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Isolable iminium ions as a platform for N-(hetero)aryl piperidine synthesis

Nature Synthesis volume 2, pages 1059–1067 (2023)Cite this article

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Abstract

Piperidines are prevalent throughout Food and Drug Administration-approved drugs and current drug candidates, and thus robust methods for preparing these heterocycles are desirable for efficiently probing structure–activity relationships during drug discovery campaigns. N-(Hetero)aryl piperidines are particularly important in pharmaceutical applications, but remain difficult to synthesize because traditional approaches based on transition-metal-catalysed cross-coupling or SNAr reactions routinely fail. Here we report a general platform for the rapid synthesis of a range of densely functionalized N-(hetero)aryl piperidine derivatives using a common iminium ion precursor. An expeditious synthesis of bench-stable cyclic iminium salts starting from widely abundant heteroaryl-amine and ketoacrylate feedstocks is disclosed. We then show that these intermediates are readily functionalized, rapidly yielding a variety of complex piperidines.

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Fig. 1: Approaches to hindered N-(hetero)aryl piperidines.
Fig. 2: Diversification of iminium salt 1a for rapid synthesis of piperidine analogues.
Fig. 3: Scope of C2-disubstituted piperidines in the one-pot process.
Fig. 4: Sequential C3/C2 difunctionalization of iminium salts.

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Data availability

All data supporting the findings of this study are available within the Article and its Supplementary Information. The X-ray crystallographic coordinates for compound 1a reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number 2170178. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements

We thank M. Gribble, E. Phillips, X. Ma, M. Mitcheltree, E. Edelstein, B. Sherry and L.-C. Campeau (Merck & Co., Inc., Rahway, NJ, USA) for helpful advice during the preparation of this manuscript. We thank D. Adpressa (Merck & Co., Inc., Rahway, NJ, USA) for preliminary NMR spectroscopy investigations. We also thank X. Wang (Merck & Co., Inc., Rahway, NJ, USA) for helpful discussions regarding NMR spectroscopy characterization.

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Author notes

  1. Matthew A. Larsen

    Present address: Promega Biosciences LLC, San Luis Obispo, CA, USA

Authors and Affiliations

  1. Process Research and Development, Merck & Co., Inc., Boston, MA, USA

    Jacob W. Greenwood & Aaron C. Sather

  2. Department of Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA

    Matthew A. Larsen

  3. Analytical Research and Development, Merck & Co., Inc., Boston, MA, USA

    Samantha A. Burgess & Yuan Jiang

  4. Analytical Research and Development, Merck & Co., Inc., Rahway, NJ, USA

    Justin A. Newman

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Contributions

All authors have given approval to the final version of the manuscript. A.C.S. and J.W.G. conceived, performed and designed the experiments, analysed the data and wrote the manuscript. M.A.L. conceived, performed and designed the experiments. S.A.B. conceived, designed and performed the NMR spectroscopy experiments and analysed the data. J.A.N. performed the single-crystal X-ray diffraction experiments and analysed the data. Y.J. performed the high-resolution mass spectrometry experiments and analysed the data.

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Correspondence to Aaron C. Sather.

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Nature Synthesis thanks Bo Qu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary handling editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Experimental details, Supplementary sections 1–9, Figs. 1–205, Tables 1–6 and Scheme 1.

Supplementary Data 1

Crystallographic data for 1a, CCDC 2170178.

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Greenwood, J.W., Larsen, M.A., Burgess, S.A. et al. Isolable iminium ions as a platform for N-(hetero)aryl piperidine synthesis. Nat. Synth 2, 1059–1067 (2023). https://doi.org/10.1038/s44160-023-00313-7

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