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Copper-Catalyzed Benzylic C–H Coupling with Alcohols via Radical Relay

preprint
submitted on 21.05.2019 and posted on 22.05.2019 by Huayou Hu, Si-Jie Chen, Shane Krska, Shannon Stahl
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 mechanistic insights that led to a novel reductant-based strategy for in situ regeneration of the active copper catalyst. The reactions employ the C–H substrate as the limiting reagent and exhibit broad scope with respect to both substrate partners. This approach to direct site-selective functionalization of sp3 C–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.

Funding

NIH R01 GM126832

Jiangsu Province BK20161307

Jiangsu Province "333" Talents Project

Huaiyin Normal University JSKC18014

Merck & Co., Inc., Kenilworth, NJ, USA

NSF CHE-1048642

NIH 1S10 OD020022-1

History

Email Address of Submitting Author

stahl@chem.wisc.edu

Institution

University of Wisconsin-Madison

Country

United States

ORCID For Submitting Author

0000-0002-9000-7665

Declaration of Conflict of Interest

No conflict of interest

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