Study On The Construction Of Pyridine/1,2-oxazine Skeleton By Cyclization Of ?,?-unsaturated Nitrones

Aza six-member ring compounds are one of the most important nitrogen heterocyclic compounds that usually have significant applications in bioactive natural products,pesticides and pharmaceuticals.It can be not only easily introduced into densely functionalized chiral compounds by simple chemical reactions,but also facilely transformed into other important heterocyclic compounds such as indoles,pyrroles and other heterocyclic skeletal compounds.Therefore,the construction of aza six-membered ring compounds is an extremely important research topic.Nitrone can be used as an important 1,3-dipole in organic synthesis due to its good stability,easy synthesis,and high reactivity.It can participate in various organic reactions(such as oxygen transfer reactions,cycloaddition reactions,rearrangement reactions and C-H bond activation,etc.).It can also be used to synthesize a wide range of heterocyclic compounds,and served as an important organic building block for the further construction of complex molecules.In recent years,?,?-unsaturated nitrone has attracted much attention by synthetic chemists because of its rich chemical transformations of?,?-unsaturated double bonds,which can participate in various novel chemical transformations to synthesize novel heterocyclic compounds.In this paper,we focused on the construction of pyridine derivatives by intramolecular nickel(II)-catalyzed oxygen transfer reactions of?,?-unsaturated nitrones;base-controlled intramolecular 6?-azaelectrocyclization for the construction of pyridine N-oxides;and asymmetric[3+3]cycloaddition reactions of?,?-unsaturated nitronse with 1,3-dipoles generated in situ from cyclopropane diesters and 2-indolyl methanols to construct chiral 1,2-oxazine derivatives.This paper is divided into four sections:In the first part,a method for the intramolecular oxygen transfer reaction of N-vinyl-?,?-unsaturated nitrones derived from dibenzylidene acetone nickel(II)-catalyzed was established to prepare polysubstituted 2-(pyridin-2-yl)ethanol compounds.The reaction features high atom economy,broad substrate scope,good functional group tolerance,simple operation,and the ability to gram-scale performance.Mechanistic studies revealed that the C-O bond formation was the rate-determining step for the construction of 2-(pyridin-2-yl)ethanols.In addition,the prepared2-(pyridin-2-yl)ethanols can be converted into a variety of functionalized pyridine derivatives.A novel pyrido-fused carbazole scaffold was prepared in moderate yield by a total two-step reaction.In the second part,a 6?-azaelectrocyclization of dibenzylideneacetone-derived N-vinyl-?,?-unsaturated nitrones as raw materials was realized in the presence of different bases,which delivered 6-alkyl pyridine N-oxides and 6-vinyl pyridine N-oxides in moderate to high yields.It was found that 6-alkyl pyridine N-oxides was obtained in toluene and DBU as base under 120?,while using i-Pr₂NEt as base,Au PPh₃Cl and Ag Sb F₆as catalysts afforded 6-vinyl pyridine N-oxides.Mechanistic studies showed that DBU played an important role in the formation of 6-alkyl pyridine N-oxides,acting as both a base and the carrier of hydrogen sources.6-Alkyl pyridine N-oxides can be prepared in gram scales and were easily converted into estrone-derived pyridine N-oxides.Finally,pyrido-fused benzocarbazole N-oxides was prepared in moderate yield by a two-step reaction.In the third part,Yb(OTf)₃combined with chiral oxazoline ligand L7 as catalysts was used to catalyze the asymmetric[3+3]cycloaddition reaction of N-vinyl-?,?-unsaturated nitrones with cyclopropane diesters to access chiral poly-substituted 1,2-oxazine derivatives.The reaction involved a[3+3]cycloaddition,elimination of alkenes,and intermolecular 1,4-addition.The reaction was required two molecules of cyclopropane diesters,and a total of 20 chiral 1,2-oxazine derivatives were obtained(up to 95%yield,96%ee).The enantioselectivity of the aza-six-membered ring products remained by further reduction and decarboxylation transformations.In the fourth part,chiral phosphoric acid 28c-catalyzed regioselective and enantioselective[3+3]cycloaddition reactions of N-aryl-?,?-unsaturated nitrones with2-indolyl methanols were developed to construct a series of chiral polysubstituted indole-based 1,2-oxazine derivatives.The reaction was carried out with chiral phosphoric acid as the catalyst and toluene as the solvent.A series of indole-based1,2-oxazine derivatives were synthesized in moderate to excellent yields with excellent regioselectivity and enantioselectivity.A total of 24 chiral indole-based 1,2-oxazine derivatives were synthesized(up to 96%yield,up to 100%ee).The control experiments showed that the hydrogen bonding in the reaction was crucial for the control of the enantioselectivity of the products.The reaction highlights simple operation,wide range of substrate scope,good functional group compatibility,and easy gram-scale preparations.