A method for preparing 3-amino-2,3-dihydrobenzofurans

Abstract

The application discloses a preparation method of 3-amino-2,3-dihydrobenzofuran compounds. Amine and 2-formylphenoxyacetic acid are used as raw materials; iron sulfate is used as a catalyst, and bis(2-pyridylmethyl)amine is used as a ligand. The mixture is added to an organic solution, and first ultrasonic or heating stirring reaction is carried out, then reaction is carried out under LED light, and a series of 3-amino-2,3-dihydrobenzofuran compounds are prepared. The method has the advantages of mild reaction condition, easy-to-obtain starting material, cheap catalyst, simple operation, low cost and the like. In the application, the two raw materials are common organic substances, and the catalyst iron sulfate is a common inorganic salt. Compared with noble metal complexes in visible light catalysts, iron is the second most abundant metal on the earth, and has low cost. The application uses a one-pot method for reaction, and has the advantages of simple operation, high yield and the like. The method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, specifically relating to a method for preparing 3-amino-2,3-dihydrobenzofuran compounds. Background Technology

[0002] The 3-amino-2,3-dihydrobenzofuran skeleton is widely found in the structures of drugs and natural products (Z. Chen, M. Pitchakuntla and Y. Jia, Nat. Prod. Rep., 2019, 36, 666), possessing unique physiological activities and pharmacological effects (a X.-X. Sun, H.-H. Zhang, G.-H. Li, L. Meng and F. Shi, Chem.Commun., 2016, 52, 2968; b RJ Nevagi, SN Dighe and SN Dighe, Eur. J.Med. Chem., 2015, 97, 561), including antiviral, antibacterial, anti-inflammatory, anti-angiogenic, and antimitotic activities. Numerous reports have been published on the synthesis of these compounds, currently mainly utilizing the [4+1] tandem cyclization reaction of salicylaldehyde-condensed imines with various amphiphilic reagents. For example, Chen constructed 3-amino-2,3-dihydrobenzofurans by reacting a sulfur ylide reagent or sulfonium salt with an imine condensed from salicylaldehyde (P. Xie, L. Wang, L. Yang, E. Li, J. Ma, Y. Huang and R. Chen, J. Org. Chem., 2011, 76, 7699.). Recently, Wang reported that Cu(I) / bisoxazoline (BOX) complexes can catalyze asymmetric tandem cyclization reaction of aryl diazonium acetate with an imine condensed from salicylaldehyde, yielding a series of chiral 3-amino-2,3-dihydrobenzofuran derivatives (X.-S. Liang, R.-D. Li and X.-C. Wang, Angew. Chem., Int. Ed., 2019, 58, 13885.). However, most reported methods are unsuitable for industrial production due to drawbacks such as difficult substrate synthesis, harsh reaction conditions, low yields, and cumbersome purification processes. Summary of the Invention

[0003] The present invention aims to provide an efficient, green and simple method for preparing 3-amino-2,3-dihydrobenzofuran compounds.

[0004] A method for preparing a 3-amino-2,3-dihydrobenzofuran compound, comprising the following chemical reactions:

[0005] ;

[0006] The amine compound shown in Formula II, the 2-formylphenoxyacetic acid compound shown in Formula I, ferric sulfate, and bis(2-pyridinemethyl)amine are added to an organic solution. After first undergoing ultrasonic or heating and stirring, the reaction is then carried out under LED light to obtain the 3-amino-2,3-dihydrobenzofuran compound shown in Formula III. In this invention, amine and 2-formylphenoxyacetic acid are used as raw materials, ferric sulfate is used as a catalyst, and bis(2-pyridinemethyl)amine is used as a ligand to prepare the 3-amino-2,3-dihydrobenzofuran compound using a one-pot, two-step reaction.

[0007] Where R 1 Selected from at least one of hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogen, nitro, trifluoromethyl, trifluoromethoxy, and aryl; R 2 Selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, aryl; R 3 and R 4 Each of these amines is independently a hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkazyl, phenyl, nitrophenyl, methoxyphenyl, or trifluoromethylphenyl amine.

[0008] Preferably, the amine compound is a primary amine or a secondary amine.

[0009] Preferably, the molar ratio of the 2-formylphenoxyacetic acid compound to the amine compound is 1:1.0-1.5.

[0010] Preferably, the molar ratio of the 2-formylphenoxyacetic acid compound: ferric sulfate: bis(2-pyridinemethyl)amine is 1:0.02-0.05:0.04-0.1.

[0011] Preferably, the molar concentration of the 2-formylphenoxyacetic acid compound in the organic solvent is 0.05-0.15 mol / ml.

[0012] Preferably, the organic solvent is 1,2-dichloroethane, dichloromethane, methanol, ethanol, acetonitrile, ethyl acetate, or dimethyl sulfoxide.

[0013] Preferably, the ultrasonic time is 1-10 minutes or the heating temperature is 25-65 ℃, and the heating and stirring time is 1-2 hours.

[0014] Preferably, the LEDs have a wavelength of 427-460nm and an illumination time of 6-10 hours.

[0015] The method used in this invention is as follows: first, an imine condensation reaction is carried out by ultrasonication or heating and stirring, followed by a decarboxylation free radical cyclization reaction under visible light conditions.

[0016] Beneficial effects: The method of this invention uses mild reaction conditions, readily available starting materials, and low cost. The synthesis of the two raw materials in this invention is simple, and the catalyst, ferric sulfate, is a common inorganic salt with low cost. The free radical decarboxylation strategy has significant advantages because carboxylic acids are stable, inexpensive, and non-toxic, with carbon dioxide as the only byproduct, which meets atom economy requirements. This invention uses a one-pot reaction, which is simple and convenient to operate, and has excellent advantages. Attached Figure Description

[0017] Figure 1 The structural formula of the 3-amino-2,3-dihydrobenzofuran compounds of the present invention is shown below. Detailed Implementation

[0018] Example 1: 2-Formylphenoxyacetic acid (0.2 mmol), aniline (0.3 mmol), ferric sulfate (0.01 mmol), and bis(2-pyridinemethyl)amine (0.02 mmol) were added to a DCE (2 mL). The mixture was first sonicated for 1 minute or heated and stirred at 65 °C for 1 hour. The reaction was then stirred under a 40 W 460 nm LED lamp, and monitored by TLC for approximately 6 hours. The mixture was washed with water, extracted with DCM (10 × 3), dried over anhydrous Na₂SO₄, concentrated, and separated by column chromatography to obtain a colorless liquid with a yield of 80%.

[0019] Colorless liquid. 1 H NMR (400 MHz, Chloroform-d) δ 7.34 (d, J = 7.4Hz, 1H), 7.26-7.13 (m, 3H), 6.96-6.84 (m, 2H), 6.77 (t, J = 7.3 Hz, 1H), 6.61(d, J = 7.9 Hz, 2H), 5.20 (s, 1H), 4.70 (dd, J = 9.6, 7.2 Hz, 1H), 4.39 (dd,J = 9.6, 4.0 Hz, 1H), 3.95 (s, 1H); 13 C NMR (101 MHz, Chloroform-d) δ 160.2,146.5, 130.2, 129.5, 127.4, 125.3, 121.0, 118.3, 113.3, 110.4, 77.7, 55.4;HRMS (ESI) Calcd. for C 14 H14 NO [M+H] + , 212.1075. Found: m / z 212.1078.

[0020] Example 2: 2-Formylphenoxyacetic acid (0.2 mmol), o-chloroaniline (0.3 mmol), ferric sulfate (0.01 mmol), and bis(2-pyridinemethyl)amine (0.02 mmol) were added to acetonitrile (2 mL). The mixture was first sonicated for 1 minute or heated and stirred at 65 °C for 2 hours. The reaction was then stirred under a 40 W 427 nm LED lamp, and monitored by TLC for approximately 10 hours. The mixture was washed with water, extracted with DCM (10 × 3), dried over anhydrous Na₂SO₄, concentrated, and separated by column chromatography to obtain a colorless liquid with a yield of 82%.

[0021] Colorless liquid. 1 H NMR (400 MHz, Chloroform-d) δ 7.40 (d, J = 7.4Hz, 1H), 7.34-7.26 (m, 2H), 7.18 (dt, J = 7.9, 3.9 Hz, 1H), 7.01-6.89 (m,2H), 6.72 (t, J = 7.5 Hz, 2H), 5.26 (td, J = 7.3, 4.3 Hz, 1H), 4.77 (dd, J =9.6, 7.4 Hz, 1H), 4.62 (d, J = 7.3 Hz, 1H), 4.41 (dd, J = 9.6, 4.3 Hz, 1H); 13 C NMR (101 MHz, Chloroform-d) δ 160.3, 142.5, 130.3, 129.6, 127.8, 126.8,125.3, 121.1, 119.7, 118.2, 111.4, 110.5, 77.7, 55.3; HRMS (ESI) Calcd. forC 14 H 13 ClNO [M+H] + , 246.0686. Found: m / z 246.0688.

[0022] Example 3: 2-Formylphenoxyacetic acid (0.2 mmol), p-methoxyaniline (0.3 mmol), ferric sulfate (0.01 mmol), and bis(2-pyridinemethyl)amine (0.02 mmol) were added to a DCE (2 mL). The mixture was first sonicated for 1 minute or heated and stirred at 65 °C for 2 hours. The reaction was then stirred under a 40 W 427 nm LED lamp, and monitored by TLC for approximately 10 hours. The mixture was washed with water, extracted with DCM (10 × 3), dried over anhydrous Na₂SO₄, concentrated, and separated by column chromatography to obtain a white solid with a yield of 81%.

[0023] White solid, mp (50.3℃). 1 H NMR (400 MHz, Chloroform-d) δ 7.33(d, J = 7.4 Hz, 1H), 7.26-7.17 (m, 1H), 6.94-6.85 (m, 2H), 6.81 (d, J = 8.9Hz, 2H), 6.60 (d, J = 8.9 Hz, 2H), 5.14 (dd, J = 7.3, 4.0 Hz, 1H), 4.68 (dd,J = 9.6, 7.3 Hz, 1H), 4.39 (dd, J = 9.6, 4.0 Hz, 1H), 3.76 (s, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 160.2, 152.8, 140.6, 130.0, 127.7, 125.3, 120.9,115.1, 114.9, 110.3, 77.6, 56.4, 55.8; HRMS (ESI) Calcd. for C 15 H 16 NO2 [M+H] + ,242.1181. Found: m / z 242.1184.

[0024] Example 4: 2-Formylphenoxyacetic acid (0.2 mmol), 1,3-benzothiazol-5-amine (0.3 mmol), ferric sulfate (0.01 mmol), and bis(2-pyridinemethyl)amine (0.02 mmol) were added to a DCE (2 mL). The mixture was first sonicated for 1 minute or heated and stirred at 65 °C for 2 hours. The reaction was then stirred under a 40 W 427 nm LED lamp, and monitored by TLC for approximately 10 hours. The mixture was washed with water, extracted with DCM (10 × 3), dried over anhydrous Na₂SO₄, concentrated, and separated by column chromatography to obtain a yellow solid with a yield of 83%.

[0025] Yellow solid, mp (50.9℃). 1 H NMR (400 MHz, Chloroform-d) δ 8.93(s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 7.4 Hz, 1H), 7.38-7.34 (m,1H), 7.29 (d, J = 8.6 Hz, 1H), 6.98-6.88 (m, 2H), 6.83-6.77 (m, 1H), 5.29 (s,1H), 4.78 (dd, J = 9.7, 7.2 Hz, 1H), 4.48 (dd, J = 9.7, 3.8 Hz, 1H), 4.21 (s,1H); 13 C NMR (101 MHz, Chloroform-d) δ 160.3, 155.0, 154.7, 145.7, 130.3,127.1, 125.3, 123.1, 122.3, 121.0, 115.2, 110.5, 105.1, 77.5, 55.7; HRMS(ESI) Calcd. for C 15 H 12 N2OS [M+H] + , 268.0670. Found: m / z 268.0672.

[0026] Example 5: 2-Formylphenoxyacetic acid (0.2 mmol), aniline (0.3 mmol), ferric sulfate (0.01 mmol), and bis(2-pyridinemethyl)amine (0.02 mmol) were added to a DCE (2 mL). The mixture was first sonicated for 1 minute or heated and stirred at 65 °C for 1 hour. The reaction was then stirred under a 40 W 427 nm LED lamp, and monitored by TLC for approximately 8 hours. The mixture was washed with water, extracted with DCM (10 × 3), dried over anhydrous Na₂SO₄, concentrated, and separated by column chromatography to obtain a yellow liquid with a yield of 85%.

[0027] Yellow liquid. 1H NMR (400 MHz, Chloroform-d) δ 7.27-7.20 (m, 3H),7.14-7.08 (m, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.84-6.78 (m, 1H), 6.69-6.63 (m,2H), 5.24 (dd, J = 7.3, 4.0 Hz, 1H), 4.74 (dd, J = 9.6, 7.3 Hz, 1H), 4.44(dd, J = 9.6, 4.0 Hz, 1H), 3.97 (s, 1H), 2.30 (s, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 158.7, 146.6, 131.2, 129.5, 126.7, 122.5, 120.9, 120.6,118.2, 113.3, 77.5, 55.9, 15.1; HRMS (ESI) Calcd. for C 15 H 15 NO [M+H] + ,225.1154. Found: m / z 225.1158.

[0028] Example 6: 2-Formylphenoxyacetic acid (0.2 mmol), aniline (0.3 mmol), ferric sulfate (0.01 mmol), and bis(2-pyridinemethyl)amine (0.02 mmol) were added to a DCE (2 mL). The mixture was first sonicated for 5 minutes or heated and stirred at 65 °C for 2 hours. The reaction was then stirred under a 40 W 427 nm LED lamp, and monitored by TLC for approximately 10 hours. The mixture was washed with water, extracted with DCM (10 × 3), dried over anhydrous Na₂SO₄, concentrated, and separated by column chromatography to obtain a colorless liquid with a yield of 86%.

[0029] Colorless liquid. 1H NMR (400 MHz, Chloroform-d) δ 7.38 (d, J = 7.4Hz, 1H), 7.34-7.26 (m, 3H), 6.98 (t, J = 7.4 Hz, 1H), 6.91 (d, J = 8.1 Hz,1H), 6.82 (t, J = 7.3 Hz, 1H), 6.72 (d, J = 7.8 Hz, 2H), 5.23 (t, J = 7.6 Hz,1H), 5.02 (p, J = 6.7 Hz, 1H), 3.91 (d, J = 8.1 Hz, 1H), 1.47 (s, 1H), 1.45(s, 2H); 13 C NMR (101 MHz, Chloroform-d) δ 159.2, 147.2, 130.0, 129.5, 128.3,125.5, 120.8, 117.9, 112.7, 110.2, 82.9, 57.4, 15.0; HRMS (ESI) Calcd. forC 15 H 15 NO [M+H] + , 225.1154. Found: m / z 225.1156。

Claims

1. A method for preparing a 3-amino-2,3-dihydrobenzofuran compound, characterized in that, Its chemical reaction includes the following steps: ； The amine compound shown in Formula II, the 2-formylphenoxyacetic acid compound shown in Formula I, ferric sulfate and bis(2-pyridinemethyl)amine were added to an organic solvent. After the reaction was first subjected to ultrasonic or heating and stirring, the reaction was then carried out under LED light to obtain the 3-amino-2,3-dihydrobenzofuran compound shown in Formula III. Where R 1 Selected from at least one of hydrogen and halogen; R 2 Selected from hydrogen; R 3 and R 4 Each is independently selected from hydrogen, phenyl, or methoxyphenyl; wherein the amine compound is a primary amine. The organic solvent is 1,2-dichloroethane or acetonitrile; The ultrasonic time is 1-10 minutes or the heating temperature is 25-65 ℃, and the heating and stirring time is 1-2 hours; The LEDs have a wavelength of 427-460nm and an illumination time of 6-10 hours.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the 2-formylphenoxyacetic acid compound to the amine compound is 1:1.0-1.

5.

3. The preparation method according to claim 1, characterized in that, The molar ratio of the 2-formylphenoxyacetic acid compound, ferric sulfate, and bis(2-pyridinemethyl)amine is 1:0.02-0.05:0.04-0.

1.

4. The preparation method according to claim 1, characterized in that, The molar concentration of the 2-formylphenoxyacetic acid compound in the organic solvent is 0.05-0.15 mol / ml.

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