Electrochemical Alkyl Displacement of Thioethers for Streamlined Trideuteromethylation.

Abstract

Deuterated compounds exhibit significant pharmacokinetic advantages and have been widely applied in drug discovery. Trideuteromethyl-containing compounds represent a substantial portion of both approved deuterated drugs and those in development. Traditional approaches to incorporate trideuterated methyl group with trideuterated methyl sources (such as iodomethane-d3, dimethyl sulfate-d6) require preactivated synthetic precursor, limiting the application for the late-stage trideuteromethyl group incorporation of pharmaceutical molecules. Herein, we develop an electrochemical approach for late-stage trideuteromethyl incorporation of thioether by using stoichiometric methanol-d4 as the trideuteromethyl isotopic source via a sulfide alkyl displacement. This protocol features operational simplicity, selectivity, and scalability, enabling direct alkyl modification of various aryl alkyl sulfides as well as gram-scale production of trideuteromethyl drugs without the need for synthetic precursors. Mechanistic studies show that the in-situ generated sulfonium salt was the key intermediate. A series of control experiments reveals that alkanes as the departing moiety are the key to alkyl displacement and precise late-stage trideuteration.