A method for preparing aromatic asymmetric Schiff bases by efficient photocatalytic oxidation of benzylamine derivatives

Abstract

The present invention belongs to the field of photocatalytic oxidation technology, and specifically relates to a method for preparing an asymmetric Schiff base containing an aromatic group by efficiently photocatalytically oxidizing a benzylamine derivative. The method comprises the following steps: using naphthalene imide flavin or riboflavin tetraacetate as a photosensitizer, dissolving the photosensitizer and two different benzylamine derivatives in an organic solvent, and conducting a light-irradiation reaction at room temperature, pressure, and air to obtain an asymmetric Schiff base containing an aromatic group. The method prepares an asymmetric Schiff base containing an aromatic group at room temperature and pressure, has low energy consumption, is simple and easy to operate, and can be used for large-scale production. No heavy metals are used in the preparation process, making it environmentally friendly and low-cost.

Description

Technical Field

[0001] The invention belongs to the technical field of photocatalytic oxidation, and particularly relates to a method for preparing an aromatic asymmetric Schiff base by efficiently photocatalytically oxidizing a benzylamine derivative. Background Art

[0002] Asymmetric Schiff bases containing aromatic groups are important chemical products for the synthesis of biologically active natural products and drug candidates. They can react with esters, acyl chlorides, and enones to form β-lactams. The widespread use of β-lactam antibiotics has made the oxidation of benzylamine to N-benzylbutylamine of great significance. Traditional synthesis methods utilize the condensation of primary amines with aldehydes and ketones. This method requires a heating dehydration unit, is cumbersome to operate, and many raw materials are difficult to prepare. In recent years, the oxidation of benzylamine derivatives to prepare asymmetric Schiff bases containing aromatic groups has become an effective method. In particular, green oxidation synthesis methods using oxygen, hydrogen peroxide, and other methods under catalytic conditions have attracted widespread attention.

[0003] In recent years, photocatalytic oxidation, which utilizes light as an energy source and molecular oxygen as an oxidant to selectively oxidize organic compounds at room or lower temperatures, has attracted considerable research attention. However, conventional organic photosensitizers often suffer from drawbacks such as poor intersystem crossing, resulting in low oxidation conversion efficiency. Therefore, the development of efficient photocatalysts for the highly selective oxidation of benzylamine to greenly synthesize aromatic asymmetric Schiff bases is of great importance and urgency. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for preparing an aromatic asymmetric Schiff base by efficiently photocatalytically oxidizing a benzylamine derivative. The method adopted by the present invention has the characteristics of being green, low cost, simple preparation method, mild experimental conditions, etc.

[0005] To achieve the above purpose, the technical solution of the present invention is as follows:

[0006] A method for preparing an aromatic asymmetric Schiff base by photocatalytic oxidation of a benzylamine derivative comprises the following steps:

[0007] With flavin naphthylimide or riboflavin tetraacetate as a photosensitizer, the photosensitizer, benzylamine derivative I and benzylamine derivative II are dissolved in an organic solvent and subjected to light irradiation reaction at room temperature, normal pressure and air to obtain an asymmetric Schiff base containing an aromatic group.

[0008] In the above technical solution, further, the synthesis route of the naphthalimide flavin is:

[0009]

[0010] The specific synthesis method comprises the following steps:

[0011] (1) Add 4-bromo-1,8-naphthoic anhydride to concentrated sulfuric acid under ice bath conditions, stir evenly, then add sodium nitrate, the molar ratio of 4-bromo-1,8-naphthoic anhydride to sodium nitrate being 1:1.3, stir at 0°C for 3 hours, then transfer to room temperature, continue stirring for 1 hour, and after the reaction is complete, pour the solution into ice water, filter, and continue drying in a vacuum drying oven overnight to obtain a yellow solid shown in Formula 2;

[0012] (2) The yellow solid obtained in step (1) was dissolved in tetrahydrofuran, and n-octylamine and triethylamine were added under a nitrogen atmosphere. The molar ratio of the yellow solid, n-octylamine and triethylamine was 1:6:2. The reaction mixture was stirred at 66° C. for 6 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using dichloromethane and petroleum ether as eluents to obtain an orange solid as shown in Formula 3.

[0013] (3) The orange solid and SnCl2 were added to a mixed solution of concentrated hydrochloric acid and ethanol under a nitrogen atmosphere. The molar ratio of the orange solid to SnCl2 was 1:8. The reaction mixture was refluxed and stirred for 3 h, then cooled to room temperature and stirred overnight. After the reaction was completed, the mixture was poured into ice water and the pH was adjusted to 11 with a 5M NaOH solution. Then, dichloromethane was added for extraction. The organic layer was washed and dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product shown in Formula 4.

[0014] (4) The crude product was added to glacial acetic acid, and alloxan and boric acid were added under nitrogen. The mixture was stirred at 60°C for 3 hours. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using a mixed solution of dichloromethane and methanol in a volume ratio of 40:1 as the eluent to obtain naphthalene imide flavin.

[0015] In the above technical solution, further, the benzylamine derivative I has a structure as shown in formula (I),

[0016]

[0017] Wherein R1 is one of methoxy and methyl;

[0018] Methylamine derivative II has the structure shown in formula (II),

[0019]

[0020] Wherein R2 is one of a hydrogen atom, a fluorine atom, and a trifluoromethyl group.

[0021] In the above technical solution, further, the molar ratio of the photosensitizer, the benzylamine derivative I, the benzylamine derivative II, and the organic solvent is 1:100:100:74000.

[0022] In the above technical solution, further, the concentration of the photosensitizer is 0.5-1 mol% of the substrate concentration.

[0023] In the above technical solution, further, the light irradiation reaction time is 1-7h.

[0024] In the above technical solution, further, the light source of the illumination reaction is an LED lamp with a wavelength of 410-470nm.

[0025] In the above technical solution, further, the organic solvent is methanol.

[0026] The beneficial effects of the present invention are:

[0027] 1) The preparation process of the present invention is simple, the preparation conditions are relatively mild, no heavy metals are used in the preparation process, and the preparation process is environmentally friendly and low in cost.

[0028] 2) The method provided by the present invention can prepare an aromatic asymmetric Schiff base under normal temperature and pressure conditions, has low energy consumption, is simple and easy to operate, and can be used for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the chromatogram after the photocatalytic reaction in Example 1. DETAILED DESCRIPTION

[0030] In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention rather than for limiting the present invention.

[0031] Example 1

[0032] The synthetic route of naphthalene imide flavin is:

[0033]

[0034] The specific synthesis method comprises the following steps:

[0035] (1) Add 4-bromo-1,8-naphthoic anhydride (5 g, 18 mmol) to concentrated sulfuric acid (20 mL) in an ice bath. Stir thoroughly and carefully add sodium nitrate (2 g, 23.4 mmol). Stir at 0°C for 3 h, then transfer to room temperature and continue stirring for 1 h. After the reaction is complete, pour the solution into ice water (200 ml), filter, and continue drying in a vacuum drying oven overnight to obtain a yellow solid (4.3 g).

[0036] (2) A yellow solid (966 mg, 3.0 mmol) was dissolved in tetrahydrofuran (THF) (60 mL), and n-octylamine (3.6 mL, 18 mmol) and triethylamine (0.9 mL) were added under a nitrogen atmosphere. The reaction mixture was stirred at 66°C for 6 h. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using dichloromethane and petroleum ether (v / v = 1 / 1) as eluent to obtain an orange solid (442 mg);

[0037] (3) Orange solid (442 mg, 0.92 mmol) and SnCl2 (1.7 g, 7.34 mmol) were added to a mixed solution of concentrated hydrochloric acid (5.0 mL) and ethanol (5.0 mL) under nitrogen atmosphere. The reaction mixture was refluxed and stirred for 3 h, then cooled to room temperature and stirred overnight. After the reaction was completed, the mixture was poured into ice water (200 mL) and the pH was adjusted to 11 with 5 M NaOH solution. Then, dichloromethane (50 mL) was added for extraction. Saturated brine (3 * 50 ml) washed with anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product (354 mg);

[0038] (4) The crude product (354 mg) was added to glacial acetic acid (10 ml), and alloxan (144 mg) and boric acid (80 mg) were added under nitrogen. The mixture was stirred at 60° C. for 3 h. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using dichloromethane and methanol (v / v = 40 / 1) as eluent to obtain naphthalene imide flavin (88 mg).

[0039] 3 ml of methanol was added to a 10 ml reaction bottle, followed by 0.1 mmol of 4-fluorobenzylamine, 0.1 mmol of 4-methoxybenzylamine and 0.001 mmol of photosensitizer naphthalene imide flavin. The reaction was carried out under normal pressure and air atmosphere with a light intensity of 1240 W / m 2 The mixed solution was irradiated with an LED lamp having a wavelength of 451 nm and reacted for 5 h, and circulating water was introduced to ensure that the reaction conditions were carried out at room temperature. The reaction progress was monitored using thin-layer chromatography. When the substrate reaction was complete or no longer changed, the illumination was stopped. The products were qualitatively analyzed using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry, and quantitatively analyzed using a gas chromatograph (GC2012) with a hydrogen flame ionization detector (Agilent, USA). The products obtained by the catalytic oxidation of benzylamine derivatives are shown in Table 1.

[0040] Table 1 Theoretical products and yields obtained by photooxidative coupling of 4-fluorobenzylamine and 4-methoxybenzylamine in Example 1

[0041]

[0042] As can be seen from Table 1, although there are four theoretical products, there are only two main products, and the asymmetric product accounts for the highest proportion.

[0043] The chromatogram after the photocatalytic reaction of Example 1 is as follows Figure 1 As shown by Figure 1 As shown in Table 2, the selectivity of the target product is high.

[0044] Table 2 Peak time and corresponding products in Example 1

[0045]

[0046] Example 2

[0047] While maintaining the same experimental conditions as in Example 1, two different benzylamine derivatives were selected, but the substituents were all electron-donating groups, and the effect of the same electron group on the selectivity of different products was discussed.

[0048] Table 3 Effect of electronic group modified substrates with the same properties on the selectivity of different products in Example 2

[0049]

[0050]

[0051] As shown in Table 3, there are only two main products of the substrate modified with the same substituent groups, of which the asymmetric product accounts for the highest proportion, and the yield is concentrated at around 70%.

[0052] Example 3

[0053] While maintaining the same experimental conditions as in Example 1, two different benzylamine derivatives were selected, but one substituent was an electron-donating group and the other was an electron-withdrawing group, to discuss the effects of different electron groups on the selectivity of different products.

[0054] Table 4 Effect of different electronic group modified substrates on the selectivity of different products in Example 3

[0055]

[0056]

[0057]

[0058] As can be seen from Table 4, there are only two main products of the substrate modified by substituents of different properties, and the asymmetric product accounts for the highest proportion, with the yield mostly above 80%. This shows that the selectivity of the asymmetric product generated by the modification of benzylamine with electronic groups of different properties is higher.

[0059] As can be seen from the above examples, the method of the present invention uses the photosensitizer naphthylimide flavin to photocatalytically oxidize phenylamine to synthesize an asymmetric Schiff base containing an aromatic group, and uses oxygen in the air as the oxidant, thereby achieving efficient preparation of an asymmetric Schiff base containing an aromatic group at room temperature and pressure.

[0060] Example 4

[0061] 3 ml of methanol was added to a 10 ml reaction bottle, followed by 0.1 mmol of two different benzylamine derivatives and 0.001 mmol of photosensitizer riboflavin tetraacetate. Under normal pressure and air atmosphere, light intensity of 1240 W / m 2 The mixed solution was irradiated with an LED lamp having a wavelength of 451 nm and reacted for 5 h, and circulating water was passed to ensure that the reaction conditions were carried out at room temperature. The reaction progress was monitored using thin-layer chromatography. When the substrate reaction was complete or no longer changed, the illumination was stopped. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry were used to carry out qualitative analysis of the product. Gas chromatograph (GC2012) with a hydrogen flame ionization detector (Agilent, USA) was used to carry out quantitative analysis of the product. The products obtained by the catalytic oxidation of the benzylamine derivatives are shown in Table 5.

[0062] Table 5 Effect of different electronic group modified substrates on the selectivity of different products in Example 4

[0063]

[0064]

[0065]

[0066] The description of the above embodiments is only used to help understand the method of the present invention. It should be pointed out that for ordinary technicians in this technical field, without departing from the principles of the method of the present invention, several improvements and adjustments can be made to the present invention, and these improvements and adjustments should also fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing an aromatic asymmetric Schiff base by photocatalytic oxidation of a benzylamine derivative, characterized in that: The method comprises the following steps: Using naphthalene imide flavin as a photosensitizer, the photosensitizer, benzylamine derivative I and benzylamine derivative II are dissolved in an organic solvent and subjected to light irradiation reaction at room temperature, pressure and air to obtain an asymmetric Schiff base containing an aromatic group. The benzylamine derivative I has a structure as shown in formula (I), Wherein R1 is one of methoxy and methyl; The benzylamine derivative II has a structure as shown in formula (II), Wherein R2 is one of a hydrogen atom, a fluorine atom, and a trifluoromethyl group. The naphthylimide flavin has a structure as shown in the following formula: The light source of the illumination reaction is an LED lamp with a wavelength of 410-470nm.

2. The method according to claim 1, characterized in that The synthetic route of the naphthalimide flavin is: The specific synthesis method comprises the following steps: (1) Add 4-bromo-1,8-naphthoic anhydride to concentrated sulfuric acid under ice bath conditions, stir evenly, then add sodium nitrate, the molar ratio of 4-bromo-1,8-naphthoic anhydride to sodium nitrate being 1:1.3, stir at 0°C for 3 hours, then transfer to room temperature, continue stirring for 1 hour, and after the reaction is complete, pour the solution into ice water, filter, and continue drying in a vacuum drying oven overnight to obtain a yellow solid shown in Formula 2; (2) The yellow solid obtained in step (1) was dissolved in tetrahydrofuran, and n-octylamine and triethylamine were added under a nitrogen atmosphere. The molar ratio of the yellow solid, n-octylamine and triethylamine was 1:6:

2. The reaction mixture was stirred at 66° C. for 6 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using dichloromethane and petroleum ether as eluents to obtain an orange solid as shown in Formula 3. (3) The orange solid and SnCl2 were added to a mixed solution of concentrated hydrochloric acid and ethanol under a nitrogen atmosphere. The molar ratio of the orange solid to SnCl2 was 1:

8. The reaction mixture was refluxed and stirred for 3 h, then cooled to room temperature and stirred overnight. After the reaction was completed, the mixture was poured into ice water and the pH was adjusted to 11 with a 5M NaOH solution. Then, dichloromethane was added for extraction. The organic layer was washed and dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product shown in Formula 4. (4) The crude product was added to glacial acetic acid, and alloxan and boric acid were added under nitrogen. The mixture was stirred at 60°C for 3 hours. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using a mixed solution of dichloromethane and methanol in a volume ratio of 40:1 as the eluent to obtain naphthalene imide flavin.

3. The method according to claim 1, characterized in that The molar ratio of the photosensitizer, the benzylamine derivative I, the benzylamine derivative II, and the organic solvent is 1:100:100:74000.

4. The method according to claim 1, wherein The concentration of the photosensitizer is 0.5-1 mol% of the substrate concentration.

5. The method according to claim 1, wherein The light reaction time is 1-7 hours.

6. The method according to claim 1, wherein The organic solvent is methanol.

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