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Differentiation and functionalization of remote C–H bonds in adjacent positions

Nature Chemistry volume 12, pages 399–404 (2020)Cite this article

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Abstract

Site-selective functionalization of C–H bonds will ultimately afford chemists transformative tools for editing and constructing complex molecular architectures. Towards this goal, it is essential to develop strategies to activate C–H bonds that are distal from a functional group. In this context, distinguishing remote C–H bonds on adjacent carbon atoms is an extraordinary challenge due to the lack of electronic or steric bias between the two positions. Herein, we report the design of a catalytic system leveraging a remote directing template and a transient norbornene mediator to selectively activate a previously inaccessible remote C–H bond that is one bond further away. The generality of this approach has been demonstrated with a range of heterocycles, including a complex anti-leukaemia agent and hydrocinnamic acid substrates.

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Fig. 1: Remote site-selective C–H functionalization.
Fig. 2: Density functional theory optimized transition state structures.

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Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information. Metrical parameters for the structure of 2ah (see Supplementary Information) are available free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/) under reference number CCDC 1890836.

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Acknowledgements

We acknowledge Scripps Research, the NIH (National Institute of General Medical Sciences grant no. R01GM102265), the National Science Foundation (NSF, CHE-1764328 to K.N.H.) and the CCI Center for Selective C–H Functionalization (CHE-1700982 to K.N.H) for financial support. Computational studies were also supported by the NSF (OCI-1053575 to K.N.H.). Y.L. and J.W. thank the China Scholarship Council for support.

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Authors and Affiliations

  1. The Scripps Research Institute, La Jolla, CA, USA

    Hang Shi, Yi Lu, Jiang Weng, Keita Tanaka, Pritha Verma & Jin-Quan Yu

  2. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Katherine L. Bay, Xiangyang Chen & Kendall N. Houk

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Contributions

J.-Q.Y. and H.S. conceived the concept. H.S. developed the remote site-selective arylation of benzoazines. H.S. and Y.L. developed the remote site-selective arylation of arenes. H.S., Y.L., J.W. and K.T. prepared templates and reaction substrates. P.V., K.L.B., X.C. and K.N.H. performed the density functional theory calculations. J.-Q.Y. directed the project.

Corresponding authors

Correspondence to Kendall N. Houk or Jin-Quan Yu.

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The authors declare no competing interests.

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Supplementary information

Supplementary information

Supplementary experimental details, compound characterization data, Supplementary tables, Supplementary figure, computational study.

Crystallographic data

Crystallographic data for compound 2ah. CCDC reference 1890836.

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Shi, H., Lu, Y., Weng, J. et al. Differentiation and functionalization of remote C–H bonds in adjacent positions. Nat. Chem. 12, 399–404 (2020). https://doi.org/10.1038/s41557-020-0424-5

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