New tricks of well-known aminoazoles in isocyanide-based multicomponent reactions and antibacterial activity of the compounds synthesized

Abstract

The well-known aminoazoles, 3-amino-5-methylisoxazole and 5-amino-N-aryl-1H-pyrazole-4-carboxamides, were studied as an amine component in Ugi and Groebke-Blackburn-Bienaymé multicomponent reactions. The first example of an application of aminoazoles in an Ugi four-component reaction was discovered and novel features of a Groebke-Blackburn-Bienaymé cyclocondensation are established and discussed. The heterocycles obtained were evaluated for their antibacterial activity and several of them demonstrated a weak antimicrobial effect, but for most of the compounds a 30-50% increase in biomass of Gram-positive strains (mainly B. subtilis) compared to control was observed.

Keywords: 3-amino-5-methylisoxazole; 5-amino-N-aryl-1H-pyrazole-4-carboxamides; Groebke–Blackburn–Bienaymé reaction; antibacterial activity; isocyanide Ugi reaction.

Scheme 1

Aminoazoles in GBB-3CR and Ugi-4CR.

Scheme 2

Reactivity of 5-amino-N-aryl-1H-pyrazole-4-carboxamide and 3-amino-5-methylisoxazole in GBB-3CR and Ugi-4CR.

Figure 1

Alternative structures A and B for compounds 4 and 6.

Figure 2

Selected data of HSQC and HMBC experiments for compound 4a.

Figure 3

Molecular structure of 3-(tert-butylamino)-2-(4-chlorophenyl)-N-(4-fluorophenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide (4e) (X-ray diffraction data). Non-hydrogen atoms are presented as thermal ellipsoids with 50% probability.

Figure 4

Selected data of NOE and HSQC experiments for compound 9d.

Figure 5

Molecular structure of N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-N-(5-methylisoxazol-3-yl)-3-phenylpropiolamide (9e) (X-ray diffraction data). Non-hydrogen atoms are presented as thermal ellipsoids with 50% probability.