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

Huayou Hu, Si Jie Chen, Mukunda Mandal, Saied Md Pratik, Joshua A. Buss, Shane W. Krska, Christopher J. Cramer, Shannon S. Stahl

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)358-367
Number of pages10
JournalNature Catalysis
Issue number4
StatePublished - Apr 1 2020

Bibliographical note

Funding 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).

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.


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