A method for photoinduced demethylation of anisole

Abstract

The invention discloses a method for photoinduced demethylation of anisole, which belongs to the field of pharmaceutical compound synthesis. The method provided by the invention uses ferric chloride as a catalyst for the main reaction, reacts under the condition of air or oxygen, and obtains a demethylated product under illumination. The catalytic efficiency of the catalyst is high, and the yield of the product obtained by dealkylation is also high, which greatly reduces the experimental cost and is suitable for the synthesis and amplification of later compounds. The method provided by the invention does not have expensive metal catalysts and oxidants, has the characteristics of high efficiency, green environmental protection, safety, saving experimental costs, and simple operation and post-processing.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical compound synthesis, and in particular to a method for light-induced demethylation of anisole. Background Art

[0002] Cleavage of the ether bond during the demethylation of anisole-containing compounds is a complete functional group transformation, primarily as a deprotection step to reveal the hydroxyl group. The use of this reaction extends to both academic and commercial fields for natural product, pharmaceutical, and fine chemical synthesis. Alcohols are a very common and versatile class of substrates in organic chemistry, and hydroxyl groups are present in everything from natural products and biopolymers to pharmaceutically active compounds. Hydroxylation is a universal synthetic process for a variety of transformations.

[0003] At present, there are many studies on the cleavage of ether bonds in the demethylation of anisole compounds, which are mainly achieved by using strong proton acids (HBr, H2SO4, HCl, TFA, I2, etc.), Lewis acids (AlCl3, BCl3, CeCl3, TMSI, BBr3, etc.), nucleophiles (LiPPh2, NaHMDS, DodSH, etc.) or reducing agents. For example, ZL2022115404939 discloses a new use of triphenylphosphine diiodide as a reaction promoter, which uses aryl ether compounds as raw materials and triphenylphosphine diiodide as a reaction promoter. The iodide ion attacks the CO bond, so that the ether bond of the aryl ether compound is broken, and then aromatic alcohol and alkyl iodide are generated. The method uses a mixed solution of aryl ether compounds, triphenylphosphine diiodide, chlorobenzene and water, and stirs and refluxes at a temperature of 80°C to 120°C for reaction; after the reaction is completed, sodium thiosulfate is added to quench. The method requires a higher reaction temperature and uses more expensive transition metal catalysts.

[0004] Photocatalysis relies on the formation of a free radical form by a photosensitizer under light, and the substrate is activated to undergo single-electron oxidation reaction. It has the advantages of simple reaction steps and mild reaction conditions. As photocatalysis is gradually being used in the field of chemical synthesis as a green and sustainable tool, studying how to use photocatalysis to solve the breakage of the CO ether bond and realize the generation of phenol compounds from anisole compounds is a technical problem that needs to be solved urgently. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a method for light-induced demethylation of anisole to solve the technical problems that such reactions require the use of expensive metal catalysts, oxidants and complex operations.

[0006] To achieve the above purpose, the technical solution provided by the present invention is as follows:

[0007] A method for photoinduced demethylation of anisole comprises the following steps: dissolving a compound represented by formula (1) in a solvent under an atmosphere containing oxygen or air, adding a catalyst, and reacting under light to obtain a demethylated product represented by formula (2);

[0008] ;

[0009] Wherein, R is a hydroxyl group, an aromatic fused ring, a benzene ring or a halogen;

[0010] Furthermore, the halogen is one of fluorine and chlorine.

[0011] Furthermore, the volume amount of the solvent is 30 times the molar amount of the compound of formula (1).

[0012] Furthermore, the catalyst is one of ferrous chloride or ferric chloride.

[0013] The catalyst is preferably ferric chloride.

[0014] Furthermore, the solvents are all acetonitrile-water with a volume ratio of 5:1.

[0015] Furthermore, the wavelength range of light used in the illumination reaction is 245-525 nm.

[0016] The wavelength of light used in the light irradiation reaction is preferably 395 nm.

[0017] Furthermore, the reaction time of the illumination is 12-48 hours.

[0018] Furthermore, the molar ratio of the compound of formula (1) to the catalyst is 2:1.

[0019] Furthermore, the temperature of the light irradiation reaction is 0 to 45° C., preferably room temperature; the reaction time is 12 to 48 hours, preferably 48 hours.

[0020] By adopting the above technical solution, the beneficial technical effects obtained by the present invention are:

[0021] (1) The method of the present invention is green, environmentally friendly, safe, and does not involve oxidants or toxic reagents;

[0022] (2) The method of the present invention is simple to operate. No expensive metal catalyst or oxidant is required in the demethylation reaction of anisole compounds. The subsequent demethylation reaction is simple to operate and the method cost is low.

[0023] (3) The method of the present invention is highly efficient. In an oxygen-containing atmosphere, the catalytic efficiency of the catalyst and the yield of the dealkylation product are relatively high (up to 97.7%), which is suitable for the synthesis and amplification of subsequent compounds and greatly reduces the experimental cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The product prepared in Example 1 1 H NMR spectra;

[0025] Figure 2 The product prepared in Example 1 13 C NMR spectra;

[0026] Figure 3 The product prepared in Example 2 1 H NMR spectra;

[0027] Figure 4 The product prepared in Example 2 13 C NMR spectra;

[0028] Figure 5 The product prepared in Example 3 1 H NMR spectra;

[0029] Figure 6 The product prepared in Example 3 13 C NMR spectra;

[0030] Figure 7 The product prepared in Example 4 1 H NMR spectra;

[0031] Figure 8 The product prepared in Example 4 13 C NMR spectra;

[0032] Fig. 9 The product prepared in Example 5 1 H NMR spectra;

[0033] Fig.10 The product prepared in Example 5 13 C NMR spectra;

[0034] Fig.11 The product prepared in Example 6 1 H NMR spectra;

[0035] Fig.12 The product prepared in Example 6 13 C NMR spectra;

[0036] Fig.13 The product prepared in Example 7 1 H NMR spectra;

[0037] Fig.14 The product prepared in Example 7 13 C NMR spectra;

[0038] Fig.15 The product prepared in Example 8 1 H NMR spectra;

[0039] Fig.16 The product prepared in Example 8 13 C NMR spectra;

[0040] Fig.17 The product prepared in Example 9 1 H NMR spectra;

[0041] Fig.18 The product prepared in Example 9 13 C NMR spectra;

[0042] Fig.19 The product prepared in Example 10 1 H NMR spectra;

[0043] Fig. 20 The product prepared in Example 10 13 C NMR spectrum. DETAILED DESCRIPTION

[0044] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with specific embodiments and with reference to the accompanying drawings. It should be understood that these descriptions are only exemplary and are not intended to limit the scope of the present invention. In addition, in the following description, the description of well-known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present invention.

[0045] Example 1

[0046] ;

[0047] In air atmosphere and room temperature, p-chloroanisole (40.87 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (6 mL), ferrous chloride (18.17 mg, 0.1 mmol, 0.5 eq) were added to a 25 mL quartz test tube and stirred for 15 hours under 395 nm illumination. After the reaction was completed, dichloromethane and water were extracted, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the demethylated product (33.76 mg, yield 91.6%).

[0048] 1 H NMR (400 MHz, CDCl3) δ 7.13 – 7.06 (m, 2H), 6.73 – 6.63 (m, 2H), 5.65 (s, 1H). Specific drawings are shown in Figure 1 shown.

[0049] 13 C NMR (101 MHz, CDCl3) δ 154.08 (s), 129.57 (s), 125.69 (s), 116.73 (s). Specific drawings are shown in Figure 2 .

[0050] Example 2

[0051] ;

[0052] Under air atmosphere and room temperature, m-fluoroanisole (48.25 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (6 mL), ferric chloride (31.02 mg, 0.1 mmol, 0.5 eq) were added to a 25 mL quartz test tube and stirred for 15 hours under 245 nm illumination. After the reaction was completed, dichloromethane and water were used for extraction, and the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the demethylated product (38.72 mg, yield 90.3%).

[0053] 1 H NMR (400 MHz, CDCl3) δ 7.08 (td, J = 8.2, 6.8 Hz, 1H), 6.61 – 6.44 (m, 3H), 5.63 (s, 1H). Specific drawings are shown in the figure. Figure 3 .

[0054] 13 C NMR (101 MHz, CDCl3) δ 163.66 (d, J = 245.2 Hz), 156.72 (d, J = 11.4 Hz), 130.57 (d, J = 10.1 Hz), 111.21 (d, J = 2.9 Hz), 107.85 (d, J = 21.2 Hz), 103.28 (d, J = 24.6 Hz). Specific drawings are shown in the figure. Figure 4 .

[0055] Example 3

[0056] ;

[0057] In air atmosphere and room temperature, 1,3-dimethoxybenzene (47.91 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (6 mL), ferric chloride (28.12 mg, 0.1 mmol, 0.5 eq) were added to a 25 mL quartz test tube and stirred for 48 hours under 395 nm light. After the reaction, dichloromethane and water were used for extraction, and the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify the demethylated product (33.10 mg, yield 86.7%).

[0058] 1 H NMR (400 MHz, DMSO) δ 9.16 (s, 2H), 6.98 – 6.84 (m, 1H), 6.21 (dt, J = 7.0, 2.2 Hz, 3H). Specific drawings are shown in Figure 5 .

[0059] 13 C NMR (101 MHz, DMSO) δ 158.90 (s), 130.20 (s), 106.70 (s), 102.96 (s). Specific drawings are shown in Figure 6 .

[0060] Example 4

[0061] ;

[0062] In air atmosphere and room temperature, p-fluoroanisole (45.26 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (6 mL), ferric chloride (29.10 mg, 0.1 mmol, 0.5 eq) were added to a 25 mL quartz test tube and stirred for 15 hours under 395 nm illumination. After the reaction was completed, dichloromethane and water were extracted, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the demethylated product (36.40 mg, yield 90.5%).

[0063] 1 H NMR (400 MHz, CDCl3) δ 6.85 – 6.78 (m, 2H), 6.73 – 6.58 (m, 2H), 5.72 – 5.51 (m, 1H). Specific drawings are shown in Figure 7 .

[0064] 13C NMR (101 MHz, CDCl3) δ 157.39 (d, J = 237.7 Hz), 151.26 (d, J = 2.0 Hz), 116.35 (d, J = 8.0 Hz), 116.08 (d, J = 23.3 Hz). Figure 8 .

[0065] Example 5

[0066] ;

[0067] Under air atmosphere and room temperature, o-fluoroanisole (45.77 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (6 mL), ferric chloride (29.43 mg, 0.1 mmol, 0.5 eq) were added to a 25 mL quartz test tube and stirred for 15 hours under 395 nm illumination. After the reaction was completed, dichloromethane and water were used for extraction, and the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify the demethylated product (37.91 mg, yield 93.2%).

[0068] 1 H NMR (400 MHz, CDCl3) δ 7.01 – 6.95 (m, 1H), 6.94 – 6.90 (m, 2H), 6.80 – 6.71 (m, 1H), 5.41 (s, 1H). Specific drawings are shown in Fig. 9 .

[0069] 13 C NMR (101 MHz, CDCl3) δ 151.18 (d, J = 237.0 Hz), 143.56 (d, J =14.1 Hz), 124.87 (d, J = 3.7 Hz), 120.84 (d, J = 6.5 Hz), 117.37 (s), 115.56 (d, J = 18.0 Hz). Specific drawings are shown in the figure. Fig.10 .

[0070] Example 6

[0071] ;

[0072] In air atmosphere and room temperature, 2-naphthyl methyl ether (50.13 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (6 mL), ferric chloride (25.70 mg, 0.1 mmol, 0.5 eq) were added to a 25 mL quartz test tube and stirred for 15 hours under 395 nm light. After the reaction was completed, dichloromethane and water were used for extraction, and the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify the demethylated product (43.49 mg, yield 95.2%).

[0073] 1 H NMR (400 MHz, CDCl3) δ 7.66 (dd, J = 13.7, 4.7 Hz, 2H), 7.57 (dd, J = 8.2, 0.5 Hz, 1H), 7.33 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.23 (ddd, J = 8.1,6.9, 1.2 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 7.01 (dd, J = 8.7, 2.5 Hz, 1H),5.44 (s, 1H). Specific drawings are shown in Fig.11 .

[0074] 13 C NMR (101 MHz, CDCl3) δ 153.37 (s), 134.64 (s), 129.90 (s), 128.98 (s), 127.82 (s), 126.57 (s), 126.43 (s), 123.67 (s), 117.82 (s), 109.58 (s). Specific drawings are shown in the figure. Fig.12 .

[0075] Example 7

[0076] ;

[0077] Under air atmosphere and room temperature, m-trifluoromethylanisole (55.63 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (6 mL), ferric chloride (25.61 mg, 0.1 mmol, 0.5 eq) were added to a 25 mL quartz test tube and stirred for 12 hours under 525 nm illumination. After the reaction was completed, dichloromethane and water were extracted, the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify the demethylated product (48.18 mg, yield 94.1%).

[0078] 1 H NMR (400 MHz, CDCl3) δ 7.23 (t, J = 8.0 Hz, 1H), 7.09 (dd, J = 7.8,0.6 Hz, 1H), 6.99 (s, 1H), 6.90 (dd, J = 8.2, 2.4 Hz, 1H), 5.78 (s, 1H). Specific drawings are shown in Fig.13 .

[0079] 13 C NMR (101 MHz, CDCl3) δ 155.50 (s), 132.11 (d, J = 32.6 Hz), 130.33(s), 123.83 (q, J = 272.2 Hz), 118.86 (s), 117.79 (d, J = 3.9 Hz), 112.35 (q, J = 3.8 Hz). Specific drawings are shown in Fig.14 .

[0080] Example 8

[0081] ;

[0082] In an oxygen atmosphere and room temperature, 4,4'-dimethoxy-1,1'-biphenyl (46.82 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (6 mL), ferric chloride (17.72 mg, 0.1 mmol, 0.5 eq) were added to a 25 mL quartz test tube and stirred for 48 hours under 395 nm illumination. After the reaction was completed, dichloromethane and water were used for extraction, and the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify the demethylated product (35.56 mg, yield 87.4%).

[0083] 1H NMR (500 MHz, DMSO) δ 9.41 (s, 2H), 7.43 – 7.31 (m, 4H), 6.93 –6.78 (m, 4H). Fig.15 .

[0084] 13 C NMR (126 MHz, DMSO) δ 156.70 (s), 131.68 (s), 127.47 (s), 116.08 (s), as shown in the attached figure Fig.16 .

[0085] Example 9

[0086] ;

[0087] In air atmosphere and room temperature, 4-methoxybiphenyl (53.17 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (6 mL), ferric chloride (23.4 mg, 0.1 mmol, 0.5 eq) were added to a 25 mL quartz test tube and stirred for 48 hours under 395 nm light. After the reaction, dichloromethane and water were used for extraction, and the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify the demethylated product (45.34 mg, yield 92.3%).

[0088] 1 H NMR (400 MHz, DMSO) δ 9.70 (s, 1H), 7.59 – 7.55 (m, 2H), 7.51 –7.46 (m, 2H), 7.41 (dd, J = 10.5, 4.9 Hz, 2H), 7.30 – 7.24 (m, 1H), 6.95 –6.83 (m, 2H). Fig.17 .

[0089] 13 C NMR (101 MHz, DMSO) δ 157.69 (s), 140.71 (s), 131.33 (s), 129.26 (s), 128.15 (s), 126.79 (s), 126.41 (s), 116.24 (s). Specific drawings are shown in the figure. Fig.18 .

[0090] Example 10

[0091] ;

[0092] In air atmosphere and room temperature, 1-methoxynaphthalene (48.54 mg, 0.2 mmol, 1 eq), acetonitrile: water = 5:1 (6 mL), ferric chloride (24.88 mg, 0.1 mmol, 0.5 eq) were added to a 25 mL quartz test tube and stirred for 15 hours under 395 nm light. After the reaction was completed, dichloromethane and water were used for extraction, and the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to purify and obtain the demethylated product (40.92 mg, yield 92.5%).

[0093] 1 H NMR (400 MHz, CDCl3) δ 8.13 – 8.04 (m, 1H), 7.74 – 7.66 (m, 1H), 7.43 – 7.31 (m, 3H), 7.19 (dd, J = 10.2, 5.5 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 5.55 (s, 1H). Specific drawings are shown in the figure. Fig.19 .

[0094] 13 C NMR (101 MHz, CDCl3) δ 151.51 (s), 134.85 (s), 127.76 (s), 126.50 (s), 125.95 (s), 125.34 (s), 124.51 (s), 121.65 (s), 120.69 (s), 108.76 (s). Specific drawings are shown in the figure. Fig. 20 .

[0095] It can be seen from the above examples that the preparation method provided by the present invention can prepare a dealkylation product with a high yield by using a simple catalyst and light in an air atmosphere or an oxygen atmosphere.

[0096] It should be understood that the above specific embodiments of the present invention are only used to illustrate or explain the principles of the present invention, and do not constitute a limitation of the present invention. Therefore, any modifications, equivalent substitutions, improvements, etc. made without departing from the spirit and scope of the present invention should be included in the protection scope of the present invention. In addition, the appended claims of the present invention are intended to cover all changes and modifications that fall within the scope and boundaries of the appended claims, or the equivalent forms of such scope and boundaries.

Claims

1. A method for light-induced demethylation of anisole, characterized in that, The method comprises the following steps: dissolving the compound represented by formula (1) in a solvent under an atmosphere containing oxygen or air, adding a catalyst, and performing a light irradiation reaction to obtain a dealkylation product represented by formula (2); ； Wherein R is one of hydroxyl, naphthalene, benzene ring or halogen; The catalyst is one of ferrous chloride or ferric chloride; The solvent is acetonitrile-water with a volume ratio of 5:1; The light wavelength used in the illumination reaction is 245-525nm; The light reaction time is 12-48 hours.

2. A method for photoinduced demethylation of anisole according to claim 1, characterized in that, The halogen is one of fluorine and chlorine.

3. A method for photoinduced demethylation of anisole according to claim 1, characterized in that, The molar ratio of the compound of formula (1) to the catalyst is 2:

1.

4. A method for photoinduced demethylation of anisole according to claim 1, characterized in that, The catalyst is ferric chloride.

5. A method for photoinitiated demethylation of anisole according to claim 1, characterized in that, The volume amount of the solvent used is 30 times the molar amount of the compound of formula (1).

6. A method for photoinitiated demethylation of anisole according to claim 1, characterized in that, The wavelength of light used in the light irradiation reaction is 395 nm.

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