Copper-catalysed benzylic C–H coupling with alcohols via radical relay enabled by redox buffering

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-catalysed oxidative cross-coupling of benzylic C–H bonds with alcohols to afford benzyl ethers, enabled by a redox buffering strategy that maintains the activity of the copper catalyst throughout the reaction. The reactions employ the C–H substrate as the limiting reagent and exhibit broad scope with respect to both coupling partners. This approach to direct site-selective functionalization of C(sp3)–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. The cross-coupling of C–H bonds with alcohols is a highly efficient route to ethers. Here the authors report such an oxidative coupling, by use of a radical relay to both promote hydrogen atom transfer and activate the copper catalyst for cross-coupling.