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.