Microwave-assisted Synthesis of Pharmacologically Active 4-Phenoxyquinolines and their Benzazole-quinoline Hybrids Through SNAr Reaction of 4,7-dichloroquinoline and Phenols Using [bmim][PF6] as a Green Solvent

Abstract

Background: Quinoline and its derivatives have been shown to display a wide spectrum of biological properties, especially anticancer activity. Particularly, diverse potent anticancer drugs are based on the 4-phenoxyquinoline skeleton, acting as small-molecules VEGR2 and/or c-Met kinase inhibitors. However, the design of new drugs based on these quinoline derivatives remains a challenge. Up now, all approaches to 4-phenoxyquinoline skeleton construction do not obey any green chemistry principles. Aim and Objective: Developing a new, efficient protocol for the synthesis of potentially bioactive 4-phenoxyquinoline derivatives and benzazole-quinoline-quinoline hybrids from commercially available 4,7-dichloroquinoline and phenol derivatives using microwave energy (MW) in the presence of 1-methyl 3-butylimidazolium hexafluorophosphate. Method: New eco-efficient protocol for valuable 7-chloro-4-phenoxyquinolines and their hybrids, which is based on SNAr reaction of 4,7-dichloroquinoline with respective simple phenols and hydroxyaryl-benzazoles under MW energy in green reaction media, is studied for the first time. Results. We found that among various solvents tested, the ionic liquid 1-methyl 3-butylimidazolium hexafluorophosphate ([bmim][PF6]) favored the SNAr reaction affording phenoxyquinolines in excellent yields (72-82%) in 10 min. The developed protocol allowed to obtain quickly in good yields (48-60%) new diverse benzazole-quinoline hybrids, which are expected to be pharmacologically active. According to the calculated bioactivity scores, new hybrids are potential kinase inhibitors that could be useful in anticancer drug research. Conclusion: We developed for the first time a new green, efficient method to prepare potentially bioactive functionalized 7-chloro-4-phenoxyquinolines and benzazole-quinoline molecules. Good to excellent yields of the quinoline products, us MW irradiation in ([bmim][PF6] as a green solvent, and short times of reactions are some of the main advantages of this new protocol.

Three-Step Synthesis of N-(7-chloro-4-morpholinoquinolin-2-yl)benzamide from 4,7-Dichloroquinoline

“…Considering the above-stated aspects and as a continuation of our efforts to prepare new bioactive 7-chloroquinoline-based molecules [33][34][35][36][37][38], we designed, prepared, and characterized the above-mentioned N-(7-chloro-4-morpholinoquinolin-2-yl)benzamide. Therefore, this work describes a practical, efficient method for synthesizing the title compound through the N-oxidation reaction/C2-amidation reaction/C4 S N Ar reaction sequence using commercially accessible reagents.…”