Additive‐Free Transfer Hydrogenative Direct Asymmetric Reductive Amination Using a Chiral Pyridine‐Derived Half‐Sandwich Catalyst

Abstract

Chiral amines are broadly used compounds in pharmaceutical industry and organic synthesis, and reductive amination reactions have been the most appreciated methods for their syntheses. However, one-step transfer hydrogenative direct asymmetric reductive amination (THDARA) that could expand the scope, simplify the operation and eliminate the use of additives has been challenging. In this work, based on the Xiao's racemic transfer hydrogenative reductive amination in 2010 and our recent work in novel chiral pyridine ligands, chiral half-sandwich iridium catalysts were rationally designed and synthesized. Using the optimized catalyst and azeotropic mixture of formic acid and triethylamine as the hydrogen source, a broad range of α-chiral (hetero)aryl amines, including various polar functional groups and heterocycles, were prepared in generally high yield and enantioselectivity under mild and operationally simple conditions. Density functional theory (DFT) calculation of the catalytically active IrÀ H species and the key hydride transfer step supported the chiral pyridine-induced stereospecific generation of the iridium center, and the enantioselection by taming the highly flexible key transition structure with multiple attractive non-covalent interactions. This work introduced a type of effective chiral catalysts for simplified approach to medicinally important chiral amines, as well as a rare example of robust enantioselective transition-metal catalysis.

Design and Application of New Pyridine-Derived Chiral Ligands in Asymmetric Catalysis

“…Mechanistically, the stereodetermining step involved an almost linear single-point interaction: an outer-sphere hydride transfer from the iridium center to the protonated imine (Figure ). Thus, we performed DFT calculations for the transition structures of the key hydride-transfer step to help understand the origin of the enantioselection. Due to the flexible nature of the single-point process, up to six ( R )- 78 and six ( S )- 78 transition structures could be located.…”