Reduction sulfenylation

Reductive sulfeuyiation. Gassman et al. have found that] Stork s method for reductive alkylation of a,/3-unsaturated ketones (1, 601-602) is applicable to reductive sulfenylation of cyclic a, 3-unsaturated ketones and has the advantage of regiospecificity in the formation of ra-methylthio ketones. Furthermore, the reaction proceeds with some preference for axial attack. 

Three substituted 5-phenyl unsymmetrical disulfides have been prepared, i, ii, and iii —compounds i and ii by reaction of a thiol with a sulfenyl halide, compound iii from a thiol and an aiyl thiosulfonate (ArS02SAr). The disulfides are cleaved by reduction (NaBH4) or by treatment with excess thiol (HSCH2CH2OH). 

A heterocyclic ring may be used in place of one of the benzene rings without loss of biologic activity. The first step in the synthesis of such an agent starts by Friedel-Crafts-like acylation rather than displacement. Thus, reaction of sulfenyl chloride, 222, with 2-aminothiazole (223) in the presence of acetic anhydride affords the sulfide, 224. The amine is then protected as the amide (225). Oxidation with hydrogen peroxide leads to the corresponding sulfone (226) hydrolysis followed by reduction of the nitro group then affords thiazosulfone (227). ... 

Williams and Rastetter also accomplished an elegant synthesis of ( )-hyalodendrin (83) in 1980 [39]. Beginning with the sarcosine anhydride-derived enolic aldehyde 78, silyl protection of the enal enabled alkylation of the glycine center with benzyl bromide and thiolation using LDA and monoclinic sulfur a la Schmidt. After protection of the thiol with methylsulfenyl chloride and deprotection of the silyl ether, the enol was sulfenylated with triphenylmethyl chlorodisulfide to afford bis(disulfide) 82 as a 2 1 mixture of diastereomers favoring the anti isomer. Reduction of the disulfides with sodium borohydride and oxidation with KI3 in pyridine afforded ( )-hyalodendrin (83) in 29 % yield (Scheme 9.4). 

To arrive at racemic coriolin, Danishef sky and coworkers chose to add an acetonyl fragment to a bicyclic enedione by Diels-Alder chemistry (Scheme LXXIII) Treatment of the resulting adduct 695 sequentially with a series of conventional reagents produced the key intermediate 696. Suitable aldolization deUvered 697, the functionality in which was adjusted by deconjugation and reduction. Fiuther reduction of dPSiwith lithium in liquid ammonia and methanol followed by epoxidation afforded 699. Selective oxidation of the more accessible hydroxyl group and phenyl-sulfenylation gave 700 which experiences smooth elimination to 701 after conversion to the sulfoxide. As before, epoxidation completed the sequence. 

The proposed mechanism of the oxidative cleavage of S-protecting groups by the chlorosilane/sulfoxide procedure is outlined in Scheme 8. 95 The first reaction is considered to be formation of the sulfonium cation 9 from diphenyl sulfoxide (7) and the oxygenophilic silyl compound 8. The formation of a sulfonium ion of this type is known and has been utilized for the reduction of sulfoxides. 97 Subsequent electrophilic attack of 9 on the sulfur atom of the S-protected cysteine residue leads to the formation of intermediate 10, whereby the nature of the silyl chloride employed should be the main factor that influences the electrophilicity of 9. The postulated intermediate 10 may then act as the electrophile and react with another S-protected cysteine residue to generate the disulfide 11 and the inert byproduct diphenyl sulfide (12). This final step is analogous to the reaction of a sulfenyl iodide as discussed in Section 6.1.1.2.1. 

Optical resolution of the dithiol The problem of optical resolution of racemic disulfides has been successfully tackled (77JOC925). The bis-thiol (128) was reacted with a chiral bis-sulfenyl chloride, the resultant mixture of diastereomers separated, and the product reconverted to the starting material by NaBH4 reduction. Subsequent iodine oxidation gave the chiral epidisulfides (Scheme 40). 

A concerted elimination-cyclization mechansim, involving a sulfenyl halide in a 1,3-butadiene-1-thio system, is the most probable mechanism for the formation of benzo[6 Jthiophenes from cinnamic acids or 4-aryl-2-butanones by treatment with thionyl chloride. The reactions shown in Scheme 5 have been carefully worked out, and the intermediates isolated (75JOC3037). The unique aspect of this synthesis is the reduction of the sulfinyl chloride (a) by thionyl chloride to form the sulfenyl chloride (b). The intermediate (b) was isolated and converted in pyridine to the 3-chlorobenzo[6]thiophene-2-carbonyl chloride in 36% yield (73TL125). The reaction is probably initiated by a sulfenyl ion attack on the aromatic ring, since it is promoted by electron-releasing groups para to the site of ring closure. For example, when X in (36) was N02, a 23% yield of (37), a mixture of 5-and 7-nitro derivatives, was obtained, but when X in (36) was OMe, a 54% yield of (37) was obtained, contaminated with some 3,4-dichloro-5-methoxybenzo[6]thiophene-2-carboxylic acid. 

Thiiranes can be formed directly and stereospecifically from 1,2-disubstituted alkenes by addition of trimethylsilylsulfenyl bromide, formed at -78 C from reaction of bromine with bis(trimethylsilyl) sulfide (Scheme 7).12 A two-step synthesis of thiiranes can be achieved by addition of succinimide-A/-sulfe-nyl chloride or phthalimide-A -sulfenyl chloride to alkenes followed by lithium aluminum hydride cleavage of the adducts (Scheme 8).13 Thiaheterocycles can also be formed by intramolecular electrophilic addition of sulfenyl chlorides to alkenes, e.g. as seen in Schemes 914 and 10.13 Related examples involving sulfur dichloride are shown in Schemes 1116 and 12.17 In the former case addition of sulfur dichloride to 1,5-cyclooctadiene affords a bicyclic dichloro sulfide via regio- and stereo-specific intramolecular addition of an intermediate sulfenyl chloride. Removal of chlorine by lithium aluminum hydride reduction affords 9-thiabicyclo[3.3.1]nonane, which can be further transformed into bicyclo[3.3.0]oct-1,5-ene.16... 

A three-step reaction sequence starting from 3,4-dichloro-l,2,5-thiadiazole (81) led to the formation of the stable sulfur-nitrogen radical [l,2,5]thiadiazolo[3,4-fl ][l,3,2]dithiazol-l-ium (14). Treatment of thiadiazole (81) with two equivalents of Na2S afforded the sodium salt (82), which reacted with chlorine gas to furnish the sulfenyl chloride (83). The reaction of this intermediate (83) with trimethylsilyl azide yielded the salt (84), reduction of which afforded the novel pentalene analogue (14) as black needle-like crystals (Scheme 18) <89AG(E)920>. 

Symmetrical 3,5-dialkyl-l,2,4-trithiolanes (178) can be synthesized in reasonable yield by chlorination of dialkyl disulfides (175) to a-chiloroalkyl sulfenyl chlorides (176), which are then reacted with potassium iodide to give di-a-chloroalkyl disulfides (177). Subsequent cyclization with sodium sulfide gave (178) (72T3489). When (176) was treated with one molar equivalent of sodium sulfide, the reductive dimerization and cyclization was effected in one step (78HCA1404). Treatment of perfluoropropene with sodium hydrogen sulfide in THF resulted in the formation of 3,5-bis(2,2,2-trifluoroethyl)-l,2,4-trithiolane (179) (72IZV2517). 

A synthesis of the 2,3-dioxabicyclo[3.3.1]nonane system 24, which is present in the antimalarial yingzhaosu, involves an initial thiol-limonene co-oxygenation reaction followed by reduction of a hydroperoxide by PPh3 and a sulfenyl —> sulfonyl oxidation <02T2449>. 

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