Unlocking IsonitrileInsertion with <i>N</i>‑Centered Radicals: A GeneralSynthetic Strategy toward QuinazolinoneAlkaloids by Synergistic Photo/Copper Catalysis

Significant progress has been achieved in radical isonitrile insertion reactions, yet the reactivity of isonitriles toward <i>N</i>-centered radicals remains underexplored. Herein, we report an efficient method that enables isonitrile insertion into <i>N</i>-centered radicals, facilitated by a synergistic photocatalyst/copper catalytic system. This insertion triggers a highly efficient cascade cyclization that constitutes a flexible strategy for synthesizing alkaloids with a fused quinolizinone scaffold. Alkaloids, including luotonin A, rutaecarpine, and 2-methoxy-13-methylrutaecarpine, along with 37 natural product-like molecules, were synthesized by this method in a single step, starting from readily synthesizable <i>ortho</i>-isocyano-<i>N</i>-tosylbenzamides as <i>N</i>-radical precursors. Mechanistic investigations, encompassing photophysical, electrochemical, Einstein–Podolsky–Rosen studies, and density functional theory calculations, imply that arylisonitrile-Cu­(I) complexes serve as effective reductants, quenching the excited iridium photocatalyst via single-electron transfer at the onset of the reaction. Crucially, the Cu­(I)/Cu­(II)/Cu­(III) catalytic cycle plays a key role in sustaining the photocatalytic process and driving the radical cascade cyclization.