This dissertation is devoted to the study of synthetic approaches towards monocyclic and fused 1,3-azolyloxoacetates, as well as their reactivity in reactions with model (bi-)nucleophiles. For this purpose, a range of condensation reactions (in particular, heterocyclizations), reductions, aminations and deoxyfluorinations were performed with azolyloxoacetates obtained in this work.
It was found that the Friedel-Crafts acylation of N-substituted imidazoles with ethyloxalyl chloride in the presence of i-Pr2NEt in CH2Cl2 is a general method for the preparation of (imidazol-2-yl)oxoacetates, which occurred selectively at C(2)-position of starting azoles.
The method proposed was general and suitable for all studied C(2)-unsubstituted imidazoles containing N-alkyl, alkenyl or aryl substituents, as well as C(5)-functional groups (Cl, Br or CN).
The transformations proceeded via C(2)-deprotonation of N(3)-acylated intermediate with subsequent transfer of the acyl group to the C(2)-position, which provided the corresponding ethyl (1,3-azole-2-yl) oxoacetates in high yields (83–96%). In turn, C(2)-unsubstituted 1H-1,2,4-triazoles and (benzo)thiazoles were less fruitful starting materials since carbonyl groups of the corresponding glyoxylates were more reactive towards their own interemediate and led to the side formation of 2-hydroxy-2, 2-bis-azolyl acetates as by-products.
Two optimized one-step methods for the preparation of imidazo[1,2]hetaryl-glyoxylates were developed. Both methods relied on the Friedel-Crafts acylation of fused imidazoles with ethyloxalyl chloride. The influence of electron-donating groups on the acylation efficiency was also evaluated, with the following order of substrate reactivity: imidazo[2,1-b]thiazoles> imidazo[1,2-a]benzimidazoles > imidazo[1,2-a]pyridines > imidazo[1,2-a]pyrimidines.
It was found that the synthesized getarylglyoxylates reacted as typical electrophiles in reactions with model H-, O- and N-nucleophiles. In particular, reductions of glyoxylates with NaBH4 could be performed selectively for the synthesis of α-hydroxyestersor 1,2-diols. The alkaline hydrolysis of glyoxylates resulted in glyoxalic acids, while treatment with NH2OH⋅HCl gave the corresponding oximes. It was also shown that glyoxylates acted as bis-electrophiles in reactions with ethylenediamine and o-phenylenediamine for the synthesis of 5,6-dihydropyrazin-2-ones and quinoxalin-2-ones, respectively.
A practical synthetic approach fot the preparation of novel 3-azolyl-1H-quinoxalin-2-ones was also proposed, which relied on the reaction of azolyl glioxylates with unsubstituted or symmetrically4,5-disubstituted 1,2-diaminobenzenes. The protocol was successfully applied to the preparation of all studied bi- and tricyclic quinoxalin-2-ones in high yields (84–99%)
Moreover, the synthetic utility of 3-azolyl-1H-quinoxalin-2-ones was demonstrated via the synthesis of an analogue of Caroverin. It was also shown that the condensation of glyoxylates with 1,2-diaminocyclohexane (used as a 1:1 mixture of cis and trans diastereomers) resulted in exclusive formation of trans-hexahydroquinazolin-2-ones in 40–85% yield due to the epimerization on the step of formation of intermediate Schiff base.
