Method for synthesizing multi-ferrocenyl compounds by using multi-component reaction and application thereof

Abstract

The application relates to a method for synthesizing a bisferrocenyl compound by using a multi-component reaction and application, and the synthesis method is as follows: adding ferrocene formaldehyde, aminoferrocene, a Lewis acid, anhydrous dichloromethane and anhydrous diethyl ether into a reaction bottle, stirring and dissolving for reaction, then adding acetylferrocene, adding trimethylchlorosilane under stirring, continuing the reaction at room temperature, adding an inorganic alkali aqueous solution after the reaction is completed, extracting with an organic solvent, combining the organic phases, concentrating the solvent, and purifying the crude product through silica gel column chromatography to obtain the target compound. The application synthesizes a novel compound 1,3-bisferrocenyl-3-ferrocenylamino propanone containing three ferrocene groups by using acetylferrocene, ferrocene formaldehyde and aminoferrocene as raw materials and through a Mannich three-component reaction under acidic conditions, and the novel compound exhibits superior antioxidant activity, and the antioxidant performance is superior to that of corresponding single ferrocene group compounds and bisferrocene group compounds, and the novel compound has potential application value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method and application for synthesizing ferrocene-based compounds using multi-component reactions. Background Technology

[0002] Integrating multiple functional skeletal structures and functional groups into a single molecule has become a hot topic in organic synthesis research. Ferrocene groups are organometallic functional groups, and their derivatives exhibit various physiological and pharmacological activities, including antioxidant, antitumor, and antibacterial effects. Therefore, integrating multiple ferrocene groups into a single molecule could lead to the development of novel compounds with even higher physiological and pharmacological activities. However, to date, only a very few bisferrocene compounds have been reported for synthesis, and no studies on the synthesis of molecules integrating three or more ferrocene groups into a single molecule and their antioxidant properties have been reported. Therefore, it is necessary to conduct research on the efficient synthesis of polyferrocene amino compounds.

[0003] Multicomponent reactions refer to synthetic methods that simultaneously add three or more raw materials to a reaction system, generating a product containing the major structural fragments of all the raw materials in a single step. In the synthesis of complex compounds, multicomponent reactions reduce the numerous separation and post-processing operations required by traditional synthetic strategies. Generally, multicomponent reactions only require starting from a few structurally simple raw materials, and the target structure can be obtained in a single step. This reduces waste, saves energy, shortens the synthetic route, and saves working time, thus significantly improving synthetic efficiency. Furthermore, the high substitutability and wide applicability of multicomponent reaction substrates give them a significant advantage in constructing complex and diverse compounds. Based on this, this study synthesized a novel compound containing three ferrocene groups, 1,3-diferrocene-3-ferroceneaminoacetone, under acidic conditions via a Mannich three-component reaction, using acetylferrocene, ferrocene formaldehyde, and aminoferrocene as raw materials, with a yield of 52.68%. Its structure was characterized by 1H NMR, 13C NMR, and HR-MS (ESI). Summary of the Invention

[0004] The purpose of this invention is to provide a method and application for synthesizing bisferrocene-based compounds using a multi-component reaction. Using acetylferrocene, ferrocene formaldehyde, and aminoferrocene as raw materials, a novel compound containing three ferrocene groups, 1,3-bisferrocene-3-ferrocene aminoacetone, with excellent antioxidant activity, was synthesized under acidic conditions via a Mannich three-component reaction.

[0005] To achieve the above objectives, this application employs the following technical solution:

[0006] A method for synthesizing a bisferrocene-based compound using a multi-component reaction, wherein the bisferrocene-based compound is 1,3-bisferrocene-3-ferroceneaminoacetone, includes the following steps:

[0007]

[0008] Ferrocene formaldehyde, aminoferrocene, Lewis acid, anhydrous dichloromethane, and anhydrous diethyl ether were added to a reaction flask. The mixture was stirred to dissolve and the reaction was allowed to proceed for a set time. Then, acetylferrocene was added, followed by trimethylchlorosilane under stirring. The reaction was continued at room temperature. After the reaction was completed, an inorganic base aqueous solution was added, followed by extraction with an organic solvent. The organic phases were combined, concentrated in the solvent, and the crude product was purified by silica gel column chromatography to obtain the target compound.

[0009] Furthermore, the molar ratio of ferrocene formaldehyde, aminoferrocene, acetylferrocene, Lewis acid and trimethylchlorosilane is 1:(1-1.2):(1-1.2):(0.05-0.2):(0.5-2).

[0010] Furthermore, the acid is one of zinc chloride, ferric chloride, or aluminum chloride.

[0011] Furthermore, the dissolution reaction time is 1-4 hours; the reaction temperature is 20-30°C; and the reaction time after adding trimethylchlorosilane is 10-20 hours.

[0012] Furthermore, the inorganic base is one of sodium hydroxide, potassium hydroxide, sodium carbonate, or sodium bicarbonate.

[0013] Furthermore, the organic solvent is dichloromethane or trichloromethane.

[0014] Furthermore, a mixed solution of petroleum ether and ethyl acetate was used as the eluent for column chromatography.

[0015] The ferrocene-based compounds mentioned above are used in antioxidant activities.

[0016] Furthermore, 1,3-di-ferrocene-3-ferroceneaminoacetone was dissolved in ethanol to form an ethanol solution, which was then added to ethanol solutions of ABTS· radicals, DPPH· radicals, and galvinoxyl· radicals, respectively. The concentrations of ABTS, DPPH·, and galvinoxyl· radicals were measured over time at maximum absorption wavelengths of 734 nm, 517 nm, and 428 nm, respectively, to determine the scavenging rate of 1,3-di-ferrocene-3-ferroceneaminoacetone radicals.

[0017] Furthermore, the concentrations of the 1,3-di-ferrocene-3-ferroceneaminoacetone in ABTS·, DPPH· and galvinoxyl· free radical ethanol solutions are 1 μmol / L, 5 μmol / L and 10 μmol / L, respectively, and the reaction time of the 1,3-di-ferrocene-3-ferroceneaminoacetone with ABTS·, DPPH· and galvinoxyl· free radicals is 30 min.

[0018] The beneficial effects of this invention are:

[0019] This invention synthesizes a novel compound, 1,3-di-ferrocene-3-ferrocene aminoacetone, containing three ferrocene groups, through a Mannich three-component reaction under acidic conditions, using acetylferrocene, ferrocene formaldehyde, and aminoferrocene as raw materials. Adding 1,3-di-ferrocene-3-ferrocene aminoacetone to ethanol solutions of ABTS, DPPH, and galvinoxyl radicals effectively scavenges these free radicals, exhibiting superior antioxidant activity. Its antioxidant performance is superior to that of corresponding mono-ferrocene and bis-ferrocene compounds, demonstrating potential application value. Attached Figure Description

[0020] Figure 1 The 1H NMR spectrum of 1,3-diferrocene-3-ferroceneaminoacetone;

[0021] Figure 2 The image shows the carbon NMR spectrum of 1,3-di-ferrocene-3-ferroceneaminoacetone. Detailed Implementation

[0022] The technical solutions of the present invention will be described in detail below through embodiments. The following embodiments are merely exemplary and can only be used to explain and illustrate the technical solutions of the present invention, and should not be construed as limiting the technical solutions of the present invention.

[0023] The main experimental reagents and instruments used in this application are as follows:

[0024] Acetylferrocene, ferrocene formaldehyde, aminoferrocene, ferric chloride (FeCl3), trimethylchlorosilane, sodium bicarbonate, dichloromethane, diethyl ether, ethyl acetate, petroleum ether, electronic balance, rotary evaporator, electromagnetic heating mantle, Bruker Avance III 400MHz nuclear magnetic resonance spectrometer (Bruker Corporation, USA).

[0025] Unless otherwise specified, all reagents used in this application are existing reagents and are commercially available.

[0026] The bisferrocene-based compound of this application is specifically 1,3-bisferrocene-3-ferroceneaminoacetone, and its structural formula is shown below:

[0027]

[0028] Example 1

[0029] 0.43 g (2.0 mmol) of ferrocene formaldehyde, 0.40 g (2.0 mmol) of aminoferrocene, 0.03 g (0.2 mmol) of FeCl3, 10 mL of anhydrous dichloromethane, and 10 mL of anhydrous diethyl ether were added to a 50 mL round-bottom flask and stirred at room temperature for 2 h. Then, 0.46 g (2.0 mmol) of acetylferrocene was added, followed by 0.22 g (2.0 mmol) of trimethylchlorosilane while stirring, and the reaction was continued at room temperature for 12 h (TLC detection). After the reaction was completed, 10% sodium bicarbonate aqueous solution was added, and the mixture was extracted with dichloromethane. The organic phases were combined, concentrated with solvent, and the crude product was purified by silica gel column chromatography [eluent: V(petroleum ether) / V(ethyl acetate) = 10 / 1] to obtain the target compound in 52.68% yield.

[0030] Example 2

[0031] 0.43 g (2.0 mmol) of ferrocene formaldehyde, 0.48 g (2.4 mmol) of aminoferrocene, 0.03 g (0.2 mmol) of FeCl3, 10 mL of anhydrous dichloromethane, and 10 mL of anhydrous diethyl ether were added to a 50 mL round-bottom flask and stirred at room temperature for 2 h. Then, 0.55 g (2.4 mmol) of acetylferrocene was added, followed by 0.22 g (2.0 mmol) of trimethylchlorosilane with stirring, and the reaction was continued at room temperature for 12 h (TLC detection). After the reaction was completed, 10% sodium bicarbonate aqueous solution was added, and the mixture was extracted with dichloromethane. The organic phases were combined, concentrated with solvent, and the crude product was purified by silica gel column chromatography [eluent: V(petroleum ether) / V(ethyl acetate) = 10 / 1] to obtain the target compound in 53.34% yield.

[0032] Example 3

[0033] 0.43 g (2.0 mmol) of ferrocene formaldehyde, 0.47 g (2.2 mmol) of aminoferrocene, 0.03 g (0.2 mmol) of FeCl3, 10 mL of anhydrous dichloromethane, and 10 mL of anhydrous diethyl ether were added to a 50 mL round-bottom flask and stirred at room temperature for 2 h. Then, 0.50 g (2.1 mmol) of acetylferrocene was added, followed by 0.22 g (2.0 mmol) of trimethylchlorosilane while stirring, and the reaction was continued at room temperature for 12 h (detected by TLC). After the reaction was completed, 10% sodium bicarbonate aqueous solution was added, and the mixture was extracted with dichloromethane. The organic phases were combined, concentrated with solvent, and the crude product was purified by silica gel column chromatography [eluent: V(petroleum ether) / V(ethyl acetate) = 10 / 1] to obtain the target compound in 52.93% yield.

[0034] The structures of the target compounds 1a–1o were detected using a Bruker Avance III 400MHz nuclear magnetic resonance spectrometer (Bruker Corporation, USA). The 1H NMR, 13C NMR, and HR-MS results are shown in the attached figures.

[0035] Structural characterization data of 1,3-diferrocene-3-ferroceneaminoacetone, as exemplified in Example 1:

[0036] 1,3-Diferrocene-3-ferroceneaminoacetone: red solid, yield 52.68%, mp 228–230 °C; ¹H NMR (400 MHz, CDCl₃) δ: 8.89 (s, 1H), 4.91 (s, 2H), 4.89 (s, 2H), 4.84 (s, 2H), 4.66 (t, J = 6.8 Hz, 1H), 4.62 (s, 2H), 4.55 (s, 2H), 4.37 (s, 2H), 4.27 (s, 5H), 4.22 (s, 5H), 4.18 (s, 5H), 4.15–4.04 (m, 2H); ¹³C NMRR(100MHz, CDCI3):161.3,81.1,79.7,74.9,72.6,71.5,69.7,69.6,68.7,68.6,68.0,64.4,59.7; HR-MS(ESI)m / z:Calcd for C33H32Fe3NO{[M+H]+}626.0527, found 626.0538.

[0037] Antioxidant performance test:

[0038] 1. ABTS· free radical scavenging performance test. First, prepare the solution: Weigh 5.0 mg ABTS and 1.5 mg K₂S₂O₈ into a 2 mL volumetric flask, add distilled water to make up to volume, and let stand in the dark at room temperature for 24 h; the color turns deep blue. Then transfer to a 100 mL volumetric flask, make up to volume with anhydrous ethanol, and stand in a 30℃ constant temperature water bath for 30 min to obtain the ABTS·ethanol solution. This solution has the highest absorbance value at 734 nm, which is 1.182, and the molar extinction coefficient of ABTS· at this wavelength is 1.6 × 10⁻⁶. 4 L / (mol·cm). The procedure for quenching ABTS· free radicals with the compound is as follows: 1.9 mL of ABTS· free radical ethanol solution and 0.1 mL of the 0.02 mmol / L stock solution of the test compound are added to a test tube. The final concentration of the test compound is 1 μmol / L of the test solution. The mixture is quickly mixed, and the absorbance value (A) at the maximum absorption wavelength over 30 min is recorded as a decay curve over time. The concentration of ABTS· free radicals at the initial and final times is obtained using the Lambert-Beer law. The scavenging rate of 1,3-diferrocene-3-ferroceneaminoacetone on ABTS· is obtained by measuring the concentration change.

[0039] 2. DPPH· free radical scavenging performance test. First, prepare the solution: Weigh 4.0 mg of DPPH and add it to a 20 mL beaker. Dissolve it with a small amount of anhydrous ethanol, then transfer it to a 100 mL volumetric flask and dilute to volume with anhydrous ethanol to obtain a DPPH·ethanol solution. The maximum absorption wavelength of this solution is at 517 nm, with an absorbance value of approximately 1.107. The molar extinction coefficient at this wavelength is 4.09 × 10⁻⁶. 3 L / (mol·cm). The procedure for quenching DPPH· is the same as that for quenching ABTS·: 1.9 mL of DPPH· ethanol solution and 0.1 mL of 0.1 mmol / L stock solution of the test compound are added to a test tube to make the final concentration of the test compound 5 μmol / L. The mixture is quickly mixed, and the absorbance value (A) at the maximum absorption wavelength over 30 min is recorded as a decay curve over time. The concentration of DPPH· free radical at the initial and final times is obtained by the Lambert-Beer law. The scavenging rate of 1,3-di-ferrocene-3-ferroceneaminoacetone on DPPH· is obtained by the concentration change.

[0040] 3. Galvinoxyl· free radical scavenging performance test. First, prepare the solution: Weigh 1.0 mg of galvinoxyl and add it to a 20 mL beaker. Dissolve it with a small amount of anhydrous ethanol, then transfer it to a 100 mL volumetric flask and dilute to volume with anhydrous ethanol to obtain a galvinoxyl· free radical ethanol solution. This solution has the highest absorbance value at 428 nm, approximately 1.523, and the molar extinction coefficient at this wavelength is 1.4 × 10⁻⁶. 5L / (mol·cm). The procedure for quenching galvinoxyl· free radicals is the same as that for quenching ABTS·: 1.9 mL of galvinoxyl· free radical ethanol solution and 0.1 mL of the 0.2 mmol / L stock solution of the test compound are added to a test tube to make the final concentration of the test compound 10 μmol / L. The mixture is quickly mixed, and the absorbance value (A) at the maximum absorption wavelength over 30 min is recorded as a decay curve over time. The concentration of galvinoxyl· free radicals at the initial and final times is obtained by the Lambert-Beer law. The scavenging rate of 1,3-di-ferrocene-3-ferroceneaminoacetone on galvinoxyl· is obtained by the concentration change.

[0041] To investigate whether concentrating multiple ferrocene groups in 1,3-diferrocene-3-ferroceneaminoacetone improves its antioxidant properties, corresponding bisferrocene compounds, monoferrocene compounds, and non-ferrocene compounds were synthesized using the same synthetic method. The scavenging rates of ABTS·, DPPH·, and galvinoxyl· free radicals were determined through experiments. The antioxidant properties of 1,3-diferrocene-3-ferroceneaminoacetone were then compared.

[0042] Table 1 shows the scavenging rates of the compounds against ABTS·, DPPH· and galvinoxyl· free radicals.

[0043]

[0044]

[0045] Note: The concentrations of the eight compounds in the ABTS· free radical scavenging performance test system were 1 μmol / L; the concentrations of the eight compounds in the DPPH· free radical scavenging performance test system were 5 μmol / L; and the concentrations of the eight compounds in the galvinoxyl· free radical scavenging performance test system were 10 μmol / L.

[0046] As shown in Table 1:

[0047] 1,3-Diferrocene-3-ferroceneaminoacetone exhibited scavenging rates of 95.67%, 89.54%, and 80.12% for ABTS·, DPPH·, and galvinoxyl· free radicals, respectively. It effectively scavenged these free radicals, with scavenging rates significantly higher than those of the corresponding bisferrocene, monoferrocene, and non-ferrocene compounds, demonstrating superior antioxidant activity and potential application value. The antioxidant activity of the compound continuously increased with the increase in the number of ferrocene groups, and the position of the ferrocene groups in the compound's structure also influenced the differences in antioxidant performance.

[0048] The above-described embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing a bisferrocene-based compound using a multi-component reaction, wherein the bisferrocene-based compound is 1,3-bisferrocene-3-ferroceneaminoacetone, and the reaction equation is as follows: ， The synthesis method includes the following steps: Ferrocene formaldehyde, aminoferrocene, Lewis acid, anhydrous dichloromethane, and anhydrous diethyl ether were added to a reaction flask. The mixture was stirred to dissolve and the reaction was allowed to proceed for a set time. Then, acetylferrocene was added, followed by trimethylchlorosilane under stirring. The reaction was continued at room temperature. After the reaction was completed, an inorganic base aqueous solution was added, followed by extraction with an organic solvent. The organic phases were combined, concentrated in the solvent, and the crude product was purified by silica gel column chromatography to obtain the target compound.

2. The method for synthesizing bisferrocene-based compounds using a multi-component reaction according to claim 1, characterized in that, The molar ratio of ferrocene formaldehyde, aminoferrocene, acetylferrocene, Lewis acid and trimethylchlorosilane is 1:(1-1.2):(1-1.2):(0.05-0.2):(0.5-2).

3. The method for synthesizing bisferrocene-based compounds using a multi-component reaction according to claim 1, characterized in that, Lewis acids are one of zinc chloride, ferric chloride, or aluminum chloride.

4. The method for synthesizing bisferrocene-based compounds using a multi-component reaction according to claim 1, characterized in that, The dissolution reaction time is 1-4 h; after adding trimethylchlorosilane, the reaction time is 10-20 h.

5. The method for synthesizing bisferrocene-based compounds using a multi-component reaction according to claim 1, characterized in that, The inorganic base is one of sodium hydroxide, potassium hydroxide, sodium carbonate, or sodium bicarbonate.

6. The method for synthesizing ferrocene-based compounds using a multi-component reaction according to claim 1, characterized in that, The organic solvent is dichloromethane or trichloromethane.

7. The method for synthesizing bisferrocene-based compounds using a multi-component reaction according to claim 1, characterized in that, The column chromatography eluent was a mixture of petroleum ether and ethyl acetate.

8. An application of a bisferrocene-based compound, characterized in that, The ferrocene-based compound obtained by the method of synthesizing ferrocene-based compounds according to any one of claims 1 to 7 is used in antioxidant activity, wherein the method is as follows: 1,3-Diferrocene-3-ferroceneaminoacetone was dissolved in ethanol to form an ethanol solution, which was then added to ethanol solutions of ABTS•, DPPH•, and galvinoxyl• free radicals, respectively. The concentrations of ABTS•, DPPH•, and galvinoxyl• free radicals were measured over time at maximum absorption wavelengths of 734 nm, 517 nm, and 428 nm, respectively, to determine the scavenging rate of 1,3-diferrocene-3-ferroceneaminoacetone free radicals.

9. The application of the bisferrocene-based compound according to claim 8, characterized in that, The concentrations of 1,3-di-ferrocene-3-ferroceneaminoacetone in ABTS•, DPPH• and galvinoxyl• free radical ethanol solutions were 1 μmol / L, 5 μmol / L and 10 μmol / L, respectively, and the reaction time of 1,3-di-ferrocene-3-ferroceneaminoacetone with ABTS•, DPPH• and galvinoxyl• free radicals was 30 min.

Images