| Objective: Heterocyclic compounds belong to cyclic organic compounds which contain at least one hetero atom in the molecular structures.Heterocyclic compounds are widely used in medicine because of their good biological activities.Organofluorinated compounds have high stability,lipid solubility and hydrophobicity.The introduction of fluorine atoms in drugs can effectively improve their pharmacodynamics and pharmacokinetics,The trifluoromethyl functional groups are one of the most important fluorine-containing groups.Construction of heterocyclic compounds containing trifluoromethylation is a key problem in the field of synthetic chemistry.At present,the method of introducing trifluoromethylation to carbon-carbon double bonds through transition metal catalysis has attracted intense attention,but the research on trifluoromethylation to carbon-carbon triple bonds is rarely reported.Therefore,in this study,indolyl-ynones was used as a substrate to study the effects of trifluoromethyl reagents,catalysts and reaction conditions on indole-aromatization and selective construction of trifluoromethylated heterocyclic compounds.The present study would provide a new insight on the trifluoromethylation of heterocyclic compounds and enrich the fluorination methodology.Methods: Target compounds I: indolyl-ynones was used as raw material,silver nitrate was used as catalyst,Togni’s reagent was used as trifluoromethyl source and acetonitrile was used as solvent to construct quinoline ring derivatives containing trifluoromethyl in a pot method under reflux condition.The optimal experimental conditions were selected,and then the substrate was expanded to synthesize a series of target compounds containing different substituents.The molecular structure and physicochemical properties were characterized by NMR,MS and X-Ray single crystal diffraction.Target compounds Ⅱ: azacyclines containing two trifluoromethyl groups.Indolyl-ynones was also used as substrate,and copper(I)was used as a catalyst to obtain a trifluoromethyl-substituted azacyclonal compound.Results:1)Using silver(I)as a catalyst,19 quinoline ring derivatives containing trifluoromethyl were synthesized;2)the issue reported in the previous literature was solved.Silver metal was used as the catalyst,and trifluoromethyl was introduced on the C-C triple bond.The reaction machanism occurred through indole dearomatization,ring expansion and oxidation;3)the mechanism study showed that the reaction occurred through a free radical mechanism.In the process of reaction,trifluoromethyl radical was generated,which then triggered a series of reactions;4)a nitrogen heterocyclic compounds containing two trifluoromethyl substituents was obtained by using copper(I)as a catalyst.Conclusion: In this paper,based on the methodological study of introducing trifluoromethyl into indolyl-ynones,the following conclusions are obtained: 1)from the perspective of synthesis,we successfully synthesized 19 novel trifluoromethyl-containing quinoline ring derivatives in medium to high yields;2)silver salt was for the first time used as a catalyst in contrast to copper catalysts.We found that silver can also be used as a catalyst to introduce trifluoromethyl group into the carbon triple bond;3)in terms of mechanism,free radical blocker was used and EPR instrument was used to monitor the reaction.The reaction occurred through a free radical-involved tandem reactions;4)The use of different metal catalysts,such as copper,under the moderate condition,can get nitrogen impurity spiro structure compounds containing double trifluoromethylation substituted,the optimum conditions have been identified,but the substrate range also needs to further expand. |
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