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.
Bibliographical noteFunding Information:
We thank B. Li (Merck) for technical assistance. This work was supported by the NIH (R01 GM126832 to S.S.S. and F32 GM129909 to J.A.B.), Jiangsu Province (BK20161307 and 333 Talent Project to H.H.), Huaiyin Normal University (JSKC18014 to H.H.) and Merck (to S.W.K.; travel funds to S.-J.C.). M.M. acknowledges a doctoral dissertation fellowship from the University of Minnesota. Spectroscopic instrumentation was supported by a gift from P. J. Bender, the NSF (CHE-1048642) and the NIH (1S10 OD020022–1).
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