Iridium-Catalyzed Asymmetric Reductive Amination Of Aliphatic Amines

Reductive amination is a highly efficient and simple method for the synthesis of chiral amines,and chiral amines have important applications in biology and medicine.Therefore,the use of asymmetric reductive amination to synthesize chiral amines has important practical significance.In the existing reports,the asymmetric reductive amination reaction of ketone compounds and aniline as the amine source is mostly,a few of them use benzylamine and benzhydrylamine as the amine source,and some use other types of amine sources.For example,ammonium salt sulfonamides and the like.Asymmetric reductive amination with fatty amines as amine sources seems to be difficult to carry out and is rarely reported.We used the use of fatty amines for the asymmetric amination of amine sources.1.Asymmetric reductive amination of α-aryl ketones with aliphatic amines: First,we used 1-acetylnaphthalene and 3-phenylpropylamine as substrates to explore the asymmetric reductive amination.We have carried out a large number of phosphoramidite ligands,as well as additives and other screening to determine the optimal reaction conditions: adding tetraisopropyl titanate(1.5 eq),triethylamine hydrochloride(0.3 equiv.),DBU(0.15 equiv.)was catalyzed by metal ruthenium,complexed with ruthenium using phosphoramidite ligand L11 k,and reacted with methyl acetate as solvent at 60 ℃ for 60 hours at 60 atm to obtain a reaction yield of 99%.The selectivity is 95% ee.After that,good results were obtained in the substrate extension.Good results were obtained in the reaction of substituted acetophenones with large steric hindrance and phenylalkyl ketones with large steric hindrance and aliphatic amines.The applicability of this reaction to fatty amines is strong.A variety of fatty amines can achieve the desired enantioselectivity,and the highest enantioselectivity of the substrate is as high as 96% ee.2.Asymmetric reductive amination of aldehyde substrates with aliphatic amines: We selected 2-phenylpropanal as the substrate and tetrahydropyrrole as the amine source to aid in the formation of enamine intermediates.Screening of metals,ligands,additives,etc.,using metal ruthenium catalyzed,adding tetraisopropyl titanate(1.2 equiv.),iodine elemental(0.1equiv.)using Ir-L4f as catalyst,toluene: tetrahydrofuran = 10:1 The solvent was mixed,1.4equivalents of tetrahydropyrrole was added,and the reaction was carried out at 40 ℃,hydrogen 40 atm to give a yield of up to 98% and an enantioselectivity of 81% ee.