Regioselectivity in the reaction of 5-amino-3-anilino-1H-pyrazole-4-carbonitrile with cinnamonitriles and enaminones: Synthesis of functionally substituted pyrazolo[1,5-a]pyrimidine derivatives

The development of efficient methods for the synthesis of polyfunctional N-heterocycles is an important area of research in organic and medicinal chemistry. Pyrazolo[1,5-a]pyrimidine derivatives are purine analogous of biomedical importance and have been extremely studied for their broad spectrum of biological activities. Recently, they have attracted great interest in materials science owing to their photophysical properties. 3(5)-Aminopyrazoles are extensively utilized in the synthesis of condensed heterocyclic systems, particularly pyrazolo[1,5-a]pyrimidines via the reaction with 1,3-biselectrophilic reagents. However, the information available in the literature provides little in the way of reasoning their cyclization, particularly the initial attack either by the exocyclic amino group or endocyclic nitrogen. Unfortunately, the relative nucleophilicity of exo- and endocyclic nitrogen atoms in 1-unsubstituted 3(5)-aminopyrazoles is not clear and contradicting. It has been found that other factors can modulate the regioselectivity rather than basicity or steric hindrance for both active sites. The reported studies in the structure-activity relationship revealed that pyrazolo[1,5-a]pyrimidines having a substitution at fifth, sixth, and seventh positions possess potent biological activities, especially those with an amino group at the seventh position. We here developed a regioselective, high yield synthesis of 7-amino-5-arylpyrazolo[1,5-a]pyrimidine-3,6-dicarbonitriles by the reaction of N-(5-amino-4-cyano-1H-pyrazole-3-yl)-benzamide with various cinnamonitriles and enaminones in pyridine at 120 degrees C under controlled microwave heating conditions. All structures of newly synthesized compounds were established by analytical and spectral data as well as single-crystal diffraction and rationalized for their formation.

Automated summary

The development of efficient methods for synthesizing polyfunctional N-heterocycles is important in the fields of organic and medicinal chemistry. Pyrazolo[1,5-a]pyrimidine derivatives have biomedical importance and have been extensively studied for their broad range of biological activities. In recent years, they have also become of interest in materials science due to their photophysical properties. However, there is limited information available on the cyclization of 3(5)-aminopyrazoles and the factors influencing regioselectivity. This study presents a regioselective synthesis of 7-amino-5-arylpyrazolo[1,5-a]pyrimidine-3,6-dicarbonitriles and provides structural confirmation and rationalization for their formation.