Abstract
N-monofluoromethyl (N-CH2F) amides, combining amide and monofluoromethyl motifs, represent a practical modification of the amide bond that can mimic N-CH3 amides. Despite the potential value in transforming peptides and peptidomimetics with N-CH2F, the very existence of this structure has been controversial. Here we report the preparation of N-CH2F amides and carbamates via simple and robust chemical methods. The syntheses of N-CH2F amides were achieved via successive acylation and fluorination of imines and directly used in the modification of drugs, peptides and heteroaryl amides without racemization or epimerization. The use of triethylamine is the key to the separation of N-CH2F amides. The stability of nine structurally diverse N-CH2F amides was tested in eight different media, showing that most compounds remained 60–100% intact for 24 h.
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Data availability
The authors declare that all the data supporting the findings of this study are available within the article and its Supplementary Information. Crystallographic data for structure 20 reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2330509. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.
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Acknowledgements
We thank funding support from the National Natural Science Foundation of China (grant numbers 82373839 and 22301315), and the Hundred Talents Programme of Sun Yat-sen University.
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M.T. and J.Q. carried out and analysed the experiment. L.D., D.M.W. and X.Z. wrote the paper. J.L., the head of the project, conceived and supervised the project.
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Supplementary Figs. 1–42, Tables 1–8, procedural details and synthesis and characterization data (NMR spectra, HRMS data, high-performance liquid chromatography spectra and X-ray crystallographic data).
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Crystallographic data for compound 20, CCDC reference 2330509.
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Tao, M., Qian, J., Deng, L. et al. Preparation, separation and storage of N-monofluoromethyl amides and carbamates. Nat. Chem. 17, 532–540 (2025). https://doi.org/10.1038/s41557-025-01767-2
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DOI: https://doi.org/10.1038/s41557-025-01767-2
