B(C6F5)3-catalyzed selective C–H chalcogenation of arenes and heteroarenes

Abstract

The synthesis of organochalcogenides remains a valuable area of research due to their widespread biological applications, particularly in pharmaceuticals. Herein, our study details the B(C₆F₅)₃-catalyzed Csp²–H functionalization of diverse arenes, heteroarenes, and pharmacophores with thiosuccinimides or selenosuccinimides, providing selective access to chalcogenated products. This protocol enables the selective late-stage chalcogenation of drug molecules such as the anti-inflammatory drug naproxen, the estrogen steroid hormone estradiol derivatives, and the industrially relevant trifluoromethylthiolation reaction. Furthermore, this C–S coupling methodology provides a facile and metal-free route to synthesize vortioxetine, an antidepressant drug, and a plethora of significant organic motifs. Detailed NMR, EPR analyses, and density functional theory (DFT) computational studies indicate that the elongation of the thiosuccinimide N–S bond is assisted by a boron-centered adduct, which then leads to a stable ion pair with an arene. The EPR analysis shows that a transient radical pair, potentially an off-cycle species, is not directly involved in the catalytic process.