Chiral ferrocene diphosphine ligand containing thiourea structure, chiral catalyst and preparation method and application thereof

Abstract

The invention discloses a chiral ferrocene diphosphine ligand containing a thiourea structure, a chiral catalyst and a preparation method and application of the chiral catalyst, and belongs to the technical field of organic synthesis. The chiral ferrocene diphosphine ligand has a structural formula as shown in a formula I or a formula II: # imgabs0 #, R1 and R2 in the formula I are independently selected from at least one of alkyl, aryl and substituted aryl, and R1 and R2 are different groups; r1 and R2 in the formula II are independently selected from at least one of alkyl, aryl and substituted aryl, and R1 and R2 can be the same or different. According to the invention, two chiral ferrocene diphosphine ligands containing thiourea structures are successfully developed, the ligands are successfully applied to asymmetric hydrogenation of cyclic imine, myomine and phosphaindole oxide, and high catalytic efficiency and excellent enantioselectivity are obtained; in addition, the catalytic system can be applied to efficient asymmetric hydrogenation of myomine, provides an effective way for preparing nicotine at low cost, and has important industrial application value.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a chiral ferrocenyldiphosphine ligand containing a thiourea structure, a chiral catalyst, and a preparation method and application thereof. Background Art

[0002] Chiral ligands can regulate the reaction activity and stereoselectivity of asymmetric catalytic reactions and play a vital role in asymmetric catalytic reactions. Therefore, the development of chiral ligands with novel structures and excellent performance has always been an important part of asymmetric catalytic reaction research.

[0003] The ferrocene skeleton is a highly effective ligand framework. Chemists have developed a series of high-performance chiral ligands based on it, including the bisphosphine ligands Josiphos, Taniaphos, Walphos, BoPhoz, and Mandyphos. In recent years, the design and synthesis of chiral ferrocenephosphine ligands with secondary interactions has attracted considerable attention and interest. Against this backdrop, Professor Zhang Xumu developed ZhaoPhos, a chiral ferrocenephosphine ligand containing a thiourea structural unit, and successfully applied this ligand to various asymmetric catalytic reactions, achieving excellent results. Although ZhaoPhos has become a leading ligand for asymmetric catalysis, the development of ferrocenephosphine ligands containing thiourea structural units remains significantly underdeveloped. Furthermore, conventional chiral ferrocenephosphine ligands either contain identical phosphine substituents on both ferrocene rings or one phosphine substituent on the ferrocene ring and the other on the ferrocene side chain. Hybrid chiral bisphosphine ligands with different phosphine substituents on the two ferrocene rings are rare. However, the different phosphine substituents in bisphosphine ligands can enhance the difference between the two phosphine substituents through steric hindrance and electronic regulation, improving the catalyst's recognition of the substrate's Re and Si faces, thereby improving the reaction activity and enantioselectivity. Therefore, the development of bisphosphine ligands containing a thiourea structural unit and different phosphine substituents attached to the cyclopentadienyl ring is of great research value. Furthermore, the ZhaoPhos ligand contains only a single thiourea structural unit. Incorporating thiourea structural units into both cyclopentadienyl ring side chains could further enhance the interaction between the catalyst and substrate, thereby improving the catalyst's activity and chiral control capabilities. More importantly, the addition of a thiourea structural unit changes the ligand's skeleton, providing a ligand with a different coordination system.

[0004] Therefore, the development of chiral ferrocenyldiphosphine ligands with dithiourea structure and their catalytic systems has important research value. Summary of the Invention

[0005] In view of the shortcomings of the prior art, one of the objectives of the present invention is to provide a chiral ferrocenyldiphosphine ligand containing a thiourea structure.

[0006] The above-mentioned object of the present invention is achieved through the following technical solutions:

[0007] A chiral ferrocenyldiphosphine ligand containing a thiourea structure has a structural formula shown in Formula I or Formula II below:

[0008]

[0009] Among them, R in formula I 1 and R 2 is independently selected from at least one of an alkyl group, an aryl group, and a substituted aryl group, and R 1 and R 2 For different groups; in formula II, R 1 and R 2 is independently selected from at least one of an alkyl group, an aryl group, and a substituted aryl group, R 1 and R 2 It can be the same or different.

[0010] Preferably, the chiral ferrocenyldiphosphine ligand includes ligands L1-L19, and the enantiomers corresponding to each ligand, and the structures of ligands L1-L19 are as follows:

[0011]

[0012] The present invention also provides a method for preparing the chiral ferrocenylbisphosphine ligand containing a thiourea structure. The method for preparing the chiral ferrocenylbisphosphine ligand represented by Formula I comprises the following steps:

[0013]

[0014] S1. Compound 1 is reacted with n-BuLi and BrCF2CF2Br to obtain compound 2;

[0015] S2. Compound 2 reacts with n-BuLi and then with R 1 2PCl, and then reacted with n-BuLi, R 2 2PCl reacted to give compound 3;

[0016] S3. Compound 3 reacts with acetic anhydride and then reacts with a methanolic ammonia solution to obtain compound 4;

[0017] S4. Compound 4 reacts with compound 5 to obtain the ligand represented by formula I.

[0018] The preparation method of the chiral ferrocenyldiphosphine ligand represented by formula II comprises the following steps:

[0019]

[0020] P1. When R 1 With R 2 When the groups are different, compound 6 reacts with n-BuLi and then with R 1 2PCl, and then reacted with n-BuLi, R 2 2PCl reaction to give compound 7; when R 1 With R 2 When they are the same groups, compound 6 reacts with 2.1 equivalents of n-BuLi and then with 2 equivalents of R2PCl to obtain compound 7;

[0021] P2. Compound 7 is reacted with acetic anhydride and then reacted with a methanolic ammonia solution to obtain compound 8;

[0022] P3. Compound 8 reacts with compound 5 to obtain the ligand represented by formula II.

[0023] The present invention also provides application of the chiral ferrocenyldiphosphine ligand in preparing a chiral catalyst for asymmetric hydrogenation.

[0024] The present invention also provides a chiral catalyst, which is a complex formed by the complexation of the chiral ferrocenyldiphosphine ligand and a transition metal salt.

[0025] Preferably, the transition metal includes at least one of Ru, Rh, Pd, Ir, Fe, Co, Ni, Cu, Sc, Ti, V, Cr, Mn, and Re.

[0026] Preferably, the preparation method of the chiral catalyst comprises the following steps:

[0027] Under an argon or nitrogen atmosphere, the chiral ferrocenyldiphosphine ligand and the transition metal salt are stirred in an organic solvent to carry out a complex reaction to obtain the corresponding metal complex; wherein the molar ratio of the ligand to the transition metal salt is (1-3):1, the reaction temperature is 0-100°C, and the complex reaction time is 0.1-20h.

[0028] The present invention also provides the use of the chiral catalyst in catalyzing asymmetric catalytic reactions, and the asymmetric catalytic reactions include: asymmetric hydrogenation, asymmetric transfer hydrogenation, asymmetric hydroamination, asymmetric hydrocyanation, asymmetric hydrosilylation, asymmetric hydroboration, asymmetric allylic alkylation, asymmetric coupling, asymmetric cyclization, asymmetric Michael addition, asymmetric epoxidation, asymmetric Aldol reaction, asymmetric Mannich reaction, asymmetric Diels-Alder reaction, and asymmetric cycloisomerization.

[0029] In particular, the chiral catalyst can be used for the asymmetric hydrogenation of prochiral imines and substituted olefin compounds to synthesize chiral amines and other chiral functional molecules. Prochiral imine compounds include simple arylalkyl imines, conjugated ketimines, cyclic imines, etc., and substituted olefins include simple open-chain olefins, conjugated olefins, cyclic olefins, etc. The method specifically comprises the following steps: under an argon or nitrogen atmosphere, adding a prochiral ketone or substituted olefin substrate to the catalyst solution, flushing hydrogen into a reactor, reacting at a certain temperature, and removing the solvent to obtain a chiral alcohol compound; wherein the molar ratio of substrate to catalyst is (100-100000):1, the reaction temperature is 0-100°C, and the hydrogen pressure is 1-100 bar.

[0030] The present invention also provides the use of the chiral catalyst in the preparation of nicotine on a gram scale.

[0031] The solvent used in the above method of the present invention can be benzene, toluene, xylene, trimethylbenzene, cyclohexane, acetonitrile, ether, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, chloroform, dichloromethane, methanol, ethanol, isopropanol, hexafluoroisopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, etc.

[0032] The transition metal salt used in the above method of the present invention can be RuX3, RuHX(L)2(diphosphine), RuX2(L)2(diphosphine), Ru(arene)X2(diphosphine), Ru(ary1group)X2, Ru(RCOO)2(diphsphine), Ru(methallyl)2(diphine), Ru(ary1group)X2(PPh3)3, Ru(COD)(COT), Ru(COD)(COT)X, RuX2(cymene), Ru(COD)n, Ru(arylgroup)X2(diphosphine), RuC12(COD), [Ru(COD)2]X, RuX2(diphosphine), RuC12(=CHR)(PR '3)2, Ru(ArH)C12, Ru(COD)(methallyl)2, Rh(CO)2C12, [Rh(NBD)2]BF4, [Rh(NBD)C1]2, [Rh (COD)C1]2, [Rh(COD)2]X, Rh(acac)(CO)2, Rh(ethylene)2(acac), [Rh(ethylene)2C1]2, RhC 1(PPh3)3, PdX2, Pd(PPh3)4, Pd(allyl)Cl, IrX3, [Ir(NBD)2)C1]2, [Ir(COD)C1]2, Ir(COD)X, FeX2, FeX3, Ni(acac)2, NiX2, [Ni(allyl)X]2, Ni(COD)2, CuX, CuX2, MoO2(acac)2, ScX2, Ti(O i Pr)4, VO (acac) 2, CrX2, CrX3, MnX2, Mn (acac) 2, MeReO3. In the above transition metal precursor salts, R and R' can be alkyl, alkoxy, substituted alkyl; aryl is aromatic; X is an anion, such as Cl-, Br - , I - 、ClO4 - 、BF4 - 、Sb6 - , PF6 - CF3SO3 - RCOO - 、BAr4 - ; L is a solvent molecule, such as acetonitrile.

[0033] When the catalyst is a complex formed by the complexation of the above-mentioned bisphosphine ligand and an Ir metal salt (such as [Ir(COD)Cl]2), it has high catalytic activity and enantioselectivity for the asymmetric hydrogenation of a series of prochiral imines and substituted olefins.

[0034] The present invention successfully developed two types of chiral ferrocenyldiphosphine ligands containing thiourea structures and successfully applied these ligands to the asymmetric hydrogenation of cyclic imines, myosmines, and phosphaindole oxides, achieving high catalytic efficiency and excellent enantioselectivity, enabling the efficient preparation of chiral amines and chiral phosphacyclopentane compounds. Furthermore, this catalytic system can be applied to the efficient asymmetric hydrogenation of myosmines, providing an effective and cost-effective route for the preparation of nicotine, with significant industrial application value.

[0035] Compared with the prior art, the present invention is beneficial in that:

[0036] (1) The chiral ferrocenylbisphosphine ligands of the present invention have the following advantages: a. Simple synthesis; most chiral ligands have a short synthesis step and a high yield; b. Stable ligands; this series of ligands are insensitive to water and oxygen, and are convenient to store and use; c. Easy modification of the ligands; by changing the substituents on the phosphine, a series of structurally rich chiral bisphosphine ligands can be quickly and efficiently synthesized, and steric and electrical properties can be regulated; d. High catalytic activity and good selectivity; this type of catalyst exhibits extremely high catalytic activity and excellent stereoselectivity in the asymmetric hydrogenation of imines and olefins.

[0037] (2) The bisphosphine ligands of the present invention have excellent performance in the asymmetric hydrogenation of a series of prochiral imines and substituted olefins, and can obtain the desired chiral products with high enantioselectivity, high yield and high turnover number (TON); this type of ligand and the corresponding catalytic hydrogenation method can be used in the synthesis of key chiral fragments of various drugs and chiral ligands, and have important application value and broad industrial application prospects.

[0038] Unless otherwise stated, the terms used in the specification and claims have the following meanings:

[0039] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.

[0040] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0041] Substituted phenyl refers to a phenyl group having at least one substituent, wherein the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate. DETAILED DESCRIPTION

[0042] The technical solutions of the present invention are described clearly and completely below. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0043] The chiral ferrocenyldiphosphine ligand containing a thiourea structure of the present invention has a structural formula shown in Formula I or Formula II below:

[0044]

[0045] Among them, R in formula I 1 and R 2 is independently selected from at least one of an alkyl group, an aryl group, and a substituted aryl group, and R 1 and R 2 For different groups; in formula II, R 1 and R 2 is independently selected from at least one of an alkyl group, an aryl group, and a substituted aryl group, R 1 and R 2 It can be the same or different.

[0046] The chiral ferrocenyldiphosphine ligands of the present invention include ligands L1-L19 and the enantiomers corresponding to each ligand. The structures of ligands L1-L19 are as follows:

[0047]

[0048] Example 1 Synthesis of ligand L5

[0049] This embodiment provides a method for synthesizing ligand L5, comprising the following steps:

[0050] S1. Synthesis of key fragment 2 (compound 2)

[0051]

[0052] Under nitrogen atmosphere and room temperature, 9.2 mL of n-BuLi in n-hexane (2.5 mol / L, 23 mmol) was added dropwise to a solution of 5.1 g (R)-Ugi's amine (20 mmol, 1.0 equiv.) in diethyl ether (70 mL). After 1.5 h, 10.0 mL of n-BuLi in n-hexane (2.5 mol / L, 25 mmol) and TMEDA (3.8 mL, 25 mmol) were added dropwise to the reaction solution, and the reaction mixture was stirred overnight. 1,2-Dibromotetrafluoroethane (5.3 mL, 48 mmol) was slowly added dropwise at -78°C, stirred for 1.0 h, and then transferred to room temperature and stirred for 2.0 h. After completion of the reaction, ice water was added to quench the reaction, and the mixture was extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oily liquid. The product, compound 2, was purified by column chromatography to obtain 6.4 g of the product, compound 2, in a 78% yield.

[0053] S2. Key fragment 3a (compound 3a) (R 1 =phenyl, R 2 =cyclohexyl)

[0054]

[0055] Under a nitrogen atmosphere and at room temperature, compound 2 (6.4 g, 15.5 mmol) was dissolved in 50 mL of diethyl ether. At -30°C, 6.2 mL of a solution of n-BuLi (2.5 mol / L, 15.5 mmol) in n-hexane was slowly added dropwise. Ph2PCl (16.0 mmol) was added dropwise to the reaction solution at -78°C. The reaction was allowed to proceed for 2 hours at this temperature, then the mixture was transferred to room temperature and stirred overnight. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted several times with n-hexane. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oily liquid. Purification by column chromatography yielded 5.6 g of the monosubstituted product. The product (5.6 g, 10.8 mmol) was dissolved in ether (50 mL). 5.2 mL of a 2.5 mol / L, 13 mmol, hexane solution of n-BuLi was slowly added dropwise at -30°C. Cy2PCl (14 mmol) was then added dropwise at -78°C, and the mixture was allowed to stir overnight at room temperature. After completion of the reaction, water was added to quench the reaction, followed by multiple extractions with EA. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oil. Purification by column chromatography afforded 5.5 g of compound 3a in a two-step yield of 56%.

[0056] S3. Key fragment 4a (compound 4a) (R 1 =phenyl, R 2 =cyclohexyl)

[0057]

[0058] Under nitrogen, a mixture of compound 3a (5.5 g, 8.6 mmol) and acetic anhydride (40 mL) was heated at 100°C for 2.0 h. After completion of the reaction, the acetic anhydride was removed under reduced pressure to yield an orange-red solid. The solid product was dissolved in NH3-methanol solution and stirred at 100°C overnight. After completion of the reaction, the solvent was removed under reduced pressure and purified by column chromatography to yield 3.9 g of the product, compound 4a, with a two-step yield of 75%.

[0059] S4. Ligand L5(R 1 =phenyl, R 2 =cyclohexyl)

[0060]

[0061] Under nitrogen atmosphere and 0°C, compound 4 (3.9 g, 6.5 mmol) was dissolved in dichloromethane (30 mL) and 3,5-bis(trifluoromethyl)phenylisothiocyanate (1.9 g, 7.0 mmol) was added dropwise. The mixture was transferred to room temperature and stirred for 6 h. After the reaction, the crude product was dried to obtain an orange-red foam. The product, ligand L5, was purified by column chromatography as an orange-red powder with a yield of 72%. 1 H NMR(400MHz, CDCl3)δ7.90(s,1H),7.85(s,2H),7.69(s,1H),7.41–7.27(m,5H),7.26 –7.22(m,3H),7.15–7.09(m,2H),5.60–5.42(m,1H),4.48–4.37(m,2H),4.31(s,1H),4 .23(t,J=2.6Hz,1H),4.05(d,J=2.6Hz,1H),3.71(s,1H),3.63(s,1H),1.89–1.83(m,1 H),1.79–1.58(m,11H),1.55(d,J=6.7Hz,3H),1.32–1.04(m,10H),0.89–0.81(m,1H). 13C NMR (101MHz, CDCl3) δ178.5, 139.6, 138.7 (d, J = 7.7Hz), 136.1 (d, J = 7.1Hz), 134.8 (d, J = 21.0Hz), 132.6, 132.3 (d, J = 17. 9Hz),129.5,128.4(d,J=6.9Hz),128.2(d,J=7.9Hz),124.4,123.8,121.7,118.7,94.8(d,J=21.8Hz),77.2,74.3(d,J=6 .6Hz),73.4(d,J=15.1Hz),72.3,71.7,70.9,50.5,33.8(d,J=11.2Hz),32.9(d,J=8.9Hz),31.1(d,J=13.9Hz),30.7(d,J =14.7Hz), 29.7 (d, J = 10.6Hz), 29.3 (d, J = 6.4Hz), 27.4 (d, J = 5.5Hz), 27.3, 27.2-27.1 (m), 27.1, 26.3, 21.8 (d, J = 5.6Hz). 19 F NMR (377 MHz, CDCl3) δ-62.84. 31 P NMR (162MHz, CDCl3) δ-8.09,-23.49.

[0062] Example 2 Synthesis of ligand L6

[0063] This embodiment provides a method for synthesizing ligand L6, comprising the following steps:

[0064] S1. Synthesis of key fragment 2 (Compound 2): The steps are the same as in Example 1;

[0065] S2. Key fragment 3b (compound 3b) (R 1 =phenyl, R 2 =tert-butyl)

[0066]

[0067] Under a nitrogen atmosphere and at room temperature, compound 2 (6.4 g, 15.5 mmol) was dissolved in 50 mL of diethyl ether. At -30°C, 6.2 mL of a solution of n-BuLi (2.5 mol / L, 15.5 mmol) in n-hexane was slowly added dropwise. Ph2PCl (16.0 mmol) was added dropwise to the reaction solution at -78°C. The reaction was allowed to proceed for 2 hours at this temperature, then the mixture was transferred to room temperature and stirred overnight. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted several times with n-hexane. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oily liquid. Purification by column chromatography yielded 5.6 g of the monosubstituted product. The product (5.6 g, 10.8 mmol) was dissolved in ether (50 mL). 5.2 mL of a 2.5 mol / L, 13 mmol, hexane solution of n-BuLi was slowly added dropwise at -30°C. t-Bu2PCl (14 mmol) was then added dropwise at -78°C. The mixture was then transferred to room temperature and stirred overnight. After completion of the reaction, water was added to quench the reaction. The mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oil. Purification by column chromatography afforded 5.2 g of compound 3b in a two-step yield of 45%.

[0068] S3. Key fragment 4b (compound 4b) (R 1 =phenyl, R 2 =tert-butyl)

[0069]

[0070] Under nitrogen, a mixture of compound 3b (2.1 g, 3.5 mmol) and acetic anhydride (20 mL) was heated at 100°C for 2.0 h. After completion of the reaction, the acetic anhydride was removed under reduced pressure to yield an orange-red solid. The solid product was dissolved in NH3-methanol solution and stirred at 100°C overnight. After completion of the reaction, the solvent was removed under reduced pressure and purified by column chromatography to yield 1.8 g of the product, compound 4b, in a two-step yield of 70%.

[0071] S4. Ligand L6(R 1 =phenyl, R 2 =tert-butyl)

[0072]

[0073] Under nitrogen atmosphere and 0°C, compound 4 (1.8 g, 2.5 mmol) was dissolved in dichloromethane (15 mL) and 3,5-bis(trifluoromethyl)phenylisothiocyanate (0.7 g, 2.6 mmol) was added dropwise. The mixture was transferred to room temperature and stirred for 6 h. After the reaction, the crude product was dried to obtain an orange-red foam. The product, ligand L6, was purified by column chromatography as an orange-red powder with a yield of 55%. 1H NMR(400MHz, CDCl3)δ7.83(s,2H),7.61(s,1H),7.35–7.21(m,6H),7.17(d,J= 3.9Hz,2H),7.09–7.01(m,2H),4.45(d,J=3.3Hz,1H),4.37(d,J=2.3Hz,1H),4. 32(s,1H),4.22(dt,J=5.4,2.5Hz,1H),4.08(t,J=2.3Hz,1H),3.65(d,J=11.6H z, 2H), 1.49 (d, J = 6.8Hz, 3H), 1.10 (d, J = 11.6Hz, 9H), 0.96 (d, J = 11.5Hz, 10H). 13 C NMR (101MHz, CDCl3) δ178.5,139.7(d,J=7.0Hz),137.8(d,J=9.6Hz),134.2,13 4.0,131.3,131.2,127.6,126.9,126.8,126.3,126.2,126.0,77.5,77.2,76.2 ,74.6,74.4,73.0(d,J=5.7Hz),71.6-71.4(m),71.2(d,J=3.1Hz),70.7,70.1( d, J=4.1Hz),56.1,56.0,37.7,31.9,31.7,31.4,31.2,30.0,29.9,29.4,29.3. 19 F NMR (377MHz,CDCl3)δ-62.71. 31 P NMR (162MHz, CDCl3) δ26.37, -23.24.

[0074] Example 3 Synthesis of ligand L8

[0075] This embodiment provides a method for synthesizing ligand L8, comprising the following steps:

[0076] S1. Synthesis of key fragment 2 (Compound 2): The steps are the same as in Example 1;

[0077] S2. Key fragment 3c (compound 3c) (R 1 =3,5-di-tert-butylphenyl, R 2 =phenyl)

[0078]

[0079] Under a nitrogen atmosphere and at room temperature, compound 2 (3.2 g, 7.8 mmol) was dissolved in 30 mL of diethyl ether. At -30°C, 3.1 mL of a solution of n-BuLi (2.5 mol / L, 7.8 mmol) in n-hexane was slowly added dropwise. (3,5-(t-Bu)2C6H3)2PCl (8.0 mmol) was added dropwise to the reaction solution at -78°C. The reaction was allowed to proceed for 2 hours at this temperature, then the mixture was transferred to room temperature and stirred overnight. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted several times with n-hexane. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oily liquid. Purification by column chromatography yielded 4.6 g of the monosubstituted product. The product (4.6 g, 6.2 mmol) was dissolved in ether (20 mL). 2.6 mL of a 2.5 mol / L, 6.5 mmol, hexane solution of n-BuLi was slowly added dropwise at -30°C. Ph2PCl (7.0 mmol) was then added dropwise at -78°C, and the mixture was allowed to stir overnight at room temperature. After completion of the reaction, water was added to quench the reaction, followed by multiple extractions with EA. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oil. Purification by column chromatography afforded 4.0 g of compound 3c in a two-step yield of 61%.

[0080] S3. Key fragment 4c (compound 4c) (R 1 =3,5-di-tert-butylphenyl, R 2 =phenyl)

[0081]

[0082] Under nitrogen, a mixture of compound 3c (3.4 g, 4.0 mmol) and acetic anhydride (20 mL) was heated at 100°C for 2.0 h. After completion of the reaction, the acetic anhydride was removed under reduced pressure to yield an orange-red solid. The solid product was dissolved in NH3-methanol solution and stirred at 100°C overnight. After completion of the reaction, the solvent was removed under reduced pressure and purified by column chromatography to yield 2.6 g of the product, compound 4c, in a two-step yield of 79%.

[0083] S4. Ligand L8(R 1 =3,5-di-tert-butylphenyl, R 2 =phenyl)

[0084]

[0085] Under nitrogen atmosphere and 0°C, compound 4 (2.6 g, 3.2 mmol) was dissolved in dichloromethane (20 mL) and 3,5-bis(trifluoromethyl)phenylisothiocyanate (0.9 g, 3.5 mmol) was added dropwise. The mixture was transferred to room temperature and stirred for 6 h. After the reaction, the crude product was dried to obtain an orange-red foam. The product, ligand L8, was purified by column chromatography as an orange-red powder with a yield of 74%.1 H NMR (400MHz, CDCl3) δ7.87(s,2H),7.68(s,1H),7.29(t,J=20.1Hz,12H),7.04(s,2H),6.95(d,J=8.1Hz,2H),5.44(s,1H),4.40(d,J= 11.1Hz,2H),4.27(s,1H),4.07(s,1H),3.82(s,1H),3.58(d,J=24.2Hz,2H),1.71(s,1H),1.45–1.35(m,3H),1.19(d,J=21.2Hz,36H). 13 CNMR (101MHz, CDCl3) δ178.3, 150.5 (d, J = 6.3Hz), 150.2 (d, J = 8.1Hz), 139.5, 138.8 (d, J = 9.3Hz), 138.1 (d, J = 9.0Hz), 137.8, 134.4 (d, J=3.3Hz),133.6(d,J=19.8Hz),133.2(d,J=19.3Hz),132.6(d,J=33.9Hz),129.2(d,J=21.1Hz),128.7(d,J=9.8Hz),128.3(d,J=6.8Hz ),128.2(d,J=7.2Hz),126.7(d,J=18.1Hz),124.3,123.3(d,J=7.9Hz),122.0,121.6,118.7,94.9(d,J=21.8Hz),77.3–77.1(m),75.1( d,J=18.6Hz),73.8,73.1(d,J=9.8Hz),72.6(d,J=3.7Hz),72.5,71.4,51.3,34.8(d,J=2.1Hz),31.4(d,J=10.3Hz),22.2(d,J=2.8Hz). 19 FNMR (377MHz,CDCl3)δ-62.71. 31 P NMR (162MHz, CDCl3) δ-17.67,-23.84.

[0086] Example 4 Synthesis of ligand L9

[0087] This embodiment provides a method for synthesizing ligand L6, comprising the following steps:

[0088] S1. Synthesis of key fragment 2 (Compound 2): The steps are the same as in Example 1;

[0089] S2. Key fragment 3d (compound 3d) (R 1=3,5-di-tert-butyl-4-methoxyphenyl, R 2 =phenyl)

[0090]

[0091] Under a nitrogen atmosphere and at room temperature, compound 2 (3.2 g, 7.8 mmol) was dissolved in 30 mL of diethyl ether. At -30°C, 3.1 mL of a solution of n-BuLi (2.5 mol / L, 7.8 mmol) in n-hexane was slowly added dropwise. (3,5-(t-Bu)2-4-MeOC6H2)2PCl (8.0 mmol) was added dropwise to the reaction solution at -78°C. The reaction was allowed to proceed for 2 hours at this temperature, then the mixture was transferred to room temperature and stirred overnight. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted several times with n-hexane. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oily liquid. Purification by column chromatography afforded 5.0 g of the monosubstituted product. The product (5.0 g, 6.2 mmol) was dissolved in ether (20 mL). 2.6 mL of n-BuLi (2.5 mol / L, 6.5 mmol) in n-hexane was slowly added dropwise at -30°C. Ph2PCl (7.0 mmol) was then added dropwise at -78°C. The reaction solution was then transferred to room temperature and stirred overnight. After completion of the reaction, water was added to quench the reaction. The mixture was extracted several times with EA. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oil. This was purified by column chromatography to afford 3.4 g of compound 3d in a two-step yield of 48%.

[0092] S3. Key fragment 4d (compound 4d) (R 1 =3,5-di-tert-butyl-4-methoxyphenyl, R 2 =phenyl)

[0093]

[0094] Under nitrogen, a mixture of compound 3d (3.6 g, 3.9 mmol) and acetic anhydride (20 mL) was heated at 100°C for 2.0 h. After completion of the reaction, the acetic anhydride was removed under reduced pressure to yield an orange-red solid. The solid product was dissolved in NH3-methanol solution and stirred at 100°C overnight. After completion of the reaction, the solvent was removed under reduced pressure and purified by column chromatography to yield 2.5 g of the product, compound 4d, in a two-step yield of 71%.

[0095] S4. Ligand L9(R 1 =3,5-di-tert-butyl-4-methoxyphenyl, R 2 =phenyl)

[0096]

[0097] Under nitrogen atmosphere and 0°C, compound 4 (2.5 g, 2.8 mmol) was dissolved in dichloromethane (20 mL) and 3,5-bis(trifluoromethyl)phenylisothiocyanate (0.8 g, 3.0 mmol) was added dropwise. The mixture was transferred to room temperature and stirred for 6 h. After the reaction, the crude product was dried to obtain an orange-red foam. The product, ligand L9, was purified by column chromatography as an orange-red powder with a yield of 54%. 1 H NMR (400MHz, CDCl3) δ7.86(s,2H),7.63(s,1H),7.27–7.20(m,4H),7.18(d,J=3.2Hz,6H),6.97(s,2H),6.89(d,J=8.0Hz,2H),5.34(s,1H) ,4.32(s,1H),4.29(s,1H),4.17(s,1H),3.95(s,1H),3.76(s,1H),3.52(d,J=13.5Hz,8H),1.33–1.29(m,3H),1.23(s,18H),1.18(s,18H). 13 C NMR (101MHz, CDCl3) δ178.41, 160.82, 159.95, 143.38 (d, J = 6.5Hz), 143.19 (d, J = 8.3Hz), 138.60 (d, J = 9.4Hz), 138.20 (d, J = 9.2Hz), 13 3.64,133.45,133.41,133.34,133.17(d,J=4.8Hz),132.84,132.50,131.70,130.80(d,J=18.7Hz),128.97,128.69,128.33(d,J=6.9Hz ),128.17(d,J=6.9Hz),124.34,123.63,121.62,118.86,94.98(d,J=21.5Hz),77.22(d,J=7.3Hz),74.82(d,J=17.5Hz),73.57,73.20(d ,J=10.9Hz),72.52(d,J=3.9Hz),72.30(d,J=3.1Hz),71.32,64.31(d,J=9.0Hz),51.41,35.73(d,J=6.1Hz),31.98(d,J=4.1Hz),22.72. 19 F NMR (377MHz,CDCl3)δ-62.71. 31 P NMR (162MHz, CDCl3) δ-17.67,-26.18.

[0098] Example 5 Synthesis of ligand L11

[0099] This embodiment provides a method for synthesizing ligand L11, comprising the following steps:

[0100] S1. Synthesis of key fragment 2 (Compound 2): The steps are the same as in Example 1;

[0101] S2. Key fragment 3e (compound 3e) (R 1 =cyclohexyl, R 2 =phenyl)

[0102]

[0103] Under a nitrogen atmosphere and at room temperature, compound 2 (6.4 g, 15.5 mmol) was dissolved in 50 mL of diethyl ether. At -30°C, 6.2 mL of a solution of n-BuLi (2.5 mol / L, 15.5 mmol) in n-hexane was slowly added dropwise. Cy2PCl (16.0 mmol) was added dropwise to the reaction solution at -78°C. The reaction was allowed to proceed for 2 h at this temperature, then the mixture was transferred to room temperature and stirred overnight. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted several times with n-hexane. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oily liquid. Purification by column chromatography yielded 5.7 g of the monosubstituted product. The product (5.7 g, 10.8 mmol) was dissolved in ether (50 mL). 5.2 mL of n-BuLi (2.5 mol / L, 13 mmol) in n-hexane was slowly added dropwise at -30°C. Ph2PCl (14 mmol) was then added dropwise at -78°C. The mixture was then transferred to room temperature and stirred overnight. After completion of the reaction, water was added to quench the reaction. The mixture was extracted several times with EA. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oil. Purification by column chromatography afforded 5.1 g of compound 3e in a two-step yield of 52%.

[0104] S3. Key fragment 4e (compound 4e) (R 1 =cyclohexyl, R 2 =phenyl)

[0105]

[0106] Under nitrogen, a mixture of compound 3e (3.6 g, 5.7 mmol) and acetic anhydride (40 mL) was heated at 100°C for 2.0 h. After completion of the reaction, the acetic anhydride was removed under reduced pressure to yield an orange-red solid. The solid product was dissolved in NH3-methanol solution and stirred at 100°C overnight. After completion of the reaction, the solvent was removed under reduced pressure and purified by column chromatography to yield 3.0 g of the product, compound 4e, with a two-step yield of 88%.

[0107] S4. Ligand L11 (R 1 =cyclohexyl, R 2 =phenyl)

[0108]

[0109] Under nitrogen atmosphere and 0°C, compound 4 (3.0 g, 5.0 mmol) was dissolved in dichloromethane (25 mL) and 3,5-bis(trifluoromethyl)phenylisothiocyanate (1.5 g, 5.5 mmol) was added dropwise. The mixture was transferred to room temperature and stirred for 6 h. After the reaction, the crude product was dried to obtain an orange-red foam. The product, ligand L11, was purified by column chromatography as an orange-red powder with a yield of 77%. 1 HNMR (400MHz, CDCl3) δ7.42–7.26(m,13H),4.36(dd,J=9.7,2.1Hz,2H),4.27(d,J=1.8Hz,1H),4.12(dt,J=7.2, 2.2Hz,2H),4.04–3.90(m,3H),2.14–1.93(m,3H),1.86–1.61(m,9H),1.40(d,J=6.7Hz,3H),1.34–1.06(m,9H). 13 C NMR (101MHz, CDCl3) δ178.6,139.1(d,J=10.0Hz),138.8(d,J=9.9Hz),133.8,133.6,133.4,133.2,128.7,128.5,128.2,101.6( d,J=23.9Hz),79.0(d,J=22.9Hz),76.3(d,J=7.3Hz),74.0(d,J=17.1Hz),73.6(d,J=11.5Hz),73.3(d,J=4.4Hz),70.9(d,J=2.8 Hz), 68.0 (d, J = 4.3Hz), 45.1 (d, J = 8.2Hz), 37.2 (d, J = 11.7Hz), 35.3 (d, J = 10.6Hz), 33.8 (d, J = 25.6Hz), 31.8 (d, J = 18.0Hz), 31. 0(d,J=10.7Hz),29.2,28.4(d,J=16.5Hz),27.7(d,J=4.3Hz),27.3(d,J=9.1Hz),27.0(d,J=11.7Hz),26.4(d,J=6.1Hz),23.61. 19 F NMR (377MHz,CDCl3)δ-62.73. 31 P NMR (162MHz, CDCl3) δ-16.16,-17.87.

[0110] Example 6 Synthesis of ligand L12

[0111] This embodiment provides a method for synthesizing ligand L12, comprising the following steps:

[0112] S1. Synthesis of key fragment 2 (Compound 2): The steps are the same as in Example 1;

[0113] S2. Key fragment 3f (compound 3f) (R 1 =3,5-di-tert-butylphenyl, R 2 =cyclohexyl)

[0114]

[0115] Under a nitrogen atmosphere and at room temperature, compound 2 (3.2 g, 7.8 mmol) was dissolved in 30 mL of diethyl ether. At -30°C, 3.1 mL of a solution of n-BuLi (2.5 mol / L, 7.8 mmol) in n-hexane was slowly added dropwise. (3,5-(t-Bu)2-4-MeOC6H2)2PCl (8.0 mmol) was added dropwise to the reaction solution at -78°C. The reaction was allowed to proceed for 2 hours at this temperature, then the mixture was transferred to room temperature and stirred overnight. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted several times with n-hexane. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oily liquid. Purification by column chromatography afforded 4.1 g of the monosubstituted product. The product (4.1 g, 5.5 mmol) was dissolved in ether (50 mL). 2.4 mL of a 2.5 mol / L, 6.0 mmol, hexane solution of n-BuLi was slowly added dropwise at -30°C. Ph2PCl (7.0 mmol) was then added dropwise at -78°C, and the mixture was allowed to stir overnight at room temperature. After completion of the reaction, water was added to quench the reaction, followed by multiple extractions with EA. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oil. Purification by column chromatography afforded 3.5 g of compound 3f in a two-step yield of 52%.

[0116] S3. Key fragment 4f (compound 4f) (R 1 =3,5-di-tert-butylphenyl, R 2 =cyclohexyl)

[0117]

[0118] Under nitrogen, a mixture of compound 3f (3.5 g, 4.1 mmol) and acetic anhydride (40 mL) was heated at 100°C for 2.0 h. After completion of the reaction, the acetic anhydride was removed under reduced pressure to yield an orange-red solid. The solid product was dissolved in NH3-methanol solution and stirred at 100°C overnight. After completion of the reaction, the solvent was removed under reduced pressure and purified by column chromatography to yield 2.7 g of the product, compound 4f, in a two-step yield of 78%.

[0119] S4. Ligand L12 (R1 =3,5-di-tert-butylphenyl, R 2 =cyclohexyl)

[0120]

[0121] Under nitrogen atmosphere and 0°C, compound 4 (2.7 g, 3.2 mmol) was dissolved in dichloromethane (15 mL) and 3,5-bis(trifluoromethyl)phenylisothiocyanate (1.0 g, 3.5 mmol) was added dropwise. The mixture was transferred to room temperature and stirred for 6 h. After the reaction, the crude product was dried to obtain an orange-red foam. The product, ligand L, was purified by column chromatography as an orange-red powder with a yield of 63%. 1 H NMR (400MHz, CDCl3) δ8.24(s,1H),7.98(d,J=1.6Hz,2H),7.58(s,1H),7.32(d,J=2.1Hz,1H),7.24(t,J=1 .8Hz,1H),7.03(d,J=8.7Hz,2H),6.92(dd,J=8.0,1.8Hz,2H),5.28(p,J=6.9Hz,1H),4.40(s,1H),4.34–4. 22(m,2H),4.13(t,J=2.5Hz,1H),3.99(s,1H),3.72(d,J=2.3Hz,1H),3.47(s,1H),1.89(d,J=6.4Hz,2H),1 .72–1.64(m,6H),1.54(dd,J=21.6,11.8Hz,8H),1.22(d,J=1.9Hz,2H),1.20–1.16(m,26H),1.12(s,18H). 13C NMR (101MHz, CDCl3) δ178.6, 150.6 (d, J = 6.5Hz), 150.3 (d, J = 7.6Hz), 140.1, 137.3 (d, J = 5.6Hz), 135.1 (d, J = 6.6Hz), 132.3 (d, J =33.8Hz),129.1(d,J=21.2Hz),126.8(d,J=18.8Hz),124.5,123.1,122.7,122.2,121.7,118.1,94.5(d,J=18.5Hz),77.2,76.5 (d,J=11.7Hz),74.5(d,J=19.9Hz),73.7,73.0,71.5,71.3,70.2,50.5,34.8(d,J=1.6Hz),33.9(d,J=9.9Hz),33.0(d,J=7.1Hz) ,31.7,31.4(d,J=8.7Hz),30.9(d,J=14.9Hz),29.8(d,J=9.1Hz),29.3(d,J=5.7Hz),27.43–26.88(m),26.2,22.10(d,J=9.4Hz). 19 F NMR (377 MHz, CDCl3) δ-62.80. 31 P NMR (162MHz, CDCl3) δ-7.92,-21.20.

[0122] Example 7 Synthesis of Ligand L13

[0123] This embodiment provides a method for synthesizing ligand L13, comprising the following steps:

[0124] P1. Key fragment 7 (compound 7) (R 1 =R 2 =phenyl)

[0125]

[0126] Under nitrogen atmosphere and room temperature, compound 6 (1.9 g, 5.8 mmol) was dissolved in 20 mL of ether. At 0°C, 7.4 mL of n-BuLi (2.4 mol / L, 17.4 mmol) in n-hexane was slowly added dropwise and stirred for 0.5 h. The reaction was allowed to proceed at this temperature for 2 h, followed by the slow addition of ClPPh2 (4.2 mL, 23.6 mmol) and the mixture was allowed to stand at room temperature overnight. After completion of the reaction, saturated aqueous sodium bicarbonate was added to quench the reaction, followed by extraction with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oily liquid. Purification by column chromatography afforded 1.6 g of product 7 in a 42% yield.

[0127] P2. Key fragment 8 (compound 8) (R 1 =R 2 =phenyl)

[0128]

[0129] Under nitrogen, a mixture of compound 7 (1.6 g, 2.32 mmol) and acetic anhydride (40 mL) was heated at 100°C for 2.0 h. After completion of the reaction, the acetic anhydride was removed under reduced pressure to yield an orange-red solid. The solid product was dissolved in a methanolic solution of NH3 and stirred at 100°C overnight. After completion of the reaction, the solvent was removed under reduced pressure and purified by column chromatography to yield 1.1 g of the product, compound 8, with a two-step yield of 71%.

[0130] P3. Ligand II (L13, R 1 =R 2 =phenyl)

[0131]

[0132] Under nitrogen atmosphere and 0°C, compound 8 (1.1 g, 1.6 mmol) was dissolved in dichloromethane (5 mL), and 3,5-bis(trifluoromethyl)phenylisothiocyanate (940 mg, 3.3 mmol) was added dropwise. The mixture was transferred to room temperature and stirred for 6 h. After the reaction, the crude product was dried to obtain an orange-red foam. The product was purified by column chromatography to obtain 940 mg of the product ligand LII as an orange-red powder in a yield of 51%. 1 H NMR (400MHz, CDCl3) δ7.81 (s, 6H), 7.25–6.92 (m, 18H), 6.78 (t, J = 8.2Hz, 2H ),6.09(qd,J=6.4,2.6Hz,1H),5.65(d,J=7.6Hz,1H),4.81(s,1H),4.61(t,J =2.5Hz,1H),4.34(q,J=1.9Hz,1H),4.16(t,J=2.5Hz,1H),3.06(s,1H),2.73 (t,J=1.6Hz,1H),1.71(d,J=6.5Hz,3H),1.36(d,J=6.9Hz,3H),1.14(s,2H). 13C NMR (101MHz, CDCl3) δ169.8,139.2,138.7,138.2,138.0,136.0,134.71(d,J=21.7Hz),134.21 (d,J=21.0Hz),132.42(d,J=18.4Hz),131.95(d,J=17.2Hz),129.37(d,J=36.6Hz),128.26(d,J = 6.8Hz), 128.09 (d, J = 9.2Hz), 127.94 (d, J = 6.2Hz), 125.1, 124.2, 121.5, 96.6, 93.63 (d, J = 24. 8Hz),78.4,78.3,78.1,77.2,73.2,72.9,72.0,71.9,68.0,67.8,53.4,52.2,51.4,19.9,18.8. 19 F NMR (376MHz,CDCl3)δ-62.76. 31 P NMR (162MHz, CDCl3) δ-25.39,-26.02.

[0133] Comparative Example 1 This comparative example provides compound 3a (R 1 =phenyl, R 2 =cyclohexyl) were used as control experiments

[0134] Synthesis Route 1

[0135]

[0136] Under nitrogen atmosphere and room temperature, 9.2 mL of n-BuLi (2.5 mol / L, 23 mmol) in n-hexane was added dropwise to a solution of 5.1 g (R)-Ugi's amine (20 mmol, 1.0 equiv.) in diethyl ether (70 mL). After 1.5 h, 10.0 mL of n-BuLi (2.5 mol / L, 25 mmol) in n-hexane and TMEDA (3.8 mL, 25 mmol) were added dropwise to the reaction solution, and the reaction mixture was stirred overnight. Ph2PCl (3.6 mL, 20 mmol) was slowly added dropwise at -78°C, stirred for 1.0 h, then transferred to room temperature and stirred for 2.0 h. Cy2PCl (5.2 mL, 24 mmol) was slowly added dropwise at -78°C, stirred for 1.0 h, then transferred to room temperature and stirred overnight. After completion of the reaction, ice water was added to quench the reaction, and the mixture was extracted with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oily liquid. TLC analysis showed that the reaction system was very complex. Column chromatography was attempted to separate the products. However, due to the large number of product types and the very small polarity differences between different products (some products may have the same Rf value), pure products could not be obtained after multiple separation and purification attempts.

[0137] Synthesis Route 2

[0138]

[0139] Under a nitrogen atmosphere and at room temperature, 4.6 mL of a 2.5 mol / L, 11.5 mmol solution of n-BuLi in n-hexane was added dropwise to a solution of 2.5 g of (R)-Ugi's amine (10 mmol, 1.0 equiv.) in diethyl ether (30 mL). Ph2PCl (2.2 mL, 12 mmol) was slowly added dropwise at -78°C, stirred for 1.0 h, then transferred to room temperature and stirred for 2.0 h. After completion of the reaction, ice water was added to quench the reaction, followed by extraction with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oil. This was then purified by column chromatography (n-hexane / ethyl acetate = 4:1) to afford product 1b (3.4 g, 78% yield).

[0140] Under nitrogen atmosphere and room temperature, 4.0 mL of n-BuLi in n-hexane (2.5 mol / L, 10 mmol) was added dropwise to a solution of compound 1b (3.4 g, 7.8 mmol, 1.0 equiv.) in diethyl ether (30 mL). Cy2PCl (2.6 mL, 12 mmol) was slowly added dropwise at -78°C, stirred for 1.0 h, and then transferred to room temperature and stirred for 12 h. TLC monitoring observed only trace conversion. The reaction was quenched by adding ice water and extracted with EA. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a red oil. This was then purified by column chromatography (n-hexane / ethyl acetate = 4:1). Product 3a was not isolated and the starting material was recovered.

[0141] From the above two routes, it can be seen that the traditional double lithiation-substitution route and the step-by-step lithiation-substitution synthesis method are not applicable to the synthesis of hybrid key intermediate 3.

[0142] Example 8 Asymmetric Hydrogenation of Pyridyl Cycloimine to Prepare Nicotine Derivatives

[0143]

[0144] Under argon atmosphere, [Ir(COD)Cl]2 (3.4 mg, 5.0×10 -3 mmol) and ligand L (1.0×10 -2 mmol) and DCE (1 mL) were added to a 2.5 mL reaction bottle and stirred at 25°C for 1 hour to prepare the catalyst in situ. The substrate 2-pyridyl cycloimine (0.1 mmol) was added to a 5.0 mL hydrogenation bottle, followed by 1.0 mL of dry DCE. Then, 100 μL (1×10 -3 mmol) was added dropwise to the reaction system. The hydrogenation reaction flask was placed in an autoclave, and the autoclave was replaced with H2 three times. The autoclave was then filled with 40 bar H2 and allowed to react at room temperature for 24 hours. After the reaction was completed, the hydrogen in the autoclave was slowly vented. The reaction liquid in the hydrogenation flask was directly subjected to rapid silica gel column chromatography using ethyl acetate as the eluent to remove the metal complex and obtain the target product. The ligand results are shown in Table 1.

[0145] Table 1 Yield and ee value of each ligand

[0146] ligand yield(%) ee(%) L5 99 96 L6 20 92 L8 20 55 L9 - - L11 27 71 L12 10 65 L13 93 88 L20 (ZhaoPhos) 84 84 L21 trace - L22 trace - L23 5 61

[0147] Note: "trace" in the table means there is almost no product. The structural formulas of ligands L20 to L23 are as follows:

[0148]

[0149] As can be seen from the data in Table 1, it is difficult to achieve excellent catalytic performance by regulating the electronic properties and steric hindrance of the phosphine substituents for ZhaoPhos-type ligands containing the same phosphine substituents. The catalytic performance of hybrid bisphosphine ligands is related to the electronic properties of the substituents and their position on the cyclopentadienyl ring. For example, by comparing the results of L5 and L11, it can be seen that the yield and ee value of the target product change significantly when the positions of the phenyl and cyclohexyl groups are swapped. This shows that hybrid bisphosphine ligands can achieve excellent catalytic performance through modification and transformation of the substituents, and are a different type of ligand from ZhaoPhos.

[0150] Example 9 Ir / L13-catalyzed asymmetric hydrogenation of pyridyl cyclic imine

[0151]

[0152] Under argon atmosphere, [Ir(COD)Cl]2 (3.4 mg, 5.0×10 -3 mmol) and ligand L13 (1.0×10 - 2 mmol) and DCE (1 mL) were added to a 2.5 mL reaction bottle and stirred at 25°C for 1 hour to prepare the catalyst in situ. The substrate pyridyl cyclic imine (0.1 mmol) was added to a 5.0 mL hydrogenation bottle, followed by 1.0 mL of dry DCE. Then, 100 μL (1×10 -3 mmol) was added dropwise to the reaction system. The hydrogenation reaction flask was placed in an autoclave, and the autoclave was replaced with H2 three times. Then, 40 bar H2 was introduced into the autoclave and the reaction was allowed to proceed at room temperature for 24 hours. After the reaction was completed, the hydrogen in the autoclave was slowly discharged. The reaction liquid in the hydrogenation flask was directly subjected to rapid silica gel column chromatography using ethyl acetate as eluent to remove the metal complex, obtaining the product as an oil with a yield of 93%. HPLC analysis of the product revealed an ee value of 88%.

[0153] Example 10 Asymmetric Hydrogenation of 2-Pyridyl Cycloimine to Prepare Nicotine Derivatives (S / C=1000)

[0154]

[0155] Under argon atmosphere, [Ir(COD)Cl]2 (3.4 mg, 5.0×10 -3 mmol) and ligand L (1.0×10 -2mmol) and DCE (1 mL) were added to a 2.5 mL reaction bottle and stirred at 25 °C for 1 hour to prepare the catalyst in situ. The substrate 2-pyridyl cycloimine (1 mmol) was added to a 5 mL hydrogenation bottle, followed by 1.0 mL of dry DCE. Then, 100 μL (1×10 -3 mmol) was added dropwise to the reaction system. The hydrogenation reaction flask was placed in an autoclave, and the autoclave was replaced with H2 three times. Then, 40 bar H2 was filled into the autoclave and the reaction was allowed to proceed at room temperature for 24 hours. After the reaction was completed, the hydrogen in the autoclave was slowly discharged. The reaction liquid in the hydrogenation flask was directly subjected to rapid silica gel column chromatography using ethyl acetate as eluent to remove the metal complex and obtain the target product. The results of the ligands are shown in Table 2:

[0156] Table 2 Yield and ee value of each ligand

[0157] ligand yield(%) ee(%) L20 (ZhaoPhos) 5 30 L5 99 96

[0158] As can be seen from the data in Table 2, the hybrid bisphosphine ligand L5 containing different phosphine substituents is significantly superior to the ligand ZhaoPhos containing the same phosphine substituent in catalytic activity and enantioselectivity control. It also shows that the hybrid bisphosphine ligand of the present invention is essentially different from the ZhaoPhos type ligand containing the same phosphine substituent in catalytic performance.

[0159] Example 11 Asymmetric hydrogenation of cyclic imine

[0160] Under argon atmosphere, [Ir(COD)Cl]2 (3.4 mg, 5.0×10 -3 mmol) and ligand L5 (1.0×10 - 2 mmol) and DCE (1 mL) were added to a 2.5 mL reaction bottle and stirred at 25°C for 1 hour to prepare the catalyst in situ. The substrate pyridyl cyclic imine (0.1 mmol) was added to a 5 mL hydrogenation bottle, followed by 1.0 mL of dry DCE. Then, 100 μL (1×10 -3 mmol) was added dropwise to the reaction system. The hydrogenation reaction flask was placed in an autoclave, and the autoclave was replaced with H2 three times. Then, 40 bar H2 was filled into the autoclave and the reaction was allowed to proceed at room temperature for 24 hours. After the reaction was completed, the hydrogen in the autoclave was slowly discharged, and the reaction liquid in the hydrogenation flask was directly subjected to rapid silica gel column chromatography using ethyl acetate as the eluent to remove the metal complex. The reaction results are shown below:

[0161]

[0162] From the above data, it can be seen that the L5 type ligand has very good catalytic performance for the asymmetric hydrogenation of -α-substituted cyclic imines and has good substrate universality.

[0163] Example 12 Asymmetric hydrogenation on a mesmink scale (L5 is a ligand, S / C = 10000)

[0164]

[0165] Under argon atmosphere, [Ir(COD)Cl]2 (10.2 mg, 1.5×10 -2 mmol) and ligand L5 (3.0×10 - 2 mmol) and DCE (3 mL) were added to a 5 mL reaction bottle and stirred at 25 °C for 1 hour to prepare the catalyst in situ. The substrate myosmin (0.25 mol) was added to a 300 mL hydrogenation cup, followed by 150 mL of dry DCE. Then, 2.5 mL (2.5×10 -2 mmol) was added dropwise to the reaction system. The hydrogenation reaction flask was placed in an autoclave, and the autoclave was replaced with H2 three times. The autoclave was then filled with 40 bar H2 and allowed to react at room temperature for 24 hours. After the reaction was completed, the hydrogen in the autoclave was slowly vented. The reaction liquid in the hydrogenation flask was directly subjected to rapid silica gel column chromatography using ethyl acetate as eluent to remove metal complexes. The solvent was then removed by rotary evaporation to obtain 37 g of the desired product. HPLC analysis of the product revealed an ee value of 96%.

[0166] Example 13 Preparation of chiral nicotine on a gram scale

[0167]

[0168] Under argon, 88% formic acid solution (150 mL) and 37% formaldehyde solution (80 mL) were added to a reaction flask. 2a (30 g, 200 mmol) was added with stirring, and the mixture was heated at 80°C for 12 h before cooling to room temperature. After the reaction, the reaction solution was cooled and solid potassium carbonate was slowly added until it became alkaline. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried, and concentrated to yield 30.5 g of an oil. HPLC analysis of the product revealed an ee value of 96%.

[0169] Example 14 Asymmetric hydrogenation of 1-(tert-butyl)-2-phenylphosphanindole 1-oxide to prepare (1R,2S)-1-(tert-butyl)-2-phenyl-2,3-dihydrophosphanin 1-oxide (S / C=10)

[0170]

[0171] Under argon atmosphere, Rh(NBD)2BF4 (3.7 mg 1.0×10 -2 mmol) and L(1.0×10 -2 mmol) and THF (1 mL) were added to a 1.0 mL reaction flask and stirred at 25°C for 1 hour to prepare the catalyst in situ. The substrate, 1-(tert-butyl)-2-phenylphosphanindole 1-oxide (0.1 mmol), was added to a 5.0 mL hydrogenation flask, followed by 1.0 mL of dry THF. The freshly prepared catalyst (1 mL) was then added dropwise to the reaction system. The hydrogenation flask was placed in an autoclave, and the autoclave was flushed with H2 three times. The autoclave was then filled with 80 bar of H2 and allowed to react at room temperature for 24 hours. After the reaction, the hydrogen in the autoclave was slowly vented, and the reaction solution was concentrated and separated by column chromatography (silica gel, eluent: ethyl acetate) to obtain the target products, (1R,2S)-1-(tert-butyl)-2-phenyl-2,3-dihydrophosphanin 1-oxide and (S)-1-(tert-butyl)-2-phenylphosphanin 1-oxide. The products were analyzed by HPLC to determine their ee values. The results for the ligands are shown in Table 3.

[0172] Table 3 Results of each ligand

[0173] ligand conversion(%) ee of 10(%) ee of 9(%) L20 (ZhaoPhos) 40 70 10 L5 6 95 5 L6 5 60 0 L8 52 84 90 L9 53 92 99 L11 20 86 16 L12 4 93 3 L13 45 87 80

[0174] From the data in Table 3, it can be seen that the hybrid bisphosphine ligands L5, L8, L9, L11, L12 and the bisthiourea ligand L13 are superior to ZhaoPhos in the chirality control (ee) of the reduction product.

[0175] Example 15 Asymmetric hydrogenation of 1-(tert-butyl)-2-phenylphosphanindole 1-oxide to prepare (1R,2S)-1-(tert-butyl)-2-phenyl-2,3-dihydrophosphanin 1-oxide (S / C=20)

[0176]

[0177] Under argon atmosphere, Rh(NBD)2BF4 (3.7 mg 1.0×10 -2 mmol) and L(1.0×10 -2mmol) and THF (1 mL) were added to a 1.0 mL reaction flask and stirred at 25°C for 1 hour to prepare the catalyst in situ. The substrate, 1-(tert-butyl)-2-phenylphosphanindole 1-oxide (0.1 mmol), was added to a 5.0 mL hydrogenation flask, followed by 1.0 mL of dry THF. Then, 500 μL of the freshly prepared catalyst was added dropwise to the reaction system using a microsyringe. The hydrogenation flask was placed in an autoclave, and the autoclave was replaced with H2 three times. The autoclave was then filled with 80 bar of H2 and allowed to react at room temperature for 24 hours. After the reaction, the hydrogen in the autoclave was slowly vented, and the reaction solution was concentrated and separated by column chromatography (silica gel, eluent: ethyl acetate) to obtain the target products, (1R,2S)-1-(tert-butyl)-2-phenyl-2,3-dihydrophosphine 1-oxide and (S)-1-(tert-butyl)-2-phenylphosphine 1-oxide. The products were analyzed by HPLC to determine the ee values. The reaction pathway is as follows, and the results of the ligands are shown in Table 4.

[0178] Table 4 Results of each ligand

[0179] ligand conversion(%) ee of 10(%) ee of 9(%) L20 (ZhaoPhos) 10 70 5 L8 34 96 46 L9 50 96 98

[0180] From the data in the table, it can be seen that the catalytic activity of ZhaoPhos decreases significantly with the decrease of catalyst dosage, but L9 can maintain excellent catalytic performance when the catalyst dosage is reduced, which further illustrates that the catalytic performance of the hybrid bisphosphine ligand L9 is significantly different from that of ZhaoPhos, and they are different types of ligands.

[0181] Example 16 Asymmetric Hydrogenation of 1-(tert-Butyl)-2-phenylphosphanindole 1-oxide to Prepare (1R,2S)-1-(tert-Butyl)-2-phenyl-2,3-dihydrophosphanin 1-oxide: Dynamic Kinetic Method (S / C = 50)

[0182]

[0183] Under argon atmosphere, Rh(NBD)2BF4 (3.7 mg 1.0×10 -2 mmol) and L9 (1.0×10 -2mmol) and THF (1 mL) were added to a 1.0 mL reaction flask and stirred at 25°C for 1 hour to prepare the catalyst in situ. The substrate, 1-(tert-butyl)-2-phenylphosphanindole 1-oxide (0.1 mmol), was added to a 5.0 mL hydrogenation flask, followed by 1.0 mL of dry THF. Then, 200 μL of the freshly prepared catalyst was added dropwise to the reaction system using a microsyringe. The hydrogenation flask was placed in an autoclave, and the autoclave was flushed with H2 three times. The autoclave was then filled with 80 bar of H2 and allowed to react at room temperature for 24 hours. After the reaction, the hydrogen in the autoclave was slowly vented, and the reaction solution was concentrated and separated by column chromatography (silica gel, eluent: ethyl acetate) to obtain the target product, (1R,2S)-1-(tert-butyl)-2-phenyl-2,3-dihydrophosphanindole 1-oxide, as a white solid in 49% yield. HPLC analysis revealed an ee of 96%. The target product (S)-1-(tert-butyl)-2-phenylphosphine 1-oxide was obtained as a white solid with a yield of 47%. The product was analyzed by HPLC and the ee value was 99%.

[0184] The structure, synthesis and application of the ferrocenylbisphosphine ligand containing a thiourea unit provided by the present invention are introduced in detail above. The principles and embodiments of the invention are described in detail using specific examples of the present invention. The description of the above embodiments is only to help understand the method and core concept of the present invention. It should be pointed out that the content of the present invention is not limited to the examples listed. For those skilled in the art, any improvements and modifications made to the present invention without departing from the principles of the present invention also fall within the scope of protection of the present invention.

Claims

1. A chiral ferrocenyldiphosphine ligand containing a thiourea structure, characterized in that: The chiral ferrocenyldiphosphine ligand has the structural formula shown in the following formula I or formula II: Among them, R in formula I 1 and R 2 is independently selected from at least one of an alkyl group, an aryl group, and a substituted aryl group, and R 1 and R 2 For different groups; in formula II, R 1 and R 2 is independently selected from at least one of an alkyl group, an aryl group, and a substituted aryl group, R 1 and R 2 It can be the same or different.

2. The chiral ferrocenyldiphosphine ligand containing a thiourea structure according to claim 1, characterized in that: The chiral ferrocenyldiphosphine ligand includes ligands L1-L19 and the enantiomers corresponding to each ligand. The structures of ligands L1-L19 are as follows:

3. The method for preparing the chiral ferrocenyldiphosphine ligand containing a thiourea structure according to claim 1 or 2, characterized in that: The preparation method of the chiral ferrocenyldiphosphine ligand represented by formula I comprises the following steps: S1. Compound 1 is reacted with n-BuLi and BrCF2CF2Br to obtain compound 2; S2. Compound 2 reacts with n-BuLi and then with R 1 2PCl, and then reacted with n-BuLi, R 2 2PCl reacted to give compound 3; S3. Compound 3 reacts with acetic anhydride and then reacts with a methanolic ammonia solution to obtain compound 4; S4. Compound 4 reacts with compound 5 to obtain the ligand represented by formula I.

4. The method for preparing a chiral ferrocenyldiphosphine ligand containing a thiourea structure according to claim 3, wherein: The preparation method of the chiral ferrocenyldiphosphine ligand represented by formula II comprises the following steps: P1. When R 1 With R 2 When the groups are different, compound 6 reacts with n-BuLi and then with R 1 2PCl, and then reacted with n-BuLi, R 2 2PCl reaction to give compound 7; when R 1 With R 2 When they are the same groups, compound 6 reacts with 2.1 equivalents of n-BuLi and then with 2 equivalents of R2PCl to obtain compound 7; P2. Compound 7 is reacted with acetic anhydride and then reacted with a methanolic ammonia solution to obtain compound 8; P3. Compound 8 reacts with compound 5 to obtain the ligand represented by formula II.

5. Use of the chiral ferrocenyldiphosphine ligand containing a thiourea structure according to claim 1 or 2 in the preparation of a chiral catalyst.

6. A chiral catalyst, characterized in that The chiral catalyst is a complex formed by the chiral ferrocenyldiphosphine ligand according to claim 1 or 2 and a transition metal salt.

7. A chiral catalyst according to claim 6, characterized in that The transition metal includes at least one of Ru, Rh, Pd, Ir, Fe, Co, Ni, Cu, Sc, Ti, V, Cr, Mn, and Re.

8. Use of the chiral catalyst according to claim 6 or 7 in catalyzing an asymmetric catalytic reaction, characterized in that: The asymmetric catalytic reactions include: asymmetric hydrogenation, asymmetric transfer hydrogenation, asymmetric hydroamination, asymmetric hydrocyanation, asymmetric hydrosilylation, asymmetric hydroboration, asymmetric allylic alkylation, asymmetric coupling, asymmetric cyclization, asymmetric Michael addition, asymmetric epoxidation, asymmetric Aldol reaction, asymmetric Mannich reaction, asymmetric Diels-Alder reaction, and asymmetric cycloisomerization.

9. The use according to claim 8, characterized in that The chiral catalyst is used in the asymmetric hydrogenation reaction of cyclic imine, phosphaindole oxide or myosmine.

10. The use according to claim 8, characterized in that Application of the chiral catalyst in nicotine synthesis.

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