Stepwise synthesis of 2,6-difunctionalized ethyl pyrazolo[1,5-a]pyrimidine-3-carboxylate via site-selective cross-coupling reactions: experimental and computational studies.

ABSTRACT

A variety of novel disubstituted 2-(alknyl, aryl and arylamine)-6-alkynylpyrazolo[1,5-a]pyrimidine derivatives was prepared via sequential site-selective cross-coupling reactions from 2,6-dibromopyrazolo[1,5-a]pyrimidine 3. The regio-controlled Sonogashira-type coupling of 3 with a wide range of terminal alkynes proceeded smoothly with excellent selectivity in favor of the C6-position through careful adjustment of the coupling conditions, followed by the subsequent introduction of alkynyl, aryl or arylamine groups at the C2-position via the Sonogashira, Suzuki-Miyaura and Buchwald-Hartwig coupling reactions, respectively. These promising results allow for further use and diversification of the chemically and biologically interesting pyrazolo[1,5-a]pyrimidine scaffold. In addition, computational studies were conducted to provide explanations for the origin of regioselectivity.