Studies On Synthesis Of Quinoline Derivatives By Copper Catalyzed Radical Cyclochemical Reaction

After more than a century of research,free radical chemistry has gradually got rid of the discrimination of"high activity but difficult to control",and its unique reactivity and selectivity have provided a new idea for solving some difficult problems.In recent years,with the rise of natural macromolecular synthesis,drug molecules synthesis,and new organic materials in areas,free radical reaction with its advantages of easy operation,environmentally friendly and efficient economic,has attracted the interest of a large number of scientists,many important research progress has been made at the same time.In this dissertation,a novel method"copper catalyzed free radical tandem cyclization of-bromide with amide"for the synthesis of quinoline derivatives with the ternary ring structure of meloscine was dicussed,which was based on the framework structure of the drug molecule meloscine.It mainly includes the following aspects:?1?The main research content and significance of this dissertation were proposed,and the methods for the synthesis of raw materials and products were described in detail.?2?Explored the reaction conditions in system.Kinds of catalysts,the base types,ligands,solvents,reaction temperature and time,and additives was investigated.The optimal reaction conditions were determined:N-?2-ethinyl phenyl?benzene sulfonamide compounds?0.2 mmol?,?-allyl bromide ester/ketone compounds?1.5 equiv?,Cu?CH₃CN?₄PF₆?10 mol%?,L₁?10 mol%?,potassium carbonate?1.1 equiv?,trifluoro toluene?3.0 mL?,in argon atmosphere,110?,reacted for 12 h,and the separation of the yield was 80%.?3?The reaction of?-bromides with amides in substitution of various functional groups was investigated.We found that both the electron-absorbing and electron-donating groups had a good yield,with the separation yield up to 38%-89%.The yield of the substituents with large space volume was lower than that of the substituents with small space volume,indicating that the steric hindrance had a certain effect on this reaction.Unfortunately,this reaction was not suitable for terminal alkynes.A total of 19 products were obtained,all of which were characterized by ¹H NMR,¹³C NMR and GC-MS.?4?The reaction mechanism was studied.Based on the results of free radical capture and other control experiments and the reference to the reported literatures,we speculated that this reaction was initiated by carbon free radicals in series cyclization reaction,and proposed a possible mechanisms:?-bromopropyl ester is debrominated under the action of univalent copper to produce free radicals,which then attack the alkynyl group on N-?2-ethylenyl phenyl?benzene sulfonamide,and then through 5-exo-trig ring closure,finally forms the final product under the nucleophilic attack of the amino group.