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A photochemical dehydrogenative strategy for aniline synthesis

Author

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  • Shashikant Dighe

    (University of Manchester)

  • Fabio Juliá

    (University of Manchester)

  • Alberto Luridiana

    (University of Manchester)

  • James J. Douglas

    (Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca)

  • Daniele Leonori

    (University of Manchester)

Abstract

Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals1,2. The introduction of amines onto functionalized aromatics at specific and pre-determined positions (ortho versus meta versus para) is currently achievable only in transition-metal-catalysed processes and requires halogen- or boron-containing substrates3–6. The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (electrophilic halogenation or C–H borylation) so selective targeting of all positions is often not possible. Here we report a non-canonical cross-coupling approach for the construction of anilines, exploiting saturated cyclohexanones as aryl electrophile surrogates. Condensation between amines and carbonyls, a process that frequently occurs in nature and is often used by (bio-)organic chemists7, enables a predetermined and site-selective carbon–nitrogen (C–N) bond formation, while a photoredox- and cobalt-based catalytic system progressively desaturates the cyclohexene ring en route to the aniline. Given that functionalized cyclohexanones are readily accessible with complete regiocontrol using the well established carbonyl reactivity, this approach bypasses some of the frequent selectivity issues of aromatic chemistry. We demonstrate the utility of this C–N coupling protocol by preparing commercial medicines and by the late-stage amination–aromatization of natural products, steroids and terpene feedstocks.

Suggested Citation

  • Shashikant Dighe & Fabio Juliá & Alberto Luridiana & James J. Douglas & Daniele Leonori, 2020. "A photochemical dehydrogenative strategy for aniline synthesis," Nature, Nature, vol. 584(7819), pages 75-81, August.
  • Handle: RePEc:nat:nature:v:584:y:2020:i:7819:d:10.1038_s41586-020-2539-7
    DOI: 10.1038/s41586-020-2539-7
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    Cited by:

    1. Le Zeng & Tiexin Zhang & Renhai Liu & Wenming Tian & Kaifeng Wu & Jingyi Zhu & Zhonghe Wang & Cheng He & Jing Feng & Xiangyang Guo & Abdoulkader Ibro Douka & Chunying Duan, 2023. "Chalcogen-bridged coordination polymer for the photocatalytic activation of aryl halides," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Tanay Pal & Premananda Ghosh & Minhajul Islam & Srimanta Guin & Suman Maji & Suparna Dutta & Jayabrata Das & Haibo Ge & Debabrata Maiti, 2024. "Tandem dehydrogenation-olefination-decarboxylation of cycloalkyl carboxylic acids via multifold C–H activation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Long Huang & Tengfei Ji & Chen Zhu & Huifeng Yue & Nursaya Zhumabay & Magnus Rueping, 2022. "Bioinspired desaturation of alcohols enabled by photoredox proton-coupled electron transfer and cobalt dual catalysis," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    4. Shuaishuai Wang & Tingrui Li & Chengyihan Gu & Jie Han & Chuan-Gang Zhao & Chengjian Zhu & Hairen Tan & Jin Xie, 2022. "Decarboxylative tandem C-N coupling with nitroarenes via SH2 mechanism," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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