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Deoxygenative photochemical alkylation of secondary amides enables a streamlined synthesis of substituted amines

Author

Listed:
  • Antonio Pulcinella

    (University of Amsterdam)

  • Stefano Bonciolini

    (University of Amsterdam)

  • Robin Stuhr

    (University of Amsterdam
    University of Hamburg)

  • Damiano Diprima

    (University of Amsterdam)

  • Minh Thao Tran

    (Janssen Pharmaceutica NV)

  • Magnus Johansson

    (AstraZeneca)

  • Axel Jacobi Wangelin

    (University of Hamburg)

  • Timothy Noël

    (University of Amsterdam)

Abstract

Secondary amines are vital functional groups in pharmaceuticals, agrochemicals, and natural products, necessitating efficient synthetic methods. Traditional approaches, including N-monoalkylation and reductive amination, suffer from limitations such as poor chemoselectivity and complexity. Herein, we present a streamlined deoxygenative photochemical alkylation of secondary amides, enabling the efficient synthesis of α-branched secondary amines. Our method leverages triflic anhydride-mediated semi-reduction of amides to imines, followed by a photochemical radical alkylation step. This approach broadens the synthetic utility of amides, facilitating late-stage modifications of drug-like molecules and the synthesis of saturated N-substituted heterocycles. The pivotal role of flow technology in developing a scalable and robust process underscores the practicality of this method, significantly expanding the organic chemist’s toolbox for complex amine synthesis.

Suggested Citation

  • Antonio Pulcinella & Stefano Bonciolini & Robin Stuhr & Damiano Diprima & Minh Thao Tran & Magnus Johansson & Axel Jacobi Wangelin & Timothy Noël, 2025. "Deoxygenative photochemical alkylation of secondary amides enables a streamlined synthesis of substituted amines," Nature Communications, Nature, vol. 16(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56234-w
    DOI: 10.1038/s41467-025-56234-w
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    References listed on IDEAS

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    1. Daniele Antermite & Stig D. Friis & Johan R. Johansson & Okky Dwichandra Putra & Lutz Ackermann & Magnus J. Johansson, 2023. "Late-stage synthesis of heterobifunctional molecules for PROTAC applications via ruthenium-catalysed C‒H amidation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Roopender Kumar & Nils J. Flodén & William G. Whitehurst & Matthew J. Gaunt, 2020. "A general carbonyl alkylative amination for tertiary amine synthesis," Nature, Nature, vol. 581(7809), pages 415-420, May.
    3. Stefano Bonciolini & Antonio Pulcinella & Matteo Leone & Debora Schiroli & Adrián Luguera Ruiz & Andrea Sorato & Maryne A. J. Dubois & Ranganath Gopalakrishnan & Geraldine Masson & Nicola Ca’ & Stefan, 2024. "Metal-free photocatalytic cross-electrophile coupling enables C1 homologation and alkylation of carboxylic acids with aldehydes," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    4. Vijaya R. Pattabiraman & Jeffrey W. Bode, 2011. "Rethinking amide bond synthesis," Nature, Nature, vol. 480(7378), pages 471-479, December.
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