Application Of Organic Phase Transfer Catalysts In Friedel-Crafts And Trifluoromethylation Reaction Of Ketimines

It is well known that 3-substituted 3-aminooxindole scaffolds are important structural fragments of various natural product related compounds,and have antitumor,antiviral and other drug activities.Therefore,in recent years,the asymmetric synthesis of 3-substituted 3-aminohydroxyindole derivatives has attracted extensive attention.In addition,the indole framework,as a biologically important structural unit,whose biological activity and medicinal value have promoted its development in the frontier of synthesis;trifluoromethyl,as a key fluorine-containing group,it exhibits unique biological properties.It is of great significance to combine these structural advantages to obtain derivatives of 3-substituted 3-aminooxindole structures containing indole or trifluoromethyl.Based on the above,in this thesis,the asymmetric synthesis of 3-amino-3-indolyl oxindoles and 3-amino-3-trifluoromethyl oxindoles was investigated.The specific work is as follows:1.A series of developed bifunctional phase transfer catalysts derived from cinchonadine were synthesized and successfully applied in the asymmetric Friedel-Crafts reaction of different substituted isatin-derived ketimines and indoles.First,a series of conditions were optimized for catalyst,base,solvent,temperature,and amino protecting group.Finally,the optimal reaction conditions were determined to be 10 mmol%of catalyst 3a,5 equiv K₃PO₄as base,reaction temperature-40℃,toluene as the solvent,and the Cbz group as the amino protecting group.Second,different substrates were investigated under the optimal conditions,and a series of3-substituted 3-aminooxindole derivatives containing different substituted indole fragments were obtained with high yield（82-91%）and medium to excellent enantioselectivity（46-94%ee）.When the reaction feed was increased to a gram-level reaction scale,it was found that the target product obtained by the reaction could still maintain excellent yield and enantioselectivity.The configuration of the product was confirmed to be S configuration by X-ray single crystal diffraction after single crystal growth.Mechanism control experiments were carried out and it was found that the NH structure on the urea part of the catalyst and the quaternary ammonium center of the catalyst play an important role in the realization of bifunctional synergistic catalysis.In addition,a possible transition state model of the reaction is proposed based on the product configuration as well as the mechanistic control experiments.2.The reaction of isatin-derived ketimines and TMSCF₃was investigated using TBAB as the phase transfer catalyst.Firstly,a series of optimizations were carried out on the base,solvent,and temperature,and it was determined that 6 equiv Cs OH·H₂O,10 equiv TMSCF₃,toluene as the solvent,and the temperature 0℃was the optimal reaction conditions.Under the optimal conditions,substrate expansion was performed and a series of 3-substituted 3-aminooxindole derivatives containing trifluoromethyl fragments were obtained in moderate to excellent yields（70-95%）.After ensuring the reactivity of the reaction,we tried to explore asymmetric version of this reaction,and synthesize a series of phase transfer catalysts using cinchonine as raw material,the corresponding product was obtained with 91%ee.Further reaction optimization is still in progress.