Synthesis And Application Of New Chiral Ferrocene P,N Ligands

Ferrocene and its derivatives are widely used in medicine,materials,catalysts,electrochemistry and other fields because of their good thermal stability,chemical stability,easy derivatization and redox reversible properties.In the field of medicine,chiral drugs with S and R configurations need to be screened to obtain more single configurations with no toxic side effects due to the experience of thalidomide.Asymmetric catalytic reaction can solve this problem,so it is widely used in the synthesis of chiral drugs.Due to the unique properties of ferrocene derivatives,which can form multi-chiral centers and complex with different metal centers to produce many new asymmetric catalysts,they are often used in asymmetric catalytic synthesis reactions of chiral drugs.After consulting a large number of data,this research group selected ferrocene P,N ligands as the target products.Since most ferrocene P,N ligands are composed of a face chirality and a center chirality at present,in order to further broaden the application range of ferrocene P,N ligands,the following two works were done in this project:(1)Synthesis of novel P,N ligands of chiral ferroceneOn the basis of(R)-Ugi's amine,three kinds of new type of chiral P,N ligands 5a and 5b and5c were synthesized.A series of new ferrocenyl P,N ligands with multichiral centers were obtained by a total of six steps:Sodium hydroxide solution hydrolysis,lithiation of n-butyl lithium and substitution of chlorinated diphenyl phosphine,reaction with anhydride,ammonolysis reaction,reaction with acetophenone derivatives,and reduction reaction with sodium borohydride.These new chiral P and N ligands have the advantages of multi-chiral centers,fine tuning of spatial stereoscopic effect and electronic effect.These intermediates and chiral P,N ligands 5a,5b and 5c were certified by ¹ H NMR and ¹³ C NMR.In addition,chiral P and N ligands were also certified by MS(ESI)and polarimeter.At the same time,the single crystal of 5a was cultured by evaporative solvent method and its crystal structure was determined by single crystal X-ray diffraction(SXRD).In older to prepare Schiff base 4d and4e,compound 3 were supposed to respectively react with 1-Phenylbutan-1-one and isobutyrophenone.Unfortunately,no corresponding compounds were obtained.Sodium borohydride was selected for hydrogenation.Compared with transition metal catalytic hydrogenation,the reaction conditions were simpler and gentler,and the configuration of the reaction product was closed to be same.(2)The study of application of chiral ferrocenyl P,N ligands in the asymmetric 1,3-dipole cycloaddition reaction of benzaldehyde imide ester with dimethyl maleateAt first,benzaldehyde and methyl glycine hydrochloride were used to prepare methylamine ylide,then the ligand and central metal were coordinated to form a catalyst,and finally the catalyst was used in the asymmetric 1,3-dipole cycloaddition reaction.The experiment selected benzaldehyde and methyl glycine hydrochloride as object,potassium carbonate as base and used 3%(mole fraction)dosage of catalyst.The yield calculated by the column chromatography separation and the ee value determination by HPLC.The effects of central metal,chiral ferrocenyl P,N ligands 5a,5b and 5c,solvent and temperature on the reaction were investigated.The results show that the catalyst formed by new chiral ferrocenyl P,N ligands and center metal were used in asymmetric 1,3-dipolar cycloaddition,success won92%of the ee value and 90%of production rate in the condition of DCM(as solvent),Ag OAc(as the center metal),the temperature of 0 degree and chiral ligands of 5a.In summary,three new chiral P,N ligands 5a,5b and 5c were synthesized with(R)-Ugi's amine as the basic structure,and the catalysts formed by coordination with the central metal were applied to the asymmetric 1,3-dipole cycloaddition reaction of imide ester and dimethyl maleate,which were obtained the excellent ee value and yield.