Effects Of C(sp~3)-C(sp~2) Bond By Activation Of Nitrogen-containing Heterocyclic Hydrocarbons Based On Radical Reaction

The sp³ C-H bond is the most common bond in organic molecules.Direct functionalization of sp³ C-H bond to construct C-C bond is the most efficient and economical transformation of organic synthesis.In recent years,the formation of free radicals through photocatalytic single electron transfer and hydrogen transfer（HAT）strategies has enabled many reactions that were difficult to achieve under heating conditions to be transformed under mild conditions.The C（sp³）-C（sp²）bond is one of the most fundamental bonds in organic molecules.Aromatics or heterocyclic aromatics are key structural units of many drug molecules.Using simple and easily available raw materials,the development of green,efficient and simple new methods to construct the chemical bonds of aromatic/heterocycle aromatics sp² C and sp³ C to achieve the modification of aromatic or heterocycle aromatics has important significance and role in the selection of bioactive molecular sieve.In this thesis,two aspects are studied:first,C（sp³）-C（sp²）bond was constructed through the formation of electron donor-acceptor complex（EDA Complex）and visible light catalyzed monoelectron transfer for the arylation of nitrogen adjacent sp³ C-H;Second,under the catalysis of copper,Selectfluor,as a hydrogen transfer reagent,performed hydrogen transfer with sp³ C-H to obtain sp³ C radical,which was then coupled with electron-poor nitrogen heterocyclic ring to achieve the construction of C（sp³）-C（sp²）bond.The first chapter introduces the background of the research.Firstly,the three strategies of C-X bond,C-C bond and C-H bond breaking to produce carbon free radicals and their applications in synthesis were introduced to show the importance of the formation and application of carbon free radicals in organic synthesis.Then,the construction methods and applications of C（sp³）-C（sp²）bond based on free radicals in recent years are described.In chapter 2,the C（sp³）-C（sp²）bond was constructed based on the strategy of EDA complex formation and single electron transfer under photocatalysis.Specific for:amine compounds（electron donor）and benzonitrile compounds（electron receiver）to form EDA complexes.Then,under visible light irradiation,the EDA complex underwent single electron transfered to realize the construction of C（sp³）-C（sp²）bond,and the arylation products of the adjacent sp³ C-H bond of nitrogen were obtained.Firstly,we optimized the reaction solvent,reactant ratio,type of base,wavelength and power of visible light,and obtained the optimal conditions:the ratio of amine compounds to p-phenylenonitrile is 2:1,N,N-dimethylacetamide（DMA）is the reaction solvent,Cs₂CO₃ is the base,and the reaction time is 40 hours under visible light irradiation at 427 nm.On this basis,the substrate universality of the synthesis strategy was explored by using different substituted tertiary amines,tetrahydroisoquinoline,tetrahydroisoquinoline,indoline and benzonitrile.Under the optimized conditions,all the selected substrates can proceed smoothly,and 41 aryl products were obtained with excellent yield,demonstrating good substrate universality and functional group compatibility.Finally,the mechanism of the reaction was preliminarily explored and the corresponding mechanism was proposed.This strategy has the advantages of mild reaction conditions,simple experimental operation and good greenness,without transition metal and oxidizer.The third chapter described the construction of C（sp³）-C（sp²）bond by Cu catalyzed Selectfluor as hydrogen transfer（HAT）reagent.Specifically,under the catalysis of Cu,Selectfluor reagent generates N radical positive ions,and then hydrogen transfer with sp³ C-H to obtain sp³ C radical.The obtained sp³C radical reacts with heterocycles to construct C（sp³）-C（sp²）bond.Firstly,we optimized the reaction conditions with 4-methyltetrahydroquinoline and cyclohexane as substrates,and obtained the optimal conditions（10 mol%CuI,2 equivalent TFA,2 equivalent Na₂S₂O₈,4 equivalent Selectfluor,acetonitrile as solvent,reaction at 50℃for 16 hours）.It was found that the amount of catalyst copper,Selectfluor,oxidant Na₂S₂O₈,acid,solvent and temperature have important effects on the reaction.Under the optimized conditions,we investigated the substrate universality of the reaction with various nitrogen-containing hybrids such as quinoline,isoquinoline,pyridine,diazaphthalene,quinoxaline,pyridazine and pyrazine and different sp³ C-H.The reaction has good substrate universality and functional group compatibility.At the same time,we also realized the coupling of Perilla lactone and 4-methylquinoline,and obtained the product with 43%separation yield.The synthetic method has potential application value in the later modification of drug molecules.Finally,the reaction mechanism was preliminarily explored and expounded.