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

Disulfide bonds are essential 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 an additional molecular complexity. Herein, we report an acid-mediated dithiocyclization that exploits the bilateral reactivity of N-(morpholine-4-dithio)phthalimide , enabling modular access to heterocycle-appended unsymmetrical disulfides via two consecutive C–SS bond formations. The method applies broadly to nucleophile-tethered alkynes and olefins, affording benzofurans, lactones, cyclic ethers, and pyrrolidines, and being also amenable to three-component couplings with olefins and TFA. Owing to its broad applicability to 1,2-difunctionalization of C–C double and triple bonds without perturbing the phthalimide moiety, this strategy provides a versatile platform for rapid access to unsymmetrical disulfides. This utility is exemplified by the efficient hybridization of natural product derivatives (e.g., Corsifuran C, Boivinianin A) with bioactive agents (e.g., trimetazidine), highlighting the potential of this method in linker chemistry and drug discovery.