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SnAP reagents for the one-step synthesis of medium-ring saturated N-heterocycles from aldehydes

Nature Chemistry volume 6, pages 310–314 (2014)Cite this article

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Abstract

Interest in saturated N-heterocycles as scaffolds for the synthesis of bioactive molecules is increasing. Reliable and predictable synthetic methods for the preparation of these compounds, especially medium-sized rings, are limited. We describe the development of SnAP (Sn amino protocol) reagents for the transformation of aldehydes into seven-, eight- and nine-membered saturated N-heterocycles. This process occurs under mild, room-temperature conditions and offers exceptional substrate scope and functional-group tolerance. Air- and moisture-stable SnAP reagents are prepared on a multigram scale from inexpensive starting materials by simple reaction sequences. These new reagents and processes allow widely available aryl, heteroaryl and aliphatic aldehydes to be converted into diverse N-heterocycles, including diazepanes, oxazepanes, diazocanes, oxazocanes and hexahydrobenzoxazonines, by a single synthetic operation.

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Figure 1: The SnAP-reagent concept.
Figure 2: SnAP reagents for seven-, eight- and nine-membered ring synthesis.
Figure 3: Gram-scale synthesis of substituted 1,4-oxazepane.
Figure 4: Proposed mechanism for copper-mediated cyclization.

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Acknowledgements

This work was supported by an ETH Research Grant (ETH-12 11-1) and the European Research Council (ERC Starting Grant No. 306793 – CASAA). The authors acknowledge L. Bertschi for assistance with mass spectrometry analysis.

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  1. Cam-Van T. Vo and Michael U. Luescher: These authors contributed equally

Authors and Affiliations

  1. Laboratorium für Organische Chemie, ETH–Zürich, Wolfgang Pauli Strasse 10, Zürich, 8093, Switzerland

    Cam-Van T. Vo, Michael U. Luescher & Jeffrey W. Bode

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  1. Cam-Van T. Vo
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  2. Michael U. Luescher
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Contributions

C-V.T.V. and M.U.L. performed the experiments, compound characterization and data analysis. All authors contributed to experiment design, discussions and writing the manuscripts.

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Correspondence to Jeffrey W. Bode.

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The authors declare no competing financial interests.

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Crystallographic data for compound 11b (CIF 362 kb)

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Vo, CV., Luescher, M. & Bode, J. SnAP reagents for the one-step synthesis of medium-ring saturated N-heterocycles from aldehydes. Nature Chem 6, 310–314 (2014). https://doi.org/10.1038/nchem.1878

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