Chemoselective Benzylic C–H Deuteration Using Deuterium Gas

Chemoselective incorporation of hydrogen isotopes is a useful tool for drug discovery and mechanistic investigation. While late-stage C–H functionalization via hydrogen isotope exchange (HIE) offers a straightforward route to isotopically labeled compounds, existing methods often use deuterated solvents which are not feasible for tritium labeling. Hence, direct use of simple deuterium gas for isotopic labeling is highly desirable. Herein, we report a palladium-catalyzed protocol for benzylic C–H deuteration using deuterium gas as the isotope donor and tert-butyl hydroperoxide (TBHP) as the oxidant to assist the turnover of catalysts. Compared to the previous protocols using deuterium gas, the use of nondeuterated protic solvents expands the scope of substrates that are only soluble in protic solvents. Notably, deuterium is exclusively incorporated into the benzylic position without scrambling on the aromatic ring.