Phenyl Benzenethiosulfonate1

[1212-08-4]  · C12H10O2S2  · Phenyl Benzenethiosulfonate  · (MW 250.36)

(sulfenylating agent)

Physical Data: mp 38-42 °C; bp 125 °C/0.01 mmHg.

Form Supplied in: white solid.

Preparative Method: prepared by oxidation of Diphenyl Disulfide with 30% Hydrogen Peroxide (72%).2

Purification: crystallization from methanol (mp 36-37 °C).2

Introduction.

Phenyl benzenethiosulfonate (PhSSO2Ph) is a preferred sulfenylating reagent to Methyl Methanethiosulfonate and Methyl p-Toluenethiosulfonate because it possesses higher intrinsic reactivity and because, at times, the latter reagents are not particularly effective, possibly due to the acidity of their methyl and p-methyl groups which are activated by the thiosulfonate group.2 PhSSO2Ph is also a more reactive sulfenylating agent than the widely used Diphenyl Disulfide, and the reactions are somewhat cleaner and less odoriferous than with PhSSPh. This reactivity difference gives PhSSO2Ph certain advantages over PhSSPh. For example, it increases the regioselectivity of sulfenylation of 2-methylcyclohexanone (eq 1).3 This regioselectivity corresponds to the kinetic selectivity in enolate generation.

Preparation of 1,2-Diketones via b-Keto Sulfides.2

Direct sulfenylation of cyclic ketone enolates with PhSSO2Ph yields b-keto sulfides which are acetoxylated by Lead(IV) Acetate in warm benzene. The b-keto acetoxy sulfide represents a monoprotected form of a 1,2-dicarbonyl compound. Oxidation and sulfoxide elimination produce, regiospecifically, the monoenol acetate of the diketone. Treatment with I2 in MeOH gives the monoacetal. Exposure to basic H2O2 leads to the ring-cleaved diacids which can also be obtained directly from the b-keto sulfides upon treatment with basic H2O2 (eq 2). Application of this methodology is exemplified by eqs 3 and 4, which show stereo- and regiospecific sulfenylation, respectively.

1,2-Carbonyl Transposition via Bissulfenylation.

Yee and Schultz have modified the above method of Trost to achieve 1,2-carbonyl transposition via bissulfenylation of the lithium enolate generated with Lithium 2,2,6,6-Tetramethylpiperidide (eq 5).4 The method has been employed successfully in a total synthesis of a more complex molecule, (±)-lycoramine, in which the carbonyl transposition was accomplished in 64% overall yield.5

Preparation of 2-(Phenylthio)alkanoic Acids and Esters.

2-(Phenylthio)alkanoic acids and esters are synthesized by successive treatment of substituted malonic esters with Sodium Ethoxide and PhSSO2Ph, followed by alkaline hydrolysis which causes concurrent decarboxylation (eq 6).6 Ogura et al. have reported7 a more convenient method for preparation of 2-(phenylthio)alkanoic esters from the 2-acetylalkanoate (eq 7).

PhSSO2Ph can be replaced with PhSSPh as the sulfenylating agent in this transformation, but the reaction with PhSSPh takes much longer. Advantages of the methods described in eqs 6 and 7 over others such as the sulfenylation of alkanoic acids and esters and the alkylation of (phenylthio)acetic acid are: (1) simplicity of the procedure; (2) efficiency and convenience of using an inexpensive base (EtONa) and EtOH as solvent with high product yields; and (3) no bissulfenylation. Moreover, the method described in eq 7 allows direct a-sulfenylation of 2-acetylalkanoates which also contain an additional unprotected keto group (see Methyl Methanethiosulfonate).

Sulfenylated Enolates for Aldol Condensation.

Bissulfenylation followed by monodesulfenylation with a Grignard reagent cleanly provides magnesium enolates of a-phenylthiocarbonyl compounds for aldol condensation (eq 8).8 The Grignard reagent serves as a nucleophile towards sulfur, not the carbonyl group, to give a clean mixture of the magnesium enolate contaminated only by the byproduct, alkyl phenyl sulfide. In cases where the competitive attack at the carbonyl may become severe, addition of 5 mol % of CuBr.SMe2 (see Copper(I) Bromide) facilitates the chemoselectivity toward sulfur. A related desulfenylation reaction induced by Lithium Diisopropylamide from a bissulfenylated cyclic imide has also been reported.9

Dimethyl [(Phenylthio)methyl]phosphonate.

Sulfenylation of dimethyl a-lithiomethylphosphonate with PhSSO2Ph is a convenient method for synthesis of the title compound. Diethyl ether is a superior solvent to THF in this sulfenylation reaction (eq 9).10 The method is applicable for the preparation of alkyl- and allylthiomethylphosphonates.

Formation of Symmetrical or Unsymmetrical Sulfides.

The nucleophilic attack of alkyl- and aryllithiums at the sulfenyl S atom in phenyl benzenethiosulfonate provides a convenient method for the synthesis of both symmetrical and unsymmetrical aromatic sulfides in excellent yields (>90%).11 The example in eq 10 shows that the reaction is not affected by the steric bulk of the lithiated species.

Stereoselective Synthesis of Ethyl (2E,4E)-Alkadienoates from Ethyl Sulfolane-2-Carboxylate.

a,b;g,d-Unsaturated esters are conveniently synthesized with high (E,E) selectivity from ethyl sulfolane-2-carboxylate through alkylation and oxidation followed by SO2 extrusion from the 3-sulfolene derivatives resulting from base-induced isomerization.12 This efficient method has been applied to the synthesis of an insecticidal compound, pellitorine, by simple operations (eq 11).

The optimal conditions for general application of this procedure are: (1) RI/PhSSO2Ph or RBr/PhSCl combination for the alkylation/sulfenylation step and THF as solvent; and (2) m-Chloroperbenzoic Acid as oxidant of the sulfide formed (critical). Alkyl bromides and alkyl tosylates can also be used in combination with PhSSO2Ph. Secondary alkyl halides, which generally do not react with the a-anion of 3-sulfolene, can also be used with this method.

Regioselective Vinylcarbene Formation and [3 + 2] Cycloaddition under Mild Conditions.

Phenylthio-substituted cyclopropenone acetals undergo highly regioselective vinylcarbene formation below room temperature to permit the thermal [3 + 2] cycloaddition to take place under extremely mild conditions (eq 12).13 The method is useful for the synthesis of substituted cyclopentenone derivatives.

N-Sulfinyloxazolidinones, a New Class of Chiral Sulfinyl Transfer Reagents.14

N-Sulfinyloxazolidinone reagents are synthesized either by sulfinylation of the metalated oxazolidinones or by oxidation of the derived N-sulfenimides, to afford the diastereomeric N-sulfinyloxazolidinones which are readily purified by chromatography (eq 13).

These sulfinylating agents react with a wide range of nucleophiles such as Grignard reagents, enolates, lithium alkoxides, or metalated amides, with inversion of configuration at the sulfur center, to afford chiral sulfoxides, sulfinate esters, and sulfinamides in high yields and enantioselectivities (eq 14). This family of chiral sulfinylating agents is at least 100 times more reactive than the corresponding menthyl sulfinate esters toward Grignard reagents.

Related Reagents.

Benzenesulfenyl Chloride; Diphenyl Disulfide.


1. Trost, B. M. CRV 1978, 78, 363.
2. Trost, B. M.; Massiot, G. S. JACS 1977, 99, 4405.
3. Trost, B. M.; Salzmann, T. N.; Hiroi, K. JACS 1976, 98, 4887. See also ref 2.
4. Yee, Y. K.; Schultz, A. G. JOC 1979, 44, 719.
5. Schultz, A. G.; Yee, Y. K.; Berger, M. H. JACS 1977, 99, 8065.
6. Ogura, K.; Itoh, H.; Morita, T.; Sanada, K.; Iida, H. BCJ 1982, 55, 1216.
7. Ogura, K.; Sanada, K.; Takahashi, K.; Iida, H. TL 1982, 23, 4035.
8. Trost, B. M.; Mao, M. K. T. TL 1980, 21, 3523.
9. Seitz, D. E.; Needham, F.-L. JHC 1983, 20, 799.
10. Smith, J. G.; Finck, M. S.; Kontoleon, B. D.; Trecoske, M. A.; Giordano, L. A.; Renzulli, L. A. JOC 1983, 48, 1110.
11. Palumbo, G.; Ferreri, C.; D'ambrosio, C.; Caputo, R. PS 1984, 19, 235.
12. Saigo, K.; Kudo, K.; Hashimoto, Y.; Kihara, N.; Hasegawa, M. CL 1989, 1203.
13. Tokuyama, H.; Isaka, M.; Nakamura, E. JACS 1992, 114, 5523.
14. Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy, J.; Cherry, D. JACS 1992, 114, 5977.

Kumiko Takeuchi

Eli Lilly and Company, Indianapolis, IN, USA



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