Nucleophilic Attack at Sulfoxide: The Methanethiol-Mediated Cleavage of a Thiane 1-Oxide

摘要

Nucleophilic attack on tricoordinate sulfur has been reported in a large number of reactions, including sulfoxide racemization in acidic solution, the Andersen procedure for the synthesis of chiral sulfoxides, and the asymmetric synthesis of sulfinamides. In the latter two cases, the reactions were reported to undergo a Walden inversion at the reaction center, presumably via an incipient σ-sulfurane intermediate. In the majority of these examples of nucleophilic attack at tricoordinate sulfur, the leaving group is a suitably activated heteroatom. We now report a novel example of a nucleophilic substitution wherein the leaving group is a stabilized carbanion, an enolate of a dithioate ester, and the nucleophile is methanethiolate. Recently, Brown et al. reported that during the synthesis of aprikalim (2), a member of a class of pharmacologically active agents classified as potassium channel openers, exposure of tetrahydro-S-methyl-2-(3-pyridinyl)-2H-thiopyran-2-carbodithioate 1-oxide (1) to aqueous methylamine produced 2 in 40% yield as the sole isolated product. Upon repeating this experimental protocol, we discovered that in addition to 2, a second product, the novel disulfide N-methyl-α-[4-(methyldithio)-butyl]-3-pyridineethanethioamide (3) was formed. We believe that 3 was formed via a sequence of reactions including a methanethiol-mediated ring fragmentation of the thiane oxide present in 1. In this report, the identification and de novo synthesis of 3 together with studies supporting our mechanistic hypothesis are described.