Chiral tetradentate nitrogen-oxygen salen ligand as well as preparation method and application thereof

Abstract

The invention relates to the technical field of organic synthesis, and particularly discloses a chiral tetradentate nitrogen-oxygen salen ligand, the structure of the ligand is shown in the following formula: in the formula, R is selected from phenyl or-(CH2) 4-, and Ad is 1-adamantyl. Compared with the existing tert-butyl substituted salen ligand, the novel chiral tetradentate nitrogen oxygen salen ligand obtained by the invention has larger steric hindrance, and can obtain more excellent enantiomer selectivity in asymmetric catalysis; the adamantyl salen Ti complex can be used for synthesizing a novel adamantyl salen Ti complex, and the variety of salen ligands and salen metal complexes is enriched.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a chiral tetradentate nitrogen oxygen salen ligand and a preparation method and application thereof. BACKGROUND

[0002] Salen is a kind of double imine tetradentate ligand. This kind of ligand is usually formed by condensation reaction of two ortho-hydroxy aromatic aldehydes and a diamine (for example: ethylenediamine). This structure gives it an active site for binding with metal ions, i.e. the phenolic hydroxyl oxygen atoms of the ortho-hydroxy aromatic aldehyde part and the nitrogen atoms of the Schiff base part. Such a tetradentate mode enables the salen ligand to form stable complexes with various metal ions, such as aluminum (III), copper (II), manganese (III), iron (III), cobalt (II), titanium (IV), etc., and is widely used in catalytic asymmetric synthesis, material science and optics (Steven W. M. Crossley et al, Chem. Rev. 2016, 116, 8912-9000).

[0003] Since Jacobsen designed and synthesized the first chiral salen Mn(Ⅲ) complex in 1990 (Zhang W, Loebach J L, Wilson S R, et al. J. Am. Chem. Soc., 1990, 112:2801~2803), a large number of chiral Schiff base complexes have been synthesized and applied to various asymmetric reactions ((1) Yu-Chao Yuan et al, Chem. Rev. 2022, 122, 8841-8883; (2) Subrata Shaw et al, Chem. Rev. 2019, 119, 16,9381-9426). For example, salen Ti(Ⅳ) has been widely used to catalyze radical coupling (Hao Xie et al, J. Am. Chem. Soc. 2020, 142, 16787-16794), radical addition (Li Lin et al, Org. Biomol. Chem., 2012, 10, 83–89) and radical cascade cyclization reactions (Sophia G. Robinson et al, J. Am. Chem. Soc. 2020, 142, 18471-18482). When using chiral salen Ti(Ⅳ), asymmetric radical reactions can be achieved (Longfei Li et al, J. Am. Chem. Soc., 2024, 146, 19, 13546-13557). Studies have shown that increasing the steric hindrance of chiral salen ligands can improve the enantioselectivity of the reaction, but the synthesis step of the large steric hindance binaphthyl salen ligand in this study is long (6 steps, see Jian Shen et al J. Am. Chem. Soc. 2023, 145, 21122-21131). Therefore, developing an efficient synthesis method for large steric hindance chiral salen ligand to replace the large steric hindance ligand in the literature to achieve efficient catalytic synthesis reaction has broad commercial application prospects and great scientific value. SUMMARY

[0004] In view of the above problems, the present application provides a chiral tetradentate nitroxide salen ligand and a preparation method thereof. The chiral tetradentate nitroxide salen ligand has large steric hindrance and is expected to improve the enantioselectivity of the reaction. The specific technical solutions are as follows: A chiral tetradentate nitroxide salen ligand, the structure of the ligand is as shown in the following formula: wherein R is selected from phenyl or -(CH2)4-, and Ad is 1-adamantyl.

[0005] In another aspect, the present application also provides a method for preparing the chiral tetradentate nitroxide salen ligand, comprising the following steps: (1) methylsulfonic acid is added dropwise to a mixture of β-naphthol 1 and 1-adamantanol in an organic solvent at 0-5°C, and then the mixture is stirred at 0-5°C for 15-45 min, and then stirred at 15-30°C for 15-18 h. After the reaction is completed, extraction, drying are performed to obtain 3,6-diamantyl-2-naphthol 2. The synthetic route of this step is as follows: ; (2) 3,6-diamantyl-2-naphthol 2 and 1,1-dichloromethyl methyl ether 3 obtained in step (1) are sequentially added to an organic solvent to obtain a mixture, and then titanium tetrachloride is slowly added dropwise at 0-5°C. After the dropwise addition is completed, the mixture is continuously stirred at 15-30°C. After the reaction is completed, extraction, washing, and drying are performed to obtain 3,6-diamantyl-2-hydroxy-1-naphthaldehyde 4. The synthetic route of this step is as follows: ; (3) 3,6-diamantyl-2-hydroxy-1-naphthaldehyde 4 and an amine compound 5 are added to ethanol, and then refluxed for 5-7 h. Filtration and washing are performed to obtain the chiral tetradentate nitroxide salen ligand 6. The synthetic route of this step is as follows: .

[0006] Preferably, in the method for preparing the chiral tetradentate nitroxide salen ligand, the molar ratio of β-naphthol, 1-adamantanol, and methylsulfonic acid in step (1) is 1:2.5-3.5:2.5-3.5.

[0007] Preferably, in the method for preparing the chiral tetradentate nitroxide salen ligand, the molar ratio of 3,6-diamantyl-2-naphthol and 1,1-dichloromethyl methyl ether in step (2) is 1-1.2:1-1.2.

[0008] Preferably, in the method for preparing the chiral tetradentate nitroxide salen ligand, the amine compound in step (3) is chiral (1 S ,2 S )-1,2-diphenylethylenediamine or (1 S ,2 S )-1,2-cyclohexanediamine.

[0009] Preferably, in the preparation method of the chiral tetradentate nitroxide salen ligand, in step (3), the molar ratio of 3,6-diamantyl-2-hydroxy-1-naphthaldehyde to the amine compound is 2-2.5:1.

[0010] Preferably, in the preparation method of the chiral tetradentate nitroxide salen ligand, in step (2), the stirring is continued at 15-30℃ for 1.5-3h.

[0011] Preferably, in the preparation method of the chiral tetradentate nitroxide salen ligand, in step (3), the reflux reaction temperature is 75-80℃.

[0012] Preferably, in the preparation method of the chiral tetradentate nitroxide salen ligand, the organic solvent is dichloromethane, chloroform, 1,2-dichloroethane or toluene.

[0013] In another aspect, the present application also provides the use of the chiral tetradentate nitroxide salen ligand in the synthesis of a chiral salen Ti complex.

[0014] Preferably, in the use, the method for synthesizing a chiral salen Ti complex from the chiral tetradentate nitroxide salen ligand comprises: adding the chiral tetradentate nitroxide salen ligand to anhydrous tetrahydrofuran in a low-temperature reaction bath below -70℃, slowly adding a titanium tetrachloride toluene solution under argon protection, allowing the mixture to naturally rise to room temperature after the addition is completed, and then refluxing at 60-70℃ for 3-5h; filtering, washing and vacuum drying to obtain the chiral salen Ti complex.

[0015] Compared with the prior art, the present application has the following advantages: The present application obtains a novel chiral tetradentate nitroxide salen ligand, which has greater steric hindrance compared with the existing tert-butyl-substituted salen ligand, and can achieve more excellent enantiomeric selectivity in asymmetric catalysis; it can be used to synthesize a novel adamantyl salen Ti complex, enriching the types of salen ligands and salen metal complexes. The preparation method of the chiral tetradentate nitroxide salen ligand of the present application has simple preparation steps (only 3 steps), the raw materials are cheap and easy to obtain, and the steric hindrance is large, which can be used to replace the large steric hindrance binaphthyl salen ligand (Jian Shen et al J. Am. Chem. Soc. 2023, 145, 21122-21131), and has broad commercial application prospects and great scientific research value. BRIEF DESCRIPTION OF DRAWINGS

[0016] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following will briefly introduce the drawings needed to be used in the embodiment description. Obviously, the drawings in the following description are some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without any creative effort on the basis of these drawings.

[0017] Figure 1 The nuclear magnetic resonance hydrogen spectrum of 3,6-diamantyl-2-naphthol 2 in the embodiment 1 of the present application; Figure 2 The nuclear magnetic resonance carbon spectrum of 3,6-diamantyl-2-naphthol 2 in the embodiment 1 of the present application; Figure 3 The nuclear magnetic resonance hydrogen spectrum of the chiral tetradentate nitroxide salen ligand 6a in the embodiment 1 of the present application; Figure 4 The nuclear magnetic resonance carbon spectrum of the chiral tetradentate nitroxide salen ligand 6a in the embodiment 1 of the present application; Figure 5 The nuclear magnetic resonance hydrogen spectrum of the chiral tetradentate nitroxide salen ligand 6b in the embodiment 2 of the present application; Figure 6 The nuclear magnetic resonance carbon spectrum of the chiral tetradentate nitroxide salen ligand 6b in the embodiment 2 of the present application. DETAILED DESCRIPTION

[0018] The specific embodiments of the present application will be described in detail below, but it should be understood that the protection scope of the present application is not limited by the specific embodiments. Unless otherwise defined, all the professional terms used in the following are the same as the meanings commonly understood by those skilled in the art. The professional terms used in this paper are only for the purpose of describing the specific embodiments and are not intended to limit the protection scope of the present application. Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present application can be purchased from the market or can be prepared by the existing method.

[0019] Embodiment 1 A chiral tetradentate nitroxide salen ligand has the following structural formula: A preparation method of a chiral tetradentate nitroxide salen ligand includes the following steps: (1) Synthesis of 3,6-diamantyl-2-naphthol 2: Methylsulfonic acid (3.0 g, 31 mmol) was added dropwise to a mixture of β-naphthol 1 (1.4 g, 10 mmol) and 1-adamantanol (4.4 g, 30 mmol) in dichloromethane at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 16 h. After the reaction was completed, the mixture was poured into saturated brine (100 mL) and extracted with dichloromethane (200 mL) twice. The organic phase was dried and concentrated, and the residue was separated by flash column chromatography (eluent: petroleum ether / ethyl acetate = 19:1, V:V) to give 3,6-diadamantyl-2-naphthol 2 (1.3 g, 3.2 mmol) in 33% yield.

[0020] 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 4.4 Hz, 2H), 7.48 (d, J = 8.8 Hz,1H), 7.39 (dd, J = 1.6, 1.6 Hz, 1H), 6.88 (s, 1H), 4.91 (s, 1H), 2.14 (d, J =2.4, 6H), 2.05 (s, 6H), 1.91 (d, J = 2.4 Hz, 6H), 1.74 – 1.70 (m, 12H). 13 C NMR (100 MHz, CDCl3) δ 152.6, 137.6, 131.7, 128.1, 126.8, 125.2,124.8, 124.0, 122.4, 109.8, 59.4, 42.2, 39.7, 39.3, 36.2, 36.1,35.9,35.6,28.0. (2) Synthesis of 3,6-diadamantyl-2-hydroxy-1-naphthaldehyde 4: To a solution of 3,6-diamantyl-2-naphthol 2 (1.3 g, 3.2 mmol) and 1,1- dichloromethyl methyl ether 3 (0.38 g, 3.2 mmol) in dichloromethane (50 mL) was added titanium tetrachloride (0.75 mL) dropwise using a constant pressure dropping funnel at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 2 h. Then, water was added to the mixture at 0 °C to quench the excess titanium tetrachloride. The mixture was extracted with dichloromethane and washed with saturated brine. The organic phase was dried and concentrated. The residue was separated by flash column chromatography (eluent: petroleum ether / ethyl acetate = 19:1, V:V) to give 3,6-diamantyl-2-hydroxy-1- naphthaldehyde 4 (1.1 g, 2.4 mmol) in 76% yield.

[0021] 1 H NMR (400 MHz, CDCl3) δ 14.01 (s, 1H), 10.72 (s, 1H), 8.15 (d, J = 8.8Hz, 1H), 7.79 (s, 1H), 7.60 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H), 2.15 (d, J = 1.2Hz, 12H), 2.07 (s, 6H), 1.93 (d, J = 1.2 Hz, 12H). 13 C NMR (100 MHz, CDCl3) δ 193.7, 165.8, 147.3, 139.0, 136.1, 129.8,127.7, 126.4, 124.8, 117.6, 111.2, 43.2, 40.1, 37.5, 37.1, 36.8, 36.1, 31.6,29.0, 22.7. (3) Synthesis of chiral tetradentate nitrogen oxygen salen ligand 6a: To a solution of 3,6-diamantyl-2-hydroxy-1-naphthaldehyde 4 (0.53 g, 1.2 mmol) and chiral (1 S ,2 S)-1,2-diphenylethylenediamine 5a (0.13 g, 0.6 mmol) to give a mixture. The mixture was refluxed at 78 °C for 6 h. Then filtered using a Buchner funnel, and the insoluble light yellow solid cake was washed with a small amount of cold ethanol (10 mL) to give the chiral tetradentate nitronyl nitroxide salen ligand 6a (0.46 g, 0.44 mmol, 73% yield).

[0022] 1 H NMR (400 MHz, DMSO) δ 15.01 (s, 2H), 9.28 (d, J = 6.4 Hz, 2H), 7.83(d, J = 9.2 Hz, 2H), 7.49 (d, J = 7.6 Hz, 4H), 7.43 (d, J = 1.6 Hz, 2H), 7.39 (s,2H), 7.35 – 7.31 (m, 6H), 7.23 (t, J = 14.4 Hz, 2H), 5.57 (s, 2H), 2.06 – 2.00(m, 24H), 1.87 (s, 12H), 1.78 – 1.69 (m, 24H). 13 C NMR (100 MHz, CDCl3) δ 166.7, 162.2, 145.2, 139.8, 139.0, 131.7,129.8, 128.5, 128.1, 128, 126.8, 124.7, 124.0, 118.0, 108.1, 79.1, 77.4,77.1, 76.7, 43.2, 40.4, 37.3, 36.9, 35.8, 29.0. Example 2 A chiral tetradentate nitronyl nitroxide salen ligand 6b has the following structure: .

[0023] A method for preparing a chiral tetradentate nitronyl nitroxide salen ligand 6b, comprising the following steps: Steps (1) and (2) are the same as in Example 1; (3) Synthesis of the chiral tetradentate nitronyl nitroxide salen ligand 6b: To ethanol (20 mL) was added 3,6-diamantyl-2-hydroxy-1-naphthaldehyde 4 (0.53 g, 1.2 mmol) and (1 S ,2 S )- 1,2-cyclohexanediamine 5b (0.068 g, 0.6 mmol) to obtain a mixture. The mixture was refluxed at 78 °C for 6 h. The mixture was then filtered using a Buchner funnel and the insoluble light yellow solid cake was washed with a small amount of cold ethanol (10 mL) to obtain the chiral tetradentate salen ligand 6b (0.48 mmol, 79% yield).

[0024] 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.35(s, 2H), 7.25 (d, 2H), 7.20 (dd, J = 1.2, 2.0 Hz, 2H), 3.43 (d, J = 10.0 Hz, 2H),2.18 (d, J = 1.6 Hz 12H), 2.10 (s, 12H), 1.89 (d, J = 1.9 Hz, 12H), 1.81 (s,12H), 1.78 – 1.73 (m, 10H), 1.25 (s, 12H). 13 C NMR (100 MHz, CDCl3) δ 172.8, 159.6, 145.1, 141.2, 132.9, 130.2,126.1, 124.7, 124.1, 117.2, 107.1, 77.3, 77.0, 76.7, 69.2, 43.3, 40.5, 37.3,36.9, 35.7, 32.7, 29.1, 24.6. Example 3 Synthesis of chiral salen Ti complex 7a Into a three-necked flask (25 mL) containing 5 mL of anhydrous tetrahydrofuran, salen ligand 6a (0.5 g, 0.47 mmol) was added at -78 °C in a water bath. The reaction was slowly added with titanium tetrachloride in toluene (0.52 mL, 0.52 mmol, 1 mol / L in toluene) under argon protection. After the addition was completed, the mixture was allowed to warm up to room temperature, and then to 65 °C for 4 h. A large amount of yellowish solid was precipitated. The solid was filtered and washed with a small amount of tetrahydrofuran. The solid was dried under vacuum to give chiral salen Ti complex 7a (0.39 g, 0.33 mmol, 71% yield).

[0025] Example 4. Synthesis of chiral salen Ti complex 7b Into a three-necked flask (25 mL) containing 5 mL of anhydrous tetrahydrofuran, salen ligand 6b (0.5 g, 0.52 mmol) was added at -78 °C in a water bath. The reaction was slowly added with titanium tetrachloride in toluene (0.57 mL, 0.57 mmol, 1 mol / L in toluene) under argon protection. After the addition was completed, the mixture was allowed to warm up to room temperature, and then to 65 °C for 4 h. A large amount of yellowish solid was precipitated. The solid was filtered and washed with a small amount of tetrahydrofuran. The solid was dried under vacuum to give chiral salen Ti complex 7b (0.52 g, 0.45 mmol yield 86%).

[0026] The foregoing description of specific exemplary embodiments of the application has been presented for the purpose of illustration and description. They are not intended to be exhaustive or to limit the application to the precise forms disclosed, and various modifications and variations are possible in light of the above teachings. The exemplary embodiments were chosen and described in order to explain the principles of the application and its practical application. This detailed description is not intended to limit the scope of the application as claimed. It is intended that the scope of the application be defined by the claims and their equivalents.

Claims

1. A chiral tetradentate nitrooxysalen ligand, characterized in that: The structure of the ligand is shown in the following formula: wherein R is selected from phenyl or -(CH2)4-, and Ad is 1-adamantyl.

2. The process for the preparation of chiral tetradentate nitrenesal en ligands according to claim 1, characterized in that, The method comprises the following steps: (1) drop methyl sulfonic acid into an organic solvent mixture containing β-naphthol and 1-adamantanol at 0-5°C, then react for 15-45 min at 0-5°C, and then continue to stir and react for 15-18 h at 15-30°C; after the reaction is completed, extraction, drying, and separation are performed to obtain 3,6-diamantyl-2-naphthol; (2) add 3,6-diamantyl-2-naphthol and 1,1-dichloromethyl methyl ether into an organic solvent in sequence to obtain a mixture, slowly drop titanium tetrachloride at 0-5°C, after the dropping is completed, continue to stir and react the mixture at 15-30°C; after the reaction is completed, perform extraction, washing, drying, and separation to obtain 3,6-diamantyl-2-hydroxy-1-naphthaldehyde; (3) add 3,6-diamantyl-2-hydroxy-1-naphthaldehyde and an amine compound into ethanol, and reflux and react for 5-7 h; perform filtration and washing to obtain a chiral tetradentate nitroxide salen ligand.

3. The process for the preparation of chiral tetradentate nitrenesal en ligands according to claim 2, characterized in that, In the step (1), the molar ratio of β-naphthol, 1-adamantanol, and methyl sulfonic acid is 1:2.5-3.5:2.5-3.

5.

4. The process for the preparation of chiral tetradentate nitrenesal en ligand according to claim 2, characterized in that, In the step (2), the molar ratio of 3,6-diamantyl-2-naphthol and 1,1-dichloromethyl methyl ether is 1-1.2:1-1.

2.

5. The process for the preparation of chiral tetradentate nitrenesal en ligands according to claim 2, characterized in that, In the step (3), the amine compound is chiral (1 S ,2 S )-1,2-diphenylethylenediamine or (1 S ,2 S )-1,2-cyclohexanediamine.

6. The process for the preparation of chiral tetradentate nitrenesal en ligand according to claim 2, characterized in that, In the step (3), the molar ratio of 3,6-diamantyl-2-hydroxy-1-naphthaldehyde and the amine compound is 2-2.5:

1.

7. The process for the preparation of chiral tetradentate nitrenesal en ligand according to claim 2, characterized in that, In the step (2), continue to stir and react for 1.5-3 h at 15-30°C.

8. The process for the preparation of chiral tetradentate nitrenesal en ligand as claimed in claim 2 wherein, The organic solvent is dichloromethane, chloroform, 1,2-dichloroethane, or toluene.

9. Application of the chiral tetradentate nitroxide salen ligand of claim 1 in synthesis of a chiral salen Ti complex.

10. The use according to claim 9, wherein the compound is ###0002### The method for synthesizing the chiral salen Ti complex from the chiral tetradentate nitroxide salen ligand comprises the following steps: add the chiral tetradentate nitroxide salen ligand into anhydrous tetrahydrofuran in a low-temperature reaction bath below -70°C, slowly drop titanium tetrachloride toluene solution under argon protection, after the dropping is completed, naturally and slowly warm the mixture, then reflux and react for 3-5 h; perform filtration, washing, and vacuum drying to obtain the chiral salen Ti complex.

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