Cesium Amide‐Catalyzed Selective Deuteration of Benzylic C‐H Bonds with D₂ and Application for Tritiation of Pharmaceuticals

Abstract

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 CÀ H bond activation and exchange labeling with gaseous isotopes D 2 and T 2 are of vital importance, in particular for highspecific-activity tritiation of pharmaceuticals. As part of our interest in exploring s-block metals for catalytic transformations, we found CsN(SiMe 3 ) 2 to be an efficient catalyst for selective HIE of benzylic CÀ H bonds with D 2 gas. The reaction proceeds through a kinetic deprotonative equilibrium that establishes an exchange pathway between CÀ H bonds and D 2 gas. By virtue of multiple CÀ 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.