A chromone derivative and its synthesis method

Abstract

The present invention discloses a chromone derivative and a synthesis method thereof. The method uses an enaminoketone compound 2 and an α-diazoester compound 3 as raw materials to generate a chromone derivative 1 at room temperature and under photocatalytic conditions. The method can avoid the use of any ligand, catalyst, additive and other reagents, has mild reaction conditions, simple operation, high atom economy, good functional group tolerance, conforms to the concept of green chemistry, and can realize gram-scale scale-up experiments, and has good industrial application prospects.

Description

Technical Field

[0001] The invention relates to a chemical synthesis method, in particular to a chromone derivative and a synthesis method thereof. Background Art

[0002] The chromone skeleton is widely present in natural products and shows strong drug activity and great application potential in anti-tumor, antibacterial and anti-inflammatory aspects (J. Med. Chem., 2014, 57: 8398). At present, 2-hydroxyphenyl enaminone has become a bright template molecule for the preparation of chromones, and there are three main synthetic reaction strategies reported. The first is the most common transition metal catalysis, and the metal catalysts used are gold, silver, iridium and palladium (Org. Lett., 2019, 21: 335; Chem. Eur. J., 2019, 8: 767). The second is organic catalysis, and the preparation of 3-sulfonylated chromone catalyzed by 1-propylphosphonic anhydride has been reported (New. J. Chem., 2019, 43: 2458). The third is photocatalysis, and the synthesis of 3-thiocyanochromone catalyzed by photosensitizer rose bengal RB has been reported (J. Org. Chem., 2019, 84: 2243).

[0003] Although the above methods have been used to synthesize chromone compounds by reacting enaminones with diazo compounds, these methods all require the use of carefully selected catalysts and usually require the addition of ligands and additives, and have the problems of high cost, harsh reaction conditions, poor economic efficiency, metal residues, large amounts of hazardous waste, and environmental damage. Therefore, from the perspective of green and sustainable chemistry, developing a method for preparing chromones using enaminones and diazo compounds as substrates under mild conditions without using catalysts, ligands, and additives will have great practical value and good prospects for industrial production. Summary of the invention

[0004] Purpose of the invention: The purpose of the present invention is to provide a method for photochemically synthesizing chromone derivatives in one step with high efficiency, simple operation and mild synthesis reaction conditions.

[0005] Technical solution: The chromone derivative has the following structure:

[0006]

[0007] in,

[0008] R 1 is selected from hydrogen, phenyl, aryl substituted with halogen, methyl or methoxy;

[0009] R 2 Selected from naphthyl, phenyl, aryl substituted with halogen, trifluoromethyl, methyl or methoxy;

[0010] R3 It is an alkyl group having 1 to 4 carbon atoms, an allyl group or a benzyl group.

[0011] Furthermore, the photocatalytic synthesis method of the ketone derivative uses an enaminoketone compound 2 and an α-diazoester compound 3 as starting materials, and realizes the construction of CC bonds and CO bonds in one step under light conditions to generate a chromone derivative 1;

[0012] The synthetic route is as follows:

[0013]

[0014] R 1 is selected from hydrogen, phenyl, aryl substituted with halogen, methyl or methoxy;

[0015] R 2 Selected from naphthyl, phenyl, aryl substituted with halogen, trifluoromethyl, methyl or methoxy;

[0016] R 3 It is an alkyl group having 1 to 4 carbon atoms, an allyl group or a benzyl group.

[0017] Furthermore, in the step, the molar ratio of the enaminone compound 2 to the α-diazo ester compound 3 is 1:1 to 1:4. Furthermore, the preferred molar ratio of the enaminone compound 2 to the α-diazo ester compound 3 is 1:2.

[0018] Further, the solvent of the reaction is one or a mixed solvent of acetonitrile, dichloromethane, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), toluene, chloroform, 1,4-dioxane, ethanol or dichloroethane. The wavelength of the light source of the photoreaction is 395-660nm, and the reaction time is 2-12h.

[0019] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0020] 1. Using light for catalysis avoids the use of transition metal catalysts and oxidants, achieving green environmental protection;

[0021] 2. It can realize the construction of CC and CO chemical bonds at the same time, and has good compatibility;

[0022] 3. Using photocatalysis, such reactions can be carried out on a gram scale and are easy to industrialize;

[0023] 4. The raw materials of this method are cheap and easy to obtain, the reaction conditions are mild, the yield is high, and it can reach the gram scale. The highest yield can reach 86%. It can tolerate a variety of functional groups, meets the requirements of green chemistry, and has practical application value. DETAILED DESCRIPTION

[0024] Example 1

[0025]

[0026] (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one 2b (0.3mmol) and ethyl 2-diazo-2-phenylacetate 3a (0.3mmol) were weighed in a photoreaction tube, 3mL of dichloromethane solvent was added under air atmosphere, and the reaction was carried out at room temperature under 495nm LEDs and 10W light. The reaction progress was detected by thin layer chromatography. After the reaction was completed for 2h, the volatile components were removed by rotary evaporator, and then separated by silica gel column chromatography (eluent was petroleum ether (60-90℃) / ethyl acetate, v / v=80:20) to obtain the white solid target product 1a (68mg, yield 74%). The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0027] Example 2

[0028]

[0029] (E)-1-(4-chloro-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one 2b (0.3mmol) and ethyl 2-diazo-2-phenylacetate 3a (0.6mmol) were weighed in a photoreaction tube, 3mL of acetonitrile solvent was added under air atmosphere, and the reaction was carried out at room temperature under 460nm LEDs and 10W light. The reaction progress was detected by thin layer chromatography. After the reaction was completed for 4h, the volatile components were removed by rotary evaporator, and then separated by silica gel column chromatography (eluent was petroleum ether (60-90℃) / ethyl acetate, v / v=80:20) to obtain the target product 1b (85mg, yield 83%) as a colorless oily liquid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0030] Example 3

[0031]

[0032] (E)-3-(dimethylamino)-1-(2-hydroxy-4-methylphenyl)prop-2-en-1-one 2c (0.3mmol) and ethyl 2-diazo-2-phenylacetate 3a (0.9mmol) were weighed in a photoreaction tube, 3mL of DMF solvent was added under air atmosphere, and the reaction was carried out at room temperature under 660nm LEDs and 10W light. The reaction progress was monitored by thin layer chromatography. After the reaction was completed for 3h, the volatile components were removed by rotary evaporator, and then separated by silica gel column chromatography (eluent was petroleum ether (60-90℃) / ethyl acetate, v / v=80:20) to obtain the white solid target product 1c (60mg, yield 62%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0033] Example 4

[0034]

[0035] (E)-1-(5-bromo-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one 2d (0.3 mmol) and ethyl 2-diazo-2-phenylacetate 3a (0.3 mmol) were weighed in a photoreaction tube, 3 mL of DMSO solvent was added under air atmosphere, and the reaction was carried out at room temperature under 400 nm LEDs and 10 W light. The reaction progress was monitored by thin layer chromatography. After 7 h of reaction, the volatile components were removed by rotary evaporator, and then separated by silica gel column chromatography (eluent was petroleum ether (60-90 ° C) / ethyl acetate, v / v = 80:20) to obtain the target product 1d as a white solid (100 mg, yield 86%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0036] Example 5

[0037]

[0038] (E)-3-(dimethylamino)-1-(2-hydroxy-5-methoxyphenyl)prop-2-en-1-one 2e (0.3mmol) and ethyl 2-diazo-2-phenylacetate 3a (0.9mmol) were weighed in a photoreaction tube, 3mL of toluene solvent was added under air atmosphere, and the reaction was carried out at room temperature under 460nm LEDs and 10W light. The reaction progress was detected by thin layer chromatography. After 5h of reaction, the volatile components were removed by rotary evaporator, and then separated by silica gel column chromatography (eluent was petroleum ether (60-90℃) / ethyl acetate, v / v=80:20) to obtain the target product 1e as a white solid (51mg, yield 50%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0039] Example 6

[0040]

[0041] (E)-3-(dimethylamino)-1-(2-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one 2f (0.3mmol) and ethyl 2-diazo-2-phenylacetate 3a (0.3mmol) were weighed in a photoreaction tube, 3mL of chloroform solvent was added under air atmosphere, 440nm LEDs, 10W light was irradiated at room temperature, and the reaction progress was detected by thin layer chromatography. After 6h of reaction, the volatile components were removed by rotary evaporator, and then separated by silica gel column chromatography (eluent was petroleum ether (60-90℃) / ethyl acetate, v / v=80:20) to obtain the white solid target product 1f (70mg, yield 69%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0042] Example 7

[0043]

[0044] Weigh (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one 2b (0.3mmol) and ethyl 2-diazo-2-(p-toluene)acetate 3b (1.2mmol) in a photoreaction tube, add 3mL of 1,4-dioxane solvent under air atmosphere, react at room temperature under 520nm LEDs and 10W light, and monitor the reaction progress with thin layer chromatography. After 12h of reaction, remove the volatile components with a rotary evaporator, and then separate with silica gel column chromatography (eluent is petroleum ether (60-90℃) / ethyl acetate, v / v=80:20) to obtain 1g (80mg, yield 83%) of white solid target product. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0045] Example 8

[0046]

[0047] (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one 2b (0.3mmol) and ethyl 2-(4-chlorophenyl)-2-diazoacetate 3c (0.9mmol) were weighed in a photoreaction tube, 3mL of ethanol solvent was added under air atmosphere, and the reaction was carried out at room temperature under 395nm LEDs and 10W light. The reaction progress was detected by thin layer chromatography. After the reaction was completed for 11h, the volatile components were removed by rotary evaporator, and then separated by silica gel column chromatography (eluent was petroleum ether (60-90℃) / ethyl acetate, v / v=80:20) to obtain the white solid target product 1h (82mg, yield 80%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0048] Example 9

[0049]

[0050] (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one 2b (0.3mmol) and ethyl 2-(4-bromophenyl)-2-diazoacetate 3d (0.9mmol) were weighed in a photoreaction tube, 3mL of dichloroethane solvent was added under air atmosphere, and the reaction was carried out at room temperature under 470nm LEDs and 10W light. The reaction progress was detected by thin layer chromatography. After the reaction was completed for 9h, the volatile components were removed by rotary evaporator, and then separated by silica gel column chromatography (eluent was petroleum ether (60-90℃) / ethyl acetate, v / v=80:20) to obtain the colorless oily liquid target product 1i (88mg, yield 76%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0051] Example 10

[0052]

[0053] (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one 2b (0.3mmol) and methyl 2-diazo-2-phenylacetate 3e (0.6mmol) were weighed in a photoreaction tube, 3mL of dichloromethane solvent was added under air atmosphere, and the reaction was carried out at room temperature under 495nm LEDs and 10W light. The reaction progress was detected by thin layer chromatography. After the reaction was completed for 10h, the volatile components were removed by rotary evaporator, and then separated by silica gel column chromatography (eluent was petroleum ether (60-90℃) / ethyl acetate, v / v=80:20) to obtain the white solid target product 1j (66mg, yield 75%). The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0054] Embodiment 11

[0055]

[0056] (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one 2b (0.3mmol) and 2-diazo-2-phenylacetic acid isobutyl ester 3f (1.2mmol) were weighed in a photoreaction tube, 3mL of acetonitrile solvent was added under air atmosphere, and the reaction was carried out at room temperature under 660nm LEDs and 10W light. The reaction progress was detected by thin layer chromatography. After the reaction was completed for 8h, the volatile components were removed by rotary evaporator, and then separated by silica gel column chromatography (eluent was petroleum ether (60-90℃) / ethyl acetate, v / v=80:20) to obtain the white solid target product 1k (73mg, yield 72%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0057] Characterization data of typical compounds

[0058] (R)-ethyl 2-(4-oxo-4H-chromen-3-yl)-2-phenylacetate (1a), white solid. 1 H NMR (400 MHz, CDCl 3 )δ8.22(dd,J=8.0,1.3Hz,1H),7.69-7.61(m,1H),7.60(d,J=0.9Hz,1H),7.44-7.3 6(m,6H),7.36-7.30(m,1H),5.17(s,1H),4.38-4.09(m,2H),1.26(t,J=7.1Hz,3H). 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ176.8,171.8,156.4,154.9,135.8,133.9,129.2,128.8,128.0,126.1,125.3,124.0,123.7,118.2,61.6,48.0,14.2.

[0059] (R)-ethyl 2-(7-chloro-4-oxo-4H-chromen-3-yl)-2-phenylacetate (1b), colorless oily liquid. 1 H NMR (400 MHz, CDCl 3 )δ8.15(d,J=8.6Hz,1H),7.56(d,J=0.9Hz,1H),7.43(d,J=1.8Hz,1H),7.41-7.31(m,6H),5.14(s,1H),4.31-4.13(m,2H),1.25(t,J=7.1Hz,3H). 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ176.0,171.7,156.4,154.9,140.0,135.5,129.2,128.8,128.1,127.5,126.2,124.4,122.2,118.2,61.7,47.9,14.2.C 19 H 16 C1O 4 The theoretical value of HRMS ([M+H] + ]):343.0732; measured value:343.0743.

[0060] (R)-ethyl 2-(7-methyl-4-oxo-4H-chromen-3-yl)-2-phenylacetate (1c), white solid. 1H NMR (400 MHz, CDCl 3 )δ8.10(d,J=8.5Hz,1H),7.55(s,1H),7.38(d,J=4.2Hz,4H),7.35-7.29(m,1H),7.20 (d,J=4.6Hz,2H),5.16(s,1H),4.34-4.11(m,2H),2.46(s,3H),1.25(t,J=7.1Hz,3H). 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ176.7,171.9,156.5,154.7,145.2,136.0,129.2,128.8,127.9,126.8,125.9,123.9,121.5,117.9,61.6,48.0,21.9,14.2.C 20 H 19 O 4 The theoretical value of HRMS ([M+H] + ]):323.1278; measured value:323.1286.

[0061] (R)-ethyl 2-(6-bromo-4-oxo-4H-chromen-3-yl)-2-phenylacetate (1d), white solid. 1 H NMR (400 MHz, CDCl 3 )δ8.33(d,J=2.2Hz,1H),7.71(dd,J=8.9,2.3Hz,1H),7.59(s,1H),7.40-7.28(m,6H),5.14(s,1H),4.30-4.13(m,2H),1.25(t,J=7.1Hz,3H). 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ175.5,171.6,155.1,155.1,136.8,135.5,129.2,128.8,128.7,128.1,124.9,124.3,120.2,118.7,61.7,47.9,14.2.C 19 H 15 B O 4 The theoretical value of HRMS of Na ([M+Na] + ]):409.0046; measured value:409.0062.

[0062] (R)-ethyl 2-(6-methoxy-4-oxo-4H-chromen-3-yl)-2-phenylacetate (1e), white solid.1 H NMR (400 MHz, CDCl 3 )δ7.58(d,J=2.8Hz,2H),7.43-7.30(m,6H),7.27-7.21(m,1H),5.16(s,1H),4.33-4.11(m,2H),3.87(s,3H),1.26(t,J=7.1Hz,3H). 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ176.6,171.9,157.0,154.7,151.3,135.9,129.2,128.8,127.9,124.2,124.1,123.2,119.6,104.9,61.6,56.0,48.1,14.2.C 20 H 19 O 5 The theoretical value of HRMS ([M+H] + ]):339.1227; measured value:339.1236.

[0063] (R)-ethyl 2-(6,8-dimethyl-4-oxo-4H-chromen-3-yl)-2-phenylacetate (1f), white solid. 1 HNMR (400MHz, CDCl 3 )δ7.84(s,1H),7.61(s,1H),7.38(d,J=4.2Hz,4H),7.34-7.27(m,2H),5.1 7(s,1H),4.31-4.13(m,2H),2.38(d,J=6.4Hz,6H),1.26(t,J=7.1Hz,3H). 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ177.2,171.9,154.6,153.2,136.1,136.0,134.6,129.1,128.8,127.9,127.2,123.6,123.2,122.9,61.5,48.0,21.0,15.5,14.2.C 21 H 21 O 4 The theoretical value of HRMS ([M+H] + ]):337.1434; measured value:337.1444.

[0064] (R)-ethyl 2-(4-oxo-4H-chromen-3-yl)-2-(p-toluene)acetate (1 g), white solid. 1H NMR (400 MHz, CDCl 3 )δ8.21(dd,J=8.0,1.4Hz,1H),7.65-7.59(m,1H),7.58(d,J=0.8Hz,1H),7.42-7.34(m,2H),7.25(d,J= 8.0Hz,2H),7.17(d,J=7.9Hz,2H),5.11(s,1H),4.32-4.09(m,2H),2.34(s,3H),1.24(t,J=7.1Hz,3H). 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ176.8,172.0,156.3,154.9,137.7,133.8,132.7,129.8,128.7,126.1,125.2,124.1,123.6,118.1,61.5,47.6,21.2,14.2.C 20 H 18 O 4 The theoretical value of HRMS of Na ([M+Na] + ]):345.1097; measured value:345.1109.

[0065] (R)-ethyl 2-(4-chlorophenyl)-2-(4-oxo-4H-chromen-3-yl)acetate (1 h), white solid. 1 H NMR (400 MHz, CDCl 3 )δ8.20(dd,J=8.0,1.3Hz,1H),7.68(d,J=0.8Hz,1H),7.65(m,1H),7.47-7.38(m ,2H),7.37-7.31(m,4H),5.13(s,1H),4.30-4.12(m,2H),1.25(t,J=7.1Hz,3H). 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ176.6,171.5,156.3,154.6,134.5,133.98,133.9,130.2,129.3,126.1,125.4,123.6,123.5,118.2,61.8,47.3,14.2.C 19 H 15 C1O 4 The theoretical value of HRMS of Na ([M+Na] + ]):365.0551; measured value:365.0562.

[0066] (R)-ethyl 2-(4-bromophenyl)-2-(4-oxo-4H-chromen-3-yl)acetate (1i), colorless oily liquid. 1 HNMR (400MHz, CDCl 3 )δ8.20(d,J=7.9Hz,1H),7.69(s,1H),7.65(t,J=7.8Hz,1H),7.49(d,J=8.3Hz,2H),7.44- 7.35(m,2H),7.27(d,J=8.3Hz,2H),5.12(s,1H),4.29-4.13(m,2H),1.25(t,J=7.1Hz,3H). 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ176.6,171.4,156.3,154.6,135.1,134.0,132.2,130.5,126.1,125.4,123.6,123.5,122.1,118.2,61.8,47.3,14.2.C 19 H 15 B O 4 The theoretical value of K by HRMS ([M+K] + ]):424.9785; measured value:424.9797.

[0067] (R)-Methyl 2-(4-oxo-4H-chromen-3-yl)-2-phenylacetate (1j), white solid. 1 H NMR (400 MHz, CDCl 3 )δ8.22(dd,J=7.9,1.3Hz,1H),7.68-7.62(m,1H),7.59(s,1H),7.46-7.36(m,6H),7.36-7.31(m,1H),5.18(s,1H),3.76(s,3H). 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ176.8,172.3,156.4,154.9,135.6,133.9,129.2,128.8,128.1,126.1,125.3,123.9,123.6,118.2,52.7,47.9.

[0068] (R)-2-(4-Oxo-4H-chromen-3-yl)-2-phenylacetic acid isobutyl ester (1k), white solid. 1 H NMR (400 MHz, CDCl 3)δ8.23(d,J=7.9Hz,1H),7.71-7.61(m,2H),7.45-7.35(m,6H),7.34-7.29(m,1H ),5.20(s,1H),4.05-3.85(m,2H),2.00-1.86(m,1H),0.87(s,3H),0.85(s,3H). 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ176.8,171.9,156.4,154.9,136.0,133.8,129.1,128.8,127.9,126.1,125.3,123.9,123.7,118.2,71.6,48.0,27.8,19.1.C 21 H 20 O 4 The theoretical value of HRMS of Na ([M+Na] + ]):359.1254; measured value:359.1266.

Claims

1. A method for synthesizing a chromone derivative, characterized in that: Using enaminoketone compound 2 and α-diazoester compound 3 as raw materials, chromone derivative 1 was generated at room temperature under photocatalytic conditions. The wavelength of the light source for the reaction was 395-660 nm. The synthetic route is as follows: ， Among them, R 1 R is selected from hydrogen, phenyl, aryl substituted with halogen, methyl or methoxy; 2 is selected from naphthyl, phenyl, aryl substituted with halogen, trifluoromethyl, methyl or methoxy; R 3 It is an alkyl group having 1 to 4 carbon atoms, an allyl group or a benzyl group.

2. The method for synthesizing a chromone derivative according to claim 1, characterized in that: The molar ratio of the enaminone compound 2 to the α-diazo ester compound 3 is 1:1 to 1:

4.

3. The method for synthesizing a chromone derivative according to claim 1, characterized in that: The reaction time is 2 to 12 hours.

4. The method for synthesizing a chromone derivative according to claim 1, characterized in that: The reaction solvent is one of acetonitrile, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chloroform, 1,4-dioxane, ethanol or dichloroethane, or a mixture of two thereof.

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