A microwave reactor was used to synthesize a series of novel 3,6-disubstituted or 3-substituted pyrazolo[1,5-a]pyrimidines in a total of 1 hour reaction time over 3 steps. The products were obtained in good to excellent yields (34-92%, ave = 52%) using a straightforward synthesis starting with the reaction of dimethylformamide-dimethylacetal with commercially available aryl acetonitriles (120C, 20 min). This was followed by treatment with H2NNH2 • HBr (120C, 20 min), and then reacted with either 1,1,3,3-tetramethoxypropane or a 2-aryl-substituted malondialdehydes (120C, 20 min). The resulting product was either collected on a sintered glass funnel or purified via column chromatography. The compounds were screened for anti-cancer activity against A2780 Ovarian and/or MCF7 breast cancer cell lines in vitro. The most active compounds were the 3-(4-(trifluoromethyl)phenyl)-6-[4-(2-(piperidin-1-yl)ethoxy]phenyl analogue and the 3-(2-fluorophenyl)-6-[4-(2-(4-methylpiperzin-1-yl)ethoxy]phenyl analogue, exhibiting EC50 values of 0.84 and 0.52 M respectively, which is 2-3 times more potent than Dorsomorphin. Several of the derivatives also showed promising activities against several viruses of emerging concern, including HBV, MERS Coronavirus, Zika, and Ebola. Use of a microwave reactor to synthesize N’-aryl/(alkyl) substituted N-[(4-hydroxy-6-phenyl)pyrimidin-2-yl]guanidines or N-[(4-hydroxy-6-trifluoromethyl)pyrimidin-2-yl]guanidines from the corresponding cyanamides with alkyl/aryl amines was achieved in good to excellent yields (39-96%, ave = 62%) in 10 minutes at 120C using only 1 equivalent of amine. Work-up was exceptionally simple, and involved collecting precipitated solids on a sintered glass funnel and washing with cold 2-propanol. Products were obtained in analytically pure form and required approximately 1 hour to prepare, start to finish. Compounds in this series showed early promise as potential inhibitors of A2780 Ovarian cancer, in vitro.



College and Department

Physical and Mathematical Sciences; Chemistry and Biochemistry



Date Submitted


Document Type





Microwave, Dorsomorphin, Pyrazolo[1, 5-a]pyrimidine, N-[(4-hydroxy-6-trifluoromethyl)pyrimidin-2-yl]guanidine, anticancer, antiviral