Ligand-Enabled CpERh(III) Catalyzed Distal C(sp3)-H Alkynylation of Native Amides

A novel catalytic strategy that harnesses native amides as directing groups for the site-selective alkynylation of C(sp3)–H sites was discovered. This protocol relies on the use of an electron-deficient CpERh(III) complex and 2-pyridone ligand to facilitate formation of new C(sp3)–C(sp) bonds at both primary and secondary beta-C(sp3)–H sites. Exceptional reactivity was observed for the distal C(sp3)–alkynylation of cyclopropane carboxamides, affording a series of unique alkynylated cyclopropane scaffolds amenable to further derivatization at both the amide and alkyne functionality. The utility of this novel catalytic strategy was further exemplified through the functionalization of pharmaceutical derivatives and rapid synthesis of drug-biotin and drug-fluorescent probe conjugates.