Nickel Catalyzed Asymmetric Transfer Hydrogenation And Deuteration Reactions Of Sulfonimides

Asymmetric hydrogenation catalyzed by transition metals is the first chiral reaction to win the Nobel Prize.After decades of development,asymmetric hydrogenation has become one of the pillar reactions for the preparation of chiral compounds in the laboratory and industry.In recent years,this classic reaction brings on a new trend of development.Traditional asymmetric catalytic hydrogenation reactions usually use precious metals as catalysts.As people's requirements for green reactions and sustainability continue to increase,researchers have begun to devote themselves to the development of inexpensive metal-catalyzed asymmetric hydrogenation reactions.The asymmetric transfer hydrogenation reaction using alcohols and formic acid as the hydrogen source has attracted more and more attentions because it does not require high-pressure hydrogen and pressure-resistant equipment.The asymmetric transfer hydrogenation reaction is a key method to obtain chiral compounds.By replacing the hydrogen source with a deuterium source,this method can also be used to perform asymmetric deuteration reactions to synthesize some deuterated drugs required by the pharmaceutical industry.In this thesis,the complex formed by inexpensive metals and chiral bisphosphine ligands was used as a catalyst to achieve high-yield and enantioselective asymmetric transfer hydrogenation and deuteration reactions.This thesis mainly includes the following two aspects:(1)Nickel-catalyzed asymmetric transfer hydrogenation reactionWe use nickel trifluoromethanesulfonate Ni(OTf)₂and chiral bisphosphine ligand(S)-Binapine in-situ generated complexes as catalysts,and isopropanol as a hydrogen source to promote the asymmetric transfer hydrogenation of sulfonimides,First,we studied the effects of metals,chiral ligands,solvents,temperature and other factors on the conversion rate and stereoselectivity of the catalytic reaction,and established the optimal reaction conditions.Under the optimal reaction conditions,We explored the suitability of the substrate.The experimental results show that a few chiral ligands can be used in this catalytic reaction,and the system has a wide range of substrate applicability.The asymmetric transfer hydrogenation reaction of various sulfonimides can achieve excellent yields and ee value.The ee value can be as high as99.6%.Finally,we confirmed the absolute configuration of the chiral center of the product in this catalytic system through single crystal X-ray diffraction analysis of the solid product.In this reaction,isopropanol is used as both solvent and hydrogen source.The operation is simple,the reaction conditions are more mild,and the functional group tolerance is higher.(2)Nickel-catalyzed asymmetric transfer deuteration reactionWe used Ni(OTf)₂/(S)-Binapine catalytic system to carry out asymmetric transfer deuteration reaction of the sulfonimide substrate,using deuterated isopropanol as the deuterium source,and finally obtained?-position deuterated products with a higher yield,Enantioselectivity and a deuteration rate of up to 99%.The biggest advantage of this method is that it achieves the specific selectivity of the?-position,the?-position of the amine group of the product molecule or other C-H bonds will not be deuterated,while other deuteration methods using heavy water(D₂O)or deuterated formic acid cannot be achieved.The?-deuterated products can be derivatized to form other chiral amine compounds such as dibenzoazepine,and the?-deuterated rate and ee value are not lost.Finally,we use the methods of elimination,capture intermediates,and kinetic experiments to study the mechanism,and prove that the reaction first generates Ni-D active species and then inserts the C=N double bond.In the above work,the method of using alcohols as hydrogen source or deuterium source which cheap metal catalyse can quickly and efficiently synthesize chiral sulfonamide compounds,and it provides a powerful reference for the synthesis of sulfonamides and deuterium-containing drugs.The reaction conditions require only 1-2%catalyst,which have simple operation,mild conditions,high yield and enantioselectivity,and it is beneficial to popularization and utilised in both various laboratory conditions and industrial-scale production.