Synthesis method of beta-thio-alpha-aminophenol compound

Abstract

The invention discloses a synthesis method of a beta-thio-alpha-aminophenol compound, which is characterized by comprising the following steps: mixing a compound 1, a compound 2 and different types of aryl phenols, adding Lewis acid as an additive, reacting in a solvent, and purifying to obtain a target compound 3. The reaction does not use concentrated hydrochloric acid, under the promotion of Lewis acid, the reaction conditions are mild, the three component raw materials are mutually coupled to react in one step to obtain the beta-thio-alpha-aminophenol compound, the reaction is performed by a one-pot method, and the operation is simple.

Description

Technical Field

[0001] The invention relates to a method for synthesizing a compound, in particular to a method for synthesizing a beta-thio-alpha-aminophenol compound. Background Art

[0002] β-Thio-α-aminophenol compounds exist in natural products and drug molecules and are structural fragments of many biologically active molecules (Org. Process Res. Dev. 2021, 25, 7, 1512–152). Therefore, the synthesis of compounds with such structures is of great research significance.

[0003] The chemical structure synthesized in the prior art is a β-thio-α-aminobenzene compound, which is generally obtained by adding a styrene-type olefin to a sulfur reagent and an aniline compound (J.Org.Chem.2018,83,2818-2829). The synthesis route is as follows:

[0004]

[0005] Concentrated hydrochloric acid is used in the synthesis method, and the reaction is carried out under high temperature conditions, and the reaction conditions are harsh. Summary of the invention

[0006] Objective of the invention: The first objective of the present invention is to provide a method for synthesizing β-thio-α-aminophenol compounds under mild reaction conditions promoted by Lewis acid.

[0007] Technical solution: The synthesis method of β-thio-α-aminophenol compounds of the present invention comprises the following steps: mixing compound 1, compound 2 and different types of aromatic phenols, adding Lewis acid as an additive, reacting in a solvent, and purifying to obtain target compound 3. The reaction formula is as follows:

[0008]

[0009] Wherein, R is H or C1-C3 alkyl; R 1 is a halogenated C1-C5 alkyl group, a C1-C5 alkyl group, a C1-C5 alkoxy group, a halogen group, an acetyl group, a benzene ring, and R 2 is H, C1-C3 alkyl, C1-C3 alkoxy or halogen, R 3 is H or halogen.

[0010] Preferably, said R is CH3, R 1 is bromoethyl, ethyl, isopropyl or isobutyl, R 2 For CH3.

[0011] Preferably, the synthesized compound results are as follows:

[0012]

[0013] Preferably, the reaction temperature is 20-30° C., and the reaction time is 5-36 hours.

[0014] Preferably, the molar ratio of the compound 1 to the aromatic phenol is 1:1.0 to 1.1.

[0015] Preferably, the molar ratio of compound 1 to compound 2 is 1:1.0-1.2.

[0016] Preferably, the yield of the target compound 3 is 76-97%.

[0017] Preferably, the molar ratio of the compound 1 to the Lewis acid additive is 1:0.5-3.

[0018] Preferably, the Lewis acid additive is methanesulfonic acid, trifluoroacetic acid, trifluoroacetic anhydride, trifluoromethanesulfonic acid, triisopropylsilyl trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate or bis(trifluoromethylsulfonyl)amide.

[0019] Preferably, the solvent is dichloromethane, acetonitrile, dichloroethane, toluene, xylene, toluene+dichloromethane, toluene+acetonitrile or dichloromethane+acetonitrile.

[0020] Preferably, the concentration of the solvent is 0.025M to 0.05M (ie, how many millimoles of reactants are dissolved in each milliliter of solvent).

[0021] The purification is as follows: the reaction mother liquor is concentrated and then directly subjected to column chromatography, and the eluent is a mixed solvent of petroleum ether and ethyl acetate.

[0022] Invention mechanism: The present invention uses an activated olefin-alkenylamine as an unsaturated hydrocarbon raw material, an aromatic sulfur cation as an electrophilic reagent, and forms an iminium cation intermediate through sulfur-mediated ring opening of a ternary cyclic onium ion intermediate or a bridged ring onium ion, and then attacks with an aromatic phenol compound as a nucleophilic reagent to finally obtain the target product β-thio-α-aminophenol compound. The possible mechanism is as follows: Figure 1 shown.

[0023] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) without using concentrated hydrochloric acid, the three components of raw materials that are simple and readily available are coupled with each other under the promotion of Lewis acid under mild reaction conditions to prepare β-thio-α-aminophenol compounds, which is a one-pot reaction and simple to operate; (2) the functional group has a wide range of applicability; (3) the reaction yield reaches 76-97%. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is the synthesis mechanism diagram of the present invention;

[0025] Figure 2 is the H NMR spectrum of the compound synthesized in Example 1;

[0026] Figure 3 The NMR carbon spectrum of the compound synthesized in Example 1;

[0027] Figure 4 is the H NMR spectrum of the compound synthesized in Example 2;

[0028] Figure 5 The NMR carbon spectrum of the compound synthesized in Example 2;

[0029] Figure 6 The NMR spectrum of the compound synthesized in Example 3;

[0030] Figure 7 The NMR carbon spectrum of the compound synthesized in Example 3;

[0031] Figure 8 The NMR spectrum of the compound synthesized in Example 4;

[0032] Fig. 9 The NMR carbon spectrum of the compound synthesized in Example 4;

[0033] Fig.10 This is the H NMR spectrum of the compound synthesized in Example 5;

[0034] Fig.11 This is the carbon NMR spectrum of the compound synthesized in Example 5. DETAILED DESCRIPTION

[0035] The technical solution of the present invention is further described below in conjunction with embodiments.

[0036] Example 1

[0037] The β-thio-α-aminophenol compound of the present invention has the following structural formula:

[0038]

[0039] Synthesis method:

[0040] Enamide (Compound 1) and phenylthio reagent (Compound 2) were synthesized according to the literature (Angew. Chem. Int. Ed. 2019, 58, 13056–13059; ACS Catal. 2019, 9, 6896-6902).

[0041] (1) Synthesis of Enamide (Compound 1) (E)-2-(Propan-1-en-1-yl)isoindole-1,3-dione

[0042]

[0043] At room temperature (25-35°C), allyl bromide (1.43 mL, 16.5 mmol, 1.1 equiv) was added to a reaction flask containing potassium phthalimide (2.78 g, 15.0 mmol, 1.0 equiv) and n-butylammonium iodide (277.0 mg, 0.75 mmol, 0.05 equiv) and DMF (8 mL). The reaction mixture was stirred at room temperature for 20 hours, and H2O (10 mL) was added to precipitate a white solid. The mixture was filtered to obtain a white filter cake, which was dissolved in EtOAc (5 mL) and the EtOAc solution was washed with H2O (10 mL × 4). The organic layers were combined and dried over anhydrous Na2SO4. The filtrate was concentrated by distillation under reduced pressure. The crude product was separated and purified by silica gel flash column chromatography (eluent: PE / EtOAc = 50:1 to 30:1, v / v) to obtain a synthetic intermediate.

[0044] Under nitrogen atmosphere, the synthetic intermediate was added to a sealed tube containing tri(triphenylphosphine)ruthenium chloride (RuCl2(PPh3)3) (100.0 mg, 0.11 mmol, 0.01 equiv). The reaction mixture was heated at 150°C for 12 hours and then cooled to room temperature. Toluene was added to dilute the reaction solution. The metal catalyst in the mixture was filtered out using diatomaceous earth. The filtrate was concentrated by vacuum distillation. The obtained brown-yellow solid was recrystallized in ethanol (20 mL). The golden-yellow solid precipitated from ethanol was the target product (1.15 g, 58% yield).

[0045] (2) Synthesis of phenylthio reagent (Compound 2) 1-(p-tolylthio)pyrrolidine-2,5-dione

[0046]

[0047] In a nitrogen atmosphere, N-chlorosuccinimide (267.1 mg, 2.0 mmol, 1.0 equiv) was slowly added dropwise to a dichloromethane (10 mL) solution of arylthiophenol (269.0 μL, 2.0 mmol, 1.0 equiv) at 0°C. The reaction solution was stirred at 0°C for 5 minutes, and a dichloromethane (5 mL) solution of triethylamine (416.0 μL, 3.0 mmol, 1.5 equiv) was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 12 hours and quenched by adding 10 mL of water. The resulting mixture was extracted with dichloromethane (15 mL×3), the organic phases were combined, dried over anhydrous Na2SO4, and the resulting filtrate was concentrated by distillation under reduced pressure. The crude product was separated and purified by silica gel flash column chromatography (eluent: PE / EtOAc=10:1 to 5:1, v / v) to obtain the target product.

[0048] (3) Synthesis of target compound 3

[0049]

[0050] In an air atmosphere, enamide (compound 1) (E)-2-(prop-1-en-1-yl)isoindole-1,3-dione (0.1mmol), phenylthio reagent (compound 2) 1-(p-tolylthio)pyrrolidine-2,5-dione (0.11mmol), 4-bromoethylphenol (0.1mmol) and trifluoromethanesulfonic acid triisopropylsilyl ester (0.15mmol) were mixed and reacted at room temperature (25-35°C) for 12 hours. The crude reaction solution was concentrated and column chromatography (the stationary phase was silica gel, and the mobile phase was a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1) was performed to obtain the target product with a yield of 94%. 1 H NMR (400MHz, CDCl3) δ7.74 (dd, J=5.6, 3.0Hz, 2H), 7.67 (dd, J=5.5, 3.1Hz, 2H), 7. 29(d,J=1.7Hz,1H),7.26(s,1H),7.24(d,J=1.6Hz,1H),7.04(dd,J=8.2,2.2Hz,1H ),6.90(dd,J=12.0,8.1Hz,3H),5.37(d,J=11.7Hz,1H),4.76(dq,J=11.8,6.8Hz, 1H),3.55–3.43(m,2H),3.05(t,J=7.6Hz,2H),2.18(s,3H),1.22(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ169.27,153.62,137.98,134.43,134.26,134.20,131.62,131.29,13 0.44,129.67,129.18,124.24,123.65,119.13,57.55,43.07,38.59,33.35,21.16,19.71.

[0051] Example 2

[0052] The β-thio-α-aminophenol compound of the present invention has the following structural formula:

[0053]

[0054] The synthetic route is as follows:

[0055]

[0056] Synthesis method: In an air atmosphere, enamide (compound 1) (E)-2-(prop-1-en-1-yl)isoindole-1,3-dione (0.1mmol), (compound 2) 1-(p-tolylthio)pyrrolidine-2,5-dione (0.11mmol), 3-ethylphenol (0.12mmol) and trifluoromethanesulfonic acid triisopropylsilyl ester (0.15mmol) were mixed and reacted at room temperature (25-35°C) for 10 hours. The crude reaction solution was concentrated and column chromatography (the stationary phase was silica gel, and the mobile phase was a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1) was performed to obtain the target product with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ7.89 (d, J=8.5Hz, 1H), 7.74 (dd, J=5.4, 3.1Hz, 2H), 7.66 (dd, J=5 .5,3.1Hz,2H),7.31(d,J=8.0Hz,2H),6.96(d,J=7.9Hz,2H),6.69(m,2H),5.52(d,J=1 1.5Hz,1H),5.32(s,1H),4.69(dq,J=13.8,6.9Hz,1H),2.94(dq,J=15.0,7.6Hz,1H),2 .73(dq,J=14.9,7.5Hz,1H),2.23(s,3H),1.22(t,J=7.5Hz,3H),1.16(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ168.78,155.48,145.25,137.76,134.14,133.85,131.90,130.8 8,129.59,127.96,123.25,115.42,113.27,55.86,44.96,25.56,21.18,19.64,15.57.

[0057] Example 3

[0058] The β-thio-α-aminophenol compound of the present invention has the following structural formula:

[0059]

[0060] The synthetic route is as follows:

[0061]

[0062] Synthesis method: In an air atmosphere, enamide (compound 1) (E)-2-(prop-1-en-1-yl)isoindole-1,3-dione (0.1mmol), (compound 2) 1-(p-tolylthio)pyrrolidine-2,5-dione (0.11mmol), 2-ethylphenol (0.12mmol) and trifluoromethanesulfonic acid triisopropylsilyl ester (0.1mmol) were mixed and reacted at room temperature (25-35°C) for 10 hours. The crude reaction solution was concentrated and column chromatography (the stationary phase was silica gel, and the mobile phase was a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1) was performed to obtain the target product with a yield of 97%. 1 H NMR (400MHz, CDCl3) δ7.77–7.70(m,2H),7.66–7.60(m,2H),7.35–7.30(m,2H),7.30–7.26(m,2H),6.96(d,J=7.8Hz,2H),6.70(d,J=8.0Hz,1H),5. 24(s,1H),5.09(d,J=11.7Hz,1H),4.65(dq,J=13.7,6.8Hz,1H),2.60(q, J=7.5Hz,2H),2.21(s,3H),1.20(t,J=7.5Hz,3H),1.15(d,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ168.48,153.52,137.89,134.52,133.84,131.99,130.59,130.38,13 0.35,129.61,129.36,127.77,123.28,115.38,61.09,44.00,23.20,21.22,20.07,14.13.

[0063] Example 4

[0064] The β-thio-α-aminophenol compound of the present invention has the following structural formula:

[0065]

[0066] The synthetic route is as follows:

[0067]

[0068] Synthesis method: In an air atmosphere, enamide (compound 1) (E)-2-(prop-1-en-1-yl)isoindole-1,3-dione (0.1mmol), (compound 2) 1-(p-tolylthio)pyrrolidine-2,5-dione (0.11mmol), 4-isopropylphenol (0.1mmol) and trifluoromethanesulfonic acid triisopropylsilyl ester (0.1mmol) were mixed and reacted at room temperature (25-35°C) for 10 hours. The crude reaction solution was concentrated and column chromatography (the stationary phase was silica gel, and the mobile phase was a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1) was performed to obtain the target product with a yield of 91%. 1 H NMR (400MHz, CDCl3) δ7.77–7.69(m,2H),7.68–7.60(m,2H),7.28–7.22(m,3H),7.06(dd,J=8.3,2.1Hz,1H),6.91(d,J=7.9Hz,3H),6.87(d,J=8.3Hz ,1H),5.36(d,J=11.7Hz,1H),4.79(dq,J=13.6,6.8Hz,1H),2.83(dq,J=13 .8,6.8Hz,1H),2.17(s,3H),1.22(d,J=6.8Hz,3H),1.19(d,J=6.9Hz,6H). 13 C NMR (101MHz, CDCl3) δ169.32,152.57,141.69,137.89,134.19,134.13,131.69,129.66,129.38,1 29.23,127.98,123.87,123.60,119.00,58.37,43.17,33.35,25.33,24.27,24.23,21.16,19.73.

[0069] Example 5

[0070] The β-thio-α-aminophenol compound of the present invention has the following structural formula:

[0071]

[0072] The synthetic route is as follows:

[0073]

[0074] Synthesis method: In an air atmosphere, enamide (compound 1) (E)-2-(prop-1-en-1-yl)isoindole-1,3-dione (0.1mmol), (compound 2) 1-(p-tolylthio)pyrrolidine-2,5-dione (0.11mmol), 4-tert-butylphenol (0.1mmol) and trifluoromethanesulfonic acid triisopropylsilyl ester (0.1mmol) were mixed and reacted at room temperature (25-35°C) for 10 hours. The crude reaction solution was concentrated and column chromatography (the stationary phase was silica gel, and the mobile phase was a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1) was performed to obtain the target product with a yield of 93%. 1 H NMR (400MHz, CDCl3) δ7.77–7.67(m,2H),7.68–7.62(m,2H),7.43(s,1H),7.28–7.24(m,2H),7.22(dd,J=8.5,2.2Hz,1H),6.90(d,J=7. 9Hz,2H),6.87(d,J=8.5Hz,1H),5.39(d,J=11.6Hz,1H),4.79(dq,J=13.6,6.8Hz,1H),2.17(s,3H),1.27(s,9H),1.22(d,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ169.31,152.26,143.98,137.87,134.17,134.12,131.70,129.66,12 9.43,128.06,127.14,123.58,123.52,118.56,58.35,43.20,34.22,31.59,21.16,19.71.

Claims

1. A method for synthesizing β-thio-α-aminophenol compounds, characterized in that: The method comprises the following steps: mixing compound 1, compound 2 and different types of aromatic phenols, adding Lewis acid as an additive, reacting in a solvent, and purifying to obtain target compound 3. The reaction formula is as follows: Wherein, R is H or C1-C3 alkyl; R 1 is a halogenated C1-C5 alkyl, a C1-C5 alkyl, a C1-C5 alkoxy, a halogen, an acetyl group, and R 2 is H, C1-C3 alkyl, C1-C3 alkoxy or halogen, R 3 is H or halogen.

2. The method for synthesizing β-thio-α-aminophenol compounds according to claim 1, characterized in that: The structural formula of the target compound is as follows:

3. The method for synthesizing β-thio-α-aminophenol compounds according to claim 1, wherein the reaction temperature is 20 to 30°C.

4. The method for synthesizing β-thio-α-aminophenol compounds according to claim 1, characterized in that: The molar ratio of the compound 1 to the arylphenol is 1:1.0-1.

1.

5. The method for synthesizing β-thio-α-aminophenol compounds according to claim 1, characterized in that: The molar ratio of the compound 1 to the compound 2 is 1:1.0-1.

2.

6. The method for synthesizing β-thio-α-aminophenol compounds according to claim 2, characterized in that: The yield of the target compound 3 is 76-97%.

7. The method for synthesizing β-thio-α-aminophenol compounds according to claim 1, characterized in that: The molar ratio of the compound 1 to the Lewis acid additive is 1:0.5-3.

8. The method for synthesizing β-thio-α-aminophenol compounds according to claim 1, characterized in that: The Lewis acid additive is methanesulfonic acid, trifluoroacetic acid, trifluoroacetic anhydride, trifluoromethanesulfonic acid, triisopropylsilyl trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate or di(trifluoromethylsulfonyl)amide.

9. The method for synthesizing β-thio-α-aminophenol compounds according to claim 1, characterized in that: The solvent is dichloromethane, acetonitrile, dichloroethane, toluene, xylene, toluene+dichloromethane, toluene+acetonitrile or dichloromethane+acetonitrile.

10. The method for synthesizing β-thio-α-aminophenol compounds according to claim 1, characterized in that: The purification is as follows: the reaction mother liquor is concentrated and then directly subjected to column chromatography, and the eluent is a mixed solvent of petroleum ether and ethyl acetate.

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