Ir-Catalyzed Asymmetric Reduction Synthesis Of Chiral Amines

Chiral amines are widely used in the fields of medicine,pesticides and materials which are an important type of functional skeleton.Therefore,efficient methods for the synthesis of chiral amines have been continuously developed.At present,there are many methods for synthesizing chiral amines,including the reduction of imines and enamines,asymmetric hydrogenation of nitrogen-containing heterocyclic compounds and direct asymmetric reductive amination,etc.Among them,nitrogen-containing heterocyclic compounds make the hydrogenation process relatively difficult due to its aromatic nature,so it is necessary to develop a new catalytic system based on existing activation strategies,making the catalytic process more suitable for industrial production.We selected the representative pharmacophores in the drug molecule such as indoline and tetrahydroquinoline derivatives for asymmetric synthesis studies.In addition,direct asymmetric reductive amination provides a more efficient,green route to the synthesis of chiral amines,which represents atomic economy.At present,asymmetric reductive amination mainly focuses on the synthesis of chiral primary amines and secondary amines.Inorganic ammonium salts and primary amines are generally used to provide the amine source.The synthesis of tertiary amines through this pathway is still a blank in the field of catalysis.We select the appropriate sources ofα-aromatic ketones and secondary amines to synthesize drug molecules or intermediates through the asymmetric reductive amination process with the help of optimal catalytic systems.1.Asymmetric hydrogenation of quinoline derivatives:The 2-methylquinoline was used as the standard substrate for the study and the catalyst activation strategy was adopted.We have used the cationic dinuclear triply chlorine-bridged iridium-(III)complexes with the BINOL framework monophosphine phosphoramidite ligand(L1e)as the catalyst,and N-chlorophthalimide as the additive.Under the optimum condition,2-methyltetrahydroquinoline achieved a yield of up to 99% and an enantioselectivity of 93%.2.Asymmetric hydrogenation of indole derivatives:The 2-methylindole was used as the standard substrate for the study,mainly using the substrate activation strategy.Studies have shown that methanesulfonic acid had the best effect of substrate activation.We used the cationic dinuclear triply chlorine-bridged iridium-(III)complexes with the BINOL framework monophosphine phosphoramidite ligand(L13i)as the catalyst,while using methanesulfonic acid and NBS as additives,chloroform and benzene as the solvent.In a mild reaction environment,99% yield and 92.6% enantioselectivity were obtained.We have extended a series of indole derivatives,and some substrates have achieved good results after asymmetric hydrogenation.3.Synthesis of Rivastigmine:We use two methods to synthesize the target product.One route is to synthesis the intermediate by reacting meta-hydroxyacetophenone with dimethylamine.We used the BINOL framework monophosphine phosphoramidite ligand(L1f)as the catalyst after complexing with iridium precursor,while using triethylamine,tetraisopropyl titanate,and iodine as additives,and a mixture of acetonitrile and tetrahydrofuran as the solvent.Under mild reaction condition,the intermediate drug gave 99% yield and 91% enantioselectivity.Finally,the final drug is obtained by reacting with N-ethyl-N-methyl carbamoylchloride.Another route is the direct synthesis of rivastigmine by the reaction of N-ethyl-N-methyl-3-acetophenyl ester with dimethylamine.The reaction condition was:BINOL framework monophosphine phosphoramidite ligand(L3f)was used as a catalyst after complexing with iridium precursor,while using triethylamine,tetraisopropyl titanate,and iodine as additives,and a mixture of acetonitrile and tetrahydrofuran as the solvent.Under mild reaction condition,greater than 90% yield and 86% enantioselectivity were achieved.4.Chair N-methyl-1-phenylethylamine:The drug intermediate was synthesized by the reaction of acetophenone with N-methylbenzylamine.The BINOL framework monophosphine phosphoramidite ligand(L3f)was used as the catalyst after complexing with iridium precursor,while using triethylamine,tetraisopropyl titanate,and iodine as additives,and a mixture of acetonitrile and tetrahydrofuran as the solvent.Under standard condition,96% yield and 92%enantioselectivity were achieved.In the follow-up,the final debenzylation will give the final chiral amine.5.Chiral α-(dimethylamino)ethylferrocene:Acetylferrocene and dimethylamine was used to synthesize the drug.We selected the BINOL framework monophosphine phosphoramidite ligand(L5f)as the catalyst after complexing with iridium precursor,while using triethylamine,tetraisopropyl titanate,and iodine as additives,and a mixture of dichloromethane and tetrahydrofuran as the solvent.Under this condition,47% yield and 43% enantioselectivity were achieved.Next we will try other types of ligands.In conclusion,we focused on the asymmetric hydrogenation of nitrogen-containing heterocyclic compounds and the synthesis of drugs or intermediates by asymmetric reductive amination.A series of catalytic systems for the synthesis of chiral amines have been successfully developed.