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A directive Ni catalyst overrides conventional site selectivity in pyridine C–H alkenylation

Abstract

Achieving the transition metal-catalysed pyridine C3−H alkenylation, with pyridine as the limiting reagent, has remained a long-standing challenge. Previously, we disclosed that the use of strong coordinating bidentate ligands can overcome catalyst deactivation and provide Pd-catalysed C3 alkenylation of pyridines. However, this strategy proved ineffective when using pyridine as the limiting reagent, as it required large excesses and high concentrations to achieve reasonable yields, which rendered it inapplicable to complex pyridines prevalent in bioactive molecules. Here we report that a bifunctional N-heterocyclic carbene-ligated Ni–Al catalyst can smoothly furnish C3–H alkenylation of pyridines. This method overrides the intrinsic C2 and/or C4 selectivity, and provides a series of C3-alkenylated pyridines in 43–99% yields and up to 98:2 C3 selectivity. This method not only allows a variety of pyridine and heteroarene substrates to be used as the limiting reagent, but is also effective for the late-stage C3 alkenylation of diverse complex pyridine motifs in bioactive molecules.

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Fig. 1: Remote C–H activation via a macrocyclophane transition state.
Fig. 2: Mechanism experiments and proposed mechanism.

Data availability

The authors declare that all data supporting the findings of this study are available within the article and its supplementary information files. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2018614 (L10). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We thank the National Natural Science Foundation of China (91856104 and 21871145), the Tianjin Applied Basic Research Project and Cutting-Edge Technology Research Plan (19JCZDJC37900) and ‘Frontiers Science Center for New Organic Matter’, Nankai University (63181206), for financial support (M.Y.). We gratefully acknowledge The Scripps Research Institute, the Lindemann Trust (N.Y.S.L.) and the NIH (National Institute of General Medical Sciences grant R01GM102265) for financial support (J.-Q.Y.).

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Contributions

J.-Q.Y., M.Y. and T.Z. conceived the concept. T.Z. developed the conditions and performed the alkenylation of pyridines. Y.-X.L., J.-F.L. and Y.L. prepared the substrates and ligands. All authors analysed the results. N.Y.S.L. provided insightful suggestions in analysing the data and editing the manuscript.

Corresponding authors

Correspondence to Mengchun Ye or Jin-Quan Yu.

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The authors declare no competing interests.

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Peer review information Nature Chemistry thanks Manmohan Kapur, Oleg Larionov and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Experimental procedures, mechanistic studies, Supplementary Figs. 1–90, Tables 1–7, X-ray crystallographic data and references.

Supplementary Data 1

Crystallographic data for L10; CCDC reference 2018614.

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Zhang, T., Luan, YX., Lam, N.Y.S. et al. A directive Ni catalyst overrides conventional site selectivity in pyridine C–H alkenylation. Nat. Chem. 13, 1207–1213 (2021). https://doi.org/10.1038/s41557-021-00792-1

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