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Metallaphotocatalytic synthesis of anilines through tandem C–N transposition and C–H alkylation of alkylamines

Nature Synthesis volume 2, pages 1171–1183 (2023)Cite this article

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Abstract

Alkylamines have a range of applications including as reagents in organic synthesis and as bioactive compounds in medicinal chemistry. Methods for the synthesis of alkylamines, however, typically suffer from low availability or inaccessibility of key reaction components and uncontrollable selectivity. While photocatalytic two-component reactions have become versatile strategies for the synthesis of alkylamines, multicomponent variants remain underdeveloped. Here we describe a metallaphotoredox-promoted three-component amination reaction using tertiary alkylamines, nitroarenes and carboxylic acids to give N-alkyl aniline products. The utility of this three-component approach is highlighted through the availability and broad scope of the reaction substrates and the application to the expedited synthesis of drug molecules and intermediates. Mechanistic investigations reveal this chemo- and regioselective transformation probably proceeds through a formal amine group transposition and C–H alkylation of a tertiary alkylamine substrate.

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Fig. 1: The development of selective multicomponent construction of N-alkyl anilines.
Fig. 2: Mechanistic hypothesis of metallaphotoredox-catalysed amination using nitroarenes, tertiary alkylamines and RAEs.
Fig. 3: Scope of tertiary alkylamines.
Fig. 4: Synthesis of N-alkyl anilines towards the synthesis of drug-like molecules.
Fig. 5: Mechanistic study of the three-component amination protocol.

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Data availability

The experimental and analytical procedures and full spectral data are available in the supplementary materials. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2209594 (59) and 2247663 (86).

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Acknowledgements

We thank the National Natural Science Foundation of China (nos. 21971186 (C.W.C.), 22271216 (C.W.C.) and 21961142015 (J.-A.M.)), the National Key Research and Development Program of China (no. 2019YFA0905100, J.-A.M.) and the Tianjin Municipal Science & Technology Commission (20JCYBJ00900, C.W.C.) for financial support. We thank the research group of Y.-L. Lei (Tianjin University) for assistance in conducting the UV–vis spectroscopic analysis.

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Authors and Affiliations

  1. Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin, People’s Republic of China

    Zhong-Wei Zhang, Zhe Feng, Jun-An Ma & Chi Wai Cheung

  2. Joint School of National University of Singapore and Tianjin University, International Campus of Tianjin University, Binhai New City, People’s Republic of China

    Jun-An Ma

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Contributions

Z.-W.Z. and C.W.C. discovered the reactions. Z.-W.Z. performed the reaction optimizations and studied the reaction scope and synthetic utility. Z.-W.Z. and Z.F. studied the reaction mechanisms. C.W.C. wrote the manuscript with help from Z.-W.Z., Z.F. and J.-A.M. C.W.C. and J.-A.M. initiated the project, designed the experiments and directed the research.

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Correspondence to Jun-An Ma or Chi Wai Cheung.

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Nature Synthesis thanks Nicholas Chiappini, Leifeng Wang 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 Figs. 1–28 and Table 1.

Supplementary Data 1

Crystallographic data for 59 (CCDC 2209594).

Supplementary Data 2

Crystallographic data for 86 (CCDC 2247663).

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Zhang, ZW., Feng, Z., Ma, JA. et al. Metallaphotocatalytic synthesis of anilines through tandem C–N transposition and C–H alkylation of alkylamines. Nat. Synth 2, 1171–1183 (2023). https://doi.org/10.1038/s44160-023-00370-y

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