Access and Regioselective Transformations of 6-Substituted 4-Aryl-2,8-dichloropyrido[3,2-d]pyrimidine Compounds

We report herein an efficient route for the synthesis of 2,4,8-trichloropyrido­[3,2-d]­pyrimidines 1 with R1 substituents at C-6. The potential of such scaffolds was demonstrated by the possibility to displace regioselectively each aromatic chloride to introduce diversity. Sequential sulfur nucleophilic addition followed by Liebeskind–Srogl cross-coupling reaction yielded unprecedented aryl introduction at C-4 on a trichloropyrido­[3,2-d]­pyrimidine derivative. The reactivity difference of the remaining two chlorides toward SNAr reactions was investigated. Amination yielded high C-2 regioselectivity, while thiolation was influenced by C-6 substituents, resulting in medium to high C-2 versus C-8 regioselectivity. The last chloride was efficiently displaced by SNAr, Suzuki–Miyaura cross-coupling reaction, or reduction. C-2 arylation as a final step was also possible by Liebeskind–Srogl cross-coupling reaction on the previously introduced C-2 thioether. A concise and highly divergent synthetic use of 1 was developed, thereby providing an efficient approach to explore the structure–activity relationship of pyrido­[3,2-d]­pyrimidine derivatives such as 9, 10, 15, and 16.