Cesium Amide‐Catalyzed Selective Deuteration of Benzylic C‐H Bonds with D ₂ and Application for Tritiation of Pharmaceuticals

Hydrogen isotope exchange (HIE) represents one of the most attractive labeling methods to synthesize deuterium- and tritium-labeled compounds. Catalytic HIE methods that enable site-selective C-H bond activation and exchange labeling with gaseous isotopes D-2 and T-2 are of vital importance, in particular for high-specific-activity tritiation of pharmaceuticals. As part of our interest in exploring s-block metals for catalytic transformations, we found CsN(SiMe3)(2) to be an efficient catalyst for selective HIE of benzylic C-H bonds with D-2 gas. The reaction proceeds through a kinetic deprotonative equilibrium that establishes an exchange pathway between C-H bonds and D-2 gas. By virtue of multiple C-H bonds activation and high activity (isotope enrichment up to 99 %), the simple cesium amide catalyst provided a very powerful and practically convenient labeling protocol for synthesis of highly deuterated compounds and high-specific-activity tritiation of pharmaceuticals.