9 Aliphatic Compounds Part (ii) Other Aliphatic Compounds By R. S. WARD Department of Chemistry University College of Swansea Swansea SA2 8PP Many recent developments in aliphatic chemistry can be directly attributed either to the continued search for new synthetic methods or to attempts at rationalizing mechanistic or stereochemical principles. Consequently current research reflects a strong interest in the following topics (a) new and improved asymmetric syntheses of chiral compounds; (b) the development of new methods for preparing lactones; (c) investigations of reversed (umpolung)reactivity and equivalent reagents; (d) the generation and reactions of regiospecific enolates; (e) studies of the stereochemistry of reactions in organo-phosphorus compounds; (f) investigations of new reactions of organo-sulphur compounds.1 Amines and Imines The polyether antibiotic lasalocid produced by Streptomyces lusuliensis has been used to resolve racemic amines by fractional crystallization of their salts.' High enantioselectivity is observed ("/o R :S-90 :10) in cases where the asymmetric carbon atom is attached directly to the primary amino-group (e.g. 1,2). When the asymmetric centre is separated from the amino-group by a methylene group (e.g. 3,4) the efficiency of the resolution is reduced (YOR :S -25 :75) and the enan- tiomer in excess has the opposite configuration (cf. 1and 4). Many enzyme-catalysed reactions involve the oxidation or reduction of nitrogen containing compounds by NAD(P) or NAD(P)H. Model studies have shown that amines can be oxidized by pyridinium salts.2 Furthermore imines can be reduced by 1,4-dihydropyridine derivatives in the presence of metal complexes (Scheme l).3 ' J.W. Westley R. H. Evans and J. F. Blount J. Amer. Chern. Soc. 1977,99,6057. 'Y.Ohnishi Tetrahedron Letters 1977,2109. U.K.Pandit H. van Dam and J. B. Steevens Tetrahedron Letters 1977,913;see also R.A. Gase and U. K. Pandit J.C.S. Chem. Comm. 1977,480. 194 Aliphatic Compounds-Part (ii) Other A lipha tic Compounds ArCH=NR HH C0,Et EtOlcQCO2 Et Eto2cj-7J Me Me Me Me H Scheme 1 The metal-ion catalysed synthesis of a-amino-esters from a-keto-esters and amines in the presence of 1,4-dihydropyridines has also been rep~rted.~ These reactions can be regarded as models for the enzyme-catalysed interconversion of a-keto- and a-amino-acids.Indeed they serve to demonstrate the importance of electrophilic catalysis in NAD(P)H mediated reduction reactions. The anions derived from dialkylallylamines (5) are useful P-acyl carbanion equivalents.' With alkyl halides the y-substituted products (6) are formed while with aldehydes and ketones a mixture of the cyclized y-adduct (7) and the a-adduct (8) is obtained. The lithium reagent (9) gives approximately equal amounts of (7) and (8)while the analogous zinc reagent (10)gives mainly the a-adduct (8). (5) (9) M=Li (10) M=Zn The anions derived from N-nitrosoamines also react with electrophilic reagents (Scheme 2).6 The reactions are regio- and stereo-selective and can be used to effect Li E LiNPr; I E+ I R CH2R' -78°C R CHR'--+R CHR' '\ N / 'N/ 'N/ I I I NO NO NO Scheme 2 electrophilic substitution at the a-carbon atom of secondary amines.The anions derived from N-nitrosoallylamines undergo alkylation at the a-position but react K Nakamura A. Ohno and S. Oka Tetrahedron Letters 1977,4593. ' S. F. Martin and M. T. DuPriest Tetrahedron LRtrers 1977 3925. D. Seebach D. Enders and B. Renger Chem. Ber. 1977,110,1852;B. Renger H.-0. Kalinowski and D. Seebach ibid. 1866; D. Seebach D. Enders R. Dach and R. Pieter ibid. 1879; B. Renger and D. Seebach ibid. 2334. 196 R. S. Ward with aldehydes and ketones reversibly to give a mixture of 0-and y-substituted products.Although reactivity at the a-position is kinetically favoured the y- products are formed exclusively under conditions which favour thermodynamic control. The vinyloxycarbonyl group (VOC) has been shown to be a versatile protecting group for amino-compounds. Amino-acids can be easily converted into their N-VOC derivatives by treating them with vinyl chloroformate. The protecting group can be selectively removed by treatment with HCI HBr or bromine in dichloromethane followed by warming in alcohol. Since vinyl chloroformate also attacks tertiary amines it provides a method for selective dealkylation of tertiary amines (1 1+E).' i HCI HBr -izz-+ H A new procedure for the NN-dimethylation of primary amines involves the preparation and reduction of the bis(alkoxymethy1)amine [RN(CH20CH3)2],8 while N-alkylation of secondary amines by alcohols can be accomplished in high yields (94-98 "/o) in the presence of aluminium t-butoxide and Raney nickel.' The conversion of primary amines into esters (13 -P 14) can be carried out by treating Ph Ph 'h'fiPh I BF4-CHzR BF4-the amine with 2,4,6-triphenyl-pyrylium tetrafluoroborate to give a pyridinium salt which is then heated in vacuo with the sodium salt of a carboxylic acid." Secondary enamines (15) are thermodynamically unstable since they exist in equilibrium with the tautomeric imines (16).However secondary enamines can be prepared by partial methanolysis of organo-tin or magnesium salts of imines." R2 R2 H R2 H I M 1H I H (15) (16) R.A. Olofson Y. S. Yamamoto and D. J. Wancowicz Tetrahedron Letters 1977 1563; R. A. Olofson R. C. Schnur L. Bunes and J. P. Pepe ibid. 1567. H. Kapnang G. Charles B. L. Sondengam and J. Hentchoya Hemo Tetrahedron Letters 1977,3469. M. Botta F. De Anngelis and R. Nicoletti Synthesis 1977 722. '" U. Gruntz A. R. Katritzky D. H. Kenny M. C. Rezende and H. Sheikh J.C.S. Chem. Comm. 1977 701. " B. De Jeso and J.-C. Pommier J.C.S. Chem. Comm. 1977 565. Aliphatic Compounds-Part (ii) Other Aliphatic Compounds They are stable at -80°C but completely isomerize within one hour at room temperature. Optically active oxaziridines (18) can be prepared by oxidation of imines (17) with m-chloroperbenzoic acid in (S)-(+)-2,2,2-trifluoro-1-phenylethanol,’* or by photochemical rearrangement of nitrones (19)in the same chiral s01vent.l~ In both cases the enantioselectivity of the reaction is increased by lowering the tempera- ture.The optical yields obtained by both methods compare favourably with those obtained by oxidation of imines with chiral peroxyacids. In the case of an optically active imine (e.g. 20) the diastereoselectivity of the reaction is not dependent upon the nature or chirality of the peroxyacid or the solvent. Indeed the configuration of the major product depends only on the configuration of the starting imine. If the substituent has the R configuration attack from the Si face is referr red.'^ 0 m-CPBA * hu Ph,C=NR -PhzC-NR 7PhZC=N 7 CF3CHPhOH CF3CHPhOH ‘0’ ‘R (17) (18) (19) Ph H Ph H H H I&’ A/‘/ (20) (21) The enantioselective alkylation of the cyclohexanone imine (22) gives a product of high optical purity (81 YO)due to the presence of a suitably situated ether group which reduces the flexibility of the metallated intermediate (23).15 The alkylation of a chiral enamine of cyclohexanone gives a product of equally high optical purity (83 O/O).~’ (22) (231 The cycloaddition of chiral carbodi-imides to achiral ketenes provides an asym- metric synthesis of p-lactams while 173-dipolar cycloaddition of chiral nitrones to achiral alkenes affords optically active isoxazolines.l6 12 A. Forni I. Moretti and G. Torre J.C.S. Chem. Comm. 1977,731; M. Bucciarelli A. Forni I. Moretti and G. Torre J.C.S. Perkin II 1977 1339.13 D. R. Boyd and D. C. Neill J.C.S. Chem. Comm. 1977,51. 14 D. Mostowicz and C. Belzecki J. Org. Chem. 1977,42,3917. 15 J. K. Whitesell and M. A. Whitesell J. Org. Chem. 1977 42 377; J. K. Whitesell and S. W. Felman ibid. 1663. 16 C. Belzecki and Z. Krawczyk J.C.S. Chem. Comm. 1977 302; C. Belzecki and 1. Panfil ibid. 1977 303. 198 R. S. Ward 2 Nitriles and Isocyanides Achiral carbocations generated from racemic alcohols react with chiral nitriles to give a mixture of diastereoisomeric amides which can be hydrolysed to give optic- ally active amines (Scheme 3).17 1 R3R4H+CHOH Scheme 3 trans-p-(1-Pyrrolidiny1)acrylonitrilereacts with lithium di-isopropylamide at -105°C to give the P-metallated derivative but at higher temperatures the a-metallated derivative is formed (Scheme 4).'' Both vinyl-lithium reagents react with electrophiles with retention of the configuration of the double bond. Scheme 4 The thermal rearrangement of nitrile oxides (24) to isocyanates (25) is limited as a preparative method by competition from the dimerization reaction. However the rearrangements can be carried out in exceilent yields under mild conditions by using a suitable catalyst such as sulphur dioxide which participates in the reaction as a dip~larophile.'~ R-CN+O * *R-N=C=O (24) (25) 4so2 t " W. Tomasik and C. Belzecki J.C.S. Chern. Comm. 1977 86. R. R. Schmidt and J. Talbiersky Angew. Chem. Internat. Edn. 1977 16 853. l9 G. Trickes and H. Meier Angew.Chetn. Internat. Edn. 1977 16,555. Aliphatic Compounds-Part (ii) Other Aliphatic Compounds N-Acyl isocyanides (26) can be prepared by treating carboxylic acid iodides with silver cyanide.20 They react with ynamines to give adducts (27) and undergo cycloaddition to electron-deficient alkynes to give heterocyclic products (28). N-Imidoyl-isocyanides have also been prepared from N-phenyl-imidoyl bromides. Me PhCOMNEt2CN +# (27) RCOI AgCNb RCONC-(26) % PhYNhx N' N(COPh) (28) (X= ester) a-Metallated isocyanides undergo cycloaddition to polar double bonds and also act as synthons for a-metallated primary amines (Scheme 5).*' They contain a Scheme 5 nucleophilic centre (the metallated carbon atom) and an electrophilic centre (the isocyanide carbon atom) and therefore undergo cycloaddition with imines e-g.,to give 2-imidazolines.The reaction with alkyl halides leads to chain extension of the amine equivalent. The reactions of metallated alkenyl isocyanides with elec- trophiles and 2-isocyanoacrylic esters with carbanions have also been studied. 3 Nitro-compounds The powerful nucleophilic toluene p-thiolate anion can displace a nitro-group from simple unactivated primary and secondary nitroalkanes yielding alkyl p-tolyl sulphides apparently by a conventional SN2displacement process.22 Several methods for converting nitroalkanes into carbonyl compounds are available including the acid-catalysed hydrolysis of nitronate salts (Nef reaction). 2o G. HoRe and B. Lange Angew. Chem.Infernat. Edn. 1977,16,262 and 727. " U. Schollkopf Angew. Chem. Infernal. Edn. 1977 16 339; U. Schollkopf K.-W. Henneke K. Madawinata and R. Harms Annalen 1977,40; U. Schollkopf D. Stafforst and R. Jentsch ibid. 1167; U. Schollkopf and R. Meyer ibid. 1174; R. Meyer U. Schollkopf and P. Bohme ibid. 1183. '' M. Benn and A. C. M. Meesters J.CS. Chem. Comm. 1977,597. 200 R. S. Ward The oxidative cleavage of nitronate anions under very mild conditions using t- butylhydroperoxide and VO(acac) as catalyst affords a simple approach to the prostaglandin intermediate (29).23The nitro to carbonyl conversion can also be (EtO),CH (EtO),CH Q-CH(OE1) fiNO VO(acac)2 -A- NO2 0 (29) achieved using basic silica gel. The usefulness of silica both as a reaction medium and as a reagent is illustrated by the synthesis of dihydrojasmone (30) from n-he~tylamine.’~ /-/-/-wNH2 nc::a* ’ /-v-4-4N02 St02 I (30) mi-Nitro-compounds are oxidized to olefinic dimers by silver ions.For example tetramethyl 1,3,5-hexatriene- 1,1,6,6-tetracarboxylate(31) is obtained by heating the silver salt of dimethyl 3-aci-nitro-l-propene-l,l-dicarboxylate (32) in aceto- nitri~e,’~ X X X ).C-CH=NO,-Ag+ 4 )= CH-CH=CH-CH =( X X X (X = C0,Me) A total synthesis of the naturally occurring azoxyalkene ‘elaiomycin (33)has been dary nitroalkanes have been reported.26 The dianions are powerful carbon nucleophiles unlike the simple monoanions which undergo 0-alkylation. 4 Azo-and Diazo-compounds A total synthesis of the naturally occurring azoxyalkene elaiomycin (33) has been rep~rted.’~ The azoxy function is generated by nitrosation of the protected 23 P.A. Bartlett F. R.Green and T. R. Webb Tetrahedron Letters 1977 33 1. 24 E. Keinan and Y. Mazur .I. Org. Chem. 1977,42 844 and J. Amer. Chem. SOC.,1977,99 3861. 2s T. Severin I. Brautigarn and K.-H. Brautigarn Chem. Ber. 1977 110,1669. 26 D. Seebach R. Henning F. Lehr and J. Gonnerrnann Tetrahedron Letters 1977 1161. 27 R. A. Moss and M. Matsuo J. Amer. Chem. SOC.,1977,99 1643. Aliphatic Compounds-Part (ii) Other Aliphatic Compounds urethane (34) followed by cleavage with potassium t-butoxide and alkylation of the diazotate so formed. HWH CH,OMe n-C,H, ."=NW.CH3 0 '0H HH (33) (34) 1-Phenyl- 1,2-diaza-allyl-lithium (35) reacts with primary alkyl halides at N-1 to give formaldehyde alkylphenylhydrazones (36) and with aldehydes and ketones at C-3 to give a-hydroxyaldehyde phenylhydrazones (37).*' R Li+ \,N-N=CH N Me /N.\\.-+,-,CHZ Ph Ph/ \N/ ph N k O (36) OH (35) I PhNHNZCHCR (37) The copper-catalysed thermolysis of a-diazo-P-dicarbonyl compounds in the presence of enol ethers provides a useful approach to p-methylfurans and their methylenelactone equivalent^.^^ The reaction of enol ether (38) with dimethyl diazo-malonate for example in the presence of trimethoxyphosphine copper(r)iodide gives the diester (39) which on treatment with sodium hydride followed by lithium aluminium hydride and finally acid yields menthofuran (40).ii,i NaH LiAIH4 (%. iii H+ (40) 5 Alcohols and Ethers A comparison of the acidities of alcohols and thiols in DMSO reveals that replacing the hydroxy group by SH results in a 16-20 kcal/mol increase in the enthalpy of T. Kauffmann D. Berger B. Scheerer and A. Woltermann Chem. Ber. 1977,110 3034. 2y E. Wenkert M. E. Alonso B. L. Buckwalter and I(.J. Chou J. Amer. Chem SOC.,1977 99,4778. 202 R. S. Ward depr~tonation.~' However while the acidity order for alcohols in DMSO is MeOH >EtOH >i-PrOH >t-BuOH the acidity order for thiols shows no apparent trend. The reversal of the acidity order for alcohols relative to the gas-phase apparently results primarily from the effect of the alkyl substituent on the heat of solvation of the alkoxide anion.The increased bulk of the alkyl residue hinders solvation of the anion and destabilizes it relative to the alcohol. In water there is apparently a complete reversal of the acidity order for both alcohols and thiols relative to the gas-phase. The main factor responsible for the reversed acidity order for thiols is the entropy of ionization in aqueous Alcohols react with diphenylphosphoryl azide along with triphenylphosphine and diethyl azodicarboxylate to give azides in 60-90 yield.32 The reaction is stereospecific involving inversion of configuration but is sensitive to steric hindrance. Trimethylsilyl iodide converts alcohols into iodides (with inversion of onf figuration).^^ The latter reagent can also be used to cleave ethers and esters under neutral conditions.The oxidative cleavage of alkyl and cycloalkyl ethers to carbonyl compounds can be accomplished using nitronium tetrafluoroborate or iodine pen tafluoride. 34 The reactions of optically active (R 2) allylic alcohols with NN-dimethyl- formamide dimethyl acetal proceeds stereoselectively via a [2,3]-sigmatropic re- arrangement to give optically active (R,E) amides with 100% transfer of chirality (Scheme 6).3' Me H Me-(MrO)zCHNM? Me,NCO HH Scheme 6 The reactions of epoxides with the sodium salts of malonate esters afford a novel approach to a-methylene y-lactones. Bis(a-methylene y-lactones) can be pre- prepared by treating diketones with 2-(bromornethyl)a~rylate.~~ 6 Aldehydes and Ketones Complete kinetic stereoselectivity can be achieved in aldol condensations of pre-formed lithium enolates (Scheme 7).37The erythro :threo ratio equals the (2):(E) ratio under appropriate conditions.By using the lithium enolate derived from a ketone containing a large alkyl group (e.g. R =But) one can obtain exclusively the erythro aldol since such ketones yield only the (2)enolate on deprotonation. '(' E. M. Arnett and L. E. Small J. Amer. Chem. SOC.,1977,99,808. 31 J. E. Bartmess and R.T. McIver J. Amer. Chem. SOC.,1977,99 4163. 32 B. Lal B. N. Pramanik M. S. Manhas and A. K. Bose Tetrahedron Letters 1977 1977. 33 M. E. Jung and P. L. Ornstein Tetrahedron Letters 1977,2659; M. E. Jung and M. A. Lyster J. Amer. Chem. SOC.,1977,99,968;see also T.-L.Ho and G.A. Olah Synthesis 1977,417 and M. E. Jung and M. A. Lyster J. Org. Chem. 1977 42 3761. 34 T.-L.Ho and G. A. Olah J. Org. Chem. 1977,42,3097; G. A. Olah and J. Welch Synthesis 1977,419. 35 K. K. Chan and G. Saucy J. Org. Chem. 1977,42,3828. 36 H. Marschall F. Vogel and P. Weyerstahl Annalen 1977 1557; N. Bensel K.-D. Klinkmiiller H. Marschall and P. Weyerstahl ibid. 1572. " W. A. Kleschick C. T. Buse and C. H. Hcathcock J. Amer. Chem. SOC.,1977,99 247; C. T. Buse and C. H. Heathcock ibid.,8109. Alipha tic Cornpounds-Part (ii ) Other Alip ha tic Compounds 203 Scheme 7 The stereoselectivity of the reaction can however be completely reversed by using the tetra-alkylammonium enolate derived from the same ketone. The stereoselective condensation of the lithium enolate (R =But) with a chiral aldehyde yields only two of the four possible diastereo-isomeric products.As a preparation reaction the aldol condensation suffers from the disadvantage that self-condensation products and a@-unsaturated carbonyl compounds are invariably formed. The aldol condensation between enol silyl ethers and carbonyl compounds (e.g. 41 +42) in the presence of tetrabutyl ammonium fluoride 38 (or titanium tetra~hloride~~) proceeds in a regiospecific manner and gives only minor quantities of the usual by-products. The use of dimethyl(methylene)ammonium trifluoroacetate and the corresponding iodide to quench regiospecifically generated enoiates affords a convenient route via the Mannich intermediate (e.g.44) to a-methylene ketones esters and lac tone^.^' OSiMe PhCHO Bu4N+F-* OSiMe 0 eNMe2 (43) (44) It has been demonstrated that the intramolecular Condensation of 1$diketones can be directed to give either of the two possible products (45 and 46) depending upon whether conditions favouring kinetic or thermodynamic control are empl~yed.~' 38 R. Noyori K. Yokoyama J. Sakata I. Kuwajima E. Nakamura and M. Shimizu J. Amer. Chem Soc. 1977,99 1265. 39 T. Mukaiyama Angew. Chem. Internat. Edn. 1977,16 817. 40 N. L. Holy and Y. F. Wang J. Amer. Gem. Soc. 1977 99 944; J. L. Roberts P. S. Borromeo and C. D. Poulter Tetrahedron Letters 1977 1621. 41 M. Larcheveque G. Valette and T. Cuvigny Synthesis 1977,424. 204 R. S. Ward 0 0 @OH Me &OH CHzR (45) (44) A difficulty which frequently arises in the alkylation of P-dicarbonyl compounds is the concurrent formation of C-and O-alkylated products.In addition the attempted monoalkylation of P -dicarbonyl compounds often gives low yields due to competition from dialkylation and othcr base-catalysed reactions. Several attempts have been made to overcome these difficulties by shielding the oxygen atom by association with a metal cation or a hydrogen-bonding solvent. A new procedure which gives high yields of mono- C-alkylated products with no apparent O-alkylation or other side reactions involves the use of monosolvates of 6-dicar-bony1 compounds with tetra-alkylammonium The oxygen atom is shielded not only by the large cation but also by the enol hydroxy-fluoride bond.Furthermore the reactivity of the P-dicarbonyl compound is enhanced by transfer of electron density from the fluoride anion via the hydrogen bond. The overall result therefore is to shield the oxygen atom while at the same time increasing the effectiveness of the molecule as a nucleophile. An n.m.r. study has shown that the anions derived from aldehyde dimethyl- hydrazones are formed with substantial stereoselectivity and do not equilibrate under the conditions usually employed for alkylation and acylation reaction^.^^ However a study of the stereospecificity of deprotonation and alkylation of ketone dimethylhydrazones has revealed a large kinetic preference for formation of the anti-anion followed by isomerization to give the thermodynamically more stable syn -anion (Scheme 8).44 In the case of unsymmetrical ketone dimethylhydrazones a primary carbanion is formed in preference to a secondary one irrespective of the hydrazone stereochemistry but subsequently isomerizes (in the case of an anti- anion) to give the syn-anion.The enantioselective alkylation of a metallated chiral hydrazone forms the basis of an asymmetric synthesis of chiral aldehydes4’ Doubly unsaturated carbonyl compounds react with nucleophiles at C-5. However this reactivity can be reversed by using the dianion formed from the 42 J. H. Clark and J. M. Miller J.C.S. Chem. Comm. 1977 64 and J.C.S. Perkin I 1977 1743. 43 M. Newcomb and D. E. Bergbreiter J.C.S. Chem. Comm. 1977,486. 44 M. E. Jung and T.J. Shaw Tetrahedron Letters 1977 3305. 45 D. Enders and H. Eichenauer Tetrahedron ktters 1977 191. Aliphatic Compounds-Part (ii) Other Aliphatic Compounds 205 analogous y8-unsaturated carbonyl compound (Scheme 9).46 The configuration of the product depends.upon the'nature of the electrophile used. 0 LE Scheme 9 There is a continued interest in the asymmetric reduction of carbonyl groups. The homogeneous hydrogenation of a-keto-esters using rhodium compIexes of chiral diphosphines gives a-hydroxy-esters with an enantiomeric excess of 66-76%.*' The complex produced by treating lithium aluminium hydride with two equivalents of a chiral amino-alcohol reduces acetylenic ketones to give chiral acetylenic alcohols with an enantiomeric excess of 60-84 YO.4H 7 Carboxylic Acids Dynamic n.m.r.spectroscopy has been used to study C-S p-pv-bonding and conformational equilibria (47 S 48) of thioacetic acid.49 The high rotational bar- Me S Me S I H (47) (48) rier that is observed is taken as evidence for an appreciable contribution from charged resonance forms and indicates that C-S and C-N p-pn-bonding are of similar importance in thioacetic acid and acetamide. Contrary to the generally accepted explanation for the activation of thiol esters the available da'ta suggests that such conjugation is less important in acetic acid itself. Two new methods for converting carboxylic acids into thiol esters have been reported The first involves treating the acid with carbonyl di-imidazole (CDI) or carbonyl di- 1,2,4-triazole (CDT) to give an activated intermediate which is then treated with the thi01.~' The second involves treating the carboxylic acid with a tris(alky1thio)borane (Scheme The kinetics and activation parameters for lactonization of a whole series (n = 3-23) of o-bromoalkanoic acids BT(CH~)"-~CO~H with strong bases in 99 Oh aqueous dimethyl sulphoxide have now been The reactivities span six " M.Pohmakotr and D. Seebach Angew. Chem. Internat. Edn. 1977,16 320. ''I. Ojima T. Kogure and K. Achiwa J.C.S. Chem. Comm. 1977,428. 48 R. S. Brinkmeyer and V. M. Kapoor J. Amer. Chem. Soc. 1977,99,8339. 49 E. A. Noe J. Amer. Chem. SOC.,1977,99 2803. '' H.-J. Gais Angew. Chem. Internat. Edn. 1977 16 244. 51 A. Pelter T.E. Levitt K. Smith and A. Jones J.C.S. Perkin I 1977 1672. 52 C. Galli G. Illuminati L. Mandolini and P. Tamborra J. Amer. Chem. Soc. 1977 99,2591 206 R. S.Ward WR’b Scheme 10 powers of ten the most reactive compound being the one for n = 5 and the least reactive being the one for n = 8. Comparison of the enthalpies of activation for ring-closure with those for the corresponding intermolecular reactions provides a quantitative estimate of the strain energies accompanying ring-closure. The highest strains are experienced for n =3 and 8. The entropies of activation confirm Ruzicka’s hypothesis that the probability of mutual approach of the two ends of a bifunctional chain decreases as the length of the chain increases. The reactions of unsaturated carboxylic acids with phenyl selenenyl halides or benzene sulphenyl halides afford a mild lactonization procedure which has the added advantage that the versatile phenylselenenyl or phenylsulphenyl group is incorporated into the product (e.g.49 + 50).53The PhSe or PhS group can then be removed by reduction to give the saturated lactone or by oxidation followed by elimination to give the unsaturated lactone (51). 8 Esters and Lactones It has been found that the order of introducing aIkyl groups (by alkylation using lithium di-isopropylamide ) into esters containing highly hindered a-carbon atoms is crucial in determining the overall yield of product ~btained.’~ Thus the yields of i-Pr,EtCCO,Et obtained by two complementary routes are shown +,:<n Scheme 11.i-Pr,CHCO,Et -f$b i-PrCH,CO,Et FK i-Pr2EtCC02Et EtI i-PrCHEtC0,Et Scheme 11 This and a number of similar examples demonstrate that a higher overall yield is obtained when the more bulky group is introduced last which is the reverse of the situation observed in the alkylation of ketones using sodium amide. The low reactivity of hindered esters may be due to the inability of the ester to form an enolate ion or to the lack of reactivity of the enolate once formed. Even highly s3 K. C. Nicolaou and Z. Lysenko J. Amer. Chem. SOC.,1977,99 3185 and J.C.S. Chem. Comm. 1977 293; D. L. J. Clive and G. Chittattu ibid. 484. s4 J. A. MacPhee and J.-E. Dubois J.C.S. Perkin I 1977 694. Aliphatic Compounds-Purt (ii) Other Aliphatic Compounds hindered esters such as i-Pr,CC02Et can be prepared in good yield (68 “/o) when hexamethylphosphoramide is present during both the.enolization and alkylation steps of the reaction. Various procedures for the mild cleavage of esters and lactones are available (e.g trimethylsilyl iodide33). The base-catalysed hydrolysis of esters by anhydrous hydroxide ions (KOBu‘:H20,2 :1)affords a very effective method for hydrolysing hindered The reaction has been shown to involve 0-acyl cleavage. Alternatively the phenylselenide anion can be used. The latter reagent provides a useful method for converting lactones (e.g. 52) into o-vinyl carboxylic esters (54) via the o-phenylselenenyl derivative (53).56 0 SePh (52) (53) (54) The rapid developments being made in the area of asymmetric synthesis have increased the need for methods for measuring enantiomeric purities.A useful method for determining the enantiomeric purity of a chiral lactone involves treating the lactone with (-)-(2R 3R )-2,3-butanediol to give a mixture of diastereoiso- meric ortho esters which can be analysed by g.1.~~’ The Pd’ catalysed cyclization of ally1 acetates provides a useful method for synthesizing large ring compounds (e.g. macrolides) by carbon-carbon bond formation (e.g. 55 -B 56).58 The reactions of a-bromo-esters of w-hydroxy-aldehydes (e.g. 57) with activated zinc and diethylaluminium chloride can also be used to prepare p -hydroxy-lactones (58).5’ Ly((fH2jn 11 (PhsP)4PdLNaH ,h H 2 ) nC0,Me CHC02Me OAc I S0,Ph SOzPh (55) G; OH 0 Br (57) ” P.G. Gassman and W. N. Schenk J. Org. Chem. 1977,42,918. 56 R. M. Scarborough and A. B. Smith Tefruhedron Letters 1977,4361; D. Liotta W. Markiewin and H. Santiesteban ibid. 4365 and 4369. ” G. Saucy R. Borer and D. P. Trullinger J. Org. Chem. 1977,42 3206. 58 Y. Kitagawa A. Itoh S. Hashimoto H. Yamamoto and H. Nozaki J. Amer. Chem. SOC.,1977 99 3864; B. M. Trost and T. R. Verhoeven ibid. 3867. 59 K. Maruoka S. Hashimoto Y. Kitagawa H. Yamamoto. and H. Nozaki. J. Amer. Chem.SOC.,1977.99 7705. 208 R. S. Ward 9 Amides and Lactams The barrier to internal rotation about the central C-N bond of NN-dialkyl-thioamides is considerably higher than in NN-dialkylamides themselves presume- ably indicating a greater contribution from polar resonance structures in the former case.A linear correlation in fact exists between the activation energy for C-N bond rotation and the 15N chemical shift in NN-dimethylamino derivatives.60 The increased polarization of thioamides also facilitates deprotonation of the NH group in N-alkylthioamides and reduces the rate of protonation of thioamides relative to amides6' Relatively few reliable methods are available for the mono-N-alkylation of amides. It has however been shown that simple amide methylols (59) can be directly coupled with trialkylaluminium reagents to produce good yields of the N-alkyl compounds (60).62 R R R CH20 N I N I N I H CHzOH CH,R' (59) (60) An efficient method for converting primary amides into nitriles involves treating the amide with trifluoroacetic anhydride and ~yridine."~ Primary thioamides on the other hand can be converted into nitriles by treating them with diethyl azodicar- boxylate and triphenylpho~phine.'~ + The reactions of various amides with phosgeniminium salts (Cl,C=NMe,CI-) have been investigated.Dicarboxamides react to give dicyanines which can be hydrolysed to give bis-malonamides and react with hydrazine to give dipyrazoles.6' N-A1 kylamides also react with phosgeniminium salts to give intermediates which on treatment with strong bases yield ynamides. Diamides (and dinitriles) can be converted into thiono- and dithio-esters of dicarboxylic acids (Scheme 12).66 i Et30+BF4-S S Me2NCO(CH2),CONMe2 -EtOy(cH2)n-f ii H~S-CSHSN OEt Scheme 12 60 G.J. Martin J. P. Gouesnard J. Dorie C. Rabiller and M. L. Martin J. Amer. Chem. SOC.,1977,99 1381. 61 B. G. Cox and P. de Maria J.C.S. Perkin 11 1977 1385. 62 A.Basha and S. M. Weinreb Tetrahedron Letters 1977 1465. 63 F.Campagna A.Carotti and G. Casini Tetrahedron Letters 1977 1813. 64 M. D.Dowle J.C.S. Chem. Comm. 1977,220. 65 M. Huys-Francotte Z.Janousek and H. G. Viehe J. Chem. Research 1977 100; E. Goffin Y. Legrand and H. G.Viehe ibid. 105;see also H.G. Viehe Chem. and Ind. 1977 386. 66 R.Hoffmann and K. Hartke Annalen 1977 1743. Aliphatic Compounds-Part (ii) Other Aliphatic Compounds 10 Anhydrides and bides Bis(thioacy1) sulphides (61) can be prepared by treating aliphatic dithiocarboxylic acids with dicyclohexylcarbodi-imide.6' They can be used to prepare sterically hindered dithio-esters (62).Acyl-thioacyl sulphides have also been prepared by treating sodium or piperidinium dithiocarboxylates with acetyl chloride. DCC t-BuSNa RCS2H --+ R-C-S-C-R -R-C-SBU' II II II ss S (61) (62) Enolate anions derived from acid anhydrides can be prepared by treating the anhydride with a sterically hindered base such as lithium l,l-bis(trimethylsilyl)-3-methyl- l-butoxide.68 Such anions react with aldehydes to give p-carbomethoxy y-butyrolactones (Scheme 13). Scheme 13 It is possible to reduce 1,3,3-trisubstituted succinimides regiospecifically at the least hindered carbonyl group by using dib~rane.~~ This should be contrasted with the reduction of the same compounds by sodium borohydride which attacks the most hindered carbonyl group.The optically active succinimide (63)is reduced by sodium borohydride to give a mixture of the diastereo-isomeric hydroxy-lactams (64) which react with methyl diethylphosphonoacetate and sodium hydride in dimethoxyethane to give a mixture of diastereo-isomeric esters (65).70This reac- tion affords a useful asymmetric synthesis of piperidine derivatives. The nature of the solvent influences the diastereoselectivity of the reaction. 0 ti-NaBH4 (EtO)ZPCHCO*Me R R 0Qo-0 O R O H oO:H2c0*Me (631 (64) (65) [R= (S)-1-phenylethyl] 11 Phosphorus Compounds Phosphinothioic methanesulphonic anhydrides react with aluminium chloride to form complexes which can be decomposed by water or methanol to give phos- 67 S.Kato T. Takagi T. Katada and M. Mizuta Angew. Chem. Internat. Edn. 1977,16,786; S. Kato A. Hori T. Takagi and M. Mizuta ibid. 787; S. Kato K. Sugino M. Yamada T. Katada and M. Mizuta ibid. 879. 68 N. Minami and I. Kuwajima Tetrahedron Letters 1977 1423. 69 R. Suess Helv. Chim. Acta 1977,60 1650. 'O T. Wakabayashi and M. Saito Tetrahedron Letters 1977,93. 210 R. S. Ward phinothioic halides with retention of configuration at the phosphorus atom.71 The reaction affords a stereoselective synthesis of the phosphinothioic halides. The assignment of configuration to the product is achieved by correlation of its optical rotation with that of the halide obtained by treating the phosphinothioic acid with phosphorus pentachloride which is known to involve inversion of configuration (Scheme 14).t-Bu S t-Bu S '\\ // i. AIC13 '\\ P// P ii H20 Ph' \OS02Me Ph' \CI t-Bu S t-Bu C1 '\\ // PCIS '\\ / P ____+ P Scheme 14 A new synthesis of imidate esters of phosphorus from amidates has been used to prepare the chiral phosphinimidate (67) from (66).72 Me-\ /NHBu' Et30+ Me NHBu' Me,, put PFg-' '\\+/ KH P P ___ P Ph' \O Ph' 'OEt Ph' \OEt The acid-catalysed alcoholysis of a series of phosphinic amides containing different leaving groups has been studied. At low concentrations of HCl the reactions proceed with inversion of configuration but at higher concentrations retention becomes increasingly important and eventually exceeds inversion for (68) and (69).73At a given acid concentration the proportion of the reaction proceeding with retention of configuration depends on the nucleophilicity of the leaving group.Ph 0 Ph 0 (68) R=Ph (69) R = P-O~NC~H~ A stereospecific route to chiral OS-dialkylphosphoramidothioateshas been devised and their acid-catalysed alcoholysis Once again two competing reactions are evident one involving inversion of configuration and favoured by low 71 J. Michalski and Z. Skrzypczynski J.C.S. Chem. Comm. 1977,66. 72 K. E. DeBruin and L. L. Thomas J.CS. Chem. Comm. 1977,33. 73 M. J. P. Harger J.C.S. Perkin I 1977 2057. 74 C. R. Hall and T. D. Inch Tetrahedron Letters 1977 3761 and 3765.Aliphatic Compounds-Part (ii) Other Aliphatic Compounds 211 acid concentrations the other involving retention of configuration and unaffected by acid strength. 12 Sulphur Compounds Enolate anions react with allenic sulphonium. salts to give a variety of products (e.g 70 and 73).75 *3C-Labelling experiments have shown that formation of the furan (70) involves attack on the a,rather than the y-carbon atom in the cyclization step. The initial adducts (71) formed with monosubstituted malonic esters undergo proton abstraction by sodium ethoxide to form an ylide (72) which then undergoes a [2,3]sigmatropic rearrangement to give (73). In the case of unsubstituted malonic esters the ylide rearrangement is preceded by a [1,3]prototropic shift to give the conjugated tautomer.+ + NCCH2COPh MezSJ ,-'='HZ CH Me2SCH=C=CH2 -OEt OLL-CN Mee(C02Et)~ I 'H I OEt Ph (70) 4 + Me2S-CH-C=CH2 -OEt ~ I -+ MeSCH2CH2C=CH2 MeC(CO,Et) I MeC(C02Et) MeC(C02Et)2 (72) (73) The anions derived from alkylphenylsulphides react with electrophiles to give a-substituted product^.'^. The anions derived from allylphenylsulphides on the other hand react with electrophiles at either the a-position (with alkyl halides) or the y-position (with carbonyl corn pound^).^' Allylphenylsulphides also readily undergo a heat light or acid catalysed [1,3]rearrangement of the phenylthio group which further increases the variety of products which can be formed from such compounds. Selenium stabilized carbanions have also acquired a justifiable reputation as useful reagents for carbon-carbon bond formation.Phenyl-propargylselenide for example reacts with two equivalents of lithium di-iso- propylamide to give a dianion which reacts with electrophilic reagents at both the a-and y-positions (attack occurring first at the a-position) to give a disubstituted product (Scheme 15)." Oxidation of the selenide affords the corresponding selenoxide which readily undergoes rearrangement leading to a selenoenone. 0 2LiNh'a /Li i,E' PhSe-* -,80c+ PhSey+ ii E2* z phseP PhSe @,' Li E' H Scheme 15 75 B. S. Ellis G. Griffiths P. D. Howes C. J. M. Stirling and B. R. Fishwick J.C.S. Perkin I 1977,286; G. Griffiths P. D. Howes and C. J. M. Stirling ibid.912. '' T. M. Dolak and T. A. Bryson Tetrahedron Letters 1977 1961. 77 P. Brownbridge and S. Warren J.C.S. Perkin I 1977 1131. H. J. Reich and S. K. Shah J. Amer. Chem. SOC.,1977,99 263. 212 R. S. Ward The double deprotonation of ally1 thiols gives thiocarbonyl dianions which react with electrophiles preferentially at the y-position leading to cis-vinyl sulphides (Scheme 16).79 SLi E' SE2 SE2 qsH'92 + +El R R R R Scheme 16 A new asymmetric synthesis of P-hydroxy-esters (75) involves condensation of the chiral a -sulphinyl ester enolate anion (74) with achiral aldehydes or ketones.80 In a similar manner reaction of the anion (76) derived from a chiral sulphoxide with undecanal forms the basis of a stereospecific synthesis of (+)-disparlure (77) the female sex pheremone of the gypsy moth.81 OH OH 0 H / 'CHR -t-BuSO ,,' RH t *.-.-s R'CHO C'-R (4 steps) .. .- - -I t-Bu (77) R = Me2CH(CH2)4 R' = Me(CH2)9 The synthesis of diselenoacetals (78)affords a convenient route to vinyl selenides (79) which can in turn be converted into a-halogenoalkylselenides(80). The latter yield selenium stabilized carbanions on treatment with n-butyl-lithium.82 RSe SeR K' SeR R'R2CHCOR3 5R'R'CH-CR DMF \ /3 Me1 RZ)=(R3 +RSeMe H2S04 orZnC12 (78) (79) SeR SeR SeR 79 K.-H. Geiss D. Seebach arid B. Sewing Chem. Ber. 1977,110 1833. 8o C. Mioskowski and G. SolladiC J.CS. Chem. Comm. 1977 162. " D. G. Famum T. Veysoglu A. M. Cardt B. Duhl-Emswiler T.A. Pancoast T. J. Reitz and R. T. Cardk Tetrahedron Letters 1977,4009. '' M. Sevrin W. Dumont and A. Krief Tetrahedron Letters 1977 3835; W. Dumont and A. Krief Angew. Chern. Internat. Edn. 1977 16 540; W. Dumont M. Sevrin and A. Krief ibid. 541. Aliphatic Compounds-Part (ii) Other Aliphatic Compounds The preparation and reactions of a series of 0-alkyl selenoesters have also been 13 Halogen Compounds Two useful extensions of the well known Gabriel synthesis have been described which allow primary secondary and t-Boc amines to be prepared from alkyl halides. Thus diphenylphosphinic amide reacts with alkyl halides in the presence of a phase-transfer catalyst to give N-monoalkyl derivatives which can be con- verted into primary amines or treated with a second alkyl halide molecule (Scheme 17).84 The potassium salt of t-butyl methyl iminodicarboxylate undergoes smooth 0 0 0 It Rx II II Ph2PNH2 -Ph2PNHR Ph2PNRR' -+ RR'NH Scheme 17 N-alkylation to give derivatives which can be converted by treatment with alkali into t-Boc amine~.'~ The use of an insoluble polymer support as a monoblocking agent to prepare mono-protected derivatives of dicarboxylic acid halides has been reported.86 83 D.H. R. Barton P.-E. Hansen and K. Picker J.C.S. Perkin I 1977 1723. 84 A. Zwierzak and I. Podslawczynska Angew. Chem. Internst. Edn. 1977,16,702. J. D. Elliot and J. H. Jones J.C.S. Chem. Comm. 1977,758. C. C. Leznoff and J. M. Goldwasser Tetrahedron Letters 1977 1875; see also D. M. Dixit and C. C.Leznoff J. CS. Chem. Comm. 1977 798.