Letter | Published:

Ligand-accelerated non-directed C–H functionalization of arenes

Nature volume 551, pages 489493 (23 November 2017) | Download Citation

Abstract

The directed activation of carbon–hydrogen bonds (C–H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups1,2,3,4,5,6. Palladium-catalysed non-directed C–H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts7,8. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used9,10,11,12,13,14,15,16,17,18, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C–H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C–H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C–H functionalization.

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Acknowledgements

We acknowledge The Scripps Research Institute, the NIH (NIGMS, 2R01 GM102265), Bristol-Myers Squibb and Shanghai RAAS Blood Products Co., Ltd. for their financial support. We also thank Novartis for providing the drug molecules.

Author information

Affiliations

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

    • Peng Wang
    • , Pritha Verma
    • , Guoqin Xia
    • , Marcus E. Farmer
    •  & Jin-Quan Yu
  2. Discovery Chemistry, Bristol-Myers Squibb Company, 350 Carter Road, Princeton, New Jersey 08540, USA

    • Jun Shi
    • , Shiwei Tao
    •  & Peter T. W. Cheng
  3. Discovery Chemistry, Bristol-Myers Squibb Company, PO Box 4000, Princeton, New Jersey 08543, USA

    • Jennifer X. Qiao
    •  & Michael A. Poss
  4. Discovery Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, USA

    • Kap-Sun Yeung

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Contributions

P.W. developed the ligands and the reactions. P.V. performed the DFT calculations. G.X. performed the kinetic study. J.S., S.T. and P.T.W.C. separated the isomers using preparative HPLC. J.X.Q. and M.A.P. participated in the screening of acrylamide-derived coupling partners and investigation of the C–H olefination reaction for amino acid substrates. M.E.F. performed preliminary studies on 2-hydroxypyridine ligands. K.-S.Y. helped with the screening of sulphonamide-derived coupling partners. J.-Q.Y. conceived the concept and prepared the manuscript with feedback from P.W., P.V. and G.X.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jin-Quan Yu.

Reviewer Information Nature thanks J. de Vries and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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DOI

https://doi.org/10.1038/nature24632

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