Abstract
Developing practical strategies to produce high-value chemicals, such as pharmacologically active molecules, from bulk starting materials is an ongoing challenge. One potential route to this goal is the C(sp3)–H fluoroalkylation of natural products, made possible by the unique physiological properties of fluorine-containing groups. However, protocols for such fluoroalkylation remain underdeveloped. Here we report a method for the site-selective allylic fluoroalkylation of olefins through a cobalt-catalysed process comprising halogen-atom transfer and hydrogen-atom transfer. This low-cost and operationally simple protocol is readily scalable to a 2 mol scale under mild conditions. Mechanistic studies indicate that both the cobaloxime catalyst and N,N-diisopropylethylamine are essential for producing fluoroalkyl radicals. Density functional theory calculations reveal that the observed site-selectivity is controlled by steric hindrance in the cobalt-promoted hydrogen-atom transfer step.
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The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information.
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Acknowledgements
This work was supported by the National Key R&D Program of China (grant number 2021YFA1500104, A.L.), the National Natural Science Foundation of China (grant number 22031008, A.L.), the Science Foundation of Wuhan (grant number 2020010601012192, A.L.), and the Postdoctoral Foundation of Hubei Province (grant number 211000025, S.W.). We thank M. Guo (WHU) and Q. Lu (WHU) for their suggestions, Shanghai Synchrotron Radiation Facility (SSRF) for XAFS testing, H. Yang (THU) and Y. Fan (Chinainstru & Quantumtech) for EPR testing with X-band EPR100, and Zhejiang Jiuzhou Pharmaceutical for 2 mol scale experiments. X.Q. acknowledges the supercomputing system in the Supercomputing Center of Wuhan University.
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A.L. and S.W. conceived the work. S.W. and D.R. designed the experiments and analysed the data. D.R. and S.W. performed the synthetic experiments. S.W., D.Y. and Y.G. contributed to the XAFS data. S.W. and P.W. contributed to the EPR data. Z.L. and X.Q. contributed to the DFT calculation. S.W. wrote the original manuscript which all authors revised.
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Nature Synthesis thanks Baomin Fan, Yu-hong Lam, Emmanuel Magnier 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 Methods, Discussion, Tables 1–6 and Figs. 1–10.
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Wang, S., Ren, D., Liu, Z. et al. Cobalt-catalysed allylic fluoroalkylation of terpenes. Nat. Synth 2, 1202–1210 (2023). https://doi.org/10.1038/s44160-023-00365-9
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DOI: https://doi.org/10.1038/s44160-023-00365-9
