Site‐Selective Carbonylation of Azetidines via Copper‐Catalyzed Difluorocarbene Insertion

Abstract γ‐Lactams are privileged five‐membered pharmaco‐phores in numerous bioactive compounds, but access to these motifs typically relies on cycloaddition/substitution chemistry involving activated substrates or CO carbonylations under harsh conditions. Here, we report a new route to functionalized γ‐lactams through formal carbonylation of azetidines under nonprecious metal catalysis. The method leverages a copper‐stabilized difluorocarbene to promote site‐selective insertion followed by in situ hydrolysis to unmask the lactam group. In contrast to most difluorocarbene reactions that cause ring cleavage of saturated heterocycles in the presence of heat, the present system operates at a low temperature and retains the integrity of the cyclic structure. Synthesis of various drug‐like lactams and a therapeutic agent for diabetes highlights utility.