Visible‐Light‐Induced Deuteration of Benzylic C( sp 3 )─H Bonds in D 2 O via Heterolytic Dissociation Mode

ABSTRACT CD 3 ‐containing molecules are promising as new drug candidates in the pharmaceutical industry. However, conventional synthetic routes via hydrogen isotope exchange (HIE) usually require expensive isotopic sources (D 2 , DMSO‐ d 6 , acetone‐ d 6 ), metal complex catalysts, or hazardous operations (e.g., ≥120 °C and 10 bar H 2 ). Here, we report a visible‐light‐induced deuteration strategy for benzylic C( sp 3 )–H bonds using a Pd/C 3 N 4 photocatalyst in D 2 O under 410 nm irradiation and 1 bar Ar at room temperature. The protocol enabled the late‐stage benzylic deuteration of 54 alkyl(hetero)arenes (containing diverse electron‐withdrawing or electron‐donating groups) with excellent deuteration incorporation up to 99%, including highly functionalized natural products and pharmaceuticals. The successful gram‐scale synthesis of a CD 3 ‐containing drug (2.17 g, 10 mmol) also demonstrated the scalability and sustainability of our photo‐induced approach. Mechanism studies revealed that active D species (Pd–D δ− and N–D δ+ ) from heterolytic dissociation at the interface between Pd nanoparticles and the C 3 N 4 support could initiate deuteration of benzylic C( sp 3 )–H bonds in D 2 O.