Synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selenoxides, sulfones and selenones CHRISTOPHER M. RAYNER School of Chemistry, Universiy of Lceds, Leeds LS2 YJ7: UK Reviewing the literature published between March 1995 and May 1996 Continuing the coverage in Contemporary Organic Synthesis, 1995, 2, 409 1 2 2.1 2.2 2.3 2.4 3 3.1 3.1.1 3.1.2 3.1.3 3.2 3.2.1 3.2.2 3.2.3 4 4.1 4.2 4.2.1 4.2.2 4.2.3 5 6 Introduction Synthesis of thiols and disulfides, selenols and diselenides, sulfides and selenides Simple alkanethiols and dialkyl disulfides, alkaneselenols and dialkyl diselenides, dialkyl sulfides and selenides Unsaturated thiols, disulfides, selenols, diselenides, sulfides and selenides Substituted thiols and disulfides, selenols and diselenides, sulfides and selenides Thiols, disulfides, selenols, diselenides, sulfides and selenides as mediators of asymmetric transformations Synthesis of sulfoxides Oxidation of sulfides and selenides Non-stereoselective oxidation Stereoselective oxidation Enantioselective oxidation Non-oxidative sulfoxide and selenoxide synthesis General methods for sulfoxide and selenoxide synthesis Functionalised sulfoxides and selenoxides Unsaturated sulfoxides and selenoxides Synthesis of Sulfones and Selenones Oxidation of sulfides and sulfoxides Non-oxidative sulfone synthesis General methods for sulfone synthesis Functionalised sulfones U ns a t u r a t e d s ul fone s Conclusion References 1 Introduction This review continues from t h e previous ones published in 1994' and 1995.* It covers new methods for the synthesis of acyclic thiols, sulfides, sulfoxides and sulfones. In addition, the coverage has now been extended to include the analogous selenium derivatives.Cyclic systems will be covered else- where. A similar format has been adopted to that of the previous review in that it is divided into three sections: thiols, selenols, sulfides and selenides; sulfoxides and selenoxides; and sulfones and selenones. Each section begins with synthetic routes to simple systems, and then goes on to consider methods leading to more complex, polyfunctional molecules. Considerable emphasis has been placed on stereo- and enantio-selective reactions, reflecting the current interest in this area. chemistry has been published which is suitable for undergraduates, postgraduates and anyone involved in research needing to refresh their knowledge of this area3 Reviews on S-cationoid reagents in organic synthesis' and recent advances in synthetic reactions using organoselenium reagents have been published.s The latter includes sections on the addition of electrophilic selenium species to double bonds, including asymmetric processes, and catalytic oxyselenation and intramolecular oxyselenation re actions .A new introductory text on organosulfur 2 Synthesis of thiols and disulfides, selenols and diselenides, sulfides and selenides Methods of preparation, reactions and physico- chemical properties of sulfides have recently been reviewed.6 The chemistry of disulfides has also been r~viewed,~ as have applications of organosulfur compounds' and elemental selenium9 in organic synthesis.The origins of acidity trends for sulfides and oxidised derivatives"'.' I and radical stabilities' ' have also been investigated. 2.1 Simple alkanethiols, dialkyl disulfides, alkaneselenols, dialkyl diselenides, dialkylsulfides and selenides The reactions of alkyl halides and related electro- philes with nuclcophilic sulfur or selenium species are amongst the most established methods of sulfide and selcnide synthesis. Recent advances have been reported which include the use of borohydride exchange resin (BER) which promotes reaction between thiols and alkyl halides or epoxides to form unsymmetrical sulfides.".'3 The use of hydrosulfide exchange resin, prepared from the chloride form of Amberlitc IRA-400 and sodium hydrosulfide, can be used for the direct synthesis of thiols from alkyl halides (cJ: Scheme Sl)." Addition of triethylamine Ruyner: Synthesis of thiols, selenols, sulfides, selenides, sidfoxides, selenoxides, sulfones and seleriories 499hydrochloride minimises formation of the more usual symmetrical sulfide products.Benzyl sulfides can be prepared by reaction of thiols with benzyl chloride in the presence of montmorillonite- 3-aminopropyl(triethoxy)silane.” Alternatively, benzyl thioacetate in the presence of NaOH and methanol generates phenylmethanethiolate which reacts with alkyl halides to give benzyl thioethers (Scheme l ) . I 6 . I 7 Symmetrical dibenzyl diselenides can be synthesised from elemental selenium, NaOH and benzyl halides under phase transfer conditions using polyethylene glycol (PEG) (Scheme 2).IX Diselenides can also be formed directly using elemental selenium and zinc in the presence of sodium hydroxide, reacting with either alkyl halides, nitrohaloaromatics and acyl halides (Scheme 3).19 Bis(benzyltriethy1ammonium) tetrathiomolybdate20.2’ reacts with alkyl halides and toluene-p-sulfonates to form disulfides directly and has found particular application in macrocyclic disulfide synthesis (Scheme 4), whereas sodium sulfide adsorbed on 0 NaOH.MeOH PhASAMe * [ PhASNa] Scheme 1 NaOH, PEG-400 ArnX + 2se CsH6.65’C ArAS&Sed Ar Scheme 2 Scheme 3 0 C6H&H2NEt3)2MOS4 1 &iCI3 y z J , 25 “C 7-20 membered rings 0 Scheme 4 500 Contemporary Organic Synthesis alumina has been used for the synthesis of macrocyclic sulfides (Scheme 5).22323 The reaction of alcohols with o-N~~C,H,S~CN under Mitsunobu conditions24 results in formation of the selenide with clean inversion of stereochemistry (Scheme has also been reported that zeolites catalyse the formation of thiols and sulfides by reaction between alcohols and hydrogen sulfide.26 It Scheme 5 BnO HO Me0 OMe OMe Scheme 6 A new method of selenolate generation relies on a thiolate-diselenide exchange reaction using the sodium salt of N-acetylcysteine (Scheme 7).The produced benzeneselenolate reacts with various electrophiles, including alkyl halides, epoxides and epoxy ketones in high yields.27 The major byproduct is the disodium salt of cystine, which is easily removed due to its high water solubility. Tin- lithium exchange can be used to prepare bis(lithiomethy1) sulfide, an unusually stable 1,3-dilithiated synthetic building block which reacts with electrophiles such as dimethylphenylsilyl chloride to give symmetrical sulfide products (Scheme 8).’? A novel route to unsymmetrical dithia compounds relies on cleavage of a disulfide by a nucleophilic reagent such as an organolithium, followed by trapping of the intermediate thiolate with an alkyl halide (Scheme 9).28 disulfides and diselenides to alkenes provides a The photochemically initiated radical addition of Na02C 2 )‘*\sH + PhSeSePh NHAC MeOH, H20 NaOH, pH 9.2 I PhSeR Scheme 7i.Na2S/A1203 S Bu3Sn-1 ii. 6uLi (2 equiv.) [ >i] 1 Me2PhSiCI (2 equiv.) PhMe2Si 7 PhMe2Si S Scheme 8 i. RLi, THF, -78 "C to rt ,, ii.RBr, rt 5-8% A Scheme 9 route to 1-thio-2-seleno substituted systems. Interestingly, the reaction is much more efficient if mixed PhSSPh-PhSeSePh reagents are used rather than individual disulfides or diselenides; however high regioselectivity is possible with a wide variety of substrates (Scheme The photochemical degradation of [bis( 1-adamant-3-yl-carbony1oxy)- iodolbenzene in the presence of disulfides provides a route to adamantyl sulfides (Scheme 11).3" Other hindered sulfides can be prepared by ligand transfer of aryl thiocyanates with higher order cyanocuprate reagents (Scheme 12).3' The reaction can be carried out in the presence of reactive groups such as aldehydes, halides and NHBoc, but nitro groups are reduced under the reaction conditions.With simple Grignard reagents, thiols are the major products. - T S P h hv, 45 "C SePh 89% Scheme 10 P hI(0COAd)z Scheme 11 + RSSR 0 AdSR + PhI + AdC02H 2340% Ad =D R = alkyl, aryl Organic thiocyanates undergo reductive dimerisa- tion to give disulfides using bis(benzyltriethy1- ammonium) tetrathiomolybdate. A wide range of structures and functional groups can be tolerated in this reaction (cf. Scheme 4).20-21732 Similarly, seleno- cyanates can be converted to diselenides using hydride reducing agents ([diisobutylaluminium hydride (DIBAL-H), LiEt,BH] even in the presence of sensitive functionality such as ketones and alkyl bromides." Use of excess reagent however does result in reduction of carbonyl groups. Other recently reported methods of symmetrical disulfide synthesis include the reductive cleavage of Bunte salts (RSS0,Na) derived from primary alkyl halides using samarium( 11) iodide;" methanolysis of thioacetates and disproportionation catalysed by nickel boride, generated in situ from nickel( 1 1 ) acetate and borohydride exchange resin (BER);3s and the copper catalysed disproportionation of thiols using copper(I1) sulfate and BER.36 Thioacetates can be converted into thiols using palladium catalysed methanolysis with BER." This has also led to the development of a one pot synthesis of thiols from alkyl halides, using thioacetate exchange resin to prepare the initial thioacetate intermediate, then followed by BER, MeOH and Pd(OAc)2 for the hydrolysis (Scheme 13).Unsymmetrical disulfides can be prepared by the reaction of dithioperoxyesters (formed by oxidation of dithiocarboxylic esters and rearrangement of the intermediate S-oxide) with thiols (Scheme 14).38 i. @AM03 AcS, MeOH ii.@-&Me3 B H I , Pd(OAc)2, R-X - RSH heat, MeOH 87-97'7'' Scheme 13 lrt, 15-20d 0 42-86% I Scheme 14 Various reagents have been developed to oxidise 0 thiols to disulfides. These include methyltrichloro- Me0 Meoq SCN silane with diphenyl sulfoxide, which regioselectively couples two cysteine residues of human endothelin- 1 in quantitative yield;39 2,2'-dithiobis(5-nitro- pyridine) 1 and the corresponding sulfenyl chloride, which have also found application in peptide ~hemistry;~' and 2-mercaptobenzothiazole 2 which has been shown to be useful in the synthesis of a H Me0 SBu' 'H (Bu')~CU(CN)L~~ -78 "C, THF 65% Scheme 12 Rayner: Synthesis of thiols, selenols, sulfides, selenides, suljoxides, selenoxides, suljones and selenones 501wide variety of symmetrical and unsymmetrical disulfides.41 An interesting enantioselective thiol synthesis by thione-thiol rearrangement catalysed by optically active pyridine N-oxides has been reported (Scheme 15).42 Low enantioselectivities have so far been achieved; however the use of diastereomeric mixtures of N-oxides and elevated temperatures may in part be responsible for this.1 2 n CH3 S 6- - R 100 "C, 24 h 1 H2N -OH 55% overall CH3 RASH up to 38% optical purity R = Et, Ph Scheme 15 One final method of synthesis of simple sulfides is by the reduction of sulfoxides. The metal ion mediated deoxygenation of sulfoxides has been reviewed.43 Ammonium iodide has been reported for the reduction of methionine sulfoxides in peptides containing cysteine and cystine residues,44 and dimethyl sulfoxide reductase from Rhodobucter sphaeroides f.s.denitrificans will reduce predomin- antly the S-enantiomer of racemic methyl phenyl sulfoxide to give thioanisole, although the unreduced optically active sulfoxide is of greater synthetic i n t e r e ~ t . ~ ~ 2.2 Unsaturated thiols, disulfides, selenols, diselenides, sulfides and selenides The reaction of arene diazonium salts with sulfur based nucleophiles provides a route to the corresponding aryl thioethers. Bis(benzyltriethy1- ammonium) tetrathiomolybdate can be used, usually to give the disulfide, but thiols can be obtained in some cases (Scheme 16).'"'' To introduce selenium, reduction of amorphous selenium with SmI, gives the diselenide dianion which reacts with aryl diazonium compounds to give the corresponding diselenides (Scheme 17).46 The diselenide dianion generated using zinc, NaOH and elemental selenium reacts with halonitroaromatics also to form aryl diselenides (cf.Scheme 3).19 The direct nucleophilic sulfenylation and thiocyanation of phenolic ethers using hypervalent iodine(ii1) provides an attractive route to aryl Scheme 16 SH Adz+ BF4- - ArSeSeAr THF se + Sm12 - lsez-1 DMF, 0 "C Scheme 17 sulfides. The reaction is believed to proceed by addition of the nucleophilic sulfur species (either a thiol, or its S-trimethylsilyl thioether) to the cation radical of the phenolic ether (Scheme 18).47 Alternatively, palladium-catalysed coupling of a variety of aromatic iodides with thiols (cysteine derivatives) provides access to mercapturic acid (N-acetylcysteine) derivatives in good yield (Scheme 19).48 The choice of catalyst is crucial for the success of this reaction with tris(dibenzy1ideneacetone)- dipalladium [Pd2(dba),] modified with 1,l '-bis(dipheny1phosphino)ferrocene (dppf) giving by far the best yields, but only if the catalyst is stirred at room temperature with the aromatic iodide for 15 min prior to addition of the thiol.OMe OMe 0 P h 1 ( 1 ~ ~ F & (CF&CHOH * qSph X = H, SiMe3, 61% 62% Pr' P i Scheme 18 * xSAr ArI, Pd2(dba)3, dppf 1 -methyl-2-pyrrolidinone NEt3, 60 "C AcHN C02Me 5948% Scheme 19 A tandem Pummerer rearrangement-Diels-Alder reaction sequence can be used for the preparation of a-thio-substituted naphthalene derivatives (Scheme 20).49 A variety of dienophiles can be used, allowing considerable variation in substitution on the new ring.A very versatile method of construct- ing conjugated arenethiols is by palladium-mediated Heck coupling of thiophenols. Choice of S-protecting group is important for the efficiency of this process, and of a variety investigated (Me, Bn, 502 Contemporary Organic Synthesissulfide, when treated with base, isomerises to the acetylenic sulfide which can then be stereoselectively converted into either the E-vinyl sulfide using LiA1H4, or the Z-vinyl sulfide using DIBAL. Reductive removal of the propyl group ( Li-NH3) gives the ethenethiolates with retention of double bond geometry. The ethenethiolates can be dimerised to the disulfides using MeS0,CI (Scheme 22).Unsymmetrical E,Z isomers can also be accessed by isolating the sulfenylsulfonate intermediates and reacting them with the appropriate ethenethiolate. Reaction between 1,l-dichloroethene and thiophenol results in formation of 2-1,2-bis(phenyl- sulfeny1)ethene in high yield (Scheme 23).“ Alternatively, thiols react with 1,172-trichloroethene via dichloroethyne to give acetylenic sulfides which can be further functionalised in one pot by lithiation and reaction with electrophiles, to give a variety of substituted acetylenic sulfides. Subsequent reduction with either LiA1H4 or LiA1H(OBu‘)3-CuBr gives the E- or 2-vinylic sulfides respectively (Scheme Acetylenic sulfides can undergo hydrozirconation followed by transmetallation to give vinyl cuprate reagents which undergo Michael additions to enones (Scheme 25).55 This has been exploited in the synthesis of prostaglandin analogues such as ( +)-15-thia-15-deoxy PGE, methyl ester.Hydrozirconation can also be used for vinyl selenide synthesis. Treatment of terminal alkynes with Schwartz’s reagent (Cp,ZrHCI) selectively generates the E-vinylzirconocene intermediate, which reacts stereospecifically with diselenides to form vinyl selenides in good overall yield (Scheme 26).” Palladium catalysed coupling of 1 -bromo- 1 -phenylthioethene to an organoborane generated in situ by hydroboration of a terminal alkene with 9-borabicyclo[3.3. llnonane (9-BBN) provides a route to a wide variety of vinyl sulfides, and has been used as a key step in the synthesis of laurencin (Scheme 27).s7 P-Sulfonylacrylates and b-sulfonyldienamides react with thiolate nucleophiles to give [j-thioacryl- ates and d-thiodienamides respectively, by stereospecific addition-elimination (Schemes 28 This reaction is successful for a wide variety of substrates, including relatively hindered thiols.The reagent 1 -(phenylseleno)-2-(p-tolyl- and 29)..iS.SS ocIo- Ph P h 0 2 S 4 y SFt 6 Scheme 20 Pd(PPh3)2C12, CUI THF, PiZNEt, 50 “C I 99% I O + O S R R = A c i. EtZNH, CHC13, 50 “C ii. Zn, HOAc, CH2C12 8&%% R = H Scheme 21 CPh3 and Ac) the acetyl derivative was found to be best for the coupling reaction and also for deprotec- tion to the thiol (Scheme zl).”’ (-)-Menthy1 chloroformate has recently been introduced as a new reagent for the resolution of 1,l ’-binaphtha- lene-2,2’-dithiol by derivatisation and fractional recrystallisation of the menthyl thiocarbonate esters.” Subsequent hydrolysis gives a high yield of the required dithiol of excellent enantiomeric purity.Some useful methods of stereoselective vinyl sulfide synthesis are demonstrated by approaches to alkenyl prop- 1 -enyl disulfides.” Prop-2-ynyl propyl B~ PrSNa H = ’ 94% H = ’ “Pr MeONa. MeOH (0.5 equii.) LiAIHl 61 -82% 81 Yo Dr I , heat,36h * H3C*s’ DIBAL I 75% 85% I - - i. LdNH3 - Men SPr ii. MeSOaCl Men s-s- Me (0.5 equi;.) 61 -82% Scheme 22 Rayrier: Synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selerioxides, sulfones and selenones 503cs,, heat, 2 h m N R 2 PT-2;;; TsvNR2 0 PhCH2Sv 0 NR2 31 43% 0 H202, AcOH EtONa, EtOH 85% SPh 95% CI + PhSH heat, 36 ht 42-65X 1 ph2s:a I Bu3SnH CH&12, rt.5 min. 1 00% Scheme 23 LWH, 91 % i. KH, MeOH (cat.) CI H RSH * RS-R' R = CsHI1, R' = Me ii. BuLi iii. R X 72-92% 72% CuBr, 20 OC Scheme 24 i. CwrHCl ii. MeLi,CuCN L H+ SCSH 1 1 Scheme 25 THF, -7W-50 "c 70% overall 6240% . L Scheme 26 OTBDMS SPh OTBDMS I I 91% Scheme 27 0 0 Scheme 29 sulfony1)ethyne 3 is a novel acetylenic sulfone that can undergo both normal and anti-Michael nucleophilic addition, and as such can be used to prepare a wide variety of substituted selenides and sulfides (Scheme 30)" Organocuprate reagents tend to add with Michael-type regioselectivity, whereas thiolate and selenolate nucleophiles tend to give mainly products of anti-Michael addition to the double bond relative to the sulfone.The precise reason for the change in regiochemistry for the nucleophilic addition is unclear at present. It has also been shown that 3 can act as a dienophile.61 Wittig-Horner methodology has been applied to the synthesis of vinyl sulfides. This can involve either phosphono sulfoxide-derived (Scheme 31),62 or phosphono sulfide-derived (Scheme 32)63 reagents. In the case of the former, use of the bis(2,2,2-trifluoroethyl)phosphono sulfoxide derivative leads to high 2-selectivity, the initially formed vinyl sulfoxide being subsequently reduced to the corresponding sulfide under mild conditions with t ributylp hosp hine. Diet hy lp hosp hono sulfoxides have also been used for the synthesis of unsaturated selenides, however little control of double bond geometry is possible and the products are 1 : 1 mixtures of E and 2 isomers (Scheme 33).@ I NaSEt Tsv PhSeCI.NEt3 Et20, rt Ts+H -Ts*SePh- / SePh 97% I N a s : z * T ~ F / SePh SePh 62% Scheme 30 0 0 i. KHMDS,lM-6 ii. ArCHO, -78 "C, THF 1 03% Scheme 28 Scheme 31 504 Contemporary Organic Synthesisi. LDA,-lOO°C ii. RCHO 0, u:qR i. separation ~~k~ 89X ii. NaH,THF HO Major diastereoisomer Scheme 32 i. Buli. THF, -78 "C ii. PhSeBr 72-76% I Scheme 33 The reaction of sulfoxides with magnesium amides provides a novel route to vinyl sulfides. A number of byproducts can also be formed during the reaction, including dithioacetals (Scheme 34).65 The allylation of silyl enol ethers and a variety of similar compounds, with Pummerer generated vinyl thionium ions provides a versatile method for the synthesis of polyfunctional vinyl sulfides (Scheme 35).66 Vinylic bis-thioethers can be synthesised from aromatic a-bromo ketones using the appropriate thiol in the presence of 2,6-lutidine (2,6-dimethyl- p~ridine).~~ The presence of HBr is essential for efficient reaction; if excess 2,6-lutidine is used then products resulting from simple thiolate displacement of the bromide are produced (Scheme 36).4R2NH-2EtMgBr Ph0'\Et Et20,O "C+rt * phxs% R*NH= f 72% Scheme 34 0 TMSOTf, PipNEt L Ph' :,),,SiMes CH2CI2, -78 OC Scheme 35 PrSH 2,blutidine (0.35 equiv.) e 60% No, Scheme 36 Ally1 sulfides and selenides are available by Lewis acid-induced cleavage of the corresponding S , O- and Se,O-acetals respectively, in the presence of an allyl-stannane or -silane (Scheme 37).6* In the case of S,O-acetals, selective C-0 bond cleavage is observed with TiCl, as the Lewis acid, however no analogous reaction is observed with a similar selenium based system.Instead, selective cleavage of the C-0 bond of the Se,O-acetal is achieved using BBr3 to give an intermediate a-bromo selenide, which then reacts under Lewis acid conditions SPh Tic14 (1.3 equiv.) SPh 54"b SnC14 (2 equiv.) H 3 Scheme 37 Rayner: Synthesis of thiols, selenols, suljides, selenides, sulfoxides, selenoxides, sulfones and selenones 505(SnC1,) with allyltrimethylsilane to give the desired allyl selenide. Ally1 sulfides can also be prepared in some cases by acid catalysed rearrangement of a 2,3-epoxy sulfide and elimination (Scheme 38).69 Alternatively, a-lithio-y-methoxyallyl phenyl sulfide will regioselectively add in a Michael fashion to enones resulting in allyl sulfide formation (Scheme 39).70 The intermediate enolate can be further reacted with electrophiles to form highly substituted ketones with good stereochemical control.The use of the triphenyltin enolate however would appear to be essential for an efficient alkylation step. Finally, sigmatropic rearrangements have been used in unsaturated sulfide synthesis. The 3-thio- Claisen rearrangement of an allyl vinyl sulfonium ion leads to formation of a sulfenium ion which can be trapped by appropriate nucleophiles (Scheme 40).7' Alternatively, the use of a chiral rhenium r ~ h .1 ( P O H Scheme 38 Scheme 39 I fast Scheme 40 I ON- - -Re- - -PPh3 ButOK, THF, -80 OC R' = H, 85%, \ - R2 = CH3, 97:3 stereoselectivw I ON- --Re- - -PPh3 BU'OK, THF. -80 "C ON- - -Re- - - PP h3 Scheme 41 auxiliary allows access to a variety of unsaturated thiols via the 2,3-sigmatropic rearrangement of ylides derived from complexes with diallyl, diprop- 2-ynyl and dibenzyl sulfide (Scheme 41).72 The i. Bu'Li, HMPA ii. T B D M S O - 0 0 - %oMe authors report that the rhenium auxiliary is easily -OM* * resolved and can be recycled. PhS TBDMSO' iii. PhBSnCl iv. R I *% PhS 2.3 Substituted thiols and disulfides, selenols and diselenides, sulfides and selenides Mixed 0,s- and 0,Se-acetals can be prepared by oxidation of dialkyl ethers using iodobenzene diacetate in the presence of a disulfide or diselenide (Scheme 42).73 Alternatively, electrochemical oxidation of a thioether in acetic acid provides access to a-acetoxy sulfides which, with suitable substituents, can undergo Lewis acid-induced cyclisation to an oxathiolane (Scheme 43).74 Another very versatile route to S,O-acetals is by Pummerer rearrangement.This has been particularly useful with the development of the asymmetric Pummerer reaction, where chirality in the original sulfoxide is relayed to the product S,O-acetal chiral centre (Scheme 44). This reaction has recently been reviewed.75 Other routes to a-acetoxy sulfides include treatment of a dithioacetal with mercuric acetate (Scheme 45),76*77 other Pummerer rearrangements (Scheme 46),"-'" and acetylation of a hemithioacetal (Scheme 46).78*79 It has recently been shown that a-acetoxy sulfides can be efficiently resolved by treatment with Pseudomonas jluorescens lipase (PFL) (Scheme 47).78*x" A further develop- R = 506 Contemporary Organic SynthesisSePh PhI(OAc)z, PhSeSePh B u ' / O V Bu' Oo, Me NaN3, rt 90% Scheme 42 R2 R2 ' ' y S + R i Pt electrode, -20- " y S A R ' AcONa,AcOH 4140% * R3 OAc R3 Scheme 43 ?- R S+ - *'pTol BF&Etp CHPCIz, heat 5-3% I Me0 &JOEt OAc Pseudomonas fluorescens lipase pH7 buffer, 30 "C, Bu'OMe I 49% yield, ~ 9 5 % ee OAc L OH J NH2 4 Scheme 47 95% >90% 88 I 0 ,,,JyS, 0 OEt y \pTol OTBDMS ment of this involves the dynamic kinetic resolution (DKR) of an epimerising hemithioacetal by ZnIp (cat.), MeCN Scheme 44 EtsY SEt EtS-OAc single diastereoisomer Scheme 45 i.CH~CI~, 4 A sieves ii. AcpO. pyridine, DMAP / 7449% Scheme 46 enzymatic acylation allowing up to 100% yield of resolved a-acetoxy sulfide (Scheme 48),79 rather than the 50% limit on yield for most enzymatic resolutions. Hemithioacetals can be made to epimerise using SO2 which plays a crucial role in the DKR process. In contrast, optically active hemithioacetals are sufficiently configurationally stable under acid conditions to allow cyclisation onto an adjacent acetal functionality to form oxathiolanes and oxathianes of high enantiomeric excess (Scheme 47)'" This has been exploited in a synthesis of the antiviral agent Lamivudine (3TC) 4.'l Finally, (ary1thio)nitrooxiranes can be accessed by nucleophilic epoxidation of the corresponding nitroalkene (Scheme 49).82 In some cases, significant stereoselectivity can be achieved, and this can be reversed by changing the metal counter-ion.One of the classic methods for the synthesis of fi-hydroxy sulfides and selenides is the nucleophilic ring opening of epoxides with thiolate and selenolate nucleophiles respectively. Recent developments include the use of thiol-diselenide exchange for the generation of benzeneselenolate using N-acetylcysteine and diphenyl diselenide (cf Scheme 7);27 silica gelx3 and polyethylene glycol (PEG)84 catalysis for the addition of thiophenol to epoxides (Scheme SO); and the use of hydrosulfide exchange resin, prepared from the chloride form of Amberlite IRA-400 and sodium hydrosulfide, for the direct synthesis of P-hydroxy thiols from epoxides (Scheme 51).14 Addition of triethylamine hydrochloride minimises formation of the more usual symmetrical sulfide products.The addition of chiral selenolates to prochiral epoxides proceeds with moderate to excellent stereoselectivity (Scheme 52).'5-'7 The selenolate can be generated from the corresponding diselenide using either LiA1H4 or NaBH,. Rayner: Synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selenoxides, sulfones and selenones 507Scheme 48 BubOM, THF, -78 "C 1 5 6 M = Li, 60% (after separation), ratio 5:6 5:l M = K, 63% (after separation), ratio 5:6 1 :6.5 Scheme 49 4' PhSH,PEG-4000 I Ph E S P h CHzCl2,2 h Ph 72% Scheme 50 Scheme 51 sek Scheme 52 i. LiAIH,, THF ii. Cyclohexene oxide, -20 "C 82%, 69% de e M? )-NMe2 HO An alternative approach to P-hydroxy sulfides and selenides is by oxysulfenylation and oxyselenylation of alkenes.This is illustrated by a recent example where N-(pheny1seleno)phthalirnide (NPSP) adds to alkenes in the presence of water to give a B-hydroxy selenide as a mixture of diastereoisomers (Scheme 53).88 Interestingly, if phenyl selenyl chloride is used instead of NPSP then simple addition is observed with no incorporation of water. Phenylselenyl nitrate can be generated in situ from diphenyl diselenide and NOz. It is a novel oxyselenylating agent, and adds to alkenes to give P-phenylseleno nitrates which are readily hydrolysed to the corresponding alcohols by silica gel (Scheme 54).89 The reagent (2,4,6-triisopropylphenyl)selenyl bromide has recently been introduced, and reportedly gives up to a 10- to 100-fold increase in stereoselectivity for selenylation reactions relative to PhSeCl and NPSP.w Asymmetric selenylating agents have also recently appeared, and can be used for P-alkoxy selenide synthesis.Selenylation of styrene with chiral selenyl trifluorornethanesulfonate 7 in the presence of methanol gives moderate to good levels of diastereoselectivity (Scheme SS)." The selenyl- 0 0 Scheme 53 CHCl R% ON02 PhSeSePh + NO2 L[ 0-25 "C PhSeONOP] - R L S e P h Si02 57-77% I OH R L S e P h Scheme 54 R ? i. (-)-DIPXI ii. NaH, R'X iii. Bu'Li, Se I i. lor2 ii. AgOTf R 1 1 R r 7 (-)-DIP-CI = (-)-B-chlorodiisopinocampheylborane Scheme 55 508 Contemporary Organic Synthesisating agent is generated in situ from the corre- sponding diselenide.In an approach to the synthesis of ( + )-samin, a diastereomeric ratio of up to 16 : 1 was achieved for addition to alkene 8 using a related system (Scheme 56).92 Selenyl bromides having chiral C2-symmetric pyrrolidine rings have also been investigated as asymmetric selenylating agents and give poor to moderate stereoselectivity in a seleno- methoxylation reaction (Scheme 57).93 A practical synthesis of the asymmetric selenylating agent 9 has been reported which is a significant improvement on the originally reported procedure (Scheme 58).94 An interesting deprotection reaction of P-hydroxy aryl selenides has been reported (Scheme 59). Photolysis of a phenylselenoalkane results in i. Br2 ii.AgOTf iii. 8, -100 "C, 15 min. iv.c-*= , -100 oc, 3 h 4" i@= OH 56% ArA'.O/ 161 diastereomeric ratio Scheme 56 pCt R2NH, DMF NaHCO, 80 "C sej-, 4849% R' R P h P h R2N= rx;'p Scheme 57 $, 0 81%, i. (+)-DIP-Cl, 99?h 88 THF, -25 "C 41:; B~ ii. NaH, EtI, 83Oh D \ / set2 iii. Bu'Li, Se, NaOH (cat.) 70-76%, >99% ee Me 9 Me (+)-DIP-CI = (+)-B-chlorodiisopinocampheylborane cleavage of the Se-aryl bond rather than the alkyl- Se bond which often occurs using conventional reductive cleavage protocols (Birch reduction). Olefinic byproducts are also formed in this react ion .95 Reduction of a P-keto sulfide using baker's yeast provides access to optically active P-hydroxy sulfides in good yield and with high enantioselectivity (Scheme 60).96 Dihydroxylation of an ally1 sulfide provides a route to P,y-dihydroxy sulfides using a modified Sharpless-style racemic dihydroxylation procedure (Scheme 61).97 Nucleophilic displacement of a glycerol-derived toluene-p-sulfonate by phenyl- methanethiolate provides access to related systems.Interestingly, alcohol protection and subsequent treatment of the benzyl thioether with tributyltin hydride produces a nucleophilic tributylstannyl sulfide which reacts with sugar derived electrophiles with good control of anomer selectivity (Scheme 62) .9s form via the Sharpless asymmetric epoxidation, represent new readily available synthons for use in asymmetric synthesis. On treatment with Lewis acids, they rearrange to the corresponding thi- iranium ions which can be trapped with various nitrogen-based nu~leophiles.~' Recent developments include the use of imines as synthetic equivalents of simple primary amines for overall clean monoalkyl- ation with the thiiranium ion intermediates.'"" The initially produced iminium ions are isolable, but are 2,3-Epoxy sulfides, available in an optically active ASph 0 baker's yeast ?H &SPh 80% 91% ee VO(acac)2 TBHP, CHpClp 74% 3: 1 diastereoselectivity I i.Ms20. NEt3 -'\ph -ii. DBU 76% I i. LiHMDS, THF I ii. O0 47% Scheme 60 Scheme 58 fYSePh hv, NEt3, MeCN Scheme 59 0 U u MeS02NH2, K2CO3 Bu'OH, H20 96% Scheme 61 Rayner: Synthesis of thiols, selenols, suljides, selenides, sulfoxides, selenoxides, surfones and selenones 509c HO $oc16H3 PhCH2SLi HO i. Mel. NaH THF. rt ii. Bu3SnH, AIBN B u ~ N ~ S O ~ C6H6. heat, 3 h Scheme 62 usually hydrolysed immediately to form the required secondary amines (Scheme 63).By comparison, with amino ester nucleophiles, polyalkylation is not a problem, and the free amines can be used with moderate to good efficiency (Scheme 63)."' In the absence of nucleophiles, related thiiranium ion intermediates undergo elimination to give allylic P-hydroxy sulfide derivatives (Scheme 38).69 to aldehydes also provides a route to /I-hydroxy selenides (Scheme 64).Io2 In this case, the organo- lithium species is generated from the selenoacetal and adds to the aldehyde to give a single stereo- isomer of the product. The enantioselective aldol reaction between benzaldehyde and P-thio-substi- tuted silyl enol ethers, catalysed by a chiral Sn" The nucleophilic addition of a-metallo selenides R3 R1 S' TMSOTf -78 "C, CHpClp .R4 I R2 OH K2co3 bq.1 R1+N0~4 3h,rt H 4446% S R3 TBDPSO 3H ( P h S e ) 2 C H 2 , B u L f o ~ THF, -78 80% "C *.H SePh 'CH3 'CH3 Scheme 64 complex, also allows access to P-hydroxy sulfide derivatives with good control of both relative and absolute stereochemistry. Interestingly, products with opposite absolute configuration can be obtained by relatively minor modification of the chiral ligand (Scheme 65).'03 Mixed 0,Se-acetals have been used for radical mediated phenylseleno group transfer reactions, adding to a wide variety of electron-rich and electron-deficient alkenes under photochemical initiation (Scheme 66).1049'0' Related systems involving sulfur stabilised radicals also add to electron-deficient alkenes with phenyl selenide transfer (Scheme 67).'"' A new route to substituted phenylmethanethiols involves the reductive ring opening of thiophthalan (dihydro-2-benzothiophene), and quenching of the resulting dianion with electrophiles such as water, aldehydes and ketones (Scheme 68).l"' Related Sn(OTf), BU~S~(OAC)~ I ligand 68%, 19:81 syn:anti P h V S E t 83% ee with ligand = SBu' Me OR Scheme 65 PMPO PMPO SePh " SOpP h Me02CA SeP h 4670 Me02C Bu3SnH, AIBN + @S02PhL 92% 1 PMPO &so2,, H? CAN Me02C hS02Ph Me02C Scheme 63 Scheme 66 5 10 Contemporaly Organic Synthesis0 n 0 baker's yeast PhS glucose, H20, pH 7 * PhS 'OBu SePh Scheme 67 Li, THF, -78 "C [ ErLi] biphenyl (cat.) as 4,4'-di-tert-butyl-* i.R'COR~ ii. H20 l 4249% ot"" Scheme 68 OMe I L OMe 1 10 Me OMe MeWOSiMe3 79% >99:1 stereoselectivity SMes I % Me Me OMe Scheme 69 systems can also be prepared by an alternative route (Scheme 69) which also allows for remote stereo- control by neighbouring group participation of the sulfenyl In this case the reaction proceeds via the cyclic sulfonium salt 10 which accounts for the stereochemical outcome of the reaction.Optically active y- and d-hydroxy sulfides can be produced in high enantiomeric excess by baker's yeast reduction of the corresponding ketone (Scheme 7O).Io9 Alternatively, y-hydroxy sulfides can be prepared by ring opening of (S)-( -)-propylene oxide with phenylthiomethyllithium (Scheme 7O),"" or the Lewis acid catalysed ring opening of oxetanes by lithium thiolates (Scheme 71).11" Finally, the dilithium salt of phenylselenoacetic acid reacts with epoxides to form y-hydroxy selenide derivatives (Scheme 72)."' The use of maleic acid in the work up procedure prevents lactonisation observed with stronger acids. 70%, 96% ee I O h I -:: P hSCH2Li i PhSCu, -78 "C 99%, 97% 88 Scheme 70 RSH, BuLi THF.-78 "C OH BFs.OEt2 Scheme 71 i. LDA (2 equiv.) OLi SePh PhSenC02H ii. BnO [ BnOAC02L] i. maleic acid, -15 "C ii. CH2N2 >72% overall I OH SePh BnO &C02Me Scheme 72 The synthesis of (R)- or (S)-2-~ulfanylpropanoic acid from ethyl lactate relies on clean inversion of configuration of the derived methanesulfonate using caesium acetate in DMF. Conventional acid or base hydrolysis of the ethyl ester usually results in some degree of racemisation, however hydrolysis using pig liver esterase (PLE) at neutral pH alleviates this problem (Scheme 73).Il2 Subsequent thioester hydrolysis is readily achieved using aqueous ammonia.The ring opening of trifluoromethyl- substituted epoxy ethers by thiolates leads to a-thiotrifluoromethyl ketones in good to moderate yield (Scheme 74).'13 Alternatively, samarium iodide induces coupling between selenyl bromides and a-bromo ketones to give or-selenyl ketones (Scheme 75).'14 Both Sm12 and Sm13 can be used to induce this reaction. OMS SAC SH i. PLE, pH 7 CsAc, DMF MeAC02Etp MeAC02Et ii. NH3, H2: MeAC02H Scheme 73 Rayner: Synthesis of thiols, selenols, suljides, selenides, sislfoxides, selenoxides, sulfones and selenones 511SR2 H 0 CF R lWoE: R'"'" 49-88"b 0 Scheme 74 &OM. Ar L B r SrnX2, RSeBr MeCN * Ar L S e R 58-72% Scheme 75 Reaction of the lithium enolate of camphor with elemental selenium results in formation of camphoryl diselenide in good yield (Scheme 76); however related reactions usually give more complex results."' Alternative new selenium transfer reagents such as PhSO2SeC1 and PhS02SeSeS02Ph have been developed which help alleviate some of these problems.'I6 The reaction between a-thio'"' or a-selenoenolates" ' with electrophiles (Schemes 65 and 72) and radical mediated phenyl selenide transfer (Schemes 66 and 67)'04*10h also provide routes to related compounds, and have been discussed previously.i. LDA, THF.40 "C ii. Se iii. H', air 76Oh Et02C.. SR' 97:3 diastereomeric ratio Scheme 77 N2CHCO2E1, CH2C12 V N .'$ PhX PhAXxPh 0-0 X=S, Se Bu' CuOTf Bur diastereomeric mixture up to 69:31 (best case) up to 41% ee, X = Se up to 20% ee, X = S Scheme 78 MeOH, 65 "C X = C02R, CONR2, CN 6597% Scheme 76 Scheme 79 Sigmatropic rearrangements have also be used to access carbonyl compounds with r-thio substituents.The [2,3]-sigmatropic rearrangement of sulfonium ylides leads to the formation of E-homoallylic sulfides with a high degree of stereocontrol (Scheme 77).' l7 Alternatively, enantioselective carbenoid addition to allylic sulfides and selenides and subse- quent [2,3]-sigmatropic rearrangement also allows access to similar compounds but with lower stereo- selectivity (Scheme 78)."* A number of different chiral catalysts were investigated, but all gave the products as a mixture of diastereomers.a, @-unsaturated carbonyl compounds is the most common method of synthesising P-thiocarbonyl compounds. Reaction of a thioacetate with boro- hydride exchange resin and Pd" catalysis generates a thiolate which efficiently adds to cqp-unsaturated esters, amides and nitriles (Scheme 79).*19 Addition of potassium thiolates and selenolates to a, P-unsat- urated nitriles have also been reported,"" as have similar additions to more complex substrates (Scheme SO).'?' Additions to a,P-unsaturated ketones have been discussed previously (Schemes 39 and 70).70,'09 Diastereoselective addition of sulfur The addition of thiolate nucleophiles to Scheme 80 nucleophiles to chiral Michael acceptors have also been reported. The use of y-(trityloxymethy1)- y-butyrolactams (Scheme 81)"' and oxazolidinones (Scheme 82)'" as chiral auxiliaries both give high levels of stereoselection. In the more complex example of the asymmetric Bayliss-Hillman reaction, the enolate formed after initial thiolate or selenolate addition to an r, P-unsaturated ketone can react with aldehydes to give mainly the syn- diastereomeric aldol-like product of moderate to excellent enantiomeric excess (Scheme 83).'24 Finally, the Lewis acid mediated reaction between 5 12 Contemporary Organic Synthesis.k P h3C0 -, Ph&O--, ' I 7 PhSH. PhSLi (cat.) Mg(C104)2, EtCN, -78 "c' Ph SPh 0 0 6 1: WX, W:I stereoselectivity Scheme 81 0 0 0 n o RCOSH up to 97: 1 VN$' (orRSH,TiCI4) * R P ~ - stereOseiectivity Ph'. Scheme 82 mainly syn 50-96Yo ee n = 0, X = 0,6&89% 88 n = 1, X = 0 or 2,64-80% ee 12 = Scheme 85 The synthesis of selenium substituted cyclo- propanes has been described using two different methods.The first involves the 12 + 11 cycloaddition of 1-seleno-2-silylethenes to unsaturated carbonyl compounds. Poor to moderate yields of the products can be isolated (Scheme 86).127 Alternatively, the phenylselenyl chloride-mediated cyclofunctionalisa- tion of y, &unsaturated carbonyl compounds also allows access to similar systems in good to moderate yield, and with high stereoselectivity (Scheme 87).12* If N-phenylselenophthalimide (NPSP) is used rather than PhSeC1, then simple a-selenylation of the carbonyl group is observed. Scheme 83 SePh sulfides and silyl enol ethers provides an alternative route to P-thio carbonyl compounds (Scheme 45) .76*77 Routes to other carbonyl containing sulfides and selenides have also been reported.An interesting reaction is the ozonolysis of unsaturated selenides. The carbon-carbon double bond is cleaved in the usual manner, and the selenide is also oxidised to the selenoxide. Under reductive work-up conditions (PPh3), the ozonide is cleaved as usual, however excess reducing agent also results in reduction of the selenoxide back to the selenide. The latter reaction is much faster than any competing selen- oxide elimination. Thus the overall transformation is selective cleavage of the carbon-carbon double bond in the presence of the selenide (Scheme 84).12' Asymmetric rhodium( 1)-catalysed hydroformylation of sulfur-containing alkenes can be used to make a variety of sulfur-substituted sulfides (Scheme 85).'26 High enantiomeric excesses can be achieved using the (R,S)-BINAPHOS ligand 12.7 SePh i. O3 (excess), -78 "C, CH2C12 ii. PPh3 (excess), -78 "C+rt I 93% H Scheme 84 + SnCi4 ____c R 1142% SiMe3 d Scheme 86 n 0 * Me+SePh L-;a;Cl, NaH, THF Me V 72%, 96% de Scheme 87 The Pummerer rearrangment of P-amido sulfox- ides leads to the formation of enantiomerically enriched P-lactams containing S , N-acetal function- ality (Scheme 88).75.129 The use of a benzylidene N, S-acetal to protect cysteine through subsequent synthetic manipulations has also been reported (Scheme 89).13' This methodology was used in an enantioselective synthesis of ( + )-biotin. Other new protection reagents for cysteine have also been introduced.13' - 84%, 80% 88 Scheme 88 Rayner: Synthesis of thiols, selenols, suljides, selenides, suvoxides, selenoxides, sulfones and selenones 513**C02H i.BH3*Me2S, THF, 82% ph--< 3 ii. Swem oxidation, 81; S Ph3P(CH2)&02H Br- / + LDA (2 equiv.), THF, rt ii. H~o+/ B o c H N , - * ~ c 0 2 H HS Scheme 89 Conjugate addition of thiols to a,P-unsaturated nitro compounds followed by reduction of the nitro group allows access to /3-amino sulfides in good overall yield (Scheme 90).132 Related compounds can be obtained in an optically active form from the corresponding amino alcohols by methanesulfonate (Scheme 91)1”3 or toluene-p-sulfonate (Scheme 92)’34 formation and thiolate displacement, or using PBu” and a diary1 disulfide on the free alcohol (Scheme 0 SPh i.MeN02, MeNH2*HCI H KzCO3, EtOH ii. PhSH, heat Me0 82% overall Me0 Zn, HCI 1 AcOH 81% SPh Me0 JpNH2 93).’”’ Alternatively, palladium-catalysed arylation of cysteine derivatives can be used to synthesise similar compounds as previously discussed (Scheme 19).48 The preparation of protected lanthionine (the monosulfide analogue of cystine) derivatives, has been achieved by selective ring opening of serine P-lactones by cysteine thiolates (Scheme 94).”‘ Use of Cs2C03 as base is crucial for this reaction as it cleanly gives 0-alkyl fission of the P-lactone ring, whereas other bases investigated led to 0-acyl fission. The preparation of more complex peptides where disulfide bonds have been replaced by thioether linkages have also been reported including an HIV-1 protease analogue which retains its enzymatic activity after modificatior~,~~’ and the cyclic 10 residue peptide CI-oxytocin.l3* Other new methods for the preparation of large cyclic disulfide peptides have also been r e ~ 0 r t e d .I ~ ~ PBu3 A~S/YCO‘~~ NHBoc + THF, pyridinr NHBoc Scheme 93 Scheme 94 Scheme 90 i. MsCI, NEt3 4 A sieves, 8847% JoH CH2C’2’ooC * Ph NHBoc NHBoc ii. EtSH, NaH Ph THF, heat, 100% Scheme 91 L O H i. LiAIH4, THF, heat H2N Aco2H ii. BocpO, Pr‘2NEt, EtOA: B ~ ~ H N Ph i. TsCI, pyridine ii. RSNa 1 L S R LiAlH4, THF, heat MeHN E S R * BocHN R = Me, Ph, Bur co + “ t N H B 0 c 0 OMe 0 CS~CO~, DMF 50-92% I FO2H VHBOC CbzHN A 4 S + ( O M e 0 The nucleophilic ring cleavage of L-homoserine lactone derivatives by selenolate can be used to prepare selenium containing amino acids.Use of the diselenide and NaBH4 to generate the nucleo- philic selenolate anion is crucial to the success of the reaction as alternative sources of selenolate led to significant racemisation (Scheme 95).14’ The coupling of amino esters with thiiranium ions derived from homochiral 2,3-epoxy sulfides under Lewis acid conditions has been reported, and provides a route to novel stereochemically defined sulfur containing amino acid derivatives (Scheme 63)*99.1” I I 7 PhSeSePh PhSe/\ Ph2CHovNHBac O V N H B O C NaBH4.DMF * Ph2CN2 83% 0 0 Scheme 92 Scheme 95 5 14 Contemporary Organic SynthesisNucleophilic ring opening of N-acylaziridines by thiolates can also lead to formation of p-amino sulfides. In the example given (Scheme 96) the product is formed as a single regioisomer, although lower selectivities are observed in other case^.'^' The facial selectivity for the reduction of a-(fluoroalky1)- b-sulfinylenamines using K- or L-Selectride, is controlled by the sulfoxide, and proceeds with high diastereoselectivity.The product can then be converted into a p-amino sulfide by reduction of the sulfoxide under standard conditions (Scheme 97).142 The synthesis of new chiral diselenides derived from a-methylbenzylamine has been reported. ortho- Lithiation, directed by the tertiary amino group, and reaction with selenium, results in diselenide forma- tion, which can be further functionalised to give a variety of new chiral selenides (Scheme 98).87 A related approach has also been adopted for the synthesis of chiral ferrocene-derived diselenides (Scheme 99).85,86.143.144 NaBH4 Meovo CHC13, EtSH, -50 BF3.OEt2 "C+tl ~ MeoYo AcHN SEt Ac 80% Scheme 96 !J2 K-selectride ~ pTol ' CF3 THF pTol' Up t0 75% 93:7 diastereoselectivity TMSCI, Nal MeCN, 0 "C 74% 1 NH2 pTol 0saCF3 Scheme 97 R = Me, Et, (CH& I se6 Scheme 98 Scheme 99 2.4 Thiols, disulfides, selenols, diselenides, sulfides and selenides as mediators of asymmetric transformations There have been a number of reports of the use of organo-sulfur and -selenium compounds for control- ling asymmetric induction in new enantioselective processes.Whilst it is beyond the scope of this review to discuss these processes in any detail, the potential importance of this area warrants a brief discussion of the structural classes of the organo- sulfur and -selenium compounds used, and the types of reaction that have been reported.When their preparation involves new synthetic methodology, this has been included in the relevant section of the review. reagents to aldehydes can be catalysed by a number of sulfur- and selenium-containing moieties. Recent developments include thiols and the related disulfides 13,145 14,146.147 and 15,14' and various amino selenides (Scheme 98)87 and ferrocenyl selenides (Scheme 52)8s986 which have been discussed previously. Asymmetric seleno-etherification and -esterification reactions have received considerable recent attention. This includes the use of C2-sym- metrical pyrrolidine-derived selenides (Scheme 57),93*149 various a-methylbenzyl alcohol derived selenides (Schemes 55, 56 and 58),9',92,9"."0 and ferrocenyl selenides (Scheme 99).143.144*'s1 Such ferro- cenyl selenides have also found application in asymmetric selenoxide elimination ~ h e m i s t r y ' ~ ~ ~ ' " ~ and/or stereoselective [2,3]-sigmatropic rearrangements.152*153 The enantioselective addition of organozinc Ph Ph n 13 F ' h Y Me SH 14 (sri- N Me 15 Some new sulfur containing chiral ligands have found application in palladium-catalysed allylic substitution reaction of allylic acetates, including 16,154 17lSs and the C2-symmetric bis-sulfoxide-Pd" complex 18.156 The asymmetric synthesis of epoxides from carbonyl compounds and sulfur ylides has also been further reported. The chiral sulfides 19,Is7 201s8 and 21,1s9 give low to excellent enantiomeric excess in the product epoxides, with 21 inducing asymmetry in a catalytic asymmetric epoxidation.IhO Other applications include the use of y-hydroxy selenoxides'b1.'62 and [j-hydroxy sulfoxides'63 for the Rayner: Synthesis of thiols, selenols, suljides, selenides, sulfoxides, selenoxides, sulfones and selenones\ rn 0 0 OH 16 II II * PhO*s'czr,s-*Ph NaOCI, TEMPO 23 ph/SM,Sxph KBr, Bu4NCI Scheme 100 19 20 18 21 enantioselective protonation of prochiral enolates, and the use of a novel C3-symmetric sulfur-based chiral stationary phase for the resolution of amino acid derivative^.'^^ 3 Synthesis of sulfoxides and selenoxides 3.1 Oxidation of sulfides and selenides The preparation of sulfoxides and selenoxides by oxidation of the corresponding sulfides and selenides respectively, continues to be an important area of research.This section is divided into three parts. The first is concerned with new methods of oxidation where chirality is not addressed. The second part is concerned with diastereoselective processes, whereas the final part concentrates on new methods for enantioselective oxidation. 3.1.1 Non-stereoselective oxidation New methods for the oxidation of simple sulfides to sulfoxides have been reported. These include methyltrioxorhenium( VI 11) with H202165 (significant amounts of sulfone by-products formed in some cases); the novel palladium catalyst 22 with O2 (1 atm);'66 various Mn"', Fe"', Co" and Ni" complexes with air, O2 or PhIO as re oxidant^;'^' tert- butyl hydroperoxide (TBHP) with silicz + pl;"' 2,2,6,6-tetramethylpiperidin-l-yloxy free 'iadical (TEMPO) 23 and NaOCl (Scheme I2;I7" fluorooxaziridines such as 24; 17' salts between selenoxides and sulfonic acids;*72 and electrolysis in the presence of meso-tetraphenylporphyrinato- manganese(rI1) chloride and 02, which is a model system for electrocatalytic cytochrome P-450 ~xidation.'~' HgO and 22 a 0 23 4 YHg F3cxcF3 HO OOH C3F7 I= 24 25 A review on a-hydroxy hydroperoxides (eg.25) as oxygen transfer reagents in organic synthesis includes a section on sulfur 0xidati0n.I~~ Mechanistic studies on sulfur oxidation using transition metal peroxide c~mplexes,"~ per acid^,'^^ 102,177 (methyl- trifluorornethyl)dio~irane,'~~ O2 with N02,179 and MOO~*HMPT'*' have also been reported. A comparative study on the oxidation of thianthrene derivatives with chromyl chloride ( Cr02C12), benzyl- triethylammonium permanganate and ruthenium tetraoxide, has been published,'*' as has a study on the oxidation of S, S-acetals using varying equiva- lents of dimethyldioxirane (DMDO).IH2 Little sulfone product is observed until > 2 equiv.of DMDO are used. Thioether-containing chromium carbene complexes undergo chemoselective oxida- tion to the sulfoxide using oxaziridines (Scheme 101).'83 An interesting new method for the oxidation of cysteine derivatives uses diphenyl sulfoxide as stoichiometric oxidant in the presence of a rhenium catalyst (Scheme 102).1"4 Excellent yields are obtained, with no overoxidation to the corre- sponding sulfone. Finally, a simple and efficient preparation of 3-aryl-3-trifluoromethyl-3H-diazirinyl sulfoxides relies on Bu'OC1 oxidation of an aryl sulfide with concomitant oxidation of the diaziridine to the diazirine (Scheme 103).'*' 0 i.BuLi. THF. -78 "C ( c o ) 5 c r q ii. PhSSPh, -20 "Cc (C0)5Cr<Sph Me 56% do& Ph I Ts' 1 CH2CI2,O"C 70% Scheme 101 516 Contemporary Organic SynthesisScheme 102 HN-NH N =N \ / S - M ~ 4 equiv., n = 2, 0348% ,?-Me Scheme 103 3.1.2 Stereoselective oxidation There have been a limited number of studies on the diastereoselective oxidation of sulfides to sulfoxides. Oxidation of a P-hydroq sulfide using VO( acac)' with TBHP as stoichiometric oxidant provides moderate stereoselectivity for sulfoxide formation (Scheme 60)96 whereas camphor-derived sulfides, oxidised using MCPBA, give high diastereoselec- tivity when the reaction is carried out at -78 "C (Scheme 104).'8" The oxidation of bis-phenylthioalk- anes with TEMPO and NaOCl (Scheme 100) proceeds to give the meso-disulfoxide with 90-98% distereosele~tivityl~~ although the actual cause of this stereoselectivity is unclear at present.&sR Me MCPBA CH2C12, -78 "C 1 1 : 1 diastereoselectivity 96% '4 i. Buli, THF, -78 "C ii. PhC02Me 74% Conditions THF, -78 "C I 26 27 DIBAL 3: 97 Scheme 104 3.1.3 Enantioselective oxidation The enantioselective oxidation of sulfides to sulfox- ides continues to be a popular and important area of organosulfur chemistry, and has been included in a recent review.lR7 The reagent (S)-a-methoxy- phenylacetic acid 28 has been introduced as a new chiral NMR shift reagent for the determination of the enantiomeric excess of sulfoxides.lR8 HO L P h OMe Me02C, Me *fie OOH 30 There are four main methods used for asymmetric sulfur oxidation. These are systems based on modified Sharpless asymmetric epoxida- tion conditions, further developed by Kagan and Modena; other metal catalysed oxidations such as the (salen)manganese( 111) complexes of Jacobsen and Katsuki; oxaziridines developed by Davis; and enzymatic procedures. These are now well estab- lished and have been discussed in previous reviews of this series.',' However significant improvements and applications will be included here. Optimised conditions for the enantioselective oxidation of alkyl aryl sulfides developed by Kagan have been reported.'*' The catalyst system is prepared from Ti(OPr'),, diethyl tartrate and water in the ratio 1 : 2: 1 , with cumene hydroperoxide (CHP) as the stoichiometric oxidant at -20 "C in CH2C12.More recently, the fury1 hydroperoxide 29 has been introduced as an alternative to more usual hydroperoxides (CHP, TBHP) for use in the titanium catalysed oxidation procedures and can give excellent enantioselectivity for sulfur oxidation (74-91% ee)."' The kinetic resolution of racemic sulfoxides using a modified Sharpless procedure has been reported, one enantiomer being oxidised to the sulfone, the slower reacting enantiomer remaining with poor to excellent enantiomeric excess (Scheme 105). Full details on the catalytic oxidation of sulfides using the (salen)manganese( 111) complex 30 and Scheme 105 Ruyner: Synthesis of thiols, selenols, suljides, selenides, suvoxides, selenoxides, sulfones and selenones 517iodosobenzene have been reported.Low to excellent enantiomeric excesses can be obtained for the oxidation of aryl alkyl thioether~.'~~ Related p-0x0 aldiminato manganese( III) complexes have also recently been reported, which are capable of asymmetric sulfur oxidation with O2 (1 atrn) as stoichiometric oxidant in the presence of pivalalde- hyde (Scheme 106).193.'93 pJs.Me X (CCH3)3CCH0, O2 (1 atm), rt c P 4693% 6 7 2 % ee Scheme 106 Recent developments on the use of oxaziridines and related compounds have led to catalytic asymmetric processes where the effective oxidising agent is generated in situ from an N-sulfonylimine and hydrogen peroxide.Interestingly, when the (3,3-dimethoxycamphorylsulfonyl)oxaziridine 31 or the corresponding imine precursor is used in the oxidation reaction, the same enantiopreference is observed. However, for the simple (camphoryl- su1fonyl)oxaziridine 32, opposite enantioselect ion is observed depending on whether the oxaziridine is used stoichiometrically, or the imine is used catalyticaIIy with hydrogen peroxide reoxidant (Scheme 107).195 This suggests that in the case of 32, 0 H202, DBU 0 I I R/S. 'Me 32-98% ee CH&I2, rt 4 Me 31 R = OMe 32R=H Scheme 107 PhSAr I I RHS'Me i. 4-cyanopyridine, (-)-menthol chlorobenzotriazole. DMF. -30 "C different active oxidants are operating in each case, either the parent oxaziridine, or an a-hydroperox- yamine generated in situ from hydrogen peroxide and the i r n i ~ ~ e .' ~ ~ Mechanistic studies on oxaziridine oxidations of sulfides have also been p~bIished.'~' A somewhat different approach to asymmetric chemical oxidation of sulfides has been applied to the synthesis of the xanthine dehydrogenase inhibitor (S)-( -)-BOF-4272 (Scheme 108). The process relies on the reaction of the required sulfide precursor with menthol and chlorobenzotriazole to give two diastereomeric sulfoxonium salts, one of which crystallises with high diastereomeric purity as the nitrate salt, the other remaining in solution. Subsequent conversion of the individual salts into the sulfoxide, either by hydrolysis (inversion of configuration) or thermolysis (retention of configuration) leads to the same desired sulfoxide whose enantiomeric purity can be further enriched by recrystallisation if There has been significant progress on the biochemical asymmetric oxidation of sulfides. The whole cell oxidation of aryl alkyl sulfides using Acinetobacter sp.NCIMB 9871 is only slightly less enantioselective than if the purified cyclohexanone monooxygenase (CMO) from the same species is similar substrates but with mostly opposite enantio- selectivity. CMO can also be used to oxidise benzyl alkyl sulfides with up to 96% ee,200*201 and dithio- acetals to form the mono S-oxide ( > 98% ee) along with a small amount of sulfone (8%).2"2 The fungus Heiminthospoiiiim sp. 4671 has been used to oxidise a wide variety of para-disubstituted benzyl methyl sulfides, including trifluoromethyl, halo, hydroxy, methoxy, acetoxy, nitro, cyano, amino, acetamido, acyl and carboxylic acid substituents with 52-98% ee*2"? The same species, along with Mortierella isabel- Zina ATCC 42613, has also been used to oxidise isothiocyanato sulfides and related compounds in approaches to the synthesis of ( -)-sulforaphane 33.Note this paper also corrects previous erroneous stereochemical assignments.'" The use of baker's yeast Saccharomyes cereiisiae NCYC73 for the oxidation of methyl aryl sulfides has been reported. The reaction involves the use of whole cells and Pseiidornonas sp. NCIMB 9872 oxidises Phc s- AF !. crystalline 1 + KOH, H20, DMF INVERSION I heat, 5 0 4 0 "C, 2 h Pk-4'- -Ar !m remzins in mother liquor 30%, ca. 40% 80 RETENTION - f - l Ph--S--Ar (S)-(-)-BOF-4272 Scheme 108 5 18 Contemporay Organic Synthesisgives the product sulfoxide in good yield and with high stereosele~tivity.~"~~~~ Toluene and naphtha- lene deoxygenases have been shown to oxidise alkyl aryl sulfides to give mainly the (S)-sulfoxide with high enantioselectivity.2"X Chloroperoxidases have also been investigated,2"Y*210 and can give mainly the (R)-sulfoxide (>98% ee) for the oxidation of aryl alkyl sulfides,208 and have also be used to prepare more complex aromatic cyclic sulfoxides of up to 99% ee.*'" Finally, in a rather different approach, the enantioselective reduction of racemic methyl phenyl sulfoxide by dimethyl sulfoxide reductase from Rhodobacter sphaeroides f.s.denitrificans leads to predominantly the (R)-sulfoxide by preferential reduction of the (S)-enantiomer to thioani~ole.~~ 3.2 Non-oxidative sulfoxide and selenoxide synthesis 3.2.1 General methods for sulfoxide and selenoxide synthesis A review on recent advances in asymmetric synthesis using organochalcogen compounds includes sections on the synthesis and utility of chiral sulfoxides and ~elenoxides."~ A review on the synthesis of sulfoxide-based ferrocenes using chiral sulfites, sulfinates and by asymmetric oxidation, has also been published.2" Studies on the stereo- chemistry of a-sulfinyl carbanions have also been An improved synthesis of methyl benzenesulfinate has been reported (Scheme 109).*13 The product reacts with various kinds of carbonyl compounds under basic conditions to produce P-carbonyl sulfox- ides in good yield.0 0 >90% Ph03'\0 Scheme 109 The reaction of resolved sulfinate esters (or their equivalents) with nucleophiles continues to be an important approach for the synthesis of optically active sulfoxides. Methods for large scale syntheses of both enantiomers of methyl p-tolyl sulfoxide from diacetone-D-glucose are significant improvements on procedures reported previously (Scheme 110).132 The required diastereomerically pure methanesulfinate or toluene-p-sulfinate ester precursors are readily prepared from diacetone-D-glucose and the appro- priate sulfinyl Menthyl sulfinate esters continue to be useful precursors for the synthesis of optically active s ~ l f o x i d e s . ~ ~ ~ - ~ ~ ~ Resolved sulfina- R = pT01 PTol\S,Me i. MeMgI ii. TFA, MeCN, H20 0 6 80% R = M e i.pTolMgBr ii. TFA, MeCN, H20 I 80% Me. ,pTol f 0 Scheme 110 i. MeMgI, 0 'C F.l O i ? S. dyNswpToi ii. Na2HP04 * Me0 'pTol R 9597% ee Scheme 111 CBH~~OH, TFA toluene, 0 "C 72%, >95% ee Ar -OCsHI Scheme 112 Scheme 113 mides can also be used in a conceptually similar approach (Scheme 111),219 and can also be used to synthesise new chiral sulfinate esters which in turn can provide access to optically active sulfoxides (Scheme 1 12).220 Camphor derived cyclic sulfinates react with organometallic reagents to give 10-isobornyl sulfoxides (Scheme 113).22' Finally, the use of sulfonic acid salts for the characterisation of selenoxides, including X-ray crystallography, have been reported, and overcome a number of problems associated with the instability of ~elenoxides."~ Recent FT-IR studies of related complexes between sulfoxides and sulfonic acids have also been reported.222 Rayner: Synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selenoxides, sulfones and selenones 519r Na 1 i.LDA, THF n P N 3.2.2 Functionalised sulfoxides The condensation between an a-metallo sulfoxide and a carboxylic acid derivative is one of the main methods for the preparation of P-keto sulfoxides. Recently N-acylimidazoles have been shown to be superior to a variety of carboxylic acid derivatives for this kind of reaction (Scheme 114 cf. Scheme 104).223 Other more complex carboxylic acid deriva- tives such as or-chloro-a-fluoroethyl acetate can also be rearrangement of a chloro alkoxide produced from the reaction between a ketone and the anion of an a-chlorosulfoxide (Scheme 115).225.22h Note that there is effectively a one carbon homologation of the ketone and, in the case of aryl alkyl ketones, the carbon is inserted between the carbonyl group and the aromatic ring.An alternative approach relies on the 0 ' \o DIBAL PTOI" pTol@' 9a%, sayo de DIBAL, ZnC12 I i. MeLi (2 equiv.),THF, -78 "C 1 ii. FIX, -78 "C-xt OH pTol ' 9a%, sayo de R 60-8570 Scheme 114 r n i 0 i. LDA, THF, I 0 to- I It HMPA. -78+30 "C Ph'svc' ii. [CHs(CH2)&0 Ph' Scheme 115 (Et02C)2CHBr R pTol NaH, THF, 0 "C t 45% 67% diastereoselectivity 0 0 R*I C02Et C02Et Scheme 116 The reduction of P-keto sulfoxides using DIBAL or DIBAL-ZnC12 is a well established method for the synthesis of diastereomerically pure P-hydroxy sulfoxides, the two reagent systems giving comple- mentary stereoselectivity. This methodology has been used for the synthesis of a variety of types of compound including or-unsubstituted aldol adducts (Scheme 114);223 (-)-(lR, 3R,5S)-endo-1,3-di- methyl-2,9-dioxabicyclo[3.3.3 Jnonane 34, an insect pheromone;229 the lactonic acid moiety 35 of ( + )-compactin and ( + )-mevinolin;"" the spiroketal (2R,5 S , 7R)-2,7-dimet hyl- 1,6-dioxaspir0[4.4]nonane 36;23' allylic alcohols;232 1,2-di01s;~~~ and or-substituted P-hydroxy ~ulfoxides.~~~ Similar methodology has also been adapted for use with P-keto sulfoxides derived from camphor (Scheme 104) achieving equally high stereocontro1.'X6 The addition of diazo- methane to P-keto sulfoxides has also been investi- gated, and proceeds with modest diastereoselectivity to give 2,3-epoxy sulfoxides (Scheme 117)."j 34 36 pTol S T O H 8 0 CH2N2 MeOH or Et20 I 4w3% 1 : 2.3 (MeOH) 1 : 2.9 (Et20) Scheme 117 The synthesis of optically active acyl(sulfiny1)- cyclopropane derivatives by addition of bromo- malonate to a-acyl vinylic sulfoxides proceeds with moderate stereoselectivity and yield.The stereo- chemical outcome can be rationalised by steric interaction between the p-tolyl group of the sulfoxide and the electrophilic tetrasubstituted carbon atom (Scheme 1 16).2279228 The other main method for the preparation of P-hydroxy sulfoxides is by addition of an a-lithio sulfoxide to a carbonyl compound. This kind of reaction has been used as one of the main coupling reactions in an approach to the synthesis of ampho- tericin B (Scheme 118) although problems of stereo- 520 Contemporaly Organic Synthesism Brio O K 0 OH i.PhSSPh, PBu3, DMF ii. MMPP, EtOH, HzO 1 i. LDA, THF, -78 "C :."rri, 66% O K 0 Scheme 118 control during C-C bond formation are not addressed.236 The addition of x-lithio sulfoxides to fluoroalkyl vinylogous esters occurs with excellent regioselectivity (exclusive 1,2-addition), but poor diastereoselectivity (Scheme 119).237 Usc of non- fluorinated carbonyl compounds gives more complex results. An alternative route to B-Auoroalkyl sulfox- ides is by conjugate addition of an ester enolate to /{-trifluoromethyl-@,/?-unsaturated sulfoxides (Scheme 120).'" High regio- and stereo-selectivity are observed in this case. Scheme 11 9 Scheme 120 Further functionalisation of 11-hydroxy sulfoxides by dianion formation and alkylation is also possible although poor stereocontrol is generally observed (Scheme 1 14).L23 Better stereoselectivity can be obtained for the allylation or deuteriation of /hhydroxy-a-sulfinyl radicals generated using azoiso- butyronitrile (AIBN) on the corresponding selenide (Scheme 121).210 The choice of protecting group plays a crucial role in the stereoselectivity of the reaction.With the free alcohol, the syn product predominates, whereas for the TBDMS-protected alcohol, high nnti selectivity is observed. Bu3SnD, AlBN CeH8,lO "C SYn anti R = H, 97%, 64:36 syn:anfi R = TBDMS, 51%, 10:90 syn:anfi Scheme 121 Relatively few new routes to [hmino sulfoxides have been reported.The addition of a-lithio methyl phcnyl sulfoxide to oxaziridines provides a route to [i-hydroxyamino sulfoxides in good yield and with moderate diastcreocontrol (Scheme 122).24" The reduction of cr-(fluoroalky1)-B-sulfinylenamines with K- or L-Selectride(") proceeds with high diastereo- selectivity (Scheme 97).14' In the enantioselective synthesis of the tetrahydroisoquinoline (R)-( + )- carncgine, the acid catalysed cyclisation of a [1-amino-H,p-unsaturated sulfoxide onto an indole proceeds to give a single diastereomeric product in good overall yield (Scheme 123).24' ? Me/ *P h it LDA, THF, -78 "C ii.ph, 0 03% 67:33 diastereoselectivity Scheme 122 M e o d N > ' w A r 0 e N Ar = O"02-C6H4 Me0 A r 4 ? ll Me0 0 TFA, CHC13.0 "C 65% Me0 Me0 (@-(+)-carnegine Scheme 123 3.2.3 Unsaturated sulfoxides and selenoxides The elimination of watcr from a b-hydroxy sulfoxide is one of the main methods !;;7ihe synthesis of a, P-unsaturated suIfoxidesoh.-'..-. and can also allow access to dienyl sulfoxides (Scheme 124).234."2 If a homochiral P-hydroxy sulfide is used as starting Rayrzer: Synthesis of ttziol.s, selenols, sidjides, selenides, suljbxides, seknoxides, sulforzes and selenones 52 1i.MeI, NaH, THF, 65% * H P ' \ p T o I ii. CuSO4. Me2C0, 1OOoh OMe 0 1 i. BULL THF, -78 "C ii. RCHO conditions: 1 V 7 % BuLi, THF, 5% ee Mainly €-isomer DBU, UCI, MeCN, >98% ee I 0 I 40-70% 9 X \pTol Scheme 124 material, the alcohol moiety can be used to control the absolute stereochemistry at sulfur in a diastereo- selective thioether oxidation to give an intermediate P-hydroxy sulfoxide.Subsequent dehydration then gives an optically active a, P-unsaturated sulfoxide (Scheme 60).9h Alternatively, the P-hydroxy sulfoxide precursors are commonly obtained by reduction of the corresponding P-keto sulfoxides (e.g. Schemes 104 and 114).'"6,22' Full details of eliminative routes to y-hydroxy-a,P-unsaturated sulfoxides from 2,3-epoxy sulfoxides and 2,3-dihydroxy sulfoxides have been p~blished.~~' Such compounds can also be accessed by baker's yeast reduction of a y-keto- a, @-unsaturated sulfoxide although yields are low (19%) and stereoselectivities only moderate (64% de, >55% ee);"' or alternatively condensation of an aldehyde with a dithioacetal bis-S-oxide. In the latter synthesis, dehydration occurs followed by a double bond migration to allow a subsequent Evans-Mislow rearrangement, which in the presence of a thiophile gives the y-hydroxy- a, P-unsaturated sulfoxide as a mixture of diastereo- isomers (Scheme 125).245 The condensation of an 3-chloro sulfoxide anion with a carbonyl compound followed by dehydration leads to formation of 1-chlorovinyl sulfoxides (Scheme 126).246 The OH P-Tol, s=o R'R~CHCHO (s.o piperidine. MeCN 4 1-10d 8 pTol 50-96% R ~ = H PCC.NaOAc CHpCI2 0 I 68-8770 0 Scheme 125 kc' i. LDA, THF, -78 "C ? ii. R2CO. 97% p ~ o l N s V c ' iii. AQO. pyridine. DMAP. 94%- S-pTo' iv. NaH, DBU, THF, 83% d' R = (CH2)14 chemoselective oxidation of vinyl sulfides using perfluorooxaziridines also provides a route to a,P-unsaturated sulfoxide~.'~' The Horner- Wadsworth-Emmons reaction and related procedures, have been widely used for a,P-unsaturated sulfoxide synthesis by condensation of a sulfinyl phosphonate with an aldehyde (Scheme 127).247,24R This can allow access to both E- and Z-alkenes (Scheme 31)."' In some cases, sulfoxide racemisation can occur2423247 however changing the base and/or substrate can in many cases alleviate such problems.f/ i. conditions s / t t N ~ - P(0Me)2 ii. MeO2CCHO * p ~ o l w ~ 0 pTol S\pTol N R' Scheme 127 Sulfinyl phosphonates can be used to prepare a,P-unsaturated sulfoxides and selenoxides by an alternative route (Scheme 33).64 Treatment with base followed by reaction with PhSeBr introduces a phenylseleno substituent to give the key synthetic intermediate. Subsequent oxidation of the selenide and selenoxide elimination leads to formation of an unsaturated sulfinyl phosphonate, or alternatively, sulfoxide elimination by thermolysis gives the corre- sponding unsaturated selenide which can be oxidised to analogous phosphoryl selenoxide.Similar procedures involving mixed S , Se-acetals have also been used to prepare camphor-derived a,P-unsaturated sulfoxides (Scheme 128).249 0 90438% R = H, neopentyl MCPBA I -7hO "C i. LDA, THF, -78 "C ii. PhSeBr I 8142% Scheme 126 Scheme 128 522 Contemporary Organic SynthesisThe synthesis of cx-methylene-P-hydroxy sulfoxides has been reported by regioselective photooxidation (Schenck reaction) of racemic vinyl sulfoxides (Scheme 129).250 The intermediate hydroperoxide can be isolated, or is readily reduced using tri- phenylphosphine.The use of chiral sulfoxides as stereocontrolling elements in SN2' reactions has also been reported. This methodology has been applied to a formal synthesis of brassinolide (Scheme 130) .25 ' Scheme 129 Me 1 1 -.-- i. Ms20, pyridine, 0 "C, 84% *-.- * St ii. MeCuCNLi, THF, 76% St " I I I St = Scheme 130 100% de @ OMe The palladium-mediated cross-coupling of vinyl stannanes with halovinyl sulfoxides has been exploited in the synthesis of a wide variety of 2-sulfinyl-substituted butadienes (Scheme 131).2'2 Similar methodology has also been used to access related systems (Scheme 132), however these undergo Diels-Alder dimerisation under the reaction conditions to give cycloadducts with remarkably high diastereoselection.25' The preparation of (phenylsulfiny1)phenols from arenesulfinates using a 'thia-Fries' rearrangment has been reported (Scheme 133)."4 An interesting enzyme-mediated kinetic resolution of the related methyl arenesulfinates by hydrolysis of pendant acetoxy groups provides access to these types of compounds in an optically active form (Scheme 134).'j5 A number of enzymes were investigated for this transformation, with cholesterol esterase (CE) giving the best results.Alternative routes to optic- ally active diary1 sulfoxides have been reported which rely on the use of menthyl toluene-p-sulfinate &SnBu3 Pd2(dba)3-CHC13 BHT, DMF. heat 1 81% f Scheme 131 pSnBu3 Pd(PPh3)4 * [ q : N - E I toluene, heat 0- 0- 0 Et/ sole product .Et Scheme 132 OH f ! o's, Ph OH 0 PhSOCl ~ R 87-92% ) / 7240% R R AIC13 ~ bsXph / / pyridine, THF CH2C12,25 "C Scheme 133 OAc f +&s*sy OH f &'\Me Me cholesterol esterase 50% conversion 62% ee 66% ee Scheme 134 to control the absolute stereochemistry of the sulfoxide.This allows access to quinol and quinone derivatives (Scheme 135),II6 and 2- or 3-sulfinyl- furans (Scheme 136).2'7 The use of unsaturated sulfoxides as dienophiles, dienes and dipolarophiles in cycloadditions has continued to be an important area of research, and the use of the (2-exo-hydroxy-10-borny1)sulfinyl Rayner: Synthesis of thiols, selenols, su@des, selenides, sulfoxides, selenoxides, sulfones and selenones 523?Me 9 ?Me 70% 1 OMe 1 OMe Ago, HN03 dioxane, rt 81 YO 0 Scheme 135 '2 i.Buli,THF ii. MgBr2.0Et2, Et20 iii. (-)-(SJ-menthyl-gtoluene sulfinate 6 86% Scheme 136 group and derivatives in Diels-Alder reactions and applications in natural product synthesis has been reviewed.256 Whilst it is beyond the scope of this review to give a detailed account of this area of chemistry, a brief discussion of the kinds of systems which have been investigated will be included.Syntheses of many of these compounds have been reported previously; any important new synthetic routes have been discussed above. The 1,3-dipolar cycloaddition of 2 - a , p-unsatu- rated sulfoxide 37 and a nitrone has been used in a synthesis of ( + )-~edridine."~ The acetylenic sulfoxide 38 has also been used in a 1,3-dipolar cycloaddition with a n i t r ~ n e . ~ ~ ~ Acetylenic sulfinates 39 have also been investigated as dienophile~.~~' The asymmetric Diels-Alder reactions of more complex a-sulfinyl acrylates including 40,*15 and related 37 (+)-sedridine 38 0 39 40 0 0 41 42 camphor derived systems (Scheme 128)24y have also been reported.The 3-(p-tolylsulfinyl)furan-2-carbal- dehyde 41 has been used as a hetero-Diels-Alder d i e n ~ p h i l e , ~ ~ ' ~ ~ ~ ~ whereas the allenic trichloromethyl sulfoxide 42 undergoes conventional [4 + 21 cyclo- addition with cyclopentadiene to give predominantly endo cycloadducts.261 Various quinone derived sulfoxides have also been used as dienophiles (e.g. 43262 and Scheme 135).216q26' Further studies on the use of 1- and 2-sulfinyl- 1,3-dienes in cycloadditions have been reported (Schemes 124, 131 and 132).24292523253-264 More recently, the use of 3-vinylsulfinylindoles as 4n components in Diels-Alder reactions has been reported (Scheme 127).248 4 Synthesis of sulfones and selenones Although this section is supposed to include methods for the synthesis of selenones as well as sulfones, very little literature has been published on them, and they have found only limited synthetic utility and so will not be discussed in any detail here.4.1 Oxidation of sulfides and sulfoxides The use of tert-butyl hydroperoxide (TBHP) in the presence of Si02 or A1203 after prolonged reaction times will efficiently oxidise alkyl and aryl sulfides to the corresponding sulfones.168 Dimethyldioxirane (DMDO) has also been used for sulfone formation in cephalosp~rins,~~~ ketene S, S-acetals,IX2 and thioether-containing chromium carbene complexes ( c j Scheme 101).2"6 Related mechanistic studies have also appeared.17"'7x The oxidation of vinyl sulfides using MCPBA or perfluoroxaziridines provides a route to vinyl sulfone~.'~~ A review of r-hydroxy hydroperoxides (e.g 25) as oxygen transfer reagents in organic synthesis includes a section on sulfone formation.174 Electron deficient sulfides can be oxidised to sulfones using HOFOM~CN.'~~ 4.2 Non-oxidative sulfone synthesis 4.2.1 General methods for sulfone synthesis A novel approach to sugar-derived sulfones utilises the benzothiazol-2-yl (Btz) group, which on treat- ment with sodium methoxide liberates a sulfinate anion, which can then react with electrophiles to give the desired products (Scheme 137).268 The Btz Scheme 137 i.MeONa, MeOH ii. RX 3748% 0 2 524 Contemporary Organic Synthesisgroup is originally introduced onto the sugar moiety by Mitsunobu reaction of the sugar alcohol and benzothiazole-2-thiol followed by oxidation. The copper-assisted displacement reaction of non- activated iodoarenes with arenesulfinates provides a convenient synthetic route to unsymmetrical diary1 sulfones (Scheme 138).269 Low yields are obtained with the corresponding bromoarenes although the use of copper( 1 1 ) bis(4-methylbenzenesulfinate) catalyst led to considerably improved yields in some cases. The asymmetric palladium-catalysed sulfonyl- ation of s(,y-disubstituted allylic acetates has been investigated with a wide variety of chiral phosphine ligands. It was found that although moderate levels of asymmetric induction were observed with most of the ligands investigated, (S)-( - )-2,2'-bis(diphenyl- phosphin0)-1,l-binaphthyl [ (S)-BINAP 441 gave highest selectivity for cy, 1'-diphenyl allylic acetates, whereas (S)-N, N-dimethyl-1-[ (R)-l',2-bis(diphenyl- p hosp hino)ferrocenyl]e thylamine [ (S)-( R)-BPPFA 451 was superior for r-methyl-yphenyl allylic acetates (Scheme 139).27') Cur.DMF, heat 46-94% Arl + Ar'S02Na * ArS02Ar' Scheme 138 R1- R2 PhS02Na, [PdCl(r-allyl)12 * R1* R2 I OAc q PPh2 ligand 14-68% I S02Ph R1 = R2 = Ph, ligand = (S)-BINAP, 98% ee R' = Ph, R2 = Me, ligand = (S)-(R)-BPPFA, 44% ee soPPh2 (S)-BINAP 44 (9-( R)-BPPFA 45 Scheme 139 4.2.2 Functionalised sulfones PhS02CH2CN Ph2Bu'sio&~ ADDP, PMe3- Ph2ButSi0 imidazole, 40 "C 82% I S02Ph Scheme 140 p ! ! 0 2 P l ] -S02Ph BuLi (2.2.equiv.) THF. TMEDA, -78 "C c'-cI 0 oc+rt, 75% I Scheme 141 of oxiranes by sodium sulfinate resulting in the synthesis of (3-hydroxy sulfones in good yield (Scheme 142).84 An alternative well-established method for the preparation of p-hydroxy sulfones is by condensation of an a-sulfonyl anion with a carbonyl compound. For example, o-bromophenyl methyl sulfone can be lithiated and undergoes clean 1,2-addition to cx, P-unsaturated aldehydes (Scheme 143).'73 The alkoxide intermediate is benzoylated and the product can then undergo radical cyclisation to give a benzo-fused seven-membered ring sulfone. The anion derived from [(methoxymethyl)sulfonyl]- benzene has also been reported to add to ketones (Scheme 144).274 The use of a Schwesinger phospha- Scheme 142 Me,S ii.slHo +Bin * OBz O2 iii. PhCOCl 72% 0 2 I The Mitsunobu reaction of alcohols with phenyl- sulfonylacetonitrile, using trimethylphosphine and 1,1'-( azodicarbony1)dipiperidine (ADDP) provides a versatile method for preparing functionalised sulfones (Scheme 140)."' With unreactive alcohol substrates, the reaction can be carried out at 40 "C in the presence of imidazole to improve yields. The reaction of cx, r-dilithiated ally1 phenyl sulfone with E-1,4-dichlorobut-2-ene gives divinyl-substituted cyclopropyl sulfones with a high degree of stereo- Scheme 143 * ,YH control (Scheme 141).272 On thermolysis, the products undergo Cope rearrangment to form cyclo- heptadienyl sulfones. 6442% Me0 S02Ph catalyse the regioselective nucleophilic ring opening i.BuLi. THF, -78 "C ii. R'R*CO MeOnS02Ph Poly(ethy1ene glycol) (PEG) is reported to Scheme 143 Bu3SnH 1 AlBN 58% I Rayner: Synthesis of thiols, selenols, su@des, selenides, suljioxides, selenoxides, suljiones and selenones 525zene base (Bu'P,) with Me3SiC1 quench gives signifi- cantly higher diastereoselectivity than other bases for the addition of a-sulfonyl anions to isopropyl- ideneglyceraldehyde (Scheme 145).275 This is rationalised by Bu'P, being a strong cation free base, which results in the formation of a 'naked' a-sulfonyl carbanion that adds to carbonyl groups with enhanced stereoselectivity. An alternative diastereoselective approach to P-hydroxy sulfones relies on the threo-selective reduction of P-keto sulfones using NaBH,-CeCl, (Scheme 146).276 The precursor is prepared by oxidation of a diastereo- meric mixture of P-hydroxy sulfones resulting from non-stereoselective addition of an a-sulfonyl anion to an aldehyde.Other related non-stereoselective processes have been reported,277 including the reaction of the dianion of a /?-amino sulfone, which adds to aldehydes to give a 1 : 1 mixture of diastereomeric P-hydroxy sulfones (Scheme 147) .278 Immobilised Candida antarctica lipase (Novozyme 435) will catalyse the stereoselective esterification (vinyl acetate) of a P-hydroxy sulfone, or the hydro- lysis of the corresponding racemic acetate with up to 99% enantiomeric excess in the products (Scheme 148).279 It has also been reported that enzymatic reduction of y-methyl-@-keto sulfones using Candida R, f i i.Burp4 S Ph 0 2 O2 OH iii. Me3SiCl 8349% diastereoselectivity 95-1 00% Scheme 145 i. PDC, 4 A sieves, CHpClp ii. NaBH4, CeCl3, MeOH 63-89% i. BuLi, TsCI, THF ii. NaOEt, EtOH 5 146% OTBDMS up to 1O:l z : E Scheme 146 Ph, I\ 4-(MeO)C6H4CH2NH2 Ph,S/\/NHPMB s \ c 0 2 TFA (cat.), THF 0 2 i. BuLi (2 equiv.), ii. RCHO THF, -78 "C I 6 1 -92% Ph ,S&NHPMB 0 2 Scheme 147 R R = Me, Bn Candida anfarctica lipase (Novozyme 435) I P O A c Scheme 148 i. BuLi. THF ii. BF3*0Et2, Scheme 149 zeylanoides or a variety of other enzymes can give excellent enantioselectivity. However conversions are generally low and limit the synthetic utility.Z8o carried out by reaction of an a-sulfonyl anion with an epoxide. This has been exploited in the synthesis of complex natural products, including key steps in the synthesis of ( + )-bullatacin,28' and ( + ) -tauto- mycin (Scheme 149); note that in the latter case the reaction is catalysed by the addition of BF3*OEt2.282 Another impressive example is the reaction between an ally1 sulfonyl anion and a diepoxide which gives a single product in excellent overall yield (Scheme 150).28' A rather different approach to yhydroxy The synthesis of 11-hydroxy sulfones is usually 526 Contemporary Organic Synthesissulfones is the stereoselective radical addition to 3-hydroxy- 1 -( methylt hio)- 1 -(p-tolylsu1fonyl)alk- 1 -enes.Excellent yields and high stereoselectivity ( > 95 : 5 ) are observed (Scheme 151).IS4 tion of the corresponding sulfide using MCPBA or oxaziridines have been r~ported.'~'~**~ Phenyl- sulfonylethene can also be prepared from thiophenol and 2-chloroethanol and oxidation;2xs and p-tolylsulfonylethene, from sodium toluene- p-sulfinate and 1 -bromo-2-chloroethane.The p-tolyl- sulfonylethene can subsequently be converted to E-l,2-bis(p-tolylsulfonyl)ethene by addition of HO--& toluene-p-sulfonyl iodide and dehydroiodination (Scheme 153)."' Similar reactions have also been reported for other electron deficient alkenes (Scheme 29)," and simple terminal alkenes (Scheme OBn P i. BuLi. THF. -78 "C -S02Ph ii. o, 0 W O B n (0.5 equiv. relative to sulfone) 95% (based on epoxide) so2 Ph' Scheme 150 154) .290 OH SMe OH i. Pr'OH, hv, Ph2C0, 97% R d s , p T o l ii. RdNi (W2), EtOH. 7 i ' ~ R ~ S - P T 0 ' 0 2 : 0 2 /T\ OH Scheme 151 There has been relatively little published on the synthesis of amino sulfones.The conjugate addition of an amine to a vinyl sulfone provides a route to {;-amino sulfones (Scheme 147).17* These can then be further functionalised by dianion formation and alkylation x-to the sulfone group. In an approach to the synthesis of /$-branched rx-amino acids, the addition of a chiral bis-lactim ether glycine synthon to an x,{&unsaturated sulfonc proceeds with high stereoselectivity (Scheme 152).2*5 OEt PhS02 ) Ph I Li I Et20, THF -70 "C 74% 9O:lO stereoselectivity Scheme 153 71% Scheme 154 The use of x-sulfonyl phosphonates for the synthesis of a wide variety of x,/hnsaturated sulfones has been reported (Scheme 155).2y' Intro- duction of the phosphonate group improves stereo- selectivity in the double bond formation.A variety of se I en i um - and s u 1 fur -su bs t i t u t e d 2, /j- unsaturated sulfones have been synthesised from 1 -(phenyl- seleno)-2-(p-tolylsuIfonyl)ethyne 3, a novel acetylenic sulfone that undergoes both normal and anti-Michael nucleophilic additions (Scheme 30).'(' Generally good to excellent control of double bond geometry is possible. Scheme 152 4.2.3 Unsaturated sulfones A review of new synthetic methods exploiting x,/j-unsaturated sulfones during the synthesis of a natural product has been published.2sh An inexpen- sive procedure for the preparation of Z- 1,2-bis- (phenylsu1fonyl)ethene and phenylsulfonylethene from 1,l -dichloroethene and thiophenol has been reported (Scheme 23).53 The initial 1,2-bis-thioether product is oxidised to the bis-sulfone which can be selectively monodesulfonylated using Bu7SnH.Other routes to x,{hnsaturated sulfones by oxida- Scheme 155 Br i. PhS02Na, DMSO ii. LDA, THF, (Et0)2POCI S02Ph I i. BuLi, THF, MeCHO ii. PhCOCl iii. B U ~ K , THF 1 S02Ph -7J Rayner: Synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selenoxides, sulfones and selenones 527Recently, the isolation of stable episulfones has led to increased interest in their synthetic potential. The base-mediated ring opening of episulfones leads to the formation of alkenylsulfinates which can undergo in situ alkylation leading to sulfone forma- tion (Scheme High E-selectivity is observed, and the final alkylation reaction is most successful with reactive alkyl halides.i. LDA, THF, -78 "C 4048% R R - >20:1 E : z Scheme 156 The p-elimination reactions of /3-hydroxy sulfone derivatives provides one of the most versatile methods for a,P-unsaturated sulfone synthesis. For example, 2,3-epoxy sulfones, when treated with base result in formation of y-hydroxy-z, P-unsaturated sulfones (Scheme 157).293 Further details on earlier examples of this reaction have also been rep~rted.'~' A particularly elegant method of controlling the double bond geometry during elimination to form an a,P-unsaturated sulfone is by controlling the relative stereochemistry of phenylsulfonyl group and the alcohol leaving group. Reduction of a P-keto sulfone using NaBH4-CeCl3 provides selectively the threo p-hydroxy sulfone.Subsequent E,-type elimi- nation leads to predominantly the Z-a,P-unsaturated sulfones (up to 10: 1) which can be separated from E-isomer by chromatography (Scheme 146).27"."9' OH BuLi, THF, 6OYo -60 "C+ +S02Ph Me Scheme 157 Iron-mediated allylic substitution reactions of y-alkoxy-a,p-unsaturated sulfones have been shown to occur with complete chirality transfer, and lead to the synthesis of functionalised 1)-substituted a, P-unsaturated sulfones of high enantiomeric purity (Scheme 158).294 Thermal sulfinate-sulfone rearrangement of allylic sulfinates leads to the formation of allyl sulfones (Scheme 159).295*296 If optically active sulfinates are used then the product allyl sulfones retain some of the optical purity after rearrangement. The allyl sulfone anion is a versatile synthetic building block for the preparation of a variety of functionalised allyl sulfones.In many cases, the a-sulfonyl anion is stabilised by coordination of an adjacent heteroatom (Cl, 0, N) to the metal counterion (usually lithium). This can then go on to react with electrophiles in good yield (Scheme 160) *297-299 One of the most important reactions of cx,p-unsat- urated sulfones is their Diels-Alder reaction. Whilst it is beyond the scope of this review to discuss this \ S02Ph i. Fe2(CO)9, CO, hexane Me OBn Fe(co)4 >99% de and ee ii. recrystallisation - 65% OBn HBF4. Et20 96% S02Ph i. RCu(CN)ZnBr Me S02Ph ii. CAN, H20 w CH2CH2CN 81% Fe(C0)4 >96% ee Scheme 158 + Et2Nm S+-pTol BF3-OEt2, toluene I 96% A O A c 96% ee DMF, 100 "C 95% 5T 40% ee OAc ' I Scheme 159 pTolYs O 4 x i.BuLi, THF, DMPU, -78 "C ii. E+ E X X = CI, OH, NHBn E+ = RHal, RCHO Scheme 160 in detail, a brief discussion of some of the substrates that have been investigated will follow. The intra- molecular cycloaddition of a variety of trienyl sulfones have been investigated (Scheme 155).276*291 The cycloaddition reactions of 1-(phenylse1eno)- 2-(p-tolylsulfonyl)ethyneh' and 1-(trimethylsily1)- 2-(phenyl~ulfonyl)ethyne"~ have been studied, the latter acting as a new acetylene equivalent in the Diels-Alder reaction. Divinyl sulfone has been shown to be a useful reagent for 173-azaprotio cyclo- transfer- 1,3-dipolar cycloadditions of oximes."" l-(Trifluoromethyl)-2-(phenylsulfonyl)ethene has also been investigated as a 1,3-dip0larophile.'~~ Allenic trichloromethyl sulfones undergo conven- tional [4 + 21 cycloadditions with dienes such as cyclopentadiene, and give much greater endo-selec- tivity than the corresponding allenic phenyl sulfones.261 E-Bis(phenylsu1fonyl)ethene has been shown to be an efficient dieneophile for reaction with isobenzofurans (Scheme 20).49 Finally, one of the most interesting examples of x,P-unsaturated sulfone cycloaddition is by long range activation of the sulfonyl dienophile via its oxosulfoxonium salt.528 Contemporary Organic SynthesisBF3.0Et2 (cat.) + I CHC13 0 0 = : 4 Scheme 161 J 1 70% o = E \ a I 0 This is formed by a reversible Lewis acid-catalysed reaction between the sulfone moiety and a suitably positioned epoxide (Scheme 161).”’3 5 Conclusion Organo-sulfur and -selenium chemistry continues to play a crucial role in organic synthesis, particularly with the new stereoselective and asymmetric pro- cesses being developed.I hope this review will encourage the further development and exploitation of these methods in the future. 6 References 1 C. 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