Zinc-Promoted Reductive Thiolation of Sulfonated Alcohols to Access C(sp3)-Enriched Sulfides.

Abstract

We report a Zn-mediated reductive cross-coupling of alkyl sulfonates with N-sulfenylsuccinimides or thiosulfonates for the efficient construction of C(sp3)-enriched sulfides. This method provides rapid access to structurally diverse unsymmetrical alkyl sulfides with broad functional group tolerance. The synthetic utility of this protocol is further demonstrated through scalable synthesis, late-stage modification of complex bioactive molecules, and downstream derivatizations. Preliminary mechanistic studies suggest the formation of a highly reactive zinc thiolate intermediate, generated from the reaction of Zn with the sulfur-transfer reagent. The in situ-formed zinc thiolates exhibit considerable nucleophilic reactivity for SN2-type thiolation of a series of primary and secondary alkyl sulfonates that are readily prepared from abundant alkyl alcohols.