TervalentPhosphorus Compounds in Organic Synthesis By J. I. G. Cadogan DEPARTMENT OF CHEMISTRY, UNIVERSITY OF EDINBURGH, WEST MAINS ROAD, EDINBURGH, EH9 3JJ R. K. Mackie DEPARTMENT OF CHEMISTRY, UNIVERSITY OF ST. ANDREWS, ST. ANDREWS, FIFE, SCOTLAND 1 Introduction The ease with which tervalent phosphorus can expand its valence shell to accommodate ten electrons, the high nucleophilic reactivity of certain tervalent phosphorus compounds, and the strong bonds which phosphorus forms with carbon, nitrogen, oxygen, and sulphur are factors which contribute to the high reactivity of materials such as trialkyl phosphites or triarylphosphines towards a wide variety of organic compounds. As a result, tervalent phosphorus com- pounds have become one of the most versatile classes of reagents available in general organic synthesis, with reactions ranging from the simple removal of hydroperoxides from ethers, or decomposition of ozonides, through the synthesis of alkenes or complex nitrogen heterocycles, to intervention in the chemistry of penicillins, or as synthetic precursors of vitamin BIZ.This review, which is not intended to be comprehensive because much of the earlier relevant work has been summarized, is directed mainly towards the use of these readily available organic reagents in general organic synthesis rather than towards the more specialist aspects of the phosphorus chemistry involved. On perusal of the literature, three main types of reaction emerge: (a) de-sulphurization, (b) deoxygenation, and (c) reaction with halogen-containing materials, all of which have major applications in organic chemistry.In addition there are those cases, not considered here in extenso, where a tervalent precursor is used to produce a quinquevalent phosphorus reagent of general synthetic value; examples of this are the Wittig and Homer reagents, the related phos- phinimines, Ramirez’ oxyphosphoranes, and triphenyl phosphite ozonide, all of which have an extensive literature of their own. 2 DesulphurizationReactions In accord with the soft character of the reactants, tervalent phosphorus has a high a5ity for free and bound sulphur, which has led to many useful synthetic reactions. The size and high polarizability of tervalent phosphorus enable it to utilize the empty orbital of sulphur more effectively than is the case for oxygen or nitrogen, and indeed elemental sulphur adds readily to phosphines and Tervalent Phosphorus Compounds in Organic Synthesis phosphites in air to give the sulphide rather than the oxide' via a Menshutkin- type reaction involving successive nucleophilic displacements of phosphorus on sulphur.a A.Alkenes from Episu1phides.-That episulphides can be converted into the corresponding alkenes by reaction with trisubstituted phosphines or phosphites has been known since 1958.3~~Unlike the corresponding deoxygenation of epox- ides: which proceeds non-stereospecifically, initially via nucleophilic attack on carbon: this reaction occurs with complete stereospecificity via a smooth displace- ment on sulphur (Scheme 1).The reaction has some synthetic value, for example Scheme 1 in the formation of thermochromic alkenes, which can only be produced with difficulty by other routes.' B. Vinylogous Amides and p-Diketones from Thioimidates and Related Com-pounds.-This method, developed by Eschenmoser et aL8 as a key step in the synthesis of corrins, involves the reaction of the thioimidate with a mixture of base and a tervalent phosphorus compound [e.g. BwP, (Et0)3P]; alkylative coupling to give an episulphide followed by desulphurization leads to the product (Scheme 2).8b,C As well as being valuable in corrin building (Scheme 3),8C the reaction, when modified, is generally useful, as shown by its extension to the synthesis of enolizable p-diketones (Scheme 4Jeb,C F.W. Hoffman and T. R. Moore, J. Amer. Chem. Soc., 1958,80, 1150; W. Strecker and R. Spiraler, Ber., 1926, 59, 1772. a P. D. Bartlett and G. Meguerian, J. Amer. Chem. SOC.,1956, 78, 3710; P. D. BartIett, E. F. Cox, and R. E. Davis, ibid., 1961, 83, 103. a R. D. Schuetz and R. L. Jacobs, J. Org. Chem., 1958,23,1799; A. Schonberg and M. M. Sidky, J. Amer. Chem. SOC., 1959, 81, 2259. R. E. Davis, J. Org. Chem., 1958,23, 1767. '(a) C. B. Scott, J. Org. Chem., 1957, 22, 1118; (b) G. Wittig and W. Haag, Chem. Ber., 1955,88, 1654.'M. J. Boskin and D. B. Denney, Chem. and Ind., 1959, 330. 7 M. M. Sidky, M. R. Mahran, and L. S. Poulos, J. prakt. Chem., 1970, 312, 51. '(a) Y.Yamada, D.Miljkovik, P. Wehrli, B. Golding, P. Loliger, R. Keese, K. Muller, and A. Eschenmoser, Angew. Chem. Internat. Edn., 1969, 8, 343; (b) M. Roth, P. Dubs, E. Gotschi, and A. Eschenmoser, Hefv. Chim. Acta, 1971, 54, 710; (c) A. Eschenmoser, Quart. Rev., 1970,24, 366. Cadogan and Mackie QS CH,BrH I Scheme 2 Scheme 3 C. Alkenes from Thionocarbonates.-That E. J. Corey and R. A. E. Winter'ss synthesis of alkenes from thionocarbonates is now widely used is not surprising: @ E. J. Corey and R. A. E. Winter, J. Amer. Chem. SOC.,1963, 85, 2677; E. J. Corey, Pure Appl. Chem., 1967, 14, 19. Tervalent Phosphorus Compounds in Organic Synthesis 1 Scheme 4 in essence it allows a diol to be converted via cis-elimination into an alkene with retention of stereochemistry.Thus, the reaction of the diol with thiophosgene or, better, thiocarbonyldi-imidazole leads to a cyclic thionocarbonate which undergoes stereospecifically cis-elimination on reaction with tervalent phosphorus reagents [e.g. (R0)3P, R3P, (R2N)3P] (Scheme 5). The observed stereospecificity f (RO),PS + co, Scheme 5 points to the absence of dipolar intermediates and to reaction via a carbene or, more likely, via a concerted loss of C02 and R3P=S. Examples demonstrating the versatility of this reaction (Scheme 6) include the synthesis of unsaturated sugars and related compoundslO and of unstable alkenes hitherto difficult to obtain such as cyclobutene,ll cis-cinnamic acid,la both enantiomers of trans-10 W.V.Ruyle, T. Y. Shen, and A. A. Patchett, J. Org. Chem., 1965,30,4353; T. L. Naga-bhushah, Canad.J. Chem., 1970,48,383; D. Horton and C. G. Tindall, jun., J. Org. Chem. 1970,35, 3558. l1 W.Hartman, H.-M. Fischler, and H.-G. Heine, Tetrahedron Letters, 1972, 853. I* C. Sandris, Tetrahedron. 1968, 24, 3589. Cadogan and Mackie 0 0 0ph3c0kl 'coid OK0S (1) Scheme 6 cyclo-octenel3 (with high optical purity), trans-cycloheptene (trapped by 2,s-diphenyl-3,4-i~obenzofuran),~*aand (+)-twistene (l).14b Similar elimination reactions occur with the corresponding 1,2-trithiocar- bonatesl*a but reactions with the related 1,3-trithiocarbonates14 proceed without complete elimination of sulphur. In this case the reaction stops at the ylide stage.Nevertheless this has its synthetic possibilities because on reaction with certain aldehydes, keten thioacetals are formed, which in turn can be hydrolysed to substituted acetic acids (Scheme 7).The reaction does not proceed with ketones. The parent keten thioacetals also have other synthetic uses.lS E. J. Corey and K. I. Shulman, Tetrahedron Letters, 1968, 3655. (a) E. J. Corey, F. A. Corey, and R. A. E. Winter, J. Amer. Chem. SOC.,1965. 87, 934; (6) M.Tichy and J. Sicher, Tetrahedron Letters, 1969,4609; (c) E. J. Corey and G. MBrkl, ibid., 1967, 3201. l6 E.J. Corey and D.Seebach, Angew. Chem. Internat. Edn., 1965,4, 1075, 1077. Tervalent Phosphorus Compounds in Organic Synthesis PhCHO1 liCHiPh Scheme 7 D.Alkenes from 1,3-Oxathiolan-5-ones and Azosu1phides.-These reactions are examples of D. H. R. Barton’s alkene synthesis by two-fold extrusion processes,lS the principle being elimination of X and Y from the species In the first, 1,3-oxathiolan-5-ones, readily prepared from thiobenzilic acid and benzaldehyde or various ketones, on treatment with (Et2N)3P at high temper- ature give alkenes in high yield (Scheme 8) even when highly sterically hindered Scheme 8 la D. H. R. Barton and B. J. Willis, Chem. Comm., 1970, 1225; J.C.S. Perkin I, 1972,305;D.H. R. Barton, E. H. Smith, and B. J. Willis. Chem. Comm., 1970, 1266. Cadogan and Mackie alkenes are required. The reaction is limited, however, by the need for incor- porating phenyl or other conjugated residues to facilitate loss of carbon dioxide. In the second related synthesis triphenylphosphine is used to extract sulphur with elimination of nitrogen from azosulphides formed from ketones by their reaction with HzS and hydrazine, followed by oxidation (Scheme 9). The cor- responding trithia-system (Scheme 9) is very much more stable and resists attack even by the strongly nucleophilic (Et2N)3P.(77%) Scheme 9 In neither case has a mechanism been established, but intermediate formation of the corresponding episulphide is a strong possibility. E, Hydrocarbons by Desulphurization of Thiols and Sulphides.-Alkanethiols readily undergo quantitative desulphurization to the corresponding alkanes17a by reaction under radical conditions (light or AIBN)with trialkyl phosphites or trialkylphosphines (Scheme 10).17b The corresponding reaction with toluene-ar- RlSH --+ R'S* RIS* + Ra3P+Ra$SR1 --r Ra3p=S + R'* R1*+ RlSH --+ RIH + RIS* et seq. Scheme 10 If(a)F.W.Hoffmann, R.J. ESS,R.C. Simmons, and R. S. Hanzel, J. Rmrr. Chem Soc. 1956,78, 6414; (6) C. Walling and R.Rabinowitz, ibid., 1957, 79, 5326. Tervalent Phosphorus Compounds in Organic Synthesis thiol and (Et2N)sP is reported to give (Et2N)2PSCH2Ph.18 The key step in the desulphurization is the reaction of a thiyl radical with tervalent phosphorus to give an intermediate thiophosphoranyl radical which subsequently decomposes via fission of the weaker PS-R bond to give a chain-carrying alkyl radical.” Thissimple method of reducing thiols to hydrocarbons has not been widely used, although it has been used by Eschenmoser to desulphurize a 5-mercaptoarrin- zinc complex cleanly (Scheme 1l).au The possibility of using this step to produce SH CHClr CN CVN Scheme 11 an alternative method of desulphurization of sulphides has been investigated by Corey and Block.a1 Thus photolysis of dibenzyl sulphide in the presence of trimethyl phosphite gives bibenzyl (59%), presumably via benzylthio-radicals which are in turn desulphurized by the phosphite to give benzyl radicals (Scheme 12).Similarly diallyl sulphide gives biallyl. Treatment of those dialkyl sulphides which give shorter-lived alkyl radicals, however, leads to mixtures of products.h* PhCHz-S-CH2Ph --+ PhCHzS. + *CH2Ph PhCHzS. + (R0)sP 4 (RO).JbSCHaPh*5. PhCHzCHzPh tPhcH2 + (RO)sPS Scheme 12 Dialkyl and diary1 monosulphides, in general, are unreactive towards tervalent phosphorus compounds under ionic conditions, but 3-substituted thietans, which are strained, are exceptional.aa Thus 3-chlorothietan on treatment with triphenyl- phosphine in boiling xylene gives ally1 chloride; possible routes are shown in Scheme 13. 18 C. Steube and H. P. Lankelma, J. Amer. Chem. Soc., 1956,78,976. 19 C. Walling and R. Rabinowitz,J. Amer. Chem. SOC.,1959, 81, 1243; C. Walling, 0. H. Basedow, and E. S. Savas, ibid., 1960, 82, 2181. 80 A. Fischli and A. Eschenmoser, Angew. Chem. Internat. Edn., 1967, 6, 866. ‘1 E. J. Corey and E.Block, J. Org. Chem., 1969,34, 1233. 98 D. C. Dittmer and S. M. Kotin, J. Org. Chem., 1967,32,2009. Cadogan and Mackie CHz=CHCHzCl + Phb:PS * 140'C *+'a/haRoutes via c1-and are also possible Scheme 13 F. Sulphides from Disu1phides.-The ease and course of desulphurization of disulphides depend on the nature of the tervalent phosphorus compound. It has long been knownz3 that triphenylphosphine reacts with acyl, thioacyl, and vinylogous acyl disulphides, via nucleophilic displacement on sulphur, to give the corresponding monosulphide (Scheme 14), whereas diethyl and dipheny *.-p t: PhdP PhCOS-SCOPh PhslPSCOPh Ph%OS' PhaFS + PhCOSCOPh Scheme 14 disulphide fail to react. Dialkenyl sulphides such as dimethylbut-2-enyl di- sulphide react, on the other hand, by way of an SNi' allylic rearrangement (Scheme 15),24a and this has been put to elegant use in a synthesis of squalene from farnesyl ~hloride.~~o The conversion of the metabolite sporidesmin into the corresponding epithiodioxopiperazine by triphenylphosphine is an example of the higher reactivity of acyl disulphides towards this reagent (Scheme 16).25 That this reaction proceeds via epimerization supports reaction as in Scheme 14.Trialkyl phosphites react even with simple sulphides such as diethyl disulphide at high temperature in a manner that is analogous to the Arbusov reaction in that the quasiphosphonium salt, formed by nucleophilic displacement on sulphur, undergoes dealkylation at the more electrophilic 0-alkyl group, rather than at S-alkyl (Scheme 17),2s to give a dialkyl S-ethyl phosphorothiolate, say.Thus 23 A. Schonberg and M. Barakat, J. Chem. SOC.,1949, 892; F. Challenger and D. Wilson, ibid, 1950, 26; A. J. Parker and N. Kharasch, Chem. Rev., 1959, 59, 621. 24 (a) M. B. Evans, G. M. C. Higgins, C. G. Moore, M. Porter, B. Saville, J. F. Smith, B. R. Trego, and A. A. Watson, Chem. and Ind., 1960, 897; (b) G. M. Blackburn, W. D. Ollis, C. Smith, and I. 0.Sutherland, Chem. Comm., 1969, 99. 25 S. Safe and A. Taylor, J. Chem. SOC.(C), 1971,1189. 86 A. C. Poshkus and J. E. Henveh, J. Amer. Chem. SOC.,1957, 79, 4245; H. I. Jacobson, R. G. Harvey, and E. V. Jensen, ibid., 1955, 77, 6064. 95 4 TervalentPhosphorus Compounds in Organic Synthesis Me2@ CH Me&e.CH,Me/CH-CHMe S-S I CPPhS -"3..........&, I I MeBC:CHeHMe Me&:CHCHMe MeBCCH:CHIMe I S I Mell CCHCHMe Scheme 15 +Ph,PS Scheme 16 EtSR + (RO)aP(O)SEt Scheme 17 in the case of triethyl phosphite and diethyl disulphide the product is diethyl sulphide in which one of the ethyl groups originates in the phosphite. An interesting variant of this reaction has recently been employed in the penicillin series.27 It had been previously established that penicillin sulphoxides rapidly undergo a thermal six-electron electrocyclic rearrangement to the isomeric open-chain sulphenic acid. D. H. R. Barton and his colleagues found that this reacted with isobutanethiol to give the corresponding 4-isobutyl dithioaceti- *' D.H. R. Barton, P. G. Sammes, M. V. Taylor, C. M. CooDer, G. Hewitt, B. F. Looker, and W. G. E. Underwood, Chem. Comm.,1971, 1137. Cadogan and Mackie dinone which, on treatment with trimethyl phosphite, gave the corresponding monothioazetidinone in good yield (Scheme 18). HH . +/OMeBu' SP-OMe PhCH,CONH t-CO,CH,CCI, Scheme 18 Under radical conditions the reaction between dialkyl disulphides and triethyl phosphite takes yet a different course, resembling that between thiols and the phosphite (Scheme 10). Di-isobutyl disulphide and triethyl phosphite under these conditions give the monosulphide and triethyl phosphorothionate in excellent yields.20 This has been adapted to provide a route to thioesters by performing the reaction under a pressure of carbon monoxide (Scheme 19).20 RIS* + (R20)sP+(R20)sl%R1--+ (R20)3PS + R'* R1* + CO -+RICO- RlCO-+ RIS*SR1+RICO*SR1+ RIS=et seq.Scheme 19 For most desulphurizations of disulphides, however, (Me2N)sP or (Et2N)sP appear to be the best reagents, leading to high yields of dialkyl sulphides under mild conditions.2sa The course of the reaction differs slightly from that described in Schemes 17 and 18, in that S-dealkylation rather than N-dealkylation of the quasiphosphonium salt to give the corresponding phosphorothionate is preferred (Scheme 20). Examples of desulphurizations by this reagent include the con- (a) D. N. Harpp and J. G. Gleason, J. Amer. Chem. SOC.,1971,93,2437; (b) D.N. Harppand J. G. Gleason, J. Org. Chem., 1970,35, 3259. 4+ Tervalent Phosphorus Compounds in Organic Synthesis +3(MeaN),?VR -3 (MesN)sP-S-R (MerN),PS + RSR GS R 3RS’ Scheme 20 version of protected cystine into L-lanthionine and of the amide of the vitamin a-lipoic acid into the corresponding thietan (Scheme 20).a8aThe latter involves intramolecular dealkylation of the type which is impossible in the steroidal disulphide shown in Scheme 21, which instead reacts to give the steroidal phosphorothiodiamidite shown,28b via thiol formation and subsequent reaction with (Et2N)sP as previously described.lB I c 0Lo 0m Scheme 21 G.Carbodi-imides from Thioureas and Disulphides from Thio1s.-Conversion of thioureas into carbodi-imides2B can be regarded as a variation of the disulphide to sulphide reaction, but it depends first on an alleged, but nonetheless intriguing, triphenylphosphine-catalysed oxidation of thiols to disulphides effected by diethyl azodicarboxylate.30 The mechanism of this reaction is obscure and more work is required, although a charge-transfer complex between phosphine and 0.Mitsunobu, K. Kato, and F. Kakese, Tetrahedron Letters, 1969, 2473. K. Kato and 0. Mitsunobu, J. Org. Chem., 1970,35,4227. Cadogan and Mackie azo-compound is probably involved (Scheme 22). Extension of this reaction to desulphurization of thioureas via the thiol tautomer, again by an obscure route, has also been PhtP Et02CN=NC02Et __+ [charge-transfer complex] JRSH RSSR + (Et02CNH)2 + Ph3P Scheme 22 H.Alkyl Halides from Thio1s.-This3l is also a variant of the disulphide desulphurization and involves conversion of the thiol into an alkyl chlorocarbonyl disulphide by reaction with chlorocarbonylsulphenyl chloride followed by reaction with triphenylphosphine (Scheme 23). RSH + CiSCOCl -RS-S-cOG0 f 1 PhPS ? RCI -PKSPSR C1' +COS Scheme 23 I. Sulphinatesfrom Thiolsu1phonates.-That alkyl but not aryl esters of aliphatic and aromatic thiolsulphonic acids react readily with trialkyl phosphites to give alkyl sulphinates was reported in 1960;32isomeric alkyl sulphones, arising from the bidentate nature of the sulphinic anion, were also sometimes formed (Scheme 24).33 The reaction was recently extended to include reactions of (Et2N)aP with acyclic and alicyclic esters (Scheme 24).34 J.Amines from Sulphenamides-The classic Gabriel synthesis fails when applied to branched primary alkylamines as a result of difficulty in forming the required N-alkyl-phthalimide. This can be overcome in some cases by synthesis of the latter using the reaction of the more easily formed sulphenamide with (Me2N)sP (Scheme 25).36 31 D. L. J. Clive and C. V. Denyer, J.C.S. Chem. Comm., 1972, 773. 9a J. Michalski, T. Modro, and J. Wieczorkowski,J. Chem. SOC.,1960, 1665. 33 D. N. Harpp, J. G. Gleason, and D. K. Ash, J. Org. Chem., 1971,36,322. 34 D. N. Harpp and J. G. Gleason, Tetrahedron Letters, 1969, 1447. 35 D. N. Harpp and B. A. Orwig, Tetrahedron Letters, 1970, 2691.99 Ter valent Phosphorus Compounds in Organic Synthesis (EtO),P + RfSOdSR2 + @tO),kR2 R'SOr'-@tO),P(O)SR* -I-R'SOOEt + R*SO,Et Scheme 24 - &N- (iMe2N)3$SR 0 0 0 Scheme 25 K. Sulphides from Sulphoxides and Sulphenates.-Simple sulphoxides are deoxygenated to sulphides by a variety of tervalent phosphorus Phosphorus trichloride appears to be particularly useful in the case of aromatic s~lphoxides.~~CPenicillin sulphoxides are also deoxygenated, but the nature of the rearranged products indicates that the reaction involves deoxygenation of the first-formed tautomeric sulphenic acid (see above) to the corresponding thiol, which then condenses with the amido side-chain to give the observed thiazoline derivative (Scheme 26).37On the other hand, alkyl sulphenates are desulphurized 36 (a) E.H. Amonoo-Neizer, S. K Ray, R. A. Shaw, and B. C. Smith, J. Chem. SOC.,1965, 4296; (6) S. Oae, A. Nakanishi, and S. Komka, Tetrahedron, 1972,28,549; (c) I. Granoth, A. Kalir, and Z. Pelah, J. Chem. SOC.(C), 1969, 2424. 37 R. D. G. Cooper and F. L. Jose,J. Amer. Chem. SOC.,1970, 92,2575. Cadogan and Mackie 7 7 OHI PhOCH,CONH d PhOCHGONH4 I$> 0 I CO,R 602R N/rph &02RH COfR Scheme 26 to There appears to be a measure of reagent specificity, however; tributylphosphine, but not triethyl phosphite or triphenylphosphine, is successful in reducing Bu~SOR.~* Trimethyl phosphite can be used with the more reactive ally1 ~ulphenates~~ but in this case deoxygenation rather than desulphurization occurs together with other reactions.L. Preparation of Amides and Applications in Peptide Synthesis.-The reaction of triphenylphosphine with sulphenamide has been used to effect condensation of amino- and carboxy-groups in peptide synthesis (Scheme 27).40The reaction i-Ph3P + R1SNR22f R3COzH--+ Ph3PSR1 + R3C02-+ R22NH , J J. R',NH + Ra2NCOR3+ Ph3PO f-Ph3POCOR3 + R'S-Scheme 27 was found to be more satisfactory when copper(II) carboxylate was ~~ed~~p~~ to precipitate copper(n) mercaptide, thus eliminating an unwanted side-reaction of 38 D. H. R. Barton, G. Page, and D. A. Widdowson, Chem. Comm., 1970, 1466. D. A. Evans and G. C. Andrews, J. Amer.Chem. SOC.,1972, p4,3672. 40 T.Mukaiyama, M. Ueki, H. Maruyama, and R. Matsueda, J. Amer. Chem. SOC.,1968, 90,4490. M. Ueki, H. Maruyama, and T. Mukaiyama, Bull Chem. SOC.Japan, 1971,44, 1108. 101 TervalentPhosphorus Compounds in Organic Synthesis the mercaptide with the starting sulphenamide [RIS- + R1SNR22-RlSSRl + Rz2N-]. An extension of the reaction enabled the free amino-compound to be used with a disulphide (Scheme 28).42a The unwanted by-product in this case + 2Ph3P + 2R1SSR1-+ 2[Ph3PSR1 -SR1] 2R'COSH +.1 CuCl, + 2Base 2RaNHa + 2R3NHCOR2+ Cu(SR1)2 + 2B,HCI -2 [Ph3POCORa RlS-1 Scheme 28 was the thiol ester R2COSR1, which was eliminated by the use of a soft metal halide such as AgCI or HgC12. In the application of this reaction to peptide synthesis, however, some racemisation occurred, e.g.in the reaction of N-benzoyl- L-leucine with ethylglycine.This was almost eliminated by the use of di-p-anisyl- mercury or anisylmercuric bromide. Racemisation was also avoided by the use of 2,2'-dipyridyl di~ulphide~~an because, in this case, the released mercaptide exists in the thione form, hence no metal ion is required for its removal. Alterna- tively, the use of the mercuric salt of the water-soluble phosphine Ph2PCsH4S03H-p eliminates racemisation in certain cases.42 The use of a water-soluble disulphide [21- (Me3NC6H4S)22+] has also been ~ecommended.~~ The disulphide method has been adapted to a solid-phase peptide synthesis.42d Triphenyl phosphite has been used in the synthesis of peptide~~~a and steroidal arnide~.~~bIn the presence of imidazole as a catalyst, good yields of unracemized material can be obtained using benzoxycarbonyl or t-butyloxycarbonyl protecting groups.Amides may also be prepared by activation of the acid component using mercuric chloride, pyridine, and mono-, di-, or tri-alkyl phosphite~.~~ M. Applications in Phosphory1ation.-The reaction of triphenylphosphine with 2,T-dipyridyl disulphide has also been utilized to phosphorylate alcohols and amines, pyrophosphates being formed as by-products (Scheme 29).44 3 Deoxygenation Reactions A. Reaction with Nitro- and Nitroso-compounds : Synthesis of Heterocycles.-Since the first report of the reaction in 1962,48use of the reductive cyclization of (a) R.Matsueda, H. Maruyama, M. Ueki, and T. Mukaiyama, Bull. Chem. SOC.Japan, 1971, 44, 1373; (6) T. Mukaiyama, R. Matsueda, and M. Suzuki, Tetrahedron Letters, 1970, 1901; (c) T. Mukaiyama, K. Goto, R. Matsueda, and M. Ueki, ibid,, 1970, 5293; (d)T. Mukaiyama, R. Matsueda, and H. Maruyama, Bull. Chem. SOC.Japan, 1970, 43, 1271. I8 Yu. V. Mitin and G. P. Vlasov, Doklady Akad. Nauk. S.S.S.R.,1968, 179, 353. " (a) Yu. V. Mitin and 0. V. Glinskya, Tetrahedron Letters, 1969, 5267; J. Gen. Chern. (U.S.S.R.), 1971, 41, 1152; (b) J. E. Herz and R. E. Mantecon, Org. Prep. Proced. Int., 1972, 4, 123; (c) T. Mukaiyama and M. Hashimoto, Bull. Chem. SOC.Japan, 1971, 44, 196, 2284. N. Yamazaki and F. Higashi, Bull. Chem. SOC.Japan, 1973, 46, 1236, 1239.I6 J. I. G. Cadogan and M. Cameron-Wood, Proc. Chern. SOC.,1962, 361. Cadogan and Mackie R'OP(O)(OH )*-1 + PhlPO HS0 ..R'NH 0 RPON,\d R!o/l'OH R'NH,, R'OP(0) (OH)* Scheme 29 aromatic nitro-compounds by trialkyl phosphite and related compounds as a general route to five, six-, and seven-membered nitrogen heterocycles has in~reased?~ In general the nitro-compound is allowed to boil under reflux, under nitrogen in a solvent, e.g. t-butylbenzene, with two equivalents or more of the phosphorus compound, usually triethyl phosphite. There is strong evidence in some cases4*a that the reaction proceeds via a nitrene, although in others a nitrene precursor cannot be e~cluded.*~~b, c + (R0)3P + ArN02 -+ (R0)3P-O-N(O-)Ar -+ (RO)sPO + ArNO + -(R0)3P + &NO --+ (R0)3P-O-NAr -+ (RO)3PO + ArN: Overall: 2(R0)3P + &NO2 -2(RO)#o + ArN: For simplicity most mechanisms in the following section are discussed in terms ofnitrenes, although this does not imply that the existence of a nitrene precursor has been established in all cases.47 (a)J. I. G. Cadogan, Quarr. Rev., 1968,22,222; (b) Synrhesis, 1969, 11 ;(c) Accounrs Chem. Res., 1972, 5, 303. 46 (a) J. I. G. Cadogan, and M.J. Todd, J. Chem. SOC.(C), 1969,2808; (6) J. I. G. Cadoganand S. Kulik, ibid., 1971, 2621; (c) P. K. Brooke, R. B. Herbert, and F. G. Holliman, Tetrahedron Letters, 1973, 761 ;(d) M. A. Amour, J. I. G. Cadogan, and D. S. B. Grace, unpublished results. 103 Tervalent Phosphorus Compounds in Organic Synthesis The intermediacy of the corresponding nitroso-compound is likely but can only be inferred because it reacts at least los times faster than the nitro-precursor under similar In accord with this the rate of deoxygenation increases with increasing nucleophilicity of the phosphorus reagent :48a9d Ph3P < (Pri0)3P z (EtO)3P < (Me0)3P c (Et0)zPNEtz < EtOP(NEt2)z c (Et0)sPMe z PhzPOEt z (Et2N)aP < (Me2N)3P, although triethyl phosphite is the most widely used reagent on grounds of availability and ease of handling and work-up.(i) Formation of five-membered nitrogen-containing heterocycles. Carba-zo1es,46,so*61 triazoles,60~SS~66carbolines,60s6ain dole^,^^^^^ inda~~le~,~~~~~~~~imi-da~oles,~~~5*~6~b furoxans,so tetrazapentalene~,~~~~~ anthranil~,~~#~~ and many re- lated polycyclic derivative^^^^^^^^^ are produced in good to excellent yields (40-95 %) if the nitrene or its precursor is generated from nitro-compounds having a suitable ortho-side-chain (Scheme 30).Given an option of forming a six-or a five-membered ring the nitrene always reacts to give the latter,so a steric pre- ference which has been used diagnostically in structure determination. Benz-l,3-oxazoles have also been produced by this route from o-nitrophenyl benzoates, -+ almost certainly, in this case, via the nitrene precursor ArN-O-P(OEt3).64 (ii) Six-membered nitrogen-containing heterocycles. Formation of phenothiazines, dihydrophenazines, quinolines, and related compounds.Despite the obvious ease with which the phosphits- nitro-group reaction proceeds to give five-membered nitrogen-containing heterocyclic compounds, it is not difficult to be persuaded on intuitive grounds that cyclization of 2-nitrophenyl phenyl sulphide to give the six-membered phenothiazine should also be easily achieved, as is the case (60% yield).66 Closer examination of substituent effects, however, revealed that the reaction does not proceed via direct nitrene insertion into the C-H bond ortho to the sulphide linkss but rather by the formation of a five-membered 4B P. J. Bunyan and J. I. G. Cadogan, J. Chem. SOC.,1963, 42. J. I. G. Cadogan, M. Cameron-Wood, R. K. Mackie, and R. J. G. Searle, J. Chem. SOC., 1965,4831.61 I. Puskas and E. K. Fields, J. Org. Chem., 1968, 33,4237. T. Kametani, T. Yamanaka, and K. Ogasawara, Chem. Comm., 1968, 996. 63 J. I. G. Cadogan and R. J. G. Searle, Chem. and Ind., 1963, 1434. b4 R. J. Sundberg, J. Org. Chem., 1965, 30, 3604; J. Amer. Chem. SOC.,1966, 88, 3781; R. J. Sundberg and T. Yamazaki, J. Org. Chem., 1967,32,290. s6 J. I. G. Cadogan and R. K. Mackie, Org. Synthesis, 1968, 48, 113. B. M. Lynch, and Y. Y. Hung, J. Heterocyclic Chem., 1965, 2, 218. M J. I. G. Cadogan, R. Marshall, D. M. Smith, and M. J. Todd, J. Chem. SOC.(C), 1970,2441. s8 H. Suschitzky and M. E. Sutton, J. Chem. SOC.(C), 1968, 3058. A. J. Boulton and A. Ur-Rahman, Tetrahedron, 1966, Suppl. 7, 49. O0 A. J. Boulton, I. J. Fletcher, and A. R. Katritzky, Chem.Comm., 1968, 62. J. C. Kauer and R. A. Carboni, J. Amer. Chem. SOC.,1967, 89,2633. Ox (a)K. E. Chippendale, B. Iddon, and H. Suschitzky, J.C.S. Perkin I, 1972, 2023; 1973, 125, 129; (6) R. Garner, G. V. Garner, and H. Suschitzky, J. Chem. SOC.(C), 1970, 825. O3 D. G. Saunders, Chem. Comm., 1969, 680. L. Leyshon and D. G. Saunders, Chem. Comm., 1971, 1608. Ob J. I. G. Cadogan, R. K. Mackie, and M. J. Todd, Chem. Comm., 1966,491. J. I. G. Cadogan, S. Kulik, and M. J. Todd, Chem. Comm., 1968,736; J. I. G. Cadogan, S. Kulik, C. Thomson, and M. J. Todd, J. Chem. SOC.(a,1970,2437. Cadogan and Mackie nitrogen-containing intermediate, thus conforming with pattern, which, after 1,Zsigmatropic shift of sulphur, followed by prototropy, leads to the ‘rearranged product (Scheme 3 1).This stabilizing prototropic shift is impossible, however, rR-W R NO* H XwyN:Oz X Y H Scheme 30 Tervalent Phosphorus Compounds in Organic Synthesis RI m3 4' NO2 Scheme 30 continued Cadogan and Mackie ONO'N=NnO,N Scheme 30 continued when both ortho-positions in the starting sulphide are blocked and under these conditions a series of intriguing molecular rearrangements arise. These include the formation of 5,1l-dihydro-4-methyldibenzo[b,e][1,4]thiazepine from 2,6-dimethylphenyl 2-nitrophenyl sulphide, rather than the expected isomeric 10,ll-dihydro-[b,fl[1,4] product which might have been expected via direct 107 Tervalent Phosphorus Compound3 in Organic Synthesis H nitrene insertion (Scheme 32).48* Also of interest are the monodemethoxylation and transmethoxylation reactions evident in the deoxygenation of 2,6-dimethoxy-phenyl2-nitrophenyl sulphide (Scheme 33).48b Perhaps most interesting of all is the isolation of 1,4a-diethoxycarbonyl-4aH-phenothiazine, which corresponds to the non-aromatic intermediate postulated in the above rearrangements, from 2,6-diethoxycarbonylphenyl2-nitrophenylsuiphide (Scheme 34).48* Formation of dihydrophenazines does not appear to occur via the phosphite- nitro-group reaction unless the vulnerable bridgehead N-H group is protected.Thus the N-H protected N-acetyl-2-nitro-2'-methylthiodiphenylaminereacted as would be expected on the basis of earlier work on related sulphur-bridged compounds (Scheme 31) ?' rearrangement of the spirodienyl intermediate gave both possible hydroaromatic species, one of which undergoes demethylthiolation while the other tautomerizes to give 1 -thiomethyl-5-acetyl-5,1O-dihydrophenazine (Scheme 35).In contrast to the corresponding S-and N-bridged compounds, 2-nitrophenyl phenyl ethers give very low, if not negligible, yields of phenoxazines,68 the major products being novel five-membered heretocycles containing N, 0, and P as described $7 Y.Maki, T. Hosokami, and M. Suzuki, Tetrahedron Letters, 1971, 3509. '8 J. I. G. Cadogan and P. K. K. Lim, Chem. Comm.,1971, 1431. '9 J. I. G. Cadogan, D. S. B. Grace, P. K. K. Lim, and B. S. Tait, J.C.S.Chem. Comm.. 1972,520. Cadogan and Mackie f Scheme 32 The reductive cyclization reaction using triethyl phosphite has been used to convert 4-(2-nitrophenyl)pyridine into a benzo [~]naphthyridine,~o formed in equal quantity with a carboline derivative (Scheme 36), the former indicating interaction with the adjacent ester carbonyl group. Similar cyclizations involving neighbouring carbonyl groups lead to oxazolo [5,4-b]quinolines, 71 quinolines,72 isoindoloquinazolines,73aand 9,9-dihydropyrazo!oquinolinylphosphonates.73* (iii) Formation of five-membered PNO Heterocycles: the 1,3,2-benzoxazaphospho- lanes. By-products found in the reductive cyclization of 2-nitroaryl aryl sulphides to phenothiazines (Scheme 31)includedN-aryl-N-2-(o-thioethylphenyl)phosphor-amid ate^,^^* presumably arising by the route outlined in Scheme 37, wherein the key intermediate spirodienyl species, as well as rearranging to the phenothiazine, T.Kametani, T. Yamanaka, and K. Ogasawara, J, Chem. Soc. (C),1969, 138. T. Kametani, T. Yamanaka, and K. Ogasawara, Chem. Comm., 1968, 786. T. Kametani, K. Nyu, T. Yamanaka, H. Yagi, and K. Ogasawara, Chem. and Pharm. Bull. (Japan), 1969, 17, 2093. (a) T. Kametani, K. Nyu, T. Yamanaka, and S. Takano, J. Heterocyclic Chem., 1971, 8, 2871; (b) T.Nishiwaki, G, Fukuhm, and T. Takahashi, J.C.S. Perkin I, 1973, 1606. Tervalent Phosphorus Compounds in Organic Synthesis OCH, OCH, OMe 0DCH2---H / OMe N - IOMe H OMe ‘ N OMe H TOMeOMe, Scheme 33 C0,Et CO,EtI COoEt Scheme 34 110 Caabgan and Mackie COMe I NO2 SCH, I COMeI COMe COMeI Scheme 35 Me Ye +- Me OEt Scheme 36 111 Tervalent Phosphorus Compounds in Organic Synthesis n Ar X=Y=Me or X= Me0 , Y=H ;Ar = 2,6-X,-4-Y-C6H, Scheme 37 also reacts with excess triethyl phosphite.In these cases the postulated inter- mediate five-membered PNS heterocycle was not detected, but in the correspond- ing reactions using 2-nitroaryl aryl ethers excellent yields (up to 95%) of the corresponding oxygen derivatives were obtained (Scheme 38).601 74 The difference in stability between the S and 0 five-membered derivatives lies in the great nucleophilicity of the sulphur atom.The new heterocycles so formed are of interest because the phosphorus atom is fully five-co-ordinate and has trigonal- bipyramidal geometry. (iv) Formation of seven-membered nitrogen heterocycles: 3H-azepines. Ring expansion of aryl azides by thermolysis in the presence of amines to give 3H-azepines is well known,76 and is generally considered to proceed via the aryl- nitrene-7-azabicyclo [4,1 ,O]hepta-2,4,6-triene (Scheme 39). In accord with this and the post~late~~ that nitrenes are formed in the deoxygenation of nitroso-arenes with tervalent phosphorus compounds, the reaction of nitro- sobenzene with triphenylphosphine in diethylamine gives 2-diethylamino-3H- azepine in 60% yield; yields with other amines are variable7* (Scheme 39).Higher yields are obtained by the reaction of the parent nitrobenzene with diethyl methylphosphonite [(EtO)aPMe] in diethylamine,48a~ 79 a reaction which is fairly general.80J’1 The only other nucleophile besides amines which has so 7p J. I. G. Cadogan, D. S. B. Grace, and B. S. Tait, unpublished observations. 76 W. Lwowski, ‘Nitrenes,’ Interscience, New York, 1970. 70 R. Huisgen, D. Vossius, and M. Appl, Angew. Chem., 1955,67, 756. 77 W. von E. Doering and R. A. Odum, Tetrahedron, 1966, 22, 81. 78 M. Brenner and R. A. Odum, J. Amer. Chem. SOC.,1966,88,2074. 7s J. I. G. Cadogan and M. J. Todd, Chem. Comm., 1967, 178. J. I. G. Cadogan and H. McWilliam, unpublished observations. *l F. R. Atherton and R. W. Lambert, J.C.S. Perkin I, 1973, 1079.Cadogan and Mackie Scheme 38 Scheme 39 I13 Tervalent Phosphorus Compounds in Organic Synthesis far been found to lead to significant ring expansion in these reactions is the tervalent phosphorus reagent itself,82 and in these cases we have the intriguing observation that the position of substitution is different (Scheme 40). The mechanism is clearly not yet fully understood, and the possible intermediacy of 1H-azepines cannot be excluded. Scheme 40 B. Reactions with Peroxides, Hydroperoxides, Peresters, and 0zonides.-Diacyl peroxides, such as benzoyl, acetyl, or malonyl peroxides, are rapidly and quanti- tatively deoxygenated via nucleophilic displacement on peroxidic oxygen to the corresponding anhydrides in the presence of triphenylpho~phine~~~ Ss or triethyl phosphite.8eThe reaction is so fast and reliable that it can be used as a monitor to study rates of decomposition of diacyl peroxides.86 * Peroxydicarbonatess7 and peresters, such as t-butyl perbenzoates,88 are similarly reduced to the corresponding phosphine oxide and dialkylcarbonic anhydride or ester, respectively.Alkyl hydroperoxides are also very rapidly reduced to the cor- responding al~~hol~,~~ again via an ionic mechanism, and this provides a very simple method for deperoxidization of contaminated ethers, and a one-step synthesis of steroidal tertiary a-ketols.go In the latter the first step is autoxidation of the ketone by oxygen, followed by deoxygenation of the hydroperoxide (Scheme 41). The powerful reducing effect of phosphites on hydroperoxide has led to an investigation of their use as antioxidants for the oxidation of cumene.In these J. I. G. Cadogan, D. J. Sears, D. M. Smith, and M. J. Todd,J. Chem. SOC.(0,1969,2813;J. I. G. Cadogan and R. K. Mackie, ibid., 1969, 2819; R. J. Sundberg, B. P. Das, and R H. Smith, J. Amer. Chem. SOC.,1969, 91, 658. 83 R. J. Sundberg, S. R. Suter, and M. Brenner, J. Amer. Chem. SOC.,1972, 94, 513. 8Q F. Challenger and V. K. Wilson, J. Chem. SOC.,1927, 209. 8b M. A. Greenbaum, D. B. Denney, and A. K. Hoffmann, J. Amer. Chem. SOC.,1956,78, 2563 ;D. B. Denney and M. A. Greenbaum, ibid., 1957,79,979; W. Adam and J. W. Kiehl, J. C. S. Chem. Comm., 1972, 797. (a) P. Bunyan, A.J. Burn, and J. I. G. Cadogan, J. Chem. SOC.,1963, 1527; (b) D. L. Brydon and J. I. G. Cadogan, J. Chem. SOC.,(C), 1968, 819. 87 W. Adam and A. Rios, J. Org. Chem., 1971,36,407. B. Denney, W. F. Goodyear, and B. Goldstein, J. Amer. Chem. SOC.,1961, 83, 1726. (a) C. Walling and R. Rabinowitz, J. Amer. Chem. SOC.,1959,81, 1243; (b) L. Horner and W. Jurgeleit, Annalen, 1955,591,138; (c) D. B. Denney, W. F. Goodyear, and B. Goldstein, J. Amer. Chem. SOC.,1960, 82, 1393. *O J. N. Gardner, F. E. Carlon, and 0.Gnoj, J. Org. Chem., 1968, 33, 3294. Cadogan and Mackie Me Me I I c=o c=o NaH -0,-Et0,PI I _IAde DhfF-Bu'OH, -25 "C Scheme 41 cases the mechanism is complicated by the intervention of free-radical processes in addition to ionic steps.Ol In contrast to the foregoing ionic reactions, triphenylphosphine and trialkyl phosphites react with di-t-butyl peroxide or di-a-cumyl peroxide via homolytic processes involving alkoxyl radicals,02 although it should be noted that the simpler diethyl peroxide reacts with cyclic phosphites to give the corresponding cyclic phosphoranes.O3 In yet another differing case ascaridole is readily deoxy- genated to give p-cymene.O* The former reaction of alkoxyI radicals with phosphites has been developed to provide a route to steroidal phosphates, using the photolysis of steroidal nitrites (RONO) in tri-isopropyl phosphite (Scheme 42),95from which it appears rn'0)sPRlONO -+ R1O*____+ R101!(OPri)34 R10P(0)(OPri2) + Pri.Scheme 42 that p-scission from the intermediate phosphoranyl radical, in these cases, proceeds largely with retention of the massive steroidal fragment. Many examples of the very valuable reduction of ozonides by tervalent phosphorus compounds have been reported, e.g. Scheme43,806s 069g7 the reaction 91 K. J. Humphris and G. Scott, J.C.S. Perkin II, 1973, 826, 831. s2 C. Walling, 0.H. Basedow, and E. S. Savas, J. Amer. Chem. SOC.,1960, 82, 2181; P. J. Krusic, W. Mahler, and J. K. Kochi, ibid., 1972, 94, 6033; A. G. Davies, D. Griller, and B. P. Roberts, J.C.S. Perkin II, 1972, 993. 93 D. B. Denney, D. Z. Denney, C. D. Hall, and K. L. Marsi, J. Amer. Chem. SOC.,1972, 94, 245. s4 T. Kametani and K. Ogasawara, Chem. and Znd., 1968, 1772. 95 D.H. R.Barton, J. T. Bentley, R.H. Hesse, F. Mutterer, and M. M. Pechet, Chem. Cumm., 1971,912. J. Carles and S. Fliszhr, Canad. J. Chem., 1970,48, 1309; 1972,50,2552. O7 J. J. Pappas, W. P. Keaveney, M. Berger, and R. V. Rush, J. Org. Chern., 1968, 33, 787; A. Furlenmeier, A. Furst, A. Langemann, G. Waldvogel, P. Hocks, U. Kerb, and R. Wiechert, Helv. Chirn. Acta, 1967,50, 2387; W. S. Knowles and Q. E.Thompson,J. Org.Chem., 1960,25, 1031. Tervalent Phosphorus Compounds in Organic Synthesis + Pha9 PhaPO Scheme 43 probably proceeding via nucleophilic attack on oxygen to give a phosphoraness rather than a dipolar intermediate. Related reactions with thio-ozonides, on the other hand, proceed via attack on sulphur and subsequent formation of a carbon- carbon bond (Scheme 44).O* Ph@ ++ PhSPO Ph Scheme 44 C.Reactions with Ozone.: the Reagent (Ph0)3PO~.-TriarylphosphinesB0 and trialkyl and triaryl phosphitesloO all react readily with ozone to give excellent J. M. Hoffmann, jun., and R. H. Schlessinger, Tetrahedron Letters, 1970, 797. a* L. Homer, H. Schaefer, and W. Ludwig,Chem. Ber., 1958,91, 75. looQ. E.Thompson, J. Amer. Chem. Soc., 1961,83, 845. Cadogan and Mackie yields of the corresponding P4compounds. In the case of triphenyl phosphite a 1:1 adduct (Ph0)3P03 can be isolated which is stable at -70 “C but which decomposes cleanly to triphenyl phosphate and oxygen at -35 “C(Scheme 45). Hac)+e ’+ Me OOH (Ph0)a PO Scheme 45 The principle of conservation of spin suggests that the oxygen so evolved should have singlet multiplicity, and this proved to be so in many, but not all, cases.1o1 Triphenyl phosphite ozonide is therefore a reagent of considerable value, and although a detailed discussion of this quinquevalent reagent is strictly outside the scope of this Review, a brief outline of some of its reactionsloa is given b Scheme 45.D. Reduction of Epoxides to Alkenes.-Both triethyl phosphite6a and triphenyl- phosphine6b smoothly reduce epoxides to the corresponding alkene. In contrast to the related desulphurization of thiirans’ the reaction is not stereospecific. Boskin and Denneys showed that tributylphosphine converted trans-2,3-epoxy- butane into a mixture of cis-(72 %) and trans-(28 %) but-2-eneY whereas the cis-epoxide gave a ratio of 19:81 cis- to trans-isomer.This suggests that there is a reaction, in the former case say, via nucleophilic attack on carbon to given an erythru-betaine, of the type familiar from the Wittig reaction; rotation and bond formation and cleavage, as in Scheme 46, then account for the formation of cis-but-Zene. The trans-isomer is accounted for on the basis of the dissociation of the betaine into aldehyde and ylide, which can then recombine to give both lo* R. W. Murray and M. L.Kaplan, J. Amer. Chem. Soc., 1968.90, 537; P. B. BartIett, and G. D. Mendenhall, ibid., 1970, 92, 210; L. M. Stevenston and D. E. McClure, ibid., 1973, 95, 3074; S. D. Razumovskii and G. D. Mendenhall, Cunud.J. Chem., 1973,51, 1257. lo*R. W. Murray, J. W. P. Ling, and M. L. Kaplan, Ann. New YorkAcd. Sci., 1970,171,121 Tervalent Phosphorus Compounds in Organic Synthesis threo- and erythro-betaines, the former giving rise to the cis-olefin on elimination. The method, although useful, is therefore limited by the lack of stereospecificity. erythro 11 R, P-CHMe NH HMe P \Me Me Me H RP threo Scheme 46 E. Deoxygenation of Amine N-Oxides, Nitrile Oxides, Isocyanates, Azoxy- compounds, and Nitrites.-Tervalent phosphorus compounds deoxygenate amine N-oxides to the corresponding amines. They are particularly useful in the heterocyclic series because, in general, deoxygenation proceeds smoothly without affecting other substituents in the ring.lo3 Phosphorus trihalides are very reactive lo3A.R. Katritzky and J. M. Lagowski, ‘Chemistry of the Heterocyclic N-Oxides,’ Academic Press, New York, 1971. Cadogan and Mackie in this respectlo4 and, in general, substitution of halogen atoms by organic groups tends to reduce the activity of the reagent. The ease of reduction of pyridine N-oxide decreases in the order PC13 > PhPCla > PhzPCl S (Ph0)3P > (Et0)sP 9 PhsP > Bu3P > Et2PPh,lo6 while electron-releasing groups in the pyridine ring increase the reaction rate towards a given phosphorus reagent.lo6 This suggests that nucleophilic attack by the N-O-function on the tervalent phos- phorus atom is occurring, but the situation is reversed in the case of deoxygenation of furoxans to furazans.lo7 Most deoxygenations proceed but in the case of the reaction of 2-nitropyridine N-oxide with triethyl phosphite, nucleo- philic displacement of the nitro-group also occurs, to give diethyl 2-pyridyl- phosphonate,lo8 thus paralleling the corresponding reaction with o-dinitro- benzene.As might be expected, nitrile oxides (RCNO), isocyanates (RNCO), and azoxy-compounds [ArNN(O)Ar] are all reduced by phosphites or phosphines @to the corresponding cyanides, lo isocyanides,llO and azo-compounds. 50 l1O, ll1 Alkyl nitrites are also reduced but the major reaction is conversion into the corresponding alcohol, there being no evidence for the intermediacy of the hoped-for alkoxynitrene.ll$ 4 Reactions with Carbonyl Compounds Only some of the many reactions of tervalent phosphorus compounds with carbonyl compounds are useful in general organic synthesis as opposed to the production of organophosphorus compounds.Some involve the formation of a quinquecovalent phosphorus reagent which is then used in a subsequent process. Of these the most important are undoubtedly the oxyphosphoranes. A. Conversion of Aromatic Aldehydes, Ketones, and Anhydrides into Arylated Olefin Oxides and 0lefins.-Aromatic aldehydes may be converted into the corresponding stilbene oxides under relatively mild conditions using (Me2N)~p.l'~ Similarly, but under more forcing conditions (1 80 "C),benzaldehyde reacts with the anion of diphenylphosphine oxide to give a good yield (85%) of cis-and trans-stilbene 0~ides.l~~ There is no direct evidence of carbene intervention in these reactions and it is more likely that wholly ionic routes are followed. In lo*E.Ochiai, J. Org. Chem., 1953, 18, 534. lo6 F. Ramirez and A. M. Aguair, Amer. Chem. SOC. Abstracts of 134th Meeting 1958, p. 42N. lo8T. R. Emerson and C. W. Rees, J. Chem. SOC.,1964, 2319. Io7 C. B. Grundmann, Chem. Ber., 1964,97,575. lo*J. I. G. Cadogan, D. J. Sears, and D. M. Smith, J. Chem. SOC.(C), 1969, 1314. lo#C. Grundmann and H.-D. Frommeld, J. Org. Chem., 1965,30,2077. T. Mukaiyama, H. Nambu, and M. Okamoto, J. Urg. Chem., 1962, 27, 3651. 111 L. Homer and H. Hoffman, Angew. Chem., 1956,68,473; W. Luttke and V. Schabacker, Annalen, 1965,687,236. lla J. H.Boyer and J. D. Woodyard, J. Org. Chem., 1968,33, 3329. n8 V. Mark, J. Amer. Chem. SOC.,1963, 85, 1884; Org. Synth., 1966, 46, 42; F. Ramirez,S. B. Bhatia, and C. P. Smith, Tetrahedron, 1967, 23,2067; F. Ramirez, A. S. Gulati, and C. P. Smith, J. Org. Chem., 1968, 33, 13. 114 W. M. Horspool, S. T. McNeilly, J. A. Miller, and I. M. Young, J.C.S. Perkin 1,1972, 1113. 119 Tervalent Phosphorus Cornpounds in Organic Synthesis other cases, notably furfural ,l6 benzop hen one, 116 and acyl-ferrocenes, 114,n olefins are formed directly, but usually in low yields. In a most interesting related reaction, phthalic anhydride is readily converted into 3,3’-biphthalidylidene (70 %),ll*a again probably via a non-carbene route1lUb (Scheme 47). B.Formation of Enamines-In contrast to the foregoing reactions of aromatic ketones, certain aliphatic ketones, e.g.cyclohexanone, react with (Me2N)sP to give enamines.llS Acetone, butan-2-oneY and propanal give normal aldol con- densates. C.Formation of Aryl Isothiocyanates.-The aryl group of the isothiocyanate ultimately produced in this reaction originates in the phosphorus reagent, a diethyl N-arylamidite.120 This, on reaction with p-nitrobenzaldehyde, gives a phosphorimidate and hence the aryl isothiocyanate by subsequent reaction with carbon disulphide (Scheme 48). ArNH,(EtO),PCl + (1EtO),PNHAa p-NO,CsH,CHO HNA” -(EtO),P \OCH~GH,NO, ArNCS 4-(EtO),P(S>OCH,C,H,NO, Scheme 48 116 B. A. Arbusov and V. M. Zoroastrova, Izvest. Akad.Nauk. S.S.S.R., Otdel. Khim. Nauk, 1960, 1030 (Chem. Abs., 1960,5424627). 116 A. C. Poshkus and J. E. Herweh, J. Org. Chem., 1964,29,2567; I. A. Degen, D. G. Saun-ders, and B. P. Woodford, Chem. and Znd., 1969, 267. 11’ P. L. Pauson and W. E. Watts, J. Chem. SOC.,1963, 2990. 118 (a) F. Ramirez, H. Yamanaka, and 0. H. Basedow, J. Amer. Chem. Suc., 1961, 83, 173; (6) C. W. Bird and D. Y. Wong, Chem. Comm., 1969, 932. llS R. Burgada and J. Roussel, BUN. SOC.chim. France, 1970, 192. noA. N. Pudovik, E. S. Batyeva, and V. D. Nesterenko, Izvest. Akad. Nauk. S.S.S.R., Ser khim, 1972, 501 (Chem. Ah., 1972,77,88604). Cadogan and Mackie D. Formation of Oxophosphoranes-a-Diketones condense with trialkyl phosphites and other tervalent reagents to give cyclic oxyphosphoranes.lal In certain cases simple monocarbonyl compounds in 2:l ratio also give oxy- phosphoranes. Extensive work on this reaction by Ramirez' school has shown that these compounds are very versatile reagents in organic synthesis.121J2* These quinquecovalent compounds of phosphorus, strictly, are outside the scope ofthis review but a few examples of their reactions are given in Scheme 49.l2l-la4 Not all oxyphosphoranes can be isolated and in some cases their intermediacy has been assumed, as in the reaction of triethyl phosphite with benzil in the presence of copper sulphate, for example.This reaction is believed to proceed via a carbenoid species (Scheme 50) on the basis of the formation of oxazole derivatives when the reaction is carried out in the presence of phenyl isocyanate and dicyclohexylcarbodi-imide.1~5In the absence of copper sulphate, diphenyl- keten dimer and diphenylacetylene are produced,126 the latter presumably via deoxygenation of diphenylketen to a carbene intermediate which then rearranges to the alkyne (Scheme 51).la7 Closely related to this is the postulated128 formation of cyanophenylcarbene by photolysis of the oxyphosphorane formed from triethyl phosphite and benzoyl cyanide.lao The carbene was trapped as a cyclo- propane.5 Reactionswith Halogens and Halogen-containing Compounds A. With Halogens and Hydrogen Halides: Formation of A1kylHalides.-The reaction of trialkyl phosphites with halogens to give the corresponding phosphoro- halidate and an alkyl halide has been known for many years.130 A recent modifica- tion has been used for the preparation of alkyl iodides.131 The preparation of optically active alkyl halides by reaction of phosphites, phosphonites, phosphi- nites, and dialkyl phosphonates has been studied extensively by Hudson et aZ.13a (Scheme 52).The reaction of phosphines with halogens gives rise to 1:1 adducts lg1 (a)F. Ramirez, Accounts Chem. Res., 1968,1,168; (b)Bull. SOC. chim. France, 1966,2443; (c) Pure Appl. Chem., 1964,9, 337; (d) F. Ramirez, G. V. Loewengart, E. A. Tsolis, and K. Tasaka, J. Amer. Chem. Soc., 1972,94, 3531. l**(a)F. Ramirez, H. J. Kugler, and C. P. Smith, Tetrahedron, 1968,24,3153; (b) F. Ramirez, A. V. Patwardhan, N. B.Desai, N. Ramanathan, and C. V. Greco, J. Amer. Chem. SOC., 1963, 85, 3056; (c) F. Ramirez, S. B. Bhatia, C. D. Telefus, and C. P. Smith, Tetrahedron, 1969,25, 771; (d) F. Ramirez, S. B. Bhatia, and C. P. Smith, J. Amer. Chem. SOC.,1967, 89, 3030. lS3 F. Ramirez, N. Ramanathan, and N. B. Desai, J. Amer. Chem. SOC.,1962,84, 1317. la' T. Mori, T.Nakahara, and H. Nozaki, Canad. J. Chem., 1969,47, 3651. m6T. Mukaiyama and T. Kumamoto, Bull. Chem. SOC.Japan, 1966,39, 879. noT. Mukaiyama, H. Nambu, and T. Kumamoto, J. Org. Chem., 1964, 29, 2243. lS7 T. Mukaiyama, H. Nambu, and M. Okamato, J. Org. Chem., 1962, 27, 3651. 11* P. Petrellis and G. W. Griffin, Chem. Comm., 1968, 1099. lagT. Mukaiyama, I. Kuwajima, and K. Ohno, Bull. Chem. SOC.Japan, 1965,38, 1954.130 H. McCombie, B. C. Saunders, and G. J. Stacey, J. Chem. Soc., 1945, 380. lS1 E. J. Corey and J. E. Anderson, J. Org. Chem., 1967, 32, 4160. lsS H. R. Hudson, Synthesis, 1969, 112; H. R. Hudson, A. R. Qureshi, and (Mrs) D. Ragoon-man, J.C.S. Perkin I, 1972, 159. Tervalent Phosphorus Compounds in Organic Synthesis -(MeO),P 4-o=(f''e O, P O=CMe Me0/p\I OMe OMe MeCOM S H (2) $-RCHO 4 O, P Me0NP\I OMe OMe Me I MeCOCCH (0H)R (Ref. 121)I OH MeCOMxC0,Me (2) 1-MeCOCOzMe -0, ,o Me0/p\I OMe OMe Me Me II MeCOC -C-C0,Me (Ref.122b)IIOH OH Scheme 49 Cadbgan and Mackie (2) + PhN=C-O J. -MeCO PhNCO O\ /O Me0yp\OMeI OMe (2) 4-Ph MeCOMMo(Ref.122c, d) PhNKNPh0 MeCO (Ref.123) to-(Ref.124) Scheme 49 continued Tervalent Phosphorus Cornpoundr in Organic Synthesis Ph Ph )=( -(EtO),PO -Phe-COPh phmph PhphNKO0 PhNR Scheme 50 em (EtOMPhC=COPh +PhzC=C=O -Ph2C=C: +PhCSPh [As from Scheme SO] Scheme 51 Hx+ PhzPOR _.+ PhzPHeOR X----t Ph#(O)H + RX Scheme 52 which are useful in the conversion of alcohols into alkyl halides.lSs The reaction is nearly always sN2, converting, for example, optically active endo-norbornol into em-norbornyl bromide with no significant racemi~ation.l~~a When, however, a similar experiment is carried out with the exo-alcohol a mixture is formed (Scheme 53).lS4b Phosphine dihalides also convert amino-alcohols into a~iridinesl~~ and acids into acyl halides.lSg Ph3PBr2 in dimethylformamide reacts with cholestJ-ene- 3p,4p-diol to give a mixture of an unsaturated bromide and an unsaturated + aldehyde, possibly by way of Me2N=CHBrlS7 in a Vilsmeier reaction (Scheme 54).Ethers are cleaved by PhsPBrz, giving good yields of alkyl bromides except ma L. Homer, H. Oediger, and H. Hoffmann, Annufen, 1959, 626, 26; G. A. Wiley, R. L. Hershkowitz, B. M. Rein, and B. C. Chung, J. Amer. Chem. SOC.,1964, 84,964; G. A. WiIey, B. M. Rein, and R. L. Hershkowitz, Tetrahedron Letters, 1964, 2509. (a)J. P. Schaefer and D. S. Weinberg, J. Org. Chem., 1965, 30, 2635; (b) ibid., p. 2639. ls6 I. Okada, K. Ichimura, and R. Sudo, Buff. Chem. SOC.Japan. 1970.43. 1185. H.-J. Bestmann and L. Mott, Annufen, 1966, 693, 132.R. Stevenson, T. Dahl, and N. S. Bhacca, J. Org. Chem., 1971,36, 3243. Cadogan and Mackie Br’ Hod ___)PhyPBr, Scheme 53 in the case of t-butyl ethers, in which case isobutene is formed.la8 Benzoins are oxidized to benzil~,~~~* and phenols give aryloximes give ketenimine~,’~~b Ph3PBro Br&‘ HOOP DMF > + OH Scheme 54 The Rydon reagent, triphenyl phosphite dihalide, and the related alkyl- triphenoxyphosphonium halides [(Ph0)3PR+ Hal-] are also useful in the lS8 A. G.Anderson and F.J. Freenor, J. Amer. Chem. Sac., 1964, 86,5037; J. Org. Chem., 1972,37, 626. (a) T.-L. Ho,Synthesis, 1972, 697; (b) M. Masaki, K. Fukui,and M. Ohta, J. Org. Chem., 1967, 32,3564. 140 J. P. Schaefer and J. Higgins,J. Org. Chem., 1967, 32, 1607.Tervalent Phosphorus Compounds in Organic Synthesis preparation of alkyl halides141 from alcohols. Receii t applications include the iodination of hydroxy-groups in nucleo~ides~~~ and carbohydrates.14a B. Reactions with Alkyl Halides: Formation of Y1ides.-The Michaelis-Arbusov of trialkyl phosphites with alkyl halides, which has been reviewed, 14& is the most widely used method of forming P-C bonds. It involves nucleophilic attack by phosphorus to give a quasiphosphonium salt which undergoes dealkylation as shown in Scheme 55. In the case of reaction with triaryl- or f a-(R'O),P R'X + (R'O),PR2 X-(R'O),P(0)RZ 4-RX .c----+ _fPh,P RCH,X Ph&-CH,R X-5 Ph,P=CHR -!-BH f X-+ PhsP-CHR3 4 Ph,P-rHR3 -phsii$-E""' O=CR'R* G-CR'R~ 0 CK'R' Scheme 55 trialkyl-phosphines, the resulting quaternary phosphonium salt is relatively stable towards dealkylation.Providing there is an available a-proton, however, these salts react readily with base to give phosphorus ylides, the reactivity of which towards carbonyl compounds is the basis of the Wittig olefin synthesis, which has proved to be so remarkably valuable in recent years (Scheme 55). An enormous number of applications of this reaction have been recorded and reviewed.14* C. Reactions with Polyhalogenomethanes-Trialkyl phosphites react with carbon tetrachloride in an Arbusov-type reaction to give dialkyl trichloromethyl- phosph~natesl~' by an ionic involving the interchangeable ion pair [(R10)3PCl+ Cch- + (R10)3PCC13+ C1-1.In the presence of an alcohol RBOH, a mixture of phosphates, alkyl chlorides, RlCl and R2C1, and chloroform results (Scheme 56).149It was soon realised that modification of this reaction by the 141 H. N. Rydon, Chem. SOC.Special Publ., 1957, 8, 61; D. K. Black, S. R. Landor, A. N. PateI, and P. F. Whiter, J. Chem. Soc. (0,1967, 2260; J. 0. H. Verheyden and J. G. Moffatt, J. Amer. Chem. SOC., 1966, 88, 5684. la* G. A. R. Johnston, Austral.J. Chem., 1968,21,513; J. P.H. Verheyden and J. G. Moffatt, J. Org. Chem., 1970, 35, 2319, 2868. la3N. K. Kochetkov and A. I. Usov, Methods Carbohydrate Chem., 1972, 6,205. 144 A. Michaelis and R. Kaehne, Ber., 1898, 31, 1048; A. E.Arbusov, J. Russ. Phys. Chem. SOC.,1906,38, 687.145 H.-G. Heaning and G. Hilgetag, 2.Chem., 1967, 7, 169. 146 A. W. Johnson, 'Ylides,' Academic Press, New York, 1966. la' G. Kamai and L. Egorava, Zhur. obshchei Khim., 1946, 16, 1521 (Chem. Abs., 1947,41, 5439).R. E. Atkinson, J. I. G. Cadogan, and J. T. Sharp, J. Chem. SOC. (B), 1969, 138. P. C. Crofts and I. M. Downie, J. Chem. Soc., 1963, 2559. 126 Cadogan and Mackie (R'O),P*3CICCI, -(R'O)a&I CCI, (R'O),GCCl, C1' R?OH-(R10)3P' C1-4-CHCI, 3 (R'0)SPO + R2Cl R'CI (R'O)ZP(O)CCI, 3-(R'O)2P(0)OR2 + R'CI I OR2 Scheme 56 use of triphenyIphosphinels0 or (Me2N)3PlS1 should lead to the ccnversion of an alcohol into the corresponding alkyl halide, and this has been achieved (Scheme 57). Considerable interest in this reaction has been shown recently, Mainly because the conditions are so mild that sensitive alcohols, such as ~arbohydrates,l5~ may be converted into chlorides, particularly since protective groups commonly -F -Ph3P Ph,PCI CCI, + CHCl3 CCII or -or +-(mN),P (MeZN),PCI CCJ, Scheme 57 used with carbohydrates (acetal, ether, ester) are stable to the reagent.Triphenyl- phosphine has been the most widely used reagent but the use of (Me2N)3P sometimes simplifies the isolation of the alkyl halide because the resulting phosphine oxide is water-soluble.lsl Trioctylphosphine has been reported as being more reactive than triphenylphosphine in this reaction.153 As expected from Scheme 57 the reaction proceeds with inversion of although there is considerable racemisation in the analogous reaction with carbon tetrabromide.lSS The method has been used successfully for conversion of hydroxy-carboxylic esters into the corresponding chlorides.ls6 Many extensions of the reaction have been reported: primary and secondary 150 A.J. Bum and J. I. G. Cadogan, J. Chem. SOC.,1963, 5788. ls1 I. M.Downie, J. B. Lee, and M. F. S. Matough, Chem. Comm., 1968, 1350. J. B. Lee and T. J. Nolan, Canad,J. Chem., 1966,44,1331; Tetrahedron, 1967,23,2789; C. R. Haylock, L. D. Melton, K. N. Slessor, and A. S. Tracey, Carbohydrate Res., 1971, 16, 375. 163 J. Hooz and S. S. H. Gilani, Canad. J. Chem., 1968,46, 86. lS4 R. G.Weiss and E. I. Snyder, J. Org. Chern., 1970,35, 1627; R. Appel, R. Kleinstiick, K.D. Ziehn, and F. Kudl, Chem. Ber., 1970, 103,3631. 16s R.G.Weiss and E. I. Snyder, J. Org. Chem., 1971, 36, 403. 16* J. B. Lee and I. M. Downie, Tetrahedron, 1967,23, 359. 127 Tervalent Phosphorus Corrrpoundr in Organic Synthesis alcohols sometimes give nitriles on treatment with triphenylphosphine, carbon tetrachloride, and sodium cyanide in DMS0,157 presumably by competitive attack by the cyanide ion on the intermediate quasiphosphonium species [Ph3POR]+. On the other hand the reaction of KCN-PhCH2CH20H-Ph3P- CC14-DMSO gave only the phenethyl ch10ride.l~~ However, Castro and Sel~el~~a have shown that at low temperatures in tetrahydrofuran the alkoxyphosphonium chloride is stable and that nucleophiles, e.g. N3-, SCN-, PhS-, CN-, and I-, can compete favourably with chloride ions in the decomposition of the salt.As a result of the greater reactivity of primary alcohols in these reactions, methyl a-D-glucopyranose reacts preferentially at C-6 and functionalization of this position is facilitated.158b Weaker nucleophiles cannot compete satisfactorily with chloride ions. However, if the chloride is converted into the perchlorate prior to reaction with primary amines, good yields of monoalkylated amines are f~rmed.l~~C It has been suggested that this reaction could be extended to introduce a primary amino-group into carbohydrates, via the 11itri1e.l~~ The reaction has also been used to convert toluene-a-thiol into benzyl Acids are readily converted into acyl halidePo and, by a modification of the reaction, amides (including peptides), nitriles, and anhydrides can be prepared (Scheme 58).ls1 Amines yield aminophosphonium salts1e2 while nifriles,168 R2NiH, C1-R1C02HR1CONHR2 -2NEt, (Me2N),POCOR1 RTOO COR~ Scheme 58 isocyanides,ls4 and carbodi-imides1s6 are formed from amides, formamides, and ureas, respectively.In some instances the reactivity of the trichloromethyl anion has been exploited. This has been described as an ametallic carbanion by lCTD. Brett, I. M. Downie, and J. B. Lee, J. Org. Chem., 1967, 32, 855. lSiB(a)B. Castro and C. Selve, Bull. SOC. chim. France, 1971,2296; (b) B. Castro, Y.Chapleur, B. Gross, and C. Selve, Tetrahedron Letters, 1972, 5001;(c) B. Castro and C. Selve, Bull.SOC.chim. France, 1971,4368. lSD R. G. Weiss and E. I. Snyder, Chem. Comm., 1968, 1358. le0 J. B. Lee, J. Amer. Chem. SOC.,1966, 88, 3440. lel B. Castro and J. R. Dormoy, Tetrahedron Letters, 1972,4747; E. Barstow and V. J. Hmby, J. Org. Chem., 1971, 36, 1305; S. Yamada and Y. Takeuchi, Tetrahedron Letters, 1971, 3595; T. Wieland and A. Seeliger, Chem. Ber., 1971, 104, 3992; R. Appel, R. Kleinstuck, and K. D. Ziehn, ibid., p. 1030. lS* R. Appel, R. Kleinstuck, K. D. Ziehn, and F. Kudl, Chem. Ber., 1970, 103, 3631. leaE. Yamoto and S. Sugasawa, Tetrahedron Letters, 1970,4383. la' R. Appel, R. Kleinstiick, and K. D. Ziehn, Angew. Chem. Znternat. Edn., 1971, 10, 132. leS R.Appel, R. Kleinstuck, and K. D. Ziehn, Chern. Ber., 1971, 104, 1335.Cadogan and Mackie Castro et aZ.166(Scheme59). The same group of workers have prepared secondary vinyl esters,168 glycidic esters,laS and a-keto-esters.lsS Other uses of carbon tetrachloride-phosphine systems include the conversion of aldehydes into acetylene~,1~~ conversion of epoxides into vic-dihalides,171 and the conversion of enolizable ketones into vinyl halides.17a + -RCHO + (Me2N)3PCl CCh +(Me2N)3PCl RCH(CCl3)O--1 + RCH=CCl2 + CCl4 + (Me2N)sPO +RCHOP(NMe2)s CCl3 + (Me2N)3PCl2Iccl3 Scheme 59 D. Reactions with vic-Diha1ides.-The most useful application is debromination but its success depends on the nature of the dihalide. Thus, 1,Zdibromoethane with triethyl phosphite gives the normal Arbusov However, when electron-withdrawing groups are attached to both carbon atoms, debromination OCCUTS.~~~J~~This also occurs in certain circumstances when only one electron- withdrawing group is present.For example, diethyl l-cyano-2-chloroethyl- phosphonate is formed from 2,3-di~hloropropionitrile~~~ 2,3-dibromo-but propionitrile gives over 80% of acry10nitrile.l~~ Similar debrominations may be accomplished using tertiary pho~phines.~~*J~~J~~ Low yields of cyclohexene are reported177 from trans-l,2-dibromocyclohexanebut up to 40 % can be obtained by use of tributylphosphine. For dihalides of the type RICHXCHXRB it is found that both meso- and erthyro-isomers as well as (k)-and threo-forms yield trans-olefin~,~~~,~~~ except in the case of (+)-stilbene dibromide when a mixture of trans-and cis-products is formed.In this case Borowitz et claim B. Castro, J. Villieras, R. Burgada, and G. Lavielle, Colloques Internationaux du C.N.R.S. No. 182, ‘Chemie Organique du Phosphore’, 1969, p. 235. lo’ B. Castro, R. Burgada, G. Lavielle, and J. Villieras, Bull. SOC.chim. France, 1969, 2770. J. Villieras, G. Lavielle, and J. C. Combret, Compt. rend., 1971, 272, C,691. 160 J. Villieras. P. Coutrot, and J. C. Combret, Compt. rend., 1970, 270, C. 1250; J. Villieras, G. Lavielle, and J. C. Combret, Bull. SOC.chim. France, 1971, 898. lP0 E. J. Corey and P. L. Fuchs, Tetrahedron Letters, 1972, 3769. 171 N. S. Isaacs and D. Kirkpatrick, Tetrahedron Letters, 1972, 3869. loa N. S. Isaacs and D. Kirkpatrick, J.C.S.Chem. Comm., 1972, 443. 17a G. M. Kosolapoff, J. Amer. Chem. SOC.,1944, 66, 109. 174 K. C. Pande and G. Trampe, J. Org. Chem., 1970,35, 1169. J. P. Schroeder, L. B. Tew, and V. M. Peters, J. Org. Chem., 1970,35, 3181. 170 V. S. Abramov and N. A. Il’ina, Zhur. obshchei Khim., 1956,26,2014 (Chern. Abs., 1957, 51, 1822). 177 I. J. Borowitz, D. Weiss, and R. K. Crouch, J. Org. Chem., 1971,36, 2377. 17B C. J. Devlin and B. J. Walker, J.C.S. Perkin I, 1972, 1249. Tervalent Phosphorus Compounds in Organic Synthesis that addition of isopropyl alcohol increases the fraction of cis-compound formed owing to the removal of PhsPBrz, which catalyses the cis-trans isomerization. The fact that pure cis-compound is not formed in the presence of the alcohol is assumed to be due to HBr.However, Devlin and Walker1'* claim that cis-trans isomerization is 'not extensive' and that the preponderance of trans-isomer formed is due to inversion and rotation of the ion pair shown in Scheme 60. Rl*I >;y$H R2 R2 Br Br + BrPPh, i-BrPPh, Scheme 60 In support of the intermediacy of this ion pair, these workers isolated ph3PCHPhCH2N02]+ Br- from the reaction of triphenylphosphine with 1,2-dibromo-l-nitro-2-phenylethanein methanol. Normally a-halogenoacyl halides undergo Arbusov and Perkow reactions with two moles of phosphite (Scheme 61). However, diphenylketen has been prepared by debromination of 4JCHMeCH,CHBrCOBr 3-2(EtO),P +(EtO)aP(0)OC Scheme 61 a-bromodiphenylacetyl bromide with triphenylpho~phine,~~~ a procedure which it is claimed has many advantages over all others for the preparation of diphenyl- keten.E. Reactions with N-Halogenoamides. Conversion of Alcohols into Alkyl Bromides and of Amides into Nitri1es.-It has been reported that ethyl bromide is formed when ethanol is added to a mixture of triphenylphosphine and N-bromo- succinimide.l*O Reaction between tervalent phosphorus compounds and N-halogenoamides has been shown to involve attack at halogenlgl and the forma- tion of the alkyl bromide can be rationalized in terms of the reaction of the 17* S. D. Darling and R. L. Kidwell, J. Org. Chern., 1968, 33, 3974. lEoS. Trippett, J. Chem. SOC.,1962, 2337. A. K. Tsolis, W. E. McEwan, and C. A. van der Werf, Tetrahedron Letters, 1964, 3217.Cadogm and Mackie alcohol with the intermediate PhPBr+ ion. The reaction has application in carbohydrate and nucleoside chemistry since amide ester and acetal functions are unaffected.18a The use of trialkyl phosphites with N-halogenoamides, on the other hand, leads to a mixture of the parent amide and the corresponding nitrile.188 6 Miscellaneous Reactions A. Reactions with Azides: Formation of Imines and their Use in Synthesis.-Both tertiary phosphinesls4 and triestersles react with azides by loss of nitrogen to give imines. In some cases isolation of the intermediate has been achieved.lsg The displacement reaction has been shown to proceed as in Scheme 62.1e7 Rl3PSNR2f Nz Scheme 62 The phosphinimines are particularly useful synthetic intermediates because they react readily with a wide variety of unsaturated compounds (Scheme 63).The Wittig reaction, which followed later, is closely related in type to these reactions, which all probably proceed via four-membered cyclic intermediates.14s An interesting variation on the intermolecular reaction of phosphinimines and carbonyl compounds outlined in Scheme 63 is Zbiral's synthesis of tetrazoles from phosphinimines and acyl halides,la8a followed by reaction with sodium azide (Scheme 64).The corresponding acylation using acyl cyanides leads to iminonitriles (Scheme 64). Intermolecular condensation of phosphinimines containing ap-carbonyl group, on the other hand, leads to pyrazines (Scheme 65).la8 Several useful syntheses of heterocyclic compounds have resulted from intra- l8' M.M. Ponpipom and S. Hanessian, Carbohydrate Res., 1971, 18, 342. 18tt J. M. Desmarchelier and T. R. Fukoto, J. Org. Chem., 1972, 37, 4218. 184 (a) H. Staudinger and E. Hauser, Helv. Chim. Ada, 1921, 4, 861 ;(b) H. Staudinger and J. Meyer, ibid., 1919, 2, 635; (c) ibid., 1919, 2, 619. lS6 M. I. Kabachnik and V. A. Gilyarov, Izvest, Akad. Nauk. S.S.S.R., Otdel. Khim. Nauk, 1956, 790 (Chem. Abs., 1957,51, 1823). 186 L. Homer and A. Gross, Annalen, 1955,591, 117. J. E. Leffler and R. D. Temple, J. Amer. Chem. SOC.,1967, 89, 5235. lS8(a) E. Zbiral and J. Stroh, Annalen, 1969, 725, 29; (6) 1969, 727, 231. 131 Tervalent Phosphorus Compouncis in Organic Synthesis ItPTR R3pyR7---+ R,PO f R2C=NR; 1, __oc RSPO -I-R2C=CHR O-CR2O-CR2 Scheme 63 3.R1,P=iNR2 R~~P-NR~ X=CNI, I -R1,PO-0--.Ic--Ra 4-R2N=C \ /Rs R'CX CN X + 3-N-NR~ NR~ II z-0 R',P-NR~ R',P-NR~ ci-nN,8bR3 f--IT 1N3CR3 0-CR' -O-TR' N3 Scheme 64 RS Rt R' R2 Scheme 65 132 Caabgan and Mackie molecular reactions of suitably substituted phosphinimines and triethyl phosphor- imidates. The alkaloid nigrifactine, for example, has been neatly synthesized from the azidotrienone shown in Scheme 66.leg The reaction with the greatest Scheme 66 potential is possibly Leyshon and Saunders' demonstration6* that the phosphor- imidates, derived from reaction of o-azidophenyl benzoate or acetate with triethyl phosphite, cannot be isolated at 20 "Cbut rapidly eliminate triethyl phosphate to give the corresponding 2-phenyl- or 2-methyl-benzoxazole (70%) (Scheme 67).This is a particularly interesting demonstration of anchimeric (EtO),PO Ph I EtO-C=O ++ EtOC(IPh)=N Ph + PhN=P(OEt), f (EtO),PO Scheme 67 acceleration, because intermolecular reaction of triethyl N-phenylphosphor- imidate with ethyl benzoate does not occur (Scheme 67). It is synthetically useful because the experimentally simpler, direct, deoxygenation of the parent nitro- compounds with triethyl phosphites3 works well only in the case of 2-aryl-benzoxazoles. Reaction of 2-azidocinnamates with triethyl phosphite under photochemical conditions similarly gives an entry to the quinoline ring system (Scheme 68).lgo No reaction of the intermediate phosphorimidate occurs in the dark, so photo-logM.Pailer and E. Haslinger, Monntsh., 1970, 101, 508. la0S. A. Foster, L. J. Leyshon, and D. G.Saunders, J.C.S. Chern. Comm., 1973, 29. Tervalent Phosphorus Compounds in Organic Synthesis - -I- (EtO),PO N Scheme 68 chemical activation is needed to isomerize the trans-to the cis-form, thus bringing the reacting ester carbonyl and phosphorimidate groups close enough for reaction to occur. Benzofurazans can be prepared via a related reaction of N-(o-nitro-aryl)-l,2,5- triphenylphospholimines,obtained by the reaction of 1,2,5-triphenylphosphole X P h o Ph Ph Scheme 69 I34 Cadogan and Mackie and suitable a-nitro-aryl azides (Scheme 69),lS1 the driving force being release of ring stain in the pentaco-ordinate intermediates.B. Reactions with Diazoalkanes: Formation of Methy1enephosphoranes.-Diazoalkanes react with tertiary phosphine~~~~c to give phosphazines, which give methylenephosphoranes on thermolysis. These, the well-known Wittig reagents, have a well-known versatility in organic synthesis but this route is not as experimentally useful as the alternative route via phosphonium salts. C. Fragmentation Reactions.-Normally furoxans are readily reduced to furazansS0~ls2but strained furoxans undergo cleavage to give dinitriles (Scheme 7O),lg3 presumably via the tautomeric form. In a closely related reaction, certain +-rCEN-0 X +-2(EtO),P LCEN-0 0-Stmined x Xzo.N -Non-strained X N/O\+ N-'0 \ / MeI Scheme 70 191 J.I. G. Cadogan, R. Gee, and R. J. Scott, J.C.S. Chem. Comm., 1972, 1242. T. Mukaiyama, H. Nambu, and M. Okamato, J. Org. Chem., 1962, 27, 3651; C. Grund-mann, Chem. Ber., 1964,97,575; A. S. Bailey and J. N. Evans, Chem. andInd., 1964,1424.*** M. Altaf-ur-Rahman and A. J. Boulton, Chem. Comm., 1968, 73; J. Ackrell, M. Altaf-ur-Rahman, A. J. Boulton, and R. C. Brown, J.C.S. Perkin I, 1972, 1587. Tervalent Phosphorus Compounds in Organic Synthesis fused furazans, normally resistant to phosphites, undergo clean, deoxygenative, cleavage to dinitriles on photolysis with phosphitesle4 (Scheme 71). Scheme 71 Nitriles are also produced by exocyclic deoxygenation of 4-nitrosopyrazole~,~@~ pathways via a nitrene or a nitrene precursor being possible (Scheme 72).n PhC=NPhIC=N Ph Scheme 72 D. Reactions with ap-Unsaturated Compounds.-In general these proceed via nucleophilic addition of the phosphorus reagent to the a$-system. Thus triphenyl- phosphine reacts with diphenylcyclopropanone to give an ylide which, although it does not react with aldehydes and ketones, does react with isocyanides to give a derivative of cyclobutenedione (Scheme 73)with elimination of triphenyl-phosphine.lDs Related to this is the reaction of 1,3-dipheny1-4-benzylidene-u4T. Mukai and M. Nitta, Chem. Comm., 1970, 1192. l.6 J. B. Wright, J. Org. Chem., 1969, 34, 2474.lw A. Hamada and T.Takizawa, TetrahedronLerrers, 1972. 1849. 136 Cadogan and Mackie Scheme 73 pyrazolin-5-one with (Me2N)3P, which gives an adduct which apparently decomposes in most solvents to give a bis(diphenylpyrazo1ine) (Scheme 74).lQ7 Ph CHPh Ph Scheme 74 Both triphenylphosphinel@* and triethyl phosphitelQQ have been used to produce telomers of activated olehs, again by addition to the a$ double bond. The postulated intermediate betaine in this reaction is also invoked to explain the catalysis by triphenylphosphine of the Michael addition of 2-nitropropane to activated olefins (Scheme 75).200The possibility that the phosphine is acting as a +-PhP + RCHSH2 + Ph3PCH2CHR+-+ PhsPCHzCHR + MezCHNO2 3 PhPCH2CH2R-+ Me2CN02-Me2CN02-+ RCH=CH2 -+ MezCNOzCH2CHR-MezCNOzCHzCHR + MezCHNO2 -+ Me2CN02CH2CH2R + Me2CN02-Scheme 75 base, i.e.by abstracting a proton rather than by adding to the double bond, is discounted on the grounds of the apparent independence of the reaction on the pK of the phosphine used.ao1 A similar reaction is probably occurring in the triphenylphosphine-ctalysedring expansion of substituted cyclopropyl ketones to 4,5-dihydrof~a.1~~'~' 1~7B.A. Arbusov, E.N. Dianova, and V. S. Vinogradova, Zhur. obshchei Khim., 1972, 42, 750 (Chem. Ah., 1972, 77, 126777). la8L. Homer, W. Jugeleit, and K. Klupfel, Annalen, 1955, 591, 108. la*V. A. Kukhtin, G. Kamai, and L. A. Sinchenko, Doklady Akad. Nauk. S.S.S.R., 1958,118, 505 (Chem. Ah., 1958, 52, 10956). 'Oe D. A. White and M. M. Baizer, Tetrahedron Letters, 1973, 3597.*01 K. Issleib and H. Bruchlos, 2.anorg. Chem., 1962, 316, 1. *09 E. E.Schweizerand C. M.Kopay, Chem. Comm., 1970,677; J. Org. Chem., 1971,36,1489.