketones on treatment with iced water. The P-ketosulphinamides are accessible from dilithiosulphiny1-N- monoalkylamides either directly by acylation or via the P-hydroxysulphin- amides formed by condensation with carbonyl compounds.The generality of a fragmentation of cyclic a-epoxyketones to give an acetylene and a ketone has been established and the process has been used in synthesis.' l8 ~ R'COCR CR3R4+ R1C-CR2 + R3R4C0 A sequence based on previously known types of reactions allows cyclic ketones to be transformed into the homologous ap-olefinic ketones via the enol acetates; the utility of the method is increased by the availability of both enol acetates of an unsymmetrical ketone.'" Full details have appeared of the syntheses reported last year of a-keto-esters (via P-ketophosphorylenes),'20 P-diketone enol ethers (from ketones),12' and of a much less drastic alternative to the Haller-Bauer procedure for the cleavage of non-enolizable ketones involving the use of potassium t-butoxide in aqueous ether at room tempera- ture.'22 Condensation of an ap-olefinic ketone with benzylamine gives an anil which with base is isomerised to the benzylidene derivative of the enamine of the saturated ketone.Hydrolysis then completes a reduction of the unsaturated ketone to the corresponding saturated ketone. 123 Ethylene thioacetals can be oxidised to cyclic disulphones by peracids and these can be cleaved by alkoxides in the presence of oxygen. This conversion of an acid-sensitive ketone protecting group into an alkali-sensitive one is clearly of considerable synthetic potential. 24 Carboxylic Acid Derivatives-Aldehydes can be converted into the next higher carboxylic acid by reaction with the ylid from trimethyl phosphite and 1,3-dithiacyclohexan-2-thione,followed by hydrolysis of the resultant keten thi~acetal.'~' Ketones can also be converted into keten thioacetals by con- densation with the anion from 1,3-dithiocyclohexane followed by dehydra- tion.' 26 T.L. Moore J. Org. Chem. 1967,32 2786. 'I7 E. J. Corey and M. Chaykovsky J. Amer. Chem. SOC.,1965,87,1345. A. Eschenmoser D. Felix and G. Ohloff Helv. Chim.Acta 1967,50,708;J. Schreiber D. Felix A. Eschenmoser M. Winter F. Gautschi K. H. Schulte-Eke E. Sundt G. Ohloff J. Kalvoda H. Kaufmann P. Wieland and G. Anner. ibid.,p. 2101 ;P. Wieland H. Kaufmann and A. Eschenmoser ibid. p. 2108; M. Tanabe D. F. Crowe R. L. Dehn and G. Detre ibid. p. 3739. G. Stork M.Nussim and B. August Tetrahedron 1966,22 Supplement 8 105. 120 R. Zbiral and E. Werner Monatsh. 1966,97 1797. 12' D. Nasipuri and K. K. Biswas J. Indian Chem. SOC. 1967,46,620. 122 P. G. Gassman J. T. Lumb and F. V. Zalar J. Amer. Chem. SOC. 1967,89,946. 12' S. K. Malhotra D. F. Moakley and F. Johnson J. Amer. Chem. SOC. 1967,89,2794. 124 S. J. Daun and R. L. Clarke Tetrahedron Letters 1967 165. 12' E. J. Corey and G. Markl Tetrahedron Letters 1967 3201. 12' E. J. Corey and D. Seebach Angew. Chem. Internat. Edn. 1965,4,1075. General Methods Malonic esters can be monodealkoxycarbonylated by the action of sodium cyanide in dimethyl sulphoxide at 160".'27 The base-catalysed condensation of aldehydes with ethyl dimethylamino- acetate leads to ethyl a-dimethylaminoacrylates,which can be hydrolysed to a-keto-esters.12* Nitriles can be prepared under very mild conditions by the treatment of amide N-sulphonylchlorides with dimethylformamide at room temperature.' 29 R-CONH-SO2-C1 -+ RCN + HCI + SO The amide derivatives can be made by the action of chlorosulphonyl isocyanate on acids.Alkylation and Related Reactions.-The uses of enolate anions as synthetic intermediates have been re~iewed.'~' The reaction of a ketone with sodium hydride to form such an anion is catalysed by small amounts of t-butyl alc~hol.'~' Further details of the Stork isoxazole annelation method'32 have appearcd.' 33 In the method a 3-alkyl-4-hnlo~cnomethyliso~a~ole is used to monoalkylate a ketone via the enolate anion.The isoxazole ring will survive certain chemical transfbrmations elsewhere in the molecule for example reduction of a conjugated double bond but on hydrogenolysis gives a p-oxo- imine which cyclises to give a vinylogous carbinolamide. This intermediate on treatment with anhydrous base loses the superfluous acyl-group and cyclisation with aqueous base then leads to a cyclic @-unsaturated ketone. During the reaction an alkyl-substituent at C-3 but not one at C-5 is in- corporated into the molecule. An example of this annelation procedure is given in Scheme 5. 0 \" CH R RI R SCHEME 5 12' A. P. Krapcho G. A. Glynn and B. J. Grenon Tetrahedron Letters 1967 215. L. Horner and E-0 Renth Annulen 1967,703,37. 129 G. Lohaus Chem.Ber. 1967,100,2719. H. 0.House Rec. Chem. Progr. 1967,28,99. :31 H. 0.House and C. J. Blankley J. Org. Chem. 1967,32 1741. 132 G. Stork Pure Appl. Chem. 1964,9 131. 13' G. Stork S. Danishefsky and M. Ohashi J. Amer. Chem. SOC. 1967,89 5459; G. Stork and J. E. McMurry ibid. p. 5463. 214 R. Brettle A totally new synthesis of 3-alkyl-4-halogenomethylisoxazolesvia 3-alkyl-isoxazole-4-carboxylic acids has been devised to make the appropriate alkylat- ing agents available.'34 Certain imine salts prepared by the addition of organometallic reagents to nitriles can be alkylated by reaction with excess of the organometallic reagent followed by treatment with an iodoalkane; hydrolysis then gives a ketone.135 R' R' (i)~31 R'CN + 2RZCH,M -f ,\ C=NM zn)C=O (M = MgX or Li) R'CHM R3CH Unstable sulphonium ylids can be prepared'36 by the alkylation procedure shown in Scheme 6 for diphenylsulphonium isopropylide.Ph,A CHzMe 1,Ph& CH Me BF4-1Me1 Ph,; 6 Me L Ph24CHMe I-Reagent l,(Me,CH)NLi CH,CI, MeO[CH,],OMe SCHEME 6 Lithium dimethyl-copper1 37 replaces the halogen atoms in alkyl aryl allyl benzyl and vinyl halides by a methyl group (see Scheme 4);96 further work will undoubtedly lead to organocopper reagents capable of introducing higher alkyl groups. Lithium dimethylcopper undergoes conjugate addition to an ethyl alkylidenecyan~acetate~~* R'R2C==C( CN)C02 Et (i)L,i+ Me,Cu- +.(ii)H * R'R2 C( Me)CH( CN)CO,Et a-Bromoketones react with zinc in .benzene-dimethyl sulphoxide to give a species which can be allylated or methylated although other alkyl groups cannot be introduced in this way.'39 Methylation occurs at the original site of the bromine atom even when that corresponds to the less stable enol; 4a-bromocholestan-3-one gives 4a-methylcholestan-3-one as the sole methy- lated product.Interest in the chemistry of di- and tri-anions has continued. Alkylation at the a-position has been observed with the dianions from a~etanilide'~'" and G. Stork and J. E. McMurry J. Amer. Chem. SOC. 1967,89 5461. 13' T. Cuvigny and H. Normant Compt. rend. 1967 265 C 245. 136 E. J. Corey M. Jautelat and W. Oppolzer Tetrahedron Letters 1967,2325. 13' c$ Ann. Reports 1966 351. ''* R. R. Sobti and S. Dev Tetrahedron Letters 1967,2893.139 T. A. Spencer R. W. Britton and D. S. Watt J. Amer. Chem. SOC. 1967,89 5729. 140 (a) R. L. Gay and C. R. Hauser J. Amer. Chem SOC. 1967 89 1647; (b) J. F. Wolfe and T.G. Rogers Chem. Comm. 1967 1040; (c)J. F. Wolfe Abstracts 154th Amer. Chem. SOC.Meeting 1967 abstract S 100. General Methods 215 glutarirnide,l4Ob and the trianion from N-acetylsalicylamide. '40c The trianion from N-acetylbenzoylacetamide undergoes electrophilic attack in the acetyl group.141 Phenylhydrazones having an a-hydrogen atom give 1,4-dianions (17) which undergo preferential C-alkylation. 142 2NH -e3 R'R2CHCH=NNHPh R'R2cCH=NNPh (17) Whereas alkyl benzyl ketones give a monoanion with an alkali metal amide in liquid ammonia and react with butyl-lithium at the carbonyl group treatment of the monoanions with butyl-lithium gives dianions susceptible to electro- philic attack in the a-position of the alkyl group.'43 NH,-PhCH,COMe liq.~~ BuLi PhcHCOMe hexanePhcHCOCH The stereochemistry of the addition of the dianion from phenylacetamide to benzaldehyde has been investigated and a route to the threo-adduct (2,3-diphenyl-3-hydroxypropionamide)has been established.144 The enamines formed from aldehydes and many secondary amines only give low yields of the C-alkylated products on attempted alkylation but better yields can be obtained by using the enamines from butylisobutylamine. 14' The acylation of aldehyde enamines provides a convenient route to P-keto- aldehydes.146 The cisoid-enamino-ketone (18) undergoes C-alkylation ;pre-vious work had shown that transoid-enamino-ketones [e.g.(19)] undergo 0-alkylation.14' 0 Treatment of P-dicarbonyl compounds with tetrakis(dimethy1amino)titanium gives bisenamines. NMe NMe Ti( NMe,) I I RCOCH,COMe -R-C-LH-C-LH2 Preliminary results suggest that alkylation of such bisenamines occurs ex- clusively at the terminal methylene group a result with important synthetic 141 J. F. Wolfe and C-L Mao J. Org. Chem. 1967,32 1977. F. E. Henoch K. G. Hampton and C. R. Hauser J. Amer. Chem. SOC.,1967,89,462. C-L Mao C. R. Hauser and M. L. Miles J. Amer. Chem. SOC.1967,89 5303. D. M. von Schriltz E. M. Kaiser and C. R. Hauser J. Org. Chem. 1967,32,2610. 14' T. J. Curphey and J. C-Y. Hung Chem. Comm. 1967,510. T.Inukai and R. Yoshizawa J. Org. Chem. 1967,32,404. 14' A. I. Meyers A. H. Reine and R. Gault Tetrahedron Letters 1967,4049. 216 R. Brettle implication^.'^^ The enamines of simple ketones at least (e.g. pinacolone) can be prepared by the action of titanium tetrachloride and a secondary amine thereby avoiding the difficulties attendant on the preparation of the tetra- kisaminotitanium reagents. 149 Miscellaneous.-A new dealing with 1,100reagents used in organic syntheses is almost certain to be of tremendous assistance in the planning and execution of laboratory work. A book on the chemistry of the ether linkage has appeared,”’ as have reviews on the synthesis and reactions of cyanic ester~,”~ the transfer of diazo groups,’ ’ advances in the chemistry of carbodi-imides,’ 54 preparative phosphorus chemistry,” ’ and current studies of free-radical reactions in preparative organic chemistry.’ ’I3 A review on the formation of carbon-carbon bonds by means of a-halogeno-ethers -sulphides and -amines covers a wide range of synthetic methods.’” A warning about a latent hazard in the widely practised method for the purification of tetrahydrofuran with potassium hydroxide has been issued.l’* Alcohols can be protected by the formation of a mixed acetal using 5,6- dihydro-4-methoxy-2H-pyran.’ ’’ The acetals have the same acid lability as the better-known tetrahydropyranyl ethers but no chiral centre is created so that diastereoisomers do not result when the alcohol is chiral.The 2,2,7-trichloroethyloxycarbonylgroup can be used as a protecting group for alcohols and amines; it is resistant to chromic and trifluoracetic acids and survives catalytic hydrogenation elsewhere in the molecule but c8n be removed by treatment with zinc under very mild conditions.The cleavage of tertiary bases with phenyl chloroformate provides a con- venient alternative to the von Braun cyanogen bromide procedure.’61 R,N + C1C02Ph + R2N C02Ph + RCl 14’ H. Weingarten M. G. Miles S. R. Byrn and C. F. Hobbs J. Amer. Chem. Soc. 1967,89 5974. 149 W. A. White and H. Weingarten J. Org. Chem. 1967 32 213; H. Weingarten J. P. Chupp and W. A. White ibid. p. 3246. L. F. and M. Fieser ‘Reagents for Organic Synthesis’ Wiley New York 1967. ’The Chemistry of the Ether Linkage’ Ed.S. Patai Wiley New York 1967. lS2 E. Grigat and R Putter Angew. Chem. Internat. Edn. 1967,6,206. M. Regitz Angew. Chem. Internat. Edn. 1967,6 733. lS4 F. Kurzer and K. Douraghi-Zadeh Chem. Rev. 1967.67 107. 15’ L. Horner Fortschr. Chem. Forsch. 1966,7 1. G. Sosnovsky Intra-Sci. Chem. Reports 1967,1,3. ”’ H. Gross and E. Heft Angew. Chem. Internat. Edn. 1967,6,335. ’’’ Issued with Org. Synth. 1966 46; cf.; Org. Synth. 1960 40 94; Coll. Vol. IV 1963 474; 792. lS9 C. B. Reese R. Saffhill and J. E. Subston J. Amer. Chem. SOC.,1967,89 3366. 160 T. B. Windholz and D. B. R. Johnston Tetrahedron Letters 1967 2555. 16’ J. D. Hobson and J. G. McCluskey J. Chem. SOC.(C) 1967,2015. General Methods Two reports on the use of urea as a base in organic reactions have appeared.It can be used in the acetolysis of sulphonate esters to neutralise the liberated sulphonic acid and does not give rise to acetate ions or itself act as a nucleo- phile.162 It can be used in place of tertiary amines in Schotten-Baumann acylations. 63 162 W. S. Trahanovsky M. P. Doyle and P. D. Bartlett J. Org. Chem. 1967,32 150. M. S. Newman and L. K. Lala Tetrahedron Letters 1967,3267.

ISSN:0069-3030    

DOI:10.1039/OC9676400199

出版商:RSC    

年代:1967

数据来源: RSC

摘要:

6. ORGANOMETALLIC COMPOUNDS By Alwyn G. Davies (Department of Chemistry University College Cower St. London. W.C.1) ACTIVITY in the field of organometallic chemistry continues to increase and it is illuminating to compare the number of references which the Annual Surveys of Organometallic Chemistry have given to the compounds of the non- transition metals in the past three years 1964,900;’“ 1965 1200;Ib 1966,1800.“ A comprehensive account of work yblished during 1967 will be available in the Annual Survey (1968);’“ this present report therefore does not attempt to cover the whole field but rather tries to point out the principsl current trends. Only review articles are listed fairly comprehensively. Three monographs on general organometallic chemistry have been published during the year two will be useful principally as textbooks in undergraduate courses.2*3 The third,4 being the first of two volumes of the third edition of G.E. Coates’s ‘Organometallic Compounds’ will be invaluable also as a reference work for specialists in the field. It deals with the organic compounds of all the non-transition metals except silicon phosphorus and arsenic. It includes many references to work published in 1967 and is the best single source of the background information to this Report. The second volume,’ covering the transition metals will be published early in 1968. The abstracts of the lectures which were presented at the Third International Symposium on Organometallic Chemistry which was held at Munich in August and September show the breadth of current work ;the plenary lectures are to be published in a volume of Pure and Applied Chemistry.General reviews published during the year include the following the mech- anisms of electrophilic substitution of metal alkyls,6 the influence of co-ordina- tion on the reactivity of organometallic compounds,’ insertion reactions of compounds of metals and metalloids involving unsaturated substrates,’ transition metal intermediates in organic synthesis,’ and organometallic pseudohalides. lo Ann. Surveys Organometallic Chem. (a) 1965 1; (b) 1966 2; (c) 1967 3; (d) 1968,4. P. L. Pauson ‘Organometallic Chemistry,’ Arnold London 1967. J. J. Eisch ‘The Chemistry of Organometallic Compounds. The Main Group Elements,’ Macmillan London 1967.G. E. Coates M. L. H. Green and K. Wade ‘Organometallic Compounds,’ vol. 1; G. E. Coates and K. Wade ‘The Main Group Elements,’ Methuen London 1967. ’ Ref. 4 vol. 2 M. L. H. Green ‘The Transition Elements,’ Methuen London 1968. ‘M. H. Abraham and J. A. Hill J. Organometallic Chem. 1967,7 11. ’ 0.Yu. Okhlobystin Russ. Chem. Rev. 1967,36 17. M. F. Lappert and B. Prokai Adv. Organometallic Chem. 1967,5 169. C. W. Bird ‘Transition Metal Intermediates in Organic Synthesis,’ Logos Press London 1967. lo J. S. Thayer and R.West Ado. Organometallic Chem. 1961,5 169. H Alwyn G.Davies Analytical Methods.-When organic derivatives of metals such as lithium magnesium or boron are used in synthesis they are usually prepared then caused to react in situ without being isolated.It is important then that simple and accurate methods should be available for detecting and analysing these compounds in solution. Reagents which will add to a carbonyl group (e.g. RLi RMgX R,Zn) are usually detected by Gilman’s ‘Colour Test 1’’ in which they are treated with Michler’s ketone to give a tertiary alcohol (1) which liberates a blue or green carbonium ion when acid is added. RM + (p-Me,N*C,H,),CO + R(p-Me,N-C,H,),C*OH (l) R(kMe2N*C6H4)2C+ Acetic acid is usually used when both alkyl- and aryl-metallic compounds respond to the test. If the weaker acid catechol is used only the triaryl- methanols (1;R = aryl) ionise enabling the alkyl- and aryl-metallic compounds to be distinguished.Alternatively the coloured solution resulting from the usual test can be treated with aqueous sodium hydrogen sulphate when the colour will be discharged only if R is alkyl.’ ’ Organolithium compounds are usually estimated by a double-titration method. The total of RLi and the ROLi which is usually present as an impurity is determined by titration with acid. The RLi is then caused to react with benzyl chloride or 1,2-dibromoethane the residual ROLi is titrated and the initial concentration of RLi is obtained by difference. Some lithium alkoxides however react slowly with the organic halides which scavenge the alkyl- lithium reducing the accuracy of the method. It is better then to titrate a known amount of benzoic acid in a dimethyl sulphoxide4imethoxyethane-hydrocarbon solvent using triphenylmethane as the indicator.” The reactions involved are RLi + PhC0,H -+ PhC0,Li + RH -+ RLi + Ph,CH -+ RH + Ph3CLi (red) Grignard reagents containing other magnesium bases can be determined by a double-titration procedure in which carbon tetrachloride is used as the organometallic scavenger.’ Alternatively an alkyl-lithium or alkyl-magnesium halide may be titrated with butanol in an ether or .hydrocarbon containing a trace of 1,lO-phenan-throline or 2,2’-biquinolyl.The amines form highly coloured charge-transfer complexes with the organometallic compounds and the colours are discharged sharply at the equivalence point. Metal alkoxides do not interfere. l4 Organoboranes are usually analysed by estimating the boric acid which is l1 J.M. Gaidis J. Organometallic Chem. 1967,8 385. l2 R. L. Eppley and J. A. Dixon J. Organometallic Chem. 1967,8 176. l3 T. Vlismas and R. D. Parker J. Organometallic Chem. 1967,10 193. l4 S. C. Watson and J. F. Eastham J. Organometallic Chem. 1967,9 165. Organometallic Compoundr 221 formed when the boron-carbon bonds are cleaved by alkaline hydrogen per- oxide. It has now been shown that trimethylamine oxide quantitatively oxidises a wide range of organoboranes to alkoxyboranes and titration of the trimethylamine which is evolved gives a method of estimating the R-B groups. It seems unfortunately that the method cannot readily be extended to include derivatives of aluminium or magnesium.' R-B< + Me,NO -+ROB<+ Me,N Group 1.-The organolithium compounds have recently been recognised to belong to the class of alkyl-bridged electron-deficient oligomers which includes also the corresponding compounds of beryllium magnesium and aluminium.Crystalline methyl-lithium contains tetrahedra of lithium atoms with a methyl group centred above each face. Hexamers may occur in solution or in the gas phase ;these probably consist of chair-shaped hexagons of lithium atoms with an alkyl group located above the exo-face of the plane formed by any three adjacent atoms.' Colligative measurements show that organolithiums in ether or tetrahydro- furan may or may not remain associated depending on the structure of the organic groups. Methyl-lithium remains predominantly a tetramer phenyl- lithium is a dimer and benzyl-lithium is a monomer ;in these last two compounds the co-ordination shell of the lithium contains also solvent molecule^.'^ The interaction of these species with other organometallic compounds in solution can be followed by 'H and 7Li n.m.r.spectra. Ethyl-lithium in benzene slowly exchanges its ethyl groups with diethylmercury ;with diethylcadium in benzene the reaction is fast but the intermediate complex LiCdEt, through which exchange occurs can be detected only in ether solution. Diethylzinc on the other hand forms the complex LiZnEt in both solvents.'8 In ethers phenyl-lithium reacts with other organometallic compounds to give the species (Li,MePh), Li,Me,Ph Li,MgMe,-,Ph, Li,MPh, and LiMPh (M = Zn or Mg)." One of the important uses of butyl-lithium is for lithiating organic compounds by the reaction Li-G Ha -+ LiR + BuH The nucleophilic power of the butyl group is increased by additives or solvents which co-ordinate to the lithi~m,~ and in the presence of potassium t-butoxide butyl-lithium will lithiate even benzene and add to ethylene at room tempera- ture.,' Butyl-lithium lithiates dimethyl sulphide in the presence of NNN'N'-tetramethylethylenediamine giving CH S *CH2Li,21 and the corresponding R.Koster and Y. Morita Annalen 1967,704 70. T. L. Brown Adv. Organometallic Chem. 1965,3 365. " P. West and R. Waack J. Amer. Chem. SOC. 1967,89,4395. '* S. Topper G. Slinex and G. Smets J. Organometallic Chem. 1967,9,205. l9 L. M. Seitz and T.L. Brown J. Amer. Chem. SOC. 1967,89 1602 1607. 2o M. Schlosser J. Organometallic Chem. 1967,8,9. D. J. Peterson J. Org.Chem. 1967,32 1717. Alwyn G.Davies oxygen compound CH3 0 CH2Li has been prepared from the reaction between chloromethyl methyl ether and metallic lithium.22 Both reagents show the usual substitution and addition reactions of organolithium compounds and are useful in preparing further methoxymethyl- and methylthiomethyl- compounds. The thioacetals are lithiated more readily than the thioethers and provide a route to ketones by the reaction :23 The extension of this to the preparation of silyl and germyl ketones (R and/or R! = R"',Ge or R"',Si) is described in a later section. The orthothioformates react with butyl-lithium in tetrahydrofuran at -78",and the products (RS),CLi are again useful intermediates in synthesis.24 Tri(pheny1thio)methyl-lithiumis interesting as it appears to present an example of a carbenoid molecule (2) in equilibrium with its carbene (3) It slowly decomposes to tetra(pheny1thio)ethylene (4) and the rate decreases if phenylthiolithium is added.Tri(pheny1thio)methyl-lithium reacts with p-tolythiolithium and tri(p-to1ythio)methyl-lithium with phenylthiolithium to give the same mixture of compounds (PhS),(C7H,S)3-nCLi (n = 0-3) and the same four compounds are formed in the ratio of approximately 1 :2:2 1 when (PhS)3CLi and (C,H,S),CLi are mixed. Electrophiles such as cyclo- hexene epoxide which cannot attack the bulky carbenoid trap the phenyl- thiolithium and drive the equilibrium to the right increasing the yield of olefin.Certain nucleophiles on the other hand will trap the carbene :tributylphosphine reacts in 5 hr. at room temperature to give the ylid (5) in 80% yield and 1,l-dimethoxyethylene and 1,l -di(phenylthio)ethylene give the corresponding cyclopropane derivative^.^' The chemistry of stable a-halogenoalkyl-lithium compounds and the mech- anisms of their carbenoid reactions have been reviewed.26 Details have been published for preparing pure phenyl- p-tolyl- p-anisyl- and p-chlorophenyl-lithium from butyl-lithium and the appropriate aryl iodide 22 U. Schtillkopf H. Kupers H.-J. Traencker and W. Pitteroff Annalen 1967,704 120. 23 E.J. Corey and D. Seebach Angew. Chem.Internat. Edn. 1965,4,1075,1077. 24 D.Seebach Angew. Chem. Internat. Edn. 1967,6,442. " D.Seebach Angew. Chem. Internat. Edn. 1967,6,443. z6 G. Kobrich Angew. Chem. Internat. Edn. 1967,6,41. Organometallic Compounds 223 crystalline phenyl-lithium for example is obtained with a purity of about 99-8%.27 Phenyl-lithium reacts with 1-chlorocyclo-pentene -hexene and -heptene to give the corresponding 1-phenylcycloalkenes. The rates and products when the alkene ring is labelled with deuterium establish that the reaction proceeds predominantly if not exclusively through an elimination-addition reaction involving the cycloalkyne intermediate.2* Group 11.-A distinction can be drawn in Group 11 between the organic compounds of beryllium magnesium zinc and cadmium and those of mercury.The first group of compounds have a very reactive carbon-metal bond (e.g. towards oxygen or water) and interest is still centered on the structures of these compounds and the equilibria they undergo. The organomercury com- pounds have a much less reactive carbon-metal bond; their constitutions are relatively simple and interest centres on the way this bond may be formed or broken and on the potential these reactions have in organic synthesis. Relatively little is known about organoberyllium chemistry. The preparation and structure of many of its simple compounds have been reported largely by G. E. Coates and his a~sociates,~’ who have also reviewed the field.30 For the past two or three years there has been general agreement that the constitution of a Grignard reagent in an ethereal solvent can be represented by the following series of mobile equilibria in which the magnesium has its co-ordination number raised to at least 4 by co-ordination of solvent.The monomeric species RMgX is the principal entity present but binuclear species may be important in concentrated solutions and in less polar solvents. The current picture has been reviewed.* 31 Recent work on the thermochemistry of the reactions between diethyl- 27 M. Schlosser and V. Ladenberger J. Organometallic Chem. 1967,8 193. ’* L. K. Montgomery and L. E. Applegate J. Amer. Chem. SOC. 1967 89 2952; L. K. Mont-gomery A. 0.Clouse A. M. Crelier and L. E. Applegate Ibid. p. 3453. 29 G. E. Coates and M.Tranah J. Chem. SOC.(A) 1967 236 615; G. E. Coates and A. H. Fish-wick ibid. p. 1199. 30 G. E. Coates Record Chem. Progr. 1967,28 3; ref. 4 pp. 103-121. 31 E. C. Ashby Quart. Rev. 1967,21,259. ” A. G. Davies and P. G. Harrison J. Chem. So?. (C),1967,298. Equilibria of this type must be expected whenever a metal which is formally not co-ordinatively saturated carries two mobile ligands at least one of which is capable of bridging. Dibutyltin chloride methoxide Bu,Sn(OMe)Cl for example has been suggested to behave in this way.” 224 Alwyn G. Davies magnesium or diphenylmagnesium with magnesium chloride or magnesium bromide,33 and on the fluorine n.m.r. spectra of p-fluorophenylmagnesium compounds has supported this.34 The halogen bridges in MgCl and MgBr in ether are much stronger than the alkyl bridges in Me,Mg and Et,Mg substan- tiating the assumption that association of the Grignard reagent occurs through the halogen rather than the alkyl groups.35 Similarly in the crystal the amine complex (EtMgBr,NEt,) is bromine-bridged with 4-co-ordinate magnesium and a trans-disposition of the remaining four ligand~.,~ There was previously some doubt whether dialkylberylliums and beryllium halides could take part in equilibria with the alkylberyllium halides.Studies of the ebullioscopy the n.m.r. spectra and the reaction with dioxan of a mixture of dimethylberyllium and beryllium bromide shows that such equilibria do indeed obtain. A 2 1 mixture of Me,Be and BeBr in ether at -75” shows two n.m.r.signals one for Me,Be and one for MeBeBr but at 35” these signals coalesce because of the rapid intermolecular exchange of methyls.37 Diethylzinc and zinc iodide or bromide react slowly in ether at room tempera- ture to give the monomeric species EtZnI and EtZnBr which can be isolated as their complexes with NNN‘N’-tetramethylethylenediamine ; the species Et,Zn and EtZnX however cannot be distinguished by ‘H n.m.r.38 In hydro- carbon solvents. on the other hand the chemical shifts are significantly different but in mixtures of Et,Zn and EtZnX (X = C1 Br I) the signals of only one type ofgroup are apparent interpolated iu position between those of the components implying that rapid exchange occurs even at -60°.39 In the crystal unsolvated ethylzinc iodide is co-ordinatively polymerised by bridging iodine ;40 in contrast the corresponding magnesium compounds consist of mixtures of the species (R,Mg) and MgX2.41 The ethylation of phenylmercuric chloride by diethylzinc is kinetically first- order in each reagent and the relative reactivity of various dialkylzincs (Me < Et < Pr < ‘Pr) has been interpreted as implying an S,i mechanism for the reaction.42 The acidolysis of dipropylzinc by p-toluidine or cyclohexyl- amine in di-isopropyl ether appears to follow a similar mechanism.43 Organozinc urea derivatives (e.g.EtZn -NPh CO NPh,) are trimeric in solution and its has been suggested that they bring about the trimerisation of co-ordinating isocyanate molecules by a ‘template’ mechanism,44 rather 33 M.B. Smith and W. E. Becker Tetrahedron 1967,23,4215. 34 D.F.Evans and M. S. Khan J. Chem. SOC.(A) 1967,1643,1648. ” E. C.Ashby and F. Walker J. Organometallic Chem. 1967,7 P17. 36 J. Toney and G. D. Stucky Chem. Comm. 1967,1168. ’’ E.C.Ashby R. Sanders and-J. Carter Chem. Comm. 1967,997. ” M. H.Abraham and P.H. Rolfe J. Organometallic Chem. 1967 7 35. 39 J. Boersma and J. G. Noltes J. Organometallic Chem. 1967,8 551. *O P.T. Moseley and H. M. M. Shearer Chem. Comm. 1966,876. 41 E. Weiss Chem. Ber. 1965,98,2805; Ann. Reports 1965,62 281. 42 M. H. Abraham and P. H. Rolfe J. Organometallic Chem. 1967,8 395. 43 M. H. Abraham and J. A. Hill J. Organometallic Chem. 1967,7 23. 44 J. G.Noltes and J. Boersma J. Organometallic Chem. 1967,7 P6.Organometallic Compoundr 225 than the repeating ‘insertion’ process which was proposed for the reaction in- volving alk~xides,~~ Improvements have been reported in the preparation of dimethylzinc and diethylzinc from the alkyl iodides and zinc and the stability of the com- plexes formed between various dialkylzincs and 2,2’-bipyridyl or tetramethyl- ethylenediamine have been inve~tiaged.~~ Mercury. Organomercury compounds are prone to react by both electro- philic attack on the carbon and by a homolytic mechanism,49 and the distinction is not always clear. For example the purported S,1 protolysis of dibenzylmercury has been reinterpreted as a homolytic reaction with oxygen,50 and it has been suggested that the exchange of organic groups between Hg” and Hgo might involve an electron-transfer process rather than a four-centre mechanism.Equilibrium constants for the reaction R,Hg + R’,Hg + 2RR’Hg show that thedistributionofthealkylgroups Rand R’may vary widely fromrand~mness.’~ The kinetics of the acidolysis of allylmercuric iodides3 and of 4-pyridiomethyl-mercuric chloride have been studied ;54 it is proposed that in water the latter reaction follows a 1-and 2-anion-catalysed SEl mechanism. Acidolysis of dibenzylmercury and of benzyldihydroxyborane is accompanied by rapid deuteriodeprotonation of the aromatic ring which was ascribed to activation of the ring by hyperconjugative electron release from the metal-carbon bond.55 Mercuric salts are unique in bringing about the rapid oxymetallation of an olefin e.g.Hg(OAc) + MeOH + CH2=CH -+ AcO-CH,*CH,*OMe + AcOH In the presence of nitrite ion the products are p-nitroalkylmercuric com- pounds rather than P-mercurialkyl nitrites. 56 1,2-Dienes in methanol have been shown to undergo 2-mercuri-l-methoxylation.57 The rapid oxymercuration of an olefin and the reductive cleavage of the carbon-mercury bond in situ by sodium borohydride provides a very rapid and convenient method for the Markownikov hydration of an olefin.” The *’ A. J. Bloodworth and A. G. Davies J. Chem. SOC.,1965,6858. 46 N. K. Hota and C. J. Willis J. Organornetallic Chem. 1967,9 169. *’ E. C. T. Gevers Rec. Trav. chim. 1967,86,572; J. G. Noltes and J. Boersma J. Organometallic Chem. 1967,9 1. *’ 0.A. Reutov Russ.Chem. Rev. 1967,36 163. 49 K. C. Bass Organometallic Chem. Rev. 1966,1 391. ’O B. F. Hegarty W. Kitching and P. R. Wells J. Amer. Chem. SOC.,1967,89,4816. ” M. M. Kreevoy and E. A. Walters J. Amer. Chem. SOC.,1967,89,2986. s2 G. F. Reynolds and S. R. Daniel Inorg. Chem. 1967,6,480. ” M. M. Kreevoy D. J. W. Goon and R. A. Kayser J. Amer. Chem. SOC. 1966,88 5529; M. M. Kreevoy T. S. Straub W. V. Kayser and J. L. Melquist J. Amer. Chem. SOC. 1967,89 1201. ’* J. R. Coad and M. D. Johnson J. Chem. SOC.(B) 1967,633. ” W. Hanstein and T. G. Traylor Tetrahedron Letters 1967,4451. ” G. B. Bachmann and M. L. Whitehouse J. Org. Chem. 1967,32,2303. 57 R. K. Sherma B. A. Shoulders and P. D. Gardner J. Org. Chem. 1967,32,241. ” H. C. Brown and P. Geoghegan J.Amer. Chem. SOC. 19;67,89,1522; H. C. Brown and W. J. Hammer ibid. p. 1524; H. C. Brown J. H. Kawakami and S. Ikegami ibid. p. 1525. Alwyn G. Davies reactions are carried out at room temperature under very mild conditions which avoid rearrangement in the alkyl groups and are complementary to the hydroboration route for anti-Markownikov hydration (see below). NaBH, 'C=C' + Hg(OAc) + H,O -,-A-A--&-A /\ I1 Hg OH Some products and yields are given in the following equations. BuCH=CH BuCH(OH)CH (96%) PhCH=CH2 + PhCH(OH)CH (96%) cis-MeCHeHEt -* MeCH(OH)CH,.Et (65%) + MeCH,CH(OH)Et (35%) norbornene 4 fiorbornanol 100"4 yield > 99.8 % em) Cycloalk-2-en- 1-01s give stereospecifically the tr~ns-1,3-diols.~~ In the past few years there has been much interest in the use of phenyl(tri-ha1ogenomethyl)mercury compounds as sources of dihalogenocarbenes by the reaction Phenyl( tribromomet hy1)mercury and phenyl(dibromoch1oromet hy1)mercury (giving PhMgBr and :CC12) react readily in boiling benzene ;phenyl(trich1oro-methy1)mercury is much less reactive but all the reactions are catalysed by iodide ion.This availability of a dihalogenocarbene unit under mild conditions is useful in synthesis and is being exploited by D. Seyferth and his collaborators who have published a review.60 Reactions which have been studied during the current year are as follows C=C -,b-C-bX2;61 HCl -,HCXzC1;62 ROH -,[RO*CHC1,];63 Et,N + Et,N.CCI:CCI ;64 (Me,M),Hg -,Me,M.CCI:CC1,;65 Ph,MH -+ Ph,M.CX,H (M=Si or Ge);66 Me,Sn-SnMe -+ Me3Sn.CC'l,.SnMe3 ;67 59 S.Moon and B. H. Waxman Chem. Comm. 1967,1283. 6o D. Seyferth M. E. Gordon J. Y.-P. Mui and J. M. Burlitch J. Amer. Chem. SOC. 1967 89 959 ;D. Seyferth Proc. Robert A. Welch Foundation Conferences on Chemical Research. IX. Organo-metallic Compounds Robert A. Welch Foundation Houston Texas U.S.A. 1966 pp. 89-135. " D. Seyferth J. Y.-P. Mui and J. M. Burlitch J. Amer. Chem. SOC. 1967,89,4953. D. Seyferth J. Y.-P. Mui L. J. Todd and K.V. Darragh J. Organometallic Chem. 1967,8,29. 63 D. Seyferth V. A. Mai J. Y.-P. Mui and K. V. Darragh J. Org. Chem. 1966 3,4079. 64 D. Seyferth M. E. Gordon and R. Damrauer J. Org. Chem. 1967,32,469. 65 D. Seyferth R. J. Cross and B. Prokai J. Organometallic Chem. 1967,7 P20. 66 D.Seyferth J. M. Burlitch H. Dertouzos and H. D. Simmons J. Organomerallic Chem. 1967 7.405. 67 D. Seyferth and F. M. Armbrecht J. Amer. Chem. SOC. 1967,89,2790. '* D. Seyferth R. Damrauer and S. S. Washburne J. Amer. Chem. SOC.,1967,89 1538. Organometallic Compound 227 Group In.-Boron. Two excellent summaries of organoboron chemistry have appeared,69* 70 together with reviews on the carborane~,~ and on boron- nitrogen and boron-phosphorous compound^.^ About 10 years ago73 it was shown that diborane B2H6 which is readily available from for example sodium borohydride and boron trifluoride would add rapidly to olefins in ethereal solvents to give alkylboranes in which the the boron is carried by the less alkylated carbon atom. These organoboranes serve as very useful intermediates in organic synthesis.Above about 160” tertiary or secondary alkyl boranes rearrange to primary alkylboranes and the rearranged or unrearranged compounds can for example be treated with alka- line hydrogen peroxide to give alcohols with carboxylic acids to give alkanes or with olefins to give alkenes. The early work is summarised in ref. 74. The hydroboration of a hindered olefin may proceed only to the stage of a mono- or di-alkylborane; three products of this type which have their own specific applications in synthesis are (from cyclohexene) dicyclohexylborane (C,H BH ; (from trimethylethylene) bis-( 1,2-dimethylpropyl)borane[(6); ‘di-s-iso-amylborane’ or ‘disiamylborane’]; and (from tetramethylethylene) 1,1,2-trimethylpropylborane[(7); ‘t-hexylborane’ or ‘the~ylborane’].~’ (HMe,C-CHMe),BH (6) Me2CH*CMe,*BH2 (7) This continues to be an active and productive field.Most of the emphasis is still on developing new or improved synthetic methods but some papers have dealt with the mechanisms of the reactions. Electron withdrawal by X in ring-substituted styrenes XC6H4*CH<H2 slightly activates attack of boron at the a-position and deactivates attack at the f3-position which is consistent with the reactions proceeding through 4-centre transition states (8) and (9).’,9 77 If a dialkylborane is prepared by hydroboration of an optically active olefin (e.g. a-pinene) the addition of a third (inactive) olefin can occur with induction 6-6+ 6+ 6-6+ 6-6-6+ (8) (9) (10) 69 M.F. Lappert ‘The Chemistry of Boron and its Compounds,’ ed. E. L. Muetterties Wiley New York ch. 8. ’O Ref. 4 pp. 177-295. R. Kiister and M. A. Grauberger Angew. Chem. Internat. Edn. 1967,6 218. ’’ H. Steinberg and R. J. Brotherton ‘Organoboron Chemistry. Boron-Nitrogen and Boron- Phosphorus Compounds,’ Interscience New York 1967. 73 Ann. Reports 1957,54 188,193. 74 H. C. Brown ‘Hydroboration,’ Benjamin New York 1962. 75 E.g. H. C. Brown and E. Negishi J. Amer. Chem. SOC.,1967,89,5478. ’‘ J. Klein E. Dunkelbaum and M. A. Wolff J. Organometallic Chem. 1967,7 377. ” H. C. Brown and R. L. Sharp J. Amer. Chem. SOC. 1966,88,5851. H* Alwyn G. Davies of asymmetry,78 of a chirality which implies a triangular (10) rather than a rectangular [e.g.(8) or (9)] transition state.79 The rearrangement of the model compounds Bu'BBu', Pr',B,and Bu",B to the appropriate primary alkylboranes are all first-order kinetically. The rates suggest that rearrangement of the t-butyl group involves complete elimination ofthe B-H bond which then adds back in the opposite sense but the (reversible) rearrangement of the isopropyl and s-butyl groups may involve separation of the B-H and olefin fragments only to the degree of a 7c-complex.'' The migration of a boron atom to the end of a carbon chain involves a pro- gression of such addition-elimination processes. The reactions provide an easy route to w-cycloalkyl-cl-alkanols8 and o-cycloalkyl-a-alkenes,82 e.g. IB... B B- A If it is difficult to displace the alkene from the alkylborane (e.g.from triethyl- borane or tri-em-norbornylborane) with decene ; an aldehyde may be used instead.83 At temperatures above those which the alkylboranes isomerise they may eliminate an olefin and hydrogen to give a heterocyclic borane. Aralkylboranes can undergo a similar cyclisation by eliminating an alkane,84 e.g. A number of new reagents (X-Y of varying charge type) have been developed for cleaving the boron-carbon bond. All these like hydrogen peroxide probably react by initial nucleophilic attack of X at boron followed by nucleophilic '' D. R. Brown S. F. A. Kettle J. McKenna and J. M. McKenna Chem. Comm. 1967,667. 79 A. Streitwieser L. Verbit and R. Bittman J. Org. Chem. 1967,32 1530.F. M. Rossi P. A. McCusker and G. F. Hennion J. Org. Chem. 1967,32,450. H. C. Brown and G. Zweifel J. Amer. Chem. SOC.,1967,89,561. H. C. Brown M. V. Bhatt T. Munekata and G.Zweifel J. Amer. Chem. SOC.,1967,89,567. 83 B. M. Mikhailov Yu. N. Bubnov and V. G. Kiselev J. Gen. Chem. (U.S.S.R.),1966,36,65. " R. Koster G. Benedict W. Fenzl and K. Reinert Annalen 1967,702,197. Organometallic Compouncis 1,2-rearrangement of an alkyl group from B to X displacirlg the good leaving group Y. This would be expected to give retention of configuration in R and the cleavage of di-isopinocampheyl-s-butylborane(from B2H6 a-pinene and cis-but-2-ene) with hydrogen peroxide to’ give (R)-s-butyl alcohol and with hydroxylamine- 0-sulphonic acid (NH2-O*S02*OH) to give (R)-s-butylamine has been used to correlate the rotatory power and configurations of these product^.^' Trimethylamine oxide (ONMe,) quantitatively oxidises a wide range of arganoboranes to alkoxyboranes and may have some advantages over alkaline hydrogen peroxide for example for base- or oxygen-sensitive boranes.The ylids CH &Me,,86 CH * 6Ph,,87 and CH iMe288 have been added to those already available (CH -G2and CH -iMe,O) for introducing a CH residue into an R-B bond. A major development in the use of organoboranes in organic synthesis makes use of their reaction with carbon monoxide,89 which will take place at room temperature in an ethereal solvent such as diglyme. The mechanisms of the reactions which occur have not been fully established but they can be reationalised in the following scheme which involves sequential migration of each of the three alkyl groups from boron to carbon.R R R 1 R3BTR2$-C0 + RCCR + kCR + 211 \/ 00 1 OOH3 HO CHzR RB(0H)- CR OH HO * CR3 (13) 1 OOH OXR2 (12) Olefin Yield (%) R(-W R RCH2*OH R,CO R,C-OH But-1-ene Bun 72 85 90 But-2-ene Bus 81 87 Cyclohexene Cyclohexyl 80 80 80 N orbornene exo-N orbornyl 85 82 80 85 L. Verbit and P. J. Hefion J. Org. Chem. 1967 32,3199 86 W. K.Musker and R. R. Stevens Tetrahedron Letters 1967,995. 87 R. Koster and B. Rickborn J. Amer. Chem. SOC.,1967,89,2782. J. J. Tufariello P. Wojtkowski and L. T. C. Lee Chem. Comm. 1967,505. B9 M. E. D. Hillman J. Amer. Chem. SOC.,1962,84,4715; 1963,85,982 1626.230 Alwyn G.Davies First if the trialkylborane R3B in diglyme is treated with carbon monoxide at 1 atm. and 100-125" 1 mol. is absorbed and the product after oxidation with hydrogen peroxide gives the tertiary alcohol (13). The yield is often im- proved by adding glycol which perhaps stabilises the final boronic anhydride as its glycol ester. Some yields are given in the Table.go Secondly if the carbonylation is carried out in the presence of water migration of the third alkyl group is inhibited perhaps by hydrolytic ring-opening of the bora-epoxide. Oxidation then give the ketone (12) as shown in the Table.g1 Thirdly if sodium borohydride or lithium borohydride is present during the carbonylation migration can be restricted to the first alkyl group :the reaction now takes place more readily and 1 mol.of carbon monoxide is absorbed at 45" in 1 hr. and the primary alcohol (11) can be isolated in good yield (see Table).92 The three alkyl groups migrate intramolecularly. No crossed products are formed when a mixture of triethylborane and tributylborane is carbonylated and the mixed dicyclohexyl- 1-octylborane (R,R'B) (from dicyclohexylborane and oct-1-ene) gives the single mixed tertiary alcohol (R,R'C-OH). The dicyclohexylboranes prove to be remarkably reactive and can be car- bonylated at 45" in tetrahydrofuran. Under these conditions the mobility of the cyclohexyl group is low and for example dicyclohexyloctylborane gives an 86% yield of ketones consisting of 92% of cyclohexyl octyl ketone and 8 % of dicyclohexyl ketone.93 The reactions are tolerant towards many func- tional groups (e.9.0-CO-Ph CO-OMe C=N) providing a route to func- tionally-substituted cyclohexyl ketones and as the cyclohexyl group has a high mobility in a Baeyer-Villiger oxidation with a peroxy-acid these ketones may then be converted into the corresponding functionally-substituted alkanecar- boxylic acids,94 e.g. CH2=CH -[CH2l8 .C02Me + 0x0* [CH,] * COzMe RCO H 2H0,~C[CH2]lo.C02Me CH,<H. [CH,] *CH2 *OH + -CO-[CH,] lo*CH2 .OH RC035 H02C* [CH,] * CH OH The 1,1,2-trimethylpropyl group has an unusually low mobility in the car- bonylation step and boranes carrying this group react readily with carbon monoxide only at 60 atm.pressure. Under these conditions two olefins can be linked through a carbonyl group to give mixed ketones by the process 90 H. C. Brown and M. W. Rathke J. Amer. Chem. SOC. 1967 89 2737; H. C. Brown and E. Negishi J. Amer. Chem. SOC.,1967,89 5478. 91 H. C. Brown and M. W. Rathke J. Amer. Chem. SOC.,1967,89,2738. 92 M. W. Rathke and H. C. Brown J. Amer. Chem. SOC.,1967,89,2740. 93 H. C. Brown and M. W. Rathke J. Amer. Chem. SOC.,1967,89,4528. " H. C. Brown G. W. Kabalke and M. W. Rathke J. Amer. Chem. SOC.,1967,89,4530. Organometaiiic Compounds 231 HBH2 olefin sB/R olefin? \H R I O==C' =-w-"' 'R' OH OH Two examples are as follows.95 Dienes can be converted into cyclic ketones by a similar pro~ess.'~ c -o$<-0=3 (78%) In most of the work described in this section the proof of structure of the organoboranes is based on the premise that alkaline hydrogen peroxide always brings about hydroxydeboration with complete retention of configuration in the alkyl group.An interesting possible exception to this rule has appeared in the diboration of alkenes and alkynes with diboron tetrachloride. The common factors between the infrared and Raman spectra show that the adduct between B2C14 and acetylene is cis-Cl,B* CH :CH BC12;97 simi-larly the adduct with but-2-yne is cleaved by base to give cis-but-2-ene. Again the adduct formed by cis-but-2-ene and by trans-but-2-ene is oxidised by hydro- gen peroxide to rneso-and (f)-butane-2,3-diol respectively and the adduct from cyclohexene give cis-cyclohexane- 1,2401.~~ All these diborations are therefore assumed to occur in a cis-sense.Cyclopentene however reacts with B,C14 to give after hydroxydeboration trans-cyclopentane- 1,2-diol; either the diboration must occur in a trans-sense or the hydroxydeboration must give retention of configuration at one site and inversion at the other.99 The 1-or 2-halogenoalkyl-boranes (R,B) or borates (R4B-) can be prepared 95 H. C. Brown and E. Negishi J. Amer. Chem. SOC. 1967.89.5285. 96 H. C. Brown and E. Negishi J. Amer. Chem. SOC.,1967,89 5477. 97 R. W. Rudolph J. Amer. Chem. SOC.,1967,89,4216. 98 M. Zeldin A. R. Gatti and T. Wartik J. Amer. Chem. SOC. 1967.89,4217. 99 H. K. Sahar L. J. Glicenstein and G. Urry,J. Organometallic Chem.1967,8 37. Alwyn G. Davies by hydroboration of a halogeno-alkene or -alkyne or by halogenation of an alkenyl- or alkynyl-borane or by halogeno-alkylation of an alkylborane. These compounds may then react in the following three ways. (1) trans-l,2,Elirnina- tion of R,B-X (X = halogen) under solvolytic conditions. (2) cis-1,2-Elimina- tion of R,B-X under thermolytic conditions. (3) Nucleophilic 1,Zmigration of a group R from boron to carbon displacing X with inversion at the carbon centre. The potential of these reactions in organic synthesis is being investigated ; some parallel work on organoaluminium compounds is described in a later section. But-1-yne reacts with diborane to give a mixture of polymeric 1,l- (mainly) and 1,2-diboroalkane~,'~~ but a dialkylborane such as dicyclohexylborane"' or bis-( lY2-dimethylpropyl)boraneadds to give a vinylborane (14) Bu I -Bu\C..,c<H -(18) IJNaOH "%c'+qc\\\\\\ BuCECH R,BH H0 BBr HI b-R I R Bu Br Bu R (16) (17) (19) trans-Addition of bromine to the double bond then gives the erythro- dibromide (1 5) which undergoes trans-dehalogenoboration to the cis-vinyl bromide (16).Thermal decomposition of the dibromide on the other hand brings about cis-dehalogenoboration to the trans-vinyl bromide (17). Phenyl-acetylene is exceptional in that the solvolytic route gives the trans-bromide and the thermolytic route the cis-isomer.'" Iodine on the other hand does not give a vinyl iodide when it reacts with the vinylborane (19).Under alkaline conditions an alkyl group migrates from boron to carbon perhaps in the iodonium ion (18) then trans-deiodoboration loo G. Zweifel and H. Arzoumanian J. Amer. Chem. SOC.,1967,89,291. G. Zweifel H. Arzoumanian and C. C. Whitney J. Amer. Chem. SOC.,1967,89,3652. lo' H. C. Brown D. H. Bowman S. Misumi and M. K. Unni J. Arner. Chem. SOC.,1967,89,4531. Organometallic Compounds leads to the cis-olefin (19) in 81 %yield. A route is thus available for stereo- selectively introducing an olefinic side-chain on to both acyclic and cyclic systems. O1 Similar rearrangement and elimination reactions occur in the halogeno- alkyl- and halogenoalkenyl-boranes obtained from the hydroboration of alkenyl and alkynyl halides. Polyhalogenated ethylenes and propenes are completely dehalogenated by a sequence of hydroborations and dehalogeno- borations to give ultimately alkylb~ranes,"~ but the adducts of vinyl chlordes or bromides with dicyclohexylborane rearrange providing a route to the secondary alcohols (20).OH (20) The adducts of iodoalkynes [e.g.(21)] do not rearrange in tetrahydrofuran and acidolysis gives the product of cis-hydrogenation. Nucleophiles such as methoxide ion however convert the borane into a borate complex which does rearrange and can then be converted into a variety of functional derivatives such as (22) and (23).'04 Bu \ BUCXI l)zBF 'cx -BU c==c ,B(C6Hl ,)OMe \ H' cBCsHl1 H' C6H 11 (21) C6Hll ( I/OMe \,,,; ki RCO,H Bu Bu H BUCH2 *CO *C6 Hi 1 \/ \Cd' C==C \ H' H H '(22) 'C6H 11 (23) A similar rearrangement also occurs in the a-halogenoalkenyl- and a-halogenoalkyl-boranes which are formed when triphenylborane is treated with the appropriate organolithium reagent,"' and in the ylid which appears to result from treating a triethylpropynyl borate with an acyl chloride.lo6 lo3 R.Koster and W. Fenzl Angew. Chem. Internat.Edn. 1967,6 802. lo4 G. Zweifel and H. Arzoumanian J. Amer. Chem. SOC. 1967,89 5087. G. Kobrich and H. R. Merkle Angew. Chem Internat. Edn. 1967 6 74; Chem. Ber. 1967 100,3371. P. Binger Ancgew. Cheni. Ilrrerrlur. Edii. 1967 6 84. Alwyn G. Davies Aluminium.From the theoretical point of view organoaluminium compounds are interesting because of their unusual structure ;from the practical standpoint they are important because they can be prepared cheaply and will take part in a number of novel and useful reactions.Both aspects have received attention during the past year. Whereas organoboranes are monomeric trimethylaluminium has a structure like diborane in which two methyl groups bridge two approximately tetra- hedrally hybridised aluminium atoms (24; R = R' = Me).'07 In hydrocarbon solvefits at -75" the 'H n.m.r. spectrum shows the presence of distinct terminal and bridging groups but at room temperature a single signal is observed because of the rapid exchange of the methyl groups. (24) The crystal structure has been redetermined,lo8 and the hydrogen as well as the aluminium and carbon atoms have been located confirming the above picture.Crystalline triphenylaluminium is a similar centrosymmetric dimer (24; R = R' = Ph) with considerably distorted bridging phenyl groups (R') which are twisted at an angle of 84.4"with respect to the central ring,lo9 and the low-temperature n.m.r. spectrum shows that in dimethylphenylaluminium it is the phenyl rather than the methyl groups which are involved in bridging (24; R = Me R' = Ph).'" Triethylaluminium is similarly a bridged dimer and the rate of uptake of ethylene by (C2D,),A12 shows that the hydrogen atoms do not participate in bridge-bonding by tunneling.' '' In the crystalline complex (Me3A1)2C4Hs02 dioxan is in the chair form with each oxygen co-ordinated to a Me,AI unit which is nearer trigonal than tetra- hedral.Much of the synthetic utility of boron compounds depends on the ability of only a boron-hydrogen bond to add (reversibly) to a C=C or C=C bond. With aluminium both the A1-H and Al-C bonds can add again reversibly the latter process leading by replication to the oligomerisation or polymerisation of ethylene and a combination of the two processes leading to the dimerisation of higher olefins. Hitherto trialkylaluminium compounds have usually been used in conjunc- tion with olefins often in catalytic reactions. The dialkylaluminium hydrides are now finding increasing use often in conjunction with acetylenes and in lo' P. H. Lewis and R. E. Rundle J. Chem. Phys. 1953,21,986. lo' R. G. Vranke and E. L. Amma J. Amer. Chem. SOC.1967,89,3121. J. F. Molone and W. S. McDonald Chem. Comm. 1967,444. 'lo E. A. Jeffery T. Mole and J. K. Saunders Chem. Comm. 1967 697. l1 ' K. H. Reichert and H. Sinn J. Organometallic Chem. 1967 7; 189. '" J. L. Atwood and G. D. Stucky J. Amer. Chem. SOC. 1967,89,5362. Organometallic Compounris non-catalytic procedures. Much of this is parallel to the work described above involving organoboron hydrides and is being carried out by the same groups of investigators. Hexa-1,5-diene reacts with diethylaluminium hydride with ring-closure but if the reaction is carried out with diethylaluminium hydride etherate the initial hydroalumination is much faster than any subsequent intramolecular organo- alumination and the a-aluminohexene (25) is formed.If a trace of triethyl- aluminium is now added this removes the ether and the aluminomethylcyclo- pentane is again formed.’ ’ I I5 Et,Al ,0Et2 + HAlEtz A dialkylalumium hydride reacts with an alkyne by cis-addition to give a vinylalane (26) ;various halogens (Br2 ICl 12)now cleave the carbon-aluminium bond with retention of configuration giving the pure trans-vinyl halide ;’l4 only bromide reacted in this way with the corresponding vinylborane (14). Methyl-lithium converts the vinylalane into the ate complex (27) which brings about vinylation with retention of configuration ; for example carbon dioxide gives trans-hex-2-enoic acid (28) and formaldehyde gives the corres- ponding alcohol (29).’ ’’ Bu Bu BuCdH Bu,’AIH+ \c_c/H -*2 ‘c=c /H /\ H AlBu ‘x H’ MeLi Bu H Bu Bu H ‘C=d H / ‘CH -OH y-I@ H ;c=c /H AIBui,Me co2 H’‘c=c’ ‘C0,H -(29) (27) (28).R. Reinlcker and G. F. Gothel Angew. Chem. Internat. Edn. 1967,6,872. ‘14 G.Zweifel and C. C. Whitney J. Amer. Chem. SOC. 1967,89,2753. G. Zweifel and R. B. Steele J. Amer. Chem. SOC.,1967,89 2754. Alwyn G.Davies In contrast lithium di-isobutylmethylaluminiumhydride reacts with an alkyne apparently by trans-addition providing a route to derivatives of the trans-oIefin,"6 e.g. R H R AIBui,Me /' R I RMR Li(Bui2MeAlHL '-/ 12 H /\ R \ H /" \R (R = Me or Et) The organic compounds of gallium indium and thallium have been re-viewed.' '' Group 1V.-Preparative and structural problems appear to be less acute in Group IV which is being used as a field for developing and testing theories of constitution and mechanism.The ethynyl' 18*' l9 and the organosulphur'20 derivatives of silicon ger-manium tin and lead have been reviewed and the second edition of Dub's register of the organic compounds of germanium tin and lead has been pub-lished.' ' Silicon. Reviews have been published on carbosilanes,'22 oligo-and poly-siloxane~,'~~ ~ilanes,'~~ siloxy-compounds of transition metals,'25 and organohalogenosilanes. Gilman's group have continued their work on silicon-silicon bonded Com-pounds which are usually prepared by a Wurtz-Fittig reaction on a halogeno-silane. They have prepared the compounds (Me,Si),Si (60-70 % yield),12' C6C1,Si(SiMe3)3,'28 and (Me3Si)3Si-Si(SiMe3)3'29by this procedure and '16 G.Zweifel and R. B. Steele J. Amer. Chem. SOC. 1967,89 5085. K. Yasuda and R.Okawara Organometallic Chem. Rev. 1967,2,255. "'W. E. Davidsohn and M. C. Henry Chem. Rev. 1967,67 73. '19 L. K. Luneva Uspekhi Khim. 1967,36,1140. 120 E. W. Abel and D. A. Armitage Ado. Organornetallic Chem. 1967,5 1. 12' 'Organometallic Cornpoi-rids. 11. Germanium Tin and Lead,' ed. M. Dub 2nd edn. ed. R. W. Weiss Springer Berlin 1967 [vol. I (1966) covered the transition metals.] G. Fritz Angew. Chem. Internat. Edn. 1967,6,677. 123 G. Schott Fortschr. Chem. Forsch. 1967,9,60. lZ4 E. Hengge Fortschr. Chem. Forsch. 1967,9 145. F. Schindler and H. Schmidbaur Angew. Chem. Internat. Edn. 1967,6,683. lZ6 R.J. H. Voorhoeve 'Organohalosilanes.Precursors to Silicones,' Elsevier Amsterdam 1967. 12' H. Gilman and L. C. Smith J. Organometallic Chem. 1967,8 245. 12' H. Gilman and K.Shiina J. Organometallic Chem. 1967,8,369. 129 H. Gilman and R. L. Harrell J. Organometallic Chern. 1967,9 67. 0rganome tal lic Compounds 237 compounds Cl(Ph,Si),Cl and Cl(Ph,Si),Cl by ring-opening of the correspond- ing tetra- and penta-silanes.I3O The silacyclobutanes are interesting because ring-strain enhances the reac- tivity of the Si-C bond. Silacyclobutane itself has been prepared; in the mass- spectrometer it loses ethylene giving the radical ion H2h * CH as the strongest peak.' ' 1,l-Dimethylsilacyclobutanesimilarly loses ethylene at 4W forming 1,1,3,3-tetramethyl-1,3-disilacyclobutane;the dissociation is inhibited by propene or ethylene and water completely suppresses the formation of the disilacyclobutane giving trimethylsilanol and hexamethylsiloxane.It was suggested that these results implied dissociation to ethylene and the molecule Me,SiCH, which if it is not a diradical is the first evidence for the existence of a silicon-carbon double bond.' 32 Me ,Si-CH , II Me,Si--CH, I I + CH,==CH2 + Me2Si==CH2/CH2-siMe2 CHZXH -%6'-Me,SiOH The first insertion of dichlorocarbene into a carbon-silicon bond has been reported for dimethylsilacyclobutane,68 and the compounds R3Si* [CH,] -GeBu,H R,Si*[CH,] *GeBu [CH,] *GeBu,H and Et3Ge[CH,] -GeBu,H have been prepared by the ring-opening of 1,l-dibutyl- germacyclobutane with the appropriate silicon or germanium hydride in the presence of chloroplatinic acid.' 33 Corey and Seebach's route to ketones2 has been extended to the preparation of some trialkylsilyl and trialkylgermyl ketones (e.g. Me,% -CO. Me Ph,Ge. CO- Me Et,Ge *CO-GeEt, Me3Si*CO-GeEt,).134' ' 35 The silyl ketones absorb strongly at 380-420cm.-' and are photolysed in alcohols to give silyl acetals with retention of configuration in the trialkylsilyl group ; the reaction may involve insertion of a siloxycarbene into the OH bond of an alcohol.' 36 Electrophilic rearrangement of the silyl group from carbon to oxygen giving ultimately a siloxyalkene may also occur when the silyl ketone is treated with diazomethane or with triphenylmethylenephosphoranes.'37 (Y R,Si.CO -R' % R,Si-C-R' + R,Si 0.C-R' =% R,Sj -0 .CHR'. OR" u H. Gilman and D. R. Chapman J. Organometallic Chem. 1967,8,451. L. Laane J. Amer. Chem. SOC.,1967,89 1144. 132 L. E. Gusel'nikov and M. C. Flowers Chem. Comm. 1967,864. 133 P. Mazerolles J. Dubac and M. Lesbre Tetrahedron Letters 1967 255. 134 E. J. Corey D. Seebach and R. Freedman J. Amer. Chem. Soc. 1967,89,434. 13' A. G. Brook J. M. Duff P. F. Jones and N. R. Davis J. Amer. Chem. SOC. 1967,89,431. 136 A. G. Brook and J. M. Duff J. Amer. Chem. SOC.,1967,89,454. 137 A. G. Brook W. W. Limburg D. M. McRae and S. A. Fieldhouse J. Amer. Chem. SOC. 1967 89.704. Alwyn G.Davies Sommer's resolution in 1959,' 38 of methyl-1-naphthylphenylsilaneinitiated a series of papers on the stereochemistry ofreactions occurring at the silicon centre.Some other optically active alkylmethylphenylsilanes (RMePhSiX; R = Et Ph2CH Me,C*CH,) have been prepared,'39 and the first disilane Ph3Si SiMePhX has been resolved.'40 Good leaving groups X,such that the pK of HX < 6 (e.g. X = C1 OAc) are displaced by a more basic nucleophile with inversion of configuration probably through a bipyramidal transition state (as for an S,2 reaction at carbon) or intermediate (cf. Me,PF,).14,' Organolithium or organomagnesium reagents however may displace fluorine with retention perhaps by an SNi rea~ti0n.l~~ Less-good leaving groups such as OR H,14 NR2,144 or SR14' are more prone to give retention. Various Group VIII metals have been evaluated in catalysing the reaction R3SiH + HX + R,SiX + H2 for preparing silylamines silanethiols and halogeno~ilanes.'~~ Like the corresponding reactions of hydroxylic com- pound~,'~' many of these reactions proceed with inversion and cannot follow a simple 4-centre mechanism involving adsorbed hydrogen The same catalysts also promote the exchange of hydrogen in the systems H,/R3SiD and R,SiH/R,SiD and catalyse the addition of R,SiH to an olefin; these re- actions now involve retention of configuration at silicon.148 1,2,3,4-Tetrahydro-2-methoxy-2-ol-naphthyl-2-silanaphthalene has also been resolved and shown to undergo many reactions at the asymmetric silicon centre with a high degree of retention of optical purity but the relative configurations of the reactants and products are not yet known.149 Germanium.Organoaluminium compounds have little advantage over Grignard reagents for alkylating germanium tetrachloride,' 50 but tetra-alkyl-lead compounds may be useful for bringing about mono- and di-alkyla- tion.' ' Arylhalogenogermanes can be prepared from the reaction between germanium tetrachloride and tetraphenylgermane in the presence of alu- minium chloride," ' or between germanium tetrachloride and aryl iodides in the presence of copper powder.'52 '" L. H. Sommer 'Stereochemistry Mechanism and Silicon,' McGraw-Hill New York 1965. 13' L. H. Sommer K. W. Michael and W. D. Korte J. Amer. Chem. SOC.,1967,89,868. ''O L. H. Sommer and K. T. Rosborough J. Amer. Chem. SOC.,1967,89 1756. L. H.Sommer G. A. Parker N. C. Lloyd C. L. Frye and K. W. Michael J. Amer. Chem. SOC.,1967,89 857. L. H. Sommer W. D. Korte and P. G. Rodewald J. Amer. Chem. Soc. 1967,89,862. 14' L. H. Sommer and W. D. Korte J. Amer. Chem. Soc. 1967,89,5802. 14' L. H. Sommer and J. D. Citron J. Amer. Chem. Soc. 1967,89,5787. L. H. Sommer and J. McLick J. Amer. Chem. SOC. 1967,89,5806. L. H. Sommer and J. D. Citron J. Org. Chem. 1967,32,2470. 14' L. H. Sommer and J. E. Lyons J. Amer. Chem. SOC.,1967,89,1521. L. H. Sommer J. E. Lyons H. Fujimoto and K. W. Michael J. Amer. Chem. SOC.,1967,89 5483; L. H. Sommer K. W. Michael and H. Fujimoto ibid. 1967,89 1519. 14' R. J. P. Corriu and J. P. Masse Chem. Comm. 1967 1287. F. Glocking and J. R. C. Light J. Chem. Soc. (A),1967,623.lS1 K. Kiihlein and W. P. Neumann Annalen 1967,702 17. lS2 V. F. Mironov and N. S. Fedotov J. Gen. Chem. (U.S.S.R.),1966,36 574. OrganometallicCompounds Trichlorogermane reacts with ketones containing a primary alkyl group condensation and dehydration is followed by addition of the germane to the double bond to give a p-trichlorogermylketone in very good yield e.g. 2 If the ketone R,CO cannot condense the corresponding alkyltrichloro- germane RzCH GeCl, is formed probably through the alcohol RzCH*OH.153 Tris(trimethylgermy1)-arsine and -phosphine have been prepared.’ 54 The Ge-0 bond in tributylmethoxygermane and dributylethoxygermane has been shown to add to the doubly-bonded systems in phenyl isocyanate phenyl isothiocyanate chloral and di-p-tolyl carbodi-imide :’’’it is thus less reactive than the Sn-0 or Pb-0 bonds but more reactive than the Si-0 bond.Tin. An excellent monograph (in German) on organotin chemistry has been published by W. P. Neumann,’” and is to be translated into English. It gives a particularly good account of the organotin hydrides which are largely omitted from this report.”* The following topics have also been reviewed structural aspect^"^ and co-ordination number ;I6’ bivalent compounds and hydrostannolysis.’62 Organotin compounds lend themselves to spectroscopic studies because the lI9Sn isotope has a nuclear spin of 3 and the “’“Sn isotope decays emitting a y-ray which can be used in Mossbauer spectroscopy.163 Some of the simple correlations which were drawn between spectra and structure have not stood up to closer examination.Heteronuclear double resonance is clearly going to be a powerful technique for studying the organic derivatives of many metals. By this method it has been shown that in compounds containing the structure H-C-Sn a plot 153 0.M. Nefedov S. P. Kolesnikov and B. L. Perlmutter Angew. Chem Internat. Edn. 1967,6 628. lS4 I. Schumann and H. Blass 2. Naturforsch. 1967,22b 1105. 15’ Y. Ishii K. Itoh A. Nakamura and S. Sakai Chem. Comm. 1967,224. lS6 Ann. Reports 1965,62,289; 1966,63,371; cf. L. Birkofer,F. Miiller and W. Kaiser Tetrahedron Letters 1967 2781 ;A. J. Bloodworth A. G. Davies and S. C. Vasishtha J. Chem. SOC. (C) 1967 1309. Is’ W. P. Neumann ‘Die Organische Chemie des Zinns,’ Enke Stuttgart 1967.E. R. Birnbaum and P. H. Javora J. Organometallic Chem. 1967,9 379; K. Hayashi J. Iyoda and I. Shiihara ibid. 1967 . 81. lS9 R. Okawara and M. Wada Adv. Organometallic Chem. 1967,5 137. M. Gielen and N. Sprecher Organometallic Chem. Rev. 1966,1,455. 16’ J. D. Donaldson Prog. Inorg. Chem. 1967,8,287. H. M. J. Creemers ‘Hydrostannolysis. A General Method for Establishing Tin-Metal Bonds,’ Schotanus and Jens Utrecht 1967. R. H. Herber Progr. Inorg. Chem. 1967,8 1. 240 Alwyn G. Davies of J(ll9Sn-H) against J('19Sn-'3C) is linear but does not pass through the origin and the assumption that there is adirect correlation between J( 'I9Sn-H) and the s-character of the Sn-4 bond is not valid.164 The correlations between the Mossbauer isomer shift and the ionic bond character in organotin compounds which were based on a limited number of compounds break down when a wider range of compounds are tested.'65 The mass spectra of the organic derivatives of the Group IY metals are characterised by the near absence of the parent ion.As would be expected most of the positive ion current is carried by metal-containing species. Initially the compound R4M decomposes to the radical R' and the ion R3M+ which has the configuration of a third-group metal. Subsequent decomposition then follows the trend towards tervalence with aluminium and predominant univalence with thallium. 66 There is now a lot of evidence that functional organotin compounds for example R3SnX are frequently co-ordinated through the functional group X into polymers containing 5-co-ordinate tin.' 58 Trimethyltin formate ap-parently is usually a polymer of this type and is virtually insoluble in organic solvents.A second soluble form has now been prepared by heating the insoluble form in cyclohexane at 100" for several hours. In carbon tetra- chloride it is a trimer or tetramer; the infrared and n.m.r. spectra suggest that there is an equilibrium in solution between the monomeric and cyclic oligomer but both the soluble and insoluble forms can be sublimed without interconverting. 67 The exchange of functional groups X between different tin sites can be followed by n.m.r. spectroscopy. In the methyltin halides Me,SnX,_, Br/C1 exchange is always very fast Br/I exchange is slower and Cl/I exchange slower still whatever the value of n.The rate decreases as n decreases and is faster in chloroform than in carbon tetrachloride suggesting that the exchange might involve a five-co-ordinate transition state.'68 On the other hand the dependence on temperature of 19Sn-H coupling in stannylamines R,Sn(NR',),_, shows that the rate of symmetrical exchange of amino-groups increases as n decreases or as the size of the organic groups is reduced.'69 In dialkyltin(rv) compounds unsymmetrical exchange between R,SnX2 and R,SnY can give new compounds R,SnXY and a series of methoxides R,Sn(OMe)X have been isolated ;32* a similar reaction involving a poly- lti4 W. McFarlane J. Chem. Soc.(A) 1967 528 165 J.J. Zuckerman J. Inorg. Nuclear Chem. 1967 29 2191; M. Cordey-Hayes R. D. Peacock and M. Vucelic ibid. p. 1177; J. Nasielski N. Sprecher J. Devooght and S. Lejeune J. Organo-metallic Chem. 1967,8,97. 166 J. J. de Ridder and G. Dijkstra Rec. Trau. chim. 1967,86,737; D. B. Chambers F. Glockling and M. Weston J. Chem. Soc.(A) 1967 1759. 16' P. B. Sirnons and W. A. Graham J. Organometallic Chem. 1967,8 479; 1967 10,457;cf. Y. Maeda and R. Okawara J. Organometallic Chem. 1967,lO. 247. E. V. van der Berghe G. P. van der Kelen and Z. Eeckhaut Bull. SOC.chim. belges 1967,76 79. 169 E. W. Randall C. H. Yoder and J. J. Zuckerman J. Amer. Chem. SOC. 1967,89,3438. A. G. Davies and P. G. Harrison J. Chem. Soc.(C) 1967,1313. Organometallic Compounds 241 meric dialkyltin oxide (R2SnO),,17' or sulphide (R2SnS)3,172 and a second component R, SnX4_, gives functionally substituted distannoxanes or dis- substituted heterostannoxanes XR2Sn*0.M (M = Hg T1 Si Ge or Pb e.g.ClBu,Sn*O*HgPh ClMe,Sn*O*SiMeCl, and ClBu,Sn* O.PbBu,Cl) are formed when dialkyltin oxides are treated with derivatives of the other metals MX.173 These reactions may be regarded formally as the insertion of R,SnO or R2SnS units into the Sn-X or M-X bond and polymeric stannoxanes e.g. C1Bu,Sn(0SnBu2),,C1 and BuSn[(OSnBu,),Cl], have been isolated from the telomerisation reaction between dibutyltin oxide and the appropriate amount of dibutyltin dichloride or butyltin trich10ride.l~~ Mixed-metal Compounds.-This topic was discussed last year.75 The stretching frequencies of the Sn-M bonds (M = Sn Ge Mn Mo Fe Co) nave been identified in the infrared spectra.176 Compounds containing the following mixed metal-metal bonds have been discussed Li_Si,'77 Li-Ge,'77.178 K-Ge,179 Hg-Si,'77.1807 181 Hg-Ge,177. 178. 180 182 T1-Ge,178 Si-Ge,177. 178 Si-Sn,177 Ge-Sn,'77* 178* Si-Sb,'84 Ge-Sb,'84 Sn-Sb,'84* 185 Si-Te,'86 Ge-Te,lS6* lS7 Sn-Te.ls6 By the hydrostannolysis reaction germono-stannanes containing up to 8 catenated metal atoms have been prepared.162* Radicals derived from compounds of the type (R,M),Hg (M = Si or Ge) have been used for silylating the aromatic ring,lS1 and for disilating and digermylating C=C C=C and N=N groups.'80 171 A. G. Davies and P. G. Harrison J. Organometallic Chem.1967 7 P13. A. G. Davies and P. G. Harrison J. Organometallic Chem. 1967 8 P19; R. C. Poller and J. A. Spillman ibid. 1967 7 259. 173 A. G. Davies and P. G. Harrison J. Organometallic Chem. 1967 10 P31. 174 A. G. Davies P. G. Harrison and P. R. Palan J. Organometallic Chem. 1967,10 P33. 17' Ann. Reports 1966 63 371. -N. A. D. Carey and H. C. Clark Chem. Comm. 1967,292; H. Schumann and S. Ronecker 2. Naturforsch. 1967,22b 452. 177 N. S. Vyazankin G. A. Razuvaev E. N. Gladyshev and S. P. Korneva J. Organometallic Chem. 1967 7 353. 178 N. S. Vyazankin E. N. Gladyshev G. A. Razuvaev and S. P. Korneva J. Gen. Chem. (U.S.S.R.). 1966,36,969. E. J. Bulten and J. G. Noltes Tetrahedron Letters 1967 1443. K. Kiihlein W. P. Neumann and H. P. Becker Angew.Chem. Internat. Edn. 1967,6 876. C. Eaborn R. A. Jackson and R. Pearce Chem. Comm. 1967,920; C. Eaborn R. A. Jackson ad R. W. Walsingham J. Chem. Soc.(C) 1967 2188. C. Eaborn W. A. Dutton F. Glockling and K. A. Hooton J. Organometallic Chem. 1967,9 175. la3 H. M. J. C. Creemers and J. G. Noltes J. Organometallic Chem. 1967,7 237. E. Amberger and R.W. Salazar G. J. Organometallic Chem. 1967,8 11 1. H. Schumann T. Ostermann and M. Schmidt J. Organometallic Chem. 1967,8 105. N. S. Vyazankin M. N. Bochkarev and L. P. Samina J. Gen. Chem. (U.S.S.R.) 1966,36 1169. N. S. Vyazankin R. V. Mitrofanova and 0.A. Kruglaya J. Gen. Chem. (U.S.S.R.) 1966 36 166.

ISSN:0069-3030    

DOI:10.1039/OC9676400219

出版商:RSC    

年代:1967

数据来源: RSC

摘要:

7. ALIPHATIC COMPOUNDS By M. F. Ansell (Chemistry Department Queen Mary College Mile End Road London E. 1.) Acetylenes.-Although the intramolecular additions of carbonium ions and free radicals to alkenes are clearly established reactions reports of cycli- sations involving acetylenic bonds are scarce. When' 6-bromo-1 ;phenylhex-1 -ene (1) reacts with an exceess of n-butyl-lithium at room temperature cyclisa- tion occurs probably by a radical mechanism to give the cycloalkene (2) the alternative product 1-phenylcyclohexene not being formed. Another but rather different intramolecular radical-reaction occurs in the peroxide-initiated addition of carbon tetrachloride to terminal alkynes (3) containing a chain of at least six carbon atoms. Beside the expected addition product (5) derivatives R[CHJ4CmCH R[CH,] 4&CH-C C13 R[CH,],CCl =CH-CCl3 / Me2C*C =CH I H (9) (1 0) H.R. Ward J. Amer. Chem. SOC.,1967,89,5517. 244 M.F. Ansell of 2,2-dichlorovinylcyclopentane(8) are formed.2u The latter are considered to arise by rearrangement of the intermediate vinyl-radical by a 1,5-hydrogen shift (4) + (6) followed by internal cyclisation (6) -+ (7) and elimination of a chlorine atom. Similarly radical addition of carbon tetrachloride to propargyl esters gives riseZb to y-lactones uia a 1,5-hydrogen shift from C* in structure (9). If the ester (9)is optically active due to asymmetry at C* then the y-lactone (10) produced retains the optical activity. The authors consider this is due to rapid trapping of the intermediate radical rather than the reaction being concerted.Trifluoroacetolysis of the m-nitrobenzenesulphonates of the 3-yn-1-01s (1 1) gives rise3 to derivatives of cyclobutanone (12) and alkylcyclopropyl ketones (13) the latter predominating in the presence of mercuric acetate. Although an ionic mechanism is involved the exact steps are not certain and two alternative routes are illustrated below for the cyclobutanone formation. By contrast with the olefinic compounds thermal rearrangement of acetylenic compounds have been little studied. It is now reported4 that 1,5-alkadiynes undergo intramolecular rearrangement at 300-400" to yield dimethylene- cyclobutenes e.g. (14) -,(15) and alken-5-ynes (16) undergo' reversible re- arrangement to 1,2,5-alkatrienes (17) which then undergo cyclisation to 3- and 0 6) (1 7) (18) (19) E.I. Heiba and R. M. Dessau J. Am. Chem. SOC.,1967,89 (a)p. 3772; (b)p. 2238. M. Hanack I. Herterich and V. Vott Tetrahedron Letters 1967 3871. W. D. Huntsman and H. J. Wristers J. Amer. Chem. SOC.,1967,89,342. W. D. Hunstman J. A. DeBoer M. H. Woosley J. Amer. Chem. Soc. 1966,88,5846. Aliphatic Compounds 4-methylenecyclopentenes (18) and (19). The thermal cyclisation of some acetylenic ketones is reported under oxygen compounds. The versatility of acetylenic compounds in organic syntheses is extended by the discovery that terminal ethynyl groups may be protected by trimethyl- silylation. Thus Grignard reagents of the type (20)may be prepared6 and also the preferential reduction (21) -,(22),of an internal triple bond in the presence of a terminal triple bond may be a~hieved.~ Desilylation is readily effected with silver nitrate solution to give the silver acetylide which with potassium Me,S i -C= C oMgBr.(a) EtMgBr then Me,SiCl (b) H,-Lindlar catalyst cyanide solution gives the free acetylene. The bis-( 1,l -diisobutylalanyl)alkanes (23) are readily available uia hydroalumination of 1-alkynes. They react with an alkyl-lithium or sodium methoxide in tetrahydrofuran to give the inter- mediates (24) which react' as shown in Scheme 1. All these reactions proceed in good yield (>70%) and appear to be general thus further enhancing the versatility of acetylenes in organic syntheses.Vinylalanes are readily available by the addition of di-isobutyl aluminium hydride to alkynes. This involves cis-addition to the triple bond yielding trans-vinylalanes from 1-alkynes and cis-vinylalanes from disubstituted alkynes. Treatment of such vinylalanes with methyl-lithium followed by carbonation yields the stereochemically pure trans-clp-unsaturated acid like- wise with aldehydes trans-allylic alcohols are f~rmed.~" Remarkably what is essentially a change in the order of addition of the two reagents namely by adding di-isobutylmethylaluminium hydride (from methyl-lithium and di- isobutylaluminium hydride) to disubstituted acetylenes resultsgb in trans-C. Eaborn A. R.Thompson and D. R. M. Walton J. Chem. SOC.(C),1967,1364. ' H. M. Schmidt and J.F. Arens Rec. Trau. Chim. 1967,86,1138. G. Zweifel and R.B. Steele Tetrahedron Letters 1966,6021. G. Zweifel and R.B. Steele J. Amer. Chem. SOC. 1967,89 (a) p. 2754; (b)p. 5085. 246 M. F. Ansell addition of the aluminium hydrogen bond to the triple bond and the resulting vinylalanates react with Grignard co-reagents to give pure cis-clfbunsaturated compounds. These reactions are illustrated by the conversion of the alkyne (25) to the acids (26) and (27). [;;c=c\Et AIBU * J LiC H\ Et/'= /COzH'\Et Et C= C Et (25) .Y Y (2 6) ' H\ 0Etc=c AlBu' Et/ \COzH (2 7) (a) AIHBui then MeLi; (b) Li[BuiCH,AlH] ;(c)C02 Synthetic routes to acetylenes containing hetero-rings have been reported. Thienyl and fury1 compounds may be synthesised by coupling a cuprous acetylide with an iodo-heterocycle in boiling pyridine" e.g.(28) + (29). This I CH,*C:C-Cu Cu.CiC.C02Me-I [LJ LrAI -CH,-C iC (2 8) CH,*C i C rnCiC.C02Me simple reaction takes advantage of the specific formation of cuprous acetylides and enables volatile acetylenic compounds to be used. It can be adapted" to the preparation of terminal acetylenes by use of a substituted acetylide having a readily removable substituent e.g. (30) -+ (31). Alternative approachesI2 consist in the condensation of propargylic aldehydes (32) with mercapto- ketones (33) in the presence of base to yield acyl-thiophens (34)and the reaction CuCi C .CH(OEt) ArCi C * Ad (30)ACu*Ci C- C0,Et lo F. Bohlman P.-H. Bonnett H. Hofmeister Chem. Bm.1967,100 1200; R E. Atkinson R F. Curtis and J. A. Taylor J. Chem. SOC.(C) 1967 578; R. E. Atkinson R F. Curtis and G. T. Philips ibid. p. 201 1. R. E. Atkinson R. F. Curtis D. M. Jones and J. A. Taylor Chem. Comm. 1967 718. l2 F. Bohlmann and E. Bresinksky Chem. Ber. 1967,100 107. Aliphatic Compounds 247 of polyacetylenes (35)with sodium sulphide to yield the thiophens (36)or with sodium bisulphide to yield the thiophen (36)and the dithiole (37). Acetylenic carotenoids have been reported for the first time (see below). -+ (32)Rl.CiCHO R'C4 CH-CH,'0 + R' aC0.R2 (34) (33)m.CH2.(-".R2 'S-cH2'c0RZ CH3 (36) CH [Ct CI2.C :C*CH* C-CH3 -CH,. [C iC] ,CHoCH3 (3 7) HS*S' s-s Carotatoxin a natural toxicant from the common carrot13 has been shown to be falcarinol (38).14 AUenes and Cumulenes.-A number of preparations of allenes have been reported which are variants of the reaction of a Grignard reagent with a propargyl halide.Thus 3-chloro-3-methylpent-2-yne with methylmagnesium CH3 :C CR .CHzX (39) halide yieldsI5 tetramethylallene free from all isomers ; allenic alcohols (39; X = OH) (80-90% purity the remainder being the acetylenic alcohol) are obtained16 by low-temperature inverse-addition of Grignard' reagents to 4-chlorobut-2-yn-l-ols and allenic bromides (39; X = Br) are the major product from Grignard reagents and 1,4-dibromobut-2-ynes.' Such reactions are considered18 to be S,2' reactions and not carbene reactions as previously suggested. l3 D. G. Crosby and N.Aharonson Tetrahedron 1967,23,465. l4 R. K. Bentley and V. Thaller Chem. Comm. 1967,439. J.-P. Bianchini and A. Guillemonat Compt. rend. 1967,264 C 600. l6 S.Gelin R. Gelin and M. Albrand Compt. rend. 1967,264 C 1183. N. Lumbroso-Bader E. Michet and C. Troyanowsky Bull. SOC.chim. France 1967 189. L. Brandsma and J. F. Arens Rec. Trav. chim. 1967,86,734. l9 F. Cerratosa. Tetrahedron L-etters 1964,895. 248 M.F. Ansell An unusual rearrangement” is the conversion of prop-2-ynyl toluene-p- sulphinate (40) in boiling chlorobenzene to propadienyl-p-tolylsulphone(41). A cyclic transition state may be involved. Cycloelimination leading to tetramethylallene (44)in good yield can be achieved2 by oxidation of 4-0~0-3,3,5,5-tetramethyl pyrazoline hydrazone (42) or by pyrolysis of the sodium salt of the toluene-p-sulphonylhydrazone (43).These are the first examples of this type of cycloelimination reaction. 92 02 (4 4) (43) Tetramethoxyallene (46) prepared” from tetramethoxyethylene (45) is the acetal of carbon suboxide. In contrast to other allenes due to the effect of the four methoxy-groups it is protonated on the central carbon atom as is shown by its conversion into dimethyl malonate by anhydrous hydrogen chloride. As a double keten acetal it is hydrolysed to dimethyl malonate and will add methanol to yield hexamethyl orthomalonate (47). (Me0)2C C(OMe) ‘f * CCl ( (45) (MeO),C CH C(OMe) CH,(CO,Me) (47) Photocatalysed di-addition of sulphur compounds such as aliphatic and aromatic thiols to allenes is a better route to trimethylene bis-sulphides than the replacement reaction of 1,3-dihalopropane~.~~ Addition of sodium thio- lates to allene24 gives in all cases more than 90% of the 2-propenyl sulphide RS-C(Me):CH,.It is probable that the reaction proceeds via propyne for with tetramethylacetylene no addition products were detected. The authors question whether any truly anionic additigns to allene have ever been effected. Cycloaddition of diazopropane to allenic esters2’ of the type (48; R = Me) when at least one of the groups R’ and R2is hydrogen give adducts of the type (49) in which as is expected electronically the nucleophilic diazocarbon atom becomes bonded to the carbon atom kto the carbonyl group. In contrast with yy-disubstituted allenes (48; R’ = R2= Me; R3 = H or Me) *’ C.J. M. Stirling Chem. Comm.,1967 131. 21 R.Kalish and W. H. Pirkle J. Amm. Chem. SOC. 1967,89,2781. 22 R.W.Hoffmann and U. Bressel Angew. Chem. 1967,79,823. 23 A. A. Oswald K. Griesbaum D. N. Hall and W. Naegele Canad. J. Chem. 1967,45 1173. ’* W.H.Mueller and K. Griesbaum J. Org. Chem. 1967,32,856. ’’ S. D.Andrews and A. C. Day Chem. Comm. 1967 902. Aliphatic Compounds (51) CH,[CH,] 16*CH:C CHCCH,] ,.C02H diazopropane adds to the @-double bond in the opposite sense to yield the isomeric 3-alkylidenepyrazolines (50). This is due to the severe overcrowding of alkyl groups see (49a) which must occur in the transition state leading to adduct of type (49) when R' = R2 = Me.Naturally occuring allenes continue to be reported and include the acid (51)26 and the carotenoid (75; X = f Y = g).27 1,2,3-Trienes can be obtained in excellent yield (7G-80% for buta-1,2,3- triene; 55 % for higher homologues) from 1,4-dichloro-2-alkynes by the action >CCl*CiC-CH,Cl L>C.C:C-CH, n. ->C:C:C:CH + [,Cl I; LlI-nI '1 I-c1-+ of zinc dust or sodium iodide (3 mole) in dimethyl sulphoxide.28 A possible mechanism is outlined in Scheme 2. These cumulenes are stable below -50° but liquefied butatriene may explode when warmed to 0".The authors state 'The cumulenes possess a very peculiar odour. After one has smelled a cumulene the smoking of cigarettes and cigars is unpleasant for at least two days'. n EtO. CH *O-mC i C -CH.0Me -R'R'C C CH -0Me I rn Me H B-(52 (53) Cumulenyl ethers (53) are prepared in good yield and reasonably pure (>90%) by addition of sodamide in liquid ammonia to the bis-ethers (52) in liquid ammonia. These ethers (53)are stable for an hour at 100-120" in an inert atmosphere but readily polymerise in the presence of oxygen.29 Progress in the chemistry of allenes has been re~iewed.~' Olefinc Compounds.-This year has seen the introduction of a number of 26 F. Bohlmann K. M. Rode and M. Grenz Chem. Ber. 1967,100,3201. 27 A. K. Mallams E. S. Waight B. C. L. Weedon L. Chohoky K. Gyorgyfy J. Szabolcs N. I. Krinsky B. P. Schimmer C. 0. Chichester T. Katayama L. Lowry and H. Yokoyama Chem. Comm. 1967,484. 28 P. P. Montijn L. Brandsma and J.F. Arens Rec. Trau. chim.,1967.86 129. 29 P. P. Montijn J. H. Van Boom,L. Brandsma and J. F. Arens Rec. Trau. chim. 1967,86 115. 30 K. Griesbaum Angew. Chem. 1966,78,953. 250 M.F. Ansell new routes to olefinic compounds. Some of them are considered later in this section under halides others under general methods. a-Lithiophosphonic acid bisamides [54; X = PO(NR,),] react with carbonyl compounds to give after protonation P-hydroxy-compounds [55 ;X = PO(NR,),] which in refluxing benzene or toluene in the presence of R3R4CLiX ('1 R'R2C=0 R1 RZC*CR 3R4X. R'RZC:CR3R4 A (2)H,O I -H OH (54) (55) (56) OLi (57) silica gel undergo an elimination reaction to give the olefin (56) in high yield. The reaction is generally more straightforward and the reagents cheaper than in the Wittig reaction.The elimination step is stereospecific and if the di- astereoisomeric intermediates can be separated then pure cis-and trans-olefins can be ~btained.~' Alkenes are also formed from 00'-dialkyl methyl- phosphon~thioates~~ as and s~lphinimides~~ illustrated by the reaction sequences (54) -,(56) X = PS(OR), and (57) -,(58) respectively. Alkynes have always been useful precursors'of alkenes and a new and convenient stereoselective syntheses of alkenes via the hydroboration-iodination of alkynes has been reported.34 Dialkylboranes (59) which are readily available from most cyclic and many acyclic alkenes readily add to alkynes to yield vinylboranes (60). On addition of iodine to the latter one alkyl group migrates from boron to carbon and subsequent hydrolytic removal of the boron gives the pure ( >99 %) cis-alkene (61)in high (63-85 %) yield.MezCH- CMe :N.NHTs MezCH.CH:CHz Sulphonylhydrazones having an a-hydrogen atom readily prepared from the corresponding carbonyl compounds react with butyl-lithium to yield alkenes which in many cases would otherwise be difficultly accessible. Thus 31 E. J. Corey and G. T. Kwiatowski J. Amer. Chem. SOC.,1966,88,5652,5653. 32 E. J. Corey and G. T. Kwiatkowski J. Am. Chem. SOC.,1966,88,5654. 33 E. J. Corey and T. Durst J. Amer. Chem. SOC.,1966,88,5656. 3* G. Zweifel H. Arzoumanian and C. C. Whitney J. Amer. Chem. SOC.,1967,89,3652. Aliphatic Compounds 251 the hydrazone (62) yields the terminal-alkene (63) probably via a carbanion me~hanism.~' Among the most characteristic reactions of alkenes is the addition of halo- gens.The addition of the pseudohalogens iodine m~noazide,~~ and NN-dichl~rourethane~(64) has now been reported. The former prepared in situ by the action of iodine monochloride on sodium azide in acetonitrile adds C12N- C0,Et +R CH:CHz -RCHCI- CH,. NH.CO,Et // NH 0-NH stereospecifically trans and with terminal alkenes the azido-function is at the 2-position. NN-Dichlorourethane is reasonably stable adding to terminal alkenes to yield P-chlorocarbamates (65) which with alcoholic potassium hydroxide yield aziridines (66) and on pyrolysis or in reflwing acetic acid give 5-substituted oxazolidones. (67). The novel 1,6-cycloaddition of sulphur dioxide to cis-hexa-1,3,5-triene yields3*2,7-dihydrothiepin-l,1 -dioxide (68).The hydroboration-oxidation of alkenes provides a highly convenient procedure for the anti-Markownikoff hydration of carbon-carbon double bonds3' A convenient indirect Markownikoff-hydration of the carbon- carbon bond by oxy-mercuration followed by in situ demercuration with Me C CH :CH Hg(oAT)-%NaBH4 Me3C-C H(0H) CH sodium borohydride is now rep~rted.~' That this reaction does not cause rearrangement is shown by the formation of 3,3-dimethylbutan-2-01 (70) from 3,3-dimethylbut-2-ene (69) in 94 %yield. A number of useful transformations of alkenes can be effected via trialkyl-borons following the discovery that the latter react with carbon monoxide.Thus trialkylborons in diglyme solution react readily with carbon monoxide at atmospheric pressure at 100-125" and subsequent oxidation of the reaction mixture with alkaline hydrogen peroxide yields a trialkyl~arbinol.~~" The reaction clearly involves migration of the .alkyl groups from boron to carbon. 35 R. H. Shapiro and M. J. Heath J. Amer. Chem. SOC.,1967,89 5735; G. Kaufman F. Cook H. Schecter J. Bayless and L. Friedman ibid. p. 5736. 36 F. W. Fowler A. Hassner and L. A. Levy J. Amer. Chem. SOC.,1967 89,2077. 37 T.A. Folgia and D. Swern J. Org. Chem. 1966 31 3625; 1967,32 75. W. L. Mock J. Amer. Chem. SOC.,1967,89 1281. 39 G. Zweifel and H. C. Brown Org. Reactions 1963,13 1. 40 H. C. Brown and P. Geoghegan J. Amer. Chem. SOC.,1967,89,1522.41 H. C. Brown and M. W. Rathke J. Amer. Chem. SOC.,1967,89 (a) 2737; (b)2738; (c) 2740. 252 M. F.Ansell Addition of a small quantity of water to the reaction mixture inhibits migration of the third alkyl group and thus subsequent oxidation of the organoborane intermediate yields a dialkyl ketone.41 If the initial reaction with carbon monoxide is carried out in the presence of sodium or lithium borohydride the reaction temperature may be reduced to 45" and the reaction controlled to achieve the transfer of only one group from boron to carbon; subsequent hydrolysis yields the homologated alcohol.41' Thus carbonylation of organo-boranes can be controlled to achieve migration of one two or three groups. All these reactions are summarised in Scheme 3.These reactions can be H,O,-NaOH -R3C*OH RB(0H)-CR,(OH) Hzoz-NaoH -.R,CO C0/45"/NaBH4 NaOH RCH,OH SCHEME3 adapted42 to prepare unsymmetrical ketones by the use of 'thexylborane' (2-butyl-2,3-dimethylborane) the alkyl group of which will not migrate from boron to carbon. This is shown in Scheme 4. By using this method ethyl Me,C:CMe + BH3 + Me,CH.CMe,*BH 4kene-% Me,CH-CMe,.BR,H 4sMe,CH.CMe,BR,R -2+ CO-H 0 Me,CH.CMe,.B(OH).CRARB(OH) Hzoz + RARBCO NaOAc SCHEME 4 7-methyl-5-0x0-octanoate (98 % pure) was prepared from isobutene and ethyl but-3-enoate in 84% yield. Conversion of an alkene RCH:CH into the corresponding acid RCH .CH .CO,H is achieved43 by formation of a cyclohexyl ketone using dicyclohexyldiborane followed by Baeyer-Villiger oxidation which occurs with preferential migration of the cyclohexyl group to form the corresponding cyclohexyl carboxylate.This is illustrated in Scheme 5. When an internal alkene is exposed to a catalyst composed of tungsten (C6HI1),BH + CH,:CH[CH,],.CH c!NaOAc C6H,,.CO-[CH,],.CH 1% CH3. [CH,],.C02H (a) Baeyer-Villiger oxidation SCHEME 5 42 H. C. Brown and E. Negishi J. Amer. Chem. SOC.,1967,89,5285. 43 H. C. Brown G. W. Kabalka and M. W. Rathke J. Amer. Chem. SOC.,1967,89,4530. Aliphatic Compounds 253 hexachloride ethanol and ethyl aluminium chloride the following novel metathesis takes place 2 R'CH :CHR @ R'CH :CHR' +R2CH:CHR2 The statistical proportion (2 1:1) of products is obtained the reaction is reversible and clean and deuteriation studies suggest that it proceeds via trans-alkylidenation rather than by trans-alkylati~n.~~ Dehydrogenation of several alk-1 -enes by lithium dispersions under mild conditions (20-120") to give the corresponding alk-1-ynyl lithium and lithium hydride has been rep~rted.~' The yield varies markedly with the chain length of the alkene reaching a maximum of 60 %with hex-1-ene.The reaction only applies to alk-1-enes. Photochemistry of alkenes is reviewed on p. 164 but attention is drawn to the photochemical dimerisation of tetramethylethylene to hexamethylcyclo- butane.46 This is one of the few examples of the photochemical dimerisation of a nonconjugated alkene. trans-Penta-1,3-diene (71) forms an inclusion compound with perhydro- triphenylene.If optically active (-)-(R)-perhydrotriphenylene is used and the inclusion compound subjected to y-irradiation the isotactic trans-1,5-poly- pentadiene (72) produced is optically active [CZ]:~~ = +9.8. The use of (+)-(S)-perhyrdotriphenylene leads to a polymer with the opposite sign of rotation. This novel example of an asymmetric synthesis shows that optical activity may be induced in simple chemical systems under rather primitive conditions in the absence of complex reagents or catalysts and by means of non-selective ionising radiati~n.~' Natural Products.-Squalene-2,3-epoxide a key compound in the biological conversion of squalene into cholesterol (see p. 524) has been found4* in cultivated tobacco tissues in uitro.Another important alka-polyene epoxide is the compound (73) which is the juvenile hormone (i.e. one of the factors C0,Me 0 44 N. Calderon Hung Yu Chen and K. W. Scott Tetrahedron Letters 1967,3327. 45 D. L. Skinner D. J. Peterson and T. J. Logan,J. Org. Chem. 1967,32 105. 46 D. R. Arnold and V. Y. Abraitys Chem. Cornrn. 1967 1053. 47 M. Farina G. Audisio G. Natta J. Amer. Chern. SOC. 1967,78 5071. 48 P. Benveniste and R. A. Massy-Westropp Tetrahedron Letters 1967 3553. 254 M.F. Ansell necessary for the post-embryonic development) of the giant silkworm moth. Its structure has been established by degradative and synthetic studies.49 The plant growth inhibitor dormin (74) shows similarities in structure to certain carotenoids and it has been shown5' that irradiated mixed carotenoids from dried nettles inhibited the growth of cress seeds as did (+)-dormin.Y (7 6) H H 49 K. H. Dahm B. M. Trost H. Roller J. Amer. Chem. SOC. 1967 89 5293; H. Roller K. H. Dahm C. C. Sweely and B. M. Trost Angew. Chem. 1967 79,190. H. F. Taylor and T. A. Smith Nature 1967 215 1513. Aliphatic Compounds A natural acetylenic sesquiterpene has been described,” as have three52 C,,-acetylenes which can be regarded as degraded sesquiterpenes. This year acetylenic carotenoids alloxanthin (75; X = Y = a)53identical with pectin- oxanthin and cynthiaxanthin,’ monoadoxanthin (75; X = a Y = c),~~ crocoxanthin (75; X = a Y = d),53 diatoxanthin (75; X = a Y = b),53 and pectenolone (75; X = a Y = e)54 have been discovered.Neoxanthin is identical27 with the allenic carotenoid folioxanthin (75 ;X = f Y = g). The carotenoids phlei-xanthophyll (76; X = H2) and (76; X = 0),isolated from mycobacterium phlei are the first reporteds5 natural tertiary D-glucosides. The first C,,-carotenoid encounted in nature isolateds6 from the non- photosynthetic bacteria Flavobacteriurn dehydrogenans has been provisionally called P439 and it is suggesteds7 that it has the structure (75; X = Y = h). Alkanes.-The gas-phase catalytic deuteriation of low molecular weight paraffins is known and it has now been shown’’ that high molecular weight hydrocarbons may be fully deuteriated in the liquid phase by passing deuterium gas through an exchange cell containing the hydrocarbon and a fixed-bed catalyst such as ruthenium palladium platinium or Raney nickel.Thus n-hexadecane is 99.4%deuteriated in 316 hr. at 190”. The ionisation of isobutane (77) -,(78) occurs in hydrogen fluoride-antimony pentafluoride solution. The reverse reaction which can be achieved” +-+-MeJCH+ HQ =Me3C++ H Me,C + H SbF -Me,C SbF + MeH (7 7) (78) (79) (80) in a two-phase solvent system (HF-Freon 113) amounts to electrophilic substitution at hydrogen. When6’ neopentane is dissolved in HF-SbF nucleophilic substitution at carbon by a proton takes place (79) + (80) and methane is evolved. The reverse reaction has not been observed. Carboxylic Acids and Related Compounds.-With very few exceptions a-metalation of aliphatic carboxylic acids has not been reported.Acetic acid with sodamide yields6 disodium acetate but homologous metalated acids are decomposed under the reaction conditions. However metalation with lithium di-isopropylamide in tetrahydrofuran or hexane appears to be a ’’ R. A. Massy-Westrop G. D. Reynolds and T. M. Spotswood Tetrahedron Letters 1966 1939 (cf. Annual Reports 1966). ’’ T. Nozoe Y. S. Cheng and T. Toda Tetrahedron Letters 1966,3663. ” A. K. Mallams E. S. Waight B. C. L. Weedon D. J. Chapman F. T. Haxo T. W. Goodwin and D. M. Thomas €hem. Comm. 1967,301. ” S. A. Campbell A. K. Mallams E. S. Waight B. C. L. Weedon M. Barbier E. Lederer and A. Salaque Chem. Comm. 1967,941. ” S. Hertzberg and S. L. Jensen Acta Chem. Scand. 1967 21 15. S. Liaanen Jensen and 0.B.Weeks Norweg. J. Chem. Mining Met. 1966,26 130. ” S. Liaanen Jensen Acta Chem. Scand. 1967,21 1972 ” J. G. Atkinson M. 0.Luke and R. S. Stuart Canad. J. Chem. 1967,445 1511. ’’ A. F. Bickel C. J. Gaasbeek H. Hogeveen J. M. Oelderik and J. C. Platteeuw Chem. Comm. 1967,634. 6o H. Hogeveen and A. F. Bickel Chem. Comm. 1967,635. 61 D. 0.DePree and R. D. Closson J. Amer. Chem. SOC.,1958,80,2311. 256 M.F. Ansell general reaction for aliphatic alkenoic and araliphatic acids.6Z This is illus- trated by the formation of lithiated-isobutyric acid (82) which is stable in the solvent system up to 40".These reagents can be alkylated with alkyl halides and with epoxides (81) (e.g. a 17,20-epoxy-steroid) yield spiro-lactones such as (83). The chlorination of the esters CH,[CH,];CO,Me where n = 2,3,4 or 5 by N-dichlorodimethylamine in an acidic medium is highly ~elective.~ In each case more than 70% of the monochlorinated material has the chlorine attached to the carbon atom adjacent to the terminal methyl group.Chlori- nated esters may also be prepared from hydroxy-esters under almost neutral conditions by heating them with triphenylphosphine and carbon tetra-chloride.64 The reaction proceeds with inversion at !he reaction centre and a possible reaction route is shown in Scheme 6. Esters of dichloroacetic acid RCH(OH)*CO,R' + [Ph,P*CCl,]+Cl-+ [Ph3P.0*CHR-C02R']+ C1- + CHC1 1 RCHCl*CO,R f Ph,PO SCHEME 6 can65 be used as the 'reactive methylene component' in the Michael reaction as shown by the formation of the ester (84) from methyl a-methylmethacrylate and ethyl dichloracetate.A disadvantage of the direct acylation of sodio-malonic esters as a route to acyl-malonic esters is that the primary product is often further acylated. This /OEt Me02C. CCl,. CH,-CHMe-CO,Me EtO,C.CH :C RCO .CH(CO,Et) \ OSiMe (84) (85) (86) 62 P. L. Creger J. Amer. Chem. SOC. 1967,89,2500. 63 F. Minisci R. Galli A. Galli R. Bernardi Tetrahedron Letters 1967 2207. 64 J. B. Lee and I. M. Downie Tetrahedron 1967,23,359. " H. Timmler and R. Wegler Chem. Ber. 1967 100,2362. Aliphatic Compounds may be overcome66 by reaction of the sodio-malonate with trimethylsilyl chloride to yield the ‘keten acetyl’ (85) which will react readily with an acyl halide RCOCl eliminating trimethylsilyl chloride to give the acylmalonic ester (86).The oxidative decarboxylation of disubstituted malonic acids (87) + (88) provides a useful route to ketones and is achieved67 in two stages by reaction with lead tetraacetate The ketones are obtained in yields of 45-70 % which is very satisfactory in view of the simplicity of the process. The existence of two forms of succinyl dichloride (89) and (90)has in the past been assumed6* in order to explain the formation of abnormal products such as (92) from its reaction with triethylaluminium trichloride. However there is no physical evidence to support the existence of the cyclic form and n.m.r. evidence shows that it exists predominantly in the acyclic form.The formation of the product (92) cap be explained on the basis of a [3,2,1]-bicyclic mecha- ni~m~~as illustrated (91) - (92). CH,. COCl . I CH,. CO C1 (89) Ci Et OAl R,I Cl Et CH * I CH,. COzH CH. Et C1I (90) Friedel-Craft reactions are usually associated with aromatic compounds however the single-step condensation of succinyl chloride with carboxylic acids RCH C02H under Friedel-Craft conditions yields” 2-alkylcyclo-pentan-1,3-diones (93; n = 1). These compounds are important in steroid syntheses and can also be obtained7’ by the cyclisation of y-0x0-carboxylic acids RCH CO. [CH,] C02H with aluminium chloride in the presence of an acylating agent such as acetyl or propionyl chloride. The use of glutaryl chlorides or 6-0x0-acids leads to the 2-alkylcyclohexane-l,3-diones (93; n r= 2).CH,.CO \ /O\ CHR CH,[CH,],.CH. CH -CH,*CH=CH[CHz],.CO2Me (94) [AH,]n.CO/ (93) (95) 66 U. Schmidt and M. Schwochau Tetrahedron Letters 1967,4191. 6’ J. Tufariello and W. J. Kissel Tetrahedron Letters 1966 6145. 68 G. H. Schmid Canad. J. Chem. 1966,44,2917. 69 M. S. Newman and C. Courduvelis J. Amer. Chem. SOC.,1964,86,2942. ’O H. Schick G. Lehmann and G. Hilgetag Angew. Chem. 1967,79,97. ’’ H. Schick G. Lehmann and G. Hilgetag Chem. Ber. 1967,100,2973. 258 M.F. Ansell The unusual rearrangement of methyl vernolate (94) in the presence of boron trifluoride etherate to the cyclopropane acid (95)has been reported.72 Nitrogen Derivatives.-In 1864 Guether7 reported correctly that triethyl- amine is converted to diethylnitrosamine by aqueous nitrous acid.Yet in 1967 a paper74 was still able to open as follows ‘The belief that tertiary aliphatic amines do not react with nitrous acid is one of the most persistent myths in organic chemistry . . . .’. In general an alkyl group is removed oxidatively and appears as an aldehyde or ketone and the nitrogenous portion is converted into a nitrosamine. The reaction is consider to proceed via hydrolysis of an immonium salt (Scheme 7). RiN-CHR; + HNO + R:k(CHRi)NO + R:I;I=CR;* + HNO HNO R:N=CR; + H2O + R;C:O + Ri6H2 -2 R:N*NO SCHEME 7 Condensation of secondary amines with ketones or aldehydes in the presence of stoicheiometric quantities of titanium tetra~hloride~~ gives rise to enamines in 55-94 % yield.(Scheme 8). The use of enaminesin the alkylation of ketones76 2R’CH,COR2 + 6R;”H + TiCl + 2R’.CH=CR2NR + 4RiNH,CI + TiOz SCHEME 8 is well established. Alkylation of enamines derived from aldehydes often leads to N-alkylation and aldol condensation. However aldehyde enamines derived from n-butylisobutylamine can often be alkylated in good yield77 (Scheme 9). C,H,. CH CHO -+ C,H,. CH=CH .NBu”Bu’ me&C,H,- CHMe -CHO SCHEME 9 Fulminic acid undergoes 1,3-dipolar cyclo-addition reactions.78 Thus with methyl acrylate methyl 2-isoxazoline-5-carboxylate(96) is formed. Such reactions are incompatible with the classical carboxine strwture C-NOH for fulminic acid but agree with the formonitrile structure (97). Thus sup- porting the recent79 i.r.spectroscopic evidence in favour of the latter structure. 72 H. B. S. Conacher and F. D. Gunstone Chem. Comm. 1967,984. 73 B. Guether Arch. Pharm. 1864 [2] 123,200. 74 P. A. S. Smith and R. N. Loeppky J. Amer. Chem. SOC. 1967,89 1147. ” W. A. White and H. Weingarten J. Org. Chem. 1967,32,213. 76 G. Stork A. Brizzolara H. Landesman J. Szmuskovicz and R. Terrell J. Amer. Chem. SOC. 1963,85 207. ” T. J. Curphey and J. C. Hung Chem. Comm. 1967,510. ” R. Huisgen and M. Christ Angew. Chem. Internat. Edn. 1967,6,456. 79 W. Beck and K. Feldl Angew. Chem. Internat. Edn. 1966,5,525. Aliphatic Compounds Monosubstituted alkyl di-imides have been postulated as reaction inter- mediates but have never been isolated. t-Butyldi-imide (98) produced by the base-catalysed decomposition of tetra-n-butyl (or tetramethy1)ammonium t-butylazoformate (99) has now been detected spectroscopically.80 Cyanogen azide N,CN which must be handled with extreme care as when it is neat it detonates violently adds to acetylene to form a 1:1-adduct,81 which is a tautomeric mixture of 1 -cyano-1,2,3-triazole (100)and a-diazo-N-cyanoethyl- - c [H-CEN-0 -H-C=N=O] (97) (98) Me3C-N:NH NC-N /N\ ‘N Ld NC -N idenimine (101).Similar results are obtained with methyl- and dimethyl- acetylene but the ethoxyacetylene adduct exists exclusively as the open-chain ethyl a-diazo-N-cyanoacetimidate (102). Cyanogen azide decomposes smoothly at ca. 40” to yield cyanonitrene :N .CN. The latter inserts stereospecifically into tertiary C-H bonds as is shown by its reaction with the 1,2-dimethyl- cyclohexanes.Each isomer yielding a single stereochemically pure cyanamide. [e.g. (103) -+ (104)]. The stereochemistry of the adduct (104) was not proved. Reversal of the assignment would mean that the reaction proceeded with inversion of configuration which the authors consider unlikely.82 (103) (1 04) +-[H,N-C-C=N ++H,N=C-C_N -H,~==c=c=N ++ P. C. Huang and E. M. Kosower J. Amer. Chem. SOC.,1967,89 391 1. M. E. Hermes and F. D. Marsh J. Amer. Chem. Soc. 1967 89,4760. ” A. G. Anastassiou and H. E. Simmons J. Amer. Chem. Soc. 1967,89 3177. I8 260 M. F. Ansell Considerable selectivity is shown by ethoxycarbonyl-nitrene from ethyl azidoformate when it undergoes insertion into C-H bonds to yield carba- mates (R-H + RNH -C0,Et).The reactivity of primary secondary tertiary C-H bonds in alkanes was found83 to be 1 10:32. With cyclic ethers,84 insertion of ethoxycarbonylnitrene occurs exclusively into the C-H bond adjacent to the oxygen atom. The carbamates (105) and (106) being the sole products from the parent ethers (105a) and (106a). Nitrenes and the decomposition of carbonylazides have been re~iewed.~ Base-catalysed polymerisation of hydrogen cyanide yields a mixture of products including a tetramer diaminomaleonitrile (1lo) a pentamer poly- meric amino-acid precursors and black intractable solids believed to have a fused-pyridine structure. Whatever the routes to these products the key intermediate is probably the dimer which in the absence of experimental evidence has been assumed to be iminoacetonitrile HN=CH * CN however it might be the isomeric iminocyanocarbene (107).Thermal or photolytic decomposition of the sodium salt of 1 -cyanoformamide toluene-p-sulphonyl- hydrazone (109) which would be expected to yield iminocyanocarbene yields86 the hydrogen cyanide tetramer diaminomaleonitrile (1 lo) as the major product. Iminocyanocarbene identified spectroscopically is formed as a yellow product on irradiation of the hydrazone (109) at -196". It exhibits no triplet state e.s.r. signals and therefore exists in the singlet state (108) with considerable dipolar character. Aminocarbene may be a key intermediate in hydrogen cyanide polymerisation and prebiological organic syntheses.Among the naturally occurring nitrogen compounds reported this year are fragin (1 11),87 isolated from Pseudornonasfragi a growth inhibitor which at a Me[CH,],.CONH.CH,-CH.CHMe HO,C.CH.CH,.N(OH).NO I I N(0H).N=O NH (1 11) (112) CH3[CH2] 12-CH(O&)-CH,. C0,[CH,],&Me3CI concentration of 20 p.p.m. inhibits the growth of Chlorella and Aspergillus niger. It contains the rare N-nitrosohydroxylamine group which is also found in the antibiotic alanosine (112),88 isolated from Streptomyces alansinicus D. S. Breslow T. J. Prosser A. F. Marcantonio and C. A. Genge J. Amer. Chem. Soc. 1967 89,2394. 84 H. Nozaki S. Fujita H. Takaya and R. Noyori Tetrahedron 1967,23,45. W. Lwowski Angew. Chem. Internat. Edn. 1967,6 897.86 R. E. Moser J. M. Fritsch T. L. Westman R. M. Kliss and C. N. Mathews J. Amer. Chem. SOC.,1967,89 5673. '' S. Tamura A. Murayama and K. Hata Agric. and Eiol. Chem. (Japan) 1967 31 758; S. Tamura A. Murayama and K. Kagel ibid. p. 996. G. C. Lancia A. Diene and E. Lazzari Tetrahedron Letters 1966 1769. Aliphatic Compounds 26 1 nsp. which has some antiviral and antitumour proper tie^.^^ Pahutoxin (113) is the poison of the blue boa fish which is toxic to fish of other species.g0 Sulphur Derivatives-Refluxing trifluoroacetic acids affords an excellent medium for the preparation of thioacetates and thioacetals. However in the absence of other carbonyl ethane thiol undergoes the un-precedented condensation with the acid giving the ortho-thiol ester (114).Esters of carboxylic acids can be C-alkylated with alkyl halides using sodamide in contrast alkylation of dithioesters RICH .CS. SR’ with R’Br occurs at sulphur to yield9’ ketone thioacetals (115). Thioketens apart from the perfluorinated compound (116)93 are very unstable.94 However some in situ reactions of thioketens have been reported. Acetylthioalkynes react as shown in Scheme 10 with diethylamine to yield probably viu a thioketen N-substituted thioamides and N-substituted acetamides. RCd-SCO-CH + Et,NH -+ [R-CS-SH] + CH3.CONEt2 RCH2.CS NEt2- Et,NH RCEI=C=S SCHEME 10 Crystalline methanesulphinic acid CH * SO.OH has been obtained9’ for the first time from its previously known acid chloride. All the molecules within a particular crystal have been shown by X-ray study to have the same chirality.That is they are all (S) or all (R). An attempt to convert a single optically active crystal of the substance into optically active methyl methane- sulphinate by the action of diazomethane failed. The first reported sulphinyl isocyanate CCl * SO-NCO is obtained96 by the action of silver cyanate on the corresponding sulphinyl chloride. Thermolysis go” of t-butylsulphoxide (117) eliminates isobutene to yieldg7 the first aliphatic sulphenic acid t-butylsulphenic acid (118). Its structure has 89 Y. K. S. Murthy J. E. Thieman C. Coronelli and P. Sensi Nature 1966 211 1198. ’O D. B. Boylan and P. J. Scheuer Science 1967,155,52. ” D. L. Coffen Chem. Comm. 1967. 1089. 92 P. J. W. Schuijl L.Brandsma and J. F. Arens Rec. Trav. chim. 1966,85,1263. ’3 M. S. Raasch Chem. Comm. 1966,577; see Ann Rep. 1966 p. 386. 94 H.E. Wijers C. H. D. Van Ginkel L. Brandsma and J. F. Arens Rec. Trao. chim. 1967,86,907. 95 F. Wudl D. A. Lightner and D. J. Cram,J. Amer. Chem. SOC. 1967,89,4099. 96 A. Senning Angew. Chem. 1966,78 1100. ’’ J. R. Shelton and K. E. Davis J. Amer. Chem. SOC. 1967,89,718. 262 M.F. Ansell been confirmed spectroscopically and from its reaction with electrophilic olefins such as ethyl acrylate with which it forms ethyl /3-(2-methylpropyl-2- sulphinyl) propionate (1 19). The N-sulphonylamines (121) are a new class of compounds and are obtained" by the action of triethylamine on sulphamoyl chlorides (120) in (Bu'),$-O Bu'S.OH But~.CHZ.CHZ.CO2Et I 0-RN=SO2 RNH .SOzCl EtNH -SOZ*NHPh Ph-C+& PhN--Ca L'N-&02 EtOI2 CO-Ph (123) (124) (125) toluene at -75". They cannot be isolated but addition of aniline to a cold toluene solution of (121 ; R = Et) yields N-phenyl-N'-ethylsulphamide(122). The analogous benzoyl derivative (124) is more electrophilic and reacts with ethyl vinyl ether to give the cycloadduct (123). If a toluene solution of the compound (124) is allowed to warm from -78" in the absence of a trapping agents exclusive formation of phenylisocyanate occurs. This reaction (124) (125) may involve the ol-elimination of sulphur dioxide. Oxidation of dialkyl disulphides with chloramine in the presence of ammonia in acetoni trile yieldsg9 the dialkyl sulphone di-imines which have been assigned structures (126)'' and (127).'0° The former structure (126) is now supported"' (126) (127) (128) by i.r.and Raman spectroscopy. These compounds are sufficiently stable to be gas chromatographed they are very soluble in water and are resistant to both acid- and base-catalysed hydrolysis. They react with halogens (CI Br and I) in aqueous solution buffered by potassium carbonate to yield NN'-dihalogeno-SS-dialkylsulphurdi-imines(128) which have the usual properties of N-halogeno-compounds. 98 G. M. Atkins jun. E. M. Burgess J. Amer. Chem. SOC.,1967,89,2502. 99 J. A. Cogliano and G. L. Brande J. Org.Chem. 1964,29,1397. loo R. H. Appel H. Fehlhaber D. Hanssgen and R. Schollhorn Chem. Ber. 1966,99 3108.R. G. Laughlin and W. Yellin J. Amer. Chem. SOC.,1967,89,2435. Io2 R.Appel and D. Hannsgen Angew. Chem. 1967,79,96. Aliphatic Compounds The highly reactive diphenylsulphonium isopropylylid (129) which can be obtained by the action of t-butyl-lithium on diphenylisopropylsulphonium fluoroborate in tetrahydrofuran at -70°,reacts with nonconjugated carbonyl compounds to yield'03" oxirans (130) but with ap-unsaturated carbonyl compounds addition occurs at the carbon-carbon double bond to yield"3b PhCHO Ph2S=C Me Me2C==CH-CH=CH -CO,Me Me2C=CH-CH-CH.C0,Me (1311 (129) MexMe + Me2 S -CH. C02R p-MeC6H,SO; Me 2S -CH2.C02Me (132) (133) gem-dimethylcyclopropanes (131). Dimethylsulphonium methoxycarbonyl-methylylid (132; R = Me) is a crystalline solid stable in an inert atmosphere at -20" for an extended period is obtained1O4 by the action of potassium t-butoxide on methyl dimethylsulphonium acetate toluene-p-sulphonate (1 33).The ethyl ester (132; R = Et) which is reasonably stable at -lo" is obtainedlo5 from the corresponding sulphonium bromide by the action of saturated potassium carbonate containing one equivalent of sodium hydroxide. Both these ylids react with ap-unsaturated carbonyl compounds to yield methoxy- carbonylcyclopropane derivatives. The polar lipids isolated to date generally consist of a long aliphatic chain of at least fourteen carbon atoms with a polar functional group at one end. 1,14-Docosyl disulphate has been isolated106 from the phytoflagellate Ochromonas danica and is the first polar lipid which has functional groups at both ends of the molecule and is the first known aliphatic sulphate lipid.Oxygen Derivatives-Trialkylborons Alk3B available via hydroboration of alkenes undergo a remarkably fast 1,4-addition to methyl vinyl ketone (134 ;R = Me) and acraldehyde (1 34 ;R = H) to yield the adducts (1 35) which CHSH-COR A1 k -CH,*CH-L R*OBAlk2 A1k .CH CH .COR (134) (135) (136) (137) (138) (1 39) lo3 (a)E. J. Corey M. Jautelat and W. Oppolzer Tetrahedron Letters 1967 2325; (b) E. J. Corey and M. Jautelat J. Amer. Chem. SOC. 1967,89 3913. lo4 J. Casanova and D. A. Rutolo Chem. Comm. 1967 1224. lo5 G. B. Payne 154th National Meeting Amer. Chem. SOC. Chicago Ill. Sept. 11-15th 1967 Organic Section Paper 158.lo6 G. L. Mayers and T. H. Haines Biochemistry 1967,6 1665. 264 M.F. Ansell on hydrolysis produce the corresponding carbonyl compounds (1 36). The complete generality of this reaction remains to be established as only the only carbonyl substrates used have been the two mentioned above.lo7 The reductive (Mg-CH3 * C02H) coupling of acetylacetone in hydrocarbon media yields as the main product the bis-acetal(l39) with the noradamantane skeleton. The reaction is considered to proceed via reductive coupling of the enol-form of acetylacetone (1 37) which cyclises to the bis-hemi-acetal (1 38) the latter on dehydration forms (139). In aqueous media in which acetyl- acetone exists in the diketone form no reductive dimerisation is observed.Io8 Dimerisation of aldoketens to their p-lactone dimers is catalysed by triethyl- amine.This catalyst is not effective in converting 0x0-ketens into p-lactone- dimers in fact dehydrohalogenation of isobutyryl chloride in the presence of triethylamine yields tetramethylcyclobutane-1,3-dione (143). It is now shown"' that the product from the triethyl phosphite-catalysed dimerisation of dimethyl- keten contains 94 % of the p-lactone dimer (142) and 3 % of the cyclobutane dione (143). A suggested mechanism for the reaction is shown in Scheme 11. /Me,C=C=O (140) I_ I 0- Me2(3=C-CMe2I I 0-C=O (142) (141) +/ €'(OR) 3 SCHEME 11 The effectiveness and selectivity of the catalyst depending on its ability to co- ordinate with the carbonyl-carbon and give the zwitterions (140) and (141).Base-catalysed (BuLi) disproportionation of the dimer (143) leads to the dimethylketen trimers (144) and (145).'" Alk-7-en-2-ones (146) on heating at 300-400" are cyclised in almost quanti- tative yield to alkylcyclopentyl ketones (148)' This reaction has been applied to many compounds having this skeleton and also to compounds which are precursors of alk-7-en-2-ones such as the derived enol-acetates ketols and 3-ethoxycarbonyl derivatives. The suggested mechanism of this reaction in- volving the intermediate enol(l47) is similar to that proposed112 for the cycli- lo' A. Suzuki A. Arase H. Matsumoto M. Itoh H. c.Brown M. M. RogiC and M.W. Rathke J. Amer. Chem. SOC. 1967,89 5708; H. C. Brown M. M. RogiC M. W.Rathke and G. W. Kabalka ibid. p. 5709. P. F. Casals and J. Wiemann Bull. SOC.chim. France 1967,3478. Io9 E.U.Elan J. Org. Chem. 1967,32,215. R. D. Clark J. Org. Chem. 1967,32 399. F. Rouessac P. LePerchec and J.-M. Conia Bull. SOC.chim. France 1967,818,822,826. W.D. Huntsman and T. H. Curry J. Amer. Chem. Soc. 1958,80,2252; W. D. Huntsman V. C. Soloman and D. Eros ibid. p. 5455. Aliphatic Compounds (146) (147) (148) (149) (150) (151) (152) (153) (157) (154) (155) sation of octa-1,6-diene and is consistent with the observed steric course of the reaction. Similar cyclisation reactions leading to five-membered rings have been reported. For example the A6-aldehyde (149) at 320" yields the aldehyde (150)' l3 and the alk-7-yne-2-one (151) at 260" yield the cyclopentenyl ketones (152) and (153).'14 These cyclisation reactions are not restricted to the formation of five-membered rings as non-8-en-2-one (154) at 360" yields (80 %) the cyclohexyl ketone (155) and dodec-11-en-2-one (156) at 390" yields (30%) the cyclodecyl ketone (1 57).' The modification of functional group properties by perfluorination can lead to novel reactions and compounds with unexpected properties.Hexafluoro- acetone reacts' with hexaphenylcarbodiphosphorane (158) in diglyme to form the cyclophosphorane (159) m.p. 155-157". This is the first stable 'Wittig intermediate' and on being heated in an inert solvent the Wittig reaction is completed to yield (160). 'I3 R. Bloch and J.-M. Conia Tetrahedron Letters 1967 3409.'I4 F. Rouessac P. LePerchec J. L. Bouk and J. M. Conia Bull. SOC. chim. France 1967,3554. 'I5 J.-M. Conia and F. Leyendecker Bull. SOC. chim. France 1967,830. '16 G. H. Birum and C. N. Mathews Chem. Comm. 1967 137. 266 M. F. Ansell The carbonyl group is normally resistant to attack by radicals. However in perfluoro-ketones the double bond more closely resembles the double bond in a weakly polarised olefin than it does the carbonyl group in a hydrocarbon ketone. This permits' ' the radical addition of a hydrocarbon to the carbonyl group (Scheme 12 R = cyclohexyl). R H +(C F3 )F=O R-orhv CF3C(OH)R+CF3CH* OR SCHEME 12 Metal fluorides catalyse the addition of fluorine to the carbonyl group in perfluoro-carbonyl compounds. In this way the fluoroxy-compound F,C- OF is obtained' l8 from perfluoroformaldehyde.Addition of fluorine to carbon dioxide"** '" gives CF,(OF) in almost quantitative yield. The latter is also obtained',' by fluorination sodium oxalate or sodium trifluoroacetate. It is a liquid b.p. -64",and has considerable thermal stability (unchanged after 6 hr. at 150")compared with other fluoroxy-compounds. It is strongly oxidising towards reducing agents such as mercury potassium iodide and aqueous alkali. The unstable and explosive bis-fluoroxy-compound FO-CF,*O-CF,*OF is obtainedI2' by addition of fluorine to the bis(fluorocarbony1)peroxide FCO -0.0 COF. The existence stability and isolation of alkyl-polyoxide has been dis- cussed,' 22 but the existence of such compounds has remained questionable.The reported'23 isolation of di-butyl peroxide was shown to be incorrect,'23* but the low temperature oxidation Df t-butyl- and cumyl-hydroperoxides apparently proceeds via the formation of tri0~ides.l~~ Evidence has now been (161) R 00.0* OR R10.0-OR2 (162) pre~ented'~' from an e.s.r. study of the irradiation products of di-t-butyl- peroxycarbonate that di-t-butyltetroxide (161) is stable below -70" and di-t- butyltrioxide (162; R' = R2 = But)is stable below -35". A further illustration of the effect of fluorine substitution on reactivity referred to above is the E. G. Howard P. B. Sargeant and C. G. Krespan J. Amer. Chem. SOC.,1967,89,1423. 'I8 M. Lustig A. R.Pitochelli and J. K. Ruff,J. Amer. Chem. SOC. 1967,89,2841.F.A.Hohorst and J. M. Shreeve J. Amer. Chem. SOC.,1967,89,1809. I2O P. G. Thompson J. Amer. Chem. SOC.,1967,89 1811. '" M.Lustig and J. K. Ruff Chem. Comm. 1967,870. '22 S. W.Benson J. Amer. Chem. SOC.,1964,863922. 12' Ann. Reports 1966,63 387. 12* P. D.Bartlett and P. Giinther J. Amer. Chem. SOC.,1966,88,3288. 12' P.D.Bartlett and G. Guaraldi J. Amer. Chem. SOC. 1967,89,4799. Aliphatic Compounds formation of bis(perfluoromethy1)trioxide (162; R' = R2 = CF,) in high yield (87%) by the reaction of one mole of oxygen fluoride with two moles of carbonyl fluoride.'26 This compound b.p. -16" is remarkably stable having a half-life of 65 weeks at 25". The trioxide (162; R' = R2 = CF,) is also formedI2' in low yield by fluorination of sodium trifluoroacetate together with the trioxide (162; R' = CF, R2 = CF,CF,) and possibly the tetroxide (161; R = CF,).Halogen Derivatives-The aliphatic halides are key compounds in organic syntheses and the past year has seen outstanding developments in this field particularly in the preparation and use of vinyl halides The conversion of alk-1-ynes to cis- and trans-vinyl bromides via hydro- boration has been reported'28 and is shown in Scheme 13. Alk-1-ynes react with bis-(3-methyl-2-butyl)boron (referred to as disiamylborane ;abbreviated to Sia,BH) to yield trans-alkenyldisiamylboranes. The latter react with c BSiaz A1k.C fCH (163) H\ c=c Br A1k0 H... I 'C-c-' -,c =c Ald \H Alk H L (164) SCHEME 13 bromine (presumably trans-addition) and the resulting dibromides will undergo elimination of the elements of disiamylboron bromide either solvolytically (trans) to yield the cis-vinyl halide or thermally (cis) (in boiling carbon tetra- chloride) to give the trans-vinyl halide.The cis-halides are obtained > 95% pure and the trans-halides > 88% pure. With phenylacetylene the stereo- chemical results obtained are reversed i.e. solvolysis gives the trans-isomer. Hydroboration of 1 -bromo- or 1-iodo-alkynes readily available by the low temperature halogenation of the corresponding lithium alkynes with dicyclo- hexylborane affords12' the trans-a-halovinylboranes (165) a new class of stable organoboranes which on protonolysis with acetic acid yield cis-vinyl halides (163) ( >85 % steric purity).The conversion of alk-1-ynes to trans-vinyl halides may be achieved',' by converting them into the corresponding vinylalanes (166) by the addition of L. R. Anderson and W. B. Fox,J. Amer. Chem. SOC.,1967,89,4313. I*' P. G. Thompson J. Amer. Chem. SOC.,1967,89,4316. H. C. Brown D. H. Bowman S. Misumi and M. K. Unni J. Amer. Chem. SOC.,1967,89,4531. G. Zweifel and H. Anoumanian J. Amer. Chem. SOC.,1967,89 5086. "O G. Zweifel and C. C. Whitney J. Amer. Chem. SOC.,1967,89,2753. 268 M.F. Ansell (165) (16 6) di-isobutylaluminium hydride followed by halogenation with iodine or bromine to give the trans-vinyl halide (164)(>98 % steric purity). The conversion of propargylic alcohols to vinyl halides has been a~hieved,'~' as is illustrated by the conversion of the alcohol (167) into the P-iodo-alcohol (168) by reduction with lithium aluminium hydride aluminium chloride followed by iodination (excess of iodine at -78").The replacement of aluminium chloride by sodium methoxide in the above reaction sequence lead specifically to the y-iodo-alcohol (170).No explanation has yet been advanced for this unprecedented positional selectivity. f RC-C*CH,OH -RpCH20H -& RpCH20H \ H H (167) (168) (16 9) H H The Wurtz-type of reaction of aliphatic halides has an attractive simplicity which is not always realised in practise. However this year has produced a number of novel improvements in the means of carrying out such reactions. The previously unreported dimerisation of vinyl halides can be achieved' 32 by the action of cuprous chloride on a tetrahydrofuran solution of a vinyl-magnesium halide at -40" to -60".A vinyl-copper@ complex is formed which on warming to + 20" gives the diene in good yield with separation of elemental copper.The symmetrical coupling of other alkyl halides may be achieved converting them via the derived organolithium or magnesium compound into the copper(1)ate complex by reaction with tetrakis [iodo-(tri-n-butylphosphine) copper(^)] which with molecular oxygen at low temperature undergoes oxidative coupling (Scheme 14).'33 This reaction resembles the oxidative- coupling of cuprous acetylides. The more difficult specific cross-coupling E. J. Corey J. A. Katzenellenbogen and G.H. Posner J. Amer. Chem. SOC. 1967,89,4245. 13' T. Kauffmann and W. Sahm Angew. Chem. 1967 79,101. "' G. M. Whitesides J. Sanfilippo jun. C. P. Casey and E. J. Panek J. Amer. Chem. SOC. 1967 89,5302. Aliphatic Compounds 02 C4H9Li+ [ICuP(C,H&] -0 C,H,CuLi -GH 18 -78" -78" SCHEME 14 reaction has been achieved'34 by the use of lithiumdialkylcopper of which the methyl isomer has been most studied. It is an ether-soluble complex prepared by the action of 1 mole equiv. of cuprous chloride on 2 mole equiv. of methyl- lithium. It reacts with a wide variety of organic halides (see organometallic section). An illustration' 31 of its reactivity is the stereospecific reaction with the halide (170) to yield trans-farnesol (171).The isomeric halide (168) yields the farnesol isomer (169). The overall reaction sequence (167) -N (169) or (174) is (172) (173) BrCH -CH=CH[CH2]n. CH=CH.CH,Br 1 (174) (175) PCH2 Br Y = [CH,],; n = 1 2,3 or 4 or CH,.O-CH applicable to a wide variety of synthetic problems in which stereospecific formation of a trisubstituted olefinic linkage is involved. Previously acetylenic precursors have been widely used for the stereospecific synthesis of cis-and trans-alkenes of the type XCH :CHY and certain trisubstituted alkenes from symmetrical acetylenes but they have not previously been used in the stereo- specific synthesis of more highly substituted olefins from unsymmetrical acetylenes. Cross couplings involving allylic halides can be achieved' 35 using n-allyl- nickel(1) bromides (172)which are readily obtained by the reaction of the allylic 134 E.J. Corey and G. H. Posner J. Amer. Chem. SOC.,1967,8!2,3911. 135 E. J. Corey and M. F. Semmelhack J. Am. Chem. SOC.,1967,89,2755. 270 M.F. Ansell bromide with an excess of nickelcarbonyl in dry benzene. The resulting complexes (172) can be recrystallised from ether at -70". In polar solvents these compounds react with a wide variety of aryl vinyl and alkyl halides (reactivity I > Br > C1) as illustrated by the formation of (173) from a-methyl- ally1 bromide (172; R = Me) and p-dibromobenzene. The intramolecular coupling of dihalides is a traditional route to cyclo- alkanes. A number of examples of this reaction reported this year show that with suitable reaction conditions good yields can be obtained.Thus 1,3- dihaloalkanes with alkali-metal vapour yield' 36 1,3-alkadiyl radicals which cyclise to cyclopropanes in yields up to 88 %. 1,3-Di-iodopropane with benzoyl peroxide or t-butyl peroxide gives 9Crl00% yieldsi3' of cyclopropane by a radical induced y-elimination reaction. No mechanistic details are available but it appears a synthetically useful reaction 1,5'di-iodopentane giving cyclo- pentane. 1,4-Dibromobutane with lithium amalgam in refluxing dioxan givesi3* cyclobutane in 70% yield; a ten-fold increase on the best reported yield with sodium metal; analogously cyclopentane is formed in 75,% yield. Electrolysis of 1,4-dibromobutane (in dimethylformamide-Bu",N ClO,) yields'39 cyclobutane (25%) but cyclopentane could not be prepared from 1,5-dibromopentane.The synthesis of large-ring 1,5-dienes (175; n = 6 8 and 12) can be a~hieved'~' by the cyclisation of allylic dibromides (174; n = 6 8 and 12)with nickelcarbonyl and a large variety of dihalides (76)can be cyclised in good yield to (176) by their reaction with triphenylphosphinemethylene." A completely different route to a cyclic compound is the peroxide-catalysed addition of methylene iodide to alkenes to yield cyclopropanes. This reaction has been applied142 to a large number of alkenes but as yet there is no informa- tion regarding the mechanism of the reaction which appears to be related to the known photochemical addition of methylene iodide to alkenes. Miscellaneous.-The insertion reaction of dichlorocarbene occurs with a very specific preference for C-H bonds located p to either silicon tin or mercury.The insertion of dichlorocarbene into the optically active mercury compound (S)-(-X178) proceeds with net inversion of configuration to yield the product (179) as is shown by conversion of the latter into the (S)-(-)-acid (180). This is an unprecedented stereochemical result from a divalent carbon insertion process. Any mechanistic path which involves direct attack of the divalent carbon atom on the carbon-hydrogen bonding electrons is clearly impossible.'43 Carbon atoms produced in a carbon arc are efficient deoxygenation agents as might be expected since the heat of combination of an oxygen atom with a 136 R.G. Doer and P.S. Skell J. Amer. Chem. SOC.,1967,89,4684. 13' L. Kaplan J. Amer. Chem. SOC. 1967,89 1753. 13' D. S. Connor and E. R. Wilson Tetrahedron Letters 1967,4925. 139 M. R. Rifi J. Amer. Chem. Soc. 1967,89,4442. 140 E. J. Corey and E. K. W. Wat J. Amer. Chem. SOC.,1967,89,2757. 14' H. J. Bestmann and E. Kranz Angew. Chem. 1967,79,95. 14f L. Kaplan J. Amer. Chem. SOC. 1967,89,4566. K. A. Landgrebe and D. E. Thurman J. Amer. Chem. SOC.,1967,89,4542. Aliphatic Compounds 27 1 HI Me I Me I I(Et-C-Me CHzhHg I(Et -C- CHJ2Hg CH C12 IEt -C.CH CO,H aCO2H (178) (179) (1 80) L+c-co+U + SCHEME P-%+C-co+ J Hg(NzC.C02Et)2 C-COzEt COzEt 0 0 carbon atom is 256.7 cal./mole.144 Examples of such reactions which are carried out at low temperature ca.-196” in the condensed phase are shown in Scheme 15. Although the chemistry of carbon atoms as well as di- and trivalent carbon intermediates has been investigated little is known about monovalent carbon intermediates. The scarcity of information on this class of carbon intermediates is related to the difficulty in generating them under conditions amenable to mechanistic study. It is now reported’45 that photolysis of diethyl mercury- bis(diaz0acetate) (181) yields ethoxycarbonylmethyne (182) as a doublet. With cyclohexene it undergoes both insertion and addition reactions to give intermediate radicals which by hydrogen abstraction lead to the products (183) and (194). A ‘compound’ which is partially aliphatic in character is (185) in which the terminal substituents of the open-chain component are too bulky to allow it to slip through the ring.It was prepared’46 by tritylation of decane-1,lO-diol in the presence of a 30-membered cyclic acyloin. Only minute quantities of Ph I /CH-c\ 144 P. S. Skell J. H. Plonka R. R. Engel J. Amer. Chem. SOC.,1967,89 1749. 14’ ThapDo Minh H. E. Gunning 0.P. Stransz J. Amer. Chem. SOC., 1967,89,6785. I. T. Harrison and S. Harrison J. Amer. Chem. SOC.,1967,89,5723. 272 M. F. Ansell the diol are tritylated while being threaded through the macrocycle. However by bonding the macrocycle by way of its half ester with succinic acid to a resin and then by repeatedly (70 times) treating the resin bonded macrocycle with a solution of the diol trityl chloride dimethyl formamide and pyridine a 6% yield of this chromatographical separable product was obtained.The name hooplane is suggested for this class of compound.

ISSN:0069-3030    

DOI:10.1039/OC9676400243

出版商:RSC    

年代:1967

数据来源: RSC

摘要:

8. AROMATIC COMPOUNDS By I. 0.Sutherland (Department of Chemistry The University Sheffield) General.-Owing to the increased selectivity of the report this year many important papers have been omitted; aspects of the subject covered by this reviewer are as far as possible those in which major advances have occurred within the last few years. The optical rotatory dispersion and circular dichroism of aromatic systems have been surveyed.' Optically active aromatic chromo- phores have been divided into three classes (a) Dissymmetric and twisted chromophores such as those in biaryls and hexhelicene ; (b) coupled oscillators consisting of two non-conjugated but interacting aryl chromophores ; such systems are observed in natural products such as the lignans and Calycanthus alkaloids ;and (c)single aryl chromophores which are perturbed by their dissymmetric surroundings as for example in 2-phenylpropionic acid.The once well established chemical criteria for the assignment of the description 'aromatic' to an organic compound are of course difficult to apply in modern organic chemistry. The possession of a diamagnetic ring current by a cyclic conjugated system situated in a magnetic field has recently become a popular criterion for aromaticity. Such a ring current may be detected either by an examination of the n.m.r. chemical shifts of protons in the vicinity of the cyclic system or less readily but possibly more reliably by the observation of a diamagnetic susceptibility greater than that expected.2 Last year it was pointed out3p4 that the ring current expected and observable in non-aromatic conjugated cyclic systems such as the [4n]-anndenes in a magnetic field is paramagnetic.The ring current concept has been criticized by Musher,' but for most chemists it continues to provide a satisfactory test of ar~maticity.~-' This approach is particularly well demonstrated" by the interpretation of the n.m.r. chemical shifts of the protons in biphenylene; the observed 't values are explained in terms of an induced diamagnetic current in the aromatic six-membered rings and a paramagnetic ' P. Crabbe and W. Klyne Tetrahedron 1967,23 3449. H. J. Dauben Science. 1965 150 370; Abstract 150th Meeting of American Chemical Society Atlantic City New Jersey September 1965,p.325. J. A. Pople and K. G. Untch J. Amer. Chem. SOC.,1966,88,4811. H.C. Longuet-Higgins Chem. SOC.Special Publ. No. 21 1967 p. 109. ' J. I. Musher,J. Chem. Phys. 1967,46 1219. F. Sondheimer Proc. Roy. SOC. 1967 A 297 173; F. Sondheimer I. C. Calder J. A. Elk Y.Gaoni P. J. Garratt K. Grohmann G. di Maio J. Mayer M. V. Sargent and R. Wolovsky Chem. SOC.Special Publ. No. 21 1967 p. 75. ' J. M. Gaidis and R. West J. Chem. Phys. 1967,46 1218. D. G. Farnum and C. F. Wilcox J. Amer. Chem. SOC. 1967,89,5379. J. D. Memory G. W. Parker and J. C. Halsey J. Chem. Phys. 1966,45,3567. lo H. P. Figeys Chem. Comm. 1967,495. I. 0.Sutherland current in the central anti-aromatic four-membered ring. Further examples of the detection of ring currents appear elsewhere in this report.Theoretical predictions concerning bond order in conjugated systems have long been tested by crystallography. The correlation between x-bond order and vicinal hydrogen-hydrogen n.m.r. coupling constants was pointed out some years ago” and is believed to hold for polycyclic benzenoid system^,^ para-disubstituted benzenes,’ and also fulvene derivatives.”* l4 It has also been observed” that the long-range coupling between the protons of methyl substituents on polycyclic benzenoid systems and the ortho-proton is only detectable when the intervening double bond cannot participate in an inherent aromatic sextet. Another type of examination of potentially aromatic systems by n.m.r. spectroscopy has been reported. The barriers to rotation about the exocyclic single and double bonds of 6-dialkylaminofulvenes (1) have been measured ;I4* 16 l7 it is clear from the rotational barriers observed for the C(l)-C(6) double bond and the C(6t-N single bond in these compounds that extensive conjugation exists in them.It should be possible to relate these rotational barriers to the calculated x-electron energies for both the planar ground-states and the non-planar transition states which may be formulated as (2) and (3); such effects have also been reported for calicene derivatives.’* (1) (2) (3 ) (4) These measurements do not however yield direct evidence for aromatic character and it has been pointed out” that for systems such as the fulvenes and fulvalenes the possession of a substantial dipole moment is predicted by the same theoretical approach that predicts substantial bond alternation and little or no resonance energy.It is also unwise to equate bond alternation with a non-aromatic character; systems such as 1,2-benzazulene (4) are pre- dictedlg to be aromatic in the sense that they possess a substantial delocalisa- tion energy but also to show strong bond alternation. Homo-uromaticity. A homo-aromatic compound is defined2’ as one which contains a cyclic delocalised (4n + 2) x-electron system in which the o-bonding I’ N. Jonathan S. Gordon and B. P. Dailey J. Chem. Phys. 1962,36 2443. W. B. Smith and T. J. Kmet J. Phys. Chem. 1966,70,4084. W. B. Smith W. H. Watson and S. Chiranjeevi,J. Amer. Chem. SOC. 1967,89 1438. I4 J. H.Crabtree and D. J. Bertelli J. Amer. Chem. SOC. 1967,89 5384. Is E. Clar B. A. McAndrew and M. Zander Tetrahedron 1967,23,985. ’‘ A. Mannschreck and U. Koelle Tetrahedron Letters 1967,863. A. P. Downing W. D. Ollis and I. 0.Sutherland Chem. Comm. 1967 143. l8 A. S. Kende P. T. Izzo and W. Fulmor Tetrahedron Letters 1966 3697. l9 M. .I. S. Dewar Tetrahedron 1966 Suppl. 8 75; Chem. SOC. Special Publ. No. 21 1967 p. 177. 2o S. Winstein Chem. SOC.Special Publ. No.21 1967 p. 5. Aromatic Compounds 275 is interrupted by one (mono) two (bis) or three (tris) bridges. This may be illustrated*’ by the relationship between the cyclopropenyl cation (5) and the monohomocyclopropenyl (6) bishomocyclopropenyl (7) and trishomocyclo- propeny121*22(8) cations.This definition also includes species such as the transition state in the Diels-Alder reaction which is the bishomoaromatic species (9) and it is noted that overlap between adjacent 2p-orbitals may be of both the n-and the a-type. Systems such as (6) (7) and (8) will be discussed more fully in another report. The definite chemical and physical recognition of homo-aromatic properties is at present confined to charged species although it is possible2* 2o that magnetic susceptibility measurements will prove to be sufficiently sensitive to discover both homo-aromaticity and homo-anti-aromaticity in neutral species. Homo-tropylium cations were discussed in last year’s report ; a further example has been reported during 1967. Although mono-homotropone (10) does not have the properties of a homo-aromatic ~ystem,~~.~~ the conjugate acid has an n.m.r.spectrum23 in accord with a 2-hydroxyhomotropylium structure (1 1). Similarly cyclo-octatrienone is satis- factorily formulated as the non-planar species (12) although the conjugate acid (13) has an n.m.r. spectrum [T~5-60,zb 8-68for (13) and z 6.82 zb 7.24 for (12)] that indicates that this species exists as a homotropylium cation and that the homo-aromatic n-electron system sustains an induced ring ~urrent.~’ The Ha and H n.m.r. signals of (13) are still sharp at 80” which indicates that the barrier to exchange of their environments possibly via a planar classical ion is at least 20 kcal./mole. The formation of (13) rather than a classical species is considered2’ to be more instructive than the formation of (ll) since in the former case homo-aromaticity is not assisted by a three-membered S.Winstein E. C. Friedrich R. Baker and Yang Lin Tetrahedron 1966 Suppl. 8 621. ” M. A. Battiste C. L. Deyrup R. E. Pincock and J. Haywood-Farmer,J. Amer. Chem. SOC. 1967,89 1954. 23 C. E. Keller and R. Pettit J. Amer. Chem. SOC. 1966,88,606. 24 J. D. Holmes and R. Pettit J. Amer. Chem. SOC. 1963,85 2531. ’’ M. Brookhart M. Ogliaruso and S. Winstein J. Amer. Chem. SOC.,1967,89 1965. I. 0.Sutherland ring and (13) is not made classical by electron donation from the hydroxy- group oxygen atom. The bishomocyclopentadienyl anion (14) has been generated26.27 by the reaction of sodium-potassium alloy with exo-4-methoxybicyclo[3,2,l]octa-2,6-diene (15); the n.m.r.spectrum of (14) has been examined and the chemical shifts of the bridging methylene protons [z 9.13 and 9.58 in (14) as compared with 8.10 and 8.34 in the parent hydro- carbon (16)] are consistent with the presence of at least some induced ring current in the bishomo-aromatic system. The deuteriation of (14) shows no stereo-selectivity,26 but the formation of (14) from the exo-ether (15) is much (18) R = H (15) R' = OMe R2 = H (20) R = D (16) R' = R2 = H (17) R' = H R2 = OMe R' R' (19) R' = D R2 = H (22) (21) R' = H R2 = D more rapid than from the endo-ether (17).27 The deuteriation of the mono- homocyclo-octatetraene dianion (1 8) by deuteriomethanol yields2* exclusively the deuteriated bicyclo[6,1,O]nonadiene (19) and similarly the deuteriated dianion (20) is protonated to give only (21); the intermediate in these reactions is probably the mono-anion (22).A further type of x-bonding in an interrupted cyclic system has been independently considered in two papers29.'13 and has been termed 'spiroconjugation'. For this type of conjugation two n-systems are arranged in two mutually perpendicular planes with the four terminal p-orbitals related by D2 symmetry; this geometrical situation is achieved in a 'spirene' system of the general type (23). Examples of such systems (24) and (25) have recently been ~ynthesised.~' The concept of spiroconjugation is well illustrated3' by consideration of the interaction between two ally1 radicals 1 and 2 arranged as in (26).The PMOS of the systems may be classified with respect to the two symmetry planes a and b as symmetric (S) and antisym- metric (A) and this classification is shown in the Figure. Only the AA orbitals S. Winstein M. Ogliaruso M. Sakai and J. M. Nicholson J. Amer. Chem. SOC.,1967,89 3656. '' J. M. Brown Chem. Comm. 1967,638. M. Ogliaruso and S. Winstein J. Amer. Chem. SOC.,1967 %9 5290. l9 H. E. Simmons and T. Fukanaga J. Amer. Chem. SOC. 1967,89,5208. 30 R. Hoffmann A. Imamura and G. D. Zeiss J. Amer. Chem. SOC.,1967,89,5215. " E. T. McBee G. W. Calundann and T. Hodgins J. Org. Chem. 1966,31,4260. Aromatic Compounds Allyl System 1 Spirarene Allyl System 2 $I3 AS-------- - - SA *3 $ AS------_ - - _-- - SA $1 Figure.Molecular Orbitals of [3,3] spirarene can interact and this leads to splitting of the AA energy level; as shown in the Figure this would lead to stabilisation of a system containing 6 n-electrons i.e. two allyl radicals. This type of stabilisation will be general for two allyl systems of rn and n carbon atoms when both rn and n are equal to (4q + 3) where q = 0 1,2,3,etc. (these are the systems for which the non-bonding MO has an odd number of nodes and therefore has AA symmetry). The stabilised diradical systems are termed [m nlspirarenes. These predictions are supported by SCF-MO calculations but experimental verification is likely to be dif- fic~lt.~O Similar reasoning has been applied2’ to the spirenes (23); although the effect upon the x-bonding energy of the system is difficult to assess the perturbation of the energy levels of interacting orbitals of AA symmetry should lead to shifts in the electronic absorption spectra as compared with those of the isolated systems.Such effects are found2’ for (24)and (25) and also for the cyclopentadienone acetals (27) and the tropone acetals (28). For (27) a shift of h,,, to longer wavelength is predicted and readily observed; for (28) the predicted shift to shorter wavelength is found experimentally but is rather less I. 0.Sutherland (27) (28) (29) (30) marked. However the effect of non-planarity upon the larger ring systems such as the seven-membered ring of (28)is not easily predictable. Consideration of charged leads to the conclusion that the anion (29) should be stabilised by spiroconjugation and that both anion and cation should be stabilised for the system (30).Other predictions have been made2' concerning the reactivity of spirene systems.There is as yet very little experimental evidence available to test these ideas. Anti-aromaticity. The term 'anti-aromatic' has been applied to cyclic con- jugated systems which are destabilised by n-electron delocalisation. Full details have been published32 of the evidence for anti-aromaticity in the cyclopropenyl anion which is presumed to be an intermediate in the base- catalysed hydrogen4euterium exchange reaction of cyclopropenes. Thus H-D exchange is 6000 times slower for the cyclopropene (31) than for the cyclopropane (32) a difference shown32 to be the result of a change in the enthalpy of activation for the exchange reaction.This is predictable on the basis of SCF-MO calculations which predict a loss in x-electron stability for the formation of an anion from the cyclopropene (33). Not surprisingly this prediction cannot be made on the basis of simple Huckel Theory. The instability of a singlet x-electron system for the anti-aromatic cyclo- pentadienyl cation has been demonstrated3 by the observation of ground state or low-lying triplets for the cations (34; R' = R2 = Cl and Ph); these results have now been extended34 to less symmetrical systems (34; R' = Ph R2 = CH, p-(OMe)C6H4 p-C1C6H4 p-MeC& P-naphthyl) as well as to other symmetrical systems.35 Benzene and Derivatives-The effects of strain in o-di-t-butylbenzene have been discussed.36 The strain energy is estimated at 22.3 & 0.5 kcal./mole from a comparison of the heats of formation of the o- rn- and p-isomers; in spite of this there is no spectroscopic evidence for loss of aromatic character 32 R.Breslow J. Brown and J. J. Gajewski J. Amer. Chem. SOC.,1967,89,4383. 33 R. Breslow R. Hill and E. Wasserman J. Amer. Chem. SOC. 1964,88,5349. 34 R. Breslow Hai Won Chang R. Hill and E. Wasserman J. Amer. Chem. Soc. 1967,89 11 12. 35 W. Broser H. Kurreck and P. Siegle Chem. Ber. 1967 100 788. E. M. Arnett J. C. Sanda J. M. Bollinger and M.Barber J. Amer. Chem. SOC.,1967,89 5389. Aromatic Compounds and X-ray crystallographic examination of 1,2,4,5-tetra-t-butylbenzene shows that the aromatic ring is nearly planar and that strain is accommodated by bending of the bonds from the aromatic ring to the t-butyl substituents.Several new reactions of benzenoid systems have been recognised. Ruthenium tetroxide efficiently oxidises a phenyl substituent to a carbo~y-group,~~ and the oxidation of the phenylcyclobutane (35) to cyclobutane-1,3-dicarboxylic acid is particularly striking. The reaction of benzenesulphenyl bromide with silver perchlorate in methylene chloride is thought to lead to the highly reactive benzenesulphenyl cation (36). If the experiment is conducted3* in the presence of nitrogen and resorcinol dimethyl ether is added to the initial products uncharacterised organic products containing nitrogen are formed ; it is suggested that this represents an example of nitrogen fixation by an organic compound (36) to give possibly the diazonium cation (37).The photo-oxida- tion of benzene leads39 to unsaturated aldehydes (38) and (39). The sequence SCHEME 1 OHC -[CHXH] ;CHO (39) shown in Scheme 1 has been suggested to account for these products. The photo-addition of polychloro-ethylenes to benzene follows a similar course4o and the reaction products are polyenes (40).rather than 1,3-adducts as ob-served in other cases.41 The scheme which has been suggested to account for the observed photo-adducts of benzene42 has now been extended43 to account ” J. A. Caputo and R. Fuchs Tetrahedron Letters 1967,4729. 38 D.C. Owsley and G. K. Helmkamp J. Amer. Chem. SOC.,1967,8!4,4558. 39 K. Wei J-C. Mani and J. N. Pit& jun. J. Amer. Chem. SOC. 1967,89,4225. 40 N. C. Perrins and J. P. Simons Chem. Comm. 1967,999. D. Bryce-Smith A. Gilbert and B. H. Orger Chem. Comm. 1966 512; K. E. Wilzbach and L. Kaplan J. Amer. Chem. SOC. 1966,88,2066. 42 D. Bryce-Smith and H. C. Longuet-Higgins Chem. Comm. 1966,593. 43 D. Bryce-Smith A. Gilbert and H. C. Longuet-Higgins Chem. Comm. 1967 240. 280 I. 0. Sutherland for the formation of products (41) and (42) from the photolysis of benzene in aqueous phosphoric acid and acetic acid respectively. It is suggested that these products arise from the allylic cation (43) a mechanism which has a parallel in the chemistry of cations derived by protonation of hexamethyl Dewar benzene (see below).The photo-addition of amines to benzene yields44 1,4-adducts; for example the addition of piperidine gives piperidinocyclohexa- 2,5-diene (44) but the reaction4' with pyrrole involves a C-H bond and gives (45). The photo-addition of 1,3-dienes to benzene is complex and leads to a mixture of 1 1- 1:2- and 2 2-add~cts.~~ The initial addition of butadiene *.-.. ex 0 0 \ " ROfJ X (41)R = H (40)X = C1 or H (42) R = (43) 0 (4 4) 0 mm (45) (4 6) (47) (4 8) (49)R' = H,R2 = CH:CH2 (50)R' = CH:CH,,R2 = H (51) (52) (53) leads to the cis-trans-cyclo-octa- 1,5-diene derivative (46) ; this either dimerises to give (47) or reacts in Diels-Alder fashion with butadiene to give (48).In addition the 1,3-adduct (49) or (50) is obtained together with a small amount of (51). In the presence of nitric oxide (46) isomerises to the cis-olefin (52) which is then the major product. Naphthalene behaves in a similar fashion to benzene and gives the 1 :2-adduct (53) analogous to (48). The Diels-Alder addition of dicyanoacetylene to benzene to give the adduct (54) proceeds without photocatalysis although a temperature of 180" is required,47 but in the presence of aluminium chloride the reaction proceeds at room tempera- ture to give (54) in 63% yield. The reaction of paracyclophane with dicyano- acetylene yields47 the 1:l-adduct (55) in addition to the 2:1-adduct (56); a 44 M. Bellas D. Bryce-Smith and A. Gilbert Chem. Comm. 1967,862.45 M. Bellas D. Bryce-Smith and A. Gilbert Chem. Comm. 1967,263. 46 K. Kraft and G. Koltzenburg Tetrahedron Letters 1967,4357,4723. 47 E. Ciganek Tetrahedron Letwrs 1967,3321. Aromatic Compounds 28 1 Diels-Alder addition product (57) is also obtained from the reaction of 1,4-diphenylnaphthalene with di~yanoacetylene.~' Ph Ph The valence tautomers of benzene have been extensively studied during the last few years. Although it is now clear4' that the vapour-phase photolysis of benzene itself yields fulvene rather than benzvalene (58) the liquid phase photolysis of benzene at 2537 A does yield5' benzvalene which may be purified by gas chromatography and characterised as 1,3-adducts with methanolic hydrogen chloride. The chemistry of Dewar benzene (bicyclo[2,2,0] hexa-2,5- diene) (59) has been examined ;5 many reactions proceed without aromatisa- tion which is of necessity a disrotatory process and therefore thermally for- bidden (Woodward-Hoffmann rules).The epoxide (60) is given by the oxidation of (59) with rn-chloroperbenzoic acid ;(60) undergoes an electrocyclic reaction at 115" to give oxepin. A mixture of cis-and trans-dibromides (61) is obtained by the addition of bromine to (59) at 0"; the intermediate cation in these reactions is apparently no more liable to aromatisation than the parent hydrocarbon in spite of its lower symmetry. The availability of large quantities of hexamethyl Dewar benzene has led to several papers concerning its reac- tion~~~ which again proceed without aromatisation although it is rapidly 48 C.Dufraisse J. Rigaudy and M. %card Tetrahedron 1966 Suppl. 8,491. 49 H. R. Ward J. S. Wishnok and P. D. Sherman jun. J. Amer. Chem SOC. 1967,89 162; L. Kaplan and K. E. Wilzbach ibid. p. 1030. K. E. Wilzbach J. S. Ritscher and L. Kaplan J. Amer. Chem. SOC., 1967,89 1031. E. E. van Tamelen and D. Carty J. Amer. Chem. SOC.,1967,89,3922. '* W. Schafer and H. Hellmann Angew. Chem. Internat. Edn. 1967,6 518. I. 0.Sutherland isomerised by Lewis acids and by U.V. irradiation. The addition of hydrogen chloride gives the adduct (62) as the minor reaction product and (63) as the major product. Nucleophilic substitution of (62) gives moderate yields of the products (64). The reactions of (63) are of considerable interest and may be rationalised in terms of the equilibrating carbonium ions (65) (66) and (67).(62) (64) (71) Thus reaction of (63) with strong base leads to the olefin (68) rather than to hexamethyl benzene ;(68) is converted back into (63) by reaction with hydrogen chloride in methylene chloride. The reaction of (63) with nucleophiles (e.g. methylmagnesium iodide or lithium aluminium hydride) gives the rearranged substitution products (69). In the presence of a weak base dimethylformamide the equilibrating set of carbonium ions loses a proton to give the olefin (70) and (70) may be produced under the appropriate conditions from (62) (63) (68) and hexamethyl Dewar benzene. These reactions of hexamethyl Dewar (6 7) or Me (70) SCHEME 2 Aromatic Compounds 283 benzene are summarised in SCHEME 2; it should be noted that these carbonium ion rearrangements have only been reported for the hexamethyl compounds.The oxidation reactions of hexamethyl Dewar benzene have also been st~died.’~ Stable mono- and di-epoxides and a stable diozonide are produced and again there is no tendency for aromatization. U.V. irradiations4. ’’ of hexamethyl Dewar benzene gives hexamethyprismane (71) in yields of up to 20%; (71) is a crystalline volatile compound the U.V. spectrum of which shows unusuallv intense end-absorption extending into the aromatic region (E~~,, 33). The action of heat on (71) slowly (0.5 hr. at 129”) converts it into a mixture of hexamethyl Dewar benzene and he~amethylbenzene,~~ but this reaction proceeds 55 even at low temperatures (-25”) in the presence of boron trifluoride and in the presence of the Lindlar catalyst hexamethylbenzvalene is also obtained.’ ’ The catalytic effect of the \Ir-dichloro-dirhodium complex of hexamethyl Dewar benzene upon this reaction is also ma~ked,’~ and 95 % of the Dewar benzene is produced with only 5 % of hexamethylbenzene.The influence of Lewis acids and organometallic catalysts upon these thermally forbidden electrocyclic processes is of considerable interest and it has been ~uggested’~*’~ that the function of the catalyst is to reduce or change the symmetry of the n-MOs of the system so that symmetry-forbidden processes become allowed. The reaction of a-pyrone with bistrimethylsilylacetylene give^,'^ surprisingly m-bistrimethylsilyl benzene (72) as the major product ; the mechanism of this reaction is uncertain but it has been pointed out that a benzvalene intermediate formed from the initial Diels-Alder adduct (73) could lead to the observed product but,a benzvalene would be unstable under the vigorous reaction conditions used.Cyclophanes. The photo-isomerisation of 2,2 metacyclophan-1-ene (74) has been e~amined.’~ The tetrahydropyrene (75) is formed when (74) is irradiated with U.V. light but (75) reverts to (74) when irradiated with visible light. As expected in the presence of oxygen (75) is oxidised to the corresponding 53 H.-N. Junker W. Schkfer and H. Niedenbriick Chem. Ber. 1967,100,2508. ’’ W.Schafer R. Criegee R. Askani and H. Griiner Angew. Chem. Internat. Edn. 1967,6 78. ” D. M. Lemal and J. P.Lokensgard J. Amer. Chem. SOC.,1966,88 5934. ” H. C. Volger and H. Hogeveen Rec. Trao.chim. 1967,86,830; H. Hogeveen and H. C. Volger Chem. Comm. 1967 1133; see also F. D. Mango and J. H. Schachtschneider J. Amer. Chem. SOC. 1967,89,2484. ” D. Seyferth D. R. Blank A. B. Evnin J. Amer. Chem. SOC. 1967,89,4793. ’* H. Blaschke and V. Boekelheide J. Amer. Chem. SOC.,1967,89,2747. K I. 0.Sutherland phenanthrene. This isomerisation of (74)contrasts with that of the [2,2]- metacyclophane- 1,g-diene (76)which is spontaneously converteds9 at room temperature into the trans-15,16-dihydropyrene (77) with its peripheral [14)annulene system.The bridged [2,2]metacyclophane- 1,9-diene (78),syn-thesised6' by the dehydrogenation of (79) exists in neutral solution as (78) @ \ (74) (7 7) OMe OMe (78) (79) (80) (81) (82) n = 2 3,4 5 6 or 8 rather than pyrene cis-15,16-epoxide but valence tautomerism in this system is rather finely balanced and in strongly acidic media the protonated compound exists as the dihydropyrene tautomer (80). A further example (81) of the bridged metacyclophane system has been synthesised,61 but in this case the 1,9-diene was not prepared. The Wurtz reaction of aa-dibromo-rn-xylene with sodium and a tetraphenylethylene catalyst in tetrahydrofuran yields62 the series of meta-cyclophanes (82). The metacyclophanes (83) were ~ynthesised~~ by ring en- largement of the indenes (84)with dichlorocarbene generated from phenyl(tri- chloromethy1)mercury.The smallest ring generated by this method had 59 H. R. Blattmann D. Meuche E. Heilbronner R. J. Molyneux and V. Boekeiheide J. Amer. Chem. Soc. 1965 W,130. 6o B. A. Hess jun. A. S. Bailey and V. Boekelheide J. Amer. Chem. SOC. 1967,89 2746. 61 H. B. Renfroe J. A. Gurney and L. A. R. Hall J. Amer. Chem SOC. 1967,89 5304. K. Bum and W. Jenny Helv. Chim. Acta. 1967,50 1978. W. E. Parham and J. K. Rinehart J. Amer. Chem. SOC. 1967,89,5668. Aromatic Compounds 285 eight bridging methylene groups ; forthe smaller ring from (85) the intermediate cyclopropane (86) does not react further. [12)Paracyclophane derivatives have been ~ynthesised~~ from suitable Diels-Alder adducts of the bridged cyclo- pentadiene (87) ;for example the reaction of (87) with benzyne gives the bridged naphthalene (88).The cage compounds (89) and (90) (and isomers) result65 n (83) n = 8 or 10 (84) n = 8 or 10 (86) n = 4 (85)n = 4 F2112 / Ph (87) (89) = 3-9 (9 1) (92) from trimerisation of the acetylene derivatives (91) and (92) with use of a Ziegler catalyst and high-dilution techniques. The compound (90) forms solvent complexes owing to inclusion of solvent within the molecule. The slow thermal (200") racemisation of optically active [2,2]paracyclophane derivatives such as (93) proceeds66 by way of a ring opened diradical inter- mediate (94); this intermediate may be trapped as the adducts (95) by heating 64 J.C. Digan and J. B. Miller J. Org. Chem. 1967,32 490. ''A. J. Hubert J. Chem. SOC.(C) 1967 6 11. 66 H. J. Reich and D. J. Cram J.her. Chem. SOC. 1967,89 3078. I. 0. Sutherland [2,2]paracyclophane at 200" in the presence of methyl fumarate or maleate ; the complete lack of stereospecificity is in accord with the trapping of a diradical. This trapping reaction also provides a synthetic route to [2,4]paracyclophane. @c02Me I -CH *CH2 (93) (94) R= H or COzMe (95) cis-and trans-isomers The novel heptacyclic hydrocarbon (96) (dibenzoequininene) is formed67 by the photocatalysed intramolecular cyclo-addition reactions of [2,2]para- cyclonaphthane (97); the reaction is reversed by heating (96) at 200" in the solid phase. Benzynes.The reaction of benzyne with benzene leads to the 1,4-addition product (98) but in the presence of silver ions68 a mixture consisting largely of biphenyl and benzocyclo-octatetraene is formed. This suggests that an intermediate benzyne-silver complex cation is formed which is more electro- philic than benzyne and that the observed products result from a two-stage reaction with the addition product (99) as an intermediate. The reaction of benzyne with tropone6' also gives a 1,4-adduct (100). The reactive acetylene cyclo-octyne gives7' the phenanthrene derivative (101) by reaction with two molecules of benzyne. It is possible71 that benzyne gives the 1,2-adduct (102) with dimethyl sulphoxide but (102) if it is formed is unstable and ring cleavage occurs to give 2-dimethylsulphoniumphenoxide(103).The reaction of tetra- chlorobenzyne with bicyclo[2,2,l]heptadiene yields72 products (104) and 67 H. H. Wassermann and P. M. Keehn J. Amer. Chm. SOC. 1967,89,2770. 68 L. Friedman J. Amer. Chem. SOC.,1967,89 3071. 69 J. Ciabattoni J. E. Crowley and A. S. Kende J. Amer. Chem. SOC. 1967,89,2778. 'O V. Frauen and H.-I. Joschek Annalen 1967,703,90. 71 M. Kise T. Asari N. Furukawa and S.Oae Chem. and Znd. 1967 276; H. H. Szmant and S. Vazquez ibid. p. 1OOO. '' H. Heaney and J. M. Jablonski Tetrahedron Letters 1967 2733. Aromatic Compounds (105) of both (2 + 2)7t and homo-(2 + 4)7t cyclo-addition reactions. The 1,4-adduct (106) of tetrafluorobenzyne and t-b~tylbenzene’~ is the first compound to show a considerable barrier to the rotation of a t-butyl substituent; this conclusion follows from the temperature dependence of the t-butyl n.m.r.signals. PAGE 26 Me\; Me Me c1 F (105) (106) Three-and Four-Membered Ring Systems.-The chemistry of cyclopropenes and related compounds including cyclopropenones and cyclopropenyl cations. has been reviewed.74 Tri-n-butylstannane reduction759 76 of tetrachloro-cyclopropene under suitable conditions gives either the dichlorocyclopropene (107) or the monochlorocyclopropene (108). Hydrolysis of (107) yields7’ unsubstituted cyclopropenone which exists in water as the free ketone but undergoes slow hydrolysis to acrylic acid (t+ ca. 1 week at 25”). The reaction of (108) with antimony pentachloride in methylene chloride gives76 cyclo- propenyl hexachloro-antimonate which is stable for several hours at room temperature.Cyclopropenyl salts are formed7’ by decarbonylation of alkyl cycloprop-2-enecarboxylates (109) with chloro- or fluoro-sulphonic acid. In particular the parent cyclopropenyl cation may be generated in solution by thermal decomposition of (110) to give dimethyl phthalate and methyl- cycloprop-2-enecarboxylate which are passed directly in the vapour phase 73 J. P. N. Brewer H. Heaney and B. A. Marples Chem. Comm. 1967 27. 74 G. L. Closs Ado. Alicyclic Chem. 1966,1 53. l5 R. Breslow and G. Ryan J. Amer. Chem. SOC. 1967,89,3073. 76 R. Breslow J. T. Groves and G. Ryan J. Amer. Chem. SOC.,1967,89 5048. l7 D. G. Farnum G. Mehta and R. G. Silberman J.Amer. Chem. SOC.,1967,89,5048. I. 0.Sutherland R R c1 c1 57c1 s (107) (108) (109) (111) R (115) (116) into chloro- or fluoro-sulphonic acid. The trichlorocyclopropenyl cation reacts with 2,6-di-t-butylphenol at 0" to give7* the diarylcyclopropenone (1 11); oxidation of (111) gives the diquinocyclopropanone (112) as a purple solid which slowly decomposes in solution to the orange-yellow diquinoethylene 78 D.C. Zecher and R. West J. Amer. Chem. SOC. 1967,89 153 Aromatic Compounds 289 (1 13). Compound (1 13) may also be obtained by oxidation of the diarylacetylene (1 14) which in turn is synthesised by photocatalysed decarbonylation of (1 11). The related triquinocyclopropane (1 15) is produced79 by oxidation of (1 16) which is obtained from the reaction of the trichlorocyclopropenyl cation with 2,6-di-t-butylphenol at 30" followed by base-catalysed proton removal from an intermediate tri-arylcyclopropenyl cation.The triquinocyclopropane (115) is a stable dark blue powder which does not give an e.s.r. spectrum at 25". Cyclobutadiene iron tricarbonyl (117) has been obtained" in one stage in in moderate yield (10-15%) by irradiation of a-pyrone in the presence of iron pentacarbonyl at -15". Photolysis of (1 17) gives" free cyclobutadiene which may be detected by mass spectrometry or converted into adducts but acetylene adducts with Dewar benzene structures are aromatised under these conditions. For example photolysis of (117) at -20" in the presence of dimethyl acetylenedicarboxylate gives dimethyl phthalate in 17 % yield as compared with a yield of 18 % when cyclobutadiene is generated by the oxida- tion of (1 17).Cyclobutadiene generated by photolysis of (117) in a rigid matrix does not have an e.s.r. spectrum,81 a result which supports the assignment of a singlet structure to cyclobutadiene previously made on the basis of stereo- specific addition reactions and theoretical considerations. The oxidative de- gradation of benzocyclobutadiene iron tricarbonyl (1 18) by lead tetra-acetate probably givessz free benzocyclobutadiene since if cyclopentadiene is present the adduct (119) is obtained. The production of a mixture of cyclobutadiene and benzocyclobutadiene by oxidation of a mixture of their iron tricarbonyl complexes gives the product (120) of a Diels-Alder reaction in which cyclo- butadiene behaves as the diene and benzocyclobutadiene as the dienophile as expected.Ferric nitrate oxidation of (1 18) yields the 'normal' dimer of benzo- cyclobutadiene (120a) but in the presence of silver ions the dimer (121) is formed. These results have been rationalised in terms Of SCHEME 3 :in the absence of silver ions the initial Diels-Alder adduct (122) aromatises to give (120a) but in the presence of silver ions the symmetry-forbidden disrotatory electro- cyclic ring opening of the benzocyclobutene moiety of (122) occurs rapidly and (123) is formed. Compound (123) then undergoes a further electrocyclic ring opening to give benzo[a,d]cyclo-octatetraene (124) which is finally isolated as its valence tautomer (121).The action of Lewis acids and metal ions 79 R. West and D. C. Zecher J. Amer. Chem. SOC.,1967,89 152. M. Rosenblum and C. Gatsonis J. Amer. Chem. SOC.,1967,89,5074. W. J. R. Tyerman M. Kato P. Kebarle S. Masamune 0.P. Strausz and H. E. Gunning Chem. Comm. 1967,497. W. Merk and R. Pettit J. Amer. Chem. SOC. 1967,89,4787. I. 0.Sutherland -%\/ (123) \ as catalysts in forbidden electrocyclic reactions has already been mentioned under the reactions of benzene valence tautomers. This effect is apparent in the above reaction sequence and alsoa3 in a number of similar reactions discussed by Merk and Pettit. These authors note that in the presence of silver fluoroborate cyclo-octatetraene is rapidly formed from anti-tricyclo-octadiene (125) benzocyclo-octatetraene from (126) and dibenzo[a,e]cyclo-octatetraene from (127).The intermediate (128) and (129) in the last two reactions may be readily trapped as Diels-Alder adducts with maleic anhydride showing that disrotatory electrocyclic cleavage of a cyclobutene ring occurs in both cases. The n.m.r. spectrum of protonated squaric acid shows84 that its structure is better represented by (130) where the positive charges reside largely on the oxygen atoms than by (131). The disodium salt (132) is synthesiseda5 by the 83 W. Merk and R. Pettit J. Amer. Chem. SOC. 1967,89,4788. 84 G. A. Olah and A. M. White J. Amer. Chem. SOC.,1967,89,4152. 85 H.-E. Sprenger and W. Ziegenbein Angew. Chem.Znternat. Edn. 1967,6 553 Aromatic Compounds 29 1 (125) (126) (1 27) + + base-catalysed reaction of dibutyl squarate with malononitrile ; there is however no evidence concerning the importance of contributions from the canonical form (133) to the structure of this compound. The reaction of the diphosphonium salt (134) with strong base generates86 carmine coloured solu- tions of the bisylid (135); this is not isolable although it is formally a derivative of the benzocyclobutadienyl dianion and it reacts with aromatic aldehydes as a bisylid system to give the dienes (136). Fulvenes Fulvalenes and Related Systems.-Considerable interest in fulvene and fulvalene systems continue to be shown although some criticism has been made of synthetic work in this field.lg The ethanolysis of the cyclo- propenylazulenium salt (137) synthesised by the reaction of 3,3-dichloro-l,2- diphenylcyclopropene with 4,6,8-trimethylazulene yields87 the cyclopropenyl ether (138) rather than a calicene derivative.The formation of (138) may well be subject to thermodynamic rather than kinetic control under the reaction conditions used and is therefore in accord with the low delocalisation energy calculated for the calicene system. The salt (139) analogous to (137) was synthesised88 by the reaction of l-ethoxy-2,3-diphenylcyclopropenyl fluoro-borate with azulene ;the synthesis of cyclopropenylcyanine systems e.g. (140) 86 A. T. Blornquist and V. J. Hruby J. Amer. Chem. SOC.,1967,89,4996. B. F6hlisch and P. Burgle Annalen 1967,705 164.T. Eicher and A. Hansen Tetrahedron Letters 1967,4321. K* I. 0.Sutherland R Me Ph Ph (137) R = Me X = CIO (139) R = H,X = BF (1 3 8) Me Eti% Ph -Ph C MeKCOMe MACOMe and (141) is described in the same paper. The oxidation89 of the calicene diriva- tives (142) and (143) leads to the allenic fulvenes (144) and (145). The cyclo- addition reactions of (142) and (143) have been described in detail :” products result from either 1,2-addition to the three-membered ring or from 1,4-addition with simultaneous cleavage of the C(l)-C(3) bond [see numbering in (142) and (143)l. A second example of the calicene system has now been examined by X-ray crystallographyg1 and in accord with a previously reported investi- gati~n,~~ the results show the strong bond alternation predicted by theory.2,6-Dimethylfulvene (146) results,93 unexpectedly from the reaction of the bicyclopropyl derivative (147) with methyl-lithium at -78”. 6,6-Dicyclo- propylfulvene (148) has been ~ynthesised;’~ the dipole moment (1.74 D) is somewhat larger than that of 6,6-dimethylfulvene (1.52 D) indicating that as expected some release of electrons from the cyclopropane ring occurs. The 89 H. Prinzbach and U. Fischer Helu. Chim. Acta 1967,50 1669. 90 H. Prinzbach and U. Fischer Helu. Chim. Acta 1967,50 1692. 91 0.Kennard D. G. Watson J. K. Fawcett K. A. Kerr and C. Romers Tetrahedron Letters 1967 3885. 92 H. Shimanouchi T. Ashida Y. Sasada M. Kakudo I. Murata and Y. Kitahara Tetrahedron Letters 1967 61.93 L. Skattebsl Tetrahedron 1967,23 1107. 94 R. C. Kerber and H. G. Linde jun. J. Org. Chem. 1967,31,4321. Aromatic Compounds (151) X = AsPh (146) (152) X = SbPh, (153) X = BiPh, + CI Me0,C Me 02Czco Me I I CO-Me C I 1118 II I CH MeCOxcoMe Ph Ph (1 54) (155) (156) C02MeC0,Me C C (15 9) c1 cl Ll (157) (158) c1 c1 (1 60) ylids (149)-(153) have been ~ynthesised~~ by the reaction of diazotetraphenyl- cyclopentadiene with the appropriate Group V triaryl derivatives and Group VI diary1 derivatives. Protonation of the anion generated by the action of lithium on the acetylenic cyclopentadiene derivative (154) gives the allenic fulvene (155).96 Tetramethyl cyclopentadiene 1,2,3,4-tetracarboxylatereacts9’ with tropone to give a high yield of the sesquifulvalene (156) and with y-pyrone derivatives to give fulvenes of the type (157).8,9-Diacetylsesquifulvalene (158) can also be prepared in high yield98 by a conventional reaction sequence starting with tropylium bromide and 1,2-diacetylcyclopentadiene.X-Ray crystallographic examination” of 8,8-dicyanoheptafulvene (1 59) shows that it has a near planar structure but considerable bond alternation. The planarity 9s D. Lloyd and M. I. C. Singer Chem. and Znd. 1967 118 510 787 1042; Chem. Comm. 1967 390. 96 G. Rio and G. Sam hll. SOC.chim. France 1966 3367. 97 G. Seitz Angew. Chem. Internat. Edn. 1967,6 82. 98 E. Koerner von Gustorf M. C. Henry and P. V. Kennedy Angew. Chem.Internat. Edn. 1967 6 627. 99 H. Shimanouchi T. Ashida Y. Sasada M. Kakudo I. Murata and Y. Kitahara &ll. Chem. SOC. Japan 1966,39,2322. I. 0. Sutherland of the seven-membered ring is interesting in view of the moderately high energy barrier observed for inversion of thecycloheptatriene ring system ;the C(1)-C(8) bond is unusually long (1.422A) for a double bond and the structure is in accord with considerable dipolar character. An earlier examination"' of the benzo- sesquifulvalene system (160) also shows a nearly planar seven-membered ring again suggesting that the increased delocalisation energy of a near planar system offsets the bond angle distortion required for planarity. Pentahendeca- fulvalene is the third member of the series that starts with calicene and sesqui- fulvalene.A symmetrical bridged derivative (161) of this system has now been prepared101 by the reaction of lithium fluorenyl with bicyclo[5,4,l]dodec- pentaenylium fluoroborate (162) followed by dehydrogenation of the initial reaction products; two compounds isomeric with (161) obtained as products of the same reaction are probably also bridged pentahendecafulvalenes. The fulvalene (161) is thermally stable and is not protonated by acid under conditions where both dibenzocalicene and dibenzosesquifulvalene exist as the conjugate acids. The heptafulvene (163) is generated'" by the action of acid on the spirononatriene (la) obtained by the addition of photochemically generated cycloheptatrienylidene to dimethyl fumarate ; in the absence of dimethyl fumarate heptafulvalene (165) is produced.The cycloheptatrienylphenol deriva- tive (166) is oxidised to a tropylium salt with phosphorus pentachloride and CO-Me CO Me 0Ac 0 (170) loo Y. Nishi Y. Sasada T. Ashida and M. Kakudo Bull Chem. SOC.Japan 1966,39,818. lo' H. Prinzbach and L. Knothe Angew. Chem. Internat. Edn. 1967,6,632. lo' W. M. Jones and C. L. Ennis J. Amer. Chem. SOC. 1967,89,3069. Aromatic Compounds hydrolysis of the tropylium salt followed by treatment with base gives the pbenzoquinocycloheptatriene (167). This and analogous substituted com-pound~"~* lo4are more stable than the unsubstituted quinocycloheptatriene. A careful analysis of the dipole moments of tropone and unsaturated cyclic ketone^''^ suggests that the former has a dipole moment contribution of only 0.55 D (4 % of the maximum possible contribution) from what may loosely be termed 'aromatic character as indicated by the dipolar canonical form (168).The stereochemistry of the (4 + 2)n tropone photodimer has now been estab- lishedlo6 as (169); in accord with this stereochemistry (169) does not dissociate into tropone when heated and must result from a two-step cyclo-addition mechanism or from the addition of tropone to a Moebius (trans) excited state tropone molecule. It is agreed that the (4 + 6)n tropone photo-dimer (170) results from a cis-(4 + 6)n cyclo-addition'07~108 and can therefore revert to tropone when heated. The formation of this dimer is however preventedlo7 by the addition of triplet quenching reagents and it therefore a stepwise photo-addition in accord with the Woodward-Hoffmann rules.The Diels- Alder addition of ethylazodicarboxylate to tropone"' follows a normal course to give the adduct (171) but the reaction of tropone with cycloheptatriene results"' in a (4 + 6)n cycio-addition followed by an intramolecular Diels- Alder reaction to produce the pentacyclic dimer (172). Yet another mode of dimerisation is exhibited by 7-methoxy-6-phenyltropone,which undergoes a photocatalysed l,&dipolar addition"' to give the dimer (173); this dimer dissociates when heated by a reverse (8 + 2)n cyclo-addition. The tetra- phenylbenzopentalene (174) has been synthesised' l2 by acid-catalysed de- hydration of the diol (175).The bisdimethylaminopentalene (176) represents \ j Ph Ph 0 lo' lo4 lo5 lo6 lo' (174) (175) T. Nozoe and K. Takahashi hll. Chem. SOC.Japan 1967,40 1473. J. J. Looker J. Org. Chem. 1967,32 2941. D.J. Bertelli and T. G. Andrews Tetrahedron Letters 1967,4467. T. Tezuka Y.Akasaki and T. Mukai Tetrahedron Letters 1967 5003. A. S.Kende and J. E. Lancaster J. Amer. Chem. SOC. 1967,89 5283. (177) lo' T. Tezuka Y. Akasaki and T. Mukai Tetrahedron Letters 1967 1397. Y. Kitahara,I. Murata and T. Nitta Tetrahedron Letters 1967 3003. 'lo '12 S. It6 Y. Fujise and M. C. Woods Tetrahedron Letters 1967 1059. W.Reid and D. Freitag Tetrahedron Letters 1967 3135. T. Mukai T. Miyashi and M. C. Woods,Tetrahedron Letters 1967,433. I. 0. Sutherland NMe2 NMez (176) the simplest pentalene system so far synthesised;' l3 the dimethylamino- substituents make (176) sufficiently stable to be isolated as a dark blcie crystalline compound.The synthesis of (176) involved the reaction of the ketone (1 77) with dimethylammonium perchlorate followed by base ;treatment of (177) with strong base gives a blue anion with an electronic absorption spec- trum resembling that of (176). Annulenes-The formation' l4 and reactions' l5 of cis-l,2-dichlorocyclo-octa-3,5,7-triene (178) have now been examined in more detail. The cis-addition of chlorine to cyclo-octatetraene proceeds stereospecifically by way of the endo-chlorohomo-aromatic species (179) ;the endo-cation (179) also results from the action of fluorosulphonic acid on (178) but (179) is thermodynamically unstable with respect to the exo-cation (180) into which it slowly isomerises at room temperature.The exo-cation (180),which can be made directly as a colour- less crystalline hexachloro-antimonate by the reaction of (178) with antimony pentachloride reacts stereospecifically with chloride ions to give 1,2-trans- dichlorocyclo-octa-3,5,7-triene(1 81). These reactions are summarised in SCHEME 4. Several reactions of the cyclo-octatetraenyl dianion have now been fully reported;"6* 'I7 in all cases the products result from 1,2- and 1,4-electro- philic attack. For example reaction with benzaldehyde116 gives the 1,Cproduct '13 K. Hafner K. F. Bangert and V. Orfanos Angew. Chem. Internat. Edn. 1967,6,451.R. Huisgen G. Boche and H. Huber J. Amer. Chem. SOC.,1967,89,3345. '15 G. Boche W. Hechtl H. Huber and R. Huisgen J. Amer. Chem. SOC. 1967,89 3344. 'I6 T. S. Cantrell and H. Schechter J. Amer. Chem. SOC.,1967,89 5877. 11' T. S. Cantrell and H. Schechter J. Amer. Chem. SOC.,1967,89,5868. Aromatic Compounds CH(0H)Ph CH(0H)Ph (182) SCHEME 4 (182) and the 1,2-product which is isolated as its valence tautomer (183). Acylation follows a more complex course;'17 acetyl chloride gives a 1,2-product which undergoes a presumed conrotratory thermal ring opening to give the tetraenedione (184). At the same time the monoacylation product undergoes self-condensation and acetylation to give the bicyclo[6,1,0]nonatriene (185) and the bicyclo[4,2,l]nonatriene (186).Methylation of the dianion' '* also results in 1,4- and 1,2-disubstitution products. The synthetic approaches to [lolannulene have now reached an interesting stage and several reactions of CloH, compounds have been observed which may involve the formation of (185) (186) [lolannulene and its derivatives as intermediates. CloH, isomers have been investigated in some detail,' '' but only those reactions which relate directly to [10Iannulene will be reported here. The Woodward-Hoffmann rules predict that the [lOIannulene isomer (187) would be obtained by photochemical conrotatory ring opening of trans-9,lO-dihydronaphthalene(1 88) and that thermal cyclisation of (187) would give cis-9,lO-dihydronaphthalene(189). The additional possibility exists of obtaining the [101annulene isomer (190) by thermal ring-opening from (191) or photochemical ring-opening of (189) but the [lolannulene isomer (190) would be highly strained and a far from planar system.Ring closure of (190) would lead to trans-9,lO-dihydronaphtha-lene. These processes are summarised in SCHEME 5 the arrows show those processes for which some evidence has been presented. The successful synthesis120 of (188) in several stages from the dione (192) enabled the photo- chemistry of (188) to be investigated and provided the clearest evidence so far for the existence of [lOlannulene as a transient species. Irradiation of (188) in a matrix at -190" followed by di-imide reduction at -70",gave cyclodecane "* D. A. Bak and K.Conrow J. Org. Chem. 1966,31,3958. '19 W. von E. Doering and J. W. Rosenthal Tetrahedron Letters 1967 349; U. Kruerke Angew. Chem. Internat. Edn. 1967,6 79; hl.Jones jun. J. Amer. Chem. SOC. 1967,89,4236. I2O E. E.van Tamelen and T. L. Burkoth J. Amer. Chem. SOC.,1967,89 151. 298 I. 0. Sutherland in 40% yield indicating that (187) was the species undergoing reduction. If the irradiation product was allowed to warm to room temperature (189) was formed as expected for (187). The formation of (188) from the carbene (193) has also been reported; the carbene is produced either by photolysis121 of the tosylhydrazone (194) or by pyrolysis'22 of the sodium salt of (194). If the photo- @ D -H ~C-NH-SO2*C6H4Me -H (192) (193) (194) 61 (195) R' = R2 = H (198) (197) R' = F R2 = CI (196) lysis products from (194) are isolated at 0" the bicyclo[6,2,0]decatetraene (195) is obtained,121 but at temperatures above 40" (195) is isomerised to (188).It is possible that this involves the route (191) -+ (190) -,(188) but there is no direct evidence for this. A dihalogeno-drivative of (195) has been synthesised' 23 by the reaction of (196) the adduct of cyclo-octatetraene with 1,l-dichloro-2,2- difluoroethylene with methyl-lithium. The product (197) of this reaction is rapidly converted at 20" into a mixture of 1-fluoro- and 1-chloro-naphthalene; this could involve dihalogeno [ 10Iannulene [with the stereochemistry of (190)] lZ1 S. Masamune C. G. Chin KOHojo,and R. T. Seidner J. Amer. Chem.SOC. 1967,89 4804. lZ2 M. Jones jun. and L. T. Scott J. Amer. Chem. Soc. 1967,89 150. G. Schroder and T.Martini Angew. Chem. Znternat. Edn. 1967,6,806. Aromatic Compounds 299 and dihalogeno-trans-9,lO-dihydronaphthalene(198) intermediates but again no direct evidence for these intermediates is available and in this case bond- rotation in the intermediate [lolannulene would also be required. To sum- marise the evidence for the existence of the [lOlannulene isomer (187) at low temperatures is good,120 but the evidence for the isomer (190) is at this stage slender. A further approach to [ lolannulene synthesis124 involved the synthesis of the chloro-compounds ( 199)125 and (200) by the action of phosphorus penta- chloride on the diene dione (201).Both (199) and (200) were converted into a mixture of (202) and naphthalene by reaction with lithium di-isopropylamide at -75" but no products were obtained which showed clear evidence for a [ lolannulene derivative as an intermediate in their formation. [ 16lAnnulene b&Qb c1 c1 c1 (199) (200) (201) (2 0 2) (206) is isomerised both photochemically and thermally.' 26 The thermal reaction gives the product (203) believed to be formed by two disrotatory electrocyclic reactions from the [ 16)annulene stereoisomer (204); the photo-isomer has the structure (205) formed by two conrotatory processes from (204) although the most stable geometrical isomer of [ 16lannulene is (206) (n.m.r. evidence). Both (203) and (205) may be dehydrogenated to give dibenzo[a,e]cyclo- octatetraene or isomerised by strong base to tetrahydrodibenzo[a,e]cyclo-octa-tetraene (207).The electrophilic substitution reactions of [ 18lannulene (208) K. Grohmann and F. Sondheimer Tetrahedron Letters 1967,3121. 0. Kennard D. G. Watson J. K. Fawcett and K. A. Kerr Tetrahedron Letters 1967 3129. G. Schriider W. Martin and J. F. M. Oth Angew. Chem. Internat. Edn. 1967,6 870. I. 0.Sutherland trifluoride gives the acetyl derivative (209) and nitration by cupric nitrate- acetic anhydride gives the nitro-derivative (210). The n.m.r. spectra of (209) and (210) are instructive at low temperature the inner and outer protons appear in the usual high and low field regions of the spectrum but at higher temperatures the signals from five of the outer protons [shown as H in (209 and (210)] remain at low field although the signals from the remaining six have been reported in detail ;Iz7 acetylation by acetic anhydride-boron outer protons and six inner protons show the usual evidence for site exchange.This effect is explained by the low population of conformation (21 l) which has the substituent in a sterically unfavourable inner position. 1,3,7,9,13,15-Hexa- R H (208)R = H (209) R = Ac (210)R = NO % fn \ /7 H c 3 (J =--(211) (212) (213) I. C. Calder P. J. Garratt H. C. Longuet-Higgins F. Sondheimer and R. Wolovsky,J. Chem. SOC.(C), 1967,1041. Aromatic Compounds 30 1 dehydro[ 18lannulene (212) has been synthesised ;128the olefinic protons give a singlet at T 2-98 in the n.m.r.spectrum providing good evidence both for a diamagnetic ring current in (212) and that the olefinic proton signal of 1,5,9- tridehydro[ 12lannulene is shifted to high field (T 5-58) by a paramagnetic ring current rather than the magnetic anisotropy of the triple bonds. The n.m.r. spectrum of [24] annulene (inner protons at z -2.9~ to 1.2 and outer protons at z 5-27 at -80') shows that paramagnetic ring currents can be induced in a 24-membered (4n x-~ystern,'~' but it was predicted some time ago that the [4n + 23 annulenes would cease to be aromatic'30 for n26. This prediction is c~nsistent'~with the n.m.r. spectrum of tridehydro[26]annulene (214) which at room temperature shows a broad n.m.r.multiplet for all the olefinic protons at z 2.04-5; this is unchanged by cooling to -60" (at this low temperature the exchange of inner and outer protons sites would be expected to be slow on the n.m.r. time scale). This lack of an induced ring current in the dehydro[26]annulene is in accord with the spectrum of dehydro[30]annulene which also shows no evidence for an induced diamagnetic ring current.6 A summary of the energy barriers to conformational interconversion for annulenes has been published;'32 the results (with the exception of those for [16]annulene) are approximate owing to the complexity of the n.m.r. changes but they do indicate that conformational changes which must involve bond rotation and therefore an interruption of the cyclic x-electron system are energetically undemanding in both [4n]- and [4n + 2)-annulenes.This is in agreement with SCF-MO calculations which show that the x-delocalisation energy even in the aromatic systems is small.' 30 The chemistry of bridged [101- and [141-annulenes has been reviewed.' 33 The crystal structure of 1,6-epoxy[lO]annulene shows that there is no tendency for bond alter- nation in the ten-membered ring although this ring is appreciably non-planar.'34 This is in agreement with the dipole moment of 0.8 D assigned to the non-planar lox-electron system of 1,6-bridged [10lannulenes on the basis of dipole moment studies.' 35 The base-catalysed hydrogen4euterium exchange reaction of tricyclo[4,3,1,O]deca-2,4,7-triene (215) is highly stereo~pecific'~~ and the results indicate that both deuteriation of the anion (216) and de- deuteriation of the product (217) occur on the a-face of the molecule only.Methylation of the anion (216) re~u1t.s'~~ in stereospecific formation of the a-methyl derivative (218) which does not undergo proton4euterium exchange even on prolonged (3 months) treatment with sodium deuteroxide in deuteriated dimethyl sulphoxide. This stereospecificity appears to results from electronic 12' W. H. Okamura and F. Sondheimer J. Amer. Chem. SOC.,1967,89,5991. I. C. Calder and F. Sondheimer,Chem. Comm. 1966,904. 130 M. J. S. Dewar and G. J. Gleicher,J. Amer. Chem. SOC.,1965,87,685. 13' C. C. Leznoffand F. Sondheimer J. Amer. Chem. SOC.,1967,89,424 7. 13' I. C. Calder and P. J. Garratt J.Chem. SOC.(4, 1967,660. 133 E. Vogel Chem. SOC. Special Publ. No. 21 1967 p. 113; E. Vogel and H. Giinther Angew. Chem. Znternat. Edn. 1967,6 385; G. Maier ibid. p. 402. 134 N. A. Bailey and R. Mason Chem. Comm. 1967 1039. W. Bremser H. T. Grunder E. Heilbronner and E. Vogel Helu. Chim. Acta 1967,50 84. 136 P. Radlick and W. Rosen J. Amer. Chem. SOC.,1967,89,5308. I. 0.Sutherland (215) R = H (217) R = D (220)X = NH,Y = S (221)x = Y = 0 (222) x = s Y = 0 rather than steric factors since the ketone (219) readily exchanges all its a-hydrogen atoms for deuterium. Another bridged [18lannulene (220) has been synthesised ;I3' its properties are those of the individual heterocyclic rings linked by olefinic bonds and the only known members of this group of com- pounds' jSwhich behave as [18)annulene derivatives are trioxido[ 18lannulene (221) and dioxidosulphido[ 18lannulene (222).SCF-MO calculations indi- cate' 39 that [18lannulene derivatives of the triphenanthrene or hexa-m-phenylene type will behave as isolated benzenoid aromatic systems and the properties of compounds of this type that have been synthesi~ed'~' confirm the predictions. Polycyclic Compouuds.-The reaction of [1-14C]naphthalene with alu-minimum chloride at 60" leads to scrambling of the 14C label and all the naphthalene carbon atoms become equally labelled. 14' The mechanism shown in SCHEME 6 has been proposed to account for this result and the process has been termed 'automerisation'. The intermediate spiro-cations in this scheme are however not those in which spiro-conjugation would lead to stabilisation since the non-bonding MO of the pentadienyl system does not have AA symmetry (see p.277). Similar effects have been observed in more complex polycyclic systems.'42 For example naphtho[2,1-~]anthracene (223) is isomerised by aluminium chloride at 72" to benzo[a]naphthacene (224). Aluminium chloride also cata- lyses rearrangement reactions and dehydrogenation reactions of polycyclic 13' G. M. Badger?G. E. Lewis and U. P. Singh Austral. J. Chem.,1967,2O 1635. 13' G. M. Badger J. A. Elix and G. E. Lewis Austral. J. Chern. 1965,18,70; 1966,19 1221; G. M. Badger G. E. Lewis and U. P. Singh ibid. 1966 19.257 1461. 139 G. Ege and H. Fischer Tetrahedron 1967,23 149.H. A. Staab and F. Binnig Chem. Ber. 1967 100 293; H. Braunling F. Binnig and H. A. Staab ibid. p. 880; H. A. Staab and F. Binnig ibid. p. 889. A. T. Balaban and D. Farcasiu J. Amer. Chem. SOC. 1967,89 1958. 142 D. Lavit-Lamy and N. P. Buu-Hoi &N. SOC.chim France 1966 2613 2619; N. P. Buu-Ho~ BLavit-Lamy and 0.Roussel-P6rin ibid. 1967 1771. Aromatic Compounds 303 * u* a a* H H a \ / SCHEME 6 systems with phenyl sub~tituents;'~~ this is illustrated by the formation of dibenzo[a,e]fluoranthene (225) from phenylbenzo[a]anthracene (226) and from the reaction of benzo[a]anthracene (227) with benzene. The bridged aromatic system named janusene (228)143 results from the cyclo-addition reaction of anthracene and the bridged anthracene (229); the greater reactivity of the starred benzene rings of (228)is possibly due to transannular activation.S.J. Cristol and D. C. Lewis J. Amer. Chem. SOC. 1967,89 1476. I. 0. Sutherland (229) \ 48) \/ (228) (230) The helical aromatic system heptahelicene (230) is formed'44 by the photo- catalysed cyclisation and oxidation of the diphenanthrylethylene (23 1) but the optical resolution of (230) has not yet been reported. The unsubstituted pyracylene system (232) has now been ~ynthesised,'~~ but in solution only by debromination of the tetrabromide (233) by iodide ions. The n.m.r. spectrum of pyracylene is more characteristic of the peripheral [12lannulene system than of a naphthalene nucleus plus two ethylene units.The unusually acidic poly- cyclic hydrocarbons (234) and (235) (pK CQ. 5.9) are as a mixture starting from the reaction of dibenzo[c,g]fluorene (236) with the bisperchlorate (237). The acidities of (234) (235) and a number of other highly acidic hydro- (234) (236) R= -CH Me,& :CH)& :CH .NMe22CI0 (237) '44 M. Flammang-Barbieux J. Nasielski and R. H. Martin Tetrahedron Letters 1967 743. B. M. Trost and G. M. Bright J. Amer. Chem. SOC. 1967 89 4244; B. M. Trost and D. R. Brittelli Tetrahedron Letters 1967 119; B. M. Trost S. F. Nelsen and D. R. Brittelli ibid. p. 3959. 146 R. Kuhn and D. Rewicki Angew. Chem. Internat. Edn. 1967,6,635. Aromatic Compounds carbons have been discussed.147 The Wolff-Kishner reduction of 1,8-( 1,8-naphthaloy1)naphthalene (238) proceeds'48 by a novel intramolecular course to give acenaphth[ 1,2,a]acenaphthylene (239) ;other intramolecular reactions of a similar type are also described for the system (238).Although dibenzo[u,q- cycloheptatrienylidine (240) and tribenzo[a,c,e]cycloheptatrienylidine (241) are recognisable as triplet species from their e.s.r. spectra in a rigid matrix at low ternperat~re,'~~ their addition reactions with olefins are stereospecific ;Iso a reminder that singlet character for a carbene species cannot be inferred with certainty from the stereospecificity of its addition reaction. Several other polycyclic systems containing seven-membered rings have been investigated. The unstable dibenzo[b,e]tropone (242) has been generated in solution151 by the reaction of the tropylium cation (243) with base; (243) was made by de- hydration of (244) with sulphuric acid.The tropone (242) dimerises in solution to give the (4 + 4)x dimer (245) which dissociates in boiling decalin to regenerate (242); the presence of (242) is proved by the formation of the maleic anhydride adduct (246). The tribenzocycloheptatrienol(247)is resolvable and must therefore possess a high energy barrier to inversion of the seven-membered ring nevertheless the U.V. spectrum of (247) in sulphuric acid shows that the cation (248) is slowly formed (ta25 min. in conc. sulphuric acid at room temperature). The introduc- tion of additional steric hindrance to planarity as in (249) prevents cation a '0 OH (242) (243) 14' R.Kuhn and D. Rewicki Annalen 1967,706,250. '" W. C. Agosta J. Amer. Chem. SOC.,1967,89,3505. 149 S. Murahasi I. Moritani and T. Nagai Bull. Chem SOC.Japan 1967 40 1655; I. Moritani S. Murahashi M. Nishino Y. Yamamoto K. Itoh and N. Mataga J. Amer. Chem. SOC. 1967 89 1259. I. Moritani S. Murahashi K. Yoshinagp and H. Ashitaka Bull. Chem. SOC.Japan 1967,40 1506; S. Murahashi I. Moritani and M. Nishino J. Amer. Chem. SOC. 1967,89 1257. '" N. L. Bauld and Yong Sung Rim J. Amer. Chem. SOC.,1967,89 179. lS2 W. Tochtermann and K. Stecher Tetrahedron Letters 1967 3847. I. 0.Sutherland (245) Ho2c4# \/ (247) R' =CO,H RZ =H (249) R' =H RZ =Me (248) formation. An interesting synthesis of the very stable benzopleiadene quinone (250) has been achieved :lS3 2-thiaphenalene (251) is probably generated as a reactive intermediate by the action of acetic anhydride upon the sulphoxide (252) and in the presence of 1,4-naphthoquinone an adduct is produced which Me M%C@ CO.CO2 Et Me Me3cB OH (254) R=H (253) (255) R =CO.CO2Et M.P. Cava N. M. Pollack and D. A. Repella J. Amer. Chem. SOC. 1967,89 3640. 307 Aromatic Compounds (256 ) (2 57) is readily converted into (250). The benzo[c,d]azulene (253) was ~ynthesised'~~ by cyclisation of the azulene-oxalic ester condensation product (254) but attempted double cyclisation of the di-ester (255) failed to yield a quinonoid derivative of cyclohepta[d,ef]fluorene. An attempted synthesis of unsubsti- tuted cyclohepta[d,ef]fluorene (256)failed :Is5 reaction of the tropylium salt (257) with base did not give (256).The cycloheptafluorene system is of interest since it is predicted to have a ground state or low-lying triplet state.'56 Phenol Oxidation; Quinones and Related Compounds.-The autoxidati~n'~ of some 1-alkyl-2-naphthols leads to the peroxides (258) by a reaction that appears to involve a radical mechanism. The oxidative condensation of 3-isopropylcatechol and orcinol gives'58 the dibenzofuran (259) ;an intermediate in this reaction is the radical anion of (259) which can be detected by e.s.r. R OOH 03-" ::Q)--fioH \ / CHMe (258) R=CHMe2 or C6H, (2 59) Me R fie R (262) R=Ph or p-OMeC,H W. K. Gibson D. Leaver J. E. Roff,and C.W. Cumming Chem. Comm. 1967,214. "' R.Munday and I. 0.Sutherland Chem. Comm.,1967,569. P. Baumgartner E. Weltin G. Wagniere and E. Heilbronner Helv. Chim. Acta 1965,48 751. "'J. Carnduff and D. G. Leppard Chem. Comm. 1967,829. A. C. Waiss jun. J. A. Kuhnle J. J. Windle and A. K. Wiersema Tetrahedron Letters 1966 6251. I. 0.Sutherland R R (263) R=Ph orp-OMeC,H (264) The trimeric oxidation product (260)of the phenol (261)represents an interesting variant upon the usual course of phenol oxidation;'59 for example the produc- tion of Pummerer's ketone from p-cresol. The reason for the formation of (260) appears to be steric hindrance to coupling in the para-position by the t-butyl substituent of (261). Several polycyclic hydrocarbons are oxidised to quinones by periodic acid,'60 but pyrene is oxidised to 1,l'-bipyrenyl presumably by a radical coupling mechanism.The intermediacy of phenoxy-radicals or phenoxy- cations in phenol oxidation reactions has long been a source of controversy ; the former have been frequently observed by e.s.r. spectroscopy and in favourable cases are relatively stable species. The synthesis of several aryl-stabilised phenoxy-cations has now been reported.16' The action of fluoroboric acid on the methoxydienones (262)gives the crystalline fluoroborates (263);the dienones (262) were obtained by lead dioxide-methanol oxidation of the phenols (264). 3,5-Bisdialkylaminophenolsare highly reactive towards electrophilic reagents and with isocyanato- or thioisocyanato-formates the substitution products (265) are formed,162 which exist in solution as the o-quinomethide tautomers.Heating (265) above the m.p. gives the oxazetidinones or thiazetidinones (266). 0 XH OR D. F. Bowman and F. R. Hewgill Chem. Comm. 1967,471. A. J. Fatiadi Chem. Comm. 1967 1087; J. Org. Chem. 1967,32 2903. 16' K. Dimroth W. Umbach and H. Thomas Chem. Ber. 1967,100 132. F. Effenberger and R. Riess Angew. Chem. Internat. Edn. 1967,6,455. Aromatic Compounds The stable p-quinomethide (267) is formed by the reaction'63 of p-benzoquinone with 1-diethylamino-2-phenylacetylene;the spiro-compound (268) may be an intermediate in this reaction. The highly stabilised o-diquinomethane (269) is formed in dimethylformamide at -40" by the reaction'64 of(270) with strong base; the presence of comparatively stable (269) in this deep blue solution is inferred from its dimerisation at room temperature with the elimination of methanethiol to give-(271) and by the formation of adducts with dieno- philes.Diquinomethanes are more readily generated in polycyclic systems and the dehydrati~n'~~ of the diol (272) in boiling diethyl phthalate gives 5,6-chrysenequinodimethane (273) which may be trapped as adducts with dieno- philes. The sterically protected 9,lO-anthracenequinodimethanes(274) and (275) are isolable166 in good yield from the dehydration of the corresponding diols (276) and (277). NC NMe Me CN (272) (273) \ / R Ph R Me H Ph (274) R = H (276) R = H (275) R = Ph (277) R = Ph 163 J.Ficini and A. Krief Tetrahedron Letters 1967 2497. 164 R. Gompper E. Kutter and H. Kast Angew. Chem. Znternat. Edn. 1967,6 171. 16' D. Cohen I. T. Millar and K. E. Richards J. Chem. SOC.(C) 1967 1499. 166 S. C. Dickerman J. H. Berg J. R. Haase and R. Varma J. Amer. Chem. SOC. 1967,89 5457.

ISSN:0069-3030    

DOI:10.1039/OC9676400273

出版商:RSC    

年代:1967

数据来源: RSC

摘要:

9. ALICYCLIC COMPOUNDS By K. Mackenzie (Organic Chemistry Department University of Bristol) Small and Medium Rings.-Reviews cover the following subjects cyclo-propenes ;' cyclohexadienones ;'hexamethyl Dewar benzene ;3 norcaradiene compounds ;4 bicyclo[n,l,l]alkanes ;5 bullvalene ;6 cyclopropyl cyclobutyl and homoallyl systems ;' eliminations in cyclic cis-trans isomers ;8 topological approach to ring structure ;' free-radical reactions in bridged bicyclic systems ;lo cyclisation of free-radicals ;' photochemistry ;12 Diels-Alder reactions;' conformational abnormalities in cyclohexanes ;l4 and orbital symmetry principles.' Non-Bridged Systems.-Dialkoxycar bonylcarbene pho tochemica Ily gener-ated from diazomalonic ester has previously been observed only in C-H insertion reactions ;similarly prepared in stereoisomeric olefins it gives cyclo- propanes stereospecifically.Benzophenone sensitization destroys this specifi- city however (singlet and triplet states) ;some evidence for multiplicity change is evident from the decline in stereospecificity observed with cis-olefins in unsensitized ester photolysis in an inert solvent with increasing dilution after an increase in specificity in the initial stages of dilution (reduced collisional deactivation of primary singlet carbene). Intersystem crossing appears to be much less favourable than with fluorenylidene.I6 Singlet carbenes may also account for the stereochemistry of the cyclopropanes produced in photolytic decomposition of p-methoxyphenylsulphonyldiazomethane in cis- and trans- 2-butenes ; here the preponderance of anti-product from the cis-olefin is ascribed to steric mitigation of the favourable Van der Waals-London forces and charge sharing in the transition state previously invoked to explain the more usual preference for syn-adduct.' G.L. Closs. Adv. Alicyclic Chmi. 1966. I. 5.7 'I A. J. Waring Ado. Alicyclic Chem. 1966 I. I29 W. Schafer and H. Hellmann Angew. Clicrri. Irrternat. Edn. 1967 6 518. G. Maier Angew. Chem. Internat. Edn. 1967,6 402 J. Meinwald and Y. C. Meinwald Adv. Alicyclic Chem. 1966 1 2. G. Schroder and J. F. M. Oth Angew. Chem. Internat. Edn. 1967,6,414. M. Hanack and H. J. Schneider Angew. Chem. Internat. Edn. 1967,6,666. * W. Hiickel and M. Hanack Angew. Chem. Internat.Edn. 1967,6 534. R. Fugman V. Dolling and H. Nickelsen Angew. Chem. Internat. Edn. 1967,6 723. lo D. I. Davies and S. J. Cristol Adu. Free Radical Chem. 1965 1 155. l1 M. Julia Pure App. Chem. 1967 15 167. '' R. N. Warrener and J. B. Bremner Rev. Pure Appl. Chem. (Australia) 1966,16 117; P. J. Kropp Org. Photochem. 1967,1,1 see also R. Padwa p. 91; K. Schaffner Adu. Photochem. 1966,4,81. l3 J Sauer Angew. Chem. Internat. Edn. 1967,6 16. l4 D. L. Robinson and D. W. Theobald Quart. Rev. 1967,21,314. Is R. B. Woodward Chem. SOC. Special. Publ. No. 21 217. l6 M. Jones A. Kulczycki and K. F. Hummel Tetrahedron Letters 1967 183. '' A. M. van Leusen R.J. Mulder and J. Strating Rec. Trao. chim. 1967,86 225. K.M ackenzie 0 t Me2 S=CH Me Me (1) R'~ S=CR~ (2)R' = Me R' = H (3)R' = Ph R2 = Me R1y: R4 R5 (5) R' = R' = Me R3 = Ac R4 = R5 = H (7) R' = R' = C02Me R3= H R4 = R5= Me or R' = C02Me R2 = R3 = B R4 = Rs = Me (6) R = H or Me H (9) R = CHO (8) (10)R = CH20H (11) R = C02H In contrast to the reaction with carbonyl compounds to give epoxides the methylide (1) reacts with @-unsaturated ketones to give acylcyclopropanes (5);18" stereospecificity is observed in some cases depending on whether C-1-C-2 rotation is possible in the intermediate (4).'*' Sulphurane (2) reacts at carbonyl generally to give oxirans but the highly reactive analogue (3),like (l),gives cyclopropanes [(6)and (7)] in low temperature reactions with ap-unsaturated carbonyl comp~unds.'~ The enhanced s-character of C-H bonds in cyclopropanes in comparison with cyclobutanes prompted examina- tion of Cannizzaro reactions with the relevant aldehydes." Cyclopropane-carboxaldehyde appears normal in this respect save for the unexplained formation of its dimethyl acetal with methoxide anion in methanol.In the cyclobutane series dimeric products [(lo) and (1 l)] are largely formed perhaps via (9) with only very small yields of the normal products reported earlier. In this connection cyclopropanecarboxaldehyde is conveniently prepared by (a)C. Agami Bull. SOC.chim.France 1967 1391 ;(b)C. Agami and C. Prevost ibid. p. 2299. l9 E. J. Corey and M. Jautelat J. Amer. Chem. Soc.. 1967.89. 3912. (a)F. P. B. ban der Maeden H. Steinberg and Th. J. de Boer Tetrahedron Letters 1967,4521 ; (b)W.H. Perkin and H. G. Coleman J. Chem. SOC. 1887 228. Alicyclic Compounds ceric ion oxidation of the carbinol; the yield is less than that from established hydride reduction methods however.21 The technique for selective removal of chlorine in gem-chlorofluorocyclopropanesby use of tri-n-butyltin hydride is stereospecific ;2 2a chlorine is also selectively removed with sodium-liquid ammonia.22b The advantageous use of chromous ion for dehalogenating cyclopropanes appears to offer scope for further study ; gern-dibromocyclo-propanes are mono-debrominated the syn-isomers arising in the case of dibromobicyclo[n,1,0]alkanes (12) but further reduction can occur. Ring opening to cyclic allenes is observed for large values of n possibly via (15) produced from the initially formed cyclopropyl radical (13) through (14); the latter is the precursor of the monobromocyclopropane when n is too small for ring expansion through (15) but neither (14) or (15) can be trapped with 01efins.~~ Ring expansion of bridgehead alkoxybicyclo[n,l,0]alkanes containing a halogenocyclopropane is known ; rearrangement of 7,7-dibromonocarane to 2-bromo-3-ethoxycycloheptene or cyclohepten-2-one in the presence of silver is therefore not surprising.A similar reaction of the bis-adduct (16) gives the 1-tetralone (19) by the sequence (16) -f (17) -+(18) -,(19).24 Allenes and polycyclic compounds are mostly formed in the reactions of dibromocarbene-2' L. B. Young and W. S. Trahanovsky J.Org. Chem. 1967,32,2349. 22 (a)T. Ando F. Numigata H. Yamanaka and W. Funaska,J. Amer. Chem. Soc. 1967,89,5719; T. Ando H. Yamanaka S. Terabe A. Horike and W. Funasaka Tetrahedron Letters 1967 1123; (b)M. Schlosser and G. Heinz Angew.Chem. 1967 6 629. 23 H. Nozaki T. Aratani and R. Noyori Tetrahedron 1967,23,3645. 24 A. J. Birch G. M. Iskander B. I. Magboul and F. Stansfield J. Chem. SOC.(C) 1967 358. 314 K. M ackenzie olefin adducts with methyl-lithi~m,~~" but 2,2,2',2'-tetrabromobicyclopropyl derivatives give fulvenes e.g. (20) + (21) and (22) + (23) whilst cyclopenta- dienes are formed from gem-dibromovinylcyclopropanes. For the latter a route uia (24) seems possible with vinylcyclopropane rearrangement ; closure to a strained tricyclopentane structure and rearrangement or insertion at vinyl C-H could lead to bicyclopentenes but since reaction still ensues when there are terminal vinylic groups and further since (25) gives equal amounts of 1- and 2-methylcyclopentadienes,(28) and (29) whereas one might expect more of the 2-methyl isomer if bicyclopentenes were involved renders these routes unlikely.Whilst vinylcyclopropane rearrangements normally require elevated temperatures favourable interaction of the carbene site and the double-bond leads through (30) and (31) to (28) and (29). The formation of fulvenes from (20) and (22) is accomodated by initial opening of one ring to an allene and similar ring-expan~ion.~~~ 'b-7 ?R; R' R2 Br Br 9;. (20) R' = H R3 = Me R3 (24) R'-5 = H (22) R' = Me R3 = H (21) R' = R3 = Me R2 = H (25) R' 3-5 = H (23) R' = R' = Me R3 = H R2 = Me d V (26)R' = Me R2 = H (28)R' = H R' = Me (27)R' = H.R' = Me (29)R' = Me. R2 = H (30) The conjugative ability of cyclopropyl groups at unsaturated centres is well known ; factors governing photolysis of bicyclo[4,l,0]hexanones [derivatives of (32)] have been studied. Cyclopropyl ring-opening only competes with C-2- C-3 cleavage as the primary process when C-3 is unsubstituted or when C-7 is substituted for that bond which is best conjugated ; if both bonds conjugate equally well that bond with the highest degree of terminal substitution is cleaved.26 The direction of bond-migration in the decomposition of alkylcyclopropyl methyl ketone tosylhydrazone to cyclobutenes has received further attention.Vicinal alkyl groups in the cyclopropane appear at C-3 and C-4 in the cyclo- butene but cases of unsymmetrically substituted cyclopropanes have only now been examined. The predominant products are those formed by migration of 25 (a) L. Skattebel Chem. and Ind. 1962 2146; (b) L. Skattebel Tetrahedron 1967 23 1107; cf. C. G. Cardenas B. A. Shoulders and P. D. Gardner J. Org. Chem. 1967 32 1220. 26 W. G. Dauben and G. W. Shaffer Tetrahedron Letters 1967,4415; cf. R. E. K. Winter and R. F. Lindauer ibid. p. 2345. Alicyclic Compounds the less-substituted bond. The reaction may not be a true carbene rearrange- ment but a concerted loss of nitrogen from the intermediate diazo-compound and because the more substituted bond is subject to a strong steric interaction with the ‘carbene’ methyl during migration the alternative course is followed.If a carbene is involved rotation through the plane of the ring in the product- forming step will be easier if rotation is away from the ring-substituted carbon e.g. (42) -+ (43).27 (33)R’ = R’ = Me (36)-438) R3 = H R4 = Me and R2 as for (33t(35) (34)R’ = Me R’ = H (39)+41) R3 = Me R4 = H (35)R’ = H R’ = Me Cyclopropylcarbinylcarbene made from cyclopropanecarboxaldehyde tosyl-hydrazone gives mainly cyclobutene with only 11 % acetylene and ethylene whereas cyclopropyldiazomethane photolyses to give mainly the latter and butadiene. In contrast cyclopropane reacts with ‘cold’ carbon atoms to give methylenecyclopropane (C-H insertion) and no ethlyene or acetylene and with ‘hot’ carbon atoms to produce only these latter products.Different factors are clearly involved in the fate of the cyclopropylcarbinylcarbene produced under the various conditions but insofar as only the singlet species can give rise to acetylene and ethylene doubt is raised as to whether ‘hot’ carbon atoms are triplets; both states may be produced in the photochemical reaction.28 Isopropylidenecarbene is formed from 1,1 -dibromo-2-methylpropene and magnesium ; reactive olefins combine with it to give methylenecyclopropanes. If capable of extension the method has obvious advantages over methods employing lithium alkyl~.~~ Prototropic rearrangement of 2.3-di-n-alkyl-’’ C.L. Bird H. M. Frey and I. D. R. Stevens Chem. Comm. 1967 707. P. B. Shevlin and A. P. Wolf J. Amer. Chem. SOC. 1966,88,4735. 29 N. Wakabayashi J. Org. Chem. 1967,32.489. 316 K. M ackenzie cycloprop-2-ene- 1-carboxylic acids also affords methylenecyclopropanes.30 Surprisingly only one example of dehydrohalogenation of a halogenocyclo- propane to a cyclopropene appears to be known but significant yields of the cycloalkene can be obtained from dichlorocarbene adducts of olefins by their addition to base in aprotic media e.g. l,l-dichloro-2,2-dimethyl-3-t-butyl-cyclopropane gives 1-t-butyl-3-chloro-2,2-dimethylcyclopropene; the vinylic chlorine is replaced by thi~alkoxide.~ Similar methods give acetylcyclo- propenes and acetylmethylenecyclopropanes from dihalogenocarbene adducts of alk-3-en- 1-ynes ;the initial ethynyldihalogenocyclopropanesare hydrated converted into acetals dehydrohalogenated and finally hydroly~ed.~~ H (44)R = CO.CHN1 (45) R = CHZ.CO.CHN2 phxph Ph hPh (46) R = CON (47)R = CH,*CON (49)R = Ph PhJi? (49),A R' = HR2 = * Ph (49),B R' = *R2 = H (50) Photolysis of (44)was earlier shown to yield an a-keto-carbene which intra- molecularly adds to the double bond in competition with Wolff rearrangement.For ,the azides (46) undergoes Curtius rearrangement when heated to the isocyanate but low temperature photolysis in ether gives a nitrene-solvent insertion product. The difference between (44)and (46) may be due to the absence of an excess of vibrational energy in the keto-nitrene in comparison with the carbene.Thermolysis of (47) gives isocyanate but low temperature photolysis in ether and ethanolysis of the products gives among other com- pounds 5,6-diphenylpyridone which could arise from the intramolecular nitrene adduct (48); the latter could also be formed from an intermediate triazoline however. Irradiation of degassed solutions of triphenylcyclopropene (49) is ineffective 'O A. W. Herriott and W. M. Jones Tetrahedron Letters. 1967,2387. 31 T. C. Shields B. A. Loving and P. D. Gardner Chem. Comm. 1967,556. 32 N. Bertrand and H. Monti Compt. rend. 1967,264 C 998. 33 N. C. Castelluchi M. Kato H. Zenda and S. Masamune Chem. Comm. 1967,473. Alicyclic Compounds but with filtered light and benzophenone dimer (50) and compound (51) are formed ; the ratio is sensitizer independent implicating triplet (49).Hydrogen transfer is clearly involved in formation of (51) but no isotope effect is observed with deuterated (49). Intermediates (49),A and (49)2B can be visualized by addition of triplet (49) to (49) and whilst the former intermediate can easily close to give (50) the latter would have to assume an unfavourable (boat) conformation and hydrogen transfer therefore supervenes. Structure (50) is supported by the extremely low-field aliphatic proton n.m.r. signals.34 The stability of NN'-di-t-butyldiazacyclopropanone encouraged the hope that sym-di-t-butylcyclopropanone might be isolable ; indeed treatment of 2,2,6,6-tetramethyl-3-bromo-heptan-4-one with base affords the trans-isomer (ti 6 hr.at 150"); the readily formed benzyl hemiacetal exhibits non-equivalent t-butyl groups in the n.m.r. spectrum.35 Pure cyclopropanone has itself finally been isolated (vmax,1816 cm.-' ;z 8-28)and is stable at -196" for a few days.36 (52) R'R' = o (55) R = 1-hydroxycyclopropyl (53)R' = OH R2 = NMe (56) R = H (54)R' = R' = NMez X 07) (58) (59) X = CH, 0or S Whilst the reactions of the ketone with water and alcohols have been known for many years its behaviour with amines has only recently been explored. Dimethylamine gives the addition compounds (53) and (54); the former can also be made from cyclopropanol and dimethylamine (molecular sieves absorb the water produced) and hydrogen cyanide in ether gives the cyanhydrin.Heterocyclic products are formed if cyclopropanone is treated with methyl- amir~e.~' At low temperatures (55) and (56) are formed with an equivalent of aniline and the latter reacts with more ketone to form (59 which however reforms (56) with aniline;38" it had earlier been suggested that (56) might be 34 C. Deboer and R. Breslow Tetrahedron Letters 1967 1033; H. Diirr ibid. p. 1649. '' J. F. Pazos and F. D. Greene J. Amer. Chem SOC.,1967,89 1030. 36 S. E. Schaafsma H. Steinberg and Th. J. de Boer Rec. Trac. chim.,1966,85 1170. 37 W. J. M. van Tilborg S. E. Schaafsma H. Steinberg and T. J. de Boer Rec. Trav. chim. 1967 86,417,419. 38 (a)N. J. Turro and W. B. Hammond Tetrahedron Letters 1967,3085;(b)€1.H. Wasserman and D. C. Clagett J. Amer. Chem. Soc. 1966,88 5368. K.M ackenzie formed via cyclopropanone in the reaction of the ethyl hemiacetal with aniline.38b The ketone reacts with dry hydrogen chloride to form the l-chloro- 1-hydroxy-compound (at room temperature in the presence of acetyl chloride which acts as polymerization inhibiter) and with acetic acid the l-acetoxy-l- hydroxy-compound forms in a reversible reaction (even at -78”); both the acetoxy- and the chloro-hydroxy-compounds form the methyl hemiacetal of cyclopropanone quantitatively with methan01.~’ Solutions of cyclopropenone have now been made by hydrolysis of 1,l-dichlorocyclopropenepresent in the reduction products of tetrachlorocyclopropene ;the free ketone is extractable into organic phases (z 14&1.1; v,,, 1835 and 1870 cm.- I) and is also present in aqueous solution.The greater stability of the enone in comparison with cyclopropanone may reflect conjugative effects and if the carbonyl dipole is taken into consideration a 2~-aromatic system is present.40 The novel reaction of (57) with N-phenacylpyridinium salts to give high yields of coumalins by the sequence (57) +(58) -,(59) is reported.41 + ClNi I S’ L-Q I--. ‘‘ (61) (62) AH2 CH2-C’ @I mI I. ClFC-CF F2C-C CIF Cope rearrangement of divinylcyclobutane is believed to be the source of cyclo-octa-1,5-diene in the thermal and Nio-catalysed dimerization of butadiene. This conclusion is confirmed and extended since the rate of catalytic re- arrangement of divinylcyclobutane is strongly dependent on catalyst con-centration and the ligands present; the activity of the bis-rally1 form (60) as source of cyclo-octadiene increases with marked back-donation of metal to ligand whereas (61) increases in activity with reduction of this effect giving vinylcyclohex-3-ene.The reaction can be diverted to give other products e.g. by addition of ethylene to give cyclodeca-cis- l-tr~ns-5-diene.~~ Another interesting nickel-catalysed process is the conversion of (2 + 2) II 3y N. J. Turro and W. B. Hammond J. Amer. Chem. Soc. 1967,89 1028. 40 R. Breslow and G. Ryan J. Amer. Chem. Sac. 1967,8!3 3073. 41 T. Eicher and A. Hansen Tetrahedron Letters 1967 1169. 42 P. Heimbach and W. Brenner Angew. Chem.Internat. Edn. 1967 6 800. Alicy clic Compounds 319 butadiene4ichloromaleic ester adducts into cyclohexa- 1,4-diene- 1,2-dicar- boxylic esters ; ring scission-valence tautomerism reclosure and isomeri- zation could be envisaged but according to orbital symmetry requirements the primary step here would lead to a trans-1,3,5-hexatriene unfavourable for recyclisation besides which the formation of 4,5-dimethylcyclohexa-1,4-diene-1,2-dicarboxylic ester from 2,3-dimethylbutadiene in a similar reaction rules out this pathway. The rearrangement is pictured as abstraction of chloronium ion and ring expansion as in (62).43 The reaction of 2-alkoxy-2,3-dihydro- pyrans with Grignard reagents is useful in that it leads to cyclobutylalkyl- carbinols rather than to the alkyldihydropyrans or ring-opened products expected.44 The photochemical addition of olefins to allenes as a source of methylenecyclobutanes is not novel ; however 4-methylpenta-1,2,4-triene thermally equilibrates with methyl-3-methylenecyclobutene;the cyclic form is stable below 350°.45 In the expectation that the allylic assistance to rearrange- ment (13.7 kcal./mole) might appear in twofold measure for the degenerate rearrangement of the 1,Zbismethylene compound the thermolysis of bis-(dideuteriomethy1ene)cyclobutanehas been studied ; in fact the further assist- ance to resonance is only ca.3 kcal. The reaction does not appear to have any kinship with the dimerization of allene since it takes place in the temperature range where the latter does not dirneri~e.~~ Reaction of allene with trifluoro- chloroethylene gives an 85 :15 mixture of 2,2-difluoro-1-methylene-and 3,3-difluoro-l-methylene-cyclobutane rather than the single adduct expected by precedent ; this is consistent with initially formed biradical intermediates (63) and (64); the former intermediate can become allylically stabilized (0-rotation) whilst the latter cannot so that the product is formed from (63) rather than (64) which preferentially dissociates in a competing process.Similar results are observed for 1,l -dichlorodifluoroethylene.47 (65)X = Y = Z = C1 (70) X = H; Y = C1; Z = OEt (66)X = Z = CI ;Y = OEt (71) X = H ; Y = OEt ; Z = CI :nZ2 (67)X= Y = C1;Z = OEt (72)X = F;Y = C1;Z = H (68)X = H; Y = Z = C1 (73)X=F:Y=Z=H (69)X = H Y = F:Z = CI (74)X= H:Y = F:Z = C1 It is known that (65) reacts with alkoxide ion to give mainly (66) with a little (67); if this had been due only to the steric effect of the dichloromethylene group one might expect a similar distribution of products from (68) and (69) in similar reactions instead of their specific and quantitative conversion into (70) and (71).For (68) the intermediate carbanion is stabilized not only by a-chlorine but also by the P-difluoro-group but for (69) a-chlorine is a better 43 H.-D. Scharfand F. Korte Chem. Ber. 1966,99 3925. 44 R. Quelet and J. D’Angelo Compt. rend. 1967 264 C 216. 45 E. Gil-Av and J. Herling Tetrahedron Letters 1967 1. 46 W. von E. Doering and W. R. Dolbier. J. Amer. Chem.SOC. 1967,89,4534;cf.J. J. Gajewski and Chung Nan Shih J. .4mer. Chem. Soc. 1967,89,4532. 47 D. R. Taylor and M. R. Warburton Tetrahedron Letters 1967. 3277 320 K.M ackenzie stabilizing influence than a combination of a-fluorine with the P-difluoro- group in the carbanion ;for the former intermediate eclipsing interactions are significantly less than for the alternative possible anion but for carbanions from (69) there are probably only small differences in eclipsing interactions between the alternatives. The important effects of halogens in these compounds is apparent from the much greater reactivity of e.g. (65) in comparison with (68) and (69). The observation of mixed products e.g. (73) and (74) in hydride reduction of (72) but only a single product in alkoxide reactions has led to the suggestion that a different mechanism obtains for hydride reduction where steric effects associated with the approach of the reagent may be more im- portant so that the most stable carbanion may not necessarily be the one most easily formed.This is also apparent in the formation of (71) from (69) in comparison with the reaction of 1-chloro-2,3,3,4,4-pentafluorocyclopentene with hydride ion where vinylic chlorine is removed. Grignard reagents also remove vinylic chlorine from chloroperfluorocycloalkenes ; the yields of products resemble in ring-size dependence those from hydride reduction and only vinylic substitution occurs if vinylic fluorine is removed. Interestingly in this context 1,1'-bi-(2-fluorocyclobuten-3-one) gives the bis-enamine with piperidine by displacement of both vinylic flu~rines.~~ (76) R' = + RC-C .[CH,] * 0-SO,Ar (77) R' = 0.C0.CF3 R CO,Et R2 = Me C1 R' = Me C02Me R2 = Me (78) R' = Co2Me R2 = Me The solvolysis of alk-3-ynyl tosylates to cyclobutanones and cyclopropyl ketones was earlier described ;the yields of cyclobutanones are quantitative in reactions of trifluoroacetic acid with nitrobenzenesulphonates.Mercury salts divert the reaction to give cyclopropyl ketones viu solvolytic ring closure of the vinyl acetate produced precluding formation of the cyclobutanone by 48 J. D. Park Ci. Groppelli and J. H. Adarns Tetrahedron Letters 1967,103; J. D. Park R. Sullivan and R. J. McMurty ibid. p. 173; J. D. Park and W. C.Frank J. Org. Chem. 1967,32 1333. Alicyclic Compounds 321 homoallylic cyclisation of a solvent adduct and implicating direct participation of the triple bond. Consistently the solvolytic rate is only slightly less than that for saturated analogues in spite of the strong inductive effect of the acetylenic group ;cyclobutenyl vinyl cations e.g. (76),are therefore likely.49 Ring-scission to keten and ethylene or decarbonylation to propene or cyclopropane occurs in photolysis of cyclobutanones ; ring expansion to tetrahydrofurans via cyclic carbenes is an especially effective alternative pathway for 2,2,4,4-tetramethylcyclobutanones,analogous to cases in the steroid field." The quest for superior syntheses of bicyclobutanes continues ;a new inter- esting route is formation and decomposition of the bis-adduct (78) which on photolysis yields (among other products) the bicyclobutane (79) (ti.3hr. at 150").51 Dimethyl ester (81) has been obtained by reaction of dimethyl 3,3- dimethylcycloprop-1-ene- 1,2-dicarboxylate with diphenylisopropylidenesul-phurane. l9 The first synthesis of 1,3-dimethylbicyclobutanewas achieved in 3 % yield from diazomethane and 1,2-dimethylcyclopropene;superior methods are the reaction of methylacetylene or allene with hydrobromic acid followed by lithium amalgam dehalogenation (25") of the isomeric 1,3-dimethyl-1,3- dibromocyclobutenes produced to give 1,3-dimethylbicyclobutane(85%),52 and electrolysis of the dibromodimethylcyclobutanes. Control of the electrode potential in the electrolytic method allows preparation of halogenobicyclo-butanes; {e.g.1,1,3,3-tetrachloro-2,2,4,4-tetramethylcyclobutane gives 1,3-di- chloro-2,2,4,4-tetramethylbicyclo[ 1,l ,O]butane (80)). Polarographic evidence suggests that electrolytic ring-closure here involves addition of two electrons to the dihalogenocyclobutane generating a halide anion and a carbanion which undergoes 173-transannular halide displacement ; cyclobutane formed in the reaction may arise from intermolecular protonation of the carbanion by a second molecule of the halogenocyclobutane the derived carbanion ex- pelling halide anion i.e. it is effectively dehydrohalogenated. Support for the intermediacy of cyclic carbanions in these reactions comes from the observation that 3-bromopropyltriethylamine bromide gives cyclopropane on electr~lysis.~~ Several investigators have shown how sensitive bicyclobutanes are to acids in addition reactions in protic media; e.g.3-methylbicyclobutanecarbonitrile requires heating in water at 100" for 3 hr. to produce the same product as reaction at 25" in dilute hydrochloric acid (not an isomer as inadvertently stated last year).54 In cases where there is additional ring-strain rapid reaction with neutral solvents is observed; a carbonium ion is presumably formed by protonation of the ring and solvent attack follows. Methanolysis of tricyclic 49 M. Hanack I. Herterich and V. Viitt. Tetrahedron Letters 1967 3871. N. J. Turro and R. M. Southam Tetrahedron Letters 1967 545; H. U. Hostettler Heh.Chirn. Acta. 1966,49 241 7. M. Franch-Neumann Angew. Chem. 1967,79,98. K. Griesbaum and P. E. Butter Angew. Chem. Ititernat. Edn.. 1967. 6. 444. 53 M. R. Rifi J. Amer. Chem. SOC. 1967,89,4442. 54 E. P. Blanchard and A Cairncross J. Amer. Chem. SOC.,1966.88.487; A. Cairncross and E. P. Blanchard ibid. p. 496. 322 K.M ackenzie compounds (82)-(85) gives mixtures of cyclopropylcarbinyl and cyclobutyl methyl ethers; the product ratio in each case resembles that from known cyclobutyl and cyclopropylcarbinyl carbonium ions similar to those expected here from protonation as first step. The relative rates are (83) > (84) > (85). Strong acid considerably increases the rates but product ratios are insignifi- cantly changed. Increasing reactivity with ring strain is consequently not due due to a change in mechanism.55 Bicyclobutane reacts with benzyne mainly to give 3-phenylcyclobutene but some 1,3-cycloaddition product is also f~rmed.~ A central bond length of 1.49 A correlates well with observed microwave spectra of bicy~lobutane.~~ Stepwise synthesis of 2-methylcyclopentane- 1,3-diones often gives poor yields but they can be made by cyclisation of y-keto-carboxylic acids with aluminium chloride or by the reaction of succinic anhydride with 2-acetoxybut- 2-ene acetate.58 An unusual reaction in the halogenoperfluorocyclopentene field is the formation of (86) by the action of cyanide ion on 1,2-dichloro- perfluorocyclopentene perhaps by vinylic chlorine displacement to give a highly reactive vinylic nitrile.” 1-(l-Bromoethyl)-2-chloroperfluorocyclo-pentene (87) reacts with Grignard reagents to give stereoisomeric l-ethylidene- 2-chloroperfluorocyclopent-2-enes (88); their ratio is insensitive to the re-agents and prior exchange at the bromoethyl group and 1,4-elimination from the carbanion obtains.Each isomer formed can displace vinylic fluorine without stereomutation so that the carbanions involved resemble other simpler allylic charged species in their stereochemical integrity.60 In the field of cyclopentadiene chemistry the question of the nature of the cyclopentadiene-o-benzoquinone adduct has been settled ;6 lo the primarily formed adduct (90)very easily rearranges to the alternative structure suggested (91).616The structure of this and analogous adducts is supported by i.r.and n.m.r. spectral data.6 Cyclohexa-1,3-diene reacts similarly.61” F c1 c1 (88)R = F (89)R = OAlk 55 W. G. Dauben and C. D. Poulter Tetrahedron Letters 1967 3021. 56 M. Pomerantz J. Amer. Chem. SOC.,1966,88 5349. 57 M. D. Harmony and K. Cox J. Amer. Chem. Soc. 1966,88 5049. 58 H. Schick G. Lehmann and G. Hilgetag Angew. Chem. Internat. Edn. 1967,6 371 ;H. Schick G. Lehmann and G. Hilgetag Chem. Ber. 1967 100 2973; V. J. Grenda G. W. Lindberg N. L. Wendler and S. H. Pines J. Org. Chem. 1967,32 1236. ’’ W. R. Carpenter and G. J. Paienik J. Org. Chem. 1967,32 1219. 6o J. D. Park and R. J. McMurty Tetrahedron Letters 1967 1301. 61 (a)W. M. Horspool J. M. Tedder and Zia ud Din Chem. Comm.1966 775; cf. F. J. Evans H. S. Wilgus and J. W. Gates J. Org. Chem. 1965 30 1655; (b)M. F. Ansell A. F. Gosden and V. J. Leslie Tetrahedron Letters 1967,4537;(c) D. D. Chapman H. S. Wilgus and J. W. Gates jun. ibid. 1966 6175. Alicyclic Compounds 323 Cycloaddition reactions of perfluorocyclopentadiene resemble those of the hydrocarbon; the two types of Diels-Alder adducts that can be formed can be distinguished by the "F magnetic resonance spectra for bridge difluoro- methano-groups formed in cycloadditions give AB patterns at higher field than those due to allylic difluoromethylene groups which arise in compounds where the diene has reacted as dienophile.62 Magnetic resonance data on nitrocyclopentadiene liberated by acidification of Thiele's sodium salt indicate that it is the l-nitro-i~omer.~~ Ethylene undergoes cycloaddition with 5,5-dichloro-1,2,3,4-tetracyanocyclo-pentadiene at room temperature ! The astonishingly reactive diene is formed by the action of chlorine on chlorotetracyanocyclopentadienide-itself pre-pared by electrophilic substitution into the tetracyanocyclopentadienide ; so low is its basicity that reactions with the latter can be carried out in acids.Nitration reduction and diazotisation of the derived amine give the previously described diazotetracyanocyclopentadienide whilst Friedel-Crafts acylations are possible in trifluoroacetic acid or with the more conventional aluminium chloride.64 X xx + (92) R' = H R' = X = C02Me (94)C = K C5 H,N (93) R2 = H R' = X = C0,Me (95) = (96) R = C0,Et ; X = C0,Me x' R (97) R = CO,Et X = C0,Me (98)R = CO2.CH,-C6H,-Br.X = COzMe 62 R.E. Banks A. C. Harrison R. N. Haszeldine and K. G. Orrell J. Chem. SOC.(C) 1967 1608. 63 R. C. Kerber and M. J. Chick J. Org. Chem. 1967 32 1329. 64 0.W. Webster J. Org. Chem. 1967,32 39. L* 324 K.M ackenzie X X H (100) X = C0,Me Diels' condensation products of dimethyl acetylenedicarboxylate with methyl malonate (acetic acid-pyridine) are (92) and (93) for the high and low m.p. tautomeric constituents as earlier suggested. Both compounds give (94) with potassium acetate which liberates the strong acid (95) on acidification (7 5.8; O.O1N-solution pH2). The acid reacts with chlorine and bromine to give powerful halogenating agents whilst the reactions with tetracyanoethylene and maleic anhydride appear to give charge-transfer complexes.In a similar reaction with cyanoacetic ester and the acetylenic compound acyclic diene salt (96) is formed; this easily loses methanol to give blue cyclic oxyanion (97). The analogous (98) adds ethanol reversibly to give the colourless (99). Acidifica- tion of (97) gives a colourless dimer which is not however the expected cyclo- pentadienone dimer since the i.r. carbonyl frequency is too low. Compound (92) is probably converted into the cyclopentadiene compounds by 1,4- transannular Michael addition [(92) + (loo)] and extrustion of trimethyl- ethylenetricarboxylate ;in support of this heptaphenylcycloheptatrienetreated with potassium gives pentapheny lcyclopen tadienide.' A novel route to a cyclopentadienone is the ring contraction of 6-acetoxy- 2,4,6-triphenylcyclohexadienoneunder mildly basic conditions to give 2-benzoyl-3,5-diphenylcyclopentadienone dimer which is thermally dissociable and is converted into monomer adducts.Benzoyldiphenylcyclopentadienolcan be isolated under carefully controlled conditions.66" Other cyclopentadienone dimers have also been discussed and their structures clarified.66b In bicyclo[2,1,0]pentane chemistry routes to novel bridgehead ethoxy- carbonyl compounds have been explored; the best routes appear to be n-amylsodium metallation and carbonation to the 1-carboxylic acid and pyrolysis or preferably photolysis of pyrazoline adducts of diazomethane with l-ethoxycarbonylcyclobutene.67The photolytic method starting from 1-ethoxycarbonyl-3,3-dimethylcyclobutenegives a high yield of l-ethoxy-carbonyl-3,3-dimethylbicyclopentane;thermolysis of the intermediate pyrazo- line follows a different course to give l-ethoxycarbonyl-2,3,3-trimethylcyclo-butene and the tautomeric exocyclicmethylene compound.Thermolysis of the bicyclopentane compound obtained here gives an almost quantitative yield of dimethyl ethoxycarbonylcyclopentenes whilst hydride reduction of the ester 65 R. C. Cookson J. B. Henstock J. Hudec and B. R. D. Whitear,J. Chem. SOC.(C),1967,1986. 66 (a) K. Dimroth H. Perst and Kart Hans Muller Ber. 1967 100 1850; (b)M. Elliott S. H. Harper and M. A. Kazi J.Sci. Food Agric. 1967 18 167. " P. G. Gassman and K. T. Mansfield J. Org. Chem. 1967,32,915. Alicyclic Compounds 325 gives the expected bicyclo[2,l,0]pentylcarbinol which rearranges rapidly in the presence of acids to 1 ,l-dimethyl-4-methylenecyclopentanol, unlike the bridgehead carboxylic ester which is quite stable under acidic conditions even on warming6* The stereochemistry of deazetation of 2,3-diazanorbornenes as a source of bicyclo[2,1,0]pentanes has been studied ; the elimination of nitrogen occurs largely with inversion of the bridge-methylene group; uiz. (101) gives the anti-2,3-dideuteriobicyclo[2,1,O]pentane. This result suggested that the addi- tion of suitably reactive azo-compounds to bicyclopentanes might also occur with inversion of the methylene group which eventually forms the bridge; indeed reaction of the bicyclopentanes (102) and (103) in a mixture of known composition with N-phenyltriazoline-2,4-dionegives the products (104) and (105) with complete stereospecificity and inversion of the spiromethylene group.It is suggested that the decomposition and addition reactions are two step processes e.g. (101) gives (106) which ring-closes as indicated in (107) with inversion of the methylene group.690 I R'&J D N R' (101) (102) R' = D RZ = H (103) R' = H. R' = D R' R1y &+ ff. &$ I IN (104) R' = D R' = H (106) (107) i 11 (106) R' = H. R' = D N A novel route to bicyclo[ l,l,l]pentanes is the formation of 2-hydroxy-2- phenylbicyclo[ l,l,l]pentane-in the irradiation of cyclobutyl phenyl ketone by 1,5-hydrogen transfer to carbonyl oxygen formation of a 1,4-diradical and ring closure.69b Possible stereospecificity in the reaction of cyclohexanes stimulates much experimental work ;sulphur halides in pyridine convert cyclohexene oxide into cis-1,2-dichlorocyclohexane(99.5"/ stereoselectivity); earlier methods give trans-contaminated product.70 The epoxide is converted into the cis-diazide 68 J.H. Kinstle R. L. Welch and R. W. Exley J. Amer. Chem. SOC. 1967,89 3661. 69 (a) W. R. Roth and M. Martin Tetrahedron Letters 1967 4695; see however E. L. Allred and R. L. Smith J. Amer. Chem. SOC.,1967,89,7133;(b)A. Padwa and E. Alexander J. -4rner. Chem. SOC.,1967,8!3,6376. 70 J. R.Campbell J. K. N. Jones and S. Wolfe Conad. J. Chem. 1966,44 2339. 326 K.Mackenzie by aide ion by further reaction of the mesylate of the initially formed trans-hydroxy-azide ; catalytic reduction of the bis-azide gives the previously described cis-1,2-diamino-~ompound.~~ Catalytic reduction of aromatic compounds as a source of di-t-butylcyclohexanes generally gives the cis-isomers ;truns,truns-l,4-di-t-butylcyclohexan-2-01 is accessible via low tempera- ture hydroboration hydrolysis and oxidation of 1,4-di-t-butylcyclohexene. The possibility of replacing the boron group by halogeno- hydroxy- or amino-groups at an intermediate stage provides a general route to this group of corn pound^.^^ In the perfluorocyclohexane series examples of syn-clinal as opposed to anti-periplanar base elimination reactions are apparent from e.g.(108),which gives 1-chloroperfluorocyclohexene,but also 14% decafluorocyclohexene ; (109A)gives 18% of 1-chloroperfluorocyclohexene as well as the more normal product. It seems possible that these eliminations involve either the boat conformers or follow an Elcb pathway but whilst (108)is readily deuteriated in base (109B)is not.730 X An interesting photochemical transformation in this field is the formation of 1-trifluoromethyloctafluorocyclopenteneand the tautomeric difluoro-methylenecyclopentane from decafluorocyclohexene.7 3b The Claisen rearrangement of 2-vinyl-2,3-dihydropyranderivatives offers promise as a route to the less accessible isomers from Diels-Alder syntheses e.g.the transformations of (1 lo) (1 12) (1 14) and (116).Where stereoisomeric vinyl groups are present the stereo-relationships are retained in the product ; as expected from models the cis-isomer of (116)is much more stable owing to crowding in the transition state and the reaction is less ~tereospecific.~~ Diverse rearrangements of cyclohexadienones continue to excite much interest. Since the presence of alkyl groups at C-2 and/or C-5 in these dienones appears to effect critically the photochemical reaction pathway examples of pentamethylcyclohexadienones with vacant ring sites have been made e.g. (1 18)-(120),by use of the recently developed boron trifluoride-trifluoroacetic acid method with pentamethylbenzene. The preponderance of (1 18) and (119) 71 G.Swift and D. Swern J. Org. Chem. 1967,32,511. ’* D. J. Pasto and F. M. Klein Tetrahedron Letters 1967,963. 73 (a) S. F. Campbell F. Lancashire R Stephens and J. C. Tatlow Tetrahedron 1967 23 4435; (b)G. Gamaggi and F. Gozzo Chem. Comm. 1967,236. l4 G. Buchi and J. E. Powell jun. J. Amer. Chem. SOC.,1967,89,4559. Alicyclic Compounds in the oxidation products is due to involvement of (121) in which 1,2-methyl migration can occur equally well in either direction before proton loss to give the product. Pentamethylhexa-3,5-dienoicester is formed in the photolysis of (1 18) only in methanol together with bicyclic (122) whereas (120) gives only the dienoic ester under these conditions; (1 19) is photolysed both in ether and in methanol to give thermally labile (123).Both reactions are faster in methanol; bicycli- sation is the more rapid. Whilst the multiplicity of states involved here is uncertain the lack of any effect by methyl at C-5 on the reaction rate suggests that if charged dipolar intermediates are involved bicyclic zwitterion (124) is more likely than diene (125); the bicyclic products are stable under the reaction conditions and postulatidn of a keten dienoic ester precursor is untenable in the solvents used.75 Me (118) R' = R3 = Me R2 =H (121) (119) R2 = R3 = Me R' =H (120) R' = R2 = Me. R3 =H MeeMe Me Me \ (124) (1 25) Formation of 1,3,4,5,6,6-hexamethylbicyclo[3,1,0] hexen-2-one from hexa- methylcyclohexadienone in ether during photolysis was earlier shown to involve bond-crossing.More rapid photolysis occurs in ethanol ;the primarily '' P. M. Collins and H. Hart J. Chem. SOC. (C) 1967,895; H. Hart and D. W. Swatton J. Amer. Chem SOC. 1967,89 1874. 328 K.M ackenzie produced bicyclohexenone reacts with the solvent to give 3-ethoxy-l,3,4,5,6,6- hexamethylcyclohexa-1,4-dien-2-ol. When warmed this eliminates ethanol to give 1,4,5,6,6-pentamethyl-3-methylenecyclohexa-1,4-dien-2-ol (also by protic catalysis). The methylene-dienol is thermally isomerised to the 2-keto-tautomer but acid catalysis yields 1,2,4,5,6,6-hexamet hylcyclohexa-2,4-dien-3-one, appar-ently by 1,2-methyl shift and ketonisation. These transformations are confirmed with 2,4,6,6-tetramethyl-3,5-bistrideuteriomethylcyclohexadienone as starting material.75 Steric inhibition of migration to a carbon atom already bearing a t-butyl group prompted further experiments with e.g.(126); its rearrangement to (128) appears to involve as precursors the bicyclic compounds (127) ('isomers at C-6) which are in fact isolable and are converted on further photolysis by an unusual exocyclic cyclopropane ring scission into (128); formation of intermediate (129) is sterically facilitated by the gem-substituted methylene and the bridgehead t-butyl group; acyl bond switch and olefin formation complete the process according to one interpretation.76 More recently photoisomerisation of 2,4,6-trit-butyl-4-methoxycyclohexadienone to analo- gous bicyclohexenones in tungsten light has been described ;further transfor- mations at shorter wavelengths here give aromatic compounds or their keto- tautomers it is supposed from zwitterionic excited species derived by endo-cyclic 1,5-ring scission which suffer 1,2-t-butyl shifts [e.g.(130)].77 Photolysis of the tri-t-butylmethoxycyclohexadienonein aqueous acetic acid-methanol however gives stereoisomeric 2,5-di-t-butyl-3-trimethylacetylcyclopent-2-enones by hydrolytic ring scission of the protonated zwitterionic bicyclic R" R3&; (126) R = Pr" (132) R = n-C,H 0 OH (128) R = Pr" (129) (133) R = n-C,H 76 B. Miller and H. Margulies J. Amer. Chem. SOC.,1967,89 1678. T. Matsuura and K. Ogura J. Amer. Chem. SOC..1967.89,3846. 7' Alicyclic Compounds (130) R'T~ = Bu' R' = OMe R4 = H (134) R' = Me R2 = But R3 = n-C3H, R4 = H (137) R' = Me R' = Bu' R3= n-C,H, R4 = H (138) R' = But.R' = H.R3 = n-C,H,. R4 = Me intermediates first formed [cf. (131)l. Cleavage of the ring a-to both carbonyl groups and 1,3-bond switch on to the double bond gives bicyclo[2,1,0]pentan- 2-0nes.~~ A further stable keto tautomer is the compound (134) derived by heating the photoisomer (133) of the dienone (132); this compound is stable below loo" in the absence of acids or bases and is catalytically hydrogenated at the allyl group! Models of the dienone show that the allyl group can assume an orientation well away from the t-butyl and t-butyl-methyl steric conflict is reduced in comparison with the phenolic structure in which the allyl and methyl groups are compressed against the t-butyl group between them.79 Cyclohexadienone (137) appears to be involved in the photoisomerisation of syn anti isomeric allyldi-t-butylmethylbicyclo[3,1,0]hexenones (135) and (1 36) to syn-6-allyl-1,3-di-t-butyl-5-methylbicyclo[3,1,0]hexen-2-one; no aromatic compounds are formed! Irradiation of (138) gives an analogous product with a trans-but-2-enyl group at C-6 which clearly indicates 1,2-shift without inversion after the initial endocyclic bond-scission in the 6-alkyl-6-alkenyl- bicyclohexenones which leads to the cyclohexadienones e.g.(137) as inter- mediates. In contrast to reactions of bicyclo[2,1,0]pentanes and bicyclo[ l,l,O]butanes bridgehead chlorocarbon is formed from photochemical chlorination of bicyclo[2,2,0]hexane.* Unexpectedly the Oppenauer oxidation of exo-2- bicyclo[2,2,0]hexano1 in the presence of quinone as hydride acceptor gives bicyclo[2,l,l]hexan-5-one.The reaction resembles a similar reaction of quadricyclanol ; without the quinone insufficient bicyclo[2,l,l]hexan-5-01 is formed to allow of a common intermediate precursor for this compound and the 'ketone which does not therefore arise from a C(l)-C(2)-C(6) delocalised ion but possibly from a C(l)-C(2jC(4) ion derived by hydride abstraction from the bicyclohexyloxyaluminium compound.82 Diels-Alder reaction of the (2 + 2)n adduct of 1,l dichlorodifluoroethylene and cyclo-octatetraene with dimethyl acetylenedicarboxylate and thermolysis of the product gives 2,2-dichloro-3,3-difluorobicyclo[2,2,O]hex-5-ene ; this " T.Matsuura and K. Ogura J. Amer. Chern. SOC. 1967,89,3850. l9 B. Miller J. Amer. Chern. SOC.,1967,89 1685. B. Miller J. Amer. Chern. SOC. 1967,89 1690. 81 R. Srinivasan and F. I. Sonntag J. Amer. Chem. SOC. 1967 89 407; R. Snnivasan and F. 1. Sonntag Tetrahedron Letters 1967 603. R. N. McDonald and C. E. Reineke J. Org. Chern. 1967,32,1888. 330 K.M ackenzie gives explosive 2-chloro-3-fluorobicyclo[2,2,0]hexa-2,5-diene on treatment with lithium methyl. The Dewar benzene has a half-life of ca. 3 weeks in solution at 25°.83 Photodecarbonylations in bridged-ring compounds are not so well known as in larger cycloalkanones ; mercury-photosensitised decarbonylation of bicyclo[2,l,l]hexan-3-one to bicyclo[ l,l,l]pentane is therefore of interest.Other reaction products probably arise from the 1,4-pentadiene concomitantly formed.84 Novel syntheses of the bicyclo[3,1,0]hexane ring system utilise (a) the reaction of 1 -chlorocyclohexanone with piperidine to give 6,6-dipiperidino- bicyclo[3,1,0] hexane by intramolecular bond-closure dechlorination in the initially formed enamine giving the quaternary iminium compound which then reacts with more piperidine,” and (b)Grignard addition to sym-trinitro- benzene bromination to isomers of 1,3,5-tribromo-2,4,6-trimethyl-1,3,5-trinitrocyclohexane and ring closure to (139) with iodide ion or (140) with borohydride.86 R1 (141) R’ = alk/aryl. (142) R’ = alk/aryl R2 = OMe R3.4 = H (143) R3 = OMe R’s4 = H R’ = alk/aryl (1441 R’.’ = H.R4 = OMe. R3 = alk/aryl Photoisomerisation of tropolone methyl ether to the bicyclo[3,2,0] hepta- diene series (142) and thence to the isomeric series (143) is well known. Thermolysis of (142) regenerates the tropolone but at lower temperatures compounds of the (144) series are also formed by a previously unobserved Cope-type rearrangement.87 Thermal tropilidene rearrangements have al- ready received detailed attention whereas photochemical reactions have not although cases of 1,7-sigmatropic shifts are known. The primary photochemical products from 3,7,7-trimethyltropolidene appear to be the 2,6,7-trimethyl 83 G. Schroder and T. Martini Angew. Chem. Internat. Edn. 1967,6,806. 84 J. Meinwald W.Szkrybalo and D. R. Dimmel Tetrahedron Letters 1967 731. 85 J. Szmuskovicz E. Cerda M. F. Grostic and J. F. Zieserl jun. Tetrahedron Letters 1967 396 9. 86 T. Severin and M. Bohn Chem. Ber. 1967,100,2532. *’ T. Miyashi M. Nitta and T. Mukai Tetrahedron Letters 1967 3433. Alicyclic Compounds 331 isomer and 2,2,6-trimethylbicyclo[3,2,0]heptadiene,formed by 1,7-sigmatropic methyl shift and cyclisation respectively. It is incidentally considered that for the first excited state of a linear heptatriene radical the symmetry-allowed migrations are not those predicted by precise reversal of the Woodward- Hoffmann selection rules but rather 1,3-antarafacial 1,5-antarafacial and 1,7-suprafacial.* Thermal rearrangement of 2,5,7-triphenylnorcaradieneyields 1,3,5-triphenyl- tropilidene presumably by 1,5-sigmatropic shift in the cycloheptatriene in equilibrium with it ; further suprafacial 1,Shydrogen shift gives the 1,3,6- triphenyl isomer ;photochemical rearrangement of the norcaradiene however proceeds reversibly to the latter compound maybe by disrotatory ring-opening to the 2,5,7-triphenyltropilideneand 1 ,7-suprafacial hydrogen transfer.The reversal of the sequence consists of photochemical 1,7-hydrogen shift to the 2,5,7-triphenyltropilideneand thermal cyclisation to the n~rcaradiene.~~ Examples of sigmatropic hydrogen shift are also seen in the formation of cyclo-octen-4-one from cyclo-octa- 1,3-dien-5-01 present as rearrangement product in hium diethylamide treatment of 5,6-epoxycyclo-octene90 and the generation of cis,cis-3-oxacyclonona-1,4-diene from pyrolysis of the 3,4-epoxy- compounds an 'oxahomodienyl' hydrogen migration [(145) + (146)l." Low temperature n.m.r.studies indicate rapid pseudo-rotation of groups between 'above' and 'below' positions in cycloheptane even at -150" in the absence of steric effects ;however 4,5-trans-dibromo-l,l-difluorocycloheptane exhibits a single 9F resonance line above -114" but below -118" two lines appear corresponding to two conformers each with equivalent fluorines but in which the two bromines are either staggered or gauche.92 The cis,trans assignment to cyclo-octa-1,5-diene prepared by Willstatter's method from NN-dimethyl-4-cyclo-octenylaminehas been confirmed; earlier Raman spectra did not resolve the two lines now observed (1622 and 1635 cm.-') indicative of two different double bonds.The finding is conformed by double- resonance n.m.r. studies.93 In the expectation of achieving transannular cyclisation with cations derived from 1,5-cyclo-octadiene the olefin was treated with methyl methoxyacetate- L. B. Jones and V. K. Jones J. Amer. Chem. SOC.,1967,89 1880. 89 T. Mukai H. Kubota and T. Toda Tetrahedron Letters 1967,3581. J. K. Crandall and Luan-Ho Chang J. Org. Chem. 1967,32,532. 91 J. K. Crandall and R. J. Watkins Tetrahedron Letters 1967 1717. 92 R. Knorr C. Ganter and J. D. Roberts Angew. Chem. Internat. Edn. 1967,6 556. 93 A. C. Cope C. F. Howell J. Bowers R. C. Lord and G. M. Whitesides J. Amer. Chem. SOC. 1967,89,4024; see however Ann.Reports 1966 p. 433. 332 K.M ackenzie boron trifluoride ; the products indicate a preference for outside exo-attack leading to cis-6-endo-or exo-acetoxy-endo-2-methoxymethylbicyclo[3,3,0]-octanes in a non-concerted pathway since introduction of the acetoxy-group lacks stereoselectivity. Products of proton elimination and 8-acetoxy-endo- methoxymethylbicyclo[3,2,l]octanes are also formed. Interestingly analogous monoacetate by-products arise in catalysed reactions of the diene with diacetoxymethane presumably by protonation of the cyclo-octadiene by cationic intermediates involved in the main ~equence.’~ Aluminium chloride- catalysed addition of acetyl chloride to the diene also gives cyclised products the e.g. cis-6-chloro-2-exo-acetylbicyclo[3,3,0]o~tane;~~ formation of cis-bicyclo[3,3,0]oct-2-ene from the octadiene with potassium hydride is also rep~rted.’~ The probable involvement of homotropylium ions in the low temperature halogenation of cyclo-octatetraene suggested examination of the reaction of cis-7,8-dich~rocyclo-octatrienewith antimony pentachloride; the exo-8-chlorohomotropilium salt (147; X == SbC1,) is indeed formed from the exo,cis-dichloro-conformerat -15”.In contrast it is the endo,cis-dichloro- conformer which forms endo-8-chlorohomotropiliumfluorosulphonate (148 ; X == FSO,) (< 0); this has only a half-life of minutes at ca. 30”and rearrange- ment gives the 8-exo-chloro-salt (147; X = FS03). The effect of the ring current in the cation can be seen from the different chemical shifts for the 8-protons ‘T 8-2 in the em-chloro-ion and 2-51 for the endo-chloro-species.For the chlorination of cyclo-octatraene the intermediate (148; X = C1) is proposed since addition of tetraethylammonium chloride to (147; X = SbCl,) gives only the trans-7,8-dichloro-compound (n.m.r. signals in sulphur dioxide at -40”) whilst similar treatment of (148; X = FSO,) gives 94 % cis-7,8-dichlorocyclo-octatriene and 6 % trans-isomer. Hence endo-attack for both homotropilium ions appears to be kinetically preferred. The initial endo- chlorohomotropilium ion is probably formed from a complex of a chlorine molecule with the tub-like cyclo-octatetraene. Models indicate that C(1)-C(7) orbital overlap in the 8-halogenohomotropylium ion is substantially larger on the exo-side of the methylene bridge; this may be the reason for the preferred endo-reaction with anion.However in the low-temperature catalysed isomeri- sation of the cis-and trans-dichlorides since ring inversion is known not to occur at the temperatures used ionisation and recombination of the two dichlorides is not completely stereo~pecific.’~ Methylation of cyclo-octatetra- ene dianion with methyl iodide involves a slow first-step monomethylation.98 Dehydrocyclo-octatetraene occurs in the products of reaction of the bromo- tetraene with strong bases ;it reacts with dienes e.g. tetracyclone in the expected 94 I. Tobushi K. Fujita and R. Oda Tetrahedron Letters 1967,3815 3755. ’’ T. S. Cantrell J. Org. Chem. 1967,32 1669.96 L. H. Slough J. Org. Chem. 1967,32 108. 97 G. Boche W. Hechtl H. Huber and R Huisgen .I.Amer. Chem SOC.,1967,89,3344; R. Huisgen G. Boche and H. Huber ibid. 3345. 98 D. A. Bak and K. Conrow J. Org. Chem. 1966,31,3958. Alicyclic Compounds (147) ex0 R' = H R2 = C1 (148) endo R' = C1 R2 = H (149) manner and forms a vinyl ether by addition of t-butyl alcoh~l.~~ The chemistry of 'simpler' cyclo-octatetraene compounds is receiving increasing attention ; the hydrogen bromide adduct of the tetraene is a valence tautomeric mixture of mono- and (30%) bi-cyclic forms which is substituted by azide to give a mixture (70% bicyclic) which decomposes rather readily to 2-trans-butadienyl- pyrrole by way of nitrene (149) and prototropy of (150).'oo Bromocyclo- octatriene is convertible into the corresponding alcohol and acetate which are largely bicyclic.Rapid ring-chain tautomerism of the alcohol and analogous carbinols obtained from the derived ketone takes place (the l-phenyl- carbinol is not isolable). The appearance of the cis,cis,trans-structure (1 54) supports ring opening of the bicyclic form from (151d) as the monocyclic form might be expected to give an all-cis non-conjugated ketone by ring scission. Terminal cis-isomers of (154) give all-trans non-conjugated ketones by 1,3-prototropy. These results suggest that the known photolysis of cyclo- octatrienone in methanol to give methyl octatrienoate might involve a hemi-acetal of bicyclo[4,2,0]octa-2,4-dien-6-one rather than the keten previously suggested e.g.(155) -+(156)."' O -R = aR X X (151) (a) R = H,X = Br (153)X = OH (155) X = OH R = OMe (b) R = H X = OH (c) R = Me,X = OH (d) R = Ph X = OH R (154) R = alk/aryl (156) R = OMe 99 A. Krebs and D. Byrd Annalen 1967,707,66. loo M. Kroner Chem. Ber. 1967 100,3162. M. Kroner Chem. Ber. 1967,100,3172. 334 K.M ackenzie Catalytic cyclisations have been further developed 1,l-bischloromethyl-ethylene (157) is converted into 1,4,7-trimethylenecyclononane (158) by nickel carbonyl ;cyclisation of 1,9-dichloro-2,5,8-trimethylenenonane with the reagent also affords (158). The reaction of (1 57) with 1,6-dichloro-2,5-dimethyl-enehexane (159) also gives (158),and studies with labelled (159) indicate that (157) reacts with it much faster than (157) combines with itself.lo2 Nickel catalysis allows synthesis of quite large rings e.g.reaction of butadiene with cyclodecyne gives (160) which on reduction to (161) oxidation and Wolff- Kishner reaction gives cycloeicosane. Similar steps can be carried through with 1,8-~yclotetradecadiyne.~~~ Cyclic cumulenes are not well known but they can be made from the dibromocarbene adducts of cyclic allenes which when treated with lithium methyl ring-expand to the cumulene e.g. cyclonona- 1,Zdiene gives (162); this is stable at low temperature is reduced to cyclodeca- 1,3-diene with sodium- ammonia and absorbs iodine to give 2,3-di-iodocyclodeca- 1,3-diene. lo4 Improved methods for the synthesis of cycloalkadiynes from ao-dibromo- alkanes with sodioacetylene have been reported and previously inaccessible members described; the reduction-prototropic rearrangement of the derived di-cis-olefins is also discussed.Geometrical factors are more important for the smaller rings e.g. difficultly formed conjugated olefins lack coplanarity and are reduced slowly. O5 Chlorination and dehydrohalogenation of cyclodecane gives pure cis-and trans-cyclodecenes depending on the base used. lo6 The sequence (163)-1166) illustrates a new fragmentation applicable to the synthesis of medium and large rings e.g. (168) from (167) in 85 % yield.lo7 E. J. Corey and M. F. Semmelhack Tetrahedron Letters 1966,6237. Io3 P. Heimbach and W. Brenner Angew. Chem. Internat.Edn. 1966,5,961. W. R. Moore and J. M. Ozretich Tetrahedron Letters 1967 3205. A. J. Hubert J. Chem. SOC.(C),1967,2149. J. G. Traynham D. B. Stone and J. L. Couvillion J. Org. Chem. 1967,32 510. lo’ A. Eschenmoser D. Felix and G. Ohloff Helv. Chim. Acta 1967 SO 708; cf. M. Yanobe D. F. Grove and R. L. Dehu Tetrahedron Letters 1967 3943. Alicy cl ic Compounds (163) (164)X = 0 (165) X = =N.NH.SO,Ar Bridged and Caged Structures(en, n 3 7).-Reports have appeared recently on the synthesis of stereomechanistically interesting em-and endo-mono- methylene adducts of norbornenes (and dienes) reaction of 7-norbornadienyl benzoate with diazomethane gives a 5 :1mixture of em- and endo-syn-tricyclo- octenyl benzoates. lo* Corresponding bridge-carbonyl compounds have also been made but an alternative pathway is the synthesis of (169) via cyclo-propene-tetrachlorodimethoxycyclopentadieneadduct by dehalogenation and hydrolysis.log The stability of these compounds depends critically on the orientation of the cyclopropane ring and to a lesser extent on the substituents in the norbornene ring (169) has a half-life of ca. 90 min. at 35",whereas the em-isomer is comparably stable at 150". It seems possible that disrotatory cyclopropane ring-opening can assist bridge-elimination leading to the boat conformer of tropilidene directly from (169) whereas the em-methylene isomer must first give the norcaradiene. Fragmentation reactions of 7,7-disubstituted norbornadienes potentially pass through norcaradienes and this is seemingly supported by the rearrange- ment of 7-alkoxy- and 7-aryl-norbornadienes to equilibrated tropilidenes.However whilst 7,7-dialkoxynorbornadienesdecompose particularly easily the isomeric geminal dialkoxytropilidenes decompose only at much higher temperatures;the products are solvent dependent and consistent with elimina- tion of dialkoxycarbene as one pathway and methoxy-radical elimination (leading to tropone) as another.' ' The photochemical ring-chain rearrangement of cycloalkanones to alkenals has been postulated to involve intramolecular hydrogen transfer from the P-position during ring scission ;compatible with this the rearrangements of bridged-bicyclic ketones fall into two rate groups depending on whether or lo' B.Halton M. A. Battiste R. Rehberg C. L. Deyrup and M. E. Brennan J. .4mer. Chem. SOC. 1967,89,5864. lo9 S. C. Clarke and B. L. Johnson Tetrahedron Letters 1967 617. 'lo R. W. Hoffmann and J. Schneider Tetrahedron Letters 1967 4347; cf. G. Maier Angew. Chem. Internat. Edn. 1967,402. 336 K.Mackenzie not geometrical factors are suitable for 1,3-hydrogen transfer e.g. (170) belongs to the faster rate group. ''' Other photochemical studies of bridged bicyclic ketones include fragmentation to bicyclo[2,1,1] hexane and bridge-switching reactions of e.g. bicyclo[3,2,l]oct-2-en-8-one.''2uv ' ' 2b Me&Me 0 Me Me exo-Addition of hydrogen in di-imide reduction of norbornadienes syn to a bridge substituent is remarkable ;calculations based on steric and entropy factors suggest that the anti-double-bond ought to be favoured to the extent of 96 %! The 99 1 predominance of the syn-addition process points to a stabilisation of the transition state of ca.4.5 kcal./mole. '' exo-syn-Addition is also favoured for epoxidation and methylenation of 7-t-butoxynorborn- adiene but phenyl azide addition prefers endo-syn-approach.' 14' It is suggested that there may be polar interactions in these alkoxy-bridge compounds ; evidence for this is the higher reactivity of t-butoxynorbornadiene than norbornadiene towards lithium alkyls and the reaction of 7-syn-t-butoxy- norbornene with isopropyl-lithium under conditions leaving the anti-isomer and norbornene virtually unchanged. The well known tendency of organo-metallics to complex with ether oxygen groups may well account for these observations.The preference for endo-attack by dipolar phenyl azide at the syn-double-bond might be due to the proximity of the electron-rich oxygen atom which initiates electrophilic attack; other reactions which can be discussed in similar terms are the epoxidation of tropilidene and cyclo-octa- tetraene maleic anhydride adducts from the same side as the.anhydride ring. These effects may be much less important with very reactive reagents e.g. benzenesulphonyl azide.' 14a The preferred exo- mode of reaction in norbornyl compounds has been generally explained in terms of torsional effects between the bridgehead hydrogen and the C-2 substituent (usually hydrogen) at the point of attack ;endo-approach and bonding requires these groups to undergo eclipsing interaction absent in the case of em-attack.' 14' From the same laboratory as the hydroboration technique for anti-Markownikov hydration comes a simple technique for stereoselective synthesis of exo-norbornan-2-01 by oxymercuration-borohydride reaction.With 2- methylnorbornene endo-2-methylnorbornan-2-01 is formed ; the method complements the hydroboration technique. The absence of rearrangement ''I T. Matsui Tetrahedron Letters 1967 3761. (a) J. E. Baldwin and J. E. Gano Tetruhedron Letters 1967 2099; (b) W. F. Erman and H. C. Kretschmar J. Amer. Chem. SOC.,1967,89 3842. W. C. Baird jun. B. Franzus and J. H. Surridge J. Amer. Chem. SOC.,1967,89,410. 11' (a) G. W. Klumpp A.H. Veefkind W. L. de Graaf and F. Bickelhaupt Annulen 1967 706 47 57; (b) P. von R.Schleyer J.Amer. Chem SOC.,1967,89 701. Alicyclic Compounds products from methylated norbornenes and similar trideuteriomethyl com-pounds appears to preclude bridged-ion intermediates in these reactions.' l5 Only exo-methylene adducts are formed from pure methyl-lithium and methyl- ene chloride in reaction with norbornenes contrary to an earlier report,"6 although the smooth dkrotatory cyclopropyl-ally1 rearrangement of the syn-chloromethylene compound is confirmed. The major and minor products from the rhodium-catalysed dimerisation of norbornadiene (among other dimers) are related by hydroiodination-Wagner-Meerwein rearrangement and de- hydrohalogenation of the minor isomer which gives the major isomer; since the minor product is believed to be (172) the major reaction product is (173).Besides the rearranged hydroiodide the minor dimer gives a cage compound which is therefore (174) and not the analogous compound with parallel methylene bridges previously suggested. The bis-nortricyclane structure earlier proposed for a further dimer is now thought to be (175) rather than the bis-cis-endo-compound. With these assignments all the catalytic dimers of norbornadiene can be rationalised by the formation of one bond between two molecules on the catalyst surface with a subsequent product-forming step in the resulting di-radical; they can also be regarded as related to the exo-trans- exo- exo-trans-endo- and endo-trans-endo-2,3 :2',3'-dimers by scission-rota- tion-recombination steps e.g.the latter dimer gives (1 76) and hence (172) via (172').''' The dimer (172) or its stereoisomers are converted over alumina at 300" into (174)"* whilst purely thermal treatment affords (222) (R' == R2= H) in contrast to the endo-trans-exo-2,3 :2',3'-dimer which gives bicyclo- [4,2,1]nona-2,4,7-trieneand its 2,5-cyclised valence tautomer [exo-cyclobutene ring cf. (177)l. Sensitized irradiation of the bicyclononatriene gives the interesting tautomer (1 77) as well as the exo-isomer.' '' 'I5 H. C. Brown and W. J. Hamnar J. Amer. Chem. SOC. 1967 89 1524; H. C. Brown J. H. Kawakami and S. Ikegami J. Amer. Chem. SOC.,1967,89,1525. C. W. Jefford E. H. Yen and R. Medary Tetrahedron Letters 1966,6317 '" T.J. Katz and N. Acton Tetrahedron Letters 1967 2601. H.-D. Scharf G. Weisgerler and H. Hover Tetrahedron Letters 1967,4227. L. G.Cannell Tetrahedron Letters 1967 5967. 338 K.M ackenzie Novel 1 -perfluorobicycloheptyl Grignard reagents form from the 1 -halo- geno-compounds accessible from 1-undecafluorobicycloheptyl-lithium ; these reagents thermally eliminate magnesium fluorohalide to yield perfluoro-l- halogenonorbornan-2-enes seemingly via transient bridgehead olefins which add halide and expel fluoride anion from C-3; further reaction with magnesium can ensue to give bicyclohept-Zen- 1-yl Grignards. The analogous 1,4-dihalo- genoperfluoronorbornanes give bis-Grignards which are actually more stable than the mono-compounds since the latter are subject to an unfavourable 1,4-transannular interaction with the C-F dipole.12' Woodward and Katz observed Oppenauer oxidation of hydroxy-cyclo- pentadiene dimer (178) to give only the Cope rearrangement product (179) of the expected ketone; either rearrangement is very fast or catalysis is involved.Chromic oxide-pyridine oxidation of (178) does give the bridged ketone k3 (178) R'. = OH R2-4= H (I 79) R3'v4 = 0,R' = R2 = H Ph CI c1 (182) however; its rearrangement at the m.p. is very fast and it is catalysed by traces of protic or Lewis acids at lower temperatures. Thermolysis of the 8-keto- compound gives more dihydroindene than that of the 7-keto-compound which suggests that decarbonylation is faster than rearrangement.Ketone (179) photochemically cages endothermically ; the product cleaves at 450" whereas the cage product from irradiation of benzoquinone-cyclopentadiene adduct is stable above 500"!'21 An intermediate such as (180) formed from a 1,2,3,4-tetrasubstituted norbornen-7-one analogue of (178) could cyclise in a number of ways; indeed hydrolysis of acetal(l8 1) gives mainly (1 83)(vmax.1745 cm. -I) via an analogous intermediate (182). Photolysis of (183) gives the em-5-phenyl isomer of the S. F. Campbell J. M. Leach R. Stephens and J. C. Tatlow Tetrahedron Letters 1967 4269. R. C Cookson J. Hudec and R. 0.Williams J. Chem. SOC.(C) 1967 1382. Alikyclic Compounds 339 minor hydrolysis product of the acetal-the expected 7-ketone-through diradical(l84).The 7-carbonyl compound is not an intermediate for rearrange- ment of (181) to (183) since it rearranges more slowly than the acetal."*' Further rearrangements of 7-norbornadienyl cations have been elegantly followed by n.m.r. techniques ; these involve bridge-flipping and degenerate five-carbon scrambling by what are designated circumambulatory processes (see chapter 3 this Section).'22b The first examples of simple norcaradienes which probably exist by virtue of a positive enthalpy difference for the norcaradiene-tropilidene equilibrium rather than steric or other factors which preclude ring-opening as in earlier more complex examples are made by the decomposition of dicyanodiazo- methane in aromatic media; thus benzene gives (185) and p-xylene (186) and (187).The n.m.r. spectrum of (185) shows a complex multiplet T 3-2-3-9 quite different from that of the isomeric tropilidene which has three groups of signals z 3-5. The significantly larger dipole moment than that of malono- nitrile supports a charge-transfer explanation for the stability of these nor- caradienes but the diene U.V. absorption appears to preclude this.lZ3 Sigma- tropic 1,5-cyano-shifts are observed in thermolytic rearrangements of these compounds and Berson- Willcott rearrangements occur in norcaradiene taut- omers of 1,2-benzo-7,7-dicyanocycloheptatriene.1 24 '(185)R' = R3 = H '(186) R' = H R' = Me R2 (187) R' = Me R' = H A new synthesis of barrellene compounds comprises the unusual Diels- Alder addition of dicyanoacetylene to benzene; the reaction is catalysed by aluminium chloride which forms an isolable complex with the dienophile; separately formed the complex reacts with benzene to give the same product of 174-addition.The rates of reaction are increased by methylation of the ring which leads e.g. with xylene to isomeric 1,4- and 2,5-addu~ts.''~ A new synthesis of bicyclo[3,2,l]oct-2-ene is based on the catalytic activity of metal hydride-anhydrous cerous chloride which converts 4-vinylcyclo- hexene into the bicyclo-octene. '26 Autocondensation of acetone morpholino- enamine gives 2-[2-methylprop-l-enyl]-6,8,8-trimethylbicyclo[4,2,0]octen-2-one ; other derivatives of the bicyclo[4,2,0]octenone system are similarly accessible. Simple methods for the preparation of 1-halogeno-4-methyl- 122 (a) L.S. Besford. R. C. Cookson. and J. Cooper J. Chem. SOC. (C). 1967. 1385 (b) R. K. Lustgarten M. Brookhart and S. Winstein J. Amer. Chem. SOC.,1967 6350 6352 6354. 123 E. Ciganek J. Amer. Chem. SOC.,1967,89 1454. E.Ciganek J. Amer. Chem. SOC.,1967,89,1458. E.Ciganek Tetrahedron Letters 1967 3321. P.R.Stapp J. Org. Chem. 1966,31,4258. G. Bianchetti D. Pocar R. Stradi P. Dalla Croce and A. Vigevani Gazzetta 1967 97 872; G. Bianchetti P. Dalla Croce D. Pocar R. Stradi and G. G. Gallo ibid. p. 564. K. M ackenzie bicyclo[2,2,2]octanes are the reactions of the l-alcohols or methoxy-com- pounds with phosphoryl and sulphuryl halides in polyphosphoric acid128a or the reaction of the same starting materials with acyl halides and stannic chloride." 8b 1,4-Dihydroxybicyclo[2,2,2]octane made in a new synthesis based on tetrahydrobenzoquinonedienoldiacetate-maleicanhydride adduct is similarly converted into the dihalogeno-compound.In the field of charged bicyclic intermediates more details of base-catalysed deuterium exchange with bicyclo-octadiene (188) have been published. Other products of protonation of the proposed 67t non-classical carbanion (189) have been observed e.g. the tautomers tetracyclo[3,2,1,02~7,06~4]octane(190) and tricycl0[3,2,1,0'*~ Joct-3-ene (191). The anion itself prepared by cleavage with sodium-potassium alloy of the ether (188; R' = MeO) has also been observed.'30"*I3Ob A theoretical discussion of bicycloaromaticity has also appeared.Isomeric 3-chloro-8-azabicyclo[3,2,l~octanes (192) and (193) illustrate in their solvolytic behaviour the steric requirements of fragmentation reactions ; the latter fragments quantitatively with cyanide ion to give (194) whilst the former displaces chlorine probably via a cation or internal quaternary salt without fragmentati~n.'~~ Application of the orbital symmetry rules continues to serve structural elucidation; thus 2,3-homotropone (195) photochemically isomerises to (196) since the alternative mode of disrotatory ring closure is sterically hindered by the clash of methylene and vinyl protons.133 The past year has seen a number of interesting developments in bicyclononane chemistry. Addition of diphenyl- keten to olefins may involve non-symmetrical a-bond formation suggesting that cases of retro-reaction might also occur with selective scission of one of the bonds in the cyclobutanone ring; such is the case in the thermal rearrange- ment of 9,9-diphenylbicyclo[5,2,O]nona-3,5-diene-2,8-dione-the sole di-phenylketen adduct of tropone-which exists in equilibrium mainly with 12* (a)J.Kopecky and J. Smejkal Tetrahedron Letters 1967 1931 ;(b)Z. Suzuki and K. Morita J. Org. Chem. 1967,32 31. 129 J. Kopecky and J. Smejkal Tetrahedron Letters 1967 389. lJo(a)S. Winstein M. Ogliaruso M. Sakai and J. M. Nicholson J. Amer. Chem. Soc. 1967,89 3656; (b)J. M. Brown Chem. Comm. 1967,638. '" M. J. Goldstein J. Amer. Chem. SOC.,1967 89,6357. 132 A. T. Bottini C. A. Grob E. Schumacher and J.Zergenyi Helv. Chim Actu 1966 49 2516. IJ3L. A. Paquette and 0.Cox J. Amer. Chem. SOC.,1967,89 5633. Alicyclic Compounds 341 NC R 4Rl k2 (194) (192) R = H or Me R' = H R' = C1 (193) R = H or Me R2= €1 R' = C1 8,8-diphenyl-10-oxabicyclo[5,3,0]decan-9-one formed by C(7)-C(8) scission in the cyclobutanone ring closure of the acyl radcal on to ring carbonyl and subsequent 1,5-sigmatropic hydrogen transfer from C-7 to C-4. 134 The route to bicyclo[3,3,l]nonane compounds described by Stork and Landesman is by now well known; a similar reaction involving acryloyl chloride and 1-morpholinocyclohexene has also been described but the yields are low. The reaction has been further investigated; mixing the reactants at the b.p.gives the bicyclo[3,3,l]nonane-2,9-dione in good yield. Use of 3,333- tetramethylcyclohexanone enamine allows isolation of the intermediate 2,2,4,4- tetramet hyl-9-morpholinylidiniumbicyclo[3,3,1]nonan-8-one chloride (197) which when decomposed with water gives the tetramethylcyclononan- 2,9-dione and tetramethyloxocyclohexylpropiopicacid. Working with cinna- moyl chloride at low temperature allows isolation of the intermediate N-cinnamoyl chloride of an enamine whose decomposition to the keten (198a) [the type precursor of (197) via (198b)l in the presence of a different enamine demonstrates the intramolecularity of the reaction.' 35 (;I c1-c1-(197) (198a) (198b) 134 A. S. Kende Tecrohedron Letters 1967,2661. IJ5 P. W. Hickmott and J. R.Hargreaves Tetrahedron 1967,23,3151. 342 K.Mackenzie A 9 @ &OH --i 3 (200),(201) R 7 (199) R = H 1.r. evidence indicates significant C3-C7 transannular interactions in the bicyclo[3,3,l]nonane system but surprisingly few hydride transfer reactions in corresponding cations appear to have been described. Formolysis of exo-2,3-epoxybicyclo[3,3,l]nonane (199) however gives besides diol esters the em-6-or 7-en-2-01 (200) or (201) and a minor component of elimination from the initial cation exo-3-en-2-yl formate (202) which accords with the steric requirement for elimination of a proton from C-4 with a developing axial hydroxy-group at C-2; transannular hydride shift and elimination compete very well here.' 36 The complex hydride reduction of the enol lactone (203) was described a decade ago but only recently has the detailed stereochemistry of these re- actions been examined.The reduction gives preferentially the less thermo- dynamically stable axial epimer (204); the structure of the lesser component rests on the n.m.r. signals for the 2-proton and the smooth bridge cleavage with ethoxide ion which requires trans-coplanar arrangement of the C(9)-C( 1) and C(2jOTs groups. Use of model compounds e.g. (206),again gives mainly the axial product (207) with an increased ratio to minor component. The reaction appears to involve the lithium salts (208) and (209) (hydride transfer to carbonyl and ring scission); both of these possible structures can give rise to an axial oxygen function at C-2 in the bicy~lononane.'~~ Enol lactone (210) similarly gives the tricyclododecandiol (21 1; R = R' = H) presumably with an axial hydroxy-group.The X-ray data on (211 ; R = H R' = p-IC6H,.CO) shows the C-4 methylene group flexed outwards to a considerable extent.'38 0 X A0 & '6 R (204) R' = OH R2 = H R3= Me (203) R = Me (205)R' = H R2 = OH R3 = Me (202) R= H. X = O-CHO (206) R = H (207) R' = OH R2 = H R3 = H 13b R. A. Appleton J. R. Dixon J. M. Evans and S. H. Graham Tetrahedron 1967,23 805. 13' J. Martin W. Parker B. Shroot and T. Stewart J. Chem. SOC.(C) 1967 101. lS8 G. Ferguson W. D. K. Macrosson J. Martin and W. Parker Chem. Comm. 1967 102. Alicyclic Compounds H (208) 4 11 Attention has been drawn to the various products of dimerization of cyclo-hexenone with basic reagents ; one interesting product is (212) which is readily convertible into bridgehead halogeno-compounds and contrary to an earlier report the halides are solvolysed in appropriate media.' 39* Orbital symmetry rules have been applied to the products of thermal valence tautomerism of bicyclo[6,2,0]dec-9-ene (21 3) -deca-2,9-diene (214) and -deca- 4,9-diene (21 5); (214) gives trans,cis,cis,cyclodeca-l ,3,5-triene by conrotatory ring opening and then cyclises more slowly in a disrotatory process to trans-1,2,3,4,9,10-hexahydronaphthalene, in analogy with known cases.141 Methods for functionalising the more readily accessible tricyclooctane (216) have been explored; nitrene insertion at C-1 and C-3 usefully gives the amine compounds (217) and (218) when the hydrocarbon is heated with methyl azidoformate.Free radical chlorination gives the 3-chloro-compound and chromyl acetate gives ketone (219) and acetate (220). Solvolysis of the 3-tosylate occurs with significant C(lbC(2) scission to give bicyclo[3,3,0]octa-2,6- diene.142 Norbornadiene 2,3-methylene adduct undergoes intramolecular .Tc-cyclo-propyl addition and this has been extended to photochemical cyclisation of the acetylenedicarboxylate adduct (222; R' = R2= C0,Me) as a route to the thermally stable pentacyclo[4,3,0,02~403~80s~7]nonane system (223) in low ~ie1d.l~~" An alternative approach based on the carbene derived from ketone 13' R. C. Duffner and F. Kurzer Chem.and Ind. 1967 1642. 140 B. Furth J. Kossanyi J.-P. Morizur and M. Vandewalle Bull. SOC.chim. France 1967 1428; cf. J.-P.Morizur B. Furth and J. Kossanyi ibid. p. 1422. P. Rodlick and W. Fenical Tetrahedron Letters 1967,4901. J. Meinwald and D. H. Aue Tetrahedron Letters 1967 2317; J. Meinwald and B. E. Kaplan J. Amer. Chem. SOC.,1967,89,2611. 143 (a)H. Prinzbach and D. Hunkler Angew. Chem. Internat. Edn. 1967,6 247; (b)P. K. Freeman and D. M. Balls J. Org. Chem. 1967,32,2354; (c) E. Wiskott and P. von R. Schleyer Angew. Chem. Internat. Edn. 1967,6,694. 344 K.M ackenzie (221) uia the tosylhydrazone sodium salt not only gives the (223) system but fragmentation to 2-ethynylnorbornene also occurs presumably by retro-carbene addition.143h Prediction that thermal isomerization of (224) to (225) is precluded by orbital symmetry has been confirmed by its synthesis from (222; R' = R2 = H);above 550" (224) is cleaved but no 3,7-methanotriasterane (225) is 0b~erved.l~~~ (215) (216) R'= R'= H (217) R~=H,R~=NHCO~M~ (2IS) R'= H R' = NHC0,Me (219) R'=O,R'a H .G8 Rl R' (220) R'= OAc,R'= 0' (223) @@&hi%: (226) R = H (227) R=-(229) RE+ Dihydro-(222; R' = R2 == H) has been shown to solvolyse to exo-2-brend- any1 derivatives; brief low temperature treatment of the acetate or the hydro- carbon with concentrated sulphuric acid gives 2-noradamantanol in high yield,'44a whilst brexane the catalytic hydrogenation product of (222 ; R' = R2 = H) gives noradamantane on treatment with aluminium bromide 'sludge' at 25" very rapidly.'44b Further details of the rational synthesis of triasterane (226) have appeared ; diazomalonic ester gives mono-diethoxycarbonyl- methylene adducts with cyclohexa-l,4-diene and further transformations of the syn-isomer give the diazoketone the precursor of triasteran-9-one.Wolff- Kishner reduction of the ketone is accompanied by ring scission reactions rationalised on the basis of carbanions e.g. (227) and (228); the latter either protonates (minor product) or undergoes prototropic rearrangement-cyclo- propane ring opening to bicyclo[3,3,l]nona-2,6-(or -2,7-)dimes whose forma- tion suggests that stabilisation of the anion (228) by the homallylic double bond cannot be very significant in comparison with the C-4 allylic carbanion formed by 1,2-proton shift-cyclopropane ring opening.14' Triasteran-9-one is the precursor of the homosemibullvalene (230) via the cation (229) by de- protonation ring opening'46 and the fluxional molecule has also been made from 2-cycloheptatrienylethylidene(C7H7CH,CH:) the major product being 144 (a)A. Nickon G. D. Pandit and R. 0.Williams Tetrahedron Letters 1967 2851 ;(b)P. von R. Schleyer and E. Wiskott ibid. 2845; cf. B. R. Vogt and J. R. E. Hoover ibid. p. 2841. 14' H. Musso and U. Biethan Chem. Ber. 1967,100,119. 146 U. Biethan H. Klusacek and H. Musso Angew. Chem. Internat. Edn. 1967,6 176. Alicyclic Compounds bicyclo[4,2,l]nona-2,4,7-triene(23l),which appears to be formed in a separate reaction pathway perhaps via intermediate (232).14' Bicyclononatriene (231) is also formed as a major product in a similar thermolysis of bicyclo[ S,l,O)octa- 2,4-dienecarboxaldehyde tosylhydrazone sodium salt along with bicyclo- [5,2,0]nona-2,4,8-triene (233) which is not however the precursor of nonatriene (231) (by orbital symmetry allowed thermal 1,5-sigmatropy) since heating (233) gives cis-dihydroindene.The products of the reaction are best explained by various ring-closure modes of the diradical(234) formed from the expected carbene ; in confirmation of the formation of this tropilidene acetylene and bicyclo[3,2,2]nona-2,5-diene are also observed. A similar scheme explains the products of reaction of the analogous cyclo-octatetraene compound which ought to give bicyclo[6,2,0]deca-2,4,6,9-tetraene (235) but instead gives among other products both stereoisomers of 9,lO-dihydronaphthalene.The preponderance of the trans-isomer strongly suggests the intermediacy of cyclodecapentaene with one trans-double-bond -the expected product of thermally allowed conrotatory cyclobutene ring-opening of (235) -which by disrotatory ring closure gives the observed trans-dihydronaphthalene.14'' (231) X = CH (244) (236) X =.CH:CH-(24') H (243) (242) Indeed low temperature photolysis of the tosylhydrazone sodium salt gives (236) and only trans-9,lO-dihydronaphthalene;here decatetraene (235) can be shown to be formed and on warming the reaction mixture trans-9,lO- dihydronaphthalene appears.148b All-cis-cyclodecapentaene (among other products) has been observed in photolysis of truns-9,lO-dihydronaphthalene (excited state conrotatory ring opening); photolysis of the dihydronaphthalene at -190" (no cis-isomer formed) followed by warming of the mixture to 25" gives a product with the spectrum of the cis-i~omer;'~~ photolysis of the cis-isomer gives bicyclo[4,2,2]deca-2,4,7,9-tetraene (236) (thermally reversed) and 147 H.Tsuruta K. Kurabayashi and T. Mukai Tetrahedron Letters 1967 3175. 14' (a) M. Jones and S. D. Reich J. Amer. Chem. SOC.,1967 89 3935; M. Jones and L. T. Scott ibid.,p. 150; (b)S. Masamune C. G. Chin KOHojo,and R. T. Seidner ibid. p. 4804. 149 E.E. van Tamelen and T. L. Burkoth J. Amer. Chem. SOC. 1967.89 151. 346 K.Mackenzie subsequently bullvalene.' 50 The bicyclodecatetraene together with its previ- ously observed valence tautomer is therefore another occupant of the energy profile connecting cis-9,lO-dihydronaphthaleneand bullvalene ;further minima on this curve are (237) theoretically predicted last year,'" and the known (238).Formation of (237) from bullvalene is a concerted suprafacial 1,3-sigmatropic shift in excited state orbital ~yrnmetry.'~~ Thermolysis of (239) gives (240) presumably via a vinylogue of bullvalene formed by sterically unfavourable ring scission [raison d'etre for (239)] ; dihydrobullvalene (241) undergoes concerted 1,5-homodienyl hydrogen shift to the single product (242).' 53 A lucid account of the development of a rational synthesis of bullvalene and other fluxional molecules e.g.barbaralone (243) has been given. Reduction of the carbene insertion product of (243) and elimination through the acetate gives bullvalene and Grignard syntheses based on the ring-expanded ketone can clearly serve as routes to mono-substituted derivatives e.g. the methyl and phenyl compounds which (like the halogeno-and t- butoxy-compounds) appear to prefer vinylic substituents. Since bullvalone can enolise the forma- tion of a dideuterio-compound in basic deuteriated media is not surprising; eventually however all hydrogen is exchanged exemplifying the compound's fluxional character. In accord with the smaller ring system rearrangements in the barbaralone series are times faster than in the bullvalene Barbara101 obtained by hydride reduction of (243) is also made from bicyclo- [3,2,2]nona-2,6,8-triene with aluminium chloride.'54b Propellatriene (244) has been made from cis-9,10-bishydroxymethylhexa-hydronaphthalene dimesylate.' 55 Syntheses of [4,4,4]propellanes and deriva- tives of the [3,3,3]-series together with rules for their nomenclature have been discu~sed.'~~"~~ Photochemical routes to cage structures continue to enjoy popularity. An interesting thermal case is the reaction of tropone with tropilidene by consecu- tive (6 + 4)n cycloaddition and intramolecular Diels-Alder reaction to give pentacyclo[ 7,5,O,O29'O59' 306.1 '' 2]tetradeca-3,lO-dien-8-one. The accessibility of cubane and homocubane derivatives has stimulated mechanistic studies in this comparatively new area ;the solvolytic properties of syn-and anti-tosylates (245) and (246) are quite different for the former reacts without rearrangement and with retained configuration whereas the latter gives besides unrearranged alcohol (246; R2 = H R' = OH) mainly W.von E. Doering and J. W. Rosenthal Tetrahedron Letters 1967 349. W. von E. Doering and J. W. Rosenthal J. Amer. Chem. SOC. 1966,88 2078. 152 M. Jones jun. J. Amer. Chem. SOC. 1967,89,4236. J. N. Labows jun. J. Meinwald H. Rottele and G. Schroder J. Amer. Chem. SOC., 1967,89,612. 154 (a)W. von E. Doering B. M. Ferrier E. T. Fossel J. H. Hartenstein M. Jones jun. G. Klumpp R M. Rubin and M. Saunders Tetrahedron 1967 23 3943; see also J. B. Lambert Tetrahedron Letters 1963 1901 ;(b)M. J. Goldstein and B.G. Odell J. -4rner. Chem Soc.. 1967.89. 6356. 155 L. A. Paquette and J. C. Phillips Tetrahedron Letters 1967,4645. ls6 J. Altman D. Becker D. Ginsburg and H. J. E. LoewenthaI Tetrahedron Letters 1967 757; cf. R. L. Cargill and J. W. Crawford ibid. p. 169. 15' J. Altman E. Babad J. Itzchaki and D. Ginsburg Tetrahedron 1966 Suppl. 8 279. 158 S. lt8 Y. Fujise and M. C. Woods Tetrahedron Letters 1967 1059. Alicyclic Compounds R' (245) R' = H R' = OTs m = 0 (246) R' = H R' = OTS n = 1 (247) R' = OH RZ = H.m = 1 n = 0 the symmetrical bishomocubane (247). Since the rates are lo3-lo4 times faster than calculated values bridged ions are postulated.' 59 Syntheses of bridgehead hydroxy- and alkyl adamantanes have been de- scribed.160 2-Substituted adamantanes are more difficultly accessible 1-adamantanol however rearranges to the 2-ketone in sulphuric acid.' 61 Photolysis of 1-adamantyl azidoformate gives the C-2 nitrene insertion product which reduces to a useful yield of 2-aminoadamantan01.'~~1,2,3,4-Tetrabromoadamantane readily made in the presence of aluminium bromide is converted into the tetraol with sulphuric acid-silver ion and Hofmann degradation of the tetracarboxylic acid gives an excellent yield of the tetra- amino-compound.'63 A rational synthesis of 1,3-diethoxycarbonyladamantaneis based on 4,4-diethoxycarbonylcyclohexanone enamine and ethyl 2-bromomethylacrylate ; these react to give 3,3,7-triethoxycarbonylbicyclo[3,3,l]nonan-9-one Dieck- mann ring-closure leading to 1,3-diethoxycarbonyladamantane-2,6-dione.159 W. L. Dilling and C. E. Reineke Tetrahedron Letters 1967,2547; P. von R. Schleyer J. J. Harper G. L. Dunn V. J. DiPasque and J. R. E. Hoover J. Amer. Chem. SOC.,1967,89,699. S. Landa J. Vais and J. Burkhard Z. Chem. 1967,7,233; W. Hoek; J. Strating and H. Wynberg Rec. Trau. chim. 1966.85 1045. W. Hoek H. Wynberg and J. Strating ibid. p. 1054. H. W. Geluk and J. L. M. A. Schlatmann Chem. Comm. 1967,426. 16' W. V. Curran and R. B. Angier Chem. Comm. 1967,563. 163 H. Stetter and M. Kranse Tetrahedron Letters 1967 1841. 164 H. Stetter and H. G. Thomas Angew. Chem. Internat. Edn. 1967,6 554.

ISSN:0069-3030    

DOI:10.1039/OC9676400311

出版商:RSC    

年代:1967

数据来源: RSC

摘要:

10. TERPENOIDS AND STEROIDS By A. B. Turner (Department of Chemistry University of Aberdeen) BIOGENETIC-TYPE syntheses continue to attract attention. Cyclisation of the terminal epoxides of simpler terpenes gives polyclic systems. Of particular interest is the terminal epoxide (1) of geranylgeranyl acetate,' which on brief treatment with stannic chloride in benzene gives the tricyclic product (2) with six asymmetric centres all having the stereochemistry of the natural diter- penoids. Mechanisms involving either a concerted cyclisation or a stepwise process via mono- and bi-cyclic carbonium ions are proposed. The non-enzymic cyclisation of squalene 2,3-epoxide leads to the tricyclic compounds (3) and (7; R = c~H) (8;R = PH) E. E. van Tamelen and R.G.Nadeau J. Amer. Chem. SOC., 1967,89 I76 350 A. B. Turner (4) under similar The former product (3) clearly arises more directly from squalene oxide while the latter (4) is formed either from the inter- mediate carbonium ion or by further reaction of (3). These results underline the need for enzymic control in the formation of ring c in Nature in order to counteract the purely chemical tendency for this ring to become five-membered. (The natural configuration of the A/B ring system is obtained by non-enzymic cyclisation of terpene terminal epoxides2‘) The selectivity of the terminal oxidation of polyolefins has been ascribed to both steric and conformational factors3 The stereochemical course of the cyclisation of the olefinic acetals (5) and (6) is dictated by the configuration of the central olefinic bonds in the substrate^,^" as previously noted for the acid-induced cyclisation of acyclic p~lyenes.~* The trans-acetal(5) gives the trans-octalin (7)whereas the cis-isomer (6)gives the cis-octalin (8).The stereospecificity again demands either a syn- chronous mechanism or cationic intermediates which maintain their stereo- chemical integrity. The chemistry of anthropod defensive substances among which the terpenes form a major group is the subject of an interesting review.’ The compounds concerned are mainly monoterpenes with some sesquiterpenes. Testosterone as well as several pregnane derivatives is present in the protective glands of water beetles6 Grasshoppers which feed on milkweeds contain cardenolides similar to those in the plant.’ These toxic materials are found in the insect’s body tissues and can also be ejected in solution from its defensive glands.The terpene constituents of the Cupressaceae have been reviewed.’ Monoterpenoids.-New examples are reported’ of the hydrolysis of phos-phate esters as model reactions for the biogenesis of monoterpenes. Acid hydro!ysis of geranyl neryl linaloyl and a-terpinyl phosphates and pyro- phosphates leads to a number of naturally occurring acyclic and monocyclic systems. Fission of the cyclopropane ring of various chrysanthemic acid derivatives (9) by generation of the appropriate carbonium ions allows rupture of each of the three ring bonds (A+) to give compounds with the santolinyl (lo) artemisyl (1 l) and lavandulyl skeltons (1 2).’ On heating linalool(l3) all four possible diastereoisomeric plinols are formed (a)E.E. van Tarnelen J. Willet M. Schwartz and R. Nadeau J. Amer. Chem. Soc. 1966 88 5937; M. Kishi T. Kato and Y. Kitahara Chem. and Pharm. WIN (Japan) 196;7,15 1071. (6)cf Ann. Reports 1966,63 443. (c) cf Ref. 65. E. E. van Tarnelen and K. B. Sharpless Tetrahedron Letters 1967 2655. (a)W. S. Johnson A. van der Gen and J. J. Swoboda J. Amer. Chem. SOC.,1967,89 170. (b)I. G. Mursakulov A. V. Sernenovsky W. A. Smit and V. F. Kucherov Tetrahedron 1967 23 1621. ’ J. Weatherston Quart. Reo. 1967 21 287. H. Schildknecht H. Birninger and U. Maschwitz Angew. Chem. 1967,79,579; H. Schildknecht R. Siewerdt and U.Maschwitz Annalen 1967,703 182. ’ J. v. Euw L. Fishelson J. A. Parsons T. Reichstein and M. Rothschild Nature 1967,214 35. H. Erdtrnan and T. Norin Fortschr. Chem. org. Naturstofle 1966 24 206. F. Crarner and W. Rittersdorf Tetrahedron 1967 23,3015 3023. lo L. Crombie R. P. Houghton and D. K. Woods Tetrahedron Letters 1967 4553. Terpenoids and Steroids 351 via an intramolecular Alder ‘ene’ synthesis’ The name ‘iridane’ is proposed for the carbon skeleton (14) of these substances which is of widespread occur- rence. Conflicting assignments of configuration to the isomeric pulegone epoxides on the basis of physical measurements have now been resolved by their stereospecific Favorskii rearrangement. l2 Abnormal opening of the cyclo- propane intermediates predominates and subsequent protonation proceeds with retention of configuration.Chemical transformation’ to diols of known configuration gives the same results (+)-and (-)-pulegone oxides are the cis-and trans-isomers (1 5)and (16) respectively. ( -)-Piperitenone dioxide has the cis-configuration (17).’ PoH q-,Q 0; (13) 9 10 (15) (14) (17) (18) (19) ‘I H. Strickler G. Ohloff and E. Kovats Helti. Chim. Acta 1967 50 759. G. W. K. Cavil1 and C. D. Hall Tetrahedron 1967 23 1119; W. Reusch and P. Mattison ibid. p. 1953. J. Katsuhara J. Org. Chem. 1967. 32 797. 352 A. B. Turner Syntheses of ( f)-genipin,14 and (i-)-bakuchiol” and its methyl ether16 have been achieved. The novel oxetone (18) and its dihydro-derivative have been obtained from hop 0i1.l~ Hydrogenation of the diene (18) in ether gives the tetrahydro- derivative whereas hydrogenation in acetic acid is accompanied by hydro- genolysis of the spiroketal linkage.The bicyclo[3,2,0] heptane ring system is recognised in the D-and L-filifolones (19) and its mirror image from Zieria and Arternisia species. ’* Sesquiterpenoids.-The chemistry of picrotoxinin and related substances has been reviewed,’ and physical data on sesquiterpenoids collected.z0 New stereospecific synthesis of farnesol” and humulene (20)” are reported from Harvard. Germacratriene is foundz3 to have the all-trans-configuration (21) by X-ray analysis of its silver nitrate adduct. The ready conversion of this triene (2 l) a possible biosynthetic intermediate into bicyclic selinane deriva- tives is ascribed to the reactivity of the 6,7-double bond towards electrophilic reagents.24“ A detailed thermodynamic argument suggests spz-spz torsional strain contributes significantly to the high reactivity of such medium-ring trans-olefins and that in the case of germacratriene this contribution may be much larger than that from the familiar sp3-spz torsional strain.24b P-Elemene (22) and elemol (23) have been synthesised from a-santonin.” The thermal interconversion of this transdivinylcyclohexane system and a cyclodeca-1,5-diene has been observedz6 in the derivatives (25) and (26) of the germacranolide (24).Increased attention has been paid to the action of juvenile hormones which regulate larval development or reproduction in insects.Methyl farnesoate dihydrochloride (27) shows lo4 times the activity of farnesyl methyl ether the most active compound previously rep~rted.’~ Work on such compounds may therefore have important implications for insect control. The ester (28) is the juvenile hormone of the giant silkworm moth.z8 In the bisabolene group dehydrojuvabione (29) which shows high juvenile hormone activity has been l4 G. Biichi B. Gubler R. S. Schneider and J. Wild J. Amer. Chem. Soc. 1967 89 2776. Is J. Carnduff and J. A. Miller Chem. Comm. 1967,606. l6 N. P. Damodaran and S. Dev Tetrahedron Letters 1967 2897. l7 Y. Naya and M. Kotake Tetrahedron Letters 1967 1715. lS R. B. Bates M. J. Onore S. K. Paknikar C. Steelink and E.P. Blanchard Chem. Comm. 1967 1037. l9 LA. Porter Chem Rev. 1967,67,441. 2o Tables of Constants and Numerical Data. 15 Sesquiterpenoids by G. Ourisson S. Munavalli and C. Ehret Pergamon Press 1966. 21 E. J. Corey J. A. Katzenellenbogen. and G. H. Posner J. Amer. Chem. SOC.,1967,89,4245. 22 E. J. Corey and E. Hamanaka J. Amer. Chem. SOC. 1967,89 2758. ” F. H. Allen and D. Rogers Chem. Comm. 1967 588. 24 (a) E. D. Brown M. D. Solomon J. K. Sutherland and A. Torre Chern. Comm. 1967 11 1. (b)F. H. Allen E. D. Brown D. Rogers and J. K. Sutherland ibid. p. 11 16. 25 L. J. Patil and A. S. Rao Tetrahedron Letters 1967 2273. N. H. Fischer and J. J. Mabry Chem. Comm. 1967 1235. 27 M. Romanuk K. Skima and F. Sorm Proc. Nat. Acad. Sci. U.S.A.,1967,57 349.28 H. Roller K. H. Dahm C. C. Sweely and B. M. Trost Angew. Chem. 1967,79 190. Terpenoids and Steroids (22; R = H) (20) (2 1) (23; R = OH) p RO c1 COzMe (24; R = H X = CHJ (27) H (25; R = Ac X = '--_Me 1 0,Me CozH isolated from the Balsam fir.29 Syntheses of both the racemic compound (29) and ( f)-juvabione are rep~rted.~' (+)-Abscissin I1 has been shown31 to have the absolute stereochemistry in (30). a-and p-Vetivone have long been regarded as the hydroazulenones (31) differing only in stereochemistry at C-6. Both structures have been drastically modified this year. a-Vetivone the less thoroughly investigated of the twe it had never in fact been chemically inter-related with its supposed epimeric counterpart-has now been shown32 to have structure (32) after its n.m.r.spectrum had been found to indicate the presence of an angular methyl group. The Canadian group related the new structure with an eremophilone deriva- ti~e,~~" while the Americans showed that dehydro-or-vetivone was identical to i~odehydronootkatone,~~~and later confirmed the structure by total ~ynthesis.~ 29 V. Cerny L. DolejS L. Labler F. Sorm and K. Slrima Coll. Czech. Chem. Comm. 1967 32 3926. 30 K. Mon and M. Matsui Tetrahedron Letters 1967,2515,4853; K. S. Agyar and G. S. Krishna Rao ibid. p. 4677. 31 J. W. Cornforth W. Draber B. V. Milborrow and G. Ryback Chem. Comm. 1967 114. 32 (a)K. Endo and P. de Mayo Chem. Comm. 1967 89. (b)J. A. Marshall and N. H. Andersen Tetrahedron Letters 1967 161 1.33 J. A. Marshall H. Faubl and T. M. Warne Chm Comm.. 1967.753. 354 A. B. Turner The synthetic studies of Marshall and his co-w~rkers~~' then surprisingly in- validated the accepted structure for p-vetivone and with it the proposed framework(3 1)of the entire class of bicyclic vetivane sesquiterpenes. The wealth of chemical and physical data on p-vetivone the n.m.r. spectrum of which was not in conflict with the old structure was then reinterpreted34b in terms of the spiro[4,5]decane structure (33). The nature of the ring system was confirmed by degradation to the known spirodecane (34).A choice between structure (33) and its mirror image was possible because of the known34c conversion of hinesol now reformulated as (39 into ( +)-p-vetivone.(The absolute configuration of hinesol is already established. 35) The group of sesquiterpenes containing the spiro[4,5]decane system which previously contained only the acorones and the agaro~pirols,~~ must now be expanded to include p-vetivone hinesol and several other ~etivanes.~~~ These results underline the caution required in interpreting the results of dehydrogenation experiments. 36 Chamigrene (36) from the leaves of Charmaecyparis taiwmensis is the Me I 0m (33) (34) (35) CH,OH I (36) (37) (3 8) 34 (a)J. A. Marshall N. H. Andersen and P. C. Johnson J.Amer. Chem. SOC.,1967,89 2748. (b)J. A. Marshall and P. C. Johnson ibid.,p. 2750. (c)cf Ann. Reports 1965 62 335. 3s cJ Ann. Reports 1962. 59.292. 36 cf M. Holub Z. Samek V. Herout and F. Sorm,CoZZ. Czech. Chem. Comm. 1967,32 591. Terpenoids and Steroids 355 first sesquiterpenoid spiro[5,5]undecane to be found in Nat~re.~'" Its occur- rence is significant since it corresponds to a probable link in the biogenesis of thujopsene cuparene and the cuprenes. It is a known isomerisation product of thujop~ene,~~' and is also formed by acid-catalysed dehydration of widdrol. Both of these compounds are also found in the leaf oil. A synthesis of (+)-chamigrene (36) is recorded,37c as well as a biogenetic-type synthesis of (+)-a-chamigrene (37) by dehydration of both the cis-and trans-monocyclofarnesols (38)? 7d The tumour inhibitor euparotin acetate (39) is the most highly oxygenated guaianolide yet discovered and the first recognised to contain a ~piro-epoxide.~~ Its epoxide and a,P-unsaturated lactone functions are common to other tumour inhibitors such as withaferin A and elephantin.In the solid state santonene exists in the keto form (40) whereas the dihydro- santonene produced by catalytic hydrogenation of the 1,2-double bond exists as the enol (41). In solution a tautomeric equilibrium is set up between keto and enol forms in both corn pound^.^^ The position of equilibrium can be de- termined using n.m.r. spectroscopy and specific rotations. Perezinone the cyclodehydration product from hydroxyperezone has the quinone methide structure (42). The highly hindered terminus of the chromophore is reflected in its slow rate of hydrogenation and its failure to add hydrogen ~hloride.~' 0 H '0 (41) (42) 37 (a)S.Ito K. Endo T. Yoshida M. Yatagai and M. Kodama Chem. Comm.. 1967 186 (b)cf Ann. Reports 1964 61 360. (c) A. Tanaka H. Uda and A. Yoshikoshi Chem. Comm. 1967 188. (4S. Kanno T. Kato and Y. Kitahara ibid.,p. 1257 ;cf A. Tanaka H. Uda and A. Yoshikoshi ibid. 1968 56. 38 S. M. Kupchan J. C. Hemingway J. M. Cassady J. R. Knox A. T. McPhail and G. A. Sim Sim J. Amer. Chem. SOC.,1967,89 465. 39 T. B. H. McMurry and R. C. Mollan J. Chem. SOC.(C),1967 1813. 40 D. A. Archer and R. H. Thomson J. Chem. SOC.(C),1967 1710. 356 A. B. Turner . CHzOH Illudol (43) a third metabolite of Clitocybe ill~dens,~~" has the carbon skeleton of a postulated biogenetic precursor of the illudins S and M.41b The cyclobutene moiety appears in the fungal metabolite fomannosin (44) the structure of which was determined by X-ray analysis of a dihydro-deriva- tive.* A preliminary report43 on the characterisation of 1,2-and 1,3-diols by gas chromatography-mass spectrometry of the derived cyclic n-butyl and phenyl- boronate esters suggests that the method may have important applications in the terpenoid and steroid fields. Diterpenoids.-The cis-configuration for abienol (45) has been confirmed by conversion into its trans-isomer (46) with mercuric acetate.44 This novel HOH2C H OH (49) 41 (a)T. C. McMorris M. S. R. Nau and M. Anchel J. Amer. Chem. SOC.,1967,89 4562. (b)cJ Ann. Reports 1965 62 332. 42 J.A. Kepler M. E. Wall J. E. Mason C. Basset A. T. McPhail and G. A. Sim J. Amer. Chem. SOC. 1967 89 1260. 43 C. J. W. Brooks and J. Watson Chem. Comm. 1967 952; c$ S. Hara T. Watabe and Y. Ike Chem. and Pharm. &U. (Japan). 1966.14. 131 1. 44 J. S. Mills J. Chem. SOC.(C) 1967 2514. Terpenoids and Steroids 357 isomerisation is thought to proceed via the intermediate acetoxymercuri- compound (47) formed by participation of the hydroxyl group. Mercuration of dihydroabienols also involves hydroxyl participation and leads to five- and six-membered ring ethers. The dust of protracted battles over the stereochemistry of marrubiin has finally settled and structure (48)has emerged.45 The common 13(R)-configura- tion in eperuic and labdanolic acids is inferred from differing behaviour of derived diketones under alkaline condition^.^^ Acids of the eperuane and labdane series co-occur in Oxystigrna oxyphyll~rn.~’ The structure of phorbol (49) for which several incorrect proposals have been made,48b is now settled by X-ray work on a bromofuroate deri~ative.~~” Details of the work of the Leeds school on taxicins I and I1 have a~peared.~’ Preferential oxidation of the vinyl group of methyl pimarate (50)with per- manganate-buffered periodate gives” the epoxy-ketoacid (52)along with the expected acid (51).The epoxide probably arises by an intramolecular process perhaps taking place in the initial permanganate-olefin complex. (50;R = CH4H2) (53;R = Me) (51 ;R = C02H) (56; R = CH21) &O H fil R *,.H HO (54;R= CH,I) (57) (58 R = Me) (55; R = Me) (59;R = CH2I) ” D. M. S. Wheeler M. M. Wheeler M. Fetizon and W. H. Castine Tetrahedron 1967,23 3909; R. A. Appleton J. W. B. Fulke M. S. Henderson and R. McCrindle J. Chem SOC.(C) 1967,931. 46 K. H. Overton and A. J. Renfrew J. Chem. SOC.(C),1967,931. 47 D. E. U. Ekong and J. I. Okogun Chem Comm. 1967 72. ‘’(a) R. C. Pettersen G. Ferguson L. Crombie M. L. Games and D. J. Pointer Chem. Comm. 716 cf E. Hecker H. Bartsch. H. Bresch. M. Gschwendt. F Harle. G Kreihich. H. Kubinyi. H. U. Schairer C. Szczepanski and H. W. Thielmann Tetrahedron Letters 1967 3 165. (b)ct Ann. Reports 1965. 62 336. 49 M. Dukes D. H. Eyre J. W. Harrison R. M. Scrowston and B. Lythgoe J. Chem. SOC. (C) 1967,448; D.H. Eyre J. W. Harrison and B. Lythgoe ibid. p. 452. J. W. ApSimon A. S. Y.Chaw W. G. Craig and H. Krehm Canad. J. Chem. 1967,45 1439. 358 A. B. Turner COzH The range of intramolecular radical reactions at saturated carbon atoms has been extended to include functionalisation of methyl groups some distance from a hydroxyl group.” Thus hypoiodite oxidation of the ketol (53) gives the iodo-derivative (54) as well as the expected ketoxide (55). The unstable iodohydrin (56)is an intermediate in the formation of (54) which arises by two oxidations of the original alcohol (53). The novel long-range oxidation which occurs in the iodohydrin (56) involves two consecutive 1,Shydrogen shifts the second of which represents the rare intramolecular abstraction of a hydrogen atom by a carbon radical.(Overoxidation in hypohalite reactions has previously been observed only at the site of initial attack of the alkoxy radical.) The double 1,5-hydrogen shift in the oxidation of the iodohydrin (56) probably reflects the steric congestion at the 10P-iodomethyl group. A second example of this type is the lead tetraacetate-iodine oxidation of friedelan-3P-01 (57) in which the major product (58) is accompanied by its iodo-derivative (59). The configuration of the secondary methyl group in vinhaticoic acid (60) is assigned as shown on the basis of a total synthesis of the (&)-methyl The final assembly of the furan ring involves 1,4-addition of carbethoxy carbene to an a-methoxy methylene ketone:52b Combined gas chromatography-mass spectrometry promises to be useful for the rapid identification of gibberellins in plants.53 Bamboo gibberellin (61) has been identified in Phaseoh rnultifurus by this method.54 The corresponding ” E.Wenkert and B. L. Mylari J. Amer. Chem. SOC. 1967,89 174. 52 (a)T. A. Spencer R. M. Villarica D. L. Storm T. D. Weaver R. J. Friary J. Posler and P. R. Shafer J. Amer. Chem. SOC.,1967 89 5497; cf D. L. Storm and T. A. Spencer Tetrahedron Letters 1967 1865. (b)cJ Ann. Reports 1966,63 456. 53 J. MacMillan; R. J. Pryce G. Eglinton and A. McCormick Tetrahedron Letters 1967 2241. 54 K.J. Pryce J. MacMillan and A. McCormick Tetrahedron Letters 1967 5009. Terpenoids and Steroids tribasic acid (62) was obtained from seeds of the same species without the guidance of bioassay.55 The three C-20 gibberellins now isolated from green plants all have a 7-hydroxy group unlike the fungal C-20 gibberellins AI2-Al5 and this suggests that 7-hydroxylation may occur at a much earlier stage of biosynthesis in the plant.The gibberellin-A,-glucopyranoside (63) is the first gibberellin glycoside isolated from natural sources. 56 Mechanisms involving fission of the C-H or C-0 bonds are ruled out for the base-catalysed epimeri- sation at position 2 in 2-hydroxygibbane 1 -+4a lactones.” There is no (61 ; R = CHO) (63) C02H (62; R = C0,H) incorporation of deuterium and the 2-methoxy derivatives are not epimerised. This leaves the possibility of proton abstraction from the 2-hydroxy group in a retro-aldol mechanism although the ring-opened intermediate could not be trapped.2-Ketogibberellins readily undergo retro-Claisen cleavage in ring A,~* with the lactone bridge remaining intact. Atractyloside the toxic glucoside from the root of Atractylis gummqera has the ( -)-kaurene structure (64).59 Sesterterpen0ids.-Agreement has been reached on the nomenclature of this group.60 The fundamental hydrocarbon of the series is named ophiobolane with the numbering and steric configuration shown in (65). Ophiobolin D ’’ R. J. Pryce and J. MacMillan Tetrahedron Letters 1967 4173. s6 K. Schreiber. J. Weiland and G. Sembdner Terrahedron Letters 1967 4285. ” J. MacMillan and R. J. Pryce J. Chem. SOC.(C‘) 1967 740. 58 I. A. Gurvich I.M. Milstein and V. F. Kucherov Tetrahedron Letters 1967 4293. ” F. Piozzi A. Quilico C. Fuganti T. Ajello and V. Sprio Gazzetta 1967 97 935. 6o K. Tsuda S. Nozoe M. Morisaki H. Hirai A. Itai S. Okuda L. Canonica A. Fiecchi M. G. Kienle and A. Scala Tetrahedron Letters 1967 3369; cf Ann. Reports 1966,63 451. 360 A. B. Turner has the structure (66),6'"and has been correlated616 with ophiobolin C. The oxygen atom at C-3 in ophiobolin A does not originate from molecular oxygen,62 unlike that at C-14. Triterpenoids-There is evidence for the presence of squalene 2,3-epoxide in tobacco tissues cultured in vitr~.~~ Lansic acid (67) from the fruit peel of Lansium domesticum is a unique onocerin variant in which both rings A and E are cleaved.64 Malabaricol (68)6' has the carbon skeleton of one of the products of the non-enzymic cyclisation of squalene epoxide (vide supra).New evidence66" is adduced for the structure of shionone which has also been correlated with friedelin.66b Full details are now available of the work on methyl angolen~ate,~~ turraeanthin 68a and melianone.68b The related melian- trio1 is the substance responsible for making certain M elia species unpalatable to the desert locust.69 Acid-catalysed rearrangement7' of the C-14 methyl group in 7a,8a-epoxy- tirucallols of type (69) gives the 7a-hydroxyapo-derivatives (70). This is an interesting model for a possible step in the biogenesis of tetranortriterpenes all of which are oxygenated at C-7. In grandifoliolenone (71) this methyl migration and C-7 oxygenation have occurred but the side-chain is not degraded.71 The tetranortriterpenes (72) (73) and (74) occur together in the same Melia H 61 (a)A.Itai S. Nozoe K. Tsuda S. Okuda Y. Iitaka and Y. Nakayama Tetrahedron Letters 1967,4111. (b)S. Nozoe A. Itai K. Tsuda and S. Okuda ibid. p. 4113. 62 S. Nozoe M. Morisaki K. Tsuda and S. Okuda Tetrahedron Letters 1967,3365; L. Canonica A. Fiecchi M. G. Kienle B. M. Ranzi A. Scala T. Salvatori and E. Pella ibid. p. 3371. 63 P. Benveniste and R. A. Massy-Westropp Tetrahedron Letters 1967 3553. 64 A. K. Kiang E. L. Tan F. Y. Lim K. Habaguchi K. Nakanishi L. Fachan and G. Ourisson Tetrahedron Letters 1967 3571. 65 A. Chawla and S. Dev Tetrahedron Letters 1967,4837; cf Ref.2. 66 (a)T. Takahashi,Y. Moriyama,T. Tanahashi and G. Ourisson Tetrahedron Letters 1967,2991. (b)T. Takahashi T. Tsuyuki T. Hoshino and M. Ito ibid. p. 2997; cf Ann. Reports 1964,61 366. 67 C. W. L. Bevan J. W. Powell D. A. H. Taylor T. G. Halsall P. Toft and M. Welford J. Chern. SOC.(C) 1967 163; W. R. Chan K. E. Magnus and B. S. Mootoo ibid. p. 171. (a) C. W. L. Bevan D. E. U. Ekong T. G. Halsall and P. Toft J. Chem. SOC.(C) 1967 820. (b)D. Lavie M. K. Jain and I. Kirson J. Chern. SOC.(C), 1967 1347. 69 D. Lavie M. K. Jain and S. R. Shpan-Gabrielith Chern. Comm. 1967 910. 'O G. P. Cotterrell T. G. Halsall and M. J. Wriglesworth Chem. Comm. 1967 1121. J. D. Connolly and R. McCrindle Chem. Comm. 1967 1193. Terpenoids and Steroids 36 1 p (69) 'YOH I "OAc (72; R = 0) (73; R = H2) species.72 This supports a proposed scheme for the biogenesis of the ring D epoxylactone system in limonin involving Baeyer-Villiger oxidation of the 14,15-epoxy- 16-ketone.Triterpenoid saponins and sapogenins have been re~iewed.'~ It is noted that hydroxylation is mainly confined to one edge of the carbon skeleton in these compounds particularly in rings D and E. Many new members of this group have been noted this year. 72 D. Lavie and M. K. Jain Chem. Comm. 1967,278; cf C. R. Nakhyanan P. V. Pachapurkar and B. M. Sawant Tetrahedron Letters 1967 3563. '' N. Basu and R. P. Rastogi Phytochemistry 1967 6 1249. 362 A. B. Turner The sapogenin (75) is a component of the defensive secretion of the sea cucumber.74 Revised structures for the cactus lactones stellatogenin (76) and thurberogenin (77) were required when their n.m.r.spectra were found to indicate that the hydroxylic terminus of the lactone bridge was secondary rather than tertiary.75 The new structures are substantiated by the appearance of a new secondary hydroxyl group after metal hydride reduction of the lactone function. The total synthesis of hydroxyhopanone has been completed.76 Serratene (76; R = CH,) (77; R = OH Me) (78; R = H) (79; R = OH) Ac 0 @I7 (82; R' = R2= H2) (83; R' = 0,R2 = H,) (85; R' = H2 R2= 0) 74 B. Tursch,I. S. S. Guimaraes B. Gibert R. T. Aplin A. M. Duffield and C. Djerassi Tetrahedron 1967 23 761. '' M. Marx J.Leclercq B. Tursch and C. Djerassi J. Org. Chem. 1967,32 3150. 76 Y. Tsuda and M. Hattori Chem and Pharm. all.(Japan) 1967 15 1073. Terpenoids and Steroids 363 (78) has now been obtained from a natural source Polypodium uulgare and is the first triterpene hydrocarbon from a fern which does not contain a hopane or rearranged hopane The detailed paper7' on serratenediol (79) includes a retro-pinacol rearrangement which establishes the identical structure ofthe terminal rings and aclassical proofthat the central ring is seven-membered. 19w79a and 20P-Hydroxyursolic and ursonic are present in apple peel which is a common source of ursolic acid. Nitration of glycyrrhetic acid and the corresponding 3-ketone gives the a-gem-dinitroketone (80) in good yield.80 Few such a,a-dinitro-ketones have been described.Although quite stable towards acids the dinitroketone (80) is instantly hydrolysed by cold aqueous bicarbonate to the ring-opened acid (8 1).Rearrange-ments of 32-oxygenated lanostanes under a variety of conditions leads to 4,4- dimet hylcholestanes." Cycloartenyl acetate (82) is much more susceptible to attack by chromic acid at C-1 1 than at C-1. The 11-ketone (83) is obtained in 25 %yield.82 The derived epoxide (84) isomerises to the 12-ketone (85) under mild conditions in accor- dance with the remarkable tendency of the cyclopropyl group to stabilize a positive charge a to the ring. Until recently the only reported fungal triterpene conjugates were acetates. This situation which resulted from the once prevalent practice of saponi- fying the extracted material has been altered b$ a re-examination of the fungus Piptoporus betulinus under conditions favourable to the isolation of conjugates.Polyporenic acid A the major triterpene constituent is present in the sporo- phores mainly in the form of conjugate^.'^ Its 3a-hydroxyl group is esterified by acetic malonic caproic and P-hydroxy-P-methylglutaric acids. The dibasic acid conjugates occur partly as mixed esters with methanol. Such combination with biologically important acids suggests that these conjugates may play a significant role in the sporophore. Steroids.-The last few years have seen the rapid acceptance of steroid hormones as oral contraceptives. The existence of an already large and potentially enormous market for 19-nor-steroids has directed more attention towards total synthesis particularly in view of the possible limitation of natural precursors.The major obstacle to the efficient large-scale operation of existing total syntheses is the formation of unwanted enantiomers and current work is aimed at circumventing this pr~blem.'~ The most promising approach appears 77 G. Berti F. Bottari A. Marsili I. Morelli and A. Mandelbaum Chem. Comm. 1967. 50. " Y. Inubushi Y. Tsuda T. Sano T. Konita S. Suzuki H. Ageta and Y. Otake Chem. and Pharm. Bull. (Japan),1967 15 1153. 79 (a)C. H. Brieskorn and H. Wunderer. Chem. Ber.. 1967. 100. 1352 (b)W. Laurie J. McLean and M. El-Garby Younes J. Chem. SOC. (C),1967. 851. J. C. Turner Chem.Comm. 1967. 396. J. Fried and J. W. Brown Tetrahedron Letters 1967 925. S. Corsano and G. Nicita Ricerca Sci. 1967,37,351;cf:R. Beugelmans and R. Toubiana Compt. rend. 1967 264C 343. 83 T. A. Bryce I. M. Campbell and N. J. McCorkindale Tetrahedron 1367,23 3427. 84 L. Velluz J. Valls and J. Mathieu Angew. Chem. 1967,79 774; L. Velluz J. Mathieu and G. Nomink Tetrahedron 1966. Suppl. 8. p. 495. 364 A. B. Turner to be that of asymmetric synthesis which avoids the difficulties of optical resolution although this has only been successful in a few cases. One is the reaction of a tartramic hydrazide with a carbonyl group of the prochiral inter- mediate (86)leading to preferential formation of one of the two compounds (87). Cyclisation and hydrolysis of this product gives the derivative (88) which has the configuration of the natural steroids at C-13 and is readily converted into ~estradiol.~’ In another approach86 involving early chemical resolution the prochiral dione (89; R = CH2CH2C0,Et) is transformed into its racemic monoacetal (90) thereby allowing resolution of the derived acid by standard methods.The unwanted isomer can be reconverted to the original dione by hydrolysis. The synthesis is completed by cyclisation of the optically active monoacetal to the lactone (91),which is used to construct the ketone (88).Other purely chemical procedures include resolution of steroidal alcohols by salt formation between the derived hemisuccinate esters and various optically active bases.87 An elegant asymmetric reduction of one carbonyl group of the dione (86) by micro-organisms allows exclusive formation of natural oestradiol 3-methyl ether.88 Related reductions of the D-homo analogue of the dione (86) by yeast fermentation lead to the corresponding ketol and di01.~~ These are very unstable and readily rearrange to the’spiro ethers (92; R,R’ = 0and R = OH R’ = H).R. Bucourt L. NMdClec J-C. Gasc and J. Weill-Raynal Bull. SOC. chim. France 1967,561. 86 R. Bucourt M. Vignau and J. Weill-Raynal Compt. rend. 1967 2692 834. G. C.Buzby D. Hartley. G. A. Hughes H. Smith B. W. Gadsby and A. B. A. Jansen J. Medicin. Chem. 1967,10 199. C. Rufer E. Schroder and H. Gibian Annafen 1967,701 206. 89 L. M. Kogan V. E. Gulaya and I. V. Torgov Tetrahedron Letters 1967 4673.Terpenoids and Steroids Mechanistic features of the condensation of vinylcyclenols with cyclic 1,3-diketones to give structures of the type (86) have been discussed.90 Several new and convenient syntheses make 2-methylcyclopentan-1,3-dione (89;R = H) readily acce~sible.~' A new annelation reaction involving isoxazoles has been developed in Stork's laboratory for the construction of cyclohexanone rings in polycyclic system^.'^ This allows a simple and efficient synthesis of steroids in which the elements of rings A and B are added at once to a bicyclic system and is illustrated by syntheses of ( )-D-homo-testosterone and ( f)-progesterone which also include stereospecific introduction of the C,,-methyl group.Alkylation of the enolate anion from 10-methyl-1(9)-octalin-2,5-dione (93) with the chloromethyl-isoxazole (94) gives the dione (99 which is converted by a series of steps into the tricyclic ketol (96). The subsequent conversion of this ketol into the pure 10P-methyl compound (97)' in almost quantitative yield by the alkylation- trapping method solves an old and troublesome problem. Conventional methylations of the ketol(96) lead to the usual mixture of lop-and 10a-A9(")-epimers. The intermediate (97) was readily converted into ( f)-~-homo-testosterone and a sequence was devised for the further transformation of this material into ( +)-progesterone. Details are publishedg3 of Johnson's total syntheses of racemic conessine progesterone and cholesterol by the hydrochrysene route.ClH,C 0dl (93) (94) 0 A. V. Zakharychev D. R. Lagidze and S. N. Ananchenko Tetrahedron Letters 1967 803. 91 H. Schick G. Lehmann and G. Hilgetag Angew. Chem. 1967 79 97; T. Miki K. Hiraga, T. Asako and H. Masuya Chem. and Pharm. Bull. (Japan),1967,15,670; V. J. Grenda G. W. Lindberg N. L. Wendler and S. H. Pines J. Org. Chem. 1967,32 1236. 92 G. Stork S. Danishefsky and M. Ohashi J. Amer. Chem. SOC. 1967 89 5459; G. Stork and J. E. McMurry ibid. pp. 5463 5464. 93 W. S. Johnson J. A. Marshall J. F. W. Keana R. W. Franck D. G. Martin and V. J. Bauer Tetrahedron 1966 Suppl. 8 p. 541. 366 A. B. Turner Elegant manipulation of metal-ammonia reductions to avoid hydrogeno- lysis of oxygen functions allows the ketone (99) to be obtained from the readily available phenanthrene (98).94uThe precursor of this phenanthrene can be converted into ( +)-equilenin methyl ether.94b The ionic A/B-aromatisation of 901,ll P-dichloro- and related derivatives of 1,4-dien-3-ones involves expulsion ofthe angular methyl group as the methyl halide.95a The 1,4,8-trien-l lp-ol(100) gives equilenin with acid under particularly mild conditions.Metal-ammonia reduction of equilenin methyl ether gives the trienol (101) which is readily transformed into equilin and 19-norte~tosterone.~~~ Birch reduction of free phenols can be achievedg6 by increasing the metal concentration thereby overcoming the high potential energy barrier to electron addition to the phenolate anion. Rate differences between the reduction of oestrone and its ethylene acetal may be due to a long-range electrostatic effect.In both cases 94 (a) A. J. Birch and G. S. R. Subba Rao Tetrahedron Letters 1967 857. (b)A. J. Birch and G. S. R. Subba Rao ibid. p. 2763 95 (a)M. Heller R. H. Lenhard and S. Bernstein J. Amer. Chem. SOC.,1967,89 1911 1919. (b)E. J. Bailey A. Gale G. H. Phillipps P. T. Siddons and G. Smith Chem. Comm. 1967 1253. 96 J. Fried N. A. Abraham and T. S. Santhanakrishnan J. Amer. Chem. SOC. 1967 89 1044; cf Ref. 94a. Terpenoids and Steroids 367 the major product is a A5('O)-3a-01 (102) and fully reduced derivatives are also formed. These products also result from solvent-dependent photoreductions of oe~tradiol.~' Use of sodium borohydride in ethanol gives the diol(lO2) and its A/B cis-fused dihydro derivative whereas photoreduction with sodium sulphite yields the corresponding A/B trans-fused oestrane.The 2- and 4-isomers of oestradiol have been prepared.'* Both are very weak oestrogens. A double iso- tope method99 for the simultaneous determination of testosterone and 17- keto-steroids in human plasma involves enzymatic aromatisation to oestradiol followed by bromination with bromine-82. The rate of acetolysis of 3P-toluene-p-sulphonates reflects the distortions produced in ring A by the introduction of double bonds into rings B or c and is correlated with changes in the C-14-4 dihedral angle.looa In 3-ketones the chemical shift of the C-19 methyl protons is affected by similar changes and in addition is proportional to the rate of benzylidene condensation at c-2.1OOb Studies on the directive effects of remote substituents show that whereas A4-3-ketones lacking polar substituents react with alkaline hydrogen peroxide to give exclusively the 4P,SP-epoxides up to 30 "/ of the a-epoxyketone results when the steroid contains a polar group at C-17 or beyond.Polar substituents at C-11 show even stronger directive effects. These results are discussed in terms of electrostatic interactions between the substituents and the anionic transition states. O1 The stereochemistry of hydrogenation of the 4,5-double bond in these ketones is also influenced by the nature of the substituent at C-17.lo2 The geometry of the perhydrophenanthrene skeleton in several steroids has been discussed along with torsional angles at ring junctions and conformational transmission effects.lo3 The dipole moment of SP-cholane-3,12- dione shows that ring A is in the chair form.lo4 This finding invalidates an earlier interpretation of the dipole moment of SP-androstan-3,17-dione in terms of an equilibrium mixture of boat and chair forms-this compound now appears to have a deformed ring D. Spectacular chemical proof of the structure of the backbone rearranged product (103) of androst-5-en-3P,17P-diol (105) is provided'05 by synthesis of the corresponding dione (104) from the ketol (106) by contraction of ring A and expansion of ring D. The 4a,Sa-epoxycholestane (107; R = Me) gives only the backbone rearranged product (108 ;R = Me) on treatment with boron 97 J.A. Waters and B. Witkop J. Amer. Chem. SOC.,1967,89 1022. 98 H. Dannenberg D. Meier and H. J. Gross Z. physiol. Chem. 1967,348 775. 99 J. Saroff R. E. Keenan A. A. Sandberg and W. R. Slaunwhite Steroids 1967 10 15. loo (a)R. Baker and J. Hudec Chem. Comm. 1967,479. (b) R. Baker and J. Hudec ibid. p. 891. lo' H. B. Henbest and W. R. Jackson J. Chem. SOC.(C),1967,2459; H. B. Henbest W. R Jackson and I. Malunowicz ibid. p. 2469; cf. J-C. Guilleux and M. Mousseron-Canet Bull. SOC.chim. France 1967 24. lo2 M. G. Combe H. B. Henbest and W. R.Jackson. J. Chern. SOC.(C) 1967,2467. lo' H. J. Geise C. Altona and C. Romers Tetrahedron 1967,23,439. lo4 N. L. Allinger and C. L. Neumann Tetrahedron 1967,23 1279.J. C. Jacquesy. J. Levisalles and J. Wagnon Chem Comm. 1967 25. 368 A. B. Turner trifluoride. A similar rearrangement occurs with the corresponding epoxide (107; R = H) but in this case hydrogen migration to C-5 is competitive and the product (108; R = H) is accompanied by the normal 4-ketone. A new example of backbone rearrangement of steroids involves the ether (109) which gives the unsaturated alcohol (1 10) with boron trichloride."' When gaseous boron trifluoride is bubbled into a solution of the epoxide (1 11) in benzene OH (103;R=(H ) (104;R = 0) OH 78H17 Ace*@ OH (105;R = H,X =<OH XdPACOaY H (106; R = Me.X = 0;-(108) R I 'CH20H -0 (109) (111) 0 0 (113) J. W. Blunt J. M. Coxon M. P.Hartshorn and D. N. Kirk Tetrahedron 1967,23 1811. lo' M. Fetizon and P. Foy Chem. Comm. 1967 1005. Terpenoids and Steroids the 9P-methyl phenol (1 12) and the 1 la-alcohol (1 13) are formed."* Migration of the angular methyl group to the cationic site generated at C-9 probably becomes competitive owing to the additional driving force derived from aromatisation of ring A. No 11-ketones are formed under these conditions in contrast to the results with boron trifluroide-etherate. The role of the solvent in this reaction remains to be clarified. Kinetic studies on the Westphalen rearrangement of 5a-hydroxycholestanes now reveal a marked dependence on the nature of the 3P-substituent as well as on the 6P-substituent. '09 A number of related rearrangements involving migration of the angular C-18 methyl group to C-17 with concomitant formation of a 13,14-double bond are reported.' lo Some,' la* and conceivably all of these proceed via a A' 7(20)-intermediate.The reaction paths followed in the dehydrogenation of various steroidal 3-ketones by high-potential quinones are rationalised by hydride abstractions from alternative enolic forms of the substrates. '' The mechanism accommo- dates the normal 1,2-dehydrogenation of A4-3-ketones by 2,3-dichloro-5,6-dicyanobenzoquinone and the change to 6,7-dehydrogenation observed in the presence of strong acids. It also allows a simple explanation of the differing effects of chloranil and dichlorodicyanobenzoquinone upon A4-3-ketones in uncatalysed reactions," lb based on the difference in oxidation potential be- tween these two quinones.These reactions involve predominant trans-diaxial elimination of hydrogen as is the case with microbiological 1,2-dehydrogena- tions. '' While hydrogen chloride-catalysed dehydrogenation of A4-3-ketones by high-potential quinones gives 4,6-dienones in good yield Michael addition of the acid to the 6-dehydro derivatives is observed in the analogous reaction with A-nor ketones.' The corresponding 7a-chloro derivatives are formed. Di- unsaturated alcohols of type (1 14) are readily oxidised to the ketones (115) by dichlorodicyanobenzoquinone at room temperature.' l4 The unusual ease of this reaction may reflect the stability of the intermediate carbonium ion; A5~'0~-3-alcohols are not attacked under these conditions.R J. W. ApSimon and R R. King Chem. Comm. 1967. 1214. A. Fischer M. J. Hardman M. P. Hartshorn D. N. Kirk and A. R. Thawley Tetrahedron 1967 23 159. B. Krieger and E. Kaspar Chem. Ber. 1967,100 1169; H. Laurent H. Miiller and R. Wiechert ibid. 1966,99 3836; H. L. Herzog 0.Gnoj L. Mandell G. G. Nathansohn and A. Vigevani J. Org. Chem. 1967,32 2906; E. A. Brown J. Medicin. Chem. 1967 10 546; F. Kohen R. A. Mallory and I. Scheer Chem. Comm. 1967 1019. (a)A. B. Turner and H. J. Ringold J. Chem. SOC.(C) 1967 1720. (b) Ann. Reports 1960 57 201 306. cf H. J. Brodie and P. A. Warg Tetrahedron 1967,23 535. P. A. Diassi S. D. Levine and R. M. Palmere J. Medicin. Chem. 1967 10 551. M. Heller R. H. Lenhard and S.Bernstein Steroids 1967 10 21 1. 3 70 A. B. Turner P (115) The stability of isolated double bonds generated by dehydration of various 14a-hydroxyandrostanes is discussed."' Dienes of type (116) obtained by acid-catalysed rearrangement of the corresponding 5,7-dienes are stable in the cholestrol series. In the progesterone series cleavage of the C,,-C, bond occurs with acid and the aromatic product (1 17) is formed."" Further examples of the dual enolization of 50-3-ketones have appeared in brominations' and dehydrogenations,' lo and the directing effect of an 110-hydroxyl group on enol acetylation in this system has been studied."7b The mechanism of formation of steroidal dithianes has been clarified."* Reaction of ethane dithiol with 6a-chloro-4-en-3-ones under mild conditions gives 3-ethylene-thioacetals (1 18) which rearrange in pyridine to the dithianes (1 19).These dithianes are also formed directly from the original chloro com- pounds and have previously been obtained from 6P-acetoxy-4-en-3-ones. It now appears that initial attack is at C-3 with rearrailgement of the inter- mediate thioacetal rather than at C-4 as suggested earlier. The chirality of the sulphur atom in steroidal sulphoxides influences the direction of pyrolytic elimination to form olefins.llg The absolute configuration of the sulphoxides is assigned from product ratios and the relative stability of transition states in which the incipent double bonds are well-developed. 4-Chloro-pregna-1,4,6-trien-3,20-dione adds two equivalents of diazo-methane.Cleavage of the crude his-pyrazoline with perchloric acid gives the 'I5 L. Mamlok hll. Soc. chim. France 1967 3827. 'I6 J. Lakeman W. N. Speckamp and H. 0.Huisman Tetrahedron Letters 1967 3699. (a)R. Jacquesy and J. Levisalles &ll. SOC.chim. France 1967 1642. (b)A. J. Liston and M. Howarth J. Org. Chem. 1907,32 1034. 'I8 G. Karmas J. Org. Chem. 1967 32 3147 cJ M. Tomoeda A Ishida and T. Koga Chem. and Pharm. Rull. (Japan),1967 15 887. D. N. Jones and M. J. Green J. Chem. Soc. (C) 1967 532. Terpenoids and Steroids 37 1 bis-methylene derivative (12O)l2O Only the 1,2-double bond is attacked in unsubstituted 1,4,6-trienones. Addition to the 6.7-double bond is made possible by the added electron-withdrawing effect of the 4-chloro substituent.The same bis-methylene compound (1 20) results from direct methylenation using dimethyl sulphoxonium methylide. An ionic mechanism is proposed for pyrolysis of nitrites in the molten phase where hydrogen atom transfer typical of photolytic reactions does not occur. Vapour-phase pyrolysis on the other hand does involve alkoxy radicals which rearrange via the usual six-membered transition states. Tracer work shows that benzylic rearrangements of cholestane-2,3-diones occur mainly after attack at C-3 and proceed predominantly through quasi- chair intermediates. 122 New natural steroids include cyasterone a novel C2 insect moulting sub-stance from Cyathda capitata. This is biogenetically related to sitosterol whereas all previously isolated compounds having this type of activity are cholesterol derivatives.3a The identity of 20-hydroxyecdysone from various crustaceans and plants has been established. '23b The presence of this compound along with its 50-hydroxy derivative in the fern P. uulgare indicates that com- pounds of this character may be exogenous factors which an insect receives with its food.L23c This assumption is indirectly borne out by the isolation of compounds having moulting hormone activity from adult insects in which the phoracic glands have degenerated. 20,25-Dihydroxyecdysone has been iso- lated from tobacco h~rnworm.'~~ Comparative experiments with ruscogenin have revealed inconsistencies between its behaviour and that of digacetigenin thereby casting doubt on the presence of an lp-acetoxy group in the latter.'25a This has led to a new lZo R.Wiechert Angew. Chem. 1967.78 815. D. H. R. Barton G. C. Ramsey and D. Wege J. Chem. Soc. 1967 1915; c$ B. W. Finucane J. B. Thomson and J. S. Mills Chem. and Id., 1967 1747. J. Levisalles and I. Tkatchenko Wtll. Soc. chim. France 1967 3125 3131. 123 (a) T. Takemoto Y. Hikino K. Nomoto and H. Hikino Tetrahedron Letters 1967 3191. (b) M. N. Galbraith D. H. S. Horn P. Hocks G. Schulz and H. Hoffmeister Naturwiss. 1967 54,47 1. (c)J. Jizha. V. Herout. and F. Sorm Tetrahedron Letters. 1967. lfiX9. 51 39. lZ4 M. J Thompson J. N. Kaplanis. W. E. Robbins. and R T Yarnamoto Chem. Comni.. 1967. 650. 125 (a)C. W. Shoppee R. E. Lack and B.C. Newman J. Chem. Soc. (C) 1967 339. (b) C. W. Shoppee N. W. Hughes R. E. Lack and B. C. Newman Tetrahedron Letters 1967 3171; R. Tschesche H. G. Berscheid H-W. Fehlhaber and G. Snatzke Chem Ber. 1967 100 3289. (c) cf D. Satoh and S. Kobayashi Chem. and Pharm. Wtll. (Jcpan) 1967. 15,248; Ann. Reports 1966 63 458. 372 A. B. Turner formulation (121)'25b which accommodates a novel mechanism for the acid-catalysed elimination of water in ring D :12" Details have appeared'26 of the synthesis of tachysterol and of a partial synthesis of aldosterone from adrenosterone.' 27 Renewed interest in steroid conjugates stems partly from their probable direct involvement as intermediates in metabolic processes rather than simply as end products. A number of oestrogen monoglucuronides have been syn-thesised,12* as well as some novel double conjugates.The latter include oestradiol-3-sulphate-17-glucuronide (l22)lZ9 and oestriol-3-sulphate-16-glucuronide (123),'30 both isolated as their dipotassium salts. The synthesis of cardenolides has been reviewed.' 31 Details of a method for converting the cardenolide to the corticoid side-chain are reported.' 32 Oxida-tion of digitoxigenin acetate with selenium dioxide gives the corresponding ,.R2 OH HOjS (122; R' = G R2 = -H)Y 'WH (123; R' = H R2= OG) C02H lZ6 R. S. Davidson S. M. Waddington-Feather D. H. Williams and B. Lythgoe J. Chem. Sod. (C) 1967 2534. W. Nagata M. Narisada and T. Sugasawa J. Chem. SOC.(C) 1967 648. lZ8 J. S. Elce J. G. D. Carpenter and A.E. Kellie J. Chem. Soc. (C) 1967 542; T. Nambara and K. Imai Chem. and Pharm. Bull. (Japan) 1967,15 1232. lZ9 E. W. Cantrall M. G. McGrath and S. Bernstein Steroids 1966,8 967. 130 J. P. Joseph J. P. Dusza and S. Bernstein J. Amer. Chem. SOC. 1967,89 5078. 13' W. W. Zorbach and K. V. Bhat Adv. Carbohydrate Chem. 1966,21 273. 13' N. Danieli Y. Mazur and F. Sondheimer Tetrahedron 1967,23 715. Terpenoids and Steroids 17whydroxy compound which on ozonolysis and saponification yields a deri- vative of cortisone. Acid-catalysed rearrangement of isodigitoxigenin (124) and derived acetals (125) lead to the novel spiro-c-nor-cardanolide (1 26) and -cardenolide (127).' 33 The remarkable ease of this C-12 -+ C-14 methylene migration contrasts with the usual methyl group migration in Westphalen rearrangements (cf.Ref. 109). Progress towards the synthesis of the natural bufadienolides continues' 34 with the conversion of digitoxigenin into 3p- acetoxyisobufalin methyl ester (1 28) via one of the isomeric acetals (1 25). Microbiological degradation of the cholestrol side-chain involves carbon- carbon bond fission at 24-25 22-23 and 17-20 with elimination of two molecules of propionic acid and one of acetic acid.'35 Although the initial cleavage finds a parallel in the conversion ofcholesterol to bile acids in mammals this mode of formation of 17-ketosteroids from cholesterol differs from the mammalian pathway which involves initial cleavage at Czo-C22 to give pregnenolone and isocaproic aldehyde.133 T. R. Kasturi. G. R. Pettit,and J. Occolowitz,Cham. Comm.. 1967,334:G.R. Pettit,J. C. Knight and T. R. Kasturi ibid. p. 688. 134 T. R. Kasturi G. R. Pettit and K. A. Jaeggi Chem. Comm. 1967,644. 13' C. J. Sih K. C. Wang and H. H. Tai J. Amer. Chem. SOC.,1967,89 1956; C. J. Sih H. H. Tai and Y. Y. Tsong ibid. p. 1957.

ISSN:0069-3030    

DOI:10.1039/OC9676400349

出版商:RSC    

年代:1967

数据来源: RSC

摘要:

11. HETEROCYCLIC CHEMISTRY By R. J. Stoodley (Department of Organic Chemistry University of Newcastle upon Tyne) Reviews.-The chemistry of oxazirans,' tetrapyrroles? glycofuranosides fur an^,^ 1,2- and 1,3-dithiolium ions,' indoxazenes,6 2-0xazolidones,~ and 1,3,4-oxadiazoles* has been reviewed. Further reviews cover quinacridones,' quinodimethane and its analogues,'O deoxy-sugars '' monocyclic sulphur- containing pyrones ' the Hilbert-Johnson reaction of 2,4-dialkoxypyrimidines with halogenoses,' isoall~xazines,'~ and cephalosporins.'6 pheno~azines,'~ The benzene oxide-oxepin and related tautomeri~ms'~ and the chemistry of diazepines' have been considered. The value in heterocyclic syntheses of activated carbon-carbon triple bonds," cyanic esters,20 sulphenes,21 sulphur dioxide imides,22 of reactions of enamines with sulphur and carbon di~ulphide~~ and of ketones with sulphur and ammonia,24 and of cycloaddition reactions2' have been discussed.More general reviews have been concerned with the literature of heterocycles,26 their conf~rmational~' and mass spectral be- ' J.-F. Dupin Bull. SOC. chim. France 1967 3085. A. W. Johnson Chem. in Britain 1967,3,253; A. H. Jackson and G. W. Kenner Nature 1967 215 1126. ' J. W. Green Adv. Carbohydrate Chem. 1966 21,95. ' P. Bosshard and C. H. Euster Adv. Heterocyclic Chem. 1966,7 378. H. Prinzbach and E. Futterer Ado. Hetericyclic Chem. 1966 7 39. K. H. Wunsch and A. J. Boulton Adv. Heterocyclic Chem. 1967,8 278. M. E. Dyen and D. Swern Chem. Rev. 1967,67 197.* A. Hetzheim and K. Mockel Adv. Heterocyclic. Chem. 1966,7 183. S. S. Labana and L. L. Labana Chem. Rev. 1967,67 1. lo G. Scheibe and E. Daltrozzo Adv. Heterocyclicrhem. 1966,7 153. S. Hanessian Ado. Carbohydrate Chem. 1966 21 143. l2 R. Mayer W. Broy and R. Zahradnik Adv. Heterocyclic Chem. 1967,8 219. l3 J. Pliml and M. Prystas Adv. Heterocyclic Chem. 1967,8 115. l4 G. R.Penzer and G. K. Radda Quart Rev. 1967,21,43. Is M. Ionescu and H. Mantsch Adv. Heterocyclic Chem. 1967,8,83. E. P. Abraham Quart. Rev. 1967,21,231; E. Van Heyningen Adv. Drug Research. 1967,4 1. I7 E. Vogel and H. Gunther Angew. Chem. Internat. Edn. 1967 6 385; G. Maier ibid. 1967 6 402. F. D. Popp and A. C. Noble Ado. Heterocyclic Chem. 1967,8 21. l9 E.Winterfeldt Angew. Chem. Internat. Edn. 1 67,6,423. 2o E. Grigat and R. Putter Angew. Chem. Internat. Edn. 1967,6 206. 21 G. Opitz Angew. Chem. Internat. Edn. 1967,6 107. 22 G. Kresze and W. Wucherpfennig Angew. Chem. Internat. Edn. 1967,6 149. 23 R. Mayer and K. Gewald Angew. Chem. Internat. Edn. 1967,6,294. 24 F. Asinger and H. Offermans Angew. Chem. Internat. Edn. 1967,6,907. 25 R. Huisgen Helv. Chim. Acta 1967 50 2421; R. Huisgen Chem. SOC. Special Publ. No. 21. '' A. R. Katritzky and S. M. Weeds Adv. Heterocyclic Chem. 1966 7,225. 27 F. G. Riddell Quart. Rev. 1967,21 364; A. R Katritzky Bull. SOC.chim. France 1967 3585. R. J. Stoodley haviour,28 their halogenation” and their electrophilic substit~tion.~~ Cyclic peroxides3’ and the hydration of the carbon-nitrogen double bond of hetero-aromatics have also been considered.3’ Three-membered Rings.-The trans-addition of iodine azide to an a1 kene followed by the azide-directed trans-elimination of hydriodic acid is a vauable route to vinyl azides which may be photochemically transformed to 2H- a~irines.~~ This reaction is of general application and it has been used to prepare fused azirines [e.g.(l)]for the first time. Moreover the lithium alumin- ium hydride reduction of suitably substituted azirines is stereospecific and cis-aziridines are formed. Therefore the method enables trans-olefins and also mixtures of cis-and trans-olefins to be converted stereospecifically into cis-aziridines. Conjugated vinyl azides [e.g.(2)] may be prepared by the addition of sodium azide to conjugated allenes and the corresponding functionalised azirines (3)may be obtained.34 Aziridines are formed in the lithium aluminium hydride reduction of benzyl ketoximes.Interestingly the reaction is stereo- selective in that the aziridine obtained depends upon the configuration of the starting ~xime.~’ For example the anti-isomer (4) is mainly reduced to the aziridine (6) whereas cis-2-methyl-3-phenylaziridineis obtained from the syn-isomer. These results contrast with those of the Neber rearrangement which is non-stereoselective and they suggest that an intermediate such as (5) may be a precursor of 3-benzyl-2H-azirine which is reduced to the aziri- dine (6). The trapping of a nitrene intermediate by olefins has been successfully applied to aziridine synthesis.36 Thus the lead tetra-acetate oxidation of (4 1 (5) (6) 28 G.Spiteller Adv. Heterocyclic Chem. 1966 7 301; N. K. Kochetkov and 0. S. Chizhov Adv. Carbohydrate Chem. 1966,21 39. 29 J. J. Eisch Adv. Heterocyclic Chem. 1966,7 1. ’O A. R. Katritzky and C. D. Johnson Angew. Chem. Internat. Edn. 1967,6,608. 31 M. Schulz and K. Kirschke Ado. Heterocyclic Chem. 1967,8 165. 32 A. Albert Angew. Chem. Internat. Edn. 1967,6,919. 33 A. Hassner and F. W. Fowler Tetrahedron Letters 1967,1545. 34 G. R. Harvey and K. W. Ratts J. Org. Chem. 1966,31 3907. 35 K. Kotera T. Okada and S. Miyazaki Tetrahedron Letters 1967 841. 36 R. S. Atkinson and C. W. Rees Chem. Comm. 1967 1230. Heterocyclic Chemistry 3-aminobenzoxazolin-2-one in the presence of cis-and trans-but-2-ene leads to stereospecific aziridine formation suggesting that the amino-nitrene is formed and trapped in its singlet state.An intramolecular trapping of a nitrene intermediate is observed in the lead tetra-acetate oxidation of &-unsaturated primary amines which results in the synthesis of novel highly strained bridged aziridine~.~~ For example l-azatricyclo[3,2,1,02~ 7]octane (8) is produced from the oxidation of the amino-cyclohexene (7). The first heterocyclic analogue of bicyclobutane 3-phenyl-l-azabicyclo[ l,l,O]butane (9) has been prepared from 3-phenyl-2H-azirine and dimethyl sulphonium meth~lide.~~ It may be purified by distillation in DQCUO and although extremely sensitive to acid it is stable to alkali and sodium borohydride.(7) (8) (9) The rearrangement of N-acylaziridines to the isomeric oxazolines is a well documented reaction which may be induced by acids nucleophiles or heat. Electronic factors play a dominant role in the sodium iodide-catalysed ring opening of the aziridines (10) and (12) since the oxazolines (11) and (13) are prod~ced.~' Although dimethyl sulphoxide attacks the aziridine (10) in a similar manner the ring-opened intermediate is trapped by oxidation to give the N-phena~ylbenzamide.~' The thermally induced isomerisation of cis- and trans- 1 -aroyl-2,3-diphenylaziridinesto the corresponding cis- and trans-2- aryl-4,5-diphenyl-A2-oxazolines3g demonstrates the stereospecific nature of this reorganisation.However thermolysis of the aziridine (12) takes an unusual course and the unsaturated amide (14) is formed; this rearrangement is pre- sumably triggered by activation of the aziridine hydrogen by the carbonyl group. N-Acyloxaziridines undergo ring enlargements which are analogous to those observed with N-acylaziridine~.~' For example 2-benzoyl-3-phenyl- oxaziridine is isomerised to 2,5-diphenyl- 1,3,4-dioxazole on heating. 2-Vinyl- aziridines may be induced to undergo comparable rearrangements. Thus a new synthetic route to pyrrolines [e.g. (16)] is available from the iodide- catalysed isomerisation of the aziridine (1 5) although an amino-Claisen re- arrangement to the dihydroazepine (17) occurs on heating.42 However the thermal rearrangement of a 2-vinylaziridine to a A'-pyrroline is achieved by heating 3-(2-vinylaziridinyl)benzoxazolinone at 180°,43 while 3-methyl-3-37 W.Nagata S. Hirai K. Kawata and T. Aoki J. Arner. Chem SOC.,1967,89 5045. 38 A. G. Hortmann and D. A. Robertson J. Amer. Chern. SOC.,1967,89 5974. 39 H. W. Heine and M. S. Kaplan J. Org. Chern. 1967,32 3069. 40 H. W. Heine and T. Newton Tetrahedron Letters 1967 1859. 41 E. Schmitz and S. Schramm Chern. Ber. 1967,100,2593. 42 P. Scheiner J. Org. Chem. 1967,32,2628. 43 R. S. Atkinson and C. W. Rees Chem. Cornrn. 1967 1232. 378 R. 3. Stoodley Ph Bz H @H -COAr vinyldiazirine is slowly changed to 3-methylpyrazole at room ternperat~re.~~ Moreover attempts to convert 3-formyl-3-methyldiazirine into its phenyl- hydrazone lead to the isolation of 1 -aniline-1,2,3-tria~ole.~~ The aziridinium ring reacts with aldehydes and ketones to form oxazolidi- nium salts and with nitriles to form imidazolinium salts.Carbonium ion stability Me accounts for the direction of aziridinium ring opening and the electrophilic intermediate reacts with the polarised carbonyl or cyano-group to give the appropriate five-membered heterocycle. This reaction has now been extended to the synthesis of novel six-membered heterocycles by employing nitrones as 1,3-dipole~.~~ For example 1,1,2,2-tetramethylaziridiniurnperchlorate and 5,5-dimethyl-A1-pyrroline 1-oxide react to give the 1:1-adduct (18). The azirine ring behaves similarly since 2,2-dimethyl-3-phenylazirineis converted into an oxazolinium salt (19) with perchloric acid in acetone and to an imidazolinium salt (20) with perchloric acid in a~etonitrile.~’ Isotopic labelling experiments have indicated that cleavage of the 1,2-bond of the azirine occurs.The chemistry of aziridinones has continued to attract interest,48 and their 44 E. Schmitz C. Horig and C. Grundemann Chem. Ber. 1967,100,2093. 45 E. Schmitz and C. Horig Chem. Ber. 1967,100,2101. 46 N. J. Leonard D. A. Durand and F. Uchimaru J. Org. Chem. 1967,32 3607. 4’ N. J. Leonard and B. Zwanenburg J. Amer. Chem. SOC.,1967,89,4456. 48 J. C. Sheehan and I. Lengyel J. Org. Chem. 1966,31,4244; J. C. Sheehan and J. H. Becson J. Amer. Chem. SOC.,1967,89,362,366;H. E. Baumgarten R. D. Clark and L. S.Endres Tetrahedron Letters 1967 5033. Heterocyclic Chemistry Me + Me Me Cl 0 Mep)===Me Me ClO Me Ph H (19) reactivity appears to be similar to that of p-lactones. Thus alcohols readily cleave the 1,3-bond to give a-substituted amides while methanolic sodium methoxide instantly disrupts the lactam linkage to give amino-esters. a-Lactams are thermally labile and as an example 1-t-butyl-3,3-dimethylaziridinoneis converted into N-t-butylmethacrylamide acetone and t-butyl isocyanide. The results implicate a dipolar intermediate (21) which may transfer a proton or rearrange to the oxiran (22). In the light of these properties the reactivity of 1,3-di-t-butylaziridinone is remarkable. It is solvolysed in methanol only after refluxing for several days and both 1,2-and 1,3-bond cleavages are observed.In the presence of an electrophilic catalyst methanol only disrupts the 1,3- bond while with methoxide the lactam is slowly broken. The thermal stability of this aziridinone is also striking in that it may be distilled under reduced pressure without decomposition; only upon heating to 175" in a sealed tube does extensive breakdown occur to give pivalaldehyde and t-butyl cyanide (arising from a thermal isomerisation of t-butyl isocyanide). The chemical unreactivity of 1,3-di-t-butylaziridinoneis clearly the result of steric shielding of the electrophilic centres by the t-butyl groups while thermal dissociation would require the formation of a relatively unfavourable secondary carbonium ion at position-3.Heine first showed that 1-thiophenoxycarbonylaziridineis rearranged on heating to 2-thiopheno~yethylisocyanate.~~ There now appears to be a whole class of related heteroatomic homoallylic rearrangements5' For example 2-chloroethyl isocyanate is formed from aziridine and phosgene while the isolation of trans-2-chlorocyclohexylisocyanatefrom 7-azabicyclo[4,10]hept- ane suggests that the rearrangement is stereospecific. A number of examples of aziridine reactions in which the carbon-carbon bond is cleaved have been reported." The most elegant of these is that described 49 H. W. Heine J. Amer. Chem. SOC.,1963,85 2743. 50 D. A. Tomalia and J. N. Paige J. Heterocyclic Chem. 1967 4 178; D. A. Tomalia and E. C. Britton Tetrahedron Letters 1967,2559;C.K. Johnson J. Org. Chem. 1967,32 1508. 51 R. Huisgen W. Scheer and H. Huber J. Amer. Chem. Soc. 1967 89 1753; A. Padwa and L. Hamilton J. Heterocyclic Chem. 1967 4 118; H. W. Heine R. Peavy and A. J. Durbetaki J. Org. Chem. 1967,3924. N 380 R. J.Stoodley by Huisgen and his co-workers. The Woodward-Hoffmann rules predict a conrotatory ring-opening of the cyclopropyl anion under thermal conditions and a disrotatory ring-opening under photolytic conditions. This prediction has now been verified in the isoelectronic aziridine system. cis- and trans-l-Aryl-2,3-dimethoxycarbonylaziridinesare equilibrated in refluxing carbon tetrachloride and this interconversion is considered to proceed via intermediate azomethine ylids which may be trapped as their dimethyl acetylenedicarboxyl- ate adducts.If a stereospecific conrotatory ring-opening of the cis-aziridine (23) occurs then the azomethine ylid (24) should be trapped by dimethyl acetylenedicarboxylate to give the trans-pyrroline (25). Moreover the trans- aziridine should yield cis-1-aryl-2,3,4,5-tetramethoxycarbonyl-A3-pyrroline. If a disrotatory ring opening occurs upon photochemical excitation then the configuration of the pyrrolines is expected to be opposite to that observed under thermal conditions. The results obtained are in full accord with these expectations. Me0,C C0,Me Me0,C COzMe H C02Me-MeO,CAiAH .VH-Ar Ar Ar Woodward-Hoffmann theory also predicts that the loss of nitrogen from a three-membered ring should be nonstereospecific.However the deamination of cis-and trans-2,3-dimethylaziridine with difluoramine gives the correspond- ing cis-and trans-but-2-enes indicating that the loss of nitrogen is stereo- specific.52 Similarly cis-ethylene episulphones undergo a stereospecific thermal loss of sulphur dioxide to give the corresponding cis-olefins a result which is also in conflict with orbital symmetry consideration^.^^ In contrast ethylene episulphoxides lose sulphur monoxide nonstereospecifically since mixtures of cis- and trans-but-2-enes are formed by heating either cis- or trans-but-2-ene episulph~xides.~~ The first example of a photochemically induced decom- position of an episulphoxide has been reported and apparently rearrangement to an oxathietan is preferred to loss of sulphur monoxide since dibenzoyl- stilbene episulphoxide is cleaved to a mixture of benzil and mon~thiobenzil.~~ The reaction of aziridinyl-lithium with a-bromocyclohexyl phenyl ketone has resulted in the isolation of the first epoxyamine (26) in a stable crystalline form.56 The electron-releasing properties of the nitrogen lone pair of electrons are presumably inhibited by incorporating the nitrogen into a three-membered 52 J.P. Freeman and W. H. Graham J. Amer. Chem. SOC.,1967,89 1761. 53 N. Tokura T. Nagai and S. Matsumura,J. Org. Chem. 1966,31 349; N. P. Neureiter J. Amer. Chem. SOC. 1966,88,558. '' G. E. Harzell and J. Paige J. Org. Chem. 1967 32 459. 55 D. C. Dittmer G. S. Levy and G. E. Kuhlmann J. Amer. Chem. SOC.,1967,89,2793.56 C. L. Stevens and P. M. Pillai J. Amer. Chem. SOC.,1967,89 3084. Heterocyclic Chemistry ring. Nevertheless these electronic factors determine the direction of epoxide ring-opening since a-hydroxycyclohexyl phenyl ketone is formed on acid hydrolysis 1-[a-( 1-aziridinyl)benzyl]cyclohexanol is obtained after borohydride reduction and 2-( l-aziridinyl)-2-phenylcycloheptanoneis the thermally re-arranged product. The deoxygenation of amine oxides with ketens probably involves a-lactone intermediates since 2-methoxy-2-methylpropionic acid is formed when isoquinoline N-oxide is treated with dimethylketen in the presence of methanol. 57 Diaziridinone intermediates may be involved in the base-catalysed ring opening of appropriately N-substituted oxaziridines since the semicarbazide (28) is formed from the oxaziridine (27) and cyclo- hexylamine.(26) (27) (2 8) Four-membered Rings.-The photoinduced ring expansion of 3-benzoyl-1-t-butyl-2-phenylazetidine to l-t-butyl-2,4-diphenylpyrroleis interesting since it involves migration of an alkyl group from an a-position to a carbonyl group in its n -+ IT*excited state.” The product arises by exclusive migration of the 3,4-bond in preference to the 2,3-bond. Irradiation of ap-unsaturated amides provides a new route to P-lactams.60 For example the cis-p-lactam (30;R = H) and its trans-isomer are obtained in low yield from the unsaturated amide (29 ;R = H). In the case of the amide (29 ;R = Ph) the yield is improved and in both examples the cis-isomer predominates a result of some importance since the thermodynamically mure stable trans-isomers are generally obtained by other procedures.Similar irradiation of a-substituted cinnamic and crotonic acids promises to be a valuable route to p-lactones in which the cis-lactone is again the major isomer. Cycloaddition of a keten and an amidine constitutes a new synthesis of substituted 4-aminoazetidin-2-0nes.~’Thus diphenylketen and 4-(N-phenylformimidoyl)morpholine gives the crystalline f3-lactam (3 1). (29) (3 0) ” R. N. Pratt and G. A. Taylor Chem. and Ind. 1967,1324. 58 E. Schmitz R. Ohme and S. Schramm Chem. Ber. 1967,100,2600. ” A. Padwa R. Gruber and L. Hamilton J. Amer. Chem. SOC.,1967,89,3077. 6o 0.L. Chapman and W. R. Adams J.Amer. Chem. SOC. 1967,89,4243. 61 A. K. Bose and I. Kugajevsky Tetrahedrun 1967,23,957. 382 R. J. Stoodley Not surprisingly these substituted p-lactams are very sensitive to moisture although the direction of cleavage is determined by the electronic nature of the C-3 substitutents. While the 3,3-dialkyl derivatives undergo disruption of the 1.4-bond to give amido-aldehydes the 3.4-bond is broken in the 3,3-diphenyl derivatives and the diphenylacetanilides are formed. 4-Alkoxyazetidin-2-ones may be formed from isocyanates and vinyl ethers. In the case of sulphonyl isocyanates and cis-1-ethoxybut-1 -ene this cycloaddition is stereospecific and only the cis-4-ethoxy-3-ethyl-1-sulphonylazetidin-2-one is formed while with trans-1-ethoxybut-1-ene a mixture of trans-and cis-p-lactams is produced in the ratio of 9 1.62 These results imply that the cycloadditions are mainly concerted processes although the dipolar intermediate (32) may be implicated in the thermal equilibration of each isomer to give a mixture containing 73 % of the trans-and 23 % of the cis-p-lactam.6-a-Hydroxypenicillanic acid (33 ; R = H) may be obtained from the deamination of 6-P-aminopenicillanic acid.63 The carbonyl group of the p-lactam might be expected to provide some activa- tion to nucleophilic displacement of potential leaving groups at C-6 although in the case of the methanesulphonate (33; R = S0,Me) preferential rupture of the p-lactam occurs. The isolation of highly strained 6-diazopenicillanic acid derivatives during deamination does indicate however activation of the hydrogen at C-6 by the p-lactam carbonyl.An interesting example of carbonyl participation in the formation of a four- membered ring is observed in the reaction of 3-phenylsulphonyloxy-2,2-diethylpropanal with meth~xide.~~ The derived acetal 3,3-diethyl-2-methoxy- oxetan may be cleaved with base to give 2-ethyl-1-methoxybut-1-eneand formaldehyde. The photocyclisation of aldehydes and ketones to olefins has been widely studied and oxetans are the major products. The scope of this reaction has now been extended to include the preparation of oxetans which are functionalised at C-Z6’ Thus styrene and diethyl oxalate give 2-ethoxy-2- ethoxycarbonyl-3,3-diphenyloxetan. Double addition of benzophenone to allene occurs under photochemical conditions to give the novel dioxaspiro- heptanes [e.g.(34)J.66 Irradiation of thiobenzophenone in the presence of F. Effenberger and G. Kiefer Angew. Chem. Internat. Edn. 1967,6,951. 63 D. Hauser and H. P. Sigg Helu. Chim. Acta 1967,50 1327. ‘* J. JanEulev F. Nerdel D. Frank and G. Barth. Chem. Ber. 1967 100 715; F. Nerdel and H. Kressin Annalen. 1967,707 1. ‘’ Y. Odaira T. Shimodaira and S. Tsutsumi Chem. Comm. 1967 757; Y. Shigemitsu Y. Odaira and S. Tsutsumi Tetrahedron Letters 1967 55; M. Hara Y. Odaira and S. Tsutsumi ibid. 1967,2981 ;T. Tominaga Y. Odaira and S. Tsutsumi Bull. Chem. SOC.Japan 1967,40 2451. 66 D. R. Arnold and A. H. Glick Chem. Comm. 1966,813. Heterocyclic Chemistry but-2-ene gives 1 ,1-diphenylpropene implying that the thietan undergoes desulphurisation.However when thiobenzophenone is irradiated in the presence of a-phellandrene the thietan (35) is formed together with 1,4-cycloaddition products,67 while the 1,4-dithian (36) is observed in the presence of cyclohexene.68 The interaction of a sulphur atom with a carbonyl group in its excited state may lead to some interesting rearrangements6' Thus thietan-2- one and t-butyl2-mercaptoethylpropionateare produced in the irradiation of thiacyclohexan-4-one in t-butyl alcohol. The thietanone (37) is implicated in the photorearrangement of isothiochroman-4-one to thiochroman-3-one since the corresponding thietanone (38) is formed in the irradiation of 3-methyl-A3-dihydrothiopyran-5-one.(3 (37) (3 8) Thiets are of interest because by loss of a proton they should give ions which are isoelectronic with cyclopentadienide. The unsubstituted thiacyclobutene has now been prepared and it undergoes ring opening with 2,4-dinitrophenyl- hydrazine to give the hydrazone of 3-mercaptopropanal.'O The desaurins. which are formed from deoxybenzoins and carbon disulphide in the presence of base are remarkable compounds since although they incorporate two sulphur atoms in a four-membered ring they are incredibly stable and unreactive. An X-ray crystallographic study has revealed that the desaurin obtained from acetophenone possesses the trans-configuration (39).71 Moreover the S-0 bond distance is 2-64A which is considerably less than the sum of the Van der Waal's radii of these atoms (ca.3-15 A) and it is tempting to suggest that tetra- covalent sulphur is stabilised in an aromatic framework (40). Five-membered Rings with One Heter+atom.-Evidence for the intermediacy 67 Y. Omote M. Yoshioka K. Yamada and N. Sugiyama J. Org. Chem. 1967,32,3676. G. Tsuchihashi M. Yamauchi and M. Fukuyama Tetrahedron Letters 1967 1971. 69 P. Y. Johnson and G. A. Berchtold J. Amer. Chem. SOC.,1967,89 2761; W. C. Lumma jun. and G. A. Berchtold ibid. 1967,89 2761. 'O D. C. Dittmer K. Takahashi and F. A. Davis Tetrahedron Letters 1967,4061. 'I T. R. Lynch I. P. Mellor S. C. Nyburg and P. Yates Tetrahedron Letters 1967 373. 384 R. J. Stoodley Ph (39) (40) of acetylenedicarboxylic acid imide in the thermal decomposition of 1,4-dithiintetracarboxydi-imides (41) comes from the isolation of the mellitri- imide (42) in good yield.72 In contrast attempts to trap acetylenedicarboxylic acid anhydride have been unsuccessful.73 R The irradiation of nitrones is known to yield the isomeric oxaziridines.Steric factors play an important role in the formation of the three-membered ring since 5,5-dimethyl-2,4-diphenyl-A'-pyrroline1-oxide gives only the trans-isomer (43).74 The oxaziridine (44)is isomerised to 3,3,5,5-tetramethyl-2-pyrrolidone on heating at 150" and similar rearrangements occur with the oxaziridines (45) and (46) at 300". However l-acetyl-3,3-dimethylazetidine is the major product from the oxaziridine (46) at I 50°.75The authors suggest that the oxaziridine ring may cleave in two ways although the results can be accom- modated by a single heterolytic cleavage of the N-0 bond.Migration of the methyl group or the ring methylene group to the electrophilic nitrogen centre may occur depending upon their migratory aptitudes and upon the steric interactions involved in the respective transition states Migration of the ring methylene group would be expected to be most favourable when there are no substitutents at C-3 and C-5 and indeed this is the occasion when ring con- traction occurs. It is interesting to note that similar products are obtained from oxaziridines (44) and (46) under photochemical condition^,^^ suggesting that similar intermediates may be involved. The first quantitative comparisons of the reactivity of hetero-aromatic five- membered rings in electrophilic substitutions have been made.77 For example 72 W.Draber Angew. Chem. Internat. Edn. 1967,6 75. 73 J. I. Jones Chem. Comm. 1967,938. 74 J. B. Bapat and D. St. C. Black Chem. Comm. 1967,73. 75 L. S. Kaminsky and M. Lamchen J. Chem. SOC.(C),1967,2128. 76 L. S. Kaminsky and M. Lamchen J. Chem. SOC.(C),1966,2295. 77 S. Clementi F. Genel and G. Marino Chem. Comm.,1967 498; P. Linda and G. Marino Tetrahedron 1967,23,1739. Heterocyclic Chemistry 385 in trifluoroacetylation the relative reactivity of pyrrole furan and thiophen is 2 x lo8:1.5 x lo2:1. There has been considerable interest in recent years in the stepwise synthesis of porphyrins especially by routes which will allow specific isotopic labelling.The Liverpool school have published details of their a and b-oxabilane routes which are exemplified in the syntheses of mesoporphyrin-IX protoporphyrin- IX chlorocruoroporphyrin and pernpt~porphyrin.~~ The Nottingham school have applied their cyclisation of 1-bromo- 1,19-dideoxy- 19-methylbiladiene-ac dibromide to the preparation of deuteroporphyrin-IX and pemptoporphyri~i.~ Electrophilic substitutions of porphyrins occur preferentially at the meso-position and a similar positional reactivity is observed with ethoxycarbonyl- nitrene.80 For example with this reagent the porphyrin (47; R = H) gives the ring enlarged derivative (48) which on heating ring contracts to the meso-substituted porphyrin (47; R = NH-C0,Et).Although the structure of M Et Me E NH N-M a Me R -N C0,Et N HN -N HN Et \ / / Me Et \ \ \ Me Me Et Me Et (471 (4 8) chlorophyll is known in considerable detail the absolute configurations of the methyl group at C-7 and the propionic ester group at C-8 were not established. These have now been shown to possess the 7s and 8R configura-tiomB1 Previously gas chromatography has had little application in por- phyrin chemistry. However the report that dietioporphyrin-I may be con- verted into a volatile tetracovalent silicon derivative illustrates the potential of this technique.82 " A. H. Jackson G. W. Kenner and G. S. Sach J. Chem. SOC.(C) 1967 2045; R. P. Carr P. J. Cook A. H. Jackson and G. W. Kenner Chem. Cornm. 1967 1025; A.H. Jackson G. W. Kenner and J. Wass ibid. 1967 1027; M. T. Cox R. Fletcher A. H. Jackson G.W. Kenner and K. M. Smith ibid. 1967 1141. l9 P. Bamfield R. Grigg R. W. Kenyon and A. W. Johnson Chem. Comm. 1967,1029. R. Grigg Chem. Comm. 1967 1238. I. Fleming Nature 1967,216 151. 82 D. B. Boylan and M. Calvin J. Amer. Chem. SOC. 1967,89 5412. 386 R. J. Stoodley Johnson and his co-workers have described a very convenient three step synthesis of a nickel corrin perchlorate starting with readily available pyrrolic precursor^.^^ The key step is the high pressure hydrogenation of the tetra- dehydrocorrin salt (49) to give the corresponding corrin (50). However this reduction is only successful when there is no severe steric crowding of the Me Me Me I+ I( M Me e rN y‘N t ClO c10; Me Me Me (49) (50) final double bond in the intermediate monodehydrocorrin.Eschenmoser and his collaborators have completed an elegant total synthesis of dicyano- (1,2,2,7,7,12,12-heptamethylcorrin)cobalt (III).84 The final step in the synthesis of corrin complexes requires the template effect of a metal cation such as cobalt (111) or nickel (11) but unfortunately these complexes are too stable to permit conversion into metal-free corrins. This problem has been ingeniously solved by the Swiss workers who have developed a novel cyclisation procedure which may be achieved with the labile zinc complex. The method for construct- ing the vinylogous amidine linkage is summarised in Scheme 1,and it has been successfully applied to the synthesis of 15-cyan0-1,2,2,7,7,12,12-heptamethyl-corrin hydrochloride (51).8 Dicyano-(7,7,12,17-tetramethylcorrin)cobalt(111) (52)undergoes preferential electrophilic substitution at position 15 with chloro- sulphonyl isocyanate while in basic media selective deprotonation occurs at position 8.Similar results are obtained with (7,7,12,12,18-pentamethylcorrin)-nickel(I1) chloride.86 Nickel 1-methyltetradehydrocorrins [e.g. (53)] are thermally rearranged to 2,2-disubstituted corroles [e.g. (54)],which the authors regard as examples of 1 - 17 alkyl shifts although they give no reasons for rejecting the direct 1 + 5 alkyl shifts.87 A new indole synthesis has been developed which involves treating an aro- matic ketone with an isocyanide in the presence of boron trifluoride.88 For example 1 -t-butyl-3-phenylindole-2-carboxylicacid t-butyl amide is readily formed from benzophenone and t-butyl isocyanide.Although the yields are 83 R. Grigg A. W. Johnson and P. van den Broek Chem. Comm. 1967 502. 84 I. Felner A. Fischli A. Wick M. Pesaro D. Bormann E. L. Winnacker and A. Eschenmoser Angew. Chem. Internat. Edn. 1967,6,864. 85 A. Fischli and A. Eschenmoser Angew. Chem. Internat. Edn. 1967,6,866. 86 D. Bormann A. Fischli R. Keese and A. Eschenmoser Angew. Chem. Internat. Edn. 1967 6 868. R. Grigg A. W. Johnson K. Richardson and K. W. Shelton Chern. Cornrn. 1967,1192. B. Zeeh Tetrahedron Letters 1967 3881. Heterocyclic Chemistry 387 i ii - Meb-aMe H-Me / C CN Me Me iii iv v I Me N-Me (51) SCHEMI~ 1 Reagents i H,S-CF CO,H ; ii Zn(C10,) ; iii (Ph CO 0),; iv CF CO,H+thylenediaminetetra-acetic acid ; v Zn(C104)? ; vi (Ph),P; vii CF C0,H-MeCN only moderate the conditions are very mild and by employing an aliphatic ketone and an aromatic isocyanide the procedure may be adapted to the synthesis of in dole nine^.^^ Electrophilic substitution of indoles takes place mainly at C-3 but if this site already contains a substituent then 2,3-disubsti- tuted indoles may be formed.It has now been shown that direct substitution at C-2 probably does not occur but rather a 3,3-disubstituted indolenine is first formed which rearranges to the product.” Thus degradation of the tetrahydrocarbazole obtained from the tritiated indolylbutanol (55) reveals Me Me Me Me Me Me-Me Me 15 Et Me Et J (53) (5 4) 89 B.Zeeh Angew.Chem. Internat. Edn. 1967,6,453. A. H. Jackson and P. Smith Chem. Comm. 1967,264. N* R. J. Stoodley * (55) * tritium labelled that only half of the radioactivity is found at C-4 and the remainder at C-1. The indole Grignard reagents are alkylated and carbonated mainly at C-3 while alkali metal derivatives give predominantly 1-substituted products. A study of the protonation of these organometallic derivatives corroborates this reactivity although the extent of protonation at C-3 of the indole Grignard is remarkably dependent upon the amount of water added.” With a moderate excess of water up to 75 % of the C-3 protons are exchanged while with a large excess of water no exchange at C-3 occurs.The course of the reduction of some indole and quinoline derivatives with lithium and methanol in liquid ammonia depends upon when the alcohol is added to the reaction mi~ture.’~ For example reduction of 5-methoxy- 1-methylindole occurs in the heterocyclic ring to give 5-methoxy-1 -methylindoline if methanol is added near the end of the reaction while 4,7-dihydro-5-methoxy-l-methylindole is the major product if methanol is present throughout the reaction. The rate of acid-catalysed proton exchange of 5-hydroxytryptophan is position 4 > 6 > 2 > 7 9a,P and conditions have been found which permit the selective deuterium labelling at each position in the aromatic nucleus.93 The 4-azapentalenyl anion is of interest because it is isoelectronic with the pentalenyl dianion.The lithium salt of this anion which may be obtained from 3H-pyrrolizine and n-butyl-lithium is quenched with deuterium oxide to give 3-deuterio-3H-pyrrolizine and it reacts with benzophenone to give a fulvene derivative which is probably the result of attack at position 3.94 These results suggest that the resonance form (56)makes an important contribution to the azapentalenyl anion structure. The 7-thiapentalenyl anion (57) has also been prepared but it is difficult to assess its site of highest electron density because of methyl ~ubstitution.~’ 91 J. C. Powers W. P. Meyer and T. G. Parsons J. Amer. Chem. Soc.1967,89,5812. 92 W. A. Remers G. J. Gibs C. Pidacks and M. J. Weiss J. Amer. Chem. Soc. 1967.89 5513. 93 G. W. Kirby S. W. Shah and M. Sandler Chem. Comm. 1967,819. 94 W. H. Okamura and T. J. Katz Tetrahedron 1967,23,2941. 9’ T. S. Cantrell and B. L. Harrison Tetrahedron Letters 1967,447’7. Heterocyclic Chemistry 389 When tetrahydrofurfuryl alcohol which is CI4-labelled in the exocyclic methylene group is passed over hot alumina it is rearranged to A2-dihydro- pyran which is equally radioactive at C-2 and at C-6. Under similar conditions the radioactivity in A*-dihydropyran which is present specifically at C-6 is randomised between C-2 and (2-6. However this rearrangement is not the result of double-bond isomerisations since A3-dihydropyran is not converted into the A2-isomer under the reaction condition^.^^ The oxonium ion (58) may account for these observations as shown in Scheme 2 in which a 1 5 hydride transfer is implicated.The lithium aluminium hydride complex of 3-0-benzyl- 1,2-O-cyclohexylidene-ar-~-glucofuranose appears to be a valu- able reagent in asymmetric synthesis since it reduces ketones to alcohols which possess the S-c~nfiguration.~' A maximum of 40% selectivity has been observed in these reductions. i,l. 6>. = CH,OH -()* SCHEME2 The oxetone (59)and its dihydro-derivative have been isolated from hop and 3S-4,5-dihydroxy-6-methoxy-3-methylphthalan (60) is formed by Cur- oularia ~iddiyui.~~ These are the first examples of naturally occurring oxetone and phthalan derivatives.It is commonly assumed that the coupling constants of protons at C-2 and C-3 in 2,3-disubstituted-2,3-dihydrobenzofuransare larger for cis-than for trans-isomers. However examples in which this situation is reversed have been recorded."' A number of new syntheses of substituted furans have been developed. For example P-chloroallyl ketones (61) which are readily available from alkylation of enolate ions are masked 1,4-diketones and may be cyclised to furans under acid conditions. Ethoxycarbonylcarbene which is conveniently generated in the copper-catalysed decomposition of diazoacetic ester adds to ar-methoxy- methylene ketones in an unusual 1,4-manner to provide an efficient synthesis of 2,3-substituted furans.lo2 96 W.J. Gender J. E. Stouffer and R. G. McInnis J. Org. Chem. 1967 32 200; G. Descotes B. Giroud-Abel and J.-C. Martin Bull. SOC.chim. Frunce 1967 2472. 91 S. R. Landor B. J. Miller and A. R. Tachell J. Chem. SOC.(C),1966,2280. 98 Y. Naya and M. Kotake Tetrahedron Letters 1967 1715. 99 A. A. Qureshi R. W. Rickards and A. Kamal Tetrahedron 1967,23 3801. loo L. H. Zalkow and M. Ghosal Chem. Comm. 1967,922. E. J. Nienhouse R. M. Irwin and G. R. Finni J. Amer. Chem. SOC.,1967,89 4557. lo' D. L. Storm and T. A. Spencer Tetrahedron Letters 1967,1865. 390 R.J. Stoodley Furan undergoes a photosensitised decarbonylation in the presence of mercury vapour at 2537 A in which its Diels-Alder adducts with cyclopropene and cyclopropenecarbaldehyde are also formed.In the presence of methanol vapour methyl but-3-enoate is produced implicating the intermediacy of the keten (62).'03 A possible decomposition route is illustrated in Scheme 3. hv CH2=CH*CH=C=0 H bHO -D + co SCHEME 3 The stereochemistry of the substituted cyclopropanes obtained from the irradiation of methyl-substituted 5-phenyl-A2-dihydrofurans,implies that the ring closure of the intermediate diradicals is sterically controlled. Thus a mixture of cis-and trans-4-methyl-5-phenyl-A2-dihydrofurans is isomerised to the cyclopropanecarbaldehyde (63).'04 Two new photoadducts (64)and (65) have been isolated from the irradiation of furan in the presence of benzo- phenone. Ph H Ph H Ph The elegant work of Wynberg and his collaborators has contributed signifi- cantly to an understanding of the photochemical behaviour of a number of arylthiophens.lo6 For example 2-phenylthiophen is irreversibly rearranged to the 3-phenyl isomer on irradiation in ether. A phenyl migration is not involved R. Srinivasan J. Amer. Chem. Soc. 1967,89 1758,4812. Io4 P. Scribe M. R. Monot and J. Wiemann Tetrahedron Letters 1967 5157. M. Ogata H. Watanabe and H. KanZi Tetrahedron Letters 1967 533; J. Leitich ibid. 1967 1937 G. R. Evanega and E. B. Whipple ibid. 1967,2163. lo6 H. Wynberg H. van Driel R. M. Kellogg and J. Buter J. Amer. Chem. Soc. 1967,89 3487; R. M. Kellogg and H. Wynberg ibid. 1967,89,3495; H. Wynberg R. M. Kellogg H. van Diel and G. E. Beekhuis ibid. 1967 89 3501. Heterocyclic Chemistry 391 in this reaction since 2-phenyl[2-14C]thiophen gives 3-phenyl[3-14C]-thiophen.The major pathway for the isomerisation which has been elucidated from a study of 5-deuterio-2-pentadeuteriophenylthiophenand methyl-substituted 2-phenylthiophens requires an interchange of position 2 and position 3. The simplest mechanism for this rearrangement involves the for- mation of the cyclopropenethiocarbaldehyde (66) which undergoes ring- expansion to 3-phenylthiophen. Although 3-phenylthiophen is stable to further photorearrangement a study of 2-deuterio-3-pentadeuteriophenylthiophen reveals that complete randomisation of the deuterium occurs ; clearly this result cannot be accommodated by the above mechanism. Evidence for the intermediacy of tetravalent sulphur species comes from pyrolytic studies on a number of sulph~xides.'~~ Thus when the sulphoxide (67) is heated in acetic anhydride in the presence of N-phenylmaleimide the exo-adduct (69) and its endo-isomer may be isolated implicating the existence of the intermediate (68).0s Five-membered Rings with Two or More Hetero-Atoms.-l,3-l)ipolar cycio-addition reactions have received considerable attention in recent years and the principle is particularly valuable in heterocyclic synthesis. Thus the nitrile imine generated from N-a-chlorobenzy1idene)-N'-phenylhydrazine reacts with olefins to provide a useful route to A2-pyrazolines.'o* The reaction is stereo- specific since the cis-pyrazoline (70)is obtained in the presence of cis-but-2-ene and the trans-isomer is formed from trans-but-2-ene.Dimethyl sulphoxonium methylide will also behave as a dipolarophile undergoing double methylene insertion with the above nitrile imine and related 1,3-dipoles. gem-Dihalo-lo' M.P. Cava and N. M.Pollack J. Amer. Chern. SOC. 1967 89 3639; R. H. Schlessinger and I. S. Ponticello ibid. 1967,89 3641 ;Tetrahedron Letters 1967,4057. "* R. Huisgen H. Knupfer R.Sustmann G. Wallbillich and V. Webendorfer Chem. Ber. 1967 100 1580; J. S. Clovis A. Eckell R. Huisgen R. Sustmann G. Wallbillich and V. Webendorfer ibid. 1967 100 1593; R. Huisgen R. Sustmafin and G. Wallbillich ibid. 1967 100 1786. lo9 G. Gaudiano A. Umani-Ronchi P. Bravo and M. Acampora Tetrahedron Letters 1967,107. 392 R. J.Stoodley genocyclopropyl acetates which are available from enol acetates and phenyl- (trichloromethyl)mercury,react with an excess of hydrazine to give pyrazoles.l10 This reaction which proceeds via intermediate a-chloro-a$-unsaturated ketones is novel and of general synthetic utility. 4-Hydroxypyrazoles are relatively inaccessible but reduction of the 3,4-diazocyclopentadienonedioxide (7 l) which is available from the reaction of nitrous acid with af3-unsaturated oximes appears to be a useful route to their synthesis.'" -0 (70) (71) The photochemical behaviour of pyrazoles indazoles and pyrazolin-5-ones has been examined and in many cases there is a close resemblance to thiophen reactivity.' For example N(1)-alkyl pyrazoles N(2)-alkyl indazoles and C(3)-alkyl pyrazoles or indazoles all give the corresponding imidazoles or benzimidazoles in which an interchange of the N-2 and C-3 atoms occurs.In the case of N(1)-alkyl indazoles cleavage of the N-N bond takes place in the initial step but a hydrogen transfer successfully competes over other pathways and 2-alkylamino-benzonitriles are formed. Irradiation of 2,3-dimethyl-1-phenyl-3-pyrazolin-5-one (72;R = H) in methanol gives the imidazolidinone (74) and urethan (75) and both products may be considered to arise from an intermediate a-lactam (73 ; R = H). Interestingly the pyrazolin-5-one (72; R = NMe,) is transformed into the imidazolidone (76) when irradiated in formamide. The results may still be accommodated by an intermediate a-lactam (73 ;R = NMe,) which possessing an electron-releasing substituent at position 3 is opened by 1,3-bond cleavage; incorporation of formamide and loss of dimethylamine could then account for the formation of the product.R J===YeJ?L0d+ge -Me cr + AcCH,NPh -C0,Me Ph Ph Ph (75) (73) / (74) Me rlNMe PhNH-OCIN& H c16) 'Io W. E. Parham and J. F. Dooley J. Amer. Chem. Soc. 1967,89,985. J. P. Freeman and D. L. Surbey Tetrahedron Letters 1967,491 7. ''' H. Tiefenthaler W. Diirscheln,H. Goth,and H. Schmid Helv. Chim. Acta 1967,50,2244; S. N. EgE Chem. Comm. 1967,488; J. Reisch and R. Pagnucco Chem. and Id. 1967 1646. Heterocyclic Chemistry 393 An amino-Claisen rearrangement is observed when 2-allyl-l-phenyl-3-pyrazolin-5-one is heated the ally1 group migrating to position 4.'13 The bicyclic ketone (77; R = Ph) is known to undergo many diverse transforma- tions.In continuation of this work Moore and his collaborators have unravelled some remarkable chemical intricacies. The reactivity of the ketones (77 ; R = Ph) and (77; R = Me) depends upon the nature of R and upon the reaction conditions."4 For example the compound (77; R = Ph) is rearranged to the isomer (78) on heating in benzene although no reaction occurs with the ketone (77 ;R = Me). The thermal isomer (78) is ring expanded to the bicyclic oxadi- azine (79) in the presence of a weak base a reaction which is reminiscent of the N-acylaziridine to oxazoline rearrangement. In the presence of methanolic sodium methoxide the ketone (77; R = Ph) is converted into a mixture of l-benzoyl-3-methyl-4-phenyl-3-pyrrolin-2-one and 6-benzamido-4-methyl-5- phenylpyridine and similar products are obtained with its counterpart (77; R = Me).However with aqueous hydroxide the benzoyl ketone (77; R = Ph) gives mainly l-amin0-2-phenylbut-l-en-3-one, while the acetyl ketone (77 ; R = Me) is converted into a mixture of 4-amino-3-hydroxypiperidin-2-ones and 3-hydroxy-4-methyl-5-phenylpiperidin-2-one. Isoamic acid which is formed from isatin and ammonia is considered to have structure (80) or (81)."' On irradiation the acid is rearranged to an isomer (83) which may be considered to arise from the diazirine intermediate (82).'16 The photochemical behaviour which is analogous to the nitrone to oxaziridine transformation is the first example of this type in which nitrogen migration occurs.The properties of azapentalenes are governed to a striking extent by the position of the hetero-atoms. Thus the azapentalenes (84) and (85)show pro- nounced aromatic character as revealed by their thermodynamic stability chemical reactivity and electronic spectra.' In these heteroaromatics the 'I3 Y. Makisumi Tetrahedron Letters 1966 6413. J. A. Moore H. Kwart G. Wheeler and H. Bruner J. Org. Chem. 1967,32 1342; J. M. Eby and J. A. Moore ibid. 1967 32 1346; J. A. Moore R. L. Wineholt F. J. Marascia R. W. Medeiros and F. J. Creegan ibid. 1967,32 1353; W. J. Theuer and J. A. Moore ibid. 1967 32 1602. 'I5 P. de Mayo and J. J. Ryan Chem. Comm. 1967,88; Canad.J. Chem. 1967,452177. 'I6 P. de Mayo and J. J. Ryan Tetrahedron Letters 1967,827. R. A. Carboni J. C. Kauer J. E. Castle and H. E. Simmons J. Amer. Chem. SOC. 1967 89 2618; R. A. Carboni J. C. Kauer W. R. Hatchard and R. J. Harder ibid. 1967,89,2626; J. C. Kauer and R. A. Carboni ibid. 1967 89 2633; Y. T. Chid and H. E. Simmons ibid. 1967 89 2638; R. J. Harder R. A. Carboni and J. E. Castle ibid. 1967,89 2643. 394 R. J. Stoodley H H (80) H (83) four nitrogen atoms contribute six electrons the the x-system and they are therefore isoelectronic with naphthalene and pentalenyl dianion. The azapenta- lene (85) shows no tendency to undergo valence tautomerism to the tetra- azacyclo-octatetraene derivative and indeed it has been suggested that the latter compound would be converted exothermically and spontaneously into the azapentalene.This statement certainly does not apply to the related dibenzo- [b f][1,5]diazocine (86) which has now been prepared and shows no tendency to isomerise to the aromatic diazopentalene.' (84) (85) (86) Dihydrobenzimidazoles may be readily obtained from anils (87) in the presence of a trace of acid.11g The failure to observe deuterium incorporation in the presence of deuteriochloric acid demonstrates the intramolecular nature of the reaction and suggests that a hydride transfer may be involved as shown in Scheme 4. Similar hydrogen transfers may be initiated by thermal or photo- chemical excitation in related systems. I2O '" W. W. Paudler and A.G. Zeiler Chem. Comm. 1967 1077. 0.Meth-Cohn and M. A. Naqui Chem. Comm. 1967,1157. I2O H. Suschitzky and M. E. Sutton Tetrahedron Letters 1967,3933;I. Baxter and D. W. Cameron Chem and Id. 1967 1403; D. J. Neadle and R. J. Pollitt J. Chem. SOC.(C) 1967 1764. Heterocyclic Chemistry -H+ (87) SCHEME 4 An improved route to 4-phenyl-1,2,4-triazolin-3,5-dioneinvolves lead tetra-acetate oxidation of its dihydro-derivative. This potent dienophile reacts with mono-olefins containing allylic hydrogen to give products [e.g. (SS)] in which a shift of the double bond has occurred and it is estimated to be approximately 3 x lo4 times more reactive than diethyl azodicarboxylate in this reaction.’ 22 The conversion of cis-l,2-di-p-tolylsulphonylethyleneto 4-p-tolylsulphonyl-lH-l,2,3-triazole with sodium azide in dimethyl sulphoxide is the first example of the formation of a triazole from a vinyl azide.lz3 The reaction presumably involves an anion in which the electron pair is cis to the azide function.R Me Me s-s-s The 6a-thiathiophthens are of interest since they may be regarded as further examples in which tetracovalent sulphur is stabilised by aromaticity In this context the thiathiophthen (89; R = H) is brominated in high yield under normal conditions to give the monobromo-derivative (89 ; R = Br).124 The 1,2-dithiolium cation is readily attacked by nucleophiles since the ether (91; X = 0)and thioether (91; X = S) are readily formed from 4-phenyl- 1,2-dithiolium hydrogen sulphate (90).12’ 12’ B.T. Gillis and J. D. Hogarty J. Org. Chem. 1967,32 330. 122 W. H. Pirkle and J. C. Stickler Chem. Comm. 1967 760. J. S. Meek and J. S. Fowler J. Amer. Chem. SOC. 1967,89 1966. lZ4 R. J. S. Beer D. Cartwright and D. Harris Tetrahedron Letters 1967,953. 12’ H. Newman and R. B. Angier Chem.Comm. 1967,353. 396 R. J. Stoodley Oximes may now be added to the list of 1,3-dipoles since they undergo cycloaddition with activated olefins ;this reaction provides a new preparative route to isoxazolidines.'26 It appears to be stereospecific since cis-4,5- bismethoxycarbonyloxazolidine is formed from formaldehyde oxime and dimethyl maleate while the trans-isomer is obtained from dimethyl fumarate. Low temperature chlorination of aldoximes in ether offers a new synthesis of chloro-oximes which serve as nitrile oxide precursors.' 27 The simplest example of these 1,3-dipoles fulminic acid may be trapped with methyl acrylate to give 5-methoxycarbonyl-A2-isoxazoline.'28 Use of a P-amino-substituted a$-unsaturated ester as the dipolophile causes reversal of this usual direction of cycloaddition and provides a general synthesis of isoxazole-4-carboxylic acids.' 29 Generally nitrile oxides do not undergo cycloaddition with aliphatic aldehydes or ketones although these reactions may be induced by use of boron trifluoride.'30 This is the first report of a cycloaddition reaction which is subject to electrophilic catalysis; an example is the formation of the dioxazole (92) from benzonitrile oxide and acetone.Mesoionic oxazolones which have been extensively investigated by Huisgen and his collaborators are examples of azomethine ylids and they show unusual 1,3-dipolar reactivity.' 31 For example the diphenyloxazolone (93) reacts readily with methyl propiolate to give 1-methyl-2,5-diphenyl-pyrrole-3-carboxylicester and carbon dioxide. The oxazole (93) shows similar reactivity towards hetero-multiple bonds ; thus 2,5-diphenyl-4-ethoxycarbonyl-l-methylimidazole and the mesoionic thiazole- thione (94) are formed from ethyl cyanoacetate and carbon disulphide respec- tively. However 4-methyl-2,5-diphenyl- 1,2,4-triazole and tetraethoxycarbonyl- hydrazine are formed from its reaction with diethyl azodicarboxylate which suggests that the expected azomethine ylid transfers two ethoxycarbonyl groups to a second molecule of the ester.In the reaction of the oxazole (93) with aldehydes ketones thiobenzophenone and nitrosobenzene the derived azomethine ylids cannot effectively stabilise their charge and consequently ring-opened products are observed. It is remarkable that no loss of carbon dioxide occurs in its reaction with benzylidenemethylamine and the formation of the p-lactam (96) implies that the keten (95) is an intermediate. This result is of special interest since a crystallographic study of the closely related syd- nones suggests that a bent keten makes a significant contribution to their structure.' 32 Sydnones are less reactive 1,3-dipoles than the mesoionic oxazo- lones. Thus although 3-phenylsydnone (97) reacts with phenyl isocyanate 126 M.Ochiai M. Obayashi and K. Morita Tetrahedron 1967 23 2641 ; E. Winterfeldt and W. Krohn Angew. Chem. Internat. Edn. 1967 6 709; A. Lablanche-Combier M. Villaume and R. Jacquesy Tetrahedron Letters 1967,4959. 12' G. Casnati and A. Ricca Tetrahedron Letters 1967,327. R. Huisgen and M. Christl Angew. Chem. Internat. Edn. 1967,6,456. 129 G. Stork and J. E. McMurry J. Amer. Chem. SOC.,1967,89,5461. 130 S. Morrocchi A. Ricca. and L. Velo Tetrahedron Letters 1967 331. 13' R. Huisgen E. Funke F. C. Schaefer H. Gotthardt and E. Brunn Tetrahedron Letters 1967 1809; R. Huisgen and E. Funke Angew. Chem. Internat. Edn. 1967,6. 365; R. Huisgen E. Funke F. C. Schaefer and R Knorr ibid. 1967,6 367. 132 W.E. Thiessen and H. Hope J. Amer. Chem. SOC.,1967,89,5977. Heterocyclic Chemistry 397 -P L2Ph -:GjPh Me Me (92) (93) (94) 0 Ph CO-NMePh I NJPh -phk pn:Me I Me (95) to give the mesoionic derivative (98) no reaction occurs with phenyl isothio- cyanate or with carbon disulphide.' 33 However the closely related 1,3,4- thiadiazoles [e.g. (99)] undergo preferential 1,4-cycloaddition with dimethyl azodicarboxylate to give a new class of six-membered mesoionic compounds [e.g. (loO)].'34 The thermal dissociation of the oxadiazoline (101) to give a-acetoxycyclohexyl phenyl ketone and the epoxy-acetate probably involves the intermediacy of a 1,3-dipolar carbonyl ylid since the adduct (102) may be isolated in the presence of N-phenylmaleimide.' 35 Ph Ph Ph Ph A variety of five-membered ring heterocycles may be synthesised by photo- cyclisation of Schiff bases.13' For example the benzylidene derivative of o-hydroxyaniline is reductively cyclised to 2-phenylbenzoxazole upon irradia- tion while the corresponding o-amino- and o-mercapto-derivatives yield 133 H. Kato S. Sato and M. Ohta Tetrahedron Letters 1967,4261. 134 R. M. Moriarty J. M. Kliegman and R. B. Desai Chem. Comm. 1967 1045. 35 P. Rajagopalan and B. G. Advani Tetrahedron Letters 1967,2689. 13' K. H. Grellmann and E. Tauer Tetrahedron Letters 1967 1909. 398 R.J.Stoodley benzimidazole and benzothiazole. The course of photocyclisation of o-hydroxy- benzaldehyde oxime is solvent dependent ; benzoxazole is formed in water while benzisoxazole is obtained in hexane.A new general class of rearrangements of substituted azoles of the type (103)+ (104) has been recognised. For example 3-acetyl-5-methylisoxazole p-nitrophenylhydrazone is rearranged to 4-acetonyl-5-methyl-2-p-nitrophenyl-1,2,3-triazole when heated while 3-acetyl-4-methylfurazanphenylhydrazone is isomerised to 4-acetyl-5-methyl-2-phenyl-1,2,3-triazole oxime with sodio- dimethyl sulphoxide. Oxazolidines may be dehydrogenated with palladium under mild condi- tion~.~~~ Thus the dimethyloxazolidine (105; R = Me) is slowly converted into dimethyl-2-(N-formyl)piperidylmethanolwhen heated under reflux in ethanol with palladised carbon. However the reaction takes a different course with the diphenyloxazolidine (105; R = Ph) and diphenyl-2-(N-formyl)piperidyl-methane is readily formed.These results suggest that the direction of opening of the cation (106)is controlled by the electronic nature of the 5-substituents. Moreover solvent attack at position 2 is preferred in the reaction with the dimethyl derivative (106;R = Me) while hydride attack at position 5 occurs with the diphenyl intermediate (106;R = Ph). Bis-(o-aminophenyl) disulphide undergoes a curious reaction with cyclo- heptanone in the presence of air and an acid catalyst to give the benzothiazoline (108). ''The expected di-imine which is formed under anaerobic conditions is readily oxidised to the sulphoxide (107) in air and the latter is rearranged to 13' A. J. Boulton A. R. Katritzky and A.M. Hamid J. Chem. Soc. (C) 1967,2005. 138 D. Ghiringhelli and L. Bernardi Tetrahedron Letters 1967 1039. 13' V. Carelli P. Marchini F. M. Moracci and G. Liso Tetrahedron Letters 1967 3421. Heterocyclic Chemistry 399 0- u;D -0;-H H (107) (108) the benzothiazoline by a trace of acid. The reactivity of 2-amino-A2-thiazoline towards electrophilic reagents is interesting since the ring nitrogen is involved in the reactions with alkyl halides sulphonyl chlorides and phenyl isothio- cyanate. It is remarkable that phenyl isocyanate and potassium cyanate are attacked by the 2-amino-gr~up.'~~ The reaction of ketens and imines is a useful route to p-lactams although if the reaction is performed in liquid sulphur dioxide a novel cycloaddition reaction occurs in which solvent is incor- porated.14' For example 2,3-diphenylthiazolidin-4-one1,l-dioxide is formed from benzylideneaniline and keten.Phenyl(trichloromethy1)methanol reacts with methoxide to give methyl a-methoxyphenylacetate. This reaction has been applied to heterocyclic synthesis by use of an ambident nucleophile to open the intermediate epoxide.14' Thus phenyl(trichloromethy1)methanol may be converted into 2-imino-5-phenylthiazolidin-4-one in good yield in the presence of thiourea. Six-membered Rings with One Hetero-atom.-Nitrogen derivatives. There has been considerable controversy in recent years over the relative sizes of a lone pair of electrons and a proton although in general the latter is considered to be larger.Lambert and Keske and their co-workers have studied the n.m.r. spectrum of P-deuterio-piperidine at a temperature in which ring inversion is slow. The results suggest that the conformer with an axial proton on the nitrogen atom is preferred to that with an equatorial proton. The conjugate acids of saturated six-membered heterocycles containing a Group VI hetero-atom also show a similar conformational preference. It has been emphasised that this effect may not be of steric origin. 143 N-Alkylpiperidines exist predominantly in the conformation in which the N-alkyl group is equatorial and they undergo preferential axial quaternisation. Katritzky and his co-workers studied the methylation of 1-ethyl-4-phenylpiperidine and reached the opposite conclusion.However this result has been shown to be in error by McKenna and his co- workers who have also unambiguously demonstrated that l-dideuterobenzyl- 4-phenylpiperidine is preferentially benzylated in the axial position. 144 The 140 D. L. Klayman J. J. Maul and G. W. A. Milne Tetrahedron Letters 1967,281;D. L. Klayman A. Senning and G. W. A. Milne Acta Chem. Scad. 1967,21 217. 14' A. Comes and M. M. Jouillit Chem. Comm. 1967,935. 142 W. Reeve and M. Nees J. Amer. Chem. SOC.,1967,89,647. 143 J. B. Lambert R. G. Keske R. E. Carhart and A. P. Javanovitch J. Amer. Chem. SOC.,1967 89,3761 ;J. B. Lambert R. G. Keske and D. K. Weary ibid. 1967,89 5921. 144 J.-L. Imbach A. R. Katritzky and R. A. Kolinski J. Chem. SOC.(B) 1966 566; D. R. Brown B.G. Hutley J. McKenna and J. M. McKenna Chem. Comm. 1966 719. 400 R. J. Stoodley tautomeric behaviour of many nitrogen-containing heterocycles has been extensively studied. It now appears that 14N n.m.r. spectroscopy is likely to be a valuable probe in this area since it is possible to distinguish the tautomers of 2-hydroxyquinoline by 14N-double-irradiation techniques. 1450 Nitrogen inversion of tertiary amines may be sufficiently slowed down in acid solution to allow detection of both diastereomeric forms by n.m.r. spectroscopy. The energy barrier to such inversion is sufficiently large in 3-phenyltropidine hydrochloride (109) to permit isolation of both isomers. 145b Me Me A number of valuable new synthetic routes to pyridine derivatives have been developed.A general synthesis of P-acylpyridines involves the hydrogenation of 4-(3-oxoalkyl)isoxazoles(1 lo),which are readily available from the alkylation of ketones with 4-chloromethyl-3,5-dimethylisoxazoles.The dihydropyridine (111) formed in this reduction may be readily oxidised to the corresponding pyridine.146 Both halogen atoms of PP-dichlorovinyl ketones may be displaced by aniline and the derived PP-dianilinovinyl ketones may be cyclised to 2-anilinoquinolines with phosphoric acid while P-chlorovinyl aldehydes and primary arylamines cyclise to quinolines when heated in acetic Yields are high in both instances and both routes are useful for preparing quinolines. A variety of active methylene compounds undergo base-catalysed addition to anthranil and to benzofurazan oxide to yield quinoline N-oxides and quin- oxaline di-N-oxides respectively in good yields.148 Thus 2-hydroxy-3- methoxycarbonylquinoline 1-oxide is formed from dimethyl malonate and anthranil.The successful application of the Skraup reaction to the appropriate aminopyridines considerably streamlines the synthesis of 1,6-and 1,8-naphthyridines. 14' The photo-induced oxidative cyclisation of cis-stilbenes to phenanthrene derivatives is well known and the reaction has been extended to benzoic acid amides.' A much more unusual nonoxidative cyclisation occurs with 14' (a) P. Hampson and A. Mathias Chem. Comm. 1967 371; (b) R. E. Lyle and C. R Ellefson J. Amer. Chem. SOC.,1967,89,4563. 146 M. Ohashi K. Kamachi H. Kakisawa and G.Stork J. Amer. Chem. SOC.,1967 89 5460. 14' R. L. Soulen D. G. Kundiger. S. Searles jun. and R. A. Sanchez J. Org. Chem. 1967,32,2661; J. M. F. Gagan and D. Lloyd Chem. Comm. 1967 1043. 148 E. C. Taylor and J. Bartulin Tetrahedron Letters 1967 2337; C. H. Issidorides and M. J. Haddadin J. Org. Chem. 1966,31,4067. 149 W. W. Paudler and T. J. Kress J. Org. Chem. 1967 32 832; T. J. Kress and W. W. Paudler Chem Comm. 1967,3. Is' B. S. Thyagarajan N. Kharasch H. B. Lewis and (in part) W. Wolf Chem. Comm. 1967 614; M. P. Cava and S. C. Havlicek Tetrahedron Letters 1967 2625. Heterocyclic Chemistry 401 a$dimethylacrylic acid anilide ; a mixture of cis-and truns-3,4-dimethyl-3,4- dihydrocarbostyrils is formed. Deuterium labelling reveals that the amide hydrogen and the C-6 aromatic hydrogen are transferred to C-3 of the car- bostyril.‘’’ A remarkable photoinduced hydrolysis of 3-bromopyridine occurs in sodium hydroxide solution to give 3-hydroxypyridine ; the reaction does not occur with 3-chloro- or 3-methoxy-pyridine or with 3-bromonitroben- zene.’ 52 The nitro-group may be converted to a hydroxy-function under photolytic conditions.Thus irradiation of 4-nitropyridine 1-oxide in ethanol in the presence of oxygen gives 4-hydroxypyridine 1 -oxide while 4-hydroxy- aminopyridine 1-oxide is formed if the reaction is performed under nitr~gen.”~ Photoexcitation of the nitrone group of pyridine 1-oxides may lead to de- oxygenation or uiu an oxaziridine intermediate to ring contraction ring expansion or rearrangement.Deoxygenation is favoured with light of short wavelength and the oxygen may undergo insertion reactions with the solvent or the derived pyridine. Pyridinium dicyanomethylide behaves similarly when irradiated in benzene and 7,7-dicyanonorcaradiene is formed together with 2-flfl-di~yanovinyl)pyrrole.’~~ Ring enlargements are observed in the photolysis of quinoline isoquinoline and quinoxaline l-oxides.’55 For example the 1,3-oxepin (1 12) is formed by irradiation of 2-cyano-4-methylquinoline 1-oxide although the N-aminocarbostyril(ll3) can be intercepted in the presence of a secondary amine. Hydrogen-deuterium exchange in pyridine derivatives has attracted con- siderable attention. The rate of acid-catalysed deuterium exchange at positions 3 and 5 of 2,6-dimethyl-4-pyridone is approximately lo5 times that observed for the 4-pyrone and 4-thiapyrone derivatives.lS6 This result shows an interest- ing parallellism to the rates of electrophilic substitution observed for the corresponding five-membered hetero-ar~matics.~~ Cobalt is a valuable catalyst for exchanging the a-hydrogens of a range of pyridine derivatives.’” The rate P.G. Cleveland and 0.L. Chapman Chem. Comm. 1967 1064. G. H. D. van der Stegen E. J. Poziomek M. E. Knonenberg and E. Havinga Tetrahedron Letters 1966 6371. lS3 C. Kaneko I. Yokoe and S. Yamada Tetrahedron Letters 1967 775; C. Kaneko S. Yamada and I. Yokoe Chem. and Pharm. Bull. (Japan),1967.15 356. lS4 J. Streith B. Danner and C. Sigwalt Chem.Comm. 1967 979. lSs 0. Buchardt Tetrahedron Letters 1966 6221 ; 0.Buchardt C. Lohnse A. M. Duffield and C. Djerassi ibid. 1967 2741; C. Kaneko S. Yamada I. Yokoe and M. Ishikawa ibid. 1967 1873; C. Kaneko I. Yokoe and M. Ishikawa ibid. 1967,5237; C. Kaneko and S. Yamada ibid. 1967,5233; 0.Buchardt Acta Chem. Scad. 1967,21 1841; 0.Buchardt and J. Feeney ibid. 1967 21 1399. lS6 P. Bellingham C. D. Johnson and A. R. Katritzky Chem. Comm. 1967,1047. 15’ G. E. Calf and J. L. Garnett Chem. Comm. 1967 306. 402 R. J. Stoodley of exchange of pyridine protons depends upon the reaction conditions and exclusive exchange occurs at positions 2 and 6 for solutions in deuterium oxide and in deuteriochloric acid although the rate diminishes as the amount of protonated pyridine increases.Although the rate of exchange of the 2- and 6-protons is greater than those of the other protons at low base concentration this order is reversed in the presence of high concentrations of sodium deuteri- oxide and the order is 4 > 3 and 5 > 2 and 6.lS8 These results implicate two mechanisms of deprotonation uia the ylid (114; R = H) under neutral or acid conditions and via the anion (1 15) under base conditions. The order of base catalysed deprotonation of 3-chloro- and 3-bromopyridine 1-oxide is position 2 > 6 > 4.”’ This acidity of the a-protons allows alkylation or acylation with preservation of the N-oxide function. For example treatment of 4-chloro- 3-methylpyridine 1 -oxide with n-butyl-lithium followed by carbon dioxide gives 2-carboxy-4-chloro-5-methylpyridine1 -oxide.’6o N-Methylpyridinium salts are similar to N-oxides in their exchange reactivity ; deprotonation occurs much more readily at the a-positions than at the methyl group. In spite of this N-methylpyridinium bromide reacts with benzaldehyde in the presence of piperidine to give the pyridinium salt (1 16) in good yield. This is the result of a more favourable reaction of the ylid (114; R = Me) with a proton source than with the aldehyde. However by decarboxylation of 2-carboxy-N-methylpyridinium chloride the ylid (114; R = Me) is generated under con- ditions of low proton concentration and it may then be trapped with benz- aldehyde.16’ Preferential exchange of the benzene ring protons occurs in quinoline and its 1-oxide under acid conditions.The observed order of reactivity is position 8 > 5 and 6 > 7 and 3 > 2 and 4 in marked contrast to the high reactivity of positions 2 and 4 towards electrophilic nitration. 162 The replace- ment of a hydrazino-group by hydrogen may be used for the selective intro- duction of deuterium. The reaction has been studied in the quinoline iso- quinoline phthalazine quinazoline and pteridine series and aqueous cupric sulphate or oxygen and ethanolic alkali appear to be the most effective reagents.163 15* J. A. Zoltewicz and C. L. Smith J. Amer. Chem. SOC. 1967,89 3358. lS9 J. A. Zoltewicz and G. M. Kauffman Tetrahedron Letters 1967 337; R. A. Abramovitch G. M. Singer and A. R. Vinutha Chem. Comm.1967 55. R. A. Abramovitch N. Saha E. M. Smith and R. T. Coutts J. Amer. Chem. SOC.,1967,89,1537. 161 R. K. Howe and K. W. Ratts Tetrahedron Letters 1967,4743. Y. Kawazoe and M. Ohnishi Chem. and Pharm. Bull. (Japan) 1967,15,826. A. Albert and G. Catterall J. Chem. SOC.(C) 1967 1533. Heterocyclic Chemistry 403 The nucleophilic substitution of hydride ion by organolithium compounds in pyridines is assumed to proceed via an addition-elimination process. Reaction of o-tolyl-lithium with 3-picoline gives 1,2,5,6-tetrahydro-3-methyl-5-o-tolylpyridine in addition to 3- and 5-methyl-2-o-tolylpyridine. The former must be formed from the corresponding dihydropyridyl-lithium and provides the first direct evidence for the two-step mechanism. '64 An oiganolithium compound will displace fluoride from pentafluoropyridine to give 4-alkyl derivatives while in the case of pentachloropyridine metal-halogen exchange occurs.The structure of the pyridyl-lithium depends markedly upon the solvent used ; in methylcyclohexane 2,3,4,5-tetrachloropyridine is the major product after hydrolysis while in diethyl ether 2,3,5,6-tetrachloropyridine is obtained. '65 When 2,3,5,6-tetrachloropyridyl-lithiumis heated under reflux in benzene the adduct (117) is formed which is good evidence for the intermediacy of the 3,4-~yridyne.'~~ The reaction of pentachloropyridine with secondary amines also displays a solvent dependence; substitution at C-2 is observed in benzene while displacement at both C-2 and C-4 occurs in ethanol.Such selectivity is not observed with pentachloropyridine 1-oxide ;in this case 2,6-disubstitution is observed in either solvent.167 (1 15) The reduction of pyridinium quinolinium and isoquinolinium salts to the dihydro- and tetrahydro-derivatives has been extensively studied. An unusual cleavage of a C-C bond occurs in the borohydride reduction of the iso- quinoline salt (1 18) in which 4,5-dimethoxy-7-nitrotoluene and 1,2,3,4-tetra- 164 R. A. Ambramovitch and G. A. Poulton Chem. Comm. 1967,274. 16' J. D. Cook B. J. Wakefield and C. J. Clayton Chem. Comm. 1967 150. J. D. Cook and B. J. Wakefield Tetrahedron Letters 1967,2535. '13' S. M. Roberts and H. Suschitzky Chem. Comm. 1967,893. 404 R. J. Stoodley hydro-6,7-dimethoxy-2-methylisoquinoline are formed.However 1-( 3,4-di- methoxy-2-nitrobenzyl)-2-methylisoquinoliniumiodide is reduced normally to its tetrahydro-derivative which suggests that if cleavage is to occur in the dihydro-intermediate the nitro-group must become coplanar with the benzene ring.'68 The acid-catalysed condensation of 2-benzoyl-1 -cyano-1,2-dihydro- isoquinoline with acrylonitrile to give the isoquinoline (1 19; R' = CN R2 =H) and with 1,l-diphenylethylene to give the isoquinolines (119; R' = R2 = Ph) and (120) have been reported. The isoquinoline (120) may be converted into its isomer (119; R' = R2 = Ph) under both strongly acidic and. strongly basic catalysis. This provides a rare example of electrophilic and nucleophilic inducement to aryl migration in which the same product is obtained.Moreover the isoquinoline (120) may be hydrolysed to a mixture of 2,3,5-triphenylpyrrole and 1-hydroxyisoquinoline in which the phenyl migration is an integral part of the cleavage reaction.'69 Oxygen derivatives. From a study of the conformational behaviour of 2-halogeno-4-methyltetrahydropyrans,the magnitudes of the anomeric effect for the chloro- and bromo-substituents are estimated to be 2.7 and 3.2 kcal./ mole respectively. This preference for an anomerically situated halogen to exist in the axial position is convincingly demonstrated by the conformational behaviour of 2,3,4-tri-O-acetyl-~-~-xylopyranosyl fluoride and chloride which exist largely in the conformation in which all the substituents are axial.I7 ' The separate conformers of 0-D-ribopyranose tetra-acetate have been observed at low temperature by use of 220 Mc./sec.n.m.r. spectrometer; this confirms that the pyranose ring undergoes rapid inversion at room temperature when a time-averaged spectrum is 0bser~ed.I~~ The hydroxy-protons of carbo- hydrates give well-resolved signals in solvents in which exchange reactions can be minimised. For example in the spectrum of P-D-glucose the anomeric hydroxy-group gives a quartet owing to coupling to H-1 (J 4 c./sec.) and long-range coupling to H-2 (J 0-7c./sec.). Examination of a number of pyrano- sides reveals that such long-range coupling only occurs between the proton of an axial hydroxy-group and a vicinal axial prot~n."~ This observation should be useful in configurational studies particularly for ketoses in which there is no proton attached to the anomeric centre and the standard method of determining configuration from vicinal coupling constants is inapplicable.It has been suggested that the stereochemistry at the tertiary centre of a branched-chain sugar may be determined by conversion into the acetoxy- derivative ;acetyl protons in an axial environment appear at lower field than their equatorial counterparts. 74 The n.m.r. method may be reliably applied 168 J. L. Neumeyer M. McCarthy and K. K. Weinhardt Tetrahedron Letters 1967 1095. 169 E. K. Evanguelidou and W. E. McEwen J. Org. Chem. 1966,31 4110; W. E. McEwen T. T. Yee,T.-K. Liao and A. P. Wolf ibid. 1967,32 1947. 170 C.B. Anderson and D. T. Sepp J. Org. Chem. 1967,32,607. 171 C. V. Holland D. Horton and J. S. Jewell J. Org. Chem. 1967,32 1818; L. D. Hall and J. F. Manville Carbohydrate Res. 1967,4 512. 172 N. S. Bhacca and D. Horton J. Amer. Chem. SOC.,1967,89,5993. 173 J. C. Jochims G. Taigel A. Seeliger P. Lutz and H. E. Driesen Tetrahedron Letters 1967,4363. 174 F. Lichtenthaler and E. Emig Tetrahedron Letters 1967 577. Heterocyclic Chemistry 405 to the assignment of sulphoxide configuration in appropriate cases. In the constrained sulphoxide (1 21) the 1-proton is significantly deshielded and this is termed the syn-axial effect. A similar deshielding is observed for the 6-proton in one of the 1,4-oxathian sulphoxides (122) which therefore possesses an axial sulphoxide group.175 -0 +QH H ! OAc ! OAc OAc OMe (121) (122) The differences in optical rotation between sugars containing vicinal hydroxy- groups in cuprammonium solution and in water was the basis of Reeves' method for investigating the conformational behaviour of sugars. This ap- proach has now been extended to sugars containing an amino-group vicinal to a hydroxy-group and it appears to be a valuable method for the determina- tion of relative and absolute stereochemistry of amino-sugars. '76 The oxidation of methyl glycopyranosides with periodic acid in dimethyl sulphoxide is remarkable in that only one equivalent of oxidant is consumed. In many cases a selective oxidation occurs in which cis-glycols (axial-equatorial) are more reactive than trans-glycols (diequatorial or diaxial).It is suggested that further oxidation is inhibited by hemiacetal formation and in the case of methyl a-L-arabinopyranoside which is selectively cleaved between C-3 and C-4 the hemiacetal (123)may be isolated.'77 The interpretation of the results of periodate oxidation may be ambiguous when active methylene compounds are involved since these molecules undergo overoxidation. 1,4-Anhydroallitol rapidly consumes two molar equivalents of periodate to produce the tri- aldehyde (124) which is a good model for the polyaldehydes formed in the periodate oxidation of many polysaccharides. The trialdehyde is cyclised to the 1,4-dioxin (125) and then hydroxylated to the 1,4-dioxan (l26) which is then cleaved in the usual manner.'78 Two mechanisms have been suggested for the acid-catalysed hydrolysis of glycosides which differ in the position of protonation of the glycoside and the subsequent cleavage.For oxygen glycosides protonation of the methoxy-group is preferred and a cyclic carbonium ion is formed by loss of methanol. However a qualitative study of the hydrolysis of methyl 1-deoxy-1-mercapto-a-D-ribo-pyranoside reveals that furanosides and P-pyranoside are formed before hydrolysis to the free sugar is complete. These results imply that anomerisation ''' A. B. Foster J. M. Duxbury T. D. Inch and J. M. Webber Chem. Comm. 1967 881. 176 C. B. Barlow and R. D. Guthrie J. Chem. SOC.(C) 1967 1194; S. Umezawa T. Tsuchiya and K. Tatsuta Bull. Chem. SOC.Japan 1967,39 1235 1244.177 R. J. Yu and C. T. Bishop Canad. J. Chem. 1967,45,2195. 17* B. G. Hudson and R. Baker J. Org. Chem. 1967,32,2101. 406 R.3. Stoodley OMe CHO CHO (124) (125) (126) and ring-contraction occur via the intermediate (1 27),although it is not certain if this mechanism is involved in hydrolysis. 79 The acid-catalysed anomerisa- tion of methyl D-glucopyranosides occurs via the cyclic carbonium ion since deuteriomethanol is incorporated into the glycoside and glucose dimethyl acetal is not an intermediate.'" The hydrolysis of 0-and of p-nitrophenyl 2-acetamido-2-deoxy-~-glucopyranosides has been studied over a wide pH range. The a-isomers show specific acid- and base-catalysed hydrolysis while the p-isomers undergo spontaneous hydrolysis.This result which implies that the neutral acetamido-group participates in the P-glycoside hydrolysis has some bearing upon the mechanism of action of lysozyme since the compounds may serve as model substrates for the enzyme.181 Formation of the allyl ether has been used for protecting alcohols; the allyl group may be removed by base-catalysed isomerization to the cis-prop-1-enyl group followed by dilute acid hydrolysis. A convenient modification involves treating the vinyl ether with buffered mercuric chloride ; the protecting group may then be removed in the presence of acid labile functions.lS2 4-Methoxy- 5,6-dihydro-2H-pyran may also be used to protect alcohols; it is acid labile and unlike tetrahydropyran it gives rise to no complications due to the 179 C.J. Clayton N. A. Hughes and S. A. Saeed J. Chem. SOC.(C) 1967,644. B. Capon Chem. Comm. 1967,21. D. Piszkiewicz and T. C. Bruicer J. Amer. Chem. SOC.,1967,89,6237. '*' R. Gigg and C. D. Warren Tetrahedron Letters 1967 1683. Heterocyclic Chemistry 407 formation of diastereois~mers.~~~ A valuable method for the selective de-N- acetylation of acetamido-deoxy-sugars with triethyloxonium fluoroborate has been described. The intermediate 0-ethylacetamidium fluoroborate is readily hydrolysed to the amine with water and the mildness of the procedure ensures that esters acetals and glycosides are unaffected.' 84 The observation that bis-2-butyl-3-methylborane will directly reduce y-and 6-aldonolactones to the free sugars considerably improves the utility of the cyanohydrin synthesis.18' Two new methods have been reported for descending the series.'86 Thus 1-t-butyl peroxide reacts with acid chlorides of acetylated aldonic acids to give the peroxy-esters [e.g. (128)]; the isomer (129) is obtained in the presence of a base. Both peroxy-esters are cleaved by methanolic sodium methoxide to D-zrabinose. A similar loss of C-1 takes place in the base-catalysed decom- position of 1-phenylazo-1-hydroperoxides[e-q. (130)l.Borohydride reduction of the vinyl ester (131) obtained by acetylation of 1,2;5,6-di-O-isopropylidene-a-~-riho-hexofuranos-3-ulose, provides a convenient synthesis of D-gulose from COsBu H02*CH*N=N-Ph 0rFfut Ac0 I CHzOAc CH,OAc CH,OAc H D-glUCOSe.'*' The stereospecific creation of two new asymmetric centres is in accord with a kinetic protonation at C-4 of the derived enol followed by a stereochemically controlled reduction at position 3.The use of Wittig and Corey reagents has been successfully applied to the synthesis of branched-chain sugars.188 NN-Dimethylchloroformiminium chloride appears to be a useful IE3 C. B. Reese R. Saffhill and J. E. Sulston J. Amer. Chern. SOC., 1967,89 3366. 184 S. Hanessian Tetrahedron Letters 1967 1549. T. A. Guidici and A. L. Fluherty J. Org. Chem. 1967,32 2043. 186 M. Schulz and P. Berlin Angew. Chem. Internat. Edn. 1967,6,950; M. Schulz and L. Somogyi ibid. 1967,6 168. W. Meyer zu Reckendorf Angew. Chem. Internat. Edn. 1967,6 177. A. Rosenthal and L.Nguyen Tetrahedron Letters 1967 2393; R. D. King W. G. Overend J. Wells and N. R. Williams Chem. Comm. 1967 726. 408 R. J. Stoodley reagent in the synthesis of chlorodeoxy-sugars. Thus 1,2;3,4-di-O-isopropyl-idene D-galactopyranose is converted into 6-chloro-6-deoxy-1,2 ;3,4-di-O-iso- propylidene-D-galactose in excellent yield. However the observation that 1,2;5,6-di-O-isopropylidene-~-glucofuranose gives 6-chloro-6-deoxy- 1,2;3,5-di-0-isopropylidene-D-glucofuranose (the mechanism suggested by the authors for this rearrangement is highly improbable) indicates that the reagent may initiate rearrangements prior to chlorination.' 89 The selective reactivity of the secondary hydroxy-groups of sugar glycosides is of considerable interest and often of practical significance.While the subtleties determining these differences in reactivity remain undisclosed some generalisations may be made as a result of selective benzoylation studies.'" In cc-glycosides with the L-arabino-(132 ; R' = CH2 OBz Me or H) or the D-lyxo-configuration (133 ; R' = CH OBz or Me) the hydroxy-groups at C-2 and C-3 are more reactive than that at C-4; this order is reversed in the case of cc-glycosides with the D-xylo-configuration (134; R' = CH OBz or H). Acetoxonium ion inter- mediates have been proposed for the acid-catalysed ring opening of vicinal epoxides with a neighbouring trans-acetoxy-group. Such an intermediate has been trapped in the boron trifluoride-catalysed opening of methyl 4-0-acetyl- 2,3-anhydro-~-~-lyxopyranoside by borohydride reduction.The derived ethyl- idene acetal (135) possesses an endo-methyl group; this acetal also appears to R' R' H O D -OR2 -OR2 HO-Q-OH bH HO OH R' HO-(4.R' oQ-~hie "".lo OH bH H k OH (134) (135) be the thermodynamically stable isomer. 19' Orthoesters may undergo inter- or intra-molecular transesterification with alcohols to give bicyclic or tricyclic orthoesters. However 4,6-0-benzylidene-1,2-0-methoxyethylidene-~-~-gluco-pyranoside undergoes trimerisation under transesterification conditions to give a unique example of a macrocyclic orthoester (136).19' An unusual S. Hanessian and N. R. Plessas Chem. Comm. 1967 1152. 190 J. M. Williams and A. C. Richardson Tetrahedron 1967,23 1369 1641 ; T.Sivakumaran and J. K. N. Jones Canad. J. Chem. 1967,452493. 19' J. G. Buchanan and A. R. Edgar Chem. Comm. 1967,29. N. K. Kochetkov and A. F. Bochkov Tetrahedron Letters 1967,4669. 19' Heterocyclic Chemistry 409 activation of a hydrogen adjacent to a benzylthio- or methylthio-group has been observed. 193 Thus although the protecting groups of methyl S-benzyl- 4,6-0-benzylidene-3-O-methyl-2-thio-a-~-altropyranoside are readily removed with sodium in liquid ammonia the elimination products (137) and (138) are obtained when the reaction medium is diluted with 1,2-dimethoxyethane. Further examples of ring contractions of carbohydrates have been described and in all cases an anti-periplanar arrangement of leaving and migrating groups is involved.Deamination of 2-amino-2-deoxy-~-g~ucose or its a-glycopyrano- side has long been known to give 2,5-anhydro-~-mannose. A similar result is obtained in the deamination of 2-amino-2-deoxy-~-~aevog~ucosan and in the solvolysis of 2-O-nitrophenylsulphonyl-a-~-glucopyranos~de, while the 1,6-anhydro-3,4-O-isopropylidene-2-O-methylsulphonyl-~-~-galactopyranose ring contracts to methyl 2,6-anhydro-3,4-0-isopropylidene-a-and P-D-talopyrano- sides.lg4 In these examples assistance to migration may be provided by the non-migrating acetal oxygen. Migration of the ring oxygen to an electrophillic centre at C-4indicates that such assistance is not obligatory. For example methyl 6-deoxy-2,3-isopropylidene-4-O-methylsulphonyl-a-~-mannopyrano-side undergoes ring contraction in the presence of aide or thiobenzoate to give the corresponding 5-substituted L-talofuranosides in which an inversion of configuration at C-4and a retention of configuration at C-5 has resulted.However a normal bimolecular displacement of the 4-0-methylsulphonyl group occurs when a nonionic nucleophile such as hydrazine is empl~yed.’~’ The major solvolysis product of methyl 4-O-p-nitrophenylsulphonyl-a-~-193 U. G. Nayak M. Sharma and R. K. Brown Canad. J. Chem. 1967,45481 1767. 194 F. Micheel W. Neier and T. Riedel Chem. Ber. 1967,100 2401 ;N. A. Hughes Chem. Comm. 1967 1072. 19’ C. L. Stevens R. P. Glinksi G. E. Gutowski and J. P. Dickerson Tetrahedron Letters 1967 649; L. N. Owen Chem. Comm.,1967 526; J.Jany P. Novbk Z. Ksandr and Z. Samek Chem. and Ind. 1967,1490. 410 R. J. Stoodley glucopyranoside is methyl a-D-glucopyranoside ; some methyl a-D-galacto- pyranoside methyl P-L-altrofuranoside and free glucose are also formed. '96 It is of interest that the furanoside is the result of an inversion of configuration at both C-4 and C-5. Generation of an electrophilic centre at C-3 may induce migration of a C-C bond. Thus solvolysis of methyl 3-0-p-nitrophenyl- sulphonyl-a-D-mannopyranoside gives 3-deoxy-3-formyl-a-~-lyxofuranoside in which preferential migration of the 4,5-bond has taken place.'" The broad spectrum antibiotic showdomycin possesses an unusual C-nucleoside structure and is formulated as 3-P-~-ribofuranosylmaleimideon the basis of chemical evidence and X-ray analysis.198 Methanolysis of aldga- mycin E liberates the a and P-methylaldgarosides (1 39) which not only possess a rare branched chain octose structure but are the first naturally occurring sugars found to incorporate a cyclic ~arb0nate.l~~ Streptozotocin is an interesting antibacterial agent which liberates diazomethane on contact with alkali and its structure (140) has been confirmed by synthesis.200 Irradiation of monoacetylfilicinic acid (141 ; R = H) affords the 2-pyrone (142) in good yield although the monomethyl ether (141 ;R = Me) is recovered unchanged. The reaction may occur via a keten intermediate which is trapped intramolecularly by the hydroxy-group."' The photoisomer (143; R = H) of 2-pyrone undergoes a remarkable rearrangement in aprotic solvents to give tricyclo[2,3~61,1,0]pyran-2-one(145; R = H).The dipolar ion (144; R = H) is suggested to be an intermediate since the deuteriated photoisomer (143; R = D) gives the pyranone (145; R = D).202The cage photodimer of 2,6-dimethyl-4-pyrone (1 46) undergoes an unusual thermal transformation to 4,6-dimethyl-2-hydroxyacetophenone,involving the intermediates (147) and (1 48). '03 P. W. Austin J. G. Buchanan and D. G. Large Chem. Comm. 1967,418. 19' P. W. Austin,.J. G. Buchanan and R. M. Saunders J. Chem. SOC.(C),1967,372. 198 Y. Nakagawa H. Kanii Y. Tsukuda and H. Koyama Tetrahedron Letters 1967 4105; Y. Tsukuda Y. Nakagawa H. Kanii T. Sato M. Shiro and H. Koyama Chem. Comm. 1967,975. 199 G. A. Ellestad M.P. Kunstmann J. E. Lancaster L. A. Mitscher and G. Morton Tetrahedron Letters 1967 3893. zoo R. R. Herr H. K. J. Jahnke and A. D. Argoudelis J. Amer. Chem. Soc. 1967,89,4808. R. H. Young and H. Hart Chem. Comm. 1967,828. 'O' E. J. Corey and W. H. Pirkle Tetrahedron Letters 1967 5255. '03 P. Yates and D. J. Macgregor Chem. Comm. 1967 1209. Heterocyclic Chemistry 41 I (141) (142) (143) (144) I Many naturally occurring phenolic derivatives are believed to be derived from a linear P-polyketo-acid. Internal aldolisation could give rise to substituted orcinols while acylphloroglucinols could originate from intramolecular Claisen condensation. Indeed the dipyrone (149) which may be regarded as a convenient precursor of the P-triketone (150) yields a number of stilbene derivatives in the presence of methanolic potassium hydroxide which pre- sumably derive from C-2 -+ C-7 aldolisation.However in the presence of methanolic magnesium methoxide the flavanone (151) is obtained by Claisen condensation between C-6 and C-1. A number of aromatic products resulting 0 000 Ph ‘OZR -C02R (149) C02Me 412 R. J. Stoodley from C-9 + C-4 aldolisation may be isolated from the reaction of the tripyrone (152) which is a source of the 0-tetraketone (153) with methanolic potassium hydroxide. With magnesium methoxide the tripyrone (1 52) gives products arising from both types of condensation. For example methyl 4-methoxy- carbonylcurvulinate (154) originates from C-3 + C-8 aldolisation of the p-tetraketone (153) and the chromone (155) is derived from C-5 + C-10 Clnisen condensation.Other products arising from aldol or Claisen condensation followed by cleavage are also observed.204 The course of sodium borohydride reduction of chalcones is markedly dependent upon the nature of the aromatic substituents. Thus the carbonyl group of the 2'-hydroxychalcone (156; R' = R3= H R2 = OH) is selectively reduced since flav-3-ene is obtained after acid induced cyclisation. However both the double bond and the keto-group of the chalcone (156; R' = OMe R2 = H R3 = OH) are reduced since 4'-methoxyflavan is formed after cyclisation. These reductions offer a convenient and novel route to flav-3-enes and fla~ans.~'~ Irradiation of qvercitin pentamethyl ether (157; R = Me) gives mainly the tetracyclic derivatives (1 58) and (1 59) while the tetramethyl ether (1 57 ;R = H) undergoes a photosensitised oxygenation to give the depside (160) together with carbon dioxide and carbon monoxide.206 .This reaction may be analogous to the oxidative decarbonylation of quercitin which can be R2 R3 \ CO-CH=CH *04 T.Money F. W. Comer G. R. B. Webster I. G. Wright and A. I. Scott Tetrahedron 1967,23 3435; J. L. Douglas and T. Money ibid. 1967 23 3545; F. W. Comer T. Money and A. I. Scott Chem. Comm. 1967,231. 205 J. W. Clark-Lewis R. W. Jemison D. C. S. Kingle and L. R. Williams Chem. and Ind. 1967 1455; L. Jurd ibid. 1967 2175. '06 A. C. Waiss jun. R. E. Lundin A. Lee and J. Corse J. Amer. Chem.SOC. 1967 89 6213; T. Matsuura H. Matsushima and H. Sakamoto ibid. 1967,89 6370. Heterocyclic Chemistry 41 3 OMe 1 achieved enzymically. Flavones and isofl avones differ in their reactivity towards dimethyl sulphoxonium methylide. Isoflavones give cyclopropanes and/or coumaran-3-ones while diketones which presumably arise by hydro- lysis of initially formed cyclopropanes are formed from flavones. Thus in the reaction of 7-methoxyisoflavone with dimethyl sulphoxonium methylide the enolate intermediate (161) may account for the formation of both the cyclo- propane (162) and the coumaran-3-one (163). This result implies that cyclo- propane formation by the Corey reagent is not a concerted process.207 / (161) o\ mT2 \ Meov (162) (163) A new approach to the synthesis of rotenoids is based upon the fact that isoflavones are readily hydrolysed to desoxybenzoins which may undergo double ring closure in the presence of acetic anhydride to dehydrorotenoids.For example dehydromunduserone (166) is prepared by cyclisation of the derrisic acid (165) which is available from the isoflavone (164).208A new class of isoflavones has been isolated from the bulbs of Eucornis bicolor. For example '07 G. A. Caplin W. D. Ollis and I. 0.Sutherland Chem. Comm. 1967 575. V. Chandrashekar,M. Krishnamurti and T. R. Seshadri Tetrahedron 1967 23,2505 414 R. J. Stoodley MeO% OCH .C0,Me -\ /OMe \ OMe 0 OMe OMe (164) (165) (166) eucomol(l67) differs from classical isoflavones in that it possesses an additional carbon atom inserted into its skeleton; this is of considerable biological inter- e~t.~" A novel series of biflavanones [e.g.(168)] has been extracted from the heartwood of Garcinia buchananii. These are of particular interest since the two flavanone units are linked between C-3 and C-8 (or C-6); this is a new mode of linkage for condensed reduced flavanoids. A closely related biflavonoid which is similarly linked but which incorporates both a flavanone and a flavone unit has also been isolated.2 The oxidative coupling of benzophenones in the 0-and p-positions to give xanthones may be achieved in the absence of blocking groups to direct the course of cyclisation. For example potassium ferricyanide oxidation of 2,3'-dihydroxybenzophenonegives mainly 2-hydroxy- xanthone together with some 4-hydro~yxanthone.~" (168) '09 P.Bohler and C. Tamm Tetrahedron Letters 1967 3479. 'lo B. Jackson H. D. Locksley and F. Scheinmann Tetrahedron Letters 1967 787; B. Jackson H. D. Locksley F. Scheinmann and W. A. Wolstenholme ibid. 1967 3049; A. Pelter ibid. 1967 1767; C. G. Karanigaokar P. V. Radhakrishnan and K. Venkataraman ibid. 1967,3195. 'I1 J. E. Atkinson and J. R. Lewis Chem. Comm. 1967 803; R. C. Ellis W. B. Whalley and (in part) K. Ball ibid. 1967 803. Heterocyclic Chemistry 41 5 Six-membered Rings with Two or More Hetero-atoms.-The base-catalysed condensation of thiourea with malononitrile to give 4,6-diaminopyrimidine-2-(1H)-thione is the first step in many purine syntheses.Thiosemicarbazide and malononitrile react under similar conditions to give the pyrimidinethione (169) which undergoes an unusual molecular rearrangement in the presence of phosphoryl chloride and dimethylformamide. The product (170) is considered to arise by the mechanism shown in Scheme 5 in which N-N cleavage occurs and doubly bonded sulphur participates in a neighbouring group reaction." ' _c_ Me,N .CH=NITHNMe -/ N=CH.NMe2 SN (169) SCHEME 5 Reagents i. POC1,-HCONMe N (1 70) A number of new routes to pyrimidinethiones have been developed. Aromatic heterocyclic and alicyclic o-aminonitriles may be cyclised to pyrimidinethiones with sodium hydrosulphide via their imino-ethers while direct base-catalgsed cyclisation to pyrimidinedithiones occurs in the presence of carbon di- ~ulphide.~'~ Most purines are prepared by a modified Traube synthesis in which the 5-amino-group of a pyrimidine reacts in the first step.Ring closure may require drastic conditions since the 4-amino-group is only poorly nucleophilic. In a new mild puiine synthesis the 5-amino-group which is formed by hydrogenation of a 5-nitroso-substituent spontaneously ring closes with a preformed 4-N-acyl derivative.214 8-Alkyl-8-azapurines are of interest since the parent 8-azapurines are highly active against mammalian tumours. 8-Methyl-8-azapurine has been synthesised by the selective N(2)-alkylation of 4-formamido-1,2,3-triazole-5-carboxarnide. The 6-hydroxy-8-methyl-8-azapur-ine which is formed after hydrolysis of the formyl group and cyclisation with 'I2 E.C. Taylor and R.W. Morrison jun. 1. Org. Chem. 1967,32 2379. 'I3 E. C. Taylor A. McKillop and S.Vromen Tetrahedron 1967.23,885; E. C.Taylor A. McKillop and R. N. Warrener ibid. 1967 23 891 ;J. A. Zoltewin and T. W. Sharples J. Org. Chem. 1967 32 2681; A. Aviram and S. Vromen Chem. and Ind. 1967,1452. '14 F. E. Kempter H. Rokos,and W. Pfleiderer Angew. Chem. Internat. Edn. 1967,6. 258. 41 6 R. J. Stoodley formamide may be converted into 8-methyl-8-azapurine in a conventional manner.2l5 Unexpectedly 6-amino-1,3-dimethyluracil is converted into the dipyrimidine (172) in dimethyl sulphoxide under reflux. The oxidative cyclisa- tion of the intermediate (171) whose bridging methylene group is derived from formaldehyde produced by thermal decomposition of the solvent represents a new type of dehydrogenation achieved by dimethyl sulphoxide.216 Three new synthetic approaches to the synthesis of alloxazine derivatives have been reported.*” Thus the alloxazine (173) is formed from the oxidation with lead tetra-acetate of 5-amino-6-anilino-l,3-dimethyluracil or from 6-anilino- 1,3-dimethyl-5-nitrouraciland triethyl phosphite.Both reactions probably involve intramolecular trapping of nitrene intermediates. The alloxazine (1 73) may also be prepared by heating 6-amino-l,3-dimethyluraciland nitro-benzene under reflux in acetic anhydride. These methods should be of general value in the synthesis of condensed pyrazine heterocycles.(171) U72) Me A remarkable photochemically induced methylation of pyrimidines and purines occurs in methanolic hydrogen chloride and provides a convenient synthesis of 2- and/or 4-alkyl derivatives.2 l8 The photochemical behaviours of pyrazine and pyridazine 1 -oxides show much in common with their pyridine counterparts. For example 3-chloro-6-methylpyridazine 1-oxide mainly under- goes deoxygenation while 2-benzoyl-3-phenylquinoxalinedi-N-oxide gives the ring-contracted product (174) in good yield.219 However the products observed from irradiation of 2,5-dimethylpyrazine 1-oxide depend markedly upon the solvent used. In benzene a mixture of 2,5-dimethyl- and 2-acetyl-5- methyl-imidazole is obtained while in water both 2,5-dimethyl-5-hydroxy- pyrazine and 1-acetamido-2-formamidopropene are produced.It is suggested 215 A. Albert Chem. Comm.,1967,684. 216 R. C. Elderfield and M. Wharmby J. Org. Chem. 1967,32 1638. 217 E. C. Taylor F. Sowinski T. Yee and F. Yoneda J. Amer. Chem. SOC. 1967,89,3369. 218 M. Ochiai and K. Morita Tetrahedron Letters 1967 2349. 219 M. Ogata and K. Kan6 Chem. Comm. 1967 1176; M. J. Haddadin and C. H. Issidorides Tetrahedron Letters 1967 753. Heterocyclic Chemistry 417 that both of the two possible oxaziridines are formed ;in the non-polar solvent they are converted into their valence bond isomers (175) and (176) which rearrange to the imidazoles while in water the derived 3,6-diazaoxepin (177) is hycirolytically ring opened.220 2,3-Dihydropyrazines also undergo ring contraction on photochemical excitation to give 1-methylimidazoles in useful yields.However the triene intermediate is implicated since if the reaction is performed in deuterioethanol one deuterium atom is incorporated into the methyl group.221 Pyrimidine derivatives are usually resistant to ring-opening by acids or bases. However 4-chloro-6-dimethylamino-5-nitropyrimidine is readily cleaved to P-amino-f3-dimethylamino-wnitroacrylonitrile in the presence of alkali because of activation of the 2-position to nucleophilic attack by the nitro- group.222 Ring contraction of pyrimidines may occur in the presence of hydrazine and 4-methoxy-Snitropyrimidine is rearranged (uia4-hydrazino-5-nitropyrimidine) to 3-amino-4-nitropyrazole at room temperature.However the presence of an activating group at position 5 is not essential for the reaction since pyrimidine and its 4,6-dimethyl derivative give the corresponding pyra- zoles under forcing conditions although cleavage now occurs between N-3 and C-4. Similarly 4,6-diethoxypyrimidine and its 5-methyl derivative ring contract to 3-methyl- and 3-ethyl-1,2,4-tria~oIe.~~~ The dithiins (1 78) are novel heterocycles containing 8n-electrons. Thermal or photochemical excitation leads to desulphurisation and ring contraction to thiophen derivatives while pyridazines are formed by reaction with hydra- zine. These reactions implicate the intermediacy of the dithioketone."' The conformational behaviour of duplodithioacetone is remarkable in that the twist boat form (179) is slightly more stable than the chair conformers.This is presumably due to the long C-S and S-S bonds and the lack of Pitzer strain R R (1 78) (179) 220 N. Ikekawa and Y. Honma Tetrahedron Letters 1967 1197. 221 P. Beak and J. L. Miesel J. Amer. Chem. SOC.,1967,89,2375. 222 J. Clark I. Gelling and G. Neath Chem. Comm. 1967 859. 223 M. E. C. Biffn D. J. Brown and Q. N. Porter Tetrahedron Letters 1967 2029; H. C. van der Plasand H. Jongejan ibid. 1967. 4385. 224 W. Schroth F. Billig and G. Reinhold Angew. Clirm. Intrrrrtrt. Edn. 1967 6 698. 418 R. J. Stoodley due to C-H bonds. However the shorter C-0 and 0-0 bonds in acetone diperoxide are sufficient to tip the balance in favour of the chair form.225 Grignard reagents react with oximes to give oxazines e.g.the diaryloxazine (180) is formed from acetophenone oxime and ethyl magnesium bromide. The oxazine (180) which may be formed by the route suggested in Scheme 6 undergoes an interesting rearrangement to 2,4-diphenylpyrrole when heated in strong hydrochloric acid. The pyrrole nitrogen is probably derived from the exocyclic nitrogen since no pyrrole is formed from the NN-dimethyl- amino-derivative.226 The isoxazolidine (181) may be ring enlarged to the CH,MgBr N I N I OMgBr I MgBr (180) SCHEME6 oxazine (183) by strong base or by irradiation which suggests that the imine intermediate (1 82) is involved.227 Under carefully controlled conditions dihydro-173-oxazines [e.g. (184)] are reduced to their tetrahydro-derivatives with sodium borohydride.Since the tetrahydro-1,3-oxazines are labile to mild acid the method offers a new route to aldehydes from nitriles and carboxylic acids and it may be readily adapted to the synthesis of l-deuterioaldehydes.228 The dihydro- 174-thiazin-3-one (1 87) has been isolated from the deamination of 6-P-aminopenicillanic acid (1 85). The rearrangement proceeds via the dihydro-1,4-thiazine (186) which is formed by methanolysis of the p-lactam and a deaminative ring expansion.229 Seven-membered and Larger Rings.-A novel route to tetrahydroazepines involves the catalytic reduction of 6-amino sugars and as an example the '*' C. H. Bushweller J.Amer. Chem. SOC.,1967,89,5978. 226 L. W. Deady. Tetrahedron 1967,23,3505."'N. A. LeBel T. A. Lajiness and D. B. Ledlie J. Amer. Chem. SOC.,1967,89,3076. 228 A. I. Meyers and A. Nabeya Chem. Comm. 1967,1163. 229 R. J. Stoodley Tetrahedron Letters 1967 941. Heterocyclic Chemistry 419 (1 84) (185) Me0,C Me0,C s Me H[:$e- H CO,H HCNYH tetrahydroazepine (1 88) is formed from 6-amino-~-glucose.~~~ Dihydro-azepines may be formed by the ring expansion of 1,4-dihydrolutidines. For example 4~hloromethyl-1,4-dihydro-3,5-dimethoxycarbonyl-2,6-lutidine is converted into the cyanodihydroazepine (189) when treated with potassium cyanide and to the bicyclic derivative (190) by sodium hydrosulphide. An analogous ring enlargement occurs with 3J-diacetyl 4-chloromethyl- 1,4- dihydro-2,6-lutidine and potassium cyanide although with water the furan (191) Meo2cf-JMe COzMe Me Meo&H H H C0,Me (188) (189) (190) and dihydrolutidine (192) are formed.231 1 H-Azepines are of interest because they are the 8n-electron azalogues of the unstable cycloheptatrienyl anion.A novel and versatile approach to their synthesis is summarised in Scheme 7.232 Irradiation of the oxaziridine (193) in the presence of diethylamine gives a surprising result in that 2-diethylamino-3H-azepine is formed ; this indicates "O H. Paulsen and K. Todt Chem. Ber. 1967,100,512. 231 J. Ashby and U. Eisner J. Chem. SOC.(C) 1967,1706; R. C. Allgrove and U. Eisner Tetrahedron Letters 1967,499. 232 L. A. Paquette and D. E. Kuhla Tetrahedron Letters 1967,4517. O+ 420 R.J. Stoodley Reagents i INCO; ii MeOH; iii. NaOMe iv. Br V NaOMe. SCHEME 7 a preference for ring enlargement of the benzene ring.233 The course of ring expansion of 2,6-dialkylphenoxides with chloramine to give 1,3-dihydro-ZH- azepin-2-ones is influenced predominantly by the steric effect of the alkyl group,. Thus only 3-t-butyl-1,3-dihydro-7-methyl-2H-azepin-2-one is pro- duced from sodium 2-t-butyl-6-methylphenoxide and ~hloramine.~~~ The chlorination of 1,3-dihydro-3,7-dimethyl-2H-azepin-2-one and its N-methyl derivative with N-chlorosuccinimide occurs exclusively at position 6 ; this involves the minimum of electron reorganisation of the dienamide in agreement with Hine's principle of least motion. However steric factors may influence this process since with 1,3-dihydro-3,5,7-trimethyl-2H-azepin-2-one halogena-tion takes place preferentially at position 4.235 The synthesis of the azabullvalene (195) has been described and is summarised in Scheme 8.236In this procedure the first example of a 1,4-cycloaddition to cyclo-octatetraene is encountered chlorosulphonyl isocyanate gives the derivative (194).The n.m.r. spectrum of the azabullvalene (195) shows an intriguing reversible temperature dependence ;at 150"the signals for the vinyl and cyclopropyl protons coalesce owing to a combination of two Cope rearrangements. U94) Reagents i. -OH ii Me30fBF iii. hv SCHEME 8 233 E. Meyer and G.W. Griffin Angew. Chem. Internat. Edn. 1967,6,634. 234 L. A. Paquette and W. C. Farley J.Amer. Chem. SOC. 1967,89 3595. 235 L. A. Paquette and W. C. Farley J. Org. Chem. 1967,32 2725. 236 L. A. Paquette and T. J. Barton J. Amer. Chem. SOC. 1967,89,5480; P. Wegener Tetrahedron Letters 1967,4985. Heterocyclic Chemistry 421 Photocyclisation of N-chloroacetyl-L-tryptophan provides an easy access to tricyclic indoles [e.g. (196)l.In contrast N-chloroacetyl-0-methyl-L-tyrosine undergoes an unusual photolysis in water in which the aromatic ring is destroyed and the aza-azulene (198) is formed. The product may arise from the inter- mediate (197) by reverse aldolisation transannular ring closure and dehydra- ti~n.'~~ Bridged biphenyls containing a medium-sized ring [e.g. (200)] may be prepared by photo-induced intramolecular arylation of the suitably substi- tuted iodobenzene (199).238 Q The valence tautomerisation of diazanorcaradienes and diazepines is of interest.Addition of cyclopropene to diphenyl-s-tetrazine gives the diazanor- cardiene derivative (201 ; R = H) which is stable at room temperature but is isomerised to the 5H-1,2-diazepine (202 ;R = H) at 180". However the product obtained from triphenylcyclopropene and diphenyl-s-tetrazine possesses the diazepine structure (202; R = Ph) at room temperature perhaps because of statilisation by phenyl conjugation. Moreover when the diazepine (202 ; R = Ph) is heated under reflux in xylene it isomerises to the bicyclic derivative (203);this process is thermally prohibited in the carbocyclic series according to Woodward-Hoffmann predictions.When further heated the diazetidine (203) is degraded to a mixture of 2,3,4,5-tetraphenylpyrroleand benzonitrile. 7-Benzyl-2,5-diphenyl-3,4,7-triaza-2,4-norcaradiene is rearranged to l-benzyl- 4-phenylimidazole and benzonitrile in a similar manner.239 The 1,2-diazepin- 4-one (204) may be selectively alkylated at position 1 or 2 depending upon the reaction conditions. Dimethyl sulphate in aqueous alkali gives a mixture of 23' 0.Yonemitsu B. Witkop and I. L. Karle J. Amer. Chem. SOC. 1967,89 1039. P. W. Jeffs and J. F. Hansen J. Amer. Chem. SOC., 1967,89 2798. 239 M. A. Battiste and T. J. Barton Tetrahedron Letters 1967 1227; H. W. Heine and J. Irving ibid. 1967 4767. 422 R. J. Stoodley Ph R Ph Ph oph phQ -'"mPh -Ph N-N N-Ph R QOO the 1-and 2-methyl-l,2-diazepin-4-ones, while the 2-methyl derivative is formed in t-butyl alcohol containing t-butoxide.Only the 1-methyl-1,2-diazepin-4-one is formed when diazomethane and boron trifluoride are employed in the alkylation. These results indicate that under conditions in which the anion is generated electrophilic attack occurs at position 2 whereas position 1 is most reactive to electrophiles with high S 1 reactivity.240 o-Halogenoacetamidobenzophenone anti-oximes [e.g. (205)] are known to undergo intramolecular N-alkylation with the formation of the benzodiazepine in the presence of one equivalent of base. However under similar conditions the corresponding syn-oxime gives the dimer (206) which contains a sixteen- membered ring.In the presence of two equivalents of base a surprising intra- molecular 0-alkylation occurs to give the novel benzoxadiazocin-2-ones (207); (205) (206) (207) (208) these readily rearrange to 3-hydroxy-1,4-benzodiazepin-2-ones (208) although the dimers are not intermediates in this reaction.241 Amino-alcohols incor- porated into medium-sized rings may undergo an interesting acid-catalysed transannular cyclisation to give bicyclic quaternary salts. For example N-methyl- 1-azacyclononan-5-01 is readily cyclised to N-methyl-l-azabicyclo- [4,3,O]nonane iodide.242 Moreover the reverse of this reaction may be accom- plished with certain nucleophiles since the indole derivative (209) can be ring opened in the presence of potassium cyanide to give the nine-membered ring (2io).243 240 W.J. Theuer and J. A. Moore J. Org. Chem. 1967,32 1602. 241 A. Stempel I. Douvan E. Reeder and L. H. Sternbach J. Org. Chem. 1967 32 2417. 242 A. J. Sisti and D. L. Lohner J. Org. Chem. 1967 32 2026. 243 G. H. Foster J. Harley-Mason and (inpart) W. R Waterfield Chern. Comm. 1967 21. Heterocyclic Chemistry QIqhy-QQqy 423 H H NC (209) (210) The benzene oxide-oxepin equilibrium is solvent- and temperature-dependent Irradiation of a mixture of these isomers in ether with light of wavelength >3 10 mp leads to a quantitative conversion into 2-oxabicyclo[3,2,0]hepta-3,6-diene. In contrast irradiation with 2537 light at low temperature when the benzene oxide concentration is high gives benzene and phenol as well as the bicyclic derivative whereas in acetone under similar conditions phenol is the sole product.The results suggest that benzene may be derived from the singlet state of benzene oxide while phenol is formed from its triplet state.244 endo-7-Chloro-7-oxanorcaraneis converted into 2,3-dihydro-oxepin when heated in quinoline. while the exo-isomer is recovered unchanged :this suggests that the electrocyclic ring opening follows a disrotatory course.245 2,7-Di- hydrothiepin 1,l-dioxide is formed in a novel 1,6-cycloaddition of sulphur dioxide to cis-hexatriene and it may be converted into thiepin 1,l-dioxide by addition of bromine followed by dehydrobromination. The properties of thiepin 1,l-dioxide are consistent with a nonplanar triene structure ; when warmed it is converted into sulphur dioxide and benzene probably oia benzene epis~lphone.~~~ 244 J.M. Holova and P. D. Gardner J. Amer. Chem. SOC. 1967,89 6390. 245 T. Ando H. Yamanaka and W. Funasaka Tetrahedron Letters 1967 2587. 246 W. L. Mock J. Amer. Chem. SOC. 1967,89,1281.

ISSN:0069-3030    

DOI:10.1039/OC9676400375

出版商:RSC    

年代:1967

数据来源: RSC

摘要:

12. ALKALOIDS By J. A. Joule (Chemistry Department University of Manchester Manchester 13) A FURTHER volume' of 'The Alkaloids' series has appeared containing reviews of the Salarnandra Nuphar mesembrine Tylophora and Galbulimirnaalkaloids all of which are new to the series. This volume also contains supplements to earlier chapters on the alkaloids of the lupin quinoline (not Cinchona) iso-quinoline (various) tropane steroid (Apocynaceae and Buxaceae) Erythrina and Sternona groups. Reviews have appeared devoted to oxindole,' Czo-diterpene~,~ and pyrrolizidine4 alkaloids to the stereochemical aspects of ephedrine pyrrolizidine granatane and tropane chemistry5 and yohimbine heteroyohimbine oxindole and Arnaryllidaceae alkaloids6 A review7 of the mass spectral behaviour of quaternary nitrogen compounds deals mainly with indole alkaloid N(b)-methosalts.Pyrrole Pyridine and Lupin Alkaloids.-Liparis species* and Malaxis congesta,' members of the Orchidaceae have yielded interesting new pyrrolizi- dine alkaloids for which the structures [l R' = Glu.Ara R2 = CH,*CH:C-(Me), R3 = a-HI nervosine [l ; R' = Glu R2 = CH2-CH:C(Me)2 R3 = P-H methosalt] kumokirine and (1 ;R' = Glu R' = H R3 = P-H) malaxin have been proposed. n Me FH20C0 Me02C (1) HO (3) ' (2) R. H. F. Manske 'The Alkaloids' Academic Press New York 1967 vol. IX. G. B. Yeoh K. C. Chan and F. Morsingh Rev. Pure Appl. Chem. (Australia) 1967 17 49. S. W. Pelletier Quart. Rev. 1967 21 525. F. L. Warren Fortschr. Chem. org. Naturstoffe 1966 24 329.G. Fodor. Recent Developments Chem. Natural Carbon Compounds 1965 1 15. G.A. Morrison Fortschr. Chem. org. Naturstoffe 1967.25,269; See also W. F.Trager C. M. Lee. and A. H. Beckett Tetrahedron 1967 23 365; N. J. Dastoor A. A. Gorman and H. Schmid Hch. Chim. Acta 1967 50 213; M. Shamma R. J. Shine I. KompiS T. Sticzay F. Morsingh J. Poisson and J.-L. Pousset J. Amer. Chem. SOC. 1967 89 1739. ' M. Hesse Fortschr. chem. Forsch. 1967,8 608. K. Nishikawa and Y. Hirata Tetrahedron Letters 1967 2591 ; K. Nishikawa M. Miyamura and Y. Hirata Tetrahedron Letters 1967 2597. K. Leander and B. Luning Tetrahedron Letters 1967 3477. 426 J. A. Joule The quaternary species (2) a new variation of the actinidine type has been obtained from Valerianu oficinulis.Fontaphilline (3) from Fontanesia philfyreoides is a related alkaloid of the same series as gentianine." A third variant on the theme is the base (4) from Rauwolfia uerticillutd2 which lacks the 3-substituent and a fourth permutation the pyridine (5)from Gentiana tibetica,' which is formally derivable from the gentianine type by ring opening rotation ring formation and loss of the 3-substituent. All these compounds almost certainly arise from loganin or some other similar monoterpenoid precursor. It is interesting that the cleavage necessary to produce (3) and (9,the loss of the carboxyl carbon necessary to form (4) and (3,and the rotation necessary for (5) are all processes recognised in the biogenesis of various indole alkaloids from a terpenoid precursor.Two more hydroxyskytanthines have been ob- tained from Skytanthus actus. l4 The relative stereochemistry of clivonine and clivimine has been revised on the basis of n.m.r. spectroscopy.15 The simple base (6)occurs in pomegranate. l6 Piperlongumine (7) has been obtained from Piper longum. Iso-orensine has been synthesised from isotripiperidine. ' The structure and absolute stereo- chemistry of an alkaloid (8) from Euphorbia atoto have been demonstrated.lg Two macrocyclic bases (9; x = y = 5) and (9; x = 5 y = 7) isolated from Azirna tetracantha are similar in type to carpaine (9;x = y = 7).20The dihydro- derivative of cassine has been obtained from Cassia carnauuL2 Lythranidine (10) is another macrocyclic piperidine base. This alkaloid is obtained from Lythrum anceps.22 lo L.K. Torssell and K. Wahlberg Acta Chem Scand. 1967,21 53. l1 H. BudzikiewicG C. Hortsmann K. Pufahl and K. Schreiber Chem. Ber. 1967,100,2798. l2 H. R. Arthur S.R. Johns J. A. Lamberton and S. N. Loo Austral. J. Chem. 1967,244 2505. F. Rulko L.DolejS A. D. Cross J. W. Murphy and T. P. Toube,Roczniki. Chemii 1967 41 56 7. l4 G. Adolphen H. H. Appel K. H. Overton and W. D. C. Warnock Tetrahedron 1967,23,3147. W. Dopke M. Bienert A. L. Burlingame H. K. Schnoes P. W. Jeffs and D. S. Farrier Tetra-hedron Letters 1967,451; See also W. Dopke and M. Bienert Arch. Pharm. 1966,299,994. l6 M. F. Roberts B. T. Cromwell and D. E. Webster Phytochem 1967,6 711. l7 A. Chatterjee and C. P. Dutta Tetrahedron 1967,23 1769. C.Schopf and W. Merkel Annalen 1967,701 180. l9 A. F. Beecham S. R. Johns and J. A. Lamberton Austral J. Chem. 1967,#) 2291; N. K. Hart S. R. Johns and J. A. Lamberton ibid. p. 561. 2o G. J. H. Rali T. M. Smalberger H. L. de Wad and R. R Amdt Tetrahedron Letrers 1967 3465. 21 D. Lythgoe and M. J. Verenengo Tetrahedron Letters 1967 1133. l2 E. Fujita K. Fuji K. Bessho and A. Sumi Tetrahedron Letters 1967 4595. Alkaloids 427 Oo co co 0 CH:CH oorLe 0 co (7) ‘’OMe Me I I cH2YgTcH2 v (10) 11-0xotetrahydrorhombifoline has been isolated from Ormosiu coutinhoi and a study made of its mass spectral beha~iour.~~ Two methods have been developed for the synthesis of lupinine in optically active form without resolu- tion at the last step.24 Qainoline Alkaloids.-Studies of the Cinchona alkaloids have been con-cerned with the relative stereochemistry at C-9,25 and with the application of 0.r.d.and c.d. to this series based on the quinoline or 4-acylquinoline chromo- phore.26 The quinolone (11)27 and acridone (12)28have been isolated from Evodia species and the furanoquinoline (13)from Choisya tern at^.^^ A synthesis of flaiamine (15)30makes a neat use of a Claisen rearrangement. The reaction was carried out in acetic anhydride which enabled the first product to be trapped (14) thereby preventing the subsequent undesired abnormal Claisen reaction. A synthesis of acronycine3’ employs as starting material 3,4-dihydro-5,7- dimethoxy-2-quinolone which contains the requisite side chain tied as the ” S.McLean,A. G. Harrison and D. G. Murray Canad. J. Chem. 1967,45,751. 24 T. Kunieda and S. Yamada Chem. and Pharm. BUM.(Japan) 1967,15,240; S. I. Goldberg and I. Ragade J. Org. Chem. 1967,3& 1046. 25 G. G. Lyle and L. K. Keefer Tetrahedron 1967,23 3253. 26 G. G. Lyle and W. Gaffield Tetrahedron 1967 23,51. ” R. Tschesche and W. Werner Tetrahedron 1967 23 1873. J. A. Diment E. Ritchie and W. C. Taylor Austral. J. Chem. 1967,20 1719. 29 S. R. Johns J. A. Lamberton and A. A. Sioumis Austral. J. Chem. 1967 20 1975. 30 T. R. Chamberlain and M. F. Grundon Tetrahedron Letters 1967 3547. 31 J. R. Beck R. W. Booher A. C. Brown R. Kwok and A. Pohland J. Amer. Chem. SOC. 1967 89,3934. 428 J. A. Joule heterocyclic ring which is later opened.The first step of the synthesis involves reaction with o-iodobenzoic acid-cuprous iodide to give (1 6). The subsequent steps to the acridone (17) suitable for further elaboration to a tetracyclic intermediate (1 8) are detailed. CH (1 3) M d0 O?L e I -& l2 Me (14) Me Me QtKT:: Reagents I Ac20-NMe piperidine 2 HBr-HOAc (15) OMe mOMe 1,2 (17) (18) Me Reagents 1 -PPA ;2 MeOH-HCl ;3 BCl ;4 MeLi ;5 Pyridine . HCI A Ikaloicis 429 Isoquinoline Alkaloids.-The structures of two simple halucinogenic bases (19) and (20; R' = Me R2 = OH R3 = Me) from species of cacti have been e~tablished.~~ Corypalline (20; R' = R2 = H R3 = Me) dimerises to (21) on electrolytic or photochemical oxidation.33 Sendaverine (alkaloid F 28) (20; R' = R2 = H R3 = CH2-Ph) from Corydalis aurea is a new type of isoquinoline alkaloid.34 When papaverine is photolysed in methanol or ethanol cleavage of the benzyl group occurs with the concomitant introduction of the alcohol alkyl residue at C-l.35The absolute stereochemistry of arge- monine [the (-) form (22) is shown] has been thoroughly e~tablished~~ by chemical correlation with L-aspartic acid and by 0.r.d.measurements. HO R2 Cryptowoline has been synthesised by routes which employ the formation of a benzyne as a last step.37 Stepharanine (23 ;R' = OMe R2 = OH R3 = H) has been obtained from Stephunia glabr~.~* Berberine has been transformed into columbamine thus completing a formal total synthesis of this widely distributed alkal~id.~' Irradiation of the amide (24) provides a novel approach to the synthesis of a methyl protoberberine system (23; R' = R2 = H R3 = Me).40 32 J.E. Hodgkins S. D. Brown and J. L. Massinghill Tetrahedron Letters 1967 1321. 33 J. M. Bobbitt J. T. Stock A. Marchand and K. H. Weisgrabar Chem. and Ind. 1966,2127. 34 T. Kametani and K. Ohkubo Chem. and Pharm. Bull. (Japan) 1967 15 608. 35 F. R. Stermitz R. Pua and H. Vyas Chem. Cornm. 1967 326. A. C. Barker and A. R. Battersby J. Chem SOC.(C),1967 1317; R. P. K. Chan J. Cymerman Craig R. H. F. Manske and T. Soine Tetrahedron 1967 23,4209; 0.brvinka A. FkbryovA and V. Novhk Tetrahedron Letters 1966 5375; M. J. Martell T. 0.Soine and L. B. Kier J. Pharm. Sci. 1967 !% 973. " F.Bennington and R. D. Morin J. Org. Chem. 1967,32,1050;T. Kametani and K. Ogasawara J. Chem. SOC.(C),1967 2208. R. W. Doskotch M. Y. Malik and J. L. Beal J. Org. Chem. 1967,32 3253. 39 M. P. Cava and T. A. Reed J. Org. Chem. 1967,32 1640. *' G. R. Lenz and N. C. Yang Chem. Comm. 1967 1136. 430 J. A. Joule Accounts of extensive investigations of the synthesis of protoberberine alka- loids using the Eschweiler-Clarke approach have been p~blished.~' Several more alkaloids based on the rhoeadine skeleton have been el~cidated.~~ including one in which the hemiacetal hydroxyl is linked to Crypto-pine can be converted into the berberinium ion by irradiati~n.~~ Macrocyclic bisbenzylisoquinoline alkaloids have been isolated from T.~implex,~~' Thalictrum fendleri,44a T.Dasyca~pum,~~~ and Cissampelos p~reira.~~~ Considerable efforts have been expended on the synthesis of this POCI, I 41 T.Kametani I. Noguchi S. Nakamura and Y.Konno,J. Pharm. SOC. Japan 1967 87 168; et seq. ; T. Kametani and T. Kikuchi Chem. and Pharm. Bull. (Japan) 1967,15,879; T. Kametani and M. Ihara J. Chem. SOC. (C) 1967 530. 42 (a) A. NemiXkovA A. D. Cross and F. Santavjr Naturwiss. 1967,54,45; (b) E. A. Guggisberg M. Hesse H. Schmid H. Bbhm H. Ronsch and K. Mothes Helv. Chim. Acta 1967,50,621; L. M. Maturovh H. PottiSilovA,F. Santavy A. D. Cross V. HanuS and L. DolejS Coll. Czech. Chem. Comm. 1967,32,419; D. W. Hughes L. Kiihn and S. Pfeifer J. Chem. SOC.(C),1967,444. 43 X.A. Dominguez and J. G. Delgado Tetrahedron Letters 1967 2493.** (a)M.Shamma R. J. Shine and B. S. Dudock Tetrahedron 1967,23 2887. (b)S. M. Kupchan T.-H. Yang G. S. Vasilkiotis M. H. Barnes and M. L. King .I.Amer. Chem. SOC. 1967,89 3075; (c) N. M.Mollov V. S. Georgiev D. Jordanov and P. Panov Compt. rend. Acad. bulg. Sci. 1966,19,491; (d)A. K. Bhatnagar and S. P. Popli Experientia 1967 23 242. Alkaloids 43 1 type of alkal~id.~’ illustrates the type of The synthesis of ~epharanthine~’” approach which is used. A di-amide macrocyclic intermediate (25)was built up from suitable ‘halves’. The amide-forming steps were used to construct the large ring. Phosphorus oxychloride treatment then caused ring closure in both halves to dihydro-isoquinoline rings and the molecule was finally modified as necessary.A basically similar approach has been used in the synthesis of the bisbenzylisoquinoline alkaloids magn~line,~~” and magnol- i~oliensinine,~~~ amine46‘ which have one ether link between the two units. Perhaps the most interesting bisbenzylisoquinoline alkaloid examined in the year under review was isolated from Daphnandra repandula. Repanduline has been assigned the novel structure (26) though the position of the spiro- linkage is not ~ertain.~’ Cleavage of the alkaloid with potassium-ammonia gave rise to hemirepanduline (27) which was synthesised. Co-occurring with repanduline is nortenuipine (28) and it seems reasonable to suppose that the (26) 45 (a) M. Tomita K. Fujitani and Y. Aoyagi Tetrahedron Letters 1967 1201 ;(b)T.Kametani 0.Kusama and K. Fukumoto Chem. Comm. 1967 1212; J. P. Sheth and 0.N. Tolkachev Tetra-hedron Letters 1967 1161; 0.N. Tolkachev L. P. Kvashnina and N. A. Preobrazhenskii Zhur. obshchei Khim. 1966. 37 1764. *6 (a) T. Kametani R Yanase S. Kano and K. Sakurai Chem. and Pharm. Bull. (Japan) 1967 15,56 ;(b)T. Kametani S. Takano and K. Satoh J. Heterocyclic Chem. 1966,3,546; (c)T. Kametani H. Yagi and S. Kaneda Chem. and Pharm. Bull. (Japan) 1966,14,974. 47 J. Harley-Mason A. S. Howard W. I. Taylor M. J. Vernengo I. R. C. Bick and P. S. Clezy J. Chem. SOC.(C) 1967 1948; I. R. C. Bick J. H. Bowie J. Harley-Mason and D. H. Williams ibid. p. 1951;K. Aoki and J. Harley-Mason ibid. p. 195?. 432 J. A. Joule novel base is derived biogenetically by a condensation involving the methoxyl carbon atom (marked *) of a nortenuipine-type precursor.Litsericine has a protoaporphine structure.48 Phenolic coupling routes have led to the syntheses of glazi~vine~~“ orientalinone corydine and iso- c~rytuberine.~~~ ( -)-Mecambrine has been transformed into ( +)-roemerine.” The widespread occurrence of plants containing aporphine alkaloids is illus- trated by the following list all of which have been reported in the year under review Lindera pipericarpa,’ la Phoebe clemensii,’ lb Croton wilsonii,5 le Fagara tinguassoiba,’ Id Papaver persicum and P. cancasium,’ le Thalictrum fer~dleri,~~“ Laurelia novae-zelandioe,’ If Cassythia racemosa,5 ‘0 and Lysichiton camtarha- tiense.”” In the development of a modified type of aporphine synthesis an unexpected cleavage to o-nitro-toluene and N-methyl tetrahydroisoquinoline occurred on attempted reduction of the intermediate (29) with borohydride.” The use of catalytic reduction overcame the problem and the synthesis was completed normally using a Pschorr reaction.(31) 32) 48 T. Nakasato and S. Asada J. Pharm. SOC.Japan 1966,86 1205. 49 (a)T. Kametani and H. Yagi J. Chem. SOC.(C),1967,2182;(b)A. H. Jackson and J. A. Martine J. Chem. SOC.jC) 1967 2222. ” J. Slavik Coll. Czech. Chem. Comm. 1966,31,4184. (a)A. K. Kiang and K. Y. Sim J. Chem. SOC.(C),1967,282; (b)S. R. Johns and J. A. Lamberton Austral. J. Chem. 1967 20 1277; (c)K. L. Stuart and C. Chambers Tetrahedron Letters 1967,4135; (d) M.Shamma and W.A. Slusarchyk Tetrahedron 1967 23 2563; (e) V. Preininger J. Appelt L. SlavikovB and J. Slavik Coll. Czech. Chem. Comm. 1967 32,2682; (f)K. Bernauer Helu. Chim. Acta 1967 50 1583; (8)S. R. Johns J. A. Lamberton and A. A. Sioumis Austral. J. Chem. 1967 20 1457; (h) N. Katsui and K. Sato Tetrahedron Letters 1966 6257. ” J. L. Neumeyer B. R Neustadt and J. W. Weintraub Tetrahedron Letters 1967 3107; J. L. Neumeyer M. McCarthy and K. K. Weinhardt ibid. p. 1095. Alkaloids 433 Acularine-type system has been synthesised by a phenolic coupling reaction.' Homo-aporphines have been isolated for the first time. Floramultine from Kreysigia rnultiflora has the structure (30)and has been synthesi~ed.~~ A homo-protoaporphine kreysiginone (31) has been isolated from the same plant,5 s after a careful search.It has proved possible to extend the oxidative coupling route developed for the synthesis of protoaporphine alkaloids and aporphine alkaloids to their homol~gues.~~~ 55* 56 Ipecoside (32) provides a fascinating compound intermediate in the bio- genetic sequence from loganin (or similar terpenoid compound) (see also under Indole Alkaloids). A careful study showed that the base has the same absolute stereochemistry as the Ipecacuanha alkaloid^.^' The mass spectral fragmentation of morphine-type alkaloids has been ex- amined.58 Acutumine (33 ; R = Me) and acutumidine (33 ; R = H) are novel chlorine-containing bases isolated from Sinorneniurn ac~turn.~~ The absolute configuration of nudaurine has been determined by oxidation to D-( -)-glyceric 0- OMe OMe acid.60 Full details have appeared of Bentley's extensive investigations of morphine and thebaine derivatives.61 Codeinone has been transformed into thebaine and northebaine.62 Morphine has been synthesised by a new Amaryllidaceae Alkaloids.-A study of the 0.r.d.and c.d. curves of lycorine and related bases has led to the development of an empirical rule which allows prediction after examination of a model of the compound of the sign and magnitude of the 290 mp Cotton effect associated with the aromatic ring 53 T. Kametani T. Kikuchi and K. Fukumoto Chem Comm. 1967 546. s4 A. R. Battersby R. B. Bradbury R. B. Herbert M. H. G. Munro and R. Ramage Chem. Comm. 1967 450.s5 A. R. Battersby E. McDonald M. H. G. Munro and R. Ramage Chem. Comm. 1967 934. 56 T. Kametani K. Fukumoto H. Yagi and F. Satch Chem. Comm. 1967 878; T. Kametani F. Saton H. Yagi and K. Fukumoto ibid. p. 1103. " A. R. Battersby B. Gregory H. Spencer J. C. Turner M.-M. Janot P. Potier P. Francois and J. Levisalles Chem. Comm. 1967 219. s8 D. M. S. Wheeler T. H. Kinstle and K. L. Rinehart J. Amer. Chem. SOC.,1967,89,4494. 59 M. Tomita Y. Okamoto T. Kikuchi K. Osaki M. Nishikawa K. Kamiya Y. Sasaki K. Matoba and K. Goto Tetrahedron Letters 1967 2421 2425. 6o D. H. R. Barton R. James G. Kirby W. Dopke and H. Flentje Chem. Ber. 1967,100,2457. 61 K. W. Bentley and D. G. Hardy J. Amer. Chem. SOC.,1967,89,3267,et seq. 62 H. Rapoport C. H. Lovell H. R. Reist and M.E. Warren J. Amer. Chem. Soc. 1967,89 1942. 63 G. C. Morrison R. 0.Waite and J. Shave] Tetrahedron Letters 1967 4055. 64 K. Kuriyama T. Iwata M. Moriyama K. Kotera Y. Hameda R. Mitsui and K. Takeda J. Chem. Soc.(B) 1967 46. 434 J. A. Joule chr~mophore.~~ Co-ordinates are set on the aromatic ring as shown (34). The rule states that when looking along the axis -z to + z there are four back octants which can contribute as indicated (39 to the Cotton effect. The stereorepresentation (35)of a-lycorane shows how the rule correctly predicts a weak negative Cotton effect for this compound. The third stereoisomer of lycorane y-lycorane has been synthesised6’ and a new synthetic route to lycoramine has been developed.66 Indole Alkaloids.-Simpler alkaloids.The carbazole heptaphylline (36) has been isolated from Clausena hept~phylla~~ and 1,5-dimethoxygramine from Gymnacranthera paniculata.68 The base (37)from Dracontomelum rnangifer~m,~~ the biogenesis of which may be related to that of the canthinone group provides an example of a natural compound previously known as a synthetic laboratory product. The natural material may be partially racemic since an optically active synthetic sample is reported’’ as having a much larger specific rotation. The methoxyolivacine (38; R1 = Me RZ = H) and the methoxy- ellipticine (38; R’ = H R2= Me) have been obtained from Aspidosperma ~argasii’~and Ochrosia elliptica respectively and the latter compound synthesi~ed.~~ 65 N. Ueda T. Tokuyama and T.Sakan Bull. Chem. SOC.,Japan 1966,39,2012. 66 Y. Misaka T. Mizutani M. Sekido and S. Uyeo Chem. Comm. 1967 1258. 15’ B. S. Josh V.N. Kamat A. K. Saksena and T. K.Govindachari Tetrahedron Letters 1967 4019. 68 S.R. Johns J. A. Lamberton and J. L. Occolowitz Austral. J. Chem. 1967,u). 1737. 69 S. R.Johns J. A. Lamberton and J. L. Occolowitz Austral. J. Chem. 1966 19 1951. 70 S. Yamada and T. Kunieda Chem. and Pharm. Bull. (Japan) 1967 15 499. ’I1 R. H. Burnell and D. D. Casa Canad. J. Chern. 1967,45,8? 72 J. W. Loder Austral. J. Chem. 1966 19 1947. A lkaloids 435 R2 R' I1 R' Me Me (40) Two independent groups have demonstrated the relative stereochemistry of uleine (39; R' = CH, R2 = Et R3 =. H).73Bases (39 R' = CH, R2 = H R3 = Et) and (39; R' = 0 R2 = H R3 = Et) epimeric at C-3 with uleine and dasycarpidone (39; R' = 0,R2 = Et R3 = H) have been isolated from Aspidosperma subincan~rn.~~' The ring system of this group of alkaloids has been synthesised for the first time.74 An X-ray analysis of the bromobenzene adduct of hodgkinsine from Hodgkinsonia fmtescens shows it to be a novel trimer (40)'5 comprised of three N(b)-methyl tryptamine units.Details have appeared of the oxidative dimerisation of the Grignard derivative of N(b)-methyl tryptamine which yields mainly a mixture of racemic-and rneso-~himonanthine.~~ Physovenine (41) has been ~ynthesised.~~ YohimbP and related alkaloids. The sign of the double Cotton effect between 295-280 and 255-250 mp can be used in the absence of strongly absorbing chromophores elsewhere in the molecule to ascertain the absolute stereo- chemistry at C-3 of yohimbane and corynantheane alkaloids7* When the C-3 hydrogen is 01 a positive Cotton effect is observed (see also Ref.70) and vice versa. A similar effect has been found for 7-substituted indolenines (42) derived 73 (a)A. J. Gaskell and J. A. Joule Chn. and Ind. 1967 1089; (b) M. Shamma J. A. Weiss and R. J. Shine Tetrahedron Letters 1967 2489. '* A. Jackson and J. A. Joule Chem. Comm. 1967,459. 75 J. Fridrichsons M. F. Mackay and A. McL. Mathieson Tetrahedron Letters 1967 3521. 76 E. S. Hall F. McCapra and A. I. Scott Tetrahedron 1967,23,4131. 77 B. Longmore and B. Robinson Coll. Czech. Chem. Comm. 1967. 32 2184. 78 W.Klyne R. J. Swan,N. J. Dastoor A. A. Gorman and H. Schmid Helv. Chim. Acta 1967 50,115. 436 J. A. Joule from yohimbane." The a-substituted compounds displayed positive Cotton effects and vice versa. A study of corynantheidine alkaloids has shown that although the c.d. and 0.r.d. curves of these compounds are more complex they can also be used in a determination of absolute stereochemistry.80 Several papers8' deal with the elucidation of the relative and absolute stereochemistry of oxindole alkaloids. It has been suggested81b that the use of the Cahn- Ingold-Prelog convention would avoid ambiguities in defining the stereo- chemistry at the spiro-C-7 in such bases. Formulation (43)represents the 7R-configurat ion. R H R =CH,Ph or OAc (42) Me0K-y R2 (44) Aspidosperrna excelsurn has yielded' excelsinine which is 1 0-methoxy corynanthine and Rauwdjk~discolor tetraphylline (44;R' = H R = OH).83 Herbaceine (44;R1 = OMe RZ = H.P-CO,Me) and herbaline (45),dihydro-bases of the heteroyohimbine and hetero-oxindole types respectively have been obtained from Vinca herb~cea.~~ The alkaloids of commercial Gambir prove to be of a ring E aromatic yohimbe type,85 gambirtannine is (46;R = H,) and oxogambirtannine (46;R = 0).Gambirine from Uncaria garnbier is 79 M. von Strandtmann R. Eilertsen and J. Shavel J. Org. Chem. 1966 31 4202. "W. F. Trager C. M. Lee and A. H. Beckett Tetrahedron 1967 23,375. 81 (a) N. K. Hart S. R. Johns and 3. A. Lamberton Chem. Comm. 1967 87; A. F.Beecham N. K. Hart S. R. Johns and J. A. Lamberton ibid. p. 535 ;(b)J. Poisson and J. L. Pousset Tetrahedron Letters 1967 1919. 82 P. R. Benoin R. H. Burnell and 3. D. Medina Canad. J. Chem. 1967,45,725. G. Combes L. Fonzes and F. Winternit& Phytochem. 1966,5 1065. I. Ognyanov B. Pyuskyulev M. Shamma J. A. Weiss and R. J. Shine Chm. Comm. 1967,579. L. Merlini R Mondelli G. Nasini and M. Hesse Tetrahedron 1967 23,3129. A lkaloids 437 formulated as (47; R' = OH R2= H R3 = Me)86 and hervin from Vinca herbacea as (47; R' = H R2 = OMe R3 = H 19,20-dehydr0).~~ Antirhine (48) isolated from Antirhea putaminosa is an alkaloid of the hunterburnine group.88 Cordifoline (49) from Adina cordifolia has an intriguing and bio- genetically significant stru~ture.~' Not only is this base unusual in retaining the tryptophan carboxyl carbon atom but it also incorporates the terpenoid precursor of the C, unit at an intermediate stage of elaboration (see also Isoquinoline Alkaloids).(45) MeO,C)\/O R' (48) (49) Me0,C \ HOCH-The isolation of another" strychnos type alkaloid (+)-lochneridine in a form enantiomeric'l with that obtained previously is also of biogenetic significance. Details have a~peared'~ of structural work on caracurine-I1 and its formation from toxiferine-I. 1 1-Methoxylimatine and 11-methoxylimatinine have been isolslted from Aspidosperma limae.' Alstonia rnacrophylla has provided a quaternary alkaloid macrosalhine for 86 L. Merlini R. Mondelli and G. Nasini Tetrahedron Letters 1967 1571.'' I. Ognyanov B. Pyuskyulev B. Bozjanov and M. Hesse Helv. Chim. Acta 1967,50 754. S. R. Johns J. A. Lamberton and J. L. Occolowitq Austral. J. Chem. 196'1 #) 1463. 89 R. T. Brown and L. R. Row Chem. Comm. 1967,453. 90 Ann. Reports 1960 56 288. 91 P. Lathuilliere L. Olivier J. Levy and J. Le Men Ann. pharmfrane. 1966 24 547. 92 A. R. Battersby H. F. Hodson G. V. Rao and D. A. Yeowell J. Chem. SOC.(C) 1967. 2335. 93 M. Pinar and H. Schmid Helu. Chim. Acta 1967 50 89. 438 J. A. Joule which the structure (50) which is a new structural type has been proposed.94 Pyrolysis of the chloride form produces a Hofmann product which has the same skeleton as alstophylline. From the same Alstonia species macralstoni- dine has been obtained." Macralstonidine is a dimer of N(a)-methylsatpagine (51) and a macroline type unit (52) utilising one mole of formaldehyde in the 9 H H i52) Me & linkage.The acidic fission of the alkaloid (53) which yields these three com- ponents is envisaged as proceeding by hydrolysis of the ketal followed by a retro Michael reaction and finally reverse aldol loss of formaldehyde. The point and mode of attachment was demonstrated by isotopic labelling. Partial 10 H H-\N/-18 94 Z. M. Khan M. Hew and H. Schmid Helv. Chim.Acta 1967 50 1002. 95 E. E. Waldner M. Hesse W. I. Taylor and H. Schmid Helv. Chirn. Acta 1967,50 1926. Alkaloids 439 hydrolysis using deuteriated hydrochloric acid allowed the isolation (with the placing of deuterium atom labels by mass spectrometry) of 10 D (53) (9,10,11 12,18,18,18,20,11',12') 9 D (52) (9,10,11,12,18,18,18,20,20),and 3 D (51) (9',11' 12').These patterns of labelling taken in conjunction with the presence of an AB quartet for two ortho aromatic hydrogen atoms in the n.m.r.spectrum of the alkaloid define the mode of linkage as shown in (53). The structure of isocorymine has been revi~ed.'~ Picraline undergoes a remarkable fission with zinc-hydrochloric acid to give an indole (54).97 Details have appeared of two methods for converting dihydrocorynantheine types into burnamicine types.98 The ring system of vobasine has been obtained by ~ynthesis.~' The important step involved formation of the medium-sized ring by intramolecular acylation of an indole a-position (55)+ (56).The ring system of mavacurine has been preparedio0 synthetically for the first time. 1 'N H \/N Et (54) CH,Ph 0-mPPA w Me Me HO,C J (55) (56) Cl The amide acid (57) underwent a double cyclisation on treatment with phosphorus pentachloride. The partial synthesis of ajmaline from deoxyajmalol-A has been completed by the development of a method for the conversion of deoxyajmaline into ajmaline."' Ajmaline has been obtained by an alternative totally synthetic 96 C. W. L. Bevan M.B. Patel A. H. Rees and A. G. Loudon Tetrahedron 1967 23 3809. 97 A. Z. Britten J. A. Joule and G. F. Smith Tetrahedron 1967,23 1971. 98 L. J. Dolby and S. Sakai Tetrahedron 1967 23 1. 99 S. Yamada and T. Shioiri Tetrahedron Letters 1967 351.loo 0.N. Tolkachev V. G. Korobko T. A. Shapiro and N. A. Preobrazhenskii Khim. getorotsikl. Soedinenii 1967 313. lo' J. D. Hobson and J. G. McCluskey .I.Chern. SOC.(C) 1967,2015. 440 J. A. Joule route ;lo2 N-methyl-3-indolylacetylchloride was condensed with the mag- nesium chelate of ethyl hydrogen A3-cyclopentenyl malonate to give (58 ; R' = C02Et R2 = 0)which was transformed to the desired amino alcohol (58; R' = CH,OH R2 = H,NH,) and its epimer by successive treatment with acetamide and lithium aluminium hydride. After protection this com- pound was cleaved as shown to a di-aldehyde which existed as (59)and cyclised to (60)on acid treatment. The aldehyde group was transformed into nitrile. the CH,OBz Me (58) / (60) 10 (61) Et Ajmaline 13,'14 11 12 Reagents 1 BzCl ;2 OsO ;3 NaIO,; 4 HOAc ; 5 H,NOH ; 6 BzCl ; 7 Ph,CNa-Etl; 8 MeONa; 9 DMSO-Ac,O; 10 HCl-HOAc; 11 H,; 12 LiAl(OEt),H; 13 H,; 14 LiAlH ethyl group introduced by base catalysed alkylation and the ester group converted to aldehyde (61).Treatment of (61) with acid afforded a cyclised product (62) and this was transformed as outlined to ajmaline. Iboga alkaloids. The hydroxyindolenine derivative of coronaridine has been isolatedlo3 from Conopharyngia durissima and synthesised from coronaridine by peracid treatment. The mono-N-oxide of voacamine obtained from Voacanga ~fricana'~~ has been prepared by acid-catalysed condensation of lo2 S. Masamune S. K. Ang C. Egli N. Nakatsuka S.K. Sarkar and Y. Yasunari J. Amer. Chem. SOC.,1967,89,2506. lo' B.C. Das E. Fellion and M. Plat. Compt. rend. 1967 264 C 1765. F.Puisieux J.-P. Devissaguet C. Mict and J. Poisson Bull. SOC.chim. France 1967 251. Alkaloids 441 the N-oxide of vobasinol and voacangine. Details have been publishedLo5 of a synthesis of desethyl ibogamine which utilises methyl 3-cyclohexene-l- carboxylate as a basis for forming the isoquinuclidine system via a 4-amino- cyclohexane carboxylic acid. A preliminary report of another way of con- structing the isoquinuclidine nucleus and of its use to synthesise desethylibog- amine has been given."' The important step involves reaction of 3-indolyl-acetic anhydride with the ethylene imine derivative (63) which provides in one step (64)both the indolylethyl isoquinuclidine ring system and the functionality necessary for closing onto the indole a-position.(63) The amide (66; R' = 0,R2 = OAc) can be obtained from (65) by treatment with acetic anhydride. The reaction must involve initial intramolecular acylation of the tertiary nitrogen with subsequent ring opening."' Standard operations were used to convert the amide (66; R' = 0 R2 = OAc) to the base (66; R' = H, RZ = OH) which in the presence of acid condensed oia an electrophilic centre generated at C-16 with vindoline to give a synthetic dimer of the vinblastine type. *05 J. W. Huffman C. B. S. Rao and T. Kamiya. J. Orq. Chem.. 1967. 32. 697. lo6 W. Nagata. S. Hirai K. Kawata. and T. Okumura J. Arner.Clirw. Soc.. 1967.89. 5046. lo' J. Harley-Mason and Atta-ur-Rahman Chem. Comm. 1967 1048. 442 J. A. Joule Aspidosperma alkaloids. A detailed studylo8 has been made of the mass spectral fragmentation of the schizozygine type of base. The structure (67) has been assigned both to voaphylline'09" from Voacanga ufiicana and to cono- florinel Ogb from Conopharyngia Zongiflora. Both bases were chemically related to (+)-quebrachamine. Rhazidine proves to be' lo a salt derived by a cyclisation (N(b)-,C-2)of the hydroxyindolenine derivative of ( +)-quebrachamine. Also in the same optical series as ( +)-quebrachamine is 16-methoxytabersonine. I 10-Oxocylindrocarpidine from Tabernaemontana arnygdalifoliu can be synthe- sised by permanganate oxidation of cylindrocarpidine.' l2 Kopsingine (68 ; R = OMe) and kopsaporine (68; R = H) have been isolated from Kopsia singapurensis.'' -OH H (67) '"'M. Hesse and U. Renner Helu. Chim.Acta 1966,49 1875. '09 (a) N. Kunesch B. C. Das and J. Poisson Bull. SOC.chim.France 1967 2155;(b)J. J. Dugan M. Hesse U. Renner and H. Schmid Helu. Chim Acta 1967,50,60. 'lo S. Markey K. Biernann and B. Witkop Tetrahedron Letters 1967 157. B. Pyuskyulev I. KompiS I. Ognyanov and G. Spiteller Coll. Czech. Chem. Comm. 1967,32 1289. H. Achenbach Tetrahedron Letters 1967 1793. 'I3 D. W. Thomas,K.Biernann A. K. Kiang and R D. Arnarasingham J. Arner. Chem.SOC. 1967 89 3235. Alkaloids 443 Leurosidine (69; R1= H R2= OH) differs'I4 from vinblastine (69; R' = OH R2= H) only in the position of the hydroxyl group in the cleavamine half.An X-ray analysis of haplophytine dihydrobromide (70) from Huplophyton cimicidum shows it to be a novel dimeric type consisting of a cimicime half-linked to a canthinone moiety.' '' The base itself is considered to be (71). Pycnanthinine (72) can be split by acid treatment into (+)-pleio- carpamine ( -)-6,7-dehydroaspidospermidine and formaldehyde.'' The Me0 MeH (71) fission (as indicated) represents the reverse of the suggested biosynthetic mode of formation. Callichiline a dimeric alkaloid from the Callichilia species proves like vobtusine to be resistant to cleavage."7 From an extensive study of the mass spectrometric fragmentation of the base and of various simple derivatives formed by modification of the chromophore of the vincadifformine half the base was shown to be composed of a beninine moiety and a modified vincadifformine unit."7 The highly hindered N-1' hydrogen of the beninine unit proved totally resistant to detection by acylation in callichiline or any of its derivatives and was only detected by its exchange with deuterium oxide in the mass spectr~meter.~"~ The position of the aromatic methoxyl group was N.Neuss L. L. Huckstep and N. J. Cone Tetrahedron Letters 1967 811. I. D. Rae M. Rosenberger A. G. Szabo C. R. Willis P. Yates D. E. Zacharias G. A. Jeffrey B. Douglas J. L. Kirkpatrick and J. A. Weisbach J. Amer. Chem. Soc. 1967.89 3061. 'I6 A. A. Gorman and H. Schmid Monatsh. 1967,98 1554. (a)M.Plat N. Kunesch J. Poisson C. Djerassi and H. Budzikiewicz,Bull. SOC.chim. France 1967 2669; (b) V. Agwada. A. A. Gorman M. Hesse and H. Schmid Helu. Chim. Acta 1967 50 1939. P 444 J. A. Joule H etc. - I deduced from the n.m.r. spectrum of the 15'-mononitro derivative of calli- chiline. The formulation (73) for the dimer is consistent with all the known facts and is considered' 17' the best working hypothesis. Structures involving linkages 2'4 3'-22'-7 and 2'-21 3'-22'-20 have also to be considered.'17' QZ Me0 OMe Alkaloids 445 A remarkable disruption of the aromatic ring of 17-alkoxyaspidosperma alkaloids occurs on oxidation with iodine-sodium hydroxide' l8 when com- pounds with a part structure (74) are formed.The earlier synthetic approach' '' which yielded stereospecifically' 2o 3a-methyl aspidospermidine by rearrange- ment of a suitable eburnea skeleton has been modified to produce aspidos- permidine itself.',' Lycopodium Alkaloids.-The novel bases cernuine (75; R' = H R2 = 0) and lycocernuine (75; R' = OH R2 = 0) from Lycopodium cernuum have been shown to have the structures and relative stereochemistry shown by a combination of chemical and spectral studies. 22 Dehydrogenation of dihydro- deoxyepiallocernuine (75; R1= H R2= H, 9 and 13a-H)gave 2-butyl-6- hexyl-4-methylpyridine derived from the c ring and containing all the carbon atoms. Central in the structure determination was the tricyclic degradation product (76) obtained from allocernuine (75; R' = H R2 = 0 13a-H) by successive reduction with sodium borohydride and lithium aluminium hydride.This tricyclic compound was obtained as an intermediate in a synthesis of dihydrodeoxyepiallocernuine,' 2b starting from 2,4,6-collidine. (75) Serrati~~e"~ have been chemically inter-related with and fa~cettimine''~ serratinine. The photochemical addition of allene to double bonds has been used in elegant syntheses of 12-epi-ly~opodine'~~ and annotinine. '26 Terpenoid and Steroidal Alkaloids.-More of the chemistry of the complex alkaloids of Duphniphyllum macropodurn has been re~0rted.l~~ It has been suggested that these bases may be derived from four isoprene and one acetate 118 B. W. Bycroft L. Goldman and H. Schmid Helo. Chim. Acta 1967,50 1193.'I9 Ann. Reports 1966,62 386. 0.Kennar K. A. Kerr Q G. Watson J. K. Fawcett and L. Riva di Sanseverino Chem. Comm. 1967 1286. J. Harley-Mason and M. Kaplan Chem. Comm. 1967,915. 122 (a)W. A. Ayer J. K. Jenkins S. Valverde-Lopez and R.H. Burnell Canad. J. Chem. 1967,45 433; W. A. Ayer J. K. Jenkins K. Piers and S. Valverde-Lopez ibid. p. 445; (b)W. A. Ayer and K. Piers Canad. J. Chem. 1967 45 451. Y. Inubushi H. Ishii and T. Harayama Chem. and Pharrn. Bull. (Japan) 1967 15 250. 124 Y. Inubushi H. Ishii T. Harayama R. H. Burnell W. A. Ayer and B. Altenkirk Tetrahedron Letters 1967 1069. 12' H. Dugas M. E. Hazenberg Z. Valenta and K. Wiesner Tetrahedron Letters 1967,4931. 126 K. Wiesner and I. Jirkovsky Tetrahedron Letters 1967 2077; K.Wiesner and L. Poon ibid. p. 4937. 12' S. Yamamura H. Irikawa and Y. Hirata Tetrahedron Letters 1967 3361; T. Nakano and Y. Saeki ibid. p. 4791. 446 J. A. Joule unit. Full details of Nagata's synthetic work on atisine veatchine and garryine have appeared.'28 Pachysandra alkaloid studies continue to produce interesting variations such as pachysandrine-B [77; R' = CO*CH:C(Me), R2 = P-OAc] and pachysandrine-D [77;R1= H R2 = ol-O*CO*CH:C(Me),J.129 The lactone alkaloids [part structure (78)] and the lactam alkaloids [part structure (79)] may arise from the pachysandrine D and B types respectively by condensations involving the N-methyl carbon atom. Veralkamine (80) from Veratrum album has the unusual 17~-methyl-18-nor-l7-isocholestane carbon ~keleton.'~' R' JeJ &?-J Me+DO Me H (79) HO Verazine (81)also from Veratrum album has been synthesised from tomatid-5- en-3P-01.' 31 The relative configuration of the 23-hydroxyl group of veratramine W.Nagata T. Sugasawa M. Narisada T. Wakabayashi and Y. Hayase J. Amer. Chem. Soc. 1967,89 1483; W. Nagata M. Narisada T. Wakabayashi and T. Sugasawa ihid. p. 1499. M. Tomita S. Uyeo and T. Kikuchi Chem. and Pharm. Bull. (Japan),1967,15 193; T. Kikuchi S. Uyeo and T. Nishinaga ibid. p. 577. 130 J. Tomko A. Vassovh G. Adam K. Schreiber and E. Hohne Tetrahedron Letters 1967 3907. 131 (a)G. Adam K. Schreiber,J. Tomko and A. VassovA Tetrahedron 1967.23,167;(b)G. Adam K. Schreiber and J. Tomko Annulen 1967,707.203. Alkaloids 447 and jervine has been revised on the basis of an n.m.r.17-Acetyl-5a-aetioJerva-12,14,16-trien-3~-ol and transformed into has been synthesi~ed'~~" veratramine and jer~ine.'~~~ Galbulimima Alkaloids.-More of the chemistry of this group has been described.'. '34 The bases so far recognised comprise variations (in the 0-acyl and 0-alkyl residues) on three skeleta the himba~ine,'~~ the hirnbosine (82; R' = Ac R2 = Ac R3= Bz R4 = OAc) and the himbadine (83; R' = Me R2 = R3= H) systems. The numbering given for himbosine is based on a postulated polyacetate biogenesis. An elegant analysis' 34a of the chemistry and spectral properties of himandridine (82; R' = H R2 = Bz R3 = Me R4 = OH) and its derivatives allowed the derivation of its structure independently of the X-ray analysis' 36 of himbosine with which it was subsequently chemically interrelated.' 34b Central in the structure deter-& '' M OR' &Me H~II 6 I! 11 Hg \\\\\ H 12 1 19 IS 18 'Me H - R4+\:3 l4 s R3H sfi:l6 17 CO,Me -R' OR3 ORz (82) (83) OMe (84) (85) 13' J.W. Scott L. J. Durham H. A. P. De Jongh U. Burckhardt and W. S. Johnson Tetrahedron Letters 196 7 2381. lJ3 (a) W. S. Johnson J. M. Cox D. W. Graham and H. W. Whitlock J. Amer. Chem. SOC.,1967 89,4524; (b)W. S. Jonnson H. A. P. de Jongh C. E. Coverdale J. W. Scott and U. Burckhardt ibid. p. 4523; T. Masamune M. Takasugie. A. Murai and K. Kobayashi ibid. p. 4521. IJ4 (a)L. bi.Mander E. Ritchie and W. C. Taylor. Austral. J. Chem. 1967,20,981; (b)L.N. Mander E. Ritchie and W. C. Taylor ibid. p. 1021 ;(c) G. B. Guise L. N. Mander R. H. Prager M. Rasmiissen E. Ritchie and W. C. Taylor ibid. p. 1029; L. M. Mander R. H. Prager M. Rasmiissen E. Ritchie and W. C. Taylor ibid. p. 1473; (d)L. N. Mander R H. Prager M. Rasmiissen E. Ritchie and W. C. Taylor ibid. p. 1705. Ann. Reports 1961,58,287. 136 F. M. Lovell Proc. Chem. SOC. 1964 58. 448 J. A. Joule mination was an aromatisation reaction to (84),brought about by the action of hot benzoyl chloride on the base. Further degradation of this product gave the naphthalene (85) which was synthesised. The N-acetyl derivative (83; R' = Ac R2 = R3 = H) of G.B.13 an alkaloid of the himbadine type has been obtained'34u from himandrine (82; R' = H R2 = Bz R3 = Me R4 = H).The crucial step in the interconversion involved the ingenious use of chromous chloride to cleave the nitrogen from a position y to an qJ.3-unsaturated ketone (86) +(83; R' = H R2 = CO,Me R3 = OMe). Miscellaneous Alkaloids.-From Cassipourea species gerrardine (87) and cassipourine (88) have been isolated and their structures determined by X-ray ~rystallography.'~' Solapalmatine [Me2N-(CH2),] N*CO*(CH,), *Me and solapalmitenine [Me2N *(CH2),I2 -N *CO .CH CH .(CH,) Me from Solanum tripartitum have tumour inhibitory properties. '38 The structure (89) 13' W. G. Wright and F. L. Waren J. Chem. SOC.(C) 1967 283 284; R. G. Cooks. F. L. Warren and D. H. Williams ibid. p. 286. 138 S. M. Kupchan A. P. Davies S. J. Barboutis H.K. Schnoes and A. L. Burlingame J. Amer. Chem. SOC.,1967,89 5718. Alkaloids 449 of stenine from Stemona tuberosa was demonstrated by interconversion with tuberstemonine. 39 Zapotidine has been synthesised. 140 Cocculolidine (90) from Cocculus trilobus has insecticidal properties. 14' Full -details have been given of the synthesis of securinine and virosecurinine. 142 139 S. Uyeo H. Irie and H. Harada Chem. and Pharm. Bull. (Japan) 1967 15 768; H. Harada H. Irie N. Masaki K. Osaki and S. Uyeo Chem. Comm. 1967,460. R. Mechoulam and A. Hirshfeld Tetrahedron 1967 23 239. 141 K. Wada S. Marumo and K. Munakata Agric. and Bid. Chem. (Japan) 1967,31,452. Z. Horii M. Hanaoka Y. Yamawaki Y. Tamura S. Saito N. Shigematsu N. Kotera H. Yoshi- kawa Y.Sato H.Nakai and N. Sugimoto Tetrahedron 1967 23 1165.

ISSN:0069-3030    

DOI:10.1039/OC9676400425

出版商:RSC    

年代:1967

数据来源: RSC

摘要:

13. AMINO-ACIDS AND PEPTIDES By H. D. Law (Liverpool Regional College of Technology Byrom Street Liverpool 3) SUPERFICIALLY, polypeptides resemble polymers to such an extent that many chemists working in other areas must have wondered at the seeming com- plexity of peptide chemistry. Even when the twenty-fold variation in the monomer unit is taken into account the problem of peptide structure or synthesis seems to be an aggregate problem requiring the repetitious application of one process for its solution. To peptide chemists the similarity to polymers has often seemed remote. Each amino-acid has its own attendant difficulties ; no two peptide bonds are exactly alike. It is not difficult to discern the general strategy of structural elucidation or synthesis but its execution has usually depended on the exploitation of a battery of techniques each possessing its own general advantages and particular shortcomings.Progress in peptide chemistry has therefore been the sum of many diverse advances. In conse- quence it is inevitable that a review of this type will be somewhat fragmentary. However sufficient is now known about the idiosyncrasies of individual amino-acids and peptide bonds for the peptide chemist to begin to reconsider polypeptides as polymers. A recurrent theme in this review is the development of techniques which can be automated. Such techniques have now been described not just for amino-acid analysis but for residue sequence determina- tion and for polypeptide synthesis as well. These techniques will certainly be improved and may even be displaced by others yet to be devised but it is no exaggeration to say that their advent marks the beginning of a new phase in polypeptide chemistry.An end to the technical difficulties of studying the covalent structures of polypeptides and proteins may be in sight and with effective automated methods a statistically useful approach to the chemistry and biology of these molecules would become possible. Amino Acids.-The diversity of form of natural r-amino-acids has long ceased to cause surprise'. Most unusual amino-acids are non-protein in origin; plants and particularly fungi are rich sources of them. and each year gives rise to a new crop of compounds of this type. New amino-acids of fungal origin include trans-l-methyl-4-n-propyl-~-proline,~ ~-2-amino-3,3-dimethyl-aminopropionic acid,3 ~-2-amino-4,4-dichlorobutyric acid,3 2,3-dihydro-2- L.Fowden Ann. Reo. Biochem. 1964 33 173; L. Fowden D. Lewis and H. Tristram. iM.. 1967; 29 89. -B. J. Magerlein R. D. Birkenmeyer R. R. Herr and F. Kagan J. Amer. Chem. SOC.. 1967. 89. 2459. ' R. R. Herr D. J. Mason T. R. Pyke and J. F. Zieserl Biochemistry 1967,6 165. P* 452 H. D.Law 0x0-oxazol-5-yl glycine4 (l) y6-dihydro~yleucine,~and dehydroalanine.6 Linatine a vitamin-B antagonist in flax seed has been identified as the N'-y-L-glutamyl derivative of 1-amino-D-proline. Seeds of Cycas circinalis have yielded 1-amino-2-methylaminopropionic acid.8 OH OH IC.-CH,*R'/'R'-CH H I C -CH2 NH,R2 .-* /\R'-CH H R' I I CH-YH,I COT (1) iI R' ,K t CH,R'I ,CH ,G=CH -R' R'- C' ICH I CH R'- I CH *N 1 R2 *N I R2 ii i CH R' *OR' R2 R2 (2 ) (3) One protein elastin is proving to be a source of unusual amino-acids and it is clear that peptide chain cross-linking of a type not yet encountered elsewhere occurs in this protein.Lysinonorleucine [NE-(5-amino-5-carboxypentyl)-ly~ine],~ desmosine [2; R' = [CH,],-CH(NH,)*CO,H R2 = [CH2I4* CH(NH,).CO,H] isodesmosine [3; R' = [CH,] -CH(NH,).CO,H R2 = [CH,] -CH(NH,) CO,H R3= [CH,] -CH(NH,) CO,H] lo and now R. Reiner and C. H. Eugster Helv. Chim. Acta 1967 50 128; see also C. H. Eugster and T. Takemoto ibid. p. 126; H. Goth A. R. Gagneux C. H. Eugster and H. Schmidt ibid. p.137. ' T. Wieland and H. Wehrt Annalen 1966 700 120; P. Pfaender and T. Wieland ibid. p. 126; T. Wieland and V. Georgi ibid. p. 133; V. Georgi and T. Wieland ibid. p. 149; T. Wieland and U. Gebert ibid. p. 157; T. Wieland and J. X. de Vries ibid. p. 174. E. Gross and J. L. Morel] J. Amer. Chem. SOC. 1967 89 2791. H. J. Klosterman G. L. Lamoureux and J. L. Parsons Biochemistry 1967,6 170. * A. Vega and E. A. Bell Phytochernistry 1967,6 759. C. Franzblau M. Sinex B. Faris and R. Lampidis Biochem Biophys. Res. Comm. 1965 21 575. lo J. Thomas D. F. Elsden and S. M. Partridge Nature 1963 200 651; S. M. Partridge D. F. Elsden J. Thomas A. Dorfman A. Telser and H. Pei-Lee Nature 1966,209 399. Amino-acids and Peptides merodesmosine which is probably one of the isomeric structures [4;R' = [CH2]2*CH(NH2)*C02H have all been R2= [CH2],*CH(NH2)*C02H]," isolated from elastin.Tracer studies indicate that these amino-acids are derived from lysine residues which are involved in an oxidative cross-linking process when elastin fibres are formed from the soluble precursor protein. The process is postulated to involve aldehyde formation by oxidative de- amination of the E-amino-groups of lysine residues followed by stepwise condensation via aldol and Schiff base intermediates. In support of this hypo- thesis merodesmosin was obtained hydrolytically from young elastin which had been treated with alkali and then reduced with borohydride. Another reported new amino acid N*-(2-amino-2-carboxyethyl)ornithine, obtained from alkali-treated proteins,I2 could have been formed presumably in a similar way.An unusual amino-acid isolated from butterflies and previously thought to be the tetrahydro-4-oxoquinolinecarboxylic acid derivative (5),' is really 3-hydroxy-~-kynurenine (6).14 The error arose because of the ready cyclization of the monocyclic compound in the mass spectrometer. Several amino-acids including ~-cystathionine," ~-allocystathionine,~~ P-methyllanthionine,' ( +)-and ( -)-cis-S-(P-styry1)-L-cysteine S-oxides,' 2,3-dihydro-~-tryptophan,'~2,3-dihydro-5-hydroxy-~~-tryptophan,'~ various proline derivatives," and 3,3,3-trifl~oroalanine,~~ have been the subjects of recent synthetic studies. A general method for the preparation of P-perfluoro- alkylalanines2' (7; R = perfluoroalkyl) utilises the reaction between the 0 OH (5) B.C. Starcher S. M. Partridge and D. F. Elsden Biochemistry 1967,6 2425. K. Ziegler I. Melchert and C. Lurken Nature 1967,214,404. l3 K. S. Brown jun. J. Amer. Chem. SOC. 1965,87,4202. l4 T. Tokuyama S. Senoh T. Sakan K. S. Brown jun. and B. Witkop J. Amer. Chem. SOC. 1967,89 1017. M. L. Snow R. S. Dombro and C. Ressler J. Org. Chem. 1967,32 246. l6 H.-D. Belitz Tetrahedron Letters 1967 749. J. F. Carson and L. E. Boggs J. Org. Chem. 1967,32 673. 18 J. W. Daly A. B. Mauger 0.Yonemitsu V. K. Antonov K. Takase and B. Witkop Bio-chemistry 1967,6 648. l9 R. H. Andreatta V. Nair A. V. Robertson and W. R. J. Simpson Austral. J. Chem. 1967 20,1493; C.B. Hudson and A. V. Robertson ibid. 1967,20,1511,1521;M. Viscontini and H. Biihler Helu. Chim. Acta 1966,49 2524. 'O F. Weygand W. Steglich and F. Fraunberger Angew. Chem. Internat. Edn. 1967,6,808. W. Steglich H.-U. Heininger H. Dworschak and F. Weygand Angew. Chem. Internat. Edn. 1967,6 807. 454 H.D. Law NH NH Ac I (7) ii R&O * C(N2)*C0,Et R FC=C -CO Et I\ 0lcP (8) 1 Me (9) Reagents i CH,CN solution light ;ii H, AcOH PtO ; iii conc. hydrochloric acid 90" 18 appropriate perfluorocarboxylic anhydride and ethyldiazoacetate to form the perfluoroacyldiazoacetic ester (8). Photoaddition of this compound to acrylo- nitrile with displacement of nitrogen gives the 2-methyl-5-perfluoroalkyl-4-oxazole carboxylic ester (9),from which the amino-acid is obtained by catalytic hydrogenolysis followed by hydrolysis of the resulting N-acetyl P-perfluoro- alkyl alanine ester.The amino-acid can be resolved by way of the corres- ponding trifluoromethyl perfluoroalkyl oxazolone (10). Trifluoromethyl-2H-(1 0) oxazoiones react with amino-esters to give predominantly the diastereoisomers with the same absolute configuration at both asymmetric centres.22a. 23 Direct asymmetric synthesis of a-amino-acids has received considerable attention,24.25 although from a preparative standpoint methods dependent >7 -Proceedings of the Eighth European Peptide Symposium Noordwijk The Netherlands September 1966 ed. H. C. Beyerman A. Van De Linde and W. Maassen Van Den Brink North- Holland Publishing Co.Amsterdam 1967; (a)W. Steglich D. Mayer X. Barocio De La Lama H. Tanner and F. Weygand p. 67; (b) E. Scoffone A. Fontana F. Marchiori and C. Benassi p. 189; (c) Review E. Lederer and B. C. Das p. 131; (6)A. Prox and F. Weygand p. 158; (e) K. PoduSka H. Maassen Van Den Brink Zimmermannovii J. Rudinger and F. S6rm p. 38; (f) Brandenburg quoted by H. Zahn p. 43 ;(9)Th. Wieland and Chr. Birr p. 103 ;(h)L. Zervas I. Photaki. C. Yovanidis J. Taylor I Phocas and V. Bardakos p. 28; (i)M. Brenner p. 1 ;0')G. T. Young p. 55; (k) J. H. Jones B. Liberek and G. T. Young p. 15; (I) V. Gut reported by J. Rudinger p. 89; (m) H. C. Beyerman C. A. M. Boers-Boonekamp W. J. Van Joest and D. Van Den Berg p. 117;(n)H. Zahn T. Okuda and Y. Shimonishi p.108; (0)A. Patchornik M. Fridkin and E. Katchalski p. 91 ;(p) I. Z. Siemion and D. Konopinska p. 79; (4)R. B. Merrifield and A. Marglin p. 85; (r) H. Klostermeyer J. Halstrm P. Kusch J. Fohles and W. Lunkenheimer p. 113;(s)J. Beacham P. H. Bentley G. W. Kenner J. J. Mendive and R. C. Sheppard p. 235; (t) J. S. Morley p. 226; (u) M. Rothe I. Rothe T. Toth and K.-D. Steffen p. 8; (0)J.-P. Carrion B. Donzel D. Deranleay K. Esko P. Moser and R. Schwyzer p. 177. 23 F. Weygand W. Steglich and X. Barocio De La Lama Tetrahedron 1966 Suppl. 8 Part 1 p. 9. 24 K. Harada and K. Matsumoto J.Org. Chem. 1967,32 1794. 25 K. Harada Nature 1966,212 1571; J. Org. Chem. 1967,32 1790. Amino-acids and Peptides 455 on resolution are still to be preferred. The resolution of t-butyl N-trifluoro- acetyl-(& )-alaninate by g.1.c.over Chromosorb W coated with cyclohexyl N-trifluoroacetyl-L-valyl-L-valinateis a noteworthy development.26 Asym- metric transformations have also been used to determine the absolute con- figuration of amine~.~'.~~ Peptides Structural Elucidation.-Now that automated ion-exchange pro- cedures for amino-acid analysis are available this facet of structural elucidation presents no general difficulties but tryptophan-containing peptides owing to the instability of the indole moiety under acidic conditions do require special treatment. In a recently developed technique reaction of the peptide with o-nitrobenzenesulphenyl chloride in acetic acid solution quantitatively con- verts tryptophan residues into the 2-o-nitrophenylsulphenyl derivatives which are estimated spectroscopically [h,,,.280 and 365 mp E 16,700and E 4400].22b Difficulties arising from the presence of tryptophan in a peptide are often more than offset by the possibility of achieving selective peptide bond cleavage at this residue notably by treating the peptide with N-bromosuccinimide.29 Ozonolysis of tryptophan-containing peptides results in the conversion of the tryptophan residues into kynurenine residues3' Cleavage at these residues Reagents i electrolytic reduction ; ii H+/H20. (11) may be brought about by electrolysis followed by mild acid hydrolysis [(11)- (12)] although some cleavage at the kynurenine amino-group occurs.22b N-Bromosuccinimide may be used for the cleavage of tyrosyl peptide bonds but when tyrosine is N-terminal a 6-hydroxyindole derivative is obtained instead of the expected ~pirolactone.~ For the determination of N-terminal residue sequences the Edman method remains supreme.32 Phenyl isothiocyanate is condensed with the peptide and the N-terminal residue is cleaved from the resulting phenylthiocarbamoyl 26 E. Gil-Av and B. Feibush Tetrahedron Letters 1967 3345. 27 0.Cervinka Coll. Czech. Chem. Comm. 1965,30 1738. 0.Cervinka Coll. Czech. Chem. Comm. 1966,31. 1371. 29 B. Witkop Adu. Protein Chem. 1961 16,221. 30 F. M. Veronesse A. Fontana E. Boccu and C. A. Benassi Gazzetta 1967,97 321. 31 M. Wilchek T. F. Spande B. Witkop and G. W. A. Milne J. Amer. Chem. SOC. 1967 89 3349. 32 R.F. Doolittle Biochem. J. 1965,94 742; D. G. Smyth and D. F. Elliott Analyst 1964,89,81. 456 H.D. Law peptide as the 2-anilinothiazolin-5-one which rearranges to the 3-phenyl-2- thi~hydantoin.~~ An apparatus the ‘protein sequenator’ has been described in which the condensation and the cleavage of the thiazolinone are performed a~tomatically.~~~ 35 The various stages of the degradation are carried out in a spinning cup so that the solution is spread as a thin film on the surface of the cup ;air is excluded to reduce oxidative desulphuration of the thiocarbamoyl derivative. All solvents and reagents are carefully purified particularly to render them aldehyde-free so that no terminal amino-groups are blocked by side reactions. The formation of the thiazolinones is carried out under anhydrous conditions and the extracted thiazolinones are subsequently con- verted into the hydantoins in a separate step.In this way exposure of the peptide to hydrolysing conditions is avoided. More than fifteen residues can be removed by this technique every 24 hr.; the yield per cycle exceeds 98%. Approximately 0-25pmoles of protein are required. The sequence of the first sixty residues in apomyoglobin (from humpback whale) was determined successfully by this method which approximates to the theoretical limit if 2% loss is made at each step. Of course a small improvement in the efficiency at each step would extend quite considerably the length of sequence which could be determined. This possibility and the difficulty created by the detection on chromatograms of increasing amounts of phenylthiohydantoins from non-terminal amino-acids as the degradation progresses are being investigated and it may be expected that the applicability of the technique will be extended.Because of solubility difficulties this automated method is not likely to be readily applied to studies of small peptides and in preliminary investigations which might lead to an automated technique the pe~tide,~~? 37 or the cyclised residue,38 has been attached to a polymeric resin. A degradation similar to the Edman in which N-thiobenzoyl peptides are cleaved by treatment with tri- fluoroacetic acid has been de~cribed.~’This method seems particularly promising in view of the water-solubility of the reagent involved sodium thiobenzoylthioglycollate and of the detailed information already available on the c.d.properties of thiobenzoyl amino-acid~.~’ Dansylation4’ [reaction with 5-dimethylaminonaphthalene-1-sulphonyl chloride] and hydrolysis of the corresponding dansyl peptide to give the fluorescent dansyl derivative of the N-terminal amino-acid is a valuable alternative to the 2,4-dinitrofluorobenzene approach for the determination of N-terminal residues. The elucidation of the amino-acid residue sequence of 33 P. Edman Acta Chem. Scand. 1956 10 761; D. Bethell G. E. Metcalfe and R. C. Sheppard Chem. Comm. 1965,10 189. 34 P. Edman Thromb. Diath. Haernorrhug. 1963 Suppl. 13. 35 P. Edman and G. Begg European J. Biochem. 1967,1 80. 36 R.A. Laursen J. Amer. Chem. SOC. 1966,88,5344. 37 H. Jeschkeit R. Henkel and H. Lehmann 2.Chem. 1967,7 191. 38 G. R. Stark Fed. Proc. 1965,24 225. 39 G. C. Barrett Chem. Comm. 1967,487. 40 G. C. Barrett J. Chem. SOC.(C),1967 1. 41 W. R. Gray and B. S. Hartley Biochem. J. 1963,89 379; L. B. Smillie and B. S. Hartley ibid. 1966 101,232; W. R. Gray “Methods in Enzymology” Vol. 11 Ed. C. W. Hirs Amino-acids and Peptides 457 apamin (13) a C.N.S. stimulator for bee venom provides a recent example of the application of this technique.42 Dansylation has been used in conjunction with hydrazinolysis for C-terminal residue identifi~ation.~~ Peptides can be recovered from dansyl derivatives by reduction with sodium-liquid ammonia at -70°.44 T>e photolytic decomposition of 2,4dinitrophenyl amino-acids proceeds with the formation of 2-substituted 6-nitrobenzimidazole 1-oxides and 4-nitro-2-nitr xoaniline; the relative proportions of each are pH de- pendent4 Peptides in dilute aqueous solution at pH 7 react stoicheiometrically with the hydroxoaquotriethylenetetraminecobalt(m) ion to form the chelate [Co trien NH2CHR*COz]+ + (14) of th'e N-terminal residue.46 Reaction with the hydroxoaquobisethylenediaminecobalt(II1)ion to form the I I I I Cys .Asn .Cys .Lys .Ala .Pro.Glu Thr. Ala. Leu. Cys. Ala. Arg. Arg. Cys. Gln .Gln .His. NH HNCH-CO. NH .CH-CO. R* RZ I R' \ r/-N 1++ (1 4) Reagents [Co trien (H,O) (HO)] ++ rate-determining step 42 R. Shipolini A. F. Bradbury G.L. Callewaert and C. A. Vernon Chem. Comm. 19i7 679. 43 B. Mesrob and V. HoleySovskjr Coll. Czech. Chem. Comm. 1967,32 1976. 44 Z. Tamura T. Tanimura and H. Yoshida Chem. and Pharm. Bull. (Japan),1967,15,252. 45 D. J. Neadle and R. J. Pollitt J. Chem. SOC. (C) 1967 1764. 46 D. A. Buckingham J. P. Collman D. A. R. Happer and L. G. Marzilli J. Amer. Chem. SOC. 1967,89 1082. 458 H.D. Law [Co en 2NH2-CHR.C02]+ complex is apparently ~imilar.~' + Studies with dipeptides indicate that the complex formed most rapidly has the L-configura- tion at the cobalt atom48 when the C-terminal residue of the dipeptide is L and D-asymmetry at the cobalt atom when the C-terminal residue is D. In contrast to these results the alkaline hydrolysis of simple peptides in the presence of copper@) or nickel(I1) is reported to give selective release of the C-terminal residue; chelation protects four or five peptide bonds from hydr~lysis.~' Mass spectrometry has proved useful for the determination of the structures of a number of small peptides and depsipeptides but a limiting factor in this approach is the volatility of the sample.22" In principle however the method could be used to elucidate the structures of peptides obtained by partial hydrolysis from larger molecules and might therefore be developed to permit sequence studies of proteins.In a model study of this kind N-trifluoroacetyl peptide methyl esters obtained by methanolysis from a cyclic nonapeptide and purified by g.l.c. were identified by mass spectrometry; this permitted the sequence of residues in the nonapeptide to be deduced.22d R .co .NH -CHR~.co ...NH .c~~n-1.c& (1 6) Cleavage of the peptide bond [(l5) -+ (16)] probably proceeding in a step- wise manner from the C-terminal residue seems to be a fundamental mode of peptide degradation in the mass spe~trometer.~~-'~ Hence if the N-terminal residue is distinguishable e.0. because it possesses a characteristic acyl substituent the sequence may be deduced by discovering what mass additions to this unit would account for the spectrum observed. Other methods of fragmentation do occur in linear peptides [e.g. (15) -+ (17)]. In cyclodepsi- peptides the initial ring opening generally involves up to three basic routes [(18) -+ (19) (18) -+ (20) and (18) -+ (21)]; the significance of each depends 47 D.E. Allen and R. D. Gillard Chem. Comm. 1967 1091. 48 R. D.Gillard Chem in Britain 1967,3 205. 49 R. H. Andreatta H. C. Freeman A. V. Robertson and R. L. Sinclair Chem. Comm. 1967,203. 50 M.Barber P. JollCs E. Vilkas and E. Lederer Biochem Biophys. Res. Cornm. 1965 18,469. 51 N.S. Wulfson V. A. Puchkov B. V. Rozinov Yu. V. Denisov V. N. Bochkarev M. M. Shemyakin Yu. A. Ovchinnikov A. A. Kiryushkin E. I. Vinogradova and M. Yu. Feigina Tetra-hedron Letters 1965,2805. 52 F. Weygand A. Prox H. Fessel and K. Kun Sun 2.Naturforsch. 1965,206 1169. 53 N. S. Wulfson V. A. Puchkov V. N. Bochkarev B. V. Rozinov A. M. Zyakoon M. M. Shemyakin Yu. A. Ovchinnikov V. T. Ivanov A. A. Kiryushkin E. I.Vinogradova M. Yu. Feigina and N. A. Aldanova Tetrahedron Letters 1964 951 ; N.S.Wulfson V. A. Puchkov B. V. Rozinov Yu. A. Ovchinnikov A. A. Kiryushkin and V. T. Ivanov ibid. 1965,2793. "W. S. Bertand M. C. Probine J. S. Shannon and A. Taylor Tetrahedron 1965,21 677,and references therein. Amino-acids and Peptides on the size of the ring.53-55 Ring-opening by reactions analogous to (18) -+ (19) and (18) + (20) are observed with cyclopeptides and in certain cases other ring-opening reactions have also been observed [e.g. (22) -,(23) and (24) + (25)JS6 The spectra of cyclic peptides and large cyclodepsipeptides (e.g. octa-and deca-depsipeptides) may be impossible to interpret because of the number of positions at which ring opening occurs.CHR'R2 CHR3R4 CHR5R6 I I O-CH-CO-0-CH-CO-0-CH-CO [CO .CHR .O], + CHR'R' CHR3R4 CHR5R6 CHR3R4 I 1 O-CH-CO-b==(!H -CH-CO (20) I 1 CHR' R2 O=C+$i II /CFo/C% R R'CH (21) .+ NH i +[CO CHR NHI [CO .CHR . NH] (22) (23) 0 6 0 NH .CHR' .c& NHKHR [CO .CHR . NH] (24) (25) Staphylomycin S (26)57gives a readily interpretable spectrum [(26) +(27)] because it contains only one ester bond.58 C0,-Type ring opening also pre- dominates for isarolides A (28; R' = Pr' R2 = CH,Ph) B (28; R' = CH2Ph R2 = Pri) and C (28; R' = R2 = CH2Ph) and the structures of these com- " C. H. Hassall and J. 0.Thomas Tetrahedron Letters 1966,4485. " B. J. Millard Tetrahedron Letters 1965 3041. " H. Vanderhaeghe and G. Parmentier J.Amer. Chem. SOC. 1960,82,4414. '* A. A. Kiryushkin V. M. Burikov and B. V. Rosinov Tetrahedron Letters 1967 2675. 460 H.D. Law CO-CH-NH-co 1 Ph CH,Ph -COz -H d I 1 L mle 122 205 290 387 548 673 778 (27) pounds could be postulated on the basis of the fragmentation patterns outlined above even though only a mixture of the compounds was available.59 Fragmentation is not confined to the peptide backbone (vide elimination in the threonine residue in staphylomycin S),but the type of side-chain fragmenta- tion which occurs is well defined.22c Arginine peptides create difficulties owing to their thermal lability but may be converted into ornithine peptides by hydrazinolysis,60 or to pyrimidylornithine derivatives by reaction with 1,3- diketones,60.61 both of which give satisfactory spectra.60 One of the attractions of the mass spectrometric approach to peptide structure is that automatic sequence determination should be possible and the development of com- puterised techniques for interpreting spectral information goes some way towards realising this end.62-64.Peptide Synthesis.-Protecting groups. There is now an almost embarrassing number of protecting groups available for peptide synthesii although synthetic successes to date have utilised relatively few of them. The preferred methods involve benzyloxycarbonyl- t-butoxycarbonyl- and o-nitrophenylsulphenyl- amino-groups; simple alkyl t-butyl benzyl and p-nitrobenzyl esters ;nitro- 59 L. H. Briggs B. J. Fergus and J.S. Shannon Tetrahedron 1966 Suppl. 8 269. 6o M. M. Shemyakin Yu. A. Ovchinnikov E. I. Vinogradova M. U. Feigina A. A. Kiryushkin 61 K. Toi E. Bynum E. Norris and H. A. Itano J. Bid. Chem. 1967 242 1036; T. P. King N. A. Aldanova Yu. B. Alakhov V. M. Lipkin and B. V. Rosinov Experientia 1967,23,428. K. Biemann C. Cone B. R. Webster and G. P. Arsenault J. Amer. Chem. SOC.,1966,88 5598. Biochemistry 1966,5 3454. 63 M. Senn R. Venkataraghavan and F. W. McLafferty J. Amer. Chem. SOC. 1966,88,5593. 64 M. Barber P. Powers,M. J. Wallington and W. A. Woistenholme Nature 1966,212 784. Amino-acids and Peptides 461 tosyl and protonated guanidino-groups; benzyl ethers and thioethers and N'"-benzyl imidazoles. The preparation of t-butoxycarbonyl amino-acids from t-butyl azido-formate has been improved (yields better than 90%) by the use of an auto- titrator to control the pH of the rea~tion.~' Removal of the p-nitrophenol is sometimes difficult if these derivatives are prepared from t-butyl p-nitrophenyl carbonate but this difficulty can be avoided if an equivalent of NN'-dicyclo- hexylcarbodi-imide is added to the mixture of t-butoxycarbonylamino-acid and p-nitrophenol so that the p-nitrophenyl active ester is prepared directly.66 An important development is the use of formic acid to cleave the t-butoxy- carbonyl group.67 The resulting peptide ester formates obtained quantitatively and generally in a non-hygroscopic crystalline form are quite stable except for dipeptide derivatives which tend to form dioxopiperazines when warmed.Formic acid also cleaves N-trityl N-o-nitrophenylsulphenyl and 0-t-butyl ether and ester groups. Further new methods for the removal of the o-nitrophenylsulphenyl group include the use of sulphonic acid imides22e and o-nitrothiophenol.22f These reactions are essentially displacement reactions requiring an excess of the nucleophile. However if the cleavage with benzenesulphonimide takes place at 70" in alcoholic solution only one equivalent of the imide is required and the process is then presumably one of acid-catalysed alcoholysis.2 2e The relative importance of the displacement and alcoholysis reactions will depend upon the nucleophilicity of the anion of the acid employed. With hydrogen chloride for example it is postulated that sulphenyl chloride formation occurs in an initial displacement reaction and the alkyl sulphenate arises from subsequent alcoholysis of this halide.When N-o-nitrophenylsulphenylcysteinederivatives are treated with acids in a variety of solvents and even in alkaline solution N - S migration of the protecting group occurs.68 Protecting groups possessing features of both benzyloxycarbonyl and t-butoxycarbonyl groups have been investigated. It was hoped that acedimethyl- benzyloxycarbonyl and PP-dimethylphenethoxycarbonyl groups would be thermolabile but heating to 130" for 10 min. was required for cleavage.22g The t-pentyloxycarbonyl group has also been extensively ~tudied.~' New protecting groups which formally resemble the benzyloxycarbonyl and t-butoxycarbonyl groups but which are resistant to hydrogen bromide in acetic acid trifluoroacetic acid etc.are the piperidino-oxy~arbonyl~~ and 2,2,2-trichloroethoxycarbony171groups. The piperidino-oxycarbonyl group has been removed by treatment with zinc or sodium dithionate in aqueous acetic acid by electrolytic reduction in a mixture of N-sulphuric acid and tetra- " E. Schnabel Annalen 1967,702 188. " Y. Wolman D. Ladkany and M. Frankel J. Chem. SOC. (C),1967,689. 67 B. Halpern and D. E. Nitecki Tetrahedron Letters 1967 3031. '* I. Phocas C. Yovanidis I. Photaki and L. Zervas J. Chem. SOC.(C) 1967 1506. 69 S. Sakakibara and M. Itoh Bull. Chem. SOC.Japan 1967,40,646. 70 D. Stevenson and G. T. Young Chem. Comm. 1967,900. " T. B. Windholz and D.B. R. Johnston Tetrahedron Letters 1967 2555. 462 H.D. Law hydrofuran (1 1) and by hydrogenolysis over palladised charcoal in aqueous acetic acid. Treatment with zinc in acetic acid at room temperature and heating the derivative under reflux briefly in methanol in the presence of zinc have been used to remove the trichloroethoxycarbonyl group. Hydrogenolysis over palladised charcoal or platinum oxide did not cleave this group. Protection with 2-iodoethoxycarbonyl was investigated a few years ago but did not find favour owing to the toxicity of some intermediate^.^^ Diphenylmethyl esters which are acid-labile do seem potentially useful in general peptide synthesis.22h- 73 Pentamethylbenzyl esters cleaved by treat- ment with trifluoroacetic acid have been advocated for depsipeptide synthesis.74 Phenacyl esters readily prepared from phenacyl bromide are cleaved by hydrogenolysis or by treatment with sodium ben~enethiolate.’~ p-Bromo- phenacyl esters undergo aminolysis too rapidly to be useful in peptide synthesis.75 Problems encountered with side-chain protection of cysteine residues are discussed below in connection with the synthesis of insulin.Presumably symmetrical thioacetals like the acetals developed for hydroxy-group protection in ribonucleotide could be adapted to give the right degree of acid lability for peptide work. An N”-ditrityl arginine derivative obtained surprisingly,~ by treating tri- or tetra-tritylarginine with hydrochloric or hydro- bromic acid might find application.The trityl groups are removed by treatment with hydrogen bromide in acetic acid.22h Formation ofthe peptide bond. Most but not methods described for peptide formation and all approaches to the synthesis of natural peptides have been dependent upon enhancement ofthe reactivity of one of the functional groups of the amino-acid. Usually but not always,77 the carboxy-group of the amino-acid is activated and where possible the activation of peptide terminal carboxy-groups is avoided because of the dangers of racemization. The classical azide route remains important because it does not cause racemization. Otherwise in the most commonly used coupling methods the carboxy-component is activated by conversion into a mixed anhydride or by reaction with NN’-dicyclohexylcarbodi-imide or by making an active ester from it.A recent reinvestigation of the mixed anhydride technique shows that under the most favourable conditions even peptide C-terminal carboxy- groups can be activated with very little ra~emization.~~ Couplings with high molecular weight carbodi-imides have been in~estigated.~~ A disadvantage of the NN‘-dicyclohexylcarbodi-imide technique the isolation of the peptide from the urea by-product should not arise with this new reagent but undesirable ’’ J. Grimshaw J. Chem. SOC.,1965 7136. 73 J. Taylor-Papadimitrion C. Yovanidis A. Paganon and L. Zervas J. Chem. SOC.(C) 1967 1830. 74 F. H. C. Stewart Chem. andZnd. 1967 1960. ” F. H. C. Stewart Austral. J. Chem. 1967,20 787. ” C. B.Reese R. Saffhill and J. E. Sulston J. Amer. Chem. SOC.,1965,89 3366. 77 G. Liisse and W. Giidicke Annalen 1967 100,3314. ’* G. W. Anderson J. E. Zimmerman and F. M. Callahan J. Amer. Chem. Soc. 1967,89 5012. 79 Y. Wolman S. Kivity and M. Frankel Chem. Comrn 1967 629. Amino-acids and Peptides acyl urea formation might prove more troublesome. N N'-Dicyclohexyl-urea can be converted into the carbodi-imide by treatment with phosphorus pentoxide." One drawback to the use of Reagent K (29; R' = Me R2 = SO, R3= H) in peptide synthesis is that the active ester (30)which is formed has a tendency to rearrange to the keto-imide (31;R' = Me R2 = SO; R3= H). N-Ethyl- isoxazolio-derivatives (29; R' = Et R2 = SO, R3= H and 29; R' = Et R2 = H R3 = SO;),'' but not N-aryl isoxazolio-derivatives (29; R' = Ph R2 = R3 = H),'* are better from this point of view.2-Ethyl-7-hydroxy- benzisoxazolium salts (32) react with N-protected amino-acid sodium salts at pH 4-5 to give the active esters (33). These substituted catechol esters are extremely resistant to racemization and can even be reacted with amino-salts to give racemate-free peptides. This reaction seems to offer a means for activating terminal carboxy-groups of peptides without danger of race-mi~ation.*~ The resistance to racemization shown by these esters is undoubtedly due to a variety of factors one of which will be availability of the o-hydroxy-group for hydrogen-bonding with the approaching amine which should facilitate aminolytic attack at the expense of the oxazolone-forming reaction.Similar effects have been observed with esters derived from catechol,22j l-hydroxy- piperidine,22k.84 and 8-hydroxyquinoline.' Esters derived from N-hydroxy- LO -CH .CH .CO .NH .CH * CO .NH * CH .CO .NH .CH .Cd I I I I [CH2I R' R2 CH 1 / '1 Me Me Et R2 NHR~ R3& C@ I Reagents CeL ,N R' .CO CH R"-NHR~ i Rb-NH .CHR"-CO2-(3 1) II 0 ''C. L. Stevens G. H. Singhal and A. B. Ash J. Org. Chem.. 1967,32 2895. " R. B. Woodward R. A. Olofson and H. Mayer Tetrahedron 1966 Suppl. 8,321. R. B. Woodward D. J. Woodman and Y. Kobayashi J. Org. Chem. 1967,32 388. 83 D. S. Kemp and S. W. Chien J. Amer. Chem. SOC.,1967,89,2743. 84 J. H. Jones B. Liberek and G. T. Young J. Chem. SOC.(C) 1967,2371." H.-D. Jakubke A. Voigt and S. Burkhardt Chem. Ber. 1967,100,2367. 464 H. D. Law OH OH 32 \ 0-CO * CHIps NHRb I (3 4) (3 3) succinimide and N-hydroxypiperidine can be prepared by the mixed anhydride method.86 Again under the most favourable conditions acyl peptides seem to couple with little racemization. N-Hydroxyphthalimide p-nitrophenol and 2,4,5-trichlorophenoI do not give active esters by this method whilst penta- chlorophenol and 8-hydroxyquinoline give partially racemized esters. Pivalohydroxamic acid esters (34; R = CMe,) may be prepared by the reaction of acyl amino-acids with pivalonitrile oxide and this approach has also been reported to give no racemization when used to activate a C-terminal carboxy-group [Z.Gly.L.Phe + Gl~.oEt].~~ N-Benzyloxycarbonylproline could not be coupled by this technique because of the prevalence of a side- reaction involving Lossen rearrangement.88 Benzohydroxamic esters (34; R’ = Ph) prepared from the silver salt of the acyl amino-acid or N-protected peptide and benzohydroximic acid chloride are also reported to be free from racemization during their formation and subsequent aminolysis.’ Halogenated phenyl esters especially tri~hloro-,~~. 93 91 penta~hloro-,’~ and pentafl~oro-’~. 94 phenyl esters have received continuing attention. Pentachloro- and pentafluoro-phenol form complexes (35; X = C1 or F) with NN’-dicyclohexylcarbodi-imide which react with acyl peptides to give the corresponding active esters once more with very little ra~emization.’~ How-ever it is thought that the complex dissociates into the phenol and ”’-dicyclohexylcarbodi-imide,and that ester formation takes place in the normal way.Racemization is possibly suppressed because the acidity of the phenol tends to depress the base-catalyzed racemization of the corresponding 86 G. W. Anderson F. M. Callahan and J. E. Zimmerman J. Amer. Chem. SOC. 1967,89 178. S. Rajappp K. Nagarajan and V. S. Iyer Tetrahedron 1967,23,4805. T. R. Govindachari S. Rajappa A. S. Akerkar and V. S. Iyer Tetrahedron 1967 23 4811. E. Taschner B. Rzeszotarska and L. Lubiewska Chem. and Ind. 1967,402. B. Rzeszotarska and G. P. Vlasov Bull. Acad. polon. Sci. SPr. Sci. Chim. 1967 15 143. 91 J. S. Morley J. Chem. SOC. (C) 1967 2410. 92 J.Kovacs M. Q. Ceprini C. A. Dupraz and G. N. Schmidt J. Org. Chem. 1967 32 3696; A. Kapoor and E. J. Davis Experientia 1967 23 253. 93 J. Kovacs L. Kisfaludy and M. Q. Ceprini J. Amer. Chem. SOC. 1967 89 183. 94 V. A. Shibnev T. P. Chuvaeva and K. T. Poroshin Izvest. Akad. Nauk. S.S.S.R.Ser. khim. 1967,954. Amino-acids and Peptides 465 oxazolone which will in any case undergo ring opening more rapidly with these strongly acidic phenols than for example with p-nitrophenol. A new technique for the preparation of p-nitrophenyl esters has been noted above. Synthesis of the elusive Na-benzyloxcarbonyl-N”-nitroarginep-nitrophenyl ester is also reported.” X (35) Amino-acid triethylenetetraminecobalt(111) complexes and the corresponding bisethylenediamine complexes (36) may be used in peptide ~ynthesis.~~ The perchlorate of the bisethylenediamineglycine methyl ester cobalt (111) complex reacts in 1 min.at 20” in ahydrous sulpholan dimethyl sulphoxide or acetone with peptide or amino-acid esters to add a glycine residue to the N-terminal amino-group. Complexing both protects the amino-group of the glycine and apparently activates the ester function. This reaction has not yet been fully studied and further information about racemization yield and generality will be required before its true significance can be estimated. However because of the strict steric requirements of both reactants and products and because of the convenience and consequent efficiency of simultaneous protection and activation it seem’s extremely promising.The technique of ‘solid-phase’ peptide synthesis developed by Mer~-ifield,~~ has made good headway although many laboratories have experienced difficulties when first using the method. In this technique the N-protected C-terminal amino-acid residue reacts as its triethylamine salt with an insoluble chloromethylated polystyrene resin to form a benzyl ester-type link. The N-protecting group is subsequentky removed and N-protected amino-acids are added to the insoluble aminoacyl polymer by a suitable succession of ‘de- blocking’ and ‘coupling’ stages. t-Butoxycarbonyl protection of amino-groups has been used almost exclusively and ”’-dicyclohexylcarbodi-imide has usually been employed in the coupling stage.Cleavage of the peptide from the resin has generally been achieved by the use of hydrogen bromide in trifluoroacetic acid. Quaternization of the chloromethylated resin has been detected as a side 95 W. Godicke and G. Losse 2.Chem. 1967,7,232. 96 D. A. Buckingham G. L. Marzilli and A. M. Sargeson J. Amer. Chem. SOC. 1967 89 2772 4539. 97 R. B. Merrifield J. Amer. Chem. SOC. 1963 85 2149; G. R. Marshall and R. B. Merrifield Biochemistry 1965,4 2394. 466 H.D. Law reaction in the esterification stage."'* 22m Studies in which glycine was bound to the resin as the C-terminal amino-acid show that there is a considerable variation in the reactivity of the various glycine moieties (aminolysis of t- butoxycarbonyl-leucine 5-chloro-8-hydroxyquinoline ester).It has been advo- cated that the first peptide bond-forming stage should be relatively short after which the unreactive sites should be irreversibly blocked to reduce the kinetic heterogeneity of subsequent peptide-forming stages.22' Asparagine and gluta- mine residues are normally introduced as active esters because of the danger of nitrile formation in the presence of NN'-dicyclohexylcarbodi-imide. In recent work on insulin peptides 0-benzyltyrosine S-benzylcysteine and N-benzyloxycarbonyl-lysine have also been incorporated as activated esters.22n 1,2,4-Triazole catalysis is reported to improve yields when active esters are employed in the solid phase technique.22m Removal of the peptide from the resin at the end of the synthesis under strongly acid conditions limits the range of peptides to which solid phase synthesis in its present form can be applied.However a tryptophan residue in a pentapeptide was found to be left intact when the cleavage was carried out with hydrogen chloride in acetic acid.98 Anhydrous hydrogen fluoride9' and hydrazinolysis' O0*'O' have both been used satisfactorily for the cleavage ;hydrolysis has been investigated. lo' Several other techniques for the synthesis of peptides without isolating the intermediates involved (see e.g. Morley' ') have been reported. Peptide synthesis has also been carried out by a 'reverse solid-phase' method in which the activated amino-acid is the insoluble phase.'*" Especially noteworthy is the use of amino-acid N-carboxy-anhydrides in stepwise peptide synthesis.'03 Racemization. The amount of racemization inherent in the use of a particular coupling technique or protecting group has usually been assessed by the synthesis of model di- and tri-peptides. Diastereoisomers resulting have been estimated by recrystallization by t.l.c. or by g.1.c. Three mechanisms oxazolone formation p-elimination and proton withdrawal have been associated with racemization during peptide synthesis and it has been suggested that three tests based on the racemization of the p-nitrophenyl esters of N-benzoyl-L- leucinate N-benzyloxycarbonyl-S-benzyl-L-cysteinateand N-benzyloxycar- bony1 L-phenylglycinate could be used to investigate separately the racemiza- tion occurring by each of these pathway^."^ Differences in the chemical shifts of the methyl protons in diastereoisomeric alanine peptides may be used to assess racemization for example in the for- mation of methyl N-acetyl-L-alanyl-L-phenylalaninate.'O5 The amino-acid 9a A. Loffet Experientia 1967 23,406. 99 J. Lenard and A. B. Robinson J. Amer. Chem. SOC.,1967,89 181. loo M. Ohno and C. B. Anfinsen J. Amer. Chem. SOC. 1967,89 5995. W. Kessler and B. Iselin Helo. Chim. Acta 1966,49 1330. A. Deer Angew. Chem. 1966,78 1064. R. Hirschmann R. G. Strachan H. Schwam L. F. Schoenewaldt H. Joshua J. Barkemeyer D. F. Verber W. J. Paleveda T. A. Jacob T. E. Beesley and R. G. Denkewalter J. Org. Chern. 1967 32 34 15. M. Bodanszky and A. Bodanszky Chem. Comm. 1967,591. 105 B. Halpern L. F.Chew and B. Weinstein J. Amer. Chem. Soc. 1967 89 505; B. Halpern D. E. Nitecki and B. Weinstein Tetrahedron Letters 1967 3075 ; J. 0.Thomas ibid. p. 335. Amino-acids and Peptides 467 analyser is used in another novel racemization test. N-Acetyl-L-isoleucine is coupled to ethyl glycinate and after hydrolysis of the resulting peptide the ratios of isoleucine and alloisoleucine are measured."' A new system for the detection of racemization by g.1.c. lo7 depends upon the coupling of N-protected (t-butoxycarbonyl) amino-acids with an optically pure asymmetric amine [( -)-2-amino-4-methylpentane] and separation of the diastereoisomers pro- duced. Phenylalanine derivatives tend to decompose under the g.1.c. conditions used in this work but the phenylalanine amides can be separated by t.1.c.The general approach has the advantage that coupling methods can be investi- gated for different amino-acids. It is also likely that the N-protecting group could be varied. Racemization during peptide synthesis most commonly occurs via the oxazolone route.2 2j N-Alkoxycarbonyl amino-acids in contrast to N-acyl amino-acids are generally resistant to racemization. Kinetic studies"* 0-I suggest that oxazolone formation occurs via the conjugate base [-N=C-] which might account for these differences. Studies of molecular models show that the amide bond must be in the trans-conformation for oxazolone formation to occur; shifts to more polar solvents tend to stabilise cis-amide bonds. The assistance of the electronic effect favouring oxazolone formation will therefore be offset to some extent in solvents of high polarity by the conformational effect of the solvent on the peptide bond.22p Once formed the oxazolone can undergo the reverse reaction to give the unchanged activated carboxy-derivative or can racemize and then be converted into the racemic starting material.The oxazolone before or after racemization can also react with the amine com- ponent to give the peptide directly. In these circumstances it is not surprising that the oxazolone may be difficult to detect even when it can be clearly demonstrated by ancillary evidence that racemization is proceeding via this mechanism."' Generally it may be taken that racemization of the oxazolone will be at least as fast and generally faster than the various ring opening reactions which the oxazolone might undergo although the rate of ring opening does vary significantly with the strength of the nucleophile involved.110 The problem of coupling acyl peptides to amino-components without racemization is therefore the problem of activating the carboxy-group towards aminolytic attack without activating it for oxazolone formation.This has been one of the outstanding problems of modern synthetic peptide chemistry and the continuing importance of the azide coupling technique is directly attributable to its success in achieving this end. The development of new techniques which might achieve racemization-free coupling of this type has lo6 M. Bodansky and L. E. Conklin Chem.Comm. 1967 773. lo' B. Halpern L. F. Chew and J. W. Westley Anafyt.Chem. 1967,39 399. D. S. Kemp and S. W. Chien J. Amer. Chem. SOC.,1967,8!4,2745. lo9 I. Antonovics and G. T. Young J. Chem. SOC.(C),1967,595. W. H. McGahren and M. Goodman Tetrahedron 1967 23 2017; M. Goodman and W. H. McGahren ibid. p. 2031. 468 H. D. Law been noted in this review. These techniques if generally applicable are likely to prove very important. Natural Peptides.-All of the natural peptides so far synthesized were first prepared by what may be regarded as the classical route which involves the isolation and where possible the characterization of all intermediates. Approaches of this kind though unequivocal would be prohibitively laborious and inefficient in the synthesis of very large compounds and unless new methods of isolation are introduced which are less dependent on fortuitous physical properties and on the chemists' manipulative skill it seems possible that insulin 111-113 will remain the largest peptide to be synthesized by this method.The alteI-.ative is to employ a route in which the isolation of intermediates is reduced to a minimum. Thanks to chromatographic and instrumental tech- niques this does not mean that characterization must be neglected. Ideally the technique should be susceptible to automation. Merrifield's solid-phase approach is the most thoroughly investigated technique of this kind and by its use variously protected A-and B-chains of insulin have been prepared in high yields in a matter of 22q* l4 Th e yield of insulin when the synthetic chains prepared in this way are combined is not as large as the yield obtained by recombination of the chains isolated from the natural hormone.However these differences seem to be due to the limitations of the protecting groups used and not to a conceptual failing of the solid-phase approach. Experiments in which o-amino-acids were incorporated into polyamides suggest that the synthesis of peptides at least twice the length of the insulin chains should offer no new fundamental difficulties.22' Several peptides smaller than insulin have been prepared by the solid-phase approach and they have generally been obtained more conveniently and in higher yield than by the classical route.'15 At least two major difficulties still beset the would-be synthesizer of insulin.The first arises from the fact that the molecule contains three disulphide bonds so that an unequivocal synthesis would require three types of sulphur pro- tecting groups with different labilities to enable the individual disulphide bonds to be made unambiguously one at a time. The second is the protecting group difficulty mentioned above. In all insulin syntheses reported to date cysteine residues have been incorporated as the benzyl thioether deriva- tive.' 11-113* Although the use of only one S-protecting group could not be expected to given an unambiguous combination of the two chains at the J. Meienhofer. E. Schnabel H. Bremer 0. Brinkhoff. R. Zabel. W. Sroka H. Klostermeyer.D. Brandenburg T. Okuda and H. Zahn Z. Naturforsch. 1963 18b. 1130. '12 P. G. Katsoyannis K. Fukuda A. Tometsko K. Suzuki and M. Tilak J. Arner. Chem. SOC. 1964,86,930. K. T. Kung Y. C. Du W. T. Huang C. C. Chen L. T. Ke S. C. Hu R. Q. Jiang S. Q. Chu C. I. Niu J. Z. Hsu W. C. Chang L. L. Chen H. S. Li Y. Wang T. P. Loh A. H. Chi C. H. Li P. T. Shi Y. H. Yieh K. L. Tang and C. Y. Hsing Sci. Sinica 1965 14 1710. 'I4 A. Marglin and R. B. Merrifield J. Amer. Chem. SOC.,1966,88 5051. G. R. Marshall and R. B. Merrifield Biochemistry 1965 4 2394; J. M. Stewart and D. W. Woolley Fed. Proc. 1965 24 657; M. C. Khosla R. R. Smeby and F. M. Bumpus Biochemistry 1967 6 754; W. K. Park R. R. Smeby and F. M. Bumpus ibid. p. 3458. '16 H. Klostermeyer and R.E. Humbel Angew. Chem. 1966,78 871 ; P. G. Katsoyannis Science 1966,154 1509. Amino-acids and Peptides conclusion of the synthesis studies with the natural chains show that a con- siderable amount of insulin activity can be obtained by recombination of the chains under appropriate conditions.' ' Sodium-liquid-ammonia reduction is necessary for the cleavage of the S-benzyl group and to remove other protecting groups N"-tosyl and N'"-benzyl used in these syntheses. This treatment has created problems in the synthesis of small peptides but these have not been insuperablq' '*whereas in the insulin work the reductive step leads to exten- sive side reactions including desulphuration' l9 and splitting of the peptide chain.'20 These side reactions account for the consistently low yields of insulin activity when recombination data for natural and synthetic chains are com- pared.An attempted synthesis of the B-chain of human insulin failed because of the destruction during the sodium-liquid ammonia treatment of the C-terminal threonine residue. ' Syntheses which employ other protecting groups are therefore required. Another approach using cystinyl peptides has recently been reported.'22 The N-benzyloxycarbonyl hexadecapeptide symmetrical disulphide possessing the residue sequence of the N-terminal portion of the B-chain was combined by the azide technique with the tetradecapeptide symmetrical disulphide equivalent to the C-terminal sequence. t-Butyl protecting groups were used on side chains and for the C-terminal carboxy-group ; arginine guanidino- groups were protonated.The main product of the coupling was a polymeric material possessing the full 1-30 amino-acid sequence. Protecting groups could be removed and the product could be cleaved by sulphitolysis to give the B-chain 17,19 S-sulphonate in 2-4 % yield based on the crude polymers. When combined with natural A-chain this material yielded 1-2.6 I.U./mg. of insulin activity whereas the B-chain after sodium-liquid ammonia reduction gave 0.5-0.75 I.U./mg. In the same experiments recombination of natural A- and B-chain S-sulphonates gave 2-3 I.U./mg. The attempt to prepare insulin by an unambiguous route employing three sulphur-protecting groups and forming each disulphide bridge in turn has the inherent difficulty that unsymmetrical cystine peptides tend to be unstable.Clearly formed disulphide bond(s) need to remain intact whilst the other protecting groups are removed and the new disulphide bond(s) formed. Several studies of the synthesis and stability of unsymmetrical open-chain cystine peptides have been reported in recent years.22h' 123,124 S-Trityl S-11' P. G. Katsoyannis A. Tometsko C. Zalut S. Johnson and A. C. Trakatellis Biochemistry 1967 6 2635; P. G. Katsoyannis A. C. Trakatellis S. Johnson C. Zalut and G. Schwartz ibid. p. 2642 and references therein. H. Nesvadba and H. Roth Monatsh. 1967,98 1432. l9 P. G. Katsoyannis Amer. J. Med. 1966,40 652. W. F. Benisek and R. D. Cole Biochem. Biophys. Res. Comm. 1965 20 655.lZ1 H. Zahn T. Okuda and Y. Shimonishi Angew. Chem. 1967,79,424. 12' H. Zahn and G. Schmidt Tetrahedron Letters 1967 5095; H. Zahn and W. Sroka Annalen 1967,706,230. 12' R. G. Hiskey and E. L. Smithwick jun. J. Amer. Chem. SOC. 1967,89,437. lZ4 R. G.Hiskey T. Mizoguichi and E. L. Smithwick jun.,J. Org. Chem. 1967,32,97 ;R. G. Hiskey J. T. Staples and R. L. Smith ihid. p. 2772 R. G. Hiskey and M. A. Harpold Tetrahedron 1967,23 3923 and references therein. 470 H.D.Law diphenylmethyl and S-acyl cysteine derivatives appear to offer the possibility of selective removal. The question of the stability of the disulphide is not so clear-cut but stability of unsymmetrical disulphides under acidic conditions has been demonstrated. For example N-diphenylmethoxycarbonyl protecting groups and t-butyl esters may be cleaved in unsymmetrical cystine peptides with boron trifluoride in acetic acid without disturbing the di~ulphide.'~~ S-Trityl groups are stable under these conditions.Ring closure of unsym-metrical cystine peptides by peptide bond formation without disruption of the disulphide has also been described but is not always satisfactory.'23-125 S03H I Elu. Gln. Asp. Tyr. Thr. Gly. Try. Met . Asp. Phe. NH 12 3 4 5 6 7 8 9 10 Isolation and structural and synthetic investigations of a new peptide caerulin (37) have been announced.'26 Caerulin which occurs in the skin of Hyla caerulea acts on vascular and extravascular smooth muscle and on external secretions. That it stimulates gastric secretion is not surprising since the C-terminal pentapeptide amides of caerulein and gastrin are the same.It has been amply demonstrated that the C-terminal tetrapeptide sequence in gastrin is all that is required for biological activity to be manifest.'27 However whereas the free phenol of gastrin and the sulphated material both occur naturally and are equally active in stimulating gastric secretion the caerulin isolated is fully sulphated and the free phenol of this peptide is not as active as the sulphate. The evolutionary significance of the similarities between these two peptides is obscure. Structures of gastrins from pig (38; A = Met B = C = Glu) human (38; A = Leu B = C = Glu) sheep (38; A = Val B = Glu C = Ala) cattle (38; A = Val B = Glu C = Ala) and dog (38; A = Met B = Ala C = Glu) are known;22s syntheses of human gastrin have recently been reported.22'* 128 919 S03H I Gh.Gly .Pro. Try. A. Glu . B. Glu . C . Ala . Tyr . Gly .Try. Met . Asp. Phe .NH 1 2 3 4 5 6-7 8 9 10 11 12 13 14 15 16 17 I. Photaki J. Amer. Chem. SOC.,1966,88 2292. D. Anastasi V. Erspamer and R. Endean Experientia 1967,23 699; L. Bernardi G. Bosisio R. de Castiglione and 0.Goffredo ibid. p. 700; V.Erspamer G. Bertaccini G. de Caro R. Endean and M. Impicciatore ibid. p. 702. J. M. Davey A. H. Laird and J. S. Morley J. Chem. SOC.(C) 1966,555 and references therein. J. Beacham P. H. Bentley G. W. Kenner J. K. MacLeod J. J. Mendive and R. C. Sheppard J. Chem. SOC.(C) 1967,2520. Amino-acids and Peptides 47 1 Standard nomenclature for analogues of natural peptides has been formu- lated.' 29 Recent studies'30* '31 of analogues of the ribonuclease S-peptide are particularly interesting because of the similarities between the activation of S-protein by S-peptide and peptide-hormone action.'Binding-sites' res-ponsible for the attachment of the S-peptide to the S-protein involve the 'Glu 14Asp and 3Met residues. These residues are not essential for biological activity although they do exert an effect. On the other hand the histidine residue in the 12-position is essential for activity. P-(Pyrazol-3-yl)-alanine is sterically similar to histidine but its acid-base properties are quite different.I3O The analogue of the 1-14 residue S-peptide containing this amino-acid residue at position 12 instead of histidine does not activate the S-protein even when present in a molar ratio of 10oO :1 but it is a potent competitive inhibitor of S-peptide a~tivation.'~' 0.r.d.studies suggest that the S-peptide has a helical configura- tion.' 32 Staphylococcal nuclease which can be cleaved into two peptides which are enzymically active when mixed although not covalently bonded provides a new system for similar studies of peptide interaction^.'^^ Cyclic Peptide.-Notable degradative studies of the amanitine cyclo- octapeptides (39; a R' = NH, R2 = OH; b R' = OH R2= OH; c R' = NH, RZ = H) derived from Arnanita phalloides have been described in full.' CH,R H a +OH Me-CH I NH-C)1-CO-NH-CH-CO-NH-CH2-C0 I I I co I Hq CILo~~ T:- CH ,Me Et HO co XH2 H I CO-CH-NHO-~I-I-NltC~CH2-NH I CH .CO.R' (3 9) Dimerisation during the cyclisation of linear peptides is well known.'34 It was originally observed during the synthesis of gramicidin S cyclo-(~-Val.~-Orn.~-Leu.~-Phe.~-Pro), via the cyclisation in pyridine solution of the IUPAC-IUB Commission on Biochemical Nomenclature Biochemistry 1967,6 362. F. M. Finn and K. Hofmann J. Amer. Chem. Soc. 1967,89,5298; K. Hofmann and H. Bohn ibid. 1966,88 5914 and references therein. 13' F. Marchiori R. Rocchi G. Vidali A. Tamburro and E. Scoffone J. Chem. SOC.(C),1967 81 ; R. Rocchi F. Marchiori A. Scatturin and E. Scoffone ibid.,p. 86; F. Marchiori R. Rocchi L. Moroder G. Vidali and E. Scoffone ibid.p. 89; E. Scoffone R. Rocchi F. Marchiori A. Marzotto A. Scatturin A. Tamburro and G. Vidali ibid. p. 606; E. Scoffone R. Rocchi F. Marchiori L. Maroder A. Marzotto and A. M. Tamburro J. Amer. Chem. SOC. 1967,89 5450. 132 E. Scoffone at the Chemical Society Anniversary Meetings Exeter April 1967. 133 H. Taniuchi C. B. Anfinsen and A. Sodja Proc. Nut. Acad. Sci. U.S.A. 1967,58 1235. 134 R. Schwyzer and P. Sieber Helv. Chim. Acta 1958,41,2186. 2190 2199. 472 H.D. Law p-nitrophenyl ester of Val.(Tos)Orn.Leu.D-Phe.Pro and was attributed to association between two pentapeptide moieties.' 34 The corresponding cyclo- pentapeptide cyclosemigramicidin S has now been obtained together with the cyclodecapeptide from a similar cyclization of the N-benzyloxycarbonyl- ornithine deri~ative.'~' Cyclosemigramicidin S is not active against a spectrum of micro-organisms tested.Retroenanti~-gly~~'~-gramicidin S which is like gly5."-gramicidin S and differs from it only in the direction of the amide bonds has antibacterial activity similar to that of the parent compound.'36 Sometimes dimerisations occur when peptides which cannot associate by hydrogen bonding are cyclised e.g. di-L-prolylglycine.22" In these cases strain or hindrance in the transition states which lead to the cyclotripeptides must account for the dimerisations. Penta- and hexa-peptides are reported to cyclise readily on treatment with o-phenylene pyrophosphite and very little cyclodimerization occurs.' 37 Other rings with less than eighteen atoms and containing N"-amino-acids can be prepared by aminoacyl insertion reactions e.g.[(40)-,(41)].22"Hydroxyacyl insertion reactions have been observed in cyclodepsipeptides and it has been postulated that biosynthesis of cyclo- depsipeptides might occur in this way. ' '* Cyclodimerisation with depsipep- tides can also be demonstrated however [e.g. (42) -+ (43; R = CHMe or OBu' or OH) and must be considered a biosynthetic possibility. The serine- containing cyclodepsipeptides (43; R = OBu' or OH) are in this case obtained in two forms which are possibly configurational isomers although the two forms (43; R = OH) can be sublimed unchanged.'39 OH (40) CH2-NH+O-CH2 / \ c\Hz /CH2 CH2-CO-NH-CH2 lJ5 M. Waki and N. Izumiya J. Amer.Chem. SOC.,1967,89 1278. 136 M. M. Shemyakin Yu. A. Ovchinnikov V. T. Ivanov and I. D. Ryabova Experientia 1967 23 326. 13' A. W. Miller and P. W. G. Smith J. Chem. SOC.(C),1967 2140. V. K. Antonov A. M. Shkrob V. I. Shchelokov and Z. E. Agadzhanyan Tetrahedron 1965 21,3537; D. W. Russell Quart. Rev. 1966,20 556. lJ9 C. H. Hassall T. G. Martin J. A. Schotield and J. 0.Thomas J. Chem. SOC.(C),1967 997. Amino-acids and Peptides 473 CH,.R I P NH CH .CO-O*CH,- CH,.CO,H yH2 \ ,NH-~H-co-o, (42) Yo c\H2 CH FH2 \ CH co ‘0 -CO-CH-NH/ (43) kH2 ‘R Peptide Conformation.-The conformations occurring in fibrous proteins and poly-ct-amino-acids and the fundamental importance of helical random coil and pleated sheet structures have been understood for some years.14’ Since poly-L-proline exists in helical forms,141 helix formation cannot be dependent on hydrogen bonding and this is further borne out by studies of poly-(N-methyl-L-alanine) which exists as a helix despite the absence of hydrogen bonds and pyrrolidine rings.’42 In conformational work interactions between side chains and between side chains and solvent molecules have to be taken into account as well as hydrogen-bonding possibilities.Recently the total configurations of several globular proteins have been determined by X-ray crystallography. 143 There is some indication of the relationship between these configurations determined for the solid state protein and the configura- tions of the proteins in solution but no methods comparable to X-ray crystallography are available for the direct determination of the configurations of proteins in solution.The best techniques available give parameters which may be interpreted in terms of postulated structures. In particular 0.r.d. and c.d. have been much used to gain an insight into the secondary structure (i.e. helix uersus random coil) of the peptide backbone. These methods give no indication of the overall three-dimensional structures of proteins because tertiary structure i.e. the folding of the helix or random coil is not taken into account. Solution experiments only give an indication of the general shape of the mole- cule; thin film dialysis’44 and tritium-hydrogen exchange145 are examples of recently developed techniques of this type.140 W. F. Harrington R. Josephs and D. M. Segal Anc. Rev. Biochem. 1966 35 599; S. N. Timasheff and M. J. Gorbunoff ibid. 1967,36 13. 14’ W. Traube and U. Shmueli Nature 1963 198 1165; P. M. Cowan and S. McGavin ibid. 1955 176;’501 ;J. Engel Biopolymers 1966,4 945. 14’ M. Goodman and M. Fried J. Amer. Chem. SOC.,1967,89,1264;J. E. Mark and M. Goodman ibid. p. 1267. 143 J. C. Kendrew H. C. Watson B. E. Strandberg R. E. Dickerson D. C. Phillips and V. C. Shore Nature 1961,190 663; C.C. F. Blake D. F. Koenig G. A. Mair A. C. T. North D. C. Phillips and V. R. Sarma ibid. 1965 206 757; D. Karthra J. Bello and D. Harker ibid. 1967 213 862; H. P. Avey M. 0.Boles C. H. Carlisle S. A. Evans S. J. Morris R. A. Palmer B. A. Woolhouse and S.Shall Nature 1967 213 557. 144 L. C. Craig E. J. Harfenist and A. L. Paladini Biochemistry 1964 3 764; M. A. Ruttenberg T. P. King and L. C. Craig ibid. 1966 5 2857. 14’ M. Saunders H. A. Jung and W. L. Hamilton J. Amer. Chem. SOC. 1967,89,472. 474 H. D. Law Important information on the effectiveness of the physical methods employed and on the basic structures involved has been derived from experiments with mixed solvents. In some solvents (e.g.deuteriochloroform) poly-z-amino-acids tend to exist in helical configurations whilst in other solvents (e.g. trifluoro-acetic acid) the random coil configuration is preferred. At intermediate solvent compositions varying proportions of helix and random coil exist and trans- formation from one form into the other can be demonstrated by changing the solvent proportions accordingly.Solvent interactions might be expected to contribute to the conformation-regulating properties of intermediate mix- ture~.'~~ Protonation of the amide'47 and hydrogen bonding of the trifluoro- acetic acid to the peptide -NH-I4* have been suggested as first steps in helix + random coil transitions but other studies have provided no support for these mechanism^.'^^ In suitable cases random coil and helical structures can be distinguished by n.m.r. studies,'" although proteins are too complex for detailed analy~is.'~ The random coil C(a)H resonance occurs downfield from the helix C(a)H peak and the random coil NH peak up-field from the corresponding helix peak. This applies to both left hand (poly-L-leucine) and right hand [poly-p- methyl-L-aspartate)] helices.149 The helix content indicated by high resolution n.m.r studies seems generally to correlate well with the helix content calculated from 0.r.d. data.149.150 but all authors do not agree on this point.'48 N.m.r. is potentially useful for conformational studies on small peptides because it also gives proton signals generated by the side chains of the residues. Optical techniques have also been used for the study of conformation in small peptides but interpretation of the results can be difficult.152 0.r.d. measurements indicate that helical structures are not important in oligopeptides of y-benzyl-L-glutamate below the pentamer-nonamer range (in dimethylformamide or rn-cresol) nor in copolymers of L-alanine and y-benzyl-L-glutamate below the cononamer (in trifluoroethanol) and this is undoubtedly because insuficient intramolecular hydrogen bonding exists in the smaller peptides to stabilise the ~t-he1ix.I~~ However it is probable that small peptides do not have random configurations.Ethyl t-butoxycarbonyl-L- valyl-L-valyl-L-alanylglycinate for example shows quite definite evidence of C.-C. W. Chao A. Veis and F. Jacobs J. Amer. Cnem. SOC.,1967,89,2219. 14' S. Hanlon Biochemistry 1966,5 2049. 148 W. E. Stewart L. Mandelkern and R. E. Glick Biochemistry 1967,6 143 150. J. A. Ferretti Chem. Comm. 1967 1030. M. Goodman and Y. Masuda Biopolymers 1964 2 107; D. I. Marlborough K. G. Orrell and H. N. Rydon Chem.Comm. 1965,518;J. L. Markey D. H. Headows and 0.Jardetsky J. MoZ. BioZ. 1967 27 25; E. M. Bradbury C. Crane-Robinson and H. W. E. Rattle Nature 1967,216 862. C. C. McDonald and W. D. Phillips J. Amer. Chem. SOC. 1967,89 6332; J. H. Bradbury and H. A. Scheraga ibid. 1966,88,4240; D. P. Hollis G. McDonald and R. L. Biltoneu Proc. Nat. Acd. Sci. U.S.A. 1967 58 758. A. F. Beecham Tetrahedron Letters 1967,211 ;P. M. Scopes D. R. Sparrow J. Beacham and V. T. Ivanov J. Chem. SOC. (C),1967,221 and references therein. M. Goodman E. E. Schmidt and D. A. Yphantis J. Amer. Chem. Soc. 1962 84 1288; M. Goodman M. Langsam and I. G. Rosen Biopolymers 1966,4,305. 14' Amino-acids and Peptides 475 secondary structure in appropriate solvents.' 54 Dielectric constant measure- ments of aqueous solutions of small peptides show that only a very small proportion of the possible conformers of these peptides can make major contributions to the conformer population.'55 In the case of L-alanine tri- and tetra-peptides the conformations making major contributiogs possess angles' 56 suggesting an elongated conformation intermediate between the extended chain and the P-pleated sheet structure.The similai ity between serine and alanine peptides indicates that these conformational preferences do not arise as a result of the hydrophilic-hydrophobic properties of the side The importance of non-bonded interactions of side chains is well illustrated by simple dipeptides in which considerations of this type alone limit the major contributing conformers to 52 % for glycylglycine 16 % for glycyl-L-alanine and 4.5 % for glycyl-L-valine of the total possible conformer population.Branching beyond the y-carbon atom imposes few further restrictions on the possible conformations. ' For larger peptides viz. oxytocin and vasopressin cal- culations based on a simplified expression for the energy of a polypeptide in aqueous solution suggest that a number of minimum energy conformations are available to the peptide.'57b Non-equivalence of the methylene group protons in the peptide backbone has been reported for glycine-containing dipeptides. It is attributed to rigidity of conformation in the dipeptide.15* The lower-field methyl doublet in LL-or DD-as opposed to DL-or LD-alanine dipeptides presumably arises because of the shielding of the methyl group by the adjacent side chain"* and as expected this is particularly marked when the shielding side-chain is aromatic.Similar differences have been reported in other dipeptides and the conformational implications discussed.' 59 Whereas the LL- and the DD-seem to exist in open form the m-dipeptides are more compact. These conclusions are also borne out by the study of dielectric constants the charge separation in all -L-or all -D-forms is consistently greater than in the corresponding diastereoisomers,' and in cyclisation experiments in which peptides and depsipeptides composed of D-and L-residues give higher yields of cyclic product than the all-L- or ali-~-isomers.'~~~ The protons on the CL-and P-carbons of aromatic residues lS4 J.E. Shields and S. T. McDowell J. Amer. Chem. SOC., 1967,89 2499. P. M. Hardy G. W. Kenner and R. C. Sheppard Tetraheron 1963 19 95; J. Beacham V. T. Ivanov G. W. Kenner and R. C. Sheppard Chem. Comm. 1965,386. J. T. Edsall P. J. Flory J. C. Kendrew A. M. Liquori G. Ntmethy G. N. Ramachandran and H. A. Scheraga Biopolymers 1966,4 130; J. Biol. Chem. 1966,241 1004; J. Mol. Biol. 1966 15 339. 15' (a)S. J. Leach G. Ntmethy and H. A. Scheraga Biopolymers 1966,4,369;see also D. A. Brant and P. J. Flory J. Amer. Chem. Soc. 1965 87 2791; P. de Santis E. Giglio A. M. Liquori and A. Ripamonti Nature 1965 206 456; (b) K. D. Gibson and H. A. Scheraga Proc. Nat. Acad. Sci. U.S.A.,1967,58 420 151 7. "13 J.W. Westley and B. Weinstein Chem. Comm. 1967 1232. 159 T. Wieland and H. Bende Chem. Ber. 1965,98 504; F. A. Bovey and G. V. D. Tiers J. Amer. Chem. SOC., 1959,81,2870. 160 G. W. Kenner P. J. Thomson and J. M. Turner J. Chem. SOC. 1958,4148;Yu. A. Ovchinnikov, V.T. Ivanov A. A. Kiryushkin and M. M. Shemyakin Bull. Acad. Sci. U.S.S.R.(Div. Chem. Sci.) 1963,153,1342. 476 H. D.Law in dioxopiperazines are shifted to high field suggesting that the arylmethyl side-chain faces the dioxopiperazine ring. l6 ' The difficulty of determining the conformations of peptides in solution is well illustrated by the case of gramicidin S. Theoreticai considerations suggest that the peptide has an antiparallel intramolecular P-sheet structure with two hydrogen bonds'62 or that it consists of two single turns of a right handed helix.'63 An antiparallel P-sheet structure with four hydrogen bonds was originally favoured by X-ray evidence,164 and because it could easily be derived from the intermolecularly hydrogen-bonded anti parallel arrangement of the linear pentapeptide molecules postulated to account for the cyclodimeri- zation reaction.'65 A third proposed structure packs like an a-helix with four intramolecular hydrogen bonds but consists of three regions; in the first (Val-Om) and third (Leu-Phe) regions the N-H bonds point in the same direction perpendicular to the plane of the ring; in the second (Orn-Leu) the N-H bonds point in opposite ways.164 Other structures have been proposed including one in which the importance of hydrophobic-hydrophilic forces is considered paramount.'66 This model can be ruled out because it involves all-cis-amide bonds whereas it is probable that the amide bonds in gramicidin S are all in the energetically more favourable trans-c~nformation.'~~ The formulation of this structure does emphasize the present difficulty of assessing the importance of hydrophilic-hydrophobic forces.Measurements involving U.V.and i.r. spectroscopy peptide hydrogen-deuterium exchange o.r.d. c.d. dialysis and surface st~dies'~' indicate that none of the proposed models is entirely sati~factory.'~~ These studies also indicate that it might be misleading to assume that only one type of structure can give rise to an a-helix type 0.r.d. pattern.'67 It is clear that new methods are required particularly for studies of peptide conformations in aqueous solution.An interesting development involves the detection and measurement of the effect exerted by one side chain on another non-bonded side chain in its vicinity. Thus 2-bromoacetamido-4-nitrophenol reacts with chymotrypsin to form a sulphonium salt at the essential methionine residue in position 192. The pH dependence of the absorption spectrum of the modified protein suggests that a positively charged imidazole ring is spacially close to the hydroxy-function of the 'reporter group' although there is not a histidine residue near to the methionine residue in the primary structure of the molecule. The reaction of chymotrypsin with ~-bromo-4-nitroacetophenone has also been studied.Monoalkylation at methionine 192 occurs and the alkylated compound exhibits a new absorption peak at A,, 350 mp. This peak 16' K. D. Kopple and D. H. Marr J. Arner. Chem. SOC.,1967,89,6193. G. Vanderkooi S. J. Leach G. Nernethy and H. A. Scheraga Biochemistry 1966,5,2991. 163 A. M. Liquori P. de Santis A. L. Kovacs. and L. Mazzarella Noture. 1966.211. 1039 164 D. C. Hodgkin and B. M. Oughton Biochern. J. 1957,65 752. R. Schwyzer Rec. Chem. Progr. 1959,20 147. D. T. Warner Nature 1961,190 120. 16' D. Balasubrarnanian J. Arner. Chem. SOC.,1967,89 5445. M. B. Hille and D. E. Koshland jun. J. Arner. Chem. SOC., 1967,89 5945. Amino-acids and Peptides is due to the formation of a charge-transfer complex with the indole moiety of a tryptophan residue.It follows that the methionine sulphur is at a distance <SA from the centre of an indole ring. The charge-transfer peak can be reversibly destroyed by denaturation in 8M-urea at pH 3.0.16' A systematic study is in progress to find charge-transfer donors and acceptors suitable for peptide work and preliminary investigations with simple inter- and intra- molecular charge-transfer complexes of amino-acid derivatives have been described.22" One possible criticism of this general approach is that the conformation of the modified protein might be different to that of the un- substituted compound. 169 D. S. Sigman and E. R. Blout J. Amer. Chem. SOC.,1967,89,1747.

ISSN:0069-3030    

DOI:10.1039/OC9676400451

出版商:RSC    

年代:1967

数据来源: RSC

摘要:

14. NUCLEIC ACIDS Part (i) By G. Michael Blackburn (Department of Chemistry University of Sheffield Sheffield S3 7Hfl MUCHof the recent excitement in nucleic acid research has originated in the continual discovery of experimental situations demanding explanation in terms of new concepts. The supply of hypotheses has barely exceeded the demand Recent literary research,’ however suggests that they are not all as new as we have thought. In 1892 J. F. Miescher2 wrote ‘To me the key to the problem of sexual reproduction is to be found in the field of stereochemistry.’ Referring to the huge molecules of albumen haemoglobin and (implicitly) nucleoprotein he continued ‘In them all the wealth and variety of hereditary transmissions can find expression just as all the words and concepts of all languages can find expression in twenty-four to thirty alphabetic letters.’ Not exactly ‘the code’.But not far off! The year’s major developments have been the controlled assembly of an octadecanucleotide and several ‘smaller’ ones in Khorana’s laboratory ; the complete sequencing of the 120 residues in 5S-RNA;3 the exploration of the topological chemistry of DNA especially circularity supercoils and catenated circles; the description of a model for the t-RNA anticodon loop with a built-in ‘wobble’ ; and the unequivocal demonstration of biological activity of enzymically synthesised DNA-‘life in the test tube’. The reviewers have been obliged reluctantly to omit the following topics nucleoproteins histones nucleases protein synthesis and its ramifications binding of metal cations dyes and hydrocarbons and huge chunks of chemistry.Some of these deficiencies can be remedied by reference to reviews on the pharmacological applications of nucleosides and nucleotides4 and on mechan- isms of nucleic acid ~ynthesis,~ and to the proceedings of symposia on the genetic code6 and on genetic element^.^ R. Olby and E. Posner Nature 1967,215 556. J. F. Miescher ‘Die histochemischen und physiologischen Arbeiten von Friedrich Miescher,’ vol. 1 Vogel Leipzig 1897. Abbreviations DNA deoxyribonucleic acid ; RNA ribonucleic acid ;t-RNA transfer RNA ; m-RNA messenger RNA ;r-RNA ribosomal RNA ;5s-RNA RNA with sedimentation coefficient of 5s; A adenosine; C cytidine; G guanosine; H hypoxanthine; I inosine; JI pseudouridine; T thymidine ; rT ribothymidine; U uridine; PA pC etc.5’-phosphates; Ap Cp etc. 3’-phosphates; AMP adenosine 5‘-phosphate ;NAD nicotinamide adenine dinucleotide ;NADP NAD phosphate ; PP,,inorganic pyrophosphate ; poly-A polyadenylic acid ; similarly poly-C etc. ; d-pTpC etc. deoxyoligonucleotides ; DCC. dicyclohexylcarbodi-imide; MS mesitylenesulphonyl chloride; TPS tri-isopropylbenzenesulphonylchloride TrT 5’-0-tritylthymidine ; r p-D -ribofuranosyl. B. R. Baker ‘Design of Active-Site-Directed Irreversible Enzyme Inhibitors,’ Wiley New York 1967. D. Hayes Ann. Rev.Microbiol. 1967 21 369. ‘Cold Spring Harbor Symp. Quant Bid 1966 31. ’ ‘Genetic Elements Properties and Function,’ ed. D. Shugar Academic Press New York 1967.480 G. Michael Blackburn Bases and Nucleosides.-One of the convincing models for prebiotic chemistry is the formation of adenine from hydrogen cyanide.* Orgel has investigated the detailed reactionsg and has shown that the cis-and trans-tetramers (1) and (2) formed in concentrated solution can be converted into 4-aminoimida- zole-5-carbonitrile (3) and -5-carboxamidine (4). These and the derived carbox- amide (5) cyclise with formamide or formamidine to give the purine bases shown. NC (3) t adenine guanine hypoxanthine isoguanine xanthine The easy reversible decarboxylation of the purine nucleotide precursor (6) AICAR suggests that the known biosynthetic pathway may have evolved from a prebiotic route. lo Chemical glimpses of evolution from terrestrial origins to t-RNA have been surveyed." The selective modification of bases has many objectives.First the sequence determination of nucleic acids by electron microscopy requires binding of heavy atoms to all the bases of one kind only. Diazotised aniline-2,5-disul- phonic acid couples predominantly with G; minor products with A and C are decomposed at low pH so that most G residues in RNA can be marked with uranium ions.12 Aceto- and malonohydrazides react with RNA and modify cytosine bases ~electively'~ and so are promising specific reagents. J. Oro 'Origins of Prebiological Systems,' ed. S. W. Fox Academic Press New York 1965 p. 131. R. A. Sanchez J. P. Ferris and L. E. Orgel J. Mol. Biol. 1967,30 223. lo M.Franks C.P. Green G.Shaw and G. J. Litchfield,J. Chem.SOC.(C) 1966,2270;N. J. Cusack G. J. Litchfield and G. Shaw Chem. Comm. 1967 799. '' H. J. Vogel and R. H. Vogel Chem. Eng. News 1967,45,90. l2 H. Erickson and M. Beer Biochemistry 1967,6 2694. l3 L. Gal-Or J. E. Mellema E. N. Moudrianakis and M. Beer Biochemistry 1967 6 1909. Nucleic Acids 481 The Girard-P reagent reacts with t-RNA giving modified cytosine residues (7). These resist attack by pancreatic ribon~clease'~ so that modified enzymic degradation is possible. Chemical reagents specific for bases in unpaired single strands can aid the identification of base-paired helical regions and so indicate such structure in RNA molecules. Osmium tetroxide oxidises pyrimidines rather than purines and with 1-methyluracil gives the 5,6-diol (8).Since its reaction with poly-U is inhibited by poly-A the reagent may be specific for loop regions in t-RNA.15 rP HN-NH -CO.CH,. N+/\ 3 OA~ OH ( 6 ) rP= ribofuranosyl Me 5'-phosphate (8) (7) A0 EtO Me (9) r = P-D-ribofuranosyl Kethoxal 3-ethoxy-2-oxobutyraIdehyde,yields an acid-stable condensation product with G probably (9).16The kinetics of its reaction with t-RNA suggest that G residues in single-strand regions are attacked first with little other change in primary str~cture.'~ Some adenine residues in t-RNA can be con- verted into their N(')-oxides. When the oxidation is effected at 40 rather than at 20° the number so modified increases by 4.5 per t-RNA molecule and is interpreted as corresponding to the loss of tertiary structure.* The reaction of bases with formaldehyde is particularly useful because it is partly reversible because it involves NH groups and so reduces hydrogen- bonding of bases and because it can be followed spectrophotometrically.'9 Formaldehyde can also link two bases in RNA by a stable methylene bridge joining the amino-groups of A or G.20 l4 K. Kikugawa H. Hayatsu and T. Ukita Biochim. Biophys. Acta 1967,134,221;K. Kikugawa A. Muto H. Hayatsu K. Miura and T. Ukita ibid. 1967 134 232. l5 K. Burton Biochem. J. 1967,104,686. l6 R. Shapiro and J. Hachmann Biochemistry 1966,5,2799;M. Staehelin Biochim. Biophys. Acta 1959,31 448. M. Litt and V. Hancock Biochemistry 1967,6 1848. la F.Crarner Angew. Chem. Internat. Edn. 1967,6,642. l9 E. J. Eyring and J. Opengand Biochemistry. 1967,6 2500; D. B. Millar and M. MacKenzie. ibid. 1967 6 2520; H. Boedker ibid.. 1967. 6 2718; S. Lewm and D. Humphreys 1.Chem. Soc. (B) 1967 562 2o M. Ya. Feldman Biochim. Biophys. Acta 1967. 149 20. 482 G. Michael Blackburn Lastly specific alteration of bases results from the action of certain chemical mutagens and carcinogens.21 Hydroxylamine and methoxyamine act on poly-C to give modified base residues. When this poly-C is used as a template in enzymic RNA synthesis it directs the incorporation of A into the poly-G produced.22.23 Brown originally formulated the reaction as involving addition of hydroxylamine (methoxyamine) to C [( 10) -+ (1 l)] followed by replacement of the amino-group by a hydroxylamino-group (12).24 At low pH N(4)-hydroxycytidine (13) is formed subsequently.Both (1 1) and (13) are expected to have tautomeric constants favouring the imino-forms (14) and (151 and these are expected to show anomalous base pairing with adenine e.g. (14):( 16) rather than the natural C :G pairing. r r r (10) (13) (15) NH,OR 1 (11) R = Hor Me r = f&D-ribofuranosyl 04) A kinetic study of the reaction between methoxyamine and poly-C indicated that in this case the formation of (11) was the primary mutational event.23 Recently other groups25 have found evidence for the direct conversion of C into both (11) and (13). Both processes probably lead to the same mispairing P. D. Lawley Progr.Nucleic Acid Res. 1966 5 89; D. M. Brown and J. H. Phillips ibid. 1968 7 in press. ” J. H. Phillips D. M. Brown R. Adman and L. Grossman J. Mol. Biol. 1965 12 816. 23 J. H. Phillips D. M. Brown and L. Grossman J. Mol. 3iol. 1966 21 405. 24 D. M. Brown and J. H. Phillips J. Mol. Biol. 1965 11 663. 25 N. K. Kochetkov E. I. Budowsky E. D. Sverdlov R. P. Shibaeva V. N. Shibaev and G. S. Monastirskaya Tetrahedron Letters 1967 3253; P. D. Lawley J. Mol. Biol. 1967 24 75. Nucleic Acids 483 and thus a mutation results from the replication of DNA containing a hydroxyl- amine-modified C. At high pH hydroxylamine disrupts pyrimidine rings uridine compounds are degraded to ribosylureas and 5-hydroxyoxazole. 26 Hydrazine shows both of the foregoing types of reaction with cytosine under more vigorous condi- tions.The carcinogen N-acetoxy-N-2-fluorenylacetamide effects28 arylamidation of guanosine giving (17) and so may covalently bond a hydrocarbon to nucleic acids. 1-Methyl-3-nitro- 1-nitrosoguanidine alkylates A and yields a mixture of 1- and 3-methyladenosines but has little effect on PG.~’ The synthesis of the glycoside bond in nucleosides combines the problems of ambident nucleophiles neighoouring group participation and kinetic uersus thermodynamic control. It is not surprising that the results appear empirical. Lewis acid-catalysed equilibration of the tetra-0-acetyl-D-gluco- pyranosides of 5-nitro-2-pyridone exhibits anomerisation of the p-0-to the a-0-glucoside. Higher catalyst concentrations convert both into the P-N-glucoside.30 Anomerisation is catalysed both by stannic chloride3’ and by mercuric bromide.30,31 0 +N-Transglycosylation has been observed for the 0-ribosides of both 2- and 4-~yridone,~~ and the possibility that such reactions involve the intermolecular rearrangement of a glycosyl cation has been considered. Nevertheless the mercuric route can give N-glycosides as kinetic products.34 The trimethylsilyl modification of the Hilbert-Johnson synthesis3’ may prove the most useful since it can be used for phosphorylated sugar derivative^,^^ and the anomeric ratio of products appears susceptible to temperature contr01.~’ Nucleoside antibiotics recently reviewed,38 provide a variety of synthetic objectives. Angustomycin has fathered the synthesis of 4’,5’-unsaturated pentofuranosides of adenine3’ and ~racil,~’ and of the branched chain nucleo- sides l-deoxypsicofuranosy1-41and sorbopyranosyl-adenine.42 A synthesis 26 N.K. Kochetkov E. I. Budowsky V. P. Demushkin M. F. Turchinsky N. A. Simukova and E. D. Sverdlov Bicchim. Biophys. Acta 1967,142,35;N. K. Kochetkov E. I. Budovskii V. N. Shibaev and G. I. Elisseva Dokludy Akud. Nauk S.S.S.R. 1967 172 603. ’’F. Lingens and H. Schneider-Bernlohr Annulen 1965,686. 134 D H Haves and F Hayes-Baron J. Chem. SOC.(C) 1967 1528. 28 E. Kriek J. A. Miller U. Johl and E. C. Miller Biochemistry 1967 6 177. 29 J. Rau and F. Lingens Naturwiss. 1967,54 517. 30 D. Thacker and T. L. V. Ulbricht Chem. Comm. 1967 122. 31 G. Wagner Z.Chem. 1966,6 367. 32 H. Pischel and G. Wagner Arch. Pharm. 1967,300,602. 33 G. Schmidt and J. FarkaS Tetrahedron Letters 1967 4251. 34 H. G. Garg and T. L. V. Ulbricht J. Chem. SOC. (C) 1967 51. 35 J. Pliml and M. PrystaS Adv. Heterocyclic Chem. 1967,8 115. 36 T. Nishimura B. Shimizu and M. Futai Biochim. Biophys. Acta 1966,129 654. 37 C. Szantay M. P. Kotick E. Shefter. and T. J. Bardos J. Amer. Chem. SOC. 1967.89. 713. 38 J. J. Fox I A. Watanabe and A Bloch Proqr Nucleic Acid Res. 1966. 5 251 39 J. R. McCarthy M. J. Robins and R. K. Robins Chem. Comm. 1967 536. 40 J. P. H. Verheyden and J. G. Moffatt J. Amer. Chem. SOC. 1966,88 5684 M. J. Robins. J. R McCarthy and R. K. Robins J. Heterocyclic Chem. 1967,4 313. 41 J. FarkaS and F. Sorm Coll.Czech. Chem. Comm. 1967,32 2663. 42 H. Paulsen H. Koster and K. Heyns Chem. Ber. 1967,100 2669. G. Michael Blackburn of toyocamycin (18) stopped short at the penultimate stage (19) when Raney nickel desulphurisation failed.43 Sho~domycin~~ has the C-glycoside structure (20) and both this45 and the structure of ari~teromycin~~ have been confirmed by X-ray crystallography. Albomycin contains a 3-methylcytosine moiety.47 Nuc1eotides.-The methylation of nucleotides shows considerable reagent specificity. At high pH methyl iodide and pG give 1-methylguanylic r HO OH (17) Ar = 2-fluorenyl (18) R = H (20) (19) R = SMe r = p-D-ribofuranosyl whereas at pH 5.5 dimethyl sulphate converts GpU into 7-MeGpU4’ and shows high selectivity for G residues in DNA.” The action of nitrogen mustard on ApA results in some chain scission to give A,51 but although diazomethane may cause cleavage of some phosph~diesters,~~ under controlled conditions its action on ApU and UpA only gives methylation of the uracil.53 In contrast phenyldiazomethane converts thymidine nucleotides into their benzyl phos- photriesters.These are crystalline and soluble in organic solvents.54 The resulting manipulative advantages have stimulated two groups to use phos- photriesters in oligonucleotide syntheses. Letsinger” has employed 2-cyano- ethyl phosphates and E~kstein~~ chose the 2,2,2-trichloroethyl esters. Phospho- diesters can be condensed with alcohols by use of arnesulphonyl chlorides MS or TPS to give triesters and at the end of the synthesis the phosphate protecting groups are removed either by ammonolysis or by reduction.43 R. L. Tolman R. K. Robins and L. B. Townsend J. Heterocyclic Chem. 1967,4 230. 44 Y. Nakagawa H. Kano Y. Tsukuda and H. Koyama Tetrahedron Letters 1967,4105;K. R. Darnall L. B. Townsend and R. K. Robins Proc. Nut. Acad. Sci. U.S.A. 1967,57 548. 45 Y. Tsukuda Y. Nagakawa H. Kano T. Sato M. Shiro and H. Koyama Chem. Comm. 1967 975. 46 T. Kishi M. Muroi T. Kusaka M. Nishikawa K. Kamiya and K. Mizumo Chem. Comm. 1967 852. 47 G. I. Lavrenova L. P. Revina and N. A. Poddubnaya Zhur. obschei Khim. 1966 36 2096 2098. 48 F. Pochon and A. M. Michelson Biochim. Biophys. Acta 1967,145 321. 49 C. B. Reese and J. E. Sulston Biochim.Biophys. Acta 1967 149 293. 50 F. Pochon and A. M. Michelson Biochim. Biophys. Acta 1967,149,99. 51 D. B. Ludlum Biochim. Biophys. Acta 1967,142,282. 52 A. Holy and K. H. Scheit Biochim. Biophys. Acta 1967 138,230. 53 B. E. Griffin J. A. Haines and C. B. Reese Biochim. Biophys. Acta 1967,142 536. 54 K. H. Scheit Tetrahedron Letters. 1967 3243. 55 R. L. Letsinger and K. K. Ogilvie J Amer. Chem. SOC. 1967,89 4801. 56 F. Eckstein and I. Rizk Angew. Chem. Internat. Edn 1967,6,695,949. Nucleic Acids 485 It might be profitable to extend the advantages of this approach to nucleotide syntheses on polymer supports. This latter field has not proved as fertile as anticipated. The results obtained with insoluble polymers5’ show that yields in successive condensation steps fall off as the number of phosphate residues increases ( > 60 % 40-50 % and cu.14 % for the first three steps). This could possibly be improved by use of uncharged phosphotriesters. Although higher yields are attained in soluble polymer systems,58 these are attended by problems of extracting the nucleotide product from the polymer after its release. Marginal advantages have been won in conventional nucleotide syntheses by the invention of innumerable protecting groups. The minimal use of such groups is seen in the efficient conversion of ribonucleosides into their 5’-phosphates with phosphoryl chloride in wet triethyl ph~sphate.’~ In similar vein the condensation of unprotected ribonucleosides with diacetylribo- nucleoside 3’-phosphates leads to dinucleoside (3’ + S)-phosphates since ammonolysis both removes acetyl groups and cleaves the (3’ -+ 2’)and (3’ - 3’)-esters.60 Models for prebiotic phosphorylation have been investigated by use of salts of phosphoric acid,6 nucleotides,62 polyphosphoric acid,63 and phenyl p~lyphosphate.~~ Oligonucleotides.-The outstanding achievement in oli gonucleot ide chemistry so far is the controlled synthesis of some octadecadeoxyribonucleo-tides and several ‘smaller’ oligomers.In a series of classic papers Khorana first outlines the strategy of polynucleotide synthesis in relation to the genetic code6’ and then presents the tactics. First to be dissected and analysed are the relative efficiencies of the available condensing reagents including DCC TPS and MS and the optimum reaction ratio of the two preformed blocks which are to be joined by the new phosphate ester bond.66 Next comes the preparation of the blocks-thirteen selected suitably-protected deoxyribotrinu~leotides~~ and two deoxyribotetranucleo- 57 G.M. Blackburn M. J. Brown and M. R. Harris J. Chem. SOC.(C) 1967,2438;R. L. Letsinger and V. Mahadevan J. Amer. Chem. SOC. 1966 88 5319; R. L. Letsinger M. H. Caruthers and D. M. Jerina Biochemistry 1967,6 1379; L. R. Melby and D. R. Strobach J. Amer. Chem. SOC. 1967,89 450. 58 H. Hayatsu and H. G. Khorana J. Amer. Chem. SOC. 1967 89 3880; F. Cramer R. Helbig H. Hettler K. H. Scheit and H. Seliger Angew. Chem. Internat. Edn. 1966 5 601. 59 M. Yoshikawa T.Kato and T. Takenishi Tetrahedron Letters 1967 5065. “ H. Follmann Tetrahedron Letters 1967,2113. M. Honjo Y. Furukawa and K. Kobayashi Chem. and Pharm. Bull. (Jupan) 1966 14 1061 ; A. Beck R. Lohrmann and L. E. Orgel Science 1967 157 952; J. Moravek and J. Skoda Coll. Czech. Chem. Comm. 1967,32 206. 62 J. MorBvek Tetrahedron Letters 1967 1707. ‘’ T. V. Waehneldt and S. W. Fox Biochim. Biophys. Acta 1967,134 1 ;A. W. Schwartz and S. W. Fox Biochim. Biophys. Acta 1967 134,9. 64 G. Schramm and I. Ulmer-Schiirnbrand Biochim. Biophys. Acta 1967 145 7; G. Schramm G. Liinzmann and F. Bechmann Biochim. Biophys. Acta 1967 145,221. ” H. G. Khorana H. Biichi T. M. Jacob H. Kossel S. A. Narang and E. Ohtsuka J. Amer. Chem. SOC. 1967,89,2154. ‘‘ H. Kossel M.W. Moon and H. G. Khorana J. Amer. Chem. SOC.,1967,89,2148. 67 S. A. Narang T. M. Jacob and H. G. Khorana J. Amer. Chem. SOC.,1967,89,2158. 486 G. Michael Blackburn tides.68 The synthesis of the protected tetranucleotide d-pABZpTpCA”pGAC is illustrated in the Scheme. Condensation of 2-cyanoethyl N(6)-benzoyldeoxyadenosine5’-phosphate (21) with 3’-O-acetylthymidine 5’-phosphate (22) alkaline hydrolysis of the acetyl group and re-esterification of the primary phosphate gives the di- nucleotide (23). Repetition of the sequence with 3’-0-a~etyl-N(~)-anisyl-deoxycytidine 5’-phosphate (24) gives the protected trinucleotide (25). The cycle is again repeated with incorporation of 3’-ON(2)-diacetyldeoxyguanosine 5’-phosphate (26) to give the tetranucleotide (27).0-0-0 I Roi-oQAB* HO (21) i ii iii + -0- -I HO (23) O-;-O-Q 0 0 (22) 0-+ I (25) R’ = NC*CH,*CH,; R2= H (28) R’ = R2 = H (29) R’ = H R2 = AC 0- I (24) +O- P -0 0 iv ii d-pABzpTpCAnpGA‘ AcO (27) (26) (29) +4(28) d-PA[PTPCPAl,PTPC (30)n = 1-4 SCHEME Reagents i DCC; ii OH-; iii DCC + ROH; iv MS; v NH,OH R = NC.CH2.CH2 Nucleic Acids 487 This stepwise procedure has been extended to prepare a dodecanucleotide,68 d-TrT[ pTpTpCpT] pTpTpC. Fortunately for one’s sanity developments in the condensation of preformed blocks make this a more efficient synthesis for oligomers with repeating sequences.A foundation block (28)is made by acetylation of a trimer e.g.(29),to protect the terminal 3’-hydroxy-group and unprotected blocks are added by polymerisation of (28) and an excess of (29) with MS as condensing reagent.Extensive chromatography after removal of all the protecting groups gives polymers with a repeating trinucleotide sequence (30).69 In the same way the hexadecanucleotide d-pA[pTpCpGpA] JpTpCpG is obtained from the tetranucleotide (27) and its 3’-O-a~etate.~~ Trinucleotide (29) and others have been synthesised in a related manner in Cramer’s laboratory and they have been polymerised. 70 The methods described above provided the polymers the use of which was instrumental in the establishment of the genetic code described in the 1966 Rep~rt.~ ’ Nevertheless future objectives of nucleic acid synthesis will require non-repetitive distribution of base residues which necessitates stepwise addition of smaller blocks.The dodecamer d-T[pApTpCpT] ,pApTpC has been made by the sequential addition of dinu~leotides,~and a hexadecanucleotide has been obtained by the addition of nucleotides four at a time,73 thus demonstrat- ing the feasibility of the method. These chemical tools coupled with the use of the ligase enzyme (p. 505) place gene synthesis within the realm of expectation. Photochemistry.-The mutagenic and lethal effects of U.V. radiation on bacteria can be traced to chemical changes in their nucleic acids,74 and princip- ally to the formation of pyrimidine dimers and hydrates. Much model photo- chemistry has used frozen aqueous solutions of pyrimidines. The primary photochemical processes have been examined by Shulman.E.s.r. and luminescence studies establish that thymine must react from an excited singlet state in though in DNA a 7c -+ 7c* triplet state is p~pulated.~~ The dimerisation of pyrimidines in ice is effectively a solid-state reaction with a high quantum yield,77 and gives structures determined by the orientation of adjacent molecules in the crystal lattice.78 Many such structures have been 68 T. M. Jacob S. A. Narang and H. G. Khorana J. Amer. Chew. SOC. 1967,89,2177. 69 T. M. Jacob S. A. Narang and H. G. Khorana J. Amer. Chem. SOC.,1967,89,2167. ’O F. Cramer W. Frolke and H. Matzura Angew. Chem. Internat. Edn. 1967,6 562. K. S. Kirby and T. L. V. Ulbricht Ann. Reports 1966,63,536. ’’ H. Kossel H.Buchi and H. G. Khorana J. Amer. Chem. SOC.,1967,89,2185. 73 E. Ohtsuka and H. G. Khorana J. Amer. Chew. SOC. 1967,89,2195. 74 A. D. McLaren and D. Shugar ‘Photochemistry of Proteins and Nucleic Acids,’ Pergamon Oxford 1964; W. Szybalski Radiation Res. Suppl. 1967 7 147. 7s J. Eisinger and R. G. Shulman Proc. Nut. Acad. Sci. U.S.A.,1967,58 895. 76 R. 0.Rahn R. G. Shulman and J. W. Longworth J. Chem. Phys. 1966,45,2955;R. 0.Rahn R. G. Shulman and J. W. Longworth Radiation Res. Suppl. 1967,7 139. W. Fiichtbauer and P. Mazur Phorochem. and Photobiol. 1966,5 323. M. D. Cohen and G. M. J. Schmidt J. Chem. SOC.,1964 1996. G.Michael Blackburn elucidated by ~hemical'~ and spectroscopic" means and the structure (31) of one of the ice-dimers of 1-methylthymine has been established by X-ray diffraction." All are cyclobutane derivatives.In solution the excited singlet state is too short-lived to be involved in bimolecular dimerisation. It decays to a triplet state of lifetime 10-sec. which in the absence of oxygen leads to dimers for many pyrimidine nucleosides and nucleotides82 with a low quantum yield. Significantly UpU and TpT give intramolecular dimers in the presence of oxygen. Alternative access to the triplet state may be achieved by photosensitisation of pyrimidines with acetone or acetophenone and this again leads to dimer formation in solution.83p84 The resulting dimers also have cyclobutane structures but usually more isomers are formed in this way than are formed in ice matrices.84 All four stereoisomeric thymine dimers have been separated and assigned configurational structures ;" one of these (32) has recently been confirmed by X-ray analysis.86 (31) R = Me (33) (32) R = H In DNA the formation of thymine dimers falls off sharply as the solution temperature approaches T (the melting temperat~re).~~ This suggests that the dimers form preponderantly in stacked regions in DNA.The major 79 G. M. Blackburn and R. J. H. Davies J. Chem. SOC.(C),1966 1342,2240; K. H. Donges and E. Fahr Z. Naturjbrsch. 1966,21b 87; E. Fahr G. Furst G. Dorhofer and H. Popp Angew. Chem. Internat. Edn. 1967,6 250. 79 T. Kunieda and B. Witkop. J. Amer. Chem. SOC.,1967,89,4232. 80 R. Anet Tetrahedron Letters 1965 3713; G. M. Blackburn and R.J. H. Davies ibid. 1966 4471 ; D. P. Hollis and S.Y. Wan& J. Org. Chem. 1967,32,1620. 81 J. R. Einstein J. L. Hosszu J. W. Longworth R. 0.Rahn and C. H. Wei Chem. Comm. 1967 1063. 82 C. L. Greenstock I. H. Brown J. W. Hunt and H. E. Johns Biochem. Biophys. Res. Comm. 1967,27 431. 83 A. A. Lamola and J. P. Mittal Science 1966 154 1560. 84 C. H. Krauch D. M. Kramer P. Chandra P. Mildner H. Feller and A. Wacker Angew. Chem. Internat. Edn. 1967,6,956;I. von Wilucki H. Matthaus and C. H. Krauch Photochem. and Photobiol. 1967,6 497 85 D. Weinblum and H. E. Johns Biochim. Biophys. Acta 1966 114 450. 86 N. Camerman S. C. Nyburg and D. Weinblum Tetrahedron Letters 1967,412 7. 87 J. L. Hosszu and R. 0.Rahn Biochem. Biophys. Res. Comm. 1967,29,327.Nucleic Acids 489 thymine dimer from DNA has been shown by chemicals8 and spectroscopics9 means to have the structure (33) expectedg0 from photoaddition of adjacent thymines in the same ordered DNA strand. Although photosensitisation of DNA by acetophenone gives high yields of thymine dimer probably via the triplet state,g1 the unsensitised reaction may involve triplet or singlet states. U.V.irradiation of DNA also leads to the isolation of a mixed U:T dimer,88,92 derived by hydrolysis of a cytosine-thymine dimer and to 5,6-dihydrothy- mine.93 Photocycloaddition reactions of DNA have been re~iewed.’~ Johns has shown that the photoaddition of water to the 5,6-double bond of uracil and cytosine basesg5 is not quenched by oxygens2 and is probably a reaction of an excited singlet state.In poly-U the production of hydrates is suppressed in all ordered structures which suggests that stacking is not conducive to phot~hydration.~~ High energy photolysis of aqueous thymine solutions gives productsg7 similar to those from aerobic y-irradiation of pyrimidines.’* 5,6-Glycols (34) and hydroxyhydroperoxides (35) are formed but anaerobic y-irradiation of thymine gives mainly 6-hydroxydihydrothymine (36)’’ Secondary Structure.-The shape assumed by the primary structure of nucleic acids and therefore in part their biological activity is largely controlled by low energy interactions. Hydrogen bonding governs interactions between bases in the same plane and ‘hydrophobic’ forces71 control interactions between bases in parallel or ‘stacked’ planes.These of course operate within the restrictions of van der Waals repulsion and the electrostatic repulsions between phosphate anions. The latter are minimised in some helical structures and are diminished when shielding by inorganic or organic cations occurs. An excellent review by Felsenfeld and Miles“’ covers structural aspects of nucleic acids and another lo is devoted to synthetic polynucleotides. Binary mixtures of alkylated purines and pyrimidines in organic solvents show changes in NH i.r. vibrations consistent with hydrogen bonding in ’* G. M. Blackburn and R. J. H. Davies Biochem. Biophys. Res. Comm. 1966 22 704; G. M. Blackburn and R. J. H. Davies J. Amer. Chem. SOC.,1967,89 5941. ’’ A.J. Varghese and S. Y. Wang Nature 1967 213 909; D. Weinblum Biochem. Biophys. Res. Comm. 1967,27 384. G. Fraenkel and D. Wulff Biochim. Biophys. Acta 1961,51,332. 91 A. A. Lamola and T. Yamane Proc. Nut. Acad. Sci. U.S.A. 1967,58,443. 92 R. B. Boyce and P. Howard-Flanders Proc. Nat. Acad. Sci. U.S.A. 1964 51 293; E. Riklis Canad. J. Biochem. 1965,43 1207. 93 T. Yamane B. J. Wyluda and R. G. Shulman Proc. Nat. Acad. Sci. U.S.A. 1967.58,439. 94 L. Musajo. Chimica e Industria 1967,49 131. 95 H. Becker J. C. LeBlanc and H. E. Johns Photochem. and Photobiol. 1967,6 733. 96 G. de Boer M. Pearson and H. E. Johns J. Mol. Biol. 1967 27 131; M. L. Pearson Diss. Abs. 1967 27 B 3014. 97 M. Daniels and A. Grimison Biochim. Biophys. Acta 1967 142 292. 98 E. Gilbert 0.Volkert and D.Schulte-Frohlinde 2. Naturforsch. 1967,22b 477; 0.Volkert W. Bors and D. Schulte-Frohlinde 2.Naturforsch. 1967 22b 480. 99 M. N. Khattak and J. H. Green Internat. J. Radiation Biol. 1966,11 577; C. Nofre and M.-H. Ogier Compt. rend. 1966 263,C 1401. loo G. Felsenfeld and H. T. Miles Ann. Rev. Biochem. 1967 36 407. lo‘ A. M. Michelson J. Massoulie and W. Guschlbauer Progr. Nucleic Acid Res. 1967,6 83. 490 G. Michael Blackburn binary complexes. A study of all possible combinations of A C G and U bases in pairs shows that A :U and C :G are the only associating mixed pairs though weak self-association is observed. lo2 The equilibrium constant for binary complexing of C G'03 is ca. 10'~-and for A:U104*lo' is ca. 102~-; self-association constants are ca.5 M-l. Hypochromic changes in U.V. spec- tralo6 and changes in n.m.r. ~pectra'~~-'~' in aprotic solvents confirm complex formation and the latter clearly distinguishes pairing from stacking inter- actions. H :I.?+J; HO-0 (34) R = OH (35) R = OaOH (37) (36) R = H The i.r. data suggest the formation of a cyclic structure with more than one hydrogen bond per base pair,'" but it is not possible to distinguish between Watson-Crick pairing and other in-plane pairing patterns seen in crystal structures of some binary c~rnplexes.'~~~ '11 However restricted rotation of the cytosine amino-gr~up'~'. '12* l3 makes it possible to identify the amino-tautomer in the hydrogen-bonded complex with G and supports Watson-Crick pairing since the correct amino-groups and G-NH are all involved in hydrogen bonding."' Whereas hydrogen bonding is associated with a downfield chemical shift an upfield n.m.r.shift is seen for protons on stacked aromatic or heteroaromatic rings. Purine nucleosides in aqueous solution show upfield shifts for H-2 and H-8 signals though two models of stacking are consistent with the data.'14 Stacking of pyrimidine nucleosides has not been detected in water but deoxy- ribotrinucleotides containing thymine show shifts in the C-Me resonance lo' R. Hamlin R. C. Lord and A. Rich Science 1965,148 1734; Y. Kyogoku R. C. Lord and A. Rich ibid. 1966 154 518. lo' J. Pitha R. N. Jones and P. Pithora Cunad. J. Chem. 1966,44 1045. lo4 Y.Kyogoku R. C. Lord and A. Rich. Proc. Nut. Acad. Sci. U.S.A. 1967,57 250. lo' J. H. Miller and H. M. Sobell J. Mol. Biol. 1967 24 345. Io6 G. J. Thomas and Y. Kyogoku J. Amer. Chem. Soa 1967,89,4170; W. B. Gratzer and C. W. F. McClare J. Amer. Chem. SOC. 1967,89 4224. lo' L. Katz and S. Penman J. Mol. Biol. 1966 15 220. lo* K. H. Scheit Angew. Chem. 1967,79 190. lo9 R. R. Shoup H. T Miles and E. D. Becker Biochem. Biophys. Res. Comm. 1966,23 194. 'lo Y. Kyogoku R. C. Lord and A. Rich J. Amer. Chem. SOC. 1967.89.496 L. Katz K. Tomita and A. Rich Actn Cryst. 1966 21 754. D. M. G. Martin and C. B. Reese Chem. Comm. 1967 1275. 'I3 R. R. Shoup H. Todd Miles and E. D. Becker J. Amer. Chem. SOC. 196/,0Y 6200. A. D. Broom M. P. Schweizer and P. 0.P. Ts'o J.Amer. Chem. SOC.,1967,89 3612. Nucleic Acids 491 in accord with stacking.'" N.m.r. spectra at 220 Mc./sec. of single stranded DNA disordered at 90",show two thymine-methyl resonances. The ratio of their intensities is that of purine :pyrimidine in the neighbouring 5'-position.' l6 Ordered helical nucleic acid structures have too much rigidity to permit resolution of n.m.r. spectra and must be investigated by light absorption or light scattering. 0.r.d. studies of pyrimidine nucleosides' l7 suggest a favoured anti-conformation in solution shown for uridine (37). The situation for purine nucleoside~'~ is less clear''* and there is some preference expressed for a syn-conformation,' shown for adenosine (38). Stacking in dinucleotides shows AHo -6 to -7-5kcal.M-'and ASo -20 to -25 e.u. from c.d. studies.'" Uracil contributes weakly and its destacking effect'21 has been confirmed by Nakanishi. 22 The ordered structure of single-stranded ribopolynucleotides is more stable than that of deoxyribo-polymers. The suggestion that it results from intra- strand i.e. intramolecular hydrogen bonding of the 2'-hydroxy-group to the adjacent nucleotide'20 123 is supported by the change in physical properties which occurs when the 2'-hydroxy-group is acetylated. '24 Finally direct evidence for structural changes in poly-A has been elegantly furnished by the application of low-angle light scattering in ideal solution- '@ condition^'.'^^ At low temperature (ca. lo")poly-A has an extended rod-like structure.When the polymer is warmed to ca. 30" sufficient kinks appear for the molecule to become bunched although most bases are still stacked in short rods. At higher temperatures the bases become completely unstacked to give a disordered bunch. Thus maximal change in hyperchromicity is seen at ca. 45" (Tm),but maximal change in extension occurs at ca. 20". K. H. Scheit F. Cramer and A. Franke Biochim. Biophys. Acta 1967,145 21. C. C. McDonald W. D. Phillips and J. Lazar J. Amer. Chem. SOC. 1967,89,4166. T. R. Emerson R. J. Swan and T. L. V. Ulbricht Biochemistry 1967,6 843. A. Hampton and A. W. Nichol J. Org. Chem. 1967,32 1688. W. A. Klee and S. H. Mudd Biochemistry 1967,6,988;M. Ikehava M. Kaneko K. Muneyama and H. Tanaka Tetrahedron Letters 1967,3477.J. Brahms J. C. Maurizot and A. M. Michelson J. Mol. Biol. 1967 25 481. M. P. Schweizer S. I. Chan and P. 0.P. Ts'o J. Amer. diem. SOC. 1965,87 524. lZ2 Y. Inoue S. Aoyagi and K. Nakanishi Tetrahedron Letters 1967 3575; Y. Inoue S. Aoyagi and K. Nakanishi J. Amer. Chern. SOC. 1967,89 5701. P. 0.P. Ts'o S. A. Rapaport and F. J. Bollum Biochemistry 1966,5,4153;A. Adler L. Gross-man and G. D. Fasman Proc. Nat. Acad. Sci. U.S.A.,1967,57,423. 124 D. G. Knorre A. M. Malysheva N. M. Pustoshilova A. P. Sevast'yanov and G. G. Shamovskii Biokhimiya 1966,31,1181;D. G.Knorre and G G. Shamovsky Biochim. Biophys. Acta 1967 142 555. H. Eisenberg and G. Felsenfeld J. Mol. Biol. 1967 30 17.

ISSN:0069-3030    

DOI:10.1039/OC9676400479

出版商:RSC    

年代:1967

数据来源: RSC