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Ligand-enabled meta-C–H activation using a transient mediator

Nature volume 519, pages 334–338 (2015)Cite this article

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Abstract

Achieving site selectivity in C–H functionalization reactions is a significant challenge, especially when the target C–H bond is distant from existing functional groups1,2,3,4,5. Coordination of a functional group to a metal is often a key driving force and control element in many important reactions including asymmetric hydrogenation6, epoxidation7,8 and lithiation9. Exploitation of this effect has led to the development of a broad range of directed C–H activation reactions10,11,12,13,14. However, these C–H activation methods are limited to proximal C–H bonds, which are spatially and geometrically accessible from the directing functional group. The development of meta-selective C–H functionalizations remains a significant challenge1,2,3,4,5,15,16,17. We recently developed a U-shaped template that can be used to overcome this constraint and have shown that it can be used to selectively activate remote meta-C–H bonds1,2. Although this approach has proved to be applicable to various substrates and catalytic transformations3,4,5, the need for a covalently attached, complex template is a substantial drawback for synthetic applications. Here we report an alternative approach employing norbornene as a transient mediator to achieve meta-selective C–H activation with a simple and common ortho-directing group. The use of a newly developed pyridine-based ligand is crucial for relaying the palladium catalyst to the meta position by norbornene after initial ortho-C–H activation. This catalytic reaction demonstrates the feasibility of switching ortho-selectivity to meta-selectivity in C–H activation of the same substrate by catalyst control.

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Figure 1: Design of a new approach for meta-C–H activation.
Figure 2: Discovery of a ligand that enables meta-C–H alkylation using norbornene as a transient mediator.
Figure 3: meta-C–H alkylation of phenylacetic amides.
Figure 4: Scope of organohalide coupling partners.

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Acknowledgements

We thank J. Spangler and A. Homs for constructive suggestions. We thank the Scripps Research Institute and the National Institutes of Health (NIGMS, 1R01 GM102265) for financial support. L.-Z.F. is a visiting scholar from School of Pharmacy, Xinxiang Medical University and is sponsored by the China Scholarship Council.

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Authors and Affiliations

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

    Xiao-Chen Wang, Wei Gong, Li-Zhen Fang, Ru-Yi Zhu, Suhua Li, Keary M. Engle & Jin-Quan Yu

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  2. Wei Gong
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Contributions

X.-C.W. and R.-Y.Z. developed the reactions. W.G. and S.L. synthesized the ligands. L.-Z.F. examined the substrate scope. K.M.E. performed preliminary studies. J.-Q.Y. conceived this concept and prepared the manuscript with feedback from X.-C.W.

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Correspondence to Jin-Quan Yu.

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The authors declare no competing financial interests.

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Wang, XC., Gong, W., Fang, LZ. et al. Ligand-enabled meta-C–H activation using a transient mediator. Nature 519, 334–338 (2015). https://doi.org/10.1038/nature14214

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