Synthesis of 4-aminoquinazolines by palladium-catalyzed intramolecular imidoylation of N-(2-bromoaryl)amidines

Compared with the widespread use of carbonylative Pd-catalyzed cross-coupling reactions, similar reactions involving isocyanide insertion are almost virgin territory. We investigated the intramolecular imidoylative cross-coupling of N-(2-bromoaryl)amidines, leading to 4-aminoquinazolines. After thorough optimization of the reaction with respect to palladium source and loading, ligand, base, temperature, and solvent, a small library of 4-aminoquinazolines was prepared to determine the scope of this method. Various substituents are tolerated on the amidine and the isocyanide, providing efficient access to a broad range of diversely substituted 4-aminoquinazolines of significant pharmaceutical interest.