Preparation method of oxygen / thioxanthone compound

Abstract

The invention discloses a preparation method of an oxygen / thioxanthone compound, which is characterized in that 2-aryloxy / sulfenyl aryl formaldehyde is heated and reacted in the presence of tetrabutylammonium iodide, water and a solvent to prepare the oxygen / thioxanthone compound. According to the method, tetrabutylammonium iodide which is low in price and easy to obtain is selected as a catalyst, in the presence of water, the oxygen / thioxanthone compound is efficiently prepared through the direct cyclization reaction of 2-aryloxy / sulfenyl aryl formaldehyde in one pot and one step, and the method has the advantages that transition metal is not needed, the substrate range is wide, the cost is low, and the method is green and environmentally friendly; the limitation of using dangerous reagents, transition metal catalysts and multi-step reaction is avoided, and industrial production is facilitated.

Description

Technical Field

[0001] The invention relates to a method for preparing an oxygen / thioxanthone compound, and belongs to the field of fine chemical synthesis. Background Art

[0002] Oxygen / thioxanthone compounds are an important class of drug molecular skeletons, which are widely used in the fields of medicine, pesticides, and materials. According to relevant literature reports, the preparation of oxygen / thioxanthone compounds mainly includes the following:

[0003] The first method: As shown in Formula 1, starting from xanthene, in the presence of an equivalent oxidant and a transition metal catalyst, xanthene is oxidized to prepare xanthone. However, this method often has the disadvantages of difficult raw materials or catalysts and the need for transition metal participation, and is not economical.

[0004]

[0005] The second method is to prepare xanthone from 2-aryloxyaromatic acid or 2-aryloxyaromatic methyl ester by Friedel-Crafts acylation in the presence of strong acid. The starting materials of this method are also difficult to prepare, and a large amount of acyl chloride reagent is required, which is not environmentally friendly and has poor practicality.

[0006]

[0007] The third method is to prepare xanthone from 2-aryloxy aromatic formaldehyde through transition metal rhodium or copper catalysis. In addition, there is also a method that requires the use of excessive and explosive peroxide TBHP for preparation, which has safety risks in industrial production. The above methods further limit the application of this method from the perspective of economy and safety.

[0008] Summary of the invention

[0009] In order to solve the problems existing in the preparation of existing oxygen / thioxanthone compounds, the purpose of the present invention is to provide a method for preparing oxygen / thioxanthone compounds using cheap, easily available, low-toxic and safe tetrabutylammonium iodide and water as reaction media. The method uses tetrabutylammonium iodide as a catalyst and water as a promoter. In the presence of a solvent, the corresponding oxygen / thioxanthone is synthesized in one pot and one step by cyclization of 2-aryloxyoxy / sulfanylaromatic formaldehyde molecules, avoiding the use of dangerous peroxides, chlorination reagents, transition metal catalysts and the limitations of multi-step reactions. The method has the advantages of low production cost, wide application range of substrates, cheap and easily available raw materials, green environmental protection, and is conducive to industrial production.

[0010] In order to achieve the above object, the present invention provides a method for preparing an oxygen / thioxanthone compound, wherein 2-aryloxy / thioaryl formaldehyde is heated to react in the presence of tetrabutylammonium iodide, water and a solvent to obtain an oxygen / thioxanthone compound, and the reaction equation is shown in Formula 4:

[0011]

[0012] Among them, Ar 1 A phenyl group or a phenyl group containing at least one of a C1-C5 alkyl group, a C1-C5 alkoxy group, a halogen substituent, a cyano group, a nitro group, and a trifluoromethyl group. The substituent may be one or more, and the position of the substitution is not limited;

[0013] Ar 2 A phenyl group, a naphthyl group, or a phenyl group containing at least one of a C1-C5 alkyl group, a C1-C5 alkoxy group, a halogen substituent, a hydroxyl group, a phenyl group, and a phenoxy group. The substituent may be one or more, and the position of the substitution is not limited;

[0014] X=O or S.

[0015] Preferably, the 2-aryloxy / thioaryl formaldehyde is selected from one of the following structural formulas:

[0016]

[0017] Preferably, the molar ratio of the 2-aryloxy / sulfanyl carboxaldehyde to tetrabutylammonium iodide is 1:0.05-0.5, and more preferably 1:0.1-0.2; the amount ratio of 2-aryloxy / sulfanyl carboxaldehyde to water is 1mmol:0.1-1mL, and more preferably 1mmol:0.2-0.5mL; the amount ratio of 2-aryloxy / sulfanyl carboxaldehyde to solvent is 1mmol:0.5-3mL, and more preferably 1mmol:1-2mL.

[0018] Preferably, the solvent is 1,2-dichloroethane, chlorobenzene, chloroform, dichloromethane, benzene, toluene or ethyl acetate; more preferably, 1,2-dichloroethane.

[0019] Preferably, the atmosphere of the heating reaction is an air atmosphere or a protective atmosphere, and more preferably an air atmosphere.

[0020] Preferably, the heating reaction temperature is 140-180° C., more preferably 150-170° C.; the heating reaction time is not less than 10 h, more preferably not less than 20 h.

[0021] Preferably, after the heating reaction is completed, the reaction solution is extracted, dried, filtered, rotary evaporated, and then separated and purified by column chromatography.

[0022] The advantages of the present invention are:

[0023] The invention provides a method for preparing an oxygen / thioxanthone compound by using tetrabutylammonium iodide and water which are cheap, easily available, low in toxicity and safe as reaction media. The method uses tetrabutylammonium iodide as a catalyst and water as a promoter. In the presence of a solvent, the corresponding oxygen / thioxanthone is synthesized in one pot and one step by endocyclic closure of 2-aryloxy / thioaromatic formaldehyde molecules. The method avoids the limitations of using dangerous peroxides, chlorination reagents, transition metal catalysts, and difficulty in obtaining raw materials. The method has the advantages of low production cost, wide application range of substrates, cheap and easily available raw materials, green environmental protection, and is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The H NMR spectrum of the sample prepared in Example 1;

[0025] Figure 2 The NMR carbon spectrum of the sample prepared in Example 1;

[0026] Figure 3 is the H NMR spectrum of the sample prepared in Example 2;

[0027] Figure 4 The NMR carbon spectrum of the sample prepared in Example 2;

[0028] Figure 5 The H NMR spectrum of the sample obtained in Example 3;

[0029] Figure 6 The NMR carbon spectrum of the sample prepared in Example 3;

[0030] Figure 7 The H NMR spectrum of the sample obtained in Example 4;

[0031] Figure 8 The NMR carbon spectrum of the sample prepared in Example 4;

[0032] Fig. 9 is the H NMR spectrum of the sample obtained in Example 5;

[0033] Fig.10 The NMR carbon spectrum of the sample obtained in Example 5;

[0034] Fig.11 is the H NMR spectrum of the sample obtained in Example 6;

[0035] Fig.12 The NMR carbon spectrum of the sample obtained in Example 6;

[0036] Fig.13 is the H NMR spectrum of the sample obtained in Example 7;

[0037] Fig.14is the NMR carbon spectrum of the sample obtained in Example 7;

[0038] Fig.15 is the H NMR spectrum of the sample prepared in Example 8;

[0039] Fig.16 The NMR carbon spectrum of the sample obtained in Example 8;

[0040] Fig.17 is the H NMR spectrum of the sample prepared in Example 9;

[0041] Fig.18 The NMR carbon spectrum of the sample prepared in Example 9;

[0042] Fig.19 is the H NMR spectrum of the sample obtained in Example 10;

[0043] Fig. 20 The NMR carbon spectrum of the sample prepared in Example 10;

[0044] Fig.21 is the H NMR spectrum of the sample prepared in Example 11;

[0045] Fig. 22 is the NMR carbon spectrum of the sample prepared in Example 11;

[0046] Fig.23 is the H NMR spectrum of the sample prepared in Example 12;

[0047] Fig.24 This is the NMR carbon spectrum of the sample prepared in Example 12. DETAILED DESCRIPTION

[0048] The following examples are intended to further illustrate the present invention, but are not intended to limit the scope of protection of the claims of the present invention.

[0049] Example 1

[0050] (1) In an air atmosphere, 2-phenoxybenzaldehyde (0.3 mmol), tetrabutylammonium iodide (0.03 mmol), water (0.1 mL) and 1,2-dichloroethane (0.6 mL) were added to a reaction flask, and the mixture was stirred in a sealed container at 160°C for 24 hours. After the reaction, a saturated saline solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was dried, filtered, and the solvent was dried, and the product was finally separated by column chromatography. The product was a white solid. The yield was 98%.

[0051] (2) Same as (1), except that the yield was 61% under nitrogen atmosphere.

[0052] (3) Same as (1), except that the reaction was stirred for 12 hours and the yield was 56%.

[0053] (4) Same as (1), except that the amount of tetrabutylammonium iodide used was 0.015 mmol, and the yield was 64%.

[0054] (5) Same as (1), except that the amount of tetrabutylammonium iodide used is 0.06 mmol, and the yield is 95%.

[0055] 1 H NMR (500MHz CDCl3): δ8.37 (dd, J=1.8Hz, J=8.0Hz, 2H), 7.77–7.73 (m, 2H), 7.52–7.50 (m, 2H), 7.42–7.39 (m, 2H).

[0056] 13 C{1H}NMR(125MHz CDCl3): δ177.24,156.17,134.83,126.74,123.92,121.85,117.99.

[0057] Example 2

[0058] In an air atmosphere, add 2-p-tolyloxybenzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) to the reaction bottle, and stir and react at 160°C for 24 hours. After the reaction, add saturated saline solution to the reaction solution, extract with dichloromethane, dry the organic phase, filter and spin dry the solvent, and finally separate the product by column chromatography. The obtained product is a white solid The yield was 97%.

[0059] 1 H NMR (400MHz CDCl3): δ8.34–8.31(m,2H),8.10(s,1H),7.72–7.67(m,1H),7.52–7.45(m,2H),7.38–7.33(m,2H),2.46(s,3H).

[0060] 13 C NMR (100MHz CDCl3): δ177.3,156.2,154.4,136.1,134.6,133.7,126.7,126.0,123.7,121.8,121.5,118.0,117.8,20.9.

[0061] Example 3

[0062] In an air atmosphere, add 2-(2,4-dimethylphenoxy)benzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) to the reaction bottle, and stir and react at 160°C for 24 hours. After the reaction, add saturated salt water to the reaction solution, extract with dichloromethane, dry the organic phase, filter and spin dry the solvent, and finally separate the product by column chromatography. The obtained product is a white solid The yield was 68%.

[0063] 1 H NMR (400MHz CDCl3): δ8.33–8.31(m,1H),7.94(s,1H),7.71–7.67(m,1H),7.51–7.48(m,1H),7.37–7.33(m,2H),2.51(s,3H),2.41(s,3H).

[0064] 13 C NMR (100MHz CDCl3): δ177.6,156.1,152.8,137.1,134.5,133.1,126.9,126.7,123.6,123.6,121.6,121.3,118.0,20.8,15.7.

[0065] Example 4

[0066] In an air atmosphere, 2-(4-methoxyphenoxy)benzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) were added to the reaction bottle, and the reaction was stirred in a closed manner at 160°C for 24 hours. After the reaction was completed, a saturated saline solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried and filtered, the solvent was dried, and finally the product was separated by column chromatography. The obtained product was a white solid The yield was 56%.

[0067] 1 H NMR (400MHz CDCl3): δ8.35–8.32(m,1H),7.72–7.68(m,2H),7.47–7.29(m,4H),3.91(s,3H).

[0068] 13 C NMR (100MHz CDCl3): δ177.1,156.1,156.0,151.0,134.6,126.7,124.9,123.7,122.1,121.2,119.4,118.0,105.8,55.9.

[0069] Example 5

[0070] In an air atmosphere, 2-(4-phenoxyphenoxy)benzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) were added to the reaction bottle, and the reaction was stirred in a closed manner at 160°C for 24 hours. After the reaction was completed, a saturated saline solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried and filtered, the solvent was dried, and finally the product was separated by column chromatography. The obtained product was a white solid The yield was 44%.

[0071] 1 H NMR(400MHz CDCl3): δ8.21(dd,J=8.0Hz,1.7Hz,1H),7.77(d,J=2.9Hz,1H),7.64–7.60(m,1 H),7.41–7.33(m,3H),7.29–7.25(m,3H),7.08–7.04(m,1H),6.97–6.94(m,2H).

[0072] 13 C NMR (100MHz CDCl3): δ175.7,155.8,155.1,152.5,151.1,133.8,129.0,125.7,125.7,122.9,122.8,121.5,120.2,118.7,118.0,116.9,113.1.

[0073] Example 6

[0074] Under air atmosphere, add 2-(4-phenylphenoxy)benzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) to the reaction bottle, and stir and react at 160℃ for 24 hours. After the reaction, add saturated salt water to the reaction solution, extract with dichloromethane, dry the organic phase, filter and spin dry the solvent, and finally separate the product by column chromatography. The obtained product is a white solid The yield was 71%.

[0075] 1H NMR(400MHz CDCl3): δ8.56(d,J=2.4Hz,1H),8.37(dd,J=7.9Hz,1.8Hz,1H),7.97(dd,J=8.7Hz,2.4Hz,1H),7. 76–7.71(m,1H),7.70–7.67(m,2H),7.56(d,J=8.7Hz,1H),7.52–7.46(m,3H),7.41–7.37(m,2H).

[0076] 13 C NMR (100MHz CDCl3): δ177.3,156.2,155.6,139.4,137.1,134.8,133.7,129.0,127.7,127.1,126.8,124.6,124.0,122.0,121.8,118.5,118.1.

[0077] Example 7

[0078] In an air atmosphere, 4-bromo-2-phenoxybenzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) were added to the reaction bottle, and the reaction was stirred in a closed manner at 160°C for 24 hours. After the reaction was completed, a saturated saline solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried and filtered, the solvent was dried, and finally the product was separated by column chromatography. The obtained product was a light yellow solid The yield was 66%.

[0079] 1 H NMR (400MHz CDCl3): δ8.31–8.20(m,2H),7.74–7.67(m,1H),7.49–7.28(m,4H).

[0080] 13 C NMR (100MHz CDCl3): δ176.4,156.3,156.1,140.9,135.1,128.1,126.8,124.8,124.4,121.8,120.4,118.0,118.0.

[0081] Example 8

[0082] In an air atmosphere, 3-trifluoromethyl-2-phenoxybenzaldehyde (0.3mmol), tetrabutylammonium iodide (0.06mmol), water (0.1mL) and 1,2-dichloroethane (0.2mL) were added to the reaction bottle, and the reaction was stirred in a closed manner at 160°C for 24 hours. After the reaction was completed, a saturated saline solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried and filtered, the solvent was dried, and finally the product was separated by column chromatography. The obtained product was a reddish brown solid The yield was 90%.

[0083] 1 H NMR(400MHz CDCl3): δ8.60(d,J=2.3Hz,1H),8.31(dd,J=8.0Hz,1.7Hz,1H),7.91(dd,J=8.8Hz,2.4Hz ,1H),7.78–7.73(m,1H),7.58(d,J=8.8Hz,1H),7.49(d,J=8.4Hz,1H),7.43–7.39(m,1H).

[0084] 13 C NMR (100MHz CDCl3): δ176.2,157.7(q,J C-F =3.3Hz),156.0,135.5,131.1(q,J C-F =3.3Hz),126.9,126.4(q,J C-F =33.4Hz),124.8(q,J C-F =4.0Hz),124.7,123.6(q,J C-F =270.5Hz),121.6(broad),121.5(broad),119.1,118.1.

[0085] Example 9

[0086] Under air atmosphere, add 3-cyano-2-phenoxybenzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) to the reaction bottle, and stir and react at 160℃ for 24 hours. After the reaction, add saturated salt water to the reaction solution, extract with dichloromethane, dry the organic phase, filter and spin dry the solvent, and finally separate the product by column chromatography. The obtained product is a light yellow solid The yield was 20%.

[0087] 1H NMR(400MHz CDCl3): δ8.66(d,J=2.1Hz,1H),8.33(dd,J=8.0Hz,1.7Hz,1H),7.94(dd,J=8.7Hz,2. 1Hz,1H),7.82–7.78(m,1H),7.62–7.60(m,1H),7.55–7.53(m,1H),7.48–7.44(m,1H).

[0088] 13 C NMR (100MHz CDCl3): δ175.5,158.1,155.9,136.9,135.8,132.4,126.9,125.1,122.2,121.7,119.7,118.2,117.7,108.1.

[0089] Example 10

[0090] In an air atmosphere, add 2-(2-naphthyloxy)benzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) to the reaction bottle, and stir and react at 160°C for 24 hours. After the reaction, add saturated salt water to the reaction solution, extract with dichloromethane, dry the organic phase, filter and spin dry the solvent, and finally separate the product by column chromatography. The obtained product is a white solid The yield was 95%.

[0091] 1 H NMR(400MHz CDCl3): δ10.08(d,J=8.6Hz,1H),8.42(d,J=8.0Hz,1H),8.08(d,J=9.0Hz,1H),7.87(d,J =8.0Hz,1H),7.79–7.69(m,2H),7.60–7.56(m,1H),7.53–7.50(m,2H),7.44–7.40(m,1H).

[0092] 13 C NMR (100MHz CDCl3): δ178.5,157.6,154.7,136.7,133.9,131.2,130.2,129.6,128.4,127.0,126.7,126.2,124.3,123.6,118.1,117.5,114.6.

[0093] Embodiment 11

[0094] Under air atmosphere, add 2-(4-methylphenylthio)benzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) to the reaction bottle, and stir and react at 160℃ for 24 hours. After the reaction, add saturated salt water to the reaction solution, extract with dichloromethane, dry the organic phase, filter and spin dry the solvent, and finally separate the product by column chromatography. The obtained product is a brown solid The yield was 44%.

[0095] 1 H NMR (400MHz CDCl3): δ8.60 (dd, J=8.1Hz, 1.5Hz, 1H), 8.41 (s, 1H), 7.60–7.52 (m, 2H), 7.46–7.39 (m, 3H), 2.46 (s, 3H).

[0096] 13 C NMR (100MHz CDCl3): δ180.0,137.4,136.3,134.1,133.7,132.1,129.8,129.6,129.2,129.0,126.1,126.0,125.8,21.2.

[0097] Example 12

[0098] Under air atmosphere, add 2-(2-naphthylthio)benzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) into the reaction bottle, and stir the reaction for 11 hours at 160℃. After the reaction, add saturated salt water to the reaction solution, extract with dichloromethane, dry the organic phase, filter and spin dry the solvent, and finally separate the product by column chromatography. The obtained product is a brown solid The yield was 84%.

[0099] 1 H NMR(400MHz CDCl3): δ9.87(d,J=8.8Hz,1H),8.61(dd,J=7.7Hz,0.7Hz,1H),7.90(d,J=8.7Hz,1H),7.83– 7.81(m,1H),7.74–7.69(m,1H),7.58–7.53(m,3H),7.52–7.48(m,1H),7.44(d,J=8.8Hz,1H).

[0100] 13C NMR(100MHz CDCl3):δ182.0,139.9,134.9,133.4,132.7,132.3,132.0,131.3,129.7,129.1,128.5,126.8,126.7,126.6,125.1,123.9,123.7.

Claims

1. A method for preparing an oxygen / thioxanthone compound, characterized in that: 2-aryloxy / thioaryl formaldehyde is heated to react in the presence of tetrabutylammonium iodide, water and a solvent to obtain an oxygen / thioxanthenone compound, the reaction equation of which is shown in Formula 4: Among them, Ar 1 A phenyl group or a phenyl group containing at least one of a C1-C5 alkyl group, a C1-C5 alkoxy group, a halogen substituent, a cyano group, a nitro group, and a trifluoromethyl group; Ar 2 A phenyl group, a naphthyl group, or a phenyl group containing at least one of a C1-C5 alkyl group, a C1-C5 alkoxy group, a halogen substituent, a hydroxyl group, a phenyl group, and a phenoxy group; X=O or S.

2. The method for preparing an oxygen / thioxanthone compound according to claim 1, characterized in that: The 2-aryloxy / thioaryl formaldehyde is selected from one of the following structural formulas:

3. The method for preparing an oxygen / thioxanthone compound according to any one of claims 1 to 2, characterized in that: The molar ratio of the 2-aryloxy / sulfur aromatic carboxaldehyde to tetrabutylammonium iodide is 1:0.05-0.5, and the amount ratio of the 2-aryloxy / sulfur aromatic carboxaldehyde to water is 1 mmol: 0.1~1mL, the usage ratio of 2-aryloxy / sulfenyl aromatic formaldehyde to solvent is 1mmol:0.5~3mL.

4. The method for preparing an oxygen / thioxanthone compound according to claim 3, characterized in that: The molar ratio of the 2-aryloxy / sulfanyl carboxaldehyde to tetrabutylammonium iodide is 1:0.1-0.2, the dosage ratio of the 2-aryloxy / sulfanyl carboxaldehyde to water is 1mmol:0.2-0.5mL, and the dosage ratio of the 2-aryloxy / sulfanyl carboxaldehyde to the solvent is 1mmol:1-2mL.

5. The method for preparing an oxygen / thioxanthone compound according to any one of claims 1 to 2, characterized in that: The solvent is 1,2-dichloroethane, chlorobenzene, chloroform, dichloromethane, benzene, toluene or ethyl acetate.

6. The method for preparing an oxygen / thioxanthone compound according to any one of claims 1 to 2, characterized in that: The atmosphere of the heating reaction is air atmosphere or protective atmosphere.

7. The method for preparing an oxygen / thioxanthone compound according to claim 6, characterized in that: The atmosphere of the heating reaction is air atmosphere.

8. The method for preparing an oxygen / thioxanthone compound according to any one of claims 1 to 2, characterized in that: The heating reaction temperature is 140-180° C.; the heating reaction time is not less than 10 hours.

9. The method for preparing an oxygen / thioxanthone compound according to claim 8, characterized in that: The heating reaction temperature is 150-170° C.; the heating reaction time is not less than 20 hours.

10. The method for preparing an oxygen / thioxanthone compound according to any one of claims 1 to 2, characterized in that: After the heating reaction is completed, the reaction is followed by extraction, drying, filtration, rotary evaporation, and then separation and purification by column chromatography.

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