Research On Synthesis Of 5-Halo-8-Aminoquinolines

Quinoline is a common nitrogen-containing heterocyclic aromatic compound.8-amidoquinoline is a class of quinoline derivatives with very broad application prospects.For example,5-chloro-8-aminoquinoline benzamide is used as a biological inhibitor;8-aminoquinoline can be used as a directing group to participate in the transition metal catalyst to direct activation of C-H bonds,so it is of great significance to study its functionalization.In this paper,we mainly have studied the preparation of corresponding chlorinated and fluorinated products by activating the 5-position C-H bond of 8-amidoquinoline compounds with hypervalent iodine reagent.A 5-position chlorination reaction of 8-amidoquinoline without transition metal catalyst was explored,and the electron-rich quinoline in 8-amidoquinoline was oxidized by a hypervalent iodine reagent to realize remote activation of 5-position C-H bond to construct C-Cl bond.The reaction used 8-aminoquinoline benzoyl as the template substrate,and the preliminary exploration determined that the method was feasible.Then,based on the control variable method,each reaction condition was optimized one by one,and the optimal chlorination reaction condition was determined,that is,phenyliodanediyl diacetate is the oxidant,lithium chloride is the chlorination reagent,and ethanol is the solvent.Using this method,14 substrates were synthesized with a yield of up to 95%.The chlorinated products were characterized by nuclear magnetic resonance.This method is universal and regionally selective.The mechanism of 5-position chlorination of 8-amidoquinoline was studied by free radical trapping experiments.The results showed that the reaction mechanism was the formation of 8-amidoquinoline free radical and phenylacetoxyiodine free radical induced by iodobenzene diacetic acid.The base,the intermediate formed by electron transfer and lithium chloride,generate a chlorinated product.A new method for the synthesis of 5-fluoro-8-amidoquinoline compounds was developed.A variety of reaction conditions were explored,which determine the combination of oxidants and nucleophiles to achieve the fluorination of such compounds,and each reaction condition were screened to obtain the appropriate reaction conditions,i.e.,phenyliodanediyl bis(2,2-dimethylpropanoate)as the oxidant,and pyridine Hydrofluoride is used as a nucleophilic fluorination reagent to synthesize 10 examples of fluorinated substrates with a yield of 6% to 30%.The structure of the product is determined by nuclear magnetic resonance.The mechanism of fluorination reaction was studied with BHT and TEMPO.The results showed that the process of 8-amidoquinoline free radical involved in iodobenzene divaleric acid reacted with pyridine hydrofluoride to generate fluorinated products.