Regioselective Synthesis of 2,4-Substituted Pyrido[1,2:1,5]pyrazolo[3,4-d]pyrimidines through Sequential Pd-Catalyzed Arylation and SNAr Reactions

The synthesis and regioselective functionalization of rare 2,4-disubstituted-pyrido[1,2:1,5]pyrazolo[3,4-d]pyrimidine derivatives is reported. C-4 aminations were performed by chlorine nucleophilic substitution SNAr reactions, and their efficiencies were compared with those for direct one-pot amide C-O activation with bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) as a reagent. The latter method was used to perform palladium-catalyzed C-4 (het)arylation. Finally, two C-4 amino and aryl derivatives were prepared on a large scale and engaged in desulfurative Liebeskind-Srogl-type reactions under microwave irradiation to afford the envisioned compound library. Each step was optimized, and the results are discussed.