Cesium Amide‐Catalyzed Selective Deuteration of Benzylic C‐H Bonds with D2 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 D2 and T2 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 D2 gas. The reaction proceeds through a kinetic deprotonative equilibrium that establishes an exchange pathway between C−H bonds and D2 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. Cesium amide catalyst establishes a new bridge between benzylic C−H bonds and D2/T2, facilitating deuteration and tritiation of pharmaceutical compounds.