5-hydroxybenzofuran derivative and preparation method thereof

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a 5-hydroxybenzofuran derivative and a preparation method thereof. The structural formula of the 5-hydroxybenzofuran derivative is as shown in formula (I), and R1, R2 and R3 are respectively C1-C20 alkyl, ester group, carbonyl, nitro and the like, and C5-C30 aryl or heteroaromatic ring group. Based on indirect oxidation and coupling cyclization strategies, a beta-dicarbonyl compound and hydroquinone which are simple and easy to obtain are used as substrate raw materials, and various 5-hydroxybenzofuran derivatives with different substituent groups are constructed in combination with an oxidizing agent and a catalyst. The 5-hydroxybenzofuran derivative disclosed by the invention is expected to obtain an excellent application prospect in later modification and development of new drugs and novel materials. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a 5-hydroxybenzofuran derivative and a preparation method thereof. Background Art

[0002] The key to effectively constructing target molecules is to install, utilize, transform, and remove functional groups to achieve the desired complexity. A powerful strategy to increase the complexity of molecules is to use a reagent that can transfer the target functional group. This strategy relies on reagents that are sufficiently active to enhance the ability of the functional group to be transferred while ensuring its chemical selectivity. For the construction of target molecules containing multiple active reaction sites, given their own good chemical activity, controlling the chemical activity and chemical selectivity of their reactions, including preventing over-functionalization reactions, is also an issue that needs to be considered when designing efficient organic chemical transformations.

[0003] Benzofuran, especially 5-hydroxybenzofuran derivatives, have a wide range of biological activities and are widely present in natural products as key structural fragments. Benzofuran derivatives are also often used as important templates and structural scaffolds for constructing target drug molecules. Therefore, chemists have developed many methods for synthesizing benzofuran derivatives. The classic synthetic strategies are: 1) Transition metal catalyzed CH bond activation and functionalization; 2) Cross-dehydrogenative coupling reaction (CDC) to form CC bonds by copper- or iron-catalyzed oxidative coupling in the presence of an oxidant; Other examples include the (3+2) cycloaddition of quinones with electron-rich olefins to prepare 2-hydrobenzofurans. Despite these reported synthetic methods for 5-hydroxybenzofuran derivatives, it is highly anticipated to develop user-friendly, universal synthetic methods for 5-hydroxybenzofuran derivatives using simple and readily available raw materials under mild conditions. Summary of the invention

[0004] The object of the present invention is to provide an economical, efficient and practical method for preparing 5-hydroxybenzofuran derivatives, so as to overcome the shortcomings of the prior art. Different from the methods for synthesizing 5-hydroxybenzofuran derivatives reported in the past, the present invention has the characteristics of wide substrate adaptability and high reaction yield. The present invention adopts a method for directly preparing 5-hydroxybenzofuran using simple and easily available hydroquinone as a substrate. Compared with directly using benzoquinone as a substrate, the hydroquinone compound is cheap and easy to obtain, and its properties are more stable than benzoquinone. By adopting the method for preparing 5-hydroxybenzofuran derivatives provided by the present invention, using substituted hydroquinone as a substrate, a multi-substituted 5-hydroxybenzofuran derivative can be obtained by a one-pot reaction.

[0005] In order to achieve the above object, the present invention provides a method for synthesizing 5-hydroxybenzofuran derivatives using hydroquinone as a substrate, and the synthesis route thereof is as follows:

[0006] Among them, R 1 , R 2 and R 3 They are respectively C1~C20 hydrocarbon group, ester group, carbonyl group, nitro group, etc., and C5~C30 aromatic group or aromatic heterocyclic group.

[0007] The method provided by the present invention comprises the following steps: 1) Compound (II), compound (III), an oxidant, a catalyst and a solvent are mixed, reacted at a certain temperature for a certain time, and then post-treated to obtain compound (I).

[0008] The solvent oxidant in the step is at least one of dichlorodicyanobenzoquinone (DDQ), trifluoroacetyl iodobenzene (PIFA), iodophenyl diacetic acid (PIDA), ceric ammonium nitrate (CAN), iodine / hydrogen peroxide, 2-iodoacylbenzoic acid (IBX), and air, preferably iodophenyl diacetic acid (PIDA).

[0009] In the step 1), the molar ratio of compound II to the oxidant is 1:1.1 to 3, preferably 1:1.1.

[0010] The solvent catalyst in the step is at least one of zinc iodide, ferric chloride, boron trifluoride etherate, aluminum chloride, lithium chloride, titanium chloride and zinc chloride, preferably zinc iodide.

[0011] In step 1), the molar ratio of compound II to catalyst is 1:0.1 to 0.5, preferably 1:0.1.

[0012] In the step 1), the solvent is one or more of dichloroethane (DCE), chlorobenzene, toluene, chloroform, N,N'-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile and ethanol, preferably chlorobenzene.

[0013] In the step 1), the concentration of compound II in the organic solvent is 0.1 mol / L to 1 mol / L, preferably 0.1 mol / L.

[0014] Due to the adoption of the above technical scheme, the present invention has the following advantages and beneficial effects: the preparation method of a 5-hydroxybenzofuran derivative provided by the present invention uses substituted hydroquinone and β-dicarbonyl compounds as raw materials, has the advantages of a wide source of raw materials, low price and easy availability, simple and easy operation, high yield, wide substrate adaptability, etc. DETAILED DESCRIPTION

[0015] In order to explain the present invention more clearly, the present invention is further described below in conjunction with preferred embodiments. It should be understood by those skilled in the art that the following specific description is illustrative rather than restrictive, and should not be used to limit the scope of protection of the present invention.

[0016] Example 1

[0017] Synthesis of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate, the structure of which is shown below:

[0018] Hydroquinone (0.5 mmol, 1.0 eq.), ethyl 3-oxobutyrate (1 mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95°C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the crude product. The above compound 1 was obtained by silica gel column chromatography (eluent: PE / EA), 96.9 mg, white solid, yield: 88%, Mp.136-137°C, 1 H NMR (400 MHz, DMSO- d 6) δ 9.37 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 2.6 Hz, 1H),6.76 (dd, J = 8.8, 2.6 Hz, 1H), 4.33 (d, J = 7.1 Hz, 2H), 2.69 (s, 3H), 1.37(t, J = 7.1 Hz, 3H).

[0019] Example 2 Synthesis of 5-hydroxy-2-n-propylbenzofuran-3-carboxylic acid ethyl ester, the structure of which is shown below:

[0020] Hydroquinone (0.5 mmol, 1.0 eq.), ethyl 3-oxohexanoate (1 mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95°C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 2, 80.7 mg, white solid, yield: 65%, Mp.105-106°C, 1 H NMR (400 MHz, DMSO- d 6) δ 9.35 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H),6.76 (dd, J = 8.8, 2.6 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.05 (t, J = 7.4Hz, 2H), 1.63-1.76 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H).

[0021] Example 3 Synthesis of ethyl 5-hydroxy-2-phenylbenzofuran-3-carboxylate, the structure of which is shown below:

[0022] Hydroquinone (0.5 mmol, 1.0 eq.), ethyl 3-oxophenylpropionate (1mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95°C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 3, 115.7 mg, white solid, yield: 82%, Mp.154-155°C, 1H NMR (400MHz, DMSO- d 6) δ 9.52 (s, 1H), 7.93 (dd, J = 6.7, 3.0 Hz, 2H), 7.53 – 7.44 (m,4H), 7.43 (d, J = 2.5 Hz, 1H), 6.89 (dd, J = 8.8, 2.6 Hz, 1H), 4.30 (q, J =7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).

[0023] Example 4 Synthesis of 5-hydroxy-2-methyl N-phenylbenzofuran-3-carboxamide, the structure of which is shown below:

[0024] Hydroquinone (0.5 mmol, 1.0 eq.), 3-oxo-N-phenylbutyric acid amide (1mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 4, 50.8 mg, brown solid, yield: 38%, Mp.210-211 °C, 1 H NMR (400MHz, DMSO- d 6) δ 10.08 (s, 1H), 9.36 (s, 1H), 7.78 (d, J = 7.5 Hz, 2H), 7.45 –7.35 (m, 3H), 7.19 – 7.04 (m, 2H), 6.79 (dd, J = 8.8, 2.5 Hz, 1H), 2.65 (s,3H).

[0025] Example 5 Synthesis of 1-(5-hydroxy-2-methylbenzofuran-3-yl)ethanone, the structure of which is shown below:

[0026] Hydroquinone (0.5 mmol, 1.0 eq.), pentane-2,4-dione (1 mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 5, 41.8 mg, yellow solid, yield: 44%, Mp.238-239 °C, 1 H NMR (400 MHz, DMSO- d 6) δ 9.33 (s, 1H), 7.40 – 7.33 (m, 2H), 6.74 (dd, J = 8.7, 2.6 Hz, 1H), 2.73 (s, 3H), 2.55 (s, 3H).

[0027] Example 6 Synthesis of (5-hydroxy-2-methylbenzofuran-3-yl)(phenyl)methanone, the structure of which is shown below:

[0028] Hydroquinone (0.5 mmol, 1.0 eq.), 1-phenylbutane-1,3-dione (1mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 6, 29.0 mg, yellow solid, yield: 23%, Mp.196-197 °C, 1 H NMR (400MHz, DMSO- d 6) δ 9.30 (s, 1H), 7.76 – 7.73 (m, 2H), 7.71 – 7.64 (m, 1H), 7.60– 7.53 (m, 2H), 7.41 (d, J = 8.8 Hz, 1H), 6.80 (d, J= 2.4 Hz, 1H), 6.75 (dd, J = 8.8, 2.5 Hz, 1H), 2.39 (s, 3H).

[0029] Example 7 Synthesis of 8-hydroxy-3,4-dihydrodibenzo[b,d]furan-1(2H)-one, the structure of which is shown below:

[0030] Hydroquinone (0.5 mmol, 1.0 eq.), cyclohexane-1,3-dione (1mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the crude product. The above compound 7, 49.5 mg, yellow solid, yield: 49%, Mp.154-156 °C, 1 H NMR (400MHz, DMSO- d 6) δ 9.42 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 2.6 Hz,1H), 6.76 (dd, J = 8.8, 2.6 Hz, 1H), 3.01 (t, J = 6.2 Hz, 2H), 2.49 (d, J =6.9 Hz, 2H), 2.16 (p, J = 6.4 Hz, 2H).

[0031] Example 8 Synthesis of ethyl 5-hydroxy-2-(4-methoxyphenyl)benzofuran-3-carboxylate, the structure of which is shown below:

[0032] Hydroquinone (0.5 mmol, 1.0 eq.), ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (1 mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 8, 148.3 mg, white solid, yield: 95%, Mp.172-173 °C, 1 H NMR (400 MHz, DMSO- d 6) δ 9.47 (s, 1H), 7.96 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.08 (d, J = 9.0 Hz, 2H), 6.86(dd, J = 8.8, 2.5 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H).

[0033] Example 9 Synthesis of ethyl 2-(3-bromophenyl)-5-hydroxybenzofuran-3-carboxylate, the structure of which is shown below:

[0034] Hydroquinone (0.5 mmol, 1.0 eq.), ethyl 3-(3-bromophenyl)-3-oxopropanoate (1 mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 9, 126.4 mg, yellow solid, yield: 70%, Mp.169-170 °C, 1 HNMR (400 MHz, DMSO- d 6) δ 9.51 (s, 1H), 8.12 (t, J = 1.8 Hz, 1H), 7.88 (d, J =8.0 Hz, 1H), 7.67 (dd, J = 8.0, 1.1 Hz, 1H), 7.48 – 7.39 (m, 2H), 7.38 (d, J = 2.5 Hz, 1H), 6.86 (dd, J = 8109, 2.6 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H),1.30 (t, J = 7.1 Hz, 3H).

[0035] Example 10 Synthesis of ethyl 2-(2-chlorophenyl)-5-hydroxybenzofuran-3-carboxylate, the structure of which is shown below:

[0036] Hydroquinone (0.5 mmol, 1.0 eq.), ethyl 3-(2-chlorophenyl)-3-oxopropanoate (1 mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the crude product. The above compound 10, 125.1 mg, white solid, yield: 79%, Mp.161-162 °C, 1 H NMR (400 MHz, DMSO- d 6) δ 9.59 (s, 1H), 7.70 (dd, J = 7.6, 1.7 Hz, 1H), 7.66(dd, J = 8.1, 1.3 Hz, 1H), 7.62 – 7.56 (m, 1H), 7.54 (d, J = 9.0 Hz, 1H),7.55 – 7.46 (m, 1H), 7.45 (d, J = 2.6 Hz, 1H), 6.93 (dd, J = 8.9, 2.6 Hz,1H), 4.20 (q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H).

[0037] Embodiment 11 Synthesis of ethyl 2-(4-trifluoromethylphenyl)-5-hydroxybenzofuran-3-carboxylate, the structure of which is shown below:

[0038] Hydroquinone (0.5 mmol, 1.0 eq.), ethyl 3-(4-trifluoromethylphenyl)-3-oxopropanoate (1 mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 11, 106.8 mg, yellow solid, yield: 61%, Mp.157-159 °C, 1 H NMR (400 MHz, DMSO- d 6) δ 9.56 (s, 1H), 8.12 (d, J = 8.1 Hz, 2H),7.83 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H),6.90 (dd, J = 8.8, 2.6 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1Hz, 3H).

[0039] Example 12 Synthesis of ethyl 2-(furan-2-yl)-5-hydroxybenzofuran-3-carboxylate, the structure of which is shown below:

[0040] Hydroquinone (0.5 mmol, 1.0 eq.), ethyl 3-(furan-2-yl)-3-oxopropanoate (1 mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 12, 77.6 mg, yellow solid, yield: 57%, Mp.155-156 °C,1 HNMR (400 MHz, DMSO- d 6) δ 9.51 (s, 1H), 7.98 (dd, J = 1.8, 0.7 Hz, 1H), 7.72(dd, J = 3.6, 0.8 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 2.5 Hz,1H), 6.85 (dd, J = 8.9, 2.6 Hz, 1H), 6.76 (dd, J = 3.6, 1.7 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H).

[0041] Embodiment 13 Synthesis of ethyl 5-hydroxy-2,6-dimethylbenzofuran-3-carboxylate, the structure of which is shown below:

[0042] 2-Methylhydroquinone (0.5 mmol, 1.0 eq.), ethyl 3-oxobutyrate (1mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 13, 35.1 mg, white solid, yield: 30%, Mp.173-174 °C, 1 H NMR (400MHz, DMSO- d 6) δ 9.34 (s, 1H), 7.31 (s, 1H), 7.27 (s, 1H), 4.32 (q, J = 7.1Hz, 2H), 2.67 (s, 3H), 2.21 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[0043] Embodiment 14 Synthesis of ethyl 5-hydroxy-2,7-dimethylbenzofuran-3-carboxylate, the structure of which is shown below:

[0044] 2-Methylhydroquinone (0.5 mmol, 1.0 eq.), ethyl 3-oxobutyrate (1mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 14, 70.3 mg, white solid, yield: 61%, Mp.175-177 °C, 1 H NMR (400MHz, DMSO- d 6) δ 9.23 (s, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 2.5 Hz,1H), 4.31 (q, J = 7.1 Hz, 2H), 2.68 (s, 3H), 2.37 (s, 3H), 1.37 (t, J = 7.1Hz, 3H)

[0045] Embodiment 15 Synthesis of 5-hydroxy-2,6,7-trimethylbenzofuran-3-carboxylic acid ethyl ester, the structure of which is shown below:

[0046] 2,3-Dimethylhydroquinone (0.5 mmol, 1.0 eq.), ethyl 3-oxobutyrate (1 mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 15, 109.3 mg, white solid, yield: 96%, Mp.142-143 °C,1 HNMR (400 MHz, DMSO- d 6) δ 9.21 (s, 1H), 7.17 (s, 1H), 4.29 (q, J = 7.1 Hz,2H), 2.64 (s, 3H), 2.28 (s, 3H), 2.12 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).

[0047] Example 16 Synthesis of ethyl 6-chloro-5-hydroxy-2-methylbenzofuran-3-carboxylate, the structure of which is shown below:

[0048] 2-Chlorohydroquinone (0.5 mmol, 1.0 eq.), ethyl 3-oxobutyrate (1mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the crude product. The above compound 16, 42.0 mg, white solid, yield: 33%, Mp.184-186 °C, 1 H NMR (400MHz, DMSO- d 6) δ 10.12 (s, 1H), 7.63 (s, 1H), 7.46 (s, 1H), 4.30 (q, J = 7.1Hz, 2H), 2.66 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).

[0049] Embodiment 17 Synthesis of ethyl 7-chloro-5-hydroxy-2-methylbenzofuran-3-carboxylate, the structure of which is shown below:

[0050] 2-Chlorohydroquinone (0.5 mmol, 1.0 eq.), ethyl 3-oxobutyrate (1mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 17, 41.5 mg, white solid, yield: 31%, Mp.109-210 °C, 1 H NMR (400MHz, DMSO- d 6) δ 9.76 (s, 1H), 7.20 (d, J = 2.3 Hz, 1H), 6.83 (d, J = 2.3 Hz,1H), 4.31 (q, J = 7.1 Hz, 2H), 2.70 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H).

[0051] Embodiment 18 Synthesis of ethyl 4-acetyl-5-hydroxy-2-methylbenzofuran-3-carboxylate, the structure of which is shown below:

[0052] 1-(2,5-dihydroxyphenyl)ethylamine-1-one (0.5 mmol, 1.0 eq.), ethyl 3-oxobutyrate (1 mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 18, 56.4 mg, yellow solid, yield: 43%, Mp.145-146 °C, 1 H NMR (400 MHz, DMSO- d 6) δ 9.87 (s, 1H), 7.46 (d, J = 8.9 Hz, 1H),6.89 (d,J = 8.9 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.61 (s, 3H), 2.53 (s,3H), 1.27 (t, J = 7.1 Hz, 3H).

[0053] Embodiment 19 Synthesis of 3-ethyl-4-methyl-5-hydroxy-2-methylbenzofuran-3,4-dicarboxylate, the structure of which is shown below:

[0054] Methyl 2,5-dihydroxybenzoate (0.5 mmol, 1.0 eq.), ethyl 3-oxobutyrate (1 mmol, 2.0 eq.), ZnI2 (0.25 mmol, 0.5 eq.), PIDA (0.55 mmol, 1.1 eq.), and PhCl 5.0 mL were added to a 10 mL reaction tube and stirred at 95 °C for 6 h. After the reaction, the reaction mixture was washed with water several times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain the above-mentioned compound 19, 114.1 mg, white solid, yield: 82%, Mp.142-143 °C, 1 H NMR (400 MHz, DMSO- d 6) δ 9.81 (s, 1H), 7.52 (d, J = 8.9 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 2.62 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0055] The above shows and describes the basic principles, main features and advantages of the present invention. The present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. The present invention may be subject to various changes and improvements without departing from the spirit and scope of the present invention. These changes and improvements fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A 5-hydroxybenzofuran derivative, characterized in that: The structural formula of the 5-hydroxybenzofuran derivative is shown in formula (I): Among them, R 1 , R 2 and R 3 They are respectively C1-C20 hydrocarbon group, ester group, carbonyl group, nitro group, etc., and C5-C30 aryl group or aromatic heterocyclic group.

2. The method for preparing a 5-hydroxybenzofuran derivative according to claim 1, characterized in that The following steps are involved: The compound represented by formula (II) and the compound represented by formula (III) are dissolved in an organic solvent and reacted under the action of a catalyst and an oxidant to obtain a 5-hydroxybenzofuran derivative; wherein R 1 , R 2 and R 3 They are respectively C1-C20 hydrocarbon groups, ester groups, carbonyl groups, nitro groups, etc., C5-C30 aryl groups or aromatic heterocyclic groups; the catalyst is zinc iodide, ferric chloride, boron trifluoride etherate, aluminum chloride, lithium chloride, titanium chloride, zinc chloride; 3. The preparation method according to claim 2, characterized in that: The reaction temperature is 75° C. to 110° C.; the reaction time is 2 h to 12 h.

4. The preparation method according to claim 2, characterized in that: The oxidant is dichlorodicyanobenzoquinone (DDQ), trifluoroacetyl iodobenzene (PIFA), iodophenyl diacetic acid (PIDA), cerium ammonium nitrate (CAN), iodine / hydrogen peroxide, 2-iodoacylbenzoic acid (IBX), and air.

5. The preparation method according to claim 2, characterized in that: The organic solvent is one or more of dichloroethane (DCE), chlorobenzene, toluene, chloroform, N,N'-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile and ethanol.

6. The preparation method according to claim 2, characterized in that : The molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:1 to 1:5; the amount of the catalyst used is 10 mol% to 50 mol% of the amount of the compound represented by formula (II); the amount of the oxidant used is 110 mol% to 300 mol% of the amount of the compound represented by formula (II); the concentration of the compound represented by formula (II) in the organic solvent is 0.1 mol / L to 1 mol / L.

7. The preparation method according to claim 6, characterized in that : The molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:3; the amount of the catalyst used is 50 mol% of the amount of the compound represented by formula (II); the amount of the oxidant used is 110 mol% of the amount of the compound represented by formula (II); the concentration of the compound represented by formula (II) in the inert solvent is 0.1 mol / L.

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