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

Abstract

The invention discloses a chiral ferrocene framework tetradentate ligand and application thereof in asymmetric hydrogenation reaction. The ligand has the advantages of low cost, simplicity and convenience in synthesis, good stability and the like. A metal complex of the ligand shows very excellent catalytic activity and extremely high enantioselectivity in an asymmetric hydrogenation reaction of ketone, can efficiently catalyze reduction of prochiral ketones such as aryl alkyl ketone, heteroaryl alkyl ketone, aryl (hetero) aryl ketone and the like into corresponding chiral alcohol, and has huge industrial application potential.

Description

Technical Field

[0001] The invention belongs to the field of fine chemicals, relates to a chiral ligand and an application thereof, and specifically relates to a chiral ferrocene skeleton tetradentate ligand and an application thereof in an asymmetric hydrogenation reaction. Background Art

[0002] Chiral alcohol building blocks are widely present in the structures of fine chemical products such as drugs, pesticides, cosmetics, health products, and flavors and fragrances. The extraction method to obtain chiral alcohols is far from meeting human needs. Therefore, it is of great practical significance to develop green, efficient and highly selective catalytic reactions to prepare chiral alcohols. Catalytic asymmetric hydrogenation has the advantages of good atom economy, high efficiency, and simple post-processing. It is the most important method for synthesizing chiral compounds in industry. The key to a practical asymmetric hydrogenation technology lies in highly active and stereoselective metal complex catalysts, and the ligand is the key and core. Therefore, the development of chiral ligands with novel structures, excellent performance, simple preparation and low cost has always been the core content of asymmetric hydrogenation research.

[0003] The catalytic asymmetric hydrogenation of prochiral ketones is the simplest and most efficient method for obtaining chiral alcohols, and is also one of the main ways to obtain chiral alcohols in industry. In the study of asymmetric hydrogenation of ketones, Noyori developed [RuCl 2The (diphosphine)(diamine)] complex is a milestone, achieving a million-level transformation number. In 2011, Professor Zhou Qilin successfully designed and synthesized the SpiroPAP tridentate ligand and applied it to the asymmetric hydrogenation of aromatic ketones, achieving a transformation number of up to four million. However, the SpiroPAP ligand has a complex synthesis route and expensive raw materials, which greatly limits its industrial application. In 2016, Professor Zhang Xumu's team replaced an oxazoline in the tridentate ligand ambox of the bisoxazoline type with a ferrocene dominant skeleton, thereby obtaining a more sterically hindered and more electrically charged tridentate ligand f-amphox. This type of ligand is not only simple to synthesize, the raw materials are cheap and easy to obtain, and it is highly stable. It has been successfully used in the asymmetric hydrogenation of a variety of ketones. Subsequently, their research group developed two types of tridentate ligands f-amphol and f-ampha. These works have greatly promoted the application of tridentate ligand catalysts in industry. In 2022, based on previous work, Professor Zhang Xumu's team developed a type of ferrocene PNNO-type tetradentate ligand f-phamidol, which achieved a record-breaking conversion number of tens of millions in the asymmetric hydrogenation of simple ketones and has been successfully applied to the industrial production of nicotine. This type of ligand can achieve extremely high catalytic activity and high selectivity probably because the tetradentate ligand and the metal center have multiple chelation sites, and the metal complex formed is usually stable and does not allow ligand dissociation and inactivation to occur. In addition, the tetradentate ligand has multiple chiral units and activity regulation units that can be modified, so the ligand can be rationally designed and modified to obtain high catalytic activity and excellent enantioselectivity.

[0004] Although the PNNO-type tetradentate ligands reported above have achieved ultra-high catalytic activity in the asymmetric hydrogenation of simple ketones, they have low catalytic activity in the asymmetric hydrogenation of some substrates with special structures, and some ligands have poor stability, which limits their application to varying degrees. Therefore, the development of new ligands and their catalytic systems still has important research value. Summary of the invention

[0005] In order to overcome the deficiencies of the above-mentioned prior art, the purpose of the present invention is to provide a class of chiral ferrocene skeleton tetradentate ligands and their application in asymmetric hydrogenation reactions, which provides an important method for the synthesis of key fragments of some drug molecules and has important application value.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is:

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

[0008] ;

[0009] in:

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

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

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

[0013] In formula I-IV, linker 1 has any of the following structures:

[0014] R 4 is hydrogen, alkyl, aryl or substituted aryl.

[0015] Furthermore, the stereoisomers included in the general structural formula I-IV are as follows:

[0016] .

[0017] Furthermore, the ligand is used to prepare a catalyst 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 salt is 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)X 2 (PPh 3 ) 3 , Ru(COD)(COT), Ru(COD)(COT)X, RuX 2 (cymene)、Ru(COD)n、Ru(arylgroup)X 2 (diphosphine), RuC1 2 (COD), [Ru(COD) 2 ]X, RuX 2 (diphosphine), RuC1 2 (=CHR) (PR' 3 ) 2 、Ru(ArH)C12 、Ru(COD)(methallyl) 2 、Rh(CO) 2 C1 2 、[Rh(NBD) 2 ]BF 4 , [Rh(NBD)C1] 2 、[Rh(COD)C1] 2 、[Rh(COD) 2 ]X、Rh(acac)(CO) 2 、Rh(ethylene) 2 (acac), [Rh(ethylene) 2 C1] 2 、RhC1(PPh 3 ) 3 、PdX 2 、Pd(PPh 3 ) 4 、Pd(allyl)Cl、IrX 3 、[Ir(NBD) 2 )C1] 2 、[Ir(COD)C1] 2 、Ir(COD)X、FeX 2 , FeX 3 、Ni(acac) 2 , NiX 2 、[Ni(allyl)X] 2 、Ni(COD) 2 ,CuX,CuX 2 、MoO 2 (acac) 2 , ScX 2 、Ti(OiPr) 4 、VO(acac) 2 ,CrX 2 ,CrX 3 、MnX 2 、Mn(acac) 2 or MeReO 3 wherein in the transition metal precursor salt, R and R' may be alkyl, alkoxy or substituted alkyl; aryl is aryl; X is an anion Cl ‐ Br ‐ , I ‐ , ClO 4 ‐ , BF 4 ‐ , Sb 6 ‐ , PF6 ‐ CF 3 SO 3 ‐ ,RCOO ‐ , BAr 4 ‐ ; L is an acetonitrile solvent molecule.

[0020] Furthermore, when the catalyst is a complex formed by the above-mentioned tetradentate ligand and Ir metal salt, it has high catalytic activity and enantioselectivity for the asymmetric hydrogenation of a series of prochiral ketone compounds including aryl alkyl ketones, heteroaryl alkyl 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 reaction includes asymmetric hydrogenation, asymmetric transfer hydrogenation, asymmetric hydroamination, asymmetric hydrocyanation, asymmetric hydrosilylation, asymmetric hydroboration, asymmetric allylic alkylation, asymmetric coupling, asymmetric cyclization, asymmetric Michael addition, asymmetric asymmetric epoxidation, asymmetric Aldol reaction, asymmetric Mannich reaction, asymmetric Diels-Alder reaction, and asymmetric cycloisomerization.

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

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

[0025] The beneficial effects of the present invention are:

[0026] This type of ligand has the advantages of low cost, simple synthesis and good stability. The metal complex of this type of ligand shows very excellent catalytic activity and extremely high enantioselectivity in the asymmetric hydrogenation reaction of ketones. It can efficiently catalyze the reduction of prochiral ketones such as aryl alkyl ketones, heteroaryl alkyl ketones, aryl (hetero) aryl ketones to the corresponding chiral alcohols, and has great potential for industrial application. DETAILED DESCRIPTION

[0027] The present invention is further described below in conjunction with embodiments, but is not intended to be limiting of the present 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., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Substituted aryl refers to an aryl group having at least one substituent, preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0030] A. Synthesis of ligands;

[0031] Embodiment 1: Synthesis of key fragment 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 completed, the reaction solution was concentrated to obtain a yellow foam. The foam was directly dissolved in methanol, and diphenylethylenediamine (22.6 mmol) was added and reacted at 60 °C overnight. After the reaction was completed, the reaction solution was concentrated and column chromatography (EA / Et 3 N) to give 5.3 g of orange-yellow foamy product 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] Embodiment 2: Synthesis of key fragment 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 completed, the reaction solution was concentrated to obtain a yellow foamy substance. The foamy substance was directly dissolved in methanol, and cyclohexanediamine (22.6 mmol) was added and reacted at 60 °C overnight. After the reaction was completed, the reaction solution was concentrated and column chromatography (EA / Et 3 N) to give 8.3 g of orange-yellow foamy product 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, CDCl 3 )δ -24.70.

[0037] Embodiment 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 completed, the yellow foamy substance in the reaction solution was concentrated. The foamy substance was directly dissolved in methanol, and cyclohexyldiamine (7.5 mmol) was added and reacted at 60 °C overnight. After the reaction was completed, the reaction solution was concentrated and column chromatography (PE / EA / Et 3 N) to give 4.1 g of orange-yellow foamy product 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, CDCl 3 )δ -24.15.

[0040] Embodiment 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 and reacted at 60 °C overnight. The next day, NaBH 4 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 extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then column chromatography (PE / EA / Et 3 N) to obtain 0.25 g of orange-yellow foamy substance 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] Embodiment 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 and reacted at 60 °C overnight. The next day, NaBH 4 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 extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then column chromatography (PE / EA / Et 3 N) to obtain 0.51 g of orange-yellow foamy substance 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, CDCl 3 )δ -24.98.

[0046] Embodiment 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 and reacted at 60 °C overnight. The next day, NaBH 4 After that, the mixture was reacted at room temperature for 1 h. After the reaction was completed, 5 mL of water was added to quench the reaction, and then extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then column chromatography (PE / EA / Et 3 N) to obtain 0.7 g of orange-yellow foamy substance 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, CDCl 3 )δ -24.71.

[0049] Embodiment 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 and reacted at 60 °C overnight. The next day, NaBH 4 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 extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then column chromatography (PE / EA / Et 3 N) to obtain 0.45 g of orange-yellow foamy substance 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] Embodiment 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 and reacted at 60 °C overnight. The next day, NaBH 4 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 extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then column chromatography (PE / EA / Et 3 N) to obtain 0.63 g of orange-yellow foamy substance 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, CDCl 3 )δ -24.57.

[0055] Embodiment 9: Synthesis of ligand L25;

[0056]

[0057] Compound 2a (0.5 g, 0.82 mmol) was dissolved in methanol (8 mL), pyridine carboxaldehyde (0.82 mmol) was added and reacted at 60 °C overnight. The next day, NaBH was added at 0 °C. 4 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 extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then column chromatography (PE / EA / Et 3 N) to obtain 0.45 g of orange-yellow foamy substance 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] Embodiment 10: Synthesis of ligand L31;

[0059]

[0060] Compound 2b (0.5 g, 0.98 mmol) was dissolved in methanol (8 mL), pyridine carboxaldehyde (0.98 mmol) was added and the mixture was reacted at 60 °C overnight. NaBH was added at 0 °C the next day. 4 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 extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then column chromatography (PE / EA / Et 3 N) to obtain 0.46 g of orange-yellow foamy substance 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, CDCl 3 )δ -24.77.

[0061] Embodiment 11: Synthesis of ligand L37;

[0062]

[0063] Compound 2a (0.5 g, 0.82 mmol) was dissolved in methanol (8 mL), 6-methylpyridine carboxaldehyde (0.82 mmol) was added and reacted at 60 °C overnight. The next day, NaBH was added at 0 °C. 4 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 extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then column chromatography (PE / EA / Et 3 N) to obtain 0.31 g of orange-yellow foamy 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] Embodiment 12: Synthesis of ligand L43;

[0065]

[0066] Compound 2b (0.5 g, 0.98 mmol) was dissolved in methanol (8 mL), 6-methylpyridine carboxaldehyde (0.98 mmol) was added and reacted at 60 °C overnight. The next day, NaBH was added at 0 °C. 4 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 extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then column chromatography (PE / EA / Et 3 N) to obtain 0.49 g of orange-yellow foamy substance 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, CDCl 3 )δ -24.79.

[0067] Embodiment 13: Synthesis of ligand L49;

[0068]

[0069] Compound 2a (0.5 g, 0.82 mmol) was dissolved in methanol (8 mL), 2-diphenylphosphinobenzaldehyde (0.82 mmol) was added and reacted at 60 °C overnight. The next day, NaBH was added at 0 °C. 4 , react at room temperature for 1 h. After the reaction, add 5 mL of water to quench the reaction, extract with dichloromethane (10 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate the reaction solution and perform column chromatography (PE / EA / Et 3 N) to obtain 0.52 g of orange-yellow foamy substance 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] Embodiment 14: Synthesis of ligand L55;

[0071]

[0072] Compound 2b (0.5 g, 0.98 mmol) was dissolved in methanol (8 mL), 2-diphenylphosphinobenzaldehyde (0.98 mmol) was added and reacted at 60 °C overnight. NaBH was added at 0 °C the next day. 4 , react at room temperature for 1 h. After the reaction, add 5 mL of water to quench the reaction, extract with dichloromethane (10 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate the reaction solution and perform column chromatography (PE / EA / Et 3 N) to obtain 0.63 g of orange-yellow foamy 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, CDCl 3 ) δ -16.08, -24.61.

[0073] Embodiment 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 and reacted at 60 °C overnight. The next day, NaBH 4 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 extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then column chromatography (PE / EA / Et 3 N) to obtain 0.51 g of orange-yellow foamy substance 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] Embodiment 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 and reacted at 60 °C overnight. The next day, NaBH 4 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 extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and then column chromatography (PE / EA / Et 3 N) to obtain 0.66 g of orange-yellow foamy substance 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, CDCl 3 )δ -24.77.

[0079] B. Catalytic asymmetric hydrogenation reaction;

[0080] Embodiment 17: Asymmetric hydrogenation of acetophenone;

[0081] Weigh the metal precursor [Ir(COD)Cl] 2 (1.6 mg, 2.4 μmol) and ligand L (5.4 μmol) were added to an ampoule, and MeOH (1 mL) was added and stirred at room temperature for 20 min. Then, KO t Bu (4.6 mg, 0.05 mmol, 10 mol %), and finally the substrate (0.5 mmol) and THF (1 mL). The ampoule was transferred into a hydrogenation reactor and heated at 10 bar H 2After three replacements, the pressure was increased to 50 bar and the reaction was carried out at 50 °C for 20 h. The heating was turned off, and the ampoule was taken out after the pressure was released in the fume hood. Water and dichloromethane were added, and the organic layer was washed with saturated NaCl solution and anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain the hydrogenated product. 1 H NMR was used to measure the conversion rate, and HPLC was used to measure the product enantioselectivity. The screening results of some ligands are as follows:

[0082] .

[0083] .

Claims

1. A chiral ferrocene framework tetradentate ligand, characterized in that: The ligands represented by the general structural formulas I-IV are as follows: ； in: In Formula I-IV, R 1 is aryl or substituted aryl; In Formula I-III, R 2 independently selected from H, R, Ar, OCR, OCAr substituents or groups; In Formula III, R 3 is aryl or substituted aryl; In formula I-IV, linker 1 has any of the following structures: R 4 is hydrogen, alkyl, aryl or substituted aryl.

2. A chiral ferrocene framework tetradentate ligand according to claim 1, characterized in that: The stereoisomers included in the general structural formula I-IV are as follows: 。 3. The chiral ferrocene framework tetradentate ligand according to claim 1, characterized in that: The ligand is used for preparing catalysts for asymmetric catalytic reactions.

4. The chiral ferrocene framework tetradentate ligand according to claim 3, characterized in that: The catalyst is a complex formed by the complexation of a tetradentate ligand and a transition metal salt.

5. The chiral ferrocene framework tetradentate ligand according to claim 3, characterized in that: The transition metal salt is 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(eth ylene)2(acac), [Rh(ethylene)2C1]2, RhC1(PPh3)3, PdX2, Pd(PPh3)4, Pd(allyl)Cl, IrX3, [Ir(NBD)2)C1]2, [Ir( One of the following: 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' may be alkyl, alkoxy or substituted alkyl; aryl is aryl; X is an anion Cl ‐ Br ‐ , I ‐ 、ClO4 ‐ 、BF4 ‐ , Sb6 ‐ , PF6 ‐ CF3SO3 ‐ ,RCOO ‐ ,BAr4 ‐ ; L is an acetonitrile solvent molecule.

6. The chiral ferrocene framework tetradentate ligand according to claim 3, characterized in that: When the catalyst is a complex formed by the above-mentioned tetradentate ligand and Ir metal salt, it has high catalytic activity and enantioselectivity for asymmetric hydrogenation of a series of prochiral ketone compounds including aryl alkyl ketones, heteroaryl alkyl ketones, and aryl (hetero) aryl ketones.

7. The chiral ferrocene framework tetradentate ligand according to claim 4, characterized in that: 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.

8. The chiral ferrocene framework tetradentate ligand according to claim 3 is used to prepare a catalyst for an asymmetric catalytic reaction, characterized in that: The asymmetric catalytic reaction includes asymmetric hydrogenation, asymmetric transfer hydrogenation, asymmetric hydroamination, asymmetric hydrocyanation, asymmetric hydrosilylation, asymmetric hydroboration, asymmetric allylic alkylation, asymmetric coupling, asymmetric cyclization, asymmetric Michael addition, asymmetric asymmetric epoxidation, asymmetric Aldol reaction, asymmetric Mannich reaction, asymmetric Diels-Alder reaction, and asymmetric cycloisomerization.

9. The chiral ferrocene framework tetradentate ligand according to claim 3 is used to prepare a catalyst for an asymmetric catalytic reaction, characterized in that: The catalyst can be applied to the asymmetric hydrogenation of prochiral ketone compounds to synthesize chiral alcohols.

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