A One-Pot Synthesis of Vinyl Sulfoximines and Their Kinetic Evaluation as Tunable Covalent Warheads

Abstract

Vinyl sulfoximines have emerged as promising electrophilic warheads for targeted covalent inhibitors owing to their tunable S(VI) framework, yet their broader application has been hindered by the lack of practical synthetic methods and systematic evaluation of their intrinsic electrophilicity. Herein, we report a mild one-pot oxidative synthesis of vinyl sulfoximines from readily accessible β-chlorosulfides, providing efficient access to structurally diverse vinyl sulfoximines. The protocol exhibits broad substrate scope and functional-group tolerance, affording the desired products in moderate to excellent yields. Systematic kinetic studies with amino acid derivatives revealed a pronounced preference for thiol nucleophiles and established quantitative structure–reactivity relationships for tuning the electrophilic reactivity of vinyl sulfoximines. By combining practical synthetic access with systematic warhead characterization, this work establishes vinyl sulfoximines as tunable electrophilic motifs for covalent inhibitor design.