Letter | Published:

Activation of remote meta-C–H bonds assisted by an end-on template

Nature volume 486, pages 518522 (28 June 2012) | Download Citation

Abstract

Functionalization of unactivated carbon–hydrogen (C–H) single bonds is an efficient strategy for rapid generation of complex molecules from simpler ones. However, it is difficult to achieve selectivity when multiple inequivalent C–H bonds are present in the target molecule. The usual approach is to use σ-chelating directing groups, which lead to ortho-selectivity through the formation of a conformationally rigid six- or seven-membered cyclic pre-transition state1,2,3,4,5,6,7,8,9,10,11,12,13,14. Despite the broad utility of this approach, proximity-driven reactivity prevents the activation of remote C–H bonds. Here we report a class of easily removable nitrile-containing templates that direct the activation of distal meta-C–H bonds (more than ten bonds away) of a tethered arene. We attribute this new mode of C–H activation to a weak ‘end-on’ interaction15 between the linear nitrile group and the metal centre. The ‘end-on’ coordination geometry relieves the strain of the cyclophane-like pre-transition state of the meta-C–H activation event. In addition, this template overrides the intrinsic electronic and steric biases as well as ortho-directing effects with two broadly useful classes of arene substrates (toluene derivatives and hydrocinnamic acids).

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Acknowledgements

We thank The Scripps Research Institute and the NIH (NIGMS, 1 R01 GM084019-03) for their financial support. We also thank the Agency for Science, Technology and Research (A*STAR) in Singapore for a postdoctoral fellowship (to D.L.).

Author information

Author notes

    • Dasheng Leow
    •  & Gang Li

    These authors contributed equally to this work.

Affiliations

  1. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

    • Dasheng Leow
    • , Gang Li
    • , Tian-Sheng Mei
    •  & Jin-Quan Yu

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Contributions

D.L., G.L. and T.-S.M. performed the experiments and analysed the data. D.L., G.L. and J.-Q.Y. designed the templates and developed the reactions. J.-Q.Y. conceived this concept and prepared this manuscript with feedback from D.L. and G.L.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jin-Quan Yu.

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    Supplementary Information

    This file contains Supplementary Text, Data and Tables; see Supplementary Table of Contents for details.

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DOI

https://doi.org/10.1038/nature11158

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