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Chapter 21. General methods

 

作者: W. B. Motherwell,  

 

期刊: Annual Reports Section "B" (Organic Chemistry)  (RSC Available online 1973)
卷期: Volume 70, issue 1  

页码: 657-695

 

ISSN:0069-3030

 

年代: 1973

 

DOI:10.1039/OC9737000657

 

出版商: RSC

 

数据来源: RSC

 

摘要:

21 General Methods By W. B. MOTHERWELL and J. S. ROBERTS Chemistry Department University of Stirling Stirling 1 Alkanes The anion derived from lithium triethylborohydride is an exceptionally potent nucleophile for displacement reactions with organic halides.’ Although tertiary halides react slowly and tend to give elimination products the corresponding alkanes are generally formed in excellent yield even from secondary cycloalkyl bromides and neopentyl systems which are normally highly resistant to sub- stitution. Studies with the readily prepared deuteriated analogue reveal that reaction occurs with clean stereochemical inversion. Masamune and his co- workers2 have also prepared a new hydride reagent by treatment of lithium trimethoxyaluminium hydride with cuprous iodide.Primary secondary tertiary allyl aryl vinyl and neopentyl bromides are all smoothly reduced to the hydro- carbons in very high yield at room temperature and primary and secondary mesylates also react. An unusual stereochemical dependence on substrate structure has however been uncovered by use of the deuteriated reagent. Thus in the 2-substituted norbornane series bromides are reduced with complete retention of configuration whereas the corresponding mesylates react with exclusive inversion. An excellent alternative to the Clemmensen method for the reduction of aryl ketones involves reaction with a trialkylsilane in trifluoroacetic acid.3 Nitriles undergo a reductive elimination of the cyano-group on treatment with alkali metals in HMPA.4 Full details have now been described for the ‘tandem alky- lation’ sequence in which treatment of an aromatic aldehyde or ketone with an organolithium reagent followed by lithium-ammonia reduction in the same vessel leads to the alkylated aromatic hydrocarbon in excellent yield.5 Pursuing their studies on organocopper chemistry Posner and his co-workers6 have now developed an efficient sequence for the conversion of an aldehyde carbonyl group into a tertiary alkyl carbon atom in which each of the three H.C. Brown and S. Krishnamurthy J. Amer. Chem. SOC. 1973,95 1669. ’ S. Masamune P. A. Rossy and G. S. Bates J. Amer. Chem. SOC.,1973 95 6452. C. T. West S. J. Donnelly D. A. Kooistra and M. P. Doyle J. Org. Chem. 1973,38 2675. T. Cuvigny M.Larcheveque and H. Normant Bull. SOC.chim. France 1973. 1174. S. S. Hall and S. D. Lipsky J. Org. Chem. 1973 38 1735. G. H. Posner and D. J. Brunelle Tetrahedron Letters 1973 935; J. Org. Chem. 1973 38 2747 ;J.C.S. Chem. Comm. 1973,907. 657 W. B. Motherwell and J. S. Roberts alkyl groups may be different (Scheme 1). Certain ketones can also be success-fully transformed. 0 II Reagents i Li '[ArSO,CHP(OR),] -; ii RiCuLi H + ;iii Na-Hg scheme 1 Phenolic hydroxy-groups in the form of their sulphonic esters can be reductively removed by catalytic hydrogenation with palladium-charcoal catalyst at mod- erate temperature and atmospheric pressure.' The cross-coupling reaction of secondary racemic Grignard reagents with aryl or unsaturated halides takes place stereospecifically in the presence of a chiral nickel complex ;although some isomerization occurs this reaction can be used to prepare optically active hydrocarbons.* The reductive coupling of aralkyl halides by bivalent vanadium complexes is unique in giving only the dimeric Wurtz prod~ct.~ The preparation of isotopically labelled aromatic substrates continues to generate interest.Perdeuteriated hydrocarbons can be conveniently prepared on a large scale either by using high temperatures and dilute acid conditions" or by employing a platinized short-fibre asbestos catalyst.' Deuterium oxide acts as the isotope source in both cases. A cautionary note on the use of organo-aluminium dihalide catalysts has been sounded.I2 Two pathways for the specific introduction of one deuterium atom are the replacement of the thallium residue in arylthallium ditrifluoroacetates with sodium borohydride in deuteriated ethanol,13 and the reduction of aryl halides with sodium borodeuteride and palladium ch10ride.l~ 2 Alkenes The Wittig reaction remains as an unchallenged cornerstone of organic synthesis not only serving in its own right but also providing inspiration for mechanistically ' K.Clauss and H. Jensen Angew. Chem. Internat. Edn. 1973 12 918. * G. Consiglio and C. Botteghi Helv. Chirn. Acta 1973 56 460. T. A. Cooper J. Amer. Chem. SOC.,1973,95,4158. lo N. H. Werstiuk and T. Kadai Canad. J. Chem. 1973 51 1485. G. Fischer and M. Puza Synthesis 1973 218. 'I J. L. Garnett M. A. Long R.F. W. Vining and T. Mole Tetrahedron Letters 1973 4075. l3 R. B. Herbert Tetrahedron Letters 1973 1375. '' T. R. Bosin M. G. Raymond and A. R. Buckpitt Tetrahedron Letters 1973 4699. General Metho& related procedures. A generally applicable method for the synthesis of substituted con-jugated cyclohexadienes has been reported independently by two groups' (Scheme2) thus extending an isolated observation by Buchi and Wuest.16 More- over the American group have shown that the use of an alicyclic enone offers a quick and convenient entry to anti-Bredt 01efins.l~ R1,)$ + Ph,P=O R2 Scheme 2 An interesting observation by Whitesides and his co-workers' relates to the use of iron-moderated carbonium ions as reagents for organic synthesis.These undergo reaction with nucleophiles as shown in Scheme 3. This approach is claimed to be especially useful for the preparation of cis-allylphosphonium salts and in conjunction with the deuteriated iron complex as a source of specifically labelled isoprene units for biosynthetic studies. A second group have also des- cribed the addition of nucleophiles to metal-activated olefins as a synthetically useful process.' 1iii Fe(CO),' + Reagents i Fe,(CO),; ii CO-HBF,-CF,CO,H; iii Nu-Scheme 3 The scope and utility of silylated reagents for olefin synthesis have been extended by the discovery that silyl-substituted carbanions of the type [(Me,Si),CH -,I -Is (a)W. G. Dauben D. J. Hart J. Ipaktschi and A. P. Kozikowski Tetrahedron Letters 1973,4425; (b)F.Bohlmann and C. Zdero Chem. Ber. 1973 106 3779. l6 G. Buchi and H. Wiiest Helo. Chim. Acta 1971 54 1767. " W. G. Dauben and J. Ipaktschi J. Amer. Chem. SOC.,1973,95 5088. T. H. Whitesides R. W. Arhart and R. W. Slaven J. Amer. Chem. SOC.,1973,95 5792. l9 A. Rosan M. Rosenblum and J. Tancrede J. Amer. Chem. SOC.,1973,95 3062. W.B. Motherwell and J. S. Roberts can be prepared by cleavage of a trimethylsilyl group from the compound [(Me,Si) +lCH -,I using sodium methoxide in HMPA.20 A sulphur analogue of the Wittig reaction involves treatment of the carbonyl compound with the carbanion derived from a t-butyl alkyl sulphoxide and reaction of the resultant /I-hydroxy-sulphoxide with N-bromo or N-chloro-succinimide to give a thermally labile B-sultine which decomposes to the olefin.21 This method is especially suited to the formation of trisubstituted olefins.P-Hydroxy- sulphoximines readily prepared by the reaction of a carbonyl compound with N-methylphenylsulphonimidoylmethyl-lithium,are also useful precursors for olefin synthesis since they undergo reductive elimination on treatment with aluminium amalgam followed by acetic acid.22 Other aspects of the chemistry of this important sulphoximine group have been concisely reviewed.23 A facile method for the conversion of a carbonyl into an exomethylene group involves sequential treatment with 3-pyrroline perchlorate diazomethane and n-butyl- lithium. The intermediate aziridinium ylide thus formed breaks down immediately to the ~lefin.~~ The ability of the sulphonyl grouping to stabilize an adjacent carbanion has been exploited by Julia and Paris2' in a new synthesis of tri- and tetra-substituted alkenes (Scheme 4) A complementary approach via up-unsaturated phenyl sulphones has also been described.26 S02Ph R S0,PhI OHI R lARz R( I I R2 R3 1ii (R'= H) S02Ph OR5 PhOzS)4R3 +-tR4 R' R2 R3 R2 'R4 Reagents i RSX;ii POCl,; iii M-Hg R5 = Ac Ms or Ts M = Na or A1 Scheme 4 Reagents for the direct deoxygenation of organic compounds continue to find application in olefin synthesis.A French group have shown that the THF complex of titanium trichloride reacts with magnesium under argon to give a H. Sakurai K. 1. Nishiwaki and M. Kira Tetrahedron Letters 1973 4193.21 F. Jung N. K. Sharma and T. Durst J. Amer. Chem. SOC.,1973.95 3420. 22 C. R. Johnson J. R. Shanklin and R. A. Kirchhoff J. Amer. Chem. Soc. 1973 95 6462. 23 C. R. Johnson Accounts Chem. Res. 1973,6 341. 24 Y. Hata and M. Watanabe J. Amer. Chem. SOC.,1973 95 8450. 25 M. Julia and J.-M. Paris Tetrahedron Letters 1973 4833. 26 (a) V. Pascali N. Tangari and A. Umani-Ronchi J.C.S. Perkin I 1973 1166; (b) V. Pascali and A. Umani-Ronchi J.C.S. Chem. Comm. 1973 351. General Methods lower-valent titanium species which has proved to be an excellent reagent for the intermolecular deoxygenation of carbonyl compounds to 01efins.~’ Unlike the lower-valent tungsten halides reported last year high yields of olefins can be obtained from both aliphatic and aromatic aldehydes and ketones.Thus acetone gives tetramethylethylene in 98 % yield ! The year under review has also witnessed the emergence of synthetically useful organoselenium reagents. Sharpless and his co-workers28 report that alkyl phenyl selenoxides eliminate under very mild conditions and triphenylphosphine selenide in trifluoroacetic acid is the reagent of choice for the preparation of olefins from epoxides with retention of stereochemistry. Conversions of the cyclohexanone -+cyclohexene type are normally carried out via reduction of an enolic derivative. Barton and his colleagues30 recommend reaction of the carbonyl group with toluene-a-thiol and subsequent desulphuri- sation with nickel boride. Iron pentacarbonyl selectively transforms enol acetates vinyl chlorides and a/?-unsaturated aldehydes into the corresponding olefins in modest yie1d.j However the reaction of a carbonyl compound with chlorotri- methylsilane and zinc in ether solution offers a new one-step method for transfor- mations of this type in preparatively useful yield.32 Bis-cyclo-octa- 1,5-(diene)nickel reacts with the thionocarbonates of vicinal diols to produce alkenes in an efficient and stereospecific manner.33 Methyltriphenoxyphosphonium iodide in HMPA is a mild reagent for the selective dehydration of secondary alcohols in the presence of tertiary with a high predominance of the more stable Saytzeff alkene.34 Further details have been published on the useful P-2 nickel catalyst which is remarkably sensitive to the steric environment of a double bond and reduces dienes and acetylenes with high ~electivity.~ In an elegant synthesis of /?-acorenol use has been made of the retro-ene reaction to transform an enone into a rearranged olefin (Scheme 5).36 C0,Et &O Me Me Reagents i MeLi; ii CICH,OMe I OMe Scheme 5 2’ S.Tyrlik and 1. Wolochowicz Bull. SOC.chim. France 1973 2147. 20 K. B. Sharpless M. W. Young and R. F. Lauer Tetrahedron Letters 1973 1979. 29 D. L. J. Clive and C. V. Denyer J.C.S. Chem. Comm. 1973,253. 30 R. B. Boar D. W. Hawkins J. F. McGhie and D. H. R. Barton J.C.S. Perkin I 1973 654. 31 S. J. Nelson G. Detre and M. Tanabe Tetrahedron Letters 1973 447. 32 W. B. Motherwell J.C.S. Chem. Comm. 1973 935. 33 M.F. Semmelhack and R:D. Stauffer Tetrahedron Letters 1973 2667. 34 R. 0.Hutchins M. G. Hutchins and C. A. Milewski J. Org. Chem. 1972 37 4190. 35 C. A. Brown and V. K. Ahuja J.C.S. Chem. Comm. 1973 553; J. Org. Chem. 1973 38 2226. 36 W. Oppolzer. Helv. Chim. Acta 1973 56 1812. 662 W.B. Motherwell and J. S. Roberts Synthetic challenges in the terpene field continue to stimulate the development of new methods for the stereospecific construction of highly functionalized olefins. Corey and Chen37 have found that the addition of organocopper re- agents to A2s4-dienoic esters results in a highly stereoselective 1,6addition to yield tri- and tetra-substituted olefins. Sigmatropic rearrangements of sulphur- containing intermediates have claimed the attention of several groups.Thus a new version of the dithioester thio-Claisen rearrangement provides a highly stereoselective synthesis of (E)-trisubstituted double bonds,38 and the [2,3] sigmatropic shift of a-substituted methylallylsulphonium ylides affords an entry to trans-trisubstituted 01efins.~’ Readily prepared ally1 sulphones undergo thermal rearrangement involving the transfer of an alkyl group from sulphur to carbon with simultaneous extrusion of sulphur dioxide.40 Evans and his co-w~rkers~~ have now described a remarkably stereoselective synthesis of trisubstituted allylic alcohols involving alkylation of sulphoxide-stabilized allylic anions (vinyl anion equivalents) followed by [2,3] sigmatropic shift and subsequent desulphurization. This clever scheme is unfortunately plagued by non-regioselec- tivity in the alkylation step.Normant and his co-~orkers~~ have also extended their work on the reactions of vinylcopper reagents to include a synthesis of stereospecifically trisubstituted allylic alcohols. A novel method for the conversion of epoxides into allylic alcohols which avoids the use of strong base has been developed (Scheme 6).43 A particularly striking and apparently general feature of this sequence is that in the decomposition of the P-hydroxy-selenoxide elimination occurs away from the hydroxy-group. An adaptation of the Julia- Johnson olefin synthesis has been used to prepare stereoselectively trisubstituted allylic alcohols in good yield.44 eL+ 0 ‘E‘ SePh 1 ii OH r OH f 1 Reagents i PhSe -;ii H 202 Scheme 6 37 E.J. Corey and R. H. K. Chen Tetrahedron Letters 1973 161 1. 38 H. Takahashi K. Oshima H. Yamamoto and H. Nozaki J. Amer. Chem. SOC.,1973 95 5803. For further extensions of this approach consult refs. 181 182. 39 P. A. Grieco D. Boxler and K. Hiroi J. Org. Chem. 1973 38 2572. 40 J. B. Hendrickson and R. Bergeron Tetrahedron Letters 1973 3609. 41 D. A. Evans G. C. Andrews T. T. Fujimoto and D. Wells Tetrahedron Letters 1973 1385 1389. 42 J. F. Normant G. Cahiez C. Chuit and J. Villieras Tetrahedron Letters 1973 2407. 43 K. B. Sharpless and R. F. Lauer J. Amer. Chem. SOC.,1973 95 2697. 44 H. Nakamura H. Yamamoto and H. H. Nozaki Tetrahedron Letters 1973. 11 1. General Methods The allylic epoxide (1) can be selectively opened either to the (2)-or (&isomer of the trisubstituted allylic alcohol (2) or to the homoallylic alcohol (3) by a judi- cious choice of reducing medium.4s A practical method for the stereospecific inversion of an acyclic di- or tri- substituted double bond has been developed by Vedejs and F~chs.~~ Conversion into the epoxide with retention of stereochemistry followed by ring opening with lithium diphenylphosphide and subsequent treatment with methyl iodide generates a phosphorus betaine which fragments to the alkene with overall inversion of stereochemistry.Organoboranes are also important intermediates in two stereospecific diene syntheses. Monochloroborane diethyl etherate reacts with alkynes to give isolable dialkenylchloroboranes which are readily converted into cis-trans-dienes by reaction with sodium hydroxide and iodine or into cis-olefins by protonoly- s~s.~~ trans-trans-Dienes can be prepared through the intermediacy of the novel organoborane (4) (Scheme 7).48 CIFR' R'C=CCl 4 H K"h H RZ (4) RZ"i LR\ R' ttB R' OMe Reagents i,+BH, -25 "C;ii R2C-CH; iii NaOMe 25 "C;iv Pr'C0,H Scheme 7 a-Mercaptoketones react with vinyltriphenylphosphonium bromide and base to give dihydrothiophens in varying yield.Oxidation to the sulphone and cheletropic fragmentation provides a regiospecific and stereospecific diene ~ynthesis.~' " R. S. Lenox and J. A. Katzenellenbogen J. Amer. Chem. SOC.,1973 95 957. 46 E. Vedejs and P. L.Fuchs J. Amer. Chem. SOC.,1973,95 822. 4' H. C. Brown and N. Ravindran J. Org. Chem. 1973.38 1617. 48 E.-I. Negishi and T. Yoshida J.C.S. Chem. Comm. 1973 606. 49 J. M. Mclntosh and H. B. Goodbrand Tetrahedron Letters 1973 3157. W. B. Motherwell and J. S. Roberts Olefins can be regenerated from their dibromides by treatment with sodium thiosulphate in DMSO.” 3 Alkynes and Allenes Trialkylalkynylborate anions formed by treatment of lithio-acetylides with trialkylboranes show promise of impressive synthetic utility. In the presence of iodine5’ or methanesulphinyl chloride” a primary or secondary alkyl group is transferred from boron to carbon yielding alkylacetylenes. Triarylboranes can also be employed in this reaction to give arylalkynes which are unobtainable by the more conventional alkylation sequence.Cuprous chloride in pyridine is an extremely efficient catalyst system for the oxidation of dihydrazones to acetylenes by molecular oxygen under very mild condition^.^ The base-induced reaction of certain non-enolizable carbonyl compounds with trimethylsilyldiazomethane or dimethylphosphonodiazomethaneprovides a simple one-step procedure for the preparation of the homologous alk~ne.’~ Diarylacetylenes can be obtained by the direct reaction of a,a-dichlorodibenzyl sulphides with triphenylphosphine and potassium t-butoxide.’ Stereospecific methods for the construction of cis-and trans-enyne units have been outlined by Corey and R~den.~~ Metallic reduction of the dibromoacetal (5) can be controlled to give either the allene (6) or the cyclopropanone acetal (7) on a preparatively useful scale.” Propargyl esters e.g.(8) can be smoothly rearranged by silver-ion catalysis to allenic esters e.g. (9).’* R’ R’ R2+C=C-R3 MR3 0-0-~4 R2 OCOR~ (8) (9) ” K. M. Ibne-Rasa A. R. Tahir and A. Rahman Chem. and Ind. 1973 232. 51 H. C. Brown J. A. Sinclair M. M. Midland A. Suzuki N. Miyaura S. Abiko and M. Itoh J. Amer. Chem. SOC. 1973 95 3080. ’’ M. Naruse K. Utimoto and H. Nozaki Tetrahedron Letters 1973 1847. Further uses of trialkylalkynylborate anions are cited in refs. 132 157 175 and 176. 53 J. Tsuji H. Takahashi and T. Kajimoto Tetrahedron Letters 1973 4573. 54 E. W. Colvin and B. J. Hamill J.C.S. Chem. Comm. 1973 151. ” R.H. Mitchell J.C.S. Chem. Comm. 1973,955. 56 E. J. Corey and R. A. Ruden Tetrahedron Letters 1973 1495. ’’ G. Giusti and C. Morales Bull. SOC.chim. France 1973 382. H. Schlossarczyk W. Sieber M. Hesse H.-J. Hansen and H. Schmid Hefu. Chim. Acta 1973 56 875. General Methods 665 a-Acetylenic epoxides are readily prepared and can be converted into a- allenic alcohols either by reaction with a dialkylcopperlithium reagents9 or by treatment with an organoborane in the presence of a small amount of oxygen.60 4 Alkyl Halides The reaction of a secondary alcohol with N-halogenosuccinimide in the presence of triphenylphosphine gives the corresponding halide under mild conditions with complete inversion of stereochemistry.6 Dimethylbromosulphonium bromide is a convenient reagent for the conversion of alcohols into bromides through a mainly inversion process.62 Alkyl iodides are obtained in good yield from primary and secondary alcohols by treatment of the tosylate with magnesium i~dide.~ The successful preparation of cycloalkyl iodides without elimination is particularly noteworthy.Yields in the Kochi decarboxylation of acids to tertiary chlorides are markedly improved by using N-chlorosuccinimide as the halogen source and DMF-acetic acid as the solvent.64 Thus for example l-chlorobicyclo[2,2,2]octanewas ob- tained from the bridgehead acid in 95 % yield. Extremely facile ionic chlorination of saturated hydrocarbons can be achieved without rearrangement by treatment with sulphuryl chloride in ~ulpholane.~~ Ultraviolet irradiation provides a smooth and mild conversion of polyhalo- genomethyl groups into di- or mono-halogenomethyls.66 Dialkylaminosulphur trifluorides react readily with acids or aldehydes and ketones to give acyl fluorides and gem-difluoro-compounds re~pectively.~ The reaction of dibromodifluoromethane with tris(dimethy1amino)phosphine in glyme provides a reagent for the conversion of a carbonyl group into a difluoro- exomethylene group.68 Phenyltrifluoromethylmercury69 and bromodi-fluoromethylphosphonium salts7' represent two new and very useful sources of difluorocarbene.A very simple and stereospecific route to trans-alkenylboronic acids from terminal alkynes involves hydroboration with catecholborane and subsequent hydroly~is.~~ The potential of these reagents lies in their complementary be- haviour towards halogens.Reaction with iodine in the presence of sodium hydroxide yields the trans-alkenyl iodide whereas treatment with bromine 59 P. R. Ortiz de Montellano J.C.S. Chem. Comm. 1973 709. 6o A. Suzuki N. Miyaura M. Itoh H. C. Brown and P. Jacob Synthesis 1973 305. 61 A. K. Bose and B. Lal Tetrahedron Letters 1973 3937. 62 N. Furukawa T. Inoue T. Aida and S. Oae J.C.S. Chem. Comm. 1973 212. 63 J. Gore P. Place and M. L. Roumestant J.C.S. Chem. Comm. 1973 821. 64 K. B. Becker M. Geisel C. A. Grob and F. Kuhnen Synthesis 1973 493. " I. Tabushi Z. Yoshida and Y. Tamaru Tetrahedron 1973 29 81. 66 N. Mitsuo T. Kunieda and T. Takizawa J. Org. Chem.1973 38 2255. 6' L. N. Markovskij V. E. Pashinnik and A. V. Kirsanov Synthesis 1973 787. 68 D. G. Naae and D. J. Burton Synthetic Comm. 1973,3 197. 69 D. Seyferth and S. P. Hopper J. Org. Chem. 1972 37 4070. 70 D. J. Burton and D. G. Naae J. Amer. Chem. SOC.,1973,95 8467. 71 H. C. Brown T. Hamaoka and N. Ravindran J. Amer. Chem. SOC.,1973 95 5786 6456. 666 W. B. Motherwell and J. S. Roberts involves inversion of configuration to give the cis-alkenyl bromide thus paving a way for the preparation of vinylorganometallics of known stereochemistry. Although many mechanistic questions remain to be settled Grob and Becker7* have defined experimental conditions which consistently lead to the predominant cis-or trans-addition of hydrogen chloride to olefins.5 Alcohols Polymethylhydrosiloxane in combination with bis(dibuty1acetoxy)tin oxide or palladium on charcoal has been introduced for the selective reduction of aldehydes and ketones under neutral condition^.^^ Potassium tri-isopropoxy- borohydride is a highly stereoselective reagent for the rapid reduction of ketones to the thermodynamically less stable epimer of the corresponding Halides esters amides nitriles and epoxides are inert. In HMPA at 25”C tetrabutylammonium cyanoborohydride is an exceptionally mild reagent which reduces only alkyl iodides and to a lesser extent bromides to the alkane. How- ever the addition of acid to the medium drastically alters the reducing ability and permits the selective reduction of aldehydes even in the presence of ketonic and iodo-group~.~’ Hydroboration-oxidation of alkenes with monochloroborane diethyletherate is claimed to give the anti-Markownikoff alcohols in 299.5 % isomeric purity thus exhibiting a stronger regiospecificity than borane itself.76 Aliphatic and aromatic carboxylic acids are rapidly and quantitatively reduced to the primary alcohols by borane in THF.77 Ester nitro- halogen nitrile and keto-groups are unaffected.An improved synthesis of secondary alcohols from terminal alkynes has been published (Scheme 8).78 B13 / RI-CECH J-B R’-CH,-CH \ lii B~ R~CH,-CH-R~ * R~CH,-CH-R~ I I OH H Reagents i ,2 moles; ii MeLi R’Br; iii NaOH-H,O 0 Me Me Scheme 8 ” K. B. Becker and C. A. Grob Synthesis 1973,789.73 J. Lipowitz and S. A. Bowman J. Org. Chem. 1973 38 162. 74 C. A. Brown S. Krishnamurthy and S. C. Kim J.C.S. Chem. Comm. 1973 391. ’’ R. 0.Hutchins and D. Kandasamy J. Amer. Chem. SOC.,1973,95,6131. ’‘ H. C. Brown and N. Ravindran J. Org. Chem. 1973 38 182. ’’ N. M. Yoon C. S. Pak H. C. Brown S. Krishnamurthy and T. P. Stocky J. Org. Chem. 1973,38 2786. 78 G. Zweifel. R. P. Fisher and A. Horng Synthesis. 1973 37. General Methods 667 The lithium-triethylcarboxide-inducedreaction of a,a-dichloromethyl methyl ether with a representative series of trialkylboranes is reported to give tertiary carbinols in very high yield at low temperat~re.~’ Improved procedures have been presented for the Prkvost reaction. Treatment of an alkene with a thallium carboxylate and iodine gives the trans-a-iodo- carboxylate in high yield which can be elaborated to the diol in standard fashion.” A second report claims that silver acetate is unnecessary and may be replaced by cupric or potassium acetate or even by acetic acid.81 A potentially more simple procedure is the oxidation of alkenes by iodine tristrifluoroacetate which gives the cis-esters of vicinal diols.82 A useful synthesis of 1,6diols involves ring opening of an epoxide with the anion derived from the reaction of a trialkylborane with a vinyl-lithium com- pound followed by oxidative work-~p.~~ The ortho-nitrobenzoate grouping is useful for the protection of alcohols and Regeneration by intramolecular displacement of the alcohol occurs on treatment with zinc dust and ammonium chloride.Corey and Suggs8’ have recommended the use of the allyloxycarbonyl group for the protection of hydroxy- and amino-functions. 6 Ethers The transition-metal-catalysed epoxidation of allylic and homoallylic alcohols by tertiary butyl hypochlorite is a highly regio- and stereo-selective process.86 An improved method for the preparation of epoxides from highly hindered ketones involves formation of a P-hydroxy-sulphide with phenylthiomethyl- lithium followed by alkylation at sulphur and subsequent base treatment.87 (NN-dialky1amino)dimethyloxosulphoniumfluoroborate has been recommended as a nucleophilic methylene-transfer reagent.88 A stereospecific method for the formation of cis- and trans-epoxides from the benzylidene acetal of the same diol has been outlined (Scheme 9).89 The photolysis of $-unsaturated nitrite esters provides a useful method for the preparation of functionalized tetrahydrofuran system^.'^ A new furan 79 (a) H.C. Brown and B. A. Carlson J. Org. Chem. 1973 38 2422; (6) H. C. Brown J.-J. Katz and B. A. Carlson ibid. p. 3968. R. C. Cambie R. C. Hayward J. L. Roberts and P. S. Rutledge J.C.S. Chem. Comm. 1973 359. ” L. Mangoni M. Adinolfi G. Barone and M. Parrilli Tetrahedron Letters 1973 4485. ” J. Buddrus. Angew. Chem. Internat. Edn. 1973 12 163. 83 K. Utimoto K. Uchida and H. Nozaki Tetrahedron Letters 1973 4527. 84 D. H. R. Barton I. H. Coates and P. G. Sammes J.C.S. Perkin I 1973 599. E. J. Corey and J. W. Suggs J. Org. Chem.1973 38 3223 3224. 86 K. B. Sharpless and R. C. Michaelson J. Amer. Chem. SOC.,1973 95 6136. 87 J. R. Shanklin C. R. Johnson J. Ollinger and R. M. Coates J. Amer. Chem. SOC. 1973.95 3428. 88 C. R. Johnson and P. E. Rogers J. Org. Chem. 1973,38 1793. 89 D. A. Seeley and J. McElwee J. Org. ChPm. 1973 38 1691. 90 (a) M. P. Bertrand and J. M. Surzur Bull. SOC.chim. France 1973,2393; (6)R. Nouguier and J. M. Surzur ibid. p. 2399. W. B. Motherwell and J. S. Roberts OTs " i. ii iii Me -+ Me$Me Me Me H Mex'i('h Br Ph meso OY Ph 1ivO \ 1 O 0Y iv1 Me\? Reagents i NBS-H,O; ii TsCl; iii NBS-CCI,; iv base; v H,O; vi Br- Scheme 9 synthesis involves the oxa-analogue of the well-known vinylcyclopropane rearrangement (Scheme Q-H R' R2 R' R2 Reagents i Me,i-CH,; ii HgSO Scheme 10 Sodium hydride in THF at room temperature has been described as a reagent for the methylation of even highly hindered phenols.92 A convenient new route to alkyl hydroperoxides in excellent yield utilizes treatment of an alkyldichloroborane with oxygen and subsequent hydroly~is.~~ Cyclic disulphides can be prepared in high yield by sulphur treatment of lead dithiolates which are obtained by the almost instantaneous reaction of an a,o-dithiol and lead acetate in aqueous solution.94 91 M.E. Garst and T. A. Spencer J. Amer. Chem. SOC.,1973,95 250. 92 B. A. Stoochnoff and N. L. Benoiton Tetrahedron Letters 1973 21. 93 M. M. Midland and H. C. Brown J. Amer. Chem. SOC.,1973,95 4069.94 R. H. Cragg and A. F. Weston. Tetrahedron Letters 1973 655. General Methods 669 Additional reagents for the deoxygenation of sulphoxides to sulphides include acetyl chloride,g5 titanium tri~hloride,~~ and dichl~roborane.~' Di-isobutyl- aluminium hydride may prove to be a most efficacious reagent for the preparation of sulphides from sulph~nes.~~ 7 Amines Alkyldichloroboranes are even more reactive than their monohalogeno counter- parts and react with azides to give secondary amines in virtually quantitative yield with retention of stereo~hemistry.~~ Full details have been published of the rapid and quantitative reduction of primary secondary and tertiary amides of both aliphatic and aromatic carboxylic acids to the corresponding amine by excess diborane."' No products arising from cleavage of the amide linkage were detected.Secondary amides can be selectively cleaved in the presence of tertiary by using a diphenyldialkoxysulphurane followed by reduction of the sulphilimine to the free amine.'" The copper or palladium salts of aromatic acids react with ammonia under pressure to give aniline derivatives by exclusive ortho-attack and decarboxylation.' O2 Another modification of the Clarke-Eschweiler method for the methylation of primary and secondary amines involves reaction in methanol solution with a large excess of formaldehyde and subsequent borohydride reduction.' O3 A very good method for the monomethylation of aromatic amines in the presence of ester amide or nitrile functions involves prior formation of the N-aryl- aminomethylsuccinimide and then cleavage with sodium borohydride in DMS0.'04 Further studies on the use of triflamides for the monoalkylation and protection of amines have been detailed."' The addition of chlorosulphonyl isocyanate to a hexane solution of a tertiary alcohol provides an exceptionally simple route to the chlorosulphonyl amine and hence to the amine itself.'06 The procedure is also successful for other alcohols which can form moderately stable carbonium ions.The ene-reaction of protected diallylamines e.g. (lo),is a very useful method for the preparation of functionalized pyrrolidines e.g.(11) O7 Corey and Snider'08 have also used an aza-ene reaction of 4-phenyl- 1,2,4-triazoline-3,5-dione in the elaboration of the cyclohexene (12) to the prostanoid precursor (13).'' T. Numata and S. Oae Chem. and Ind. 1973 277. 96 T. L. Ho and C. M. Wong Synthesis 1973 206; S.vnthetic Comm. 1973 3 37. 97 H. C. Brown and N. Ravindran Synthesis 1973 42. 98 J. N. Gardner S. Kaiser A. Krubiner and H. Lucas Canad. J. Chem. 1973 51 1419. 99 H. C. Brown M. M. Midland and A. B. Levy J. Amer. Chem. Sor. 1973,95 2394. loo H. C. Brown and P. Heim J. Org. Chem. 1973,38 912. lo' J. A. Franz and J. C. Martin J. Amer. Chem. SOC. 1973 95 2017. Io2 G. G. Arzoumanidis and F. C. Rauch J.C.S. Chem. Comm. 1973 666. Io3 B. L. Sondengam J. H. Hemo and G. Charles Tetrahedron Letters 1973 261. Io4 S. B. Kadin J. Org. Chem. 1973,38. 1348. I"' (a)J. B. Hendrickson and R.Bergeron Tetrahedron Letters 1973 3839 4607 (b).I.B. Hendrickson R. Bergeron A. Giga and D. Sternbach J. Amer. Chem. Sor. 1973,95 3412. Io6 J. B. Hendrickson and I. Joffee J. Amer. Chem. Sor. 1973,95 4083. Io7 W. Oppolzer E. Pfenninger and K. Keller ffelu. Chim. Acta 1973 56 1807. lo* E. J. Corey and B. B. Snider Tetrahedron Letters 1973 3091. W.B. Motherwell and J. S. Roberts (13) Very good yields are obtained for the reduction of aromatic nitro-compounds to amines by using sodium borohydride dihalogenobis(tripheny1phosphine)-nickel(rr).'O9 Tri-iron dodecacarbonyl and methanol shows promise as a syn- thetically useful reagent for the reduction of the carbon-nitrogen double bond.' ' The Friedel-Crafts alkylation of anilines is often beset with experimental difficulty.In an extended investigation Gassmann and his colleagues" ' have shown that the azasulphonium salt (14) gives rise to an ylide which undergoes intramolecular ortho-alkylation to afford the thioether (15). Subsequent de- sulphurization yields the alkyl derivative. Two distinct routes are now available to these important salt precursors and simple modifications have led to the development of new indole and oxindole syntheses. Several additional methods are now available for the dequaternization of ammonium salts.' ' In particular the exceptional nucleophilic displacement ability of lithium n-propyl mercaptide in HMPA provides a mild and rapid method for the dealkylation of aromatic and aliphatic quaternary ammonium salts.Moreover this reagent displays a superior selectivity for the removal of methyl groups and hence paves the way for a general synthesis of tertiary amines.' ' On the other side of thecoin ethylene oxide has been found to facilitate the quater- nization of sterically hindered amines.' l4 Io9 K. Hanaya N. Fujita and H. Kudo Chem. and Ind. 1973 794. lo H. Alper J. Org. Chem. 1972 37 3972. 'I' P. G. Gassmann and T. J. van Bergen J. Amer. Chem. Soc. 1973 95 590 591 2718; P. G. Gassmann T. J. van Bergen and G. Gruetzmacher ibid.,p. 6508. 'Iz (a)T. L. Ho Synthetic Comm. 1973 3 99; (b) S. Gerszberg R. T. Gaona H. Lopez and J. Comin Tetrahedron Letters 1973 1269; (c) D. Aumann and L. W. Deady J.C.S. Chem. Comm. 1973 32. 'I3 R. 0.Hutchins and F.J. Dux J. Org. Chem. 1973 38 1961. A. Donetti and E. Bellora Tetrahedron Letters 1973 3573. General Methods 671 The vast array of new methods for protection of the amino-function have been the subject of a useful review.'15 Two reports describe the use of the iso- bornyloxycarbonyl group,' l6 and the ortho-nitrobenzoyl group is also useful for peptide synthesis.' ' An interesting example of tertiary amine protection during phenolic oxidative coupling involved use of the borane complex.' '' 8 Aldehydes and Ketones The specific oxidation of primary alcohols can be achieved in high yield with the commercially available chromium trioxide intercalated in graphite.' Dimethyl sulphide can be replaced by dirnethyl sulphoxide in the Corey-Kim oxidation of alcohols;'20 the only drawback to this modification is that chlorination of double bonds is a competing process.The same disadvantage is experienced in the use of the iodobenzene dichloride-pyridine oxidant.I2' The interesting observation has been made' 22 that sterically hindered secondary alcohols can be oxidized in the presence of DDQ ;unhindered alcohols e.g. cyclohexanol and cyclopentanol are recovered unchanged. High-yield oxidations of primary and secondary alcohols can be achieved with the chromium trioxide-3,Sdirnethyl- pyrazole complex.'23 Trityl ethers can be converted into aldehydes or ketones by disproportionation in the presence of catalytic quantities of salts of the tri- phenylmethyl cation.' 24 Dehalogenation of a-halogeno-ketones can be readily accomplished with titanium trichloride.' 25 Mild hydrolytic conditions using titanium tetrachloride have also been found for the conversion of vinyl chlorides' 26 and vinyl sulphides' into ketones.Grignard reagents react cleanly with S-(2-pyridyl)thioates (16) to give ketones in high yield.'28 The absence of tertiary alcohols can be rationa- lized in terms of the slow reaction of the Grignard reagent with the co-ordinated 'Is L. A. Carpino Accounts Chem. Res. 1973,6 191. I' (a)G. Jager and R. Geiger Annafen 1973 1535; (bJM. Fujino T. Fukuda S. Kobayashi and M. Obayashi Chem. and Pharm. Bull. (Japan) 1973,21 87. 'I7 A. K. Koul J. M. Bachhawat B. Prashad N. S. Ramegowda A. K. Mathur and N. K. Mathur Tetrahedron 1973 29 625. I M.A. Schwartz B. F. Rose and B. Vishnuvajjala J. Amer. Chem. Soc. 1973,95 612. I19 J.-M. Lalancette G. Rollin. and P. Dumas Canad. J. Chem. 1972 50 3058. 120 E. J. Corey and C. U.Kim Tetrahedron Letters 1973 919. J. Wicha A. Zarecki and M. Kocor Tetrahedron Letters 1973 3635. 122 J. Iwamura and N. Hirao Tetrahedron Letters 1973 2447. 123 E. J. Corey and G. W. J. Fleet Tetrahedron Letters 1973 4499. M. P. Doyle D. J. DeBruyn and D. J. Scholten J. Org. Chem. 1973 38 625. 125 T.-L. Ho and C. M. Wong Synthetic Comm. 1973,3 237. 126 T. Mukaiyama T. Imamoto and S. Kobayashi Chem. Letters 1973 715. T. Mukaiyama K. Kamio S.Kobayashi and H. Takei Bull. Chem. SOC.Japan; 1972 45 3723. 12* T. Mukaiyama. M. Araki and H. Takei J. Amer. Chem. SOC.,1973 95 4763.672 W. B. Motherwell and J. S. Roberts Yamamoto et ~1.'~~ have found that s-butyl-lithium in HMPA-THF is an efficient base for the generation of 1-(alky1thio)vinyl-lithium (18) which as was reported earlier by Corey and Seebach is an acyl anion synthon of considerable importance. A good method for converting a ketone into its methyl ketone analogue which is superior to the Wittig reaction involving a-methoxyethyli- denetriphenylphosphorane has been reported (Scheme 1l).' 30 Li OH .CO,H 0-c //O I II II MeCC0,Li R'C-COMe R'C-COMe I II II OMe R2 Me R2 Me 111 1 R' R' \ No lv \ /OMe CH-C + c=c / /\ R2 'Me R2 Me Reagents i R'R2CO; ii PhS0,Cl-py; iii heat K,CO,; iv H,O' Scheme 11 Both methyl-and phenyl-methoxycarbenepentacarbonyltungsten(o) react with diazoalkanes to form enol ethers in high ~ie1d.l~' A useful route to substituted ketones involves the alkylation or protonation of trialkylalkynylborate salts (19) followed by oxidation (Scheme 12)' 32 Over the past four years Meyers and his co-workers have amply demonstrated the tremendous versatility of 5,6-dihydro-l,3-oxazinesin the syntheses of a large array of aldehydes and ketones and functionalized derivatives thereof.Much of this elegant research has now been reported in and reviewed.'34 R' -I R:B + LiCECR2 + RiBCrCR' Li' RiBC=CRZR3 1 R C -CHR2 R3 II 0 Reagents i R3X (R3 = alkyl allyl or H); ii H,02-OH Scheme I2 K. Oshima K. Shimoji H. Takahashi H. Yamamoto and H. Nozaki J. Amer. Chem. SOC.,1973 95 2694.I3O G. Caron and J. Lessard Canad. J. Chem. 1973.51 981. 131 C. P. Casey S. H. Bertz and T. J. Burkhardt. Tetrahedron Letters 1973 1421. 13' A. Pelter C. R.Harrison and D. Kirkpatrick J.C.S.Chem. Comm. 1973 544. 33 A. I. Meyers and E. M. Smith J. Org. Chem. 1972,37,4289; A. I. Meyers A. Nabeya H. W. Adickes I. R. Politzer G. R. Malone A. C. Kovelesky R. L. Nolen and R.C. Portnoy ibid. 1973 38 36; A. I. Meyers E. M. Smith and M. S. Ao ibid. p. 2129; A. I. Meyers A. C. Kovelesky and A. F. Jurjevich ibid. p. 2 136. 134 E. W. Collington Chem. andhi. 1973 987. General Methods A new synthesis of ketones from olefins involves the reaction of dialkyl- borinates (available from dialkylchloroboranes) with a,a-dichloromethyl methyl ether in the presence of lithium triethylcarboxide followed by basic oxidation of the intermediate (20) (Scheme 13).13' B-Alkyl-3,5-dimethylborinans(21) react with aa-unsaturated enones by conjugate transfer of the alkyl group to give substituted ketones.'36 R:BOR2 + C1,CHOMe + LiOCEt -+ RiCB,OMe R:C=O I\ C1 OR2 Reagents i H,O,-OH (20) ~ Scheme 13 Acid chlorides can be converted into ketones with alkylrhodium(1) complexes (22)(Scheme 14).137The benefits of this route are that the initial chlororhodium(1) complex is recycled in the synthesis and the complex (22) is unreactive towards aldehydes esters and nitriles.Further synthetic interest in bis(methy1thio)- cyclopropanes is witnessed by their conversion into ketones with aqueous trifluoroacetic acid e.g.the obtention ofcycloheptanone in 90%yield from(23).' " Rh'CI(CO)(Ph,P) + RIM -+ MCI + [Rh'R'(CO)(Ph,P),] (22) '1 Rh'CI(CO)(Ph,P) + R'CR2 + [Rhll'R'(CI)(RZCO)(CO)(Ph,P)z] II 0 Reagents i R'COCI M = Li or MgX Scheme 14 cis-1,2-Diols and conformationally mobile trans-1 ,Zdiols can be cleanly cleaved into dicarbonyl compounds by activated manganese dioxide.' 39 B.A. Carlson and H. C. Brown J. Amer. Chem. SOC.,1973,95 6876. 13' E. Negishi and H. C. Brown J. Amer. Chem. Soc. 1973 95 6757. 137 L. S. Hegedus S. M. Lo and D. E. Bloss J. Amer. Chem. SOC.,1973. 95 3040. 138 D. Seebach M. Braun and N. Du Preez Tetrahedron Letters 1973 3509. G. Ohloff and W. Giersch Angew. Chem. Internat. Edn. 1973 12 401. W.B. Motherwell and J.S. Roberts Useful experimental modifications for acetal formation and hydrolysis are contained in a paper by Andersen and Uh.14' New carbonyl-protecting groups include mono- and di-2,2,2-trichloroethyl acetals (24 ;X = OEt or OCH2CC13)141 and bromomethylmethylene acetals (29.' 42 Regeneration of the carbonyl compound from these two derivatives involves reductive cleavage with activated zinc in ethyl acetate (or THF) and methanol respectively. Ketones can also be protected against a range of hydrolytic reductive and oxidative reagents via the oxime (26) from which the parent carbonyl compound can be regenerated by suitable hydrolysis condition^.'^^ In addition to the numerous reports last year concerning the dethioacetalization of 1,3-dithiolans and 1,3-dithians further work reveals that sulphuric acid,' 44 0-mesitylenesulphonylhydroxylamine,'45 and cupric chloride-cupric oxide'46 are also effective reagents.In a series of papers Evans et ~1.'~'have described the useful technique of cyanosilylation of aldehydes and ketones with trimethylsilyl cyanide. According to the substrate this reaction is efficiently catalysed either by cyanide ion or a Lewis acid. In addition to its protective property (removal with silver fluoride) the silyloxynitrile group of an aromatic aldehyde can function as a useful acyl anion equivalent (Scheme 15).14* Relevant to the above results is the fact that aromatic aldehydes undergo conjugate addition to aB-unsaturated carbonyl systems with cyanide ion catalysis probably via the corresponding cyanohydrin anion.'49 OSiMe OSiMe, I ArCH 2ArLR + ArCR I I II CN CN 0 Reagents i LiNPr',; ii RX Scheme 15 I4O N.H. Andersen and H. Uh Synthetic Comm. 1973 3 125. 14' J. L. Isidor and R. M. Carlson J. Org. Chem. 1973 38 554. 14' E. J. Corey and R. A. Ruden J. Org. Chem. 1973,38,834. 143 I. Vlattas L. Della Vecchia and J. J. Fitt J. Org. Chem. 1973 38 3749. 144 T.-L. Ho H. C. Ho and C. M. Wong Canad. J. Chem. 1973,51 153. 14' Y. Tamura K. Sumoto S. Fujii H. Satoh and M. Ikeda Synthesis 1973 312. 14' K. Narasaka T. Sakashita and T. Mukaiyama Bull. Chem. SOC.Japan 1972,453124. 147 D. A. Evans L. K. Truesdale and G. L. Carroll J.C.S. Chem. Comm. 1973,55; D. A. Evans. J. M. Hoffman and L. K. Truesdale J. Amer.Chem. Soc. 1973 95 5822; D. A. Evans and L. K. Truesdale Tetrahedron Letters 1973 4929; see also W. Lidy and W. Sundermeyer Chem. Ber. 1973 106 587. 14* K. Deuchert U. Hertenstein and S. Hunig Synthesis 1973 777; c$ G. Stork and L. Maldonado J. Amer. Chem. SOC.,1971 93 5286. 149 H. Stetter and M. Schreckenberg Angew. Chem. Internat. Edn. 1973 12 81; Tetru-hedron Letters 1973 1461. General Methods Functionalized Aldehydes and Ketones.-Addition of chromyl chloride to di- and tri-substituted olefins using acetone as solvent produces a-chloro-ketones in good yield -a reductive work-up with zinc and acetic acid yields the correspond- ing ketone.' "The reaction of organocuprates with a-chloro-acid chlorides also produces a-chloro-ketones in moderate yields.' '' Many synthetic schemes depend at some point or other on the use of ap-unsaturated ketones (and esters) as building blocks.In the year under review a number of new or modified ways of generating these intermediates have been reported. Three groups,' 52 working independently have utilized the fact that selenoxides readily undergo syn-elimination to form olefins. Thus an efficient de- hydrogenation can be achieved by introducing the phenylseleno-moiety a to a carbonyl function (ketone aldehyde ester) and subsequently oxidizing the product (Scheme 16). In the case of aldehydes and ketones the simplest procedure R q 9 0 -R q O PI[R~] 0; + -R T O X X (X = H alkyl Ar or alkoxy) Scheme 16 for the first step is the direct addition of benzeneselenenyl chloride to the carbonyl compound.' 52c For esters three methods of introducing the a-phenylseleno- group are available (Scheme 17).lS2' Sulphur can replace selenium in this Br R -CO,Et RdCO,E~ PhSeCH,CO,Et Reagents i R,NLi; ii PhSeCl; iii RCH,X; iv PhSe-Na+ Scheme 17 process as evidenced by the work of Trost and Sal~mann.''~ In this case the carbonyl enolate is quenched by dimethyl disulphide (selective for esters) or 150 K.B. Sharpless and A. Y. Teranishi J. Org. Chem. 1973 38 185. N. T. L. Thi H. Riviere and A. Spassky Bull. SOC.chim. France 1973 2102. lS2 (a) H. J. Reich I. L. Reich and J. M. Renga J. Amer. Chem. SOC. 1973 95 5813; (b)D. L. J. Clive J.C.S. Chem. Comm. 1973 695; (c) K. B. Sharpless R. F. Lauer and A.Y. Teranishi J. Amer. Chem. SOC. 1973 95 6137. 153 B. M. Trost and T. N. Salzmann J. Amer. Chern. SOC.,1973 95 6840; see also D. Seebach and M. Teschner Tetrahedron Letters 1973 51 13; J. L. Herrmann M. H. Berger and R. H.Schlessinger J. Amer. Chem. SOC.,1973 95 7923. W.B. Motherwell and J. S. Roberts diphenyl disulphide followed by oxidation to the sulphoxide and subsequent pyrolysis. Hooz and Brids~n'~~ have found a neat solution to the problem associated with the regiospecificity of the Mannich condensation when an unsymmetrical ketone is used. The success of this new method hinges upon the reaction of di-methyl(methy1ene)ammonium iodide (in DMSO) with an enol borinate as the latent carbonyl function (Scheme 18). Since it has already been shown that enol R2 CH2NMe2 I R:BOC=CHRi R2c-LHR1 II 0 + Reagent i Me,N=CH I-Scheme 18 borinates can be obtained either by the reaction of trialkylboranes with a-diazo- ketones or by conjugate addition of organoboranes to a&unsaturated ketones this method is highly versatile.An alternative approach'55 t0 this problem involves the Mannich reaction (followed by quaternization) of an a-substituted /I-keto-ester. Heating the intermediate salt in DMF effects the conversion into the a-methylene ketone. One of the classical methods of introducing ap-unsaturation into a ketone involves an a-halogenation-dehydrohalogenationsequence. Like the Mannich reaction this route usually suffers from the lack of regiospecificity in the formation of the a-halogeno-ketone from an unsymmetrical ketone.Stotter and Hill156 have explored this problem with the result that the necessary control can be achieved under the correct experimental conditions using position-specific lithio-enolates (Scheme 19). OSiMe 0 111. IV ___) vi. iv OBr Reagents i LiNPr',; ii CISiMe,; iii MeLi (1 equiv.); iv Br, -78 "C;V AcZO-HCIO,; vi MeLi (2 equiv.) THF Scheme 19 154 J. Hooz and J. N. Bridson J. Amer. Chem. SOC., 1973 95 602. 155 R. B. Miller and B. F. Smith Tetrahedron Letters 1973 5037; Synthetic Comm. 1973 3 359. ISh P. L. Stotter and K. A. Hill J. Org. Chem. 1973. 38 2576. General Methods 677 Trialkylalkynylborates (19) appear under several headings in this chapter and are proving to be extremely versatile synthetic intermediates.Their reaction with acyl chlorides yields A4-1,2-oxaborolens (27) which can be oxidized to ap-unsaturated ketones (Scheme 2O).' Enol acetates of P-diketones (and R' R' (27) Reagents i AcCl; ii Cr0,-H + Scheme 20 /I-keto-esters) react with one molar equivalent of a lithium dialkylcuprate to give P-substituted enones (and ap-unsaturated esters).' 58 Ketenthioacetals' 59 featured strongly last year as valuable intermediates. In extending the scope of their versatility Seebach et ~1.'~'have shown that the conjugated derivatives undergo nucleophilic attack by alkyl-lithiums to give a carbanion which can be quenched by an alkyl halide i.e. addition at C(4)of a masked ap-unsaturated ketone (Scheme 21).Another useful synthesis of ap-unsaturated ketones (and Reagents i Bu"Li; ii MeI iii hydrolysis Scheme 21 R' R' R'CECCH,OMe 2 \ \ /H /c=c=c \ -/c=c\ RZ H R2 /c=o R3 Reagents i Bu"Li-TMEDA; ii R'X; iii Bu"Li; iv R3X; v H,O+ Scheme 22 aldehydes) involves the metallation of propargyl and allenic ethers (Scheme 22).I6l Acid chlorides can be homologated to aP-unsaturated aldehydes in good overall yield by a four-step sequence (Scheme 23).' 62 Addition of dichloromethyl-lithium to a ketone followed by rearrangement to an a-chloro-aldehyde and 15' M. Naruse T. Tomita K. Utimoto and H. Nozaki Tetrahedron Letters 1973 795. 158 C. P. Casey D. F. Marten and R. A. Boggs Tetrahedron Letters 1973 2071; see also G. H. Posner and D.J. Brunelle J.C.S. Chem. Comm. 1973 907. D. Seebach M. Kolb and B.-T. Grobel Chem. Ber. 1973 106 2277. I6O D. Seebach M. Kolb and B.-T. Grobel Angew. Chem. Internat. Edn. 1973 12 69. 16' Y.Leroux and C. Roman Tetrahedron Letters 1973 2585. H. Newman J. Org. Chem. 1973 38 2254. W.B. Motherwell and J. S. Roberts subsequent dehydrochlorination serves as a route to aP-unsaturated aldehydes (Scheme 24).' OH RCOCl A RCOCECSiMe '* RAHCH,CH(OMe) % RCH=CHCHO Reagents i Me,SiCECSiMe, AlCl,; ii OMe- MeOH; iii NaBH,; iv H,O+ Scheme 23 R2 R2 I HCI R'CH2CRZ R'CH,&OLi 5 R'CH,CCl -P R'CH=C I1 I I \ 0 CHCI CHO CHO Reagent i C1,CHLi Scheme 24 Further work on the thermal cyclization of unsaturated ketones has revealed a method of preparing alkylidene-cyclopentanones and -cyclohexanones.' 64 Cyclic 1,3-diketones can be converted into the corresponding @-unsaturated enones either by reduction of the derived P-halogeno-afi-unsaturated enones with zinc-silver couple'65 or by mild base treatment of the mono-tosylhydra- zones.'66 Stork and Danhei~er'~~ have described a beautiful method for the synthesis of 4-alkylcyclohexenones.The success of this route lies in the regio- specific monoalkylation of P-diketone enol ethers followed by hydride reduction and acid hydrolysis (Scheme 25). This methodology has permitted a short and Reagents i LiNPr',; ii RX; iii LiAIH,; iv H,O* Scheme 25 efficient synthesis of ( & )-P-vetivone.' 68 Like P-keto-phosphonium salts P-keto- phosphonate~"~ also form dianions which can be alkylated at the y-carbon.' 70 Using this procedure Grieco et have generated the 1,Sdiketone (28) by alkylation with 1,3-dichlorobut-2-ene followed by acid hydrolysis.An intra- 163 H. Taguchi S.Tanaka H. Yamamoto and H. Nozaki Tetrahedron Lerrers 1973 2465. 164 M. Bortolussi R. Bloch and J. M.Conia Tetrahedron Letters 1973 2499. 165 R. D. ClarkandC. H. Heathcock J. Org. Chem. 1973 38 3658. 166 G. A. Hiegel and P. Burk J. Org Chem. 1973 38 3637. 167 G. Stork and R.L. Danheiser J. Org. Chem. 1973 38 1775. 168 G. Stork R. L. Danheiser and B. Ganem J. Amer. Chem. SOC.,1973,95 3414. 169 M.S. Chattha and A. M. Aguiar J. Org. Chem. 1973 38 2908. P.A. Grieco and C. S. Pogonowski J. Amer. Chem. SOC., 1973,95 3071.P. A. Grieco and C. S. Pogonowski Synthesis 1973 425. General Methods molecular Horner-Wittig reaction of (28) produces the substituted cyclic enone (29). 00 0 I1 II I1 (MeO),PCH ,CCH(CH,),CMe I R Buchi and Vederas172 have described an alternative method to the Wharton reaction for the transposition of a keto-group and a double bond in conjugated ketones (Scheme 26). Recently a new oxidative procedure for the cyclization of ketoximes to isoxazoles has been reported.' 73 Reagents i 12-KI NaHCO,; ii Na-NH,-Bu'OH Scheme 26 Enol borinates react with ketones and aldehydes to produce /3-hydroxy- ketones and appropriate modifications in the enol borinate structure permit the formation of /I-hydroxy-esters and -thi~esters.'~~ Further examples of the versatility of trialkylalkynylborates are illustrated by the important conversions shown in Scheme 27.'75*'76 by-Unsaturated ketones can be obtained by the reaction of allylic Grignard reagents with 2-substituted 4,4-dimethyloxazolines followed by hydrolysis.' 77 Another synthesis of @-unsaturated aldehydes,' 78 based on a [2,3] sigmatropic rearrangement has been recorded (Scheme 28). In polar solvents (e.g. sulphur dioxide) the silver-ion-induced dechlorination of a-chloro-aldonitrones in the presence of certain olefins can give substituted nitrones predominantly G. Buchi and J. C. Vederas J. Amer. Chem. SOC. 1972,94 9128. "' K. Maeda T. Hosokawa S. Murahashi and I. Moritani Tetrahedron Letters 1973 5075. 174 T.Mukaiyama K. Inomata and M. Muraki J. Amer. Chem. SOC. 1973 95 967; Bull. Chem. SOC. Japan 1973,46 1807. 175 M. Naruse K. Utimoto and H. Nozaki Tetrahedron Letters 1973 2741. 176 A. Pelter C. R. Harrison and D. Kirkpatrick Tetrahedron Letters 1973 4491. 177 C. Lion and J.-E. Dubois Bull. SOC. chim. France 1973 2673. 17' L. Mander and J. V. Turner J. Org. Chem. 1973,38 2915. W.B. Motherwell and J. S. Roberts f iv R' R2 R' R2 R:BC=CR~Li + LRiB2 ii iii H? Ref. 175 \ Ref. 17ivi R3 HO R3 R' R2 1iii v H RiB CH,COX R' RZ R'MR2 x HO R3 H CH2COX 0 CH,COX (X = alkyi aryl or alkoxy) Reagents I y R 3 ;ii AcOH; iii NaOH; iv H,O,-OH-; v I,; vi BrCH,COX Scheme 27 CN Reagent i H,O ' Scheme 28 which on hydrolysis lead to By-unsaturated aldehydes (Scheme 29).'79 In effect this means that a-chloro-aldonitrones are a-acyl carbonium ion equivalents.This substitution process also occurs in high yield with a number of aromatic systems affording P-aryl aldehydes. With acetylenes conjugated nitrosonium ions give cycloaddition products (30) which after base treatment (e.g. basic alumina) undergo a retro-Diels-Alder reaction to yield aP-unsaturated enone systems (Scheme 30).I8O S. Shatzmiller P. Gygax D. Hall and A. Eschenmoser Helv. Chim.Acru 1973 56 2961. S. Shatzmiller and A. Eschenmoser Helv. Chim. Am 1973 56. 2975. General Methods 681 I Me Me 0-Reagents i AgBF, SO,; ii H,O+ Me Scheme 29 A general route to trans-76-unsaturated aldehydes involves alkylation of (1-vinylthio)allyl-lithium followed by a thio-Claisen rearrangement and sub- sequent hydrolysis (Scheme 3 l).I8' Substitution of an ethoxy-group at C(2) in the sulphide precursor results in a new route to y-keto-aldehydes.'82 An aza- Claisen rearrangement of N-allyl N-vinyl quaternary ammonium salts also provides an interesting route to $-unsaturated aldehydes.' 83 Scheme 31 Schlessinger and his co-workers have had a fruitful year in the area of carbonyl anion equivalents and new Michael receptors which in many cases provide efficient routes to various 1,4-dicarbonyl systems.Of particular interest is the generation of the carbanions (31),184 (32),'85 and (33).186 Both (31) and (32) I81 K. Oshima H. Takahashi H. Yamamoto and H.Nozaki J. Amer. Chem. SOC.,1973 95 2693. 182 K. Oshima H. Yamamoto and H. Nozaki J. Amer. Chem. SOC.,1973,95 4446. 183 P. M. McCurry,jun. and R. K. Singh Tetrahedron Letters 1973 3325. I84 R. J. Cregge J. L. Herrmann J. E. Richman R. F. Romanet and R. H. Schlessinger Tetrahedron Letters 1973 2595. 185 J. L. Herrmann J. E. Richman and R. H. Schlessinger Tetrahedron Letters 1973 2599. I86 J. E. Richman J. L. Herrmann and R. H. Schlessinger Tetrahedron Letters 1973 3267 3271 3275; J. L. Herrmann J. E. Richman P. J. Wepplo and R. H. Schlessinger ;bid. p. 4707. W.B. Motherwell and J. S. Roberts P 0 0 MeS SMe "+JMe MeS Xplt-fytR SMe R SMe (35) (36) (37) have been used for conjugate addition to ap-unsaturated carbonyl compounds while the more versatile anion (33) can be mono-alkylated (leading to aldehydes) di-alkylated (leading to ketones) acylated (leading to a-functionalized carbonyl compounds) and undergo Michael addition to electron-deficient olefins (leading to a variety of 1,4-dicarbonyl systems).The same synthetic goal can be achieved by using the opposite strategy whereby the thioacrylate (34)lg7 functions as a Michael receptor for such nucleophilic species as enamines and lithio-enolates of esters and lactones. In a similar vein the keten thioacetal monoxides (35; R = H or alkyl)' can be used as Michael receptors for a wide variety of nucleo-philic species. With lithio-enolates the resultant anion (36)' 89 can either be quenched (leading to substituted aldehydes) alkylated (leading to substituted ketones) or in the case where R = vinyl or a carbonyl function alkylated via the stabilized anion (37).9 Acids and Anhydrides Further work on disodium tetracarbonylferrate( -11) has extended the utility of this reagent by the demonstration that the intermediate anionic complexes (38) and (39) can be oxidized in high yield in the presence of water an alcohol and a secondary amine to give the corresponding acid ester and amide re- spectively.'g' Trimethylsilyl enol ethers of cyclic ketones react with arenesulphonyl azides to give unstable A2-triazolines e.g. (a), which lose nitrogen easily and rearrange to imidate esters e.g. (41) which in turn are hydrolysed to the corresponding acid^.'^' The Lansbury chloro-olefin annelation method has been adapted for an interesting cycloalkanecarboxylic acid synthesis.' 92 This is achieved by R.J. Cregge J. L. Herrmann and R. H. Schlessinger Tetrahedron Letters 1973 2603. "'J. L. Herrmann G. R. Kieczykowski R. F. Romanet P. J. Wepplo and R. H. Schles- singer Tetrahedron Letters 1973 47 11. J. L. Herrmann G. R. Kieczykowski R. F. Romanet and R. H. Schlessinger Tetra-hedron Letters 1973 47 15. I9O J. P. Collman S. R. Winter and R. G. Komoto J. Amer. Chem. SOC.,1973 95 249; see also S. N. Anderson C. W. Fong and M. D. Johnson J.C.S. Chem. Comm. 1973 163; K. M. Nicholas and M. Rosenblum J. Amer. Chem. SOC. 1973,95,4449. R. A. Wohl Helv. Chim. Acta 1973 56 1826; Tetrahedron Letters 1973 31 11. 192 P. T. Lansbury and R.C. Stewart Tetrahedron Letters 1973 1569. General Methods co Na,Fe(CO) + RX * [RFe(CO),]--+ [RCFe(CO),]-II 0 SO,Ar OSiMe C=N-S0,Ar (41) (40) introduction of a 1,l-dichloromethylene grouping in the correct juxtaposition with respect to an incipient cationic centre (Scheme 32). n = 3or4 Reagent i HC0,H Scheme 32 Fetizon et ut.193have described a method for the stepwise degradation of a carboxylic acid (viaits ester) by either one two or three carbon atoms. The first sequence is the familiar Barbier-Wieland degradation. Further developments in the use of photosensitive carboxy-pr'otecting groups have been reported (Scheme 33).194*195 In the case of the nitroanilide~,'~' the reaction only works if R2 # H (e.g. R2 = Me CH2Ph or Ph).The methyl- thiomethyl ester function can also be used as an acid-protecting group.196 Trifluoroacetic acid or methyl iodide regenerates the free acid ; alternatively alcoholysis and aminolysis conditions permit the conversion into esters and amides respectively.' 97 Reagents i EtOH; ii EtOH-H,O NO Scheme 33 A new method ofsynthesizing disubstituted maleic anhydrides involves the pyrolysis of the esters (42; R' = Me or Ph R2 = alkyl) which are derived from lg3 M. Fetizon F. J. Kakis and V. Ignatiadou-Ragoussis J. Org. Chem. 1973 38 1732. Ig4 J. C. Sheehan and K. Umezawa J. Org. Chem. 1973,38 3771. Ig5 B. Amit and A. Patchornik Tetrahedron Letters 1973 2205. 196 T. L. Hoand C. M. Wong J.C.S. Chem. Comm. 1973 224. 19' T. L. Ho and C.M. Wong Synthetic Comm. 1973 3 145. 684 W.B. Motherwell and J. S. Roberts an a-keto-acid and an ethoxyacetylene (Scheme 34).19*Acids can be dehydrated in good yield with cyanogen bromide in the presence of pyridine to give an- hydride~.~~~ A short-cut to the mono-homologation of a dicarboxylic acid has been reported.200 In this method the corresponding anhydride is allowed to react with excess diazomethane and the resultant ring-opened diazo-ketone methyl ester is subjected to the normal Arndt-Eistert conditions. //O 1 0 (42) Scheme 34 Functionalized Acids.-Malonic acid half-esters react with diphenylphosphoryl azide in the presence of triethylamine with transfer of the azido-group and the derived isocyanates (after Curtius rearrangement) react further with an alcohol to give urethane esters which can be readily converted into a-amino-acids.201 An interesting new synthesis of 8-hydroxy-acids has been reported,202 (Scheme 35) involving initial addition of a t-hexylmonoalkylborane to ethyl propiolate R' R' R' H c=c H /\ C02Et H iii ivl R 'CHCH2C02H I OH Reagents i HC=CCO,Et; ii NaOR'; iii HOR'; iv H,O,-OH- Scheme 35 followed by base-induced alkyl migration.Rathke and Sullivan203 have per- fected a technique permitting the isolation of the remarkably stable enolate 19* M. S. Newman and W. M. Stalick J. Org. Chem. 1973 38 3386. 199 T. L. Ho and C. M. Wong Synthetic Comm. 1973,3 63. 'OD E. W. Della and M. Kendall J.C.S. Perkin I 1973 2729. 201 S. Yamada K.Ninomiya and T. Shioiri Tetrahedron Letters 1973 2343. 202 E. Negishi and T. Yoshida J. Amer. Chem. SOC. 1973,95 6837. ,03 M. W. Rathke and D. F. Sullivan J. Amer. Chem. SOC. 1973,95 3050. General Methods 685 lithio t-butyl acetate which in toluene solution reacts rapidly with ketones to give P-hydroxy-t-butyl esters. Following on from last year's report on the [3,3] sigmatropic rearrangement of lithio-enolates of allylic esters Baldwin and Walker204 have shown that zinc enolates (43) also undergo the same type of reaction leading to $-unsaturated acids (Scheme 36). The same basic principle lies behind the report by Yamamoto Reagents i 'ko ;ii Zn Br Scheme 36 et that ally1 keten thioacetals undergo a thio-Claisen rearrangement to give stereoselectively the (E)-isomer acid derivative (Scheme 37).Reagents i BuSLi (2 equiv.); ii RX; iii MeI; iv CuC1,-CuO Scheme 37 Moderate yields of (E)-ap-unsaturated acids can be obtained by dehydrogena- tion of their a-lithiated salts with DDQ.205The direct conversion of an ester into an acid halide can be achieved with such reagents as Ph3PX (X = C1 or Br)206*207 and PhiPC1 BF3Cl-.206 10 Esters Methyl esters can be obtained in high yield by heating the corresponding tri- methylanilinium carboxylate salts.208 Trimethyl phosphate can be substituted for dimethyl sulphate in the formation of methyl esters even for hindered acids.209 204 J. E. Baldwin and J. A. Walker J.C.S. Chem. Comm. 1973 117. 205 G. Cainelli G. Cardillo and A.Umani-Ronchi J.C.S. Chem. Comm. 1973 94. 20h D. J. Burton and W. M. Koppes J.C.S. Chem. Comm. 1973 425. 207 A. G. Anderson jun. and D. H. Kono Tetrahedron Lerters 1973 5121. *08 I. Gan J. Korth and B. Halpern Synthesis 1973 494. *09 M M Harris and P. K. Patel. Chem. and Ind.. 1973 1002. W.B. Motherwell and J. S. Roberts Functionalid Esters-cr-Keto-esters can be prepared in moderate yield by ozonolysis of l-bromoacetylenes.2 Some new and interesting reactions leading to P-keto-esters have been reported (Scheme 38).21 '-'14 R I MeSC=CC H( 0Et),R*l MeSC=C=C(0Et) MeSC=C=C(0Et) R2 RCOCH,CO,Et I v Vl R1COCH,R2 R$2 R'COC=C(SMe) 4R'COCHR2C02R3 OSi(Me),Bu' / CH,=C + RCH,COCI \ OEt OSi(Me),Bu' OSi(Me),Bu' I I RCH=C-CH,CO,Et + RCH,C=CHCO,Et viill RCH ,COCH,CO,Et R2 I R'COCC0,Et 5R1COCHR2C0,Et fNH3 cl-Ref.214 I Reagents i LiNEt,; ii RX; iii H,O Hg2+; iv NaH-CS, 2MeI; v R30H-H +;vi H,O; vii Et,N; viii H,O + Scheme 38 The work of Hooz and Smith2" serves as a caveat to those carrying out alkylations of P-keto-esters (and P-diketones) via thallium enolates. Contrary to earlier reports exclusive mono-C-alkylation could not be achieved. The decarboxylation of P-keto-esters (and geminal diesters) can be carried out in wet dimethyl sulphoxide in the presence of catalytic quantities of sodium chloride.21 Alternatively for P-keto methyl esters lower temperatures can be used if lithium chloride or sodium cyanide in HMPA are the reagents.217 Boric acid treatment of an acylated succinic acid diester followed by hydrolysis of the intermediate enol borinate yields y-keto-esters directly.218 In addition to their ability to under- go alkylation keten N,O-acetals (44)can also be used for Michael addition to 'lo S.Cacchi L. Caglioti and P. Zappelli J. Org. Chem. 1973 38 3653. R. M. Carlson and J. L. Isidor Tetrahedron Letters 1973 4819. 'I2 I. Shahak and Y. Sasson Tetrahedron Letters 1973 4207. M. W. Rathke and D. F. Sullivan Tetrahedron Letters 1973 1297. 2 I4 K. Matsumoto M. Suzuki T. Iwasaki and M. Miyoshi J. Org. Chem. 1973,38 2731. 'Is J. Hooz and J. Smith J. Org. Chem. 1972,37,4200. 'I6 A. P. Krapcho and A. J. Lovey Tetrahedron Letters 1973 957. "' P. Miiller and B. Siegfried Tetrahedron Letters 1973 3565.'I8 P. A. Wehrli and V. Chu J. Org. Chem. 1973 38 3436. General Methods 687 electron-deficient olefins.’ Thus addition of (44)to cyclohexenone followed by hydrolysis and transesterification yields (45). (44) (45) An improved experimental procedure for ester alkylation has been noted’” -the main modifications are the use of lithium di-isopropylamide as base in THF to generate the enolate and carrying out the alkylation at -78 “C. This alkylation technique can also be applied to hydracrylates thus affording a-substituted acrylates on subsequent dehydration.221 The simple expedient of adding one molar equivalent of HMPA to the above base permits deconjugative a-mono- and di-alkylation of for example ethyl crotonate.”’ Pichat and Beau~ourt’’~ have reported good yields in the syntheses of the important annelating agents (46; R’ = Me R2 = H and R’ = H R2 = Me); 3-ethoxypropionyl chloride is used for the synthesis of (46 ;R‘ = R2 = H) (Scheme 39).R‘ COCl \/ + LiCH/CozSiMe3 \ R2 C0,EtH /c=c\ -4 /C02SiMe3COCH \C02Et ] ‘1 R’ COCH,CO,Et\/)c=c’\H R’ Reagent i H 2O Scheme 39 Lactone.-The cr-methylenation of y-and &lactones has again been actively pursued.224 The report by Grieco and Hir~i’’~~ of their new technique has ’I9 A. 1. Meyers and N. Nazarenko J. Org. Chem. 1973,38 175. ”O R. J. Cregge J. L. Herrmann C. S. Lee J. E. Richman and R. H. Schlessinger Tetra-hedron Letters 1973 2425. ”’ J. L. Herrmann and R. H. Schlessinger Tetrahedron Letters 1973 2429. 222 J. L. Herrmann G.R. Kieczykowski and R. H. Schlessinger Tetrahedron Letters 1973 2433. ’” L. Pichat and J.-P. Beaucourt. Synthesis 1973 537. 224 ((1) A. D. Harmon and C. R. Hutchinson Tetrahedron Letters. 1973 1293; (6) K. Yamada M. Kato and Y. Hirata. ibid. p. 2745; (c) R. C. Ronald ibid. p. 3831 (d) P. A. Grieco and K. Hiroi J.C.S. Chem. Comm. 1973. 500. 688 W. B. Motherwell and J. S. Roberts the advantages of better overall yield and simplicity with respect to the other methods. Achieving the same result but conceptually different are the methods of Hudrlik et and Eschenmoser et ~11.~~~ The first depends upon the cyclo- propylcarbinyl-homoallyl rearrangement of e.g. (47) in the presence of excess zinc bromide in 48% hydrobromic acid to give (48).The second method is an WH20H C0,Et (47) extension of Eschenmoser’s recently developed work on a-chloro-aldonitrones (Scheme 40). N H H CH, CH,Cl Reagents i AgBF,; ii KCN; iii KOBu’; iv aq. H,SO Scheme 40 Two papers by Trost et ~11.~~’ report on the formation of spiro-lactones the latter of which is a follow-up to the secoalkylation process reported last year (Scheme 41). Many important natural products incorporate a lactone ring and thus in order to facilitate the syntheses of such compounds an efficient lactone- protecting group has become increasingly desirable. The synthetic organic chemist now has the means to achieve this in the light of the work by Corey and 225 P. F. Hudrlik L. R. Rudnick and S. H. Korzeniowski J.Amer. Chem. Soc. 1973,95 6848. 226 M. Petrzilka D. Felix and A. Eschenmoser Heh. Chim. Acra 1973 56 2950. ”’ (a)B. M. Trost and H. C. Arndt J. Org. Chem. 1973,38 3140; (b)M. J. Bogdanowicz, T. Ambelang and B. M. Trost Tetrahedron Letters 1973 923. General Methods 0 0 Ref 2270) CN CN Reagents i Ph,S 4; ii H + ; iii NaOBr Scheme 41 Beames.228 This involves the addition of bis(dimethyla1uminium) ethane- 1,2-dithiolate (49) to e.g. y-butyrolactone to give the intermediate hydroxy-keten thioacetal (50) which rapidly cyclizes in the presence of toluene-p-sulphonic acid to yield the dithio-ortho-lactone (51). Such compounds are reasonably stable to aqueous acetic acid methanolic potassium hydroxide LiAlH, and MeLi and are reconverted into the parent lactone by treatment with mercuric oxide and boron trifluoride etherate.This same protective sequence can be applied to esters (except those which do not possess an or-hydrogen) to give keten thioacetals whose synthetic value has been of increasing interest recently. I1 Amides and Nitriles Last year it was reported that diphenylphosphoryl azide was very effective in promoting formation of the amide linkage with little or no racemization; a similar efficiency has now been noted with diethylphosphoryl cyanide in the presence of trieth~lamine.~~~ As an alternative to the Ritter reaction Barton et ~1.~~" have found that treatment of an alcohol with chlorodiphenylmethylium hexachloroantimonate in the presence of nitrile solvents gives the corresponding amide.The synthesis .of amides by the reaction of isocyanates with organolithium reagents has been shown to be quite general.231 Some new or modified nitrile 228 E. J. Corey and D. J. Beames J. Amer. Chem. Soc. 1973 95 5829. 229 S. Yamada Y. Kasai and T. Shioiri Tetrahedron Letters 1973 1595. 230 D. H. R. Barton P. D. Magnus and R. N. Young J.C.S. Chem. Comm. 1973 331 13' N. A. LeBel R. M. Cherluck and E. A. Curtis Synthesis 1973 678. 690 W.B. Motherwell and J. S. Roberts syntheses have been noted (Scheme 42).232-235For aryl aldoximes trichloro- a~etonitrile~~~ can be used as the dehydrating and dicyclohexylcarbodi-imide237 agents. RCOX Ref 233' (Re[ 235) RCONH,,RCSNH,,RCH=NOHR-&4 RCNo,:,i:r ,,,,RCH=NOH Reagents i (PNCI,),; ii CHCI, aq.NaOH PhCH,N'Et C1-; iii 1,1 -dicarbonylbi-imidazole CH ,CI Scheme 42 A general method of converting ketones and aldehydes into nitriles involves the reaction of the carbonyl compound with tosylmethylisocyanide in the presence of base.238*239 Tetra-alkylammonium cyanides are reported to be more powerful nucleophiles than sodium cyanide for displacement reactions.240 B-Keto-nitriles are readily accessible by the reaction of the ketone with chlorosulphonyl iso- cyanate followed by treatment with DMF.241 12 Alkylation and Coupling Reactions Several annelation sequences of wide-ranging practical utility have been developed. These are discussed in Chapter 18. A useful compendium of articles on the topic of alkylation has been The synthetic merits of potassium hydride over sodium hydride for the rapid formation of anions include the formation of highly hindered alkoxides and boro- hydrides the preparation of dimsyl anion at room temperature and the acces- sibility of new and powerful proton-specific bases which catalyse the aromatization of limonene to para-cymene in five minutes at room temperature.243 Much attention has been devoted this year to the development of practical methods for the monoalkylation of ketones.Conia and his co-worker~~~~ recommend stereoselective conversion into the silyl enol ether followed by their modified Simmons-Smith cyclopropanation and ring opening with sodium hydroxide in aqueous methanol. In a conceptually identical approach use has 232 G.Rosini. G. Baccolini and S. Cacchi J. Org. Chem.. 1973 38 1060. 23J J. C. Graham Tetrahedron Letters 1973 3825. 234 T. Saraie T. Ishiguro K. Kawashima and K. Morita Tetrahedron Letters 1973,2121. 235 H. G. Foley and D. R. Dalton J.C.S. Chem. Comm. 1973 628. 236 T. L. Ho and C. M. Wong J. Org. Chem. 1973,38 2241. T. L. Ho Syntheric Comm. 1973 3 101. 0. H. Oldenziel and A. M. van Leusen Tetrahedron Letters 1973 1357. 239 U. Schollkopf and R. Schr(ider Angew. Chem. Internat. Edn. 1973 12,407. 240 D. A. White and M. M. Baizer J.C.S. Perkin I 1973 2230. *'I J. K. Rasmussen and A. Hassner Synthesis 1973 682. 2'2 D. Burns Chem. and Ind. 1973 870; R. 0.C. Norman ibid. p. 874; R. Baker ibid. p. 877 T. L. Gilchrist ibid. p. 881 ; W. Carruthers ibid.p. 931 ; D. C. Ayres. ibid. p. 937; R. W. Alder ibid. p. 983. ''j C. A. Brown J. Amer. Chern. SOC.,1973,95 982,4100. 2J4 J. M. Conia and C. Girard Tetrahedron Letters 1973 2767. General Methods 69 1 been made of the enamine derivatives followed by thermal opening of the cyclo- propane with aqueous methanol.245 The introduction of a tertiary alkyl group adjacent to a ketonic functionality can be accomplished by the reaction of the a,a'-dibromoketone with the mixed organocopper reagent [Bu'OBU'CUL~].~~~ This procedure is however clearly limited to symmetrical ketones. In an alter- native approach which is also the method of choice for the introduction of a secondary alkylidene group Corey and Chen247 have employed a-dithiomethyl- ene ketones as versatile intermediates (Scheme 43).0 Li+ A/ 0 SMe WSMe 0 Me O+Li' Reagents i. '"PBu', CS,; ii MeI; iii Me,CuLi -78 "C,20 min iv Me,CuLi 0°C. 1 hour Scheme 43 Improvements in classical condensation reactions continue to be made. Dimethyl malonate reacts with ketones in the presence of titanium tetrachloride and pyridine to give good yields of +unsaturated compounds even in previously cited unsuccessful cases.248 The reaction of morpholinocyclohexene with malonic acid derivatives in DMF or ethanol or without solvents leads to the correspond- ing cyclohexylidenes in a process which is more effective than the Knoevenagel 14' M. E. Kuehne and J. C. King J. Org. Chem. 1973. 38 304. 246 G. H. Posner and J.J. Sterling J. Amer. Chem. Soc. 1973. 95. 30-6 247 E. J. Corey and R. H. K. Chen Tetrrrhedron Letters 1973. 3817. 248 W. Lehnert Tetrahedron 1973. 29 635. W. B. Motherwell and J. S. Roberts condensation and more convenient than the Reformatsky reaction.249 The direct alkylation of aldehydes possessing an a-hydrogen atom with an alkyl halide can be conveniently carried out wing phase-transfer catalytic techniques.250 House and his co-~orkers~~ have controlled thecrossed aldol reaction by treating a pre-formed lithium enolate with an aldehyde in the presence of magnesium bromide or zinc chloride when the product is presumably trapped as the metal chelate. Treatment of an a-diketone with two equivalents of lithium di-isopropyl- amide generates a dianion which can undergo C-alkylation in' good yield.252 Lithium secondary amide bases also provide an effective method for the irrever- sible generation of the conjugated bases of ap-unsaturated ketone^.^ Sub-sequent methylation then gives the a' product.The reductive methylation of enolizable aldehydes or ketones can be achieved using formaldehyde and an alkali-metal iron ~arboxylate.~~~ An efficient and generally applicable method for the stepwise a-alkylation of esters ketones and nitriles via their cr-t-butylthio- derivatives has been described (Scheme 44).255 R' R' R' I I R'R'CHY * C R3-C-Y I xs/ I 'y R2 R2 X = halide; Y = C02Me CN or COMe Reagents i base R'X; ii Raney Ni; iii base R'X; iv 2Li H'; v 2Li R3X Scheme 44 Me Me 14' F.S. Prout J. Org. Chem. 1973 38 399. 150 H. K. Diet1 and K. C. Brannock Tetrahedron Letters 1973 1273. H. 0.House D. S. Crumrine and A. Y.Teranishi J. Amer. Chem. Soc. 1973,95,3310. 2sz A. S. Kende and R. G. Eilerman Tetrahedron Letters 1973 697. 253 R. A. Lee C. McAndrews K. M. Patel and W. Reusch Tetrahedron Letters 1973,965. 254 G. Cainelli M. Panunzio and A. Umani-Ronchi Tetrahedron Letters 1973 2491. lS5 S. Kamata S. Uyeo. N. Haga and W. Nagata Synthetic Comm. 1973 3 265. General Methods 693 A new general method for the alkylation of enamino-ketones at the y-position e.g. (52; R = H) to (52; R = alkyl) has been The conjugate addition reaction of trans-alkenyl-alanes to enone systems occurs in a stereo- specifically trans manner to give y6-unsaturated ketone^.^ s ' Olah and his co-~orkers~~ have described methoxycarbenium hexafluoro- antimonate as a new methylating agent and also claim that the hexafluoro- phosphate gegenion gives the most convenient stable and soluble Meerwein sah2s9 Organocopper chemistry maintains its rapid pace of development.In addition to the various aspects already cited three groups have described unsymmetrical organocuprates RR'CuLi which operate with selective transfer of R'.260 Normant and his colleagues26 have reported further studies on vinylcopper reagents culminating in a stereospecific synthesis of ap-unsaturated acids. Lithium dialkylcuprates react more rapidly in ether solution with tosylates than with halides.262 The cross-coupling reaction between alkylthioallylcopper and allylic halides proceeds regiospecifically in excellent yield.263 Further information is now available on the selective cross-coupling reaction which utilizes an allylic mesitoate The metallation of limonene with the complex of n-butyl-lithium and tetramethylethylenediamine was described last year.A second group have now reported the generation of allyl-lithium and methallyl-%thium from propene and isobutene by this method.26s These reagents couple with organic halides in very good yield. Trost and his co-workers266 continue to develop new and elegant synthetic methods. In their allylic alkylation sequence the interaction of a nucleophile with a readily prepared n-allylpalladium complex is used to construct a new carbon-carbon bond (Scheme 45).Further- more in the presence of a chiral phosphine ligand exceptionally high optical yields of 12-24 %.have been obtained ;this degree of asymmetric induction is exceeded only by the Wilke oligomerization process.267 Tertiary-butyl trifluoroacetate in trifluoroacetic acid is an effective reagent for the rapid alkylation of activated aromatic compounds.268 Thallium trifluoroacetate is not only useful for the oxidation of phenols to quinones but also acts as a highly efficient two-electron oxidant for intra- 256 M. Yoshimoto N. Ishida and T. Hiraoka Tetrahedron Letters 1973 39. 257 J. Hooz and R. B. Layton Canad. J. Chem. 1973,51 2098. 258 G. A. Olah and J. J. Svoboda Synthesis 1973 52. 259 G.A. Olah J. A. Olah and J. J. Svoboda Synthesis 19j3 490. 260 (a) H. 0. House and M. J. Umen J. Org. Chem. 1973 38 3893; (6) J.-P. Gorlier L. Hamon J. Levisalles and J. Wagnon J.C.S. Chem. Comm. 1973 88; (c) G. H. Posner and C. E. Whitten Tetrahedron Letters 1973 1815. 261 J. F. Normant G. Cahiez C. Chuit and J. Villieras J. Organometallic Chem. 1973 54. C53. 262 C. R. Johnson and G. A. Dutra J. Amer. Chem. SOC.,1973 95 777 7783. 263 K. Oshima H. Yamamoto and H. Nozaki J. Amer. Chem. SOC.,1973,95 7926. 264 J. A. Katzenellenbogen and R. S. Lenox J. Org. Chem. 1973 38 326. 265 S. Akiyama and J. Hooz Tetrahedron Letters 1973 41 15. 266 B. M. Trost and T. J. Fullerton J. Amer. Chem. SOC.,1973 95 292. "' B. M. Trost and T. J. Dietsche J. Amer. Chem.SOC.,1973,95 8200. 268 U. Svanholm and V. D. Parker J.C.S. Perkin I 1973 562. W. B. Motherwell and J. S. Roberts R Reagents i PdCI,; ii Na' (CO,Et),C- 4Ph,P Scheme 45 molecular phenolic oxidative coupling.' ' Vanadium oxytrifluoride is the reagent of choice for the smooth inter- and intra-molecular coupling of non-phenolic benzylis~quinolines.~~~ Facile coupling of sterically hindered 2,6-dialkylphenols has been realized with periodic acid.270 13 Miscellaneous Neckers et al. have been carrying out some interesting research on the use of polymer-protected reagents. One such reagent is the water-stable polystyrene- aluminium chloride complex which in appropriate swelling solvents e.g. benzene can be used as a catalyst for ether27' and ester272 syntheses.Another is the Rose Bengal-chloromethylated polystyrene complex which functions as an insoluble sensitizer for photo-o~idations.~~~ A similar heterogeneous system can be realized with Rose Bengal and Methylene Blue attached to basic anion- exchange and acidic cation-exchange resins respectively.274 Further work by Rieke et al. has led to the discovery of methods for preparing highly activated metals e.g. and magnesium.276 A method of preparing aluminium hydride which is soluble in diethyl ether has been reported.277 Kwart and C~nley~~~ have described modified Birch reduction conditions which may prove useful in certain cases ; conjugation of 1-methoxycyclohexa- 1,4-dienes can be achieved with a number of catalyst^.^^" The use of lithium 2,2,6,6-tetra- methylpiperidide as a potent and relatively cheap base for effecting a number of 269 S.M. Kupchan A. J. Liepa V. Kameswaran and R. F. Bryan J. Amer. Chem. SOC. 1973,95 6861. 270 A. J. Fatiadi Synthesis 1973 357. 271 D. C. Neckers. D. A. Kooistra and G. W. Green J. Amer. Chem. Suc. 1972,94,9284. 272 E. C. Blossey L. M. Turner and D. C. Neckers Tetrahedron Letters 1973 1823. 273 E. C. Blossey D. C. Neckers A. L. Thayer and A. P. Schaap J. Amer. Chem. SOC. 1973,95 5820. 274 J. R. Williams G. Orton and L. R. Unger Tetrahedron Letters 1973 4603. 27s R. D. Rieke S. J. Uhm and P. M. Hudnall J.C.S. Chem. Comm. 1973 269. 276 R. D. Rieke and S. E. Bales J.C.S. Chem. Comm. 1973 879. 277 E. C. Ashby J. R. Sanders P. Claudy and R.Schwartz J. Amer. Chem. SOC.,1973 95 6485. "* H. Kwart and R. A. Conley J. Org. Chem. 1973 38 201 1. 279 A. J. Birch and K. P. Dastur J.C.S. Perkin I 1973 1650. General Methods chemical transformations e.g. carbene benzyne and enolate formation has been advocated.280 Enamines can be prepared in high yield by condensation of the carbonyl compound with trimethylsilyl derivatives of secondary amines.28 For aldehyde enamines the reaction of Grignard reagents with NN-dialkylformamides has been found to be In Diels-Alder reactions the dienophiles 2-phenyl- and 2-thiono-A4- 1,3-dioxolen can act as acetylene equivalents283 while a-bromoacrolein functions as an allene R. A. Olofson and C. M. Dougherty J. Amer. Chem. SOC.,1973,95 582. R.Comi R. W. Franck M. Reitano and S. M. Weinreb Tetrahedron Letters 1973 3107. 282 C. Hansson and B. Wickberg J. Org. Chem. 1973 38 3074. 283 W. K. Anderson and R. H. Dewey J. Amer. Chem. SOC.,1973,95 7161. 284 B. B. Snider J. Org. Chem. 1973 38 3961.

 



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