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Atroposelective isoquinolinone synthesis through cobalt-catalysed C–H activation and annulation

Nature Synthesis volume 1, pages 709–718 (2022)Cite this article

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Abstract

Enantioselective C–H functionalization for the synthesis of chiral molecules is a challenge in organic synthesis. Although there are several methods for atroposelective C–H functionalization to form C–N axially chiral anilides based on preformed aromatic ring systems, methods that construct N-heterocycles are relatively under-explored. Here we report a cobalt-catalysed enantioselective C–H activation and annulation process for the atroposelective synthesis of isoquinolines. The reaction proceeds under mild conditions using Co(OAc)2·4H2O with a chiral salicyl-oxazoline (Salox) ligand and O2 as an oxidant. The reaction tolerates a broad range of benzamides and internal and terminal alkynes, producing a range of C–N axially chiral isoquinolinones in excellent yield and enantioselectivity (up to 98% yield and 98% e.e.). Mechanistic studies infer that the process proceeds through a CoIII/CoI catalytic cycle, with the C–N reductive elimination step being stereo-determining. The isoquinolinone products show atropostability and thermal resistance and are suitable ligands for the Pd-catalysed enantioselective C–H functionalization of indole.

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Fig. 1: Background and project synopsis.
Fig. 2: Study on product stability.
Fig. 3: Synthetic applications.
Fig. 4: Control experiments and computational mechanistic studies.

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Data availability

All data relating to the experimental procedures, optimization studies and characterization of the new compounds are in the Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2121762 (3aa), CCDC 2129412 (3ar), CCDC 2165266 (3av-major), CCDC 2165270 (3av-minor) and CCDC 2165271 (9). Copies of the CCDC data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (21772179 to J.-L.N.) and the Program for Science & Technology Innovation Talents in Universities of Henan Province (19HASTIT038 to J.-L.N.).

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Author notes

  1. These authors contributed equally: Xiao-Ju Si, Dandan Yang.

Authors and Affiliations

  1. Green Catalysis Center, College of Chemistry, Zhengzhou University, Zhengzhou, China

    Xiao-Ju Si, Dandan Yang, Meng-Chan Sun, Donghui Wei, Mao-Ping Song & Jun-Long Niu

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Contributions

J.-L.N., D.Y. and X.-J.S. conceived the concept and prepared the manuscript. X.-J.S., D.Y. and M.-C.S. conducted the experiments and analysed the data. D.W. performed the DFT study. M.-P.S. provided revisions. All authors participated in the discussion and preparation of the manuscript. J.-L.N. directed the project.

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Correspondence to Jun-Long Niu.

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Nature Synthesis thanks Naohiko Yoshikai, Qianghui Zhou and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Supplementary Data 1

Crystallographic data for compound 3aa, CCDC 2121762

Supplementary Data 2

Crystallographic data for compound 3ar, CCDC 2129412

Supplementary Data 3

Crystallographic data for compound 3av-major, CCDC 2165266

Supplementary Data 4

Crystallographic data for compound 3av-minor, CCDC 2165270

Supplementary Data 5

Crystallographic data for compound 9, CCDC 2165271

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Si, XJ., Yang, D., Sun, MC. et al. Atroposelective isoquinolinone synthesis through cobalt-catalysed C–H activation and annulation. Nat. Synth 1, 709–718 (2022). https://doi.org/10.1038/s44160-022-00114-4

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