932 Diversity-oriented Multicomponent Heterocyclizations Involving Derivatives of 3(5)-Aminoisoxazole, Aldehydes and Meldrum’s or N,N′-Dimethylbarbituric Acid Vol 54 Alisa D. Morozova, a Elena A. Muravyova, a Svitlana V. Shishkina, a,b Elena V. Vashchenko, a Yulia V. Sen’ko, a and Valentin A. Chebanov a,b * a State Scientific Institution “Institute for Single Crystals” of National Academy of Sciences of Ukraine, Nauky Ave. 60, 61072 Kharkiv, Ukraine b Chemistry Faculty, Karazin Kharkiv National University, Svobody sq. 4, 61022 Kharkiv, Ukraine *E-mail: chebanov@isc.kharkov.com Received December 12, 2015 DOI 10.1002/jhet.2656 Published online 2 May 2016 in Wiley Online Library (wileyonlinelibrary.com). 5-Amino-3-methylisoxazole and 3-amino-5-methylisoxazole were studied in details in the multicompo- nent heterocyclizations with aromatic aldehydes and Meldrum’s or N,N′-dimethylbarbituric acid with help of classical and non-classical (microwave and ultrasonic irradiation) activation methods. J. Heterocyclic Chem., 54, 932 (2017). INTRODUCTION Isoxazole scaffold plays an important role in drug devel- oping for search of substances having high biological ac- tivity, for example, antiproliferative [1], analgesic [2], and antipsychotic actions [3]. Molecular drug targets in- clude muscarinic receptors M 1 and M 2 [4], dopamine D 2 , serotonin 5-HT 2A and 5-HT 2C [3], β-adrenergic receptors of all subtypes [5], and voltage-gated sodium channels [6]. The role of isoxazole moiety is various: from the de- veloping of conformational rigid systems [3] to the en- hancement of affinity of a drug for a receptor [4]. The wide variety of molecular drug targets for isoxazole deriv- atives, as well as diversity of problems solved with the help of such compounds, determines the high interest to them. Multicomponent reactions are proved as fast and efficient method for the formation of azoloazine systems [7–9]. The application of multicomponent approach allows obtaining arrays of compounds with high diversity because of the var- iation of substituents, skeleton and stereochemistry. Similar to other aminoazoles, 5-amino-3-methylisoxazole in most cases reacts as 1,3-binucleophile in such reactions: the ac- tive sites of the molecule are exocyclic amino group and methine carbon atom. For instance, there are literature data on the formation of different structures like I–VIII based on the treatment of 5-amino-3-methylisoxazole, aromatic alde- hydes, and non-cyclic or cyclic active methylene com- pounds under different conditions (Fig. 1) [10–16]. Multicomponent reactions of aminoazoles and carbonyl compounds with Meldrum’s acid are of interest because of the possibility of their proceeding in several alternative directions as well [8,9]. For example, in case of 5-amino- 3-methylisoxazole under microwave irradiation the forma- tion of two heterocyclic systems IX [14] and X [10] was observed (Fig. 2). However, it should be noted that the reason of change in the direction of the treatment from spiro-compounds towards isoxazolodihydropyridone under the very similar conditions is not clear. Indeed, our attempts to reproduce the described procedures [10,14] led either to the mixture of compounds IX and X or to sole spiro-heterocycle IX in lower yields in comparison with the literature data. N,N′-Dimethylbarbituric acid likewise Meldrum’s acid may also acts as C 1 synthon in the formation of spiroisoxazolopyridines under microwave irradiation [15]. On the other hand, multicomponent reactions involving isomeric 3-amino-5-methylisoxazole, to the best of our knowledge, are not adequately explored. Its reactivity has been only described in synthesis of pyrrolones [17], in Hantzsch [18] and Betti [19] reactions, and in four-component reactions for construction of imidazole moiety [20]. Therefore, the main goal of the present work was to study in details the multicomponent reactions of 5-amino- 3-methylisoxazole and 3-amino-5-methylisoxazole with aro- matic aldehydes and Meldrum’s or N,N′-dimethylbarbituric acid, to develop simple and reproducible synthetic © 2016 Wiley Periodicals, Inc.