Study On Catalyzed Oxidative System Of N-containing Heterocycles Under Coupling Mechanism

N-formamide is one of the most valuable intermediates in pharmacological synthesis.Medicinal materials such as oxazolidone,bridging N-heterocyclic ring,2,5-dimethoxy-formylaniline are prepared by N-formamide as intermediates.At present,the classical synthesis methods of N-containing heterocycles are formic acid,formate,methanol and carbon dioxide as N-formylation reagents and amine reaction,methanol and amine direct coupling reaction（oxidation coupling,dehydrogenative coupling with hydrogen acceptor or acceptor-less dehydrogenative coupling）.However,formylation of N-heterocycles with methanol as the formylation reagent is rare and still difficult to achieve,owing to the transformation of methanol into its oxidation state need to overcome higher stable thermodynamic energy than N-heterocycles,which generally result in an unavoidable effect for N-heterocycles on account of its sensitive to many catalytic oxidation or dehydrogenation systems Based on this,this paper developed a Cu^I catalytic system for N-heterocyclic reaction with methanol N-formylation using 1,2,3,4-tetrahydroquinoline as substrate.In addition to N-containing heterocyclic compound,anilines and alkyl amines can also be converted to the corresponding N-formamide at a moderate yield.Based on the observation of the key intermediates,the characterization of their structures and the results of theoretical calculations,the possible reaction mechanisms and pathways were proposed.On this basis,it is also proved that the concentration of·O₂^-in the catalytic system is related to the formation of tar-like products.The main contents of this paper are:1.The reported synthesis strategies of N-formamide are summarized comprehensively:transition metals and ionic liquids catalyze N-formylation reactions of different N-formylation reagents with amine,and direct coupling of methanol with amines,such as N-formylation by oxidation coupling,dehydrogenative coupling with hydrogen acceptor or acceptor-less dehydrogenative coupling.2.To explore the optimal reaction conditions and application range of the in-situ generated Cu^I catalytic system for the formylation reaction system of N-containing heterocycles with methanol.In this work,the oxidizer in the catalytic system was screened first and H₂O₂ was determined as the best oxidizer in the system.Then,the amount of solvent in the system was investigated.When 8 m L methanol and 4 m L acetonitrile were used as solvents,the conversion rate of substrate could reach 99%,the yield of target product was significantly increased,and the formation of tarification products was effectively inhibited.Finally,the optimal dosage of catalyst was screened,and the experimental results showed that 12 mol%was the optimal dosage of catalyst,and the product yield could reach 70%.Under the model conditions,the system showed good universality to other N-heterocyclic,aromatic and fatty amines with various structures,and the corresponding N-formamide could be obtained at a moderate yield.The results also show that the electron deficiency effect can improve the stability of N-heterocyclic molecules in catalytic oxidation system.3.Explore the catalytic reaction mechanism and reaction path of Cu^I catalytic system generated in situ through various characterization methods,and study the formation factors of tar-like products in the system.Firstly,the characterization results of EPR spectrum,FT-IR spectrum,UV/Vis diffuse reflection spectrum and electrospray ionization mass spectrometer confirm that Cu ion exists in the form of Cu^I in the catalytic system,and interacts with the nitrogen atom of THQ to form the[THQxCu^I]complex.The acetonitrile molecule and Quinoline generated in the system are then coordinated with the complex[THQxCu^I]to form the active substance complex[Quinoline（MeCN）Cu^I]that plays a catalytic role in the reaction system.The results of EPR spin capture experiment and in situ infrared spectroscopy showed that the reaction system was carried out through free radical pathway,and·OH effectively participated in the whole reaction process.The low concentration of the·O₂^-radicals that formed in the reaction system can effectively trigger the chain reaction of oxidative dehydrogenation of THQ,while with high concentration,it will promote the excessive oxidation of THQ or quinoline to form the tar-like products.4.Theoretical calculation was used to explore the process of formylation of N-containing heterocycles with methanol catalyzed by Cu^I catalytic system generated in situ.Firstly,we calculate DFT-B3PW91 of frontier molecular orbitals（FMOs）to determine the values of the coordination number x,y and z of the complexes formed during the reaction of the system.Due to the instability of·CH₂OH formed in the catalytic reaction system,it reacts with·NR₁R₂ radical to form hemiacetal amine and is further oxidized by H₂O₂ to form amide.We reasonably propose three possible reaction pathways for coupling reactions and further prove that the third possible pathway is the most suitable for our experimental conditions by DFT-B3PW91/TZVP calculation.