Synthesis method for preparing 3,4-dichlorocoumarin from 4-chlorocoumarin

Abstract

The invention discloses the synthetic method for preparing 3,4-dichlorocoumarins by 4-chlorocoumarins, using 4-chlorocoumarin derivatives as raw materials, using hydrochloric acid as chlorine source, in the presence of visible light catalyst and external oxidant, selective chlorination reaction occurs in an organic solvent by visible light irradiation, and 3,4-dichlorocoumarin derivatives are obtained. Application of the present invention 3,4-dichlorocoumarin derivatives can be prepared under mild conditions using simple and easy-to-get 4-chlorocoumarins under visible light drive, the yield of product can reach up to 98%, and the fastest reaction can be completed in 10 minutes, also with the characteristic of safety and environmental protection and high regioselectivity and substrate adaptability. In short, the present invention overcomes the reaction efficiency of Lewis acid activation method is not enough, the defect of large excess reagent use and the dependence on substrate substituents, also solves the deficiencies such as not safe, low efficiency when 4-chlorocoumarins are further chlorinated under visible light catalysis in the prior art.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of 4-chlorocoumarin derivatives, and in particular relates to a synthesis method for preparing 3,4-dichlorocoumarin from 4-chlorocoumarin. Background Art

[0002] Coumarin compounds, with their cyclic lactone structure, are building blocks of pharmaceuticals with several physiological activities. Their derivatives also exhibit excellent fluorescence properties from the blue to near-infrared region, making them suitable for fluorescent labeling. Based on their structure, various functionalization methods are effective approaches to obtain more functional molecules. Selective chlorination of coumarins followed by conversion is a pre-activation method required for functionalization and is of great significance for enriching the applications of compounds of this structural type. Currently, commonly used methods rely on the activation of various halogen sources, such as N-chlorosuccinimide (NCS), with metal salts such as CuCl2 to generate orthochlorine reagents for the reaction. For example, the Chinese patent "A Method for Preparing 3-Chlorocoumarin Derivatives" (Patent No. 201511018479.2, Publication Date 20160504) provides a high yield (88.1%), but suffers from low reaction efficiency (reaction time 24 hours), limited substrate adaptability, and the need for a large excess of chlorination reagent and accelerator. In addition, the applicant's previous article "Selective Chlorination of Coumarin Catalyzed by Visible Light" (Journal of Guangxi University (Natural Science Edition), 2023, 48(02): 407-13) disclosed the use of CuCl2 under visible light catalysis. . 2H2O was used as the auxiliary catalyst and oxygen in the air was used as the oxidant. The reaction time was longer (2.5 hours) and the yield was moderate (51.9%). Summary of the Invention

[0003] The technical problem to be solved by the present invention is to provide a synthesis method for preparing 3,4-dichlorocoumarin from 4-chlorocoumarin with high reaction efficiency and yield and no heavy metal pollution.

[0004] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0005] The invention discloses a method for preparing 3,4-dichlorocoumarin from 4-chlorocoumarin. The method comprises the following steps: using a 4-chlorocoumarin derivative as a raw material, hydrochloric acid (HCl) as a chlorine source, and subjecting an organic solvent to a selective chlorination reaction under visible light irradiation in the presence of a visible light catalyst and an external oxidant to obtain a 3,4-dichlorocoumarin derivative.

[0006] The above synthesis method complies with the following reaction formula:

[0007]

[0008] Wherein, the 4-chlorocoumarin derivative conforms to the chemical formula I, and the 3,4-dichlorocoumarin derivative conforms to the chemical formula II;

[0009] In Chemical Formula I or Chemical Formula II, the substituent R is hydrogen (H), phenyl (Ph), an electron-donating group or an electron-withdrawing group, and the substituent R is at position 5, 6, 7 or 8 of the benzene ring; the electron-donating group is methyl (-CH3), methoxy (-OCH3), dimethylamino (-N(CH3)2)), and the electron-withdrawing group is chlorine (Cl), fluorine (F), or trifluoromethyl (CF3).

[0010] The visible light photocatalyst is 9-thioxanthone, eosin Y, 4CzIPN, rose Bengal, and rhodamine 6G, and its structural formula is as follows:

[0011]

[0012] The amount of the visible light catalyst is about 1% to 10% of the amount of the 4-chlorocoumarin derivative.

[0013] The added oxidants are ammonium persulfate, sodium persulfate, potassium hydrogen persulfate, potassium chlorate, and sodium hypochlorite.

[0014] The amount of the externally added oxidizing agent is about 1 to 5 times the amount of the 4-chlorocoumarin derivative.

[0015] The organic solvent is a polar solvent, and the polar solvent is acetonitrile, 1,2-dichloroethane, chloroform, dichloromethane, and 1,4-dioxane.

[0016] Visible light comes from 400-600nm LED lamps or white light energy-saving lamps with a power of 1-30W.

[0017] The reaction is carried out at 30°C to 70°C.

[0018] The amount of hydrochloric acid is about 3 to 10 times the amount of 4-chlorocoumarin derivative.

[0019] To address the current challenges of selective chlorination of coumarins, the inventors have developed a synthetic method for preparing 3,4-dichlorocoumarin from 4-chlorocoumarin. Using a 4-chlorocoumarin derivative as the starting material and hydrochloric acid (HCl) as the chlorine source, a selective chlorination reaction occurs in an organic solvent under visible light irradiation in the presence of a visible light catalyst and an external oxidant, yielding the 3,4-dichlorocoumarin derivative. To improve reaction efficiency and eliminate heavy metal contamination, the synthesis method does not add copper salts. After the reaction, the reaction solution undergoes post-treatment and column chromatography to yield the 3,4-dichlorocoumarin derivative product. This method, driven by visible light, uses readily available 4-chlorocoumarin to prepare 3,4-dichlorocoumarin derivatives under mild conditions. Yields can reach up to 98%, and the reaction can be completed in as little as 10 minutes. Furthermore, the method is safe and environmentally friendly, with high regioselectivity and substrate adaptability. In summary, the present invention overcomes the shortcomings of the Lewis acid activation method, such as low reaction efficiency, use of large excess reagents, and dependence on substrate substituents, and also solves the shortcomings of the prior art, such as insufficient safety and low efficiency in further chlorination of 4-chlorocoumarin under visible light catalysis. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the H NMR spectrum of 3,4-dichlorocoumarin 2.

[0021] Figure 2 This is the carbon NMR spectrum of 3,4-dichlorocoumarin 2.

[0022] Figure 3 This is the H NMR spectrum of 6-methyl-3,4-dichlorocoumarin 4.

[0023] Figure 4 This is the carbon NMR spectrum of 6-methyl-3,4-dichlorocoumarin 4.

[0024] Figure 5 This is the H NMR spectrum of 3,4,6-trichlorocoumarin 6.

[0025] Figure 6 This is the carbon NMR spectrum of 3,4,6-trichlorocoumarin 6.

[0026] Figure 7 This is the H NMR spectrum of 7-methyl-3,4-dichlorocoumarin 8

[0027] Figure 8 This is the C NMR spectrum of 7-methyl-3,4-dichlorocoumarin 8 DETAILED DESCRIPTION

[0028] Example 1

[0029] Using 4-chlorocoumarin as the raw material, that is, R5-R8 and R3 in reaction formula 1 are all H, the reaction formula is:

[0030]

[0031] At room temperature, 18.0 mg (0.1 mmol) of 4-chlorocoumarin, 45.6 mg (0.2 mmol) of ammonium persulfate, and 1.6 mg (0.002 mmol, 2 mol%) of the photocatalyst 4CzIPN were weighed and added to a jacketed photoreactor tube. 2 mL of acetonitrile was then added to fully dissolve the photocatalyst and 4-chlorocoumarin, and a small amount of ammonium persulfate was dissolved. Under illumination from a 440-460 nm LED light, 100 mg (83 μL, 1 mmol) of 37% concentrated HCl was added and the reaction was controlled at 50°C for approximately 10 minutes. Thin-layer chromatography (TLC) confirmed complete reaction of the 4-chlorocoumarin. The reaction mixture was poured into ice water and extracted three times with 10 mL of ethyl acetate. The upper organic phases were combined and dried over anhydrous sodium sulfate. After removing the solvent by vacuum distillation, the mixture was dissolved in a minimal amount of acetone and adsorbed onto a small amount of 100-200 mesh silica gel. Column chromatography was then performed using a mixed solution of petroleum ether:ethyl acetate (50:2) as the mobile phase to obtain 21.1 mg of a white blocky solid (yield: 98%).

[0032] The physicochemical characteristics of the obtained 3,4-dichlorocoumarin 2 are as follows:

[0033] Molecular formula: C9H4Cl2O2, molecular weight: 215.03.

[0034] White crystals, melting point: 102-104°C; chloroform: petroleum ether (1 / 2, v / v), soluble in organic solvents such as ethyl acetate, chloroform, acetone, methanol, ethanol, and poorly soluble in water;

[0035] 3,4-Dichlorocoumarin H NMR spectrum Figure 1 As shown, the carbon NMR spectrum is as Figure 2 shown.

[0036] H NMR spectrum: 1 H NMR (600MHz, CDCl3) δ7.88(dd,J=8.0,1.5Hz,1H),7.65–7.61(m,1H),7.44–7.41(m,1H),7.40(d,J=8.0Hz,1H).

[0037] C NMR spectrum: 13 C NMR (151MHz, CDCl3) δ156.0,150.9,145.8,133.1,125.9,125.51,121.55,118.3,117.1.

[0038] Example 2

[0039] Using 6-methyl-4-chlorocoumarin as the raw material, that is, R6 in reaction formula 1 is methyl, and R3, R5, R7, and R8 are all H, the reaction formula is:

[0040]

[0041] At room temperature, 19.4 mg (0.1 mmol) of 6-methyl-4-chlorocoumarin, 47.6 mg (0.2 mmol) of sodium persulfate, and 4.8 mg (0.006 mmol, 6 mol%) of the photocatalyst 4CzIPN were weighed and added to a jacketed photoreactor tube. 2 mL of 1,4-dioxane was then added to fully dissolve the photocatalyst and 6-methyl-4-chlorocoumarin, and a small amount of sodium persulfate was dissolved. Under illumination at 540-550 nm, 100 mg (83 μL, 1 mmol) of 37% concentrated HCl was added and the reaction was controlled at 50°C for approximately 10 minutes. Thin-layer chromatography (TLC) confirmed complete reaction of the 6-methyl-4-chlorocoumarin. The reaction solution was poured into ice water and extracted three times with 10 mL of ethyl acetate. The upper organic phases were combined and dried over anhydrous sodium sulfate. After removing the solvent by vacuum distillation, the solution was dissolved in a minimal amount of acetone and adsorbed onto a small amount of 100-200 mesh silica gel. Column chromatography was then performed using a mixed solution of petroleum ether:ethyl acetate (50:2) as the mobile phase to obtain 18.5 mg of a white blocky solid (yield: 83%).

[0042] The physicochemical characteristics of the obtained 6-methyl-3,4-dichlorocoumarin 4 are as follows:

[0043] Molecular formula: C 10 H6Cl2O2, molecular weight: 222.97.

[0044] White crystals, melting point: 160-164°C; chloroform: petroleum ether (1 / 2, v / v), soluble in organic solvents such as ethyl acetate, chloroform, acetone, methanol, ethanol, and hardly soluble in water.

[0045] 6-Methyl-3,4-dichlorocoumarin H NMR spectrum Figure 3 As shown, the carbon NMR spectrum is as Figure 4 shown.

[0046] H NMR spectrum: 1 H NMR (500MHz, Chloroform-d) δ7.56 (s, 1H), 7.35 (d, J = 8.5Hz, 1H), 7.20 (dd, J = 8.2, 1.7Hz, 1H), 2.39 (s, 3H).

[0047] C NMR spectrum:13 C NMR (126MHz, Chloroform-d) δ156.22,149.07,145.78,135.52,134.11,125.54,121.35,117.88,116.80,21.12.

[0048] Example 3

[0049] Using 4,6-dichlorocoumarin as the raw material, that is, R6 in reaction formula 1 is Cl, and R3, R5, R7, and R8 are all H, the reaction formula is:

[0050]

[0051] At room temperature, 24.9 mg (0.1 mmol) of 4,6-dichlorocoumarin, 152.2 mg (1 mmol) of potassium persulfate, and 0.5 mg (0.002 mmol, 2 mol%) of the photocatalyst 9-thioxanthone were weighed and added to a jacketed photoreactor tube. 3 mL of 1,2-dichloroethane was added to fully dissolve the photocatalyst and 4,6-dichlorocoumarin, along with a small amount of sodium persulfate. Under illumination from a 440-460 nm LED light, 100 mg (83 μL, 1 mmol) of 37% concentrated HCl was added and the reaction was controlled at 30°C for 3 h. Thin-layer chromatography (TLC) confirmed complete reaction of the 6-methyl-4-chlorocoumarin. The reaction solution was poured into ice water and extracted three times with 10 mL of ethyl acetate. The upper organic phases were combined and dried over anhydrous sodium sulfate. After removing the solvent by vacuum distillation, the solution was dissolved in a minimal amount of acetone and adsorbed onto a small amount of 100-200 mesh silica gel. Column chromatography was then performed using a mixed solution of petroleum ether:ethyl acetate (50:2) as the mobile phase to obtain 17.2 mg of a white blocky solid (yield: 69%).

[0052] The physicochemical characteristics of the obtained 3,4,6-trichlorocoumarin 6 are as follows:

[0053] Molecular formula: C9H3Cl3O2, molecular weight: 249.47.

[0054] White crystals, melting point: 130-132°C; chloroform: petroleum ether (1 / 2, v / v), soluble in organic solvents such as ethyl acetate, chloroform, acetone, methanol, ethanol, and hardly soluble in water.

[0055] 3,4,6-Trichlorocoumarin H NMR spectrum Figure 5 As shown, the carbon NMR spectrum is as Figure 6 shown.

[0056] H NMR spectrum: 1H NMR(500MHz,Chloroform-d)δ7.85(d,J=2.4Hz,1H),7.60–7.55(m,1H),7.34(d,J=8.8Hz,1H).

[0057] C NMR spectrum: 13 C NMR (126MHz, Chloroform-d) δ155.41,149.28,144.51,133.04,131.23,125.30,122.79,119.35,118.57.

[0058] Example 4

[0059] Using 7-methyl-4-chlorocoumarin 7 as the raw material, that is, R7 in reaction formula 1 is methyl, and R3, R5, R6, and R8 are all H, the reaction formula is:

[0060]

[0061] At room temperature, weigh 19.4 mg (0.1 mmol) of 7-methyl-4-chlorocoumarin 7, 45.6 mg (0.2 mmol) of ammonium persulfate, and 2 mg (0.004 mmol, 4 mol%) of the photocatalyst rhodamine 6G were added to a jacketed photoreactor tube. 2 mL of acetonitrile was added to fully dissolve the photocatalyst and 7-methyl-4-chlorocoumarin, and a small amount of ammonium persulfate was dissolved. Under illumination from a 440-460 nm LED light, 100 mg (83 μL, 1 mmol) of 37% concentrated HCl was added and the reaction was controlled at 70°C for approximately 30 minutes. Thin-layer chromatography (TLC) confirmed complete reaction of the 7-methyl-4-chlorocoumarin. The reaction solution was poured into ice water and extracted three times with 10 mL of ethyl acetate. The upper organic phases were combined and dried over anhydrous sodium sulfate. After removing the solvent by vacuum distillation, the solution was dissolved in a minimal amount of acetone and adsorbed onto a small amount of 100-200 mesh silica gel. Column chromatography was then performed using a mixed solution of petroleum ether:ethyl acetate (50:2) as the mobile phase to obtain 20.2 mg of a white blocky solid (yield: 88%).

[0062] The physicochemical characteristics of the obtained 7-methyl-3,4-dichlorocoumarin 8 are as follows:

[0063] Molecular formula: C9H4Cl2O2, molecular weight: 215.03.

[0064] White crystals, melting point: 108-110°C; chloroform: petroleum ether (1 / 2, v / v), soluble in organic solvents such as ethyl acetate, chloroform, acetone, methanol, ethanol, and hardly soluble in water.

[0065] The H NMR spectrum of 7-methyl-3,4-dichlorocoumarin 8 is as follows Figure 7 As shown, the C NMR spectrum of 7-methyl-3,4-dichlorocoumarin 8 is as follows Figure 8 shown.

[0066] H NMR spectrum: 1 H NMR (500MHz, Chloroform-d) δ7.74 (d, J = 8.1Hz, 1H), 7.21 (dd, J = 8.3, 1.5Hz, 1H), 7.19 (s, 1H), 2.48 (s, 3H).

[0067] C NMR spectrum: 13 C NMR (151MHz, Chloroform-d) δ156.37,150.98,146.01,144.73,126.73,125.60,120.27,117.13,115.95,21.86.

Claims

1. A method for preparing a 3,4-dichlorocoumarin derivative from a 4-chlorocoumarin derivative, characterized in that: Using 4-chlorocoumarin derivatives as raw materials and hydrochloric acid as a chlorine source, a selective chlorination reaction occurs in an organic solvent under visible light irradiation in the presence of a visible light catalyst and an external oxidant to obtain 3,4-dichlorocoumarin derivatives. The synthesis method conforms to the following reaction formula: Wherein, the 4-chlorocoumarin derivative conforms to the chemical formula I, and the 3,4-dichlorocoumarin derivative conforms to the chemical formula II; In Chemical Formula I or Chemical Formula II, the substituent R is hydrogen, phenyl, an electron-donating group, or an electron-withdrawing group, and the substituent R is located at position 5, 6, 7, or 8 of the benzene ring; the electron-donating group is methyl, methoxy, or dimethylamino, and the electron-withdrawing group is chlorine, fluorine, or trifluoromethyl; the visible light catalyst is 9-thioxanthone, Eosin Y, 4CzIPN, Rose Bengal, or Rhodamine 6G; and the external oxidant is ammonium persulfate, sodium persulfate, potassium persulfate, potassium chlorate, or sodium hypochlorite.

2. The synthesis method according to claim 1, wherein: The amount of the visible light catalyst is 1% to 10% of the amount of the 4-chlorocoumarin derivative.

3. The synthesis method according to claim 1, wherein: The amount of the external oxidant is 1-5 times the amount of the 4-chlorocoumarin derivative.

4. The synthesis method according to claim 1, wherein: The organic solvent is a polar solvent, and the polar solvent is acetonitrile, 1,2-dichloroethane, chloroform, dichloromethane, and 1,4-dioxane.

5. The synthesis method according to claim 1, wherein: The visible light comes from a 400-600nm LED lamp or a white energy-saving lamp, and its power is 1-30W.

6. The synthesis method according to claim 1, wherein: The reaction is carried out at 30°C to 70°C.

7. The synthesis method according to claim 1, wherein: The amount of the hydrochloric acid is 3-10 times the amount of the 4-chlorocoumarin derivative.

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