A preparation method of oxygen / thioxanthone compound
Through the intramolecular ring-closure reaction of tetrabutylammonium iodide and water catalyst, the problems of difficult raw material acquisition and safety in the preparation of oxygen/thioxanthone compounds are solved, and a low-cost and environmentally friendly preparation method is realized, which is suitable for the fields of medicine, pesticides and materials.
Patent Information
- Application Number
- CN202411545825.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-01
- Publication Date
- 2025-10-03
- Estimated Expiration
- 2044-11-01
AI Technical Summary
Existing preparation methods for oxygen/thioxanthone compounds have problems such as difficulty in obtaining raw materials, the use of hazardous reagents and catalysts, high costs, and environmental impact, which limit their application in the fields of medicine, pesticides, and materials.
Tetrabutylammonium iodide and water are used as catalysts and promoters in the presence of solvents to synthesize oxygen/thioxanthenones through a one-pot intramolecular ring closure of 2-aryloxy/thioaryl formaldehydes, avoiding the use of hazardous reagents and multi-step reactions.
The invention realizes the low-cost and environmentally friendly preparation of oxygen/thioxanthone compounds, which has a wide range of applications and is suitable for industrial production.
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Figure CN119192126B_ABST
Abstract
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, widely used in medicine, pesticides, and materials. According to relevant literature reports, the preparation of oxygen / thioxanthone compounds mainly includes the following methods:
[0003] The first method, as shown in Formula 1, involves oxidizing xanthenes to produce xanthenes in the presence of an equivalent oxidant and a transition metal catalyst. However, this method often suffers from drawbacks such as the difficulty in obtaining raw materials or catalysts and the need for a transition metal, making it less economical.
[0004]
[0005] The second method involves preparing xanthone from 2-aryloxyarylcarboxylic acids or 2-aryloxyarylmethyl esters via a Friedel-Crafts-like acylation reaction in the presence of a strong acid. This method also requires complex starting materials, requires a large amount of acyl chloride reagent, is environmentally unfriendly, and has limited practicality.
[0006]
[0007] The third method involves preparing xanthone from 2-aryloxyaromatic formaldehydes using transition metal rhodium or copper catalysis. Alternatively, some methods require the use of excessive amounts of the explosive peroxide TBHP, posing a safety hazard in industrial production. These methods further limit their applicability from the perspectives of cost-effectiveness and safety.
[0008] Summary of the Invention
[0009] In order to solve the problems existing in the preparation of existing oxygen / thioxanthenone compounds, the purpose of the present invention is to provide a method for preparing oxygen / thioxanthenone compounds using inexpensive, 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 / thioxanthenone is synthesized in a one-pot step by intramolecular ring closure 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, a wide range of substrate applications, inexpensive and readily available raw materials, environmental friendliness, and is conducive to industrial production.
[0010] To achieve the above objectives, the present invention provides a method for preparing an oxygen / thioxanthone compound. 2-aryloxy / thioaryl formaldehyde is heated and reacted in the presence of tetrabutylammonium iodide, water, and a solvent to prepare an oxygen / thioxanthone compound. The reaction equation is shown in Formula 4:
[0011]
[0012] Among them, Ar 1 Phenyl or phenyl containing at least one substituent selected from C1-C5 alkyl, C1-C5 alkoxy, halogen, cyano, nitro, and trifluoromethyl. The substituent may be one or more, and the position of the substituent is not limited.
[0013] Ar 2 A phenyl group, a naphthyl group, or a phenyl group containing at least one substituent selected from the group consisting 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 substituent 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 aromatic carboxaldehyde to tetrabutylammonium iodide is 1:0.05-0.5, more preferably 1:0.1-0.2; the amount ratio of 2-aryloxy / sulfanyl aromatic carboxaldehyde to water is 1 mmol:0.1-1 mL, more preferably 1 mmol:0.2-0.5 mL, and the amount ratio of 2-aryloxy / sulfanyl aromatic carboxaldehyde to solvent is 1 mmol:0.5-3 mL, more preferably 1 mmol:1-2 mL.
[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, 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 present invention provides a method for preparing an oxygen / thioxanthone compound using tetrabutylammonium iodide and water as reaction media, which are cheap, easily available, low in toxicity and safety. 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 a one-pot step by endocyclic closure of 2-aryloxy / thioaryl formaldehyde molecules. The method avoids the use of dangerous peroxides, chlorination reagents, transition metal catalysts, and the difficulty in obtaining raw materials. The method has the advantages of low production cost, a wide range of substrate applications, cheap and readily available raw materials, is environmentally friendly, and is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 This is 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 This 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 This is the H NMR spectrum of the sample prepared in Example 3;
[0029] Figure 6 This is the NMR carbon spectrum of the sample prepared in Example 3;
[0030] Figure 7 This is the H NMR spectrum of the sample prepared in Example 4;
[0031] Figure 8 This is the NMR carbon spectrum of the sample prepared in Example 4;
[0032] Figure 9 This is the H NMR spectrum of the sample prepared in Example 5;
[0033] Figure 10 This is the NMR carbon spectrum of the sample prepared in Example 5;
[0034] Figure 11 This is the H NMR spectrum of the sample prepared in Example 6;
[0035] Figure 12 This is the NMR carbon spectrum of the sample prepared in Example 6;
[0036] Figure 13 This is the H NMR spectrum of the sample prepared in Example 7;
[0037] Figure 14This is the NMR carbon spectrum of the sample obtained in Example 7;
[0038] Figure 15 This is the H NMR spectrum of the sample prepared in Example 8;
[0039] Figure 16 This is the NMR carbon spectrum of the sample prepared in Example 8;
[0040] Figure 17 This is the H NMR spectrum of the sample prepared in Example 9;
[0041] Figure 18 This is the NMR carbon spectrum of the sample prepared in Example 9;
[0042] Figure 19 This is the H NMR spectrum of the sample prepared in Example 10;
[0043] Figure 20 This is the NMR carbon spectrum of the sample prepared in Example 10;
[0044] Figure 21 This is the H NMR spectrum of the sample prepared in Example 11;
[0045] Figure 22 This is the NMR carbon spectrum of the sample prepared in Example 11;
[0046] Figure 23 This is the H NMR spectrum of the sample prepared in Example 12;
[0047] Figure 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 stirred in a sealed container at 160°C for 24 hours. After the reaction, a saturated aqueous solution of common salt 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 obtained product was a white solid. The yield was 98%.
[0051] (2) Same as (1), except that under nitrogen atmosphere, the yield was 61%.
[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 was 0.06 mmol, and the yield was 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] Under air atmosphere, 2-p-tolyloxybenzaldehyde (0.3 mmol), tetrabutylammonium iodide (0.03 mmol), water (0.1 mL) and 1,2-dichloroethane (0.6 mL) were added to the reaction flask and stirred in a sealed container at 160°C for 24 hours. After the reaction, saturated saline solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried, filtered and the solvent was dried, and finally the product was separated by column chromatography. The obtained product was 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] Under air atmosphere, 2-(2,4-dimethylphenoxy)benzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) were added to the reaction bottle and stirred in a sealed manner at 160°C for 24 hours. After the reaction, saturated salt water was added to the reaction solution, extracted with dichloromethane, the organic phase was dried, filtered and the solvent was dried, and finally the product was separated by column chromatography. The obtained product was 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] Under 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 flask and stirred in a sealed manner at 160°C for 24 hours. After the reaction, saturated saline solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried, filtered and 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] Under 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 flask and stirred in a sealed manner at 160°C for 24 hours. After the reaction, saturated saline solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried, filtered and 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, 2-(4-phenylphenoxy)benzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) were added to the reaction flask and stirred in a sealed manner at 160°C for 24 hours. After the reaction, saturated saline solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried, filtered and the solvent was dried, and finally the product was separated by column chromatography. The obtained product was 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] Under 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 flask and stirred in a sealed manner at 160°C for 24 hours. After the reaction, saturated saline solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried, filtered and 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] Under 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 flask and stirred in a sealed manner at 160°C for 24 hours. After the reaction, saturated saline solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried, filtered and 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, 3-cyano-2-phenoxybenzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) were added to the reaction bottle and stirred in a sealed manner at 160°C for 24 hours. After the reaction, saturated salt water was added to the reaction solution, extracted with dichloromethane, the organic phase was dried, filtered and the solvent was dried, and finally the product was separated by column chromatography. The obtained product was 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] Under air atmosphere, 2-(2-naphthyloxy)benzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) were added to the reaction flask and stirred in a sealed manner at 160°C for 24 hours. After the reaction, saturated saline solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried, filtered and the solvent was dried, and finally the product was separated by column chromatography. The obtained product was 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] Example 11
[0094] Under air atmosphere, 2-(4-methylphenylthio)benzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) were added to the reaction flask and stirred in a sealed manner at 160°C for 24 hours. After the reaction, saturated saline solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried, filtered and the solvent was dried, and finally the product was separated by column chromatography. The obtained product was 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, 2-(2-naphthylthio)benzaldehyde (0.3mmol), tetrabutylammonium iodide (0.03mmol), water (0.1mL) and 1,2-dichloroethane (0.6mL) were added to the reaction flask and stirred in a sealed manner at 160°C for 11 hours. After the reaction, saturated saline solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried, filtered and the solvent was dried, and finally the product was separated by column chromatography. The obtained product was 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 Phenyl or phenyl containing at least one substituent selected from C1-C5 alkyl, C1-C5 alkoxy, halogen, cyano, nitro, and trifluoromethyl; Ar 2 Phenyl, naphthyl, or phenyl containing at least one of C1-C5 alkyl, C1-C5 alkoxy, halogen substituent, hydroxyl, phenyl, and phenoxy; X=O or S.
2. The method for preparing an oxygen / thioxanthone compound according to claim 1, wherein: 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 / sulfanyl aromatic formaldehyde to tetrabutylammonium iodide is 1:0.05-0.5, and the amount ratio of the 2-aryloxy / sulfanyl aromatic formaldehyde to water is 1 mmol: 0.1~1mL, the ratio of 2-aryloxy / sulfanylaryl 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 aromatic formaldehyde to tetrabutylammonium iodide is 1:0.1-0.2, the usage ratio of the 2-aryloxy / sulfanyl aromatic formaldehyde to water is 1 mmol:0.2-0.5 mL, and the usage ratio of the 2-aryloxy / sulfanyl aromatic formaldehyde to the solvent is 1 mmol:1-2 mL.
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.