13 Synthetic Methods By R. BRETTLE Department of Chemistry The University Sheffield S3 7HF 1 Alkanes Primary amines can be directly deaminated a process not really possible hitherto by treatment with hydroxylamine O-sulphonic acid and alkali. An important paper covering reductive displacements by tetrahydridoborate in polar aprotic solvents gives full details of the reductive amination of primary amines via NN-disulphoni-mides.2 Sterically hindered acetates of secondary and tertiary alcohols are predominantly deoxygenated by lithium in eth~lamine;~ 3~,5a-diacetoxycholestanegives 5a-cholestan-36-01. Reduction of 0-(NN-dimethylsulphamoyl) derivatives of secon-dary alcohols with sodium in liquid ammonia likewise effects smooth deoxy- genati~n.~ The cyclopentadienylvanadium tricarbonylhydride anion transfers hydrogen faster than tributyltin hydride so that for example very little cyclization occurs in the reductive debromination of 6-bromohex-1 -ene.’ 2 Alkenes The Silver Jubilee volume of Organic Reactions deals with two important olefin syntheses the use of condensations of carbonyl compounds with phosphoryl- stabilized anions,6 and the Ramberg-Backlund rearrangement starting from a-halos~lphones.~ Another review deals with the synthetic uses of the intramolecular ene reaction; a recent example of the commonest reaction of this type is shown in Scheme 1.8 MeJ-jJ 3oo”c1 Me0,C Scheme 1 C0,Me G.A. Doldouras and J. Kollonitsch J. Amer. Chem. Soc.. 1978 100 341. * R. D. Hutchins D. Kandasamy F.Dax C. A. Maryanoff D. Rotstein B. Goldsmith W. Burgoyne F. Cistone J. Dalessandro and J. hglis J. Org. Chem. 1978,43 2259. R. B. Boar L. Joukhadar J. F. McGhie S. C. Misra A. G. M. Barrett D. H. R. Barton and P. A. Prokopiou J.C.S. Chem. Comm. 1978,68. T. Tsuchiya I. Watanabe M. Yoshida F. Nakamura T. Usui M. Kitamura and S. Umezawa Tetrahedron Letters 1978 3365. R. J. Kinney W. D. Jones and R. G. Bergman J. Amer. Chem. SOC. 1978,100,635. ‘W. S. Wadsworth jun.,Org. Reactions 1977,25,73. L. A. Paquette Org. Reactions 1977,25 1. W. Oppolzer and V. Snieckus Angew. Chem. Internat. Edn. 1978,17,476. 303 304 R.Brettle A new synthesis' of trans-alkenes which is an attractive alternative to the Wittig reaction is particularly useful for the reaction of the carbonyl group with a secondary centre (Scheme 2).An improvement on methylenation with methyl-enetriphenylphosphorane is to use di-iodomethane-zinc-trimethylaluminium or dibromomethane-zinc-titanium tetrachloride." v SO Ph * ;4 i ii Reagents i BuLi; ii PhCOCl; iii Na/Hg; MeOH/EtOAc. Scheme 2 Modifications to the selenoxide elimination route," making it for example useful for primary alkyl aryl selenides have been reported.'* Either a-or y-alkylation of a primary alkyl benzothiazolyl sulphide can be achieved by using a Grignard reagent in the presence of copper(1) iodide and choice of a particular reaction medium (Scheme 3).13 'Et20 THF qR Et,O-RI-R R' Scheme 3 A general method for the syn-carbometallation of alkynes both internal and terminal now seems to have been found in which the alkyne is treated with zirconocene dichloride and a trialkylaluminium.l4 The metal-alkenyl can then be converted into both simple and functionalized alkenes by well-established 'P. J. Kocienski B. Lythgoe and S. Ruston J.C.S. Perkin 1 1978 829. lo K. Takai Y. Hotta K. Oshima and H. Nozaki Tetrahedron Letters 1978 2417. l1 cf. D. L. J. Clive Tetrahedron 1978 34 1049. l2 D. Labar L. Hevesi W. Dumont and A. Krief Tetrahedron Letters 1978 1141; H. J. Reich S. Wollowitz,J. E. Trend F. Chow and D. F. Wendelborn J. Org. Chem. 1978,43 1697. l3 P. Barsanti V. Calo L. Lopez G. Marchese F. Naso and G. Pesce J.C.S. Chem. Comm. 1978 1085. l4 D. E. Van Horn and E.-i. Negishi J. Amer. Chem.Soc. 1978,100 2252. Synthetic Methods method^.'^ This procedure can be used to introduce a methyl group,14 although earlier difficulties in the use of methylcopper reagents have now largely been overcome.l6 Another advance shows that methylmagnesium bromide can be added to silylacetylenes in the presence of a nickel catalyst." Cycloalkenes are produced by the reduction of vicinal cyanohydrin mesylates (l) derivable from imino-nitriles formed by the Thorpe-Ziegler cyclisation." Reduc-tion of specific enol phosphates can now be best accomplished by the use of freshly formed titanium metal; the method" can be used to generate 1,3-dienes [e.g. (2)] which are not reduced under these conditions. Interest continues in other syntheses of 1,3-dienes.The reaction of l-alkenyl-zirconium derivatives (see above) with alkenyl halides with palladium catalysis provides a highly stereo- and regio-selective synthesis2' which is also applicable to more highly substituted alkenylzirconium chloride derivatives provided that the coupling is further promoted by zinc chloride2' (Scheme 4). Et Et Et Et \/ Et-C=C-Et & \C=C / /c=c\ /Me H /' \ZrCp2C1 H H/c=c \C02Me Br Me Reagents i Me,AI/Cp,ZrCl,; ii 'CS ,Pd(PPh& ZnC1 H / 'C0,Me Scheme 4 An equally good method is the palladium-catalysed coupling of alkenylmagnesium halides with alkenyl iodides.22 1,3-Dienes can also be prepared from alkynes through the palladium-catalysed condensation of the derived alkenyl-mercury Is N. Okukado and E.-i.Negishi Tetrahedron Letters 1978 2357. l6 A. Marfat P. R. McGuirk and P. Helquist Tetrahedron Letters 1978 1363. l7 B. B. Snider M. Karras and R. S. E. Conn J. Amer. Chem. SOC.,1978 100,4624. '* J. A. Marshall and L. J. Karas Synth. Comm. 1978 8 65. l9 S. C. Welch and M. E. Walters J. Org. Chem. 1978,43 2715. 2o N. Okukado D. E. Van Horn W. L. Klima and E.-I. Negishi Tetrahedron Letters 1978 1027. 21 E.-i. Negishi N. Okukado A. 0.King D. E. Van Horn and B. I. Spiegel J. Amer. Chem. SOC.,1978 100,2254. '* H. P. Dang and G. Linstrumelle Tetrahedron Letters 1978 191. 306 R. Brettle derivatives which leads to the head-to-tail dimer~.~~ A new regiospecific 1,3-diene synthesis starting from ally1 involves the intermediacy of allylic sulphox- ides produced by a [2,3] sigmatropic rearrangement (Scheme 5).Ar Reagents i ArSCI Et,N; ii A Ar = 2,4-dinitrophenyl. Scheme 5 1,4-Dienes can be prepared by the palladium-catalysed allylation of alkenyl pentafluorosilicates (3)which are available from the hydrosilylation of alkynes. An ester group survives the operations as in the preparation of methyl dodeca-8,ll- dienoate from methyl nor1-8-ynoate.~~ 3 Alkynes Disubstituted alkynes need not be made from alk-1-ynes. They can be prepared also by the reductive elimination of enol-phosphates of a-phenylsulphonyl ketones with sodium in liquid ammonia or sodium amalgam in aprotic solvents; the procedure26 has been applied to the preparation of medium ring cycloalkynes and conjugated enynenes (Scheme 6).Cyclic amidines uniquely permit the condensation of alk-l-ynes with primary halides in the presence of copper(1) halide.27 Reagents i LiN(Pr’),; ii CIPO(OEt),; iii Na/Hg THF DMSO Scheme 6 cui HOCH,C-CH + CH2=CHCH2Br DSV; HOCH2CzC-CH2CH=CH2 * DBU = 1,5-diazabicyclo[5,4,O]undec-5-ene *’ R. C. Larock and B. Riefling J. Org. Chem. 1978,43 1468. 24 H.J. Reich I. L. Reich and S. Woilowitz J. Amer. Chem. SOC.,1978 100 5981. ’’J.-I. Yoshida K. Tamao M. Takahashi. and M. Kumada Tetrahedron Letters 1978 2161. 26 B.Lythgoe and I. Waterhouse Tetrahedron Letters 1978,2625;P.A.Bartlett F. R. Green and E. H. Rose J. Amer. Chem. SOC.,1978 100,4852. 27 K.Eiter F.Lieb H. Disselnkotter and H. Oediger Annalen 1978 658. Synthetic Methods 4 Halides The anti-Markovnikov addition of hydrogen halide to an alkene can be achieved through the alkyl pentafluorosilicate derived by hydrosilylation.Preferential addi- tion to a terminal double bond in the presence of a more highly substituted double bond is observed and the method can also be applied to (3) to give the alkenyl halide.28 Oxidation of the intermediate alkyl pentafluorosilicate with meta-chloro- perbenzoic acid gives the corresponding alcohol providing a competitive method of anti-Markovnikov hydration.29 Although alk-1-ynes are reduced to alkanes by di-imide 1-iodoalkynes are reduced to alkenyl iodides.30 RCH(0H) \ I \/ RCH(OH)C=CI -* /c=c\H H 5 Alcohols Many routes to allylic alcohols have been discussed this year.Several use the reaction of aldehydes or ketones with the carbometallation products of alkynes15-” (see above). Warren who has reviewed organic syntheses using the migrating functional groups Ph,PO and PhS,31 has introduced a versatile synthesis in which the adducts of aldehydes to the anions of ally1 phosphine oxides are reduced with loss of phosphorus and regiospecific and stereoselective transposition of the double bond.32 In the example shown (Scheme 7) an endocyclic double bond moves to an exocyclic Scheme 7 location. Trisubstituted alkenes with ‘phenylselenenic acid’ give selenohydrins which on oxidation with t-butyl hydroperoxide in the presence of magnesium sulphate give the tertiary allylic The reagent is prepared from either diphenylselenide or hypophosphorous acid and phenylseleninic acid.Alternatively selenohydrins can be prepared from formaldehyde and the anions produced by the action of butyl-lithium on selenoacetal~.~~ The analogous P-hydroxysulphoxides give allylic alcohols on refluxing in xylene containing suspended sodium arbo on ate.^^ K.Tamao J.-I. Yoshida M. Takahashi H. Yamamoto T. Kakui H. Matsumoto A. Kuriba and M. Kumada J. Amer. Chem. SOC.,1978,100 290; J.-I. Yoshida K. Tamao K. Kurita and M. Kumada Tetrahedron Letters 1978 1809. 29 K. Tamao T. Kakui and M. Kumada J. Amer. Chem. Soc. 1978,100,2268. 30 C. Luthy P. Konstantin and K. G. Untch J. Amer. Chem. SOC.,1978,100,6211. 31 S. Warren Accounts Chem. Res. 1978 11,401. 32 R. R. Arndt and S. Warren Tetrahedron Letters 1978,4089.33 T. Hori and K.B. Sharpless J. Org. Chem. 1978 43 1689; D. Labor A. Krief and L. Hevesi Tetrahedron Letters 1978 3967. 34 D. Labor W. Dumont L. Hevesi and A. Krief Tetrahedron Letters 1978 1145. 35 J. Nokami K.&La dlld R. Okaware Tetrahedron Letters 1978,4903. 308 R. Brettle The stereo- and regio-selective rearrangement [e.g. (4) + (5)] of oxirans to allylic alcohols by organoaluminium compounds has been reviewed;36 in hexamethyl- phosphoric amide lithium di-isopropylamide achieves the same end.37 ap-Olefinic (4) (5) ketones give almost exclusively the allylic alcohols on reduction with borohydride in methanolic cerium tri~hloride,~~ while the corresponding aldehydes are similarly reduced on treatment with hydridoiridium sulphoxide complexes in propan-2-01.~’ The 1,3-transposition of primary allylic alcohols [e.g.(6)-+(7)] can be achieved through selenium intermediates under mild condition^.^' (TOH -OOH (6) (7) A highly stereoselective synthesis of homoallylic alcohols containing a Z-tri- substituted double bond invoives a pseudoaxially-substituted transition state in a [2,3] sigmatropic rearrangement;41 it is illustrated (Scheme 8)for the synthesis of a natural sex-attractant (8). (8) Reagents i KH; ii Bu,SnCH,I; iii BuLi Scheme 8 A major improvement in the osmium-catalysed vicinal hydroxylation of alkenes by t-butyl hydroperoxide makes this the most economic catalytic method although it is still not successful with hindered and highly substituted alkene~.~* anti-Hy-droxyphenylsulphenylationof an alkene can be effected by treatment with diphenyl disulphide lead tetra-acetate and trifluoracetic acid followed by a basic work-~p.~~ Oxyamination of alkenes is considered in Section 7.’‘ H. Yamamoto and H. Nozaki Angew. Chem. Internat. Edn. 1978,17 169. 37 M. Apparu and M. Barrelle Tetrahedron 1978 34 1541. J.-L. Luche J. Amer. Chem. SOC.,1978 100,2226. 39 B. R. James and R. H. Morris J.C.S. Chem. Comm. 1978,929. 40 D. L. J. Clive G. Chittattu N. J. Curtis and S. M. Menchen J.C.S. Chem. Comm. 1978 770. 41 W. C. Still and A. Mitra J. Amer. Chem. Soc. 1978,100 1927. 42 K. Akashi R. E. Palermo and K. B. Sharpless J. Org. Chem. 1978 43 2063. 43 B. M. Trost M. Ochiai and P. C. McDougal J. Amer.Chem. SOC.,1978,100 7103. Synthetic Methods 6 Nitro-compounds Corey has described a new synthesis of conjugated nitro-cycloalkenes (Scheme 9) and has summarized their many synthetic transformation^.^^ The method is also Reagents i HgCI,; ii NaNO,; iii NaOH Scheme 9 applicable to acyclic alkenes. Various helpful modifications to the alternative nitro-aldol reaction have also been reported.45 Condensation of a phenyl ester with a nitronate anion leads to an a-nitroketone under mild condition^;^^ an application in the biotin field is illustrated (Scheme 10). Reagent i C,HSCHMeNH Scheme 10 7 Amines Propane- 1,3-dithiol is an extremely selective reagent for the reduction of functionalized alkyl and aryl azides to the corresponding primary amine~.~~ Alkyl-lithium type reagents react with NN-dialkyl- 0-arylsulphonylhydroxylaminesto give tertiary amines and in this way some amines which were hitherto unobtainable [e.g.(9)] have finally been ~repared.~’ Certain highly hindered primary amines can be (9) 44 E. J. Corey and H. Estreicher J. Amer. Chem. SOC.,1978 100,6294. ” (a)E. W. Colvin and D. Seebach J.C.S. Chem. Comm. 1978,689;(b)R. H. Wollenberg and S.J. Miller Tetrahedron Letters 1978,3219. 46 J. Vasilevskis,J. A. Gualtieri S. D. Hutchings R. C. West J. W. Scott D. R. Parish F. T. Bizzarro and G. F. Field J. Amer. Chem. SOC.,1979,100 7423. 47 H. Bayley D. N. Standring and J. R. Knowles Tetrahedron Letters 1978.3633;J. V.Staros H. Bauley D. N. Standring and J. R. Knowles Biochem.Biophys. Res. Comm. 1978,80 568. 48 G. Boche N. Mayer M. Bernheim and K. Wagner Angew. Chem. Internat. Edn. 1978 17,687. 310 R. Brettle made by the a-allylation of N-sulphinylamines themselves readily available from primary amines (Scheme 1l).49Treatment of diphenyl disulphide with chloramine T NH -!+ NH Reagents i SOCl,; ii Ph,CLi’; iii h C Scheme 11 affords reagents which react with alkenes to give adducts which on reduction with borohydride give vicinal phenylsulphenyl N-toluenesulphonamides; cyclohexene for example gives (1O).” Raney nickel desulphurization gives the N-toluenesul- phonamides. The corresponding hydroxy-N-toluenesulphonamidesand hydroxy- N-tertiary alkylamines had been made previously using osmium-based processes.OSPh ‘NHTOS (10) However in all these cases liberation of a primary amino-group is scarcely possible. A modified process in which alkenes undergo an osmium-catalysed vicinal oxy- amination through the agency of N-chloro-N-argentocarbamatesnow permits the introduction of nitrogen in a conventionally protected urethane form5’ (Scheme 12). (11) Reagents i AgNO,; ii 1% OsO,; iii MeCN/H20 Scbeme 12 The process works satisfactorily with electron-deficient alkenes and the regioselec- tivity is greater than in the other catalytic processes. A warning is given about the instability in quantity of the N-chlorosodiocarbamates (11)used as reagents. Vicinal ditertiary amines can be obtained by an aminopalladation-oxidation sequence,” with overall syn-addition an alternative to routes using osmium-based reagents or via aziridines.Two preliminary reports on metallo-oxaziridines have appea~ed.’~ They were expected to show ‘nitrenoid’ behaviour but with alkenes the products are 49 F. M.Schell J. P. Carter and C. Wiaux-Zamar J. Amer. Chem. SOC.,1978 100,2894. 50 D. H. R. Barton M.R. Britten-Kelly and D. Ferreira J.C.S.Perkin 1 1978 1090 or 1682. 51 E. Herranz S. A. Biller and K. B. Sharpless J. Amer. Chem. SOC.,1978 100 3596. ” J.-E. Backvall Tetrahedron Letters 1978 163. ’’ L. S. Liebeskind K.B. Sharpless R.D. Wilson and J. A. Ibers J. Amer. Chem. Soc. 1978,100,7061;D. A. Muccigrosso S. E. Jacobson P. A. Apgar and F. Mores J. Amer. Chem. Soc. 1978 100,7063. Synthetic Methods 311 allylamines formed by transposition of the double bond as in an ‘ene’ reaction and not aziridines (Scheme 13).NHAr 0 L,II 0 Reagent i Mo I L’/ \ NPh LL Scheme 13 8 Aldehydes and Ketones The search for new reagents for the preparation of aldehydes and ketones by the oxidation of alcohols has continued. Tetrabutylammonium permanganate seems an attractive po~sibility,’~ but a strong warning has been given about the inherent instability of the crystalline reagent following a fire.” Barium manganate worked well in several casess6 and an operationally simple procedure based on phase transfer catalysis of oxidation by dichromate has been reported.” Chromic acid adsorbed on silica gels8 and polyEvinylpyridinium chlorochr~mate]~~ are two other useful reagents which have been investigated; in these cases there is the well recognised advantage with insoluble reagents of ease of workup.Oxalyl chloride should be added to the list of generally effective activators of dimethyl sulphoxide in alcohol oxidations.60 Benzeneseleninic anhydride gives high yields in the oxidation of various alcohols under essentially neutral conditions.61 For steroids with a hydroxyl group at C-3 the oxidation is accompanied by dehydrogenation of ring A as exemplified in Scheme 14.62 p-0x0-bis(chlorotripheny1bismuth)is another mild oxidant,63 particularly useful for the oxidation of allylic alcohols e.g. vitamin A alcohol. Scheme 14 54 T. Sala and M. V. Sargent J.C.S. Chem. Comm. 1978 253. 55 J. A. Morris and D.C. Mills Chem. Brit. 1978,326. 5‘ H. Firouzabadi and E. Ghaderi Tetrahedron Letters 1978 839. ” D. Pletcher and S.J. D. Tait Tetrahedron Letters 1978 1601. ’’ E. Santanielle F. Ponti and A. Manzocchi Synthesis 1978 534. 59 J. M. J. Frechet J. Warnock and M. J. Fowall J. Org. Chem. 1978,43 2618. “ K. Omura and D. Swern Tetrahedron 1978,34 1651. “ D. H. R. Barton A. G. Brewster R. A. H. F. Hui D. J. Lester S. V. Ley and T. G. Back J.C.S.Chem Comm. 1978,952. 62 D. H. R. Barton D. J. Lester and S. V. Ley J.C.S. Chem. Comm. 1978 130. ” D. H. R. Barton 3.P. Kitchin and W. B. Motherwell J.C.S. Chem. Comm. 1978. 1099. 312 R. Brettle Aldehydes and ketones can be prepared conveniently on occasion by the reduction of the corresponding ap-olefinic compounds and this can be done rather simply by their palladium-catalysed reduction with triethylammonium f~rmate.~~ The reduction of an acid chloride to an aldehyde has always caused some difficulty but it has now been shown that this can be done by sodium borohydride provided that it is used in dimethylformamide containing cadmium or by bis(tri- phenylphosphine)copper(1)borohydride in acetone.66 The McFadyen and Stevens synthesis of aromatic aldehydes has been modified so that it now works well for aliphatic aldehydes too.Vacuum pyrolysis of the dry alkali-metal salts of 1-acyl-2-arylsulphonylhydrazines achieves this.67 An efficient formylation of Grignard reagents leading directly to the aldehyde,68 uses N-formyl- N-methyl-2-aminopyridineas the reagent in a manner reminiscent of the earlier Mukaiyama ketone synthesis.Vinyl chlorides can be hydrolysed to ketones under mild conditions by a combination of-mercury(I1) acetate and boron trifluoride etherate; this method was successful where previously recommended methods f ailed.69 The 1,2-transposition of a keto-group is an important part of synthetic methodology. Paquette has now introduced a method based on vinylsilanes (Scheme 15) which complements earlier methods and is rapid despite the several OH Reagents i ArSO,NHNH,; ii R'Li; iii Me,SiCI; iv m-C1C6H,CO0,H; v LiAIH,; vi CrO, Et,O H20 HzS04 Scheme 15 steps inv01ved.'~ It is regioselective since the deprotonation of the ketone aryl- sulponylhydrazone in the Shapiro reaction normally occurs at the lesser-substituted of the a-positions; thus cholestan-3-one goes to cholestan-2-one.An earlier method due to Trost began with a-sulphenylation. If the Shapiro alkene synthesis is applied to the resultant a-sulphenyl-ketone the product is a vinyl sulphide which en hydrolysis gives the transposed ketone.71 Alternatively a methylative trans- position can be achieved by Wittig methylenation of the a-sulphenyl ketone followed by alkyl-lithium-catalysed isomerisation of the resultant alkyl sulphide to the vinyl ~ulphide.~~ Deprotection is often a vital step in the synthesis of aldehydes and ketones. Treatment of thioacetals with pentyl nitrite followed by hydrolysis provides a mild route to the carbonyl compound; selective cleavage of a fully protected ketoaldehyde 64 N.A. Cortese and R. F. Heck J. Org. Chem. 1978,43,3985. 65 R. A. W. Johnstone and R. P. Telford J.C.S. Chem. Comm. 1978 354. G.W. J. Fleet C.J. Fuller and P. J. C. Harding Tetrahedron Letters 1978 1437; T. N.Sorrel1 and R. J. Spillane Tetrahedron Letters 1978 2473. 67 M. Nair and H. Shechter J.C.S. Chem. Comm. 1978 793. " D.Cornins and A. I. Meyers Synthesis 1978,403. 69 S. F. Martin and T. Chou J. Org. Chem. 1978 1027. 70 W.E.Fristad T. R. Bailey and L. A. Paquette J. Org. Chem. 1978 43 1620. " S.Kano T. Yokomatsu T. Ono S. Hibino and S. Shibuya J.C.S. Chem. Comm. 1978 414. Synthetic Methods 313 to free the aldehyde group has been demonstrated with this The utility of wet silica gel for dea~etalization,~~ particularly to produce acid-sensitive cup-olefinic carbonyl compounds was quickly recognised.Olefinic Aldehydes and Ketones.-Imaginative syntheses of ap-olefinic aldehydes and ketones continue to appear. Hooz has developed a synthesis from alkynes (Scheme 16)which is notable for the selective oxidation of boron in the presence of iii RCH2C=CLi R:BC=CCH,R Li+ A R:BHSePh _+ RlqSePh R' CH,R CH,R Reagents i. R:B; ii PhSeCI; iii H20 Me,&-O; iv H202 Scheme 16 selenium by trimethylamine N-o~ide.~~ Vinylmercurials accessible by the hy- drozirconation of alkynes give ap-olefinic ketones in a stereospecific fashion on treatment with acid chlorides in the presence of aluminium cup-Olefinic ketones can be prepared in a very high yield by the regiospecific desaturation of the saturated ketones brought about by the treatment of a specific enol trimethylsilyl ether with palladium(I1) acetate.76 Photo-oxygenation of enol methyl ethers avail- Pd(0Ac) OSiMe able by the Wittig route by singlet oxygen gives intermediates (11)which are readily transformed into ap-olefinic aldehydes (Scheme 17).77An earlier method for the o-,i_ \ OMe A ROMe 2% Q,/ II OOH 0 (11) Reagents i Ph36-cHOMe; ii lo2; iii Ph3P Scheme 17 72 K.Fuji K.Ichikawa and E.Fujita Tetrahedron Letters 1978 3561. 73 F. Huet A. Lechevallier M. Pellet and J. M. Conia Synthesis 1978 63. 74 J. Hooz and R. D. Mortimer Canad. J. Chem. 1978,562786. 75 R. C. Larock and J. C. Bernhardt J. Org. Chem. 1978,43,710. 76 Y. Ito T. Hirao and T.Saegusa J. Org. Chem. 1978,43 1011. 77 G. Rousseau P. Le Perchec and J. M.Conia Synthesis 1978 67. 3 14 R. Brettle conversion of a ketone into the ap-olefinic aldehyde with two more carbon atoms has been improved by the introduction of a more accessible ~eagent.'~ A modification of the Mannich route uses trioxan and N-methylanilinium trifluoroacetate and is widely applicable to the synthesis of a-methylene-substituted and vinyl ketones." The p-acylenamines (12) obtained by the action of dimethyl- formamide acetals with ketones react with alkyl-lithiums to give ap-olefinic (12) Routes to cup-olefinic ketones based on 1-methoxyallene are illustrated in Scheme 18.81Thiolcarbamates already known as precursors of ap-olefinic aldehydes [see -.-/ OMe i v vi =*q: MeS-0 RZ II I 111 1i; i! o ki Me0 RZL.<OMe -\r-u"' R1 R RZ p Reagents i BuLi; ii R'X; iii R'X; iv H,O'; v R'R'CO; vi MeSOCI Et,N; vii [RCuBrIMgX LiBr Scheme 18 Ann.Reports (B) 1977 74 p 3281 have now been used to prepare a@-olefinic ketones8' and so have olefinic dithioesters for which a new synthesis has been reporteds3 (Scheme 19). L~~~uSMe i,ii,iii MeS SMe Reagents i PhNCS; ii MeI; iii H,S; iv Me,CzCHCH,Br; v AgN03 CdCO, H,O; vi base Scheme 19 '' A. I. Meyers K. Tomioka and M. P. Fleming J. Org. Chem. 1978,43 3788. 79 J.-L. Gras Tetrahedron Letters 1978 211 1 and 2955. R. F. Abdulla and K. H. Fuhr J. Org. Chem. 1978,43,4248. H. Kleijn H. Westmijze and P. Vermeer Tetrahedron Letters 1978 1133; J.C. Clinet and G. Linstrumelle Tetrahedron Letters 1978 1137. T. Nakai T. Mimura and T. Kurokawa Tetrahedron Letters 1978 2895. 83 P. Gosselin S.Masson and A. Thuiller Tetrahedron Letters 1978 2715 and 2717. Synthetic Methods 315 Two sequences (Scheme 20) based on selenium intermediates construct a& olefinic ketones from ketones and o~iranes~~ and from alkenes and halo alkane^^^ respectively. R' R'bo i,ii R' FSeR A A hR2 R' R' 2 R R' 0 Reagents i RSeH/ZnCI,; ii BuLi; iii CH,-CHR2; iv CrO,/Me,CO; v PhSeBr/EtOH; vi NaIO,; vii heat; viii R'CH,X Scheme 20 Cookson has developed versatile syntheses of enones dienones and dienals using a sulphur based methodology the principal features of which are summarized in Scheme 21.86 R' >L.-/~~~ R 'CH iii,iv v ,"y.cb,-RZ?'"i R2 R2 R3 R3 0 Fi OH RICH2 R'cH,+-& )=.& SOAr iii,vi RICH2 SOAr .RICH SAr b )=4A G.4 R2 R2 R2 R3 R2 R3 f (13) Jvii R' R3 R5 R'CH SOAr R'CH2 ix R2+~4 tR'vR3 0 OXR6 \ R2+?rR3 0 R6 R4 R5 viii R6 R4 /JSPh o+ EOgR6d-Ho<R6 R4 R5 R5 R4 R5 (14) Reagents i p-MeC6H4SCI; ii PzSs CsHsN; iii BuLi; iv R3CHO; v HCI/H,O/MeCN m-C1C6H4CO02H; heat; vi R3X; vii HgCI,/H,O/MeCN; viii (13)/NaH; ix ZnCO, distil; x PhSCrC-Na'; xi m-CIC,H,COO,H; xii (14)/NaH %heme 21 '* M. Sevrin and A. Krief Tetrahedron Letters 1978 187. 85 T. Takahashi H. Nagashima and J. Tsuji Tetrahedron Letters 1978,799. 86 R. C. Cookson and R. Gopalan J.C.S. Chem. Comm. 1978 608 and 924; R.C. Cookson and P. J. Parsons J.C.S. Chem. Comm. 1978,821 and 822. 316 R. Brettle Fleming has shown that P-silylated ketones act as masked cup-olefinic ketones into which they can be converted by bromination-desilylbromination. This is demon- strated by the use of the P-keto-ester (15)as a synthon for olefinic ketones of the type (16)and by the sequence shown in Scheme 22.'' MeCOCHC02Me MekR I CH2SiMe3 CH2 (15) (16) Some other routes to aldehydes and ketones based on the alkylation of anion equivalents are discussed in Section 10. Reagents i LiSiMe,Ph CuI; ii R'X; iii CuBr, base Scheme 22 9 Carboxylic Acids and Derivatives Carboxylic acids can be prepared directly from organoboranes by reaction with the dianion from phenoxyacetic acid.88 A selective functionalization of a diene is illustrated by Scheme 23.A new high yielding version of the ester Claisen rear- Reagents i 9-BBN*; ii PhOCHCO;; iii H+/*9-BBN = 9-Borabicyclo[3,3,1]nonane Scheme 23 rangement employing selenium intermediates has been described" and is shown in Scheme 24. 0 Reagents i PhSeBr; ii,'h ; iii NaIO,; iv C6H13NH2 139 "C OH Scheme 24 '' I. Fleming and J. Goldhill J.C.S. Chem. Comm. 1978 176; D. J. Ager and I. Fleming J.C.S. Chem. Comm. 1978,177. S. Hara K. Kishimura and A. Suzuki Tetrahedron Letters 1978 2891. 89 M. Petrzilka Helv. Chim. Acta 1978 61 2286. Synthetic Methods 317 The use of reagents like 4-dimethylaminopyridine (DMAP) and 4-pyrrolidinyl- pyridine (PPY) as highly active acylation catalysts has been reviewed.” They are now used routinely to catalyse the acylation of alcohols using acid anhydrides and it has now also been shown that a direct room temperature esterification of carboxylic acids by alcohols and thiols is possible using dicyclohexylcarbodi-imideas the acti- vator and DMAP or PPY as a catalyst.9* Several other new mild procedures for the direct esterification of acids by alcohols have been recommended based on the use of cyclic amidines (DBU),92 dimethylformamide imide~hloride,~~ NN-dimethyl-phosphoramidic di~hloride,~~ Each of them like the or phenyl dichlor~phosphate.~~ previous procedure” offers advantages for thermally sensitive sterically hindered or chiral reactants.The carboxyl group in amino- hydroxy- and mercapto-carboxylic acids can be specifically activated by 4-dimethylamino-3-butyn-2-one (17) and the resultant enol-ester (18) can then for example be treated with a thiol to give the thiolester (Scheme 25).95 Dimethylaluminium methylselenolate (from tri-methylaluminium and selenium) converts alkyl esters into methylselenol esters which are very promising acyl transfer reagents; for example they react with amines in the presence of mercury(r1) chloride and calcium carbonate to give amide~.~~ Me,N I .Me2NKOCOR Me2N“i.. -% RCOSR’ I IllI CH H\ COMe COMe OCOR (17) (18) Reagents i RC0,H; ii spontaneous at 0 “C; iii R’SH Scheme 25 Acids can also be activated by reaction with catecholborane; an amine then reacts to give the amide.This method9’ hi-is some disadvantages for the preparation of medium ring lactams due to solubility problems but the reaction of the tetrabutyl- ammonium salts of w-amino-acids with B-chlorocatecholborane in pyridine gives better yields of the lactams under homogeneous condition^.^^ Corey’s first total synthesis of a maytansenoid macrocyclic lactam9* employs a characteristically effective new lactamization procedure in which a benzene solution of the tetrabutyl- ammonium salt of the w-amino-acid is added by syringe to a solution of excess mesitylsulphonyl chloride and di-isopropylethylamine in benzene. In the macrolide field 4,4’-bis(2-amino-6-methylpyrimidyl) disulphide has some advantage over 2,2’- bipyridyl disulphide in the activation of w-hydroxy-acids as thiol esters prior to their silver ion catalysed lact~nization.~~ 90 G.Holfe W. Steglich and H. Vorbriiggen Angew. Chem. Internat. Edn. 1978 17,569. 91 A. Hassner and V. Alexaman Tetrahedron Letters 1978 4475; B. Neises and W. Steglich Angew. Chem. Internat. Edn. 1978 17 522. 92 N. Ono T. Yamada T. Saito K. Tanaka and A. Kaji Bull. Chem. SOC.Japan 1978,51,2401. 93 P. A. Stadler Helv. Chim. Acta 1978,61 1675. 94 H.-J. Liu W. H. Chan and S. P. Lee Tetrahedron Letters 1978 4461. 95 H.-J. Gais and T. Lied Angew. Chem. Internat. Edn. 1978,17 267. 96 A. P. Kozikowski and A. Ames J. Org. Chem. 1978,43 2735. 97 D. B. Collum S.-C. Chen and B. Ganem J. Org. Chem. 1978,43,4393. 98 E. J. Corey L. 0.Weigel D. Floyd and M.G. Bock J. Amer. Chem. SOC.,1978 100,2917. 99 J. S. Nimitz and R. H. Wollenberg Tetrahedron Letters 1978 3523. 318 R. Brettle In a quite different type of macrolide Synthesis"' (Scheme 26) an o-hydroxy- iodide is converted into its (phenylsulpheny1)acetyl derivative the anion from which can then displace the iodine; the sulphur substituent permits the optional intro- duction of a conjugated olefinic bond. Reagents i PhSCH,COCI; ii (Me,Si),NK Scheme 26 10 Nitriles The hydrocyanation of conjugated carbonyl compounds has been covered by Organic Acetylenic alcohols [e.g. (191 can be reductively hy- drocyanated to give P-hydroxynitriles [e.g. (20)] by aqueous pentacyanocobaltate(I1) and hydrogen at atmospheric pressure.lo2 Aldoximes can be dehydrated to give nitriles by triethylamine-sulphur dioxide lo3 or by selenium dioxide.lo4 11 Alkylation A bewildering variety of carbanions is now used in synthesis. They are frequently based on the 'Urnpolung' reversed polarity principle so that they are the masked equivalents of hypothetical anions. Many reactions of this type employed to synthesise primarily one particular class of compound have been dealt with in earlier sections. The reactions of other with a wide variety of electrophilic alkylating reagents including halides epoxides aldehydes and ketones and conjugated carbo- nyl systems are discussed in this section. Acyl carbanion equivalents continue to appear. A cyanohydrin ether cannot be used as a masked formaldehyde equivalent but NN-diethylamino acetonitrile can be used instead,"' and in some cases is preferable to 1,3-dithiane.The carbonyl function in the products can be unmasked by copper(r1)-assisted hydrolysis.'06 loo T. Takahashi S. Hashiguchi K. Kasuga and J. Tsuji J. Amer. Chem. Soc. 1978,100,7424. lo' W. Nagata and M. Yoshioka Org. Reactions 1977,25 255. Io2 T. Kunabiki Y. Yamazaki and K. Tarama 112s.Chem. Comm. 1978,63. lo3 G. A. Olah and Y. D. Vankar Synthesis 1978 702. Io4 G. Sosnovsky and J. A. Krogh Synthesis 1978,703. lo' G. Stork A. A. Ozario and A. Y. W. Leong Tetrahedron Letters 1978 5175. G. Buchi P.H. Liang and H. Wuest Tetrahedron Letters 1978 2763. Synthetic Methods Other convenient acyl carbanion equivalents are 2-substituted I,3-benzo-dithiole~,'~~ 1-phenylselenoalkenes,lo8 and bis(phenylseleno)acetals;'08 the selenium based reagents require potassium diisopropylamide-lithium-butoxidefor their deprotonation.The reagent (21) derived from a dithioester by the action of lithium diisopropylamide is the equivalent of the acyl dianion (CHz-C=O) a hitherto unreported specie^.'^' Its application in synthesis is shown in Scheme 27. Et Reagents i RCHO; ii H20; iii EtOCH=CH, H'; iv EtMgX; v E' Scheme 27 R Masked enolate anions continue to be reported and full details have appeared of Corey's earlier work with metallated dimethylhydrazones.' lo Corey has more recently done extensive work in the use of alkenylbenzothiazoles which are readily synthesized from ketones in carbanion chemistry.''* Reduction and metallation gives an enolate anion equivalent (22) which can be alkylated and the carbonyl function then unmasked (Scheme 28a). On the other hand metallation of the alkenylbenzothiazole gives the equivalent of a vinylogous enolate anion (23) which undergoes exclusively a-alkylation; unmasking of the carbonyl group leads to the by-olefinic aldehyde with no isomerization of the double bond (Scheme 28b). (22) major product BT BT BT CH,Ph OHC CH,Ph BT= us> N Reagents i HJPdC; ii BuLi; iii mBr; iv MeOS0,F; v NaBH,; vi MeOS0,F; K2C03 H20; vii LiN(Pr'),; viii PhCH2Br; ix AgNO, H,O; Et3N Scheme 28 lo' S. Ncube A. Pelter K. Smith P. Blutcher and S. Warren Tetrahedron Letters 1978 2345. lo* S.Raucher and G. A. Koolpe J.Org Chem. 1978,43 3794. lW A. 1. Meyers T. A. Tant and D. L. Comins Tetrahedron Letters 1978,4657. 'lo E. J. Corey and D. Enders Chem. Ber. 1978,111 1337 and 1362. E. J. Corey and D. L. Boger Tetrahedron Letters 1978,5,9.and 13. 320 R. Brettle Regiospecifically generated lithioenamines (24) which are available from various precursors can be used as enolate equivalents (Scheme 29),'12 and so can 2-2- ethoxyvinyl-lithi~n;''~the analogous vinylogous anion equivalent 4-ethoxybuta- 193-dienyl-lithium has also been reported.' l4 CHPh CHPh BuCHPh BuCHPh It II I 1 N EtO,RARl -b P R' R' EtO' Reagents i R3COCH2R2; ii BuLi; iii E; iv H,O'; v K'Bu'O-Scheme 29 An a-formylvinyl anion equivalent is available' '' in 1-bromo-2-ethoxycyclo-propyl-lithium (Scheme 30) and the anion (25) is one of several a-ketoanion equivalents now reported116 (Scheme 31).OEt OEt 11 &-i &.(OH). 3OHC OH Br Br Reagents i RCHO; ii EtOH K2C0,; iii H30+ Scheme 30 Reagents i BuLi; ii E; iii (C0,H)2 H20 Scheme 31 "* P. A. Wender and M. A. Eissenstat J.Amer. Chem. SOC.,1978,100,292;P. A. Wender and J. M. Schaus J. Org. Chem. 1978 43 782; S. F. Martin and G. W. Phillips J. Org. Chem. 1978 43 3792. 'I3 K. S. Y. Lau and M. Schlosser I. Org. Chem. 1978,43 1594. 'I4 R. H. Wollenberg Tetrahedron Letters 1978 717. 'I5 T. Hiyama A. Kanakura H. Yamamoto and H. Nozaki Tetrahedron Letters 1978,3047; and 3051. 'I6 M. A. Guaciaro P. M. Wookulich and A. B. Smith Tetrahedron Letters 1978,4661;S. f. Branca and A.B. Smith J. Amer. Chem. Soc. 1978 100,7767. Synthetic Methods Homoenolate anion equivalents are available in the form of a-silyloxyallyl-~ilanes,~"and the anions from Bdiphenylphosphinoyl acetals.118 The former react with acyl halides to give yketoaldehydes and the latter with aldehydes and ketones to give intermediates (26)which can be converted into By-olefinic a~etals"~ (Scheme 32). Lithium p-lithiopropionate reacts with aldehydes and ketones as a homo- enolate dianion thus providing a route to yy-disubstituted y-lactones. Reagents i BuLi; ii R3R4CO; iii NaH THF Scheme 32 Two routes to a-methylene-substituted esters make use of the anions of methyl P-dimethylaminopropionatelzo and ethyl acetoacetate"' as substituted vinyl anion equivalents (Scheme 33).The second of these sequences is just one example of a -C02R C02R Me2N Me2N -f CH3COCH2CO2R2CH3COCHCO2R i,vi.vii vCO2R RI R' Reagents i. LiN(Pr'),; ii R'X; iii MeI; iv DBU*; v NaOR/ROH; vi (CH,O), ;vii heat *DBU = 13-diazobicyclo[5,4,0]undec-5-ene Scheme 33 more general deacylative condensation which is applicable to other active methylkne compounds. A substituted vinyl anion also figures in a new a-methylene-lactone synthesis (Scheme 34);lz2in this work the mesitylsulphonylhydrazone was used but NHS0,Ar NS0,Ar . ... 1. 111 iv v i ii 3R2 R2 5R2 -Reagents i BuLi; ii R1R2CO; iii -70 "C +-3 "C +-70 "C; iv CO,; v CF,CO,H Scheme 34 'I7 A. Hosomi H. Hashimoto and H. Sakurai J. Org. Chem. 1978,43 2551.''' A.Bell A. H. Davidson C. Earnshaw H. K. Norrish R. S. Torr and S.Warren J.C.S. Chem. Comm. 1978,988. 'I9 D. Caine and A. S. Frobese Tetrahedron Letters 1978 883. L.-C. Yu and P. Helquist Tetrahedron Letters 1978 3423. Y. Ueno H. Setoi and M. Okawara Tetrahedron Letters 1978 3753. R. M.Adlington and A. G. M.Barrett J.C.S. Chem. Comm. 1978 1071. 12' 322 R. Brettle the 2,4,6-tri-isopropylsulphonylhydrazone has been recommended recently for this Shapiro-type of vinyl anion generation. lZ3 Carbinyl anion equivalents e.g. (27)124and those of type (28),'25which are readily prepared from aldehydes using tin intermediates have been reported and shown to react with halides and carbonyl compounds to give the protected forms of alcohols and diols respectively.(27) (28) Michael reactions and many other kinds of base-catalysed reactions are well known to be catalysed by fluoride ion in non-protic media. It has now been shown that this catalyst can conveniently be used either immobilized on a polymer or bound to silica gel with the usual advantages of such systems.'26 Several acylanion equivalents have been used as Michael donors. A synthesis of dienones uses the addition of a cyanohydrin ether to a dienylic ~ulphoxide'~~ and a synthesis of y-keto-aldehydes uses the addition of tris(pheny1thio)methyl-lithiumto an a@-olefinic ketone; the aldehyde group is produced by reduction of the adduct by chromium(I1) chloride to the thioacetal which is then unrnasked.l2' A hetero-cuprate derived from acetone NN-dimethylhydrazone has been added to an ap-olefinic ester to give after unmasking a 6-keto-e~ter,'~' and the corresponding lithium salt was added to an alkenyl benzothiazole to give an intermediate which could be converted into a 6-keto-aldehyde; 1-methoxyvinyl-lithium similarly added to give a protected yketo-aldehyde.The Michael addition of ethyl P-nitropropionate to an ap-olefinic ketone intro- duces an acrylic ester residue since the first formed p-nitroester eliminates nitrous acid. This p-acylvinyl anion equivalent has also been used in aldol-type conden- sations. The Michael addition can also be applied to the introduction of an ap-olefinic ketone unit provided that the acetal is used to prevent premature elimination of the nitro group.These Michael additions are illustrated in Scheme 35.130A rather similar result can be achieved by the use of a P-chloroacrylate ester as a Michael acceptor and a preformed ketone enolate as the donor.'31 C02Me WCO2Me 123 A. R. Chamberlin,J. F. Stenke and F. T. Bond J. Org. Chem. 1978,43 147. 124 P.Beak M. Baillargeon and L. G. Carter J. Org. Chem. 1978,43 4255. "'W.C.Still J. Amer. Chem. Sac. 1978,100,1481. J. M. Miller K.-H. So and J. H. Clark J.C.S. Chem. Comm. 1978 466; J. H.Clark J.C.S. Chem. Comm. 1978,789. '" E. Guittet and S. Julia Tetrahedron Letters 1978 1155. '" T.Cohen and S. M. Nolan Tetrahedron Letters 1978 3533. E. J. Corey and D. L. Boger Tetrahedron Letters 1978,4597. P.Bakuzis M.L. F. Bakuzis and T.F. Weingartner Tetrahedron Letters 1978 2371. G.Dionne and Ch. R. Engel Canad. J. Chem. 1978,56,419. Synthetic Methods 0 0 Reagents i Et0,CCH2CH,N0,; ii K' Bu'O-; iii MeOH; iv RC(OMe),CH,CH,NO,; v PriNH; vi H,O+ Scheme 35 The 1,4-addition of the enolate anion from ethyl acetate to an cup-olefinic ketone cannot be achieved directly but two ways of surmounting this difficulty have recently been reported. In the thiolester anion is used (Scheme 36)and in the which is only applicable to disubstituted olefinic ketones the decarboxylative addition of magnesium ethyl malonate gives the desired product directly. COSR COSR CO R I 111 0-Li + Reagents i CH,COSR/LiN(Pr'),; ii R'X or (R'= H),H,O'; iii Hg" Scheme 36 Shono has developed a versatile method for the alkylation of alkenes activated by conjugation to an electron-withdrawing substituent.Reaction with a halide in the presence of zinc leads to an anion which is then trapped by an electrophile for example an aldehyde or ketone or acetic anhydride (Scheme 37). Cyclization can occur with an appropriate halogen-substituted carbonyl compound. 134 The reactions of organocuprates may not be as restricted as earlier reports suggested. Two noteworthy prostanoid syntheses feature a high yield conjugate addition of a vinylcuproate to a y-acyloxy-ap-olefinic aldehyde without loss of the acyloxy group or 1,2-additi0n,'~~ and a facile oxiran ring opening with a mixed cuprate reagent. 136 Corey has developed (3-methyl-3-methoxy-1-butyny1)copper as R'X + R2CH=CR3Y + R4R5C0 M-R'R2CHCYR3C(OH)R4R5 Y = CN or COzMe Scheme 37 132 H.Gerlach and P. Kiinzler Helv. Chim. Acta 1978,61,2503. J. E. McMuny W. A. Andrus and J. H. Musser Synth. Comm. 1978,8 53. T. Shono I. Nishimuchi and M. Sasaki J. Amer. Chem. SOC.,1978 100,4314. 135 B.M.Trost J. M. Timko and J. L. Stanton J.C.S. Chem. Comm. 1978,436. 136 R. F.Newton C. C. Howard D. P. Reynolds A. H. Wadsworth N. M. Crossland and S. M. Roberts J.C.S. Chem. Comm. 1978,663. 324 R. Brettle a superior reagent for the generation of mixed cuprates due to their increased solubility in THF and used it in the preparation of a key intermediate for maytansine synthesis.13' Several other conjugate additions not achievable by organocuprates can now be accomplished in other ways.Conjugate addition to highly-substituted ap-olefinic esters and to ap-olefinic acids can be achieved by using the copper-boron reagents formed from alkyl-lithium copper(1) iodide and boron trifluoride. 13* Conjugate alkynylations can be achieved by the use of a nickel-catalysed reaction with an organoaluminium alkyne; ethynylation requires the use of tri-methylsilylethyne with subsequent deprotection. 139 cup-Olefinic amides perform unsatisfactorily in attempted conjugated addition reactions but the corresponding thioamides undergo 1,4-addition with organolithium and organomagnesium reagents and the products can readily be converted into their oxygen analogue^.'^^ 12 Ring Synthesis Corey has developed two new extremely versatile routes to cyclic systems.The basic reactions have been described in earlier Sections. l1 Addition reactions with alkenyl benzothiazoles make available a variety of dicarbonyl compounds which can then be cyclized by intramolecular aldol reactions to give annelated cup-olefinic ketones. This method is particularly suitable for spiroannelations; one of the many examples is shown in Scheme 38. Corey's 6-keto-ester synthe~is'~' provides an intermediate from which a wide selection of oxygenated decalins can be constructed. Reagents i BTLi; ii P,O,/MeSO,H 60 "C; iii MeLi; iv BrCH,CrCH; v MeOS0,F; vi NaBH,; vii K,CO,/H,O; viii H,SO,; Hg"; ix NaOH/EtOH Scheme 38 The Robinson annelation involves the reaction of a cyclic ketone with an acyclic ap-olefinic ketone.An example of the reverse process has now been re~0rted.l~' It leads to functionalized 9-methyl-& -decalins related structurally to natural sesqui- terpenes (Scheme 39). Much use has been made of the intramolecular versions of reactions better known in their intermolecular modes. For example the first example of an intramolecular De Mayo reaction has been reported as part of a clever total synthesis of longifolene 13' E. J. Corey D. Floyd and B. H. Lipshutz J. Org. Chem. 1978,43,3418; E. J. Corey M. G. Bock A. P. Kozikowski A. V. Rama Rao D. Floyd and B. H. Lipshutz Tetrahedron Letters 1978 1051. Y. Yamamoto and K. Maruyama J. Amer. Chem. SOC.,1978,100 3240. 139 R. T. Hansen D. B. Carr and J. Schwartz 1.Amer. Chern. Soc. 1978,100,2244.Y. Tamura T. Harada H. Iwamoto and 2.4.Yoshida J. Amer. Chem. SOC.,1978 100 5221. H. Irie J. Katakawa Y. Mizuno S. Udaka T. Taga and K. Osaki J.C.S. Chem. Comm. 1978 717. Synthetic Methods C0,Me Me C0,Me O&.+ F- O e O H C0,Me C0,Me H Scheme 39 (Scheme 40).14*Examples of the intramolecular Diels-Alder reaction include the first application to the synthesis of an anti-Bredt ~lefin'~~ (Scheme 41). 0 eoCH 0 Ph O<OCH *Ph .. ... 11 111 0 Reagents i hv; ii Hz,Pd/C; iii spontaneous retroaldolization Scheme 40 Conditions 8 s at 405 "C. Yield 16% Scheme 41 A splendid example of the intermolecular Diels-Alder reaction is provided in Stork's synthesis of Cytochalasin B the major synthetic triumph of 1978,'44in which the reduced iso-indoline unit was constructed by the reaction shown in Scheme 42.The dienophile added to the expected diene component of the triene system and the addition had the expected regioselectivity >80% of the product having the orien- tation shown. Me g$ / H + H OAc Ph 'N Ph H Ac Me 0x0 Scheme 42 W.Oppolzer and T. Godel J. Arner. Chem. Soc. 1978,100,2583. 143 K. J. Shea and S.Wise J. Amer. Chem. S~C., 1978,100,6519. 144 G. Stork Y. Nakahara Y. Nakahara and W. J. Greenlee J. Amer. Chem. Soc. 1978,100,7775. 14' 326 R. Brettle The regioselectivities of several intermolecular Diels-Alder reactions with hetero- substituted dienes have been investigated with a view to obtaining otherwise difficultly available substitution patterns.The nitrogen-substituted diene (29)gives predominantly the 'ortho'-isomer with considerable endo-selectivity (Scheme 43).145The 'rneta'-isomer (30),not accessible using an acetylenic dienophile can be < -cJ:;; i'/CHO NHC0,Et NHC0,Et (29) Scheme 43 obtained by the route shown (Scheme 44)by using methyl P-nitroacrylate where the nitro-group exercises the regiochemical control. 146 In the diene (31)the regioselec- tivity is controlled by the trimethylsilyloxy group;147 the adduct is a protected form of C02Me OMe OMe OMe (30) Reagent i DBU = 1,5-diazabicyclo[5,4,O]undec-5-ene Scheme 44 the ap-olefinic ketone (32) into which it can be converted by standard methods87 (Scheme 45).Phenyl vinyl sulphoxide acts as an acetylene equivalent in the Diels-Alder rea~ti0n.l~~ Me,Si Me,Si 0' i,ii Me,SiO d + MeKCo2Me * Me,SiO C0,Me -odco2Me (31) (32) Reagents i N-brornosuccinimide; ii Me,SO Scheme 45 145 L. E. Overrnan G. F. Taylor K. N. Houk and L. N. Domelsmith,J. Amer. Chem. SOC.,1978,100,3182; L. E. Overman and P. J. Jessup J. Amer. Chem. Soc. 1978 100 5179. 146 S. Danishefsky M. P. Prisbylla and S. Hiner J. Amer. Chem. SOC.,1978 100,2918. 147 I. Fleming and A. Percival J.C.S. Chem. Comm. 1978 178. 14' L. A. Paquette R. E. Moerck B. Harichian and P. D. Magnus J. Amer. Chem. Soc. 1978,100 1597. Synthetic Methods Yamamoto’s modified aldol condensation has been applied intramolecularly to an ap-olefinic aldehyde;14’ only 1,2-addition occurred (Scheme 46).Medium and large B0’ L! Reagents i Et,AICI; ii Zn Scheme 46 ring cycloalk-2-ene- 1,4-diones predominantly with the trans-configuration can be prepared by the intramolecular coupling of aw-bisdiazoketones (Scheme 47). 150 Reagents i Cu(AcAc), C,H, 60 “C Scheme 47 149 J. Tsuji and T.Mandai Tetrahedron Letters 1978 1817. S. Kulkowit and M. A. McKervey J.C.S. Chem. Comm. 1978,1069.