14 Synthetic Methods ByR. BRE'ITLE Department of Chemistry The University Shefield S3 7HF 1 Introduction This Report like those of the two previous years is highly selective. Priority has been given to truly original methods that are thought to be capable of wide general use and to significant modifications of earlier procedures; full accounts of work that has previously been reported in outline have generally not been reported. 2 Alkanes The hydrogenolysis of organic halides has been reviewed,' and a comparison of many hydride reducing agents shows that the best for the reduction of halides are lithium tetrahydridoaluminate and triethylhydridoborate.2 Certain modified molyb- denum carbonyl species are good reagents for the desulphurization of thi01s.~ Esters of the type (l),preparable in conventional ways from the carboxylic acids undergo reductive cleavage to the alkanes on treatment with tributyltin hydride in a refluxing aromatic s~lvent.~ Similar conditions also convert the readily accessible phenyl- selenoesters into hydrocarbons; many common functional groups are unaffected.' /p \ (1) X = C1or SPh The conversion of tertiary halides into alkanes can be accomplished in rather good yields by dimethyltitanium(1v) dichloride; mixed-order dihalides react selec- tively at the tertiary site and other functionality (alkene ester) is tolerated.6 The whole range of methodologies for the construction of quaternary carbon centres has been reviewed.' * A.R. Pinder Synthesis 1980,425. S. Krishnamurthy and H.C. Brown J. Org. Chem. 1980,45,849. ' H. Alper and C. Blais J. Chem. SOC.,Chem. Commun. 1980,169. D. H.R. Barton H. A. Dowlatshahi W. B. Motherwell and D. Villemin J. Chem. SOC. Chem. Commun. 1980,732. J. Pfenninger C.Henberger and W. Graf Helv. Chim. Acta 1980,63 2328. M. T.Reetz J. Westermann and R. Steinbach Angew. Chem. Znt. Ed. Engl. 1980,19 900. S. F.Martin Tetrahedron 1980 36,419. 263 264 R. Brettle 3 Alkenes Allylic alcohols can be regiospecifically deoxygenated by conversion into the xan- thates followed by a [3,3] sigmatropic rearrangement and treatment with tributyltin hydride; protonolysis of the resultant allyltin gives the alkene.8 (See Scheme 1). R' R' Reagents i NaH CS,; ii MeI heat; iii Bu,SnH; iv H' Scheme 1 Lithium dialkylcuprates react with allylic sulphoxides and sulphones (2) to give trisubstituted alkenes (3);the reaction shows considerable regio- and stereo-selec- tivity.' Enol trifluoromethanesulphonates which are stable and easily available from ketones react with lithium dialkylcuprates to give alkenes." A similar and perhaps more convenient approach uses silyl enol ethers readily available regio- specifically which couple with Grignard reagents in the presence of dichlorobis- (triphenylphosphine)nickel(II) as a catalyst." Both reactions proceed regio- specifically with retention of the geometry of the double-bond.(2) n = 1or 2 (3) [major product] Reduction of alkynes with a zinc-copper couple in boiling methanol gives the (Z)-alkenes.12 The hexamethylphosphoric-trimiade-catalysed elimination of vicinal threo-bromo-trifluoromethanesulphonatesat last seems to have provided a satisfactory solution to the problem of converting threo -bromohydrins into the (Z)-alkenes with complete stereo~pecificity.'~ Krief has provided a survey of synthetic methods using Q -heterosubstituted ~rganometallics,'~ which naturally covers many alkene-forming reactions.Bestmann has reviewed" old and new ylide chemistry including the transylidation sequence leading to trisubstituted alkenes that is shown in Scheme 2. Several Wittig reactions which would not proceed at lower temperatures occurred when the I SiMe3 Reagents i Me,SiCI; ii transylidation; iii R'X; iv F-; v R3CH0 Scheme 2 Y. Ueno,H. Sano and M.Okawara Tetrahedron Lett. 1980,21 1767. 'Y.Masaki K.Sakuma and K.Kaji J. Chem. SOC.,Chem. Commun. 1980,434. J. M. McMurry and W. J. Scott Tetrahedron Lett. 1980 21,4313. T. Hayashi Y.Katsuro and M. Kumada Tetrahedron Lett.,1980,21,3915. B.L.Sondengam G. Charles and T. M. Akam Tetrahedron Lett. 1980 21 1069. l3 E. J. Corey A. Morfat J. R. Falck and J. 0.Albright J. Am. Chem. SOC.,1980,102 1433. I4 A. Krief Tetrahedron 1980,36,2531. H. J. Bestmann Pure Appl. Chem. 1980,52 771. Synthetic Methods reaction mixtures were heated to 160"C in acetonitrile in a pressure vessel.16 The preparation of cycloalkenes by the intramolecular Wittig reaction has been reviewed.17 The direct Peterson methylenation using trimethylsilylmethyl-lithium becomes more attractive with the discovery of a less tedious route to the silicon- based reagent.I8 The reaction of a@ -epoxy-silanes with Grignard reagents leads via a -trimethylsilyl-substitutedcarbonyl compounds to predominantly the erythro-p-hydroxy-silanes which can then be transformed stereospecifically into either (E)-or (2)-alkenes by the standard methods.'' Methods for the inversion of alkene geometry have been reviewed.20 Very large rate accelerations are observed when alkylaluminium chlorides are used to catalyse ene reactions.Moreover when dimethylaluminium chloride is used in the reaction with aldehydes the resultant alcohol-Lewis acid complex breaks down to give methane and a non-acidic aluminium oxide so that acid-sensitive products can be made in this way.Ipsenol (4) can be made in one step as shown g.";u-,= (4) though only in low yield owing to a competing [4 + 21 cycloaddition.21 The first example of an ene-reaction that produces chiral centres in a 1,3-relationship proved to be very stereospecific22 (Scheme 3). A strikingly high asymmetric induction and a very high 1,2-diastereoselectivity have also now been recorded in a low-temperature alkylaluminium-chloride-promotedintramolecular cyclization of the ene type.23 C1 EtAICI2 ~ &co2Me -tH2C AC02Me PhH at 25 "C CH2 [85% of product mixture] Scheme 3 The 'ate' complexes formed by the action of sodium methoxide on appropriate alkenyldialkylboranes which are accessible with either geometry of the alkene react with copper(1) bromide and dimethyl sulphide to give alkenylcopper intermedi- ates; at 0 "C,these couple to give 1,3-dienes with retention of the geometry of the alkene in the original borane~.*~ At -15 "C the intermediates can be trapped by ally1 halides to give 1,4-diene~;~' prenyl bromide gives 75% of the a-coupled T.F. Tam and B. Fraser-Reid J. Org. Chem. 1980,45 1344. '' K.B. Becker Tetrahedron 1980,36,1717. l8 D. E.Seitz and A. Zapata Tetrahedron Lett. 1980,21,3451. l9 P. F. Hudrlik A. M. Hudrlik R. N. Misra D. Peterson G. P. Withers and A. K. Kulkami J. Am. Chem. SOC. 1980,102,4444. 2o P. E. Sonnet Tetrahedron 1980,36,557. 21 B. B. Snider Acc. Chem. Res. 1980,13,426;B. B. Snider and D. J. Rodini Tetrahedron Letr. 1980 21 1815; B. B. Snider D.M. Roush D. J. Rodini D. Gonzalez and D. Spindell J. Org. Chem. 1980,452773. 22 B. B. Snider and J. V. DunEia J. Am. Chern. SOC. 1980,102,5926. 23 W.Oppolzer and C. Robbiani Helv. Chim. Acta 1980 63 2010; W. Oppolzer C. Robbiani and K. Battig ibid. p. 2015. 24 J. B. Campbell Jr. and H. C. Brown J. Org. Chem. 1980,45,549. 25 H.C. Brown and J. B. Campbell Jr. J. Org. Chern. 1980,45,550. 266 R. Brettle product. Many functional groups are tolerated. Alkenyl-zirconium species couple with (?r-ally1)palladium complexes of alkenes to give 1,4-dienes; the complex from a steroidal 17(20)-alkene undergoes coupling mainly at C-20 to give the product with the natural steroid configuration at that position.26 The palladium-catalysed elimination of acetic acid and carbon dioxide from the easily constructed p -acetoxy-y6-alkenoic acids shows a high preference for the (E) configuration at the new double-bond irrespective of the relative stereochemistry of the acetoxy and car- boxyl groups whereas earlier related syntheses normally required pure diastereoisomers; the stereochemistry of the 76-double-bond is ~naffected.'~ These first examples of palladium-catalysed decarboxylation occur in preference to loss of acetic acid to give a dienoic acid although the palladium-catalysed route from allylic acetates to dienes is now well established.Acyclic 1,3-dienes are available from cyclobutanone by known selenium chemistry the crucial step being the regiospecific formation of the cyclobutene by base-catalysed elimination of a selenonium salt.28 This provides another short route to ipsenol (4) as shown in Scheme 4.An example of the increasing importance.of tin derivatives in synthesis is provided by the use of a trimethylstannyl-transfer agent to prepare both the (2)-and (E)-forms of P-(trimethylstannyl)alk-2-enoates from alk-2-ynoates; further transformations including transmetallation then pro- vide a versatile route to substituted dienes (Scheme 5).29 Reagents i MeSeH ZnC1,; ii BuLi; iii m0 ;iv M;I,AgBF,; v KH DMSO; vi heat Scheme 4 -i-iii MeHCHO % MeC-CCO,R + Me,Sn H Li H EH Reagents i PhS(Me,Sn)CuLi kinetic control at -100 "C; ii MeOH; iii DIBAL; iv Ph,P=CH,; v MeLi; vi E' (E= electrophile) Scheme 5 Dienes can be prepared by the reaction of organocopper(1) species with the methanesulphinates of allenic alcohols as shown in the synthesis of myrcene (5).30 1,3-Dienyl esters are formed by the isomerization of prop-2-ynylic esters with silver trifluoroacetate in boiling benzene.,l Pearson has shown in a series of papers,32 how the iron tricarbonyl complexes of cyclohexa-1,3-dienes can be used to provide routes to quite complex structures.26 J. S. Temple and J. Schwartz J. Am. Chem. Soc. 1980,102,7381. 27 B.M. Trost and J. M. Fortunak J. Am. Chem. Soc. 1980,102,2841. S. Halazy and A. Krief Tetrahedron Lett. 1980 21 1997. 29 E.Piers and H. E. Morton J. Org. Chem. 1980,45,4263. 30 H. Kleijn H. Westmijze J. Meijer and P. Vermeer Reel. Trau. Chim. Pays-Bas 1980,99 340. 31 R. C. Cookson M.C. Cramp and P. J. Parsons J. Chem. Soc. Chem. Commun. 1980,197. 32 A. J. Pearson and P. R. Routhby J. Chem. Soc. Perkin Trans. 1 1980 395; A. J. Pearson ibid. p. 400;A. J. Pearson and M. Chandler ibid. p. 2238;A. J. Pearson E. Mincione M. Chandler and P. R. Raithby ibid. p. 2774;A. J. Pearson and M. Chandler Tetrahedron Lett. 1980 21 3933; A. J. Pearson and D. C. Rees ibid. p. 3937;A. J. Pearson ,P. Ham and D. C. Rees ibid. p. 4637;A. J. Pearson and C. W. Ong ibid. p. 4641. Synthetic Methods 267 (5) The derived complexes of hexadienyl cations are susceptible to stereospecific nucleophilic attack in both inter- and intra-molecular processes; the sequence chosen for illustration in Scheme 6 shows a route to cis-hydrindenes. The import- ance of this metholology would be further increased by the use of chiral tricarbonyl- cyclohexadienyliumiron salts so that Birch's resolution of tricarbonyl( 1-carboxy-cy~lohexa-l,3-diene)iron,~~ and the determination of the absolute configuration of the enantiomers points the way forward.C0)3Fea A (CO)3Fea \ -CH(C02Me)2 BF4-CH20H iv-vi/ -(cO),,a vii,viii CH,OAc * .* I CH-CHz-CH(C02Me)z Y H ,OAc Reagents i N_a+CH(CO,Me),; ii DIBAL; iii Tl(O,CCF,),; iv C,H,SO,Cl C,H,N; v K+CH(CO,Me),; vi HBF, Ac,O; vii DBU at -78 "C; viii Me,NO Scheme 6 4 Alkynes A considerable improvement in the conversion of methyl ketones into terminal alkynes through the enol phosphates results from the use of lithium tetramethyl- piperidide in the elimination Two new routes to 1,Senynes have been reported.In one cobalt complexes of propargyl cations are coupled with allyl-silanes (Scheme 7),35and the other employs the palladium-catalysed cross-coupling of alkenyl halides with homopropargylic organozinc ~hlorides.~~ R' R' R2 6' BF,-WR3 =+OH a RZ (CO)6C0z RZ R4 RS Reagents i Co(CO),; ii HBF, at -45 "C; iii Me3Si*R' ;iv Fe(NO,) R3 R4 Scheme 7 5 Alcohols Interest in the protection of hydroxyl groups continues. The use of allyl-silanes as silylating agents for alcohols has some advantages in terms of the by-products over the use of the trialkylsilyl chloride-tertiary amine method;37 catalysis 33 A. J. Birch and B. M. R. Bandara Tetrahedron Lett. 1980,21,2981. E.-I. Negishi A. 0. King W.L. Klima W. Patterson and A. Silveira Jr. J. Org. Chem. 1980,45 2526. 35 J. E. O'Boyle and K. M. Nicholas TetrahedronLen.,1980,21 1595. 36 E-I. Negishi L. F. Valente andM. Kobayashi J. Am. Chem. SOC., 1980,102 3298. 37 T.Morita Y. Okamoto and H. Sakurai Tetrahedron Lett. 1980,21.835. 268 R. Brettle especially by dimethyl sulphoxide makes the older method effective for tertiary The p-(trimethylsily1)ethoxymethyl group has been recommended as a new ether-type protecting group; it survives under acidic conditions which would cleave trialkylsilyl and tetrahydropyranyl ethers but is readily removed by treatment with fluoride ion.39 Two additional reagents for the cleavage of silyl ethers have been reported uiz. lithium tetraflu~roborate~' and N-bromosuccinimide in aqueous dimethyl sulphoxide,"' the latter being a very mild cheap system which is useable in the presence of many functions including tetrahydropyranyl ethers.A (2-methoxyethoxy)methyl (MEM) ether was cleaved through an intermediate 0-isopropylthiomethyl ether using conditions which did not cleave a t-butyldimethyl- silyl ether or a dithi~acetal.~' A comprehensive review of photo-removable protecting groups covers inter alia protection of hydroxyl groups in the carbohydrate field.43 Aldehydes react with methyltri-isopropoxytitaniumto give secondary alcohols under conditions where ketones esters epoxides and nitriles do not react; cinnamaldehyde gives only the allylic Markovnikov hydration of an isopropenyl group was only finally achieved in the total synthesis of picrotin by the route shown in Scheme 8 but the low yield shows the desirability of finding a -__* '"O& iii,iv ~0%~ i,ii HgCl Reagents i (CF,CO,),Hg; ii KCl; iii Bu3SnH; iv NaHCO, H,O MeOH Scheme 8 better demercuriation proced~re.~' Anti-Markovnikov hydration of alkenes can be achieved conveniently by the use of titanium tetrachloride with sodium borohy- dride.46 The epoxide group in (6) has been reductively opened in the presence of the ketone function by using tellurium hemi is try.^^ Two mild methods for the hydrolysis of primary iodides avoiding the expense of silver salts use copper(1) Me Me 38 R.G. Visser H. J. T. Bos and L. Brandsma Red. Trav. Chim. Pays-Bas 1980,99,70. 39 B.H. Lipshutz and J. J. Pegram Tetrahedron Lett. 1980 21 3343. 40 B. W. Metcalf J. P. Burkhart and K. Jund Tetrahedron Lett. 1980,21 35. 41 R. J. Batten A. J. Dixon R. J. K. Taylor and R. F. Newton Synthesis 1980 234. 42 E. J. Corey L. 0. Weigel A. R. Chamberlin H. Cho and D. H. Hua J. Am. Chem. SOC.,1980 102,6613. 43 V. N. R. Pillai Synthesis 1980 1. 44 B. Weidmann and D. Seebach Helv. Chim. Acta 1980 63 2451. 45 E. J. Corey and H. L. Pearce TetrahedronLett. 1980,21 1823. 46 S. Kano Y. Tanaka and S. Hibino J. Chem. SOC.,Chem. Commun. 1980,414. 47 D. L. J. Clive G. J. Chitattu V. Farina W. A. Kiel S. M. Menchen C. G. Russell A. Singh C. K. Wong and N. J. Curtis J. Am. Chem. SOC.,1980 102 4438. Synthetic Methods 269 oxide and methyl toluene-p-sulphonate as the iodide ~cavengers.~’ The reduction of aldehydes and ketones to alcohols by ammonia-borane and t-butylamine-borane has been compared with their reduction by borane and sodium b~rohydride.~~ The reagent prepared from N-isopropylcyclohexylamine and methylmagnesium iodide (MICA) is the best ever for the conversion of epoxides into allylic alcohol^.'^ The di-isobutylaluminium hydride-butyl-lithium ‘ate’ complex selectively reduces an cup-olefinic ester to the allylic alcohol in the presence of a carboxyl A more direct Wittig route to (2)-trisubstituted allylic alcohols has been de~eloped.~’ Homoallylic alcohols are formed when allyl-tin compounds obtainable by the reduction of allylic sulphones with tributyltin hydride are treated with trioxad2 (cf.Scheme 1).The syn-hydroxylation of alkenes by osmium tetroxide has been comprehensively reviewed;53 addition of trimethylamine N-oxide and pyridine results in a high yield even with a tetrasubstituted alkene.54 The methodology for the stereocontrolled construction of acyclic molecules continues to develop rapidly spurred on by the desire to synthesize complex ionophore and macrolide antibiotics where the stereochemical problems can often be reduced by convergency to the formation of vicinal stereo-relationships with control by pre-existing stereo-relationships. Fortunately a timely review appeared at the start of the year.55 Many of the reactions are of the aldol type. Chelation- controlled (or anti-Cram) nucleophilic addition to a-alkoxycarbonyl compounds received a lot of attention and highly stereoselective procedures for the preparation of both threo- and erythro-1,2-diols are now available and have been used in the synthesis of natural p -Hydroxy-acids and substituted homoallylic alcohols which can be converted into p -hydroxy-ketones by palladium-catalysed oxidation have been further in~estigated,~’ as have direct routes to p -hydroxy-ketone^,^' where the relative py-stereochemistry can now be controlled by the use of a new highly enantioselective chiral reagent59 which counteracts the normally small selectivity of aldehydes in the formation of the a@-bond.Diastereoselectivity has also been observed in the Michael addition of a doubly deprotonated chiral 48 M.Yoshioka T. Tsuji S. Uyeo S. Yamamoto T. Aoki Y. Nishitani S. Mori H. Satoh Y. Hamada H. Ishitobi and W. Nagata Tetrehedon Lett. 1980 21 351. 49 G. C. Andrews and T. C. Crawford Tetrahedron Lett. 1980,21 693 697. ” B. M. Trost G. T. Rivers and J. M. Gold J. Org. Chem. 1980,45 1835. 51 C. Sreekumar K. P. Darst and W. C. Still J. Org. Chem. 1980,45,4260. 52 Y.Ueno S. Aoki and M. Okawara J. Chem. SOC.,Chem. Commun. 1980,683. 53 M. Schroder Chem. Rev. 1980,80,187. ” R. Ray and D. S. Matteson Tetrahedron Len.,1980,21,449. 55 P. A. Bartlett Tetrahedron 1980,36 2. 56 W.C. Still and J. H. McDonald Tetrahedron Lett. 1980 21 1031; W.C. Still and J. A. Schneider ibid. p. 1035;D. B. Collum J. H. McDonald and W. C. Still J. Am. Chem. SOC.,1980 102 2117 2118,and 2120;C.H.Heathcock S. D. Young J. P. Hagen M. C. Pirrung C. T. White and D. Van Derveer J. Org. Chem. 1980,45,3846;K. C.Nicolaou D. A. Claremon and W. E. Barnette J. Am. Chem. Soc. 1980,102,6611. ” M.C.Pirrung and C. H. Heathcock J. Org. Chem. 1980 45 1727; H.Yatagai Y. Yamamoto and K. Maruyama J. Am. Chem. SOC.,1980,102,4548; R. W.Hoffmann and H-J. Zeiss Angew. Chem. Int. Ed. Engl. 1980 19 218; Y. Yamamoto H. Yatagai and K. Maruyama J. Chem. SOC.,Chem. Commun. 1980 1072; Y. Yamamoto H. Yatagai Y. Naruta and K. Maruyama J. Am. Chem. SOC. 1980,102,7107. 58 I. Kuwajima M. Kato and A. Mori Tetrahedron Lett. 1980 21 4291; Y. Yamamoto and K. Maruyama ibid. p. 4607;D. A. Evans and L. R. McGee ibid. p. 3975. 59 S. Masamune Sk. A. Ali D. L. Snitman and D.S. Garvey Angew. Chem. Znt. Ed. Engl.. 1980 19 557. 270 R. Brettle @ -hydroxy-ester to a nitro-alkene,60 and in the cyclic hydroboration of non-conju- gated dienes to give diolsm61 6 Ethers In a synthesis of a very labile epoxide leukotriene A methyl ester (8) from the chiral hydroperoxide (7) conditions were established62 which generated an elec- trophilic oxygen centre by loss of a good leaving group in the presence of a hindered base at low temperatures thereby minimizing both a competing carbonyl- forming elimination and the acid-catalysed decomposition of the product (8). (7) (8) Ally1 ethers can conveniently be isomerized to vinyl ethers by heating them with palladium charcoal (Pd/C) in an aromatic solvent.63 Phenyl and vinyl allyl ethers isomerize more slowly than alkyl allyl ethers thus permitting the preparation of the vinyl allyl ether (9) by the route shown.TOT pd/c.+yoy PhH for 3 5 h (9) Milder catalytic conditions using trimethylsilyl trifluoromethanesulphonate have been developed for the condensation of acetals with enol silyl ethers and allyl-silanes to give substituted 7 Halides Trialkylboranes react with iodine chloride in methanol that contains sodium acetate to give alkyl iodides; this is a milder and more economical method than earlier related ones.65 It had been reported earlier that trimethylsilyl chloride-sodium iodide or hexamethyldisilane-iodine converted alcohols into iodides. Now it has been shown that trimethylsilyl chloride-sodium bromide or hexamethyldisilane- pyridinium tribromide similarly convert alcohols into bromides;66 the second reagent converts a secondary-tertiary diol into the hydroxylated tertiary bromide selectively.1 1 -Bromoundecyl tosylate is reduced by lithium aluminium hydride in diglyme to undecyl tosylate but if the solvent is changed to diethyl ether the reduction product is undecyl bromide; this is a remarkable effect of the solvent on chemo~electivity.~' 6o M. Zuger T. Weller and D. Seebach Helv. Chim. Acra 1980,63,2005. " W. C. Still and K. P. Darst J. Am. Chem. Soc. 1980,102,7385. E.J. Corey A. E. Barton and D. A. Clark J. Am. Chem. SOC.,1980 102,4278. 63 H.A.J. Carless and D. J. Haywood J. Chem. Soc. Chem. Commun. 1980,980. 64 T.Tsumoda M. Suzuki and R.Noyori Tetrahedron Lett. 1980.21,71:S. Murata M.Suzuki. and R. Noyori J. Am. Chem. SOC.,1980 102 3248; Tetrahedron Lett. 1980,21,2527. " G. W. Kabalka and E. E. Gooch J. Org. Chem. 1980,45,3578. " G. A.Olah B. G.B. Gupta R. Malhotra and S. C. Narang J. Org. Chem. 1980,45 1638. 67 S.Krishnamurthy J. Org. Chem. 1980,45,2550. Synthetic Methods 27 1 8 Nitriles Phenyl cyanate for which an improved preparation has been developed is a convenient source of electrophilic cyanide in the preparation of acetylene nitriles from lithium acetylides; with lithio-alkenes the substitution occurs stereospecifically with retention of configuration.68 A rapid and efficient procedure for the dehydration of saturated ap-olefink and aromatic primary amides involves the addition of the amide to a pre-formed suspension of the Vilsmeier reagent chloro-NN-dimethyl- forminium chloride in acetone at 0°C; the addition of pyridine then leads to the formation of the nitrile within a few minutes.69 Reduction of a hexaquinane bis(aP -0lefinic nitrile) by Corey's magnesium and methanol method unexpectedly gave a p-p -coupled saturated dinitrile but the use of Semmelhack's copper hydride complex used earlier on enones gave the desired saturated dinitrile with no formation of a transannular bond.70 9 Nitro-compounds The synthesis and reactions of nitro-compounds in genera171 and of cyclic a-nitro- ketones in particular7* have been reviewed.An effective mild and selective method for the conversion of ketoximes into secondary nitro-compounds has been reported (Scheme 9).73Conjugated olefinic nitro-compounds can be prepared from the Reagents i HOCl benzene/H,O pH 5.5 at 25 "C; ii Bu',N'OCI- benzene/H,O; iii Mg THF then CH3C02H,or Zn aq.THF NH30H'C1- or H2 Pd/C aq. MeOH NaOH then CH3C02H Scheme 9 saturated compounds by a selenation-selenoxide elimination route,73 or from vinyl- stannanes obtainable from ketones by a modified Shapiro reaction by treatment with tetranitromet hane in dimet hyl ~ulphoxide.~~ 10 Amines The synthesis of allylic amines from allylic alcohols via imidic esters has been reviewed;75 the review75 also covers the use of trichloroacetamido-l,3-dienesin cycloaddition reactions. Organocopper reagents like other organometallics react with Mannich reagents to give aminomethylated products.Alkenyl-copper and cuprate reagents give the tertiary allylamines with cis geometry; alkenyl-alanes and alanates give the trans-amines (Scheme Saturated amines can be prepared by the reductive alkylation of amines with carbonyl compounds under very mild 68 R. E. Murray and G. Zweifel Synthesis 1980 150. 69 T.M.Bargar and C. M. Riley Synth. Commun. 1980,10,479. 70 M. E. Osborn J. F. Pegues and L. A. Paquette J. Org. Chem. 1980,45 167. 71 R.H. Fischer and H. M. Weitz Synthesis 1980 261. 72 D.Seebach E. W. Colvin F. Lehr and T. Weller Chimia 1979,33 1. 73 E.J. Corey and H. Estreicher Tetrahedron Lett. 1980,21 1117. 74 E. J. Corey and H. Estreicher Tetrahedron Lett. 1980 21 1113. 75 L.E.Overmann Acc. Chem.Res. 1980,13 218. 76 C. Germon A. Alexakis and J. F. Normant Tetrahedron Lett. 1980 21 3763. 272 R. Brettle HCGCH RC=CH li 1iii R+ (RdguLi AIBu', 1ii 1iv Rm CHZNEt R Reagents i R,CuLi; ii PhSCH,NEt,; iii DIBAL; iv Bu'OCH,N Scheme 10 conditions by using phenylselenol as the reducing agent; alkene nitrile amide and ester functions are not reduced by this reagent.77 Carboxamides can be reduced to amines in the presence of alkene ester nitro and sulphonamide functions by the method shown in Scheme 11.78 Reaction times are shorter than in other procedures S SEt II I R3CONR'R2 R3-C-NR'R2 A R3-&R'R2 -!!+ R3CH2NR'R2 Reagents i Ar,P2S (Ar = p-MeC,H,); ii Et,O'BF,-; iii NaBH Scheme 11 RCOCl ,0SiMe3 R-C -% RNCO 2RNH2 RCONHOH \NOSiMe3 Reagents i Me,SiONHSiMe,; ii (Me,Si),NH; iii heat at 120"C; iv conc.H,SO,; v ice Scheme 12 and primary amides are reduced without any competing dehydration. Amines can be prepared cleanly from acid derivatives by the routes shown in Scheme 12 incorporating an improved procedure for the hydrolysis of iso~yanates.~~ An excel-lent general method for the preparation of vicinal primary amines (Scheme 13) 0 0 I1 N N R3 H,N NH, /\ II RiR3 11 x:41 + cp-co-co-~p .Lcp-cy ' A R'R3C-CR2R4 Rz R4 \/ N N II II R2 0 0 (CP = 77-C5H5) Reagents i NO at 0 "C; ii LiAlH Scheme 13 77 K. Fujimari H. Yoshimoto and S. Oae Tetrahedron Lett. 1980,21 3385. S. Raucher and P. Klein Tetrahedron Lett. 1980 21,4061. 79 J. Rigaudy E.Lytwyn P. Wallach and N. K. Cuong Tetrahedron Lett. 1980,21,3367;F. D. King S. Pike and D. R. M. Walton J. Chem. SOC.,Chem Commun. 1978,351. Synthetic Methods 273 results from following up some earlier organometallic work; unfortunately the reaction shows rather poor stereoselectivity." 11 Aldehydes and Ketones In a new synthesis treatment of a primary azide with 'magic methyl' (FS03Me) followed by the action of an aqueous buffer at pH4 generated an aldehyde at room temperature.'l New methods for the conversion of highly hindered ketones into the next higher aldehyde have been reported which employ ingenious variants of the Peterson and Wittig reactions to generate enol ethers.82 Acyl chlorides can be reduced to aldehydes satisfactorily by tributyltin hydride provided that a pal- ladium catalyst is alternative new reducing systems are sodium borohydride -dimethylformamide in acetonitrile in the presence of cadmium(I1) ions84 or the cyanoborohydride (10) under neutral ~onditions.~~ The anion (1 1) is an improved equivalent of the formyl anion with greater nucleophilicity; regeneration of the aldehyde occurs under much milder conditions than in the better-known 1,3-dithian procedure .86 (P~~P)~CUBH~CN PhSCHSiMe3 (10) (11) Sodium hypochlorite is a cheap convenient reagent for oxidizing secondary alcohols to ketone^;^' the transformation can also be accomplished under very mild conditions by the complex formed from dimethyl sulphoxide and chlorosul- phony1 isocyanate at -78 0C.88Alternative methods for the conversion of secondary nitro-compounds into ketones have been de~eloped,~~ and the oxidative desul- phonylation of secondary sulphones to give ketones has been achieved" with molybdenum peroxide; the use of molecular oxygen led to an explosion in one case.Sodium hydrogen telluride reduces the carbon-carbon double-bond in conju- gated olefinic ketones (and related systems) without affecting isolated double- bonds." The same reduction when conducted using lithium in ethylamine contain- ing 2-methylpropan-2-01 is considerably improved9* by lowering the reaction temperature to -78 "C. Ketones or their enol silyl ethers or enol acetates react with cobalt complexes of propargyl cations (cf.Scheme 7)to give after demetalla- tion acetylenic ketones.93 Site-specific monoalkyl-substituted acyclic ketones can so P.N Becker M. A. White andR. G. Bergmann J. Am. Chem. SOC.,1980,102 5676. 81 E.J. Corey J. W. Ponder and P. Ulrich Tetrahedron Lett. 1980,21 137. 82 E.J. Corey and M. A. Tuis Tetrahedron Lett. 1980 21 3535; E.J. Corey M. A. Tuis and J. Das J. Am. Chem. SOC.,1980,102 1742. 83 F. Ginke P.Four and H. RivBre J. Chem. Soc. Chem. Commun. 1980,432. 84 I. D.Entwistle P. Boehm R. A. W. Johnstone and R. P. Telford J. Chem. Soc. Perkin Trans. 1 1980,27. R.0.Hutchins and M. Markowitz Tetrahedron Lett. 1980,21 813. 86 P. J. Kocienski Tetrahedon Lett. 1980,21 1559; D. J. Ager and R. C. Cookson ibid. p. 1677. " R. V. Stevens K. T. Chapman and H. N. Weller J. Org. Chem. 1980,45,2030. G.A. Olah Y. D. Vankar and M. Arvanaghi Synthesis 1980 141. 89 G. A. Olah and B. G. B. Gupta Synthesis 1980,44;G. A. Olah M. Arvanaghi Y. D. Vankar and G. K.S.Prakash ibid. p. 662. 90 R. D. Little and S. 0.Myong Tetrahedron Left. 1980 21 3339. 91 M. Yamashita Y. Kato and R. Suemitsu Chem. Left. 1980,847. 92 A. W. Burgstahler and M. E. Sanders Synthesis 1980,400. 93 K. M. Nicholas M. Mulvaney and M. Bayer J. Am. Chem. SOC.,1980,102 2508; S.Padmanabhan and K. M. Nicholas Synth. Commun. 1980 10 503. 274 R. Brettle be obtained from the specific enol boranes routes to which are available by the use of alkyl halides in the presence of lithium 2-(dimethylarnino)etho~ide.~~ a -Allyl-substituted ketones can be prepared by the decarboxylation of ally1 0 -keto-esters as shown in Scheme 14.95 0 Reagent i [Pd(PPh,),] DMF at 20 OC Scheme 14 Alkenyl- (but not alkyl-) zirconium species undergo conjugate addition to ap-olefinic and acetylenic ketones in the presence of a catalyst prepared from nickel acetylacetonate and DIBAL followed by quenching with acid.96 A lot of attention has been given to the reactions of organocopper compounds and organocuprates with cup-olefink carbonyl compounds especially with conjugated olefinic aldehydes leading to /3 -alkylation or conjugate red~ction.~' Selenium-based methodology for the synthesis of ap-olefinic aldehydes and ketones continues to develop.For the preparation of ap-olefinic aldehydes the reaction of an enol silyl ether,98 en~l-borane,~~ or enamine"' with phenylselenyl chloride occurs readily at low temperatures to give the a -phenylselenyl-substituted aldehyde; subsequent oxidative elimination then introduces the conjugated olefinic bond.These methods avoid the problems sometimes encountered in the direct selenylation of aldehydes. The direct selenylation of ketones (and esters) can be conducted through the reaction of selenium metal with lithium enolates,"' as shown in Scheme 15.The regiospecificity that is observed in the addition of phenylselenyl chloride to allylic alcohols is vital to a new 1,3-enone transposition procedure,"' an example of which is shown in Scheme 16. Reagents i LDA 3 moles of HMPT; ii black selenium; iii Me1 Scheme 15 94 J. Hooz and J. Oudenes Synth. Commun.1980,10,139. 95 T. Tsuda Y.Chujo S-i. Nishi K. Tawara and T. Saegusa I. Am. Chem. Soc. 1980,102,6381. 96 J. Schwartz M. J. Loots and H. Kosugi J. Am. Chem. Soc. 1980,102,1333. 97 C. Chuit J. P. Foulou and J. F. Normant Tetrahedron 1980,36 2305;M. Suzuki T. Suzuki T. Kawagishi and R. Noyori TetruhedronLett.,1980,21,1247;S. H. Bertz ibid. p. 3151;A. B. Smith B. A. Wexler and J. S. Slade ibid. p. 3237;T. Ibuka H. Minakata Y. Mitsui K. Kinoshita and Y. Kawami J. Chem. SOC., Chem. Commun. 1980,1193;T.Ibuka H. Minakata Y. Mitsui K. Kinoshita Y. Kawarni and N. Kimura Tetrahedron Lett. 1980 21 4073; T.Tsuda T.Fujii K. Kawasaki and T. Saegusa J. Chem. Soc. Chem. Commun. 1980 1013. 98 K. C. Nicolaou R. L. Magolda and W. J. Sipio Synthesis 1979,982;K. C. Nicolaou R.L. Magolda and D. A. Claremon J. Am. Chem. Soc. 1980,102,1404. 99 J. Hooz and J. Oudenes Synth. Commun. 1980,10,667. loo D. R. Williams and K. Nishitani Tetrahedron Lett.. 1980 21,4417. D. Liotta G. Zima C. Barnum and M. Saindane Tetrahedron Lett. 1980 21 3643. D. Liotta and G. Zima J. Org. Chem. 1980,45,2551. Synthetic Methods C1 OH Reagents i LiAlH,; ii PhSeC1 at -78°C; iii 0,; iv Et,NH CH2Cl2 heat; v MeCOCl C5H5N; vi Hg(02CCHA CFSCOzH Scheme 16 Reagents i MeOS0,F; ii BuLi; iii at -20°C; iv MCPBA at -4O"C then work up; v (CO2H), THF-water at 20 "C Scheme 17 A new synthesis of Py-olefinic aldehydes (Scheme 17) is related to the synthesis of saturated aldehydes using the reagent (ll),that is described above and the synthesis involves a [2,3] sigmatropic rearrangement of a silicon-stabilized sulphur ~1ide.l'~ The selectivity in the acetylenic oxy-Cope arrangement of 3-hydroxy-alk-5- en-1-ynes is much improvedlM by carrying out the reaction in boiling N-methyl- pyrrolidinone in the presence of a halogen catalyst such as iodine and has led to an industrial-scale synthesis of pseudoionone (12).P-Diketones can be prepared from ap-epoxy-ketones in a rather slow reaction conducted at elevated temperatures in the presence of a palladium(0) catalyst (Scheme 18).'05 1,SDiketones result from the addition of (1-alkyny1)trialkylborates lo' P. J. Kocienski J. Chem. SOC.,Chem. Commun. 1980 1096. '04 Y. Fujita T. Onishi K.Hino and T. Nishida Tetrahedron Lert. 1980 21 1347 M. Suzuki A.Watanabe and R. Noyori J. Am. Chem. SOC.,1980,102 2095. 276 R. Brettle 0 00 Reagents i [Pd(PPh,),] (Ph2PCH2)2 PhMe at 80-140 "C Scheme 18 to butenone in the presence of titanium(1v) chloride followed by oxidation with alkaline hydrogen peroxide. lo6 New syntheses have been developed for Q -keto-esters (from a-a~ido-esters),~'' for certain P-keto-esters108 (see Scheme 19),for y-keto-ester~"~ (see Scheme 20) and for y-substituted-& keto-esters"' (see Scheme 21). R' *C02Me \ R2 R2+ C02Me R' Reagents i [Pd(PPh,),] (Ph2PCH2), MeOCH2CH20Me reflux Scheme 19 C02Me R' i h4e3!3iO&R3 R,* C02Me Me3si0wR3 0 R2 -R1 R2 R2 R3 Reagents i N2CHC02Me [Cu(acac),] at 90 "C; ii Et,NH+F- THF at 20 "C Scheme 20 OSiMe Me Me Me Reagents i ,MeCN; ii RCHCl(SPh) ZnBr,; iii Raney nickel MeO'OSiMe3 Scheme 21 12 Carboxylic Acids and their Derivatives Recent developments in methods for the protection and esterification of the carboxyl group have been reviewed."' P -Chloroethyl esters can be cleaved reductively with zinc (or electrochemically) in the presence of catalytic amounts of aquocobalamin or synthetic analogues of vitamin B12.Since the end of the reduction is signalled by a colour change from red to green it has been dubbed the 'traffic-light reac- '06 S.Hara K. Kishimura and A. Suzuki Chem. Lett. 1980 221. lo7 P. A. Manis and M. W. Rathke J. Org. Chem. 1980,454953. lo' B. M. Trost T. A. Runge and L. N. Jungheim J. Am. Chem. SOC.,1980,102,2841; cf.G. Valavoine and F. Guibe Tetrahedron Lett. 1979 3949. lo9 H-U. Reissig and E. Hirsch Angew. Chem. Znt. Ed. Engl. 1980 19,813. 'lo Y. Kita J. Segawa J. Haruta T. Fujii and Y. Tamura Tetrahedron Lett. 1980 21 3779. '11 E. Haslam Tetrahedron 1980 36 2409. Synthetic Methods tion'.'12 The /3 -chloroethyl group and a second new carboxyl-protecting group,l13 the p -methoxycarbonylbenzyl group (which can be removed by electrochemical reduction) have both been used to protect sensitive /3 -1actam antibiotic acids. Continued interest in the activation of carboxylic acids by their conversion into thiol esters has led to some further methods for achieving this with advantages in terms of mildness cheapness and procedural ~0nvenience.l~~ -0lefinic acid CUP derivatives including thiolesters can be prepared by using the phosphorus-based route exemplified in Scheme 22.l" Trimethylsilyldiazomethane which is thermally stable has been recommended in preference to diazomethane for the Arndt-Eistert homologation of acids.116 ..... +-+-Ph3P-CHC02Me 5Ph,P-C=C=O aR2CH=CHCOYR' Reagents i Na[N(SiMe,),]; ii R'YH (e.g.PhSH); iii R'CHO Scheme 22 a-Phenylselenylation of a hindered ester as part of an ap-desaturation pro- cedure was only successful with diphenyl diselenide and potassium hydride which is a convenient combination for general use."' Following earlier work on thioamides it has now been shown that certain organometallic reagents undergo Michael addition to relatively lightly substituted a@ -0lefinic amides and trimethyl- hydrazides and that the initially formed anion can then be trapped by electrophiles; e.g.see (13).'18A wider range of conjugated olefinic amides can be reduced to the saturated amides by magnesium in The dimetallation of ap-0lefinic amides is possible too and the reaction of the dianion gives substitution at the P'-position; the procedure has been used as part of a route to a-methylene-lactones (see Scheme 23).'*' Another route to a-methylene-lactones is based on [2-(alkoxy- carbonyl)allyl]trimethylsilanes (Scheme 24).12' The Baeyer-Villiger oxidation of P-(trimethylsilyl)cycloalkanones,followed by hydrolytic ring-opening gives esters that contain a remote P -trimethylsilyl alcohol function which is easily convertible (by standard methods) into a double-bond.A '" R. Scheffold and E. Amble Angew. Chem. Int. Ed. Engl. 1980,19,629. 'I3 D. F.Corbett and A. J. Eglington J. Chem. SOC.,Chem. Commun. 1980 1083. 0. Piepers and R. M. Kellog J. Chem. SOC. Chem. Commun. 1980 1147; H-U.Reissig and B. Scherer Tetrahedron Lett. 1980,21,4259;H-J. Lui and S. I. Sabesan Can. J. Chem. 1980,58,2645. '15 H.J. Bestmann G. Schmid and D. Sandmeier Chem. Ber. 1980,113 912; H. J. Bestmann and D. Sandmeier ibid. p. 274;cf. H. J. Bestmann Angew. Chem. Int. Ed. Engl. 1977,16 348. '16 T.Aoyama and T. Shioiri Tetrahedron Lett. 1980,21,4461. '" A. L. Cossey L. Lombardo and L. N. Mander Tetrahedron Lett. 1980 21,4383. '" J. E.Baldwin and W. A. Dupont Tetrahedron Lett. 1980,21,1881; G. B. Mpango K. K.Mahalanabis Z. Mahdavi-Damghani and V. Snieckus Tetrahedron Lett. 1980,21,4823;S. Knapp and J. Calienni Synth. Commun. 1980,10 837. '19 R. Brettle and S. M. Shibib Tetrahedron Lett. 1980 21 2915. 120 J. J. Fitt and H. W. Gschwend J. Org. Chem. 1980,45,4257;P. Benk and D. J. Kempf J. Am. Chem. SOC.,1980,102,4550. '" A. Hosomi H. Hashimoto and H. Sakurai Tetrahedron Lett. 1980,21,951. 278 R. Brettle Reagents i 2 moles of BuLi TMEDA THF at -70 "C;ii PhCOPh; iii H20; iv xylene reflux Scheme 23 Me,SiCH,C=CH i HzC=C-CH2CHR2 ii,iii I -* I I C02R' C02R' OR3 Reagents i RZCH(OR3)2 BF,*Et20; ii Me,SiI; iii MeOH Scheme 24 Me,SiI Me,Si Reagents i MCPBA in phosphate buffer; ii MeOH MeONa; iii BF3-Et,0 Scheme 25 simple example is shown in Scheme 25.'22 The use of cuprates on (Z)-vinyl- substituted lactones leads to chirality transfer with inversion and it provides for example a route to the olefinic acid (14).12,An earlier palladium-catalysed process using stabilised anions went with retention.H Me Me2CH(CH2),CHZCuCN O W H ether at -20 to0 'C \ ' H02C1 (14) Me A development of a synthesis of ap-olefinic esters that uses the Claisen orthoester rearrangement (reported last year) uses trimethyl @ -methoxyorthopropionate in the reaction with the allylic alcohol; base-catalysed elimination of methanol from the rearrangement product gives an a-substituted acrylic ester.'24 The use of diethyl oxomalonate in the ene-reaction has been extended and routes to olefinic acids that are based on it (see Scheme 26) have been deve10ped.l~~ In a new route to y6-olefinic acids the key step is the Claisen rearrangement of vinyl-substituted silyl ethers of lactones which can be constructed by a variety of methods.The example shown (Scheme 27) is a step from a synthesis of widdrol and it illustrates the control of remote relative chirality which can be achieved.'26 cyp -0lefinic esters 122 P. F. Hudrlik A. M. Hudrlik G. Nagendrappa T. Yimenu E. T. Zellers and E. Chin J. Am. Chem. Soc. 1980 102,6894. B. M. Trost and T. P. Klun J. Org. Chem. 1980,45,4256. lZ4 S. Raucher J. E. Macdonald and R. F. Lawrence Tetrahedron Lett. 1980,21,4335. lZ5 M. F. Salornon S. N. Pardo and R. G. Salomon J. Am. Chem. SOC.,1980,102 2473. S. Danishefsky R. L.Funk and J. F. Kerwin Jr. J. Am. Chem. SOC.,1980,102,6889; S. Danishefsky and K. Tsuzuki ibid. p. 6891. Synthetic Methods C0,Me 7-+ -v+ C0,Me Reagents i OC(CO,Et), at 180°C for 48h; ii KOH H20; iii HCI; iv NaIO, H20 C,H,N; v CH,N2; vi OC(CO,Et), SnCI, for 5 min at 0 "C Scheme 26 Reagents i toluene at 110OC; ii Bu,N+F- Scheme 27 unlike cup-olefinic ketones cannot be alkylated by allyl-silanes but very good yields of alkylated products are obtained in the reaction of allyl-silanes with ap-0lefinic acyl cyanides in the presence of titanium(1v) chloride;'*' the products can readily be transformed into esters and other acid derivatives by standard methods. Silver silicate was used to oxidize a lactol to a lactone after bromine water had proved unsatisfactory.12' Aldehydes and ketones react regiospecifically with metal- lated keten thioacetals to give products which can readily be converted into y-lactone~.'~~ The palladium-catalysed carbonylation of halogeno-alcohols is a very general route to lactones which is particularly useful for the preparation of ap-butenolides from (Z)-p-(hydroxymethy1)vinyl iodides. 130 Another route to ap-butenolides starts from ap-olefink aldehydes the 0-trimethylsilyl cyanohydrins of which are oxidized by pyridinium dichromate to give the lactones;131 the reaction is restricted to those cases where the p-position is disubstituted and there is a hydrogen at the y-position. The reaction of a Grignard reagent (which unlike lithium di-isopropylamide does not introduce an amine into the system) with an aa-diphenylsulphenylated lactone generates the magnesium enolate of the monosulphenylated lactone which can successfully be condensed with an aldehyde when prepared in this way (see Scheme 28).132 The bis-lactonization of unsaturated 0 OMgBr 0 SPh o*sph SPh '-0 3SPh __* ii,iii o* OH Reagents i EtMgBr Et20; ii MeCHO; iii H,O+ Scheme 28 lZ7 A.Jellal and M. Santelli Tetrahedron Lett. 1980 21 4487. 12' A. Pierdet L. Nedelec V. Delaroff and A. Allais Tetrahedron 1980,36 1763. lZ9 A. P.Kozikowski and Y.-Y. Chen J. Org. Chem. 1980,452236. 130 A. Cowell and J. K. Stille J. Am. Chem. SOC.,1980,102,4193. 13' E.J. Corey and G. Schmidt Tetrahedron Lett. 1980,21,731. 13' B.M.Trost and M. K. T. Mao Tetrahedron Lett.1980.21 3523. 280 R. Brettle Reagents i Bu,N'OH-; ii dry; iii Pb(OAc) (6-15equivalents) MeCN ?t 75-80"C Scheme 29 diacids that was reported last year can be controlled to produce efficient syn-addition of the two carbonyl groups to the double-bond (Scheme 29).133 Macrocyclic lactones containing a p-keto function for example diplodiolide A can be synthesized by using a modification of the Eschenmoser sulphide contraction (see Scheme 30) in which the bond that is being formed in the ring-closure step is actually a carbon-sulphur bond.134 Olefin metathesis has been used for the forma- tion of the carbon-carbon double-bond in the synthesis of olefinic macrocyclic lactones (see Scheme 31).13' A further method for the lactonization of w-hydroxy- acids uses the cyanuric chloride-triethylamine combination in acetone at room temperature.136 FrJrMe] ii,iii _3 (170 0 0 Reagents i Pr',NEt; ii (EtO),P; iii H,O' Scheme 30 Reagents i WC16 Me& in PhCl at 75"C; very high dilution Scheme 31 13 Alkylation A description of a simple preparation of lithium di-isopropylamide (LDA) which does not require an alkyl-lithium reagent has appeared and this should facilitate the many uses of LDA for example in the formation of en01ates.~~' Alkylation through tris(dialky1amino)sulphonium enolates has been in~estigated.'~~ The prob- lems with traces of water that are encountered with quaternary ammonium salts are avoided and as there is negligible interaction with the cation what is in effect a naked enolate anion is produced.An example of this methodology is shown in Scheme 32. Freeze-dried potassium fluoride shows enhanced catalytic activity over 13' E. J. Corey and A. W. Cross Tetrahedron Lett. 1980 21 1819. 134 R. E.Ireland and F. R. Brown Jr. J. Org. Chem. 1980,45 1868. D. Villemin Tefrahedron Left. 1980 21 1715. 136 K. Venkataraman and D. R. Wagle Tetrahedron Lett. 1980,21 1893. "'M. T.Reetz and W. F. Maier Liebigs Ann. Chem. 1980 1471. R. Noyori I. Nishida J. Sakata and M. Nishizawa J. Am. Chem. Soc. 1980 102 1223; R. Noyori I. Nishida and J. Sakata Tetrahedron Lett. 1980,21,2085. ''13 281 Synthetic Methods Scheme 32 other sources of fluoride ion in alkylation reactions; pentane-2,4-dione (15) for example undergoes C-alkylation at room temperat~re.'~~ Another simple system for the alkylation of p -dicarbonyl and related compounds uses potassium hydroxide in dimethyl sulphoxide that contains some trifluoromethanesulphonic acid; no special precautions to exclude water are necessary and elimination is not a problem with secondary halides.14' Bis(pentane-2,4-dionato)nickel is at least as good a catalyst as alkoxide for the Michael reaction;141 an interesting Knoevenagel-Michael reaction has been reported using this catalyst.(15) Trost has given full details of his work on inter- and intra-molecular allylic alkylation through the palladium-catalysed substitution of allylic carbo~ylates,~~~ and has reviewed the selectivity observed in such A review covering this and wider aspects of displacement reactions of allylic compounds has also appeared.144 A recent example,14' which illustrates the very high regio- and stereo- selectivity of these palladium-catalysed processes is shown in Scheme 33.In a new CHC0,Me OH OAc Reagents i Na[CH(CO2Me)SO2PhI;ii [Pd(PPh,),] Scheme 33 route to conjugated trienone~,~~~ an initial displacement of this type is followed by a palladium-catalysed elimination reaction (see Scheme 34). Scheme 34 shows the allylation of a sulphone-stabilized anion. Ally1 sulphones can themselves act as the allylating agent in this type of rea~fion,'~~ even though in the absence of catalysis by palladium the phenylsulphinyl group is not normally displaced as a leaving group.An example of this is given in Scheme 35. A modification of the Trost procedure permitting the use of lower temperatures has been reported and N. Ishikawa T. Kitazume and M. Nakabayashi Chem. Lett. 1980 1089. '*' R. A.W. Johnstone D. Tuli and M. E. Rose J. Chem. Res. (Sj,1980 283. 14' J. M. Nelson P. N. Howells G. C. DeLullo G. L. Landen and R. A. Henry J. Org. Chem. 1980 45 1246. B. M. Trost and T. R. Verhoeven J. Am. Chem. SOC.,1980,102,4730,4743. 143 B.M. Trost Acc. Chem. Res. 1980 13 385. R. M. Magid Tetrahedron 1980.36 1901. 14' J. P.Genet F. Piau and J. Ficini TetrahedronLett. 1980 21 3183. B.M. Trost N. R. Schmuff and M.J. Miller J. Am. Chem. Soc. 1980,102 5979. 282 R. Brettle S0,Ph i-iii @-0 0 Reagents i NaH; ii ,[Pd(PPhJ,]; iii DBU [Pd(PPh,),l OAc Scheme 34 Me0,C H2C S0,Ph Reagents i Na[CH(CO,Me),l; ii [Pd{(Ph2PCH2)2121 Scheme 35 successfully applied using the cyclopentadienyl anion as the n~cleophile.'~' Another modification uses stannyl enol ethers rather than the usual stable anions thus allowing the allylation of ketones.Simple enolates or enol silyl ethers were consider- ably less satisfactory but the tin derivatives led quite generally to monoallylation with toleration of a range of f~nctiona1ity.l~~ Regiospecific formation of a carbon-carbon bond at the y-position of allylic halides occurs when a-(thiomethyl)carbonyl compounds are used in a two-phase alkaline system (see Scheme 36).14' Electrophiles whether reactive halides or ' 'Me COR COR Reagents i MeSCH,COR; ii K2C03 Scheme 36 carbonyl compounds react regiospecifically at the a-position of the aluminium 'ate' complexes of heterosubstituted allylic carbanions; the uncomplexed carbanions may react at either the a-or the y-position depending on the heteroatom and the nature of the ele~trophile.'~' The use of enol and dienol silyl ethers leads to excellent regiospecificity in the Mannich reaction with Eschenmoser's and in ureidoalkylation using N-chloromethyl-N-methyl-urethanesin conjunction with titanium(1v) chloride.'52 14' J.C. Fiaud and J. L. Malleron Tetrahedron Lett. 1980 21,4437. B. M. Trost and E. Keinan Tetrahedron Lett. 1980,21,2591. 149 K. Ogura S. Furukawa and G-i. Tsuchihashi J. Am. Chem. SOC.,1980,102,2125.150 Y. Yamamoto H. Yatagai and K. Maruyama J. Org. Chem. 1980,45 195. 151 S. Danishefsky M. Prisbylla and B. Lipisko Tetrahedron Lett. 1980,21,805. S.Danishefsky A. Guingant and M.Prisbylla Tetrahedron Lett. 1980 21 2033. 14' Synthetic Methods 283 14 Ring Synthesis The Diels-Alder reaction continues to achieve new levels of sophistication par- ticularly in its intramolecular mode which has been reviewed.lS3 By using a bis-diene and a bis-dienophile in both of which the duplicated functional groups differ in reactivity a sequential reaction can occur in which first the more reactive diene reacts with the more reactive dienophile intermolecularly after which under altered conditions the remaining groups undergo an intramolecular reaction.''* The final product is tricyclic. An application in the reduced fluorenone system is shown in Scheme 37. It is not unknown for the diene component or the dienophile to be incorporated in a protected form from which the required group is liberated when the compound is heated to bring about the intramolecular cycloaddition. For example benzo[c]thiophen dioxide is a useful masked o -quinodimethane unit'" and acylnitroso-groups can be masked as their adducts with 9,lO-dimethyl- anthracene.ls6 Two new syntheses'" illustrate cases where both components of an intramolecular Diels-Alder addition are in masked forms (Scheme 38). The first R2 R2 R' ii 4 RQD2 R3 0 Reagents i CC14 at 78 "C;ii toluene at 240 "C Scheme 37 i,ii -Conditions i at 185 "C for 30 min; ii at 170-180 OC for 2.5 h in a sealed tube; iii at 370-390 "C in toluene Scheme 38 lS3 G.Brieger and J. N. Bennett Chem. Rev. 1980,80,63. lS4 G. A. Kraus and M. J. Taschner J. Am. Chem. SOC.,1980,102 1974. 155 K. C. Nicolaou W. E. Barnette and P. Ma J. Org. Chem. 1980 45 1463; W. Oppolzer and D. A. Roberts Helu. Chim. Acta 1980 63 1703; R. L. Funk and K. P. C. Vollhardt Chem. SOC.Rev. 1980,9,41. 156 G. E. Keck and D. G. Nickell J. Am. Chem. SOC.,1980 102 3632; G. E. Keck Tetrahedron Lett. 1978,4767. 157 A. Ichihara R. Kimura S. Yamada and S. Sakamura J. Am. Chem. SOC.,1980 102 6353; H. F. Schmitthenner and S. M. Weinreb I. Org. Chem. 1980,45 3372. 284 R. Brettle significant example of the effect of catalysis by a Lewis acid on an intramolecular Diels-Alder reaction has been reported acceleration of the rate and enhanced stereoselectivity were observed (Scheme 39).The use of phenyl vinyl sulphone as a dienophile has been investigated systematically; it reacts regiospecifically with unsymmetrical dienes and the sulphone group in the product permits a variety of further synthetic operation^.^'^ Me0,C Me0,C -0 +& H H Conditions no catalyst at 150 "C 60 parts 40 parts EtAICI, at 23 "C sole product Scheme 39 Reagents i Bu,SnH at 80 "C Scheme 40 The stereoselectivity of the ring-closure of substituted hex-5-enyl radicals has been studied (cf. Scheme 40) and the results with others have been generalized to provide some guidelines that are of predictive use.'6o The synthesis of (17) is an example of an ScN' reaction with its stringent geometrical requirements in which the nucleophile attacking the allylic MEM-ether is the radical anion that is produced by reduction of the ketone (16).161 The first example of addition of a cuprate to an enone together with intramolecular reaction of the resultant enolate with an ester group has been reported (Scheme 41).16' W.R. Roush and H. R. Gillis J. Org. Chem. 1980 45,4264. lS9 R.V.C. Carr and L. A. Paquette J. Am. Chem. SOC.,1980,102,853. A. L. J. Beckwith T. Lawrence and A. K. Serelis J. Chem. SOC. Chem. Commun. 1980 484; A. L. J. Beckwith C. J. Easton and A. K. Serelis ibid. p. 482. M. Bertrand P. Teisseire and G. Pelerin Tetrahedron Lett..1980 21 2051 2055. A. J. Pearson Tetrahedron Lett. 1980 21 3929. 16' Synthetic Methods Reagents i H2C=CH(CH,),Mgbr CuBr THF at -28 to -12 "C; ii aq. NHiCl Scheme 41 The cyclocarbonylation of unsaturated tosylates that was reported last year (see Annu. Rep. Prog. Chem. Sect. B. 1979,76,359)turns out to be exceptional since in general the method is only applicable to monosubstituted 01efins.l~~The intramolecular addition of sulphur ylides to ketones has been studied in detail by two groups,'64 and the limits of its applicability have been defined. Cyclic compounds can be prepared from triphenyl(phenyliminoviny1idene)phosphorane and keto- acids. The octalone synthesis shown in Scheme 42is an alternative to the Robinson annelation procedure with the advantage that none of the non-conjugated isomer is formed.165 A new alkyl-tin(1v)-mediated carbo-cyclization can be used to prepare spiro-ketones or bicyclic ketones from cup -0lefinic ketones.166 The requisite w -stannyl-substituted side-chain can easily be introduced using either electrophilic or nucleophilic methods of alkylation.The latter procedure is illustrated in Scheme 43.The intramolecular addition of the 1:2 complex of an cup-olefinic ketone with Ir(M>2 nl(M) iii,iv 00HO O ,c,o Ph,P CONHPh Reagents i Ph,$-C=C=NPh; ii EtOAc reflux; iii PhMe reflux; iv EtOH (to remove PhNCO) Scheme 42 Reagents i. Me,Sn(CH,),MgCl THF; ii H20 H2S04;iii TiCl,; iv HzO Scheme 43 ethylaluminium chloride to an alkene proceeds with high regio- and stereo- specificity as the example in Scheme 44 The palladium-catalysed intramolecular cyclization of /3 -keto-esters with allylic phenol ethers is particularly useful for the preparation of five-membered rings,'68 although six-membered rings can also be prepared by this method.An example of J. E. McMurry and A. Andrus Tetrahedron Lett. 1980 21,4687. 164 J. K. Crandall H. S. Magaha R. K. Widener and G. A. Thorp,Tetrahedron Lett. 1980,21,4807. 16' H.J. Bestmann G. Schade and G. Schmid Angew. Chem. Znr. Ed. Engl. 1980 19 822. 166 T. L.Macdonald and S. Mahalingam J. Am.Chem. SOC.,1980 102 2113. 16' B. B.Snider D. J. Rodini and J. van Straten J. Am. Chem. SOC.,1980,102 5872. 168 J. Tsuji Y. Kobayashi H. Kataoka and T. Takahashi Tetrahedron Lett.1980 21 1475 3393. 286 R. Brettle Reagents i EtAICl, CH,Cl, at 20 OC Scheme 44 ,OPh Reagents i [Pd(OAc),J Ph3P MeCN reflux Scheme 45 the preparation of a percursor for rings c and D of a steroid is shown in Scheme 45. Alkenyl-substituted /3 -dicarbonyl systems can be cyclized by phenylselenylating agents in which the counter-ion is non-nucleophilic. 169 Sometimes the products are carbocyclic but in other cases cyclization occurs via an enolic form and an oxygen heterocycle is produced; some of these can be rearranged by tin(1v) chloride to give carbocyclic products as in the palladium-catalysed reactions discussed earlier in this Report. An example of direct cyclization to a carbocyclic product is shown in Scheme 46.The product from the 1,4-addition of Me,AlSPh to an a@-olefinic 0 0 Ztiiii -SePh Reagents i PhSe'SbF,- CH,CI, at -78 "C; ii warm to 20 OC; iii NaHCO, H,O Scheme 46 SPh Reagents i Me,AlSPh; ii NaIO,; iii silica gel Scheme 41 ketone undergoes an aldol condensation with an aldehyde. An intramolecular example is shown in Scheme 47 together with its conversion into a desulphurised product. 170 An unusual three-carbon ring-expansion sequence171 has been applied in a short synthesis of muscone from dodecanone (see Scheme 48). 169 W. P. Jackson S. V. Ley and A. J. Whittle J. Chem. SOC.,Chem. Commun. 1980 1173. 170 A. Itoh S. Ozawa K. Oshima and H. Nozaki Tetrahedron Lett. 1980 21 361. 17' B. M. Trost and J. E. Vincent J. Am. Chem.SOC.,1980,102,5680. Synthetic Methods SiMe v,vi muscone t S0,Ph CH Reagents i Br,; ii PhS0,Na; iii,Me,Si&OMes ;iv Bu,N+F-; v H, Pd/C; vi NaHg Na,HPO Scheme 48