Synthesis Of Quinolines Based On Cyclization Of Anthranils And Enaminones

Quinoline derivatives have biological activities such as antibacterial,antifungal,and antiviral properties.They are widely used in the pharmaceutical industry and are chemical intermediates of many important drugs.Among the quinoline derivatives,3-acylquinoline and its derivatives are novel inhibitors of p-hydroxyphenylpyruvate dioxygenase,which are commonly used in the synthesis of drugs,natural products and materials,showing broad application prospect.Although some literatures have reported the synthesis methods of 3-acylquinoline compounds,these methods often have some disadvantages of not easy to obtain raw materials,many reaction steps,poor atom economy,environmental pollution and the like,and do not accord with the requirements of the development of green chemistry,so that their application in practical production is greatly limited.In this thesis,a transition metal-free method was developed for the synthesis of 3-substituted quinolines by the intramolecular cyclization of enaminones with 2,1-benzisoxazole via aza-Michael addition.Notably,both methane sulfonic acid and sodium iodide play an important role in the reaction.The ring-opening/reconstruction strategy is simple to operate,high in yield,wide in substrate range and high in efficiency.The main contents are as follows:1.According to the characteristic that the N-O bond of 2,1-benzisoxazole is easy to break,a metal-free catalysis method for constructing quinoline skeleton is proposed,wherein an enaminone is inserted into the N-O bond of 2,1-benzisoxazole to form a new C-N/C-C bond through ring-opening recombination.2.After a series of conditions screening,the target product was obtained in 90% yield.The method has good tolerance to substrates with different functional groups,and a series of 3-substituted quinoline compounds are synthesized with high yield(60-90%).In order to facilitate the industrial production,the subsequent gram scale amplification reaction was carried out,and the yield(85%)obtained was within the ideal range.After that,the mechanism of the experiment was explored by control experiment,and the possible reaction mechanism was deduced.3.In this subject,the reaction does not require transition metal catalysis,the catalyst used is methane sulfonic acid,the additive is sodium iodide,the methane sulfonic acid is capable of activating enamine ketone,and the sodium iodide is used for improving the stability of the intermediate formed by ring opening of benzisoxazole under acidic conditions in the reaction.