Study On The Intramolecular Amination Of C(sp~3)-H Bonds Based On Copper Catalysis

Saturated Nitrogen-containing heterocycles are common in natural products,pharmaceuticals and optical materials,which often exhibit high levels of biological and optical activities.In particular,the pyrrolidine derivatives are privileged structural units,and they are a common skeleton in natural products and pharmaceuticals.They are used in the synthesis of antineoplastic drugs and hypoglycemic drugs.They have many medicinal values in clinical medicine.Therefore,the development of efficient methods to construct this ubiquitous structure unit is highly desirable.Traditional methods for constructing nitrogen-containing heterocyclic structures are nucleophilic substitution,Buchwald-Hartwig Cross-Coupling and Ullmann Coupling,alkylation of imine and reductive amination,etc.This method is widely used in synthetic chemistry.Nevertheless,these methods require pre-installation in a synthetic sequence,step lengthy and cumbersome,long period,limits the scope of the substrate.Carbon-hydrogen bonds are common inert chemical bonds and are widely found in organic compounds.The development of more efficient carbon-hydrogen bond activation and carbon-nitrogen bond reactions is of great significance in the synthesis of nitrogen-containing heterocyclic compounds.Directing conversion from hydrocarbon bonds can avoids pre-functionalization.That is a simple and green method of chemical conversion.A notable challenge in this field is to achieve C(sp~3)-H functionalization.Due to its high bond dissociation energy,weak coordination and diversity,the selective functionalization of the C(sp~3)-H bond has become a very challenging task and has become a goal pursued by organic chemists.The direct functionalization of an inert C-H bond is of great importance as it improves the atom-and step-economy of organic synthesis.This chemistry can directly convert simple and easily available raw materials to valuable products.The radical-mediated strategies that enable C-H direct functionalization with transition-metal catalyzed.It can effectively avoid the pre-functionalization of the substrate,simplify the raw materials,shorten the reaction process,and successfully realize the direct amination of long-range intramolecular C(sp~3)-H bonds,providing a new idea for the synthesis of traditional organic chemistry.We report a copper-catalyzed remote C(sp~3)-H bond amination reaction that converts acyclic amines to pyrrolidines.Using benzene sulfonamide compounds as starting materials,CuI or Cu(OTf)2 as catalyst,and PhI(OTFA)2 as oxidant,the intramolecular remote C(sp~3)-H bond direct alination reaction was successfully realized without the presence of other ligands and additives.we developed the reaction methods are mild,simple,and highly efficient.The reaction substrate has wide applicability and can work well in primary,secondary and tertiary C(sp~3)-H bonds.It also shows that the totally reactivity of hydrogen atoms decreases in the order tertiary>secondary>primary.This reaction has very good functional group compatibility,and linear amino acid ester substrates can be used to synthesize unnatural proline derivatives in one step.It has a good application prospect in drug synthesis and synthesis of natural products.In this thesis,three common reaction strategies for the a1imation of inert C(sp~3)-H bonds were first reviewed.The advantages and disadvantages of different reaction strategies were compared.The results showed that the transition metal copper catalyzed by the radical-mediated strategy ?-C(sp)-H amination reaction has the advantages of less environmental pollution,less by-products,and high yields.Secondly,we choose the sulfonamide compound as the starting material,and optimize the reaction factors such as oxidant,catalyst and solvent to obtain the best reaction conditions.Afterwards,the optimal conditions were used to investigate the generality of the method,and a series of pyridine derivatives with different substituents were synthesized with high yield.Especially for some linear sulfonamide substrates,it is very beneficial,and non-constrained amine substrates also have good yields in this system.This is a great breakthrough in the HLF reaction of the previous radical-mediated strategy,to a large extent Increase the scope of application of the substrate.At the same time,we discovered the synthesis of two polycycle product,which have great potential in the application of complex natural products.In addition,the possibility of radicals was verified by intramolecular competition experiments and radical capture experiments,and based on these result,the possible pathway described was proposed.