11 General Methods By P. G. SAMMES Chemistry Department Imperial College London SW7 2AY 1 Reduction Catalytic Hydrogenation.-Development of homogeneous catalysts has turned a full circle with the preparation of rhodium(1) catalysts chelated to a phosphine polymer.' The advantages of such heterogeneous catalysts are that they have uniform properties and that they can be easily recovered and re-used.2 Whereas normal heterogeneous catalysts often cause disproportionation and hydrogeno- lysis it is becoming apparent that the homogeneous catalysts such as chlorobis- (triphenylphosphine)rhodium(r),are much more selective. Thus cyclohexadienes are reduced with little or no formation of benzene derivatives. The griseofulvin precursor (l) for example is reduced to the compound (2) with no hydrogeno- lysis of the spiro-ether link in contrast to the result observed with heterogeneous X0ZPPh2 0 H PPh (3) catalyst^.^ In the year under review emphasis has been on the development of asymmetric reducing agents in particular of homogeneous catalysts bearing asymmetric ligand~.~ For example use of the ligand (3) in the reduction with ' M.Capka P. Svoboda M. Cerny and J. Hetfleje Tetrahedron Letters 1971 4787. R. H. Grubbs and L. C. Kroll J. Amer. Chem. SOC.,1971 93 3062. A. J. Birch and K. A. M. Walker Austral. J. Chem. 1971 24 513. (a) T. P. Dang and H. B. Kagan Chem. Comm. 1971 481; (b) P. Abley and F. J. McQuillin J. Chem. SOC.(0,1971 844; (c) J. D. Morrison R. E. Burnett A. M. Aguiar C. J. Morrow and C.Phillips J. Amer. Chem. SOC.,1971 93 1301. 365 P.G.Sammes rhodium of r-acetamidocinnamic acid gives (R)-N-acetylphenylalanine in an optical yield of 72 %.4a Heterogeneous catalysts on an asymmetric support generally only give a few percent of enantioselectivity. Metal Reductants.-The reduction of ketones with active metals in liquid ammonia is subject to stereochemical control,6 but the mechanism for such reductions has not hitherto been completely resolved. It has now been found that the nature of the associated cation is imp~rtant.~ With d-camphor the yield of isoborneol relative to that of borneol was found to increase as the cation size increased from Li' to Cs'. The reaction scheme is outlined (Scheme 1). M + M'Br + M+ + M'' + e-+ Br-(1) \ \ 2 C'-O-+ M+ + M'' + \C-0-Mi + C-0-M'' (3) / / / Scheme 1 After reduction in the absence of a proton donor an irreversible complexing of the metal cations with the radical anion occurs (step 3).It is this step which determines the stereochemical result. Thus use of the dangerous and expensive metal caesium to control the stereochemistry of the reduction can be avoided by the simple expedient of using a caesium salt in the presence of a simpler alkali metal such as lithium. The hydrogenolysis of aromatic ketones and benzylic alcohols by lithium in liquid ammonia has also been rescrutinized. In the absence of a proton source the initial product is the corresponding alcoholate salt. If the reaction mixture is worked up in the normal manner with ammonium chloride the alcoholate is immediately quenched and the initial reaction is followed by a very rapid reduc- tion by the excess of lithium generally present eventually producing the hydro- carbon.If an aprotic quenching agent such as sodium benzoate is used the excess of lithium is destroyed without further reduction of the substrate and the benzylic alcohol can be recovered.8 The intramolecular cyclization of radical anions on to olefinic bonds is a well- established reaction. A remarkably efficient and stereoselective electrolyte reduction occurs with non-conjugated olefinic ketones at a carbon electrode in methanolic dioxan. Thus the ketone (4)produces the tertiary alcohol (5) in 66% yield.' Zinc dust is a very mild and useful reducing agent.It has now been used to reduce epoxides to olefins by heating them with a zinc-copper couple in ethanol ' Y. Izumi Angew. Chem. Internat. Edn. 1971 10 871. G. Ourisson and A. Rassat Tetrahedron Letters 1960 16. ' W. S. Murphy and D. F. Sullivan Tetrahedron Letters 1971 3707. S. S. Hall S. D. Lipsky F. J. McEnroe and A. P. Bartels J. Org. Chem. 1971,36,2588. T. Shono and M. Mitani J. Amer. Chem. SOC., 1971 93 5285. General Methods for several days." Reduction of ethynyl acetates with zinc dust gives allenes [e.g. (6)-(7)],and this reaction h6s been used as an entry into the dihydroxy- acetone side-chain of the corticoid steroids. Aluminium Hydrides.-Lithium aluminium hydride will reduce 1-fluoro-1-bromocyclopropanes in a stereospecific manner retention of configuration being observed ; a four-membered transition state was postulated.l2 Reduction of 2-phenyl-allylic alcohols' 3n produces the reduced isomeric olefin in contrast to cinnamic alcohols in which reduction of the double bond occurs.13b Thus the alcohol (8) gives the olefin (9). An elegant example of the addition of hydride ions H)J+3d Ph H >-( H OH Me Bu' across triple bonds has been provided by the reduction of the diacetylene (10) with lithium aluminium hydride in the presence of sodium meth~xide.'~ The complex (11) forms which reacts with iodine to give the vinyl iodide (12) that is used in a route to the Cecropiu juvenile hormone. lo S. M. Kupchan and M. Manyama J. Org. Chem. 197 1 36 1187.'I M. Biollaz W. Haefliger E. Velarde P. Crabbe and J. H. Fried Chem. Comm. 1971 1322. I' H. Yamanaka T. Yagi K. Teramura and T. Ando Chem. Comm. 1971 380. " (u) W. T. Borden and M. Scott Chem. Comm. 1971 381 ; (6) W. T. Borden J. Amer. Chem. SOC.,1970 92,4898. l4 E. J. Corey J. A. Katzenellenbogen S. A. Roman and N. W. Gilman Tetrahedron Letters I97 1 182 1. P.G. Sammes Further reductions with sodium bis-(2-methoxyethoxy)aluminiumhydride have been revealed. Epoxides are more readily reduced than with lithium aluminium hydride and the reduction is more selective;” sodium and mag- nesium salts of carboxylic acids are also reduced.16 Mixtures of lithium alu- minium hydride and cupric chloride reduce allylic sulphides and this reduction has been used to develop a new method for preparing olefins (Scheme 2).17 Reagents i 2-mercaptopyridine; ii PhLi; iii RBr; iv 1 2 CuC1,-LiAIH,.Scheme 2 Because of its dimeric nature in concentrated solutions lithium trimethoxy- aluminium hydride is often more stereoselective than the tri-t-butoxy-deriva- tive. Boron Hydrides-Sodium borohydride in sulpholane is an efficient reducing agent for nitro-groups yielding azo- and azoxy-compounds. l9 Organomercury compounds are also readily reduced by sodium borohydride. Since mercuric acetate metallates enamines at the P-position consequent reduction affords a simple route to tertiary amines; mercuric chloride or bromide tends to give N-metallated derivatives which with sodium borohydride do not lead to reduc- tion of the enamine.20 Epimerization of asymmetric ketones can occur at a greater rate than reduction under the basic conditions associated with sodium borohydride and this danger can be averted by using instead sodium cyanoborohydride.21 Full details of the use of the latter reagent have now appeared.22 Oximes are reduced to alkyl- hydroxylamines and enamines to amines at pH 7.The combination of sodium cyanoborohydride and toluene-p-sulphonylhydrazide is an efficient reagent for the complete reduction of ketones and aldehydes to the corresponding l5 T. K. Jones and J. H. J. Peet Chem. and Ind. 1971 995. l6 M. Cerny and J. Malek Coil. Czech. Chem. Comm. 1971 36 2394. T. Mukaiyama K. Narasaka K. Maekawa and M. Furusato Bull. Chem. Soc.Japan 197 1,44 2285. E. C. Ashby J. P. Serenain and F. R. Dobbs J. Org. Chem. 1971 36 197. l9 R. 0. Hutchins D. W. Lamson L. Rua C. A. Miiewski and B. E. Maryanoff J. Org. Chem. 1971 36 803. ’ R. D. Bach and D. K. Mitra Chem. Comm. 1971 1433. V. Hach E. C. Fryberg and E. McDonald Tetrahedron Letters 197 1 2629. ’’ R. F. Borch M. D. Bernstein and H. D. Durst J. Amer. Chem. Soc. 1971 93 2897. General Methods hydrocarbon^.^^" The reaction proceeds cleanly at 100 "C in a mixture of sul- pholane and dimethylformamide and is more selective than that which occurs using the analogous reagent incorporating sodium b~rohydride.~ Alkyl 3b iodides bromides and primary toluene-p-sulphonates are selectively reduced by sodium borohydride in hexamethylphosphoramide even in the presence of carbonyl or epoxide functions.24 Considerable effort has been made in the current year to develop asymmetric reducing agents.Reaction of ( +)-limonene with thexylborane followed by reaction of the resultant borane with n-butyl-lithium produced the hydride reagent (13).25 This reduced an aP-unsaturated ketone to give a 4.5 1 ratio of Li + -H CMe,CHMe, ".J'*' the two epimeric alcohols (optical yield ca. 64 %). Similarly lithium butyl- (hydro)dipinan-3a-y1 borate prepared from the reaction of diborane with ( +)-pin-2-ene followed by reaction of the product with butyl-lithium also reduced ketones producing optical yields of 5-45 %.26 Sulphurated borohydrides prepared by the addition of sulphur to sodium borohydride in tetrahydrofuran sometimes have advantages over the virgin reagent.Aromatic nitro-groups are completely reduced to yield the corres- ponding aniline whilst nitrile amide and nitroso-groups are also reduced with this reagent.27 A novel route to allylic alcohols has been devised. Addition of diborane to enamines followed by oxidation produces P-hydroxy-amines. Oxidation of the amine function to the corresponding N-oxide and pyrolysis affords the allylic alcohols.28 Reduction of hindered esters can lead to ether formation rather than alcohol^.^ Hindered boranes such as dicyclohexylborane and thexylborane (1,1,2-trimethylpropylborane),add to acetylenes to give mainly mono-adducts. After peroxide oxidation these mono-adducts afford the corres- ponding ketones.For monoalkylated acetylenes addition gives the terminal borane whereas with disubstituted acetylenes steric effects are important with these reagents and addition is predominantly with the boron attached to the 23 (a) R. 0. Hutchins B. E. Maryanoff and C. A. Milewski J. Amer. Chem. Soc. 1971 93 1793; (b)cJ L. Cagliotti Tetrahedron 1966 22 487. 24 R. 0. Hutchins B. E. Maryanoff and C. A. Milewski Chem. Comm. 1971 1097. 2s E. J. Corey S. M. Albonico K. Koeliker T. K. Schaaf and R. K. Varma J. Amer. Chem. SOC.,1971,93 1491. 26 M. F. Grundon W. A. Khan D. R. Boyd and W. R. Jackson J. Chem. SOC.(C),1971 2557. 21 J. M. Lalanchette and J. R. Brindle Canad. J. Chem. 1971 49 2990. 28 J.-J. Barieux and J. Gore Bull. SOC.chim.France 1971 3978. 29 J. R. Dias and G. R. Pettit J. Org. Chem. 1971 36 3485. 370 P.G. Samrnes less hindered side.30 Borane-sulphide adducts are more stable than the corres- ponding borane-tetrahydrofuran complex but as a consequence they are slightly less active.31 The adduct (1.4)can be distilled and should be of use in synthetic I Me (14) OtherMethods.-Titanous chloride in buffered acetic acid is an efficient reducing agent for converting oximes into imines and hence for the re-conversion of oximes into the parent carbonyl compounds.33 Nitro-compounds can also be reduced with this reagent to give ketones and this reaction has been used in a route to cyclopentenones including the perfume jasmone (Scheme 3).34 The jasmone Reagents i base; ii TiCl ; iii Lindlar reduction.Scheme 3 reduction of dihalogenocyclopropanes to cyclopropanes and monohalogeno- cyclopropanes has been re~iewed.~ The reductants sodium hydride in hexa-methylph~sphoramide~~ behave as one-electron and sodium na~hthalenide~~ reducing agents towards these systems. The former reagent is also strongly basic so that with medium-ring adducts such as (15a) reduction is followed by an elimination reaction to give the allene (15b). 30 G. Zweifel G. M. Clark and N. L. Polston J. Amer. Chem. SOC. 1971 93 3395. L. M. Braun R. A. Braun H. R. Crissman M. Oppenauer and R. M. Adams J. Org. Chem. 1971 36 2388. ” R.A. Braun D. C. Brown and R. M. Adams J. Amer. Chem. SOC. 1971,93 2823. 33 C. H. Timms and E. Wildsmith Chem.Comm. 1971 195. 34 J. E. McMurray and J. Melton J. Amer. Chem. SOC. 1971 93 5309. 35 R. Barlet and Y. Vo Quang Bull. SOC. chim. France 1969 3729. 36 J. Moreau and P. Caubere Tetrahedron 1971 27 5741. 37 D. B. Ledlie R. L. Thorne and G. Weiss J. Org. Chem. 1971 36 2186. General Method 371 (154 (133) a-Diketones can be selectively reduced to a-hydroxy-ketones by heating them with benzpinacol. The reaction proceeds by initial homolysis of the benz- pinacol. The diphenylcarbinol radicals so formed donate hydrogen to the substrate in collapsing to ben~ophenone.~~ Allylic sulphoxides are in thermal equilibrium with their isomeric sulphenate esters the equilibrium generally favouring the sulphoxide form. Alkylation of allyl sulphoxide (Scheme 4) followed by heating the sulphoxide in the presence R 0 0 Reagents i BuLi; ii RX; iii heat; iv (MeO),P-MeOH.Scheme 4 of trimethyl phosphite in methanol results in desulphurization and formation of the isomerized allyl alcohol.39 Cyclic thiolsulphonates react with tris(di- methy1amino)phosphine to give cyclic thiolsulphinates and not sulphites as reported previou~ly.~~ 2 Oxidation Oxidations by organic peracids are enhanced in the presence of a strong mineral acid. In this way the N-oxidation of polyhalogenated N-heteroaromatic com- pounds becomes possible and as catalyst concentrated sulphuric acid is re- ~ommended.~' Internal acid catalysis is observed with the sulphonic acid deriva- tive of perbenzoic acid (16). Olefins produce trans-glycols directly with this peracid.42 Oxidation of imines produces oxaziridines and a useful reagent for this purpose is t -amyl hydroperoxide in benzene using molybdenum hexacarbonyl as a catalyst.With this reagent pyridine gives the N-~xide.~~ Amides can also be (16) 38 M. B. Rubin and J. M. Ben-Bassat Tetrahedron Letters 1971 3403. 39 D. A. Evans G. C. Andrews and C. L. Sims J. Amer. Chem. SOC.,1971,93,4956. 40 Ann. Reports (B),1969 66 250. 41 G. E. Chivers and H. Suschitzky Chem. Comm. 1971 28. 42 J. M. Bachawat and N. K. Mathur Tetrahedron Letters 1971 691. 43 G. A. Tolsts'kov U. M. Jemilov V. P. Jurgev F. P. Gershanov and S. R. Rafikov Tetrahedron Letters 1971 2807. 372 P.G. Sammes indirectly oxidized to the corresponding hydroxamic acids via peracid oxida- tion of the derived imino-ethers.Better yields albeit still low are obtained with the cinnamyl ethers rather than the methyl ethers.44 The combination of hydrogen peroxide and aluminium chloride is useful for the selective hydroxylation of aromatic substrates anisole for example giving 70 % of the monohydroxylated phenols.45 An interesting appraisal of a variety of inorganic oxidants has been made using the Zimmerman treatment of electrocyclic reactions. For example a simple rationale for the different behaviour towards olefins of manganese(viI) which cis-hydroxylates them and the isoelectronic chromium(vI) which initially epoxidizes them is possible.46 Various modified inorganic oxidants have also been reported.Two variants of the chromium trioxide oxidation have been suggested. Dipyridine chromium(v1) oxide in acetic acid is recommended as a rapid and efficient oxidant of alcohols to aldehydes and ketones. The reagent is not quite as selective as the Collins reagent using dichloromethane as solvent but has the advantage of being easily prepared.47 The use of a two-phase ether- aqueous chromic acid system for the oxidation of secondary alcohols gives remarkably clean products and gives no epimerization in alcohols with an adjacent chiral carbon atom.48 Allylic oxidation of acetylenes is a relatively rare achievement. It has now been found that either the use of an excess of Collins reagent or of sodium chromate in acetic acid-acetic anhydride produces the conjugated acetylenic ketones ; terminal alkynes do not react.49 Oxidation of alkylcarboxylic acids with the PbIV Co"' and Tl"' ions generally occurs via decarboxylation with concomitant formation of the alkyl radical.However the thermal decomposition of manganic carboxylates can proceed via the alternative non-decarboxylative route to produce the a-carboxy-radical.50" It has now been shown that ceric carboxylates decompose in a similar way and that the radicals produced add across double bonds. The final products are lactones formed in synthetically useful amounts. Manganic and ceric ace- tates will also oxidize ketones to the a-keto-radical which can also add to alkenes to produce y-keto-radicals (Scheme 5).51 These adduct radicals are further oxidized by the metal salt to the corresponding carbonium ion which can then collapse either by quenching with acetate ion or by elimination of a proton.The success of this reaction and of the lactone-forming reaction relies on the selective nature of the oxidant. Because of the electron-withdrawing nature of the carbonyl group a-carbonyl radicals are not easily oxidized to the corres- ponding carbonium ion. 44 D. St. C. Black R. F. C. Brown and A. M. Wade Tetrahedron Letters 1971 4519. 45 M. E. Kurz and G. J. Johnson J. Org. Chem. 1971 36 3184. 46 J. S. Littler Tetrahedron 1971 27 81. 47 K.-E. Stensio Acta Chem. Scand. 1971 25 1125. 48 H. C. Brown C. P. Garg and K.-T. Liu J. Org. Chem. 1971 36 387. 49 J. E. Shaw and J. J. Sheng Tetrahedron Letters 1971 4379.50 (a) E. 1. Heiba R. M. Dessau and W. J. Koehl jun. J. Amer. Chem. SOC.,1969 91 138; (b) E. I. Heiba and R. M. Dessau ibid. 1971 93 995. 51 E. I. Heiba and R. M. Dessau J. Amer. Chem. Soc. 1971 93 524. General Methods R’COCH -$ R’COkH 4 R2kHCH2CH2COR’ + R2CHC H ,C H ,CO R -+ R2C H =CHCH ,CO R + R2CH(0Ac)C H ,CH ,CO R ’ Reagents i Ce(OAc),; ii R2CH =CH2 Scheme 5 Further selective oxidations have been reported. p-Benzoquinone can be cis-hydroxylated by osmium tetr~xide,’~ and ruthenium oxide will oxidize non-terminal alkynes to a-diketones. Sodium metaperiodate is a useful oxidizing agent for the preparation of di-imide from hydrazine and hence for the reduction of ole fin^,^^ and periodic acid will convert aryl azines into the corres- ponding aryl aldehydes in high yield thus representing a useful method for the removal of the azine group; azine oxides are not atta~ked.’~ Thallic sulphate is an excellent reagent for the oxidation of rigid olefins producing the corresponding trans-diols.56 Further ramifications of thallium(II1) nitrate oxidations have also been reported. For example oximes can be oxi- datively deoximated with the reagent to regenerate the aldehyde or ketone function.57 Oxidation of acetophenones with this reagent in methanol produces the corresponding methyl arylacetate by rearrangement.’ * Palladium(I1) acetate is also a valuable oxidant. With aromatic compounds acetoxylation occurs but with a reversal of the normal isomer distribution QAC PdOAc H pattern.Thus anisole mainly gives rn-acetoxyanisole presumably through an initial adduct such as (17).59 The oxidation of a-amino-ketones to the corres- ponding 1,2-dicarbonyl compounds is readily effected with mercury(1r) acetate and this is an efficient method for the preparation of glyoxals.60 ’’ J. Y. Savoic and P. Brassard Canad. J. Chem. 1971 49 3515. 53 H. Gopal and A J. Gordon Tetrahedron Letters 1971 2941. 54 J. M. Hoffman and R. H. Schlessinger Chem. Comm. 1971 1245. 55 A. J. Fatiadi Chem. and Znd. 1971 64. 56 C. Freppel R. Favier J.-C. Richer and M. Zador Cunud. J. Chem. 1971 49 2586. 57 A. McKillop J. D. Hunt R. D. Naylor and E. C. Taylor J. Amer. Chem. Soc. 1971 93 4918. 58 A. McKillop B. P. Swann and E.C. Taylor J. Amer. Chem. SOC.,1971 93 4912. 59 L. Eberson and L. Gomez-Gonzales Chem. Comm. 1971 263. 6o H. Mohrle and D. Schittenhelm Chem. Ber. 1971 104 2475. P.G.Sammes Organoboranes are generally oxidized with alkaline hydrogen peroxide to the corresponding alcohols. It has now been found that stoicheiometric amounts of oxygen also effect the same oxidation in almost quantitative yield.61 A detailed re-examination of the ozonolysis of olefins has revealed a unified picture which serves to correlate the diverse aspects of this reaction.62 Three ozonide intermediates are postulated which form in the sequence a-complex (18) Staudinger molozonide (19) and trioxolan (20). The intermediates (18) and (19) may form directly from the olefin (Scheme 6).Formation of the initial inter- mediate (18) can be used to explain the occasional formation of epoxides from o-o-0-I +/ 0 0-0 /O; R'CH,CH=CHR2 -+ R'CH,CH-CHR' -+ R'CH,&H-&HR' -+ (18) (19) (20) 0-0 R'CH,OOOCH=CHR~ reduction R'CHO + OCHCH,R2 0-0 (23) R4CH0 J (21) 0-0 R"C/H ,kHR2 0 (24) Scheme 6 olefins by loss of oxygen and the formation of anomalous products (path a) as observed for some isopimarane derivative^.^^ Subsequent formation of the molozonide (19) can lead to redox reactions with an aldehyde (path b) or ketone 61 H. C. Brown M. M. Midland and G. W. Kabalka J. Amer. Chem. SOC.,1971 93 1024. " P. R. Story J. A. Alford W. C. Ray and J. R. Burgess J. Amer. Chem. SOC.,1971,93 3044.63 Cf. C. R. Enzell and B. R. Thomas Tetrahedron Letters 1965 225. General Methods 375 (path c) producing the dioxetan (21). Dioxetans readily collapse into the car- bony1 components. In the absence of these reducing agents the molozonide (19) can rearrange to the trioxolan (20) or the ozonide (22),or the Criegee zwitterion (23) the latter allowing the formation of crossed ozonides (24) in the presence of low concentrations of aldehydes. Acetals can be ozonized to produce the corresponding ester and this reaction has been adapted for the cleavage of tetrahydropyranyl ethers and benzylidene and ethylidene protecting-groups under non-acidic condition^.^^ The scope of the triphenylmethyl cation (trityl cation) as an oxidizing agent has been greatly extended by the discovery that it will abstract hydride ions from a~etals~~ and benzyl ethers.Thus trityl fluoroborate with 3~-benzyloxycholest- 5-ene gave >90% cholesterol and benzaldehyde as the products.66 Since the trityl cation is a hindered species it shows selectivity in its hydride-abstracting properties. With the even more hindered perchlorotriphenylcarbonium hexa-chloroantimonate or the perchlorodiphenylcarbonium salt (25) a two-step hydride shift occurs via a one-electron transfer mechanism. With aromatic substrates radical cations are rapidly f~rrned.~' (C6C15)2CCI+ SbC1,- OCO(CH,) @4(=J\ / (25) CfP (26) The biomimetic oxidation of remote carbon atoms in steroid substrates has been gaining increased attention.A highly successful method involves photo- chemical intramolecular hydrogen abstraction with a rigid benzophenone reagent. Thus the derivative (26) undergoes selective attack at positions 9 and 14 on photolysis. Subsequent oxidation with lead tetra-acetate gives the olefins (27) and (2Q6* (27) (28) 65 P. Deslongchamps and C. Moreau Canad. J. Chem. 1971 49 2463. " D. H. R. Barton P. D. Magnus G. Smith and D. Zurr Chem. Comm. 1971 861. 6h D. H. R. Barton P. D. Magnus G. Streckert and D. Zurr Chem. Comm. 1971 1109. " M. Ballester J. Riera-Figueras J. Castaiier and A. Rodriguez-Siurana Tetrahedron Letters 1971 2079. 68 R. Breslow and P. Kalicky J. Amer. Chem. SOC.,1971 93 3540. 376 P.G.Sammes 3 Olefins The Chugaev reaction involves pyrolysis of xanthate esters.It has now been shown that the reaction can often be improved by pyrolysis of the potassium xanthate salts thus avoiding the need to prepare the corresponding esters. l'er- tiary alcohols are efficiently dehydrated in this manner the olefin distribution being similar to that obtained with the esters.69 Radical coupling is an efficient method for making carbonsarbon bonds and the principle has now been adapted for the preparation of 01efin.s.~' Coupling of a-bromonitroalkanes with the anion from a nitroalkane proceeds via a radical reaction to the vic-dinitroalkane. These can be made to undergo reduc- tive elimination reactions with sodium sulphide or sodium thiophenoxide to give the olefin. A simple geometrical isomerization of olefin bonds is effected by epoxidation reaction with lithium diphenylphosphide methylation with methyl iodide and then heating (Scheme 7).71 ..... 1 Reagents i peracid; ii LiPPH,; iii MeI; iv heat. Scheme 7 Cyclopropyl ring formation by the reaction of epoxides with simple Wittig reagents is well established. Use of the Wittig ylide (29) prepared via the stable enaminophosphonates (30) allows extension of this reaction to the formation of cyclopropyl ketones and ketimine~.~~ A timely review on the reactions and stereoselectivity of P-oxidophosphorus ylides has appeared.73 HNR' Ph2P(0)CH=LR2 (30) An isomerization of allylic esters is effected by palladium(rr) acetate. The reaction proceeds via the n-metal complex which then collapses to the a-complex [e.g.(31)] in a reversible manner eventually leading to equilibration of the two 69 K. G. Rutherford R. M. Ottenbrite and B. K. Tang J. Chem. SOC.(C),1971 582. 70 N. Kornblum S. D. Boyd H. W. Pinnick and R. G. Smith J. Amer. Chem. SOC. 1971,93 4317. E. Vedejs and P. L. Fuchs J. Amer. Chem. SOC.,1971 93 4070. l2 N. A. Portnoy K. S. Yang and A. M. Aguiar Tetrahedron Letters 1971 2559. 73 M. Schlosser F. K. Christmann A. Piskala and D. Coffinet Synthesis 1971 29. General Methods possible allylic esters.74 Catalysts such as chlorobis(tripheny1phosphine)rho-dium(r) normally give very little olefin isomerization. The addition of hydro- peroxides to such olefin+atalyst mixtures enhances double-bond migration and the reasons for this have been given7' R X OAO x-Ph C =C =CN 0 S (32) 02 Pd X (31) (33) The diazoallene (32) has been prepared.On heating the corresponding carbene is produced and this adds across olefins to form the corresponding cyclo- propyl addu~t.~~ Full details of the preparation of l,l-dialkyl-3-iodoallenes and 1,l-dihalogenoallenes have now been reported.77 Sulpholene undergoes cheletropic elimination of sulphur dioxide on heating. The homologues (33)have now been used for the formation of divinyl carbamates and divinyl Skipped dienes can be prepared from the corresponding cyclopropyl deri~ative.~~ Interest in the stereoselective synthesis of trisubstituted olefins continues.80 Two modified sigmatropic reactions have been reported.In the first the silyl ether (34)rearranges to the diene (39 which with acid yields the py-unsaturated aldehyde. Alternatively the cyclopropyl derivative (36) undergoes a similar OSiMe OSiMe F' 4 G (34) (35) 74 P. M. Henry Chern. Cornrn. 1971 328. 75 J. E. Lyons Chern. Cornrn. 1971 562. 76 D. J. Northington and W. M. Jones Tetrahedron Letters 1971 317. 77 P. M. Greaves M. Kalli P. D. Landor and S. R. Landor J. Chern. Soc. (C),1971,667. 78 A. I. Meyers and T. Takaya Tetrahedron Letters 1971 2609. 79 W. L. Mock J. Arner. Chern. SOC.,1970 92 6918. J. Reucroft and P. G. Sammes Quart. Rev. 1971 25 135; D. J. Faulkner Synthesis 1971 175. 378 P.G. Sammes 1,Shydrogen shift to give the 76-unsaturated aldehyde (37) (Scheme 8) of use in the preparation of Cecropiajuvenile hormone.81 Silyl ethers of allylic alcohols have also been used in a ring-expansion reaction.The derivative (38) reacts to give the isomer (39) by a 1,3-sigmatropic shift. The competing Cope rearrange- ment product (40)is formed reversibly; the protection of the alcohol prevents ketonization and hence the thermodynamic product is produced.82 The use of optically active allylic ethers in Claisen rearrangements leads to induced asym- metry in the products. This method allows the direct preparation of optically active juvenile h~rmone.~ A potentially useful procedure for protecting acetylenic bonds is to make their dicobalt hexacarbonyl complex. These complexes are remarkably stable to a wide range of reaction conditions for example hydrogenation but the acetylenic group can be released by mild oxidation with cerium(1v) salts.84 New electrophilic addition reagents for olefins include dipyridine iodonium nitrate (41) which can lead to vicinal iodo- nitrate^.^ Nitrosonium fluoroborate in acetonitrile adds to 1,2-disubstituted olefins to form salts of the type (42) which can easily be reduced to the corresponding irnida~ole.~~ Allylic anions RR rr (PY),i + NO -H py = pyridine HNYNoH (41) Me BF4-(42) " E.J. Corey and D. K. Herron Tetrahedron Letters 1971 1641. R. W. Thies Chem. Comm. 1971 237. 83 P. Loew and W. S. Johnson J. Amer. Chem. SOC.,1971,93 3765. K. M. Nicholas and R. Pettit Tetrahedron Letters 1971 3475.U. E. Diner and J. W. Lown Canad. J. Chem. 1971,49,403; U. E. Diner M. Worsley and J. W. Lown J. Chem. Soc. (C) 1971 3131. n6 M. L. Scheinbaum and M. B. Dines Tetrahedron Letters 1971 2205. General Methods react with diborane to form the 1,3-disubstituted adduct. Oxidation produces the corresponding 1,3-di0ls.~~9-Borabicyclo[3,3,1]nonane will add across trisubstituted olefins in an anti-Markovnikoff manner. Reaction of the resulting borane with bromine gives high yields of the corresponding alkyl bromide i.e. with the overall anti-Markovnikoff addition of hydrogen bromide.88 A promising new method for the preparation of benzynes has appeared,89 which involves diazotization of acetanilides under anhydrous conditions. The diazotization reagent of choice is the mixed anhydride p-chlorobenzoyl nitrite.The reaction proceeds via diazonium-acylate ion pairs and with care the com- peting radical reaction pathway can be avoided." 4 Carbonyl Compounds A new synthesis of aldehydes has been devised (Scheme 9) starting with 2-methyl- thiazoles.' + Reagents i BuLi ; ii RX; iii Me,O BF -;iv NaBH ;v HgO-H jO + Scheme 9 A problem often encountered with the use of dithioketals as protecting groups is how to remove them to release the carbonyl group. In a modified synthesis of aldehydes via the 1,3-dithian the hydrolysis was smoothly carried out by using a combination of mercuric oxide or acetate with boron trifluor- ide.92b Oxidative conditions have also been recommended the resulting mono- or di-sulphoxides hydrolysing under much milder conditions.Amongst oxidants recommended have been l-chlorobenzotriazole,93"N-halogenosuccini-mide~,~~~ In the synthesis of alde-chloramine T,93c and sodium peri~date.~~~ hydes a further modification is to alkylate methyl methylthiomethylsulphoxide (43) rather than use 1,3-dithians. The resulting dithioacetal monosulphoxides are relatively easily hydroly~ed.~~ '' J. Klein and A. Medlik J. Amer. Chem. Sac. 1971 93 6313. '' C. F. Lane and H. C. Brown J. Organornetallic Chem. 1971 26 C51. 89 J. I. G. Cadogan J. R. Mitchell and J. J. Sharp Chem. Comm. 1971 1. 90 B. H. Klanderman D. P. Maier G. W. Clark and J. A. Kampmeier Chem. Comm. 1971 1003. 91 L. J. Altman and S. L. Richheimer Tetrahedron Letters 1971 4709.92 (a) D. Seebach Angew. Chem. 1965 77 1134 1135; (b) E. Vedejs and P. L. Fuchs J. Org. Chem. 1971 36 366. 93 (a)P. R. Heaton J. M. Midgley and W. B. Whalley Chem. Comm. 1971 750; (b) E. J. Corey and B. W. Erickson J. Org. Chem. 1971,36 3553; (c) D. W. Emerson and H. Wynberg Tetrahedron Letters 1971 3444; (d) H. Nieuwenhuyse and R. Louw ibid. 1971 4141. 94 K. Ogura and G. Tsuchihashi Tetrahedron Letters 197I 3151. P.G. Sammes Aldehydes can be homologated by reaction with the ylide (44) to form the keten-dithioacetal (45) which can then be reduced and hydr~lysed.~~ Vinyl-silanes formed by the addition of trialkylsilanes across terminal acetylenes can also be used to prepare aldehyde^,^^ via epoxidation and mild hydrolysis.Hindered ketones can be prepared by the alkylation of a-bromoketones with lithium cuprates. 97 1,4-Diketones are of interest in the preparation of cyclopentenones. A new route to these involves condensation of 1,2-diketones with the Wittig reagent (46) followed by reduction with sodium hydr~sulphite.~' An alternative novel route to 1,4-diketones makes use of the intermolecular copper-catalysed addition of diazoketones to vinyl acetates. The resulting cyclopropyl acetate [e.g. (47)] is hydrolysed by base to the corresponding 1,4-diketone and hence to a cyclo- penten~ne.~~ A clever route to cyclopentenones is by ring contraction of a cyclohexane-l,3-dione. Monochlorination of these and treatment with base gives the unstable Favorski intermediate (48),which eliminates carbon monoxide to form the cyclopentenone (49).'0° 0 Poly-/3-ketomethylenes (polyketides) are of interest in biosynthetic-type studies.The 1,3,5,7,9-pentacarbonyl chain (50) has now been synthesized. The method used involved the poly-anion of the trione (51) generated by use of an excess of lithium di-isopropylamide at low temperatures followed by condensation with methyl benzoate. Previously diazoalkanes have received little notice as potential C -alkylating agents under acidic conditions. Diazoketones have now been used for this PhCOCH,COCH,COCH,COCH~COPh MeCOCH,COCH,COMe (50) (51) 95 F. A. Carey and J. R. Neergaard J. Org. Chem. 1971 36 2731. 96 G. Stork and E. Colvin J. Amer. Chem. Soc. 1971 93 2080. 97 J.-E. Dubois C.Lion and C. Moulineau Tetrahedron Letters 1971 177. 98 E. Ritchie and W. C. Taylor Austral. J. Chem. 1971 24 2137. 99 J. E. McMurry and T. E. Glass Tetrahedron Letters 1971 2575. loo G. Buchi and B. Eggers J. Org. Chem. 1971 36 2021. lo' T. M. Harris and G. P. Murphy. J. Amer. Chem. SOC.,1971 93 6708. General Methods 381 purpose.1oZa For example the phenol (52) produces the bridged dienone (53) in good yield by treatment with trifluoroacetic acid in nitromethane.'02b Enol acetates can also be used as alkylating agents in the presence of Lewis acid cata- lysts such as boron trifluoride.' O3 (52) (53) Several interesting routes to ap-unsaturated ketones have been devised. Enamine phosphonates can be prepared from ethynyl phosphonates and amines (Scheme 10) and they react with ketones to give conjugated imines which can HNR~ NR2 11 (EtO),POC=CR' 1,(EtO),POCH=LR' 3R3R4C=CHCR' 3 R3R4C=CHCOR1 Reagents i RZNH,;ii NaH; iii R3R4CO; iv H30+.Scheme 10 readily be hydrolysed to the unsaturated ketone.lo4 Reduction of the acetal (54) with lithium in liquid ammonia produces the dihydro-compound (55) which with dilute acid produces the enone (56).'05 (54) (55) (56) The products from the Robinson annelation reaction of 2-methylcyclo-hexanone with methyl propenyl ketone depend on the conditions selected and the reaction is remarkably stereoselective. When the cyclohexanone is pretreated with sodium hydride in dioxan followed by addition of the enone condensation produces the compound (57).By a similar sequence but in dimethyl sulphoxide as solvent the isomer (58) is formed. The course of reaction under the two sets of conditions is explained by proton transfer in dimethyl sulphoxide producing the anion of the acyclic ketone; such an exchange does not occur in dioxan.'06 Robinson annelation reactions can proceed efficiently under acid-catalysed condition^.'^' A further modification of this reaction is to condense an enolate 102 (a)W. F. Erman and L. C. Stone J. Amer. Chem. SOC.,1971,93,2821; (b)D. J. Beames T. R. Klose and L. N. Mander Chem. Comm. 1971 773. 103 G. L. Hodgson D. F. MacSweeney and T. Money Chem. Comm. 1971 766. 104 M. S. Chattha and A. M. Aguiar Tetrahedron Letters 1971 1419. 105 L. J. Dolby and E. Adler Tetrahedron Letters 1971 3803.'06 C. J. V. Scanio and R. M. Starrett J. Amer. Chem. SOC.,1971 93 1539. lo7 C. H. Heathcock J. E. Ellis J. E. McMurry and A. Coppolino Tetrahedron Letrers 1971,4995. P.G. Sammes anion from a cyclohexanone with 1,4-dichlorobutan-2-one; the product is mainly the epoxy-ketone [e.g.(59)],notable in being the trans-fused isomer. lo8 Chloro-olefins are useful since they can be considered to be potential carbonyl groups. A simple method for their incorporation into carbon systems is by Claisen rearrangement. Thus the ether (60) rearranges to the ketone (61) on heating and this in turn is transformed into the cyclopentenone (62) with sulphuric acid.' O9 Cyclopropanols are becoming attractive synthetic intermediates.Thus the alcohol (63) prepared by reduction of the diketone (64) using lithium in ammonia can react in several ways leading to azulene indane and spiro-type carbon skeletons (Scheme 1l).' lo Another route to spiro-ketones is via a double enamine Reagents i Li-NH,; ii NaH-THF; iii MeOH (rapid addition); iv MeOH (slow addi- tion); v TsC1-pyridine; vi NaOAc-HOAc. Scheme 11 S. Danishefsky and G. A. Koppel Chem. Comm. 1971 367. Io9 P. T. Lansbury P. C. Briggs T. R. Demmin and C. E. DuBois J. Amer. Chem. SOC. 1971 93 1311. 'lo P. S. Venkataramani J. E. Karoglan and W. Reusch J. Amer. Chem. SOC.,1971 93 269; K. Grimm P. S. Venkataramani and W. Reusch ibid. p. 270. General Methods alkylation using the reagent (65). Thus with the enamine (66),the spiro-derivative (67) is produced.''' Enamines have also been used as an entry into the perhydro- azulene system. '' Under appropriate conditions imines which can tautomerize into enamines behave as effectively as enamines in Michael addition reactions. For example the imine (68) adds to acrylamide to give the lactam (69) in good yield.'' 0 Factors affecting the extent of O-versus C-alkylation of b-dicarbonyl systems such as ethyl acetoacetate continue to be explored. As established previously lithium derivatives give rise to more C-alkylation than salts of the higher alkali metals ;conformations of the enolate anions are also important. 'l4 Bromination of ketones in methanol occurs at the least substituted carbon atom in contrast to the result obtained in ether or carbon tetrachloride.This is explained in terms of rapid formation of the ketal in methanol the species brominated being the vinyl ether rather than the eno1."5 Various methods for controlling the direction of alkylation of ketones have been devised. Selectivity is obtained by using lithium di-isopropylamide in dimethoxyethane the least sterically hindered enolate ion forming. In contrast silylation gives the enol ether directed towards the most hindered carbon atom and these ethers can be selectively alkylated at this point.'16 Regiospecific enolate formation also occurs in the reaction of methyl-lithium with enol phosphates [e.g.(70)]and related derivatives.' D. J. Dunham and R. G. Lawton J. Amer. Chem. SOC.,1971,93 2074. '' J.B. Hendrickson and R. K. Boeckman J. Amer. Chem. SOC.,1971 93 1307. l3 I. Ninomiya T. Naito S. Higuchi and T. Mori Chem. Comm. 1971 457. A. L. Kurts A. Macias I. P. Beletskaya and 0. A. Reutov Tetrahedron Letters 1971 3037. M. Gaudry and A. Margult Tetrahedron 1970 26 561 1. H. 0. House M. Gall and H. D. Olmstead J. Org. Chem. 1971,36 2361. 1. J. Borowitz E. W. R. Casper and R. K. Crouch Tetrahedron Letters 1971 105. 384 P.G.Sammes The y-halogenation of ap-unsaturated aldehydes is readily achieved by initial preparation of their enol acetates which can be made by exchange with iso- propenyl acetate using cupric acetate as catalyst.' l8 Selective dehydrobromination of a-bromo-ketones is effected with either tetramethylammonium dimethyl phosphate or the salt of methyl methyl- phosphonate.'' 5 Carboxylic Acids and Derivatives Isonitriles can be prepared from primary formamides by reaction with carbon tetrachloride and triphenylphosphine in the presence of a tertiary base. 120 Normal nitriles can be obtained from aldoximes by dehydration with titanium(1v) chloride in pyridine. l2 Formerly the formation of enolate ions from simple esters has been frustrated by problems such as self-condensation. Conditions whereby such anions can be formed have now been elucidated. Low temperatures are essential and lithium salts of hindered secondary amines are recommended as the base; the use of lithium N-isopropylcyclohexylamide has been advocated. '22a The resulting ester enolates can be alkylated,'22a halogenated,' 22b and acylated ;122c carboxyl-ation has also been reported,'23 The lithium salt (71) has also been made and Li I EtCCO Et I OC0,Et (71) used in a synthesis of the alkaloid ~amptothecin.'~~ The dianions of P-keto-esters can also be prepared the bases of choice again being the lithium salts of hindered secondary amines in this case lithium di-isopropylamide.As expected alkylation or condensation with aldehydes or ketones initially occurs at the least substituted point.'25 Dianions from carboxylic acids126a can be oxidized by air to the corresponding a-hydroxycarboxylic acids in good yields.'26b They can also participate in Michael condensation reactions. 126c P-Hydroxy-acids are obtained 'lS M. J. Berenguer J. Castells J.Fernandez and R. M. Galard Tetrahedron Letters 1971,493. 'I9 J. L. Kraus and G. Sturtz Bull Sac. chim. France 1971 2551. R. Appel R. Kleinstiick and K.-D. Ziehn Angew. Chem. Internat. Edn. 1971 10 132. 12' W. Lehnert Tetrahedron Letters 1971 559. lZ2 (a) M. W. Rathke and A. Lindert J. Amer. Chem. Soc. 1971 93 2318; (6) M. W. Rathke and A. Lindert Tetrahedron Letters 1971 3995; (c) M. W. Rathke and J. Deitch ibid. p. 2953. 123 S. Reiffers H. Wynberg and J. Strating Tetrahedron Letters 1971 3001. Iz4 G. Stork and A. G. Schultz J. Amer. Chem. Soc. 1971 93 4074. 125 G. Brieger and D. G. Spencer Tetrahedron Letters 1971 4585; S. N. Huckin and L. Weiler ibid. p. 4835. (a)Ann. Reports (B) 1970 67 260; (b)G. W. Moersch and M. L. Zwiesler Synthesis 1971 647; (c) Y.-N.Kuo J. A. Yahnev and C. Ainsworth J. Amer. Chem. Soc. 1971,93,6321. General Methods 385 by carrying out the Reformatsky reaction with the carboxylic acid function protected as its trimethylsilyl ester.'27 Phenols are often difficult to esterify but the reaction can be smoothly and efficiently catalysed by the use of a mixture of boric and sulphuric acids.128 Sterically hindered acids can be alkylated with trialkyloxonium salts in the presence of a hindered base such as di-isopropylethylamine. '29 Furthermore hindered esters can also be selectively cleaved in the presence of phenyl ethers by reaction with boron trichloride in dichloromethane.' 30 The trans-esteri- fication of esters is enhanced by carbon dioxide which catalyses the exchange via formation of the monoalkylcarbonate with the alcohol.31 A catalytic de- hydrator for producing acetates of alcohols has been de~cribed'~'" and the system has also been adapted for the preparation of acetals from the lower ketones and a1deh~des.I~~' A new synthon for the nucleophilic introduction of acyl groups has been de~cribed.'~~ This is the oxazolinone derivative (72) prepared from a carboxylic acid and valine. Alkylation or Michael addition reactions occur at position 2. Subsequent hydrolysis of the product leads to the corresponding ketone. + Me2N=CC1 C1- I (74) R C02Bu' (72) (73) Mixed carboxylic-sulphonic acid anhydrides are extremely powerful acylating agents.' 34a They cleave alkyl ethers and aromatic substrates can be acylated.134b These mixed aghydrides are simply prepared by mixing carboxylic anhydrides with sulphonic acid anhydrides.' 34c A simple method for the trifluoroacetylation of amino-acids is to use 1,l,l-trifluoro-3,3,3-trichloroacetone in dimethyl sulphoxide.'35 A further useful acylating agent is the water-soluble and stable salt (73) which can be used to insert t-butyloxycarbonyl groups into amines in aqueous solution.'36 Phosgene immonium chloride (74) is another stable com- pound useful for the introduction of carboxy-groups.'37 '27 A. Horeau Tetrahedron Letters 1971 3227. W. C. Lowrance Tetrahedron Letters 1971 3453. lZ9 D. J. Raber and P. Gariano Tetrahedron Letters 1971 4741. 130 P. S. Manchand Chem. Comm. 1971 667.13' Y. Otsuyi N. Matsumura and I. Imoto Bull. Chem. SOC.Japan 1971 44 852. 132 (a)G. F. Vesley and V. I. Stenberg J Org. Chem. 1971 36 2548; (6)V. I. Stenberg G. F. Vesley and D. Kubik ibid. p. 2550. 133 W. Steglich and P. Gruber Angew. Chem. Internat. Edn. 1971 10 655. 134 (a) M. H. Karger and Y. Mazur J. Org. Chem. 1971 36 532; (6) ibid. p. 540; (c) ibid. p. 528. '35 C. A. Panetta and T. G. Casanova J. Org. Chem. 1970 35 4275. 136 E. Guibe-Jampel and M. Wakselman Chem. Comm. 1971 267. 13' H. G. Viehe and Z. Janousek Angew. Chem. Internat. Edn. 1971. 10. 573. 386 P. G. Sammes Mercuric carboxylates can be converted into the corresponding acid anhydrides by reaction with a thione ester.I3* Thione esters can also be made to rearrange into the corresponding thiol ester by the use of catalytic quantities of triethyl-oxonium fluoroborate.' 39 Keten does not react with 1,3-dienes in a Diels-Alder manner cyclobutane formation being preferred.A useful 'keten synthon' is 2-chloroacryloyl chloride a powerful dienophile. Addition across dienes can be followed by liberation of the masked carbonyl group by a Curtius reaction.'40 6 Alkylation and Coupling Reactions Steric effects are often difficult to separate from strain effects etc. A useful probe for assessing the steric bulk of ketones appears to be their reaction with t-butyl- allylmagnesium bromide. The ratio of the allylic adducts obtained is a measure of the bulkiness of the ketone used.14' In the alkylation of allylic carbanions the nature of the leaving group affects the orientation of substitution with un- symmetrical substrates.In methylation reaction at the most stabilized carbanion centre increases in the order 1 < Br < C1 < tosylate when steric effects are not predominant. 14' Grignard additions to ketones often follow an abnormal course resulting in reduction. In a comparative study of a variety of organometallic compounds it has been established that organocadmium reagents gave the least amount of reduction besides giving a good yield of the addition ~r0duct.l~~ Whereas Grignard reactions on a-hydroxy-ketones are extremely stereoselective additions to acyclic P-hydroxy-ketones show little selectivity. ln contrast it has now been established that 2-a-hydroxyalkyl-cyclopentanonesreact with Grignard reagents in a highly stereoselective manner.'44 The addition of organolithium compounds to olefins is aided by neighbouring sulphur and nitrogen groups provided they are near enough to complex the adduct initially formed in an unstrained manner.145 Primary amines however react in an anomalous manner resulting in the formation of lithium hydride and the formation of a ketone after hydrolysis (Scheme 12).146 Interest in the use of lithium dialkylcuprates for conjugate addition to un- saturated ketones continues. A novel method for making substituted cyclo- pentenones is by alkylation of the ketone (75) in the P-position with these reagents. The enolate ion initially produced can be further alkylated in the a-position by *''J.Ellis R. D. Freier and R. A. Schibecki Austral. J. Chem. 1971 24 1527. T. Oishi M. Mori and Y. Ban Tetrahedron Letters 1971 1777. 140 E. J. Corey T. Ravindranathan and S. Terashima J. Arner. Chem. Sac. 1971 93 4326. 14' A. J. Kresge and V. Nowlan Tetrahedron Letters 1971 4297; M. Cherest H. Felkin and C. Frajeman ibid. p. 379. 142 W. S. Murphy R. Boyce and E. A. O'Riordan Tetrahedron Letters 1971 4157. 143 P. R. Jones W. J. Kauffman and E. J. Goller J. Org. Chem. 1971 36 186. 144 E. Ghera and S. Shoua Chern. Cornrn. 1971 398. 14' A. H. Veefkind J. V. D. Schaaf F. Bickelhaupt and G. W. Klumpp Chem. Cornrn. 1971 722. 146 H. G. Richey W. F. Erickson and A. S. Heyn Tetrahedron Letters 1971 2183. General Methods R'CH,NH 1,R'CH,NLi R'CH=NLi -$ R'R'CHNLi -% R'RZC-NLi 3 R'R2CO Reagents i R'Li; ii -LiH; iii H,O+.Scheme 12 alkyl iodides. Pyrolysis then lea& to elimination of a 4,5-disubstituted cyclo- pent-2-enone.14' Addition of lithium dimethylcuprate to cyclohexenones probably proceeds via a step involving electron transfer to form a complexed radical anion. Thus the cyclopropyl enone (76) reacts to give both the exDected 0 -0 023 product (77) and the ring-opened product (78) which must arise via collapse of the radical anion (79) followed by aikylati~n.'~~ A similar mechanism may be involved in the alkylation of allylic epoxides with lithium dialkylcuprates. Conjugate addition occurs in a trans-manner p.g. (80)-+(Sl)] indicating a non-concerted transfer of the alkylating agent.49 6 14' G. Stork G. L. Nelson F. Rouessai and 0. Gringore J. Amer. Chem. Soc. 1971 93 3091. 14' J. A. Marshall and R. A. Ruden Tetrahedron Letters 1971 2875. 149 D. M. Wieland and C. R. Johnson J. Amer. Chem. SOC.,1971 93 3047; J. Staroscik and B. Rickborn ibid. p. 3046. 388 P.G. Sammes Lithium dialkenylcuprates also add to a/3-unsaturated ketones in a 1,4-manner.' 50 However with the vinylic reagents isolated free-radical species are not involved in either the conjugate addition reaction to unsaturated ketones' la or in self-coupling reactions,I5 lbsince in both of these the stereochemical integrity of the alkenyl groups is maintained. The effect of various metal cations on Grignard reagents has also been re- examined.Copper@) halides have been used to moderate the addition of both lithium and magnesium Grignard reagents to acid chlorides ; hindered ketones can be prepared in this way.' 52 Copper(1) is particularly effective for the cross- coupling of alkylmagnesium halides with alkyl halides provided the reaction is carried out at low temperatures with tetrahydrofuran as solvent.' 53a Primary halides react most efficiently whereas secondary and tertiary halides tend to disproportionate before coupling. Silver(1) ions are recommended for symmetrical coupling reactions,' 3b and vinyl bromides can be coupled with Grignard reagents most effectively in the presence of iron(m) salts.' 53c Trialkylboranes can be alkylated with chloroform in the presence of the hindered alkoxide base (82).Oxidation gives the corresponding carbinol ; thus tributylborane gives tributylcarbinol in high yield. '54 The selective transfer of an alkyl group from certain trialkylboranes can now be achieved. For example B-butyl-3,5-dimethylborinane(83) reacts with ap-unsaturated ketones under radical-induced conditions by selective transfer of the butyl group.' 55 Alkylated olefins can be prepared by the hydroboration of acetylenes using a dialkylborane followed by coupling of the alkyl and alkenyl units by oxidation with iodine and base (Scheme 13).'56" 1,4-Dienes can be made in a similar manner.'56b Allylic epoxides also react with trialkylboranes by conjugate addition of an alkyl group and formation of the alkylated allylic alcohol.' 57 Di-isobutylaluminium hydride is becoming of increasing importance for use in synthetic work.It adds in a trans-fashion across acetylenic bonds and 150 E. J. Corey and R. L. Carney J. Amer. Chem. Soc. 1971,93 7318. (a) C. P. Casey and R. A. Boggs Tetrahedron Letters 1971,2455;(6)G. M. Whitesides C. P. Casey and J. K. Krieger J. Amer. Chem. SOC., 1971 93 1379. J. E. Dubois M. Boussu and C. Lion Tetrahedron Letters 1971 829. 153 (a) M. Tamura and J. Kochi J. Amer. Chem. SOC.,1971 93 1485; (b) ibid. p. 1483; (c) ibid. p. 1487. 154 H. C. Brown B. A. Carlson and R. H. Prager J. Amer. Chem. Soc. 1971,93 2070. 15' H. C. Brown and E. Negishi J. Amer. Chem. Soc. 1971 93 3777. 156 (a)G. Zweifel R. P. Fisher J. T. Snow and C. C. Whitney J.Amer. Chem. Soc. 1971 93 6309; (6) B. M. Mikhailov and Y. N. Bubnov Tetrahedron Letters 1971 2127. 15' A. Suzuki N. Miyaura M. Itoh H. C. Brown G. W. Holland and E. Negishi J. Amer. Chem. Soc. 1971 93 2792. General Methods Reagents i RCEECH; ii I,-NaOH. Scheme 13 the vinylalane so formed adds across ketones to form allylic aic~hols.'~~ Vinylic alanes also react with the Simmons-Smith reagent to give cyclopropylalanes which react with acid to give the hydrocarbon and with halogens to form cyclo- propyl halides. 59 Several new ylide-type reagents have been reported. Lithiumbromomethanes prepared from gem-dibromoalkanes are carbenoid precursors. They react with a variety of ketones to form epoxides.16' Spirocyclopropanes can be made by reaction of ap-unsaturated carbonyl compounds with the ylide (84).16' Thus methyl acrylate forms the product (85).Spirocyclopropanation is also 0 0 wco2Me PSPh Ph!d 7. I1 Bu-S-Me (84) (85) NMe2 effected with the reagent (86).162 Ylide intermediates prepared from the optically active sulphoxide (87) have also been used in the preparation of optically active cyclopropanes and epoxides. 163 An interesting method for the preparation of cyclopropanes is by use of the vinyloxosulphonium salts such as (88) (Scheme 14). Nucleophiles add at the 0 0 II . )I ..... AC0,Me PhCH=CHSPh 1 PhCH=CHSPh '3 II II NMe BF,-+NMe Ph CN Reagents i Me,O+ BF,-; ii MeO,CCH,CN; iii base. Scheme 14 58 H. Newman Tetrahedron Letters 197 1 457 1. G.Zweifel G. M. Clark and C. C. Whitney J. Amer. Chem. SOC.,1971 93 1305. I6O G. Cainelli A. U. Ronchi F. Bertini P. Grasselli and G. Zubiana Tetrahedron 1971 27 6109. 16' B. M. Trost and M. J. Bogdanowicz J. Amer. Chem. SOC.,1971 93 3773. 16' C. R. Johnson G. F. Katekar R. F. Huxol and E. R. Janiga J. Amer. Chem. SOC. 1971,93 3773. 163 C. R. Johnson and C. W. Schroeck J. Amer. Chem. SOC.,1971,93 5303. 390 P.G. Sammes /3-position7 and further treatment with base catalyses the elimination of the sulphinamide group.' 64 1,3-Bismethylthioallyl-lithium(89) behaves as a masked aldehyde group. For example alkylation of (89)with pentyl bromide followed by hydrolysis with mercuric chloride in aqueous acetonitrile leads to oct-2-enal in high yield.'6s Li + (89) The a-butylthiomethylene group has been recommended for directing alkyl- ation in cyclic ketones in much the same way as the hydroxymethylene group is used. Its advantage over the latter is that it can be used in reductive alkylation reactions for example with lithium in liquid ammonia followed by addition of an alkylating agent conditions under which the butylthiomethylene group is reduced to the corresponding methyl group.'66 Dimethyl oxalate has also been recommended as a means of activating ketones by condensing with them.'67 Details of the use of propane-1,3-dithiotoluene-p-sulphonatehave emerged. This reagent reacts with ketones possessing a-methylene groups to form the act-dithioacetal. Hydrolysis produces a-diketones. '68 The monoalkylation of a/3-unsaturated ketones is often complicated by dialkylation which occurs by proton transfer from the monoalkylated product.By using imine derivatives the proton transfer is curtailed and selective monoalkylation is effected. Cyclo- hexylamine and 1,l-dimethylhydrazine derivatives are re~0mmended.I~~ The coupling of alkyl halides can be aided by first making the thiazoline derivative (Scheme 15). Generation of the alkyl anion with butyl-lithium is aided by chela- tion to the thiazoline nitrogen. Alkylation with an alkyl halide followed by Raney nickel reduction liberates the coupled product. "* Arylpalladium salts are extremely useful in coupling reactions (the Heck reaction). It has now been found that vinylpalladium compounds can be made by exchange of palladium salts with vinylsilanes themselves readily accessible by the addition of trialkylsilanes across acetylenic bonds.l7 ' These vinyl- palladium derivatives also participate in coupling reactions. 7 Miscellaneous Alkyl and ally1 cations can easily be generated by the reaction of the appropriate halides with silver trifluoroacetate in either liquid sulphur dioxide or n-pentane. 164 C. R. Johnson and J. P. Lockard Tetrahedron Letrers 1971 4589. 165 E. J. Corey B. W. Erickson and R. Noyori J. Amer. Chem. Sac. 1971 93 1724. 166 R. M. Coates and R. L. Sowerby J. Amer. Chem. SOC.,1971 93 1027. 167 E. Brown M. Ragault and J. Touet Tetrahedron Letters 1971 1043. 168 R. B. Woodward I. J. Pachter and M. L. Scheinbaum J.Org. Chem. 1971,36 1137. G. Stork and J. Benam J. Amer. Chem. SOC.,1971,93 5938. I7O K. Hirai H. Matsuda and Y. Kishida Tetrahedron Letters 1971 4359. 171 W. P. Weber R. A. Felix A. K. Willard and K. E. Koenig. Tetrahedron Letters f971 4701. 39 1 li 1iii R' R~CH Reagents i BuLi; ii R2X; iii Raney nickel. Scheme 15 Collapse of the cations by further reactions to the ester or olefin is slow thus allowing the chemistry of these species to be studied.'72 A large number of substrates form 1,l-dianions with butyl-lithium. For example phenylacetonitrile and sulphones give such species which can be dia1k~lated.l~~ Acetophenone oxime can also form a dianion (90). With car- boxylic esters this forms iso~azoles.'~~ Polymetallation of alkynes is also possible and in this way alkylated allenes can be prepared.'75 PhCCH Lit Q+S JQ II NO-Li' SPPh (90) N-Alkylated sulphenamides can be made either by the reaction of an amine with N-alkylthiophthalimide' 76 or by the reaction of a disulphide with an amine in the presence of a silver salt.'77 Bis-(2-pyridyl) disulphide is a useful reagent for condensation reactions.With triphenylphosphine the intermediate salt (91) forms. This reacts with carboxylate anions and the product reacts with an amine to form an amide; 17' H. M. R. Hoffmann G. F. P. Kernaghan and G. Greenwood J. Chem. Soc. (B) 1971 2257. E. M. Kaiser L. E. Solter R. A. Schwarz R. D. Beard and C. R. Hauser J. Amer. Chem. Soc. 1971,93,4237; W. E. Truce and L. W.Christensen Chem. Comm. 1971 588. 174 J. S. Griffiths C. F. Beam and C. R. Hauser J. Chem. SOC.(0,1971 974. '' Y. Leroux and R. Mantione Tetrahedron Letters 197 1 59 1. 176 D. N. Harpp and T. G. Back Tetrahedron Letters 1970 4953. 177 M. D. Bentley 1. B. Douglass J. A. Lacadie D. C. Weaver F. A. Davis and S. J. Eitelman Chem. Comm. 1971 1625. 392 P.G. Sammes peptide bonds can be efficiently formed in this way'7a and phosphate esters can also be prepared in a similar manner. 179 Tertiary phosphine dihalides also react with epoxides to give the cis-and trans-172-dihalides. The ratio of the isomeric addition products depends on the solvent and a considerable degree of control is possible by selecting the solvent used.lBO Cyanuric chloride is a useful reagent for converting alcohols into the corres- ponding chlorides.It does not require the presence of a base and rearrangements are avoided.lB1 The bromine derivative (92) is a selective brominating agent ; it gives only monosubstitution with phenols. '82 Tetra-alkylammonium salts are in some ways superior to salts of alkali metals in specific reactions. Thus tetrabutylammonium cyanide is far superior to sodium cyanide as a catalyst for the benzoin condensation. lB3 Me,SiN=NSiMc I1 0 (93) Amines can be deaminated with dinitrogen tetroxide to give nitrate esters often in high yields. '84 Another nitrogen derivative nitrosyl cyanide formed in situ from silver cyanide and nitrosyl chloride adds across dienes to form N-cyano-oxazines a potentially useful way of introducing amino-groups.'* Bistrimethylsilyldi-imine (93) is another interesting compound which can be used either to transfer azo-groups or as an oxidizing agent.'86 The salt (94) can be isolated and finds use as a Mannich reagent.'87 + Me,NCH,I I-(94) Amongst new protecting groups developed in the current year are mesitylene- sulphonates prepared with the selective sulphonating agent mesitylenesulphonyl chloride.'88 N-Toluene-p-sulphonyl groups are useful for the protection of '18 R. Matsueda H. Maruyama M. Ueki and T. Mukaiyama Bull. Chem. SOC.Japan 1971,44 1373. '19 T. Mukaiyama and M. Hashimoto Bull. Chem. Soc. Japan 1971,44 196. A. N. Thakore P. Pope and A. C. Oehlschlager Tetrahedron 1971 27 2617. la' S.R. Sandler J. Org. Chem. 1970 35 3967. V. Calo F. Cinimale L. Lopez and P. E. Todesco J. Chcm. SOC.(0,1971 3652. Ia3 J. Solodar Tetrahedron Letters 1971 287. F. Wudl and T. B. K. Lee J. Amer. Chem. SOC.,1971 93 271. Ig5 P. Horsewood and G. W. Kirby Chem. Comm. 1971 1139. 186 N . W'iberg Angew. Chem. Internat. Edn. 1971 10 374. J. Schrieber H. Maag N. Hashimoto and A. Eschenmoser Ancew. Chem. Internat. Edn. 1971 10 330. '*' S. E. Creasey and R. D. Guthrie Chem. Comm. 1971 801. General Methods indoles; they can be removed by hydrolysis with dilute base.lE9 The acetylene derivative of amines (95) can be removed from sulphur-containing peptides by hydrogenolysis.' 90 Anew photosensitive protecting group for acids is the benzoin derivative (96),' 91 which is a useful complement to those already described.19' I (95) Me0 (96) la9 R. E. Bowman D. D. Evans and P. J. Islip Chem. and Ind. 1971 33. I9O G. L. Southard B. R. Zabrowsky and J. M. Petter J. Amer. Chem. SOC.,1971 93 3302. 19' J. C. Sheehan F. M. Wilson and A. W. Oxford J. Amer. Chem. SOC.,1971,93 7222. 19' A. Patchornik B. Amit and R. B. Woodward J. Amer. Chem. SOC.,1970 92 6333.