Electricity-driven site-selective deuteration of pharmaceuticals

Abstract

Precision deuteration at metabolically vulnerable sites of pharmaceuticals can enhance drug stability and therapeutic efficacy, yet existing methods often suffer from poor selectivity and inefficiency. Here, we report an electricity-driven bromine-mediated deuteration strategy that enables late-stage site-selective deuteration of pharmaceuticals using D₂O as the deuterium source. This approach involves a two-step process: (i) bromination of labile C–H bonds using Br₂, followed by (ii) electricity-driven deuterodebromination using a palladium membrane reactor. This design leverages in situ Br₂ generation at the anode and selective deuterium permeation through the palladium membrane cathode, thereby significantly improving atom economy and energy efficiency. Our method achieves nearly complete conversion and >90% deuterium incorporation for a range of aryl, heteroaryl, benzylic, and unactivated alkyl bromides, including ten marketed drug molecules. Furthermore, gram-scale synthesis of D-clonidine demonstrates the scalability of this approach. By integrating high selectivity, broad substrate scope, and operational efficiency, this method offers a practical solution for deuterated drug synthesis, with potential applications in pharmaceutical development and metabolic stabilization.