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α-Fluorination of carbonyls with nucleophilic fluorine

Nature Chemistry volume 11, pages 329–334 (2019)Cite this article

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Abstract

Given the unique properties of fluorine, and the ability of fluorination to change the properties of organic molecules, there is significant interest from medicinal chemists in innovative methodologies that enable the synthesis of new fluorinated motifs. State-of-the-art syntheses of α-fluorinated carbonyl compounds invariably rely on electrophilic fluorinating agents, which can be strongly oxidizing and difficult to handle. Here we show that reversing the polarity of the enolate partner to that of an enolonium enables nucleophilic fluorinating agents to be used for direct chemoselective α-C–H-fluorination of amides. Reduction of these products enables facile access to β-fluorinated amines and the value of this methodology is shown by the easy preparation of a number of fluorinated analogues of drugs and agrochemicals. A fluorinated analogue of citalopram, a marketed antidepressant drug, is presented as an example of the preserved biological activity after fluorination.

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Fig. 1: Importance of fluorination in medicinal chemistry and approaches to α-fluorinated amides.
Fig. 2: Preparation of fluorinated analogues of pharmaceutical and agrochemical compounds.

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Data availability

The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

A. Roller (University of Vienna) is thanked for X-ray crystallographic determination, E. Macoratti (University of Vienna) for preparative HPLC and G. Di Mauro for assistance with LigandScout. The authors thank the University of Vienna for continued support of their research programmes. Financial support by the Austrian Research Fund/FWF (grant F3506 to H.S.S.; grant M2274 to C.J.T.; grant P30226 to N.M.) and the Austrian Academy of Sciences (DOC-fellowship to D.K.) is acknowledged.

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Author notes

  1. These authors contributed equally: Pauline Adler and Christopher J. Teskey.

Authors and Affiliations

  1. Institute of Organic Chemistry, University of Vienna, Vienna, Austria

    Pauline Adler, Christopher J. Teskey, Daniel Kaiser & Nuno Maulide

  2. Centre of Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria

    Marion Holy & Harald H. Sitte

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  1. Pauline Adler
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Contributions

P.A., C.J.T and D.K. performed and analysed the chemical experiments. P.A., C.J.T and N.M. co-wrote the manuscript. M.H and H.H.S. performed the biological testing. N.M. directed the project.

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Correspondence to Nuno Maulide.

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Supplementary information

Supplementary Information

Supplementary optimization data, experimental details and compound characterization data

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Crystallographic data

CIF for compound (S,S)−9-L-DBTA; CCDC reference: 1866533

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Adler, P., Teskey, C.J., Kaiser, D. et al. α-Fluorination of carbonyls with nucleophilic fluorine. Nat. Chem. 11, 329–334 (2019). https://doi.org/10.1038/s41557-019-0215-z

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