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

Nat Catal. 2020 Apr;3(4):358-367. doi: 10.1038/s41929-020-0425-1. Epub 2020 Feb 24.

Abstract

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.