Terungwa H. Iorkula

Pyrazolo[1,5-a]pyrimidines are a notable class of heterocyclic compounds with potent protein kinase inhibitor (PKI) activity, playing a critical role in targeted cancer therapy.

An efficient method has been developed for the rapid production of diverse arrays of 3,5-bis-aminated pyrazolo[1,5-a]pyrimidines. The method utilizes CuI (5 mol%) and carbazole-based ligand L-1 (N-(9H-carbazol-9-yl)-1H-pyrrole-2-carboxamide) (10 mol%) for efficient Ullmann-type coupling of various amines to 5-amino-3-bromopyrazolo[1,5-a]pyrimidine precursors after heating in diethylene glycol (DEG) for only 1 h at 80 °C (microwave heating). 3,5-Bis-aminated products were obtained in good to excellent yields (60–93%, 83% average for 29 examples). 1° and 2° alkylamines, as well as a variety of aryl- or heteroarylamines coupled efficiently, and 1° and 2° alkyl (or aryl) amines at C-5 were well tolerated. The optimized conditions worked well on both the 50 mg and 1.0 g scales and gave products in only two steps from commercially available 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine. Advantages provided by this method include short reaction time, excellent yields, broad substrate scope, and avoidance of toxic reagents commonly utilized for reductive aminations of C-3 NH₂ substituted precursors.