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Enantioselective nickel-catalysed electrochemical cross-dehydrogenative amination

Nature Synthesis volume 2, pages 1184–1193 (2023)Cite this article

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Abstract

Enantio-enriched amines are found in a wide range of bioactive natural products and pharmaceutical agents. However, radical-based asymmetric cross-dehydrogenative amination via electrochemical oxidative C–H/N–H coupling to facilitate catalytic C(sp3)–N bond formation remains a largely unsolved challenge in organic synthesis. In the present study, we present nickel-catalysed, anodically coupled electrolysis for the stereoselective, cross-dehydrogenative amination of acylimidazoles, with commercially available nitrogen nucleophiles as coupling partners to access structurally diverse α-amino carbonyls. This method involves the coupling of an electrogenerated nickel-bound α-keto radical species and an aminyl radical to provide a stereoselective approach for the cross-dehydrogenative amination. The utility of this anodic oxidative strategy has been highlighted through the stereoselective synthesis of (+)-γ-secretase inhibitor, (+)-flamprop-methyl and (+)-flamprop-isopropyl.

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Fig. 1: Overview of the asymmetric electrochemical cross-dehydrogenative amination.
Fig. 2: Synthetic utility.
Fig. 3: Mechanistic investigation for asymmetric electrochemical cross-dehydrogenative amination.

Data availability

The experimental data as well as the characterization data for all the compounds prepared during these studies are provided in the Supplementary Information. Nuclear magnetic resonance data in a mnova file format and HPLC traces are available at Zenodo at https://zenodo.org/record/7902667#.ZFZK23ZBwuW, under the Creative Commons Attribution 4.0 International licence. Crystallographic data for the structures reported in the present study have been deposited at the Cambridge Crystallographic Data Centre, under deposition nos. CCDC 2234466 (3s) and CCDC 2234467 (21a). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures.

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Acknowledgements

We thank the National Natural Science Foundation of China (grant nos. 21971227 and 22222113 to C.G.), CAS Project for Young Scientists in Basic Research (grant no. YSBR-054 to C.G.) and the Fundamental Research Funds for the Central Universities (grant nos. WK9990000090 and WK9990000111 to C.G.) for financial support.

Author information

Authors and Affiliations

  1. Hefei National Research Center for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, China

    Kang Liang, Qinglin Zhang & Chang Guo

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  1. Kang Liang
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  2. Qinglin Zhang
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  3. Chang Guo
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Contributions

C.G. conceived the project. K.L. performed the experiments and analysed the data. Q.Z. synthesized some of the substrates and ligands. All authors discussed the results and prepared the manuscript.

Corresponding author

Correspondence to Chang Guo.

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The authors declare no competing interests.

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Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary information

Experimental details, Supplementary Figs. 1–8 and Tables 1–7.

Supplementary Data 1

Crystallographic data for compound 3s, CCDC 2234466.

Supplementary Data 2

Structure factors for compound 3s, CCDC 2234466.

Supplementary Data 3

Crystallographic data for compound 21a, CCDC 2234467.

Supplementary Data 4

Structure factors for compound 21a, CCDC 2234467.

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Liang, K., Zhang, Q. & Guo, C. Enantioselective nickel-catalysed electrochemical cross-dehydrogenative amination. Nat. Synth 2, 1184–1193 (2023). https://doi.org/10.1038/s44160-023-00372-w

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