Study On C-H/C-C Coupling Reaction Of N-heterocycles Participated By Free Radicals

N-heterocyclic compounds exist widely in nature in the form of nucleic acids,vitamins,hormones,pigments and alkaloids.N-heterocyclic compounds has been deeply explored by researchers worldwide,and have been widely used in the fields of biological engineering,food flavor,dye chemistry and organic synthesis.According to existing studies,most of the traditional synthetic methods of nitrogen-containing heterocyclic compounds suffer from non-trivial synthesis process,multiple reaction steps,harsh reaction conditions,requiring ligand or precious metal catalysis,and low reactivity.Minisci reaction has the advantages of high atom economy,high efficiency,simple operation,mild reaction conditions,etc.And Minisci radical reaction is a common method to synthesize N-heterocyclic compounds by constructing C-C bonds through C-H activation.Therefore,in this thesis,carbonyl compounds were used as hydrocarbon reagents to form C-C bonds through the Minisci reaction with nitrogen containing heterocycles.The Minisci arylation of N-heterocyclic compounds with aryl peroxides catalyzed by organic acid and the Minisci alkylation of N-heterocyclic compounds with aliphatic aldehydes involving free radicals were studied.The main research contents are as follows:（1）A new method for the synthesis of a series of 1-aryl isoquinoline derivatives by metal-free C-C（sp²）coupling was established using isoquinoline as substrate,benzoyl peroxide as radical source and trifluoroacetic acid as acid catalyst.At the same time,the effects of temperature,reaction solvent,amount of reactant and catalyst,and reaction time on the reaction were investigated.and the optimal reaction conditions were determined,that was,the reaction of isoquinoline with benzoyl peroxide（2.0 equiv）,trifluoroacetic acid as the acid catalyst,ethyl acetate as the reaction solvent,the reaction system was stirred for 12 hours at 90 ^oC.The arylation of C1 position of isoquinoline compounds was achieved.26 examples of arylated isoquinoline derivatives were synthesized with appreciable yields,and 32 examples were applied to other heterocyclic compounds.The method has the advantages of simple operation,high reaction efficiency,simple reaction conditions,good reaction yield,and can be applied to the gram reaction and bioactive molecules.It provides an efficient and feasible method for the arylation of N-heterocyclic compounds.（2）Using quinoxaline-2（1H）-one as substrate,cyclohexyl formaldehyde as alkyl source,and Ph I（TFA）₂as catalyst,a new method for the preparation of 3-alkyl quinoxaline-2（1H）-one derivatives via selective C-H/C-C coupling involving free radicals was established.The reaction was selective,the decarbonylated 3-alkyl quinoxaline-2（1H）-one derivatives were generated under light reaction condition,the dehydrogenated and decarbonylated 3-alkyl quinoxaline-2（1H）-one derivatives were generated under heating condition.The effects of solvent,time,amount of reactant and catalyst on the reaction were investigated,and the optimum reaction conditions were obtained,that was,the reaction of quinoxaline-2（1H）-one with cyclohexylformaldehyde（2.0 equiv）,iodobenzene ditrifluoroacetate as additive,ethyl acetate as solvent,under 10 W blue light at room temperature for 12 hours.The decarbonylation of quinoxaline-2（1H）-one with aldehydes was achieved.At the same time,the reaction of quinoxaline-2（1H）-one with cyclohexylformaldehyde（4.0 equiv）,iodobenzene ditrifluoroacetate as additive and acetonitrile as solvent was conducted at70 ^oC for 24 hours to achieve the carbon-carbon coupling reaction of dehydrogenation/decarbonylation of quinoxaline-2（1H）-one with aldehyde.29examples of decarbonylated 3-alkyl quinoxaline-2（1H）-one derivatives,7 examples of decarbonylated 3-aryl quinoxaline-2（1H）-one derivatives and 6 examples of heterocyclic compounds were synthesized with appreciable yield;16 examples of dehydrogenated 3-alkyl quinoxaline-2（1H）-one derivatives were synthesized.This method has high selectivity and is more suitable for secondary aldehydes.The mechanism of the reaction was explored by free radical inhibition experiment,and the possible reaction mechanisms of decarbonylation and dehydrogenation were proposed respectively.This reaction has improved the traditional harsh reaction conditions and low selectivity,which has high potential and research value.