Stereoselective [3+n] Cycloaddition Reactions Of Pyrazolone-based Dipoles Toward Novel Spirocyclic Compounds

The 1,3-dipolar cycloaddition reactions are powerful synthetic techniques for building heterocyclic molecules.As an important class of 1,3-dipoles,the cycloaddition reaction of azomethine ylides with dipolarophiles has been extensively documented.This reaction is typically employed to create significant nitrogen-containing heterocyclic compounds.Considering that synthetic chemistry is moving toward a greener,more efficient,low-cost,and low-emissions chemistry,it is critical to develop novel reactions while incorporating green chemistry features.The cycloaddition reaction involving the azomethine ylide generally has the characteristics of green chemistry such as atom and step economy,mild reaction conditions,and high yield,which has attracted considerable attention from synthetic and medicinal communities.Spiropyrazolones are an essential class of potentially bioactive compounds in a wide range of natural and pharmaceutical molecules.In recent years,the synthetic and therapeutic communities have paid close attention to the development and functionalization of these compounds.Several methods have been developed for their construction.According to the literature survey,the synthetic methods for these compounds are divided into the following main types based on starting raw material: 4-unsubstituted pyrazolones,4-monosubstituted pyrazolones,α,β-unsaturated pyrazolones,α,β-unsaturated pyrazolones with a γ-hydrogen.Among them,the constructions of spiropyrazolones utilizing 4-monosubstituted pyrazolones having a heteroatom at 4-position are rarely explored.Particularly,from 4-monosubstituted pyrazolone-based dipoles via [3+n] cycloadditions are seldom reported.This dissertation focuses on the stereoselective construction of spiropyrazolones by exploiting the reactivity of 4-aminopyrazolone-derived azomethine ylides via [3+n]cycloaddition reactions.The main contents of this thesis include the following three parts.1.Construction of spiro[pyrazolone-4,2′-pyrrolidine] scaffolds via [3+2] cycloaddition of an in situ generated azomethine ylides and nitroolefin.This reaction offers the desired products with high yields and excellent diastereoselectivities under mild reaction conditions(up to 98% yield,and >20:1 dr).2.Diastereoselective synthesis of indolenine-based spiro[pyrazolone-4,2′-pyrrolidine]scaffolds via [3+2] cycloaddition of 4-aminopyrazolone-derived azomethine ylide and 2-methylindolenines.This reaction gave novel cycloadducts in high yields with excellent diastereoselectivities(up to 95% yield,and >20:1 dr)and wide substrates scope under mild reaction conditions.Remarkably,no catalyst and base have been used in this reaction.3.Construction of a spiro[pyrazolone-pyridoindol] scaffold through a [3+3]cycloaddition of pyrazolone-based azomethine ylide and 2-indolylmethanol featuring a sixmembered heterocyclic ring fused with an indole moiety.The reaction proceeded without catalyst at ambient temperature to afford desired products in high yields with excellent diastereoselectivity(up to 94% yield,and >20:1 dr).Remarkably,this [3+3] cycloaddition process is free of catalyst and base.