Controle regioquímico na síntese de 1-Aril-3(5)-carboxialquil-1H-pirazóis

Abstract

The present dissertation reports the development of a methodology for the regiochemical control in the synthesis of 1-aryl-3(5)-carboxyalkyl-1H-pyrazoles, through cyclocondensation reactions using 4-alkoxy-1,1,1-trichloromethyl-3-alken-2- ones (enones) as dielectrophiles and arylhydrazines as dinucleophiles. During the initial studies, it was found that the regioselectivity of the reaction is determined by the nature of the hydrazine used (free or in hydrochloride form). In this way, 1-aryl-3- carboxyalkyl-1H-pyrazoles (1,3-regioisomer) were prepared with up to 97% selectivity using arylhydrazine hydrochlorides (24 examples, 37 – 97% yield). The corresponding regioisomers 1-aryl-5-carboxyalkyl-1H-pyrazoles (1,5-regioisomer) were selectively prepared using phenylhydrazine (12 examples, 52 – 83% yield). Different variables that might influence the selectivity during the cyclocondensation reaction (time, solvent, temperature and effect of substituents of the starting materials) were evaluated. Recognizable, the effect caused by different substituents in position 4 of the starting enone in the cyclocondensation reaction showed that groups with electron donating characteristics cause a reduction in the reaction yield (~12%), while electron withdrawing groups showed no significant influence. It is important to note that in none of the aforementioned groups the loss of selectivity was observed. In addition, the use of alcohols as a reaction solvent promoted the hydrolysis of the trichloromethyl group and the formation of esters with different side chains. Additionally, it was observed that the presence of electron-withdrawing substituents at the N1- position inhibit the hydrolysis of the trichloromethyl group. The presence of electron-donating groups, on the other hand, promoted the elimination of this group, simultaneously with the cyclization of the ring, providing the corresponding NH-pyrazoles. The products obtained in this work were characterized by ¹H and ¹³C nuclear magnetic resonance analyses, high resolution mass spectrometry and the determination of isomers was performed by X-ray diffraction analysis of single crystals of the synthesized compounds.