A KOtBu-mediated strategy for pyrimidine synthesis via selective three-component coupling reactions has been disclosed. This chemistry, in which a series of pyrimidines (20 examples) can be prepared with moderate to excellent yields, has high potential for large-scale operation owing to its metal-free conditions, atom and step economy. According to mechanistic studies, oxidative species can be generated from KOtBu or toluene in the presence of air, which can initiate the oxidation of alcohols to aldehydes (or ketones). Meanwhile, KOtBu not only promotes the condensation-cyclization process, but also triggers the dehydrogenation of dihydropyrimidine ring.