Distal C(sp³)-H Amidation via Ind*Rh^III Catalyzed Nitrene Transfer

The Ind*Rh^III catalyzed distal amidation of C(sp³)-H sites was explored, harnessing amides as weakly coordinating directing groups. The combined use of an Ind*Rh^III complex and 2-pyridone ligand delivered the enhanced catalytic activity required to functionalize both primary and secondary β-C(sp³)-H sites. The accelerated nitrene transfer catalysis facilitated the late-stage functionalization of pharmaceutical derivatives and the synthesis of drug conjugates bearing peptides, biotin, or E3-ligase binders. The post-polymerization modification of poly(2-alkyl-2-oxazoline)s and poly(2-alkyl-2-oxazine)s using Ind*Rh^III nitrene transfer catalysis involving the site-selective C-H amidation of polymer side chains was also achieved.