Metal-free Photocatalytic Cross-Electrophile Coupling enables C1 Homologation and Alkylation of Carboxylic Acids with Aldehydes

    Stefano Bonciolini, Antonio Pulcinella, Matteo Leone, Debora Schiroli, Adrian Luguera Ruiz, Andrea Sorato, Maryne Dubois, Ranganath Gopalakrishnan, Geraldine Masson, Nicola Della Ca', Stefano Protti, Maurizio Fagnoni, Eli Zysman-Colman, Magnus Johannsson, Timothy Noel

    • University of Amsterdam

    In contemporary drug discovery, enhancing the sp3-hybridized character of molecular structures is paramount, necessitating innovative synthetic methods. Herein, we introduce a deoxygenative cross-electrophile coupling technique that pairs easily accessible carboxylic acid-derived redox-active esters (RAEs) with aldehyde sulfonyl hydrazones, employing Eosin Y as an organophotocatalyst under visible light irradiation. This approach serves as a versatile, metal-free C(sp3)−C(sp3) cross-coupling platform. We demonstrate its synthetic value as a safer, broadly applicable C1 homologation of carboxylic acids, offering an alternative to the traditional Arndt-Eistert reaction. Additionally, our method provides direct access to cyclic and acyclic β-arylethylamines using diverse aldehyde-derived sulfonyl hydrazones. Notably, the methodology proves to be compatible with the late-stage functionalization (LSF) of peptides on solid-phase, streamlining the modification of intricate peptides without the need for exhaustive de-novo synthesis.

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