Chiral Organocatalysts And Their Application To Friedel-Crafts Reaction Of The Indole And Aza-Henry Reaction Of Ketimines

In recent years,asymmetric reactions catalyzed by small organic molecules have made rapid progress.It is well known that Friedel-Crafts reaction and aza-Henry reaction are two efficient methods for constructing carbon-carbon bonds.As two privileged classes of nitrogen-containing heterocycles,indole and pyrazoline are frequently found in natural products and medicinal agents.Because of the wide biological and synthetic applications,the development of highly effective and reliable methods for the construction of structurally diverse organic molecules bearing an indole moiety or a pyrazoline moiety has become one of the most studied topics over the past century.Therefore,it is of great significance to develop organic-catalyzed asymmetric Friedel-Crafts reactions and aza-Henry reactions to synthesize novel optically active indole and pyrazoline derivatives.In this paper,two bifunctional organic catalysts are applied to the asymmetric Friedel-Crafts cyclization tandem reaction ofthe indole carbocyclic ring and the asymmetric aza-Henry reaction of pyrazolinone-derived ketimines.The specific research work as follows:1.A novel bifunctional chiral urea catalyst derived from?R,R?-1,2-diphenylethane-1,2-diamine was synthesized and successfully applied to the enantioselective Friedel-Crafts alkylation/cyclization tandem reaction of4-hydroxyindole with isatylidene malononitriles.The indole benzene ring was functionalized without the presence of deactivating or blocking substituents in the azole ring.The optimal reaction conditions were determined by optimizing the conditionssuch as catalyst,solvent,temperature,additives,catalyst loading,and substrate equivalent.A series of experiments with different substituted isatylidene malononitriles were performed at room temperature using m-xylene as the solvent in the presence of 10 mol%catalyst,and the corresponding spirooxindole-pyranoindoles including both indole moiety and spirooxindole with chiral all-carbon quaternary carbon centers were obtained in high yields?up to 98%?and moderate to good enantioselectivities?up to 85%ee?.When the reaction scale was scaled up to grams,the target product could still be obtained in excellent yield and enantioselectivity,which proved the feasibility of the reaction.The absolute configuration of the product was determined to be R through single crystal diffraction experiments.In addition,we proposed a possible transition state,explaining the possible catalytic mechanism of the reaction.2.A series of pyrazolinone-derived ketimines derived from pyrazolin-5-ones were synthesized.A series of bifunctional phase transfer catalysts derived from cinchona alkaloids were synthesized and successfully applied to the enantioselective aza-Henry reaction of pyrazolinone-derived ketimines.The optimal reaction conditions were determined by optimizing the conditions such as catalyst,base,solvent,temperature,catalyst loading,and substrate equivalent.Using 10 mol%catalyst,LiOH·H₂O as base and dichloromethane as solvent,reacting at-30°C for 5hours,the corresponding product with a quaternary carbon centerwas obtained with medium yield?63%?and high enantioselectivity?92%ee?.