Unlocking Isonitrile Insertion with N-Centered Radicals: A General Synthetic Strategy toward Quinazolinone Alkaloids by Synergistic Photo/Copper Catalysis

Abstract

Significant progress has been achieved in radical isonitrile insertion reactions, yet the reactivity of isonitriles toward N-centered radicals remains underexplored. Herein, we report an efficient method that enables isonitrile insertion into N-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 ortho-isocyano-N-tosylbenzamides as N-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.