Heterogeneous Palladium‐Catalyzed Trideuteromethylation and 13 C‐Trideuteromethylation of Arylboron Compounds via D 2 O as the Deuterium Source

Integrating the “magic methyl” effect and deuterium kinetic isotope effect, trideuteromethyl (CD 3 ) modification is a robust strategy for pharmaceutical development. Accordingly, the development of cost‐effective and practical methods to install CD 3 moieties into drug‐like molecules is highly desirable. Herein, we develop a reusable heterogeneous Pd‐catalyzed trideuteromethylation of arylboron esters, with D 2 O serving as the sole deuterium source. Methylthianthrenium salts (TT‐Me) act as key precursors, undergoing facile H/D exchange to in situ produce CD 3 synthons for efficient one‐pot cross‐coupling with arylboron esters. This protocol features outstanding functional group compatibility and an extraordinarily broad substrate applicability. It enables the trideuteromethylation of diverse biologically relevant scaffolds, as well as the modular two‐step synthesis of aryl‐CD 3 skeletons starting from commercially available aryl chlorides, phenols, anilines, and benzoic acids. It also facilely affords 13 CH 3 / 13 CD 3 dual‐labeled analogs for pharmaceutical and analytical use. Combined with C─H borylation, this one‐pot platform achieves direct trideuteromethylation of inert aryl C─H bonds, allowing divergent installation of two site‐specific CD 3 moieties into lidocaine isotopologues. Mechanistic investigations reveal a surface‐mediated heterogeneous pathway, where K 2 CO 3 dually activates TT‐Me and arylboron esters. This work offers a practical, scalable and sustainable route for constructing aryl–CD 3 isotopic architectures.