Abstract
A series of indazoles substituted at the N-1 and N-2 positions with ester-containing side chains -(CH2)(n)CO2R of different lengths (n = 0-6, 9, 10) are described. Nucleophilic substitution reactions on halo esters (X(CH2)(n)CO2R) by 1H-indazole inalkaline solution lead to mixtures of N-1 and N-2 isomers, in which the N-1 isomer predominates. Basic hydrolysis of the ester derivatives allowed the synthesis of the corresponding indazole carboxylic acids. All compounds were fully characterised by multinuclear NMR and IR spectroscopies, MS spectrometry and elemental analysis; the NMR spectroscopic data were used for structural assignment of the N-1 and N-2 isomers. The molecular structure of indazol-2-yl-acetic acid (5b) was determined by X-ray diffraction, which shows a supramolecular architecture involving O2-H...N1 intermolecular hydrogen bonds.
Highlights
Indazoles constitute an important class of heterocycles that display interesting biological properties [1,2], such as anti-depressant [3], anti-inflammatory [4,5], analgesic and antipyretic [6], dopamine antagonistic [7], anti-tumor [8], anti-emetic [9] and anti-HIV activities [10]
We report the synthesis, starting from 1H-indazole (1), of several indazole derivatives substituted at the N-1 and N-2 positions with side chains of different lengths and functionalised with ester or carboxylic acid groups
Comparison of the spectra of indazole carboxylic acid derivatives 4d, 4e and 4f and indazole esters 2d, 2e and 2f in the same solvent (CDCl3), reveal no differences between their 13C-NMR spectra, with the exception of the CO carbon atom. These observations confirm that, despite the change in the functional groups of indazole derivatives the chemical shifts of indazole ring carbon atoms remain constant, which allows the assignment of N-1 and N-2 isomers of carboxylic acid derivatives by 13C-NMR spectroscopy
Summary
Indazoles constitute an important class of heterocycles that display interesting biological properties [1,2], such as anti-depressant [3], anti-inflammatory [4,5], analgesic and antipyretic [6], dopamine antagonistic [7], anti-tumor [8], anti-emetic [9] and anti-HIV activities [10]. We report the synthesis, starting from 1H-indazole (1), of several indazole derivatives substituted at the N-1 and N-2 positions with side chains of different lengths and functionalised with ester or carboxylic acid groups. Their full characterization was achieved by IR and multinuclear NMR, mass spectrometry, mp and elemental analysis. The recrystallization of indazol-2-yl-acetic acid 5b afforded crystals suitable for X-ray diffraction studies, which confirm the proposed structure Application of these compounds to the synthesis of novel biologically active compounds is under investigation and will be reported in due course
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