A preparation method for constructing polysubstituted furan compounds from phenylacetylene compounds and benzaldehyde compounds

Abstract

The present invention provides a preparation method for constructing polysubstituted furan compounds from phenylacetylene compounds and benzaldehyde compounds, which relates to the technical field of preparation methods for polysubstituted furan compounds. By reacting compound 1 with compound 2 in the presence of a catalyst, a solvent, and an additive at a predetermined temperature to generate a solution containing compound 3; subjecting the solution containing compound 3 to extraction, drying, vacuum distillation, and column chromatography separation and purification to obtain compound 3. Using a non-metal catalyst enables the reaction of phenylacetylene compound 1 with benzaldehyde compound 2 to generate polysubstituted furan compounds. The reaction process is simple, easy to operate, the raw materials are easily obtained at low cost, and it is green and safe.

Description

Technical Field

[0001] The present invention belongs to the technical field of preparation methods of polysubstituted furan compounds, and particularly relates to a preparation method of constructing polysubstituted furan compounds from phenylacetylene compounds and benzaldehyde compounds. Background Art

[0002] In the field of organic chemistry, polysubstituted furan compounds are an important type of five-membered heterocyclic compounds, which are commonly present in many natural molecules with biological activities and can be used to construct many drug molecules or as synthetic intermediates. Therefore, the research and development of efficient synthesis processes for polysubstituted furan compounds have attracted extensive attention from scientific researchers.

[0003] In the prior art, for example, the Chinese invention patent with the application number: 201310234976.0 discloses a preparation method of polysubstituted furanone compounds. Specifically, a metal salt, an alkyl-substituted ketone, and an α,β-unsaturated carboxylic acid are added to an organic solvent, heated to 120 °C to 150 °C, and after the reaction is complete, the polysubstituted furan compound is obtained through post-treatment. The metal salt therein is composed of a monovalent copper salt and a divalent copper salt. Although the preparation method for polysubstituted furan compounds provided by this invention is easy to operate and the post-treatment is simple, it requires the use of a metal catalyst, resulting in high costs and being prone to metal poisoning. Summary of the Invention

[0004] In view of this, the present invention provides a preparation method of constructing polysubstituted furan compounds with simple operation, without the need for complex reaction substrates and metal catalysts, using phenylacetylene compounds and benzaldehyde compounds as substrates.

[0005] The technical solution adopted by the present invention to solve its technical problems is as follows:

[0006] A preparation method of constructing polysubstituted furan compounds from phenylacetylene compounds and benzaldehyde compounds, comprising the following steps,

[0007] S1: Reacting compound 1 with compound 2 in the presence of a catalyst, a solvent, and an additive at a predetermined temperature to form a solution containing compound 3;

[0008] S2: Extracting, drying, distilling under reduced pressure, and purifying by column chromatography the solution containing compound 3 to obtain compound 3; The synthetic route is as follows:

[0009]

[0010] Said R 1 is: hydrogen, methyl, methoxy, fluorine, trifluoromethyl

[0011] R 2They are: hydrogen, methyl, fluorine, chlorine, trifluoromethyl.

[0012] Preferably, the catalyst is selenium dioxide.

[0013] Preferably, the solvent is one of dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide.

[0014] Preferably, the additive is one of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, potassium methoxide, tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide.

[0015] Preferably, the predetermined temperature is 60°C - 100°C.

[0016] Preferably, the molar ratio of compound 1 to compound 2 and the catalyst is: 1:2 - 5:2 - 3.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0018] A preparation method of constructing polysubstituted furan compounds from phenylacetylene compounds and benzaldehyde compounds provided by the present invention, by reacting compound 1 with compound 2 in the presence of a catalyst, a solvent and an additive at a predetermined temperature to generate a solution containing compound 3; extracting, drying, distilling under reduced pressure, and purifying by column chromatography the solution containing compound 3 to obtain compound 3. Using a non-metallic catalyst, the reaction of phenylacetylene compound 1 with benzaldehyde compound 2 generates polysubstituted furan compounds. The reaction process is simple, easy to operate, the raw materials are readily available, the cost is low, and it is green and safe. Description of the Drawings

[0019] Figure 1 It is the 1H NMR spectrum of Example 1.

[0020] Figure 2 It is the 13C NMR spectrum of Example 1.

[0021] Figure 3 It is the 1H NMR spectrum of Example 2.

[0022] Figure 4 It is the 13C NMR spectrum of Example 2.

[0023] Figure 5 It is the 1H NMR spectrum of Example 3.

[0024] Figure 6 It is the 13C NMR spectrum of Example 3.

[0025] Figure 7 It is the 1H NMR spectrum of Example 4.

[0026] Figure 8 It is the nuclear magnetic resonance carbon spectrum of Example 4.

[0027] Figure 9 It is the nuclear magnetic resonance hydrogen spectrum of Example 5.

[0028] Figure 10 It is the nuclear magnetic resonance carbon spectrum of Example 5.

[0029] Figure 11 It is the nuclear magnetic resonance hydrogen spectrum of Example 6.

[0030] Figure 12 It is the nuclear magnetic resonance carbon spectrum of Example 6.

[0031] Figure 13 It is the nuclear magnetic resonance hydrogen spectrum of Example 7.

[0032] Figure 14 It is the nuclear magnetic resonance carbon spectrum of Example 7.

[0033] Figure 15 It is the nuclear magnetic resonance hydrogen spectrum of Example 8.

[0034] Figure 16 It is the nuclear magnetic resonance carbon spectrum of Example 8.

[0035] Figure 17 It is the nuclear magnetic resonance hydrogen spectrum of Example 9.

[0036] Figure 18 It is the nuclear magnetic resonance carbon spectrum of Example 9.

[0037] Figure 19 It is the nuclear magnetic resonance hydrogen spectrum of Example 10.

[0038] Figure 20 It is the nuclear magnetic resonance carbon spectrum of Example 10. Specific Embodiments

[0039] The following further elaborates in detail on the technical solutions and technical effects of the embodiments of the present invention in conjunction with the drawings of the present invention.

[0040] A preparation method for constructing polysubstituted furan compounds from phenylacetylene compounds and benzaldehyde compounds, comprising the following steps:

[0041] S1: React compound 1 with compound 2 in the presence of a catalyst, a solvent, and an additive at a predetermined temperature to form a solution containing compound 3;

[0042] S2: Extract, dry, distill under reduced pressure, and purify by column chromatography the solution containing compound 3 to obtain compound 3; The synthesis route is as follows:

[0043]

[0044] The said R 1 is: hydrogen, methyl, methoxy, fluorine, trifluoromethyl

[0045] R 2 is: hydrogen, methyl, fluorine, chlorine, trifluoromethyl.

[0046] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0047] A preparation method for constructing polysubstituted furan compounds from phenylacetylene compounds and benzaldehyde compounds provided by the present invention reacts compound 1 with compound 2 in the presence of a catalyst, a solvent and an additive at a predetermined temperature to generate a solution containing compound 3; the solution containing compound 3 is subjected to extraction, drying, distillation under reduced pressure, and column chromatography separation and purification to obtain compound 3. By using a non-metallic catalyst, the reaction of phenylacetylene compound 1 with benzaldehyde compound 2 generates polysubstituted furan compounds. The reaction process is simple, easy to operate, the raw materials are easily available and the cost is low, and it is green and safe.

[0048] Furthermore, the catalyst is selenium dioxide. Selenium dioxide acts as an oxidant and a catalyst / promoter in this reaction. Under alkaline conditions, selenium dioxide catalyzes the coupling of benzaldehyde and phenylacetylene to form an alkynone intermediate. Subsequently, the alkynone intermediate forms a resonance cumulene, and the cumulene undergoes an addition coupling reaction with another molecule of benzaldehyde to form a cumulene ketone intermediate. Finally, this intermediate forms a polysubstituted furan product through an intramolecular cyclization reaction.

[0049] Furthermore, the solvent is one of dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, and N,N-dimethylacetamide.

[0050] Furthermore, the additive is one of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, potassium methoxide, tetrabutylammonium hydroxide, and benzyltrimethylammonium hydroxide to provide a suitable alkaline environment to promote the reaction.

[0051] Furthermore, the predetermined temperature is 60°C - 100°C.

[0052] Furthermore, the molar ratio of compound 1 to compound 2, the catalyst, and the solvent is: 1:2 - 5:2 - 3.

[0053] Furthermore, in the S1 step, argon needs to be filled during the reaction, and nitrogen is used as a protective gas to isolate air and prevent oxygen from affecting the reaction.

[0054] Furthermore, in the S1 step, thin-layer chromatography is used to monitor the reaction process until the reaction is complete.

[0055] Further, in the step S2, the specific steps of extraction are as follows: extract with ethyl acetate and saturated sodium chloride solution.

[0056] Further, in the step S2, the drying is carried out with anhydrous sodium sulfate.

[0057] Further, in the step S2, the specific steps of column chromatography separation and purification are as follows: the residue after reduced pressure distillation is separated and purified by silica gel column chromatography with petroleum ether / ethyl acetate (40:1) as the mobile phase to obtain Compound 3.

[0058] Examples 1 to 10:

[0059] In a 10 mL round-bottom flask, successively add Compound 1 (2 mmol, 204 mg), Compound 2 (6 mmol, 636 mg), selenium dioxide (4 mmol, 444 mg), sodium ethoxide (4 mmol, 272 mg), DMSO (2 mmol, 10 ml). Fill the round-bottom flask with argon and react at 80 °C for 10 h. Monitor the reaction process by thin-layer chromatography until the reaction is complete; extract with ethyl acetate and saturated sodium chloride solution, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and separate and purify the residue by silica gel column chromatography with petroleum ether / ethyl acetate (40:1) as the mobile phase to obtain Compound 3 with a yield of 83%.

[0060] The starting materials Compound 1, Compound 2, the product Compound 3 and the yield of Compound 3 are shown in Table 1:

[0061] Table 1

[0062]

[0063]

[0064] Perform NMR characterization on the Compound 3 obtained in Examples 1 to 10, and the data are as follows:

[0065] Example 1: 1 HNMR(400MHz,CDCl3,ppm)δ7.78 - 7.75(m,2H),7.62 - 7.60(m,2H),7.48 - 7.45(m,2H),7.43 - 7.40(m,2H),7.39 - 7.36(m,2H),7.35 - 7.22(m,5H),6.81(s,1H); 1313C NMR (100 MHz, CDCl3, ppm) δ 152.56, 147.90, 134.33, 131.12, 130.54, 128.78, 128.73, 128.71, 128.44, 127.56, 127.53, 127.34, 126.15, 124.54, 123.83, 109.49. HRMS calcd for C 22 H 17 O [M+H] + 297.1274; found: 297.1275.

[0066] Example 2: 1 1H NMR (400 MHz, CDCl3, ppm) δ 7.67 - 7.65 (m, 2H), 7.54 - 7.52 (m, 2H), 7.33 - 7.25 (m, 4H), 7.21 - 7.08 (m, 6H), 6.92 (s, 1H), 2.30 (s, 3H); 13 13C NMR (100 MHz, CDCl3, ppm) δ 152.58, 147.84, 137.16, 131.44, 131.39, 130.73, 129.52, 128.86, 128.68, 128.51, 127.60, 127.52, 126.21, 124.64, 123.94, 109.71, 21.39. HRMS calcd for C 23 H 19 O [M+H] + 311.1431; found: 311.1434.

[0067] Example 3: 1 1H NMR (400 MHz, CDCl3, ppm) δ 7.79 - 7.77 (m, 2H), 7.46 - 7.40 (m, 4H), 7.31 - 7.16 (m, 8H), 6.70 (s, 1H), 2.19 (s, 3H); 13 13C NMR (100 MHz, CDCl3, ppm) δ 152.08, 147.81, 136.89, 134.15, 131.25, 130.60, 130.37, 130.16, 128.79, 128.47, 127.90, 127.52, 127.06, 126.16, 124.68, 123.79, 123.76, 110.33, 20.13. HRMS calcd for C 23 H 19 O2 [M+H] +327.1380; found: 327.1385.

[0068] Example 4: 1 H NMR (400 MHz, CDCl3, ppm) δ 7.76 - 7.74 (m, 2H), 7.59 - 7.56 (m, 2H), 7.43 - 7.39 (m, 4H), 7.33 - 7.23 (m, 4H), 7.10 - 7.04 (m, 2H), 6.77 (s, 1H); 13 C NMR (100 MHz, CDCl3, ppm) δ 162.19 (d, J = 244.9 Hz, 1C), 152.63, 147.91, 130.94, 130.36 (d, J = 8.0 Hz, 1C), 130.33, 130.27, 128.80, 128.51, 127.66, 127.64, 126.11, 123.84, 123.51, 115.71 (d, J = 21.2 Hz, 1C), 109.35. HRMS calcd for C 22 H 16 FO[M + H] + 315.1180; found: 315.1172.

[0069] Example 5: 1 H NMR (400 MHz, CDCl3, ppm) δ 7.77 - 7.75 (m, 2H), 7.64 - 7.61 (m, 2H), 7.59 - 7.56 (m, 4H), 7.44 - 7.40 (m, 2H), 7.36 - 7.29 (m, 4H), 6.81 (s, 1H); 13 C NMR (100 MHz, CDCl3, ppm) δ 153.07, 148.63, 138.07, 130.62, 130.23, 129.45, 128.87, 128.84, 128.64, 128.06, 127.84, 126.43, 125.67 (q, J = 3.8 Hz, 1C), 123.89, 123.06, 122.89, 108.82. HRMScalcd for C 23 H 16 F3O[M + H] + 365.1148; found: 365.1147.

[0070] Example 6: 11H NMR (400 MHz, CDCl3, ppm) δ 7.65 (d, J = 8.0 Hz, 2H), 7.50 - 7.45 (m, 4H), 7.39 - 7.31 (m, 3H), 7.22 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.75 (s, 1H), 2.38 (s, 3H), 2.35 (s, 3H); 13 13C NMR (100 MHz, CDCl3, ppm) δ 152.51, 147.78, 137.31, 134.54, 129.42, 129.11, 128.67, 128.62, 128.43, 127.94, 127.13, 126.11, 123.73, 108.64, 21.35, 21.33. HRMS calcd for C 24 H 21 O [M+H] + 325.1587; found: 325.1587.

[0071] Example Seven: 1 1H NMR (400 MHz, CDCl3, ppm) δ 7.50 - 7.48 (m, 1H), 7.44 - 7.28 (m, 9H), 7.25 - 7.19 (m, 1H), 6.99 - 6.90 (m, 2H), 6.78 (s, 1H); 13 13C NMR (100 MHz, CDCl3, ppm) δ 163.23 (d, J = 243.9 Hz, 1C), 162.84 (d, J = 243.6 Hz, 1C), 151.64 (d, J = 3.2 Hz, 1C), 146.93 (d, J = 3.0 Hz, 1C), 133.64, 132.80 (d, J = 8.5 Hz, 1C), 132.30 (d, J = 8.4 Hz, 1C), 130.45 (d, J = 8.4 Hz, 1C), 130.04 (d, J = 8.4 Hz, 1C), 128.90, 128.74, 127.82, 125.68, 121.64 (d, J = 2.9 Hz, 1C), 119.57 (d, J = 2.9 Hz, 1C), 114.58 (d, J = 21.3 Hz, 1C), 114.52 (d, J = 21.2 Hz, 1C), 112.76 (d, J = 23 Hz, 1C), 110.75 (d, J = 23.4 Hz, 1C), 110.69. HRMS calcd for C 22 H 15 F2O [M+H] + 333.1086; found: 333.1084.

[0072] Example VIII: 1 H NMR(400MHz,CDCl3,ppm)δ7.69 - 7.66(m,2H),7.55 - 7.51(m,2H),7.42 - 7.31(m,5H),7.10 - 7.06(m,2H),7.00 - 6.95(m,2H),6.70(s,1H); 13 C NMR(100MHz,CDCl3,ppm)δ162.33,(d,J=246.0Hz,1C),162.21(d,J=246.5Hz,1C),151.76,147.10,134.02,128.82,128.64,127.99(d,J=7.9Hz,1C),127.49,127.29(d,J=3.3Hz,1C),126.84(d,J=3.0Hz,1C),125.57(d,J=8.0Hz,1C),124.28,115.85(d,J=21.8Hz,1C),115.53(d,J=21.6Hz,1C),109.06.HRMS calcdfor C 22 H 15 F2O[M + H] + 333.1086; found:333.1086.

[0073] Example IX: 1 H NMR(400MHz,CDCl3,ppm)δ7.66 - 7.63(m,2H),7.51 - 7.48(m,2H),7.43 - 7.34(m,7H),7.27 - 7.24(m,2H),6.76(s,1H); 13 C NMR(100MHz,CDCl3,ppm)δ151.74,147.07,133.77,133.36,129.33,129.04,128.88,128.81,128.72,128.64,127.67,127.29,125.13,125.05,110.00.HRMS calcd for C 22 H 15 Cl2O[M + H] + 365.0495; found:365.0497.

[0074] Example X: 1HNMR(400MHz, CDCl3, ppm) δ 7.87 - 7.85 (d, J = 8.0Hz, 2H), 7.14 - 7.67 (m, 4H), 7.57 - 7.55 (d, J = 8.4Hz, 2H), 7.45 - 7.39 (m, 5H), 6.94 (s, 1H); 13 C NMR(100MHz, CDCl3, ppm) δ 151.95, 147.41, 134.04, 133.44, 133.37, 129.70 (q, J = 15Hz, 1C), 129.38 (q, J = 15Hz, 1C), 129.13, 128.80, 128.16, 126.80, 126.16, 126.02 (q, J = 3.8Hz, 1C), 125.62 (q, J = 3.9Hz, 1C), 124.09, 122.88, 122.84, 111.78. HRMS calcd for C 24 H 15 F6O [M + H] + 433.1022; found: 433.1025.

[0075] By characterizing the compound 3 prepared in the above Examples 1 to 10, it can be seen that the required products can be prepared by the preparation method of the present invention.

[0076] Comparative Example 1 (selenium dioxide without catalyst)

[0077] In a 10 mL round-bottom flask, compound 1 (2 mmol, 204 mg), compound 2 (6 mmol, 636 mg), sodium ethoxide (4 mmol, 272 mg), and DMSO (2 mmol, 10 ml) were added in sequence. The round-bottom flask was filled with argon and reacted at 80 °C for 10 h to obtain Comparative Product 1.

[0078] Comparative Examples 2 to 11 (no reaction with acidic or basic catalysts)

[0079] In a 10 mL round-bottom flask, compound 1 (2 mmol, 204 mg), compound 2 (6 mmol, 636 mg), catalyst (4 mmol, 444 mg), sodium ethoxide (4 mmol, 272 mg), and DMSO (2 mmol, 10 ml) were added in sequence. The round-bottom flask was filled with argon and reacted at 80 °C for 10 h to obtain Comparative Products 2 to 11.

[0080]

[0081]

[0082] The comparative products one to eleven obtained from Comparative Examples One to Eleven were monitored by thin-layer chromatography, and it was found that no polysubstituted furan compounds were formed.

[0083] The above-disclosed are only the preferred embodiments of the present invention. Of course, the scope of the rights of the present invention cannot be limited thereby. Those of ordinary skill in the art can understand all or part of the processes of implementing the above embodiments, and the equivalent changes made according to the claims of the present invention still fall within the scope covered by the invention.

Claims

1. A preparation method for constructing polysubstituted furan compounds from phenylacetylene compounds and benzaldehyde compounds, characterized in that: including the following steps, S1: React compound 1 with compound 2 in the presence of a catalyst, a solvent and an additive at a predetermined temperature to form a solution containing compound 3; the molar ratio of compound 1 to compound 2 and the catalyst is: 1:2 - 5:2 - 3, the catalyst is selenium dioxide, the solvent is dimethyl sulfoxide, the additive is sodium ethoxide, and the predetermined temperature is 60°C - 100°C; S2: Extract, dry, distill under reduced pressure and purify by column chromatography the solution containing compound 3 to obtain compound 3; The synthetic route is as follows: The R 1 is: hydrogen, methyl, methoxy, fluorine, trifluoromethyl R 2 are: hydrogen, methyl, fluorine, chlorine, trifluoromethyl.

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