The use of the electrophilic intramolecular cyclization (EIC) strategy for annulation of an additional heterocycle is an inexhaustible source of synthetic heterocycle design, and its research with a view to synthesizing condensed and functional symmetric triazoles is both relevant and of theoretical and practical importance.
The dissertation is devoted to the development of new methods of obtaining condensed and functional derivatives of 1,2,4-triazole-3-thione via using the IEC strategy.
To achieve the goal of dissertation the following tasks have been solved: (1) the methods for obtaining model functionally substituted 1,2,4-triazole-3-thiones were developed, which contain an unsaturated moiety suitable for carrying out EIC reactions; (2) the interaction of electrophilic reagents (iodine, iodine bromide, bromine, acids, selenium (IV) chlorides, selenium (IV) bromides, tellurium (IV) chlorides, tellurium (IV) bromides) with unsaturated derivatives of functionally substituted 1,2,4-triazole-3-thiones were studied; (3) the regioselectivity of annulation of an additional heterocycle to the 1,2,4-triazole backbone and to identify factors that influence the realization of the EIC process was investigated; (4) the optimal conditions for obtaining the target annulation products by the EIC method were found; (5) the energy-saving methods for the synthesis of condensed 1,2,4-triazoles that meet the requirements of green chemistry were developed; (6) the probable mechanisms of EIC on model unsaturated 1,2,4-triazole derivatives was found out; (7) the chemical properties of condensed 1,2,4-triazole derivatives in order to further functionalize symmetric triazoles were investigated; (8) the biological properties of new condensed and functional derivatives of 1,2,4-triazole were studied.
In the dissertation the 4-alkenyl substituted 5-amino-1,2,4-triazole-3-thione and butenyl, cinnamyl and pentenyl thioethers of 4,5-disubstituted 3-mercapto-1,2,4-triazoles have firstly been synthesized. The factors of influence on the stability of unsaturated aroylbisthioureas and their conversion to model 4-aroyl-5-amino-1,2,4-triazol-3-thion have been investigated for the first time. The optimal conditions for the interaction of unsaturated 1,2,4-triazole-3-thione derivatives with electrophilic reagents have been found, which allow to achieve maximum regio- (stereo-)-selectivity of the process. The patterns of selective annulation of a five- or six-membered cycle to the backbone of 1,2,4-triazole have been identified; the influence of the nature of the reacting components, the nature of the solvent and the conditions of the reaction on the regiodirection of the process are investigated. For the first time, the decisive influence of the nature of the alkenyl moiety and the heteroatom linked to the unsaturated substituent on the regiodirection of the EIC is shown. The mechanisms for the course of EIC reactions of the unsaturated 1,2,4-triazol-3-thione derivatives have been proposed, based on the empirical material obtained and the methods of computer simulation. The efficiency of using 13C NMR spectroscopy in the analysis of the EIC regioselectivity has been shown.
A series of convenient techniques for the introduction of selenium trihalide and tellurium-trihalide fragment into the thiazolo[3,2-b][1,2,4]triazoles and thiazolo[2,3-c][1,2,4]triazoles have been developed vie EIC based using low-toxic solvents, available reagents and meeting the criteria of green chemistry.
An effective method for the functionalization of the triazole cycle has been elaborated via selectively opening the thiazolinium ring in the thiazolo[3,2-b][1,2,4]triazolium salts under the action of nucleophilic reagents; the optimal process conditions have been determined depending on the structure of the source salts – this made it possible to obtain the inaccessible polyfunctional 1,2,4-triazoles. The optimal conditions for the action of nucleophilic reagents on halogenation products have been established; the regiodirection of the process was determined depending on the nature of the nucleophile. A convenient way of functionalizing of thiazolo[3,2-b][1,2,4] triazoles by elimination and nucleophilic substitution reactions has been developed. Preparative techniques for introducing of functional groups into the second position of the 1,2,4-triazole cycle have been developed via the dithiocarbonation reaction, and the Mannih reaction – as result, the promising bioactive and analytical reagents containing 1,2,4-triazole ring were received.
