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Remote site-selective C–H activation directed by a catalytic bifunctional template


In chemical syntheses, the activation of carbon–hydrogen (C–H) bonds converts them directly into carbon–carbon or carbon–heteroatom bonds without requiring any prior functionalization. C–H activation can thus substantially reduce the number of steps involved in a synthesis. A single specific C–H bond in a substrate can be activated by using a ‘directing’ (usually a functional) group to obtain the desired product selectively1,2,3,4,5. The applicability of such a C–H activation reaction can be severely curtailed by the distance of the C–H bond in question from the directing group, and by the shape of the substrate, but several approaches have been developed to overcome these limitations6,7,8,9,10,11,12. In one such approach, an understanding of the distal and geometric relationships between the functional groups and C–H bonds of a substrate has been exploited to achieve meta-selective C–H activation by using a covalently attached, U-shaped template13,14,15,16,17. However, stoichiometric installation of this template has not been feasible in the absence of an appropriate functional group on which to attach it. Here we report the design of a catalytic, bifunctional nitrile template that binds a heterocyclic substrate via a reversible coordination instead of a covalent linkage. The two metal centres coordinated to this template have different roles: one reversibly anchors substrates near the catalyst, and the other cleaves remote C–H bonds. Using this strategy, we demonstrate remote, site-selective C–H olefination of heterocyclic substrates that do not have the necessary functional groups for covalently attaching templates.

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Figure 1: Design of a cooperative bimetallic approach for remote, site-selective C–H activation.
Figure 2: Discovery of a template that enables site-selective, remote C–H activation.
Figure 3: Results of remote, site-selective C–H olefination of heterocycle-containing substrates using a catalytic template.
Figure 4: Extending the reaction principle to the site-selective C–H olefination of quinolines and other heterocycles.

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We acknowledge The Scripps Research Institute and the United States National Institutes of Health (the National Institute of General Medical Sciences, grant no. 1R01 GM102265) for financial support. We thank the Ito Foundation for International Education Exchange (predoctoral fellowship to K.T.).

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Authors and Affiliations



Z.Z. developed the catalytic bidentate template for 3-phenylpyridine and other heterocycles. K.T. developed the non-covalent tridentate template for quinoline and other heterocycles. J.-Q.Y. conceived the concept and prepared the manuscript with feedback from Z.Z. and K.T.

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Correspondence to Jin-Quan Yu.

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The authors declare no competing financial interests.

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Zhang, Z., Tanaka, K. & Yu, JQ. Remote site-selective C–H activation directed by a catalytic bifunctional template. Nature 543, 538–542 (2017).

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