Ferrocene nitrogen phosphine chiral ligand and preparation method thereof
Through a simplified method for preparing ferrocene-type nitrogen phosphine chiral ligands, the problems of complex structure and cumbersome synthesis path of existing PN-type chiral ligands are solved, and efficient and simple enantioselective preparation is achieved, which is suitable for asymmetric catalytic reactions.
Patent Information
- Application Number
- CN202510961758.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-14
- Publication Date
- 2025-10-17
AI Technical Summary
Existing PN-type chiral ligands have complex structures, cumbersome synthetic routes, and limited enantioselectivity and substrate adaptability, which restricts their promotion and application in catalytic systems.
The invention adopts a method for preparing a ferrocenyl nitrogen phosphine chiral ligand, wherein 2-ferrocenyl vinylquinoline compound and diphenylphosphine oxide are dissolved in a dry solvent under an inert gas atmosphere, a chiral phosphoric acid catalyst is added for reaction, and the molar ratio and reaction conditions are optimized to obtain a ferrocenyl nitrogen phosphine chiral ligand.
The synthesis conditions are mild, the operation is simple, the environmental compatibility is good, the yield is high, the enantioselectivity is excellent, it is suitable for asymmetric catalysis, and has strong practical value.
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Figure CN120795041A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of chemistry, and particularly relates to a ferrocene type nitrogen phosphine chiral ligand and a preparation method thereof. BACKGROUND
[0002] Chiral ligands play a core role in asymmetric catalysis, and can realize efficient enantioselective conversion by regulating the stereochemical environment of metal catalytic centers. Among them, P-N type bidentate chiral ligands containing phosphine and nitrogen donor groups have strong coordination ability, good electronic regulation and adjustable spatial configuration, and show excellent performance in transition metal catalyzed addition, coupling, hydrogenation and other reactions. Ferrocene is a rigid, electron-rich and easily functionalized sandwich type metal organic framework, and has unique advantages in constructing chiral ligands with stereo recognition ability, and is widely used in developing efficient ligands with planar chirality or central chirality. Although a variety of P-N type chiral ligands have been developed for asymmetric catalytic reactions, their structures are generally complex, most of the synthesis paths depend on multi-step reactions, the preparation process is complicated, and the enantioselectivity and substrate adaptability are still limited. These factors limit the popularization and application of the chiral ligands in actual catalytic systems to some extent. Therefore, developing P-N type chiral ligands with simpler structure, mild synthesis conditions, wide applicability and high enantioselectivity is still an important research direction of current chiral catalytic ligand design. SUMMARY
[0003] To solve or partially solve the problems in the related art, the application provides a ferrocene type nitrogen phosphine chiral ligand and a preparation method thereof.
[0004] The application provides a preparation method of a ferrocene type nitrogen phosphine chiral ligand, which comprises the following steps: under an inert gas atmosphere, 2-ferrocene vinyl quinoline compounds and diphenyl phosphine oxide are dissolved in a dry solvent, and then a chiral phosphoric acid catalyst is added to react to obtain the ferrocene type nitrogen phosphine chiral ligand.
[0005] Preferably, the molar ratio of the 2-ferrocene vinyl quinoline compounds and the diphenyl phosphine oxide is 1:1-1:5, and more preferably, the molar ratio of the 2-ferrocene vinyl quinoline compounds and the diphenyl phosphine oxide is 1:2.
[0006] Preferably, the structure formula of the 2-ferrocene vinyl quinoline compounds is as follows: In the formula, R is any one of hydrogen, an alkyl group and a halogen-substituted group.
[0007] Preferably, the chiral phosphoric acid catalyst is ( S)-3,3'-bis(9-anthryl)-1,1'-binaphthyl phosphonate, (S)-3,3'-diphenyl-1,1'-binaphthyl phosphonate or (S)-3,3'-bis(2-naphthyl)-1,1'-binaphthyl phosphonate. S )-3,3'-bis(9-anthryl)-1,1'-binaphthyl phosphonate.
[0008] Preferably, the molar ratio of the diphenyl phosphine oxide to the chiral phosphoric acid is 1:0.05-0.15; more preferably, the molar ratio of the diphenyl phosphine oxide to the chiral phosphoric acid is 1:0.1.
[0009] Preferably, the reaction temperature is 50-120℃ and the reaction time is 2-6h; more preferably, the reaction temperature is 70℃ and the reaction time is 4h.
[0010] Preferably, the dry solvent is one or more of dry toluene, dry tetrahydrofuran, dry dichloromethane, dry acetonitrile, dry cyclopentyl methyl ether; more preferably, the dry solvent is dry cyclopentyl methyl ether.
[0011] Preferably, the inert gas is nitrogen or argon; more preferably, the inert gas is argon.
[0012] The present application also claims the ferrocene type nitrogen phosphine chiral ligand prepared by the method for preparing a ferrocene type nitrogen phosphine chiral ligand, and the structural formula is: The ferrocene type nitrogen phosphine chiral ligand can be used as a chiral control ligand in asymmetric reactions.
[0013] The technical scheme provided by the present application has the following beneficial effects: the synthesis method has mild reaction conditions and simple operation, does not need to use metal catalysts or harsh conditions, and has good environmental compatibility. The raw materials used are easy to obtain, have wide application range, the prepared chiral ligand has high yield and excellent enantioselectivity, is suitable for conventional use in asymmetric catalysis, and has strong practical value and popularization potential. BRIEF DESCRIPTION OF DRAWINGS
[0014] Figure 1 The nuclear magnetic spectrum of the target product prepared in Example 1.
[0015] Figure 2 The nuclear magnetic spectrum of the target product prepared in Example 2.
[0016] Figure 3 The HPLC chromatogram of the target product prepared in Example 1, (a) is the liquid phase spectrum of the racemic product, and (b) is the liquid phase spectrum of the chiral product.
[0017] Figure 4HPLC chromatograms of the target product prepared in Example 2, (a) is the liquid phase spectrum of the racemic sample of the product, and (b) is the liquid phase spectrum of the chiral sample of the product.
[0018] Figure 5 This is the NMR spectrum of the target product prepared in Example 3.
[0019] Figure 6 HPLC chromatograms of the target product prepared in Example 3, (a) is the liquid phase spectrum of the racemic sample of the product, and (b) is the liquid phase spectrum of the chiral sample of the product.
[0020] Figure 7 This is the NMR spectrum of the target product prepared in Example 4.
[0021] Figure 8 HPLC chromatograms of the target product prepared in Example 4, (a) is the liquid phase spectrum of the racemic sample of the product, and (b) is the liquid phase spectrum of the chiral sample of the product. DETAILED DESCRIPTION
[0022] In the present invention, the NMR spectrum is measured by a Bruker AV400 superconducting nuclear magnetic resonance instrument, wherein the deuterated reagent is deuterated chloroform (CDCl3), and the hydrogen spectrum uses tetramethylsilane as the internal standard.
[0023] 200-300 mesh silica gel columns for column chromatography were purchased from Beijing Inokai Technology Co., Ltd.; 0.2 mm thin-layer chromatography silica gel plates for TLC were purchased from Yantai Institute of Chemical Industry. Unless otherwise specified, all reagents and solvents used in this invention were purified using standard methods (see the Reagent Purification Handbook).
[0024] The structural formula of the novel ferrocenyl PN bidentate chiral ligand reaction substrate of the present invention is shown below: The ferrocenyl PN bidentate chiral ligand and its synthesis method of the present invention are as follows: 2-ferrocenyl vinylquinoline compound and diphenylphosphine oxide are added to a dry solvent under an inert gas atmosphere, and then a chiral phosphoric acid catalyst is added to react at 50-120°C to obtain the target product. The general reaction formula is as follows: Wherein: R is any one of hydrogen, alkyl, and halogen.
[0025] The chiral phosphoric acid catalyst is ( S )-3,3'-bis(9-anthryl)-1,1'-binaphthol phosphate, (S)-3,3'-diphenyl-1,1'-binaphthol phosphate or (S)-3,3'-bis(2-naphthyl)-1,1'-binaphthol phosphate; the molar ratio of the diphenylphosphine oxide to the 2-ferrocenylvinylquinoline compound is 1:(1~1.5).
[0026] ( S) the CSA of 3,3'-bis(9-anthryl)-1,1'-binol phosphate: 361342-52-1, the CSA of (S)-3,3'-diphenyl-1,1'-binol phosphate: 874948-59-1, the CSA of (S)-3,3'-bis(2-naphthyl)-1,1'-binol phosphate: 874948-60-4, the chiral phosphoric acid catalysts used in the experiment are all purchased from the official website of Leyen Reagent.
[0027] The molar ratio of the diphenyl phosphine oxide and the chiral phosphoric acid is 1:(0.05~0.15).
[0028] The inert gas is nitrogen or argon.
[0029] The dry solvent is one or more of dry toluene, dry tetrahydrofuran, dry dichloromethane, dry acetonitrile, and dry cyclopentyl methyl ether.
[0030] More preferably, the temperature of the reaction is 70℃, and the reaction time is 3~6 hours.
[0031] The preparation method of 2-ferrocenylvinyl-4-chloroquinoline, 2-ferrocenylvinyl-7-chloroquinoline, 2-ferrocenylvinylquinoline, and 2-ferrocenylvinyl 6-methyl-quinoline used in the embodiments of the present application respectively comprises the following steps: In a dry round-bottom flask equipped with a magnetic stirrer, ferrocene formaldehyde (5.0 mmol, 1.0 equiv.), 2-methyl quinoline compound (6.0 mmol, 1.2 equiv.) (the used quinoline compounds are shown in the following formula, and are all purchased from the official website of Leyen Reagent) and ferrous acetate (10 mol%) are sequentially added. Then 30 mL of anhydrous toluene is added as a reaction solvent, and the mixture is fully dissolved before gas replacement operation is performed. Nitrogen is blown to ensure that the reaction system is in an inert atmosphere. Then trifluoroacetic acid (10 mol%) is added as a co-catalyst. Under continuous nitrogen protection, the reaction system is heated and stirred in an oil bath at 120℃ for 72 hours. After the reaction is completed, it is cooled to room temperature, concentrated under reduced pressure, and then the crude product is separated and purified by silica gel column chromatography (PE / EA: 15:1) to obtain the target product.
[0032] Among them, the raw material 2-methyl quinoline compound used for 2-ferrocenylvinyl-4-chloroquinoline is 4-chloroquinaldine; The raw material 2-methyl quinoline compound used for 2-ferrocenylvinyl-7-chloroquinoline is 7-chloroquinaldine; The raw material 2-methyl quinoline compound used for 2-ferrocenylvinylquinoline is 2-methyl quinoline; The raw material 2-methylquinoline compound used in 2-ferrocenylvinyl 6-methyl-quinoline is: 2,6-dimethylquinoline. Example 1
[0033] Under argon atmosphere, 0.2 mmol of diphenylphosphine oxide, 0.24 mmol of 2-ferrocenylvinyl-4-chloroquinoline and 10 mol% of catalyst ( S )-3,3'-bis(9-anthryl)-1,1'-binaphthol phosphate was added to a Schlenk tube equipped with a magnetic stirrer. 2 ml of cyclopentyl methyl ether was then added dropwise as a solvent to dissolve the system. Under argon protection, the reaction was stirred in an oil bath at 70°C and monitored by TLC until the diphenylphosphine oxide was completely consumed. Wherein diphenylphosphine oxide, 2-ferrocenylvinyl-4-chloroquinoline and catalyst ( S The residue was purified by silica gel column chromatography to obtain the target product as a yellow liquid with a yield of 95% and an ee value of 93%. like Figure 1 and 3 , 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 18.5, 8.1 Hz, 2H),7.76 (t, J = 7.4Hz, 1H), 7.57 (dd, J = 18.5, 10.8 Hz, 5H), 7.39 (d, J = 7.1 Hz, 1H),7.31 (s,2H), 7.10 (d, J = 8.0 Hz, 2H), 6.97 (s, 2H), 4.43 (s, 1H), 4.31 (s, 1H), 4.13(d, J = 7.1 Hz, 6H), 3.83 (d, J = 56.7 Hz, 3H), 3.58 (s, 1H); HPLC analysis: chiracel-ADH, n -heptane / i- PrOH 80:20, 1ml / min, 20℃, detection at254nm.Retention time (min):20.44(major) and 26.45(minor). Example 2
[0034] A Schlenk tube equipped with a magnetic stirrer was charged with 0.2 mmol of diphenylphosphine oxide, 2-dicyclohexylvinyl-7-chloroquinoline and catalyst S )-3,3'-bis(9-anthryl)-1,1'-binol phosphate. Then 2 ml of cyclopentyl methyl ether as solvent was added dropwise to dissolve the system. The reaction was stirred at 70 °C under argon protection. TLC was used to monitor until the complete consumption of diphenylphosphine oxide. The molar ratio of diphenylphosphine oxide, 2-dicyclohexylvinyl-4-chloroquinoline and catalyst S )-3,3'-bis(9-anthryl)-1,1'-binol phosphate was 1:1.2:0.1. The residue was purified by silica gel column chromatography to give the target product as a yellow solid with a yield of 96% and an ee value of 99%. As Figure 2 and 4 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.72 (d, J = 8.4 Hz,1H), 7.60 (dd, J = 11.6, 8.1 Hz, 3H), 7.51 (dd, J = 11.0, 7.7 Hz, 2H), 7.46 – 7.37 (m,2H),7.30 (td, J = 7.6, 2.5 Hz, 2H), 7.13 (t, J = 7.5 Hz, 1H), 7.06 – 6.96 (m,3H), 4.55– 4.49 (m, 1H), 4.29 (s, 1H), 4.12 (s, 1H), 4.06 (s, 5H), 3.89 (s,1H), 3.81 (ddd, J =15.3, 10.6, 5.9 Hz, 2H), 3.55 (s, 1H) ; HPLC analysis:chiracel-ADH, n -heptane / i- PrOH 70:30, 1ml / min, 20℃, detection at 254nm.Retention time (min):14.55(major) and 18.30(minor). Example 3
[0035] Under argon atmosphere, 0.2 mmol diphenylphosphine oxide, 2-ferrocenylvinylquinoline and catalyst (S)-3,3'-diphenyl-1,1'-binol phosphate were added into a Schlenk tube equipped with a magnetic stirrer. Then 2 ml cyclopentyl methyl ether as solvent was added dropwise to dissolve the system, the reaction was stirred in an oil bath at 50 °C under argon protection, and monitored by TLC until the complete consumption of diphenylphosphine oxide. The molar ratio of diphenylphosphine oxide, 2-ferrocenylvinylquinoline and catalyst (S)-3,3'-diphenyl-1,1'-binol phosphate was 1:1:0.15. The residue was purified by silica gel column chromatography to obtain the target product as a yellow liquid with a yield of 94% and an ee value of 61%. As Figure 5 and 6 , 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.3 Hz,1H), 7.71 (dd, J = 12.3, 7.8 Hz, 2H), 7.62 (dd, J = 10.7, 7.9 Hz, 2H), 7.51(dq, J = 14.2, 7.6 Hz, 3H), 7.39 (t, J = 7.4 Hz, 1H), 7.30 (td, J = 7.7, 2.7Hz, 2H), 7.13 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.99 (dt, J =7.9, 3.9 Hz, 2H), 4.56 (d, J = 6.5 Hz, 1H), 4.32 (s, 1H), 4.12 (s, 1H), 4.04(s, 5H), 3.89 (s, 1H), 3.81 (dd, J = 15.9, 6.6 Hz, 2H), 3.55 (s, 1H). Example 4
[0036] Under argon, 0.2 mmol of diphenylphosphine oxide, 2-ferrocenylvinyl-6-methylquinoline, and the catalyst (S)-3,3'-bis(2-naphthyl)-1,1'-binaphthol phosphate were added to a Schlenk tube equipped with a magnetic stirrer. 2 ml of cyclopentyl methyl ether was then added dropwise to dissolve the system. Under argon, the reaction was stirred in an oil bath at 120°C and monitored by TLC until the diphenylphosphine oxide was completely consumed. The molar ratio of diphenylphosphine oxide, 2-ferrocenylvinyl-6-methylquinoline, and the catalyst (S)-3,3'-bis(2-naphthyl)-1,1'-binaphthol phosphate was 1:1.5:0.05. The residue was purified by silica gel column chromatography to obtain the desired product as a yellow liquid in a 98% yield and 45% ee. like Figure 7 and 8 , 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.6 Hz, 1H), 7.69 – 7.62 (m, 3H), 7.55 – 7.50 (m, 3H), 7.45 (s, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.32 – 7.27 (m,2H), 7.15 (t, J = 7.5 Hz, 1H), 7.01 (dd, J = 8.8, 5.5 Hz, 3H), 4.56 (q, J =6.4 Hz, 1H), 4.31 (s, 1H), 4.13 – 4.09 (m, 1H), 4.01 (s, 5H), 3.88 (s, 1H), 3.77 (dd, J = 16.7, 5.9 Hz, 2H), 3.55 (s, 1H), 2.52 (s, 3H). Comparative Example 1 Under argon atmosphere, 0.2 mmol of diphenylphosphine oxide, 2-ferrocenylvinylquinoline and catalyst ( S )-3,3'-bis(9-naphthyl)-1,1'-binaphthol phosphate was added to a Schlenk tube equipped with a magnetic stirrer. 2 ml of cyclopentyl methyl ether was then added dropwise as a solvent to dissolve the system. Under argon protection, the reaction was stirred in an oil bath at 70°C and monitored by TLC until the diphenylphosphine oxide was completely consumed. SThe molar ratio of )-3,3'-bis(9-naphthyl)-1,1'-binaphthol phosphate was 1:1.5:0.05. The residue was purified by silica gel column chromatography to obtain the target product as a yellow liquid with a yield of 91% and an ee value of 54%.
[0037] Comparative Example 2 Under argon atmosphere, 0.2 mmol of diphenylphosphine oxide, 2-ferrocenylvinylquinoline and catalyst ( S )-3,3'-bis(9-phenyl)-1,1'-binaphthol phosphate was added to a Schlenk tube equipped with a magnetic stirrer. 2 ml of cyclopentyl methyl ether was then added dropwise as a solvent to dissolve the system. Under argon protection, the reaction was stirred in an oil bath at 70°C and monitored by TLC until diphenylphosphine oxide was completely consumed. S The residue was purified by silica gel column chromatography to obtain the target product as a yellow liquid with a yield of 90% and an ee value of 52%.
[0038] While various embodiments of the present invention have been described above, the foregoing description is intended to be illustrative, non-exhaustive, and not limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is selected to best explain the principles of the embodiments, their practical applications, or improvements to existing technologies, or to enable others skilled in the art to understand the embodiments disclosed herein.
Claims
1. A method for preparing a ferrocene-based nitrogen phosphine chiral ligand, characterized in that: The method comprises the following steps: dissolving 2-ferrocenyl vinylquinoline compounds and diphenylphosphine oxide in a dry solvent under an inert gas atmosphere, and then adding a chiral phosphoric acid catalyst to react and obtain a ferrocenyl nitrogen phosphine chiral ligand.
2. The method for preparing the ferrocenium nitrogen phosphine chiral ligand according to claim 1, wherein: The molar ratio of the 2-ferrocenylvinylquinoline compound to diphenylphosphine oxide is 1:1-1:
5.
3. The method for preparing the ferrocenium nitrogen phosphine chiral ligand according to claim 1, characterized in that: The structural formula of the 2-ferrocenylvinylquinoline compound is: ; Wherein R is any one of hydrogen, alkyl, and halogen.
4. The method for preparing the ferrocenium nitrogen phosphine chiral ligand according to claim 1, wherein: The chiral phosphoric acid catalyst is ( S )-3,3'-bis(9-anthryl)-1,1'-binaphthol phosphate, (S)-3,3'-diphenyl-1,1'-binaphthol phosphate or (S)-3,3'-bis(2-naphthyl)-1,1'-binaphthol phosphate.
5. The method for preparing the ferrocenium nitrogen phosphine chiral ligand according to claim 1, characterized in that: The molar ratio of the diphenylphosphine oxide to the chiral phosphoric acid is 1:(0.05-0.15).
6. The method for preparing the ferrocenium nitrogen phosphine chiral ligand according to claim 1, characterized in that: The reaction temperature is 50-120°C.
7. The method for preparing the ferrocenium nitrogen phosphine chiral ligand according to claim 1, characterized in that: The dry solvent is one or more of dry toluene, dry tetrahydrofuran, dry dichloromethane, dry acetonitrile, and dry cyclopentyl methyl ether.
8. The ferrocenyl phosphine chiral ligand prepared by the method for preparing the ferrocenyl phosphine chiral ligand according to any one of claims 1 to 7 has the structural formula: .