Synthesis and structural characterization of 1- and 2-substituted indazoles: ester and carboxylic acid derivatives

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.

Figure 1

Annular tautomerism of indazole (1a: benzenoid 1H-indazole tautomer; 1b: quinonoid 2H-indazole tautomer).

Figure 2

ORTEP [23] view of compound 5b showing the atomic labelling scheme and the relative positioning of the indazole ring and the carboxylic moiety.

Figure 3

(a) and (b) View along axis a and b respectively, showing the C(6) hydrogen bond synthon, responsible for the zigzag chain. (c) Packing diagram along axis c shows the weak interaction between the zigzag neighbouring chains, due to the π…π contacts (drawings done with Mercury) [24b].