Deuterodehalogenation Under Net Reductive or Redox-Neutral Conditions Enabled by Paired Electrolysis

Interest in deuterated de novo active pharmaceutical ingredients (APIs) is increasing due to the release of the first FDA approved deuterated drug, deutetrabenazine. Deuteration also holds promise for kinetic isotope effect (KIE) regulated fine-tuning of active pharmaceutical ingredient performance. As such, methods for highly selective deuteration of organic molecules—particularly at positions that are prone to undergoing biochemical reactions—are highly desirable. Herein, we present an electrochemical method for the selective deuterodehalogenation of benzylic halides via a radical-polar crossover mechanism, using inexpensive deuterium oxide (D2O) as the deuterium source. We demonstrate broad functional group compatibility across a range of aryl and heteroaryl benzylic halides. Furthermore, we uncover a sequential paired electrolysis regime, which permits switching between net reductive and overall redox-neutral reactions of sulfur-containing substrates simply by changing the identity of the sacrificial reductant employed.