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

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.

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.

References

  1. 1.

    Trost, B. M. Selectivity: a key to synthetic efficiency. Science 219, 245–250 (1983).

    CAS  Article  Google Scholar 

  2. 2.

    Baran, P. S., Maimone, T. J. & Richter, J. M. Total synthesis of marine natural products without using protecting groups. Nature 446, 404–408 (2007).

    CAS  Article  Google Scholar 

  3. 3.

    Young, I. S. & Baran, P. S. Protecting-group-free synthesis as an opportunity for invention. Nat. Chem. 1, 193–205 (2009).

    CAS  Article  Google Scholar 

  4. 4.

    Wender, P. A. & Miller, B. L. Synthesis at the molecular frontier. Nature 460, 197–201 (2009).

    CAS  Article  Google Scholar 

  5. 5.

    Zhao, D., Candish, L., Paul, D. & Glorius, F. N-Heterocyclic carbenes in asymmetric hydrogenation. ACS Catal. 6, 5978–5988 (2016).

    CAS  Article  Google Scholar 

  6. 6.

    Wei, Y., Rao, B., Cong, X. & Zeng, X. Highly selective hydrogenation of aromatic ketones and phenols enabled by cyclic (amino)(alkyl)carbene rhodium complexes. J. Am. Chem. Soc. 137, 9250–9253 (2015).

    CAS  Article  Google Scholar 

  7. 7.

    Wiesenfeldt, M. P., Nairoukh, Z., Li, W. & Glorius, F. Hydrogenation of fluoroarenes: direct access to all-cis-(multi)fluorinated cycloalkanes. Science 357, 908–912 (2017).

    CAS  Article  Google Scholar 

  8. 8.

    Wiesenfeldt, M. P., Knecht, T., Schlepphorst, C. & Glorius, F. Silylarene hydrogenation: a strategic approach enabling direct access to versatile silylated saturated carbo- and heterocycles. Angew. Chem. Int. Ed. 57, 8297–8300 (2018).

    CAS  Article  Google Scholar 

  9. 9.

    O’Hagan, D. Pyrrole, pyrrolidine, pyridine, piperidine and tropane alkaloids. Nat. Prod. Rep. 17, 435–446 (2000).

    Article  Google Scholar 

  10. 10.

    Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).

    CAS  Article  Google Scholar 

  11. 11.

    Müller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: Looking beyond intuition. Science 317, 1881–1886 (2007).

    Article  Google Scholar 

  12. 12.

    Shah, P. & Westwell, A. D. The role of fluorine in medicinal chemistry. J. Enzyme Inhib. Med. Chem. 22, 527–540 (2007).

    CAS  Article  Google Scholar 

  13. 13.

    O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C–F bond. Chem. Soc. Rev. 37, 308–319 (2008).

    Article  Google Scholar 

  14. 14.

    Thiehoff, C., Rey, Y. P. & Gilmour, R. The fluorine gauche effect: a brief history. Isr. J. Chem. 57, 92–100 (2017).

    CAS  Article  Google Scholar 

  15. 15.

    Wang, J. et al. Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001−2011). Chem. Rev. 114, 2432–2506 (2014).

    CAS  Article  Google Scholar 

  16. 16.

    Gillis, E. P., Eastman, K. J., Hill, M. D., Donnelly, D. J. & Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 58, 8315–8359 (2015).

    CAS  Article  Google Scholar 

  17. 17.

    Li, X. et al. Process development for scale-up of a novel 3,5-substituted thiazolidine-2,4-dione compound as a potent inhibitor for estrogen-related receptor 1. Org. Process Res. Dev. 18, 321–330 (2014).

    CAS  Article  Google Scholar 

  18. 18.

    Goldberg, N. W., Shen, X., Li, J. & Ritter, T. AlkylFluor: deoxyfluorination of alcohols. Org. Lett. 18, 6102–6104 (2016).

    CAS  Article  Google Scholar 

  19. 19.

    Liu, W. et al. Oxidative aliphatic C–H fluorination with fluoride ion catalyzed by a manganese porphyrin. Science 337, 1322–1325 (2012).

    CAS  Article  Google Scholar 

  20. 20.

    Ventre, S., Petronijevic, F. R. & MacMillan, D. W. C. Decarboxylative fluorination of aliphatic carboxylic acids via photoredox catalysis. J. Am. Chem. Soc. 137, 5654–5657 (2015).

    CAS  Article  Google Scholar 

  21. 21.

    Snyder, J. P., Chandrakumar, N. S., Sato, H. & Lankin, D. C. The unexpected diaxial orientation of cis-3,5-difluoropiperidine in water: a potent CF- - -NH charge-dipole effect. J. Am. Chem. Soc. 122, 544–545 (2000).

    CAS  Article  Google Scholar 

  22. 22.

    Glorius, F., Spielkamp, N., Holle, S., Goddard, R. & Lehmann, C. W. Efficient asymmetric hydrogenation of pyridines. Angew. Chem. Int. Ed. 43, 2850–2852 (2004).

    CAS  Article  Google Scholar 

  23. 23.

    Zhou, Y.-G. Asymmetric hydrogenation of heteroaromatic compounds. Acc. Chem. Res. 40, 1357–1366 (2007).

    CAS  Article  Google Scholar 

  24. 24.

    Whittlesey, M. K. & Peris, E. Catalytic hydrodefluorination with late transition metal complexes. ACS Catal. 4, 3152–3159 (2014).

    CAS  Article  Google Scholar 

  25. 25.

    Dyson, P. J. Arene hydrogenation by homogeneous catalysts: fact or fiction? Dalton Trans. 2003, 2964–2974 (2003).

    Article  Google Scholar 

  26. 26.

    Park, S. & Chang, S. Catalytic dearomatization of N-heteroarenes with silicon and boron compounds. Angew. Chem. Int. Ed. 56, 7720–7738 (2017).

    CAS  Article  Google Scholar 

  27. 27.

    Oshima, K., Ohmura, T. & Suginome, M. Regioselective synthesis of 1,2-dihydropyridines by rhodium-catalyzed hydroboration of pyridines. J. Am. Chem. Soc. 134, 3699–3702 (2012).

    CAS  Article  Google Scholar 

  28. 28.

    Jazzar, R. et al. Intramolecular ‘hydroiminiumation’ of alkenes: application to the synthesis of conjugate acids of cyclic alkyl amino carbenes (CAACs). Angew. Chem. Int. Ed. 46, 2899–2902 (2007).

    CAS  Article  Google Scholar 

  29. 29.

    Lankin, D. C., Chandrakumar, N. S., Rao, S. N., Spangler, D. P. & Snyder, J. P. Protonated 3-fluoropiperidines: an unusual fluoro directing effect and a test for quantitative theories of solvation. J. Am. Chem. Soc. 115, 3356–3357 (1993).

    CAS  Article  Google Scholar 

  30. 30.

    Silla, J. M. et al. Gauche preference of β-fluoroalkyl ammonium salts. J. Phys. Chem. A 118, 503–507 (2014).

    CAS  Article  Google Scholar 

  31. 31.

    Pereiro, A. B. et al. Fluorinated ionic liquids: properties and applications. ACS Sustain. Chem. Eng. 1, 427–439 (2013).

    CAS  Article  Google Scholar 

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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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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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