Article | Published:

Benzazetidine synthesis via palladium-catalysed intramolecular C−H amination

Nature Chemistry volume 8, pages 11311136 (2016) | Download Citation

Abstract

Small-sized N-heterocycles are important structures in organic synthesis and medicinal chemistry. Palladium-catalysed intramolecular aminations of the C−H bonds of unfunctionalized amine precursors have recently emerged as an attractive new method for N-heterocycle synthesis. However, the way to control the reactivity of high-valent Pd intermediates to form the desired C−N cyclized products selectively remains poorly addressed. Herein we report a strategy to control the reductive elimination (RE) pathways in high-valent Pd catalysis and apply this strategy to achieve the synthesis of highly strained four-membered benzazetidines via the Pd-catalysed intramolecular C−H amination of N-benzyl picolinamides. These reactions represent the first practical synthetic method for benzazetidines and enable access to a range of complex benzazetidines from easily obtainable starting materials. The use of a newly designed phenyliodonium dimethylmalonate reagent is critical, as oxidation of Pd(II) palladacycles with this reagent favours a kinetically controlled C−N RE pathway to give strained ring-closed products.

  • Compound

    N-picolinoyl-2-methoxybenzylamine

  • Compound

    N-picolinoyl-2-nitro-6-acetoxybenzylamine

  • Compound

    N-picolinoyl-3-methoxybenzazetidine

  • Compound

    dimethylmalonic acid

  • Compound

    Iodobenzene dimethylmalonate oligomer

  • Compound

    N-picolinoyl-2-methoxy-6-isobutyryloxybenzylamine

  • Compound

    N-picolinoyl-3-trifluoromethylbenzazetidine

  • Compound

    N-picolinoyl-2-trifluoromethyl-6-isobutyryloxybenzylamine

  • Compound

    N-picolinoyl-3-nitrobenzazetidine

  • Compound

    N-picolinoyl-2-nitro-6-isobutyryloxybenzylamine

  • Compound

    N-picolinoyl-3-iodobenzazetidine

  • Compound

    N-picolinoyl-2-iodo-6-isobutyryloxybenzylamine

  • Compound

    N-picolinoyl-3-carbomethoxybenzazetidine

  • Compound

    N-picolinoyl-2-carbomethoxy-6-isobutyryloxybenzylamine

  • Compound

    N-picolinoyl-3-(2-methyl-1,3-dioxolan-2-yl)-benzazetidine

  • Compound

    N-picolinoyl-2-(2-methyl-1,3-dioxolan-2-yl)-6-isobutyryloxybenzylamine

  • Compound

    N-picolinoyl-3-isopropylbenzazetidine

  • Compound

    N-picolinoyl-2-isopropyl-6-isobutyryloxybenzylamine

  • Compound

    N-picolinoyl-3-carbomethoxy-5-bromobenzazetidine

  • Compound

    N-picolinoyl-2-carbomethoxy-4-bromo-6-isobutyryloxybenzylamine

  • Compound

    N-picolinoyl-3-trifluoromethyl-5-carbomethoxybenzazetidine

  • Compound

    N-picolinoyl-2-trifluoromethyl-4-carbomethoxy-6-isobutyryloxybenzylamine

  • Compound

    N-picolinoyl-3-trifluoromethyl-5-(benzylcarbamoyl)-benzazetidine

  • Compound

    N-picolinoyl-3-(3-nitrophenyl)-benzazetidine

  • Compound

    N-picolinoyl-3-(2-chloropyridin-4-yl)-benzazetidine

  • Compound

    N-picolinoyl-2-chloro-3-aza-5,6-dihydrophenanthridine

  • Compound

    N-picolinoyl-3-(3,5-ditrifluoromethyl-phenyl)-benzazetidine

  • Compound

    N-picolinoyl-2-(3,5-ditrifluoromethyl-phenyl)-6-isobutyryloxybenzylamine

  • Compound

    N-picolinoyl-3-(3-acetyl-phenyl)-benzazetidine

  • Compound

    N-picolinoyl-2-acetyl-5,6-dihydrophenanthridine

  • Compound

    3-nitrobenzazetidine

  • Compound

    3-trifluoromethyl-5-(benzylcarbamoyl)-benzazetidine

  • Compound

    bimetallic palladium complex of N-picolinoyl-2-trifluoromethylbenzylamine with two acetate bridge ligands

  • Compound

    monometallic palladacycle complex of N-picolinoyl-2-trifluoromethylbenzylamine with an acetonitrile ligand

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Acknowledgements

G.C. thanks the State Key Laboratory of Elemento-Organic Chemistry at Nankai University and the Pennsylvania State University for financial support for the experimental part of this work. P.L. thanks the University of Pittsburgh for financial support for the computational part of the work. Calculations were performed at the Center for Simulation and Modeling at the University of Pittsburgh and the Extreme Science and Engineering Discovery Environment (XSEDE) supported by the National Science Foundation.

Author information

Affiliations

  1. State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China

    • Gang He
    • , Zhengwei Guo
    •  & Gong Chen
  2. Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA

    • Gang Lu
    •  & Peng Liu
  3. Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA

    • Gong Chen

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Contributions

G.H. discovered the benzazetidine synthesis via the Pd-catalysed IDCA reaction of benzylamines, introduced the PhI(DMM) reagent, carried out most of the reaction optimization and structural determination of the reaction products and prepared the Supplementary Information. Z.G. helped in the preparation of some benzylamine substrates and contributed to the reaction optimization. G.L. conducted the computations. P.L. directed the computational studies. P.L. and G.L. prepared the computational sections of the manuscript. G.C. formulated the initial ideas of this work, supervised all the experiments, coordinated with P.L. on the computational studies and prepared most of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Gang He or Peng Liu or Gong Chen.

Supplementary information

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    Supplementary information

    Supplementary information

Crystallographic information files

  1. 1.

    Supplementary information

    Crystallographic data for compound 5.

  2. 2.

    Supplementary information

    Crystallographic data for complexA.

  3. 3.

    Supplementary information

    Crystallographic data for compound 21N.

  4. 4.

    Supplementary information

    Crystallographic data for compound 26.

  5. 5.

    Supplementary information

    Crystallographic data for palladacycle complexE.

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DOI

https://doi.org/10.1038/nchem.2585

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