Selective Deuterium Incorporation into Azetidines and Cyclobutanes by Harnessing an Iodomethylthianthrenium Reagent

Abstract Deuterium incorporation at metabolically labile C–H bonds is an appealing strategy for improving metabolic stability and pharmacokinetic attributes in drug design campaigns. However, conventional H/D exchange methods often suffer from significant reactivity and selectivity challenges, limiting access to diverse deuterated structures. Here, we introduce a deuterium-labeled iodomethylthianthrenium reagent, readily prepared via H/D exchange with D2O, that directly converts alkenes into deuterated azetidines or cyclobutanes via a common 1,3-dielectrophilic intermediate. This method is compatible with a wide range of functional groups and is operationally simple, providing a reliable way to install deuterium at targeted positions in strained-ring scaffolds with high molecular complexity.