Asymmetric Transfer Hydrogenative Amination of Benzylic Ketones Catalyzed by Cp*Ir(III) Complexes Bearing a Chiral N-(2-Picolyl)sulfonamidato Ligand

Abstract

A convenient asymmetric reductive amination of benzylic ketones (α-arylated ketones) catalyzed by newly designed Cp*Ir complexes bearing a chiral N-(2-picolyl)­sulfonamidato ligand was developed. Using readily available β-amino alcohols as chiral aminating agents, a range of benzo-fused and acyclic ketones were successfully reduced with formic acid in methanol at 40 °C to afford amines with favorable chemo- and diastereoselectivities. The amino alcohol-derived chiral auxiliary was easily removed by mild periodic oxidants, leading to optically active primary β-arylamines without erosion of the optical purity (up to 97% ee). The excellent catalytic performance was retained even upon lowering the amount of catalyst to a substrate/catalyst (S/C) ratio of 20,000, and the amination could be performed on a large scale exceeding 100 g. The precise hydride transfer to iminium species generated from the ketonic substrate and the chiral amine counterpart was suggested by the mechanistic studies on stoichiometric reactions of isolable hydridoiridium complexes and model intermediates such as N,O-acetal, enamine, and iminium compounds.

Ammonia surrogates in the synthesis of primary amines

“…Furthermore, a notable utilization of primary amines as substitutes for ammonia was described by Kawada and co-workers, 39 employing chiral amino alcohols. This reaction…”

“…Furthermore, a notable utilization of primary amines as substitutes for ammonia was described by Kawada and co-workers, 39 employing chiral amino alcohols. This reaction offers a fascinating characteristic: the hydrogenative amination proceeds with exceptional diastereoselectivity.…”

Recent advances of Cp*Ir complexes for transfer hydrogenation: focus on formic acid/formate as hydrogen donors

“…Recently, Kuwata's group reported the reductive amination of benzylic ketones with chiral amino alcohols as the chiral source, resulting in chiral primary amines with favourable yields and excellent enantioselectivities. 66 In this catalytic system, the newly designed N-(2-picolyl)sulfonamidato/Cp*Ir complexes facilitated the production of chiral primary β-arylamines with high efficiency (Scheme 24). Mechanistic study demonstrated that β-amino alcohols serving as amine sources appeared to play a strong role in this transformation, in which the key iminium intermediate would be stabilized via the hydrogen bond of hydroxyl on β-amino alcohols.…”

“…70 A variety Scheme 24 Asymmetric direct reductive amination of benzylic ketones. 66 Scheme 26 Transfer hydrogenation of N-heteroarenes.…”

Asymmetric Reductive Amination of α-Keto Acids Using Ir-Based Hydrogen Transfer Catalysts: An Access to Unprotected Unnatural α-Amino Acids

“…In the generation of iminium species from the α-keto acids and ( S )-2-phenylglycinol, an E isomer exhibiting intramolecular hydrogen bonding between the iminium nitrogen and carboxy group is favored for the hydride attack rather than a Z isomer with hydrogen bonding interaction between the iminium and OH groups. In the same manner as the reductive amination of ketones with ( S )-Ir- L4 , the chiral hydrido-Ir complex imposes its one-sided approach to the Si face of the E iminium to minimize steric repulsion with the N-substituent, allowing the synthesis of enantiopure R -configured α-amino acids.…”