Application Of 4-aminopyrazolone In The Construction Of Novel Spiro Heterocycles

Pyrazolone skeleton as a nitrogen-containing heterocycle,it is widely present in many natural alkaloids and drug molecules.In recent years,research on the biological activity of pyrazolone compounds and new synthetic methods has attracted the attention of many scholars.Many asymmetric synthesis strategies for pyrazolone have been developed.There are a large number of literature reports on the synthesis strategies of chiral 4-full-carbon pyrazolones,but there are few studies on the preparation of chiral 4-heteroatom substituted pyrazolones.At the same time,there are relatively few studies on the synthesis methods of 5-spiropyrazolones in these strategies.In view of the structural novelty and potential biological activity of5-spiropyrazolone compounds,it is of great value to carry out research on synthetic methodology for these structures.Nitrile-containing heterocyclic compounds can be constructed efficiently by the 1,3dipolar cycloaddition reaction in which methylimine ylide participates.The reaction conditions are mild,the atom economy is high,and it is in line with the characteristics of green organic synthesis.Spiropyrrolidine is an important component of pyrrolidine molecules,and its structure is ubiquitous in natural products,drugs and biologically active compounds.Therefore,the skeleton structure of pyrazolone spiropyrrolidine has potential application value.In this thesis,a one-pot method is used,using 4-aminopyrazolone and methyl 2-butenoate derived from salicylaldehyde as a template reaction,and an intramolecular[3+2]cycloaddition reaction occurs to realize the construction of spiropyrazolone skeleton.This strategy provides a synthetic idea for the construction of spiropyrazolone.Through the screening of reaction conditions such as catalyst,solvent,base and molecular sieve,the final reaction conditions were determined as follows:1,2-dichloroethane as solvent（0.1 mol/L）,and 10 mol%p-toluenesulfonic acid（TsOH）as a catalyst,using sodium bicarbonate（NaHCO₃）as a base,adding 3?molecular sieves,and reacting at room temperature under an air atmosphere to obtain a cycloaddition product with 90%yield and 6.0:1 dr.The reaction substrate has a wide scope,and a series of spiropyrazolone products can be constructed.