Synthesis method of a cyclohexyl-substituted styrene compound

Abstract

The present invention discloses a method for synthesizing cyclohexyl-substituted styrene compounds. The synthesis method comprises the following steps: A β-nitrostyrene derivative shown in Formula I and cyclohexylboronic acid shown in Formula II react in a solvent in the presence of a photocatalyst and a base under visible light irradiation. After the reaction is completed, the reaction mixture is separated and purified to obtain the cyclohexyl-substituted styrene compound shown in Formula III. The present invention can achieve an improvement in the overall yield of the target product, with good product quality, simple operation, mild reaction conditions, and low prices for the raw materials and solvents used throughout the process, which is beneficial to cost control.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemical synthesis, and particularly relates to a method for synthesizing cyclohexyl-substituted styrene compounds. Background Art

[0002] Alkylstyrene compounds including (E)-alkylstyrene are important industrial compounds and are useful intermediates, which are widely used in organic synthesis, materials, medicine, and the synthesis of natural compounds. Traditional methods for synthesizing olefins include Heck reaction, Wittig reaction, Julia olefination reaction, Peterson olefination reaction, and other traditional methods. However, these reactions all require metal catalysts and high temperatures, and the reaction conditions are harsh.

[0003] With the increasing attention to the application of photoredox catalysis in organic chemistry, reports on photoredox alkenylation reactions have emerged in recent years. In 2012, [Chemistry Open, 2012, 1(3): 130 - 133] reported that using nitroolefins as the olefin source, [Ru(bpy)3] 2+ catalyzes the arylation of diazonium salts under visible light to generate stilbene. In this reaction, nitroolefins undergo cross-coupling with NO2 as the leaving group, however, the product yield is only 37%. In 2016, Molander [J. Org. Chem. 2016, 81, 7308] reported a visible light-mediated coupling reaction of vinyl sulfones and potassium α-pyrrolidinyltrifluoroborate to obtain cyclohexyl-substituted styrene compounds, but the reaction has low yield and limited substrate scope.

[0004] In 2017, Wang [Org. Lett. 2017, 19, 6412 - 6415] reported a regio- and stereoselective decarboxylative coupling of α,β-unsaturated acids and alkyl iodides induced by ultraviolet light and catalyzed by copper to obtain 1-alkyl-2-aryl ethylene. In 2021, the Lu research group [Tetrahedron, 92(2021), 132259] developed the first photoinduced copper-catalyzed double decarboxylative cross-coupling of α,β-unsaturated carboxylic acids and redox-active esters to obtain 1-alkyl-2-aryl ethylene. In 2021, the Yue research group [Org. Lett. 2021, 23, 2477 - 2481] reported a visible light-mediated allylation reaction of nitroolefins and alkylboronic acids directly at room temperature without an external Lewis base as an activator. Although the above reactions can all obtain the target products, the final yields are relatively low.

[0005] Therefore, it is necessary to develop a synthesis method with mild reaction conditions, simple operation, and high yield. Summary of the Invention

[0006] The object of the present invention is to provide a synthesis method of cyclohexyl-substituted styrene compounds with mild reaction conditions, simple operation and high yield.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] A synthesis method of cyclohexyl-substituted styrene compounds shown in Formula III, the synthesis method comprising the following steps: a β-nitrostyrene derivative shown in Formula I and cyclohexylboronic acid shown in Formula II react in a solvent in the presence of a photocatalyst and a base under visible light irradiation. After the reaction is completed, the reaction mixture is separated and purified to obtain the cyclohexyl-substituted styrene compound shown in Formula III;

[0009] The solvent is selected from at least one of dichloromethane (DCM) and N-methylpyrrolidone (NMP);

[0010] The photocatalyst is selected from at least one of Ir[dF(CF3)ppy]₂(dtbbpy)PF₆ and Eosin Y;

[0011] The base is selected from at least one of Na₂CO₃, K₂CO₃, K₂HPO₄, K₃PO₄, and Na₂HPO₄;

[0012]

[0013] Wherein, R is hydrogen, C₁-C₄ alkyl, halogen, aryl or trifluoromethyl, preferably the aryl is phenyl.

[0014] Preferably, R is hydrogen or C₁-C₄ alkyl, more preferably hydrogen.

[0015] Preferably, the solvent is dichloromethane (DCM).

[0016] Preferably, the photocatalyst is Ir[dF(CF3)ppy]₂(dtbbpy)PF₆.

[0017] Preferably, the base is K₃PO₄.

[0018] Preferably, the molar ratio of the β-nitrostyrene compound to cyclohexylboronic acid, photocatalyst and base is 1:1-4:1%-4%:1-2, more preferably 1:3-4:1.5%-2.5%:1.5-2, and even more preferably 1:4:2%:1.5.

[0019] Preferably, the volume dosage of the solvent is 8-12 mL / mmol based on the molar dosage of the β-nitrostyrene compound, more preferably 10 mL / mmol.

[0020] Preferably, the light source used for the illumination is a 5W blue LED lamp, a 5W green LED lamp or a 5W white LED lamp, more preferably a 5W blue LED lamp.

[0021] Preferably, the reaction conditions are: stirring reaction at room temperature and monitoring the completion of the reaction by TLC.

[0022] Preferably, the separation and purification are carried out by the following steps: after monitoring the completion of the reaction by TLC, adding distilled water to quench the reaction, extracting the obtained mixture with ethyl acetate, washing the collected organic layer successively with deionized water and saturated brine, drying with anhydrous sodium sulfate, filtering, removing the solvent and then purifying by column chromatography to obtain cyclohexyl-substituted styrene compounds. Further preferably, the column chromatography uses a silica column, and the washing reagent is a mixed solvent of petroleum ether and ethyl acetate; more preferably, in the elution reagent, V 石油醚 :V 乙酸乙酯 = 5:1.

[0023] In the present invention, the synthesis of the raw material β-nitrostyrene derivative can refer to the literature [Org Lett. 2013, 15, 11, 2660 - 2663], and the specific synthesis method is: reacting benzaldehyde shown in formula IV with MeNO2 shown in formula V in AcOH and NH4OAc to generate β-nitrostyrene shown in formula VI; the reaction equation is as follows:

[0024]

[0025] In formula IV or VI, the definition of R is the same as that in formula I.

[0026] The cyclohexyl-substituted styrene compounds synthesized in the present invention can be used as organic synthesis intermediates. For example, referring to the literature [ACS Catal. 2020, 10, 8, 4617–4629], diketone compounds are obtained by oxidizing cyclohexyl-substituted styrene compounds as raw materials, and diketone compounds are important intermediates for synthesizing quinoxaline derivatives. For example, referring to the literature [Bioorganic & Medicinal Chemistry Letters 17(2007)

[0027] 1663–1666], substituting quinoxaline amide derivatives with drug activity are obtained by reacting diketone compounds and 3,4-diaminobenzoic acid as raw materials.

[0028] Compared with the prior art, the beneficial effects of the present invention are as follows: a rapid synthesis method of cyclohexyl-substituted styrene compounds is provided, which can improve the overall yield of the target product, the product quality is good, the operation is simple, the reaction conditions are mild, and the raw materials and solvents used in the whole process are low in price, which is beneficial to cost control. Description of the Drawings

[0029] Figure 1 and Figure 2 are the hydrogen spectrum and carbon spectrum of 1-phenyl-2-cyclohexylethylene synthesized in Example 1, respectively.

[0030] Figure 3 and Figure 4 are the hydrogen spectrum and carbon spectrum of 1-(2-cyclohexylethynyl)-4-methylbenzene synthesized in Example 2, respectively.

[0031] Figure 5 and Figure 6 are the hydrogen spectrum and carbon spectrum of 1-bromo-4-(2-cyclohexylethynyl)benzene synthesized in Example 3, respectively.

[0032] Figure 7 [[ID=2l]]and Figure 8 are the hydrogen spectrum and carbon spectrum of 1-(2-cyclohexylethynyl)-4-trifluoromethylbenzene synthesized in Example 4, respectively.

[0033] Figure 9 and Figure 10 are the hydrogen spectrum and carbon spectrum of 4-(2-cyclohexylethynyl)-1,1'-biphenyl synthesized in Example 5, respectively. Detailed implementation manners

[0034] The technical features in the technical solutions provided by the present invention will be further clearly and completely described below in conjunction with the detailed implementation manners. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0035] Example 1: Synthesis of 1-phenyl-2-cyclohexylethylene

[0036] 0.0298 g of β-nitrostyrene (0.2 mmol), 0.1024 g of cyclohexylboronic acid (0.8 mmol), 0.06368 g of K3PO4 (0.3 mmol), 0.0049 g of Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2% mol) and 2 mL of DCM were added to a dry 25 mL reaction tube. Under a nitrogen atmosphere, the reaction was carried out at room temperature for 16 h under the irradiation of a 5 W blue lamp. After monitoring the completion of the reaction by TLC, the reaction was quenched by adding distilled water. The obtained mixture was extracted three times with ethyl acetate (25 mL). The collected organic layer was washed twice with distilled water, then washed with saturated NaCl water, dried over anhydrous Na2SO4, filtered, and finally the solvent was removed by rotary evaporation. Using petroleum ether and ethyl acetate in a volume ratio of V 石油醚 : V 乙酸乙酯Using a mixed solvent with a volume ratio of 5:1 as the eluent, the target product was separated and purified by silica gel column (silica column) chromatography, and the yield was 93%.

[0037] Product characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.43–7.22 (m, 5H), 6.39 (t, J = 13.4 Hz, 1H), 6.23 (dd, J = 16.0, 6.9 Hz, 0.16H), 5.54 (t, J = 10.9 Hz, 0.73H), 2.74–2.57 (m, 0.83H), 1.90–1.70 (m, 5H), 1.41–1.19 (m, 5H). 13 C NMR (101 MHz, CDCl3) δ 139.01, 138.10, 138.01, 1,36.86, 128.63, 128.47, 128.20, 127.28, 126.88, 126.74, 126.43, 125.97, 41.19, 36.94, 33.31, 33.01, 26.23, 26.08, 25.72.

[0038] Example 2: Synthesis of 1-(2-cyclohexylvinyl)-4-methylbenzene

[0039] 0.0326 g of 1-methyl-4-(2-nitrovinyl)benzene (0.2 mmol), 0.1024 g of cyclohexylboronic acid (0.8 mmol), 0.06368 g of K3PO4 (0.3 mmol), 0.0049 g of Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2% mol) and 2 mL of DCM were added to a dry 25 mL reaction tube. Under a nitrogen atmosphere, the reaction was carried out at room temperature for 16 h under the irradiation of a 5 W blue lamp. After monitoring the completion of the reaction by TLC, the reaction was quenched by adding distilled water. The resulting mixture was extracted three times with ethyl acetate (25 mL). The collected organic layer was washed twice with distilled water and then with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and finally the solvent was removed by rotary evaporation. Using a mixed solvent with a volume ratio of V 石油醚 :V 乙酸乙酯 = 5:1 as the eluent, the target product was separated and purified by silica gel column (silica column) chromatography, and the yield was 95%.

[0040] Product characterization data: 11H NMR (400 MHz, CDCl3) δ 7.31–7.24 (m, 1H), 7.22–7.11 (m, 3H), 6.34 (t, J = 13.8 Hz, 1H), 6.16 (dd, J = 16.0, 6.9 Hz, 0.27H), 5.48 (dd, J = 11.6, 10.2 Hz, 0.73H), 2.70–2.51 (m, 0.95H), 2.37 (d, J = 11.4 Hz, 3H), 2.20–2.10 (m, 0.37H), 1.86–1.68 (m, 5H), 1.38–1.19 (m, 5H). 13 13C NMR (101 MHz, CDCl3) δ 138.39, 136.40, 136.10, 135.87, 135.28, 135.09, 129.16, 128.90, 128.53, 127.02, 126.68, 125.83, 41.17, 36.94, 33.32, 33.04, 26.10, 26.08, 25.74, 21.19.

[0041] Example 3: Synthesis of 1-Bromo-4-(2-cyclohexylvinyl)benzene

[0042] 0.0456 g of 1-bromo-4-(2-nitrovinyl)benzene (0.2 mmol), 0.1024 g of cyclohexylboronic acid (0.8 mmol), 0.06368 g of K3PO4 (0.3 mmol), 0.0049 g of Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2% mol) and 2 mL of DCM were added to a dry 25 mL reaction tube. Under a nitrogen atmosphere, the reaction was carried out at room temperature for 16 h under the irradiation of a 5 W blue lamp. After the reaction was completed as monitored by TLC, the reaction was quenched by adding distilled water. The resulting mixture was extracted three times with ethyl acetate (25 mL). The collected organic layer was washed twice with distilled water, then washed with saturated NaCl water, dried over anhydrous Na2SO4, filtered, and finally the solvent was removed by rotary evaporation. Using a mixed solvent of petroleum ether and ethyl acetate with V 石油醚 : V 乙酸乙酯 = 5:1 as the eluent, the target product was purified by silica gel column (silica column) chromatography, and the yield was 96%.

[0043] Product characterization data: 11H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.5 Hz, 0.65H), 7.23 (d, J = 8.4 Hz, 0.76H), 7.14 (d, J = 8.3 Hz, 2H), 6.25 (d, J = 11.7 Hz, 1.33H), 6.19 (dd, J = 16.0, 6.7 Hz, 0.39H), 5.58–5.50 (m, 1H), 2.51 (dt, J = 10.5, 7.0 Hz, 1H), 2.28–2.15 (m, 0.35H), 1.80–1.70 (m, 5H), 1.21 (dd, J = 21.8, 9.9 Hz, 5H). 13 13C NMR (101 MHz, CDCl3) δ 139.76, 137.71, 137.02, 136.83, 131.50, 131.28, 130.22, 127.51, 126.14, 125.72, 120.30, 120.24, 41.15, 36.94, 33.14, 32.83, 26.13, 26.01, 25.97, 25.64.

[0044] Example 4: Synthesis of 1-(2-Cyclohexylvinyl)-4-trifluoromethylbenzene

[0045] 0.0434 g of 1-(2-Nitrovinyl)-4-trifluoromethylbenzene (0.2 mmol), 0.1024 g of cyclohexylboronic acid (0.8 mmol), 0.06368 g of K3PO4 (0.3 mmol), 0.0049 g of Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2% mol) and 2 mL of DCM were added to a dry 25 mL reaction tube. Under a nitrogen atmosphere, the reaction was carried out at room temperature for 16 h under the irradiation of a 5 W blue lamp. After the reaction was monitored by TLC and completed, the reaction was quenched by adding distilled water. The resulting mixture was extracted three times with ethyl acetate (25 mL). The collected organic layer was washed twice with distilled water, then washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and finally the solvent was removed by rotary evaporation. Using a mixed solvent of petroleum ether and ethyl acetate with V 石油醚 :V 乙酸乙酯 = 5:1 as the eluent, the target product was purified by silica gel column (silica column) chromatography, and the yield was 94%.

[0046] Product characterization data: 11H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.2 Hz, 0.54H), 7.45 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.0 Hz, 0.57H), 6.38 (dd, J = 19.0, 14.1 Hz, 1.24H), 5.67–5.58 (m, 0.87H), 2.55 (d, J = 10.5 Hz, 1H), 2.22–2.14 (m, 0.41H), 1.83–1.72 (m, 5H), 1.26 (ddd, J = 17.8, 16.6, 10.0 Hz, 5H). 13 13C NMR (101 MHz, CDCl3) δ 141.57, 141.05, 140.99, 139.59, 128.76, 126.14, 126.05, 125.67, 125.40, 125.37, 125.14, 41.23, 37.03, 33.11, 32.76, 26.11, 25.98, 25.94, 25.59.

[0047] Example 5: Synthesis of 4-(2-Cyclohexylvinyl)-1,1'-biphenyl

[0048] 0.045 g of 4-(2-Nitrovinyl)-1,1'-biphenyl (0.2 mmol), 0.1024 g of cyclohexylboronic acid (0.8 mmol), 0.06368 g of K3PO4 (0.3 mmol), 0.0049 g of Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2% mol) and 2 mL of DCM were added to a dry 25 mL reaction tube. Under a nitrogen atmosphere, the reaction was carried out at room temperature for 16 h under the irradiation of a 5 W blue lamp. After monitoring the completion of the reaction by TLC, the reaction was quenched by adding distilled water. The resulting mixture was extracted three times with ethyl acetate (25 mL). The collected organic layer was washed twice with distilled water, then washed with saturated NaCl water, dried over anhydrous Na2SO4, filtered, and finally the solvent was removed by rotary evaporation. Using a mixed solvent of petroleum ether and ethyl acetate with V 石油醚 : V 乙酸乙酯 = 5:1 as the eluent, the target product was purified by silica gel column (silica column) chromatography, and the yield was 94%.

[0049] Product characterization data: 11H NMR (400 MHz, CDCl3) δ 7.61 (ddd, J = 24.4, 12.3, 4.8 Hz, 4H), 7.52–7.43 (m, 3H), 7.41–7.33 (m, 2H), 6.39 (dd, J = 17.5, 13.9 Hz, 1H), 6.26 (dd, J = 16.0, 6.9 Hz, 0.36H), 5.55 (dd, J = 11.6, 10.2 Hz, 0.62H), 2.76–2.57 (m, 1H), 2.25–2.14 (m, 0.44H), 1.88–1.70 (m, 5H), 1.39–1.21 (m, 5H). 13 13C NMR (101 MHz, CDCl3) δ 140.92, 140.88, 139.50, 139.29, 139.21, 137.16, 137.11, 137.02, 129.07, 128.79, 128.76, 127.21, 127.19, 127.13, 126.99, 126.91, 126.78, 126.41, 126.36, 41.25, 37.07, 33.29, 32.98, 26.20, 26.06, 25.72.

[0050] Comparative Example 1: Synthesis of 1-phenyl-2-cyclohexylethylene (using Eosin Y as photocatalyst)

[0051] 0.0298 g of β-nitrostyrene (0.2 mmol), 0.1024 g of cyclohexylboronic acid (0.8 mmol), 0.06368 g of K3PO4 (0.3 mmol), 0.0026 g of Eosin Y (2% mol) and 2 mL of DCM were added to a dry 25 mL reaction tube. Under a nitrogen atmosphere, the reaction was carried out at room temperature for 16 h under irradiation with a 5 W blue lamp. After monitoring the completion of the reaction by TLC, the reaction was quenched by adding distilled water. The resulting mixture was extracted three times with ethyl acetate (25 mL). The collected organic layer was washed twice with distilled water, then washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and finally the solvent was removed by rotary evaporation. Using a mixed solvent of petroleum ether and ethyl acetate with V 石油醚 :V 乙酸乙酯 = 5:1 as the eluent, the target product was purified by silica gel column (silica column) chromatography, and the yield was 73%.

[0052] Comparative Example 2: Synthesis of 1-phenyl-2-cyclohexylethylene (using K2CO3 as base)

[0053] 0.0298 g of β-nitrostyrene (0.2 mmol), 0.1024 g of cyclohexylboronic acid (0.8 mmol), 0.0414 g of K2CO3 (0.3 mmol), 0.0049 g of Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2% mol) and 2 mL of DCM were added to a dry 25 mL reaction tube. Under a nitrogen atmosphere, the reaction was carried out at room temperature for 16 h under irradiation with a 5 W blue lamp. After the reaction was monitored by TLC and completed, the reaction was quenched by adding distilled water. The resulting mixture was extracted three times with ethyl acetate (25 mL). The collected organic layer was washed twice with distilled water, then washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and finally the solvent was removed by rotary evaporation. Using a mixed solvent of petroleum ether and ethyl acetate with V 石油醚 :V 乙酸乙酯 = 5:1 as the eluent, the target product was purified by silica gel column (silica column) chromatography, and the yield was 59%.

[0054] Comparative Example 3: Synthesis of 1-phenyl-2-cyclohexylethylene (using N-methylpyrrolidone as the solvent)

[0055] 0.0298 g of β-nitrostyrene (0.2 mmol), 0.1024 g of cyclohexylboronic acid (0.8 mmol), 0.0414 g of K2CO3 (0.3 mmol), 0.0049 g of Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2% mol) and 2 mL of NMP were added to a dry 25 mL reaction tube. Under a nitrogen atmosphere, the reaction was carried out at room temperature for 16 h under irradiation with a 5 W blue lamp. After the reaction was monitored by TLC and completed, the reaction was quenched by adding distilled water. The resulting mixture was extracted three times with ethyl acetate (25 mL). The collected organic layer was washed twice with distilled water, then washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and finally the solvent was removed by rotary evaporation. Using a mixed solvent of petroleum ether and ethyl acetate with V 石油醚 :V 乙酸乙酯 = 5:1 as the eluent, the target product was purified by silica gel column (silica column) chromatography, and the yield was 68%.

Claims

1. A method for synthesizing a cyclohexyl-substituted styrene compound represented by Formula III, characterized in that: The synthesis method comprises the following steps: a β-nitrostyrene derivative shown in Formula I reacts with cyclohexylboronic acid shown in Formula II in a solvent in the presence of a photocatalyst and a base under visible light irradiation. After the reaction is completed, the reaction mixture is separated and purified to obtain a cyclohexyl-substituted styrene compound shown in Formula III; The solvent selected is at least one of dichloromethane and N-methylpyrrolidone; The photocatalyst selected is at least one of Ir[dF(CF3)ppy]2(dtbbpy)PF6 and Eosin Y; The base is at least one of K2CO3 and K3PO4; The light source used for light irradiation is a 5W blue LED lamp; Wherein, R is hydrogen, C1-C4 alkyl, halogen, phenyl or trifluoromethyl.

2. The synthesis method according to claim 1, characterized in that: The molar ratio of the β-nitrostyrene compound, cyclohexylboronic acid, photocatalyst and base used in the feed is 1:1-4:1%-4%:1-2.

3. The synthesis method according to claim 2, characterized in that: The molar ratio of the β-nitrostyrene compound, cyclohexylboronic acid, photocatalyst and base used in the feed is 1:3-4:1.5%-2.5%:1.5-2.

4. The synthesis method according to claim 3, characterized in that: The molar ratio of the β-nitrostyrene compound, cyclohexylboronic acid, photocatalyst and base used in the feed is 1:4:2%:1.

5.

5. The synthesis method according to claim 2, characterized in that: The volume dosage of the solvent is 8-12 mL / mmol based on the molar dosage of the β-nitrostyrene compound.

6. The synthesis method according to claim 1, characterized in that: The reaction conditions are: stirring reaction at room temperature, and monitoring the completion of the reaction by TLC.

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