Isolation, Conformational Analysis and X-Ray Structure Determination of a Trifluoromethyl-stabilized Hexahydropyrimidine — An Intermediate in the Biginelli Reaction

Hexahydropynmidine-5-carboxylic acid ethyl ester (8) was obtained from Birinelli-twe condensation of ethvl rntluoroacetoacrtatc with urea and belualdehyde.he' conformational featthes of this hexahydropyrimidine were investigated by computational and X-Ray crystallographic studies.The geometries of the four possible diastereoisomers were fully optimized using semiempirical (AM1, AMI/MM) methods.The structure of the thermodynamically most stable diastereoisomer was further studied by ab inilio (HF13-21G) methods.The cyclocondensation of benzaldehyde (1) with urea (2) and ethyl acetoacetate (4), known as the Biginelli reaction(Scheme I ) , ~ has attracted considerable attention in recent years.3'20This is mainly due to the fact that this multicomponent condensation protocol provides a pyrimidine derivative (i.e.7) of proven pharmacological e f f i c i a ~~." ~ Although alternative strategies for the synthesis of dihydropyrimidines of type ( 7) have been reported in the literature?'' the classical Biginelli one-pot approach is still the most effective."-l8In recent years, several improved procedures for the Biginelli reaction have been published,'.'1'"including various solid-phase modifications suitable for combinatorial chemistry."-'8Despite this interest, the mechanism of the Biginelli reaction itself has not been elucidated until 1997.19In very recent work, Hu el a1.I4 were able to isolate an open-chain ureide of type (5) by using a sterically bulky acetoacetate (1.e. 4, R = tert-butyl) in a Lewis acid-mediated Biginelli reaction.We now report the isolation of an hexahydropyrimidine intermediate of type (6) by employing an electron-deficient acetoacetate (i.e. 4, R = CF3) in this reaction.The relative stereochemistry and conformational properties of this hexahydropyrimidine (6; R = CF3) were investigated by computational and X-Ray crystallographic studies.Note that for the sake of continuity the terms dihydropyrimidine (7) and hexahydropyrimidine (6) are used through& this article; the W A C names are given in the Experimental.