Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary Alkylamines

    • Hannah E. Askeya
    • James D. Graysona
    • Joshua D. Tibbettsa
    • Jacob C. Turner-Dorea
    • Jake M. Holmesa
    • Gabriele Kociok-Kohnb
    • Gail L. Wrigleyc
    • Alexander J. Cresswella
    • aDepartment of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
    • bMaterials and Chemical Characterisation Facility (MC), University of Bath, Claverton Down, Bath BA2 7AY, U.K.
    • cOncology R&D, Research & Early Development, AstraZeneca, Darwin Building, 310, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.

    Catalytic, intermolecular hydroaminoalkylation (HAA) of styrenes provides a powerful disconnection for pharmacologically relevant γ-arylamines, but current methods cannot utilize unprotected primary alkylamines as feedstocks. Metal-catalyzed HAA protocols are also highly sensitive to α-substitution on the amine partner, and no catalytic solutions exist for α-tertiary γ-arylamine synthesis via this approach. We report a solution to these problems using organophotoredox catalysis, enabling a direct, modular, and sustainable preparation of α-(di)substituted γ-arylamines, including challenging electron-neutral and moderately electron-rich aryl groups. A broad range of functionalities are tolerated, and the reactions can be run on multigram scale in continuous flow. The method is applied to a concise, protecting-group-free synthesis of the blockbuster drug Fingolimod, as well as a phosphonate mimic of its in vivo active form (by iterative α-C–H functionalization of ethanolamine). The reaction can also be sequenced with an intramolecular N-arylation to provide a general and modular access to valuable (spirocyclic) 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydronaphthyridines. Mechanistic and kinetic studies support an irreversible hydrogen atom transfer activation of the alkylamine by the azidyl radical and some contribution from a radical chain. The reaction is photon-limited and exhibits a zero-order dependence on amine, azide, and photocatalyst, with a first-order dependence on styrene.

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