Preparation method of substituted cyclobutene compound
Through a metal-free cyclization reaction using potassium hexamethyldisilazide as an alkaline catalyst, the problems of cumbersome operation and metal pollution in the preparation of cyclobutene compounds were solved, and the green and efficient preparation of cyclobutene compounds was achieved.
Patent Information
- Application Number
- CN202410327311.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-03-21
- Publication Date
- 2025-09-23
AI Technical Summary
Existing preparation methods for cyclobutene compounds have problems such as cumbersome operations, metal contamination, and poor substrate universality, and lack environmentally friendly and efficient synthesis methods.
Under the protection of inert gas, the compound is dissolved in an aprotic solvent, an organic base is added to react, and by controlling the temperature and time, subsequent filtration, washing, reduced pressure evaporation and column chromatography separation are carried out. Potassium hexamethyldisilazide is used as an alkaline catalyst to avoid transition metal catalysis and adopt a metal-free catalytic cyclization reaction.
The green, safe and efficient preparation of cyclobutene compounds is achieved with high yield, avoiding metal pollution and simplifying the operation process.
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Figure CN120682113A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of organic synthesis, and in particular to a method for preparing a substituted cyclobutene compound. Background Art
[0002] Cyclobutenes are important building blocks for natural products and bioactive compounds. Their unique structural features and inherent ring strain make them active intermediates in organic synthesis, useful for the synthesis of linear, carbocyclic, and cyclic compounds. Natural products containing a cyclobutene nucleus include neofavelanone, fomagnosin, lludolactone A, and taynudol.
[0003]
[0004] As shown in the formula below, existing synthetic strategies for cyclobutene mainly include [2+2] cycloaddition reactions of alkenes and alkynes, [3+1] cycloaddition reactions of alkenyldiazo compounds and sulfur ylides or diazo compounds, and asymmetric transformation reactions of four-membered carbocyclic compounds.
[0005]
[0006] In general, cyclobutene compounds are the core structures of numerous important physiologically active compounds and are widely used in the fields of organic chemistry and agriculture. However, existing methods for preparing these compounds suffer from numerous issues, including cumbersome procedures, metal contamination, and poor substrate compatibility. Therefore, developing more environmentally friendly, environmentally friendly, and efficient synthetic methods for preparing these compounds is not only of great practical value but also of great scientific significance. Summary of the Invention
[0007] In response to the shortcomings of the existing technology, the present invention proposes a method for preparing substituted cyclobutene compounds. Compared with the existing technology, this method is more environmentally friendly, more efficient, and easier to operate. The specific technical solution is as follows:
[0008] A method for preparing a substituted cyclobutene compound, the preparation method is as follows:
[0009] Under the protection of an inert gas, the compound represented by formula (I) and the compound represented by formula (II) are dissolved in an aprotic solvent, and an organic base is added under stirring, wherein the molar ratio of the compound represented by formula (I), the compound represented by formula (II), and the organic base is 3:2:6. Then, an aprotic solvent is added, and the mixture is reacted at 0-60°C for 2-4 hours. Then, water is added to quench the mixture, the mixture is filtered, washed, and evaporated to dryness under reduced pressure to obtain product (III). Methanol is then added, and NaBH4 is added for reduction for 6-12 hours, wherein the molar ratio of the product (III) to NaBH4 is 1:5. Then, water is added to quench the mixture, the mixture is filtered, washed, and evaporated to dryness under reduced pressure. Product (IV) is separated by column chromatography.
[0010]
[0011] Among them, Ar 1 Any one selected from phenyl, substituted phenyl, and naphthyl, Ar 2 Any one selected from phenyl, substituted phenyl, naphthyl, and aromatic heterocyclic groups.
[0012] The first step reaction is carried out in the temperature range of 0 to 60°C, where the yield of product (III) is the highest. If the temperature is lower than this range, the reaction will be incomplete. If the temperature is higher than this range, the structure of product (III) will be destroyed, and the ideal yield cannot be obtained.
[0013] The first step reaction is carried out within a time range of 2-4 hours, and the yield of product (III) is the highest. A time shorter than 2 hours will result in incomplete reaction, and a time longer than 4 hours will cause the structure of product (III) to be destroyed, and the ideal yield cannot be obtained.
[0014] The second step reaction is carried out within a time range of 6-12 h, and the yield of product (IV) is the highest. A reaction time of less than 6 h will result in incomplete reaction, and the reaction can be completed in about 12 h. A reaction time exceeding 12 h will result in a decrease in the overall reaction efficiency.
[0015] Furthermore, the aprotic solvent is selected from any one of toluene, dioxane, ethylene glycol dimethyl ether, cyclopentyl methyl ether, and tetrahydrofuran, which helps to improve the yield.
[0016] Furthermore, the base is selected from potassium hexamethyldisilazide, which helps to improve the yield.
[0017] Furthermore, after quenching, neutral alumina and silica gel powder are added for filtration.
[0018] Further, washing was performed with ethyl acetate.
[0019] Furthermore, in the column chromatography separation, the eluent system PE:EA=8:1 to 1:1, and the separation effect is best under this eluent condition.
[0020] A series of substituted cyclobutene compounds were obtained using the method of the present invention, and the structures are as follows:
[0021]
[0022] The present invention has the following beneficial effects compared to the prior art:
[0023] The present invention proposes a scheme for synthesizing cyclobutenes without transition metal catalysis, ligands, or additives. Compared to the [3+1]-cycloaddition of alkenyldiazo compounds with sulfur ylides or diazo compounds, or the conversion of four-membered carbocyclic compounds, the reaction is highly safe, mild, and environmentally friendly. The readily available raw materials also offer a significant advantage. Compared to traditional [2+2]-cycloaddition reactions of alkenes and alkynes, the reaction does not require the introduction of transition metals or strong light irradiation, making it easy to operate and highly atom-economical. In summary, the present invention utilizes readily available cinnamamides as raw materials under metal-free conditions, which are then cyclized with diphenylmethyl-3-phenylprop-2-yn-1-imine compounds under alkaline conditions to produce a series of representative substituted cyclobutene compounds. DETAILED DESCRIPTION
[0024] The present invention will be described in detail below based on preferred embodiments, and the purpose and effect of the present invention will become more apparent. The present invention will be further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.
[0025] Example 1
[0026] Preparation and characterization of compound IV-1:
[0027]
[0028] Under nitrogen, the compound represented by Formula I-1 (44.3 mg, 0.15 mmol) and the compound represented by Formula II-1 (17.5 mg, 0.1 mmol) were dissolved in 1.0 mL of dioxane. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of dioxane. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-1. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-1 was separated by column chromatography (PE:EA = 3:1) to obtain product IV-1 as a white solid with a yield of 77%. 1H NMR (400MHz, CDCl3): δ7.44 (dd, J=7.7, 2.5Hz, 4H), 7.34-7.29 (m, 8H), 7.24-7.20 (m, 3H), 7.18-7.11(m,5H),4.96(s,1H),4.14(s,1H),3.83-3.69(m,3H),2.95(s,3H),2.86(s,3H).
[0029] Example 2
[0030] Preparation and characterization of compound IV-2:
[0031]
[0032] Under nitrogen, the compound represented by Formula I-1 (44.3 mg, 0.15 mmol) and the compound represented by Formula II-2 (18.9 mg, 0.1 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of toluene. The mixture was reacted at 0°C for 4 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-2. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 6 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-2 was separated by column chromatography (PE:EA = 8:1) to obtain product IV-2 as a white solid with a yield of 57%. 1 H NMR (400MHz, CDCl3): δ7.49-7.47(m,4H),7.36-7.32(m,4H),7.29-7.23(m,5H),7.19-7.13(m,6H) ,5.0(s,1H),4.13(s,1H),3.87-3.70(m,2H),3.70(s,1H),2.98(s,3H),2.88(s,3H),2.36(s,3H).
[0033] Example 3
[0034] Preparation and characterization of compound IV-3:
[0035]
[0036] Under nitrogen, the compound represented by Formula I-1 (44.3 mg, 0.15 mmol) and the compound represented by Formula II-3 (25.9 mg, 0.1 mmol) were dissolved in 1.0 mL of ethylene glycol dimethyl ether. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of ethylene glycol dimethyl ether. The mixture was reacted at 60°C for 2 h, quenched with water, filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-3. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h, quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-3 was separated by column chromatography (PE:EA = 3:1) to obtain product IV-3 as a white solid with a yield of 77%. 1 H NMR (400MHz, CDCl3): δ7.42-7.39(m,4H),7.31-7.26(m,5H),7.227.07(m,10H),4.91(s, 1H), 4.16 (s, 1H), 3.72 (dd, J = 26.0, 12.0Hz, 2H), 3.62 (s, 1H), 2.92 (s, 3H), 2.85 (s, 3H).
[0037] Example 4
[0038] Preparation and characterization of compound IV-4:
[0039]
[0040] Under nitrogen, the compound represented by Formula I-1 (44.3 mg, 0.15 mmol) and the compound represented by Formula II-4 (26.7 mg, 0.1 mmol) were dissolved in 1.0 mL of cyclopentyl methyl ether. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of cyclopentyl methyl ether. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-4. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-4 was separated by column chromatography (PE:EA = 2:1) to obtain product IV-4 as a white solid with a yield of 83%. 1H NMR (400MHz, CDCl3): δ7.49-7.47(m,4H),7.40-7.30(m,10H),7.28-7.24(m,3H),7.19-7.14(m,3H),7.05(d, J=7.6Hz,2H),6.99(d,J=8.5Hz,2H),4.99(s,1H),4.18(s,1H),3.87-3.71(m,3H),3.00(s,3H),2.94(s,3H).
[0041] Example 5
[0042] Preparation and characterization of compound IV-5:
[0043]
[0044] Under nitrogen, the compound represented by Formula I-1 (44.3 mg, 0.15 mmol) and the compound represented by Formula II-5 (18.9 mg, 0.1 mmol) were dissolved in 1.0 mL of tetrahydrofuran. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of tetrahydrofuran. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-5. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-5 was separated by column chromatography (PE:EA = 8:1) to obtain product IV-5 as a white solid with a yield of 48%. 1 H NMR (400MHz, CDCl3): δ7.46 (d, J = 7.2Hz, 4H), 7.37-7.33 (m, 4H), 7.29-7.22 (m, 5H), 7.21-7.10 (m, 6H ),4.98(s,1H),4.55(s,1H),3.81-3.71(m,2H),3.68(s,1H),3.01(s,3H),2.97(s,3H),2.46(s,3H).
[0045] Example 6
[0046] Preparation and characterization of compound IV-6:
[0047]
[0048] Under nitrogen, the compound represented by Formula I-1 (44.3 mg, 0.15 mmol) and the compound represented by Formula II-6 (25.1 mg, 0.1 mmol) were dissolved in 1.0 mL of dioxane. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of dioxane. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-6. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-6 was separated by column chromatography (PE:EA = 5:1) to obtain product IV-6 as a white solid with a yield of 68%. 1 H NMR (400MHz, CDCl3): δ7.44-7.39(m,6H),7.35-7.28(m,10H),7.24-7.15(m,8H),4.91(s,1H),4.46(s,1H),3.71-3.59(m,3H),2.81(s,6H).
[0049] Example 7
[0050] Preparation and characterization of compound IV-7:
[0051]
[0052] Under nitrogen, the compound represented by Formula I-1 (44.3 mg, 0.15 mmol) and the compound represented by Formula II-7 (22.5 mg, 0.1 mmol) were dissolved in 1.0 mL of dioxane. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of dioxane. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-7. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-7 was separated by column chromatography (PE:EA = 3:1). Product IV-7 was obtained as a white solid with a yield of 70%. 1H NMR (400MHz, CDCl3): δ8.12(d,J=8.1Hz,1H),7.83(d,J=8.0Hz,1H),7.67(d,J=8.0Hz,1H),7.51-7.45(m,2H),7.34 (t,J=6.8Hz,4H),7.27-7.20(m,6H),7.19-7.13(m,7H),4.89(s,1H),3.73-3.63(m,3H),2.94(s,3H),2.75(s,3H).
[0053] Example 8
[0054] Preparation and characterization of compound IV-8:
[0055]
[0056] Under nitrogen, the compound represented by Formula I-1 (44.3 mg, 0.15 mmol) and the compound represented by Formula II-8 (25.1 mg, 0.1 mmol) were dissolved in 1.0 mL of dioxane. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of dioxane. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-8. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-8 was separated by column chromatography (PE:EA = 3:1). Product IV-8 was obtained as a white solid with a yield of 59%. 1 H NMR (400MHz, CDCl3): δ7.39-7.35(m,4H),7.25-7.21(m,5H),7.19-7.13(m,4H),7.12-7.01(m,6H),6.68(d,J=4.5Hz,2 H),6.66-6.63(m,1H),5.87(d,J=20.2Hz,2H),4.92(s,1H),4.23(s,1H),3.82-3.64(m,3H),2.88(s,3H),2.82(s,3H).
[0057] Example 9
[0058] Preparation and characterization of compound IV-9:
[0059]
[0060] Under nitrogen, the compound represented by Formula I-1 (44.3 mg, 0.15 mmol) and the compound represented by Formula II-9 (18.1 mg, 0.1 mmol) were dissolved in 1.0 mL of dioxane. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of dioxane. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-9. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-9 was separated by column chromatography (PE:EA = 3:1) to obtain product IV-9 as a white solid with a yield of 50%. 1 H NMR (400MHz, CDCl3): δ7.50-7.46(m,4H),7.35(t,J=7.5Hz,4H),7.31-7.26(m,3H),7.23-7.17(m,6H),7.07(d,J=3.7Hz,1H) ,4.98(s,1H),4.32(d,J=2.3Hz,1H),3.83(d,J=14.4Hz,1H),3.78(s,1H),3.72(d,J=14.5Hz,1H),3.00(s,3H),2.97(s,3H).
[0061] Example 10
[0062] Preparation and characterization of compound IV-10:
[0063]
[0064] Under nitrogen, the compound represented by Formula I-1 (44.3 mg, 0.15 mmol) and the compound represented by Formula II-10 (21.9 mg, 0.1 mmol) were dissolved in 1.0 mL of dioxane. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of dioxane. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-10. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-10 was separated by column chromatography (PE:EA = 1:1) to obtain product IV-10 as a white solid with a yield of 58%. 1H NMR (400MHz, CDCl3): δ7.46-7.42(m,4H),7.31(t,J=7.5Hz,4H),7.24-7.20(m,2H),7.19-7.13(m,5H),6.76(d,J=5.0Hz,2H),6.74 -6.70(m,1H),5.98(d,J=1.4Hz,1H),5.93(d,J=1.3Hz,1H),4.97(s,1H),4.29(s,1H),3.82-3.67(m,3H),2.96(s,3H),2.90(s,3H).
[0065] Example 11
[0066] Preparation and characterization of compound IV-11:
[0067]
[0068] Under nitrogen, the compound represented by Formula I-2 (46.4 mg, 0.15 mmol) and the compound represented by Formula II-1 (17.5 mg, 0.1 mmol) were dissolved in 1.0 mL of dioxane. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of dioxane. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-11. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-11 was separated by column chromatography (PE:EA = 3:1) to obtain product IV-11 as a white solid with a yield of 73%. 1 H NMR (400MHz, CDCl3): δ7.52 (d, J = 7.4Hz, 4H), 7.41-7.35 (m, 8H), 7.31-7.27 (m, 3H), 7.11-7.0 2(m,4H),5.03(s,1H),4.20(s,1H),3.89-3.74(m,3H),3.02(s,3H),2.91(s,3H),2.33(s,3H).
[0069] Example 12
[0070] Preparation and characterization of compound IV-12:
[0071]
[0072] Under nitrogen, the compound represented by Formula I-3 (52.7 mg, 0.15 mmol) and the compound represented by Formula II-1 (17.5 mg, 0.1 mmol) were dissolved in 1.0 mL of dioxane. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of dioxane. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-12. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-12 was separated by column chromatography (PE:EA = 3:1) to obtain product IV-12 as a white solid with a yield of 69%. 1 H NMR (400MHz, CDCl3): δ7.51-7.47(m,4H),7.40-7.32(m,9H),7.30-7.27(m,2H),7.24-7.21(m,2H),7.1 1(d,J=8.2Hz,2H),5.00(s,1H),4.16(s,1H),3.86-3.70(m,3H),2.98(s,3H),2.88(s,3H),1.29(s,9H).
[0073] Example 13
[0074] Preparation and characterization of compound IV-13:
[0075]
[0076] Under nitrogen, the compound represented by Formula I-4 (47.0 mg, 0.15 mmol) and the compound represented by Formula II-1 (17.5 mg, 0.1 mmol) were dissolved in 1.0 mL of dioxane. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of dioxane. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-13. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-13 was separated by column chromatography (PE:EA = 3:1) to obtain product IV-13 as a white solid with a yield of 49%. 1H NMR (400MHz, CDCl3): δ7.45-7.43(m,4H),7.33-7.29(m,8H),7.25-7.20(m,3H),7.08(t,J=7.0Hz ,2H),3.77-3.62(m,2H),4.93(s,1H),4.09(s,1H),3.78-3.62(m,3H),2.95(s,3H),2.84(s,3H).
[0077] Example 14
[0078] Preparation and characterization of compound IV-14:
[0079]
[0080] Under nitrogen, the compound represented by Formula I-7 (56.9 mg, 0.15 mmol) and the compound represented by Formula II-1 (17.5 mg, 0.1 mmol) were dissolved in 1.0 mL of dioxane. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of dioxane. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-14. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-14 was separated by column chromatography (PE:EA = 2:1) to obtain product IV-14 as a white solid with a yield of 76%. 1 H NMR (400MHz, CDCl3): δ7.57-7.53(m,4H),7.45-7.40(m,9H),7.38-7.33(m,4H),7.11(d ,J=8.2Hz,2H),5.05(s,1H),4.22(s,1H),3.91-3.73(m,3H),3.06(s,3H),2.96(s,3H).
[0081] Example 15
[0082] Preparation and characterization of compound IV-15:
[0083]
[0084] Under nitrogen, the compound represented by Formula I-8 (48.8 mg, 0.15 mmol) and the compound represented by Formula II-1 (17.5 mg, 0.1 mmol) were dissolved in 1.0 mL of dioxane. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of dioxane. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-15. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-15 was separated by column chromatography (PE:EA = 2:1) to obtain product IV-15 as a white solid with a yield of 53%. 1 H NMR (400MHz, CDCl3): δ7.61-7.57(m,4H),7.48-7.43(m,8H),7.41-7.36(m,3H),7.21(d,J=8.9Hz, 2H), 6.84 (d, J = 9.0Hz, 2H), 5.11 (s, 1H), 4.25 (s, 1H), 3.93-3.79 (m, 6H), 3.09 (s, 3H), 3.00 (s, 3H).
[0085] Example 16
[0086] Preparation and characterization of compound IV-16:
[0087]
[0088] Under nitrogen, the compound represented by Formula I-10 (51.8 mg, 0.15 mmol) and the compound represented by Formula II-1 (17.5 mg, 0.1 mmol) were dissolved in 1.0 mL of dioxane. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added with stirring, followed by 1.0 mL of dioxane. The mixture was reacted at 25°C for 2 h, then quenched with water. The mixture was filtered through a small amount of neutral alumina and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure to obtain product III-16. 2 mL of methanol and NaBH4 (19.0 mg, 0.5 mmol) were then added for reduction for 12 h. The mixture was then quenched with water, filtered through a small amount of silica gel powder and anhydrous sodium sulfate, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The product IV-16 was separated by column chromatography (PE:EA = 3:1) to obtain product IV-16 as a white solid with a yield of 43%. 1H NMR (400MHz, CDCl3): δ7.60-7.57(m,2H),7.55-7.51(m,4H),7.48-7.44(m,5H),7.43-7.41(m,2H),7.40 -7.36(m,6H),7.33-7.28(m,3H),5.05(s,1H),4.24(s,1H),3.93-3.77(m,3H),3.02(s,3H),2.92(s,3H).
[0089] Those skilled in the art will understand that the foregoing descriptions are merely preferred embodiments of the invention and are not intended to limit the invention. Although the invention has been described in detail with reference to the foregoing examples, those skilled in the art will still be able to modify the technical solutions described in the foregoing examples or substitute equivalents for some of the technical features therein. Any modifications, equivalent substitutions, etc. made within the spirit and principles of the invention shall be included within the scope of protection of the invention.
Claims
1. A method for preparing a substituted cyclobutene compound, characterized in that: The preparation method is as follows: Under the protection of an inert gas, the compound represented by formula (I) and the compound represented by formula (II) are dissolved in an aprotic solvent, and an organic base is added under stirring, wherein the molar ratio of the compound represented by formula (I), the compound represented by formula (II), and the organic base is 3:2:
6. Then, an aprotic solvent is added, and the mixture is reacted at 0-60°C for 2-4 hours. Then, water is added to quench the mixture, the mixture is filtered, washed, and evaporated to dryness under reduced pressure to obtain product (III). Methanol is then added, and NaBH4 is added for reduction for 6-12 hours, wherein the molar ratio of the product (III) to NaBH4 is 1:
5. Then, water is added to quench the mixture, the mixture is filtered, washed, and evaporated to dryness under reduced pressure. Product (IV) is separated by column chromatography. Among them, Ar 1 Any one selected from phenyl, substituted phenyl, and naphthyl, Ar 2 Any one selected from phenyl, substituted phenyl, naphthyl, and aromatic heterocyclic groups.
2. The method for preparing a substituted cyclobutene compound according to claim 1, wherein: The aprotic solvent is selected from any one of toluene, dioxane, ethylene glycol dimethyl ether, cyclopentyl methyl ether, and tetrahydrofuran.
3. The method for preparing a substituted cyclobutene compound according to claim 1, wherein: The base is potassium hexamethyldisilazide.
4. The method for preparing a substituted cyclobutene compound according to claim 1, wherein After quenching, neutral alumina and anhydrous sodium sulfate, or silica gel powder and anhydrous sodium sulfate are added and filtered.
5. The method for preparing a substituted cyclobutene compound according to claim 1, wherein: Washing was carried out with ethyl acetate.
6. The method for preparing a substituted cyclobutene compound according to claim 1, wherein: The eluent system in column chromatography separation is PE:EA=8:1~1:1.