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

Antonio Pulcinella, Stefano Bonciolini, Robin Stuhr, Damiano Diprima, Minh Thao Tran, Magnus Johansson, Axel Jacobi Wangelin and Timothy Noël ()
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Antonio Pulcinella: University of Amsterdam
Stefano Bonciolini: University of Amsterdam
Robin Stuhr: University of Amsterdam
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

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56234-w

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