2-amino-3-arildiazenil-pirazolo[1,5-a]pirimidinas trifluormetilsubstituídas: síntese, derivatizações e avaliação das propriedades fotofísicas

Abstract

This thesis presents the results on the synthesis, structural study, and evaluation of the photophysical properties of new (E)-5-(alkyl/aryl/heteroaryl)-2-amino-3-(aryldiazenyl)-7-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine (5a-q), which were obtained using intramolecular cyclization reactions of the precursors (E)-3,5- diamino-4-(heteroaryldiazenyl)-1H-pyrazoles (3a-g) and 4-alkoxy-4-alkyl[aryl(heteroaryl)]-1,1,1-trifluor-3-alken2-ones (β-ATC) (4a-j) in 50-90% yields. Emission and UV-Vis properties were investigated in different solvents. All compounds were absorbed in the ultraviolet region showing low fluorescence in the solution. In sequence, initiating the derivatization reactions of the heterocyclic system 5, Sonogashira reactions were carried out, and three new series of derivative aryacetylenes were synthesized (6-8). These reactions were carried out exclusively for the 4-bromophenyl substituents at the 5-position and/or at the 3-position (3-diazenyl) in the pyrazolo[1,5- a]pyrimidine series (5). Thus, series of (E)-2-amino-5-phenyl-3-((4-(heteroarylethynyl)phenyl)diazenyl)-7- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine (6a-e), (E)-2-amino-3-(phenyldiazenyl)-5-(4- (arylethynyl)phenyl)phenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (7a-e) and (E)-2-amino-5-(4- (arylethynyl)phenyl)-3-((4-(arylethynyl)phenyl)diazenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (8a-c) were isolated in 20-87% yields. Subsequently, compounds 6–8 had their photophysical properties (absorption and emission) obtained, and their interaction studies on human serum albumin (HSA) biomolecules were evaluated. Afterwards, selected pyrimidines from the series 5a-q were used as starting materials in reaction with sodium azide. These reactions unexpectedly resulted in an unprecedented series of twinned triazoles in the form of 2,8- (aryl/heteroaryl)-6-(trifluoromethyl)-1ʎ2 ,2ʎ4 -1H-[1,2,3]triazolo[4',5':3,4]pyrazolo[1,5-a]pyrimidine (9a-k), which can be obtained by two different methodologies in 25-85% yields. In the second part of this thesis, other structural variations were developed based on pyrazolo[1,5-a]pyrimidines (11). Therefore, from 5-amino-3- methyl-1H-pyrazole (10) and β-ATC (4), a series of 2-methyl-5-(alkyl/aryl/heteroaryl)-7- (trifluormethyl)pyrazolo[1,5-a]pyrimidine (11) was obtained. Compounds 11 have already been described in the literature. Additionally, the fluorescent properties and UV-Vis absorption in different solvents were investigated, and as a result, it was found that all compounds show high fluorescence in solution. Furthermore, solid-state stabilities were evaluated via thermogravimetric analysis. Compounds (11) were then used as starting materials for the synthesis of heterocycles produced in the second part of this study, which evaluated the reactivity of position 3 of the pyrazolo[1,5-a]pyrimidine system (11) with the insertion of halogens and derivatization through the study of Sonogashira reactions. Halogenation reactions using NBS and NIS as the halogenating reagent allowed for obtaining 3-bromo and 3-iodo derivatives (12, 14). In sequence, the regioselectivity of C-C bond formation was studied using Sonogashira reactions, which provided the phenylacetylene derivatives 15-16 in yields of 45-79%. Furthermore, the novel compounds 2-methyl-3-iodo-5-aryl-pyrazolo[1,5-a]pyrimidines (14), led to the formation ix of substituted bis-trifluoromethyl systems, 2-methyl-5-aryl(heteroaryl)-3,7-bis(trifluoromethyl)pyrazolo[1,5- a]pyrimidine (17), in 30-85% yields, using MFSDA as the trifluoromethylating agent. As final derivatizations, the following were applied: a classical formylation reaction (Vilsmeier-Haack) functionalizing the 3-position of compounds 11, which provided the formation of an unprecedented series of 3-formyl-2-methyl-5-(aryl/heteroaryl)- 7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (18) in yields between 60-90%, and (ii) reaction of aldehydes 18 with malononitrile. This final reaction enabled the synthesis of a novel series of 2-((2-methyl-5-(aryl/heteroaryl)- 7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl)methylene)malononitriles (19) in yield of 40-85%. All chemical compounds related to the unpublished series produced in this thesis were characterized by melting point and structurally elucidated via routine spectroscopic and spectrometric techniques, that is, ¹H, ¹³C, and 19F NMR, oneand two-dimensional (HSQC, HMBC), CHN or HRMS elemental analysis, and single-crystal X-ray diffraction (CCDC recording) when appropriate.