Regioselective synthesis of 2,8-disubstituted 4-aminopyrido[3,2-d]pyrimidine-6-carboxylic acid methyl ester compounds.

We report herein the synthesis of 4-amino-2,8-dichloropyrido[3,2-d]pyrimidine derivatives 2 and their regioselective diversification through SNAr and metal-catalyzed cross-coupling reactions. While amination of 2 took place selectively at C-2, the regioselectivity of thiol or thiolate addition depended on the reaction conditions. Selective C-8 addition was obtained in DMF with Hunig’s base and C-2 addition in iPrOH. These C-2 or C-8 regioselective thiolations provided an opportunistic way to selectively activate either of the two positions toward the metal-catalyzed cross-coupling reaction. The chloride could be efficiently substituted by Suzuki–Miyaura reaction and the sulfanyl group by Liebeskind–Srogl cross-coupling reaction, demonstrating the orthogonality of both reactive centers. The development of regioselective conditions for these different transformations yielded the synthesis of 4-amino-2,6,8-trisubstituted pyrido[3,2-d]pyrimidine derivatives, with various substituents.