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Direct regioselective C-3 halogenation of pyridines

Nature Synthesis volume 5, pages 36–45 (2026)Cite this article

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Abstract

Pyridine derivatives are one of the most common heterocycles in chemistry. The 3-halopyridines are generally synthesized by indirect methods, including functional group conversion or a temporary dearomatization–rearomatization process. Although the direct electrophilic halogenation of pyridines provides straightforward access to 3-halopyridines, it has been rarely reported owing to the poor π nucleophilicity of pyridines. Here we describe a general direct regioselective C-3 halogenation of pyridines promoted by an ether solvation effect. This radical process enables the regioselective reaction to occur at the C-3 position of pyridines, rather than other aromatic C–H bonds, and can be applied to the late-stage halogenation of complex molecules. The mechanistic studies show that the interaction between the pyridine substrate, ether solvent and haleniums plays a dominant role in the reactivity and regioselectivity.

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Fig. 1: Strategies for regioselective C-3 halogenation of pyridines.
Fig. 2: C-3 halogenation of pyridines.
Fig. 3: Comparison of selectivity with literature methods.
Fig. 4: Applications of 3-halopyridines.
Fig. 5: Mechanistic investigations.
Fig. 6: Density functional theory analysis of C-3 halogenation of pyridines.

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The data that support the findings of this study are available in the Article and its Supplementary Information. Source data are provided with this paper.

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Acknowledgements

We acknowledge the National Key Research and Development Project (grant no. 2023YFF1205103 to S.S.) and the National Natural Science Foundation of China (grant nos. 22071005 and 22371007 to S.S.) for financial support.

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Author notes

  1. These authors contributed equally: Chao Li, Xinyao Li, Jiaxing Li.

Authors and Affiliations

  1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China

    Chao Li, Jiaxing Li, Zhixing Wang, Dunhuang Ouyang, Ning Jiao & Song Song

  2. Department of Chemistry, College of Sciences, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai, China

    Xinyao Li

  3. Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Peking University, Beijing, China

    Song Song

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  1. Chao Li
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Contributions

C.L. and S.S. conceived and designed the experiments. X.L. supervised the mechanistic studies. C.L., J.L., Z.W. and D.O. performed the experiments. C.L., J.L., Z.W., D.O., N.J. and S.S. analysed data. C.L., N.J. and S.S. wrote the paper. N.J. and S.S. directed the project.

Corresponding authors

Correspondence to Ning Jiao or Song Song.

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Nature Synthesis thanks Xiao-Chen Wang 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 Sections 1–9, Tables 1–5 and Schemes 1–23.

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Source Data Fig. 5

13C NMR spectroscopy data for Fig. 5b,c.

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Li, C., Li, X., Li, J. et al. Direct regioselective C-3 halogenation of pyridines. Nat. Synth 5, 36–45 (2026). https://doi.org/10.1038/s44160-025-00915-3

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