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Photoinduced benzene ring contraction of arylhydrazines for the synthesis of fused pyridines

Nature Synthesis (2026)Cite this article

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Abstract

The skeletal remodelling of benzene has been widely acknowledged as an attractive yet challenging approach for utilizing the extensive array of aromatic compounds. A primary challenge lies not only in overcoming the high activation barrier associated with the dearomatization step but also in achieving site-selective skeletal modifications within a single operational sequence. Here we present a photothermal cascade activation mode that unlocks the photoactivation reactivity of the transiently generated light-absorbing intermediate formed during interrupted Fischer indolization. Complementary to arene ring expansion methodologies, this protocol offers a practical ring contraction approach for the modular synthesis of fused pyridines with good functional group tolerance and predictable regioselectivity. This strategy is expected to broaden the chemical landscape for the design of innovative photochemical reactions.

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Fig. 1: Introduction.
Fig. 2: Reaction development.
Fig. 3: Scope of the benzene contraction protocol.
Fig. 4: Mechanistic studies and synthetic application.
Fig. 5: Synthetic transformations of the pyrindane products.

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Data availability

Crystallographic data for 3n reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number 2385332. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data supporting the findings of this study are available within this article and its Supplementary Information. The experimental procedures and characterization of all new compounds are provided in the Supplementary Information.

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Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (grant numbers 22571130, 22071086 and 21801165 to A.H., and grant numbers 22201113 and 22371106 to J.-J.G.), the Science and Technology Major Program of Gansu Province of China (22ZD6FA006, 23ZDFA015) and the Fundamental Research Funds for the Central Universities (lzujbky-2020-ct01, lzujbky-2023-ct02). We thank Z. Zuo, Y. Li and Y.-T. Ding for helpful discussions and advice during the preparation of this paper. We also thank the Supercomputing Center of Lanzhou University for providing the computing time.

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Authors and Affiliations

  1. State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China

    Kun Li, Yin Zeng, Kai-Hang Li, Yifan Yang, Jinhui Shen, Huifeng Guo, Yingfei Tan, Jing-Jing Guo & Anhua Hu

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Contributions

J.-J.G. and A.H. designed and conceived the project. K.L., Y.Z., K.-H.L., Y.Y., J.S., H.G. and Y.T. conducted all the synthetic reactions. K.L., Y.Z., K.-H.L., Y.Y. and A.H. analysed and interpreted the experiment data. K.-H.L., Y.Y., J.-J.G. and A.H. designed and performed the mechanistic experiments. K.L. performed the high-resolution mass spectrometry experiments and analysed the data. J.-J.G. performed the DFT calculations. A.H. prepared the paper. K.-H.L., Y.Y., J.-J.G. and A.H. prepared the Supplementary Information.

Corresponding authors

Correspondence to Jing-Jing Guo or Anhua Hu.

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Nature Synthesis thanks Daniel Werz 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 (download PDF )

–Supplementary Sections 1–9, Figs. 1–22 and Tables 1–4.

Supplementary Data 1

Crystallographic data for 3n. CCDC 2385332.

Supplementary Data 2 (download ZIP )

Source data for Supplementary Figs. S8–S11.

Supplementary Data 3 (download ZIP )

Raw NMR data for compounds 1b to 1s.

Supplementary Data 4 (download ZIP )

Raw NMR data for compounds 2 and 6 to 15.

Supplementary Data 5 (download ZIP )

Raw NMR data for compounds 3a to 3r.

Supplementary Data 6 (download ZIP )

Raw NMR data for compounds 3aa to 3aq.

Supplementary Data 7 (download ZIP )

Raw NMR data for compounds 3ar to 3bj.

Supplementary Data 8 (download ZIP )

Raw NMR data for compound 3bd (1).

Supplementary Data 9 (download ZIP )

Raw NMR data for compound 3bd (2).

Supplementary Data 10 (download ZIP )

Raw NMR data for compounds 3s to 3z.

Supplementary Data 11 (download ZIP )

Raw NMR data for compound 4 (1).

Supplementary Data 12 (download ZIP )

Raw NMR data for compound 4 (2).

Supplementary Data 13 (download ZIP )

Raw NMR data for compound 4HCl (1).

Supplementary Data 14 (download ZIP )

Raw NMR data for compound 4HCl (2).

Supplementary Data 15 (download ZIP )

Raw NMR data for compound 4HCl (3).

Supplementary Data 16 (download ZIP )

Raw NMR data for compound 10 (1).

Supplementary Data 17 (download ZIP )

Raw NMR data for compound 10 (2).

Supplementary Data 18 (download ZIP )

Raw NMR data for demethoxysitamaquine and onychine.

Supplementary Data 19 (download ZIP )

Raw NMR data for compounds in Figs. S12 to S17.

Supplementary Data 20 (download ZIP )

Raw NMR data for compounds S1 to S16.

Source data

Source Data Fig. 4 (download XLS )

Statistical source data for Fig. 4.

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Li, K., Zeng, Y., Li, KH. et al. Photoinduced benzene ring contraction of arylhydrazines for the synthesis of fused pyridines. Nat. Synth (2026). https://doi.org/10.1038/s44160-025-00976-4

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