Ir-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles:Scope Investigations and Mechanistic Studies

Transition metal-catalyzed asymmetric hydrogenation(AH)of unprotected indoles has mainly been applied to alkyl substituted unprotected indoles.However,the challenging aryl substituted unprotected indoles with poor reactivity and enantioselectivity(≤42%ee)could not be hydrogenated well.In this work,a highly efficient Ir/bisphosphine-thiourea ligand ZhaoPhos catalytic system for the AH of challenging aryl substituted unprotected indoles has been successfully developed for the first time with high reactivity and excellent stereoselective control.Moreover,a series of 2-alkyl-substituted and 2,3-disubstituted unprotected indoles were also well tolerated in this catalytic system.A wide variety of chiral indoline derivatives were obtained in good to high yields with excellent stereoselectivities(75–99%yields,>20:1 dr,and 86–99%ee).The anion-binding activation strategy played an important role in accessing both high reactivity and excellent stereoselectivity,which was formed between the catalyst and unprotected indoles in situ-generating iminium ion with the assistance of Brønsted acid.A possible catalytic mechanism was proposed for this Ir-catalyzed AH according to density functional theory calculations and control experiment results.Readily available substrates,a broad range of substrate tolerance,an efficient chiral catalytic system,and a gram-scale protocol further demonstrated the potential practicality of this methodology.