Homogenous Palladium-Catalyzed Dehalogenative Deuteration and Tritiation of Aryl Halides with D2/T2 Gas

Catalytic dehalogenative deuteration and tritiation with D2/T2 gas is a widely employed method for precisely introducing hydrogen isotopes into specific positions within organic molecules. While palladium(0) based heterogeneous catalysts, such as Pd/C, are commonly used for this purpose, challenges related to functional group tolerance and incomplete iso-tope incorporation are often encountered, particularly with respect to aryl bromides and chlorides. These long-standing issues pose a hurdle to achieving optimal results in tracer synthesis. The limited incorporation of isotopes for aryl bro-mides and chlorides presents a significant obstacle to the application of this method in the preparation of high specific activity tritium tracers. Herein, we present a novel palladium catalytic system using Zn(OAc)2 as an additive, which ena-bles homogeneous dehalogenative deuteration and tritiation using D2/T2 gas. Under mild reaction conditions, a wide range of drug-like aryl halides and pseudohalides undergo selective deuteration with complete isotope incorporation. The reaction displays excellent compatibility with diverse functional groups, including multiple bonds, O/N-benzyl, and cy-ano groups, which are frequently problematic in Pd/C reactions. Furthermore, this method was successfully applied to the tritiation of four halogenated pharmaceutically relevant molecules, resulting in predictable high specific activity per halogen atom (26.5-27.7 Ci/mmol). Notably, the developed system allows gram-scale preparation of a deuterium-containing intermediate, a crucial step in synthesizing a deuterium-labeled drug molecule. A reaction pathway involving a key intermediate, Pd(Ar)OAc, was proposed to activate hydrogen gas during dehalogenative deuteration and tritiation. This innovative method has potential to change the practice of dehalogenative deuteration and tritiation in the realm of hydrogen isotope labeling.