Asymmetric Reductive Amination Utilizing Ammonium Salt As Nitrogen Source For The Synthesis Of Primary Amines

Chiral amines are widely found in natural products,drugs and agrochemicals,such as ritonavir,a drug that treats AIDS,and amphetamine,which treats ADHD.At present,asymmetric reductive amination is one of the most direct and efficient methods for the synthesis of chiral amines.It has avoided the steps of the preparation,separation and purification of intermediate imines or enamines,and can directly synthesize chiral amines by one-pot method.However,amination arylamines or benzylamines are used as the amine source in most of the reported literatures of asymmetric reductive,which obtaine chiral secondary amines as products.It is necessary to remove the protecting groups on the nitrogen atoms in order to obtain more valuable chiral primary amines,and then to obtain active intermediates or drug molecules.In order to improve atomic economy and reduce the cost of synthesis,it is of great significance to develop a method for directly synthesizing chiral primary amines in one step.Therefore,we choose cheap and readily available inorganic ammonium salts as the amine sources to carry out asymmetric reductive amination reaction with the ketones,and directly construct the chiral primary amines in one step.The research contents are as follows:1.Asymmetric reductive amination of β-aryl ketone with ammonium salt: The primary1-(4-methoxybenzyl)ethylamine has been directly synthesized in one step with high yield and moderate enantioselectivity catalyzed by iridium-chiral phosphine ligand under the reaction conditions that 4-methoxyphenylacetone as ketone raw material,ammonium iodide as amine source,n-hexane and isopropanol as mixed solvent with volume ratio of1:1.No additives are needed in the reaction catalytic system,which is more economical and green.2.Asymmetric reductive amination of aromatic 1,2-diketones with ammonium salt:Carcinone was synthesized directly in one step with high enantioselectivity(98%)and moderate yield catalyzed by iridium-chiral phosphoramidite ligand(L1p’)under the reaction conditions that 1-phenyl-1,2-propanedione as ketone raw material,ammonium iodide as amine source,1,4-dioxane and methanol as mixed solvents with a volume ratio of 1:1.We subsequently tested the reactions of 19 different substituted aromatic 1,2-diketones compounds in this catalytic system.The results show that the correspondingα-ketoamines can be produced in the intermediate-high yield and the enantioselectivity of higher than 90% except for the aromatic 1,2-diketones whose ortho-substituents are Br,Cl and OMe.We selected several alpha-ketamine compounds to screen the antifungal activities of six plant pathogenic fungi,and found that their inhibition rates on these six plant pathogenic fungi were relatively low(<50%).In this study,iridium-catalyzed asymmetric reductive amination of chiral primary amines with β-aryl ketone and aromatic 1,2-diketones has been realized.This catalytic system does not need any additives and is a potential method for the efficient synthesis of primary β-arylamines,α-ketoamines and related drugs.