Merging directed sp and nondirected sp C-H functionalization for Pd-catalyzed polydeuteration of (hetero)arenes.

Polydeuteration has emerged as a key strategy in the development of pharmaceuticals and functional organic materials, advancing beyond monodeuteration and trideuteromethylation. We have developed methods for the polydeuteration of a wide range of organic compounds through Pd-catalyzed directed sp C-H activation and nondirected sp C-H activation, using readily available deuterium source, AcOH- . This approach addresses the challenge of facilitating both directed and nondirected C-H functionalization of electronically and sterically diverse (hetero)aromatic compounds through the use of a versatile [2,2'-bipyridin]-6(1)-one (BpyOH) ligand. This method demonstrates high functional group compatibility, readily applicable in the presence of directing functional groups such as carboxylic acids, amides, and azoles, as well as nondirecting electron-withdrawing groups such as nitro, sulfonamide, and ester groups. DFT calculations reveal that ligands influence intermediates and transition states by providing bidentate chelation, internal base, and hydrogen bonding. The Pd(BpyOH) complex exhibits well-balanced reactivity for C-H cleavage while readily forming complexes with substrates, which is relevant to other Pd-catalyzed C-H functionalization reactions. Our approach significantly broadens the scope of deuterated building blocks and late-stage deuteration, thereby facilitating evaluation of the deuterium effect in various applications across medicinal chemistry, materials science, and beyond.