Method for constructing chiral ferrocene phosphine ligand

Abstract

The invention belongs to the technical field of catalyst preparation, and discloses a method for constructing a chiral ferrocene phosphine ligand. According to the invention, a ferrocene phosphine-containing substrate and an imidoium cation salt are used as reaction substrates, and the chiral supramolecular catalyst is accurately regulated and controlled under mild conditions, so that synergistic induction of a phosphine substitution site and an ethylamine group chiral center is realized, and double stereo centers are effectively constructed. The obtained target product has excellent enantioselectivity (ee value is greater than or equal to 96%), is clear and stable in structure, and is suitable for subsequent derivative development of chiral ligands or catalysts. Moreover, the reaction system is mild and safe, the process flow is simple, the catalyst can be recycled, the yield of the target product reaches 90% or above, and the method is green and environment-friendly, has good industrial amplification potential and green synthesis advantages, and provides a brand-new chiral construction strategy for synthesis of the chiral ferrocene phosphine ligand.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of catalyst preparation, in particular to a method for constructing a chiral ferrocenyl phosphine ligand. BACKGROUND

[0002] With the wide application of chiral catalysis technology in the fields of medicine, pesticides and fine chemicals, its role in constructing efficient and green synthesis path is increasingly prominent. Therefore, the development of chiral phosphine ligands with high efficiency and high enantioselectivity has become one of the core hotspots of asymmetric catalysis research. Among them, the ferrocene phosphine ligand with planar chirality has great application potential in various asymmetric catalytic reactions due to its unique three-dimensional structure, excellent thermal stability and air stability, good electronic tunability and controllable steric hindrance characteristics. Especially, (R)-N,N-dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine, as a chiral intermediate containing nitrogen and phosphorus bifunctional groups, can be directly used as a chiral catalyst or ligand, and can be further derived into various novel chiral phosphine ligands, which has been widely used in asymmetric hydrogenation, asymmetric coupling reaction, allyl alkylation and other reactions.

[0003] The traditional synthesis route of chiral ferrocene phosphine ligand usually takes chiral Ugi's amine (1-[dimethylamino]ethyl ferrocene) as the starting material, reacts with phosphorus trichloride (PCl3) after lithiation, and then introduces Grignard reagent or organolithium reagent to complete the construction of phosphine group. Although this method has certain modularity and stereoselectivity, it still has many limitations. For example, chiral Ugi's amine is expensive; the lithiation reaction has very high requirements for temperature and atmosphere, and must be slowly added with n-butyllithium at low temperature (about -78℃); the reaction process must be strictly protected by inert gas and accompanied by severe heat release, which has great safety hazards in ordinary reaction kettle operation; in addition, this method is easy to generate by-products, and the purification difficulty is large, which greatly limits the possibility of its industrial application.

[0004] In recent years, with the continuous deepening of the research on supramolecular chemistry and chiral recognition mechanism, researchers have gradually explored the use of supramolecular chiral assemblies to construct new asymmetric catalytic systems. By embedding chiral sources into the skeleton of ligand or catalyst through non-covalent interactions (such as hydrogen bonding, π-π stacking, electrostatic interaction, etc.), the conformation of metal active center can be finely controlled, so as to induce and stabilize the transition state structure in the catalytic process. This strategy has achieved preliminary success in enzyme-mimic catalysis, metal-organic framework materials (MOFs) and polymer block polymer supported catalysts, and shows good enantioselectivity and reaction compatibility.

[0005] However, the research on the construction of chiral ferrocene phosphine ligands guided by supramolecular chiral assemblies has not been reported yet. Therefore, it is of great scientific significance and industrial value to develop a new, mild, safe, selective and industrially feasible synthetic method for expanding the application of such chiral intermediates in asymmetric catalysis. SUMMARY

[0006] The present application aims to provide a method for constructing chiral ferrocene phosphine ligands, which has excellent enantioselectivity, and the reaction system for preparing the target product is mild and safe, and the catalyst can be recycled.

[0007] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions: The present application provides a method for constructing chiral ferrocene phosphine ligands, comprising the following steps: In a protective atmosphere, a ferrocene phosphine substrate, an iminium cation salt, a chiral supramolecular catalyst, a base and an organic solvent are mixed to perform an asymmetric catalytic reaction, and a chiral ferrocene phosphine ligand is obtained. The chiral supramolecular catalyst is a six-membered metal ring complex.

[0008] Further, in the method for constructing chiral ferrocene phosphine ligands, the preparation method of the chiral supramolecular catalyst comprises the following steps: In a protective atmosphere, a chiral imine-phenolic ligand, a divalent metal salt and an organic solvent are mixed to perform a self-assembly reaction, and a chiral supramolecular catalyst is obtained. The divalent metal ion in the divalent metal salt includes Zn 2+ , Ni 2+ , Fe 2+ , Co 2+ or Ru 2+ .

[0009] Further, in the method for constructing chiral ferrocene phosphine ligands, the ferrocene phosphine substrate includes 1-diphenylphosphinoferrocene or 1,1'-bis(diphenylphosphino)ferrocene.

[0010] Further, in the method for constructing chiral ferrocene phosphine ligands, the iminium cation salt includes N-ethylidene-N-methylmethanamine salt or N-benzylidene-N-methylmethanamine salt.

[0011] Further, in the method for constructing chiral ferrocene phosphine ligands, the base includes potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate or triethylamine.

[0012] Further, in the method for constructing a chiral ferrocenyl phosphine ligand, the organic solvent comprises one or more of acetonitrile, diethyl ether, tetrahydrofuran, ethyl acetate, 1,4-dioxane.

[0013] Further, in the method for constructing a chiral ferrocenyl phosphine ligand, when the ferrocene phosphine-containing substrate is 1-diphenylphosphinoferrocene, the molar ratio of the ferrocene phosphine-containing substrate, the iminium cation salt and the base is 1:1-2:1.075-2. When the ferrocene phosphine-containing substrate is 1,1'-bis(diphenylphosphino)ferrocene, the molar ratio of the ferrocene phosphine-containing substrate, the iminium cation salt and the base is 1:2-4:2-4.

[0014] Further, in the method for constructing a chiral ferrocenyl phosphine ligand, the molar ratio of the ferrocene phosphine-containing substrate and the chiral supramolecular catalyst is 1:0.03-0.06.

[0015] Further, in the method for constructing a chiral ferrocenyl phosphine ligand, the asymmetric catalytic reaction condition comprises: a temperature of 20-25 DEG C, and a time of 6-10 h.

[0016] Further, in the method for constructing a chiral ferrocenyl phosphine ligand, after the asymmetric catalytic reaction is completed, the reaction product is sequentially subjected to filtration, reduced pressure concentration and vacuum drying.

[0017] According to the above technical solution, compared with the prior art, the present application has the following beneficial effects: The present application provides a method for asymmetric synthesis of a chiral ferrocenyl phosphine ligand (such as (R)-N,N-dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine) by a chiral supramolecular catalyst. The method uses a ferrocene phosphine-containing substrate and an iminium cation salt as reaction substrates, and a chiral supramolecular catalyst precisely regulates the transition state conformation under mild conditions, realizes the cooperative induction of the phosphine substitution site and the chiral center of the ethylamine group, and effectively constructs double stereocenters. The obtained target product has excellent enantioselectivity (ee value ≥ 96%), a clear structure and stability, and is suitable for subsequent development of chiral ligands or catalysts.

[0018] The method of the present application is to synthesize chiral ferrocenyl phosphine ligand by asymmetric catalysis. Compared with the traditional lithiumation-phosphination route relying on chiral Ugi's amine, the present application does not use expensive and easily oxidized Ugi's amine as a substrate, and avoids the safety risks and side reaction problems caused by the operation of metal organic reagents (such as n-BuLi, PhMgBr) at low temperature. The traditional method is not only complicated, but also requires harsh temperature, low yield, poor enantioselectivity and difficult purification. The reaction system of the present application is mild and safe, the process flow is simple, the catalyst can be recycled, the yield of the target product is more than 90%, it is green and environmentally friendly, suitable for large-scale application, has good industrialization amplification potential and green synthesis advantage, and provides a new chiral construction strategy for the synthesis of chiral ferrocenyl phosphine ligand. BRIEF DESCRIPTION OF DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiment or prior art description.

[0020] Figure 1 NMR hydrogen spectrum of (R)-N,N-dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine obtained in Example 1; Figure 2 NMR hydrogen spectrum of ((S,S)-(-)-2,2'-bis-[(N,N-dimethylaminophenylmethyl-1,1'-bisdiphenylphosphino]ferrocene obtained in Example 2; Figure 3 HPLC chiral spectrum of (R)-N,N-dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine prepared in Example 1; Figure 4 HPLC racemic spectrum of (R)-N,N-dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine prepared in Example 1; Figure 5 HPLC chiral spectrum of ((S,S)-(-)-2,2'-bis-[(N,N-dimethylaminophenylmethyl-1,1'-bisdiphenylphosphino]ferrocene prepared in Example 2; Figure 6 HPLC racemic spectrum of ((S,S)-(-)-2,2'-bis-[(N,N-dimethylaminophenylmethyl-1,1'-bisdiphenylphosphino]ferrocene prepared in Example 2. DETAILED DESCRIPTION

[0021] The present application provides a method for constructing chiral ferrocenyl phosphine ligand, comprising the following steps: The ferrocene phosphine substrate, the iminium cation salt, the chiral supramolecular catalyst, the base and the organic solvent are mixed under a protective atmosphere to perform an asymmetric catalytic reaction, so as to obtain a chiral ferrocene phosphine ligand. The chiral supramolecular catalyst is a six-membered metal ring compound.

[0022] In the present application, the preparation method of the chiral supramolecular catalyst comprises the following steps: The chiral imine-phenolic ligand and the divalent metal salt are mixed in an organic solvent to perform a self-assembly reaction, so as to obtain the chiral supramolecular catalyst. The divalent metal ion in the divalent metal salt includes Zn 2+ , Ni 2+ , Fe 2+ , Co 2+ or Ru 2+ .

[0023] In the present application, the chiral imine-phenolic ligand is preferably a conventional commercial product (CAS No. 351498-13-0) with a structural formula as follows: .

[0024] In the present application, the divalent metal salt is preferably zinc acetate dihydrate (Zn(OAc)2·2H2O), nickel nitrate hexahydrate (Ni(NO3)2·6H2O), cobalt acetate tetrahydrate (Co(OAc)2·4H2O), iron chloride dihydrate (FeCl2·2H2O) or tetracarbonyl dichlororuthenate (Ru(CO)4Cl2).

[0025] In the present application, the molar ratio of the chiral imine-phenolic ligand to the divalent metal salt is preferably 1:1; the solvent is preferably N,N-dimethylformamide and methanol, and the volume ratio of N,N-dimethylformamide to methanol is preferably 1:1. The present application does not have special limitations on the amount of the solvent, which can be adjusted according to requirements.

[0026] In the present application, the temperature of the self-assembly is preferably 70-90 ℃, more preferably 80 ℃, and the time is preferably 20-30 h, more preferably 24 h.

[0027] After the self-assembly is completed, the present application preferably cools the reaction system to room temperature and crystallizes, removes impurities by washing with diethyl ether, and dries in air to obtain the chiral supramolecular catalyst.

[0028] The chiral supramolecular catalyst in the present application refers to a six-membered metal ring compound formed by self-assembly of a single chiral metal complex, which is formed by a chiral imine-phenolic ligand and a divalent metal ion M (including Zn 2+ , Ni 2+Fe 2+ Co 2+ or Ru 2+ ) spontaneously assemble into a supramolecular metallacycle (see prior art: Chiral NH-Controlled Supramolecular Metallacycles (J. Am. Chem. Soc. 2017, 139, 1554-1564 )). The resulting six-membered ring complex is composed of six metal centers and six ligand units, and the whole presents a regular hexagonal ring structure, and each metal center presents a nearly square pyramid configuration. The hydrophobic substituents (such as tert-butyl) on the ligand are arranged alternately along the inner side of the ring, forming six local hydrophobic pockets. This configuration makes the inside of the ring cavity present a chiral microenvironment, so that the whole assembly exhibits global chirality, and the catalytic system formed thereby has both metal activation ability and chiral space recognition ability.

[0029] In the present application, the preparation reaction formula of the chiral supramolecular catalyst is as follows: .

[0030] In the present application, the ferrocene phosphine substrate preferably includes 1-diphenylphosphinoferrocene or 1,1'-bis(diphenylphosphino)ferrocene.

[0031] In the present application, the iminium cation salt preferably includes N-ethylidene-N-methylmethanamine salt or N-benzylidene-N-methylmethanamine salt.

[0032] In the present application, the iminium cation salt is preferably an iminium cation hydrochloride.

[0033] In the present application, the preparation method of the iminium cation salt includes the following steps: The dimethylamine salt, aldehyde organic matter, organic solvent and acetic acid are mixed and reacted, and after the reaction is completed, cooling crystallization and drying are performed to obtain the iminium cation salt; wherein the dimethylamine salt is dimethylamine hydrochloride; the aldehyde organic matter is benzaldehyde or acetaldehyde.

[0034] In the present application, the molar ratio of the dimethylamine salt to the aldehyde organic matter is preferably 1:1.05-1.2, and further preferably 1:1.05.

[0035] In the present application, the organic solvent is preferably ethanol.

[0036] In the present application, the ratio of the molar amount of the dimethylamine salt to the volume of the organic solvent is preferably 50 mmol: 40-60 mL, and further preferably 50 mmol: 40 mL.

[0037] In the present application, the molar ratio of the dimethylamine salt to the acetic acid is preferably 1:0.05~0.1, further preferably 1:0.05.

[0038] In the present application, the reaction conditions include: the temperature is preferably 20~25 ℃, further preferably 25 ℃; the time is preferably 24~48 h, further preferably 36 h.

[0039] In the present application, the temperature of the cooling crystallization is preferably -4~5 ℃, further preferably 0 ℃.

[0040] In the present application, other parameters in the preparation method of the iminium cation salt are not limited, and the schemes well known to those skilled in the art can be used.

[0041] In the present application, the base preferably includes potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate or triethylamine.

[0042] In the present application, the organic solvent preferably includes one or more of acetonitrile, diethyl ether, tetrahydrofuran, ethyl acetate, 1,4-dioxane.

[0043] In the present application, when the organic solvent is selected as two or more, the ratio of each organic solvent is not limited, and the schemes well known to those skilled in the art can be used. In the embodiments of the present application, the organic solvent is preferably a mixed solvent of acetonitrile and diethyl ether, and the volume ratio of acetonitrile to diethyl ether is preferably 1:1.

[0044] In the present application, when the ferrocene phosphine substrate is 1-diphenylphosphinyl ferrocene, the molar ratio of the ferrocene phosphine substrate, the iminium cation salt and the base is 1:1~2:1.075~2, further preferably 1:1~1.5:1.075~1.5, more preferably 1:1:1.075; When the ferrocene phosphine substrate is 1,1'-bis(diphenylphosphino) ferrocene, the molar ratio of the ferrocene phosphine substrate, the iminium cation salt and the base is preferably 1:2~4:2~4, further preferably 1:2~3:2~3, more preferably 1:2:2.

[0045] In the present application, the molar ratio of the ferrocene phosphine substrate to the chiral supramolecular catalyst is preferably 1:0.03~0.06, further preferably 1:0.03 or 1:0.06.

[0046] In the present application, the amount of the organic solvent is not particularly limited, and can be adjusted according to the needs to ensure the smooth progress of the reaction.

[0047] In the present application, the specific way of mixing the ferrocene phosphine substrate, iminium cation salt, chiral supramolecular catalyst, base and organic solvent is preferably as follows: The iminium cation salt, chiral supramolecular catalyst and organic solvent are stirred, and then the ferrocene phosphine substrate and base are added, and the reaction is carried out under stirring.

[0048] In the present application, the protective atmosphere is preferably nitrogen or argon.

[0049] In the present application, the conditions of the asymmetric catalytic reaction include that the temperature is preferably room temperature, and the time is preferably 6-10 h, and further preferably 6 or 10 h.

[0050] In the present application, after the asymmetric catalytic reaction is completed, the obtained product is sequentially subjected to filtration, reduced pressure concentration and vacuum drying.

[0051] In the present application, the insoluble impurities are removed by diatomite filtration, and the filtrate is subjected to reduced pressure concentration; the reduced pressure concentration and the vacuum drying are not particularly limited, and can be carried out according to the processes well known in the art. In the embodiments of the present application, the vacuum drying is carried out for 2 h.

[0052] The technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without creative labor fall within the protection scope of the present application.

[0053] The experimental methods in the embodiments of the present application are all conventional methods unless otherwise specified; and the reagents and raw materials are all commercially available products unless otherwise specified.

[0054] Preparation Example 1: The preparation method of the chiral supramolecular catalyst (M=Zn) is as follows: Zinc acetate dihydrate (Zn(OAc)2·2H2O, 0.05 mmol) and chiral imine-phenol ligand (commercially available) (0.05 mmol) are added to a mixed solution containing N,N-dimethylformamide (DMF, 5 mL) and methanol (5 mL), and heated at 80 ℃ for 24 h in a sealed 10 mL reaction bottle. After the reaction is completed, the reaction mixture is cooled to room temperature, and then left to stand for crystallization. The yellowish crystals precipitated are washed with diethyl ether and dried in air to obtain the chiral supramolecular catalyst (M=Zn).

[0055] Preparation Example 2: Preparation method of chiral supramolecular catalyst (M=Ni), which is different from preparation example 1 in that zinc acetate dihydrate is replaced by nickel nitrate hexahydrate (Ni(NO3)2·6H2O), the precipitated crystal is green, and other parameter conditions are the same as preparation example 1.

[0056] Preparation Example 3: Preparation method of chiral supramolecular catalyst (M=Co), which is different from preparation example 1 in that zinc acetate dihydrate is replaced by cobalt acetate tetrahydrate (Co(OAc)2·4H2O), the precipitated crystal is pink, and other parameter conditions are the same as preparation example 1.

[0057] Preparation Example 4: Preparation method of N-ethylidene-N-methylmethanamine hydrochloride is as follows: A magnetic stirrer is placed in a 100 mL round-bottom flask, dimethylamine hydrochloride (50 mmol), 40 mL of anhydrous ethanol and acetic acid (2.5 mmol) are added, and acetaldehyde (52.5 mmol) is slowly added dropwise at 25°C under stirring with a constant-pressure dropping funnel. After the dropwise addition is completed, the reaction is stirred at 25°C for 36 h. After the reaction is completed, the system is cooled in a 0°C refrigerator, and a large amount of crystals is precipitated during cooling. The product is dried overnight after filtration, and N-ethylidene-N-methylmethanamine hydrochloride is obtained.

[0058] Preparation Example 5: Preparation method of N-benzylidene-N-methylmethanamine hydrochloride, which is different from preparation example 4 in that acetaldehyde is replaced by benzaldehyde, and other parameter conditions are the same as preparation example 4.

[0059] Example 1

[0060] Under the protection of a nitrogen atmosphere, chiral supramolecular catalyst of preparation example 1 (1.2 mmol) and N-ethylidene-N-methylmethanamine hydrochloride of preparation example 4 (40 mmol) are dissolved in a 50 mL acetonitrile-ether mixed solution (volume ratio 1:1), and a stable chiral catalyst complex system is formed by pre-stirring at 25°C for 30 min in a clean and dry 250 mL round-bottom flask. Subsequently, 1-diphenylphosphinoferrocene (40 mmol) and potassium carbonate (43 mmol) are added to the pre-stirred catalyst complex system, and the reaction is continued under a nitrogen atmosphere at 25°C for 6 h. During the reaction, the reaction progress is monitored by TLC, and the substrate consumption and product generation are observed. The reaction liquid gradually changes from orange red to light purple, indicating that the reaction is basically completed. The insoluble impurities are removed by filtration through diatomite, the filtrates are combined, concentrated under reduced pressure, and dried in a vacuum drying box for 2 h to obtain the target product (R)-N,N-dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine, which is a purple crystalline powder, with a net mass of 17.1 g, a yield of 97%, and an ee value of 99%.

[0061] The reaction formula for preparing (R)-N,N-dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine obtained in Example 1 is as follows: .

[0062] The nuclear magnetic hydrogen spectrum of (R)-N,N-dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine obtained in Example 1 is shown in Figure 1 . 1 H NMR (400 MHz, CDCl3) δ 7.59 (dq, J = 7.6, 3.1 Hz, 2H), 7.36 (dq, J = 3.7, 1.2 Hz, 3H), 7.24 – 7.13 (m, 5H), 4.37 (q, J = 1.9 Hz, 1H), 4.25 (t, J = 2.5 Hz, 1H), 4.16 (qd, J = 6.7, 2.6 Hz, 1H), 3.95 (s, 5H), 3.85 (dt, J =2.4, 1.1 Hz, 1H), 1.77 (s, 6H), 1.26 (d, J = 6.8 Hz, 3H).

[0063] Example 2

[0064] Under the protection of nitrogen atmosphere, the chiral supramolecular catalyst of Preparation Example 1 (2.4 mmol) and N-benzylidene-N-methylmethanamine hydrochloride of Preparation Example 5 (80 mmol) were weighed and dissolved in 100 mL of acetonitrile-ether mixed solution (volume ratio 1:1) in a clean and dry 500 mL round-bottom flask, and pre-stirred at 25 ℃ for 30 min to form a stable chiral catalyst composite system. Then, 1,1’-bis(diphenylphosphino)ferrocene (40 mmol) and potassium carbonate (80 mmol) were added to the above pre-stirred catalyst composite system, and the stirring reaction was continued at 25 ℃ for 10 h under nitrogen atmosphere. During the reaction, the reaction progress was monitored by TLC, and the substrate consumption and product generation were observed. The reaction liquid gradually changed from orange red to light purple, indicating that the reaction was basically completed. The insoluble impurities were removed by diatomite filtration, the filtrate was combined, concentrated under reduced pressure, and dried in a vacuum drying box for 2 h to obtain the target product ((S,S)-(-)-2,2’-bis[-(N,N-dimethylaminophenylmethyl-1,1’-bis(diphenylphosphino)]ferrocene as a light yellow powder, with a net mass of 31.5 g, a yield of 96%, and an ee value of 99%.

[0065] The reaction formula for preparing (S, S)-(-)-2, 2'-bis-[-(N, N-dimethylaminophenylmethyl-1, 1'-bisdiphenylphosphine] ferrocene obtained in Example 2 is as follows: .

[0066] The nuclear magnetic resonance hydrogen spectrum of (S, S)-(-)-2, 2'-bis-[-(N, N-dimethylaminophenylmethyl-1, 1'-bisdiphenylphosphine] ferrocene obtained in Example 2 is shown in Figure 2. Figure 2 1 H NMR (400 MHz, CDCl3) 7.27 – 7.10 (m, 30 H), 4.46(d, J = 4.3 Hz, 2 H), 4.34 (m, 2 H), 3.29(s, 2 H), 3.15 (s, 2 H), 1.51 (s, 12H)。

[0067] Example 3

[0068] The difference between Example 1 and Example 3 is that the chiral supramolecular catalyst of Preparation Example 1 is replaced by the chiral supramolecular catalyst of Preparation Example 3, and other conditions are the same as those of Example 1, to obtain a purple crystalline product with a yield of 94% and an ee value of 98%.

[0069] Example 4

[0070] The difference between Example 1 and Example 4 is that the chiral supramolecular catalyst of Preparation Example 1 is replaced by the chiral supramolecular catalyst of Preparation Example 2, and other conditions are the same as those of Example 1, to obtain a purple crystalline product with a yield of 95% and an ee value of 97%.

[0071] Example 5

[0072] The difference between Example 1 and Example 5 is that the base K2CO3 is replaced by K3PO4, and other conditions are the same as those of Example 1, to obtain a purple crystalline product with a yield of 93% and an ee value of 96%.

[0073] Example 6

[0074] The difference between Example 1 and Example 6 is that the base K2CO3 is replaced by Et3N, and other conditions are the same as those of Example 1, to obtain a purple solid product with a yield of 91% and an ee value of 96%.

[0075] Example 7

[0076] The difference between Example 1 and Example 7 is that the organic solvent acetonitrile-ether (1:1) is replaced by THF, and other conditions are the same as those of Example 1, to obtain a light purple crystalline product with a yield of 90% and an ee value of 98%.​

[0077] Example 8

[0078] The difference between Example 1 and Example 8 is that the organic solvent is replaced by 1,4-dioxane instead of acetonitrile-ethyl ether (1:1), and other conditions are the same as Example 1. The product is a purple powder with a yield of 90% and an ee value of 97%.

[0079] The products prepared in Example 1 and Example 2 are detected by HPLC. The detection conditions are as follows: AD-H chiral column (0.46 cm x 25 cm), mobile phase is n-hexane / isopropyl alcohol = 90 / 10 (volume ratio), flow rate is 1.0 mL / min, detection wavelength is 254 nm, and the results are shown in Table 1. Figures 3-6

[0080] The above only describes the preferred embodiments of the present application. It should be noted that those skilled in the art can make several improvements and refinements without departing from the principles of the present application, and these improvements and refinements should also be considered within the scope of protection of the present application.​

Claims

1. A method for constructing chiral ferrocene phosphine ligands, characterized in that, Includes the following steps: Under a protective atmosphere, a ferrocene phosphine substrate, an imineonium cation salt, a chiral supramolecular catalyst, a base, and an organic solvent are mixed and subjected to an asymmetric catalytic reaction to obtain a chiral ferrocene phosphine ligand. The chiral supramolecular catalyst is a six-membered metal cyclic compound.

2. The method for constructing a chiral ferrocene phosphine ligand according to claim 1, characterized in that, The preparation method of the chiral supramolecular catalyst includes the following steps: Under a protective atmosphere, chiral imine-phenolic ligands, divalent metal salts, and organic solvents are mixed and subjected to a self-assembly reaction to obtain a chiral supramolecular catalyst. The divalent metal ions in the divalent metal salt include Zn. 2+ Ni 2+ Fe 2+ Co 2+ Or Ru 2+ .

3. The method for constructing a chiral ferrocene phosphine ligand according to claim 1, characterized in that, The ferrocene-containing phosphine substrates include 1-diphenylphosphinoferrocene or 1,1'-bis(diphenylphosphine)ferrocene.

4. A method for constructing chiral ferrocene phosphine ligands according to claim 1 or 3, characterized in that, The imineonium cationic salt includes N-ethylidene-N-methylmethylamine salt or N-benzylidene-N-methylmethylamine salt.

5. The method for constructing a chiral ferrocene phosphine ligand according to claim 4, characterized in that, The alkali includes potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, or triethylamine.

6. The method for constructing a chiral ferrocene phosphine ligand according to claim 1, characterized in that, The organic solvent includes one or more of acetonitrile, diethyl ether, tetrahydrofuran, ethyl acetate, and 1,4-dioxane.

7. The method for constructing a chiral ferrocene phosphine ligand according to claim 5, characterized in that, When the ferrocene phosphine-containing substrate is 1-diphenylphosphinoferrocene, the molar ratio of the ferrocene phosphine-containing substrate, the imineonium cationic salt, and the base is 1:1~2:1.075~2; When the ferrocene phosphine-containing substrate is 1,1'-bis(diphenylphosphine)ferrocene, the molar ratio of the ferrocene phosphine-containing substrate, the imineonium cation salt, and the base is 1:2~4:2~4.

8. A method for constructing a chiral ferrocene phosphine ligand according to claim 1 or 2, characterized in that, The molar ratio of the ferrocene phosphine-containing substrate to the chiral supramolecular catalyst is 1:0.03~0.

06.

9. A method for constructing a chiral ferrocene phosphine ligand according to claim 8, characterized in that, The conditions for the asymmetric catalytic reaction include: a temperature of 20-25 °C and a time of 6-10 h.

10. A method for constructing a chiral ferrocene phosphine ligand according to claim 9, characterized in that, The asymmetric catalytic reaction, after completion, also includes: sequentially filtering, concentrating under reduced pressure, and drying under vacuum of the resulting products.

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