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Dual ligands relay-promoted transformation of unstrained ketones to polyfluoroarenes and nitriles

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Abstract

C-C bond activation has emerged as a powerful tool for the construction of complex molecules. Herein, we report a dual ligands relay-promoted transformation of unstrained aryl, alkenyl and alkynyl ketones to the corresponding polyfluoroarenes and nitriles via C-C (=O) bond cleavage and subsequent decarboxylative arylation process. Various polyfluoroarene and nitrile products are obtained in one pot under cyanide-free conditions. The protocol features high atom economy, broad functional group tolerance and excellent heterocyclic compatibility. The late-stage functionalization of the drug and natural product demonstrated the synthetic utility of our protocol. Furthermore, the decisive role of the dual ligands was clarified and the mechanistic rationale including the β−C elimination as the rate-limiting step was supported by detailed density functional theory (DFT) studies.

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Acknowledgements

This work was supported by the Shanghai Institute of Materia Medica, the Chinese Academy of Sciences, the National Natural Science Foundation of China (21772211, 21920102003), the Institutes for Drug Discovery and Development, Chinese Academy of Sciences (CASIMM0120163006), the Science and Technology Commission of Shanghai Municipality (17JC1405000, 18431907100), the Program of Shanghai Academic Research Leader (19XD1424600), the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (2018ZX09711002-006) and the China Postdoctoral Science Foundation (2019M662854).

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Zhen-Yu Wang, Xu Zhang & Hui-Xiong Dai

  2. CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Xing Wang, Hui Xu & Hui-Xiong Dai

  3. School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China

    Huiying Xu & Hui Gao

  4. University of Chinese Academy of Sciences, Beijing, 100049, China

    Hui-Xiong Dai

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  1. Zhen-Yu Wang
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Correspondence to Hui Xu, Hui Gao or Hui-Xiong Dai.

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Supporting information The supporting information is available online at https://chem.scichina.com and https://link.springer.com/journal/11426. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

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Wang, ZY., Xu, H., Zhang, X. et al. Dual ligands relay-promoted transformation of unstrained ketones to polyfluoroarenes and nitriles. Sci. China Chem. 66, 2037–2045 (2023). https://doi.org/10.1007/s11426-023-1653-3

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