Tesis
Síntese, estrutura e avaliação antimicobacteriana de novos 1- (espiro[croman-2,1’-cicloalcan]-4-il)-1h-1,2,3-triazóis
Fecha
2018-08-03Autor
Stefanello, Felipe Salvador
Institución
Resumen
This thesis describes the synthesis, structural study and antimycobacterial evaluation of a series of novel
4-(alkyl/aryl)-1-(spiro[chroman-2,1'-cycloalkan]-4-yl)-1H-2,3-triazoles having as substituent aryl = phenyl, 4-
aminophenyl, 3-methoxyphenyl and alkyl = n-hexyl and hydroxymethyl, for the cycloalkanes corresponding to
cyclopentane, cyclohexane and cycloheptane.
The regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles was performed from 4-azidospiro
[chroman-2,1'-cycloalkanes], which in reactions with different terminal alkynes provided cycloaddition reactions
1,3-dipolar regioselective (Click Chemistry) leading to formation of the above-mentioned 1H-1,2,3-triazoles in
yields of 47-97%. The novel series of azido spirocycloalkanes precursors were previously obtained in yields of
60-80%, starting from nucleophilic substitution reaction involving a series of 4-mesyl spirochromanes and sodium
azide. It is necessary to optimize the reaction conditions due to the occurrence of competition between nucleophilic
substitution reactions, which led to the desired azides and elimination, which led to the respective alkenes. The
precursor series of 4-mesyl spirochromanes was obtained in two reaction steps comprising a reduction of the
respective spiro-chromanones with NaBH4, followed by a mesylation reaction of the secondary alcohols initially
originated with mesyl chloride (67-85%).
In order to obtain fluorine-derived compounds, fluorination reactions were performed from examples of
1-(spiro [chroman-2,1'-cycloalkan]-4-yl)-1H-1,2,3-triazol-4-yl)methanol which led to the formation of a new
series of 4-(fluoroethyl)-1-(spiro[chroman-2,1'-cycloalkan]-4-yl)-1H-1,2,3-triazoles using DAST as a fluorinating
agent in yields of 60-73%.
The structural study of the novel molecules isolated during this dissertation was performed using 1H, 13C,
19F NMR, 2D 1H-13C HSQC and 1H-13C HMBC NMR, mass spectrometry and by single crystal X-ray diffraction.
The present study evaluate the antimicrobial activity of 4-azido-spiro[chroman-2,1'-cycloalkanes] and 4-
(alkyl/aryl)-1-(spiro[chroman-2,1'-cycloalkan]-4-yl)-1H-1,2,3-triazoles, which showed low activity at the highest
concentrations evaluated against the strain of Micobacterium tubeculusis [H37Rv (ATCC 27294)], with MICs >
20-80 μg/mL versus Isoniazid (MIC 0.31 μg/mL) for both series.