Photoredox/Copper-Catalyzed C(sp3)–H Bond Functionalization for Radical Cross-Coupling to Construct C(sp3)–C(sp3) Bonds

Abstract The construction of C(sp3)–C(sp3) bonds is a pivotal transformation in medicinal chemistry, as it introduces three-dimensional complexity that is crucial for improving a compound's druggability and target selectivity. However, strategies for efficiently forming C(sp3)–C(sp3) bonds via C(sp3)–H alkylation have developed slowly, as the high bond dissociation energy of inert C(sp3)–H bonds renders their selective activation and functionalization challenging. Herein, we report a photoinduced copper-catalyzed C(sp3)–H bond functionalization strategy for constructing C(sp3)–C(sp3) bonds through the radical–radical cross-coupling of cyclopropanols with N-fluoroamides. This process precisely activates the C(sp3)–H bond of N-fluoroamide via an intramolecular 1,5-hydrogen atom transfer (1,5-HAT), followed by selective cross-coupling with the key radical generated from the ring-opening of a cyclopropanol. The copper center may play an important role in the cross-selective coupling of C(sp3)–C(sp3) bonds. The reaction exhibits good functional group tolerance, allowing the preparation of a variety of C(sp3) alkylation products encompassing 1°–1°, 1°–2°, and other C(sp3)–C(sp3) bond types. The practical utility of this method is further demonstrated through scale-up experiments, product transformations, and late-stage functionalization of complex natural products and drug molecules.