Deuterium-labeled compounds are widely used in drug discovery and absorption, distribution, metabolism, and excretion (ADME) studies, yet precise control over the site and extent of deuterium incorporation remains challenging in organic synthesis. Here, we report a nickel-catalyzed defluorinative deuteration of polyfluoroarenes using methanol-d (MeOD) as a readily available deuterium source. This method enables highly selective deuteration at C-F sites and programmable installation of one-to-four deuterium atoms. Mechanistic studies reveal an interesting cooperative effect in Ni-catalyzed C-F bond activation, where the lithium salts can improve the reactivity and selectivity toward C-F bond activation, while zinc salts can facilitate the transmetalation and suppress over-reduction. This approach establishes polyfluoroarenes as versatile feedstocks for precision deuterium labeling and the synthesis of deuterium-enriched fluoroarenes for drug development and metabolic studies. It represents a new synthetic platform for the selective synthesis of multideuterated compounds from commercially available starting materials.
Liu et al. (Mon,) studied this question.