Preparation method of 3-amino-2, 3-dihydrobenzofuran compound

Abstract

The invention discloses a preparation method of a 3-amino-2, 3-dihydrobenzofuran compound and a preparation method of the 3-amino-2, 3-dihydrobenzofuran compound. Amine and 2-formylphenoxyacetic acid are used as raw materials; ferric sulfate is used as a catalyst, and bis (2-picolyl) amine is used as a ligand. The preparation method comprises the following steps: adding 2-amino-2, 3-dihydrobenzofuran into an organic solution, firstly carrying out ultrasonic or heating stirring reaction, and then carrying out reaction under the illumination of LEDs (Light Emitting Diodes) lamps, so as to prepare a series of 3-amino-2, 3-dihydrobenzofuran compounds. The method has the advantages of mild reaction conditions, easily available initial raw materials, cheap catalyst, simple operation, low cost and the like. The two raw materials are common organic matters, the catalyst ferric sulfate is a common inorganic salt, and compared with a noble metal complex in a visible-light-driven photocatalyst, iron is a second abundant metal on the earth, so that the cost is low. The method adopts a one-pot method for reaction, and has the advantages of simplicity and convenience in operation, high yield and the like. The method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and specifically relates to a method for preparing 3-amino-2,3-dihydrobenzofuran compounds. Background Art

[0002] The 3-amino-2,3-dihydrobenzofuran skeleton is widely present in the structure of drugs and natural products (Z. Chen, M. Pitchakuntla and Y. Jia, Nat. Prod. Rep., 2019, 36, 666), and has unique physiological activities and pharmacodynamics (a X.-X. Sun, H.-H. Zhang, G.-H. Li, L. Meng and F. Shi, Chem. Commun., 2016, 52, 2968; b RJ Nevagi, S. N. Dighe and S. N. Dighe, Eur. J. Med. Chem., 2015, 97, 561), including antiviral, antibacterial, anti-inflammatory, anti-angiogenic and anti-mitotic biological activities. There are also a large number of reports on the synthesis of this type of compound, which is currently mainly obtained by using the [4+1] tandem ring-closing reaction of the imine condensed with salicylaldehyde and different amphiphilic reagents. For example, Chen used sulfur ylide reagents or sulfonium salts to react with salicylaldehyde to form 3-amino 2,3-dihydrobenzofuran (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 the asymmetric tandem cyclization of aryl diazoacetate and salicylaldehyde to obtain 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 of the reported methods are not suitable for industrial production due to the difficulties in substrate synthesis, harsh reaction conditions, low yield, and cumbersome purification process. Summary of the invention

[0003] The present invention aims to provide a method for preparing 3-amino-2,3-dihydrobenzofuran compounds which is efficient, green and easy to operate.

[0004] A method for preparing 3-amino-2,3-dihydrobenzofuran compounds, wherein the chemical reaction comprises the following steps:

[0005]

[0006] An amine compound shown in formula II, a 2-formylphenoxyacetic acid compound shown in formula I, ferric sulfate and bis(2-pyridylmethyl)amine are added to an organic solution, and an ultrasonic or heated stirring reaction is first performed, and then an LED light is used for reaction to prepare a 3-amino-2,3-dihydrobenzofuran compound shown in formula III. The invention uses amine and 2-formylphenoxyacetic acid as raw materials, ferric sulfate as a catalyst, and bis(2-pyridylmethyl)amine as a ligand, and adopts a one-pot method and a two-step method to prepare a 3-amino-2,3-dihydrobenzofuran compound.

[0007] Where R 1 At least one selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogen, nitro, trifluoromethyl, trifluoromethoxy, and aryl; R 2 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, aryl; R 3 and R 4 Each is independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylnitro, phenyl, nitrophenyl, methoxyphenyl, and 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-pyridylmethyl)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° C., and the heating stirring time is 1-2 hours.

[0014] Preferably, the wavelength of the LEDs lamp is 427-460nm; the illumination time is 6-10 hours.

[0015] The method used in the present invention is: firstly, ultrasonic or heating stirring is performed to cause an imine condensation reaction, and then a decarboxylation free radical ring-closing reaction is performed under visible light conditions.

[0016] Beneficial effects: The method of the present invention has mild reaction conditions, easy to obtain starting materials, and low cost. In the present invention, the two raw materials are easy to synthesize, and the catalyst iron sulfate is a common inorganic salt with low cost. The free radical decarboxylation strategy has obvious advantages because carboxylic acid is stable, cheap and non-toxic, and the only by-product is carbon dioxide, which meets the atomic economy. The present invention uses a "one-pot method" to react, which is simple and convenient to operate and has great advantages. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is the structural formula of the 3-amino-2,3-dihydrobenzofuran compound of the present invention. DETAILED DESCRIPTION

[0018] Example 1 2-Formylphenoxyacetic acid (0.2 mmol), aniline (0.3 mmol), ferric sulfate (0.01 mmol) and bis(2-picolylmethyl)amine (0.02 mmol) were firstly ultrasonicated for 1 minute or heated and stirred at 65°C for 1 hour, and then stirred under 40W 460nm LED lamp for about 6 hours. The reaction was followed by TLC detection. The reaction was washed with water, extracted with DCM (10×3), and anhydrous Na 2 SO 4 Dry, concentrate and separate by column chromatography to obtain a colorless liquid with a yield of 80%.

[0019] Colorless liquid. 1 H NMR(400MHz,Chloroform-d)δ7.34(d,J=7.4Hz,1H),7.26-7.13(m,3H),6.96-6.84(m,2H),6.77(t,J=7.3Hz,1 H),6.61(d,J=7.9Hz,2H),5.20(s,1H),4.70(dd,J=9.6,7.2Hz,1H),4.39(dd,J=9.6,4.0Hz,1H),3.95(s,1H); 13 C NMR(101MHz,Chloroform-d)δ160.2,146.5,130.2,129.5,127.4,125.3,121.0,118.3,113.3,110.4,77.7,55.4; HRMS(ESI)Calcd.for C 14 H 14 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-picolylmethyl)amine (0.02 mmol) were dissolved in acetonitrile (2 mL) and firstly ultrasonicated for 1 minute or heated and stirred at 65° C. for 2 hours, then stirred and reacted under a 40 W 427 nm LED lamp, followed by TLC detection for about 10 hours. Washed with water, extracted with DCM (10×3), anhydrous Na 2 SO 4 Dry, concentrate and separate by column chromatography to obtain a colorless liquid with a yield of 82%.

[0021] Colorless liquid. 1 H NMR(400MHz,Chloroform-d)δ7.40(d,J=7.4Hz,1H),7.34-7.26(m,2H),7.18(dt,J=7.9,3.9Hz,1H),7.01-6.89(m,2H),6.72( t,J=7.5Hz,2H),5.26(td,J=7.3,4.3Hz,1H),4.77(dd,J=9.6,7.4Hz,1H),4.62(d,J=7.3Hz,1H),4.41(dd,J=9.6,4.3Hz,1H); 13 C NMR(101MHz,Chloroform-d)δ160.3,142.5,130.3,129.6,127.8,126.8,125.3,121.1,119.7,118.2,111.4,110.5,77.7,55.3; 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-picolylmethyl)amine (0.02 mmol) were firstly ultrasonicated for 1 minute or heated and stirred at 65°C for 2 hours, and then stirred under a 40W 427nm LED lamp for about 10 hours. The reaction was followed by TLC detection. The reaction was washed with water, extracted with DCM (10×3), and anhydrous Na 2 SO 4 Dry, concentrate and separate by column chromatography to obtain a white solid with a yield of 81%.

[0023] White solid, mp(50.3℃). 1H NMR(400MHz,Chloroform-d)δ7.33(d,J=7.4Hz,1H),7.26-7.17(m,1H),6.94-6.85(m,2H),6.81(d,J=8.9Hz,2H),6.6 0(d,J=8.9Hz,2H),5.14(dd,J=7.3,4.0Hz,1H),4.68(dd,J=9.6,7.3Hz,1H),4.39(dd,J=9.6,4.0Hz,1H),3.76(s,3H); 13 C NMR(101MHz,Chloroform-d)δ160.2,152.8,140.6,130.0,127.7,125.3,120.9,115.1,114.9,110.3,77.6,56.4,55.8; HRMS(ESI)Calcd.for C 15 H 16 NO 2 [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), iron sulfate (0.01 mmol) and bis(2-picolylmethyl)amine (0.02 mmol) were first ultrasonicated for 1 minute or heated and stirred at 65°C for 2 hours, and then stirred under a 40W 427nm LED lamp for about 10 hours. The reaction was followed by TLC detection. Wash with water, extract with DCM (10×3), and dry with NaOH. 2 SO 4 Dry, concentrate and separate by column chromatography to obtain a yellow solid with a yield of 83%.

[0025] Yellow solid, mp(50.9℃). 1 H NMR(400MHz,Chloroform-d)δ8.93(s,1H),7.72(d,J=8.6Hz,1H),7.40(d,J=7.4Hz,1H),7.38-7.34(m,1H),7.29(d,J=8.6Hz, 1H),6.98-6.88(m,2H),6.83-6.77(m,1H),5.29(s,1H),4.78(dd,J=9.7,7.2Hz,1H),4.48(dd,J=9.7,3.8Hz,1H),4.21(s,1H); 13C NMR(101MHz,Chloroform-d)δ160.3,155.0,154.7,145.7,130.3,127.1,125.3,123.1,122.3,121.0,115.2,110.5,105.1,77.5,55.7; HRMS(ESI)Calcd.for C 15 H 12 N 2 OS[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-picolylmethyl)amine (0.02 mmol) were firstly ultrasonicated for 1 minute or heated and stirred at 65°C for 1 hour, and then stirred under 40W 427nm LED lamp for about 8 hours. The reaction was followed by TLC detection. The reaction mixture was washed with water, extracted with DCM (10×3), and anhydrous Na 2 SO 4 Dry, concentrate and separate by column chromatography to obtain a yellow liquid with a yield of 85%.

[0027] Yellow liquid. 1 H NMR(400MHz,Chloroform-d)δ7.27-7.20(m,3H),7.14-7.08(m,1H),6.88(t,J=7.5Hz,1H),6.84-6.78(m,1H),6.69-6.63 (m,2H),5.24(dd,J=7.3,4.0Hz,1H),4.74(dd,J=9.6,7.3Hz,1H),4.44(dd,J=9.6,4.0Hz,1H),3.97(s,1H),2.30(s,3H); 13 C NMR(101MHz,Chloroform-d)δ158.7,146.6,131.2,129.5,126.7,122.5,120.9,120.6,118.2,113.3,77.5,55.9,15.1; 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-picolylmethyl)amine (0.02 mmol) were firstly ultrasonicated for 5 minutes or heated and stirred at 65°C for 2 hours, and then stirred under 40W 427nm LED lamp for reaction, and followed by TLC detection for about 10 hours. Washed with water, extracted with DCM (10×3), anhydrous Na 2 SO 4 Dry, concentrate and separate by column chromatography to obtain a colorless liquid with a yield of 86%.

[0029] Colorless liquid. 1 H NMR(400MHz,Chloroform-d)δ7.38(d,J=7.4Hz,1H),7.34-7.26(m,3H),6.98(t,J=7.4Hz,1H),6.91(d,J=8.1Hz,1H),6.82(t,J= 7.3Hz,1H),6.72(d,J=7.8Hz,2H),5.23(t,J=7.6Hz,1H),5.02(p,J=6.7Hz,1H),3.91(d,J=8.1Hz,1H),1.47(s,1H),1.45(s,2H); 13 C NMR(101 MHz,Chloroform-d)δ159.2,147.2,130.0,129.5,128.3,125.5,120.8,117.9,112.7,110.2,82.9,57.4,15.0; HRMS(ESI)Calcd.forC 15 H 15 NO[M+H] + ,225.1154.Found:m / z 225.1156.

Claims

1. A method for preparing 3-amino-2,3-dihydrobenzofuran compounds, characterized in that: The chemical reaction includes the following steps: The amine compound of formula II, the 2-formylphenoxyacetic acid compound of formula I, ferric sulfate and bis(2-pyridylmethyl)amine are added to an organic solution, first subjected to ultrasonic or heating stirring reaction, and then subjected to LED light illumination to react to obtain a 3-amino-2,3-dihydrobenzofuran compound of formula III; Where R 1 At least one selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogen, nitro, trifluoromethyl, trifluoromethoxy, and aryl; R 2 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, aryl; R 3 and R 4 Each is independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylnitro, phenyl, nitrophenyl, methoxyphenyl, and trifluoromethylphenyl amine.

2. The preparation method according to claim 1, characterized in that: The amine compound is a primary amine or a secondary amine.

3. 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.

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

1.

5. 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.

6. The preparation method according to claim 1, characterized in that: The organic solvent is 1,2-dichloroethane, dichloromethane, methanol, ethanol, acetonitrile, ethyl acetate, and dimethyl sulfoxide.

7. The preparation method according to claim 1, characterized in that: The ultrasonic time is 1-10 minutes or the heating temperature is 25-65° C., and the heating stirring time is 1-2 hours.

8. The preparation method according to claim 1, characterized in that: The wavelength of the LEDs lamp is 427-460nm; the illumination time is 6-10 hours.

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