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

Nature Catalysis volume 3, pages 358–367 (2020)Cite this article

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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.

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Fig. 1: Cross-coupling reactions of benzylic C–H bonds and alcohols via a radical relay pathway.
Fig. 2: Cu-catalysed benzylic C–H functionalization with NFSI as the oxidant.
Fig. 3: Electronic effects and site selectivity observed in the oxidative coupling of ethylarenes and methanol.
Fig. 4: Calculated reaction pathways and energy landscape for (biox)CuI/NFSI-mediated methoxylation of ethylbenzene.
Fig. 5: Assessment of different benzylic C–H substrates in oxidative cross-coupling reactions with methanol.
Fig. 6: Assessment of different alcohols and C–H/alcohol coupling partners in benzylic C–H etherification reactions.

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Data availability

All of the data supporting the findings of this study are available within the paper and its Supplementary Information file.

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Acknowledgements

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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  1. These authors contributed equally: Huayou Hu, Si-Jie Chen.

Authors and Affiliations

  1. Department of Chemistry, University of Wisconsin−Madison, Madison, WI, USA

    Huayou Hu, Si-Jie Chen, Joshua A. Buss & Shannon S. Stahl

  2. Jiangsu Key Laboratory for Chemistry of Low-Dimensional Materials, School of Chemistry and Chemical Engineering, Huaiyin Normal University, Huaian, People’s Republic of China

    Huayou Hu

  3. Department of Chemistry, Chemical Theory Center and Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA

    Mukunda Mandal, Saied Md Pratik & Christopher J. Cramer

  4. High-Throughput Experimentation and Lead Discovery Capabilities, Merck, Kenilworth, NJ, USA

    Shane W. Krska

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Contributions

H.H. and S.-J.C. performed the experimental work and led the data interpretation and analysis. S.-J.C. and J.A.B. designed and implemented the mechanistic experiments. M.M. and S.M.P. conducted the computational studies. All work was done in consultation with S.S.S., S.W.K. and C.J.C. All authors contributed to preparation of the manuscript.

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Correspondence to Shannon S. Stahl.

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Supplementary information

Supplementary Information

Supplementary methods, Figs. 1 and 2, Tables 1–13 and references.

Supplementary Data 1

Cartesian coordinates of all density functional theory-optimized structures.

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Hu, H., Chen, SJ., Mandal, M. et al. Copper-catalysed benzylic C–H coupling with alcohols via radical relay enabled by redox buffering. Nat Catal 3, 358–367 (2020). https://doi.org/10.1038/s41929-020-0425-1

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