Preparation method of tetrahydrobenzofuranone oxime derivative

Abstract

The invention belongs to the field of organic matter preparation, and particularly relates to a preparation method of a tetrahydrobenzofuranone oxime derivative, which comprises the following steps: mixing a compound I, a compound II and a Lewis acidic zinc-based catalyst in a solvent, and reacting at 60-85 DEG C for 1.5-3 hours; and separating the product after complete reaction. The method provided by the invention has the advantages of simple steps, controllability, high yield and low requirements on the preparation environment, and realizes efficient synthesis of the tetrahydrobenzofuranone oxime derivative.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic matter preparation, and particularly relates to a preparation method of tetrahydrobenzofuran ketone oxime derivative. BACKGROUND

[0002] Tetrahydrobenzofuran ketone oxime derivative is a kind of compound containing tetrahydrobenzofuran skeleton and oxime group, which occupies an important position in modern chemistry and medicine. They are important structural units of many organic synthesis raw materials, natural product molecules and biological drug intermediates. This kind of compound has great potential in the modification and derivation of bioactive molecules, and can be combined or modified with other bioactive molecules, thereby changing its biological activity and chemical properties.

[0003] β-nitrostyrene is an important organic synthesis intermediate. The nitro group in its molecular structure endows it with strong electron-withdrawing properties, which makes the electron cloud of the olefin double bond polarized, and easy to undergo Michael addition reaction, substitution, cyclization and other types of reactions with nucleophilic or electrophilic reagents. In 1958, Stetter first reported the Michael / cyclization tandem reaction of β-nitroethylene, realizing the efficient synthesis of tetrahydrobenzofuran ketone oxime derivative. This method uses β-nitroalkene and 1,3-cyclohexanedione as starting materials, and under the catalysis of sodium alcohol, the reaction does not generate the general addition product by traditional Michael addition, but the cyclization product tetrahydrobenzofuran ketone oxime. The traditional synthesis method of tetrahydrobenzofuran ketone oxime derivative has complicated steps and low yield, so it is particularly important to explore an efficient and economical synthesis route. SUMMARY

[0004] In order to solve the problems of low yield of tetrahydrobenzofuran ketone oxime derivative, difficult post-treatment and difficult separation of catalyst in the prior art, the present application mainly provides a preparation method of tetrahydrobenzofuran ketone oxime derivative with high yield and easy separation of catalyst. The technical scheme is as follows:

[0005] A preparation method of tetrahydrobenzofuran ketone oxime derivative, comprising the following steps: the reaction formula is as follows:

[0006]

[0007] In the formula, R 1 is hydrogen or methyl; R 2 is hydrogen or methyl; and a Lewis acid zinc-based catalyst is used for the reaction.

[0008] Further, the compound I is one or more of 4-methyl-β-nitrostyrene, 2-methyl-β-nitrostyrene, 3-methyl-β-nitrostyrene, 4-chloro-β-nitrostyrene, 2-bromo-β-nitrostyrene or β-nitrostyrene.

[0009] Further, the compound II is one or more of 1,3-cyclohexanedione, 5-methyl-1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione.

[0010] Further, the method comprises the following steps: mixing the compound I, the compound II and the zinc-based catalyst in a solvent, and reacting at 60-85°C for 1.5-3h; and separating the product after the reaction is completed.

[0011] Further, the molar ratio of the compound I to the compound II is 1:1-1.5, and the molar ratio of the compound I to zinc in the zinc-based catalyst is 1:0.5-1.5.

[0012] Further, the solvent comprises one or more of dimethyl sulfoxide or N,N-dimethylformamide.

[0013] Further, the preparation of the zinc-based catalyst comprises the following steps: modifying a hydroxyl polymer with 4-toluenesulfonyl chloride to obtain a sulfonate polymer; reacting the sulfonate polymer with diethanolamine to obtain a complex matrix; and loading zinc chloride on the complex matrix to obtain the zinc-based catalyst.

[0014] Further, the method comprises the following steps:

[0015] a. dissolving hydroxypropyl cellulose and 4-toluenesulfonyl chloride in an aqueous solution of N,N-dimethylformamide at 0-10°C, and mixing uniformly; increasing the temperature to 20-30°C and adding N-methylmorpholine dropwise, maintaining the pH of the system at 7-8, and reacting for 4-6h; adding excess ethanol for precipitation to separate the product, washing thoroughly and drying to obtain sulfonate cellulose;

[0016] b. mixing the sulfonate cellulose with diethanolamine, stirring uniformly at 45-65°C, and reacting for 8-12h; adding excess acetone, separating the product and washing thoroughly, and drying to obtain the complex matrix;

[0017] c. preparing a methanol solution of zinc chloride; dispersing the complex matrix in methanol, adding the methanol solution of zinc chloride, refluxing for 10-16h, separating the solid product, washing thoroughly and drying to obtain the zinc-based catalyst.

[0018] Further, in the aqueous solution of N,N-dimethylformamide in step a, the volume ratio of N,N-dimethylformamide to water is 1-3:1; the mass ratio of the hydroxypropyl cellulose to 4-toluenesulfonyl chloride is 1:1.2-1.8; the mass ratio of the N-methylmorpholine to 4-toluenesulfonyl chloride is 1:1.2-1.5; and the volume of the excess ethanol is 3-6 times the volume of the liquid in the system.

[0019] Further, the mass ratio of the sulfonate cellulose to diethanolamine in step b is 1:4-6; the volume of the excess acetone is 3-6 times of the liquid in the system; and the mass ratio of the complexing matrix to zinc chloride in step c is 1:0.5-0.8.

[0020] By using the above scheme, the method has the following advantages:

[0021] 1. The preparation method can generate the cyclization product tetrahydrobenzofuran ketoxime in one step, and has simple and controllable steps, high yield, and low requirement for the preparation environment, thereby solving the problems of poor stability of sodium methoxide and easy over-reaction or decomposition of the substrate caused by excessive alkalinity of the catalyst.

[0022] 2. The preparation method has mild conditions, wide substrate application range, high product yield, and simple and efficient post-treatment, and provides a more simple and new way for efficient synthesis of tetrahydrobenzofuran ketoxime derivatives.

[0023] 3. The method uses the Lewis acidic activated electrophilic reagent in the prepared catalyst to promote nucleophilic addition and cyclization, has strong selectivity for the reaction, and has few by-products and stable yield. The hydroxypropyl cellulose ligand is combined with zinc chloride to adsorb the reaction raw materials, promote the contact between the reactants and the catalyst, and catalyze the reaction.

[0024] 4. The method first esterifies the sulfuryl chloride group with hydroxypropyl cellulose, and then substitutes with diethanolamine to prepare a complexing matrix capable of being combined with zinc chloride and fully retaining Lewis acidity, so that the zinc chloride is fixed and loaded on the cellulose carrier. Compared with the homogeneous catalyst, the catalyst is easier to separate, has less pollution to the product, has high product purity, and is more than 90%, can be reused, and the catalytic performance is not easy to decay.

[0025] 5. The catalyst has Lewis acidity, and the strength and distribution density of the acid site and the morphology of the carrier are designed, the adsorption of cellulose is used to promote the catalytic effect of Michael / cyclization series, and the selectivity of tetrahydrobenzofuran ketoxime is strong. DETAILED DESCRIPTION

[0026] The technical solutions in the embodiments of the present application will be described below. Obviously, the described embodiments are only part of the embodiments of the present application, not all. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0027] Example 1: (1) 1 g of hydroxypropyl cellulose and 1.5 g of 4-toluenesulfonyl chloride were dissolved in an aqueous solution of N,N-dimethylformamide in a volume ratio of 2:1 under ice bath and mixed uniformly; the temperature was raised to 25°C and 1.2 g of N-methylmorpholine was slowly added dropwise, maintaining the pH of the system at 7-8, and the reaction was carried out for 5 h; an excess of ethanol 4 times the volume of the system was added to precipitate the product, the product was dissolved in acetone, and then precipitated with ethanol, the above operation was repeated 3 times and then freeze-dried to obtain sulfonate cellulose;

[0028] (2) Mix 1 g of sulfonated cellulose and 5 g of diethanolamine, heat to 60°C, stir evenly, and react for 10 h; add excess acetone to separate the product, place the separated product in water, add acetone again, repeat the above operation three times, and then freeze-dry to obtain the complex matrix;

[0029] (3) Take 0.68g of zinc chloride and prepare a methanol solution of zinc chloride; disperse 1g of the ligand in methanol, add the methanol solution of zinc chloride, reflux for 14h, separate the solid product, wash it with water and methanol three times, and then dry it in vacuum at 80°C to obtain a zinc-based catalyst.

[0030] (4) 1 mmol of 1,3-cyclohexanedione, 1 mmol of 4-methyl-β-nitrostyrene, and 0.3 g of a zinc-based catalyst were placed in a solvent of dimethyl sulfoxide and reacted at 80°C. The reaction was tracked and detected by TLC (developing solvent: petroleum ether: ethyl acetate = 2:1). The reaction was carried out for 1.5 hours, and the liquid was extracted with dichloromethane (10 mL × 2) and water (15 mL). The obtained aqueous phase was recovered by the method of step (3), and the obtained organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain a yellow oily substance, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to obtain (Z) 2-(hydroxyimino)-3-(p-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one with high purity. Its structural formula is as follows:

[0031]

[0032] The sample is a white solid; yield: 46%; mp 186.5~188.1℃; R f =0.4(EA:PE=1:2); IR(KBr,cm -1 ):ν3254,2953,1695,1630,1389,1362,1166,953,791; 1H NMR(400MHz,(CD3)2CO)δ(ppm):9.49(s,1H),7.14–7.06(m,4H),4.77(s,1H),2.85– 2.76(m,1H),2.75–2.67(m,1H),2.40–2.31(m,2H),2.27(s,3H),2.24–2.11(m,2H); 13 C{ 1 H}NMR(100MHz,(CD3)2CO)δ(ppm):193.2,173.8,157.8,137.4,137.1,129.8(2C),128.4(2C),118.5,46.1,37.5,23.5,22.1,21.0; HR-MS(ESI)calcd.for C 15 H 15 NNaO3[(M+Na) + ]:280.0944; Found:280.0946.

[0033] (E)-2-(hydroxyimino)-3-(p-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one. Its structural formula is as follows:

[0034]

[0035] The sample is a white solid; yield: 46%; mp 194.3~195.6℃; R f =0.5(EA:PE=1:2); IR(KBr,cm -1 ):ν3254,3144,2899,1701,1629,1393,1358,1207,1165,1060,1002,803; 1 H NMR (400MHz, (CD3)2CO) δ (ppm): 9.31 (s, 1H), 7.16 (d, J = 8.0Hz, 2H), 7.05 (d, J = 8.0Hz, 2 H),5.03(s,1H),2.82–2.64(m,2H),2.32–2.28(m,2H),2.27(s,3H),2.17–2.12(m,2H); 13 C{ 1 H}NMR(100MHz,(CD3)2CO)δ(ppm):192.7,174.1,166.9,137.2,134.6,129.7(2C),128.9(2C),119.3,45.5,37.5,23.6,22.2,21.0; HR-MS(ESI)calcd.for C 15H 15 NNaO3[(M+Na) + ]: 280.0944; Found: 280.0942.

[0036] Example 2: differs from Example 1 in that:

[0037] Step (4) took 1 mmol of 1,3-cyclohexanedione and 1 mmol of 2-methyl-β-nitrostyrene to react. (Z) 2-(hydroxyimino)-3-(o-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one was obtained. Its structural formula is as follows:

[0038]

[0039] The sample was a white solid; yield: 36%; m.p. 212.3-214.1 °C; R f = 0.4 (EA:PE = 1:2); IR (KBr, cm -1 ): v 3263, 2882, 1700, 1652, 1633, 1464, 1395, 1182, 1166, 955, 764, 732; 1 H NMR (400 MHz, (CD3)2CO) δ (ppm): 9.46 (s, 1H), 7.17-7.13 (m, 1H), 7.13-7.05 (m, 2H), 6.98 (dd, J = 7.0, 1.8 Hz, 1H), 5.05 (s, 1H), 2.85-2.78 (m, 1H), 2.77-2.68 (m, 1H), 2.46 (s, 3H), 2.40-2.27 (m, 2H), 2.23-2.16 (m, 2H); 13 C{ 1 H} NMR (100 MHz, (CD3)2CO) δ (ppm): 193.1, 173.9, 157.9, 138.4, 137.0, 131.3, 127.9, 127.8, 126.9, 118.6, 43.2, 37.5, 23.5, 22.2, 19.9; HR-MS (ESI) calcd. for C 15 H 15 NNaO3[(M+Na) + ]: 280.0944; Found: 280.0942.

[0040] (E)-2-(hydroxyimino)-3-(o-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one; its structural formula is as follows:

[0041]

[0042] Sample: white solid; yield: 37%; m.p. 187.4-189.2 °C; Rf = 0.4 (EA:PE = 1:2); IR (KBr, cm"1): v 3245, 2892, 1709, 1634, 1392, 1181, 1059, 1005, 753; f -1 1 H NMR (400 MHz, (CD3)2CO) δ (ppm): 9.24 (s, 1H), 7.14-7.10 (m, 1H), 7.10-7.03 (m, 2H), 6.97-6.94 (m, 1H), 5.18 (s, 1H), 2.86-2.78 (m, 1H), 2.75-2.67 (m, 1H), 2.56 (s, 3H), 2.34-2.20 (m, 2H), 2.19-2.09 (m, 2H); 13 C{ 1 H} NMR (100 MHz, (CD3)2CO) δ (ppm): 192.6, 173.8, 168.0, 137.4, 136.8, 130.7, 127.5, 127.2, 126.9, 120.4, 42.2, 37.4, 23.5, 22.2, 20.0; HR-MS (ESI) calcd. for C 15 H 15 NNaO3[(M+Na) + ]: 280.0944; Found: 280.0945.

[0043] Example 3: differs from Example 1 in that:

[0044] Step (4) take 1 mmol 1,3-cyclohexanedione, 1 mmol 3-methyl-β-nitrostyrene reaction. Get (Z) 2-(hydroxyimino)-3-(m-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one. Its structural formula is as follows:

[0045]

[0046] Sample: white solid; yield: 41%; m.p. 179.2-181.0 °C; Rf = 0.4 (EA:PE = 1:2); IR (KBr, cm"1): v 3254, 2949, 1692, 1632, 1390, 1364, 1181, 1061, 952, 759; f -1 1 ​​​​H NMR (400 MHz, (CD3)2CO) δ (ppm): 9.51 (s, 1 H), 7.16 (dd, J1= J2= 8.2 Hz, 1 H), 7.03 (dd, J1= 8.4, J2= 6.6 Hz, 3 H), 4.77 (s, 1 H), 2.86 - 2.77 (m, 1 H), 2.75 - 2.67 (m, 1 H), 2.41 - 2.30 (m, 2 H), 2.28 (s, 3 H), 2.22 - 2.14 (m, 2 H); 13 C{ 1 H} NMR (100 MHz, (CD3)2CO) δ (ppm): 193.2, 173.9, 157.7, 140.0, 138.6, 129.2, 129.1, 128.6, 125.6, 118.4, 46.4, 37.5, 23.5, 22.1, 21.4; HR-MS (ESI) calcd. for C 15 H 15 NNaO3[(M+Na) + ]: 280.0944; Found: 280.0940.

[0047] (E)-2-(hydroxyimino)-3-(m-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one; the structural formula of which is as follows:

[0048]

[0049] Sample: white solid; yield: 42%; m.p. 183.2-184.5 °C; R f = 0.4 (EA:PE = 1:2); IR (KBr, cm -1 ): v 3394, 2957, 1072, 1633, 1395, 1357, 1171, 1060, 999, 754; 1 H NMR (400 MHz, (CD3)2CO) δ (ppm): 9.33 (s, 1 H), 7.17 - 7.11 (m, 2 H), 7.08 (d, J = 7.6 Hz, 1 H), 7.01 (d, J = 6.0 Hz, 1 H), 5.02 (s, 1 H), 2.85 - 2.75 (m, 1 H), 2.74 - 2.64 (m, 1 H), 2.31 - 2.25 (m, 5 H), 2.16 - 2.08 (m, 2 H); 13 C{ 1H} NMR (100 MHz, (CD3)2CO) δ (ppm): 192.7, 174.0, 166.8, 138.3, 137.5, 129.5, 128.8, 128.4, 126.0, 119.3, 45.7, 37.4, 23.5, 22.1, 21.4; HR-MS (ESI) calcd. for C 15 H 15 N NaO3[(M + Na) + ]: 280.0944; Found: 280.0945.

[0050] Example 4: differs from Example 1 in that:

[0051] Step (4) take 1 mmol 5,5-dimethyl-1,3-cyclohexanedione, 1 mmol 2-bromo-β-nitrostyrene reaction. Get (Z) 3-(2-bromophenyl)-2-(hydroxyimino)-6,6-dimethyl-3,5,6,7- tetrahydrobenzofuran-4(2H)-one. Its structural formula is as follows:

[0052]

[0053] Sample is a white solid, yield: 45%; m.p. 161.8-162.5 °C; Rf = 0.4 (EA: PE = 1:2); IR (KBr, cm"1): v 3291, 2964, 1693, 1654, 1395, 1171, 1026, 963, 745;1H NMR (400 MHz, (CD3)2CO) δ (ppm): 9.54 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.31 (dd, J 1 = J 2 = 7.6 Hz, 1H), 7.24-7.14 (m, 2H), 5.33 (s, 1H), 2.71 (d, J = 18, 1H), 2.68 (d, J = 18, 1H), 2.31 (d, J = 16, 1H), 2.23 (d, J = 16, 1H), 1.22 (s, 3H), 1.19 (s, 3H);13C{1H} NMR (151 MHz, (CD3)2CO) δ (ppm): 192.4, 173.1, 156.9, 134.0 133.8, 130.4, 129.9, 129.0, 128.7, 51.7, 46.3, 37.0, 34.7, 28.9, 28.6; HR-MS (ESI) calcd. for C16H16BrNNaO3[(M + Na)+]: 372.0206; Found: 372.0203.

[0054] (E)-3-(2-bromophenyl)-2-(hydroxyimino)-6,6-dimethyl-3,5,6,7- tetrahydrobenzofuran-4(2H)-one; the structural formula of which is as follows:

[0055]

[0056] White solid, yield: 32%; m.p. 151.3-153.2 °C; Rf f = 0.4 (EA:PE = 1:2); IR (KBr, cm -1 ): v 3274, 3150, 2869, 1707, 1652, 1635, 1394, 1236, 1180, 1030, 994, 752; 1 H NMR (400 MHz, (CD3)2CO) δ (ppm): 9.36 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.28 (dd, Ji = J2= 7.6 Hz, 1H), 7.25 - 7.17 (m, 1H), 7.13 (dd, Ji = J2= 8.0 Hz, 1H), 5.49 (s, 1H), 2.68 (d, J = 18, 1H), 2.63 (d, J = 18, 1H), 2.23 (d, J = 16, 1H), 2.16 (d, J = 16, 1H), 1.16 (s, 2 x 3H); 13 C{ 1 H} NMR (151 MHz, (CD3)2CO) δ (ppm): 191.8, 173.2, 166.6, 137.5, 133.6, 129.4, 128.5, 110.9, 51.6, 46.1, 37.1, 34.7, 28.8, 28.5; HR-MS (ESI) calcd. for C 16 H 16 BrNNaO3[(M + Na) + ]: 372.0206; Found: 372.0204.

[0057] Example 5: differs from Example 1 in that:

[0058] Step (4) takes 1 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 1 mmol of β-nitrostyrene to react. (Z) 2-(hydroxyimino)-6,6-dimethyl-3-phenyl-3,5,6,7- tetrahydrobenzofuran-4(2H)-one is obtained. The structural formula of which is as follows:

[0059]

[0060] The sample is a white solid; yield: 46%; m.p. 173.5-176.2 °C; Rff =0.4(EA:PE=1:2); IR(KBr,cm -1 ):ν3246,2955,2889,1702,1620,1400,1163,1148,1032,956,727; 1 H NMR(400MHz,(CD3)2CO)δ(ppm):

[0061] 9.55(s,1H),7.32–7.26(m,2H),7.25–7.20(m,3H),4.85(s,1H),2.78–2.58(m,2H),2.33–2.20(m,2H),1.20(s,3H),1.17(s,3H); 13 C NMR(100MHz,(CD3)2CO)δ(ppm):192.6,172.5,157.9,140.1,129.2(2C),128.5(2C),127.9,117.2,51.8,46.4,37.0,34.7,28.7,28.6; HR-MS(ESI)calcd.for C 16 H 17 NNaO3[(M+Na) + ]:294.1101; Found:294.1104.

[0062] (E)-2-(Hydroxyimino)-6,6-dimethyl-3-phenyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-one; its structural formula is as follows:

[0063]

[0064] The sample is a white solid; yield: 29%; mp 193.0~194.2℃; R f =0.4(EA:PE=1:2); IR(KBr,cm -1 ):ν3372,2960,2880,1708,1652,1636,1399,1036,992,746; 1 H NMR(400MHz,(CD3)2CO)δ(ppm):9.36(s,1H),7.32–7.27(m,3H),7.28–7.25(m,1H),7.22–7.17(m ,1H),5.08(s,1H),2.73–2.59(m,2H),2.21(dd,J1=17.8,J2=16.2Hz,2H),1.15(d,J=5.2Hz,6H); 13 C{ 1H} NMR (100 MHz, (CD3)2CO) δ (ppm): 192.1, 172.7, 167.0, 137.7, 129.0 (2C), 128.8 (2C), 127.6, 118.1, 51.7, 45.8, 37.0, 34.7, 28.7, 28.5; HR-MS (ESI) calcd. for C 16 H 17 NNaO3[(M+Na) + ]: 294.1101; Found: 294.1102.

[0065] Example 6: differs from Example 1 in that:

[0066] Step (4) take 1 mmol 5-methyl-1,3-cyclohexanedione, 1 mmol 4-methyl-β-nitrostyrene reaction. Get (Z) 2-(hydroxyimino)-6-methyl-3-(p-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-ketone. Its structural formula is as follows:

[0067]

[0068] Sample is a white solid; yield: 41%; m.p. 180.0-181.9 °C; R f = 0.4 (EA: PE = 1:2); IR (KBr, cm -1 ): v 3270, 2956, 2923, 1691, 1633, 1389, 1168, 1022, 948, 893; 1 H NMR (400 MHz, (CD3)2CO) δ (ppm): 9.52 (d, J = 4.4 Hz, 1H), 7.13-7.08 (m, 4H), 4.80-4.75 (m, 1H), 2.87-2.74 (m, 1H), 2.62-2.54 (m, 1H), 2.51-2.40 (m, 1H), 2.38-2.30 (m, 1H), 2.27 (d, J = 2.0 Hz, 3H), 2.25-2.10 (m, 1H), 1.17 (dd, J1= 6.4, J2= 3.6 Hz, 3H); 13 C{ 1 H} NMR (100 MHz, (CD3)2CO) δ (ppm): 192.9, 173.1, 158.0, 137.3, 137.0, 129.8, 128.4, 118.0, 46.2, 46.0, 31.2, 30.6, 29.8, 21.1, 21.0; HR-MS (ESI) calcd. for C 16 H 17NNaO3[(M+Na) + ]: 294.1101 ; Found: 294.1100.

[0069] (E)-2-(hydroxyimino)-6-methyl-3-(p-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one; the structural formula of which is as follows:

[0070]

[0071] The sample was a white solid; yield: 37%; m.p. 165.4-167.2 °C; Rf= 0.4 (EA:PE = 1:2); IR (KBr, cm"1): v 3269, 2960, 2907, 1709, 1645, 1634, 1392, 1197, 1044, 1023, 999, 798; f -1 ): v 3269, 2960, 2907, 1709, 1645, 1634, 1392, 1197, 1044, 1023, 999, 798; 1 H NMR (400 MHz, (CD3)2CO) δ (ppm): 9.33 (d, J = 8.0 Hz, 1 H), 7.17 (m, 2 H), 7.07 (d, J = 2.4 Hz, 1 H), 7.05 (d, J = 3.2 Hz, 1 H), 5.01 (s, 1 H), 2.87 - 2.72 (m, 1 H), 2.60 - 2.36 (m, 2 H), 2.34 - 2.27 (m, 1 H), 2.26 (s, 3 H), 2.15 - 2.07 (m, 1 H), 1.14 (d, J = 6.4 Hz, 3 H); 13 C{ 1 H} NMR (100 MHz, (CD3)2CO) δ (ppm): 192.3, 173.7, 167.0, 137.1, 134.6, 129.6, 128.8, 119.1, 45.7, 45.3, 31.4, 30.3, 21.0, 20.9; HR-MS (ESI) calcd. for C 16 H 17 NNaO3[(M+Na) + ]: 294.1101 ; Found: 294.1100.

[0072] Example 7: differs from Example 1 in that:

[0073] Step (4) was reacted at 60 °C for 3 h. The sample obtained had a yield of 27% and 35%.

[0074] Example 8: differs from Example 1 in that:

[0075] ​In step (4), 0.15 g of zinc-based catalyst was used and the reaction was carried out at 80° C. for 3 h. The sample yields obtained were 28% and 22%.

[0076] Example 9: The difference from Example 1 is that:

[0077] Step (4) used 0.45 g of zinc-based catalyst, and the sample yields obtained were 47% and 46%.

[0078] Example 10: The difference from Example 1 is that:

[0079] Step (4) used 1.5 mmol of 4-methyl-β-nitrostyrene, and the sample yields were 46% and 46%.

[0080] Comparative Example 1: The difference from Example 1 is:

[0081] Step (4) was reacted at 40° C. for 4 h. The yield was 0.

[0082] Comparative Example 2: The difference from Example 1 is:

[0083] In step (4), dichloromethane was used as solvent and the reaction was refluxed for 4 h. The yield was 0.

[0084] Comparative Example 3: The difference from Example 1 is:

[0085] In step (4), aluminum chloride was used as a catalyst and the reaction was carried out at 60° C. for 24 h. The yields were 10% and 11%.

[0086] Comparative Examples 1 to 6 show that the method of the present invention can be applied to the preparation of various tetrahydrobenzofuranone oxime derivatives with high and stable product yields, indicating that the method of the present invention has a wide range of applications and is easy to implement.

[0087] Comparison of Example 1, Examples 7-10, and the various comparative examples shows that the catalyst significantly affects product yield in the method of the present invention. In Example 8, the yield dropped to 28% by reducing the catalyst dosage, while the yield of Comparative Example 3, which did not reduce the dosage and directly replaced it with aluminum chloride, was only 10%. This demonstrates that the catalyst employed in the present invention possesses unique catalytic properties for the preparation of tetrahydrobenzofuranone oxime derivatives, while the catalytic efficiency of other Lewis acids is less than one-quarter that of the catalyst of the present invention. The reaction temperature used for the catalyst of the present invention significantly affects the yield. When the reaction temperature in Comparative Example 1 was reduced from 80°C to 40°C, the reaction yield dropped directly from 46% to 0. The reaction solvent also significantly affects product yield. Using dimethyl sulfoxide as the reaction solvent, various products of Examples 1-6 were obtained with stable yields. However, using dichloromethane as the reaction solvent in Comparative Example 2 resulted in a product yield of 0, making dichloromethane unsuitable for the preparation of tetrahydrobenzofuranone oxime derivatives.

[0088] Those skilled in the art can make various other corresponding changes and deformations based on the technical solutions and concepts described above, and all of these changes and deformations should fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing a tetrahydrobenzofuranone oxime derivative, characterized in that: The general reaction formula is as follows: Where: R 1 is hydrogen or methyl; R 2 is hydrogen or methyl; the reaction is carried out using a Lewis acidic zinc-based catalyst.

2. The method for preparing a tetrahydrobenzofuranone oxime derivative according to claim 1, wherein: Compound I is one or more of 4-methyl-β-nitrostyrene, 2-methyl-β-nitrostyrene, 3-methyl-β-nitrostyrene, 4-chloro-β-nitrostyrene, 2-bromo-β-nitrostyrene or β-nitrostyrene.

3. The method for preparing a tetrahydrobenzofuranone oxime derivative according to claim 1, wherein: Compound II is one or more of 1,3-cyclohexanedione, 5-methyl-1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione.

4. The method for preparing a tetrahydrobenzofuranone oxime derivative according to claim 1, wherein: The following steps are involved: Compound I, compound II and a Lewis acidic zinc-based catalyst are placed in a solvent and mixed, and reacted at 60-85° C. for 1.5-3 hours; after the reaction is complete, the product is separated.

5. The method for preparing a tetrahydrobenzofuranone oxime derivative according to claim 4, wherein: The molar ratio of the compound I to the compound II is 1:1-1.5; the molar ratio of the compound I to the zinc in the zinc-based catalyst is 1:0.5-1.

5.

6. The method for preparing a tetrahydrobenzofuranone oxime derivative according to claim 4, wherein: The solvent includes one or more of dimethyl sulfoxide and N,N-dimethylformamide.

7. The method for preparing a tetrahydrobenzofuranone oxime derivative according to claim 1, wherein: The preparation of the zinc-based catalyst comprises the following steps: modifying a hydroxyl polymer with 4-toluenesulfonyl chloride to obtain a sulfonate polymer; reacting the sulfonate polymer with diethanolamine to obtain a coordination matrix; and loading zinc chloride on the coordination matrix to obtain a zinc-based catalyst.

8. The method for preparing a tetrahydrobenzofuranone oxime derivative according to claim 1, wherein: The following steps are involved: a. Dissolve hydroxypropyl cellulose and 4-toluenesulfonyl chloride in an aqueous solution of N,N-dimethylformamide at 0-10°C and mix well; raise the temperature to 20-30°C and add N-methylmorpholine dropwise, maintaining the pH of the system at 7-8, and react for 4-6 hours; add excess ethanol to precipitate the product, wash thoroughly, and then dry to obtain sulfonated cellulose; b. Mix cellulose sulfonate and diethanolamine, raise the temperature to 45-65°C, stir evenly, and react for 8-12 hours; add excess acetone, separate the product, wash it thoroughly, and dry it to obtain a complex matrix; c. Prepare a methanol solution of zinc chloride; disperse the coordination matrix in methanol, add the methanol solution of zinc chloride, reflux the reaction for 10 to 16 hours, separate the solid product, wash it thoroughly, and then dry it to obtain a zinc-based catalyst.

9. The method for preparing a tetrahydrobenzofuranone oxime derivative according to claim 8, wherein: In the aqueous solution of N,N-dimethylformamide in step a, the volume ratio of N,N-dimethylformamide to water is 1 to 3:1; the mass ratio of hydroxypropyl cellulose to 4-toluenesulfonyl chloride is 1:1.2 to 1.8; the mass ratio of N-methylmorpholine to 4-toluenesulfonyl chloride is 1:1.2 to 1.5; and the volume of the excess ethanol is 3 to 6 times that of the liquid in the system.

10. The method for preparing a tetrahydrobenzofuranone oxime derivative according to claim 8, wherein: In step b, the mass ratio of the sulfonate cellulose to diethanolamine is 1:4-6; the volume of the excess acetone is 3-6 times the volume of the liquid in the system; and in step c, the mass ratio of the ligand to zinc chloride is 1:0.5-0.8.

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