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

• Published in: Journal of the American Chemical Society 2024-11, Vol.146 (46), p.31497-31506
• Main Authors: Li, Jingwei, Lin, Qiao, Dungan, Otto, Fu, Yue, Ren, Sumei, Ruccolo, Serge, Moor, Sarah, Phillips, Eric M.
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.4c08176

Hydrogen isotopically labeled compounds have extensive utility across diverse domains, especially in drug discovery and development. However, synthesis of the labeled compounds with exclusive site selectivity and/or high isotope incorporation is challenging. One widely employed method is heterogeneous palladium(0)-catalyzed (such as Pd/C) dehalogenative deuteration and tritiation with D2/T2 gas. While commonly used, the method faces two long-standing challenges related to insufficient isotope incorporation and functional group tolerance, particularly with aryl bromides and chlorides. These long-standing issues pose a substantial obstacle in the synthesis of deuterated drug molecules and high-specific-activity tritium tracers. Herein, we present a novel palladium catalytic system using Zn­(OAc)2 as an additive, enabling novel homogenous dehalogenative deuteration/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 and O/N-benzyl, and cyano groups, which are frequently problematic in the 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 key intermediate, Pd­(Ar)­OAc, is proposed to activate hydrogen gas during dehalogenative deuteration and tritiation, and Zn­(OAc)2 plays an essential role in inhibiting Pd poisoning by halides.