Substituent-Driven Selective N-/O-Alkylation of 4-(Trihalomethyl)pyrimidin-2(1H)-ones Using Brominated Enones.

The selective N- or O-alkylation of 4-(trihalomethyl)pyrimidin-2(1H)-ones, using 5-bromo enones/enaminones as alkylating agents, is reported. It was found that the selectivity toward the N- or O-regioisomer is driven by the substituent present at the 6-position of the pyrimidine ring, thus enabling the preparation of each isomer as the sole product, in 60-95% yields. Subsequent cyclocondensation of the enaminone moiety with nitrogen dinucleophiles led to pyrimidine-azole conjugates in 55-83% yields.

Regiocontrolled Synthesis of 1-Substituted-3(5)-carboxyalkyl-1H-pyrazoles Using Trichloromethyl Enones.

In this work, we present a regiocontrolled methodology to prepare 1-substituted-3(5)-carboxyalkyl-1H-pyrazoles using trichloromethyl enones as starting materials. It was found that the selectivity of the reaction depends on the nature of the hydrazine: when using arylhydrazine hydrochlorides, synthesis of the 1,3-regioisomer was achieved (22 examples, 37-97% yields), while the corresponding free hydrazine led exclusively to the 1,5-regioisomer (12 examples, 52-83% yields). The trichloromethyl group was used as a precursor for the carboxyalkyl moiety, furnishing a one-pot three-component regioselective protocol suitable for preparing both isomers at moderate to excellent yields. The selectivity of the reaction was investigated through NMR analyses and the structures of the products were unambiguously determined by SCXR analyses.

Chemoselective O-Alkylation of 4-(Trifluoromethyl)pyrimidin-2(1H)-ones Using 4-(Iodomethyl)pyrimidines.

This study reports two strategies for preparing O-alkyl derivatives of 6-substituted-4-(trifluoromethyl)pyrimidin-(1H)-ones: a linear protocol of alkylation, using a CCC-building block followed by [3 + 3]-type cyclocondensation with 2-methylisothiourea sulfate and a convergent protocol based on direct alkylation, using 4-(iodomethyl)-2-(methylthio)-6-(trihalomethyl)pyrimidines. It was found that the cyclocondensation strategy is not feasible; thus, the direct chemoselective O-alkylation was performed, and 18 derivatives of the targeted pyrimidines were obtained in 70-98% yields. The structure of the products was unambiguously determined via single crystal X-ray analyses and two-dimensional nuclear magnetic resonance experiments.