Optimization of the Reaction Conditions for Synthesis of 3-(Aryloxy)quinoline Derivatives via Friedländer's Cyclization Reaction

Abstract

6,7-Dimethoxy-2-methyl-3-(4-nitrophenoxy)quinoline was synthesized by Friedlander's cyclization reaction. Different bases and solvents were tested in order to optimize the reaction conditions. The highest yields were obtained using piperidine in refluxing ethanol. Further reactions were carried out in order to prepare different diarylamide and diarylurea derivatives in moderate to high yields in order to examine their anticancer activities. Herein, we optimized the optimum reaction conditions to synthesize 3-(aryloxy)quinoline derivatives in terms of higher yield and by avoiding lengthy workup and column puri- fication. Our optimized reaction conditions can be applied to scale up to large scales with simple isolation of the pure product. In the present investigation, we report the optimized reaction conditions for preparation of 3-aryloxy- quinoline via Friedlander's cyclization, followed by synthesis of diarylurea and diarylamide derivatives possessing quino- line nucleus. Results and Discussion Herein we report an efficient method for the synthesis of novel quinoline derivatives via the Friedlander's reaction through condensation of dimethoxy substituted o-amino- benzaldehyde with a ketone, 1-(4-nitrophenoxy)propan-2- one (2), in the presence of different bases and solvents. Among all the bases tested, piperidine was found to be the Table 1. Optimization of Friedlander's cyclization reaction condition using different bases and solvents