Behavior of 5-amino-3-methylisoxazole in multicomponent heterocyclizations with carbonyl compounds under thermal heating and non-classical conditions

Abstract

Three-component heterocyclizations of 5-amino-3-methylisoxazole, cyclohexanedione derivatives, and aromatic aldehydes, including salicylic aldehydes, are studied under conventional thermal heating, microwave irradiation and ultrasonication. A dependence of the direction of the reaction on the structure of the aldehyde and the reaction conditions was found, which allowed selective synthesis of 6,7,8,9-tetrahydroisoxazolo[5,4-b]quinolin-5(4H)-ones and 2,3,4,9-tetrahydro-1H-xanthen-1-ones. Key stages of the reaction mechanisms are discussed.

The unexpected influence of aryl substituents in N-aryl-3-oxobutanamides on the behavior of their multicomponent reactions with 5-amino-3-methylisoxazole and salicylaldehyde

“…It was established that the three-component cyclocondensation of the starting compounds under ultrasonication at room temperature for 4 h led to the selective formation of the substituted chroman-3-carboxamide 4a in 58% yield (Scheme 3). In contrast to the similar reaction involving derivatives of 1,3-cyclohexanedione [13], here the final product was formed with participation of the exocyclic NH 2 -group of aminoisoxazole but not with its 4-CH center that may be linked via different mechanisms (see below).…”

“…In all cases of three-component reactions involving aminoazoles and carbonyl compounds, which were previously studied in our group [13,18,21–24], the substitution of mechanical stirring by ultrasonication did not change the structure of the final products but only affected the purity and yields of the final compounds as well as the reaction rate.…”

“…It should be firstly noted that the formation of any of the compounds 4 – 6a through the intermediate 7 (pathway A) as for cyclic 1,3-diketones [13,25] was excluded because the latter does not react with amide 3a under any comparable conditions.…”

“…In some cases when the reaction could proceed in two alternative pathways the conditions enabling to control the interaction direction were determined, which made it possible to obtain the desired azoloazine with high chemo- and regioselectivity [11,13–15]. In particular, three-component heterocyclizations involving 3-amino-1,2,4-triazoles or 4-substituted 5-aminopyrazoles yielded either 4,5,6,7-tetrahydroazolo[1,5- a ]pyrimidine-6-carboxamides under ultrasonication at room temperature (kinetic control) or 4,7-dihydroazolo[1,5- a ]pyrimidine-6-carboxamides at reflux in an applicable solvent (thermodynamic control), respectively (Scheme 1).…”

“…Here we disclose our recent findings of three-component heterocyclizations involving 5-amino-3-methylisoxazole, salicylaldehyde and N -aryl-3-oxobutanamides that were found to differ from similar reactions of cyclic CH acids [13]. …”