Alkali Metal Amide–Catalyzed Deuteration and Tritiation of Pharmaceuticals

Deuterium- and tritium-labeled compounds play a crucial role in various studies throughout the drug discovery and development process. Although numerous hydrogen isotope exchange (HIE) labeling methods have been developed for deuteration and tritiation of organic molecules, most of them relays heavily on transition metal catalysts. It still remains highly desirable to develop complementary and operationally simple methods to enable HIE of a wide range of C–H bonds while using readily accessible catalysts and isotope sources of deuterium and tritium. To this end, we report the deuteration and tritiation of arenes and heteroarenes, including pharmaceutical molecules, by alkali metal amide catalysts MN(SiMe3)2 (M = K, Rb, Cs). The reactions proceed through a kinetic deprotonative equilibrium that establishes an exchange pathway between C–H bonds and D2 or T2 gas. The use of alkali metal amides in combination with D2/T2 promoted HIE of both benzylic and aromatic C–H bonds of various arenes, and allowed high regioselectivity and high isotope enrichment (up to 99%) for a large scope of organic compounds and pharmaceuticals. In view of the abundance, low cost, and low toxicity of alkali metals and the broad availability of D2 and T2 gas, the present combination of alkali metal amide catalysts and D2/T2 provided a practical and sustainable protocol for HIE labeling method.