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.