5-Triazolyluracils and Their N1-Sulfonyl Derivatives: Intriguing Reactivity Differences in the Sulfonation of Triazole N1-Substituted and N1-Unsubstituted Uracil Molecules

We describe the synthesis of novel C5-triazolyl derived N-1-sulfonylpyrimidines through Cu-I-catalyzed alkyne-azide cycloaddition followed by sulfonylation of the formed C5-triazolyl derivatives with various sulfonyl chlorides under basic conditions. In the latter step, an intriguing difference in the reactivity of the pyrimidine N-1 was observed that depended on the nature of the substituent at a distant triazole N-1 site. The N-1-unsubstituted compounds gave very small amounts of sulfonylation products, whereas N-1-substituted systems produced high yields of the respective N-1-sulfonyl-5-(1,2,3-triazol-4-yl)uracils. Computational analysis revealed a close correlation between the strength of the employed base catalysts and their abilities to increase the nucleophilicity of the uracil N-1 atom through subsequent deprotonation, leading to more products. Following this step, the phosphazene tBu-P4 superbase was applied in the sulfonylation, resulting in exclusive formation of the triazole N-1-unsubstituted N-1-sulfonylpyrimidines.