8 General Methods By P. G. SAMMES Chemistry Department Imperial College London S.W.7 1 Reduction Catalytic Hydrogenation.4ptimum conditions for the use of homogeneous catalysts are still being thrashed out. Wilkinson’s catalyst chlorotris(tripheny1- phosphine)rhodium(I) has to be activated before it becomes effective. This is achieved by ‘dissociation’ to the active species chlorobis(tripheny1phosphine) rhodium(1). Dissociation occurs in the presence of traces of oxygen when aprotic solvents such as benzene or chloroform are used.’ In alcohol oxygen reacts with the catalyst to give a less active reducing agent which also causes extensive double-bond isomerisation.2 Addition of more triphenylphosphine to the latter system appears to reactivate the catalyst as well as to inhibit the isomer is at ion^.^ The use of homogeneous catalysts in dehydrogenations has also been investi- gated.4 They are more selective than heterogeneous catalysts and less dispropor- tionation of the substrate occurs; again Wilkinson’s catalyst was the most effec- tive.The dimeric species rhodium@) acetate and ruthenium@) acetate function as homogeneous hydrogenation catalysts in a wide range of solvents. The latter rhodium catalyst does not reduce allylic alcohols or trans-oriented double bonds ; the ruthenium catalyst is more a~tive.~ Rhodium catalysts with more basic phosphine ligands (1 ;L = solvent) readily reduce aliphatic ketone^.^ The reduction of ketones is enhanced by traces of water [RhH2(PPhMez)2Lz 3’ PF -(1) in contrast to the reduction of olefins which is inhibited by moisture.A hydride transfer is implied since reduction does not proceed through the enol ;4-t-butyl-cyclohexanone gives 86 % of the trans-alcohol. In complete contrast iridium tetrachloride-phosphorous acid in isopropanol reduces 4-t-butylcyclohexanone to the cis-alcohol with 97 % ~electivity.~ The catalyst prepared from chloro- trispyridinerhodium(1) and sodium borohydride in dimethylformamide is active ’ D. D. Lehman D. F. Shriver and I. Wharf Chem. Comm. 1970 1486. R. L. Augustine and J. F. Van Peppen Chem. Comm. 1970 571. R. L. Augustine and J. F. Van Peppen Chem. Comm.. 1970,497. J. Blum and S. Biger Tetrahedron Letters 1970 1825. B. C. Hin and G. L. Rempel Chem. Comm. 1970 1195. ’ R.R. Schrock and J. A. Osborn Chem. Comm. 1970 567. H. B. Henbest and T. R. B. Mitchell J. Chem. SOC.(C) 1970,785. 242 P.G. Sammes for the reduction with hydrogen of azo-groups to hydrazines imines and nitro- groups to amines and pyridine to piperidines.* The homogeneous hydrogenation of 1,3-dienes to cis-2-enes occurs with aromatic tricarbonylchromium com-plexes.' Full details of the P-1 nickel boride catalyst have appeared."" The reduction of alkynes with these catalysts proceeds in two distinct steps allowing selective partial reduction to the olefin.'" The reduction of substituted aromatic com- pounds has been found to be more specific with osmium and iridium catalysts which give more cis-hydrogenation products.' ' The nature of the support in heterogeneous catalysts has long been known to be important.With a carbon on molecular sieve support platinum preferentially catalysed the reduction of straight-chain rather than branched olefins.I2 Aluminium Hydrides.-The role of steric approach control and product develop- ment control in the reduction of alkylcyclohexanones with lithium aluminium hydride has been studied.' Contrary to earlier work steric approach control is predominant and appears to operate uiaeclipsing in the transition state between the incoming hydride ion and neighbouring substituents. The reduction of salts of alkylated malonic esters to ally1 alcohols was reported several years By reduction of allyl-substituted derivatives [e.g.(2) to (3)] the usefulness of this reaction has been considerably e~tended.'~' CO Me II @ OH (3) Further reductions with the benzene-soluble reductant sodium bis-(2-methoxy- ethoxy)aluminium hydride have been reported.Hydrogenolysis of 0-and p-hydroxy-' and -amino-substituted'sb aryl ketones carbinols and carboxylic acids is possible under forcing conditions. At low temperatures (-70 "C)methyl esters are converted into aldehydes in good yields.' 5c Di-isobutylaluminium hydride is more selective than alane for the reduction of @unsaturated ketones to allylic alcohols.'6 ' I. Jardine and F. J. McQuillin Chem. Comm. 1970 626. E. N. Frankel and R. 0. Butterfield J. Org. Chem. 1969 34 3930. lo (a)C. A. Brown J. Org. Chem. 1970,35 1900; (6) C. A. Brown Chem. Comm. 1970 139.' S. Nishimura F. Mochizuki and S. Kobayakawa Bull. Chem. Soc. Japan 1970 43 1919. * D. L. Trimm and B. J. Cooper Chem. Comm. 1970,477. l3 E. L. Eliel and Y.Senda Tetrahedron 1970 26 241 1. l4 (a)J. A. Marshall N. H. Anderson and A. R. Hochstetler J. Org. Chem. 1967 32 1 13 ; (h) W. Sucrow Tetrahedron Letters 1970 143 1. l5 (a) M. Cerny and J. Malek Coll. Czech. Chem. Comm. 1970 35 2030; (b)M. Cerny and J. Malek ibid. p. 1216; (c) See J. Org. Chem. 1970 35 issue 10 p. 12A. 35 issue 10 p. 12A. K. E. Wilson R. T. Seidner and S. Masamune Chem. Comm. 1970,213. General Methods Boron Hydrides.-The borohydride anion exchanges hydrogens with protic solvents. Thisincludes tritiated water and represents a simple way for the reductive tritiation of compounds.' 'Whereas esters of simple carboxylic acids are normally resistant to sodium borohydride esters of phenols or acidic alcohols such as 2,2,2-trifluoroethanol are reduced allowing selectivity.'* In dimethyl sulphoxide sodium borohydride can reduce alkyl halides and the mechanism has been studied ;I9 in dimethylformamide alkyl bromides and iodides and allylic chlorides are reduced by an S,2 mechanism i.e.with inversion of configuration.20 Sodium borohydride is superior to lithium aluminium hydride for the selective reduc- tion of cyclic anhydrides to lactones.21 Whereas both ketals and toluene-p- sulphonate esters are normally resistant to reduction by sodium borohydride P-ketal esters (e.g.4) reduce with fragmentation. Hydrolysis of the resulting ketal affords an aldehyde and an olefin in this case (5).22 The reduction of oximes to OTs (4) (5) alcohols proceeds smoothly with aqueous alkaline sodium borohydride.The reduction is very selective since conjugated oximes are unaffected but a-oximino- ketones give ~r-glycols.~~ Lithium cyanohydridoborate (LiBH,CN) is a versatile reducing agent stable up until pH 3.24a At these low pH values very rapid exchange of the hydride ions with protic solvents or deuterium oxide occurs the latter permitting reductive deuteriation. At about pH 6 the rate of reduction of imines is much faster than that of carbonyl groups allowing selective reductive amination of ketones. Pyruvic acids give the corresponding a-amino-acids in high yield.24b Sulphurated borohydrides prepared by the addition of hydrogen sulphide to sodium borohydride are more reactive than the parent hydride and are claimed to be useful at or below room temperat~re.~~ A powerful stereo- selective reducing agent is lithium perhydro-9B-boraphenalylhydride ;2-methyl-cyclopentanone gives 94 % of the cis-alcohol with this reagent.26 Synthetic applications of the boranes continue to abound.The reduction of functional groups with diborane has now been summari~ed.~' t-Butyl esters are " R. H. Cornforth Tetrahedron 1970 26 4635. 'I1 S. Takahashi and L. A. Cohen J. Org. Chem. 1970,35 1505. J. Jacobus Chem. Comm. 1970 338. 2o M. Vol'pin M. Dvolaitzky and 1. Levitin Bull. SOC.chim. France 1970 1526. D. M. Bailey and R. E. Johnson J. Org.Chem. 1970,35 3574. 22 W. Kraus and C. Chassin Annalen 1970,735 198. 23 K. H. Bell Austral. J. Chem. 1970 23 1415. (a)R. F. Borch and H. D. Durst J. Amer. Chem. Soc. 1969 91 3996; (6) M. M. Kreevoy and J. E. C. Hutchins ibid. p. 4329. 25 J. M. Lalancette and A. Frecke Canad.J. Chem, 1970,48 2366. 26 H. C. Brown and W. C. Dickason J. Amer. Chem. SOC.,1970,92 709. '' H. C. Brown P. Heim and N. M. Yoon J. Amer. Chem. Soc. 1970,92 1637. 244 P. G. Sammes reduced with the sodium borohydride-boron trifluoride etherate reagent into t-butyl ethers. &Lactones are slowly reduced by one equivalent of diborane into dihydropyrans.28 Terminal olefins can be converted into alkylmercuric salts by reaction of the derived boranes with mercuric acetate.The alkyl mercuric salts thus formed have a variety of uses including ready reduction with sodium borohydride into the corresponding alkane.29 Reduction of azines or hydrazones with diborane stops cleanly at the hydrazine stage.30 The hydroboration of propargyl chlorides is a convenient method for the preparation of terminal allenes [e.g. (6) to (7)].3' Bu-CrC-CH,Cl Bu-CH=C=CH (6) (7) Other Methods.-Diazonium salts are smoothly reduced by a radical mechanism with silyl and stannyl hydride~.~~ Aromatic carboxylic acids can be completely reduced to the corresponding aryl-methane by reduction with trichlorosilane followed by base hydrolysis. Further reduction of the 1-methoxycyclohexa-1,4-diene intermediates from the Birch reduction of anisoles proceeds in the absence of a proton source to give mainly cyclohexenes ;conjugation of the diene is the first step in the further red~ction.~~" In the reductive methylation of naphthalene with sodium in liquid ammonia stereospecific alkylation to cis- 1,4-dimethyl-1,4-dihydronaphthalene(8) With lithium in ammonia H (8) (9) only monoalkylation results.Phenanthrene is also alkylated stereospecifically to the cis-product (9);34'such reductions have been reviewed.34d The reduction of cyclopropyl ketones by lithium in liquid ammonia occurs stereoselectively (Scheme 1)35 and can also be effected with tributyltin hydride on photolysi~.~~ 28 G. R. Pettit and J. R. Dias Chem. Comm. 1970,901. 29 R. C. Larock and H. C. Brown J. Amer. Chem. SOC.,1970,92 2467.30 J. A. Blair and R. J. Gardner J. Chem. SOC.(C),1970 1714. 31 G. Zweifel A. Horng and J. T.Snow J. Amer. Chem. SOC.,1970,92 1427. 32 J. Nakayama M. Yoshida and 0.Simamura Tetrahedron 1970,26,4609. 33 R. A. Benkeser K. M. Foley J. M. Gaul and G. S. H. Li J. Amer. Chem. SOC.,1970 92 3232. 34 (a) A. J. Birch and G. S. R. Subba Rao Austral. J. Chem. 1970 23 1641; (b)P. W. Rabideau and R. G. Harvey Tefrahedron Letters 1970 4139; (c) P. W. Rabideau and R. G. Harvey J. Org. Chem. 1970 35 25; (6) R. G. Harvey Synthesis 1970 2 161. " W. G. Dauben and R. E. Wolf J. Org. Chem. 1970,35,2361. 36 M. Pereyre and J. Godet Tetrahedron Letters 1970 3653. General Methods Reagent i Li-NH,. Scheme 1 During the year under review a variety of new methods for dissolving the alkali metals have been investigated.Cyclohexyl-18-crown-6 (10) dissolves potassium in diethyl ether to give a characteristic blue solution with potential reducing proper tie^.^^ Trimesitylborane and related hindered boranes are electron acceptors and also react with the alkali metals.38 The anion radical formed mediates the transfer of electrons to organic systems in a variety of solvents. The reduction of conjugated enones to ketones was effected in this manner. 2,6-Diphenylpyridine can also be used as an electron transfer agent for the metallation of acidic carbon-hydrogen bonds.39 The combination of sodium in hexamethylphosphoramide containing t-butanol is powerful enough to reduce 01efins.~' The reduction of ap-unsaturated ketones with sodium or lithium in hexamethylphosphoramide has been carefully st~died.~' Amalgamated aluminium in dichloromethane is better than magnesium for the pinacolic reduction of ketones.42 1,3-Diolmonoesters are not reduced by zinc dust but instead undergo fragmentation to give olefins (Scheme 2).43 Chromous chloride is a selective reducing agent and nitro-compounds can be reduced to oximes without further reduction.44 The 0-acetates of oximes how- ever are reduced by chromous salts to give the imine.Mild hydrolysis of the J. L. Dye M. G. De Backer and V. A. Nicely J. Amer. Chem. SOC.,1970,92 5226. 38 S. D. Darling 0.N. Dergan and R. E. Cosgrove J. Amer. Chem. SOC. 1970,92 696. 39 B. Angelo Bull. SOC.chim. France 1969 1710. 40 G. M.Whitesides and W. J. Ehmann J. Org. Chem. 1970 35 3565. 41 K. W. Bowers R. W. Giese J. Grimshaw H. 0. House N. H. Kolodny K. Kron-berger and D. K. Roe J. Amer. Chem. SOC. 1970 92 2783; H. 0. House R. W. Giese K. Kronberger J. P. Kaplan and J. F. Simeone J. Amer. Chem. Soc. 1970 92,2800. 42 A. A. P. Schreibman Tetrahedron Letters 1970 4271. 43 E. Ghera Tetrahedron Letters. 1970 1539. 44 J. R. Hanson and T. D. Organ J. Chem. Sot.(C),1970 1182. 246 P.G. Sammes imine regenerates the ketone and this route has been proposed as a method for the regeneration of carbonyl groups from oximes under mild conditions as required for example in synthetic approaches to the prostaglandin^.^^ Zinc dust in aqueous acetic acid also reduces oximes to the parent ketones in good yields.46 R6 40-*Zn C I R ’R2CCR3 R4CHR ’ HOJ @ AH OCOR6 -+R1R2C=CR3R4 + R6C0,H + R’CHO -+ ~iw;~ R2 R3 R4 Scheme 2 Synthetic applications of the reductive extrusion of sulphur with trivalent phosphorus continue to interest chemists.The N-thioalkylphthalimides (11) react with tris(dimethy1amino)phosphine to give the N-alkylphthalimide thus opening a route from thiols to amine~.~’ Simple t-butylsulphenic esters react with tributylphosphine to produce ethers.48 dNSR \ 0 (1 1) 2 Oxidation Selective N-demethylation of amines is a potentially useful process. This has now been achieved by catalytic oxidation of the corresponding amine salt in aqueous solutions using a platinum catalyst.49 The scope of catalytic oxidations using palladium chloride has been enlarged.An interesting example of its use is oxidation of the sesquiterpene (12) as its palladium complex to give the lactone (13),via allylic attack.” (12) (13) (14) 45 E. J. Corey and J. E. Richman J. Amer. Chem. SOC.,1970,92 5276. ‘‘ M. S. Ahmad and A. H. Siddiqui J. Indian Chem. SOC.,1969 46 44. ” D. N. Harpp and B. A. Orwig Tetrahedron Letters 1970 2691. 48 D. H. R. Barton G. Page and D. A. Widdowson Chem. Comm. 1970 1466. 49 R. D. Birkenmeyer and L. A. Dolak Tetrahedron Letters 1970 5049. 50 H. Yanagawa T. Kato and Y. Kitahara Synthesis 1970 2 257. General Methods 247 The relatively stable phosphite-ozone complex (14)is claimed to be a source of singlet oxygen at temperatures above 0 OC.” However differences are observed in using such complexes as singlet oxygen sources compared to freshly generated material the triphenyl phosphite complex appears to oxidise by at least two different mechanism^.^^" At -90 “C the complex oxidises amines which are stable to singlet oxygen.52b Singlet oxygen generated by a microwave discharge has been efficiently used in the oxidation of organic compounds in the solid state dispersed on cellulose powder or silica gel.53 Ozonolysis of primary organo- mercurials gives the corresponding carboxylic acid ; secondary organomer- curials give the ketone.54 Compelling evidence that the primary step in the oxidation of olefins by chromic acid involves epoxide formation has been pre~ented.~~ By adding lithium chloride the normal course of the oxidation is diverted and chloro- ketones could be isolated.An improved safer method for making the pyridine- chromic oxide complex involves its in situ preparation in dichl~romethane.~~ The monoepoxidation of dienes with t-butyl hydroperoxide catalysed by molyb- denum hexacarbonyl is a useful reaction :57 squalene is oxidised into its epoxides quite effi~iently.~~ Epoxidation of allylic alcohols with t-butyl hydroperoxide is best catalysed with vanadium acetylacetonate. Manganese salts can be used to catalyse the oxidation of lactams to imides with t-butyl hydr~peroxide.~~ Olefins can also be converted into their epoxides by using hydrogen peroxide with isocyanates as co-reactants.60a Use of the hydrogen peroxide adduct of /OOH (CF,),C\ OH (15) hexafluoroacetone (1 5) has been advocated as a powerful electrophilic oxidant.Aniline is oxidised to nitrobenzene and ketones undergo Baeyer-Villiger oxi- dation.60b Bis-(3-nitrobenzenesulphonyl)peroxideis another powerful oxidant and can be employed for the hydroxylation of aromatic compounds by an ionic mechanism in good yield although the reagent is dangerous.61 ” M. E. Brennan Chem. Comm. 1970 956. 52 (a) P. D. Bartlett and G. D. Mendenhall J. Amer. Chem. SOC.,1970 92 210; (6) E. Koch Tetrahedron 1970 26 3503. 53 J. R. Scheffer and M. D. Ouchi Tetrahedron Letters 1970 223. 54 P. E. Pike P. G. Marsh R. E. Erickson and W. L. Waters Tetrahedron Letters 1970 2679. 55 J. Rocek and J.C. Drozd J. Amer. Chem. SOC.,1970,92 6668. 56 R. Ratcliffe and R. Rodehorst J. Org. Chem. 1970 35 4000. ’’ M. N. Sheng and J. G. Zajacek J. Org. Chem. 1970 35 1839. 58 S. A. Matlin and P. G. Sammes unpublished observations. 59 A. R. Doumaux and D. J. Trecker J. Org. Chem. 1970,35 2121. ‘(’ (a)N. Matsumura N. Sonoda and S. Tsutsumi. Tetrahedron Letters 1970 2029; (b) R. D. Chambers and M. Clark ibid. p. 2741. h1 E. M. Levi P. Kovacic and J. F. Gormish Tetrahedron 1970 26 4537. P.G. Sammes The Wessely acetoxylation of phenols with lead tetra-acetate proceeds by a very rapid electrophilic attack at both ortho-and para-positions and is not selec- tive for the ortho-position only.62 The combination of lead tetra-acetate and trimethylsilylazide will oxidise olefins ; 1,2-disubstituted olefins form azido- ketones or allylic a~ides~~" but trisubstituted olefins are cleaved to the keto- nitrile cholesteryl acetate forming the nitrile ( 16).63bThe oxidation of ketone hydrazones with iodine64" is general and chlorine bromine and the pseudo- halogens can also react to give vinyl plus geminal halides.64b The persulphate anion is a useful but underemployed one-electron oxidant.New applications should rectify this situation. It will oxidise the sodium salts of secondary nitroalkanes to vicinal dinitro-compounds in a manner analogous to pinacolic coupling. Allylic nitro-compounds as their nitronate salts are converted into ap-unsaturated ketones [e.g.(17) to (18)].65 Persulphate ions will also decarboxylate aliphatic carboxylic acids the reaction being catalysed by silver ions.66 In the presence of acids the reagent oxidises alcohols to peroxides.The acid then catalyses the cleavage of the peroxide (Scheme 3). The latter reagent is superior to other peracids for Baeyer-Villiger oxidation^.^' Tr + RCH20H -+ R-CHdO-yH2 -+ R-O=CH -+ ROH R'R2CHOH -+ R'R'CHOOH 4 R'R2C=0 + R'CHO + R'CHO Scheme 3 " W. A. Bubb and S. Sternhell Tetrahedron Letters 1970 4499. 63 (a)K. Kischa and E. Zbiral Tetrahedron 1970,26 1417; (b)E. Zbiral and G. Nestler ibid. p. 2945. 64 (a)D. H. R. Barton R. E. O'Brien and S. Sternhell J. Chem. SOC.,1962 470; (6) A. Pross and S. Sternhell Austral. J. Chem. 1970 23 989. 65 A. H. Pagano and H. Schechter J. Org.Chem. 1970,35 295. " J. M. Anderson and J. K. Kochi J. Amer. Chem. SOC.,1970,92 1651. '' N. C. Deno W. E. Billups K. E. Kramer and R. R. Lastoniwsky J. Org. Chem. 1970 35 3080. General Methods lP-Diketones can be prepared by the oxidation of ketones with lead dioxide although in toluene coupling to the solvent occurs.68 Azines (19) as their anions are oxidised by cuprous chloride to a dimer from which the 1,4-diketone (20) can be obtained by hydr~lysis.~’ Fremy’s salt was the reagent of choice for the oxidation of the acid-sensitive enol ether (21) to the quinone (22) many other reagents failing.70 PhR’C=N-N=CR2-CH2R3 R2CO-CHR 3CHR3COR* (19) (20) 0 0 Me0f?J$ Me0 0 0 (21) (22) @-Methylstyrene undergoes an interesting oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone.Initially an unstable bis-aryl ether (23) forms which is solvolysed by alcohols to give predominantly the thermodynamically less favoured unconjugated ether (24).7 Quinone dehydrogenations of steroids have been reviewed.72 Whereas the silver oxide oxidation of a-amino-acids gives mainly the nor-acid silver(I1) picolinate produces the nor-aldehydes almost q~antitatively.’~ The oxidation of secondary alcohols by silver oxide in the presence of bromine has been examined in more detail. The solvent is of the utmost importance. The presence of added ethers such as 2,5-dimethyltetra- hydrofuran dramatically increases the proportion of product tetrahydrofuran f~rrned.’~ 68 R. Brettle Chem. Comm. 1970 342; R.Brettle and D. Seddon J. Chem. SOC.(0 1970 2175. 69 T. Kauffmann and M. Schoenfelder Annalen 1970,731 37. 70 V. H. Powell Tetrahedron Letters 1970 3463. 71 F. E. Lutz and E. F. Kiefer Chern. Comm. 1970 1722. ’’ H. Dannenberg Synthesis 1970 2 74. 73 T. G. Clarke N. A. Hampson J. B. Lee J. R. Morley and B. Scanlon J. Chem. SOC. (C) 1970 815. 74 A. Delazarche A. Maillard P. Rimmelin F. Schue and J. M. Sommer Chem. Comm. 1970 976. P.G. Sammes Thallium(n1) trifluoroacetate readily thallates aromatic Oxi-dation of these metallated intermediates with lead tetra-acetate forms phenolic trifluoroacetates which are readily hydrolysed to the corresponding phen01.~ 5b Reaction of the aromatic thallates with potassium cyanide followed by photo- lysis can give the corresponding aromatic nitrile.Thallium(II1) trifluoroacetate is itself an oxidant and produces quinones from phenols. 75c Thallium(II1) nitrate Reagents i TI"'(NO,),-MeOH; ii H,O+. Scheme 4 in methanol oxidises olefins with rearrangement to aldehydes or ketones via the corresponding ketal (Scheme 4).76 Olefins are also oxidised with cleavage to the ketone or aldehyde by bistriphenylsilylchromate (25).77 0 Oxidations with ruthenium tetroxide are usually performed with catalytic amounts of ruthenium trichloride in the presence of a regenerative oxidant such as sodium periodate. A much cheaper reagent is prepared from the trichloride with sodium hypochlorite. The latter oxidant can also be used in conjunction with osmium tetroxide and rhodium and iridium chloride^.'^ Simple arylalkynes can be prepared in good yields by the oxidation of semi- carbazones with selenium di~xide.'~" This oxidant can also be used to cleave allylic and benzylic ethers producing the alcohol and the conjugated aldehyde.79b An improved preparation of manganese dioxide has been reported.Use of de- colourising charcoal as support during the preparation aids isolation and the product is as active as that prepared by other methods.*' Iodohydrins are readily prepared from olefins by reaction with iodine and water in the presence of an oxidising agent such as iodic acid or oxygen catalysed by nitrous acid." 75 (a) A. McKillop J. S. Fowler M. J. Zelesko J. D. Hunt E. C. Taylor and G. McGillivray Tetrahedron Letrers 1969 2423; (6)E.C. Taylor H. W. Altland R. H. Danforth G. McGillivray and A. McKillop J. Amer. Chem. SOC., 1970 92 3520; (c) A. McKillop B. P. Swann and E. C. Taylor Tetrahedron 1970,26,4031. 76 A. McKillop J. D. Hunt E. C. Taylor and F. Kienzle Tetrahedron Letters 1970 5275. 77 L. M. Baker and W. L. Carrick J. Org. Chem. 1970,35,774. 78 S. Wolfe S. K. Hasan and J. R. Campbell Chem. Comm. 1970,1420. 79 (a) I. Lalizari A. Shafiei and M. Yalpani Angew. Chem. Internat. Edn. 1970 9 464; (b) K. Kariyone and H. Yazawa Tetrahedron Letters 1970 2885. L. A. Carpino J. Org. Chem. 1970 35 3971. *'J. W. Cornforth and D. T. Green J. Chem. SOC.(0,1970 846. General Methods 25 1 3 Olefins Extrusion reactions of sulphur in the preparation of carbon-carbon bonds were highlighted last year.A new general route for the preparation of double bonds from sulphides has now been developed (Scheme 5).8247b This has been success- fully adapted to the preparation of the highly-strained aromatic system (26).82c Reagents i Mel; ii NaH-THF; iii (MeO),CH+BF,-;iv KOBu'. Scheme 5 'Double' extrusion reactions [e.g.(27) to (28)] are also potentially useful especially for the synthesis of highly-substituted olefins. Thus the sulphide (29) gives the olefin (30) on heating with tri~(diethy1amino)phosphine.~~" The thialactone (31) also reacts.83b R' R3 \/ -+ R2/c=c\ R4 oso N=N --+ 00 0' (31) Alkenes can be obtained from epoxides by their reduction with magnesium amalgam in the presence of magnesium bromide.84 Other new methods for the preparation of olefins include the pyrolysis of O-alkyl-N-(toluene-p-sulphony1)-car barn ate^,^^ N-carbalkoxy~ulphamates,~~ the latter and thiono~arbamates,~' 112 (a)V.Boekelheide and J. L. Mondt Terrahedron Lerters 1970. 1203; (6)R. H. Mitchell and V. Boekelheide ibid. p. 1197;(c)V. Boekelheide and R. A. Hollins J. Amer. Chem. Sac. 1970 92 3512. 83 (a)D. H. R. Barton. E. H. Smith and B. J. Willis Chem. Comm.. 1970. 1226;(6)D. H. R. Barton and B. J. Willis ibid. p. 1225. 84 F. Bertini P. Grasselli G. Zubiani and G. Gainelli Chem. Comm. 1970 144. 85 L. C. Roach and W. H. Daly Chem. Comm. 1970 606. 86 E. M. Burgess H. R. Penton and E. A. Taylor J. Amer. Chem. Soc.1970,92,5225. 87 M. S. Newman and F. W. Hetzel J. Org. Chem. 1969 34 3604. 252 P. G. Sammes undergoing smooth cis-elimination at much lower temperatures than do xanthates. The pyrolysis of quaternary ammonium hydroxides occurs much more cleanly and at lower temperatures when very low pressures are employed.88 Thus the base (32) is pyrolysed at 60 "C (0.005 mm Hg pressure) to give cyclo- (32) propene in good yield. The direction of elimination of these quaternary salts (the syn-anti dichotomy) has been explained in terms of steric effects and suitable predictions should now be po~sible.'~ The reaction of some steroidal toluene- p-sulphonylhydrazones with lithium alkyls gave good yields of the olefins but the amount of base used was critical best yields being obtained with three equivalent^.^^ A reinvestigation of the preparation of alkynes via 1,2-dibromides has been made.The eliminations proceed smoothly in dimethyl sulphoxide with sodium hydride or sodamide at room temperature but on heating isomeri- sation of the double bond occurs.91 Steroidal dienes can be prepared from epoxides by their dehydration the reagent of choice being pyridine hydro- chloride.92 The Claisen reaction has been modified in order to yield trisubstituted olefins with high ~tereoselectivity.~~ In related work the use of keten acetals has been strikingly successful (Scheme The product ester can be further modified 0 'R2 Reagents i MeC(OEt),-H +; ii Heat; iii LiAIH,; iv Cr0,-pyridine; v ,)-Li. Scheme 6 D.A. Archer Tetrahedron Letters 1970 1325. 89 D. S. Bailey and W. H. Saunders J. Amer. Chem. SOC.,1970,92,6904. J. E. Hey E. Gonzalez and B. Mardell Austral. J. Chem. 1970,23 857. 91 J. Klein and E. Gurfinkel Tetrahedron 1970 26 2127. 92 I. Morelli and A. Marsili J. Org. Chem. 1970 35 567. 93 W. S. Johnson T. J. Brocksom P. Loew D. H. Rich L. Werthemann R. A. Arnold T. Li and D. J. Faulkner J. Amer. Chem. SOC.,1970 92 4463. 94 W. S. Johnson L. Werthemann W. R. Bartlett T. J. Brocksom T. Li D. J. Faulkner and M. R. Peterson J. Amer. Chem. SOC.,1970 92 741. General Methods for the extension of the chain thus making the method of general synthetic utility in the terpene field. A further stereospecific synthesis of trisubstituted olefins has made use of the pyrolysis of vinyl cyclopropanes [e.g.(33) to (34)].95 H (33) (34) (35) (36) 0 0 1,2-Divinyl-1,2-glycols rearrange.on heating in a Cope reaction to form the diketone. This reaction has been used for an entry into medium ring compounds [e.g.(35) to (36)]96"and the reaction is stereospecific [cf. (37a) to (38a); (37b) to (38b)].96b A further entry into medium ring compounds has also been de- veloped (Scheme 7).97" It is general and has been applied to the synthesis of perhydroa~ulenes,~~~ and heterocyclic systems.97d 0dacyclic 1,5-diene~,~~' OMS 1 4 (MeO)ZB0 HO B(OMe) Reagents i B,H then MeOH; ii NaOMe. Scheme 7 45 E. J. Corey H. Yamamoto D. K. Herron and K. Achiwa J. Amer. Chem. Soc. 1970 92 6635.96 (a)P. Leriverend and J. M. Conia Bull. SOC. chim. France 1970 1040; E. N. Marvell and T. Tao Tetrahedron Lerters 1969 1337; (b) E. N. Marvell and W. Whalley Tetrahedron Letters 1970 509. 97 (a) J. A. Marshall Rec. Chem. Progr. 1969 26 4781; (b) J. A. Marshall and W. E. Hoffman J. Amer. Chem. Soc. 1970 92 6358; (c) J. A. Marshall and J. H. Babler Tetrahedron Letters 1970 3861 ; (6)J. A. Marshall and J. H. Babler J. Org. Chem. 1969.34.4186. 254 P.G.Sammes Dihalogenocarbene adducts of olefins undergo the cyclopropyl-ally1 rearrange- ment under the influence of silver ions;98 these products are useful in the stereo- specific synthesis of trans-hydrindane derivatives (Scheme 8).99 The Simmons- Smith cyclopropane synthesis is improved by dropwise addition of di-iodomethane to a catalyst prepared from zinc dust and cuprous chloride and H Br I -+ 06 Reagents I CBr ii.AgOAc-AcOH ; iii aqueous N-bromosuccinimide Scheme 8 the olefin."' The 1,3-cyclohexadiene system of ergosteryl acetate has been cleverly protected by formation of the adduct (39). The 22-olefin bond of the adduct is preferentially ozonised allowing modification of the side-chain. The diene function was then regenerated by reduction with lithium aluminium hydride. ' NN-Dichlorophosphoramides add across olefins to give after acid hydrolysis the 2-aminoalkylchloride.'02 In the presence of a halogen cyanamide also adds across double bonds,'03 whilst iodonium nitrate adds without the need for a cataly~t."~ Normally olefins are inert to attack by N-chlorocarbamates but the reaction can be promoted by chromous chloride.A radical process is implied 98 C. B. Reese and A. Shaw J. Amer. Chem. SOC.,1970 92 2567; D. Duffin and J. K. Sutherland Chem. Comm. 1970 627. 99 D. Duffin and J. K. Sutherland Chem. Comm. 1970 627. loo R. J. Pawson and I. T. Harrison J. Org. Chem. 1970 35,2057. D. H. R. Barton T. Shiori and D. A. Widdowson Chem. Comm. 1970,939. lo' A. Zwierzak and A. Koziara Tetrahedron 1970 26 3521 3527. lo' K. Ponsold and W. Ihn Tetrahedron Letters 1970 1125. Io4 U. E. Diner and J. W. Lown Chem. Comm. 1970 333. General Methods in the latter reaction as both cis-and trans-addition OCCU~S.'~~~ Enol ethers react and after hydrolysis afford P-carbamidoketones.105b Olefins can be converted into secondary and tertiary amines by prior amino- mercuration followed by reduction with sodium borohydride.lo6 Full de- tails of the Markownikov hydration of olefins by oxymercurationdemercura-tion have appeared. The reaction is general but sensitive to steric effects."' Alkyl bromides can now be made from olefins via their borane derivatives which react with bromine in the presence of base. An anti-Markownikov bro- mination results. log Alternatively the alkylboranes can be converted into the corresponding mercury derivatives and these react smoothly with bromine. 'O9 Terminal acetylenes can be converted into their silyl derivatives (e.g.40) in the presence of a silylating catalyst such as (41).The products behave as protected R'C-CSiRi R,Si-SiR (40) (41) acetylenes since mild acid regenerates the parent function.' lo A new cumulene synthesis albeit of limited use has been devised which proceeds via carbene intermediates (Scheme 9).'l1 R' R2/ I C-CSZCH X \ [::;c=c=c]-b 5 R'R';c=c-C R3 R4 / \ X = leaving group Reagents i Bu'O-Bu'OH; ii R3R4CN Scheme 9 4 Carbonyl Compounds Dihydro-1,3-oxazines are much more versatile than would at first appear.' 12' A novel ketone synthesis is achieved by alkylation of the nitrogen atom to form salts of the type (42). Addition of Grignard reagent gives (43) and subsequent mild hydrolysis liberates the ketone in high yield.' '2b Another useful synthetic intermediate in this area is the isonitrile 1,1,3,3-tetramethylbutyl isocyanide (44).lo5 (a)J. Lessard and J. M. Paton Tetrahedron Letters 1970 4883; (6) J. Lessard H. Driguez and J. P. Vermes Tetrahedron Letters 1970,4887. 'Oh J. J. Perie and A. Lattes Bull. SOC. chim. France 1970 583. H. C. Brown and P. J. Geoghegan J. Org. Chem. 1970,35 1844. '08 H. C. Brown and C. F. Lane J. Amer. Chem. SOC. 1970,92 6660. J. J. Jufarullo and M. M. Hovey J. Amer. Chem. SOC.,1970,92 3221. 'lo R. Calas and P. Bourgeois Compt. rend. 1969,268 C 72. ' ' H. Reimlinger and R. Paulissen Tetrahedron Letters 1970 3 143. ' (a) Ann. Reports (B) 1969 66 259; (b)A. I. Meyers and E. M. Smith J. Amer. Chem. Soc. 1970 92 1084. 256 P.G.Sammes Grignard reagents add on to the carbon atom to give the imine anion (45) which can react in a variety of ways (Scheme 10).'l3 Symmetrical ketones can be easily prepared from alkylboranes via their cyanoborate derivatives (e.g.46). Under the influence of electrophilic reagents (trifluoroacetic anhydride is particularly effective) these rearrange into the adducts e.g. (47) from which the ketone is liberated with alkaline hydrogen peroxide.' l4 RCPO RCOCH(0H)Ph4 9RCOC02H Ti \ (45) R RCOCH,CH(OH)Me )" -%RCOR' RCOSiMe A Reagents i H,O; ii CO,; iii R'X; iv Me,SiCI; v MeCH -CH,; vi PhCHO. Scheme 10 The conjugate addition of alkyl groups from trialkylboranes on to ap-un- saturated carbonyls is a free-radical process and is catalysed by traces of air. Under these conditions reproducible high yields of ketones or aldehydes can be obtained.' ' A new /?-keto-ester synthesis uses the homologation of ketones with diazoacetic esters and is efficiently catalysed by triethyloxonium fluoro- borate.In this way cyclohexanone was converted into the cycloheptanone (48) in over 90% yield."6 Enamines derived from aldehydes react with N-chloro- succinimide to give the appropriate a-chloro-aldehyde. ' ' R,BCN Na' R-B N (46) \// 0-c CF3 (47) H. M. Walborsky W. H. Morrison and G. E. Niznik J. Amer. Chem. SOC.,1970,92 6675. 'I4 A. Pelter M. G. Hutchings and K. Smith Chem. Comm. 1970 1529. I I H. C. Brown and G. W. Kabalka J. Amer. Chem. SOC.,1970,92,712,714. 'Ih W. L. Mock and M. E. Hartman J. Amer. Chem. Soc. 1970 92 5767. 'I' J. J. Riehl and F.Jung Compt. rend. 1970 270 C 2009. General Methods The homologation of aldehydes with enol ethers to give up-unsaturated alde- hydes has been extended ; the method is more adaptable and efficient than the aldol method. It proceeds uiu the ketal(49) which gives the desired product upon 0 CO1Et R' "QR2 OEt 0 mild acid hydrolysis.' y-Hydroxyketones can be dehydrated with carbodi- imides to give cyclopropyl ketones in good yields. The method is general since the starting materials can be obtained from reaction between ketones and epoxides.' Many examples of the thermocyclisation of 68-and &(-unsaturated ketones have recently been recorded and the process can now be considered general occurring with a defined stereochemistry.120" Thus the enone (50) reacts uia its enol (51) to give the bicyclic ketone (52).120b A novel precursor of aldehydes is the Wittig species (53).The vinyl ally1 sulphide produced (e.g. 54) undergoes Claisen rearrangement on heating and in the presence of mercuric oxide generates a new aldehyde (55).' la Vinyl sulphides are produced with ketones and the Wittig reagent precursor (56)l2Iband the products are readily hydrolysed with mercuric chloride in aqueous acetonitrile to give the homologous aldehyde. The acidic nature of sulphides has also been 0 Ph,P=CHSCH,CH=CH / s-(53) 0-MeSCH,-PO(OEt) (54) (55) 'I8 S. Satsumabayashi K. Nakajo R. Soneda and S. Motoki Bull. Chem. SOC.Japan, 1970,43 1586. l9 C. Alexandre and F. Rouessac Terrahedron Lerters 1970 101 1.(a)F. Legendecker G. Mandville and J.-M. Conia Bull. Soc. chim. France 1970,549; (b) F. Legendecker G. Mandville and J.-M. Conia ibid. p. 556. (a)E. J. Corey and J. I. Shulman J. Amer. Chem. Soc. 1970,92 5522; (6) E. J. Corey and J. I. Shulman J. Org. Chem. 1970 35 777. 258 P.G. Sammes exploited in a preparation of ap-unsaturated aldehydes. The lithium salt (57) reacts with epoxides to give the product (58). Mild hydrolysis under the con- ditions mentioned above affords the aldehyde (59).122 Further ramifications of the Wittig reaction have been explored. The betaine adducts (e.g. 60) are known to react with base to form a new ylide (61). These ylides can react in a variety of ways all of which are notably stereoselective (Scheme 11).lz3 Arsonium ylides appear to have properties in between those of H R YR* OH y:*OH T / RHc' + 0-PPh 0-PPh, I1 I1 RCH-CHMe 5R-CH-C-Me (60) / (61) \ 1 H 'HC1 Reagents i PhLi; ii R'CHO; iii paraformaldehyde; iv PhICl,; v N-chlorosuccinimide ; vi I,-H20 ; vii Hg(OAc),-LiI-I .Scheme 11 phosphorus and sulphur ana10gues.l~~ A reaction analogous to the Wittig process is that between ketones and a-silanyl-Grignard reagents. Thus the reagent (62) reacts with cyclohexanone to give after base hydrolysis the corres- ponding methylenated product.' 25 12 E. J. Corey and R. Noyori Tetrahedron Letters 1970 31 1. 123 E. J. Corey J. I. Shulman and H. Yamamoto Tetrahedron Letters 1970 447; E. J. Corey and H. Yamamoto J.Amer. Chem. Soc. 1970 92 226; cf. M. Schlosser and K. F. Christmann Synthesis 1969 1 38. 124 P. Bravo G. Gaudiano P. P. Ponti and M. G. Zubiani Tetrahedron Letters 1970 4535. 125 T. H. Chan E. Chang and E. Vinokur Tetrahedron Letters 1970 11 37. General Methods A simple method for the a-cleavage of ketones involves the process outlined (Scheme 12).126 The trimethylsilyl ethers of enols are readily prepared by the reaction of a ketone and trimethylsilyl chloride using lithium diethylamide as Me,SiCH,MgCl (62) base.I2' Pyridine hydrochloride is the recommended catalyst for the Semmler reaction being superior to the hydrochloric acid-acetic anhydride mixture gen- erally employed.' 28 The decarbonylation of aldehydes ,using chlorotris(tri- phenylphosphine)rhodiurn(~)as catalyst is very stereoselective proceeding with Reagents i ArSO,S(CH,),SSO,Ar ;ii NaOMe-dimethyl sulphoxide.Scheme 12 overall retention of configuration about the adjoining carbon centre. For example the aldehyde (63a) gives the hydrocarbon (63b) virtually quantita- tively.' 29 Finally further reactions of P-keto-esters have been recorded. Derived di-anions from these systems can be made by a two-step procedure. The mono- anion is made first using sodium hydride in tetrahydrofuran followed by genera- tion of the di-anion with butyl-lithium. Selective alkylation occurs at carbon only. no oxygen alkylation being ~bserved.'~' 5 Carboxylic Acids A general method for making a-chloro-nitriles and dialkyl nitriles in preparative yields has been developed by reaction of dichloroacetonitrile with trialkyl- boranes under the influence of a hindered base such as potassium 2,6-di-t- J.A. Marshall and H. Roebke Tetrahedron Letters 1970 1555. 12' H. 0.House L. J. Czuba M. Gall and H. D. Olmstead J. Urg. Chem. 1969,34,2324. ''' R. Royer P. Demerseman and G. Colin Bull. SOC. chim. France 1970 1026. 129 H. M. Walborsky and L. E. Allen Tetrahedron Letters 1970 823. 13* L. Weiler J. Amer. Chem. SOC. 1970,92 6702. 260 P.G. Summes b~tylphenoxide.'~'" This method has also been adapted to alkylate ethyl 4-bromocrotonate when the by-unsaturated ester results.' '' A variety of alter- native methods for preparing nitriles have been introduced. The sulphonyl nitrile (64) is a useful source of 'positive' cyanide.Reaction with Grignard CIC-0 4(3S02CN S I1 reagents produces the corresponding nitrile.I3' Dehydration of primary amides can be effected under almost neutral conditions by heating them in tetrahydro- furan in the presence of carbcn tetrachloride and triphenylph~sphine,'~~ reaction going via the iminochloride. The dehydration of oximes to produce nitriles can be conveniently carried out by reaction at room temperature with chlorothionoformate esters such as (65),in ~yridine.'~~ Ynamines can be pre- pared by conversion of thionamides in one step by reaction with sodamide in xylene the yields being better than those obtained in longer synthetic se-quence~.'~'A rapid simple method for esterifying acids is to use boron tri- fluoride as catalyst.Fewer side-reactions occur compared to the classical Fischer-Speier method.'36 The aminolysis of esters has also been improved. The lithium salts of amines react more cleanly than the corresponding sodium salts. The lithium derivatives are easily prepared using butyl-lithium. '37 Amides are also formed in high yield by reaction between tris(dialky1amino)boranes and carboxylic acids.'38 Conjugated dienoic acids are readily synthesised from the reaction of tertiary acetylenic carbinols with excess malonic acid. Presumably the carbinol is initially isomerised to the ap-unsaturated aldehyde before condensation and decar- boxylation.' 39 The preparative usefulness of the cr-anions of aliphatic carboxylic acids is recorded.These anions (e.g. 66)can be prepared by the reaction of the 13' (a)H. Nambu and H. C. Brown J. Amer. Chem. Soc. 1970,92,5790;(6)H. C. Brown and H. Nambu ibid. p. 176 1 13' A. M. van Leusen and J. C. Jagt Tetrahedron Letters 1970 967. 133 E. Yamato and S. Sugasawa Tetrahedron Letters 1970 4383. 134 D. L. J. Clive Chem. Comm. 1970 1014. 13' A. Halleux H. Reimlinger and H. G. Viehe Tetrahedron Letters 1970 3141. 136 J. L. Marshall K. C. Erickson and T. K. Folsom Tetrahedron Letters 1970 4011. 13' K.-W. Yang J. G. Cannon and J. G. Rose Tetrahedron Letters 1970 1791. 13' A. Pelter and T. E. Levitt Tetrahedron 1970 26 1899. J. Ploquin and L. Sporfel Ann. Chirn. (France),1970 5 143. General Methods 26 1 acid with lithium isopropylamide in tetrahydrofuran containing hexamethyl- phosphoramide.Reaction with ethyl formate followed by decarboxylation gives the corresponding aldehyde. 140a Alkylation and nitrations have also been recorded.14*' 0-and p-Toluic acids can also form dianions (67) capable of similar reactions. An interesting temperature effect in the synthesis of carboxylic acids by the alkylation of anions from dihydro-1,3-oxazines (68; R = alkyl) has been investi- gated. At -78 "C alkylation proceeds cleanly. However at room temperature these anions rearrange to the ketenimines (69)which do not alkylate.14* Whereas the dihydro-oxazines add Grignard reagents across the double bond the corres- ponding oxazolines do not 143a and this system has been used as a protecting group for aromatic carboxylic Thus the derivatives (70) could be converted into their Grignard derivatives caused to react and hydrolysed with release of the carboxylic acid function.The parent system forms anions at the 2-position (71) which can be alkylated to produce mono- and di-alkylated carboxylic acids.143c Ethyl acetate is cleanly transformed into its enolate anion by reaction with lithium bis(trimethylsily1)amide in tetrahydrofuran at -78 "C at which it is stable. The anion readily adds to carbonyl groups to produce P-hydroxy-esters in high yield.144 1-Ethoxyvinyl esters (e.g. 72) rearrange in the presence of zinc salts to give enol-acylated P-keto-esters (73) and this reaction is potentially useful for the preparation of certain P-keto-esters. 14' The Michael addition of Refor- matsky reagents to unsaturated ketones is sensitive to steric effects.1,4-Addition OCOR R (72) (73) I4O (a)P. E. Pfeffer and L. S. Silbert Tetrahedron Letters 1970 699; (b) P. E. Pfeffer and L. S. Silbert J. Org. Chem. 1970 35 262. 14' P. L. Creger J. Amer. Chem. SOC.,1970,92 1396 1397. 142 A. I. Meyers and E. M. Smith Tetrahedron Letters 1970 4355 143 (a) A. I. Meyers and E. W. Collington J. Amer. Chem. SOC.,1970.92 6676; (b)A. I. Meyers and D. L. Temple ibid. P.6646; (c) A. I. Meyers and D. L. Temple ibid. p. 6644. 144 M.W. Rathke J. Amer. Chem. SOC.,1970 92 3222. 145 H. H. Wasserman and S. H. Wentland Chem. Comm. 1970 1. 262 P.G. Sarnrnes is enhanced by using bulky acid groups such as ethyl a-bromomalonate instead of ethyl br0moa~etate.l~~ The a-bromination of acyl halides with N-bromosuccinimide long considered to be a free-radical process is in fact an ionic reaction and is definitely catalysed by acid.14' In concentrated sulphuric acid chlorination of aliphatic acids proceeds via cation radicals the chlorine preferentially entering into the y-position as well as into the terminal methyl group.14' Ethyl P-ketocarboxylates can be decarboxylated at fairly low temperatures (Q 150 "C)by use of boric anhydride as catalyst.'49 Orthoformic acid dimethyl ester dimethylamide (74) is a good dehydrating agent.Epoxides are formed (MeO),CHNMe (74) Ph Ph (75) (76) from 1,2-glycols and it has been found that in cyclic systems only trans-glycols react.15* However in the presence of acetic anhydride a reductive elimination occurs [e.g.(75)to (7611 and in this case cis-glycols react preferentially. lS Orthoesters of the mixed arylalkyl group react with Grignard reagents with preferential displacement of the aryl groups. Thus the orthoester (77) yields the acetal (78).'52 The reduction of carboxylic acids to aldehydes is achieved with PhOCH(OEt) -+ RCH(OEt) (77) (78) lithium in methylamine. The initial product is the imine which can either be hydrolysed to the aldehyde or reduced to the substituted N-methylamine.'53 Dramatically increased yields of the expected products from the Knoevenagel reaction are obtained using titanium tetrachloride and pyridine as catalyst.' 54 6 Alkylations and Couplings Coupling is enhanced between Grignard reagents and alkyl halides if the latter possess neighbouring groups capable of complexation.Thus whereas pentyl bromide does not react with iodomagnesium phenylacetylide ethoxyethyl 14' C. Gandolfi G. Doria M. Amendola and E. Dradi Tetrahedron Letters 1970 3923. L47 J. G. Gleason and D. N. Harpp Tetrahedron Letters 1970 3431. 14* N. C. Deno R. Fishbein and J. C. Wyckoff J. Amer. Chem. Soc. 1970,92 5274. 149 J. M. Lalancette and A. Lachance Tetrahedron Letters 1970 3903. I5O H. Neumann. Chimiu (Switz.) 1969 23 267. 151 F. W. Eastwood K. J. Harrington J. S. Josan and J. L. Pura Tetrahedron Letfers 1970 5223. H. Stetter and E. Reske Chem. Ber. 1970 103 643. 153 A. 0.Bedenbaugh J. H. Bedenbaugh and W.A. Bergin J. Amer. Chem. Soc. 1970 92 5774. 154 W. Lehnert Tetrahedron Letters 1970 4723. General Methods 263 bromide does. The effect is general and allows selectivity in coupling reactions.'55 A similar co-ordination precedes the addition of lithium alkyls to alkenyl ethers.' 56 Reduction often accompanies alkylation by hindered Grignard reagents but reduction can be inhibited in the presence of salts. Tetrabutyl-ammonium bromide is particularly effe~tive.'~' A 'one-step' alternative to the Grignard reaction is to add a 1 1 mixture of the ketone and the alkyl halide to lithium suspended in tetrahydrofuran. Excellent yields of alkylation products are thus obtained.'58 The coupling of allylic Grignard reagents to allylic alcohols is catalysed by magnesium bromide.' 59 The reaction of allylic Grignard reagents with car- bony1 functions is reversible resulting in a non-stereoselective addition.' 6o A good method for the coupling of allylic halides with the propargyl moiety is to make the Grignard derivative followed by trimethylsilylation of the crude product.Subsequent detrimethylsilylation gave better yields ofproduct acetylenes than were obtained previously (Scheme 13.)16' Ally1 ethers are cleaved by mag- nesium in the presence of ethylene dibromide.'62 The coupling of benzyl halides with sodium hydride in hexamethylphosphoramide is activated by the presence SiMez I %Mez Reagents i CH =C=CHMgBr; ii EtMgBr-Me,SiCl; iii alcoholic AgNO,; iv. aqueous NaCN. Scheme 13 of alkoxides.Sodium hydride alone tends to react as a reducing agent.'63"*b Other evidence that sodium hydride can often react as a reducing agent has been acquired in that in dimethylformamide it appears to react as the anion (79).'(j3' A mixture of sodium hydride and a sodium alkoxide formed from a hindered alcohol reacts cleanly with 1,2-dibromides in tetrahydrofuran to give acetylenes.' 64 155 G. W. Cooper and R. P. Houghton Tetrahedron Letters 1970. 3915. L5b A. H. Veefkind F. Bickelhaupt and G. W. Klumpp Rec. Trau. chim. 1969 88 1058. Is' M. Chastrette and R. Anouroux Chem. Comm. 1970,470. 58 P. J. Pearce D. H. Richards and N. F. Scilly Chem. Comm. 1970 1160. H. Felkin and C. Kaeseberg Tetrahedron Letters 1970,4587. Iho P. Miginiac Bull.SOC.ehim. France 1970 1077. 16' R. E. Ireland M. I. Dawson and C. A. Lipinski Tetrahedron Letters 1970 2247. A. Maercker J. Organometallic Chem. 1969 18 249. 163 (a)P. Caubere and J. Moreau Bull. SOC. chim. France 1970 1986; (6)S. Bank and M. C. Prislopski Chem. Comm. 1970 1624; (c)J. M. Z. Gladych and R.Hornby Chem. and Ind. 1970 652. P. Caubere and J. Moreau Tetrahedron 1970 26 2637; cf Ann. Reports (B) 1969 66 260 ref. 122 where aprotic conditions were in fact also employed. 264 P.G. Summes Metallation of alkylbenzenes is readily effected with n-butyl-lithium and N N N' N'-tetramethylethylenediamine.65 Resonance-stabilised organolithium compounds react with secondary halides with inversion of configuration-non-resonance-stabilised lithium compounds are less discriminating.Very high selectivity is observed in the reaction of unsymmetrical epoxides with lithium diethylamide in their isomerisation to allylic alcohols. Thus the epoxide (80) gives virtually only the alcohol (81) probably by ~yn-elimination.'~~ Lithium dialkyl copper complexes react smoothly with epoxides,' 68a as do dialkylmagnesium compounds in the absence of magnesium halides.' 68b The conjugate addition of alkyl groups to unsaturated epoxides has also been recorded and is favoured by use of the lithium dialkyl copper reagents.169 Acid chlorides react with the same alkylating agents to give ketones."' The alkylating properties of a variety of transition metal complexes have been studied and as a result vinyl bromides and iodides were found to couple cleanly with lithium trimethyliron ;I7 allylic bromides also react.95 Another method of coupling two allyl groups used in a synthesis of squalene involved alkylation of an allylphosphonium ylide with another allyl bromide.Reduction of the phosphonium salt was achieved by use of lithium in ethylamine (Scheme 14).'72 R +-CH-~B~ Me + > * L R+R + PBu Br-BrCH -CH=CR1 Me Scheme 14 165 C. D. Broaddus J. Org. Chem. 1970 35 10. L. H. Sommer and W. D. Korte J. Urg. Chem. 1970,35 22. 167 B. Rickborn and R. P. Thummel J. Org. Chem. 1969,34 3583. 168 (a) R. W. Herr D. M. Wieland and C. R. Johnson J. Amer. Chem. SOC.,1970 92 3813; (b)J. D. Morrison R. L. Atkins and J. E. Tomaszewski Tetrahedron Letters 1970,4635.169 R. J. Anderson J. Amer. Chem. SOC.,1970,92 4978; R. W. Herr and C. R. Johnson J. Amer. Chem. SOC., 1970,92 4979. "O G. H. Posner and C. E. Whitten Tetrahedron Letters 1970 4647. E. J. Corey and G. H. Posner Tetrahedron Letters 1970 315. cf. E. J. Corey and 1. Kawazima J. Amer. Chem. SOC.,1970 92 395. '72 E. H. Axelrod G. M. Milne and E. E. van Tamelen J. Amer. Chem. SOC.,1970 92 2139. General Methods The B-methoxydialkylboranes add to olefins in the presence of lithium aluminium hydride to give mixed trialkylboranes thus opening up several variants of the synthetic uses for these compounds.’ 73 Sodium tetracarbonyl- ferrate( -11) homologates alkyl bromides to the corresponding aldehyde.’ 74 Another new class of organometallic compound is exemplified by cis-and tratzs-P-styrylpyridinecobaloximes (82).Both isomers can be isolated and each PhC H =C H.Co(DH)2,py DH = dimethylglyoxime monoanion py = pyridine (82) reacts with halogens stereospecifically with retention of configuration to give P-styrylhalides. This latter reaction should be general for these compounds.’ 75 Thallium(1) bromide catalyses the coupling of aryl magnesium compounds to biaryls probably uia the aryl radical.’ 76 Another novel radical reaction has been developed for substitution at tertiary carbon centres. Thus p-nitrocumyl chloride (83) will accept an electron from isopropyl-2-nitronate anions (84) to form a radical anion. Loss of chloride produces a radical which can couple with more 60-(83) NO2 -P ‘5 N? *o’ ‘0- -b 6/N ’0 0->;NO -‘0/N\ 0-gNo2 + + I )NO2 )-NO2 Scheme 15 I” H.C. Brown E. Negishi and S. K. Gupta J. Amer. Chem. SOC.,1970,92,6648. M. P. Cooke J. Amer. Chem. SOC.,1970,92 6080. ”’ M. D. Johnson and B. S. Meeks Chem. Comm. 1970 1027. ”‘A. McKillop L. F. Elsam and E. C. Taylor Tetrahedron 1970,26,4041. P.G.Sammes of the nitronate anion (84) to produce a new anion radical eventually oxidised to the coupled product. (Scheme 15)' 77a Tertiary nitro-compounds can also be alkylated in this manner since the nitro-group behaves as an excellent leaving group.' Several new sulphur ylides have been prepared. The reagent (85c) inserts carboxymethyl groups into ketones or conjugated olefinic bonds,' 78 whilst the stable ylides (85a)179 and (85b)' similarly transfer methylene groups.N-Cyano- ammonium salts such as (86) behave as potent alkylating agents."l 0 II + Ph-S-CH -Me2kHC0 -Na' I NMe (85b) LiCH,CI R CN (87) The lithium alkyl(87) is superior to the analogous bromide and iodide for the transfer of the methylene group to olefins.lB2 Another method for preparing cyclopropanes is to add di-iodomethane in the presence of diethylzinc.' 83 7 Miscellaneous 1-(2-Carboxyphenyl)triazenes (88) are stable crystalline compounds which give benzyne either on warming or by addition of one equivalent of trichloro- acetic acid.' 84 o-Benzenediazonium carboxylate cannot be used as a benzyne precursor in acetonitrile and related solvents since reaction with the solvent occurs to form (4H)-3,1 -benzoxazin-4-one derivatives (89).18' An improved method for the preparation of methanesulphonate esters has been described.'86 Trifluoromethanesulphonic imidazolide (90) is a convenient reagent for the preparation of 'triflate' esters.'87 Alcohols can be converted into "'(a)N. Kornblum R. T. Swiger G.W. Earl H. W. Pinnick and F. W. Stuchal. J. Amer. Chem. SOC. 1970 92 5513; (6) N. Kornblum S. D. Boyd and F. W. Stuchal ibid. p. 5783. J. Adams L. Hoffman and B. M. Trost J. Org. Chem. 1970 35 1600. C. R. Johnson and G. F. Katcha J. Amer. Chem SOC.,1970,92 5753. I8O C. R. Johnson M. Haake and C. W. Schroeck J. Amer. Chem. SOC.,1970,92 6594. Ia1 J. V. Paukstelis and M. Kim Tetrahedron Letters 1970 4731.la* U. Burger and R. Huisgen Tetrahedron Letters 1970 3049. J. Furukawa N. Kawabata and T. Fujita Tetrahedron 1970 26 243. J. Nakayama 0.Simamura and M. Yoshida Chem. Comm. 1970 1222. R. R. Schmidt and W. Schneider Tetrahedron Letters 1970 5095. R. K. Crossland and K. L. Servis J. Org. Chem. 1970,35 3195. la' F. Effenberger and K. E. Mack Tetrahedron Letters 1970 3947. General Methoh chlorides by reaction with the reagent (91) in the presence of lithium chloride bromides are similarly prepared.’88 Bromides can be converted into chlorides by reaction with the barbiturate derivative (92).18’ aCOzH N=N-NMe (88) Et2NCF2 -CFClH (91) CH,C1 (92) The selective mono-chlorination of phenols and aniline is normally difficult.Use of the mild reagent trichloroisocyanuric acid in the presence of some acid catalyst is now recommended for this transformation.’ 90 The fluorination of aromatic compounds with the mild reagent xenon difluoride is catalysed by hydro- fluoric acid.”’ The fluorination of olefins can be achieved with potassium tetra- fluor~cobaltate.’~~ Iron carbonyl complexes are useful for trapping diene systems. An elegant example is the use of iron(0) pentacarbonyl to trap the Kekule structures (93) and (94) obtained from 3,a-dimethyl~tyrene.’~~ Extrusion of sulphur dioxide from aromatic sulphonyl chlorides is effected with complexes of the platinum group. Good yields of the corresponding chloride are often Iodine in oleum is a powerful iodinating reagent.Even nitro-aromatics are attacked.195 E. J. Bailey H. Fazakerley M. E. Hill C. E. Newall G. H. Phillipps L. Stephenson and A. Tulley Chem. Comm. 1970 106. lS9 J. A. Vida Tetrahedron Letters 1970 3447. 190 E. C. Juenge D. A. Beal and W. P. Duncan J. Org. Chem. 1970,35 719. l9 M. J. Shaw J. A. Weil R. Filler and H. H. Hyman J. Amer. Chem. Soc. 1970,92,5096. IV2 J. C. Tallow. J. Burdon P. L. Coe G.P. 1970 no. 1,925,836 (Chem.Abs. 1970 72 78104). 193 R. Victor R. Ben-Shoshan and S. Sarel Chem. Comm. 1970 1680. 194 J. Blum and G. Scharf J. Org. Chem. 1970,35 1895. J. Arotsky R. Butler and A. C. Darby J. Chem. Soc. (0,1970 1480. 268 P.G. Sammes Primary alkylamines can be prepared by alkylation of the precursor (95). Hydrochloric acid liberates the amine hydr~chloride.'~~ Several methods for the preparation of unsymmetrical disulphides have been reported.Thus sul-phenic esters react with trialkylthioboranes to give unsymmetrical disulphides. 19' Moregeneral is the reaction ofmercaptans with N-(alky1thio)phthalimides (11).19' Active methylene compounds such as 0-keto-esters can also react with the latter derivatives to give the thioalkylated derivative^.'^^ OMe 1 ( Ph S),NLi Ph -C -CO H 1 (95) CF (96) An effective way to demethylate aryl ethers is to react them with lithium200" or sodium200b mercaptides in polar aprotic solvents. Dialkyl ethers can also be rapidly cleaved by aluminium tri-iodide in carbon R' H RZ iii H NH HN+ + H R3 H,N+vco; :\ H R3 Reagents i R3COC0,Me; ii AI-He; iii H,-Pd-C; iv H,O+.Scheme 16 An efficient method for the stereospecific synthesis of a-amino-acids from pyruvic esters has been developed (Scheme 16).202 a-Methoxy-a-trdluoro-methylphenylacetic acid (96) is a good reagent for testing the optical purity of alcohols and amines203" and its preparation has been The use of thallium in organic chemistry has been reviewed204 and a book on modern organic reactions emphasising synthetic methods has been pub- lished. O5 196 T. Mukaiyama and T. Taguchi Tetrahedron Letters 1970 341 1. 191 R. H. Cragg J. P. N. Husband and A. F. Weston Chem. Comm. 1970 1701. 19 8 K. M. Bousfang and A. B. Sullivan Tetrahedron Letters 1970 3547; K. Boustang Chimia (Switz.) 1970,24,396; D.N. Harpp D. K. Ash T. G.Back J. G. Gleason B. A. Orwig and W. F. Van Horn Tetrahedron Letters 1970 1970 3551. 199 T. Mukaiyama S. Kobayashi and T. Kumamoto Tetrahedron Letters 1970 51 15. 200 (a)P. A. Bartlett and W. S. Johnson Tetrahedron Letters 1970,4459; (6) G. I. Feutrill and R. N. Mirrington ibid. p. 1327. 20 I E. Mincione Ricerca sci. 1969 39 424. 20 2 E. J. Corey R. J. McCaully and H. S. Sachdev J. Amer. Chem. Soc. 1970,92,2476. 203 (a)J. A. Dale D. L. Dull and H. S. Mosher. J. Org. Chem. 1969,34 2543; (h)L. Hub and H. S. Mosher ibid. 1970 35,3691. 204 E. C. Taylor and A. McKillop Accounts Chem. Res. 1970 3 338. 20 s 'Modern Reactions in Organic Synthesis' ed. C. J. Timmons Van Nostrand Reinhold Company London 1970.General Methods The ‘crownanes’ (e.g.10) are useful chelating agents and the properties of some of them have been reported.206 A short review on the use of NNN’N’-tetra-methylethylenediamine in organometallic chemistry has appeared.*07 C. J. Pederson J. Amer. Chem. SOC.,1970 92 386 391 207 C. Agami Bull. SOC. chim. France 1970 1619.