Synthesis And Application Of Diethyl2-(Bromomethyl) Quinoline-3,4-dicarboxylates

Various halomethylquinolines,especially bromomethyl quinolines have proven to be valuable building blocks to participate in a range of chemical transformations,and have attracted significant interest in revealing the synthetic potential of these platforms for the construction of more complex and intriguing types of quinoline-based derivatives.In view of these facts and considering structural diversity as an essential component for the search of new lead compounds in drug discovery,we felt that it would be an attractive idea to look into the synthesis and application of new bromomethylquinoline derivatives to access structurally novel quinoline derivatives with potentially biological activity for current medicinal chemistry needs.Accordingly,in this thesis we designed and synthesized a new type of diethyl 2-（bromo-methyl）quinoline-3,4-dicarboxylates and their applications in the Williamson ether synthesis reaction and Rap-Stoermer reaction for the flexible synthesis of diversely substituted quinoline-based derivatives.Our thesis was mainly divided into five parts as follows:In the first part,on the basis of a survey of the related literature,a recent advance on the synthesis and application of halomethylquinolines were briefly reviewed.In the second part,the required substrates,namely diethyl2-methylquinoline-3,4-dicarboxylate（2a-2g）were firstly prepared through the Pfitzinger reaction between ethyl 3-oxobutanoate and different substituted isatins in absolute ethanol with the presence of TMSCl as catalyst.Subsequently,the resulting（2a-2g）were subjected to NBS-mediated radical bromination reaction to give the corresponding 2-（bromomethyl）quinoline-3,4-dicraboxylate（3a-3g）.The structures of these newly-synthesized compounds（2b-2g）and（3a-3g）were confirmed by spectral ¹H NMR and ¹³C NMR data and elemental analyses.In the third part,the application of the newly-synthesized 3a-3g in the nucleophilic substitution reaction with benzo[d]oxazole-2-thiol and benzo[d]imidazole-2-thiol for the synthesis novel and intriguing sulfur methylene linked bisheterocycles i.e.,diethyl 2-（（benzo[d]oxazol-2-ylthio）methyl）quinoline-3,4-dicarboxylates 4a-4g and diethyl 2-（（（1H-benzo[d]imidazol-2-yl）thio）methyl）quinoline-3,4-dicarboxylates 5a-5g has been accomplished with good yields.Their structures were readily confirmed by spectral data and elemental analyses.Finally,the antibacterial test results showed that these newly-synthesized products exhibited moderate to good inhibitory activity against Escherichia coli.In the fourth part,we selected 2-（bromomethyl）-6-bromo quinoline-3,4-dicraboxylate（3e）as substrate to investigate its one-pot sequential Rap-Stoermer reaction/ester hydrolysis with various salicylaldehydes.We found that the best results could be achieved when the reaction was conducted under K2CO3/Me CN system followed by KOH hydrolysis,giving the desired quinoline-benzofuran bisheterocycles hybrids,namely,2-（benzofuran-2-yl）-6-bromoquinoline-3,4-dicarboxylic acids（7a-7i）in good yields.The structure of these newly-synthesized compounds were easily identified by spectral data and elemental analyses.The subsequent antibacterial test results revealed that these compounds had the inhibitory activity against Staphylococcus aureus and Bacillus subtilis.In the fifth part,we further explored the one-pot sequential Williamson reaction/ester hydrolysis of 3e with various substituted phenols,naphthols and8-hydroxyquinoline.The reaction proceeded very smoothly in Me CN media with the presence of K₂CO₃as base followed by KOH-mediated hydrolysis,giving rise to the corresponding ethers 6-bromo-2-（phenoxymethyl）quinoline-3,4-dicarboxylic acids 9a-9k,11a and 13a with good yields.Their structure were readily established by spectral data and elemental analyses.