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5‐Bromo‐1,1,1‐trifluoro‐4‐methoxypent‐3‐en‐2‐one was used as an efficient precursor for the synthesis of a new series of (1,2,3‐triazol‐1‐yl)methyl‐pyrimidine biheterocycles. For this stepwise synthesis, the 5‐bromo‐1,1,1‐trifluoro‐4‐methoxypent‐3‐en‐2‐one was first converted into 5‐azido‐1,1,1‐trifluoro‐4‐methoxypent‐3‐en‐2‐one through a nucleophilic substitution of the bromine by an azide group. This was then followed by an azide–alkyne cycloaddition reaction (click chemistry) to give the key intermediate 5‐[4‐alkyl(aryl)‐1H‐1,2,3‐triazol‐1‐yl]‐1,1,1‐trifluoro‐4‐methoxypent‐3‐en‐2‐ones. These were cyclocondensed with 2‐methylisothiourea sulfate to give a series of 2‐(methylthio)‐4‐(1,2,3‐triazol‐1‐yl)methyl‐6‐(trifluoromethyl)pyrimidines. Additionally, the 2‐methylthiopyrimidine products were used to prepare a new series of 2‐amino‐4‐(1,2,3‐triazol‐1‐yl)methyl‐6‐(trifluoromethyl)pyrimidines.

The reaction of pyrazoles with 5-bromo enones furnished an unexpected series of stable N,O-aminals in a chemo- and regioselective and metal free reaction.

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This study reports the chemo‐ and regioselective synthesis, at good yields, of (E)‐4‐(amino)‐1,1,1‐trifluoro‐5‐(4,5‐alkyl‐3‐(trifluoromethyl)‐1H‐pyrazol‐1‐yl)pent‐3‐en‐2‐ones (pyrazole‐enaminones), from the of N‐alkylation reaction of trifluoromethyl pyrazoles with 5‐bromo enaminones. The obtained compounds were tested as potential analgesics in a screening test involving mice. Three of these compounds significantly reduced the spontaneous nociception induced by the application of capsaicin, which is an algogenic substance. Compound 5 g presented satisfactory antinociceptive activity compared to celecoxib, a drug used as a positive control, without promoting locomotor changes in the mice. Moreover, molecular modeling simulations showed that compound 5 g interacts with the cyclooxygenase enzyme at the same binding site as celecoxib. Together, our data suggest that compound 5 g is a promising prototype for the development of new analgesic drugs.

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