Convenient, direct, metal-free, regioselective and de novo synthesis of 2,4,5-trisubstituted pyrimidines using α-aryl-β, β-ditosyloxy ketones

Abstract

An efficient and environmentally benign approach was developed for the synthesis of 4,5-diphenylpyrimidin-2-amine from chalcones after considering the various limitations of earlier methodologies reported in the literature. The synthesis was initiated by treating chalcones with two equivalents of hydroxy(tosyloxy)iodobenzene, which resulted in the formation of geminal ditosyloxy ketones via 1,2-aryl migration. These geminal ditosyloxy ketones served as 1,3-dielectrophilic carbon atom precursors and subsequently cyclized with guanidine hydrochloride in the presence of a base to synthesize scarcely explored targeted pyrimidine molecules. This strategy offers several key advantages in terms of operational simplicity, high regioselectivity, shorter reaction time and facile reactivity because of the two p-toluenesulfonyl groups, which have the dual functions of being excellent leaving groups and having a strong electron-withdrawing nature. Moreover, the use of a hypervalent iodine reagent, i.e., Koser's reagent, in the present protocol makes this synthesis eco-friendly in nature. A total of twelve derivatives of the product were synthesized in moderate to good yields. The complete structural elucidation of the final compounds was achieved by employing various spectroscopic techniques (IR, ¹H-NMR and ¹³C-NMR) and HRMS analysis.