Visible-Light-Induced Deuteration of Benzylic C(sp3)─H Bonds in D2O via Heterolytic Dissociation Mode.

CD3-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 (D2, DMSO-d6, acetone-d6), metal complex catalysts, or hazardous operations (e.g., ≥120 °C and 10 bar H2). Here, we report a visible-light-induced deuteration strategy for benzylic C(sp3)-H bonds using a Pd/C3N4 photocatalyst in D2O 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 CD3-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-Dδ- and N-Dδ+) from heterolytic dissociation at the interface between Pd nanoparticles and the C3N4 support could initiate deuteration of benzylic C(sp3)-H bonds in D2O.