γ-Selective Deuteration of Unactivated C(sp3)–H Bonds of Aliphatic Amines via Pd Catalysis in D2O

Abstract

Abstract Selective γ-deuteration of unactivated C(sp3)–H bonds in aliphatic amines is achieved using D2O as the sole deuterium source via Pd catalysis with 3-formyl-2-pyridone as a transient directing group. The reaction proceeds in aqueous medium without acidic or fluorinated co-solvents. Branched and cyclic amines are deuterated regioselectively at γ-methyl sites (up to 89% D). The utility is demonstrated by concise synthesis of deuterated scaffolds (rimantadine, ethambutol, and dobutamine) otherwise inaccessible by conventional methods, together with a one-pot γ-deuteration/γ-arylation sequence. Mechanistic studies establish that the pyridone moiety dominates the CMD step and intrinsically favors H/D exchange.