Site-Selective Silver-Catalyzed C-H Bond Deuteration of Five-Membered Aromatic Heterocycles and Pharmaceuticals

Catalytic methods for the direct introduction of hydrogen isotopes into organic molecules are essential to the development of improved pharmaceuticals and to the alteration of their absorption, distribution, metabolism, and excretion (ADME) properties. However, the development of homogeneous catalysts for selective incorporation of isotopes in the absence of directing groups under practical conditions remains a long-standing challenge. Here, we show that a phosphine-ligated, silver-carbonate complex catalyzes the site-selective deuteration of C-H bonds in five-membered aromatic heterocycles and active pharmaceutical ingredients that have been resistant to catalytic H/D exchange. The reactions occur with CH3OD as a low-cost source of the isotope. The silver catalysts react with five-membered heteroarenes lacking directing groups, tolerate a wide range of functional groups, and react in both polar and nonpolar solvents. Mechanistic experiments, including deuterium kinetic isotope effects, determination of kinetic orders, and identification of the catalyst resting state, support C-H bond cleavage from a phosphine-ligated, silver-carbonate intermediate as the rate-determining step of the catalytic cycle.

Automated summary

A new phosphine-ligated, silver-carbonate complex catalyst has been developed for the site-selective deuteration of C-H bonds in five-membered aromatic heterocycles and active pharmaceutical ingredients. The reactions occur using CH3OD as a low-cost source of the isotope and show tolerance towards a wide range of functional groups in both polar and nonpolar solvents. Mechanistic experiments support C-H bond cleavage from a phosphine-ligated, silver-carbonate intermediate as the rate-determining step of the catalytic cycle.