Direct Conversion of Aryl Iodides Into Benzylamines by Aminomethylation: Reaction Scope, Mechanistic Studies, and Applications

Despite the high utility and value of benzylamines and their derivatives, their synthesis is hindered by a limited substrate availability and nonreusable transition‐metal catalysts. To that end, this study develops an aminomethylation strategy using aryl iodides and formamides while examining the substrate scope and underlying mechanism for synthesizing benzylamines under parts‐per‐million‐level (65 ppm) reusable palladium catalysis. This method can accommodate a wide range of substrates, including electron‐rich and electron‐deficient aryl, polyaryl, and heteroaryl iodides. Similarly, various formamide derivatives yield aminomethylated products. This aminomethylation strategy is used to directly synthesize biologically active molecules, such as a rivastigmine analog, and natural products, e.g., gramine. In addition, tryptamine, a serotonin receptor, and diindolylmethane, a metabolite, are successfully produced by derivatizing the aminomethylated products. Isotope‐labeling experiments indicate that formamide derivatives were precursors for the reducing agent, in addition to providing both amines and carbon. A plausible catalytic pathway is proposed based on isotope‐labeling experiments and density functional theory calculations, providing insights for future research and new applications in organic synthesis and medicinal chemistry.