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


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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Figure 1: C–H functionalization of arenes.
Figure 2: C–H olefination of arenes and heterocycles.
Figure 3: Scope of olefin partners and carboxylation.
Figure 4: Late-stage functionalization of natural products and drug molecules.

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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.

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Authors and Affiliations



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.

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Correspondence to Jin-Quan Yu.

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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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Wang, P., Verma, P., Xia, G. et al. Ligand-accelerated non-directed C–H functionalization of arenes. Nature 551, 489–493 (2017).

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