Article | Published:

Direct α-C–H bond functionalization of unprotected cyclic amines

Nature Chemistry volume 10, pages 165169 (2018) | Download Citation

Abstract

Cyclic amines are ubiquitous core structures of bioactive natural products and pharmaceutical drugs. Although the site-selective abstraction of C–H bonds is an attractive strategy for preparing valuable functionalized amines from their readily available parent heterocycles, this approach has largely been limited to substrates that require protection of the amine nitrogen atom. In addition, most methods rely on transition metals and are incompatible with the presence of amine N–H bonds. Here we introduce a protecting-group-free approach for the α-functionalization of cyclic secondary amines. An operationally simple one-pot procedure generates products via a process that involves intermolecular hydride transfer to generate an imine intermediate that is subsequently captured by a nucleophile, such as an alkyl or aryl lithium compound. Reactions are regioselective and stereospecific and enable the rapid preparation of bioactive amines, as exemplified by the facile synthesis of anabasine and (–)-solenopsin A.

  • Compound

    (±)-2-phenylpyrrolidine

  • Compound

    (R)-2-phenylpyrrolidine

  • Compound

    (±)-2-(4-methoxyphenyl)pyrrolidine

  • Compound

    (±)-2-(p-tolyl)pyrrolidine

  • Compound

    (±)-2-(4-fluorophenyl)pyrrolidine

  • Compound

    (±)-2-(4-chlorophenyl)pyrrolidine

  • Compound

    (±)-2-(4-bromophenyl)pyrrolidine

  • Compound

    (±)-2-(4-(trifluoromethyl)phenyl)pyrrolidine

  • Compound

    (±)-2-(m-tolyl)pyrrolidine

  • Compound

    (±)-2-(2-methoxyphenyl)pyrrolidine

  • Compound

    (±)-2-(o-tolyl)pyrrolidine

  • Compound

    (±)-2-(naphthalen-2-yl)pyrrolidine

  • Compound

    (±)-2-(naphthalen-1-yl)pyrrolidine

  • Compound

    (±)-(E)-2-styrylpyrrolidine

  • Compound

    (±)-3-(pyrrolidin-2-yl)pyridine

  • Compound

    (±)-2-(thiophen-2-yl)pyrrolidine

  • Compound

    (±)-1-phenyloctahydrocyclopenta[c]pyrrole

  • Compound

    (±)-1-phenyl-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole

  • Compound

    (±)-2-phenylpiperidine

  • Compound

    (±)-anabasine

  • Compound

    (±)-(E)-2-styrylpiperidine

  • Compound

    (±)-1-benzyl-3-phenylpiperazine

  • Compound

    (±)-trans-2,4-diphenylpiperidine

  • Compound

    (±)-1-phenyl-1,2,3,4-tetrahydroisoquinoline

  • Compound

    (±)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline

  • Compound

    (±)-2-phenylazepane

  • Compound

    (±)-2-phenylazocane

  • Compound

    (±)-2-phenylazacyclotridecane

  • Compound

    (±)-2-butylazacyclotridecane

  • Compound

    (2R,5S)-2-phenyl-5-(((triisopropylsilyl)oxy)methyl)pyrrolidine

  • Compound

    (2S,5S)-2-phenyl-5-(((triisopropylsilyl)oxy)methyl)pyrrolidine

  • Compound

    (±)-trans-2-methyl-5-phenylpyrrolidine

  • Compound

    (±)-trans-2-butyl-5-phenylpyrrolidine

  • Compound

    (±)-trans-2,5-diphenylpyrrolidine

  • Compound

    (2R,5R)-2,5-diphenylpyrrolidine

  • Compound

    (±)-3-(trans-5-phenylpyrrolidin-2-yl)pyridine

  • Compound

    (±)-trans-2-phenyl-6-(((triisopropylsilyl)oxy)methyl)piperidine

  • Compound

    (±)-trans-2-methyl-6-phenylpiperidine

  • Compound

    (±)-trans-2-butyl-6-phenylpiperidine

  • Compound

    (±)-trans-2,6-diphenylpiperidine

  • Compound

    (±)-trans-2,7-diphenylazepane

  • Compound

    (±)-trans-2-(4-methoxyphenyl)-7-phenylazepane

  • Compound

    (±)-trans-2-(4-chlorophenyl)-7-phenylazepane

  • Compound

    (R)-2-methylpiperidine

  • Compound

    (–)-solenopsin A

  • Compound

    (±)-3-(trans-6-phenylpiperidin-2-yl)pyridine

  • Compound

    (±)-2-phenyl-2,3,4,5-tetrahydro-1H-1,5-methanobenzo[d]azepine

  • Compound

    (±)-2-butyl-2,3,4,5-tetrahydro-1H-1,5-methanobenzo[d]azepine

  • Compound

    (±)-trans-6-fluoro-3-(2-phenylpiperidin-4-yl)benzo[d]isoxazole

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Acknowledgements

Financial support from the NIH–NIGMS (R01GM101389) is gratefully acknowledged. We thank T. Emge (Rutgers University) for the crystallographic analysis.

Author information

Author notes

    • Anirudra Paul
    •  & Daniel Seidel

    Present address: Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA

    • Weijie Chen
    •  & Longle Ma

    These authors contributed equally to this work.

Affiliations

  1. Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA

    • Weijie Chen
    • , Longle Ma
    • , Anirudra Paul
    •  & Daniel Seidel

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Contributions

W.C. and L.M. developed the amine α-functionalization and contributed equally to this work. A.P. further developed the reaction and expanded the scope. D.S. conceived and supervised the project and wrote the manuscript. All the authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Daniel Seidel.

Supplementary information

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    Supplementary information

    Supplementary information

Crystallographic information files

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    Supplementary information

    Crystallographic data for compound ±45.

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DOI

https://doi.org/10.1038/nchem.2871

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