Unlocking Isonitrile Insertion with <i>N</i>-Centered Radicals: A General Synthetic Strategy toward Quinazolinone Alkaloids by Synergistic Photo/Copper Catalysis
Xiao-Yu Guo, Hui Wang, Zhongyan Hu, Yu Zhao, Jinhuan Dong, Kangbao Zhong, Yu Lan, Xianxiu Xu
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.