CN111072476B - Method for high-selectivity fluoromethylation of beta-keto ester compounds on oxygen - Google Patents
Method for high-selectivity fluoromethylation of beta-keto ester compounds on oxygen Download PDFInfo
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Abstract
The invention discloses a method for high-selectivity fluoromethylation of beta-keto ester compounds on oxygen. The method comprises the steps of adding a substrate alpha-position unsubstituted beta-keto ester derivative, a fluoromethylation reagent, namely monofluoroiodomethane and cesium fluoride into an organic solvent, stirring for reaction at 40-60 ℃, and separating to obtain an O-fluoromethylated olefine acid compound after the reaction is finished. The method has the advantages of simple process operation, no metal catalysis, no reducing agent, mild and easily controlled conditions, and is a synthetic method of alpha-unsubstituted beta-keto ester compounds with high oxygen selectivity and high yield of monofluoromethylation.
Description
Technical Field
The invention relates to a method for high-selectivity fluoromethylation of alpha-unsubstituted beta-keto ester compounds on oxygen, belonging to the technical field of organic chemical synthesis.
Background
The fluorine or fluorinated moiety in fluorinated organic compounds can significantly improve the lipophilicity, metabolic stability and bioavailability of the parent molecule and have been widely used in pharmaceuticals and agrochemicals. Among all fluorinated functional groups, monofluoromethyl (CH 2F), because of its widespread presence in many biologically active molecules, can mimic the CH3 and CH2OH groups often encountered in biologically active molecules and is therefore used in the synthesis of many drug molecules, such as fluoroquinolones (therapeutic paralytic), fluticasone (anti-inflammatory), and sevoflurane (anesthetic), of which the structural formulae are given below:
the high selectivity of the monofluoromethylation caused by keto-enol tautomerism of β -keto acid esters has been a research hotspot. From the history of the development of monofluoromethylation, the method of introducing monofluoromethoxy groups belongs to the indirect method, i.e., the method of alkylating oxygen atoms with monofluoromethylating agents. However, depending on the kind of the oxygen-containing substrate and the monofluoromethylation reagent, the introduction range of the functional group is greatly limited.
Hu Jinbo et al found that fluorochloromethane and phenol formed a fluoromethyl product under the action of a base, which was also suitable for electron rich aromatic rings (1-naphthol) or electron deficient aromatic rings (2,4-dichlorophenol), the synthetic route was as follows:
Olah group developed a fluoromethylation reagent, S-fluoromethyl bisphenyl sulfonium tetrafluoroborate, which reacted with nucleophilic substrates such as imidazole, phenol, etc. to produce the corresponding fluoromethyl product. Such O-CH 2 The procedure of the F method is complicated and the restriction of the reaction substrate is large, and it can be used only for the above-mentioned several kinds of substrates (Prakash G K S, ledneczki I, chacko S, et al]Organic Letters,2008,10 (4): 557-560.), S-fluoromethyl bisphenylsulfonium tetrafluoroborate was synthesized as follows:
the Norio Shibata group of subjects developed a novel monofluoromethylating reagent monofluoromethyl sulfoxide salt for electrophilic monofluoromethylation. In alkylation of beta-keto esters with substituents at the alpha position, CH in the reagent 2 The F cation exhibits a unique inherent preference for oxygen atoms to become an enolate saltHigh selectivity of O-CH 2 Rare example of F (selectivity)>80%) provides a new synthetic route for monofluoromethyl ethers relevant to the pharmaceutical and agrochemical industries. But this O-CH 2 The F method is not only complicated in steps and difficult in preparation, but also has a problem of restriction of the substrate having a substituent at the alpha-position of beta-ketoester (Nomura Y, tokunaga E, shibata N. Endogenous Oxygen Preference in enzyme monofluoro and a Synthetic enzyme to monofluoro Ethers [ J].Angewandte Chemie,2011,123(8):1925-1929.)。
Disclosure of Invention
The invention aims to provide a method for high-selectivity monofluoromethylation of alpha-unsubstituted beta-keto ester compounds.
The technical scheme for realizing the purpose of the invention is as follows:
the method for high-selectivity fluoromethylation of beta-keto ester compounds on oxygen comprises the following steps:
adding a substrate alpha-unsubstituted beta-keto ester derivative, a fluoromethylation reagent, fluoroiodomethane and cesium fluoride into an organic solvent, stirring for reaction at 40-60 ℃, and after the reaction is finished, filtering, distilling and carrying out column chromatography separation to obtain the O-fluoromethylated olefine acid compound.
Preferably, the organic solvent is selected from N, N dimethylformamide or N, N dimethylacetamide.
Preferably, the alpha-unsubstituted beta-keto ester derivative is selected from ethyl benzoylacetate, ethyl p-methoxybenzoylacetate, ethyl p-fluorobenzoylacetate or ethyl p-nitrobenzoylacetate.
Preferably, the reaction time is 2 to 3 hours.
Preferably, the mole ratio of the alpha-unsubstituted beta-keto ester derivative, monofluoroiodomethane and cesium fluoride is 1: 1.2-1.5: 0.2 to 0.5.
Preferably, the eluent for column chromatography separation is 95:5 to 99:1 of petroleum ether/ethyl acetate.
Compared with the prior art, the invention has the following remarkable advantages:
(1) The method can realize the alpha-position unsubstituted beta-keto ester high selectivity (the selectivity is as high as 100 percent) and high yield (the yield is more than 70 percent) of monofluoromethylation on oxygen.
(2) In the process of fluoromethylation on beta-keto ester compounds, only cesium fluoride is used as a catalyst, the system is simple, the reaction is carried out by a one-pot method, high temperature and nitrogen protection are not needed, and the beta-keto ester compounds are generated at the oxygen position with high selectivity to contain CH 2 F'.
Drawings
FIG. 1 shows beta-monofluoromethoxy cinnamic acid ethyl ester 1 H-NMR spectrum.
FIG. 2 shows beta-monofluoromethoxy p-methoxypropenoic acid ethyl ester 1 H-NMR spectrum.
FIG. 3 shows beta-monofluoromethoxy p-fluorophenylacrylic acid ethyl ester 1 H-NMR spectrum.
FIG. 4 shows beta-monofluoromethoxy p-nitrophenylacrylate ethyl ester 1 H-NMR spectrum.
Detailed Description
The present invention will be described in further detail with reference to the following examples and the accompanying drawings.
The invention relates to a synthesis method of alpha-unsubstituted beta-keto ester compound oxygen high-selectivity fluoromethylation, which has the following reaction formula:
example 1
Ethyl benzoylacetate (1.0 g) and cesium fluoride (0.158 g) were charged into a reactor containing N, N-dimethylformamide (10 ml) as a solvent, and after stirring at room temperature for 30 minutes, iodofluoromethane (0.998 g) was slowly added dropwise and reacted at 40 ℃ for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml. Times.3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of beta-monofluoromethoxy ethyl acrylate. The concentration was calibrated by fluorimetry using trifluorotoluene as reference, with a yield of about 80% and a selectivity of 100%.
Example 2
Ethyl benzoylacetate (1.0 g) and cesium fluoride (0.158 g) were charged into a reactor containing N, N-dimethylacetamide (10 ml) as a solvent, and after stirring at room temperature for 30 minutes, iodofluoromethane (0.998 g) was slowly added dropwise and reacted at 40 ℃ for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml. Times.3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of beta-monofluoromethoxy ethyl acrylate. The concentration of the product is calibrated by fluorine spectrum by using trifluorotoluene as a reference substance, the yield is about 70 percent, and the selectivity is 100 percent.
Comparative example 1
Ethyl benzoylacetate (1.0 g) and cesium fluoride (0.158 g) were charged into a reactor containing acetonitrile (10 ml) as a solvent, and after stirring at room temperature for 30 minutes, iodofluoromethane (0.998 g) was slowly added dropwise and reacted at 40 ℃ for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml. Times.3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of beta-monofluoromethoxy ethyl acrylate. The concentration was calibrated by fluorimetry using benzotrifluoride as a reference, the yield was about 35% and the selectivity was 100%.
Comparative example 2
Ethyl benzoylacetate (1.0 g) and cesium fluoride (0.158 g) were charged into a reactor containing dimethyl sulfoxide (10 ml) as a solvent, and after stirring at room temperature for 30 minutes, iodofluoromethane (0.998 g) was slowly added dropwise and reacted at 40 ℃ for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml. Times.3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of beta-monofluoromethoxy ethyl acrylate. The concentration of the product is calibrated by fluorine spectrum by using trifluorotoluene as a reference substance, the yield is about 40 percent, and the selectivity is 100 percent.
It can be seen from examples 1-2 and comparative examples 1 and 2 that the yield of the corresponding monofluoromethoxylated product is significantly reduced by replacing N, N-dimethylformamide and N, N-dimethylacetamide with other aprotic polar solvents, with essentially no effect on selectivity.
Comparative example 3
Ethyl benzoylacetate (1.0 g) and potassium fluoride (0.06 g) were charged into a reactor containing N, N-dimethylformamide (10 ml) as a solvent, and after stirring at room temperature for 30 minutes, iodofluoromethane (0.998 g) was slowly added dropwise and reacted at 40 ℃ for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml. Times.3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of beta-monofluoromethoxy ethyl acrylate. The concentration was calibrated by fluorimetry using benzotrifluoride as a reference, the yield was about 34% and the selectivity was 83%.
Comparative example 4
Ethylbenzoylacetate (1.0 g) and cesium hydroxide (0.156 g) were charged into a reactor containing N, N-dimethylformamide (10 ml) as a solvent, and after stirring at room temperature for 30 minutes, iodofluoromethane (0.998 g) was slowly added dropwise, followed by reaction at 40 ℃ for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml. Times.3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of beta-monofluoromethoxy ethyl acrylate. The concentration of the product is calibrated by fluorine spectrum by using trifluorotoluene as a reference substance, the yield is about 54 percent, and the selectivity is 92 percent.
As can be seen from example 1 and comparative examples 3 and 4, the yield and selectivity of the corresponding monofluoromethoxylated product are significantly reduced by replacing cesium fluoride with another inorganic base.
Comparative example 5
Ethyl benzoylacetate (1.0 g) and cesium fluoride (0.158 g) were charged into a reactor containing N, N-dimethylformamide (10 ml) as a solvent, and after stirring at room temperature for 30 minutes, iodofluoromethane (0.998 g) was slowly added dropwise and reacted at 30 ℃ for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml. Times.3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of beta-monofluoromethoxy ethyl acrylate. The concentration of the product is calibrated by fluorine spectrum by using trifluorotoluene as a reference substance, the yield is about 40 percent, and the selectivity is 100 percent.
Example 3
Ethyl benzoylacetate (1.0 g) and cesium fluoride (0.158 g) were charged into a reactor containing N, N-dimethylformamide (10 ml) as a solvent, and after stirring at room temperature for 30 minutes, iodofluoromethane (0.998 g) was slowly added dropwise and reacted at 60 ℃ for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml. Times.3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of beta-monofluoromethoxy ethyl acrylate. The concentration of the product is calibrated by fluorine spectrum by using trifluorotoluene as a reference substance, the yield is about 60 percent, and the selectivity is 100 percent.
Comparative example 6
Ethyl benzoylacetate (1.0 g) and cesium fluoride (0.158 g) were charged into a reactor containing N, N-dimethylformamide (10 ml) as a solvent, and after stirring at room temperature for 30 minutes, iodofluoromethane (0.998 g) was slowly added dropwise, and the reaction was carried out at 70 ℃ for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml. Times.3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of beta-monofluoromethoxy ethyl acrylate. The concentration was calibrated by fluorimetry using trifluorotoluene as reference, with a yield of about 30% and a selectivity of 100%.
As can be seen from examples 1 and 3 and comparative examples 5 and 6, the change in the reaction temperature has a large influence on the reaction yield and substantially no influence on the selectivity, and the optimum reaction temperature is about 40 ℃ to 60 ℃.
Example 4
Ethyl p-methoxybenzoylacetate (1.0 g) and cesium fluoride (0.158 g) were charged into a reactor containing N, N-dimethylformamide (10 ml) as a solvent, and after stirring at room temperature for 30 minutes, iodofluoromethane (0.998 g) was slowly added dropwise and reacted at 40 ℃ for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml. Times.3), dried with sodium sulfate, and filtered to obtain a dichloromethane solution of beta-monofluoromethoxy p-methoxypropenoic acid ethyl ester. And using trifluorotoluene as a reference substance, calibrating the concentration by fluorine spectrum, and obtaining the yield of about 75% and the selectivity of 100%.
Example 5
Ethyl p-fluorobenzoylacetate (1.0 g) and cesium fluoride (0.158 g) were charged into a reactor containing N, N-dimethylformamide (10 ml) as a solvent, and after stirring at room temperature for 30 minutes, iodofluoromethane (0.998 g) was slowly added dropwise, and the reaction was carried out at 40 ℃ for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml. Times.3), dried with sodium sulfate, and filtered to obtain a dichloromethane solution of beta-monofluoromethoxy p-fluorophenylacrylic acid ethyl ester. The concentration of the product is calibrated by fluorine spectrum by using trifluorotoluene as a reference substance, the yield is about 80 percent, and the selectivity is 100 percent.
Example 6
Ethyl p-nitrobenzoyl acetate (1.0 g) and cesium fluoride (0.158 g) were charged into a reactor containing N, N-dimethylformamide (10 ml) as a solvent, and after stirring at room temperature for 30 minutes, iodofluoromethane (0.998 g) was slowly added dropwise and reacted at 40 ℃ for 2.5 hours. After the reaction, the reaction mixture was poured into saturated brine, extracted three times with dichloromethane (30 ml. Times.3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of ethyl β -monofluoromethoxy p-nitrophenylacrylate. The concentration was calibrated by fluorimetry using benzotrifluoride as reference, the yield was about 83% and the selectivity was 100%.
As can be seen from examples 1 and 4, 5 and 6, the presence of an electron withdrawing group or an electron donating group on the phenyl group has little effect on the reaction yield and substantially no effect on the selectivity.
Comparative example 7
Methyl p-1-oxo-2-indanate (1.0 g) and cesium fluoride (0.158 g) were charged in a reactor containing N, N-dimethylformamide (10 ml) as a solvent, and after stirring at room temperature for 30 minutes, iodofluoromethane (0.998 g) was slowly added dropwise and reacted at 40 ℃ for 2.5 hours. After the reaction, the reaction mixture was poured into saturated brine, extracted three times with dichloromethane (30 ml. Times.3), dried over sodium sulfate, and filtered to give methyl 2- (fluoromethyl) -1-oxo-2,3-dihydro-1H-indene-2-carboxylate. The concentration was calibrated by fluorimetry using benzotrifluoride as a reference, the yield was about 47% and the selectivity was 83%.
As can be seen from example 1 and comparative example 7, when the same O-CH 2 When the F synthesis method is used for alpha-substituted beta-ketonic acid ester compounds, the product does not have high yield.
Claims (4)
1. The method for high-selectivity fluoromethylation of beta-keto ester compounds on oxygen is characterized by comprising the following steps:
adding a substrate alpha-unsubstituted beta-keto ester derivative, a fluoromethylation reagent fluoroiodomethane and cesium fluoride into an organic solvent, stirring and reacting at 40-60 ℃, filtering, distilling and carrying out column chromatography separation after the reaction is finished to obtain an O-fluoromethylated olefine acid compound, wherein the organic solvent is selected from N, N-dimethylformamide or N, N-dimethylacetamide, and the alpha-unsubstituted beta-keto ester derivative is selected from ethyl benzoylacetate, ethyl p-methoxybenzoylacetate, ethyl p-fluorobenzoylacetate or ethyl p-nitrobenzoylacetate.
2. The method of claim 1, wherein the reaction time is 2 to 3 hours.
3. The method of claim 1, wherein the molar ratio of the alpha-unsubstituted beta-ketoester derivative to monofluoroiodomethane to cesium fluoride is 1:1.2 to 1.5:0.2 to 0.5.
4. The method as claimed in claim 1, wherein the eluent for the column chromatography separation is 95:5 to 99:1 of petroleum ether/ethyl acetate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102675092A (en) * | 2011-03-14 | 2012-09-19 | 江苏中丹药物研究有限公司 | Method for preparing 2-aryl-2,2-dimethyl methyl acetate |
| CN109879733A (en) * | 2019-04-03 | 2019-06-14 | 上海应用技术大学 | A kind of synthetic method of list fluorine bromo acetone derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675092A (en) * | 2011-03-14 | 2012-09-19 | 江苏中丹药物研究有限公司 | Method for preparing 2-aryl-2,2-dimethyl methyl acetate |
| CN109879733A (en) * | 2019-04-03 | 2019-06-14 | 上海应用技术大学 | A kind of synthetic method of list fluorine bromo acetone derivatives |
Non-Patent Citations (1)
| Title |
|---|
| Highly Carbon-Selective Monofluoromethylation of β‑Ketoesters with Fluoromethyl Iodide;Tianqi Ding等;《Organic Letters》;20190724;第21卷;第6025-6028页 * |
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