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Oxidative aliphatic C-H fluorination with manganese catalysts and fluoride ion


Fluorination is a reaction that is useful in improving the chemical stability and changing the binding affinity of biologically active compounds. The protocol described here can be used to replace aliphatic, C(sp3)-H hydrogen in small molecules with fluorine. Notably, isolated methylene groups and unactivated benzylic sites are accessible. The method uses readily available manganese porphyrin and manganese salen catalysts and various fluoride ion reagents, including silver fluoride (AgF), tetrabutylammonium fluoride and triethylamine trihydrofluoride (TREAT·HF), as the source of fluorine. Typically, the reactions afford 50–70% yield of mono-fluorinated products in one step. Two representative examples, the fragrance component celestolide and the nonsteroidal anti-inflammatory drug ibuprofen, are described; they produced useful isolated quantities (250–300 mg, 50% yield) of fluorinated material over periods of 1–8 h. The procedures are performed in a typical fume hood using ordinary laboratory glassware. No special precautions to rigorously exclude water are required.

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Figure 3: Reaction setup.
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Figure 7: Monitoring the reaction by GC-MS.
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C-H fluorination of hydrocarbons and method development were supported by the Center for Catalytic Hydrocarbon Functionalization, an Energy Frontier Research Center, US Department of Energy, Office of Science, Basic Energy Sciences, under award no. DE SC0001298. Fluorination of biomolecules and mechanistic analyses were supported by the US National Science Foundation (CHE-1148597). Purchase of the GC-mass spectrometer was supported by the National Institutes of Health (2R37 GM036298). Partial support of this work, including the purchase of flash chromatographic equipment, was provided by Merck, Inc.

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W.L., X.H. and J.T.G. designed the experiments; W.L. and X.H. conducted the experiments; W.L., X.H. and J.T.G. analyzed the data and wrote the manuscript.

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Correspondence to John T Groves.

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The authors declare no competing financial interests.

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Liu, W., Huang, X. & Groves, J. Oxidative aliphatic C-H fluorination with manganese catalysts and fluoride ion. Nat Protoc 8, 2348–2354 (2013).

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