A kind of DBDMH promoted synthesis method of benzofuran compound

Abstract

The present invention relates to a DBDMH-promoted method for synthesizing benzofuran compounds. Using an enaminone compound (I) and an o-hydroxybenzaldehyde compound (II) as raw materials, DBDMH as a promoter, and DMF as a reaction solvent, the o-hydroxybenzaldehyde compound (II) and the enaminone compound (I) undergo instantaneous halogenation coupling under alkaline conditions and room temperature to produce an imine intermediate (III), which is then synthesized into a benzofuran compound (IV) through a cascade reaction in the presence of an ammonium chloride solution. The present invention provides a new method for synthesizing benzofuran compounds. This method efficiently prepares benzofuran compounds through the intermolecular reaction of enaminone and o-hydroxybenzaldehyde, and has the advantages of a wide substrate range, strong functional group compatibility, simple and safe operation, short reaction time, and readily available and inexpensive raw materials.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry, and in particular is a method for synthesizing benzofuran compounds promoted by DBDMH. Background Art

[0002] Benzofuran compounds are special structural units in many natural products with important biological activities and potential medicinal value. It is reported that 30 FDA-approved drugs contain benzofuran as the core skeleton. For example, amiodarone, a prescription drug containing a benzofuran ring, was approved by the FDA in 1985 for the treatment of life-threatening ventricular tachyarrhythmias. Rugchalcone A and Rugchalcone B are natural 2-aroylbenzofuran derivatives isolated from rose flowers, which have anti-tobacco mosaic virus (TMV) and anti-inflammatory activities. Therefore, in the past few decades, researchers have invested considerable efforts to develop effective methods for the synthesis of benzofuran derivatives. The structural formulas of amiodarone, Rugchalcone A, and Rugchalcone B are as follows:

[0003]

[0004] Traditional methods for synthesizing benzofuran derivatives typically utilize intramolecular reactions. However, existing methods suffer from harsh reaction conditions, the use of expensive noble metal catalysts, and the difficulty of synthesizing starting materials.

[0005] Intermolecular cascade reactions are an effective means of synthesizing benzofurans because they can form multiple C-C / C-O bonds in the same reaction, allowing for efficient, economical, and functionally compatible construction of benzofurans. Despite significant progress in the synthesis of benzofurans, methods for synthesizing benzofurans from enaminones remain unreported. Enaminones are synthetic precursors for the synthesis of various heterocycles and other useful intermediates, and the synthesis of heterocycles via direct C-H functionalization reactions has attracted increasing interest among researchers. Recently, the present research group reported a transient halogenation C-H functionalization reaction of enaminones to construct C-S, C-N, and C-O bonds. Despite extensive research on C-H functionalization reactions of enaminones, the construction of benzofurans via transient halogenation of enaminones has been reported. Summary of the Invention

[0006] The present invention aims to provide a method for synthesizing benzofuran compounds by DBDMH-promoted coupling reaction of enaminones and o-hydroxybenzaldehydes, which can efficiently prepare benzofuran compounds through intermolecular reactions. The method has the advantages of simple and safe operation, cheap and readily available raw materials, a wide range of substrates, strong functional group compatibility, and a short reaction time.

[0007] The present invention solves the technical problem by adopting the following technical solution. According to the DBDMH-promoted synthesis method of benzofuran compounds proposed in the present invention, an enaminone compound (I) and an o-hydroxybenzaldehyde compound (II) are used as raw materials, DBDMH is used as a promoter, and DMF is used as a reaction solvent. Under alkaline conditions and room temperature conditions, the o-hydroxybenzaldehyde compound (II) and the enaminone compound (I) are instantaneously halogenated and coupled to produce an imine intermediate (III), which is then synthesized into a benzofuran compound (IV) through a cascade reaction in the presence of an ammonium chloride solution. The reaction formula is:

[0008]

[0009] Among them, R 1 represents phenyl or 3-methoxyphenyl or 4-bromophenyl or 4-chlorophenyl or furyl;

[0010] R 2 represents phenyl or 4-chlorophenyl or 4-methylphenyl;

[0011] R 3 represents H or 5-methyl or 5-methoxy or 5-F or 5-Cl or 5-Br or 4-methyl or 4-Br.

[0012] The aforementioned DBDMH-promoted synthesis method of benzofuran compounds comprises the following specific steps: mixing DBDMH and an enaminone compound (I) in a solvent, DMF, stirring at room temperature for 5 minutes, adding an o-hydroxybenzaldehyde compound (II) and a base thereto, stirring the reaction mixture at room temperature and in an air atmosphere for 2 hours, adding ammonium chloride and water, raising the temperature of the reaction system to 100° C. and stirring in an air atmosphere for 2 hours; after the reaction is complete, washing the reaction mixture three times with a saturated NaCl solution, combining the aqueous phases after the three washes and extracting them three times with ethyl acetate, drying the combined organic phases of the three extractions over anhydrous Na2SO4, removing the solvent by distillation under reduced pressure, and finally purifying the mixture by silica gel flash column chromatography to obtain a benzofuran compound (IV).

[0013] In the aforementioned DBDMH-promoted synthesis method of benzofuran compounds, the base is one of potassium carbonate, sodium hydride, sodium hydroxide, potassium tert-butoxide, cesium carbonate, and triethylamine.

[0014] In the aforementioned DBDMH-promoted synthesis method of benzofuran compounds, the structural formula of the enaminone compound (I) at least includes:

[0015] In the aforementioned DBDMH-promoted synthesis method of benzofuran compounds, the o-hydroxybenzaldehyde compound (II) is one of o-hydroxybenzaldehyde, 2-hydroxy-5-methylbenzaldehyde, 2-hydroxy-5-methoxybenzaldehyde, 2-hydroxy-5-fluorobenzaldehyde, 2-hydroxy-5-chlorobenzaldehyde, 2-hydroxy-5-bromobenzaldehyde, 2-hydroxy-4-methylbenzaldehyde, and 2-hydroxy-4-bromobenzaldehyde.

[0016] In the aforementioned DBDMH-promoted synthesis method of benzofuran compounds, the molar ratio of the enaminone compound (I), DBDMH, o-hydroxybenzaldehyde compound (II), base, and ammonium chloride is 1.2:0.6:1:4:1.2.

[0017] The DBDMH-promoted synthesis method of benzofuran compounds has a yield of 50-84% for the benzofuran compound (IV).

[0018] Compared with the prior art, the present invention has the following advantages:

[0019] The present invention uses enaminone compounds and o-hydroxybenzaldehyde compounds as raw materials, DBDMH (1,3-dibromo-5,5-dimethylhydantoin) as a promoter, and DMF as a reaction solvent. Under alkaline conditions and room temperature conditions, the o-hydroxybenzaldehyde compounds and the enaminone compounds are instantaneously halogenated and coupled to produce an imine intermediate, which is then synthesized into a benzofuran compound through a cascade reaction in the presence of an ammonium chloride solution. The present invention provides a new method for synthesizing benzofuran compounds. The benzofuran compound is efficiently prepared through the intermolecular reaction of the enaminone compounds and the o-hydroxybenzaldehyde compound. The method has the advantages of a wide substrate range, strong functional group compatibility, simple and safe operation, short reaction time, and inexpensive and readily available raw materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is the hydrogen spectrum of compound III-a;

[0021] Figure 2 is the carbon spectrum of compound III-a;

[0022] Figure 3 is the hydrogen spectrum of compound IV-a;

[0023] Figure 4 is the carbon spectrum of compound IV-a;

[0024] Figure 5 is the hydrogen spectrum of compound IV-b;

[0025] Figure 6 is the carbon spectrum of compound IV-b;

[0026] Figure 7 is the hydrogen spectrum of compound IV-c;

[0027] Figure 8 is the carbon spectrum of compound IV-c;

[0028] Figure 9 is the hydrogen spectrum of compound IV-d;

[0029] Figure 10 is the carbon spectrum of compound IV-d;

[0030] Figure 11 is the hydrogen spectrum of compound IV-e;

[0031] Figure 12 is the carbon spectrum of compound IV-e;

[0032] Figure 13 is the hydrogen spectrum of compound IV-f;

[0033] Figure 14 is the carbon spectrum of compound IV-f;

[0034] Figure 15 is the hydrogen spectrum of compound IV-g;

[0035] Figure 16 is the carbon spectrum of compound IV-g;

[0036] Figure 17 is the hydrogen spectrum of compound IV-h;

[0037] Figure 18 is the carbon spectrum of compound IV-h;

[0038] Figure 19 is the hydrogen spectrum of compound IV-i;

[0039] Figure 20 is the carbon spectrum of compound IV-i;

[0040] Figure 21 is the hydrogen spectrum of compound IV-j;

[0041] Figure 22 is the carbon spectrum of compound IV-j;

[0042] Figure 23 is the hydrogen spectrum of compound IV-k;

[0043] Figure 24 is the carbon spectrum of compound IV-k;

[0044] Figure 25 is the hydrogen spectrum of compound IV-1;

[0045] Figure 26This is the carbon spectrum of compound IV-1. DETAILED DESCRIPTION

[0046] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with specific embodiments, but the following embodiments should not be regarded as limiting the present invention.

[0047] The present invention provides a method for synthesizing benzofuran compounds by using DBDMH to promote the reaction of enaminones and o-hydroxybenzaldehyde compounds. The method comprises the following steps: using an enaminone compound (I) and an o-hydroxybenzaldehyde compound (II) as raw materials, DBDMH (1,3-dibromo-5,5-dimethylhydantoin) as a promoter, and DMF as a reaction solvent; under alkaline conditions and room temperature, the o-hydroxybenzaldehyde compound (II) and the enaminone compound (I) undergo instantaneous halogenation coupling to produce an imine intermediate (III), which is then synthesized into a benzofuran compound (IV) through a cascade reaction in the presence of an ammonium chloride solution; the reaction formula is:

[0048]

[0049] Among them, R 1 represents phenyl or 3-methoxyphenyl or 4-bromophenyl or 4-chlorophenyl or furyl;

[0050] R 2 represents phenyl or 4-chlorophenyl or 4-methylphenyl;

[0051] R 3 represents H or 5-methyl or 5-methoxy or 5-F or 5-Cl or 5-Br or 4-methyl or 4-Br.

[0052] Preferably, the molar ratio of the enaminone compound (I), DBDMH, o-hydroxybenzaldehyde compound (II), base, and ammonium chloride is 1.2:0.6:1:4:1.2.

[0053] The following is a detailed description using specific examples. The enaminone compound (I) used in the following examples was prepared according to the literature method ([1] Zhang, Y.; Zhao, X.; Zhuang, C.; Wang, S.; Zhang-Negrerie, D.; Du, Y. Adv. Synth. Catal., 2018, 360, 2107-2112. [2] Zhao, X.; Zhang, Y.; Deng, J.; Zhang-Negrerie, D.; Du, Y. J. Org. Chem. 2017, 82, 12682-12690. [3] Yu, X.; Wang, L.; Feng, X.; Bao, M.; Yamamoto, Y. Chem. Commun., 2013, 49, 2885-2887.). The o-hydroxybenzaldehyde compound (II), solvent DMF, base and ammonium chloride used were all purchased commercially.

[0054] Example 1

[0055] Preparation of imine intermediate 2-((1-imino-3-oxo-3-phenyl-1-(p-methylphenyl)propan-2-yl)oxy)benzaldehyde (III-a):

[0056]

[0057] DBDMH (1,3-dibromo-5,5-dimethylhydantoin, 171.6 mg, 0.6 mmol) and enaminone compound Ia (284.5 mg, 1.2 mmol) were mixed in DMF (2 mL of N,N'-dimethylformamide) and stirred at room temperature for 5 minutes. Then, o-hydroxybenzaldehyde compound II-a (122.1 mg, 1.0 mmol) and KCO (552.8 mg, 4.0 mmol) were added. The resulting mixture was stirred at room temperature under air for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was washed three times with saturated NaCl solution. The washed aqueous phases were combined and extracted three times with ethyl acetate, using 15 mL of saturated NaCl solution and ethyl acetate each time. The combined organic phases from the three extractions were dried over anhydrous NaSO, and the solvent was removed by distillation under reduced pressure. Finally, the mixture was purified by silica gel flash column chromatography to obtain imine intermediate III-a. The yield and yield are: 299 mg, 84%. Melting point: 139–140℃. 1H NMR (400MHz, CDCl3): δ=10.37(s,1H),7.77–7.75(m,2H),7.54–7.52(m,1H),7.45(d,J =8.1Hz,2H),7.31–7.22(m,5H),7.12(d,J=8.0Hz,2H),6.85–6.76(m,2H),2.29(s,3H). 13 CNMR (100MHz, CDCl3): δ=191.0,189.1,161.6,157.4,140.7,138.9,135.5, 131.4,130.7,129.3,127.9,125.1,124.2,121.1,21.4.HRMS(ESI):m / z[M+H + ]calcdfor C 23 H 20 NO3:358.1438; found:358.1432.

[0058] Example 2

[0059] Preparation of product benzofuran-2-yl (phenyl) ketone (IV-a):

[0060]

[0061] DBDMH (1,3-dibromo-5,5-dimethylhydantoin, 171.6 mg, 0.6 mmol) and enaminone compound Ib (267.7 mg, 1.2 mmol) were mixed in DMF (N,N'-dimethylformamide, 2 mL) and stirred at room temperature for 5 minutes. Then, o-hydroxybenzaldehyde compound II-a (122.1 mg, 1.0 mmol) and K2CO3 (552.8 mg, 4.0 mmol) were added. The reaction mixture was stirred at room temperature and in air for 2 hours. Ammonium chloride (64.2 mg, 1.2 mmol) and water (2 mL) were added. The temperature of the reaction system was raised to 100°C and stirred in air for 2 hours. After the reaction was complete as monitored by TLC, the reaction mixture was washed three times with saturated NaCl solution. The aqueous phases were then combined and extracted three times with ethyl acetate, using 15 mL of saturated NaCl solution and ethyl acetate each time. The combined organic phases from the three extractions were dried over anhydrous Na2SO4, the solvent was removed by distillation under reduced pressure, and the product IV-a was purified by silica gel flash column chromatography. The yield was 166 mg, 75%, and the melting point was 90–92°C. 1H NMR (400MHz, CDCl3): δ=8.06–8.00(m,2H),7.71(d,J=7.8Hz,1H),7.64–7.59(m,2H),7.54–7.44(m,4H),7.33–7.29(m,1H). 13 C NMR (100MHz, CDCl3): δ = 184.3, 155.9, 152.0, 137.1, 132.8, 129.3, 128.4, 128.3, 126.9, 123.9, 123.2, 116.5, 112.4.

[0062] Example 3

[0063] Preparation of product benzofuran-2-yl (3-methoxyphenyl) ketone (IV-b):

[0064]

[0065] DBDMH (1,3-dibromo-5,5-dimethylhydantoin, 171.6 mg, 0.6 mmol) and enaminone compound Ic (303.7 mg, 1.2 mmol) were mixed in DMF (N,N'-dimethylformamide, 2 mL) and stirred at room temperature for 5 minutes. Then, o-hydroxybenzaldehyde compound II-a (122.1 mg, 1.0 mmol) and K2CO3 (552.8 mg, 4.0 mmol) were added. The reaction mixture was stirred at room temperature and in air for 2 hours. Ammonium chloride (64.2 mg, 1.2 mmol) and water (2 mL) were added. The temperature of the reaction system was raised to 100°C and stirred in air for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was washed three times with saturated NaCl solution. The washed aqueous phases were then combined and extracted three times with ethyl acetate, using 15 mL of saturated NaCl solution and ethyl acetate each time. The combined organic phases from the three extractions were dried over anhydrous Na2SO4, the solvent was distilled off under reduced pressure, and finally purified by silica gel flash column chromatography to obtain product IV-b. The yield and yield were 126 mg, 50%, respectively. 1 H NMR (400MHz, CDCl3): δ = 7.72 (d, J = 7.9Hz, 1H), 7.64 (d, J = 8.5Hz, 2H), 7.55–7.52 (m, 2H), 7. 52–7.46(m,1H),7.43(t,J=7.9Hz,1H),7.35–7.30(m,1H),7.19–7.16(m,1H),3.88(s,3H). 13C NMR (100MHz, CDCl3): δ=184.1,159.6,155.9,152.1,138.4,129.5,128.3,126. 9,123.9,123.3,122.0,119.2,116.6,113.9,112.5,55.4.HRMS(ESI):m / z[M+H + ]calcd for C 16 H 13 O3:253.0859;found:253.0857.

[0066] Example 4

[0067] Preparation of product benzofuran-2-yl (4-bromophenyl) ketone (IV-c):

[0068]

[0069] DBDMH (1,3-dibromo-5,5-dimethylhydantoin, 171.6 mg, 0.6 mmol) and enaminone compound Id (361.2 mg, 1.2 mmol) were mixed in DMF (N,N'-dimethylformamide, 2 mL) and stirred at room temperature for 5 minutes. Then, o-hydroxybenzaldehyde compound II-a (122.1 mg, 1.0 mmol) and K2CO3 (552.8 mg, 4.0 mmol) were added. The reaction mixture was stirred at room temperature and in air for 2 hours. Ammonium chloride (64.2 mg, 1.2 mmol) and water (2 mL) were added. The temperature of the reaction system was raised to 100°C and stirred in air for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was washed three times with saturated NaCl solution. The washed aqueous phases were then combined and extracted three times with ethyl acetate, using 15 mL of saturated NaCl solution and ethyl acetate each time. The combined organic phases from the three extractions were dried over anhydrous NaSO, the solvent was removed by distillation under reduced pressure, and the product IV-c was purified by silica gel flash column chromatography. The yield was 183 mg, 62%, respectively. Melting point: 142–143°C. 1 HNMR (400MHz, CDCl3): δ = 7.94 (d, J = 8.6Hz, 2H), 7.73 (d, J = 7.8Hz, 1H), 7.70–7.66 (m, 2H),7.64–7.62(m,1H),7.54(d,J=0.8Hz,1H),7.54–7.50(m,1H),7.36–7.32(m,1H). 13C NMR (100MHz, CDCl3): δ=183.1,156.0,152.0,135.8,131.8,131.0,128.5,128.1,126.9,124.1,123.3,116.5,112.5.

[0070] Example 5

[0071] Preparation of product benzofuran-2-yl (4-chlorophenyl) ketone (IV-d):

[0072]

[0073] DBDMH (1,3-dibromo-5,5-dimethylhydantoin, 171.6 mg, 0.6 mmol) and enaminone compound Ie (350.4 mg, 1.2 mmol) were mixed in DMF (N,N'-dimethylformamide, 2 mL) and stirred at room temperature for 5 minutes. Then, o-hydroxybenzaldehyde compound II-a (122.1 mg, 1.0 mmol) and K2CO3 (552.8 mg, 4.0 mmol) were added. The reaction mixture was stirred at room temperature and in air for 2 hours. Ammonium chloride (64.2 mg, 1.2 mmol) and water (2 mL) were added. The temperature of the reaction system was raised to 100°C and stirred in air for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was washed three times with saturated NaCl solution. The washed aqueous phases were then combined and extracted three times with ethyl acetate, using 15 mL of saturated NaCl solution and ethyl acetate each time. The combined organic phases from the three extractions were dried over anhydrous NaSO, the solvent was removed by distillation under reduced pressure, and the product IV-d was purified by silica gel flash column chromatography. The yield was 179 mg, 70%, respectively. Melting point: 148–149°C. 1 HNMR (400MHz, CDCl3): δ = 8.01 (d, J = 8.5Hz, 2H), 7.72 (d, J = 7.9Hz, 1H), 7.62 (d, J = 8.4Hz, 1H), 7.53 (s, 1H), 7.51–7.47 (m, 3H), 7.32 (t, J = 7.5Hz, 1H). 13 CNMR (100MHz, CDCl3): δ=182.8,155.9,152.0,139.3,135.3,130.8,128.8,128.5,126.8,124.0,123.3,116.4,112.4.

[0074] Example 6

[0075] Preparation of product benzofuran-2-yl (furan-2-yl)methanone (IV-e):

[0076]

[0077] DBDMH (1,3-dibromo-5,5-dimethylhydantoin, 171.6 mg, 0.6 mmol) and enaminone compound If (255.7 mg, 1.2 mmol) were mixed in DMF (N,N'-dimethylformamide, 2 mL) and stirred at room temperature for 5 minutes. Then, o-hydroxybenzaldehyde compound II-a (122.1 mg, 1.0 mmol) and K2CO3 (552.8 mg, 4.0 mmol) were added. The reaction mixture was stirred at room temperature and in air for 2 hours. Ammonium chloride (64.2 mg, 1.2 mmol) and water (2 mL) were added. The temperature of the reaction system was raised to 100°C and stirred in air for 2 hours. After the reaction was complete as monitored by TLC, the reaction mixture was washed three times with saturated NaCl solution. The washed aqueous phases were then combined and extracted three times with ethyl acetate, using 15 mL of saturated NaCl solution and ethyl acetate each time. The combined organic phases from the three extractions were dried over anhydrous NaSO, the solvent was removed by distillation under reduced pressure, and the product IV-e was purified by silica gel flash column chromatography. The yield was 106 mg, 50%, respectively. Melting point: 95–96°C. 1 HNMR (400MHz, CDCl3): δ = 7.84 (d, J = 0.8Hz, 1H), 7.74–7.68 (m, 2H), 7.65 (d, J = 3.6H z,1H),7.61–7.57(m,1H),7.49–7.41(m,1H),7.31–7.26(m,1H),6.62–6.61(m,1H). 13 C NMR (100MHz, CDCl3): δ=169.9,155.5,151.4,151.3,147.1,128.2,126.9,123.8,123.2,120.2,115.3,112.5,112.2.

[0078] Example 7

[0079] Preparation of product (5-methylbenzofuran-2-yl)(phenyl)methanone (IV-f):

[0080]

[0081] DBDMH (1,3-dibromo-5,5-dimethylhydantoin, 171.6 mg, 0.6 mmol) and enaminone compound Ib (267.7 mg, 1.2 mmol) were mixed in DMF (N,N'-dimethylformamide, 2 mL) and stirred at room temperature for 5 minutes. Then, o-hydroxybenzaldehyde compound II-b (136.2 mg, 1.0 mmol) and K2CO3 (552.8 mg, 4.0 mmol) were added. The reaction mixture was stirred at room temperature and in air for 2 hours. Ammonium chloride (64.2 mg, 1.2 mmol) and water (2 mL) were added. The temperature of the reaction system was raised to 100°C and stirred in air for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was washed three times with saturated NaCl solution. The washed aqueous phases were then combined and extracted three times with ethyl acetate, using 15 mL of saturated NaCl solution and ethyl acetate each time. The combined organic phases from the three extractions were dried over anhydrous NaSO, the solvent was removed by distillation under reduced pressure, and the product IV-f was purified by silica gel flash column chromatography. The yield was 198 mg, 84%, respectively. Melting point: 87–89°C. 1 H NMR (400MHz, CDCl3): δ=8.04–7.99(m,2H),7.64–7.57(m,1H),7.52–7.48(m,4H),7.42(s,1H),7.29–7.26(m,1H),2.43(s,3H). 13 C NMR (100MHz, CDCl3): δ=184.2,154.4,152.2,137.1,133.4,132.7,129.9,129.3,128.4,126.9,122.6,116.3,111.9,21.1.

[0082] Example 8

[0083] Preparation of product (5-methoxybenzofuran-2-yl)(phenyl)methanone (IV-g):

[0084]

[0085] DBDMH (1,3-dibromo-5,5-dimethylhydantoin, 171.6 mg, 0.6 mmol) and enaminone compound Ib (267.7 mg, 1.2 mmol) were mixed in DMF (N,N'-dimethylformamide, 2 mL) and stirred at room temperature for 5 minutes. Then, o-hydroxybenzaldehyde compound II-c (152.2 mg, 1.0 mmol) and K2CO3 (552.8 mg, 4.0 mmol) were added. The reaction mixture was stirred at room temperature and in air for 2 hours. Ammonium chloride (64.2 mg, 1.2 mmol) and water (2 mL) were added. The temperature of the reaction system was raised to 100°C and stirred in air for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was washed three times with saturated NaCl solution. The washed aqueous phases were then combined and extracted three times with ethyl acetate, using 15 mL of saturated NaCl solution and ethyl acetate each time. The combined organic phases from the three extractions were dried over anhydrous NaSO, the solvent was removed by distillation under reduced pressure, and the product IV-g was purified by silica gel flash column chromatography. The yield was 164 mg and 65%, respectively. Melting point: 86–88°C. 1 H NMR (400MHz, CDCl3): δ=8.04–8.01(m,2H),7.64–7.58(m,1H),7.55–7.48(m,3H),7.46(s,1H),7.12–7.09(m,2H),3.84(s,3H). 13 C NMR (100MHz, CDCl3): δ=184.2,156.6,152.9,151.1,137.2,132.8,129.4,128.4,127.4,118.5,116.5,113.1,103.9,55.8.

[0086] Example 9

[0087] Preparation of product (5-fluorobenzofuran-2-yl)(phenyl)methanone (IV-h):

[0088]

[0089] DBDMH (1,3-dibromo-5,5-dimethylhydantoin, 171.6 mg, 0.6 mmol) and enaminone compound Ib (267.7 mg, 1.2 mmol) were mixed in DMF (N,N'-dimethylformamide, 2 mL) and stirred at room temperature for 5 minutes. Then, o-hydroxybenzaldehyde compound II-d (140.1 mg, 1.0 mmol) and K2CO3 (552.8 mg, 4.0 mmol) were added. The reaction mixture was stirred at room temperature and in air for 2 hours. Ammonium chloride (64.2 mg, 1.2 mmol) and water (2 mL) were added. The temperature of the reaction system was raised to 100°C and stirred in air for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was washed three times with saturated NaCl solution. The washed aqueous phases were then combined and extracted three times with ethyl acetate, using 15 mL of saturated NaCl solution and ethyl acetate each time. The combined organic phases from the three extractions were dried over anhydrous Na2SO4, the solvent was removed by distillation under reduced pressure, and the product IV-h was purified by silica gel flash column chromatography. The yield was 120 mg, 50%, respectively. Melting point: 135–136°C. 1 HNMR (400MHz, CDCl3): δ=8.05–7.98(m,2H),7.64–7.59(m,1H),7.57–7.48(m,3H),7.46(d,J=0.8Hz,1H),7.35–7.32(m,1H),7.22–7.17(m,1H). 13 CNMR (100MHz, CDCl3): δ = 183.9, 159.4 (d, J = 240Hz), 153.6, 152.1, 136.8, 133.0, 129.3, 1 28.5, 127.6, 127.5, 116.7, 116.4, 116.0 (d, J = 4Hz), 113.4 (d, J = 9Hz), 108.2 (d, J = 25Hz).

[0090] Example 10

[0091] Preparation of product (5-chlorobenzofuran-2-yl)(phenyl)methanone (IV-i):

[0092]

[0093] DBDMH (1,3-dibromo-5,5-dimethylhydantoin, 171.6 mg, 0.6 mmol) and enaminone compound Ib (267.7 mg, 1.2 mmol) were mixed in DMF (N,N'-dimethylformamide, 2 mL) and stirred at room temperature for 5 minutes. Then, o-hydroxybenzaldehyde compound II-e (156.6 mg, 1.0 mmol) and K2CO3 (552.8 mg, 4.0 mmol) were added. The reaction mixture was stirred at room temperature and in air for 2 hours. Ammonium chloride (64.2 mg, 1.2 mmol) and water (2 mL) were added. The temperature of the reaction system was raised to 100°C and stirred in air for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was washed three times with saturated NaCl solution. The washed aqueous phases were then combined and extracted three times with ethyl acetate, using 15 mL of saturated NaCl solution and ethyl acetate each time. The combined organic phases from the three extractions were dried over anhydrous Na2SO4, the solvent was removed by distillation under reduced pressure, and the product IV-i was purified by silica gel flash column chromatography. The yield was 136 mg, 53%, respectively. Melting point: 137–139°C. 1 HNMR (400MHz, CDCl3): δ=8.03–8.01(m,2H),7.68(d,J=2.0Hz,1H),7.67–7.61(m,1H),7.58–7.51(m,3H),7.46–7.41(m,2H). 13 C NMR (100MHz, CDCl3): δ=184.0,154.1,153.1,136.7,133.1,129.5,129.4,128.6,128.5,128.1,122.5,115.4,113.5.

[0094] Example 11

[0095] Preparation of product (5-bromobenzofuran-2-yl)(phenyl)methanone (IV-j):

[0096]

[0097] DBDMH (1,3-dibromo-5,5-dimethylhydantoin, 171.6 mg, 0.6 mmol) and enaminone compound Ib (267.7 mg, 1.2 mmol) were mixed in DMF (N,N'-dimethylformamide, 2 mL) and stirred at room temperature for 5 minutes. Then, o-hydroxybenzaldehyde compound II-f (201.0 mg, 1.0 mmol) and K2CO3 (552.8 mg, 4.0 mmol) were added. The reaction mixture was stirred at room temperature and in air for 2 hours. Ammonium chloride (64.2 mg, 1.2 mmol) and water (2 mL) were added. The temperature of the reaction system was raised to 100°C and stirred in air for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was washed three times with saturated NaCl solution. The washed aqueous phases were then combined and extracted three times with ethyl acetate, using 15 mL of saturated NaCl solution and ethyl acetate each time. The combined organic phases from the three extractions were dried over anhydrous Na2SO4, the solvent was removed by distillation under reduced pressure, and the product IV-j was purified by silica gel flash column chromatography. The yield was 183 mg and 61%, respectively. Melting point: 106–107°C. 1 HNMR (400MHz, CDCl3): δ=8.06–8.00(m,2H),7.86(d,J=1.7Hz,1H),7.68–7.63(m,1H),7.60–7.50(m,4H),7.46(d,J=0.7Hz,1H). 13 C NMR (100MHz, CDCl3): δ=184.1,154.5,153.1,136.8,133.2,131.3,129.4,128.8,128.6,125.7,117.0,115.3,114.1.

[0098] Example 12

[0099] Preparation of product (6-methylbenzofuran-2-yl)(phenyl)methanone (IV-k):

[0100]

[0101] DBDMH (1,3-dibromo-5,5-dimethylhydantoin, 171.6 mg, 0.6 mmol) and enaminone compound Ib (267.7 mg, 1.2 mmol) were mixed in DMF (N,N'-dimethylformamide, 2 mL) and stirred at room temperature for 5 minutes. Then, o-hydroxybenzaldehyde compound II-g (136.2 mg, 1.0 mmol) and K2CO3 (552.8 mg, 4.0 mmol) were added. The reaction mixture was stirred at room temperature and in air for 2 hours. Ammonium chloride (64.2 mg, 1.2 mmol) and water (2 mL) were added. The temperature of the reaction system was raised to 100°C and stirred in air for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was washed three times with saturated NaCl solution. The washed aqueous phases were then combined and extracted three times with ethyl acetate, using 15 mL of saturated NaCl solution and ethyl acetate each time. The combined organic phases from the three extractions were dried over anhydrous Na2SO4, the solvent was removed by distillation under reduced pressure, and finally purified by silica gel flash column chromatography to obtain product IV-k. The yield and yield were 142 mg and 60%, respectively. 1 H NMR (400MHz, CDCl3): δ=8.05–7.96(m,2H),7.64–7.55(m,2H),7.51(t,J=7.5Hz,2H),7.47–7.40(m,2H),7.16–7.10(m,1H),2.49(s,3H). 13 C NMR (100MHz, CDCl3): δ = 184.2, 156.4, 151.6, 139.3, 137.2, 132.6, 129.2, 128.4, 125.7, 124.4, 122.7, 116.9, 112.3, 22.0. HRMS (ESI): m / z [M+H + ]calcd for C 16 H 13 O2:237.0910;found:237.0911.

[0102] Example 13

[0103] Preparation of product (6-bromobenzofuran-2-yl)(phenyl)methanone (IV-1):

[0104]

[0105] DBDMH (1,3-dibromo-5,5-dimethylhydantoin, 171.6 mg, 0.6 mmol) and enaminone compound Ib (267.7 mg, 1.2 mmol) were mixed in DMF (N,N'-dimethylformamide, 2 mL) and stirred at room temperature for 5 minutes. Then, o-hydroxybenzaldehyde compound II-h (201.0 mg, 1.0 mmol) and K2CO3 (552.8 mg, 4.0 mmol) were added. The reaction mixture was stirred at room temperature and in air for 2 hours. Ammonium chloride (64.2 mg, 1.2 mmol) and water (2 mL) were added. The temperature of the reaction system was raised to 100°C and stirred in air for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was washed three times with saturated NaCl solution. The washed aqueous phases were then combined and extracted three times with ethyl acetate, using 15 mL of saturated NaCl solution and ethyl acetate each time. The combined organic phases from the three extractions were dried over anhydrous Na2SO4, the solvent was removed by distillation under reduced pressure, and the product IV-1 was purified by silica gel flash column chromatography. The yield was 219 mg, 73%, and the melting point was 110–112°C. 1 H NMR (400MHz, CDCl3): δ=8.04–7.98(m,2H),7.79(s,1H),7.66–7.60(m,1H),7.59–7.49(m,3H),7.48–7.41(m,2H). 13 C NMR (100MHz, CDCl3): δ = 183.9, 156.0, 152.6, 136.8, 133.0, 129.3, 128.5, 127.6, 125.9, 124.1, 121.9, 115.9, 115.8. HRMS (ESI): m / z [M+H + ]calcd for C 15 H 10 BrO2:300.9859; found:300.9858.

[0106] It should be noted that the potassium carbonate in the above embodiments can also be replaced by sodium hydride, sodium hydroxide, potassium tert-butoxide, cesium carbonate or triethylamine. The preparation method is the same and will not be repeated here.

[0107] The above description is merely an embodiment of the present invention and does not constitute any form of limitation to the present invention. The present invention may also have other forms of embodiments based on the above description, which are not listed here one by one. Therefore, any simple modification, equivalent variation, and modification made by any person skilled in the art to the above embodiment in accordance with the technical essence of the present invention without departing from the scope of the technical solution of the present invention shall still fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing benzofuran compounds promoted by DBDMH, characterized in that Using enaminone compounds (I) and o-hydroxybenzaldehyde compounds (II) as raw materials, DBDMH as a promoter, DMF as a reaction solvent, and potassium carbonate, o-hydroxybenzaldehyde compounds (II) and enaminone compounds (I) undergo instantaneous halogenation coupling at room temperature to produce imine intermediates (III), which are then synthesized into benzofuran compounds (IV) through a cascade reaction under the action of ammonium chloride solution; the reaction formula is: Among them, R 1 represents phenyl or 3-methoxyphenyl or 4-bromophenyl or 4-chlorophenyl or furyl; R 2 represents phenyl or 4-chlorophenyl or 4-methylphenyl; R 3 represents H or 5-methyl or 5-methoxy or 5-F or 5-Cl or 5-Br or 4-methyl or 4-Br.

2. the synthetic method of the benzofuran compound that DBDMH as claimed in claim 1 promotes, it is characterized in that The specific steps include: mixing DBDMH and an enaminone compound (I) in a solvent DMF, stirring at room temperature for 5 minutes, adding an o-hydroxybenzaldehyde compound (II) and potassium carbonate thereto, stirring the reaction mixture at room temperature under an air atmosphere for 2 hours, adding ammonium chloride and water, raising the temperature of the reaction system to 100° C. and stirring for 2 hours under an air atmosphere; after the reaction is complete, adding a saturated NaCl solution to the reaction mixture and washing it three times, combining the aqueous phases after the three washes and extracting it three times with ethyl acetate, drying the combined organic phases of the three extractions over anhydrous Na2SO4, removing the solvent by distillation under reduced pressure, and finally purifying it by silica gel flash column chromatography to obtain a benzofuran compound (IV).

3. the synthetic method of the benzofuran compound that DBDMH as claimed in claim 1 or 2 promotes, it is characterized in that The structural formula of the enaminone compound (I) is selected from:

4. the synthetic method of the benzofuran compound that DBDMH as claimed in claim 1 or 2 promotes, it is characterized in that The o-hydroxybenzaldehyde compound (II) is one of o-hydroxybenzaldehyde, 2-hydroxy-5-methylbenzaldehyde, 2-hydroxy-5-methoxybenzaldehyde, 2-hydroxy-5-fluorobenzaldehyde, 2-hydroxy-5-chlorobenzaldehyde, 2-hydroxy-5-bromobenzaldehyde, 2-hydroxy-4-methylbenzaldehyde and 2-hydroxy-4-bromobenzaldehyde.

5. the synthetic method of the benzofuran compound that DBDMH as claimed in claim 1 or 2 promotes, it is characterized in that The molar ratio of the enaminone compound (I), DBDMH, o-hydroxybenzaldehyde compound (II), base and ammonium chloride is 1.2:0.6:1:4:1.

2.

6. the synthetic method of the benzofuran compound that DBDMH promotes as claimed in claim 1 or 2, is characterized in that The yield of benzofuran compound (IV) is 50-84%.

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