Copper-Catalyzed Alkenylation Of Pyridine-N-Oxides And Nitrones

Organic compounds containing pyridine structure play an important role in organic synthesis,medicine,agricultural chemicals and other fields.Among them,alkenyl pyridine is the core structure of currently listed drugs for treating depression and allergic diseases,such as cimetidine,triprolidine,loratadine,acitinib,montelukast and other drugs.On the other hand,alkenyl imine（α,β-unsaturated imine）has two active reaction sites of carbon-carbon double bond and imine.As a general synthesis block,it is an important intermediate of complex molecules such as synthetic drugs and natural products,and is often used in the synthesis of antimalarial,antitumor drugs and plant antitoxins.Therefore,it is of great significance to explore the efficient and selective synthesis of alkenyl pyridine and alkenyl imine.In this context,pyridine-N-oxide and nitrone were used as substrates,copper carbene was used as catalyst,and alkynes or alkenes were used as alkenylation reagents,respectively,and2-alkenylpyridine and alkenylimine（α,β-unsaturated imine）were successfully constructed,It includes the following two aspects:Work 1:2-alkenyl pyridine compounds were successfully synthesized by using pyridine-N-oxide and alkyne as starting materials,copper carbene as a catalyst and triethoxysilane as a hydrogen donor.Firstly,the reacton of triethoxysilane and copper generate a copper-hydrogen species,captured by a molecular alkyne resulting in alkenyl copper species via migratory insertion mode.Then,pyridine-N-oxide capture the in-situ-generated alkenyl copper intermediate,providing corresponding 2-alkenyl pyridine compounds.Using cheap copper as catalyst,2-alkenyl pyridine compounds were synthesized in one step,with mild reaction conditions,wide substrate scope and good regioselectivity.Work 2:α,β-unsaturated imine（ethylenimine）was successfully synthesized with nitrone,styrene and B₂pin₂ as starting materials and copper carbene as a catalyst.First,under the activation of alkali,the reaction copper catalyst reacts with B₂pin₂ reagent to form an intermediate copper-boron reagent,and olefin performs an insertion reaction on Cu-B to form an alkyl copper intermediate.Nitrone is used as an electrophilic trapping reagent to capture the alkyl copper and generateβ-boron-based imine.Then,a series ofα,β-unsaturated imines are synthesized by oxidation in oxygen atmosphere.The reaction between nitrone and unsaturated hydrocarbon usually forms cycloaddition products,and it is difficult to retain the imine structure.In this study,through the intermediateβ-boronimine,the boron structure can be directly converted into alkenyl structure,the C-H alkenylation reaction of nitrone was successfully realized,and a series of alkenylimine compounds are synthesized.The reaction conditions are mild and simple,not only the double bond of C=N is retained,but also the original N-O group of nitrone is complexed with B₂pin₂ to remove oxygen in the reaction process.In this context,2-alkenylpyridine and alkenylimine compounds were successfully synthesized involving a copper-mediated insertion reaction of unsaturated hydrocarbon compounds.In these reactions,insertion reactions of unsaturated hydrocarbon by Cu-H or Cu-B species to generate corresponding alkenylcopper reagent or alkyl copper species captured by electrophilic reagent（pyridine-N-oxide,nitrone）delivered target products.This study not only provides a new method for the construction of carbon skeleton,enriches the methodology of carbon-carbon bond formation,but also provides a theoretical basis for drug synthesis.This thesis has 62 pictures,12 tables and 73 references.