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Tunable molecular editing of indoles with fluoroalkyl carbenes

Nature Chemistry (2024)Cite this article

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Abstract

Building molecular complexity from simple feedstocks through precise peripheral and skeletal modifications is central to modern organic synthesis. Nevertheless, a controllable strategy through which both the core skeleton and the periphery of an aromatic heterocycle can be modified with a common substrate remains elusive, despite its potential to maximize structural diversity and applications. Here we report a carbene-initiated chemodivergent molecular editing of indoles that allows both skeletal and peripheral editing by trapping an electrophilic fluoroalkyl carbene generated in situ from fluoroalkyl N-triftosylhydrazones. A variety of fluorine-containing N-heterocyclic scaffolds have been efficiently achieved through tunable chemoselective editing reactions at the skeleton or periphery of indoles, including one-carbon insertion, C3 gem-difluoroolefination, tandem cyclopropanation and N1 gem-difluoroolefination, and cyclopropanation. The power of this chemodivergent molecular editing strategy has been highlighted through the modification of the skeleton or periphery of natural products in a controllable and chemoselective manner. The reaction mechanism and origins of the chemo- and regioselectivity have been probed by both experimental and theoretical methods.

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Fig. 1: Molecular editing of heterocycles.
Fig. 2: Skeletal editing of indoles with fluoroalkyl N-triftosylhydrazones.
Fig. 3: Peripheral editing of indoles with fluoroalkyl N-triftosylhydrazones.
Fig. 4: Scale-up synthesis, chemodivergent molecular editing of natural products and mechanistic study.
Fig. 5: Computational investigations.

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Data availability

The data that support the findings of this study are available in this paper and its Supplementary Information. Crystallographic data for the structures reported in this paper have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers CCDC 2223703 (3), 2220789 (51), 2259107 (72) and 2194938 (127). 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. 22331004, 21871043 and 21961130376 to X.B., and grant no. 22371035 to Z.L.) and the Department of Science and Technology of Jilin Province (grant no. 20230508054RC to Z.L.). We thank W. Guan of Northeast Normal University for assistance with the computational studies.

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Author notes

  1. These authors contributed equally: Shaopeng Liu, Yong Yang, Qingmin Song.

Authors and Affiliations

  1. Department of Chemistry, Northeast Normal University, Changchun, China

    Shaopeng Liu, Yong Yang, Qingmin Song, Zhaohong Liu, Ying Lu, Zhanjing Wang, Paramasivam Sivaguru & Xihe Bi

  2. State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China

    Xihe Bi

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Contributions

S.L. and Y.Y. conducted and analysed the experiments described in this paper. Y.L. and Z.W. helped with substrate synthesis and data collection. Q.S. carried out the DFT calculations. Z.L. and X.B. conceived the concept, supervised the experiments and prepared the paper with P.S. All authors discussed the results and commented on the manuscript.

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Correspondence to Zhaohong Liu or Xihe Bi.

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The authors declare no competing interests.

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Nature Chemistry thanks Yu-hong Lam and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Materials and Methods, Supplementary Figs. 1–586, Tables 1–4 and spectral data for all new compounds.

Supplementary Data 1

Crystallographic data for compound 3; CCDC reference 2223703.

Supplementary Data 2

Crystallographic data for compound 51; CCDC reference 2220789.

Supplementary Data 3

Crystallographic data for compound 72; CCDC reference 2259107.

Supplementary Data 4

Crystallographic data for compound 127; CCDC reference 2194938.

Supplementary Data 5

Computational data for DFT calculations.

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Liu, S., Yang, Y., Song, Q. et al. Tunable molecular editing of indoles with fluoroalkyl carbenes. Nat. Chem. (2024). https://doi.org/10.1038/s41557-024-01468-2

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