Synthesis And Characterization Of Heterocyclic Compounds Containing Chloroquinoline Skeleton

Quinoline and quinolinederivatives representa particularly fascinating class of nitrogen-containing heterocycles compounds exhibiting a broad spectrum of significantbiological and pharmacological activities.Therefore,during the past several decades the syntheses of structurally novel and intriguing quinoline-based compounds through simple and effective synthetic methods have been an attractive synthetic target for both organic and medicinal chemists.Especially,chlorine-functionalized quinolines have recently received considerable interest from the medicinal,ligand and pesticide fields because compounds bearing this moiety have been widely applied as fundamental building blocks to participate in a wide array of chemical transformations in organic chemistry.As a consequence,considerable synthetic efforts have been devoted involving the corresponding synthesis of various structurally new and interesting chloroquinoline-based compounds so as to further reveal the synthetic and utilization potentiality of this class of compounds with the aim of accessing important drug-like small molecules or new quinoline luminescent materials.Taking these observations into account and in view of structural diversity playing a prominent role for the current medicinal chemistry needs,in this thesis we designed and synthesized a series of structurally diverse and promising 2-chloroquinoline derivatives by using2-chloroquinoline-3-carbaldehyde as the starting material.All these obtained chloroquinoline-based compounds have never been reported,and thus a preliminarily evaluation for their antibacterial activity against Mycobacterium smegmatis（M.smegmatis）Leucyl-t RNA synthetase and Methionyl-t RNA synthetase was conducted.The results showed that some compounds possess significant biological activities and might be potentially applied as useful candidates for the development of new antituberculosis drugsproducts with interesting properties.Our thesis was mainly divided into five parts:In the first part,a brief advance on the synthesis,application and biological activityof chlorine-functionalized quinolines has been reviewed by the survey of the related literature of the recent research progress.In the second part,a simple and facile synthesis of a new series of structurally intriguing bisquinoline oxime ethers,namely（E）-ethyl-2-（（（（（2-chloroquinolin-3-yl）methylene）amino）oxy）methyl）-4-methylquinoline-3-carboxyla tes（3a-3h）has been successfully achieved in good yields of 61.3-85.9%,involving the Williamson reaction between various substituted 2-chloroquinoline-3-carbaldehyde oximes,readily obtained from 2-chloroquinoline-3-carbaldehydes and ethyl 2-（chloromethyl）-4-methylquinoline-3-carboxylate using anhydrous K₂CO₃as base in Me CN solution.The structures of these targeted bisquinoline-based oxime ether hybrids were well characterized through the spectraldata of ¹H and ¹³C NMR as well as CHN elemental analyses,and their anti-tuberculotic activity against Mycobacterium smegmatis（M.smegmatis）Leucyl-t RNA synthetase and Methionyl-t RNA synthetase has also been conducted.In the third part,various substituted 2-chloro-3-（chloromethyl）quinolines,obtained by reduction and chlorination of the corresponding 2-chloroquinoline-3-carbaldehydes,were subjected to the sequential two-step one-pot reaction with sodium azide and ethyl 3-oxobutanoate,giving rise to a series of novel methylene-linked quinoline-triazole bis（heterocycle）derivatives,i.e.,ethyl 1-（（2-chloroquinolin-3-yl）methyl）-5-methyl-1H-1,2,3-triazole-4-carboxylates（6a-6h）in good yields of 69.6-80.2%.In addition,we also conducted the Williamson reaction of 2-chloro-3-（chloromethyl）quinolines with 1-hydroxybenzotriazole to synthesize the corresponding quinoline-benzotriazole ethers 3-（（（1H-benzo[d][1,2,3]triazol-1-yl）oxy）methyl）-2-chloroquinolines（7a-7i）with the range of acceptable to good yields of 69.6-80.2%.Their molecular structures were easily established by spectral data and elemental analyses.In the fourth part,a simple and facile synthesis of a new class of bisheterocycles of 2-chloroquinoline-based barbituric acid derivatives（8a-8i）has been achieved in high yields of 73.2-85.7%by the Knoevenagel condensation reaction of 2-chloroquinoline-3-carbaldehydes with barbituric acid.Their structures were well characterized by spectral data and elemental analyses,and their anti-tuberculotic activities against Mycobacterium smegmatis（M.smegmatis）Leucyl-t RNA synthetase and Methionyl-t RNA synthetase were also been evaluated.In the fifth part,we further investigated the Williamson ether synthesis reaction of 2-chloro-3-（chloromethyl）quinolines with various substituted phenols and naphthols under K₂CO₃/Me CN system.The Williamson reaction proceeded very smoothly,furnishing the corresponding 2-chloro-3-（aroxymethyl）quinolines（9a-9n）as the sole products in good yields of 69.8-86.6%after separation by column chromatography.Their structures were explicitly characterized based on the spectral and analytical data.