Synthesis and competitive functionalization of ethyl 4-aryl-2-oxo- and ethyl 4-aryl-2-thioxo-6-(trifluoromethyl)tetrahydropyrimidine-5-carboxylates

Efficient conditions were found for the dehydration of ethyl 6-aryl-4-hydroxy-2-oxo- and ethyl 6-aryl-4-hydroxy-2-thioxo-4-(trifluoromethyl)hexahydropyrimidine-5-carboxylates that formed in the Biginelli reaction from trifluoroacetoacetic ester, aldehyde, and (thio)urea. In the presence of thionyl chloride and pyridine, the dehydration affords tetrahydropyrimidines. Under these conditions, 4-CF3-2-thioxohexahydropyrimidine bearing an ortho-hydroxy group in the aryl substituent undergo cyclization to form ethyl 4-thioxotetrahydromethanobenzo[g][1,3,5]oxadiazocine-11-carboxylate. In the methylation and alkoxymethylation reactions, ethyl 4-aryl-2-oxo(thioxo)-6-(trifluoromethyl)tetrahydropyrimidine-5-carboxylates show an ambident nucleophilic character, reacting at the N(1), N(3), O, or S centers. Methyl-N(1)-tetrahydropyrimidines were obtained as the major methylation products; while the alkoxymethylation with paraformaldehyde and various alcohols afforded N(3)-substituted derivatives.