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