Preparation method of oxygen / thioxanthene compound

Abstract

The invention discloses a preparation method of an oxygen / thioxanthene compound, which is characterized in that 2-aryloxy / sulfenyl aryl formaldehyde is heated and reacted in the presence of phosphorous acid, iodine and a solvent to prepare the oxygen / thioxanthene compound. According to the method, phosphorous acid and iodine which are low in price and easy to obtain are selected as reaction media, preparation of the oxygen / thioxanthene compound is efficiently achieved through direct intramolecular reduction and ring closing of 2-aryloxy / sulfenyl arylformaldehyde in one pot and one step, the method has the advantages of being free of participation of transition metal, simple in condition, high in yield, low in cost, environmentally friendly and the like, and industrial production is facilitated.

Description

Technical Field

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

[0002] The oxygen / thioxanthene skeleton is the core skeleton of some natural products, and its related derivatives have biological activity and are widely used in the fields of medicine, pesticides, and materials. According to relevant literature reports, the preparation of oxygen / thioxanthene compounds mainly includes the following:

[0003] The first method: as shown in Formula 1, a xanthene compound is prepared by reacting a cyclic ketone with a salicylaldehyde derivative in the presence of a transition metal catalyst such as scandium through intermolecular cross-condensation to form a ring.

[0004]

[0005] The second method is to prepare xanthenes through intramolecular cyclization reaction starting from the corresponding aromatic triflate under the catalysis of precious metal palladium.

[0006]

[0007] The third method is to prepare xanthenes starting from the corresponding high-valent iodine reagent or lactone compound through the catalysis of transition metal copper or nickel.

[0008]

[0009] The fourth method is to prepare xanthene from 2-aryloxyaromatic formaldehyde through indium or titanium catalysis. Among them, the titanium tetrachloride-mediated method is to prepare xanthene through disproportionation reaction, and its maximum reaction yield does not exceed 50%, there are large reaction defects, and separation is relatively difficult.

[0010]

[0011] In summary, all of the above methods require the use of transition metal catalysts, which increases costs and has the risk of metal residues. In addition, the starting materials of some methods are not easy to obtain, difficult to prepare, and even require the use of specific ligands. The reaction yield is low, which further limits the application of these methods and has poor practicality. Summary of the invention

[0012] In order to solve the problems existing in the preparation of existing oxygen / thioxanthine compounds, the purpose of the present invention is to provide a method for preparing oxygen / thioxanthine compounds using cheap, easily available, low-toxic and safe phosphorous acid and iodine as reaction media. The method uses phosphorous acid as a reducing agent and iodine as a promoter. In the presence of a solvent, the corresponding oxygen / thioxanthine is synthesized in one pot and one step by intramolecular reduction and ring closure of 2-aryloxy / sulfanyl aromatic formaldehyde, avoiding the use of transition metal catalysts. 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.

[0013] In order to achieve the above object, the present invention provides a method for preparing an oxygen / thioxanthine compound, wherein 2-aryloxy / thioxanthine formaldehyde is heated to react in the presence of phosphorous acid, iodine and a solvent to prepare an oxygen / thioxanthine compound, and the reaction equation is shown in Formula 5:

[0014]

[0015] 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;

[0016] 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;

[0017] X=O or S.

[0018] Preferably, the 2-aryloxy / thioaryl formaldehyde is selected from one of the following structural formulas:

[0019]

[0020]

[0021] Preferably, the molar ratio of the 2-aryloxy / sulfur aromatic carboxaldehyde to phosphorous acid is 1:1.0-5.0, and more preferably 1:1.5-3.5; the molar ratio of the 2-aryloxy / sulfur aromatic carboxaldehyde to iodine is 1:0.2-2.0, and more preferably 1:0.5-1.5; the amount ratio of the 2-aryloxy / sulfur aromatic carboxaldehyde to the solvent is 1 mmol:1-4 mL, and more preferably 1 mmol:2-3 mL.

[0022] Preferably, the solvent is 1,2-dichloroethane, chlorobenzene, acetonitrile, dichloromethane, benzene, or toluene; more preferably, it is 1,2-dichloroethane, chlorobenzene, benzene, or toluene.

[0023] Preferably, the atmosphere of the heating reaction is a protective atmosphere or an air atmosphere, and more preferably a protective atmosphere, such as a nitrogen, argon atmosphere, etc.

[0024] Preferably, the heating reaction temperature is 60 to 130° C., more preferably 80 to 100° C.; the heating reaction time is not less than 12 h, more preferably 18 to 24 h.

[0025] Preferably, after the heating reaction is completed, the reaction solution is extracted, dried, filtered, rotary evaporated, and then separated and purified by column chromatography.

[0026] The advantages of the present invention are:

[0027] The present invention provides a method for preparing an oxygen / thioanthene compound, wherein 2-aryloxy / thioaryl carboxaldehyde is heated and reacted in the presence of phosphorous acid, iodine and a solvent to prepare the oxygen / thioanthene compound. The present invention selects cheap and readily available phosphorous acid and iodine as reaction media, and efficiently realizes the preparation of the oxygen / thioanthene compound in one pot and one step through the direct cyclization reaction of 2-aryloxy / thioaryl carboxaldehyde, which has the advantages of no need for transition metal participation, simple conditions, high yield, low cost, green environmental protection, etc., and is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The H NMR spectrum of the sample prepared in Example 1;

[0029] Figure 2 The NMR carbon spectrum of the sample prepared in Example 1;

[0030] Figure 3 is the H NMR spectrum of the sample prepared in Example 2;

[0031] Figure 4 The NMR carbon spectrum of the sample prepared in Example 2;

[0032] Figure 5 The H NMR spectrum of the sample obtained in Example 3;

[0033] Figure 6 The NMR carbon spectrum of the sample prepared in Example 3;

[0034] Figure 7 The H NMR spectrum of the sample obtained in Example 4;

[0035] Figure 8 The NMR carbon spectrum of the sample prepared in Example 4;

[0036] Fig. 9 is the H NMR spectrum of the sample obtained in Example 5;

[0037] Fig.10The NMR carbon spectrum of the sample obtained in Example 5;

[0038] Fig.11 is the H NMR spectrum of the sample obtained in Example 6;

[0039] Fig.12 The NMR carbon spectrum of the sample obtained in Example 6;

[0040] Fig.13 is the H NMR spectrum of the sample obtained in Example 7;

[0041] Fig.14 is the NMR carbon spectrum of the sample obtained in Example 7;

[0042] Fig.15 is the H NMR spectrum of the sample prepared in Example 8;

[0043] Fig.16 The NMR carbon spectrum of the sample obtained in Example 8;

[0044] Fig.17 is the H NMR spectrum of the sample prepared in Example 9;

[0045] Fig.18 The NMR carbon spectrum of the sample prepared in Example 9;

[0046] Fig.19 is the H NMR spectrum of the sample obtained in Example 10;

[0047] Fig. 20 The NMR carbon spectrum of the sample prepared in Example 10;

[0048] Fig.21 is the H NMR spectrum of the sample prepared in Example 11;

[0049] Fig. 22 is the NMR carbon spectrum of the sample prepared in Example 11;

[0050] Fig.23 is the H NMR spectrum of the sample prepared in Example 12;

[0051] Fig.24 This is the NMR carbon spectrum of the sample prepared in Example 12. DETAILED DESCRIPTION

[0052] 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.

[0053] Example 1

[0054] (1) Under nitrogen atmosphere, add 2-phenoxybenzaldehyde (0.3mmol), phosphorous acid (0.75mmol), iodine (0.21mmol) and 1,2-dichloroethane (0.6mL) into a reaction bottle, and stir the reaction at 80°C for 24 hours. After the reaction, add 5% Na2S2O3 aqueous 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%.

[0055] (2) Same as (1), except that the yield was 73% under air atmosphere.

[0056] (3) Same as (1), except that the reaction was stirred for 18 hours and the yield was 92%.

[0057] (4) Same as (1), except that the amount of phosphorous acid used is 0.45 mmol, and the yield is 74%.

[0058] (5) Same as (1), except that the amount of iodine used was 0.06 mmol and the yield was 40%.

[0059] (6) Same as (1), except that the temperature was 130°C and the yield was 64%.

[0060] (7) Same as (1), except that when the solvents are chlorobenzene, acetonitrile, dichloromethane, benzene and toluene, the yields are 83%, 51%, 53%, 80% and 93%, respectively.

[0061] 1 HNMR (400MHz CDCl3): δ7.25–7.18(m,4H),7.09–7.04(m,4H),4.07(s,2H).

[0062] 13 C{1H}NMR(100MHzCDCl3): δ152.0,128.9,127.6,123.0,120.6,116.5,27.9.

[0063] Example 2

[0064] Under nitrogen atmosphere, add 2-p-tolyloxybenzaldehyde (0.3mmol), phosphorous acid (0.75mmol), iodine (0.21mmol) and 1,2-dichloroethane (0.6mL) into the reaction bottle, and stir the reaction for 24 hours at 80℃. After the reaction, add 5% Na2S2O3 aqueous 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 product is a white solid The yield was 98%.

[0065] 1 HNMR (400MHz CDCl3): δ7.22–7.16(m,2H),7.06–6.95(m,5H),4.02(s,2H),2.32(s,3H).

[0066] 13 C{1H}NMR(100MHzCDCl3): δ152.1,149.8,132.3,129.2,128.9,128.2,127.6,122.8,120.6,120.2,116.4,116.2,27.9,20.7.

[0067] Example 3

[0068] Under nitrogen atmosphere, add 2-(2,4-dimethylphenoxy)benzaldehyde (0.3mmol), phosphorous acid (0.75mmol), iodine (0.21mmol) and 1,2-dichloroethane (0.6mL) into the reaction bottle, and stir and react for 24 hours at 80℃. After the reaction, add 5% Na2S2O3 aqueous 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 light yellow oily liquid The yield was 94%.

[0069] 1 HNMR (400MHz CDCl3): δ7.30–7.23(m,2H),7.18–7.16(m,1H),7.12–7.08(m,1H),6.95(s,1H),6.90(s,1H),4.08(s,2H),2.43(s,3H),2.37(s,3H).

[0070] 13C{1H}NMR(100MHzCDCl3): δ152.4,148.1,131.6,129.7,128.8,127.4,126.6,125.4,122.7,120.9,119.9,116.5,28.2,20.6,15.9.

[0071] Example 4

[0072] Under nitrogen atmosphere, add 2-(4-methoxyphenoxy)benzaldehyde (0.3mmol), phosphorous acid (0.75mmol), iodine (0.45mmol) and 1,2-dichloroethane (0.6mL) into the reaction bottle, and stir and react for 24 hours at 80℃. After the reaction, add 5% Na2S2O3 aqueous 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 pink solid The yield was 70%.

[0073] 1 HNMR(400MHzDMSO-d6): δ9.18(s,1H),7.22–7.17(m,2H),7.04–7.00(m,2H),6.90–6.87(m,1H),6.63–6.61(m,2H),3.96(s,2H).

[0074] 13 C{1H}NMR(100MHzDMSO-d6): δ153.5,152.2,144.5,129.5,128.1,123.2,121.7,120.7,117.1,116.4,115.1,114.9,27.7.

[0075] Example 5

[0076] Under nitrogen atmosphere, add 2-(4-phenoxyphenoxy)benzaldehyde (0.3mmol), phosphorous acid (0.75mmol), iodine (0.21mmol) and 1,2-dichloroethane (0.6mL) into the reaction bottle, and stir and react for 24 hours at 80℃. After the reaction, add 5% Na2S2O3 aqueous 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 product is a light yellow solid The yield was 53%.

[0077] 1HNMR (400MHz CDCl3): δ7.36–7.31(m,2H),7.24–7.15(m,2H),7.12–6.99(m,6H),6.91–6.86(m,2H),4.03(s,2H).

[0078] 13 C{1H}NMR(100MHzCDCl3): δ158.0,152.0,151.9,148.0,129.7,128.8,127 .7,122.9,122.8,121.8,119.8,119.4,118.9,118.0,117.5,116.4,28.1.

[0079] Example 6

[0080] Under nitrogen atmosphere, add 2-(4-chlorophenoxy)benzaldehyde (0.3mmol), phosphorous acid (0.75mmol), iodine (0.21mmol) and 1,2-dichloroethane (0.6mL) into the reaction bottle, and stir and react for 24 hours at 80℃. After the reaction, add 5% Na2S2O3 aqueous 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 68%.

[0081] 1 HNMR(400MHzCDCl3): δ7.26–6.96(m,7H),4.02(m,2H).

[0082] 13 C{1H}NMR(100MHzCDCl3): δ151.6,150.5,128.9,128.6,127.9,127.7,127.6,123.3,122.2,119.7,117.8,116.5,27.8.

[0083] Example 7

[0084] Under nitrogen atmosphere, add 2-(4-bromophenoxy)benzaldehyde (0.3mmol), phosphorous acid (1.05mmol), iodine (0.21mmol) and 1,2-dichloroethane (0.6mL) into the reaction bottle, and stir and react for 24 hours at 80℃. After the reaction, add 5% Na2S2O3 aqueous 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 82%.

[0085] 1 HNMR (400MHz CDCl3): δ7.27–7.22(m,2H),7.17–7.11(m,2H),7.03–6.98(m,2H),6.90–6.87(m,1H),3.99(s,2H).

[0086] 13 C{1H}NMR(100MHzCDCl3): δ151.6,151.1,131.5,130.6,128.9,127.9,123.3,122.7,119.7,118.2,116.5,115.0,27.7.

[0087] Example 8

[0088] Under nitrogen atmosphere, add 2-(4-phenylphenoxy)benzaldehyde (0.3mmol), phosphorous acid (0.45mmol), iodine (0.15mmol) and 1,2-dichloroethane (0.6mL) into the reaction bottle, and stir and react for 24 hours at 80℃. After the reaction, add 5% Na2S2O3 aqueous 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 product is a light yellow solid The yield was 72%.

[0089] 1 HNMR (400MHz CDCl3): δ7.57–7.55(m,2H),7.44–7.38(m,4H),7.33–7.29(m,1H),7.23–7.00(m,5H),4.10(s,2H).

[0090] 13 C{1H}NMR(100MHzCDCl3): δ151.9,151.5,140.6,136.1,129.0,128.8,127 .7,127.6,127.0,126.8,126.5,123.1,120.8,120.4,116.8,116.5,28.0.

[0091] Example 9

[0092] Under nitrogen atmosphere, add 3-trifluoromethyl-2-phenoxybenzaldehyde (0.3mmol), phosphorous acid (0.75mmol), iodine (0.45mmol) and 1,2-dichloroethane (0.6mL) into the reaction bottle, and stir and react for 24 hours at 80℃. After the reaction, add 5% Na2S2O3 aqueous 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 60%.

[0093] 1 HNMR (400MHz CDCl3): δ7.50–7.47(m,2H),7.29–7.20(m,2H),7.15–7.08(m,3H),4.11(s,2H).

[0094] 13 C{1H}NMR(100MHzCDCl3):δ154.33(q,J C-F =4.0Hz),151.3,128.9,128.0,126.3(q,J C-F =3.9Hz),124.9(q,J C-F =3.7Hz),124.3(q,J C-F =64.9Hz),124.2(q,J C-F =269.8Hz),123.7,121.0,119.6,116.9,116.6,27.6.

[0095] Example 10

[0096] Under nitrogen atmosphere, add 2-(2-naphthyloxy)benzaldehyde (0.3mmol), phosphorous acid (0.75mmol), iodine (0.21mmol) and 1,2-dichloroethane (0.6mL) into the reaction bottle, and stir and react for 24 hours at 80℃. After the reaction, add 5% Na2S2O3 aqueous 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 gray-green solid The yield was 46%.

[0097] 1HNMR (400MHz CDCl3): δ7.86–7.81(m,2H),7.71(d,J=8.9Hz,1H),7.58–7.54(m,1H),7.45 –7.40(m,1H),7.29(d,J=7.5Hz,1H),7.25–7.20(m,2H),7.11–7.505(m,2H),4.35(s,2H).

[0098] 13 C{1H}NMR(100MHzCDCl3): δ151.0,148.6,132.0,130.1,129.4,128.4,128 .2,127.7,126.7,124.1,123.1,122.2,119.5,117.9,116.4,111.5,24.7.

[0099] Embodiment 11

[0100] Under nitrogen atmosphere, add 2-(4-methylphenylthio)benzaldehyde (0.3mmol), phosphorous acid (0.6mmol), iodine (0.21mmol) and 1,2-dichloroethane (0.6mL) into the reaction bottle, and stir and react for 24 hours at 80℃. After the reaction, add 5% Na2S2O3 aqueous 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 44%.

[0101] 1 HNMR (400MHz CDCl3): δ7.46–7.44(m,1H),7.35–7.31(m,2H),7.23–7.16(m,3H),7.03–7.01(m,1H),3.83(s,2H),2.35(s,3H).

[0102] 13 C{1H}NMR(100MHzCDCl3): δ136.5,136.4,136.2,134.3,130.4,128.8,127.9,127.3,126.9,126.7,126.5,126.5,39.3,21.0.

[0103] Example 12

[0104] Under nitrogen atmosphere, add 2-(2-naphthylthio)benzaldehyde (0.3mmol), phosphorous acid (0.6mmol), iodine (0.21mmol) and 1,2-dichloroethane (0.6mL) into the reaction bottle, and stir and react for 24 hours at 80℃. After the reaction, add 5% Na2S2O3 aqueous 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 93%.

[0105] 1 HNMR (400MHz CDCl3): δ8.24–8.21(m,1H),7.83–7.80(m,1H),7.67–7.64(m,1H),7.59–7.40(m,5H),7.25–7.17(m,2H),4.27(s,2H).

[0106] 13 C{1H}NMR(100MHzCDCl3): δ135.5,133.9,132.6,131.4,130.6,128.9,128.3,126.7,126.6,126.6,126.5,125.2,125.2,122.5,33.5.

Claims

1. A method for preparing an oxygen / thioxanthene compound, characterized in that: 2-aryloxy / thioaryl formaldehyde is heated to react in the presence of phosphorous acid, iodine and a solvent to obtain an oxygen / thioxanthine compound, and the reaction equation is shown in Formula 5: 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 / thioxanthene 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 / thioxanthine compound according to any one of claims 1 to 2, characterized in that: The molar ratio of the 2-aryloxy / thioaryl carboxaldehyde to phosphorous acid is 1:1-5, the molar ratio of the 2-aryloxy / thioaryl carboxaldehyde to iodine is 1:0.2-2, and the dosage ratio of the 2-aryloxy / thioaryl carboxaldehyde to the solvent is 1mmol:1-4mL.

4. The method for preparing an oxygen / thioxanthene compound according to claim 3, characterized in that: The molar ratio of the 2-aryloxy / sulfur aromatic carboxaldehyde to phosphorous acid is 1:1.5-3.5, the molar ratio of the 2-aryloxy / sulfur aromatic carboxaldehyde to iodine is 1:0.5-1.5, and the dosage ratio of the 2-aryloxy / sulfur aromatic carboxaldehyde to the solvent is 1mmol:2-3mL.

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

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

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

8. The method for preparing an oxygen / thioxanthene compound according to any one of claims 1 to 2, characterized in that: The heating reaction temperature is 60-130° C.; the heating reaction time is not less than 12 hours.

9. The method for preparing an oxygen / thioxanthene compound according to claim 8, characterized in that: The heating reaction temperature is 80-100° C.; the heating reaction time is not less than 18-24 hours.

10. The method for preparing an oxygen / thioxanthene 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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