The work is devoted to the study of the three-component condensation of 3-amino-1,2,4-triazole derivatives with salicylic aldehydes and CH-acids (ketones, acetoacetic esters and 3-acetylbutyrolactone), its regularities, chemo-, regio-, stereoselectivity, development of methods for the preparation of new triazolopyrimidine’s derivatives and the establishment of mechanism of these reactions.
Theoretically a reaction of 3-amino-1,2,4-triazole with aromatic aldehydes and CH-acids (ketones, acetoacetic esters and 3-acetylbutyrolactone) may lead to formation of at least eight products comprising two rows of isomers of tetrahydro- and dihydropyrimidine derivatives. At the time of setting aim for this dissertation, there were only four of these isomers reported in the literature. Different products were formed under the influence of various specific factors including the nature of the starting compounds and the reaction conditions and fixed in or isolated from the reaction mixture. One of these product types described in the vast majority of publications can be considered a classical reaction direction product, where the aldehyde component is bonded to the hydrazine endocyclic nitrogen atom of the triazole.
It was shown that in contrast to the literature data on the reaction of aminotriazole with salicylic aldehyde and carbonyl CH-acides the reaction with aceton under the mild conditions proceeds via alternative direction leading to stereospecific formation of 5-aryl-substituted tetrahydrotriazolopyrimidines, the products of the addition of aldehyde to the exocyclic triazole nitrogen atom are formed.
It is known that in case of salicilyc aldehyde threecomponent condensation may not stop on the stage of dihydropyrimidine derivative, and proceed to the formation of benzoxadiazocines by addition of the 2-hydroxy group of salicylic aldehyde to the double bond of the dihydrotriazolopyrimidine derivative. Thus, obtained tetrahydro[1,2,4]triazolo[1.5-a]pyrimidines may be considered as intermediates in the formation of [1,2,4]triazolo[1,5-c][1,3,5]benzoxadiazocine derivatives under the harsh conditions under microwave heating. The key intermediate structure and the structure of a bеnzoxadiazocine representative were unambiguously confirmed by single crystals X-ray diffraction study in addition to other spectral data. Variation of ketones showed limitations of the reaction protocol due to the loss of the stereo- and regioselectivity or decreased reactivity of substituted ketones. A general procedure was developed for the synthesis of benzoxadiazocine derivatives with the use of acetone which made it possible to obtain derivatives with variable substituents in triazole and benzene cycles. The use of acetoacetic ester instead of ketones under mild conditions also leads to formation of the alternative products, corresponding 5-aryl-substituted tetrahydrotriazolopyrimidines, at which 6-C-H chiral center epimerizes in DMSO solution. In case of the aldehydes lacking 2-OH group such compounds under harsh conditions undergo rearrangement with the formation of the known 7-aryldihydrotriazolopyrimidines – products of the classical reaction direction. However, the use of 3-acetobutyrolactone instead of acetoacetic ester made it possible to obtain stable spiro-derivatives of tetrahydrotriazolopyrimidine, where mobile protone at 6-C-H was replaced by an alkyl substituent. This made it possible to establish the stereochemistry of the formation of the tetrahydropyrimidine ring and to propose the mechanisms of alternative reactions pathways that could explain all the details of their course. Beside the obtained data on the studied reaction an interactions using 2,3 dihydrofuran and 3,4-dihydro-2H-pyran as models of enol forms of the carbonyl CH acids were carried out mimicking one of the key stage of the studied reaction mechanism: interaction of the enol form with the Schiff base made from 3-aminothriazole and salicylic aldehyde. Another key stage is the stereospecific closure of the tetrahydropyrimidine ring proceeding within simultaneous formation of two (in the case of acetone) or three (in the case of acetylbutyrolactone) chiral centers. This stage is an intramolecular attack of the pyridine nitrogen atom of the triazole ring on the carbonyl group that can take place on the most favorable trajectory located in the plane orthogonal to the carbonyl group, at the Burgie-Dunitz angle, (α) Nu...C=O , which is equal to 107 ± 5°. Due to the steric hindrances of the substituents, such angle is realized only in the conformations of intermediates, leading to the formation of the observed configuration of the tetrahydropyrimidine ring. The closure of the oxygen bridge is consistent with the mechanism known in literature.
