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Benzazetidine synthesis via palladium-catalysed intramolecular C−H amination

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.

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Figure 1: Strategy for the synthesis of small-sized N-heterocycles via Pd-catalysed IDCA.
Figure 2: Synthesis of benzazetidine via Pd-catalysed IDCA of PA-coupled benzylamine.
Figure 3: Substrate scope of benzazetidine synthesis.
Figure 4: Facile removal of the PA group.
Figure 5: Computational studies of Pd-catalysed IDCAs of N-benzyl PAs with PhI(OAc)2 and PhI(DMM) (R, CF3).

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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.

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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.

Corresponding authors

Correspondence to Gang He or Peng Liu or Gong Chen.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 20978 kb)

Supplementary information

Crystallographic data for compound 5. (CIF 13 kb)

Supplementary information

Structure factors file for compound 5. (FCF 157 kb)

Supplementary information

Crystallographic data for complexA. (CIF 16 kb)

Supplementary information

Structure factors file for complexA. (FCF 179 kb)

Supplementary information

Crystallographic data for compound 21N. (CIF 15 kb)

Supplementary information

Structure factors file for compound 21N. (FCF 178 kb)

Supplementary information

Crystallographic data for compound 26. (CIF 11 kb)

Supplementary information

Structure factors file for compound 26. (FCF 62 kb)

Supplementary information

Crystallographic data for palladacycle complexE. (CIF 25 kb)

Supplementary information

Structure factors file for palladacycle complexE. (FCF 351 kb)

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He, G., Lu, G., Guo, Z. et al. Benzazetidine synthesis via palladium-catalysed intramolecular C−H amination. Nature Chem 8, 1131–1136 (2016). https://doi.org/10.1038/nchem.2585

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