| After a large number of clinical studies,it has been found that nitrogen-containing heterocycles have become the core framework of many drugs.Among them,quinoline derivatives and isoquinoline derivatives are relatively common nitrogen-containing heterocyclic compounds with biological and pharmaceutical activities.Although quinoline and isoquinoline derivatives extracted from natural products exhibit various physiological activities,the treatment methods of some diseases are still limited.More and more studies have shown that after modification of various functional groups on the quinoline and isoquinoline skeletons,it can be used in medicines for anti-malaria,anti-tumor,anti-tuberculosis,and anti-thrombosis.Therefore,the efficient construction of quinoline and isoquinoline skeletons have always been the focus of research by chemists.This thesis mainly studies the efficient synthesis of functionalized quinoline,isoquinoline and bromoisoquinoline derivatives through the strategy of free radical C-H bond activation,which might provide an effective method for the further synthesis of related drugs in the future.The specific content is as follows:1.In the presence of tris(4-bromophenyl)aminium hexachloroantimonate(TBPA)and oxygen,an oxidative Povarov-type reaction occurs between glycine derivatives and methylene cyclopropanes(MCP),constructing chloroquinoline skeleton in high yields through the radical C-H bond activation.Mechanistic studies have shown that antimony chloride(SbCl3 or SbCl6-),as a new type of chlorine atom donor,may participate in the chlorination reaction mediated by free radical intermediates.2.Using α-phosphorylated tetrahydroisoquinolines as the starting materials and tert-butyl nitrite(TBN)/O2 as the catalyst system,a series of isoquinoline derivatives were synthesized through the radical C-H bond activation relay strategy(CHAR).This reaction opens up an unprecedented way to realize the functionalization of the C-H bonds in tetrahydroisoquinolines.According to the mechanistic study,oxygen capture and further intramolecular hydrogen atom transfer process(HAT)are the key steps to promote the functionalization of C-H bonds on 3-and 4-positions.3.On the basis of the aforementioned results,we found that initiated by tert-butyl nitrite(TBN)and oxygen,a series of brominated isoquinoline derivatives could be obtained in the presence of one equivalent of CuBr through the radical C-H bond activation relay(CHAR).At current stage,it is found that the introduction of the phosphate group at theα-position of tetrahydroisoquinolines may not be the best choice,and further screen of otherα-substituents might be necessary to construct more complicated structures. |
