Equilibrium-driven decarbonylative multi-deuteration enables access to highly deuterated carbon frameworks

Abstract

Deuterium incorporation is a powerful strategy for modulating metabolic stability and probing reaction mechanisms. However, existing approaches based on defunctionalization or hydrogen-deuterium exchange are typically limited to mono-deuteration or suffer from poor site selectivity, restricting access to multi-deuterated carbon centers. Herein, we report a cost-effective strategy for decarbonylative multi-deuteration of aldehydes by integrating polar alpha-deuteration, thiyl radical-mediated hydrogen atom transfer (HAT), and decarbonylative deuteration. A key feature of this approach is an equilibrium-controlled radical-polar process, in which multiple reversible steps are directed toward productive pathways through irreversible trapping of alkyl radicals. The method employs inexpensive, commercially available reagents and exhibits a broad substrate scope encompassing primary, secondary, and tertiary aldehydes, including structurally complex substrates. This strategy provides a practical platform for the synthesis of highly deuterated carbon frameworks, offering new opportunities for isotopic labeling and medicinal chemistry.