Synthesis Of Quinoline And Benzoxazine Drug Molecular Skeletons

Heterocycles are ubiquitous in organic compounds.They can exhibit various physiological activities,and attracted extensive attention in the synthesis of organic medicines.With the development of science and technology,how to treat the newly emerged diseases,becomes a hot area in the study of heterocyclic medicines.Among them,quinoline and benzoxazine derivatives are extremely important pharmaceutical intermediates as well as the active units of many natural medicines.Herein,quinoline fused lactones,quinoline carboxylate esters and benzoxazines were focused to explore new and efficient synthetic routes and obtain potentially bioactive chemical substances.1.Synthesis of quinoline fused lactonesIn recent years,a series of quinoline compounds have been synthesized by our group through the aerobic oxidation of C-H bonds initiated by radical cation salt.Based on this,an aerobic C-H oxidation of glycine derivatives were realized in the presence of catalytic amount of radical cation salt copper salt,synthesizing a series of functionalized dihydroquinoline lactones in high efficiency.This method is superior in simple starting materials,mild reaction conditions and short synthetic route,avoiding the overuse of an excessive amount of peroxide.In addition,this facile synthesis also exhibits good functional group tolerance,high reaction efficiency and wide applications in preparation of the corresponding pharmaceutical analogues.2.Synthesis of quinoline carboxylate estersThe quinoline carboxylate derivatives exhibit various pharmaceutical activities,such as antipyretic,analgesic.In our recent research,we have found that under the oxygen atmosphere,the ?,?-C-H bonds adjacent to nitrogen atom of N-aryl alanine esters could be smoothly oxidized in the presence of radical cation salt,yielding an enamine intermediate.At the same time,another molecule of N-aryl alaninate reacted with benzaldehyde,forming an iminium intermediate in situ,which was attacked by the enamine intermediate.After further oxidative Povarov cyclization,the desired quinoline-4-carboxylate esters were provided in moderate yields.This reaction avoids the use of an excess amount of peroxide,and the reaction conditions are mild,providing a new method for the synthesis of nitrogen-containing heterocyclic compounds.According to the control experiments,a possible reaction mechanism was proposed.3.Synthesis of benzoxazinesBenzooxazine is a unique biologically active structure and widely exists in drug molecules and functional materials.Recently,we have successfully developed an intramolecular C-O bond cyclization of N-phenylacetamide using azobisisobutyronitrile as a catalyst,oxygen as an oxidant and ytterbium triflate as an additive,obtaining a series of benzoxazines in high yields.This method is superior in mild reaction conditions and accessible availability of starting materials,providing a simple method for the synthesis of benzoxazine derivatives.