Research Report Of Organocatalytic Asymmetric Friedel-crafts Reaction Of Isatin Derivatives

Indole structures containing C-3 carbon stereocenter have attracted much attention for their existence in many bioactive natural products and active compounds.Friedel-crafts reaction of isatin and its derivatives is one of the most effective methods to obtain chiral 3,3-disubsubstituted 2-indolones.The asymmetric Friedel-Crafts reaction of C-3 carbonyl group with aromatic compounds of isatin can produce optically pure 3-hydroxy-2-indoleone compounds.The asymmetric aza-Friedel-Crafts reaction between the C-3 site C=N of isatin-derived ketimines and aromatic compounds is an important method to obtain chiral 3-amino-2-oxindoles compounds.Takemoto type（thio）urea catalysts with chiral cyclohexanediamine as the framework have been widely used many asymmetric reactions,but the asymmetric Friedel-Crafts reaction of isatin or isatin-derived using Takemoto’s catalyst has not been reported.In this study,Takemoto’s catalysts were applied in the reaction with isatins or isatin-derived ketimines as substrates to obtain 3-hydroxy（amine）-3-aryl-2-indoleones with C-3 carbon stereocenter.The catalyst type and the substrate scope were broadened.1)In the study of asymmetric aza-Friedel-Crafts reaction of isatin-derived ketimines and 2-naphthol catalyzed by Takemoto type catalyst,the optimal reaction conditions were determined to be 1.5 m L Et2O as the solvent with a 10 mol%loading of catalyst 1f at rt.The screened catalyst system was used in the reaction of 9 different isatin-derived ketimines and 6 different substituted 2-naphthol to afford chiral3-amino-2-indolones in 89%-95%yields and 90%-97%ees.2)In the study of asymmetric Friedel-Crafts reaction of isatins and electronic-rich phenol catalyzed by Takemoto type catalyst,the optimal reaction conditions were comirmed as follows:10 mol%catalyst 1c,Et₂O 1.0 m L,0℃.It was applied in Friedel-Crafts reaction of 12 different substituted isatins and phenols（3,4dimethoxy phenol,3,5 dimethoxy phenol sesamol,3,4-thylene dioxide phenols）.The3-hydroxy-2-indolones compounds were obtained in 82%-93%yields and up to 99%ee.3)In the study of asymmetric aza-Friedel-Crafts reaction between isatin-derived ketimines and 6-hydroxyl quinoline catalyzed by Takemoto type catalyst,the optimal reaction conditions were screened as follows:10 mol%catalyst 1d,Et₂O 1.5 m L,0℃.It was applied to Friedel-Crafts reactions of 12 different isatin-derived ketimines and6-hydroxyl quinoline,the target products were obtained in 70%-80%yields and22%-91%ees.The results showed that Takemoto type（thio）urea catalysts could induced the enantioselective Friedel-Crafts reaction of isatin or isatin-derived ketimines with phenols,especially in the reaction of naphthol and phenol derivatives,the excellent stereoselectivities,yields and general generalities were observed.Takemoto’s catalysts were first applied in aza-Friedel-Crafts reaction of 2-naphthol and isatin-derived ketimines,and the Friedel-Crafts reaction of isatin and phenols.In addition,the Friedel-Crafts reaction of isatins and 3,4-thylene dioxide phenols has not been reported.