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Regioselective umpolung para-C–H functionalization of arylhydroxylamines

Nature Synthesis volume 2, pages 778–788 (2023)Cite this article

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Abstract

Regioselective arene C–H functionalization has widespread applications in synthetic chemistry, materials science and fine chemical industries. Catalytic methods for the ortho- and meta-C–H functionalization of arenes are well developed; however, para-C–H bond functionalization is much less developed and is more challenging due to the distal relationship of the para-C–H bond with the para-directing group. Here we report an umpolung method for the synthesis of para-functionalized anilides from arylhydroxylamines and O- and S-nucleophiles in the presence of fluorosulfuryl imidazolium triflates. Proceeding at low temperature under air, this process is tolerant of a diverse range of arylhydroxylamines and O- and S-nucleophiles giving para-functionalized anilide derivatives in good yields and excellent para-selectivity. Mechanistic studies reveal that the reaction process probably proceeds through a polarity inversion sequence, which comprises O-fluorosulfonation of the arylhydroxylamine substrate followed by N–O bond cleavage and nucleophilic addition. The synthetic utility of the reaction was demonstrated through reaction scale-up and onward synthetic transformations of the reaction products.

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Fig. 1: Synthetic strategies for C–H functionalization of N-arylhydroxylamines.
Fig. 2: Synthetic application of the para-functionalized anilide.
Fig. 3: Control experiments and proposed reaction pathway.
Fig. 4: DFT analysis.

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Data availability

The X-ray crystallographic coordinates for the products reported in the present article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition nos. CCDC 2156664 (3p), CCDC 2160531 (5q) and CCDC 2165574 (7e). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures. Experimental procedures and characterization of new compounds are available in the Supplementary Information.

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (grant nos. 22271176, 21933003 and 91856105), the Key Technology Research and Development Program of Shandong Province (grant no. 2019GSF108056) and Shandong University. This work was also supported by the High-Performance Computing Platform of Peking University. We thank D. Sun at Shandong University for the X-ray diffraction and data analysis.

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Authors and Affiliations

  1. School of Chemistry and Chemical Engineering, Shandong University, Ji’nan, China

    Zhenguo Xi, Zhaoquan Guo, Zhiwei Gao & Hongyin Gao

  2. Beijing National Laboratory for Molecular Sciences Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing, China

    Xi-Jia Liu & Zhi-Xiang Yu

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  1. Zhenguo Xi
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Contributions

H.G. conceived and directed the project. Z.X. designed and performed experiments. X.-J.L. performed the DFT calculations and mechanism analysis. Z.Q.G. and Z.W.G. helped with the collection of some new compounds and data analysis. H.G., Z.-X.Y. and X.-J.L. wrote the paper with input from all other authors. All authors discussed the results and commented on the paper.

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Correspondence to Zhi-Xiang Yu or Hongyin Gao.

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Competing interests

Shandong University has filed a patent application (patent application no. 202210215790.X, China). The competing interest is related to H.G., Z.X., Z.Q.G. and Z.W.G. X.-J.L. and Z.-X.Y. declare no competing interests.

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Nature Synthesis thanks Jesus Jover and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–5, Discussion and Tables 1–8.

Supplementary Data 1

Crystallographic data for 3p, CCDC 2156664.

Supplementary Data 2

Crystallographic data for 5q, CCDC 2160531.

Supplementary Data 3

Crystallographic data for 7e, CCDC 2165574.

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Xi, Z., Liu, XJ., Guo, Z. et al. Regioselective umpolung para-C–H functionalization of arylhydroxylamines. Nat. Synth 2, 778–788 (2023). https://doi.org/10.1038/s44160-023-00293-8

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