Open-chain imine axially chiral compound and synthesis method thereof

Abstract

The invention discloses an open-chain imine axially chiral compound and a synthesis method thereof. According to the method, MBH carbonate and a (2-methoxynaphthalene-1-yl) (phenyl) methylenimine derivative are taken as raw materials, palladium acetate and a chiral phosphoramidite ligand are taken as catalysts, lithium carbonate is taken as alkali, methylbenzene is taken as a solvent, and the enantiomer-enriched open-chain imine axially chiral compound is obtained. The compound can react with m-chloroperoxybenzoic acid to realize efficient conversion from axial chirality to central chirality. The method has the advantages of mild reaction conditions, easily available raw materials, high product enantioselectivity and excellent yield, and provides a simple and efficient way for preparation and conversion application of open-chain imine axially chiral compounds.

Description

Technical Field

[0001] This invention relates to an open-chain imine axially chiral compound and its synthesis method, belonging to the field of organic synthesis chemistry technology. Background Technology

[0002] Chiral imines contain carbon-nitrogen double bonds, and the presence of the nitrogen atom increases their polarity and reactivity, making them more likely to participate in nucleophilic addition and condensation reactions. Chiral imines have broad application prospects as catalysts and chiral ligands (such as Salen ligands) in many fields of asymmetric synthesis. (Consiglio, G.; Oliveri, IP; Failla, S. Molecules, 2019, 4, 2413-2514.; A. Rosenthal, R.; Fish, B.; P. Hill, R. Anti-Cancer Agents in Medicinal Chemistry, 2011, 11, 359-372.; Liu, Y.; Xi, X.; Ye, C. Angewandte Chemie International Edition, 2014, 53, 13821-13825.; Zhu, W.; Du, L.; Li, W. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2018, 203, 501-509.) Due to the ease of hydrolysis and elimination of imine structures, they have poor stability and often appear as key intermediates. There is relatively little research on them, and maintaining their stability during the synthesis of imine raw materials and products remains a challenge.

[0003] Compared to cyclic axial chiral compounds, open-chain axial chiral compounds offer greater structural flexibility due to the lack of rigid constraints inherent in cyclic structures. This allows for adjustments to the molecular conformation and spatial arrangement as needed, facilitating more diverse molecular designs. In terms of applications, open-chain axial chiral compounds can be used to design catalysts, drug molecules, and polymer materials with specific properties. For instance, their optical activity can be modulated by altering the molecular conformation, providing possibilities for designing dynamically responsive materials. Summary of the Invention

[0004] The purpose of this invention is to provide a method for synthesizing open-chain imine axially chiral compounds, and to further achieve efficient conversion of them from axial chirality to central chirality.

[0005] The technical solution for achieving the objective of this invention is as follows:

[0006] An open-chain imine axially chiral compound has the following structural formula:

[0007]

[0008] Where R 1 Selected from hydrogen, methyl, or bromine, R 2 Selected from hydrogen, methoxy, or phenyl.

[0009] The method for synthesizing the above-mentioned open-chain imine axially chiral compounds includes the following steps:

[0010] Using (2-methoxynaphth-1-yl)(phenyl)methylimine derivative 1 and MBH carbonate 2 as reactants, palladium acetate and chiral phosphoramide ligand L as catalysts, lithium carbonate as base, and toluene as solvent, open-chain imine axial chiral compounds were synthesized.

[0011] The synthesis route is as follows:

[0012]

[0013] Preferably, the molar ratio of MBH carbonate to (2-methoxynaphth-1-yl)(phenyl)methylimine derivative is 3:1.

[0014] Preferably, the molar amount of palladium acetate is 10% of the molar amount of the (2-methoxynaphth-1-yl)(phenyl)methylimine derivative.

[0015] Preferably, the molar amount of lithium carbonate is 200% of the molar amount of the (2-methoxynaphth-1-yl)(phenyl)methylimine derivative.

[0016] Preferably, the molar amount of chiral phosphoramide ligand L is 25% of the molar amount of the (2-methoxynaphth-1-yl)(phenyl)methylimine derivative.

[0017] Preferably, the reaction temperature is -35℃ and the reaction time is 96h.

[0018] This invention utilizes an asymmetric allylation strategy to construct open-chain imine axially chiral compounds. Stable and readily available MBH carbonate and (2-methoxynaphth-1-yl)(phenyl)methylimine derivatives are used as reactants. The reaction conditions are mild, and the products exhibit excellent stereoselectivity and yield.

[0019] The open-chain imine axially chiral compound synthesized in this invention reacts with m-chloroperoxybenzoic acid to achieve the transformation from axial chirality to central chirality. Attached Figure Description

[0020] Figure 1 The hydrogen spectrum of tert-butyl acrylate (compound 3a) prepared in Example 1 is shown.

[0021] Figure 2 The carbon spectrum of tert-butyl acrylate (compound 3a) prepared in Example 1 is shown.

[0022] Figure 3 The photoluminescence spectrum of tert-butyl acrylate (compound 3b) prepared in Example 2 is shown.

[0023] Figure 4 The carbon spectrum of tert-butyl acrylate (compound 3b) prepared in Example 2 is shown.

[0024] Figure 5 The photoluminescence spectrum of tert-butyl acrylate (compound 3c) prepared in Example 3 is shown.

[0025] Figure 6 The carbon spectrum of tert-butyl acrylate (compound 3c) prepared in Example 3 is shown.

[0026] Figure 7 The 1H NMR spectrum of 2-((((2,6-dimethoxynaphthyl-1-yl)(phenyl)methylene)amino)methyl)tert-butyl acrylate (compound 3d) prepared in Example 4.

[0027] Figure 8 The carbon spectrum of 2-((((2,6-dimethoxynaphthyl-1-yl)(phenyl)methylene)amino)methyl)tert-butyl acrylate (compound 3d) prepared in Example 4.

[0028] Figure 9 The 1H NMR spectrum of 2-((((2,7-dimethoxynaphthyl-1-yl)(phenyl)methylene)amino)methyl)tert-butyl acrylate (compound 3e) prepared in Example 5.

[0029] Figure 10 The carbon spectrum of tert-butyl acrylate (compound 3e) prepared in Example 5 is shown.

[0030] Figure 11 The hydrogen spectrum of 2-((((2-methoxy-6-phenylnaphth-1-yl)(phenyl)methylene)amino)methyl)tert-butyl acrylate (compound 3f) prepared in Example 6.

[0031] Figure 12The carbon spectrum of tert-butyl acrylate (compound 3f) prepared in Example 6 is shown.

[0032] Figure 13 The 1H NMR spectrum of 2-[(3-(2,6-dimethoxynaphthyl-1-yl)-3-phenyl-1,2-oxazolidine-2-yl)methyl]tert-butyl acrylate (compound 4) prepared by application example 1.

[0033] Figure 14 The carbon spectrum of tert-butyl 2-[(3-(2,6-dimethoxynaphthyl-1-yl)-3-phenyl-1,2-oxazolidine-2-yl)methyl]acrylate (compound 4) prepared by application example 1. Detailed Implementation

[0034] The present invention will now be described in detail through specific embodiments. However, the uses and purposes of these examples are merely illustrative and do not constitute any limitation on the actual scope of protection of the present invention, nor are they intended to restrict the scope of protection of the present invention to these examples. The present invention will be further described in detail below through embodiments and accompanying drawings.

[0035] Example 1: Synthesis of tert-butyl 2-((((2-methoxynaphthyl-1-yl)(phenyl)methylene)amino)meth)acrylate 3a, the structure of which is:

[0036]

[0037] The specific steps are as follows:

[0038] Under an argon atmosphere, palladium acetate (2.2 mg, 0.01 mmol), chiral phosphoramidide ligand L (14.4 mg, 0.025 mmol), and 0.5 mL of toluene were sequentially added to a 4 mL reaction flask and pre-stirred at room temperature for 30 min. Then, MBH carbonate (77.4 mg, 0.03 mmol), (2-methoxynaphthyl-1-yl)(phenyl)methylimine (26.1 mg, 0.1 mmol), lithium carbonate (14.8 mg, 0.2 mmol), and 0.5 mL of toluene were added to the reaction flask, and the reaction was carried out at -35 °C. The reaction was monitored by TLC until complete. The crude product was purified by column chromatography to give open-chain imine axial chiral compound 3a, a pale yellow solid, with a yield of 70% and an ee value of 90%. The 1H and 1C spectra of the obtained compound 3a are shown below. Figure 1 and Figure 2 As shown.

[0039] 1H NMR(500MHz,Chloroform-d)δ7.94(d,J=9.0Hz,1H),7.87–7.81(m,1H),7.71–7.65(m,2H),7.42–7.37(m,1H),7.37–7.3 4(m,2H),7.34–7.26(m,4H),6.22(q,J=1.8Hz,1H),5.99(q,J=2.0Hz,1H),4.09–3.95(m,2H),3.82(s,3H),1.42(s,9H).

[0040] 13 C NMR(126MHz,Chloroform-d)δ166.06,165.88,153.41,140.58,139.39,131.46,130.50,130.03,128 .82,128.24,127.70,127.30,124.29,124.27,124.01,119.21,112.99,80.48,56.30,53.17,28.07.

[0041] Example 2: Synthesis of tert-butyl acrylate 3b of 2-((((2-methoxynaphthyl-1-yl)(p-tolyl)methylene)amino)methyl)methacrylate, the structure of which is:

[0042]

[0043] The specific steps are as follows:

[0044] Under an argon atmosphere, palladium acetate (2.2 mg, 0.01 mmol), chiral phosphoramide ligand L (14.4 mg, 0.025 mmol), and 0.5 mL of toluene were sequentially added to a 4 mL reaction flask and pre-stirred at room temperature for 30 min. Then, MBH carbonate (77.4 mg, 0.03 mmol), (2-methoxynaphthyl-1-yl)(p-tolyl)methylimine (27.6 mg, 0.1 mmol), lithium carbonate (14.8 mg, 0.2 mmol), and 0.5 mL of toluene were added to the reaction flask, and the reaction was carried out at -35 °C. The reaction was monitored by TLC until complete. The crude product was purified by column chromatography to give open-chain imine axial chiral compound 3b, a pale yellow solid, with a yield of 68% and an ee value of 90%. The 1H and 1C spectra of the obtained compound 3b are shown below. Figure 3 and Figure 4 As shown.

[0045] 1H NMR(500MHz,Chloroform-d)δ7.93(d,J=9.0Hz,1H),7.87–7.79(m,1H),7.57(d,J=7.9Hz,2H),7.44–7.28(m,4H),7.10( d,J=7.9Hz,2H),6.21(d,J=2.2Hz,1H),5.98(q,J=2.1Hz,1H),4.06–3.92(m,2H),3.81(s,3H),2.33(s,3H),1.42(s,9H).

[0046] 13 C NMR(126MHz,Chloroform-d)δ166.10,153.40,140.70,140.19,131.53,130.39,129.00,128.85,12 8.19,127.71,127.26,124.38,124.21,124.00,113.07,80.43,56.35,53.07,29.37,28.08,21.38.

[0047] Example 3: Synthesis of tert-butyl 2-((((2-methoxynaphthyl-1-yl)(p-bromophenyl)methylene)amino)methyl)acrylate 3c, the structure of which is:

[0048]

[0049] The specific steps are as follows:

[0050] Under an argon atmosphere, palladium acetate (2.2 mg, 0.01 mmol), chiral phosphoramide ligand L (14.4 mg, 0.025 mmol), and 0.5 mL of toluene were sequentially added to a 4 mL reaction flask and pre-stirred at room temperature for 30 min. Then, MBH carbonate (77.4 mg, 0.03 mmol), (2-methoxynaphthyl-1-yl)(p-bromophenyl)methylimine (33.9 mg, 0.1 mmol), lithium carbonate (14.8 mg, 0.2 mmol), and 0.5 mL of toluene were added to the reaction flask, and the reaction was carried out at -35 °C. The reaction was monitored by TLC until complete. The crude product was purified by column chromatography to give open-chain imine axial chiral compound 3c, a pale yellow solid, with a yield of 70% and an ee value of 90%. The 1H and 1C spectra of the obtained compound 3c are shown below. Figure 5 and Figure 6 As shown.

[0051] 1H NMR(500MHz,Chloroform-d)δ7.95(d,J=9.1Hz,1H),7.86–7.82(m,1H),7.56–7.52(m,2H),7.43–7.39(m,2H), 7.37–7.32(m,4H),6.21(q,J=1.8Hz,1H),5.93(q,J=2.0Hz,1H),4.04–3.93(m,2H),3.82(s,3H),1.42(s,9H).

[0052] 13 C NMR(126MHz,Chloroform-d)δ166.00,164.88,153.46,140.48,138.33,131.44,131.33,130.76,129.30 ,128.85,128.34,127.49,124.59,124.26,124.14,124.04,118.57,112.95,80.56,56.30,53.33,28.08.

[0053] Example 4: Synthesis of tert-butyl 2-((((2,6-dimethoxynaphthyl-1-yl)(phenyl)methylene)amino)meth)acrylate 3d, the structure of which is:

[0054]

[0055] The specific steps are as follows:

[0056] Under an argon atmosphere, palladium acetate (2.2 mg, 0.01 mmol), chiral phosphoramide ligand L (14.4 mg, 0.025 mmol), and 0.5 mL of toluene were sequentially added to a 4 mL reaction flask and pre-stirred at room temperature for 30 min. Then, MBH carbonate (77.4 mg, 0.03 mmol), (2,6-dimethoxynaphthyl-1-yl)(phenyl)methylimine (29.1 mg, 0.1 mmol), lithium carbonate (14.8 mg, 0.2 mmol), and 0.5 mL of toluene were added to the reaction flask, and the reaction was carried out at -35 °C. The reaction was monitored by TLC until complete. The crude product was purified by column chromatography to obtain open-chain imine axial chiral compound 3d, a pale yellow solid, with a yield of 80% and an ee value of 96%. The proton and carbon spectra of the obtained compound 3d are shown below. Figure 7 and Figure 8 As shown.

[0057] 1H NMR(500MHz,Chloroform-d)δ7.82(d,J=9.0Hz,1H),7.70–7.64(m,2H),7.38–7.27(m,5H),7.14(d,J=2.6Hz,1H),7.01(dd, J=9.2,2.6Hz,1H),6.21(q,J=1.8Hz,1H),5.97(q,J=2.0Hz,1H),4.08–3.93(m,2H),3.89(s,3H),3.79(s,3H),1.43(s,9H).

[0058] 13 C NMR(126MHz,Chloroform-d)δ166.08,165.95,156.35,151.96,140.61,139.43,130.05,129.89,129.03,12 8.26,127.72,126.79,125.85,124.27,120.17,119.62,113.71,106.28,80.49,56.45,55.34,53.22,28.10.

[0059] Example 5: Synthesis of tert-butyl 2-((((2,7-dimethoxynaphthyl-1-yl)(phenyl)methylene)amino)meth)acrylate 3e, the structure of which is:

[0060]

[0061] The specific steps are as follows:

[0062] Under an argon atmosphere, palladium acetate (2.2 mg, 0.01 mmol), chiral phosphoramide ligand L (14.4 mg, 0.025 mmol), and 0.5 mL of toluene were sequentially added to a 4 mL reaction flask and pre-stirred at room temperature for 30 min. Then, MBH carbonate (77.4 mg, 0.03 mmol), (2,7-dimethoxynaphthyl-1-yl)(phenyl)methylimine (29.1 mg, 0.1 mmol), lithium carbonate (14.8 mg, 0.2 mmol), and 0.5 mL of toluene were added to the reaction flask, and the reaction was carried out at -35 °C. The reaction was monitored by TLC until complete. The crude product was purified by column chromatography to give the open-chain imine axial chiral compound 3e, a pale yellow solid, with a yield of 73% and an ee value of 87%. The 1H and 1C spectra of the obtained compound 3e are shown below. Figure 9 and Figure 10 As shown.

[0063] 1H NMR(500MHz,Chloroform-d)δ7.84(d,J=9.0Hz,1H),7.74–7.66(m,3H),7.39–7.28(m,3H),7.17(d,J=9.0Hz,1H),6.99(dd,J=9.0,2.5Hz ,1H),6.64(d,J=2.5Hz,1H),6.21(q,J=1.8Hz,1H),5.96(q,J=2.0Hz,1H),4.06(t,J=1.6Hz,2H),3.79(s,3H),3.66(s,3H),1.43(s,9H).

[0064] 13 C NMR(126MHz,Chloroform-d)δ166.33,166.03,158.83,154.19,140.78,139.45,132.85,130.18,129.98,12 9.79,128.24,127.71,124.34,124.12,118.34,116.94,110.32,102.42,80.51,56.22,55.22,53.25,28.08.

[0065] Example 6: Synthesis of tert-butyl 2-((((2-methoxy-6-phenylnaphth-1-yl)(phenyl)methylene)amino)methyl)acrylate 3f, the structure of which is:

[0066]

[0067] The specific steps are as follows:

[0068] Under an argon atmosphere, palladium acetate (2.2 mg, 0.01 mmol), chiral phosphoramide ligand L (14.4 mg, 0.025 mmol), and 0.5 mL of toluene were sequentially added to a 4 mL reaction flask and pre-stirred at room temperature for 30 min. Then, MBH carbonate (77.4 mg, 0.03 mmol), (2-methoxy-6-phenylnaphth-1-yl)(phenyl)methylimine (33.7 mg, 0.1 mmol), lithium carbonate (14.8 mg, 0.2 mmol), and 0.5 mL of toluene were added to the reaction flask, and the reaction was carried out at -35 °C. The reaction was monitored by TLC until complete. The crude product was purified by column chromatography to give the open-chain imine axial chiral compound 3f, a pale yellow solid, with a yield of 80% and an ee value of 95%. The 1H and 1C spectra of the obtained compound 3f are shown below. Figure 11 and Figure 12 As shown.

[0069] 1H NMR(500MHz,Chloroform-d)δ7.95(d,J=1.9Hz,1H),7.91(d,J=9.0Hz,1H),7.65–7.62(m,2H),7.60–7.56(m,2H),7.52(dd,J=8.7,1.8H z,1H),7.40–7.34(m,3H),7.31–7.20(m,5H),6.15(d,J=1.9Hz,1H),5.93(q,J=2.1Hz,1H),4.06–3.90(m,2H),3.75(s,3H),1.34(s,9H).

[0070] 13 C NMR(126MHz,Chloroform-d)δ166.09,165.81,153.57,140.88,140.61,139.41,136.82,130.83,130.68,130.10,129.12 ,128.88,128.31,127.75,127.28,127.25,127.09,126.10,124.88,124.31,119.17,113.45,80.53,56.36,53.25,28.10.

[0071] Application Example 1: Synthesis of tert-butyl 2-[(3-(2,6-dimethoxynaphthyl-1-yl)-3-phenyl-1,2-oxazolidine-2-yl)methyl]acrylate, the structure of which is:

[0072]

[0073] Under an argon atmosphere, 3D (43.1 mg, 0.01 mmol), m-chloroperoxybenzoic acid (34.5 mg, 0.02 mmol), and dichloromethane (1 mL) were added to a reaction flask. The reaction was carried out at room temperature for 1 h, and the reaction was monitored by TLC until complete. Dichloromethane was removed by rotary evaporation, and the crude product was purified by column chromatography to obtain a central chiral compound 4 with an oxazine heterocyclic propane structure, a pale yellow solid, with a yield of 78% and an ee value of 93%. The proton and carbon spectra of the obtained compound 4 are shown below. Figure 13 and Figure 14 As shown.

[0074] 1H NMR(500MHz,Chloroform-d)δ8.13–8.07(m,2H),7.89(d,J=9.1Hz,1H),7.46(d,J=9.2Hz,1H),7.32(d,J=9.1Hz,1H),7.29(td,J=5.5,5.0,1.5Hz,3H),7.15(d,J=2.6Hz,1H),7.09(dd,J=9.2,2.6Hz,1H),6.27(d,J=1.1Hz,1H),5.94(q,J=1.5Hz,1H),4.67–4.52(m,2H),3.89(s,3H),3.83(s,3H),1.36(s,9H).

[0075] 13 C NMR(126 MHz,Chloroform-d)δ164.55,156.51,153.33,141.47,134.93,133.19,130.60,130.03,129.67,129.49,127.94,127.18,125.77,120.77,117.42,113.49,106.34,81.05,62.92,56.25,55.36,27.92.

Claims

1. An open-chain imine-based axially chiral compound, characterized by, The structural formula is as follows: wherein, when R 1 is selected from hydrogen, methyl or bromo, R 2 is selected from hydrogen, methoxy or phenyl.

2. A method for synthesizing an open-chain imine-based axially chiral compound according to claim 1, characterized by, The method comprises the following steps: The open-chain imine axial chiral compound is synthesized by using (2-methoxynaphthalen-1-yl)(phenyl)methyl imine derivative 1 and MBH carbonate 2 as reaction raw materials, using palladium acetate and chiral phosphoramidite ligand L as a catalyst, using lithium carbonate as a base, and using toluene as a solvent. wherein, when R 1 is selected from hydrogen, methyl or bromo, R 2 is selected from hydrogen, methoxy or phenyl.

3. The method of synthesis of claim 2, wherein, The molar ratio of the MBH carbonate and the (2-methoxynaphthalen-1-yl)(phenyl)methyl imine derivative is 3:

1.

4. The method of synthesis of claim 2, wherein, The molar amount of the palladium acetate is 10% of the molar amount of the (2-methoxynaphthalen-1-yl)(phenyl)methyl imine derivative.

5. The method of synthesis of claim 2, wherein, The molar amount of the lithium carbonate is 200% of the molar amount of the (2-methoxynaphthalen-1-yl)(phenyl)methyl imine derivative.

6. The method of synthesis of claim 2, wherein, The molar amount of the chiral phosphoramidite ligand L is 25% of the molar amount of the (2-methoxynaphthalen-1-yl)(phenyl)methyl imine derivative.

7. The method of synthesis of claim 2, wherein, The reaction temperature is -35 DEG C, and the reaction time is 96 h.

8. Use of an open-chain imine-based axially chiral compound according to claim 1, characterized in that The axial chirality is converted into central chirality by reacting with meta-chloro peroxybenzoic acid.

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