RESUMO
A tandem transformation that involves the formation of three bonds and two heterocyclic rings in a one-pot fashion through amino-alkylation of an ionic-liquid-immobilized diamine with keto acids followed by successive double intramolecular cyclizations to afford a tricyclic framework has been explored. This tandem cyclization has been utilized to develop a rapid and efficient method to synthesize various pyrrolo[1,2-a]benzimidazolones and pyrido[1,2-a]benzimidazolones on an ionic-liquid support by using focused microwave irradiation. The application of this tandem cyclization was further extended to the aromatic keto acids to provide isoindolinone-fused benzimidazoles, a structurally heterogeneous library with skeletal diversity. The outcome of the cascade reaction was confirmed by the X-ray crystallographic study of the product directly attached to the ionic-liquid support. Use of the ionic liquid as a soluble support facilitates purification by simple precipitation along with advantages like high loading capacity, homogeneous reaction conditions, and monitoring of the reaction progress by regular conventional spectroscopic methods, whereas application of microwave irradiation greatly accelerates the rate of the reactions.
Assuntos
Líquidos Iônicos/química , Isoindóis/química , Micro-Ondas , Pirróis/química , Benzimidazóis/síntese química , Benzimidazóis/química , Cristalografia por Raios X , Ciclização , Conformação MolecularRESUMO
Traceless synthesis of 2-aminoimidazoquinoxalinones has been performed on soluble polymer support under open-vessel microwave dielectric heating. The reaction progression is monitored directly by the conventional proton NMR which indicated no release of the substrate from the support. Fmoc-deprotected amino acid polymer conjugates react with 1,5-difluoro-2,4-dinitro benzene to yield polymer bound dinitro fluoro amines, which are further substituted by various primary amines to yield PEG-immobilized dinitrodiamines. Simultaneous reduction of aromatic meta-dinitro group leads to the traceless release of 2-quinoxalinones, followed by N-hetero cyclization with various isothiocyanates in the presence of mercury(II)chloride to furnish 2-aminoimidazoquinolinone rings with three points of diversity at rapid pace.
Assuntos
Técnicas de Química Combinatória/métodos , Descoberta de Drogas/métodos , Imidazóis/química , Imidazóis/síntese química , Micro-Ondas , Ciclização , Dinitrofluorbenzeno/análogos & derivados , Dinitrofluorbenzeno/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Pharmaceutically interesting, angular bis-benzimidazoles with three appendages have been synthesized successfully through a diversity-oriented approach with soluble support under microwave irradiation. Polymer immobilized o-phenylenediamine was selectively N-acylated with 2-chloro-3-nitrobenzoic acid in a primary aromatic amino moiety. The obtained amide was cyclized to benzimidazole in an acidic condition, and subsequently nucleophilic aromatic substitution with different amines was performed. Successive reduction, cyclization with various aldehydes and activated isothiocyanates yielded angular biheterocyclic benzimidazoles in good quantities. Reaction progress on polymer support was precisely monitored using the conventional proton NMR spectroscopy. Preliminary screening results showed some of these interesting compounds exhibited moderately to good inhibition against vascular endothelial growth factor receptor 3 (VEGFR-3), which is related to invasion and migration of cancer cells.
Assuntos
Benzimidazóis/síntese química , Técnicas de Química Combinatória/métodos , Micro-Ondas , Benzimidazóis/química , Estrutura Molecular , EstereoisomerismoRESUMO
Based on the earlier results of our in-house database and compound library, a series of novel clubbed thienyl triazoles was designed which may emerge as potential cdk5/p25 inhibitors, for the treatment of Alzheimer's disease. A benign synthesis was planned so as to take an advantage of MAOS (Microwave Assisted Organic Synthesis) method. Evaluation of the SAR of this series has allowed the identification of compounds 4, 5, 7 and 8 from series I while 13, 14, 16 and 17 from series II as significant cdk5/p25 inhibitors and thus have potential as possible treatments for Alzheimer's disease.