Chiral phosphine-phosphoramidite ester ligand as well as preparation method and application thereof

Abstract

The invention provides a novel chiral phosphine-phosphoramidite ester ligand which is based on an achiral methylene bisphenol phosphoramidite ester structural unit and only has skeleton single-center chirality, and a preparation method and application thereof. Different from a traditional chiral phosphine-phosphoramidite ester ligand, the novel chiral phosphine-phosphoramidite ester ligand has the advantage that a phosphoramidite ester structural unit in the novel chiral phosphine-phosphoramidite ester ligand does not have a chiral element. The novel ligand is prepared by taking a chiral phosphine / amine intermediate (R)-or (S)-DPPNHMe, a methylene bisphenol compound and PC13 as raw materials under a mild condition. The novel chiral phosphine-phosphoramidite ligand provided by the invention has the characteristics of cheap and easily available raw materials, simple synthesis, stable properties, adjustable space structure and electronic properties, excellent activity and enantioselectivity in catalysis of asymmetric hydrogenation reaction, and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a novel chiral phosphine-phosphine ester ligand based on a non-chiral methylene bisphenol phosphoramide ester structure, possessing only a single-center chirality of the skeleton, its preparation method, and its application. Background Technology

[0002] Catalytic asymmetric hydrogenation is one of the most efficient and economical methods for obtaining chiral compounds. The development of highly efficient chiral catalysts plays a crucial role in the field of asymmetric catalytic hydrogenation and is a key factor in realizing this technology. In the development of asymmetric catalytic hydrogenation, the design and synthesis of chiral phosphine ligands occupy a very important position [(a)Tang, W.-J.;Zhang, X.-M. New Chiral Phosphorus Ligands for Enantioselective Hydrogenation, Chem. Rev. 2003, 103, 3029-3069.], and the development of novel chiral ligands remains the core of asymmetric catalytic hydrogenation research.

[0003] Recent studies have shown that asymmetric hybrid chiral phosphine-phosphoramidite ligands exhibit comparable or even superior activity and optical selectivity to C2-symmetric chiral bisphosphine ligands in many asymmetric catalytic reactions [[(b)Chen, S.-S.;Hou, C.-J.;Hu, X.-P. Chiral phosphine-phosphoramidite ligands in asymmetric catalysis, Synth. Commun. 2016, 46, 917;(c)Hou, Chuanjin; Liu, Xiaoning; Xia, Ying; Hu, Xiangping. Advances in the application of asymmetric hybrid chiral phosphine-phosphoramidite ligands in asymmetric catalytic reactions, <<Organic Chemistry>>, 2012, 32, 2239.]. Since the two non-equivalent phosphorus coordinating atoms in the ligand are introduced stepwise during ligand synthesis, this provides more convenient conditions for subsequent optimization and regulation of the ligand structure. By separately adjusting the electronic and spatial properties of the two coordinating atoms, highly efficient chiral phosphine-phosphamide ester ligands with unique structural features and meeting the requirements of specific catalytic reactions can be synthesized. In traditional chiral phosphine-phosphamide ester ligands, the phosphoramide ester structural unit is usually derived from a rigid, axially chiral binaphthyl skeleton or a spirochiral spirodiol skeleton. Because these chiral skeletons are typically expensive and difficult to optimize, the synthesis cost of chiral phosphine-phosphamide ester ligands is greatly increased, limiting their industrial application. Recent studies have shown that introducing achiral bicyclic phosphoramidite structural units to increase steric hindrance of ligands can effectively replace the use of axially chiral binaphthyl skeletons or spirochiral spirodiol skeletons [(d)Du,H.-Q.;Hu,X.-P.Bicyclic Bridgehead Phosphoramidite-Based Hybrid Diphosphorus Ligands: Design, Synthesis, and Application in Catalytic Asymmetric Hydrogenation. Org. Lett. 2021, 23, 7678-7682]. However, the construction of bicyclic phosphoramidite structural units is difficult and cannot substantially reduce the synthesis cost of chiral phosphine-phosphine ester ligands. Therefore, developing novel chiral phosphine-phosphine ester ligands with inexpensive and readily available raw materials and simple synthesis remains of great significance for their large-scale practical application. The present invention aims to develop a novel chiral phosphine-phosphine ligand based on a non-chiral methylene bisphenol phosphorimide ester structural unit, which has only a single-center chirality in the skeleton. This ligand has the advantages of inexpensive and readily available raw materials, simple synthesis, stable properties, tunable spatial structure and electronic properties, and excellent activity and enantioselectivity in catalytic asymmetric hydrogenation reactions. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a novel chiral phosphine-phosphine ester ligand with a non-chiral methylene bisphenol phosphorimide ester structure and a single-center chirality in the skeleton, as well as its preparation method. The method involves reacting a chiral phosphonamine intermediate, such as (R)- or (S)-DPPNHMe, with PCl3 in a triethylamine solution in dichloromethane to obtain a chlorophosphonamine compound, which is then reacted with a methylene bisphenol compound in a dichloromethane solution to obtain the chiral phosphine-phosphine ester ligand.

[0005] To achieve the above objectives, the present invention provides a chiral phosphine-phosphine ester ligand having the following (R)-I or (S)-I structural formula:

[0006]

[0007] (R)-I and (S)-I are enantiomers of each other.

[0008] In the formula:

[0009] R1 is selected from hydrogen, C1-C 40 Alkyl (preferably C1-C) 20 Alkyl), C1-C 40 Alkoxy (preferably C1-C) 20 One or more of alkoxy groups, etc., wherein the number of substituents is 1-4;

[0010] R2 is selected from hydrogen, C1-C 40 Alkyl (preferably C1-C) 20 Alkyl), C1-C 40 Alkoxy (preferably C1-C) 20 One or more of alkoxy, halogen, nitro, trifluoromethyl, etc., wherein the number of substituents is 1-4;

[0011] This invention provides a method for preparing chiral phosphine-phosphine ester ligands:

[0012] Under nitrogen protection, 1-2 equivalents of PCl3 were added to a Schünk flask containing a dichloromethane solution of 1-10 equivalents of triethylamine. The reaction flask was placed at 0-25°C, and a dichloromethane solution containing the chiral phosphine / amine intermediate (R)- or (S)-DPPNHMe(II) (1-1.2 equivalents) was added dropwise. After the addition was complete, the reaction solution was brought back to room temperature and stirred for 3-12 hours. The reaction was then placed at 0-25°C again, and a dichloromethane solution containing 1 equivalent of a methylene bisphenol compound (III) was added dropwise. After the addition was complete, the reaction solution was brought back to room temperature and stirred for 12-24 hours. After the reaction was confirmed by TLC, the solution was concentrated under reduced pressure until almost solvent-free, separated by silica gel column chromatography, concentrated under reduced pressure, and dried under vacuum to obtain the chiral phosphine-phosphonamide ester ligand (R)-I or (S)-I.

[0013] In this invention, the molar ratio of the chiral phosphine / amine intermediate (II): methylene bisphenol compound (III): PCl3: Et3N is 1-1.2:1:1-2:1-10. A preferred ratio is 1:1:1-1.5:6-10.

[0014] In the steps described in this invention, the reaction medium is selected from one or more of dichloromethane, chloroform, dichloroethane, and toluene; especially when the reaction medium is dichloromethane, the reaction yield is higher.

[0015] In this invention, the chiral phosphine / amine intermediate II has the following structure:

[0016]

[0017] In the formula, R1 is an equivalent group to R1 in structure I.

[0018] The preferred structure of this phosphine / amine intermediate is as follows:

[0019]

[0020] The structure of the methylene bisphenol compound III described in this invention is as follows:

[0021]

[0022] In the formula, R2 is an equivalent group to R2 in structure I.

[0023] The preferred structure of this methylene bisphenol compound is as follows:

[0024]

[0025] In this invention, the chiral phosphine-phosphine ester ligand is synthesized via the following route:

[0026]

[0027] In the formula, R1 is an equivalent group to R1 in structure I.

[0028] In the formula, R2 is an equivalent group to R2 in structure I.

[0029] The present invention also relates to the application of the above-mentioned ligands in the asymmetric hydrogenation reaction of C=C double bonds, exhibiting excellent activity and enantioselectivity.

[0030] The chiral phosphine-phosphamide ester ligand provided by this invention can be used in asymmetric hydrogenation reactions in C=C bonds. The chiral phosphine-phosphamide ester ligand is combined with Pt, Pd, Ir, Ru or Rh in a molar ratio of 1.1-2.2:1, preferably 1.1-1.5:1 to form a catalyst. The ratio of reaction substrate to catalyst is 100-10000:1, preferably 100-1000:1, and the reaction time is 0.1-24 hours, preferably 12-24 hours.

[0031] The asymmetric hydrogenation reaction described herein is a catalytic asymmetric hydrogenation reaction of the following types of substrates:

[0032] (1) Catalytic asymmetric hydrogenation of α-dehydroamino acids;

[0033] (2) Catalytic asymmetric hydrogenation of β-dehydroamino acids;

[0034] (3) Catalytic asymmetric hydrogenation of itaconic acid esters and their β-substituted itaconic acid esters;

[0035] (4) Catalytic asymmetric hydrogenation of α-acyclic and cyclic amides;

[0036] (5) Catalytic asymmetric hydrogenation of α-acyclic and cyclic enol esters;

[0037] (6) Catalytic asymmetric hydrogenation of α-acetoxy-β-substituted acrylates;

[0038] (7) Catalytic asymmetric hydrogenation of benzene or substituted benzoyl acetate esters;

[0039] (8) Catalytic asymmetric hydrogenation of benzene or substituted benzoyl carbamates;

[0040] (9) Catalytic asymmetric hydrogenation of 1,1-disubstituted aryl olefins.

[0041] The beneficial effects of this invention are:

[0042] The chiral phosphine-phosphamide ester ligand described in this invention possesses only one chiral skeletal center, with its phosphoramide ester structural unit derived from the achiral methylene bisphenol skeleton. This ligand is characterized by inexpensive and widely available raw materials, simple synthesis, stable properties, tunable spatial structure and electronic properties, and excellent activity and enantioselectivity in catalytic asymmetric hydrogenation reactions. The catalysts formed with metal precursors such as Pt, Pd, Ir, Ru, or Rh are stable, exhibiting good tolerance to air and humidity. The asymmetric hydrogenation reactions it participates in are mild, can occur at room temperature, and have a wide applicable hydrogen pressure range, from atmospheric pressure to high pressure without affecting the catalyst's activity and stereoselectivity. The catalysts formed by the chiral phosphine-phosphamide ester ligand prepared in this invention and metal precursors can achieve an enantioselectivity of up to 99% ee for the asymmetric hydrogenation of C=C double bonds; the catalyst activity is high, with a TON as high as 10000.

[0043] Unlike traditional chiral phosphine-phosphamide ester ligands, the phosphoramidite structural unit in this novel chiral phosphine-phosphamide ester ligand does not possess a chiral element. The new ligand is prepared under mild conditions using chiral phosphine / amine intermediates (R)- or (S)-DPPNHMe, methylene bisphenol compounds, and PCl3 as raw materials. The novel chiral phosphine-phosphamide ester ligand provided by this invention features readily available and inexpensive raw materials, simple synthesis, stable properties, tunable spatial structure and electronic properties, and excellent activity and enantioselectivity in catalytic asymmetric hydrogenation reactions. Attached Figure Description

[0044] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0045] Figure 1 The 1H NMR spectrum of chiral phosphine-phosphine ester ligand compound I-1;

[0046] Figure 2 Carbon NMR spectrum of chiral phosphine-phosphine ester ligand compound I-1;

[0047] Figure 3 The phosphorus NMR spectrum of chiral phosphine-phosphine ester ligand compound I-1;

[0048] Figure 4 The 1H NMR spectrum of chiral phosphine-phosphine ester ligand compound I-2;

[0049] Figure 5 Carbon NMR spectrum of chiral phosphine-phosphine ester ligand compound I-2;

[0050] Figure 6 The phosphorus NMR spectrum of chiral phosphine-phosphine ester ligand compound I-2;

[0051] Figure 7 The 1H NMR spectrum of chiral phosphine-phosphine ester ligand compound I-3;

[0052] Figure 8 Carbon NMR spectrum of chiral phosphine-phosphine ester ligand compound I-3;

[0053] Figure 9 The phosphorus NMR spectrum of chiral phosphine-phosphine ester ligand compound I-3;

[0054] Figure 10 The hydrogen NMR spectrum of the hydrogenation product N-(2-(1-phenylethyl)phenyl)acetamide;

[0055] Figure 11 Carbon NMR spectrum of the hydrogenation product N-(2-(1-phenylethyl)phenyl)acetamide;

[0056] Figure 12 The 1H NMR spectrum of chiral phosphine / amine intermediate (R)-II-1;

[0057] Figure 13 Carbon NMR spectrum of chiral phosphine / amine intermediate (R)-II-1;

[0058] Figure 14 NMR spectrum of chiral phosphine / amine intermediate (R)-II-1; Detailed Implementation

[0059] Preparation of novel chiral phosphine-phosphite ester ligands

[0060] The preparation of novel chiral phosphine-phosphamide ester ligands is first carried out by reacting chiral phosphine / amine intermediates such as (R)- or (S)-DPPNH2 with PCl3 in a dichloromethane solution of triethylamine to obtain chlorophosphine amine compounds, which are then reacted with methylene bisphenol compounds in a dichloromethane solution.

[0061] The present invention is described in detail below through examples, but the present invention is not limited to the following examples. Nuclear magnetic resonance (NMR) was measured using a Bruker NMR spectrometer, and high performance liquid chromatography (HPLC) was measured using an Agilent 1100 series HPLC system.

[0062] Reagents: [Rh(COD)2]BF4 was purchased from Bidex Pharmaceuticals. PCl3, triethylamine, substituted methylene bisphenol, and substituted α-phenylethylamine were all purchased from Energie. The chiral phosphine / amine intermediate was synthesized according to the literature [Huang, J.-D.; Hu, X.-P.; Zheng, Z. Readily Available Phosphine-Phosphoramidite Ligands for Highly Efficient Rh-Catalyzed Enantioselective Hydrogenations. Org. Lett. 2006, 8, 19, 4367–4370]. The solvent, dichloromethane, was treated to ultra-dry solvent using standard methods. Hydrogen gas, 99.999% pure, was used directly in the reaction.

[0063] Preparation of chiral phosphine / amine intermediates

[0064]

[0065] At -35°C, 4.0 mL (10.0 mmol) of a 2.5 M n-BuLi hexane solution was added dropwise to 10 mL of a (R)-1-(3,4-dimethoxyphenyl)ethylamine (1.81 g, 10.0 mmol) solution in diethyl ether. The resulting solution was stirred at -35°C for 15 minutes, and then 1.39 mL (11.0 mmol, 1.1 equivalent) of Me3SiCl was slowly added at the same temperature. The reaction mixture was stirred for 1 hour, and then 12.0 mL (30.0 mmol, 3 equivalents) of a 2.5 M n-BuLi solution was added dropwise. After the addition was complete, the reaction mixture was stirred at -35°C for 3 hours. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was cooled back to -35°C, and 1.80 mL (10.0 mmol) of a diphenylphosphine chloride solution in 10 mL of diethyl ether was added dropwise over 1 hour. The reaction mixture was stirred at the same temperature for another 3 hours, and then warmed to room temperature. After stirring for another 4 hours, 1M HCl aqueous solution was slowly added until both phases of the reaction mixture became clear. The aqueous phase was extracted with diethyl ether (3 × 10 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1.5 g (40% yield) of target (R)-diMeODPPNHMe(II-1) as a white solid. The 1H, 1C, and 1N NMR spectra are as follows: Figure 12 , Figure 13 and Figure 14 As shown: 1HNMR (400MHz, CDCl3) δ7.28-7.15(m,10H),7.05(d,J=3.9Hz,1H),6.27(d,J=4.0Hz,1H),4. 45(dq,J=13.0,6.4Hz,1H),3.83(s,3H),3.41(s,3H),2.11(s,3H),,1.12(d,J=6.4Hz,1H). 13 C NMR (101MHz, CDCl3) δ150.34,147.56,143.70,143.47,137.84,137.73,137.44,137.33,133.87,133.73,133.68,133.54,128.6 1,128.58,128.51,128.48,128.44,128.41,125.57,125.46,116.08,108.68,108.61,56.61,56.36,55.90,55.47,34.51,23.45. 31 P NMR (162MHz, CDCl3) δ-18.02.

[0066] Example 1

[0067] Preparation of chiral phosphine-phosphine ester ligand (R)-I-1

[0068]

[0069] Under nitrogen protection, PCl3 (1.0 mmol, 1.0 equiv) and triethylamine (6.0 mmol, 6.0 equiv) were added to a Shoelock flask containing 10 mL of dichloromethane. The reaction flask was placed at 0 °C, and a solution of chiral phosphine / amine intermediate (R)-diMeODPPNHMe(II-1) (1.0 mmol, 1.0 equiv) in 10 mL of dichloromethane was added dropwise. After the addition was complete, the reaction was brought back to room temperature and stirred for 3 h. The reaction was then placed at 0 °C again, and a solution of 2,2-methylenebis-(4,6-dimethylphenol)(III-1) (1.0 mmol, 1.0 equiv) in 10 mL of dichloromethane was added dropwise. After the addition was complete, the reaction was brought back to room temperature and stirred for 12 h. After the reaction was confirmed by TLC, the solution was concentrated under reduced pressure until almost solvent-free. Separation was performed by silica gel column chromatography, followed by concentration under reduced pressure and drying under vacuum to obtain a white foamy solid in 75% yield.

[0070] The proton, phosphorus, and carbon NMR spectra of the chiral phosphine-phosphonamide ester ligand (R)-I-1 are as follows: Figure 1 , Figure 2 and Figure 3 As shown: 1H NMR (400MHz, CDCl3) δ7.24-7.19(m,11H),6.84-6.83(m,2H),6.69(s,2H),6.35(d,J=3.9Hz,1H),6.76(dd,J=13.3,6.8Hz,1H),4.24(dd,J=12.4,3. 0Hz,1H),3.82(s,3H),3.42(s,3H),3.24(d,J=12.5Hz,1H),2.68(d,J=4. 1Hz,1H),2.15(s,3H),2.10(d,J=6.7Hz,9H),1.53(dd,J=6.5,4.0Hz,3H). 31 P NMR (162MHz, CDCl3) δ-19.06 (d, J = 7.5Hz), 137.78 (d, J = 7.6Hz). 13 CNMR(101MHz, CDCl3)δ150.64,147.92,147.75,147.70,147.57,147.52,143.73,143.68,143.49,143.44,137.83,13 7.72,137.49,137.38,135.56,135.53,135.47,133.90,133.71,133.52,133.38,133.20,130.61,130.58,130.38,130 .35,129.72,129.67,128.75,128.67,128.65,128.61,128.58,128.51,128.02,127.85,125.57,125.42,116.70,109 .13,109.07,57.79,57.52,57.25,56.08,55.64,34.14,31.09,23.76,23.47,20.82,17.58,17.55,17.28,17.26.HRMS calc.for C 40 H 43 NO4P2[M+H] + :664.2740,found:664.2749.

[0071] Ligand stability study: 100 mg of chiral phosphine-phosphine ester ligand (R)-I-1 was placed in an open environment for one month. The properties, state and color of the sample did not change. NMR detection showed no changes in the proton and phosphorus spectra of the sample, indicating that the ligand is stable and insensitive to air and humidity.

[0072] Example 2

[0073] Preparation of chiral phosphine-phosphine ester ligand (R)-I-2

[0074]

[0075] The reaction substrate 2,2-methylenebis-(4,6-dimethylphenol)III-1 in Example 1 was replaced with 2,2-methylenebis-(4-tert-butyl-6-methylphenol))(III-2, and the rest of the process and conditions were the same as in Example 1, to obtain the chiral phosphine-phosphamide ester ligand (R)-I-2 shown in the figure below, with a yield of 78%.

[0076] The proton, phosphorus, and carbon NMR spectra of the chiral phosphine-phosphonamide ester ligand (R)-I-2 are as follows: Figure 4 , Figure 5 and Figure 6 As shown: 1 H NMR(400MHz, CDCl3)δ7.37(d,J=4.1Hz,1H),7.33–7.29(m,10H),7.18(dd,J=3.7,2 .5Hz,2H),7.00(s,2H),6.47(d,J=3.9Hz,1H),5.44(dd,J=13.1,6.8Hz,1H),4.46( dd,J=12.3,2.6Hz,1H)3.93(s,3H),3.53(s,3H),3.43(d,J=12.4Hz,1H),2.80(d,J =4.0Hz,3H),2.31(s,3H),2.25(s,3H),1.65(dd,J=6.1,3.9Hz,3H),1.26(s,18H). 31 P NMR (162MHz, CDCl3) δ137.14 (d, J = 7.6Hz), -19.14 (d, J = 7.6Hz). 13C NMR (101MHz, CDCl3) δ150.72,147.99,147.62,147.57,147.47,147.43,146.75,146.74,146.60,146.59,143.81,143.76,143.57,1 43.52,137.93,137.81,137.55,137.44,135.62,135.60,135.51,135.48,133.94,133.74,133.55,130.09,130.06,129.87,129.84, 128.79,128.71,128.64,128.61,128.54,125.92,125.89,125.62,125.49,124.44,124.27,116.81,109.24,109.18,57.87,57.60,5 7.33,56.14,55.67,34.78,34.28,32.08,31.63,31.08,29.86,29.52,23.81,23.51,22.85,18.00,17.97,17.70,17.68,14.31.HRMS calc.for C 46 H 55 NO4P2[M+H] + :748.3679,found:748.3683.

[0077] Example 3

[0078] Preparation of chiral phosphine-phosphine ester ligand (R)-I-3

[0079]

[0080] In Example 1, the phosphonamine intermediate (R)-diMeODPPNHMe (II-1) was replaced with (R)-DPPNHMe (II-2), and the phenolic substrate 2,2-methylenebis-(4,6-dimethylphenol) (III-1) was replaced with 2,2-methylenebis-(tetramethylphenol) (III-3). The remaining processes and conditions were the same as in Example 1, resulting in the chiral phosphonium-phosphine ester ligand (R)-I-3 shown in the figure below, with a yield of 69%.

[0081] The proton, phosphorus, and carbon NMR spectra of the chiral phosphine-phosphonamide ester ligand (R)-I-3 are as follows: Figure 7 , Figure 8 and Figure 9 As shown: 1H NMR (400MHz, CDCl3) δ7.72 (dd, J=7.0, 4.6Hz, 1H), 7.43 (td, J=7.7, 1.1Hz, 1H), 7.37 -7.22(m,10H),7.18(td,J=7.5,1.1Hz,1H),7.12-7.06(m,2H),7.00-6.84(m,4H),6 .76(d,J=8.1Hz,1H),5.44-5.24(m,1H),4.28(dd,J=12.7,2.8Hz,1H),3.42(d,J=12 .8Hz,1H),2.60(d,J=3.7Hz,3H),2.26(d,J=7.9Hz,6H),1.61(dd,J=6.9,2.8Hz,3H). 31 P NMR (162MHz, CDCl3) δ141.54 (d, J = 17.7Hz), -17.82 (d, J = 17.8Hz). 13 C NMR (101MHz, CDCl3) δ149.50,149.44,149.26,149.21,148.77,148.71,148.54,148.49,137.15,137.07,137.04,136.9 6,135.68,135.53,135.13,135.10,134.93,134.91,134.22,134.18,133.97,133.77,133.69,133.67,130.32,130.25, 129.36,128.76,128.62,128.55,128.48,128.46,127.31,126.45,126.42,126.40,126.37,122.75,122.72,122.57,12 2.54,57.60,57.35,57.31,57.06,34.03,31.64,29.69,29.66,22.71,22.24,21.99,20.82,20.79,14.19.HRMScalc.for C36H 35 NO2P2[M+H] + :576.2216,found:576.2216.

[0082] II. Asymmetric hydrogenation reaction

[0083] Example 4

[0084]

[0085] Under nitrogen protection, [Rh(COD)2]BF4 (0.00125 mmol, 1.0 mol%) and chiral phosphine-phosphonamide ligand ((R)-I-1) (0.001375 mmol, 1.1 mol%) were dissolved in dichloromethane (1.0 mL). The mixture was stirred at room temperature (25 °C) for 1 hour. A dichloromethane (1.0 mL) solution of the substrate N-(2-(1-phenylvinyl)phenyl)acetamide (0.125 mmol) was added. The mixture was placed in an autoclave, purged with hydrogen three times, and then purged with 50 bar of hydrogen. The reaction was carried out at room temperature (25 °C) for 24 hours. After slowly releasing hydrogen and removing the solvent, the product N-(2-(1-phenylethyl)phenyl)acetamide was obtained by silica gel column chromatography, with a con. > 99%. 99%ee was determined by chiral HPLC (chiralcel AD-H, n-hexane / i-PrOH=96:4, 0.8mL / min, 254nm, 40℃): t R (major) = 14.6 min, t R (minor) = 20.0 min.

[0086] The proton and carbon NMR spectra of the product are as follows: Figure 10 , Figure 11 As shown: 1 H NMR(400MHz, CDCl3)δ7.65(d,J=7.4Hz,1H),7.40(d,J=7.0Hz,1H),7.31-7.19(m,5H),7.1 6(d,J=7.4Hz,2H),6.89(s,1H),4.17(q,J=6.9Hz,1H),1.93(s,3H),1.60(d,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ168.4,145.3,137.0,135.2,129.1,127.4,127.3,127.2,126.8,125.7,125.1,40.7,24.0,21.7.

[0087] Example 5

[0088] The substrate in Example 4 was replaced with N-(4-fluoro-2-(1-phenylvinyl)phenyl)acetamide, and the rest of the process and conditions were the same as in Example 4. The reaction yielded 100% chiral N-(4-fluoro-2-(1-phenylethyl)phenyl)acetamide with an enantioselectivity of 99% ee.

[0089] Example 6

[0090] The substrate in Example 4 was replaced with N-(4-chloro-2-(1-phenylvinyl)phenyl)acetamide, and the rest of the process and conditions were the same as in Example 4. The reaction yielded 100% chiral N-(4-chloro-2-(1-phenylethyl)phenyl)acetamide with an enantioselectivity of 99%ee.

[0091] Example 7

[0092] The substrate in Example 4 was replaced with N-(4-bromo-2-(1-phenylvinyl)phenyl)acetamide, and the rest of the process and conditions were the same as in Example 4. The reaction yielded 100% chiral N-(4-bromo-2-(1-phenylethyl)phenyl)acetamide with an enantioselectivity of 93%ee.

[0093] Example 8

[0094] In Example 4, the substrate was replaced with N-(4-methyl-2-(1-phenylvinyl)phenyl)acetamide, and the rest of the process and conditions were the same as in Example 4. The reaction yielded 100% chiral N-(4-methyl-2-(1-phenylethyl)phenyl)acetamide with an enantioselectivity of 99%.

[0095] Example 9

[0096] The substrate in Example 4 was replaced with N-(4-methoxy-2-(1-phenylvinyl)phenyl)acetamide, and the rest of the process and conditions were the same as in Example 4. The reaction yielded 100% chiral N-(4-methoxy-2-(1-phenylethyl)phenyl)acetamide with an enantioselectivity of 99% ee.

[0097] Example 10: Asymmetric hydrogenation reaction of N-acetyl-α-styrene catalyzed by (R)-I-1 as ligand and [Rh(COD)2]BF4 as metal precursor.

[0098]

[0099] Under nitrogen protection, [Rh(COD)₂]BF₄ (0.00125 mmol, 1.0 mol%) and (R)-I-1 (0.001375 mmol, 1.1 mol%) were dissolved in dichloromethane (1.0 mL). The mixture was stirred at room temperature (25 °C) for 1 hour. A dichloromethane solution of N-acetyl-α-styrene (0.125 mmol) (1.0 mL) was then added. The mixture was placed in a high-pressure reactor, purged three times with hydrogen, and then purged with 50 bar of hydrogen gas. The reaction was carried out at room temperature (25 °C) for 24 hours. After slowly releasing the hydrogen and removing the solvent, the product N-acetyl-α-phenylethylamine was obtained by silica gel column chromatography, with con. > 99% and enantioselectivity of 98% ee.

[0100] In Example 11, the substrate in Example 10 was replaced with N-acetyl-α-(4-fluorophenyl)ethylene, and the remaining procedures and conditions were the same as in Example 10. The reaction yielded 100% chiral N-acetyl-α-(4-fluorophenyl)ethylamine with a selectivity of 98% ee.

[0101] In Example 12, the substrate in Example 10 was replaced with N-acetyl-α-(4-chlorophenyl)ethylene, and the remaining procedures and conditions were the same as in Example 10. The reaction yielded 100% chiral N-acetyl-α-(4-chlorophenyl)ethylamine with a selectivity of 98% ee.

[0102] In Example 13, the substrate in Example 10 was replaced with N-acetyl-α-(4-bromophenyl)ethylene, and the remaining procedures and conditions were the same as in Example 10. The reaction yielded 100% chiral N-acetyl-α-(4-bromophenyl)ethylamine with a selectivity of 99% ee.

[0103] In Example 14, the substrate in Example 10 was replaced with N-acetyl-α-(4-methylphenyl)ethylene, and the remaining procedures and conditions were the same as in Example 10. The reaction yielded 100% chiral N-acetyl-α-(4-methylphenyl)ethylamine with a selectivity of 98% ee.

[0104] Example 15: The substrate in Example 10 was replaced with N-acetyl-α-(4-methoxyphenyl)ethylene, and the remaining procedures and conditions were the same as in Example 10. The reaction yielded 100% chiral N-acetyl-α-(4-methoxyphenyl)ethylamine with a selectivity of 97% ee.

[0105] In Example 16, under nitrogen protection, [Rh(COD)₂]BF₄ (0.00125 mmol, 1.0 mol%) and (R)-I-1 (0.001375 mmol, 1.1 mol%) were dissolved in dichloromethane (1.0 mL). The mixture was stirred at room temperature (25 °C) for 1 hour. A dichloromethane solution of methyl 2-acetaminopropionate (0.125 mmol) (1.0 mL) was then added. The mixture was placed in a high-pressure reactor, purged three times with hydrogen, and then purged with 10 bar of hydrogen. The reaction was carried out at room temperature (25 °C) for 24 hours. After slowly releasing the hydrogen and removing the solvent, the product methyl 2-acetaminopropionate was obtained by silica gel column chromatography with a con. > 99% and an enantioselectivity of 95% ee.

[0106] In Example 17, under nitrogen protection, [Rh(COD)₂]BF₄ (0.00125 mmol, 1.0 mol%) and (R)-I-1 (0.001375 mmol, 1.1 mol%) were dissolved in dichloromethane (1.0 mL). The mixture was stirred at room temperature (25 °C) for 1 hour. A dichloromethane solution (1.0 mL) of methyl 2-acetamidocinnamate (0.125 mmol) was then added. The mixture was placed in a high-pressure reactor, purged three times with hydrogen, and then purged with 10 bar of hydrogen. The reaction was carried out at room temperature (25 °C) for 24 hours. After slowly releasing the hydrogen and removing the solvent, the product methyl 2-acetamidophenylpropionate was obtained by silica gel column chromatography with a con. > 99% and an enantioselectivity of 95% ee.

[0107] In Example 18, under nitrogen protection, [Rh(COD)₂]BF₄ (0.00125 mmol, 1.0 mol%) and (R)-I-1 (0.001375 mmol, 1.1 mol%) were dissolved in dichloromethane (1.0 mL). The mixture was stirred at room temperature (25 °C) for 1 hour. A dichloromethane solution of itaconic acid dimethyl ester (0.125 mmol) (1.0 mL) was added, and the mixture was placed in a high-pressure reactor. The reactor was purged with hydrogen three times, and then 10 bar of hydrogen was introduced. The reaction was carried out at room temperature (25 °C) for 24 hours. After slowly releasing the hydrogen and removing the solvent, the product 2-methylsuccinate was obtained by silica gel column chromatography with a con. > 99% and an enantioselectivity of 93% ee.

[0108] In Example 19, under nitrogen protection, [Rh(COD)₂]BF₄ (0.00125 mmol, 1.0 mol%) and (R)-I-1 (0.001375 mmol, 1.1 mol%) were dissolved in dichloromethane (1.0 mL). The mixture was stirred at room temperature (25 °C) for 1 hour. A dichloromethane solution (1.0 mL) of dimethyl β-phenylitaconate (0.125 mmol) was then added. The mixture was placed in a high-pressure reactor, purged three times with hydrogen, and then purged with 10 bar of hydrogen gas. The reaction was carried out at room temperature (25 °C) for 24 hours. Hydrogen gas was slowly released, and after removing the solvent, the product, dimethyl 2-phenylmethylsuccinate, was obtained by silica gel column chromatography with a con. >99% and an enantioselectivity of 92% ee.

[0109] In Example 20, under nitrogen protection, [Rh(COD)₂]BF₄ (0.00125 mmol, 1.0 mol%) and (R)-I-1 (0.001375 mmol, 1.1 mol%) were dissolved in dichloromethane (1.0 mL). The mixture was stirred at room temperature (25 °C) for 1 hour. A dichloromethane solution of methyl 3-aminocrotonate (0.125 mmol) (1.0 mL) was added, and the mixture was placed in a high-pressure reactor. The reactor was purged with hydrogen three times, and then 10 bar of hydrogen was introduced. The reaction was carried out at room temperature (25 °C) for 24 hours. Hydrogen was slowly released to remove the solvent amino group. The product, methyl 3-acetamido-2-butyrate, was obtained by silica gel column chromatography with con. > 99% and enantioselectivity of 90% ee.

[0110] In Example 21, under nitrogen protection, [Rh(COD)₂]BF₄ (0.00125 mmol, 1.0 mol%) and (R)-I-1 (0.001375 mmol, 1.1 mol%) were dissolved in dichloromethane (1.0 mL). The mixture was stirred at room temperature (25 °C) for 1 hour. A dichloromethane solution (1.0 mL) of methyl 2-acetoxy-2-acrylate (0.125 mmol) was added, and the mixture was placed in a high-pressure reactor. The reactor was purged with hydrogen three times, and then 10 bar of hydrogen was introduced. The reaction was carried out at room temperature (25 °C) for 24 hours. After slowly releasing the hydrogen and removing the solvent, the product methyl 2-acetoxy-2-propionate was obtained by silica gel column chromatography with con. > 99% and enantioselectivity of 88% ee.

[0111] In Example 22, under nitrogen protection, [Rh(COD)₂]BF₄ (0.00125 mmol, 1.0 mol%) and (R)-I-1 (0.001375 mmol, 1.1 mol%) were dissolved in dichloromethane (1.0 mL). The mixture was stirred at room temperature (25 °C) for 1 hour. A dichloromethane solution of α-acetoxystyrene (0.125 mmol) (1.0 mL) was then added. The mixture was placed in a high-pressure reactor, purged three times with hydrogen, and then purged with 10 bar of hydrogen gas. The reaction was carried out at room temperature (25 °C) for 24 hours. Hydrogen gas was slowly released, and after removing the solvent, the product was separated by silica gel column chromatography to obtain α-acetoxyphenylethane with con. > 99% and enantioselectivity of 90% ee.

[0112] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A chiral phosphine-phosphine ester ligand, characterized in that: The chiral phosphine-phosphine ester ligand has the following (R)-I and / or (S)-I structural formulas: Among them, (R)-I and (S)-I are enantiomers; In the formula: R1 is selected from hydrogen, C1-C 40 Alkyl (preferably C1-C) 20 Alkyl), C1-C 40 Alkoxy (preferably C1-C) 20 One or more of alkoxy groups, etc., wherein the number of substituents is 1-4; R2 is selected from hydrogen, C1-C 40 Alkyl (preferably C1-C) 20 Alkyl), C1-C 40 Alkoxy (preferably C1-C) 20 One or more of alkoxy, halogen, nitro, trifluoromethyl, etc., wherein the number of substituents is 1-4.

2. A method for preparing the chiral phosphine-phosphamide ester ligand according to claim 1, characterized in that: Chlorophosphine amine compounds were obtained by reacting chiral phosphine / amine intermediates such as (R)- or (S)-DPPNHMe(II) with PCl3 in a dichloromethane solution of triethylamine, and then reacted with methylene bisphenol compounds (III) in a dichloromethane solution to obtain the target chiral phosphine-phosphamide ester ligands (R)-I and / or (S)-I. The structure of the chiral phosphine / amine intermediate (R)- or (S)-DPPNH2(II) is as follows: (R)-II and (S)-II are enantiomers of each other; In the formula, R1 is an equivalent or identical group to R1 in claim 1; The structure of the methylene bisphenol compound (III) is as follows: In the formula, R2 is an equivalent or identical group to R2 in claim 1.

3. The preparation method according to claim 2, characterized in that, Specifically as follows: Under nitrogen protection, 1-2 molar equivalents of PCl3 were added to a reaction flask containing a dichloromethane solution of 1-10 molar equivalents of triethylamine. The reaction flask was placed at 0-25°C, and a dichloromethane solution containing 1-1.2 molar equivalents of chiral phosphine / amine intermediate (R)- or (S)-DPPNHMe(II) was added dropwise. After the addition was complete, the reaction solution was brought back to room temperature and stirred for 3-12 hours. The reaction was then placed at 0-25°C again, and a dichloromethane solution containing 1 molar equivalent of methylene bisphenol compound (III) was added dropwise. After the addition was complete, the reaction solution was brought back to room temperature and stirred for 12-24 hours. After the reaction was completed by TLC, the solvent was removed by vacuum concentration, and the mixture was separated by silica gel column chromatography, concentrated under vacuum, and dried under vacuum to obtain chiral phosphine-phosphine amide ligands (R)-I and / or (S)-I.

4. The preparation method according to claim 2 or 3, characterized in that: The molar ratio of the chiral phosphine / amine intermediate (II): methylene bisphenol compound (III): PCl3: Et3N is 1-1.2:1:1-2:1-10; the preferred ratio is 1:1:1-1.5:6-10.

5. The preparation method according to claim 2 or 3, characterized in that: Chiral phosphine-phosphine ester ligands were synthesized via the following route:

6. An application of the chiral phosphine-phosphine ester ligand according to claim 1, characterized in that, This ligand is used in the asymmetric hydrogenation of C=C double bonds.

7. The application according to claim 6, characterized in that, The asymmetric hydrogenation reaction is one or more of the following types of substrate-catalyzed asymmetric hydrogenation reactions: (1) Catalytic asymmetric hydrogenation of α-dehydroamino acids; (2) Catalytic asymmetric hydrogenation of β-dehydroamino acids; (3) Catalytic asymmetric hydrogenation of itaconic acid esters and their β-substituted itaconic acid esters; (4) Catalytic asymmetric hydrogenation of α-acyclic and cyclic amides; (5) Catalytic asymmetric hydrogenation of α-acyclic and cyclic enol esters; (6) Catalytic asymmetric hydrogenation of α-acetoxy-β-substituted acrylates; (7) Catalytic asymmetric hydrogenation of benzene or substituted benzoyl acetate esters; (8) Catalytic asymmetric hydrogenation of benzene or substituted benzoyl carbamates; (9) Catalytic asymmetric hydrogenation of 1,1-disubstituted aryl olefins.

8. The application according to claim 6 or 7, characterized in that, A catalyst is formed by combining a chiral phosphine-phosphine ester ligand with one or more of Pt, Pd, Ir, Ru or Rh in a molar ratio of 1.1-2.2:1, preferably 1.1-1.5:

1. The ratio of substrate to catalyst is 100-10000:1, preferably 100-1000:1, and the reaction time is 0.1-24 hours, preferably 12-24 hours.

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