CN108727323B - Method for catalytically synthesizing trifluoromethyl substituted homoisoflavone compound by using N-heterocyclic carbene - Google Patents
Method for catalytically synthesizing trifluoromethyl substituted homoisoflavone compound by using N-heterocyclic carbene Download PDFInfo
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- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
Abstract
The invention belongs to the field of organic synthetic chemistry, and particularly relates to a method for synthesizing trifluoromethyl substituted homoisoflavone compounds by using nitrogen heterocyclic carbene as a catalyst. The invention takes trifluoromethyl substituted olefine aldehyde compound as raw material, under the action of organic solvent and alkali, nitrogen heterocyclic carbene is taken as catalyst under room temperature environment, intermediate flavonoid compound is prepared after reaction for several hours, then under the action of simple substance iodine, concentrated sulfuric acid and organic solvent, trifluoromethyl substituted homoisoflavonoid compound is prepared after reaction at 50-100 ℃, and the obtained product is separated and purified through recrystallization or thin layer chromatography or column chromatography. The preparation method is green and efficient, and compared with the existing method, the method has the advantages of wide applicable substrate range, convenient and easily obtained substrate, mild reaction conditions, simple and convenient operation, high reaction efficiency and good selectivity.
Description
Technical Field
The invention belongs to the field of organic synthetic chemistry, and particularly relates to a method for synthesizing trifluoromethyl substituted homoisoflavone compounds by using nitrogen heterocyclic carbene as a catalyst.
Background
Homoisoflavonoid compounds as antitumor agentsAre an important class of organic compounds which have a very important role in biomedical and synthetic research (Mulholland, d. a.; Schwikkard, s. l.; Crouch, n. R).Nat. Prod. Rep.2013, 30, 1165.). At present, a representative synthesis scheme for synthesizing homoisoflavonoids compounds is a coupling reaction of bio-enzyme catalysis chromone and halogenated hydrocarbon; lewis acids catalyze the dehydration coupling reaction of chromone derived alcohols with terminal alkynes ((a) Singh, P.; Kumar, A.; Kaur, S.; Kaur, J.; Singh, H).Chem. Commun.2016, 52, 2936. (b) W. Chen, Z. Hao, L. Zhe, L. Li, W. Dong and C. Yongjun, Chin. J. Chem., 2011, 29, 2732-2738.). However, these methods have limitations such as the need for pre-functionalization of the starting materials, relatively complicated and harsh reaction conditions (expensive catalysts, etc.), low yields (low atom economy), limited substrate latitude and green chemistry, which limits their application in mass reactions or industrial production. Therefore, the development of a method for synthesizing the trifluoromethyl substituted homoisoflavonoid compound, which has the advantages of cheap and easily obtained raw materials, simple steps, convenient operation, mild conditions, wide substrate application range and high efficiency, is a key point and a difficult point. The method for synthesizing the trifluoromethyl substituted homoisoflavonoid compound under the action of the iodine simple substance and concentrated sulfuric acid by taking the olefine aldehyde compound as a raw material and N-Heterocyclic Carbene (NHC) as a catalyst and adopting a proper alkali for reaction is a simple, convenient and practical synthetic method.
Disclosure of Invention
The invention aims to provide a method for synthesizing trifluoromethyl substituted homoisoflavonoid compounds by using N-heterocyclic carbene as a catalyst.
In order to achieve the purpose, the invention adopts the following technical method:
the invention takes trifluoromethyl substituted olefine aldehyde compound as raw material, under the action of organic solvent and alkali, nitrogen heterocyclic carbene is taken as catalyst, reaction is carried out for 3-10 hours under room temperature environment to prepare intermediate flavonoid compound, then under the action of simple substance iodine, concentrated sulfuric acid and organic solvent, reaction is carried out at 50-100 ℃ to prepare trifluoromethyl substituted homoisoflavone compound, and the obtained product is separated and purified through recrystallization, thin layer chromatography or column chromatography.
Can be represented by the following formula:
the molecular general formula of the olefine aldehyde compound is as follows:
(ii) a The molecular general formula of the synthesized homoisoflavonoid compound is as follows:
. In the formula: r1Is one of alkyl, halogen atom, hydrogen atom, alkoxy, ester group and nitro; r2Is one of alkyl, alkenyl and aryl.
The N-heterocyclic carbene (NHC) is one of imidazole, triazole and thiazole salt;
the alkali is one of common inorganic alkali such as potassium carbonate, sodium carbonate, potassium phosphate, potassium acetate, sodium alkoxide, sodium hydroxide, potassium hydroxide and the like and common organic alkali such as triethylamine, 1, 8-diazabicycloundecene-7-ene and the like;
the molar ratio of the trifluoromethyl-substituted olefine aldehyde compound to the N-heterocyclic carbene is 1: 0.1-1: 0.2;
the molar ratio of the trifluoromethyl substituted olefine aldehyde compound to the alkali is 1: 0.1-1: 1.5;
the organic solvent is one of acetonitrile, toluene, tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, dichloromethane, 1, 4-dioxane, dimethyl sulfoxide and dimethylformamide.
Elemental iodine is used as an oxidizing agent.
The product prepared by the method is separated by methods such as recrystallization, thin-layer chromatography or column chromatography. For example, by recrystallization, the solvent is preferably a mixed solvent of a polar solvent and a nonpolar solvent, and the solvent is preferably a mixed solvent of dichloromethane-n-hexane, isopropanol-petroleum ether, ethyl acetate-n-hexane, or isopropanol-ethyl acetate-petroleum ether. By thin layer chromatography and column chromatography, the developing solvent is a mixed solvent of polar solvent and nonpolar solvent, the recommended solvent can be mixed solvent of isopropanol-petroleum ether, ethyl acetate-n-hexane or isopropanol-ethyl acetate-petroleum ether, and the volume ratio can be respectively: polar solvent: the nonpolar solvent is 1: 3 to 1: 10. For example: ethyl acetate: petroleum ether is 1: 3 to 1:10, and isopropanol: the petroleum ether is 1: 3-1: 10.
The invention has the beneficial effects that:
the invention provides a method for synthesizing trifluoromethyl substituted homoisoflavonoid compounds by using N-heterocyclic carbene as a catalyst. Compared with the prior art, the method is applicable to various olefine aldehyde compounds of different types, has mild reaction conditions, cheap and easily obtained raw materials, simple and convenient operation, high reaction yield and atom economy, and well embodies the concept of green chemistry.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a substrate 1 a;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the substrate 1 b;
FIG. 3 is a NMR hydrogen spectrum of the product of example 1;
FIG. 4 is a NMR carbon spectrum of the product of example 1;
FIG. 5 is a NMR hydrogen spectrum of the product of example 2;
FIG. 6 is a NMR carbon spectrum of the product of example 2.
Detailed Description
The following examples will help to understand the present invention, but do not limit the contents of the present invention.
Substrate 1a Synthesis
To a dry three-necked flask, salicylaldehyde (10.0 mmol), K2CO3 (15 mmol) and DMF (30 mL) were added sequentially under nitrogen, and stirred(4-bromo-1, 1, 1-trifluorobut-2-en-2-yl) benzene (10.0 mmol) (Jeong, I.H., Park, Y.S., Chung, M.W.),& Kim, B. T. Synth. Commun.,200131, 2261-. The reaction mixture was then quenched with water and extracted with ether (50 mL. times.3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure and the residue was purified by silica gel column chromatography (10: 1 hexane/ethyl acetate) to give the corresponding product as a white solid, (E) -2- ((4,4, 4-trifluoro-3-phenylbutyl-2-en-1-yloxy) benzaldehyde the structural formula is as follows:
the melting point of the product compound is as follows: the nuclear magnetic resonance hydrogen spectrum data of the compound are as follows:1H NMR (400 MHz, Chloroform-d) δ 10.45 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.59 – 7.39 (m, 4H), 7.37 – 7.20 (m, 2H), 7.03 (t, J = 7.5 Hz, 1H), 6.84 – 6.57 (m, 2H), 4.63 (d, J = 4.2 Hz, 2H)。
substrate 1b Synthesis
To a dry three-necked flask, 5-chlorosalicylaldehyde (1.0 mmol), K2CO3 (608 mg, 1.5 mmol) and DMF (2.5 mL) were added sequentially under nitrogen, and (4-bromo-1, 1, 1-trifluorobut-2-en-2-yl) benzene (1.0 mmol) was added with stirring and stirred at room temperature overnight until the salicylaldehyde was completely consumed (monitored by TLC). The reaction mixture was then quenched with water and extracted with ether (8 mL. times.3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure and the residue was purified by silica gel column chromatography (10: 1 hexane/ethyl acetate) to give the corresponding product as a white solid, (E) -5-chloro-2- ((4,4, 4-trifluoro-3-phenylbutyl-2-en-1-yloxy) benzaldehyde the structural formula is as follows:
the melting point of the product compound is as follows: the NMR data of the compound are as follows:1H NMR (400 MHz, Chloroform-d) δ 10.36 (s, 1H), 7.76 (d, J = 2.6 Hz, 1H), 7.50 – 7.36 (m, 4H), 7.33 – 7.26 (m, 2H), 6.69 (t, J = 8.6 Hz, 2H), 4.76 – 4.45 (m, 2H)。
example 1
Substrate 1a (4 mmol), NHC (0.4 mmol), Na were added sequentially to a dry reaction tube under nitrogen protection2CO3 (0.8 mmol), 80 mL of DMSO was then added to the system, and the reaction was terminated at room temperature for 10 hours, and the stirring was stopped. Adding I2 (0.8 mmol) in 40 mL DMSO and concentrated H added2SO4(4 mmol) and reacted at 50 ℃ for 5 hours. Washing with water to remove DMSO, extracting with diethyl ether, and recrystallizing with ethyl acetate and petroleum ether at a volume ratio of 1:10 to obtain the corresponding product as white solid with a yield of 87.6%. The name of the product is: 3- (2,2, 2-trifluoro-1-phenylethyl) -4H-chromen-4-one. The structural formula is as follows:
the melting point of the product compound is as follows: mp 123.8 ℃; the nmr hydrogen spectra data for the compounds are as follows:1H NMR (400 MHz, Chloroform-d) δ 8.18 (d, J = 9.5 Hz, 2H), 7.70 – 7.58 (m, 1H), 7.44 (q, J = 3.4 Hz, 3H), 7.34 (tt, J = 16.9, 7.3 Hz, 4H), 5.33 (q, J= 10.3 Hz, 1H), nuclear magnetic resonance carbon spectrum data of the compound are as follows:13C NMR (101 MHz, Chloroform-d) δ 175.54 , 156.03 , 154.02 (q, J = 2.6 Hz), 134.01 , 133.64 (d, J = 1.5 Hz), 128.97 , 128.77 , 128.28 , 126.09 , 126.04 (q, J = 279.8 Hz),125.44 , 123.46 , 120.25 , 118.05 , 44.31 (q, J = 29.0 Hz)。
example 2
To a dry reaction tube, substrate 1b (0.3 mmol), NHC (0.05 mmol), Et were added sequentially under nitrogen3N (0.06 mmol), 3 mL of DMF was then added to the system, and the reaction was terminated at room temperature for 3 h, and the stirring was stopped. Adding I2 (0.06 mmol) was dissolved in 1.5 mL DMSO and concentrated H was added2SO4(0.3 mmol) and reacted at 70 ℃ for 2 hours. Washing with water to remove the solvent, extracting with ethyl acetate, performing column chromatography, and eluting with an eluent: ethyl acetate and petroleum ether were mixed in a volume ratio of 1:1, and the fractions were collected to give the corresponding product as a white solid in 91% yield. The name of the product is: 6-chloro-3- (2,2, 2-trifluoro-1-phenylethyl) -4H-chromen-4-one. The structural formula is as follows:
the melting point of the product compound is as follows: mp 120-; the nmr hydrogen spectra data for the compounds are as follows:1H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J = 16.6 Hz, 2H), 7.61 (d, J = 9.0 Hz, 1H), 7.48 – 7.39 (m, 3H), 7.35 (q, J = 7.4 Hz, 3H), 5.29 (q, J= 10.5 Hz, 1H), nuclear magnetic resonance carbon spectrum data of the compound are as follows:13C NMR (100 MHz, Chloroform-d) δ 174.49 , 154.41 , 154.17 (q, J = 2.6 Hz), 134.31 , 133.40 , 131.53 , 128.96 , 128.87 , 128.43 , 125.95 (d, J = 279.9 Hz), 125.56 , 124.42, 120.47, 119.86 , 44.38 (q, J = 29.1 Hz);。
the above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.
Claims (5)
1. A method for synthesizing trifluoromethyl substituted homoisoflavone compounds by using N-heterocyclic carbene as a catalyst is characterized by comprising the following steps: using trifluoromethyl substituted olefine aldehyde compound as a raw material, reacting for 3-10 hours under the action of an organic solvent and alkali and at room temperature environment by using azacyclo-carbene as a catalyst to prepare an intermediate flavonoid compound, then reacting at 50-100 ℃ under the action of elemental iodine, concentrated sulfuric acid and the organic solvent to prepare the trifluoromethyl substituted homoisoflavone compound, and separating and purifying the obtained product by recrystallization or thin-layer chromatography or column chromatography;
the structural formula of the trifluoromethyl substituted olefine aldehyde compound is as follows:
，R1is H or Cl, R2Ph; the structural formula of the trifluoromethyl substituted homoisoflavonoid compound is shown in the specification
，R1Is H or Cl, R2Ph; the azaheterocyclic carbene is
。
2. The method for synthesizing trifluoromethyl substituted homoisoflavonoid compounds by using nitrogen heterocyclic carbene as claimed in claim 1, which is characterized in that: the alkali is one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, potassium acetate, sodium alkoxide, triethylamine and 1, 8-diazabicycloundecen-7-ene.
3. The method for synthesizing trifluoromethyl substituted homoisoflavonoid compounds by using nitrogen heterocyclic carbene as claimed in claim 1, which is characterized in that: the organic solvent is one of acetonitrile, toluene, tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, dichloromethane, 1, 4-dioxane, dimethyl sulfoxide and dimethylformamide.
4. The method for synthesizing trifluoromethyl substituted homoisoflavonoid compounds by using nitrogen heterocyclic carbene as claimed in claim 1, which is characterized in that: the molar ratio of the trifluoromethyl-substituted olefine aldehyde compound to the N-heterocyclic carbene is 1: 0.1-0.2.
5. The method for synthesizing trifluoromethyl substituted homoisoflavonoid compounds by using nitrogen heterocyclic carbene as claimed in claim 1, which is characterized in that: the molar ratio of the trifluoromethyl substituted olefine aldehyde compound to the alkali is 1: 0.1-1.5.
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| 2,6-Dimethoxyphenyl-Substituted N-Heterocyclic Carbenes (NHCs): A Family of Highly Electron-Rich Organocatalysts;Michael Schedler et al.;《Eur. J. Org. Chem.》;20120619;第4164-4171页 * |
| Design and Synthesis of Novel Nonsteroidal Phytoestrogen-based Probes as Potential Biomarker: Evaluation of Anticancer Activity and Docking Studies;Sumit Kumar et al.;《Journal of Heterocyclic Chemistry》;20170731;第54卷;第2242-2257页 * |
| DTBP/TBHP-Promoted Hydroacylation of Unactivated Alkenes;Huei-Shu Jhuang et al.;《Asian J. Org. Chem.》;20161028;第5卷;第1452-1456页 * |
| Efficient Synthesis of 3-Methyl-flavanones and Evaluation of Their Anti-bacterial Activity;Nawghare et al.;《Chin. J. Chem.》;20120711;第30卷;第1695-1698页 * |
| N-Heterocyclic Carbene-Catalyzed Hydroacylation of Unactivated Double Bonds;Keiichi Hirano et al.;《J. AM. CHEM. SOC.》;20090917;第131卷;第14190-14191页 * |
| Scope of the Asymmetric Intramolecular Stetter Reaction Catalyzed by Chiral Nucleophilic Triazolinylidene Carbenes;Javier Read de Alaniz et al.;《J. Org. Chem.》;20080227;第73卷;第2033-2040页 * |
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