Copper-Catalyzed Benzylic C–H Coupling with Alcohols via Radical Relay

Cross coupling reactions enable rapid convergent synthesis of diverse molecules and provide the foundation for modern chemical synthesis. The most widely used methods employ sp2-hybridized coupling partners, such as aryl halides or related pre-functionalized substrates. Here, we demonstrate copper-catalyzed oxidative cross-coupling of benzylic C–H bonds with alcohols to afford benzyl ethers, enabled by mechanistic insights that led to a novel reductant-based strategy for in situ regeneration of the active copper catalyst. The reactions employ the C–H substrate as the limiting reagent and exhibit broad scope with respect to both substrate partners. This approach to direct site-selective functionalization of sp3 C–H bonds provides the basis for efficient three-dimensional diversification of organic molecules and should find widespread utility in organic synthesis, particularly for medicinal chemistry applications.