Asymmetric Synthesis Of 3-indolylmethanamines Via Friedel–crafts Reaction Catalyzed By Cooperative Cation-binding Catalyst

3-Indolylmethanamine is a unique structural skeleton that is widely present in drug molecules and natural products.Due to its important biological activity and pharmacological activity,numerous research has been focused on the synthesis of 3-indolylmethanamine derivatives.Among the numerous synthesis methods,the asymmetric Friedel–Crafts reaction between indole and imine is the main method for the synthesis of chiral 3-indolylmethanamine derivatives.In this study,we used highly accessible chiral oligoethylene glycol(oligoEG)as the cation-binding catalyst and KF as the base,asymmetrically catalyzed the Friedel–Crafts reaction of indoles,4,7-dihydroindoles,and pyrrole with bench-stable α-amido sulfones as in-situ equivalents of sensitive imines.Through the optimization of catalysts,solvents,reaction equivalents and concentrations,chiral 3-indolylme thanamine derivatives were obtained with high yields and high ee values.The scope of this new catalytic protocol was not limited to aromatic imines.Heteroaromatic and aliphatic substrates as well as α-iminoethyl glyoxylate also afforded the desired products with excellent yields and ees.Finally,we also studied the mechanism of this reaction.We used high-resolution mass spectrometry to detect the transition state that occurred during the reaction,and speculated the possible reaction mechanism.First,the crown ether catalyst was complexed with potassium ions to release fluoride ions.The fluoride ion then attacked α-aminosulfone and formed the imine intermediate in situ.Then,the imine and indole undergo Friedel–Crafts reaction to produce the desired chiral 3-indolylmethanamines.