Light-induced Cross-dehydrogenative Coupling Reaction Of N-heteroarenes With Ethers

N-heteroarenes constitute the core skeleton of pharmaceuticals,natural products and bioactive compounds.The modifications of N-heterocycles play an important role in medicinal chemistry.Among them,the direct C?H functionalization of N-heteroarenes is a powerful and efficient means to achieve this goal,and it has been widely used in the construction and late-stage functionalization of drug molecules.Classic Minisci-type alkylation is commonly used for the direct construction of C(sp~2)?C(sp~3)bond between electron-deficient aromatics and electron-rich alkyl radicals.However,due to the harsh reaction conditions,its utilization value for the functionalization of complex pharmaceuticals and sensitive-functional-group-containing compounds is significantly limited.Therefore,environment-benign photocatalytic Minisci reaction has become one of the research focuses for medicinal chemists.In this thesis,the direct C?H oxyalkylation of N-heteroarenes was achieved under mild conditions by combining light-induced hydrogen atom transfer process with the Minisci reaction.Moreover,this strategy could be applied to the late-stage functionalization of pharmaceuticals and total synthesis of natural products.The whole work mainly includes two parts as follows:Firstly,the light-induced oxyalkylation of pyridines and further derivatization were realized.We chose 3-acetylpyridine and tetrahydrofuran as model substrates,and the reaction conditions were screened upon literature and experiment investigation.The optimal reaction conditions were found to be 20 mol%4,4’-dibromobenzophenone as photosensitizer,10 mol%sodium pentafluoropropionate as additive and air as oxidant,under the irradiation of 40 W lamp(365 nm),at room temperature for 24 h.From substrate scope screening,ethers such as dimethoxymethane and ambroxan and ethanol could react with3-acetylpyridine smoothly,and the yields of the products were mostly above 40%.When pyridines bearing groups such as phenyl and trimethylsilyl participated in the reaction,additional 50 mol%ammonium chloride was required.In addition,late-stage functionalization of pyridine drugs such asα-tocopherol nicotinate,loratadine,and abiraterone was completed.Tetrahydrofuran or 1,3-dioxolane was successfully introduced to the pyridine.Secondly,the cross-dehydrogenative coupling of fused N-heteroarenes with ethers induced by light was performed.Under the above optimal conditions,it was found that fused N-heteroarenes bearing various electron-withdrawing or electron-donating groups,such as halogen and methyl,at different positions on the fused ring were all dehydrogenatively coupled with cyclic ethers.The corresponding functionalized products were obtained in moderate to excellent(40%-85%)yields.In addition,late-stage functionalization of isoquinoline drug fasudil hydrochloride was conducted.Tetrahydrofuran was successfully introduced to the N-heterocycle.Further,total synthesis of the natural product luotonin A was accomplished with3-quinolinecarboxaldehyde as the starting material,by integrating the conventional synthetic strategies and photocatalytic Minisci reaction method.