Synthesis of 8-aryl-substituted 4-(5-chloropyrido[4,3-d]pyrimidine-2-yl)morpholines as intermediates of potential PI3K inhibitors via selective Suzuki-Miyaura cross-coupling reaction

The selective Suzuki cross-coupling reaction of 4-(5-chloro-8-iodopyrido[4,3-d]pyrimidin-2yl) morpholine and 4-(8-bromo-5-chloropyrido[4,3-d]pyrimidin-2-yl) morpholine catalyzed by palladium has been studied during the preparation of 8-aryl-substituted 4-(5-chloropyrido[4,3-d] pydimidin-2-yl)morpholines as key intermediates of potential PI3K inhibitors. This is the first report of the selective Suzuki cross-coupling reaction of fused pi-deficient heterocycles containing a 2-chloro-5-halopyridine. The selectivity of the reaction is highly dependent on the nature of the palladium catalyst, solvent, base and temperature. Under optimized conditions, a variety of aryl boronic acids and even heteroaryl boronic acids were coupled in high yield and selectivity.