From Installation to Editing: The Rise of d 3 ‐Deuteromethylation

The site‐selective incorporation of deuterium into biologically active molecules has emerged as a powerful strategy for tuning the absorption, distribution, metabolism, and excretion (ADME) properties of pharmaceuticals. Among various deuterated motifs, the d 3 ‐deuteromethyl (CD 3 ) group has gained particular attention as a privileged pharmacophore, highlighted by its presence in three of five deuterated drugs approved thus far. By uniting the beneficial “magic methyl effect” with the kinetic isotope effect imparted by deuterium, d 3 ‐deuteromethylation can effectively reduce metabolic liabilities while preserving biological activity, leading to improved pharmacokinetic performance and enhanced therapeutic potential. In recent years, the development of novel CD 3 ‐containing reagents, together with advances in photocatalytic and electrocatalytic methodologies, has enabled the efficient installation of CD 3 groups with high selectivity under mild conditions. In parallel, hydrogen–deuterium (H‐D) exchange strategies enable precise d 3 ‐deuteromethylation at specific sites (such as α‐thio C(sp 3 )─H bonds and benzylic C(sp 3 )─H bonds), providing a complementary approach to isotopic incorporation. This review summarizes the major advances in d 3 ‐deuteromethylation over the past five years (from 2021 to 2026), with a particular focus on the design of novel CD 3 reagents, the application of H‐D exchange strategy in d 3 ‐deuteromethylation, and the mechanistic principles underlying these transformations.