Directed Aromatic Deuteration and Tritiation of Pharmaceuticals by Heavy Alkali Metal Amide Catalysts

Deuterium- and tritium-labeled compounds play a significant role in the pharmaceutical development process. Ortho-directed hydrogen isotope exchange (HIE) with transition metal catalysts is one of the most well-developed methods for the labeling of various aromatic compounds, but met with limited success with aromatic ethers and fluorides. Herein, we present a practical method for the directed HIE of aromatic ethers and fluorides with D₂/T₂ gas catalyzed by heavy alkali metal amides. Using commercially available potassium amide KN(SiMe₃)₂ as an HIE catalyst, we successfully achieved tritiations of complex pharmaceutical compounds with high specific activities. This straightforward and practical method provides a valuable complement to transition metal-catalyzed HIE, enabling expanded substrate scope and broadening the HIE toolbox for efficient isotope labeling. Control experiments and density functional theory (DFT) calculations reveal an intriguing kinetic deprotonative equilibrium between aromatic C–H bonds and alkali amides and well explain the obviously different behaviors of the alkali amide catalysts MN(SiMe₃)₂ (M = Cs, K, and Na).