Enantioselective Pyrazole Alkylation via Iridium and Squaramide Catalyzed N-H Insertion

While pyrazoles are privileged scaffolds in medicinal chemistry, their tautomerization and Lewis-basicity pose challenges for enantioselective catalytic alkylation. Here, we report an iridium and squaramide catalyzed N-H insertion that provides a site-selective and enantioselective route to α-pyrazole esters. An Ir catalyst promotes site-selective insertion at the less sterically hindered nitrogen (N_β); the combination of Ir and squaramide catalysts mediates asymmetric protonation with excellent enantiocontrol. These findings establish a strategy for the asymmetric N-H insertion of pyrazoles, providing access to chiral nitrogen heterocycles previously inaccessible by asymmetric catalysis. This concept extends to indazole functionalization and enables the first disclosed asymmetric synthesis of a PARP7 inhibitor.