Síntese de novos derivados híbridos de 1,2,4-oxadiazol contendo núcleos de cumarina e piridina

Abstract

The synthesis of hybrid compounds has attracted considerable interest in Organic and Medicinal Chemistry, since the combination of different bioactive scaffolds within a single molecular framework may lead to molecules with enhanced pharmacological properties and increased structural diversity. In this context, the incorporation of the 1,2,4-oxadiazole core into widely studied heterocyclic systems, such as coumarins, represents a promising approach, considering the well-documented biological activities associated with both classes of compounds. Accordingly, the present work focused on the investigation and application of an efficient synthetic methodology for the preparation of novel coumarin–1,2,4-oxadiazole–pyridine hybrid derivatives through a one-pot coupling between coumarin-3-carboxylic acid and pyridinyl amidoximes. The first step involved the synthesis of coumarin-3-carboxylic acid (1) via a Knoevenagel condensation, employing chitosan as a recyclable catalyst in an aqueous medium, affording an isolated yield of 82% within a short reaction time (10 min). In parallel, three pyridinyl amidoxime isomers (2a–c) were synthesized from hydroxylamine hydrochloride and the corresponding cyanopyridines, using water and ethanol as solvents at room temperature, with satisfactory reaction times (30–120 min) and high yields (82–92%). In the subsequent step, the coupling between the precursors was carried out using different activation systems for coumarin-3-carboxylic acid, namely EDCI/HOBt and DCC in DMF under reflux conditions. Among the conditions evaluated, the EDCI/HOBt system proved to be the most efficient for the formation of the 1,2,4-oxadiazole hybrid derivatives, furnishing products 3a and 3b in moderate yields (60–65%) after six hours of reaction. The obtained compounds were characterized by 1H and 13C Nuclear Magnetic Resonance spectroscopy, confirming the formation of the 1,2,4-oxadiazole core and the structural consistency with the proposed molecular structures.