Read an Excerpt
Organic Compounds of Sulphur, Selenium, and Tellurium Volume 2
A Review of the Literature Published Between April 1970 and March 1972
By D. H. Reid The Royal Society of Chemistry
Copyright © 1973 The Chemical Society
All rights reserved.
ISBN: 978-1-84755-681-3
CHAPTER 1
Aliphatic Organo-sulphur Compounds, Compounds with Exocyclic Sulphur Functional Groups, and their Selenium and Tellurium Analogues
BY G. C. BARRETT
1 General
For every literature report, describing a new detail of the properties of sulphur functional groups, there now appears a matching publication in which an implication of new knowledge is followed through, enriching broad areas of organic synthesis and reaction mechanism. This process, the putting to use of knowledge acquired for its own sake, is well illustrated in the literature from which this Chapter is built.
Text-books and Reviews. — Volumes I — III of a detailed coverage of sulphur chemistry augment the sparse textbook coverage in this field; analytical aspects are exhaustively covered.
Reviews cover the topics : alkynethiolates in synthesis; oxygen-exchange reactions of sulphoxides; sulphonyldiazomethanes; C — S bond cleavage; acyl isothioyanates; radical reactions of sulphur compounds; addition of sulphenyl halides to olefins; sulphenamides; mercaptoethylation of amines; sulphur as a chiral centre; stereochemistry of SIV and SVI compounds; reductive cleavage of sulphides, synthetic uses of alkene- and alkyne-thiolates, and thio-Claisen rearrangements; nucleophilic displacements at sulphur in disulphides; aromatic sulphonation; neighbouring-group participation by sulphinyl oxygen; rearrangement of allylic sulphinates to sulphones, and related sigmatropic rearrangements; conversion of thiols into disulphides via sulphenyl iodides; methanesulphenyl chloride as an electrophile; nucleophilic attack at sulphur; elimination and addition reactions of sulphur compounds; synthesis; oxidation, reduction, and addition reactions of sulphenyl halides; sulphonylnitrenes; protonation of sulphur functional groups; synthesis of sulphinyl chlorides, solvolysis of organosulphur trichlorides, chlorinolysis of disulphides in AcOH or Ac2O; insertion of SO2 and SO3 into metal–carbon bonds; free-radical addition of thiols to unsaturated compounds; stereochemistry of polysulphides; modification of — SH and — S — S — groupings in proteins; broad possibilities of the use of organic sulphur compounds in synthesis.
Spectroscopic studies (n.m.r., i.r., u.v., m.s.) of o-hydroxyphenyl alkyl sulphides, sulphoxides, and sulphones have been reported, bringing together basic correlations, including hydrogen-bonding effects, into one review.
Important general principles of structure have been surveyed, based on molecular orbital considerations. The essentials of d–p, d–sp3, and d–d interactions have been set out, providing a background for the interpretation of experimental data on bivalent sulphur compounds. Wolfe and co-workers have collected data from the literature concerning the conformations adopted by groupings in which lone pair–lone pair or lone pair-polar bond interactions may occur. Preferred conformations for α-sulphonyl-, -sulphinyl-, and -sulphenyl-carbanions, R1 — X — [bar.C]H — R2, are those involving maximum gauche interactions of the pyramidal carbanion with the S — O polar bond(s) or lone pairs on sulphur; the skew conformation of the disulphide grouping is an example of gauche lone pair–lone pair interactions. There is a satisfying generality to the principle (the stabilization of an axial 1-hydroxy-group in a pyranose sugar – the 'anomeric effect' – is a further example), and for sulphur compounds it gives general reinforcement to the idea that the disposition of d-orbitals does not determine conformational preferences.
2 Thiols
Methods employed for the synthesis of new thiols RSH are mainly those which have already proved themselves. The properties and reactions of compounds of this class are well documented, and although new data do not upset existing foundations, there are many points of interest.
Preparation. — For those interested in the past, the report, that irradiation (185 and/or 254 nm) of mixtures of CH4, C2H6, NH3, H2O, and H2S gives cysteine and cystine, among other products, will give a basis for speculation on developments in pre-biotic Earth history. Among well-tried procedures, the preparation of naphthalene-2-thiol from 2-naphthol is notable; the thionocarbamate RO•CS•Nme2, obtained from the reaction of the phenol with Me2N•CS•Cl, gives the thiol on pyrolysis.
Routes of widest applicability involve nucleophilic displacement of halide or toluene-p-sulphonate, or disulphide cleavage, or the less widely used reduction of thione to thiol. 2-Benzamido-2-mercaptopropionica cid (1) has been prepared from 2-phenyl-4-methyloxazol-5(4H)-one (2), though the corresponding route from the thiazolone failed at the last step. The trifunctional grouping — NH — CR(S —) — CO — is a feature of the structure of gliotoxin and related natural products (see Vol. 1, p. 104). β-Chlorolactic acid serves as starting material for the synthesis of α-hydroxy-analogues of S-benzylcysteine ; reaction 25 with benzylmercaptan is followed by debenzylation with Na-NH3 in an efficient route to the mercapto-acid (3), and D- and L-isomers are available in this way.
3-Mercapto-4-phenylcyclobutene-1,2 -dione (4) is even more acidic than its oxygen analogue (the latter has pKa = 0.37 [+ or -] 0.04) but can be liberated from its pyridinium salt with conc. hydrochloric acid, as pale yellow crystals.
Nucleophilic replacement reactions (by AcS-, Ph•CO•S-, MeS-, and PhCH2S-) with methyl O-toluene-p-sulphonyl-L-lactatea and sodium L-2-chloropropionate give 2-acylthio- and 2-alkylthio-~-propionic acids and esters. Extensive racemization accompanies the use of excess thioacetate or thiobenzoate, due to further SN2 replacement reactions, as observed for LiAlH4 reduction of L-(2-methylthio)propionic acid or its methyl ester. Diborane reduction gives optically pure L-(2-methylthio)propanol, however. This work includes a new synthesis of (+)-2-mercaptopropionic acid, though by known methods, and establishes the D configuration for this isomer.
Adamantanone with P2S5 gives the corresponding thione, which can be reduced to the thiol with sodium borohydrides; success in this example should not be taken as an indication of a similar result in other cases, in general.
A simple method for reducing diselenides to alkylselenols RSeH by warming with aq. H3PO2 at 80–100 °C gives high yields. Other cleavage reactions, exposing as a thiol group a sulphur atom that was present in some other form, include further details on the ring-opening of 4H-thiopyran-4-thiones by sulphide or hydroxide ions, the demonstration of the existence of equal amounts of thiol and thiazoline isomers in solutions of S-(2-aminoethyl)isothiowea at pH 4.2 [i.e. (5), (6), and (7) in equilibrium], and some novel reactions of penicillin derivatives. The epimerization at C(6) in penicillins (8) may be accounted for by β-elimination, giving (9), which gives back the epimer mixture in the reverse step, though enethiolate or enolate intermediates are alternative possibilities, with the enethiolate (10) as a likely intermediate in the conversion of a penicillin chloromethyl ketone into the cepham (1 1) by treatment with NEt3.
Monosaccharides with OH groups replaced by SH are being studied systematically ; their synthesis requires carefully planned multi-step routes. Addition of PhCH2S- Na+ to 1,6:2,3-dianhydr0-β-D-mannopyranose gives 1,6-anhydro-3-deoxy-3-benzylthio-β-D-atlropyranose (major product) and 1,6-anhydro-2-deoxy-2-benzylthio-β-D-glucopyranose, latter giving 2-thio-β-D-glucopyranose through further reactions (the benzylthio-sugars result from di-equatorial and di-axial epoxide ring-opening of a 2,3-epoxide, respectively). Complementary routes to 2-thio-D-glucose and -mannose involve addition of PhCH2SH to the olefinic double bond in D-arabino-3,4,5,6-tetra-acetoxy-1-nitrohex-1-ene, in the presence of pyridine; elaboration of S-benzyl-1,2-O-isopropylidene-5-thio-D-xylionsteo 1-thio-L-xylitol illustrates the satisfactory removal of protecting groups, just the aspect of any synthesis of a multi-functional compound which must go well to justify the route.
The use of N-(benzoylthiomethyl)piperidine hydrochloride (1 2) as a reagent for introducing a mercaptomethyl group into an active-methylene position has been demonstrated; dimedone gives (13). N-Methylation of sulphonamides is the net result of mercaptomethylation in this way followed by reductive desulphurization using Raney nickel.
A convenient synthesis of benzene-l,2-dithiol (14), and another involving replacement of the NH2 group by SH to give the biologically important 4-thiouridine and its analogues from cytidines (but in low yield) [e.g. (15) -> (1 6)] illustrate additional synthetic methods.
Spectroscopic and Related Properties of Thiols. — The n.m.r. absorption of the thiol proton moves to lower field in the order PhCH2•SH, Ph2CH•SH, Ph3C•SH; corresponding hydrotrisulphides RSS•SH show the opposite sequence, due to over-riding inductive and anisotropic effects within the cumulative sulphur chain.
The ultraviolet c.d. of 2-(R)-mercaptopropionic acid is dominated by the n -> π* Cotton effect (near 220 nm) of the carboxy-group, while the S-methyl homologue shows, in addition to the positive n + σ* thioether Cotton effect at 238 nm, a weak negative c.d. maximum at 271 nm, ascribed to electrostatic coupling of the carboxyl and thioether transitions.
Pulse radiolysis of penicillamine in aqueous solution gives thiyl radicals RS•, λmax 330 nm, and the radical anion RSSR-, λmax 450 nm, formed from RS• and RS-. Photolysis of propanethiol tritiated at SH, in the presence of a hydrogen donor, results in tritium scrambling in the propyl group and in the hydrogen donor, suggesting that such a system is a useful source of H atoms in solutuion. Increased yields of the products of sensitized photodecarboxylation of R•X•CH2•CO2H(X = O, S, or NH) are obtained in the presence of thiophenol as hydrogen donor. Butanethiol quenches triplet acetophenone only slowly (k = 1.4 x l07 1 mol-1 s-1), and it can be included in the reaction systems of ketone photo-reactions as a radical trap without interfering with the photo-excited
Thiols as Nuc1eophiles. — Rates of nucleophilic substitution and addition reactions of thiols vary over several orders of magnitude, and studies of structure-reactivity relationships are now being supplemented by studies of other factors influencing transition-state energy. Isotope effects on the ionization of arenethiols (Ph, 4-NO2-Ph, pentafluoro-Ph), AcSH, HSCH2CO2H and its methyl ester, and HSCH2•CH2OH, in D2O and H2O, range from KRSH/KRSD = 2.0 — 2.5, the isotope effect increasing with decreasing acidity. These data are discussed in terms of isotope effects on the interaction of the thiolate anion with solvent. Copper (I) thiobutoxide and thiophenoxide show unusual solvent and ligand effects in displacement of Br from pentafluorobromobenzene, or of I from trans-l,2-di-iodoethylene. S-Alkylation of pentafluorothiophenol in the presence of base gives low yields, due to polymerization (nucleophilic displacement of the para-substituent), but the yields may be increased by addition of the thiol to the alkyl halide in DMF. Substituent effects on the proton and carbon basicities of thiophenol have been studied thiopicrate anion is an exceedingly poor leaving group, while its oxygen analogue has uses in synthesis.
Second-order rate constants have been reported for reactions of thiolates with l-aryl-2-hal0geno-alkynes, and with 3-bromo-2(or 4)-nitro-4(or 2)-substituted thiophens, showing in the latter case that the conjugative effect from C(2) is greater than that from C(4) in thiophen. These examples illustrate the study of structure-reactivity relationships in organic halides, the choice of a thiolate as reactant for this purpose being based on the considerations that reaction rates may be measured conveniently and monitoring of the progress of the reaction is simple.
Preparative uses of thiolates, quite apart from syntheses of other sulphur functional groups discussed elsewhere in this Volume, include the demethylation of aryl methyl ethers with EtS- in hot DMF, and a similar use of thiophenol for demethylating aza-heterocyclic O-methyl ethers, of type =N — C(OMe)=. 2-Methylthio-l-methylbenzimidazole does not react with thiophenol, though an alternative reaction path is available for certain hetero-aryl methyl sulphides (17).
Equilibrium constants for the reactions of cysteine derivatives with formaldehyde, and proton dissociation constants for the eight species of cysteine which exist in solution within the pH range 0 — 14, provide essential background information for evaluating the complex pH–rate profile for the formation of L-thiazolidine-4-carboxyliacc acid (18) from L-cysteine and formaldehyde.
Reactions of Thiols with Organoboron, Organophosphorus, and Organotin Compounds. — The high affinity for sulphur that is shown by both boron and phosphorus can result in excision of a sulphur atom from a variety of compounds on treatment with trivalent boron and phosphorus compounds. This may be exploited in a number of ways in synthesis; the reagents used are easily available and the immediate appeal and implications of some recent work are certain to stimulate further studies. Thiobenzilic acid, Ph2C(SH)CO2H, has been used as a source of 1,l-diphenyl-alkenes through its condensation with benzaldehyde or a ketone, followed by treatment of the resulting oxathiolan-5-one (19) with warm tris(diethylamino)phosphine.
Trialkylboranes react with butanethiol giving the corresponding thioboronite R2BSBun, through a free-radical mechanism (e.s.r. of the displaced alkyl radical), and disulphides react to give the same product. The reaction of benzaldehyde, keten, and Bu2BSBu leads to PhCH(OH)•CH2•-CO• SBU. Preparation of tris(organose1eno)boranes from a boron trihalide and selenols, and their reactions with representative nucleophiles and electrophiles, have been reported. The use of ethylthio-groups as protecting groups facilitates the preparation of mono-alkyl phosphates (20).
Photochemical addition of arenethiols to allyltrialkyltin compounds gives 3-( trial kyls tanny1)pr op yl ar yl sul phides R3Sn(CH2)3SAr . Di splacement of the ally1 group as propene, with the formation of Bu3SnSPh, was observed in one case, providing an interesting analogy to boron-carbon bond cleavage.
Addition of Thiols to Multiple Bonds. — The optical purity of (S)-(-)-phenyl-ethyl vinyl sulphide, prepared in good yield from acetylene and (S)-lphenylethanethiol in alkaline solution, was assessed by hydride reduction back to the thiol followed by esterification with (R)-(+)-α-methoxy-α- trifluoromethylphenylacetic acid, the resulting diastereoisomer mixture being analysed by n.m.r. spectrometry. Further examples of basecatalysed addition include the formation of 2-benzylthiocycloalkane-1-carboxylic acids by interaction of benzylmercaptan and 4-, 5-, or 6- membered cycloalkene-1-carboxylic acids, giving mixtures of geometrical isomers, then diastereoisomer mixtures after oxidation to the sulphoxides (stereochemical assignments from n.m.r. data and reaction rates); and also Michael addition of thiols to αβ-unsaturated lactones. A method for the protection of the conjugated olefinic double bond in α-methylene-γ-lactones has emerged from such studies, illustrated by the formation of (21) by addition of propanethiol to the corresponding naturally occurring tri-olefin. Reduction of the vinyl group located at the ring junction, and removal of the two protecting groups with MeI, was shown to be feasible.
The more common free-radical addition path provides the anti-Markownikov adduct predominantly with terminal olefins, though isomer ratios depend to some extent on the structures of the reactant. Increasing tendency towards Markownikov addition through a series has been linked with increasing dipolar character in the double bond, from one compound to the next in the series. A number of free-radical thiol addition reactions reported during the period under review show unusual features. α-Pinene gives (22) and β-pinene gives (23), on treatment with thiols in the presence of di-t-butyl peroxide, while unsaturated epoxides (24) give MeSCH2•CH=CH•O•CHR1R2(R1 = Ph, R2 = H; or R1 = R2 = Me) and MeS•CH2•CH=CH•O•CH=CH•Me(R1 = H, R2 = CH = CH2), through conjugate addition with homolytic C &mash; C bond cleavage. Concurrent studies with (24; R1 = R2 = H) have been reported, continuing earlier work (see Vol. 1, p. 54), while the reaction of styrene epoxide with ethyl thioglycollate, giving PhCH(OH)•CH2SCH2•CO2Et, illustrates a straightforward epoxide-opening path whose direction is little influenced by substituents in the phenyl group. Addition of ethane-1,2-dithiol to furan gives the 1,2- and 1,4-adducts (overall yield 55%) in the ratio 18 : 82 under BF3 catalysis, while free-radical addition of ethanethiol to ethoxy-acetylene involves an intermediate cis-1 -ethoxyvinyl radical, which proceeds to trans-1-ethoxy-2-ethylthioethene under kinetic control, with concurrent equilibration to give the reaction product, a mixture of cis- and trans-isomers. Reversibility of addition of ethyl thioglycollate to acrolein and the cyclization of the adduct to a tetrahydrofuran has been studied.
(Continues...)
Excerpted from Organic Compounds of Sulphur, Selenium, and Tellurium Volume 2 by D. H. Reid. Copyright © 1973 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.
