2-Pyridinesulfenyl Bromide

(X = Br)

[66715-65-9]  · C5H4BrNS  · 2-Pyridinesulfenyl Bromide  · (MW 190.07) (X = Cl)

[59089-57-5]  · C5H4ClNS  · 2-Pyridinesulfenyl Chloride  · (MW 145.62)

(electrophilic sulfenylation agents used for unsymmetrical disulfide synthesis,1 deprotection of specific thiol protecting groups,2 enolate sulfenylation,3 and N-sulfenylation of amides4)

Physical Data: yellow powder.

Solubility: normally used in anhydrous HOAc; may also be used in dry DMF; rapidly decomposes in the presence of moisture.

Preparative Method: the 2-pyridinesulfenyl halides are generated as needed from 2,2-Dipyridyl Disulfide. Treatment of 2,2-dipyridyl disulfide in petroleum ether or dichloromethane with either Chlorine or Bromine at 20 °C results in 2-pyridinesulfenyl halide generation after 1-2 h. Isolation through evaporation of solvent provides a yellow powder with a pungent odor.1,2,5

Handling, Storage, and Precautions: the 2-pyridinesulfenyl halides demonstrate instability, especially in the presence of moisture. Although the isolated powder may tolerate short-term storage in a well sealed vial or ampule, most work involving these reagents has utilized freshly prepared material. Solutions in anhydrous HOAc are reported to be stable for several hours.2 The reagent is corrosive and must be handled accordingly. The reaction with moisture generates HCl and 2-pyridylsulfenic acid (stench, toxic). Handling of these reagents should be confined to a fume hood.

Deprotection of the Thiol Group.

The initial application of 2-pyridinesulfenyl chloride as a deprotection reagent focused on a synthesis program based on cysteine.2 Specifically, cysteine residues protected as the trityl, diphenylmethyl, or acetamidomethyl derivatives, or as the t-butyl sulfide or the t-butyl disulfide, react with 2-pyridinesulfenyl chloride to generate a mixed disulfide (eq 1).

This reaction occurs rapidly at room temperature and can be conducted to utilize the endpoint provided by the bright yellow 2-pyridinesulfenyl chloride solution. Deprotection under these conditions tolerates 10-20 mol % of Triethylamine for the protection of the Boc group from any HCl generated from residual moisture. 2-Pyridinesulfenyl chloride avoids the use of strong acid (TFA, HBr) conditions that are associated with the removal of the listed protecting groups. The resulting mixed disulfide is stable to acids, but is unstable to alkali. Several equivalents of 2-Mercaptoethanol generates a cysteine thiol group from the mixed disulfide.

Unsymmetrical Disulfides.

The mixed disulfide indicated in eq 1 provides a route to other mixed disulfides through the reaction of a thiol with the intermediate disulfide in HOAc. Unsymmetrical 2-pyridyl disulfides result from the reaction of 2-pyridinesulfenyl chloride and a thiol (eq 2).1,5

Enolate Sulfenylation.

2-Pyridinesulfenyl bromide provides an opportunity for regiocontrol in the synthesis of methyl dehydrojasmonate.3 A 2,3-disubstituted cyclopentenone is regiochemically activated through formylation, resulting in a b-diketo enolate. 2-Pyridinesulfenyl bromide reacts with the enolate and promotes a deformylation (eq 3). 2,2-Dipyridyl disulfide also provides the desired product, but in a lower yield. Attempts to trap the enolate with dimethyl disulfide or diphenyl disulfide are not successful. Subsequent oxidation and sulfoxide thermolysis provides the desired cyclopentenone product.

N-Sulfenylation of Amides.

A solution of 2-pyridinesulfenyl bromide in DMF has been used to sulfenylate a deprotonated amide (eq 4).4

1. (a) Senter, P. D.; Pearce, W. E.; Greenfield, R. S. JOC 1990, 55, 2975. (b) Another reagent used as an electrophilic sulfenylation agent is N-(2-pyridinesulfenyl)morpholine: Barton, D. H. R.; Hesse, R. H.; O'Sullivan, A. C.; Pechet, M. M. JOC 1991, 56, 6697, 6702.
2. Castell, J. V.; Tun-Kyi, A. HCA 1979, 62, 2507.
3. Dubs, P.; Stüssi, R. HCA 1978, 61, 998.
4. Tachikawa, R.; Wachi, K.; Sato, S.; Terada, A. CPB 1981, 29, 3529.
5. Shval'e, A. F.; Ofitserov, V. I.; Samukov, V. V. ZOB 1985, 55, 2152 (JGU 1985, 55, 1909).

Edward J. Adams

E. I. DuPont de Nemours & Co., Newark, DE, USA

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