Copper-catalyzed Benzylic C–H Coupling with Alcohols via Radical Relay Enabled by Redox Buffering

Hu, H.; Chen, S.-J.; Mandal, M.; Pratik, S. M.; Buss, J. A.; Krska, S. W.; Cramer, C. J.; Stahl, S. S.
Nature Catal. 2020, 3, 358 (doi:10.1038/s41929-020-0425-1).

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 a redox-buffering strategy that maintains the activity of the copper catalyst throughout the reaction. The reactions employ the C&nsash;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.