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

Nature volume 486, pages 518–522 (2012)Cite this article

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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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Figure 1: A template strategy for the activation of distal meta -C–H bonds (more than ten bonds away).
Figure 2: Template-directed meta -selective C–H olefination of toluene derivatives.
Figure 3: Template-directed meta -selective C–H olefination of hydrocinnamic acid derivatives.

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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.).

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Author notes

  1. Dasheng Leow and Gang Li: These authors contributed equally to this work.

Authors and 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.

Corresponding author

Correspondence to Jin-Quan Yu.

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The authors declare no competing financial interests.

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Leow, D., Li, G., Mei, TS. et al. Activation of remote meta-C–H bonds assisted by an end-on template. Nature 486, 518–522 (2012). https://doi.org/10.1038/nature11158

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