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Switchable skeletal editing of quinolines enabled by cyclizative sequential rearrangements

Nature Chemistry volume 17, pages 952–960 (2025)Cite this article

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Abstract

The rapid diversification of core ring structures in complex molecules through switchable skeletal editing is valuable in the drug discovery process. However, controllable methods for chemically divergent modifications of azaarene frameworks using common substrates are challenging, despite the potential to maximize structural diversity and complexity. Here we report the tunable skeletal editing of quinolines through Brønsted acid-catalysed multicomponent reactions of quinoline N-oxides, dialkyl acetylenedicarboxylates and water to generate nitrogen-containing heteroaromatic compounds together with linear compounds in a modular fashion. Specifically, in a one-pot procedure, after cyclization and sequential rearrangement processes, the quinoline N-oxides are easily converted into unique 2-substituted indolines. These then undergo acid-promoted fragmentation to give indoles, base-facilitated ring-opening to afford 2-alkenylanilines and oxidative cyclization to yield isoquinolinones. Catalytic asymmetric skeletal editing of quinolines is also realized, providing enantioenriched benzazepines bearing quaternary stereocentres, and late-stage skeletal modification of quinoline cores in several drugs is demonstrated.

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Fig. 1: Skeletal editing of heterocycles.
Fig. 2: Scale-up reactions, synthetic transformation of the products, control experiments and reaction pathways.

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Data availability

The data supporting the findings of this study are available within the Article and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2334869 (84), CCDC 2401914 (103), CCDC 2385984 (109) and CCDC 2334870 (110). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (grant nos. 22371183 and 22101172 to H.W.). We thank L.-L. Li for the X-ray structural analysis of compounds 84, 103, 109 and 110.

Author information

Authors and Affiliations

  1. Shanghai Frontiers Science Center for Drug Target Identification and Delivery, Laboratory of Innovative Immunotherapy, and Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China

    Di Tian, Yu-Ping He, Lu-Sen Yang, Zhuo-Chen Li & Hua Wu

  2. Department of Chemistry, College of Sciences, Shanghai University, Shanghai, China

    Yu-Ping He

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  1. Di Tian
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Contributions

D.T., Y.-P.H., L.-S.Y. and Z.-C.L. designed the experiments and collected and analysed the data. D.T. optimized the reaction conditions and performed the experiments. Y.-P.H. determined and optimized the initial reaction conditions for asymmetric skeletal editing. L.-S.Y. and Z.-C.L. contributed to the preparation of substrates. H.W. supervised the research and conceived the project. H.W. wrote the paper with input from all authors.

Corresponding author

Correspondence to Hua Wu.

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The authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks Sunewang R. Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Fig. 1, Tables 1–11, experimental procedures, synthetic procedures, characterization data, NMR spectra and HPLC traces.

Supplementary Data 1

Crystallographic data for compound 84; CCDC reference 2334869.

Supplementary Data 2

Structure factors of compound 84; CCDC reference 2334869.

Supplementary Data 3

Crystallographic data for compound 103; CCDC reference 2401914.

Supplementary Data 4

Structure factors of compound 103; CCDC reference 2401914.

Supplementary Data 5

Crystallographic data for compound 109; CCDC reference2385984.

Supplementary Data 6

Structure factors of compound 109; CCDC reference 2385984.

Supplementary Data 7

Crystallographic data for compound 110; CCDC reference 2334870.

Supplementary Data 8

Structure factors of compound 110; CCDC reference 2334870.

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Tian, D., He, YP., Yang, LS. et al. Switchable skeletal editing of quinolines enabled by cyclizative sequential rearrangements. Nat. Chem. 17, 952–960 (2025). https://doi.org/10.1038/s41557-025-01793-0

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