Regioselective Synthesis of 2,8-Disubstituted 4-Aminopyrido[3,2-<i>d</i>]pyrimidine-6-carboxylic Acid Methyl Ester Compounds

We report herein the synthesis of 4-amino-2,8-dichloropyrido­[3,2-<i>d</i>]­pyrimidine derivatives <b>2</b> and their regioselective diversification through S_NAr and metal-catalyzed cross-coupling reactions. While amination of <b>2</b> 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 Hünig’s base and C-2 addition in ^<i>i</i>PrOH. 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-<i>d</i>]­pyrimidine derivatives, with various substituents