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

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 till now, all approaches to 4-phenoxyquinoline skeleton construction do not obey any green chemistry principles.

Aims and objectives: Developing a new, and 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.

Methods: Neweco-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 MWenergy 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, use of MW irradiation in ([bmim] [PF₆] as a green solvent, and short times of reactions are some of the main advantages of this new protocol.