Synthesis Of 2-(3-chromenyl)-4-ethoxycarbonyl-1-(4-fluorobenzyl)-5- methylimidazole 3-oxides

Abstract

In addition to our search for probable HIV-1 integrase inhibitors in the series of imidazole derivatives a possibility of preparation of 2-(3-chromenyl)substituted imidazole 3-oxides containing fluorobenzyl moiety in position 1 of imidazole ring as a potential pharmacophore was demonstrated. 4-ethoxycarbonyl-1-(4-fluorobenzyl)-5-methyl-2-(4-oxo-4H-chromen-3-yl)imidazole 3-oxide 4a and 4-ethoxycarbonyl-2-(6-hydroxy-4-oxo-4H-chromen-3-yl)-1-(4-fluorobenzyl)-5-methylimidazole 3-oxide 4b were synthesized starting with fluorobenzylamine 1, ethyl 2-(hydroxyimino)- 3-oxobutanoate 2 and 4-oxo-4H-chromen-3-carbaldehyde 3a or 6-hydroxy-4-oxo-4H-chromen-3- carbaldehyde 3b, respectively. The condensation was carried out at room temperature in glacial acetic acid. Two novel imidazole N-oxides were characterized by 1H NMR and IR spectroscopy and mass-spectrometry. It should be noted that in 1H NMR spectra of the discussed imidazole N-oxides recorded in deuterated DMSO) the singlet of the proton in the position 2 of chromenyl ring is shifted to lower field (8.70 and 8.78, respectively) as compared with the signals of other aromatic protons. Such deshielding is typical for this kind of heterocyclic system and may be explained by the influence of the electron-withdrawing of N-oxide moiety. In the IR spectrum of 4-ethoxycarbonyl- 1-(4-fluorobenzyl)-5-methyl-2-(4-oxo-4H-chromen-3-yl)imidazole 3-oxide 4a the absorption bands corresponding to the carbonyl groups appear at 1641 cm-1 (for C=O in the position 4 of chromenyl ring) and 1641 cm-1 (C=O of the ester moiety). In the IR spectrum of 4-ethoxycarbonyl- 2-(6-hydroxy-4-oxo-4H-chromen-3-yl)-1-(4-fluorobenzyl)-5-methylimidazole 3-oxide 4b the position of the former band remains practically unchanged (1646 cm-1), whereas the latter band is shifted to higher frequencies (1715 cm-1) due to intermolecular interactions with OH-group in the position 6 of the chromene. The absorption band for this group appears as a broad band with medium intensity and maximum absorption at 3228 cm-1. In the mass spectra of imidazole N-oxides under consideration peaks of the molecular ions (M+) and peaks (M-16) are observed. The demonstrated possibility of the synthesis of the titled compounds allows the further planning of the synthesis of a series of such structures varying the substituents in both chromenyl and imidazole rings.