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Late-stage azolation of benzylic C‒H bonds enabled by electrooxidation

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Abstract

The installation of azoles via C–H/N–H cross-coupling is significantly underdeveloped, particularly in benzylic C–H azolation due to the requirement for external chemical oxidants and the challenge in controlling the site- and chemo-selectivity. Herein, a late-stage azolation of benzylic C‒H bonds enabled by electrooxidation is described, which proceeds in an undivided cell under mild, catalyst- and chemical-oxidant-free reaction conditions. The strategy empowers the C‒H azolation on primary, secondary, and even challenging tertiary benzylic positions selectively. The remarkable synthetic utility of our approach is highlighted by its easy scalability without overoxidation of products and ample scope with valuable functional groups. The approach can be directly used to install benzyl and azole motifs on highly functionalized drug molecules.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (21901052, 81872759), the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2019), the Guangzhou Education Bureau University Scientific Research Project (201831845) and the Guangdong Basic and Applied Basic Research Foundation (2020A1515010722).

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China

    Zhixiong Ruan, Zhixing Huang & Zhongnan Xu

  2. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, College of Pharmacy, Jinan University, Guangzhou, 510632, China

    Shaogao Zeng & Ping-Hua Sun

  3. Department of Chemistry, Jinan University, Guangzhou, 510632, China

    Pengju Feng

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  1. Zhixiong Ruan
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  2. Zhixing Huang
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  3. Zhongnan Xu
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  4. Shaogao Zeng
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  5. Pengju Feng
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  6. Ping-Hua Sun
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Correspondence to Zhixiong Ruan, Pengju Feng or Ping-Hua Sun.

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Conflict of interest The authors declare no conflict of interest.

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Ruan, Z., Huang, Z., Xu, Z. et al. Late-stage azolation of benzylic C‒H bonds enabled by electrooxidation. Sci. China Chem. 64, 800–807 (2021). https://doi.org/10.1007/s11426-020-9938-9

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  • DOI: https://doi.org/10.1007/s11426-020-9938-9

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