Pyrazolo[1,5-a]Pyrimidine: Synthesis and Regiospecific Electrophilic Substitution in the Pyrazole and/or Pyrimidine Rings

Abstract

A general cyclization route to pyrazolo[1,5-a]pyrimidines from 3-aminopyrazole and 1,3-dicarbonyl compounds is applied to synthesis of the parent ring system. In nitration of this species the orientation of substitution is strongly reagent dependent. Mixed nitric and sulfuric acids yield the 3-nitro compound, whereas nitric acid in acetic anhydride yields the 6-nitro compound. Brominations yield 3-bromo and 3,6-dibromo species.The majority reacting species in the strongly acidic medium is identified as the 1-protonated entity by conjoint use of approximate molecular orbital calculations and the variation of coupling constant patterns accompanying protonation. The molecular orbital calculations predict successive 3- and 6-substitution by electrophiles in pyrazolo[l,5-a]pyrimidine and its conjugate acid, and an addition–elimination sequence is proposed to account for the observed 6-nitration.