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The formation of all-cis-(multi)fluorinated piperidines by a dearomatization–hydrogenation process

Nature Chemistry volume 11, pages 264–270 (2019)Cite this article

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Abstract

Piperidines and fluorine substituents are both independently indispensable components in pharmaceuticals, agrochemicals and materials. Logically, the incorporation of fluorine atoms into piperidine scaffolds is therefore an area of tremendous potential. However, synthetic approaches towards the formation of these architectures are often impractical. The diastereoselective synthesis of substituted monofluorinated piperidines often requires substrates with pre-defined stereochemistry. That of multifluorinated piperidines is even more challenging, and often needs to be carried out in multistep syntheses. In this report, we describe a straightforward process for the one-pot rhodium-catalysed dearomatization–hydrogenation of fluoropyridine precursors. This strategy enables the formation of a plethora of substituted all-cis-(multi)fluorinated piperidines in a highly diastereoselective fashion through pyridine dearomatization followed by complete saturation of the resulting intermediates by hydrogenation. Fluorinated piperidines with defined axial/equatorial orientation of fluorine substituents were successfully applied in the preparation of commercial drugs analogues. Additionally, fluorinated PipPhos as well as fluorinated ionic liquids were obtained by this dearomatization–hydrogenation process.

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Fig. 1: Preparation of all-cis-(multi)fluorinated piperidines by the dearomatization–hydrogenation process.
Fig. 2: Selected mechanistic experiments for the DAH process.
Fig. 3: Application of the all-cis-(multi)fluorinated piperidine building blocks.

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Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers CCDC 1845054 (29) and 1845055 (60). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data supporting the findings of this study are available within the Article and its Supplementary Information, or from the corresponding author upon reasonable request.

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Acknowledgements

The authors acknowledge financial support from the Hans-Jensen-Minerva Foundation (Z.N.), the Deutsche Forschungsgemeinschaft IRTG 2027 (M.W.) and the European Research Council (ERC Advanced Grant Agreement no. 788558). The authors thank M.P. Wiesenfeldt, M. Teders, M.J. James and M. van Gemmeren for helpful discussions. C.G. Daniliuc is acknowledged for X-ray crystallographic analysis. 1-(cis-3,5-difluoropiperidin-1-yl)-2,2,2-trifluoroethan-1-one (3) is available from Sigma-Aldrich (product no. 903817).

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Authors and Affiliations

  1. Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Münster, Germany

    Zackaria Nairoukh, Marco Wollenburg, Christoph Schlepphorst, Klaus Bergander & Frank Glorius

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  1. Zackaria Nairoukh
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  2. Marco Wollenburg
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  3. Christoph Schlepphorst
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  4. Klaus Bergander
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Contributions

Z.N., M.W., C.S. and F.G. designed, performed and analysed experiments. K.B. performed and analysed NMR data. Z.N. and F.G. prepared the manuscript with contributions from all authors.

Corresponding author

Correspondence to Frank Glorius.

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Competing interests

Z.N., C.S. and F.G. are inventors on German patent application DE 10 2018 104 201.9 held by WWU Muenster, which covers the DAH process for the synthesis of all-cis-(multi)fluorinated aliphatic heterocycles.

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Supplementary information

Supplementary information

Detailed experimental procedures, extensive optimization data, comprehensive NMR analysis and MS data of all new compounds, crystallographic reports and mechanistic studies

Crystallographic data

CIF for compound 29; CDCC reference 1845054

Crystallographic data

CIF for compound 60; CDCC reference 1845055

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Nairoukh, Z., Wollenburg, M., Schlepphorst, C. et al. The formation of all-cis-(multi)fluorinated piperidines by a dearomatization–hydrogenation process. Nature Chem 11, 264–270 (2019). https://doi.org/10.1038/s41557-018-0197-2

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