5-(R)BENZYLIDENE-2,2-DIMETHYL-1,3-DIOXANE-4,6-DIONES IN SYNTHESIS OF AROMATIC OXIMES, THIOSEMICARBAZONES AND HYDRAZONES

The behavior of some derivatives of Meldrum's acid, namely, 5-(R)benzylidene-2,2-dimethyl-1,3-dioxane-4,6-diones (a well-known synthetic platform) was studied with mono- and biazanucleophiles (hydrochloric hydroxylamine, thiosemicarbazide, hydrazine hydrate). The reaction of the reagents was carried out in acetic acid in a 1:1 molar ratio at 75 °C for 6-8 h, which resulted in aromatic oximes, thiosemicarbazones and hydrazones. The synthesis of (E)-4-chlorobenzaldoxime, (E)-N-(4-nitrobenzylidene) hydroxylammonium chloride, (E)-2-(4-chloro)- and (E)-2-(4-nitrobenzylidene) hydrazine-1-carbothioamides is probably accompanied by the formation of the Michael β-adduct with the subsequent elimination of Meldrum's acid. The interaction of nitrobenzylidene dioxanedione with hydrazine hydrate occurs to form a mixture of (E)-N-(4-nitrobenzylidene) acetohydrazide, (E)-(4-nitrobenzylidene) hydrazine and acetate of the latter in a ratio of 17:3:1, found from the integral signal intensity in the 1Н NMR spectrum (the ratio of similar products was 6:2:1 for chlorobenzylidene dioxanedione). It has been shown that during the reaction the studied substrates are attacked by two hydrazine molecules at the arylidene fragment and the carboxyl group of the opened dioxane cycle of Meldrum's acid. Further, the intermediates are recondensed to form hydrazones and acetylhydrazides. The latters interact with the aromatic aldehydes arising under these conditions as a result of the Knoevenagel retro-reaction of the substrates, with the formation of major products, mixtures of (E)-N-(4-chloro)- or (E)-N-(4-nitrobenzylidene) acetohydrazides. Thus, under the selected conditions, in contrast to the common mechanism presented in the periodicals, no formation of N-heterocyclic systems is observed. The structure of the compounds obtained was confirmed on the basis of 1H, 13C NMR spectroscopy data, as well as elemental analysis. Methods of two-dimensional heteronuclear correlation spectroscopy (HSQC) were also used for more reliable identification of the signals of the products (the components of mixtures).

Synthesis and biological activity of 2-[2-(7-chloroquinolin-4-ylthio)-4-methylthiazol-5-yl]-N-phenylacetamide derivatives as antimalarial and cytotoxic agents

A novel series of 2-[2-(7-chloroquinolin-4-ylthio)-4-methylthiazol-5-yl]- N-phenylacetamide derivatives is synthesized via substitution with 2-mercapto-4-methyl-5-thiazoleacetic acid at position 4 of 4,7-dichloroquinoline to obtain an intermediate acetic acid derivative. The chemical behavior of these reactants was investigated using different reaction conditions to optimize the nucleophilic substitution at position 4. The final compounds are prepared using a modified version of the Steglich esterification reaction between the acetic acid intermediate 3 and different anilines. The structures are confirmed by infrared, 1H, 13C, distortionless enhancement by polarization transfer 135°, Correlated Spectroscopy, heteronuclear correlation spectroscopy and (Long range HETCOR using three BIRD pulses) FLOCK-NMR spectral studies, and by elemental analysis. The synthesized compounds are tested in vitro and in vivo for their potential antimalarial and anticancer activities, with derivative 11 being the most promising candidate.