Nickel-free cross-electrophile coupling of unactivated alkyl bromides with thiosulfonates and sulfinyl sulfones

Abstract

An unusual zinc-promoted reductive coupling between alkyl bromides and thiosulfonates under nickel-free conditions is described. This practical strategy provides an attractive approach to access a series of structure-varied sulfides, which are privileged motifs in ligands, pharmaceuticals and materials. Moreover, a one-step synthesis of alkyl-substituted thiosulfonates directly from readily accessible alkyl bromides, S powder and PhSO₂Na is developed under mild reaction conditions. Scale-up reaction, late-stage thiolation of biologically active molecules and downstream synthesis have also been achieved to further demonstrate the synthetic utility of the current method. The mechanistic studies reveal that an isolable zinc thiolate acts as the crucial intermediate coupling with alkyl electrophiles via a nucleophilic pathway. The present findings offer new insights into understanding the roles of Zn in the reductive formation of C–S bonds and an opportunity to explore the potential applications of zinc thiolates in organic synthesis.