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 Bronsted 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. [GRAPHICS] .