Síntese de 3-(trifluormetil)-4H-pirido[1,2-a]pirimidin-4-onas 2-substituídas via reação de trifluormetilação usando MFSDA

Abstract

The present work aims to perform a synthetic feasibility study following a satisfactory procedure to obtain a novel compound denominated 2-phenyl-3- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4b) by using MFSDA as a nucleophilic trifluoromethylation reagent. This procedure in the future may be used for the synthesis of similar compounds with reduced reaction steps. Initially, the synthesis of a series of 2-substituted 4H-pyrido[1,2-a]pyrimidin-4- ones from the cyclocondensation between (Z)-1,1,1-trichloro-4-methoxy-4-alkyl(aryl)- but-3-alken-2-ones, wherein R = CH 3 , C 6 H 5 , p-CH 3 -C 6 H 4 , p-NO 2 -C 6 H 5 , and the dinucleophile 2-aminopyridine based on a methodology described in the literature, resulting in the isolation of a series of 4 structures containing the “4H-pyrido[1,2-a]pyrimidin-4-one” nucleus in 55-81% yields. Subsequently, aiming to synthesize 3-bromo substituted 4H-pyrido[1,2-a] pyrimidin-4-one derivatives (3), the respective heterocycles 2a-d were halogenated by electrophilic substitution of hydrogen from C-3 per bromine employing NBS as an essential prerequisite for subsequent trifluoromethylation. The bromination reactions provided the 2-substituted 3-bromo-4H-pyrido[1,2-a]pyrimidin-4-ones (3a-d) as synthetic intermediates in 45-82% yields, being 3c and 3d unpublished compounds in the literature. Finally, trifluoromethyl insertion reactions were performed using derivative (3b) as an example and employing MFSDA as a nucleophilic trifluoromethylating agent, CuI as a catalyst and HMPA as an additive. This optimized reaction condition afforded the isolation of 2-phenyl-3-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4b) in 30% yield. The obtained compounds were structurally characterized by 1 H, 13 C and 19 F NMR and GC-MS.