Chiral ferrocene skeleton tetradentate ligand and application thereof in asymmetric hydrogenation reaction

Abstract

The application relates to a kind of chiral ferrocene skeleton tetradentate ligand and its application in asymmetric hydrogenation reaction, the ligand has the advantages such as low cost, simple synthesis and good stability.The metal complex of the ligand shows very excellent catalytic activity and extremely high enantioselectivity in the asymmetric hydrogenation reaction of ketone, can efficiently catalyze prochiral ketone such as arylalkyl ketone, heteroarylalkyl ketone, aryl(hetero)aryl ketone into corresponding chiral alcohol, and has great industrial application potential.

Description

Technical Field

[0001] This invention belongs to the field of fine chemicals and relates to chiral ligands and their applications, specifically to a chiral ferrocene framework tetradentate ligand and its application in asymmetric hydrogenation reactions. Background Technology

[0002] Chiral alcohol building blocks are widely found in the structures of fine chemical products such as pharmaceuticals, pesticides, cosmetics, health products, and fragrances. Extraction methods for obtaining chiral alcohols are far from meeting human needs; therefore, developing green, efficient, and highly selective catalytic reactions to prepare chiral alcohols is of significant practical importance. Catalytic asymmetric hydrogenation reactions offer advantages such as good atom economy, high efficiency, and simple post-processing, making them the most important method for synthesizing chiral compounds industrially. The key to a practical asymmetric hydrogenation technology lies in highly active and stereoselective metal complex catalysts, with ligands being crucial and central. Therefore, developing chiral ligands with novel structures, excellent performance, simple preparation, and low cost has always been a core focus of asymmetric hydrogenation reaction research.

[0003] The asymmetric hydrogenation of pre-chiral ketones via catalysis is the simplest and most efficient method for obtaining chiral alcohols, and it is also one of the main industrial routes for obtaining chiral alcohols. In the study of asymmetric hydrogenation of ketones, Noyori's development of the [RuCl2(diphosphine)(diamine)] complex in 1995 was a milestone, achieving millions of conversions. In 2011, Professor Zhou Qilin successfully designed and synthesized the SpiroPAP tridentate ligand and applied it to the asymmetric hydrogenation of aromatic ketones, obtaining conversions as high as four million. However, the complex synthetic route and expensive raw materials of the SpiroPAP ligand greatly limit its industrial application. In 2016, Professor Zhang Xumu's team replaced one of the oxazoline groups in the bisoxazoline-type tridentate ligand ambox with a ferrocene-dominant skeleton, resulting in the more sterically hindered and electronegatively charged tridentate ligand f-amphox. This type of ligand is not only simple to synthesize, but also uses inexpensive and readily available raw materials and exhibits high stability. It has been successfully used in the asymmetric hydrogenation of various ketones. Subsequently, their research group developed two more types of tridentate ligands, f-amphol and f-ampha, which greatly promoted the industrial application of tridentate ligand catalysts. In 2022, based on previous work, Professor Zhang Xumu's team developed a ferrocene PNNO-type tetradentate ligand f-phamidol. This type of ligand achieved record-breaking conversion numbers in the tens of millions during the asymmetric hydrogenation of simple ketones and has been successfully applied to the industrial production of nicotine. The extremely high catalytic activity and selectivity of this type of ligand may be due to the multiple chelation sites between the tetradentate ligand and the metal center. The resulting metal complexes are generally stable and do not readily undergo ligand dissociation and deactivation. Furthermore, tetradentate ligands contain multiple modifiable chiral units and activity-regulating units, allowing for the rational design and modification of ligands to achieve high catalytic activity and excellent enantioselectivity.

[0004] While the aforementioned PNNO-type tetradentate ligands exhibited extremely high catalytic activity in the asymmetric hydrogenation of simple ketones, their catalytic activity was lower in the asymmetric hydrogenation of some substrates with special structures, and some ligands also showed poor stability, limiting their applications to varying degrees. Therefore, the development of novel ligands and their catalytic systems remains of significant research value. Summary of the Invention

[0005] To overcome the shortcomings of the prior art, the purpose of this invention is to provide a class of chiral ferrocene framework tetradentate ligands and their application in asymmetric hydrogenation reactions. This provides an important method for the synthesis of key fragments of some drug molecules and has significant application value.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] A class of chiral ferrocene framework tetradentate ligands, with general structural formulas represented as I-IV, are as follows:

[0008] ;

[0009] in:

[0010] In formulas I-IV, R 1 It is aryl or substituted aryl;

[0011] In formulas I-III, R 2 The substituents or groups are independently selected from H, R, Ar, OCR, and OCAr;

[0012] In Formula III, R 3 It is aryl or substituted aryl;

[0013] Linker 1 in equations I-IV has any of the following structures:

[0014] R 4 It can be hydrogen, alkyl, aryl, or substituted aryl.

[0015] Furthermore, the stereoisomers of the structural formulas I-IV are as follows:

[0016] .

[0017] Furthermore, this ligand is used to prepare catalysts for asymmetric catalytic reactions.

[0018] Furthermore, the catalyst is a complex formed by the complexation of a tetradentate ligand and a transition metal salt.

[0019] Furthermore, the transition metal salts mentioned are RuX3, RuHX(L)2 (diphosphine), RuX2(L)2 (diphosphine), Ru(arene)X2 (diphosphine), Ru(arylgroup)X2, Ru(RCOO)2 (diphsphine), Ru(methallyl)2 (diphine), Ru(arylgroup)X2 (PPh3)3, Ru(COD)(COT), Ru(COD)(COT)X, RuX2 (cymene), Ru(COD)n, Ru(arylgroup)X2 (diphosphine), RuCl2 (COD), [Ru(COD)2]X, RuX2 (diphosphine), and RuCl2 (=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, RhC1(PPh3)3, PdX2, Pd(PPh3)4, Pd(allyl)Cl, IrX3, [Ir(NB D)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(OiPr)4, VO(acac)2, CrX2, CrX3, MnX2, Mn(acac)2, or MeReO3, wherein in the transition metal precursor salt, R and R' can be alkyl, alkoxy, or substituted alkyl; aryl is aryl; X is an anion Cl ‐ ,Br ‐ I ‐ ClO4 ‐ BF4 ‐ Sb6 ‐ PF6 ‐ CF3SO3 ‐ RCOO ‐ ,BAr4 ‐ L represents an acetonitrile solvent molecule.

[0020] Furthermore, when the catalyst is a complex formed by the above-mentioned tetradentate ligand and Ir metal salt, it exhibits high catalytic activity and enantioselectivity for the asymmetric hydrogenation of a series of prochiral ketones, including arylalkyl ketones, heteroarylalkyl ketones, and aryl(hetero)aryl ketones.

[0021] Furthermore, the transition metal in the transition metal salt is one of Ru, Rh, Pd, Ir, Fe, Co, Ni, Cu, Sc, Ti, V, Cr, Mn, or Re.

[0022] Furthermore, the asymmetric catalytic reactions include asymmetric hydrogenation, asymmetric transfer hydrogenation, asymmetric hydroamylation, asymmetric hydrocyanation, asymmetric hydrosilylation, asymmetric hydroboration, asymmetric allyl alkylation, asymmetric coupling, asymmetric cyclization, asymmetric Michael addition, asymmetric asymmetric epoxidation, asymmetric Aldol, asymmetric Mannich, asymmetric Diels-Alder, and asymmetric cycloisomerization.

[0023] Furthermore, the catalyst can be applied to the asymmetric hydrogenation of prochiral ketones to synthesize chiral alcohols.

[0024] Furthermore, the catalyst preparation process can be represented by the following reaction formula: ligand + metal salt → catalyst (ligand-metal complex).

[0025] The beneficial effects of this invention are:

[0026] These ligands possess advantages such as low cost, simple synthesis, and good stability. Their metal complexes exhibit excellent catalytic activity and extremely high enantioselectivity in the asymmetric hydrogenation of ketones, and can efficiently catalyze the reduction of prochiral ketones such as arylalkyl ketones, heteroarylalkyl ketones, and aryl(hetero)aryl ketones to the corresponding chiral alcohols, demonstrating enormous potential for industrial applications. Detailed Implementation

[0027] The present invention will be further described below with reference to embodiments, but this is not intended to limit the invention.

[0028] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0029] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. A substituted aryl group refers to an aryl group with at least one substituent, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0030] A. Ligand synthesis;

[0031] Implementation Example 1: Synthesis of key segment 2a;

[0032]

[0033] Compound 1 (10.0 g, 22.6 mmol) was dissolved in acetic anhydride (20 mL) and stirred at 60 °C for 2 h. After the reaction was complete, the reaction solution was concentrated to give a yellow bubbly substance. This bubbly substance was directly dissolved in methanol, and diphenylethylenediamine (22.6 mmol) was added. The reaction was carried out overnight at 60 °C. After the reaction was complete, the reaction solution was concentrated, and column chromatography (EA / Et3N) gave 5.3 g of orange-yellow bubbly substance 2a, with a yield of 39%. 1 H NMR (400 MHz, Chloroform-d) δ 7.54 – 7.45 (m, 2H), 7.41 –7.30 (m, 8H), 7.21 – 7.14 (m, 3H), 7.12 – 7.05 (m, 3H), 6.94 (tt, J = 7.2,2.0 Hz, 4H), 4.37 (q, J = 1.9 Hz, 1H), 4.24 (t, J = 2.6 Hz, 1H), 3.91 (s,5H), 3.80 – 3.72 (m, 2H), 3.67 (dt, J = 2.5, 1.2 Hz, 1H), 3.45 (d, J = 7.0Hz, 1H), 1.25 (d, J = 6.8, 3.3 Hz, 3H). 31 P NMR (162 MHz, Chloroform-d) δ -23.58.

[0034] Implementation Example 2: Synthesis of key segment 2b;

[0035]

[0036] Compound 1 (10.0 g, 22.6 mmol) was dissolved in acetic anhydride (20 mL) and stirred at 60 °C for 2 h. After the reaction was complete, the reaction solution was concentrated to give a yellow bubbly substance. This bubbly substance was directly dissolved in methanol, and cyclohexanediamine (22.6 mmol) was added. The reaction was carried out overnight at 60 °C. After the reaction was complete, the reaction solution was concentrated, and column chromatography (EA / Et3N) gave 8.3 g of orange-yellow bubbly substance 2b, with a yield of 72%. 1 H NMR (400 MHz, Chloroform-d) δ 7.52 (ddt, J = 6.9, 4.9, 3.0 Hz, 2H), 7.37 (dq, J = 5.1, 2.3, 1.5 Hz, 3H), 7.31 – 7.19 (m, 5H), 4.50 (dt, J =2.8, 1.6 Hz, 1H), 4.29 (t, J = 2.5 Hz, 1H), 4.15 (qd, J = 6.2, 2.8 Hz, 1H), 4.04 (s, 5H), 3.69 (dt, J = 2.3, 1.1 Hz, 1H), 2.05 – 1.99 (m, 1H), 1.96 –1.88 (m, 1H), 1.74 – 1.64 (m, 1H), 1.64 – 1.47 (m, 3H), 1.38 (d, J = 6.3 Hz, 3H), 1.26 – 0.97 (m, 1H), 0.94 (dd, J = 11.4, 8.4 Hz, 2H), 0.07 (tdd, J =12.8, 10.9, 3.5 Hz, 1H). 31 P NMR (162 MHz, CDCl3) δ -24.70.

[0037] Implementation Example 3: Synthesis of Key Fragment 2c;

[0038]

[0039] Compound 3 (5.0 g, 7.5 mmol) was dissolved in acetic anhydride (15 mL) and stirred at 60 °C for 2 h. After the reaction was complete, the yellow vesicular residue was concentrated. This vesicular residue was then dissolved directly in methanol, and cyclohexyldiamine (7.5 mmol) was added. The reaction was carried out overnight at 60 °C. After the reaction was complete, the reaction solution was concentrated, and column chromatography (PE / EA / Et3N) yielded 4.1 g of orange-yellow vesicular residue 2c, with a yield of 72%. 1H NMR (400 MHz, Chloroform-d) δ 7.39 (d, J = 2.0 Hz,1H), 7.36 (d, J = 1.8 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.31 (d, J = 1.8 Hz,1H), 7.14 (dd, J = 8.0, 1.8 Hz, 2H), 4.46 (p, J = 1.4 Hz, 1H), 4.24 (t, J =2.6 Hz, 1H), 4.15 – 4.11 (m, 1H), 4.08 (s, 5H), 3.56 (dd, J = 2.5, 1.3 Hz, 1H), 2.01 – 1.92 (m, 1H), 1.88 (td, J = 10.7, 10.2, 3.6 Hz, 1H), 1.73 – 1.64 (m, 1H), 1.57 – 1.42 (m, 4H), 1.37 (d, J = 6.1 Hz, 3H), 1.33-1.20 (m, 2H), 1.28 (s, 18H), 1.22 (s, 18H), 1.09 – 0.98 (m, 1H), 0.91 (td, J = 12.6, 10.6,5.6 Hz, 2H), -0.11 (qd, J = 12.9, 3.5 Hz, 1H). 31 P NMR (162 MHz, CDCl3) δ -24.15.

[0040] Implementation Example 4: Synthesis of ligand L1;

[0041]

[0042] Compound 2a (0.5 g, 0.82 mmol) was dissolved in methanol (8 mL), and the corresponding aldehyde (0.82 mmol) was added. The reaction was carried out overnight at 60 °C. The next day, NaBH4 was added at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then subjected to column chromatography (PE / EA / Et3N) to give 0.25 g of orange-yellow bubbly precipitate L1, with a yield of 43%. 1H NMR (400 MHz, Chloroform-d) δ 7.48– 7.40 (m, 2H), 7.37 – 7.26 (m, 6H), 7.21 (tt, J = 6.7, 1.6 Hz, 2H), 7.14(dd, J = 5.1, 1.9 Hz, 3H), 7.11 – 7.04 (m, 4H), 6.90 (ddd, J = 6.8, 5.4, 1.8Hz, 3H), 6.83– 6.76 (m, 3H), 6.72 (td, J = 7.4, 1.2 Hz, 1H), 4.37 (dt, J =2.9, 1.5 Hz, 1H), 4.25 (t, J = 2.5 Hz, 1H), 3.92 (s, 5H), 3.78 (d, J = 8.9Hz, 1H), 3.71 (qd, J = 5.5, 4.6, 2.8 Hz, 1H), 3.65 – 3.56 (m, 2H), 3.43 (d, J= 13.6 Hz, 1H), 3.06 (d, J = 8.9 Hz, 1H), 1.23 (d, J = 6.3 Hz, 3H). 31 P NMR (162 MHz, Chloroform-d) δ -24.11.

[0043] Implementation Example 5: Synthesis of ligand L7;

[0044]

[0045] Compound 2b (0.5 g, 0.98 mmol) was dissolved in methanol (8 mL), and the corresponding aldehyde (0.98 mmol) was added. The reaction was carried out overnight at 60 °C. The next day, NaBH4 was added at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then subjected to column chromatography (PE / EA / Et3N) to give 0.51 g of orange-yellow bubbly precipitate L7, with a yield of 84%. 1H NMR (400 MHz, Chloroform-d) δ 7.54– 7.46 (m, 2H), 7.37 (dqd, J = 4.7, 3.4, 1.3 Hz, 3H), 7.32 – 7.25 (m, 3H), 7.21 (tt, J = 6.6, 1.9 Hz, 2H), 7.12 (td, J = 7.8, 1.7 Hz, 1H), 6.92 (dd, J =7.5, 1.6 Hz, 1H), 6.81 – 6.68 (m, 2H), 4.46 (dt, J = 2.8, 1.5 Hz, 1H), 4.28(t, J = 2.4 Hz, 1H), 4.18 – 4.10 (m, 1H), 4.04 (s, 5H), 3.77 (d, J = 14.1 Hz,1H), 3.70 – 3.65 (m, 2H), 2.14 (d, J = 13.8 Hz, 2H), 1.90 (d, J = 12.1 Hz,1H), 1.57 (t, J = 12.0 Hz, 2H), 1.43 – 1.35 (m, 2H), 1.31 (d, J = 6.2 Hz, 3H), 1.18 – 0.82 (m, 4H), 0.32 – 0.09 (m, 2H). 31 P NMR (162 MHz, CDCl3) δ -24.98.

[0046] Implementation Example 6: Synthesis of ligand L11;

[0047]

[0048] Compound 2c (0.72 g, 0.98 mmol) was dissolved in methanol (8 mL), and the corresponding aldehyde (0.98 mmol) was added. The reaction was carried out overnight at 60 °C. The next day, NaBH4 was added at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then subjected to column chromatography (PE / EA / Et3N) to give 0.7 g of orange-yellow bubbly precipitate L11, with a yield of 85%. 1H NMR (400 MHz, Chloroform-d) δ7.42 – 7.38 (m, 1H), 7.36 – 7.31 (m, 3H), 7.12 (ddd, J = 12.9, 7.7, 1.7 Hz, 3H), 6.87 (dd, J = 7.5, 1.6 Hz, 1H), 6.77 (dd, J = 8.1, 1.2 Hz, 1H), 6.72 (td, J = 7.3, 1.2 Hz, 1H), 4.44 (dt, J = 2.9, 1.5 Hz, 1H), 4.24 (t, J = 2.6Hz, 1H), 4.15 (qd, J = 6.1, 2.5 Hz, 1H), 4.06 (s, 5H), 3.74 (d, J = 14.2 Hz,1H), 3.65 – 3.52 (m, 2H), 2.08 (dd, J = 19.8, 8.2 Hz, 2H), 1.93 – 1.82 (m,1H), 1.65 – 1.48 (m, 3H), 1.43 (s, 2H), 1.35 (d, J = 6.1 Hz, 3H), 1.28 (s,18H), 1.24 (s, 18H), 1.15 – 0.93 (m, 2H), 0.92 – 0.76 (m, 3H), -0.01 – -0.12(m, 1H). 31 P NMR (162 MHz, CDCl3) δ -24.71.

[0049] Implementation Example 7: Synthesis of ligand L13;

[0050]

[0051] Compound 2a (0.5 g, 0.82 mmol) was dissolved in methanol (8 mL), and the corresponding aldehyde (0.82 mmol) was added. The reaction was carried out overnight at 60 °C. The next day, NaBH4 was added at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then subjected to column chromatography (PE / EA / Et3N) to give 0.45 g of orange-yellow bubbly precipitate L13, with a yield of 66%. 1H NMR (400 MHz, Chloroform-d) δ13.63 (s, 1H), 8.03 (s, 1H), 7.44 – 7.25 (m, 11H), 7.15 (dd, J = 5.2, 1.9 Hz,3H), 7.11 – 7.00 (m, 6H), 6.90 (dt, J = 6.7, 3.6 Hz, 2H), 4.34 (q, J = 2.0Hz, 1H), 4.24 (d, J = 8.4 Hz, 1H), 4.19 (t, J = 2.5 Hz, 1H), 3.89 (s, 5H), 3.78 (d, J = 8.4 Hz, 1H), 3.72 – 3.62 (m, 2H), 3.48 (s, 1H), 1.45 (s, 9H), 1.32 (s, 9H), 1.27 (d, J = 6.5 Hz, 3H). 31 P NMR (162 MHz, Chloroform-d) δ -23.82.

[0052] Implementation Example 8: Synthesis of ligand L19;

[0053]

[0054] Compound 2b (0.5 g, 0.98 mmol) was dissolved in methanol (8 mL), and the corresponding aldehyde (0.98 mmol) was added. The reaction was carried out overnight at 60 °C. The next day, NaBH4 was added at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then subjected to column chromatography (PE / EA / Et3N) to give 0.63 g of orange-yellow bubbly precipitate L19, with a yield of 88%. 1H NMR (400 MHz, Chloroform-d) δ 7.83(s, 1H), 7.51 (dt, J = 9.5, 3.7 Hz, 2H), 7.38 – 7.31 (m, 4H), 7.29 – 7.17 (m,6H), 7.03 (d, J = 2.4 Hz, 1H), 4.38 (s, 1H), 4.19 (d, J = 9.1 Hz, 2H), 3.94(s, 5H), 3.71 (s, 1H), 2.66 (s, 1H), 2.25 (s, 1H), 2.01 (d, J = 12.2 Hz, 1H),1.66 – 1.55 (m, 2H), 1.44 (s, 11H), 1.32 (s, 13H), 1.24 – 1.01 (m, 1H), 0.93 – 0.69 (m, 3H). 31 P NMR (162 MHz, CDCl3) δ -24.57.

[0055] Implementation Example 9: Synthesis of ligand L25;

[0056]

[0057] Compound 2a (0.5 g, 0.82 mmol) was dissolved in methanol (8 mL), and pyridinecarboxaldehyde (0.82 mmol) was added. The reaction was carried out overnight at 60 °C. The next day, NaBH4 was added at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then subjected to column chromatography (PE / EA / Et3N) to give 0.45 g of orange-yellow bubbly precipitate L25, with a yield of 48%. 1H NMR (400 MHz, Chloroform-d) δ8.49 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 7.56 (td, J = 7.7, 1.8 Hz, 1H), 7.51 –7.42 (m, 3H), 7.35 (tt, J = 5.4, 2.4 Hz, 4H), 7.27 (d, J = 2.2 Hz, 4H), 7.23 (d, J = 7.9 Hz, 2H), 7.16 – 7.05 (m, 5H), 7.01 (q, J = 3.8 Hz, 3H), 6.91 (dt,J = 6.1, 3.3 Hz, 2H), 6.70 – 6.62 (m, 2H), 4.45 – 4.42 (m, 1H), 4.27 (t, J =2.4 Hz, 1H), 3.92 (s, 5H), 3.75 (d, J = 8.5 Hz, 1H), 3.72 – 3.63 (m, 2H), 3.57 (d, J = 3.0 Hz, 2H), 3.17 (d, J = 8.6 Hz, 1H), 1.30 (d, J = 6.3 Hz, 3H). 31 P NMR (162 MHz, Chloroform-d) δ -23.82.

[0058] Implementation Example 10: Synthesis of ligand L31;

[0059]

[0060] Compound 2b (0.5 g, 0.98 mmol) was dissolved in methanol (8 mL), and pyridinecarboxaldehyde (0.98 mmol) was added. The reaction was carried out overnight at 60 °C. The next day, NaBH4 was added at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then subjected to column chromatography (PE / EA / Et3N) to give 0.46 g of orange-yellow bubbly precipitate L31, with a yield of 74%. 1H NMR (400 MHz, Chloroform-d) δ8.55 – 8.44 (m, 1H), 7.60 (td, J = 7.7, 1.9 Hz, 1H), 7.52 (td, J = 7.6, 6.8,3.0 Hz, 2H), 7.43 – 7.29 (m, 4H), 7.27 – 7.05 (m, 7H), 4.51 (s, 1H), 4.29 (d,J = 2.6 Hz, 1H), 4.14 (dt, J = 8.1, 4.0 Hz, 1H), 4.04 (s, 5H), 3.83 (d, J =14.6 Hz, 1H), 3.74 – 3.60 (m, 2H), 2.87 (s, 1H), 2.23 (td, J = 10.8, 4.1 Hz, 1H), 2.11 – 1.99 (m, 1H), 1.86 (d, J = 10.4 Hz, 1H), 1.51 (tt, J = 13.3, 6.4Hz, 3H), 1.40 (d, J = 6.2 Hz, 3H), 1.26 (d, J = 5.3 Hz, 1H), 1.13 – 0.97 (m,1H), 0.92 (td, J = 10.8, 10.3, 5.0 Hz, 2H), 0.34 (s, 1H), 0.17 – 0.01 (m,1H). 31 P NMR (162 MHz, CDCl3) δ -24.77.

[0061] Implementation Example 11: Synthesis of ligand L37;

[0062]

[0063] Compound 2a (0.5 g, 0.82 mmol) was dissolved in methanol (8 mL), and 6-methylpyridinecarboxaldehyde (0.82 mmol) was added. The reaction was carried out overnight at 60 °C. The next day, NaBH4 was added at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then subjected to column chromatography (PE / EA / Et3N) to give 0.31 g of orange-yellow bubbly substance L37, with a yield of 53%. 1H NMR (400 MHz, Chloroform-d)δ 7.49 – 7.43 (m, 3H), 7.35 (d, J = 1.6 Hz, 3H), 7.25 (s, 4H), 7.15 (d, J =4.2 Hz, 1H), 7.08 – 6.98 (m, 8H), 6.90 (dd, J = 6.7, 2.9 Hz, 2H), 6.69 – 6.56(m, 2H), 4.45 (p, J = 1.6 Hz, 1H), 4.27 (t, J = 2.5 Hz, 1H), 3.92 (s, 5H),3.67 (d, J = 12.4 Hz, 3H), 3.53 (d, J = 6.3 Hz, 2H), 3.16 (d, J = 8.5 Hz, 1H), 2.48 (s, 3H), 1.32 (d, J = 6.3 Hz, 3H). 31 P NMR (162 MHz, Chloroform-d) δ-23.83.

[0064] Implementation Example 12: Synthesis of ligand L43;

[0065]

[0066] Compound 2b (0.5 g, 0.98 mmol) was dissolved in methanol (8 mL), and 6-methylpyridinecarboxaldehyde (0.98 mmol) was added. The reaction was carried out overnight at 60 °C. The next day, NaBH4 was added at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then subjected to column chromatography (PE / EA / Et3N) to give 0.49 g of orange-yellow bubbly precipitate L43, with a yield of 82%. 1H NMR (400 MHz, Chloroform-d) δ7.56 – 7.46 (m, 3H), 7.36 (dp, J = 5.7, 2.0 Hz, 3H), 7.23 – 7.16 (m, 5H), 7.13 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 4.52 (dt, J = 2.9, 1.6Hz, 1H), 4.28 (t, J = 2.5 Hz, 1H), 4.17 – 4.09 (m, 1H), 4.04 (s, 5H), 3.82(d, J = 14.6 Hz, 1H), 3.73 – 3.58 (m, 2H), 3.07 (s, 1H), 2.52 (s, 3H), 2.21 (d, J = 11.8 Hz, 1H), 2.03 (d, J = 12.1 Hz, 1H), 1.87 (d, J = 11.0 Hz, 1H), 1.59 – 1.45 (m, 3H), 1.42 (d, J = 6.2 Hz, 3H), 1.14 – 0.99 (m, 1H), 0.99 –0.82 (m, 2H), 0.31 (s, 1H), 0.10 – -0.06 (m, 1H). 31 P NMR (162 MHz, CDCl3) δ -24.79.

[0067] Implementation Example 13: Synthesis of ligand L49;

[0068]

[0069] Compound 2a (0.5 g, 0.82 mmol) was dissolved in methanol (8 mL), and 2-diphenylphosphine benzaldehyde (0.82 mmol) was added. The reaction was carried out overnight at 60 °C. The next day, NaBH4 was added at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then subjected to column chromatography (PE / EA / Et3N) to give 0.52 g of orange-yellow bubbly precipitate L49, with a yield of 60%. 1H NMR (400 MHz, Chloroform-d) δ 7.51 – 7.42 (m, 2H), 7.35 (q, J = 5.1, 4.2 Hz, 4H), 7.32 –7.27 (m, 5H), 7.24 – 7.11 (m, 11H), 7.09 – 6.93 (m, 7H), 6.87 – 6.79 (m, 3H), 6.48 (d, J = 7.3 Hz, 2H), 4.46 (t, J = 2.1 Hz, 1H), 4.26 (q, J = 2.1 Hz, 1H), 3.93 (d, J = 1.4 Hz, 5H), 3.71 – 3.58 (m, 4H), 3.52 (d, J = 13.9 Hz, 1H), 3.10 (d, J = 8.5 Hz, 1H), 1.29 (d, J = 6.3 Hz, 3H). 31 P NMR (162 MHz, Chloroform-d) δ -16.21, -23.79.

[0070] Implementation Example 14: Synthesis of ligand L55;

[0071]

[0072] Compound 2b (0.5 g, 0.98 mmol) was dissolved in methanol (8 mL), and 2-diphenylphosphine benzaldehyde (0.98 mmol) was added. The reaction was carried out overnight at 60 °C. The next day, NaBH4 was added at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then subjected to column chromatography (PE / EA / Et3N) to give 0.63 g of orange-yellow bubbly substance L55, with a yield of 82%. 1H NMR (400 MHz, Chloroform-d) δ 7.49 (tdd, J = 12.3, 5.2, 1.8 Hz, 3H), 7.40 – 7.27 (m, 10H), 7.25 – 7.17 (m, 5H), 7.17-7.07 (s, 5H), 6.81 (ddd, J = 7.7, 4.5, 1.4 Hz, 1H), 4.49 (dt, J = 3.0, 1.5 Hz, 1H), 4.27 (q, J = 2.8 Hz, 1H), 4.12 (dd, J = 6.7, 2.6 Hz, 1H), 4.03 (s, 5H), 3.76 (q, J = 15.5, 15.0 Hz, 2H), 3.68 (dt, J =2.5, 1.1 Hz, 1H), 2.84 (s, 1H), 2.17 (s, 1H), 2.02 (d, J = 19.0 Hz, 1H), 1.75(d, J = 10.6 Hz, 1H), 1.49 (d, J = 12.2 Hz, 2H), 1.43 (s, 1H), 1.38 (d, J =6.2 Hz, 3H), 1.09 – 0.94 (m, 1H), 0.91 – 0.75 (m, 2H), 0.29 (s, 1H), 0.03(dd, J = 14.8, 3.6 Hz, 1H). 31 P NMR (162 MHz, CDCl3) δ -16.08, -24.61.

[0073] Implementation Example 15: Synthesis of ligand L61;

[0074]

[0075] Compound 2a (0.5 g, 0.82 mmol) was dissolved in methanol (8 mL), and binaphthol aldehyde (0.82 mmol) was added. The reaction was carried out overnight at 60 °C. The next day, NaBH4 was added at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then subjected to column chromatography (PE / EA / Et3N) to give 0.51 g of orange-yellow bubbly precipitate L61, with a yield of 69%. 1H NMR (400 MHz, Chloroform-d) δ7.50 (dd, J = 5.0, 2.9 Hz, 3H), 7.42 – 7.27 (m, 12H), 7.23 – 6.98 (m, 11H), 6.98 – 6.86 (m, 5H), 4.36 (p, J = 1.6 Hz, 1H), 4.24 (t, J = 2.5 Hz, 1H), 4.16– 4.05 (m, 1H), 3.91 (s, 5H), 3.78 – 3.72 (m, 3H), 3.70 – 3.65 (m, 1H), 3.44(d, J = 7.0 Hz, 1H), 1.24 (d, J = 6.4 Hz, 3H). 31 P NMR (162 MHz, Chloroform-d)δ -23.56.

[0076] Implementation Example 16: Synthesis of ligand L67;

[0077]

[0078] Compound 2b (0.5 g, 0.98 mmol) was dissolved in methanol (8 mL), and binaphthol aldehyde (0.98 mmol) was added. The reaction was carried out overnight at 60 °C. The next day, NaBH4 was added at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then subjected to column chromatography (PE / EA / Et3N) to give 0.66 g of orange-yellow bubbly precipitate L67, with a yield of 84%. 1H NMR (400 MHz, Chloroform-d) δ7.88 (d, J = 8.9 Hz, 1H), 7.84 (dt, J = 8.2, 0.9 Hz, 1H), 7.79 – 7.74 (m,1H), 7.62 (s, 1H), 7.53 – 7.46 (m, 2H), 7.41 – 7.34 (m, 4H), 7.32 – 7.26 (m,5H), 7.20 (dddt, J = 15.3, 6.7, 3.5, 1.8 Hz, 5H), 7.13 – 7.06 (m, 2H), 4.41(dt, J = 2.9, 1.5 Hz, 1H), 4.26 (t, J = 2.5 Hz, 1H), 4.14 – 4.10 (m, 1H), 4.04-3.97 (m, 2H), 4.03(s, 5H) 3.67 (dt, J = 2.4, 1.2 Hz, 1H), 2.55 (d, J =7.2 Hz, 0H), 2.11 (q, J = 6.0, 3.9 Hz, 2H), 1.88 (d, J = 12.1 Hz, 1H), 1.52 (td, J = 10.3, 4.1 Hz, 2H), 1.29 – 1.20 (m, 4H), 1.10 – 0.82 (m, 5H), 0.23 –0.07 (m, 1H). 31 P NMR (162 MHz, CDCl3) δ -24.77.

[0079] B. Catalytic asymmetric hydrogenation reaction;

[0080] Implementation Example 17: Asymmetric hydrogenation of acetophenone;

[0081] Weigh out the metal precursor [Ir(COD)Cl]₂ (1.6 mg, 2.4 μmol) and ligand L (5.4 μmol) and add them to an ampoule. Add MeOH (1 mL) and stir at room temperature for 20 min. Then add KO tBu (4.6 mg, 0.05 mmol, 10 mol%) was added, followed by the substrate (0.5 mmol) and THF (1 mL). The ampoule was transferred to a hydrogenation reactor, purged three times with 10 bar H2, and then pressurized to 50 bar. The reaction was carried out at 50 °C for 20 h. The heating was turned off, and the ampoule was removed after depressurization in a fume hood. Water and dichloromethane were added, and the organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the hydrogenated product. 1 Conversion was determined by 1H NMR, and enantioselectivity of the product was determined by HPLC. The screening results for some ligands are as follows:

[0082] .

[0083] .

Claims

1. A class of chiral ferrocene framework tetradentate ligands, characterized in that, Its stereoisomers are as follows: 。 2. The use of a chiral ferrocene framework tetradentate ligand according to claim 1, characterized in that, This ligand is used to prepare catalysts for asymmetric hydrogenation reactions.

3. The use of a chiral ferrocene framework tetradentate ligand according to claim 1 as described in claim 2, characterized in that, The catalyst is a complex formed by the complexation of a tetradentate ligand and a transition metal salt; the transition metal in the transition metal salt is Ir.

4. The use of a chiral ferrocene framework tetradentate ligand according to claim 1 as described in claim 2, characterized in that, The transition metal salt is one of IrX3, [Ir(NBD)2)Cl]2, [Ir(COD)Cl]2, and Ir(COD)X, wherein in the transition metal precursor salt, X is an anion Cl. ‐ ,Br ‐ I ‐ ClO4 ‐ BF4 ‐ Sb6 ‐ PF6 ‐ CF3SO3 ‐ RCOO ‐ ,BAr4 ‐ .

5. The use of a chiral ferrocene framework tetradentate ligand according to claim 1 as described in claim 2, characterized in that, When the catalyst is a complex formed by the combination of the above-mentioned tetradentate ligand and Ir metal salt, it exhibits catalytic activity and enantioselectivity for the asymmetric hydrogenation of arylalkyl ketones, heteroarylalkyl ketones, arylaryl ketones, and arylheteroaryl ketones.

6. The use of a chiral ferrocene framework tetradentate ligand according to claim 1 as described in claim 2, characterized in that, The catalyst described above can be used for the asymmetric hydrogenation of prochiral ketones to synthesize chiral alcohols.

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