Electrochemical Alkyl Displacement of Thioethers for Streamlined Trideuteromethylation

Abstract

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‐ d 3 , dimethyl sulfate‐ d 6 ) 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‐ d 4 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.