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A ring expansion strategy towards diverse azaheterocycles

Nature Chemistry volume 13, pages 1006–1016 (2021)Cite this article

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Abstract

The development of innovative strategies for the synthesis of N-heterocyclic compounds is an important topic in organic synthesis. Ring expansion methods to form large N-heterocycles often involve the cycloaddition of strained aza rings with π bonds. However, in some cases such strategies suffer from some limitations owing to the difficulties in controlling the regioselectivity and the accessibility of specific π-bond synthons. Here, we report the development of a general ring expansion strategy that involves a formal cross-dimerization between three-membered aza heterocycles and three- and four-membered-ring ketones through synergistic bimetallic catalysis. These formal cross-dimerizations of two different strained rings are efficient and scalable, and provide a straightforward and broadly applicable means of assembling diverse N-heterocycles, such as 3-benzazepinones, dihydropyridinones and uracils, which are versatile units in numerous drugs and biologically active compounds. Preliminary mechanistic studies revealed that the C–C bond of strained ring ketones is first cleaved by the Pd0 species during the reaction.

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Fig. 1: Examples of important N-heterocycles and our reaction design.
Fig. 2: Synthetic applications.
Fig. 3: Mechanistic studies.
Fig. 4: DFT calculations.

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Data availability

All the data generated or analysed during this study are included in this article and its Supplementary Information. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre (CCDC) as CCDC 2008377 (3aa), 2008376 (5sa), 2008375 (7a) and 2010994 ((R)-8a) and can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/getstructures.

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Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (22022103, 21871146 and 22071114), the National Key Research and Development Program of China (2019YFA0210500), the 1000-Talent Youth Program (020/BF180181), the Natural Science Foundation of Tianjin (18JCYBJC20400) and the Fundamental Research Funds for the Central Universities and Nankai University.

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Authors and Affiliations

  1. State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, China

    Ruirui Li, Bo Li, Hongpeng Zhang, Cheng-Wei Ju, Ying Qin, Xiao-Song Xue & Dongbing Zhao

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Contributions

R.L., H.Z., C.-W.J. and Y.Q. performed the experiments. B.L. and X.-S.X. conducted the DFT calculations. D.Z. developed the concept, directed the project and wrote the paper. All the authors approved the final version of the manuscript.

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Correspondence to Dongbing Zhao.

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Peer review information Nature Chemistry thanks Matthew Grayson, Masahiro Murakami and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Tables 1–17, Figs. 1–14, methods, text, experiments, NMR, HPLC spectra and references.

1

Crystallographic data for compound 3aa. CCDC reference 2008377.

2

Crystallographic data for compound 5sa. CCDC reference 2008376.

3

Crystallographic data for compound 7a. CCDC reference 2008375.

4

Crystallographic data for compound (R)-8a. CCDC reference 2010994.

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Li, R., Li, B., Zhang, H. et al. A ring expansion strategy towards diverse azaheterocycles. Nat. Chem. 13, 1006–1016 (2021). https://doi.org/10.1038/s41557-021-00746-7

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