Synthesis of Pyridopyrimidines by Palladium-Catalyzed Isocyanide Insertion

A new synthetic approach to 4-aminopyrido[2,3-d]pyrimidines and 4-aminopyrido[3,2-d]pyrimidines based on palladium-catalyzed reaction of isocyanides with readily available N-(bromopyridyl)amidines is reported. The target heterocycles were obtained in generally good to excellent yield. For the two regioisomeric pyrimidopyrimidines, we compared our approach involving oxidative addition with the analogous C-H activation protocol because both methods have been reported for the synthesis of 4-aminoquinazolines. We found that the C-H activation protocol does not allow one to obtain the target pyridopyrimidines, but the imidoylative cross-coupling protocol provided a new entry to the synthesis of these medicinally important scaffolds. © 2013 American Chemical Society.