Abstract
Discovery and application of reactive intermediates has prominently expedited the development of organic chemistry. In this respect, while ketene has been well recognized as a versatile intermediate for a wide range of transformations, practical application of difluoroketene remained virtually unrealized because of its highly reactive nature. Herein, we present a transition-metal-free approach for in situ generation of difluoroketene using difluorobromoacetylsilane as a precursor. The controlled release of chemically labile difluoroketene under mild conditions, achieved through desilylative β-elimination, establishes a foundation for successful development of its Belluš-Claisen rearrangement with allylic amines, Staudinger [2 + 2] cycloaddition with imines, [4 + 2] cycloaddition, as well as insertion into alcohols, amines, and thiols for their difluoroacetylation. A series of mechanistic experiments provide concrete support for the involvement of difluoroketene in these transformations.
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Data availability
The data generated in this study relating to the characterization of starting materials and products, general methods, optimization studies, experimental procedures, mechanistic studies, and NMR spectra are available in Supplementary Information. Data supporting the findings of this manuscript are also available from the corresponding author upon request.
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Acknowledgements
The authors gratefully acknowledge the financial support of the National Natural Science Foundation of China (grant no. 22271151 (C.F.), 22571158 (C.F.), 22301133 (C.Z.)), the State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials (grant no. 2026PT0009 (C.F.)), the State Key Laboratory of Materials-Oriented Chemical Engineering (grant no. SKL-MCE-25A17 (C.F.)).
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C.F. conceived the project and directed the investigations. S.X., C.Z., and L.F. performed the reaction development and condition optimization. S.X. and L.F. performed the synthetic experiments, mechanistic study, and analyzed the experimental data with contributions from H.G., H.Z., and Y.L. C.Z., X.C., Y.Z., and C.F. wrote and revised the manuscript with input from all authors. W.J. contributed to the revision of the manuscript. K.G. and C.F. supervised the project.
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Xi, S., Zhang, C., Fu, L. et al. Unlocking the reactivity of difluoroketene and its synthetic applications. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71202-8
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DOI: https://doi.org/10.1038/s41467-026-71202-8
