Divergent Radical and Ionic Electroreductive Regulation for Disulfuration

Disulfides are pivotal chemical motifs in life science, biomedicine, and materials science; nevertheless, their efficient construction arouses tremendous challenges due to inherent fragility to redox environments. Herein, we disclosed an electroreductive disulfuration protocol, leveraging readily accessible electrophiles to achieve divergent coupling via the tetrasulfide radical anion [^tBuSSSS^tBu]^•- with tunable radical and ionic routes, respectively. The distinct reductive potential of the electrophilic partners relative to the tetrasulfide reduction potential (^tBuSSSS^tBu, E_p = -1.08 V vs Ag/AgCl) served as the electrochemical switch. The dissociation of the [^tBuSSSS^tBu]^•- generated from single-electron reduction regulated the reaction pathway toward radical (favored by higher potential electrophiles, E_p = -0.8 to -1.5 V vs Ag/AgCl) and ionic (favored by lower potential electrophiles, E_p = -2.0 to -3.0 V vs Ag/AgCl) pathways. This protocol afforded straightforward access to unsymmetric disulfides with diversely functional pharmaceutical, agrochemical, and natural product scaffolds. Density functional theory (DFT) calculations elucidated the crucial role of the central S-S bond lability from tetrasulfide for two distinct mechanistic pathways. Gram-scaled continuous flow synthesis showcased the operational robustness and scalability of this protocol. The potent antibacterial activity observed against Staphylococcus aureus underscored its great potential for accelerating the discovery of disulfide-based therapeutic agents.