Dithiofunctionalization: A Versatile Approach for Constructing Complex Disulfides from Alkenes and Alkynes

Abstract

Disulfide bonds are key structural motifs in bioactive natural products, linker chemistry, and functional materials; however, the selective synthesis of unsymmetrical disulfides remains a significant challenge. In particular, the dithiofunctionalization of C-C unsaturated bonds is underdeveloped, despite its promise for introducing additional molecular complexity. In this work, we report an acid-mediated dithiocyclization strategy for the preparation of heterocycle-appended unsymmetrical disulfides using N-(morpholine-4-dithio)phthalimide. The method applies broadly to nucleophile-tethered alkynes and olefins, affording benzofurans, lactones, cyclic ethers, and pyrrolidines, and it is also amenable to three-component couplings with olefins and TFA. Owing to its wide applicability for 1,2-difunctionalization of C-C unsaturated bonds and the bilateral reactivity of N-(morpholine-4-dithio)phthalimide, this approach provides modular access to heterocycle-appended unsymmetrical disulfides via two consecutive C-SS bond formations. The utility of this method is exemplified by the efficient hybridization of natural product derivatives (e.g., Corsifuran C, Boivinianin A) with bioactive agents (e.g., trimetazidine), highlighting its potential in linker chemistry and drug discovery.