Preparation method of polysubstituted isocoumarin compound

Abstract

The invention provides a preparation method of a polysubstituted isocoumarin compound, which comprises the following step: reacting a benzoyl peroxide compound with an alkyne derivative in an organic solvent under the action of a catalyst, a free radical initiator and illumination to obtain the polysubstituted isocoumarin compound. The raw materials are cheap and easily available; the reaction operation is simple; the product yield is high; the substrate application range is wide; the obtained isocoumarin compound can be used as a potential drug molecular unit.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing a polysubstituted isocoumarin compound. Background Art

[0002] Isocoumarin compounds are the basic structure of many natural products and are widely distributed in nature. Many derivatives of isocoumarin have excellent biopharmacological activities such as anti-allergic, antibacterial, anti-inflammatory, anti-tumor and anti-HIV (Li Li, Yang Jinfei, Yuan Xiangai. Synthesis and New Progress of Isocoumarin Compounds [J]. Journal of Nanjing Normal University: Engineering Technology Edition 2005 5 (2): 64-67.), as well as excellent photoluminescence properties (Monago-Marana, Olga, Munoz, et al. Fluorescence properties of flavonoid compounds. Quantification in paprika samples using spectrofluorimetry coupled to second order chemometric tools [J]. Food Chemistry, 2016, 196 (Apr. 1): 1058-1065.). At present, the synthesis and activity research of isocoumarin compounds is very active. The known synthesis methods mainly focus on obtaining isocoumarins of different structures through electrophilic cyclization reaction of o-alkynylbenzoic acid and its esters. However, the synthesis process requires the use of inorganic acids, tetrafluoroboric acid, silver salts, mercuric salts, copper salts, etc. to promote the reaction. At the same time, there are disadvantages such as cumbersome steps, low yield, harsh conditions, and not being economical and green (Guda R, Kumar G, Korra R, et al. EGFR, HER2 target based molecular docking analysis, invitro screening of 2,4,5-trisubstituted imidazole derivatives as potential anti-oxidant and cytotoxic agents [J]. Journal of Photochemistry and Photobiology B: Biology, 2017, 176: 69-80.). Therefore, the development of green, simple and efficient synthesis strategies for isocoumarin compounds will greatly promote the application of such compounds in biomedicine. Summary of the invention

[0003] The object of the present invention is to provide a method for preparing a polysubstituted isocoumarin compound. The method has simple steps, mild conditions, and a wide range of substrate applications. The obtained products are isocoumarin compounds and derivatives containing various substituted groups.

[0004] To achieve the above object, the present invention adopts the following technical solution: A method for preparing a polysubstituted isocoumarin compound comprises the following steps: Under the action of a catalyst, a free radical initiator and light, a benzoyl peroxide compound (II) reacts with an alkyne derivative (III) in an organic solvent, and after the reaction, the polysubstituted isocoumarin compound (I) is obtained by post-treatment: The reaction formula is as follows:

[0005] Among them, R 1 is alkyl, halogen, methoxy or methylthio; R 2 is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is an alkyl group, a methoxy group or a halogen group.

[0006] Preferably, the R 1 is H, methyl, fluoro, bromo, methoxy or methylthio.

[0007] Preferably, the R 2 is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is selected from methyl, n-propyl, n-butyl, methoxy, fluorine or chlorine.

[0008] Preferably, the catalyst is one of ferrocene, ferrous bromide, ferric bromide, ferric sulfate, ferrous sulfate, ferrous chloride and ferric chloride, preferably ferrocene.

[0009] Preferably, the free radical initiator is one of tert-butyl hydroperoxide, di-tert-butyl peroxide, diisopropylbenzene peroxide, and 2,2,6,6-tetramethylpiperidine-nitrogen-oxide, preferably tert-butyl hydroperoxide.

[0010] Preferably, the light source is 250 W ultraviolet light with a maximum wavelength of 365 nm.

[0011] Preferably, the organic solvent is one of acetonitrile, toluene, N-methylpyrrolidone, N,N-dimethylformamide and dimethyl sulfoxide, preferably acetonitrile.

[0012] Preferably, the molar ratio of benzoyl peroxide compound: alkyne derivative: catalyst: free radical initiator is 1:1.2-2.5:0.10-0.005:2.0-5.0, preferably 1:1.5:0.005:3.0.

[0013] Preferably, the reaction temperature is 80-140°C, preferably 120°C, and the reaction time is 24-48 h, preferably 30 h.

[0014] Preferably, the structure of the polysubstituted isocoumarin compound includes the following: .

[0015] The advantages of the present invention are: The raw materials of the invention are cheap and easy to obtain; the reaction operation is simple; the product yield is high; the substrate has a wide range of applicability; and the obtained isocoumarin compounds can be used as potential drug molecular units. DETAILED DESCRIPTION

[0016] In order to make the above features and advantages of the present invention more clearly understood, the following embodiments are given for detailed description. The methods of the present invention are all conventional methods in the art unless otherwise specified.

[0017] Example 1 3,4-Diphenylisocoumarin, its structural formula is:

[0018] Add 0.5 mmol of dibenzoyl peroxide, 0.75 mmol of diphenylacetylene, 0.0025 mmol of ferrocene, 1.5 mmol of tert-butyl hydroperoxide, and 2.0 mL of acetonitrile to a 10 mL reaction tube, place in an oil bath at 120°C under 250 W UV light, and react for 30 h. Stop the reaction and cool to room temperature. The reaction solution was diluted with dichloromethane, extracted three times with water, and the organic phase was dried with anhydrous Na2SO4, filtered, and separated by column chromatography to obtain 130 mg of the target product with a yield of 87%. The NMR characterization of the compound is as follows: 1 H NMR (400 MHz, CDCl3) d 8.40 (dd, J = 7.9, 1.0 Hz, 1H), 7.66 – 7.61(m, 1H), 7.56 – 7.50 (m, 1H), 7.44 – 7.37 (m, 3H), 7.35 – 7.31 (m, 2H), 7.27(d, J= 2.8 Hz, 1H), 7.26 – 7.25 (m, 1H), 7.25 – 7.16 (m, 4H); 13 C NMR (100 MHz,CDCl3) d 9, 162.3, 151.0, 138.9, 134.6, 134.3, 132.9, 131.2, 129.6, 129.2, 129.1,128.9, 128.1, 128.1, 127.9, 125.4, 120.5,116.9.

[0019] Example 2 6-Methyl-3,4-diphenylisocoumarin, its structural formula is:

[0020] 0.5 mmol of bis(4-methylbenzoyl)peroxide (CAS: 895-85-2), 0.75 mmol of diphenylacetylene, 0.0025 mmol of ferrocene, 1.5 mmol of tert-butyl hydroperoxide, and 2.0 mL of acetonitrile were added to a 10 mL reaction tube, placed in an oil bath at 120 °C under 250 W UV light, and reacted for 30 h. Stop the reaction and cool to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, and the organic phase was dried with anhydrous Na2SO4, filtered, and separated by column chromatography to obtain 128 mg of the target product with a yield of 82%. The NMR characterization of the compound is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J =8.1 Hz, 1H), 7.44 (m, 3H), 7.37 – 7.29 (m, 3H), 7.28 – 7.24 (m, 2H), 7.24 –7.15 (m, 3H), 6.96 (s, 1H), 2.37 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 162.3,151.0, 145.8, 138.9, 134.4, 133.1, 131.3, 129.6, 129.5 129.2, 129.0, 128.8, 128.0, 127.8, 125.3, 118.1, 116.8, 22.2.

[0021] Example 3 6-Methoxy-3,4-diphenylisocoumarin, its structural formula is:

[0022] 0.5 mmol of 4-methoxy-substituted dibenzoyl peroxide (CAS: 849-83-2), 0.75 mmol of diphenylacetylene, 0.0025 mmol of ferrocene, 1.5 mmol of tert-butyl hydroperoxide, and 2.0 mL of acetonitrile were added to a 10 mL reaction tube, placed in an oil bath at 120 °C under 250 W UV light, and reacted for 30 h. Stop the reaction and cool to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, and the organic phase was dried with anhydrous Na2SO4, filtered, and separated by column chromatography to obtain 140 mg of the target product with a yield of 85%. The NMR characterization of the compound is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.33(d, J = 8.8 Hz, 1H), 7.43 – 7.37 (m, 3H), 7.33 – 7.30 (m, 2H), 7.26 – 7.24 (m,3H), 7.22 – 7.15 (m, 3H), 7.06 (dd, J = 8.8, 2.5 Hz, 1H), 3.75 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 164.6, 162.0, 151.5, 141.2, 134.4, 133.0, 131.9, 131.2,129.3, 129.1, 128.9,128.1, 127.8, 116.9, 115.6, 113.7, 108.5, 55.5.

[0023] Example 4 6-Methylthio-3,4-diphenylisocoumarin, its structural formula is:

[0024] 0.5 mmol of 4-methylthio-substituted dibenzoyl peroxide (CAS: 257932-41-5), 0.75 mmol of diphenylacetylene, 0.0025 mmol of ferrocene, 1.5 mmol of tert-butyl hydroperoxide, and 2.0 mL of acetonitrile were added to a 10 mL reaction tube, placed in an oil bath at 120 °C under 250 W UV light, and reacted for 30 h. Stop the reaction and cool to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, and the organic phase was dried with anhydrous Na2SO4, filtered, and separated by column chromatography to obtain 129 mg of the target product with a yield of 75%. The NMR characterization of the compound is as follows: 1HNMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 5.8, 4.2 Hz, 3H), 7.34 – 7.29 (m, 3H), 7.25 –7.15 (m, 5H), 6.91 (d, J = 1.7 Hz, 1H), 2.37 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ162.0, 151.6 148.2, 139.1, 134.1, 132.8, 131.1, 129.6, 129.1, 129.0, 129.0,128.1, 127.8, 124.8, 120.4, 116.7, 116.3, 14.5.

[0025] Example 5 6-Fluoro-3,4-diphenylisocoumarin, its structural formula is:

[0026] 0.5 mmol of 4-fluoro-substituted dibenzoyl peroxide (CAS: 582-92-3), 0.75 mmol of diphenylacetylene, 0.0025 mmol of ferrocene, 1.5 mmol of tert-butyl hydroperoxide, and 2.0 mL of acetonitrile were added to a 10 mL reaction tube, placed in an oil bath at 120 °C under 250 W UV light, and reacted for 30 h. Stop the reaction and cool to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, and the organic phase was dried with anhydrous Na2SO4, filtered, and separated by column chromatography to obtain 115 mg of the target product with a yield of 73%. The NMR characterization of the compound is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.44 (dd, J =8.8, 5.8 Hz, 1H), 7.45 – 7.39 (m, 3H), 7.36 – 7.31 (m, 2H), 7.29 – 7.27 (m,1H), 7.25 (d, J = 2.5 Hz, 1H), 7.24 – 7.23 (m, 1H), 7.21 (dd, J = 3.5, 2.0 Hz,1H), 7.21 – 7.17 (m, 2H), 6.84 (dd, J = 10.1, 2.5 Hz, 1H);13 C NMR (100 MHz, CDCl3) δ 166.8 (d, J = 256 Hz), 161.2, 152.1, 141.8 (d, J = 10 Hz), 133.7, 132.8(d, J = 10 Hz), 132.5, 131.0, 129.2 (d, J = 3 Hz), 128.3, 127.8, 116.8 (d, J = 2Hz), 116.3 (d, J = 24 Hz), 116.3, 116.3, 116.1, 111.3 (d, J = 24 Hz); 19 F NMR (376MHz, CDCl3) δ -101.1(s).

[0027] Example 6 6-Bromo-3,4-diphenylisocoumarin, its structural formula is:

[0028] 0.5 mmol of 4-bromo-substituted dibenzoyl peroxide (CAS: 1712-82-9), 0.75 mmol of diphenylacetylene, 0.0025 mmol of ferrocene, 1.5 mmol of tert-butyl hydroperoxide, and 2.0 mL of acetonitrile were added to a 10 mL reaction tube, placed in an oil bath at 120 °C under 250 W UV light, and reacted for 30 h. Stop the reaction and cool to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, and the organic phase was dried with anhydrous Na2SO4, filtered, and separated by column chromatography to obtain 122 mg of the target product with a yield of 65%. The NMR characterization of the compound is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.26 (d, J =8.4 Hz, 1H), 7.65 (dd, J = 8.4, 1.6 Hz, 1H), 7.49 – 7.39 (m, 3H), 7.35 – 7.28(m, 3H), 7.27 (d, J = 2.6 Hz, 3H), 7.23 – 7.16 (m, 2H); 13C NMR (100 MHz, CDCl3)δ 161.7, 140.6, 133.7, 132.7, 131.6, 131.3, 131.2, 130.5, 129.4, 129.4,129.3,128.6, 128.2, 127.9, 119.2, 116.1. This compound is a very promising class of organic light-emitting structures and can be used as an important organic precursor for the synthesis of organic optoelectronic materials, such as diphenylamine derivatives. Its emission quantum yield in the purple-blue region (370–480 nm) can be as high as 95% (Fedina ES, Arsenov MA, Isakovskaya, KL, Muratov DV, Loginov DA. Synthesis and photophysical activity of 6-substituted isocoumarins[J]. Mendeleev Communications, 2024, 34(1):107-109.).

[0029] Example 7 3,4-bis(4-methoxyphenyl)isocoumarin, its structural formula is:

[0030] 0.5 mmol of dibenzoyl peroxide, 0.75 mmol of di(4-methoxyphenyl)acetylene (CAS: 2132-62-9), 0.0025 mmol of ferrocene, 1.5 mmol of tert-butyl hydroperoxide, and 2.0 mL of acetonitrile were added to a 10 mL reaction tube, placed in an oil bath at 120 °C under 250 W UV light, and reacted for 30 h. Stop the reaction and cool to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, and the organic phase was dried with anhydrous Na2SO4, filtered, and separated by column chromatography to obtain 140 mg of the target product with a yield of 78%. The NMR characterization of the compound is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.38 (d, J =7.8 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 8.7Hz, 2H), 7.17 (dd, J = 12.0, 8.3 Hz, 3H), 6.96 (d, J= 8.4 Hz, 2H), 6.72 (d, J =8.7 Hz, 2H), 3.85 (s, 3H), 3.76 (s, 3H); 1 3 C NMR (100 MHz, CDCl3) δ 162.6,160.1, 159.5, 151.1, 139.7, 134.6, 132.5, 130.8, 129.7, 127.9, 126.8, 125.7,125.4, 120.4, 115.6, 114.8, 113.5, 55.5,55.4.

[0031] Example 8 3,4-di(4-methylphenyl)isocoumarin, its structural formula is:

[0032] 0.5 mmol of dibenzoyl peroxide, 0.75 mmol of di(4-methylphenyl)acetylene (CAS: 2789-88-0), 0.0025 mmol of ferrocene, 1.5 mmol of tert-butyl hydroperoxide, and 2.0 mL of acetonitrile were added to a 10 mL reaction tube, placed in an oil bath at 120 °C under 250 W UV light, and reacted for 30 h. Stop the reaction and cool to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, and the organic phase was dried with anhydrous Na2SO4, filtered, and separated by column chromatography to obtain 116 mg of the target product with a yield of 71%. The NMR characterization of the compound is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.38 (d, J =7.8 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.26 – 7.20 (m,4H), 7.18 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 7.9 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 2.40 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.5, 151.1, 139.4,139.1, 137.9, 134.6, 131.5, 131.2, 130.3, 129.8, 129.5,129.1, 128.6, 127.8,125.3, 120.4, 116.3, 21.4, 21.3.

[0033] Example 9 3,4-bis(4-trifluoromethylphenyl)isocoumarin, its structural formula is:

[0034] 0.5 mmol of dibenzoyl peroxide, 0.75 mmol of di(4-trifluoromethylphenyl)acetylene (CAS: 119757-51-6), 0.0025 mmol of ferrocene, 1.5 mmol of tert-butyl hydroperoxide, and 2.0 mL of acetonitrile were added to a 10 mL reaction tube, placed in an oil bath at 120 °C under 250 W UV light, and reacted for 30 h. Stop the reaction and cool to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, and the organic phase was dried with anhydrous Na2SO4, filtered, and separated by column chromatography to obtain 137 mg of the target product with a yield of 63%. The NMR characterization of the compound is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.45(d, J = 7.8 Hz, 1H), 7.72 (dd, J = 17.3, 7.8 Hz, 3H), 7.61 ( t , J = 7.5 Hz, 1H),7.50 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 4H), 7.13 (d, J = 8.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 161.5, 149.9, 137.9, 137.8, 136.0, 135.2, 131.8, 131.3 (q, J = 33 Hz), 131.0 (q, J = 33 Hz), 130.1, 129.6, 129.1, 126.4 (q, J = 3 Hz),125.3,125.2 (q, J= 3 Hz), 120.5 (q, J = 272 Hz),123.7 (q, J = 272 Hz), 120.7, 117.1; 19 FNMR (376 MHz, CDCl3) δ -62.7 (s), -63.0 (s).

[0035] Example 10 3,4-bis(4-chlorophenyl)isocoumarin, its structural formula is:

[0036] 0.5 mmol of dibenzoyl peroxide, 0.75 mmol of di(4-chlorophenyl)acetylene (CAS: 1820-42-4), 0.0025 mmol of ferrocene, 1.5 mmol of tert-butyl hydroperoxide, and 2.0 mL of acetonitrile were added to a 10 mL reaction tube, placed in an oil bath at 120 °C under 250W UV light, and reacted for 30 h. Stop the reaction and cool to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, and the organic phase was dried with anhydrous Na2SO4, filtered, and separated by column chromatography to obtain 125 mg of the target product with a yield of 68%. The NMR characterization of the compound is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.40 (dd, J =7.9, 1.0 Hz, 1H), 7.70 – 7.62 (m, 1H), 7.57 – 7.51 (m, 1H), 7.45 – 7.39 (m,2H), 7.27 – 7.25 (m, 1H),7.25 – 7.23 (m, 1H), 7.22 – 7.17 (m, 4H), 7.15 (d, J =8.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 161.7, 150.0, 138.1, 135.2, 134.8,134.4, 132.4, 131.0, 130.4, 129.7, 129.5, 128.4, 128.3, 125.0, 120.3, 116.0.

[0037] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made according to the scope of the patent application of the present invention should fall within the scope of the present invention.

Claims

1. A method for preparing a polysubstituted isocoumarin compound, characterized in that: The following steps are involved: Under the action of a catalyst, a free radical initiator and light, a benzoyl peroxide compound reacts with an alkyne derivative in an organic solvent to obtain the polysubstituted isocoumarin compound; The structure of the benzoyl peroxide compound is as follows: The structure of the alkyne derivative is as follows: The structure of the polysubstituted isocoumarin compound is as follows: Among them, R 1 is alkyl, halogen, methoxy or methylthio; R 2 is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is an alkyl group, a methoxy group or a halogen group.

2. The method for preparing a polysubstituted isocoumarin compound according to claim 1, characterized in that: The R 1 is H, methyl, fluoro, bromo, methoxy or methylthio.

3. The method for preparing a polysubstituted isocoumarin compound according to claim 1, characterized in that: The R 2 is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is methyl, n-propyl, n-butyl, methoxy, fluorine or chlorine.

4. The method for preparing a polysubstituted isocoumarin compound according to claim 1, characterized in that: The catalyst is one of ferrocene, ferrous bromide, ferric bromide, ferric sulfate, ferrous sulfate, ferrous chloride and ferric chloride.

5. The method for preparing a polysubstituted isocoumarin compound according to claim 1, characterized in that: The free radical initiator is one of tert-butyl hydroperoxide, di-tert-butyl peroxide, diisopropylbenzene peroxide and 2,2,6,6-tetramethylpiperidine-nitrogen-oxide.

6. The method for preparing a polysubstituted isocoumarin compound according to claim 1, characterized in that: The light source is ultraviolet light.

7. The method for preparing a polysubstituted isocoumarin compound according to claim 1, characterized in that: The organic solvent is one of acetonitrile, toluene, N-methylpyrrolidone, N,N-dimethylformamide and dimethyl sulfoxide.

8. The method for preparing a polysubstituted isocoumarin compound according to claim 1, characterized in that: In terms of molar amount, benzoyl peroxide compound: alkyne derivative: catalyst: free radical initiator = 1: 1.2-2.5: 0.10-0.005: 2.0-5.

0.

9. The method for preparing a polysubstituted isocoumarin compound according to claim 1, characterized in that: The reaction temperature is 80-140°C, and the reaction time is 24-48 h.

10. The method for preparing a polysubstituted isocoumarin compound according to claim 1, characterized in that: The structures of the polysubstituted isocoumarin compounds include the following: 。

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