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Conformation-induced remote meta-C–H activation of amines

Nature volume 507, pages 215–220 (2014)Cite this article

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Abstract

Achieving site selectivity in carbon–hydrogen (C–H) functionalization reactions is a long-standing challenge in organic chemistry. The small differences in intrinsic reactivity of C–H bonds in any given organic molecule can lead to the activation of undesired C–H bonds by a non-selective catalyst. One solution to this problem is to distinguish C–H bonds on the basis of their location in the molecule relative to a specific functional group. In this context, the activation of C–H bonds five or six bonds away from a functional group by cyclometallation has been extensively studied1,2,3,4,5,6,7,8,9,10,11,12,13. However, the directed activation of C–H bonds that are distal to (more than six bonds away) functional groups has remained challenging, especially when the target C–H bond is geometrically inaccessible to directed metallation owing to the ring strain encountered in cyclometallation14,15. Here we report a recyclable template that directs the olefination and acetoxylation of distal meta-C–H bonds—as far as 11 bonds away—of anilines and benzylic amines. This template is able to direct the meta-selective C–H functionalization of bicyclic heterocycles via a highly strained, tricyclic-cyclophane-like palladated intermediate. X-ray and nuclear magnetic resonance studies reveal that the conformational biases induced by a single fluorine substitution in the template can be enhanced by using a ligand to switch from ortho- to meta-selectivity.

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Figure 1: Design of a versatile template to direct meta-C–H activation.
Figure 2: Development of templates to direct meta-C–H olefination.
Figure 3: Template-directed remote C–H olefination of N-methylanilines.
Figure 4: Meta-C–H acetoxylation of N-methylanilines and benzylamine derivatives.

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Acknowledgements

We gratefully acknowledge The Scripps Research Institute and the NIH (NIGMS, 1R01 GM102265) for their financial support. R.-Y.T. is a visiting scholar from Wenzhou University and is sponsored by the National Natural Science Foundation of China (21202121).

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Authors and Affiliations

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

    Ri-Yuan Tang, Gang Li & Jin-Quan Yu

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Contributions

R.-Y.T. and G.L. performed the experiments and developed the reactions. R.-Y.T. and J.-Q.Y. designed the templates. J.-Q.Y. had the idea for this work and prepared this manuscript with feedback from R.-Y.T. and G.L.

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Correspondence to Jin-Quan Yu.

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The authors declare no competing financial interests.

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Tang, RY., Li, G. & Yu, JQ. Conformation-induced remote meta-C–H activation of amines. Nature 507, 215–220 (2014). https://doi.org/10.1038/nature12963

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