CN114956927B - Preparation method of beta-halogenated olefine acid ester derivative - Google Patents

Preparation method of beta-halogenated olefine acid ester derivative Download PDF

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CN114956927B
CN114956927B CN202210713171.3A CN202210713171A CN114956927B CN 114956927 B CN114956927 B CN 114956927B CN 202210713171 A CN202210713171 A CN 202210713171A CN 114956927 B CN114956927 B CN 114956927B
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CN114956927A (en
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曾小宝
程振凤
顾清云
谢雨杉
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Nantong University
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B41/12—Formation or introduction of functional groups containing oxygen of carboxylic acid ester groups
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method of a beta-halogenated olefine acid ester derivative, which comprises the following steps: sequentially adding an alpha-keto acid compound, a halogenated alkyne compound and a catalyst into an organic solvent, and reacting at a certain temperature; then adding alkali and halohydrocarbon into a reaction system, and reacting at a certain temperature to obtain the beta-halogenated olefine acid ester derivative. The invention takes the alpha-keto acid compound and the halogenated alkyne compound as raw materials to prepare the beta-halogenated olefine acid ester under the condition of one-pot method, and the method has the advantages of high reaction yield, simple operation, high atom economy, good functional group compatibility and wide substrate application range. Provides a new synthetic route for the preparation of the beta-halogenated olefine acid ester derivative, can play an important role in the fields of active pharmaceutical intermediates, pesticides, material science and the like, and has great application value and potential in industrial production and scientific research.

Description

Preparation method of beta-halogenated olefine acid ester derivative
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of a beta-halogenated olefine acid ester derivative.
Background
The cross-coupling reactions of metal-catalyzed haloolefins have played an important role in building complex molecular structures over the last decades (Angew.Chem.Int.Ed.2017, 56,2;Chem.Rev.2016,116,12564). Halogenated olefins are widely used to build carbon-carbon bonds, carbon-nitrogen bonds, carbon-oxygen bonds, and the like in pharmaceutically active molecules. Thus, the synthesis of halogenated olefins is of great importance (Angew.Chem.Int.Ed.2012, 51,5062;Angew.Chem.Int.Ed.2011,50,6723).
Beta-haloolefine acid ester is an important halogenated olefine subclass, and related literature for synthesizing tetra-substituted beta-haloolefine acid ester derivatives is not reported at present. The usual method for preparing iodo-olefin derivatives mainly comprises the carbometallation/iodiphilic halogenation of a directing group-directed alkyne to prepare beta-haloalkenyl esters (J.Am. Chem. Soc.2000,122, 3228) and magnesium iodide (MgI) 2 ) The promoted reaction of beta-Hillman (Morita-Baylis-Hillman) synthesizes cis beta-halo olefins (Tetrahedron Lett.2015,56,3285). The existing methods for synthesizing iodo olefin derivatives have the defects of difficult raw material acquisition, multiple side reactions and the like. At present, a method for preparing the beta-halogenated enoate derivative with high efficiency and wide adaptability does not exist.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of a beta-halogenated enoate derivative, which has the advantages of mild reaction conditions, simple operation, easily available raw materials, good compatibility of functional groups and wide application range of substrates.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the preparation method of the beta-halogenated olefine acid ester derivative specifically comprises the following steps:
step A, sequentially adding an alpha-keto acid compound shown in a formula (II), a halogenated alkyne compound shown in a formula (III) and a catalyst into an organic solvent, and reacting at a certain temperature;
step B, continuously adding alkali and halohydrocarbon into a reaction system, reacting at a certain temperature, and purifying through post-treatment to obtain the beta-halogenated olefine acid ester derivative (I), wherein the reaction structural formula is shown as follows;
wherein R is 1 、R 2 Independently selected from any one of phenyl, substituted phenyl, C1-C6 alkyl, C1-C6 alkenyl; r is R 3 Independently selected from any one of halogen fluorine, chlorine, bromine and iodine.
Wherein C1-C6 alkyl refers to a straight or branched alkyl group having 1 to 6 carbon atoms, comprising: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexylcyclohexyl, and the like;
C1-C6 alkenyl means a straight or branched carbon-carbon double bond containing substituent having 1 to 6 carbon atoms comprising: ethenyl, propenyl, butenyl, pentenyl, hexenyl, cyclohexenyl.
Preferably, in step a, the organic solvent comprises: toluene, fluorobenzene, benzotrifluoride, chlorobenzene, benzene, xylene, tetrahydrofuran, methanol, ethanol, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide and N-methylpyrrolidone.
Preferably, in step a, the catalyst comprises: boron trifluoride diethyl etherate, trifluoromethanesulfonic anhydride, p-toluenesulfonic acid, ferric chloride, bismuth trifluoromethanesulfonate, zinc trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, copper trifluoromethanesulfonate, aluminum chloride, titanium tetrachloride.
Preferably, in step A, the molar ratio of the alpha-keto acid compound (II) to the haloalkyne compound (III) is 1 (1-3); the molar ratio of the alpha-keto acid compound (II) to the catalyst is 1 (0.05-1); the dosage ratio of the alpha-keto acid compound (II) to the organic solvent is 1mmol (2-15) mL.
Preferably, in step A, the reaction temperature is 25 to 120℃and the reaction time is 1 to 12 hours.
Preferably, in step B, the base comprises any one of potassium carbonate, potassium acetate, sodium carbonate, sodium acetate, sodium bicarbonate, potassium phosphate, sodium hydroxide, lithium carbonate, sodium hydroxide, potassium bicarbonate, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene.
Preferably, in step B, the halogenated hydrocarbon comprises any one of methyl iodide, butyl iodide, perfluorobutyl iodide, 1, 4-diiodobutyl bromide, ethyl bromide, isopropyl bromide.
Preferably, in step B, the molar ratio of the alpha-keto acid compound (II) to the base is 1 (0.5-3); the ratio of the alpha-keto acid compound (II) to the halogenated hydrocarbon is 1 (5-15).
Preferably, in step B, the reaction temperature is from-30 to 25℃and the reaction time is from 1 to 12 hours.
Preferably, in the step B, the eluent used for column chromatography purification is a mixed solvent of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is (50-100): 1.
The invention has the beneficial effects that:
1. the invention adopts cheap and easily available alpha-keto acid compound and halogenated alkyne as raw materials, takes acid as a catalyst, and synthesizes the beta-halogenated olefine acid ester derivative by a one-pot method.
2. The invention can be operated under the air condition, is insensitive to water and oxygen, has mild reaction condition and is simple to operate.
3. The invention has the advantages of good compatibility of functional groups, simple post-treatment, high atom economy and the like.
4. The invention provides a new synthetic route for the preparation of the beta-halogenated olefine acid ester derivative, and the prepared beta-halogenated olefine acid ester derivative can play an important role in the fields of active drug intermediates, pesticide intermediates and the like, and has great application value and potential in industrial production and scientific research.
Detailed Description
The technical scheme of the present invention is further illustrated and described below by means of specific embodiments, but the embodiments of the present invention are not limited thereto.
Example 1:
adding the above formula of benzoic acid (II), iodoalkyne compound (III), and trifluoro-boric acid diethyl ether (BF) into toluene 3 ·Et 2 O), and then stirring and sealing at 40 ℃ for 2 hours. After the reaction system was cooled to 0 ℃, potassium carbonate and methyl iodide were added, and the reaction was continued for 12 hours.
Wherein the molar ratio of the benzoic acid (II) to the iodoalkyne compound (III) is 1:1.2; benzoic acid (II) and boron trifluoride diethyl etherate (BF) 3 ·Et 2 O) is 1:0.2; the ratio of benzoic acid (II) to toluene was 1mmol:4mL; the molar ratio of the benzoic acid (II) to the potassium carbonate is 1:2; the molar ratio of the benzoic acid (II) to the methyl iodide is 1:20.
After the reaction is finished, adding a mixed solution of ethyl acetate and saturated saline in equal volume ratio into a reaction system, carrying out oscillation extraction for 3 times, collecting an organic layer, drying, rotationally evaporating and concentrating to obtain a crude product, carrying out 300-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:20, thus obtaining a target product of the formula (I) compound (C 17 H 13 IO 3 )。
For the compound (C) of formula (I) obtained in this example 17 H 13 IO 3 ) Nuclear magnetic resonance analysis was performed, with the following results: 1 h NMR (400 MHz, deuterated chloroform CDCl) 3 )δ8.03–8.01(m,2H),7.63–7.59(m,1H),7.55–7.41(m,5H),7.39–7.37(m,2H),3.50(s,3H).
13 C NMR (100 MHz, deuterated chloroform CDCl) 3 )δ191.7,162.8,142.0,138.4,133.7,132.6,129.3(2C),128.9(2C),128.8(2C),128.7,128.4(2C),116.8,52.7.
Through calculation: compounds of formula (I) (C 17 H 13 IO 3 ) Yield of 83%, melting point: 110-112 ℃.
Example 2:
adding the above formula of benzoic acid (II), 4-methyl iodoalkyne compound (III), and trifluoro-boric acid diethyl ether (BF) into toluene 3 ·Et 2 O), and then stirring and sealing at 40 ℃ for 2 hours. After the reaction system was cooled to 0 ℃, potassium carbonate and methyl iodide were added, and the reaction was continued for 12 hours.
Wherein the molar ratio of the benzoyl formic acid (II) to the 4-methyl iodinated alkyne compound (III) is 1:1.2; benzoic acid (II) and boron trifluoride diethyl etherate (BF) 3 ·Et 2 O) is 1:0.2; the ratio of benzoic acid (II) to toluene was 1mmol:4mL; the molar ratio of the benzoic acid (II) to the potassium carbonate is 1:2; the molar ratio of the benzoic acid (II) to the methyl iodide is 1:20.
After the reaction is finished, adding a mixed solution of ethyl acetate and saturated saline in equal volume ratio into a reaction system, carrying out oscillation extraction for 3 times, collecting an organic layer, drying, rotationally evaporating and concentrating to obtain a crude product, carrying out 300-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:20, thus obtaining a target product of the formula (I) compound (C 18 H 15 IO 3 )。
For the compound (C) of formula (I) obtained in this example 18 H 15 IO 3 ) Nuclear magnetic resonance analysis was performed, with the following results: 1 h NMR (400 MHz, deuterated chloroform CDCl) 3 )δ7.92(d,J＝8.1,2H),7.51–7.41(m,3H),7.40–7.35(m,2H),7.32(d,J＝8.0,2H),3.51(s,3H),2.45(s,3H).
13 C NMR (100 MHz, deuterated chloroform CDCl) 3 )δ191.4,162.8,144.7,141.7,138.4,130.0,129.5(2C),129.4(2C),128.8(2C),128.7,128.4(2C),116.9,52.6,21.7.
Through calculation: compounds of formula (I) (C 18 H 15 IO 3 ) Yield of 78%, melting point: 110-112 ℃.
Example 3:
adding the above formula of benzoic acid (II), 4-bromoiodoalkyne compound (III), and trifluoro-boric acid diethyl ether (BF) into toluene 3 ·Et 2 O), and then stirring and sealing at 40 ℃ for 2 hours. After the reaction system was cooled to 0 ℃, potassium carbonate and methyl iodide were added, and the reaction was continued for 12 hours.
Wherein the molar ratio of the benzoyl formic acid (II) to the 4-bromoiodoalkyne compound (III) is 1:1.2; benzoic acid (II) and boron trifluoride diethyl etherate (BF) 3 ·Et 2 O) is 1:0.2; the ratio of benzoic acid (II) to toluene was 1mmol:4mL; the molar ratio of the benzoic acid (II) to the potassium carbonate is 1:2; the molar ratio of the benzoic acid (II) to the methyl iodide is 1:20.
After the reaction is finished, adding a mixed solution of ethyl acetate and saturated saline in equal volume ratio into a reaction system, carrying out oscillation extraction for 3 times, collecting an organic layer, drying, rotationally evaporating and concentrating to obtain a crude product, carrying out 300-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:20, thus obtaining a target product of the formula (I) compound (C 17 H 12 BrIO 3 )。
For the compound (C) of formula (I) obtained in this example 17 H 12 BrIO 3 ) Nuclear magnetic resonance analysis was performed, with the following results: 1 h NMR (400 MHz, deuterated chloroform CDCl) 3 )δ7.90–7.85(m,2H),7.67(m,2H),7.51–7.42(m,3H),7.38–7.34(m,2H),3.54(s,3H).
13 C NMR (100 MHz, deuterated chloroform CDCl) 3 )δ190.8,163.0,142.4,138.1,132.3(2C),131.5,130.7(2C),129.0,128.9,128.8(2C),128.5(2C),116.1,52.9.
Through calculation: compounds of formula (I) (C 17 H 12 BrIO 3 ) Yield of 82%, melting point: 120-122 ℃.
Example 4:
adding 4-methylbenzoyl formic acid (II), iodoalkyne compound (III) and trifluoro-boric acid diethyl ether (BF) into toluene 3 ·Et 2 O), and then stirring and sealing at 40 ℃ for 2 hours. After the reaction system was cooled to 0 ℃, potassium carbonate and methyl iodide were added, and the reaction was continued for 12 hours.
Wherein the molar ratio of the 4-methylbenzoyl formic acid (II) to the iodinated alkyne compound (III) is 1:1.2; 4-Methylbenzoic acid (II) with boron trifluoride diethyl etherate (BF) 3 ·Et 2 O) is 1:0.2; the ratio of 4-methylbenzoyl formic acid (II) to toluene was 1 mmol/4 mL; the molar ratio of the 4-methylbenzoyl formic acid (II) to the potassium carbonate is 1:2; the molar ratio of 4-methylbenzoyl formic acid (II) to methyl iodide is 1:20.
After the reaction is finished, adding a mixed solution of ethyl acetate and saturated saline in an equal volume ratio into a reaction system, carrying out oscillation extraction for 3 times, collecting an organic layer, drying, rotationally evaporating and concentrating to obtain a crude product, carrying out 300-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:20, thus obtaining a target product with white solid appearanceCompounds of formula (I) (C 18 H 15 IO 3 )。
For the compound (C) of formula (I) obtained in this example 18 H 15 IO 3 ) Nuclear magnetic resonance analysis was performed, with the following results: 1 h NMR (400 MHz, deuterated chloroform CDCl) 3 )δ8.04–7.99(m,2H),7.63–7.58(m,1H),7.54–7.50(m,2H),7.31–7.25(m,4H),3.50(s,3H),2.42(s,3H).
13 C NMR (100 MHz, deuterated chloroform CDCl) 3 )δ191.8,163.1,142.1,138.8,135.4,133.7,132.7,129.3(2C),129.2(2C),128.8(2C),128.7(2C),116.4,52.7,21.4.
Through calculation: compounds of formula (I) (C 18 H 15 IO 3 ) Yield of 81%, melting point: 148-150 ℃.
Example 5:
adding 4-bromobenzoyl formic acid (II), iodoalkyne compound (III), and trifluoro boric acid diethyl ether (BF) into toluene 3 ·Et 2 O), and then stirring and sealing at 40 ℃ for 2 hours. After the reaction system was cooled to 0 ℃, potassium carbonate and methyl iodide were added, and the reaction was continued for 12 hours.
Wherein the molar ratio of the 4-bromobenzoyl formic acid (II) to the halogenated alkyne compound (III) is 1:1.2; 4-bromobenzoic acid (II) and boron trifluoride diethyl etherate (BF) 3 ·Et 2 O) is 1:0.2; the ratio of 4-bromobenzoic acid (II) to toluene was 1 mmol/4 mL; the molar ratio of the 4-bromobenzoyl formic acid (II) to the potassium carbonate is 1:2; the molar ratio of 4-bromobenzoic acid (II) to methyl iodide is 1:20.
After the reaction is finished, adding a mixed solution of ethyl acetate and saturated saline in equal volume ratio into a reaction system, carrying out oscillation extraction for 3 times, collecting an organic layer, drying, rotationally evaporating and concentrating to obtain a crude product, carrying out 300-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:20, thus obtaining the product with the appearance of whiteTarget product of color solid compound (C) of formula (I) 17 H 12 BrIO 3 )。
For the compound (C) of formula (I) obtained in this example 17 H 12 BrIO 3 ) Nuclear magnetic resonance analysis was performed, with the following results: 1 h NMR (400 MHz, deuterated chloroform CDCl) 3 )δ8.02–7.97(m,2H),7.65–7.59(m,3H),7.52(m,2H),7.26(m,2H),3.51(s,3H).
13 C NMR (100 MHz, deuterated chloroform CDCl) 3 )δ191.5,162.5,141.1,137.2,133.8,132.5,131.8(2C),130.7(2C),129.3(2C),128.9(2C),123.1,117.5,52.8.
Through calculation: compounds of formula (I) (C 17 H 12 BrIO 3 ) Yield of 82%, melting point: 130-132 ℃.
Example 6:
adding the 2-thiopheneacetic acid compound (II), the iodoalkyne compound (III) and the trifluoro-boric acid diethyl ether (BF) into toluene 3 ·Et 2 O), and then stirring and sealing at 40 ℃ for 2 hours. After the reaction system was cooled to 0 ℃, potassium carbonate and methyl iodide were added, and the reaction was continued for 12 hours.
Wherein the molar ratio of the 2-thiopheneacetic acid compound (II) to the halogenated alkyne compound (III) is 1:1.2; 2-thiopheneacetic acid compound (II) and boron trifluoride diethyl etherate (BF 3 ·Et 2 O) is 1:0.2; the ratio of the 2-thiopheneacetic acid compound (II) to toluene is 1 mmol/4 mL; the molar ratio of the 2-thiopheneacetic acid compound (II) to the potassium carbonate is 1:2; the molar ratio of the 2-thiopheneacetic acid compound (II) to methyl iodide is 1:20.
After the reaction is finished, adding a mixed solution of ethyl acetate and saturated saline with equal volume ratio into a reaction system, oscillating and extracting for 3 times, collecting an organic layer, drying, rotationally evaporating and concentrating to obtain a crude product, subjecting the crude product to 300-mesh silica gel column chromatography, and using the mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the ethyl acetate and the petroleum ether are mixed into a solid phase, and the solid phase is prepared by the steps ofThe volume ratio is 1:20, and the target product of the compound (C) with the formula (I) is obtained 15 H 11 IO 3 S)。
For the compound (C) of formula (I) obtained in this example 15 H 11 IO 3 S) performing nuclear magnetic resonance analysis, wherein the result is as follows: 1 h NMR (400 MHz, deuterated chloroform CDCl) 3 )δ8.03–8.01(m,2H),7.63–7.59(m,1H),7.55–7.41(m,5H),7.39–7.37(m,2H),3.50(s,3H).
13 C NMR (100 MHz, deuterated chloroform CDCl) 3 )δ191.7,162.8,142.0,138.4,133.7,132.6,129.3(2C),128.9(2C),128.8(2C),128.7,128.4(2C),116.8,52.7.
Through calculation: compounds of formula (I) (C 15 H 11 IO 3 S) yield 73%, melting point: 94-96 ℃.
Example 7:
adding the above formula of benzoic acid (II), bromoalkyne compound (III), and trifluoro-boric acid diethyl ether (BF) into toluene 3 ·Et 2 O), and then stirring and sealing at 40 ℃ for 2 hours. After the reaction system was cooled to 0 ℃, potassium carbonate and methyl iodide were added, and the reaction was continued for 12 hours.
Wherein the molar ratio of the benzoic acid (II) to the bromoalkyne compound (III) is 1:1.2; benzoic acid (II) and boron trifluoride diethyl etherate (BF) 3 ·Et 2 O) is 1:0.2; the ratio of benzoic acid (II) to toluene was 1mmol:4mL; the molar ratio of the benzoic acid (II) to the potassium carbonate is 1:2; the molar ratio of the benzoic acid (II) to the methyl iodide is 1:20.
After the reaction is finished, adding a mixed solution of ethyl acetate and saturated saline in equal volume ratio into a reaction system, carrying out oscillation extraction for 3 times, collecting an organic layer, drying, rotationally evaporating and concentrating to obtain a crude product, carrying out 300-mesh silica gel column chromatography on the crude product, and taking the mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:20 to obtainTo the target product compound of formula (I) (C) as a white solid in appearance 17 H 13 BrO 3 )。
For the compound (C) of formula (I) obtained in this example 17 H 13 BrO 3 ) Nuclear magnetic resonance analysis was performed, with the following results: 1 h NMR (400 MHz, deuterated chloroform CDCl) 3 )δ8.03–8.00(m,2H),7.65–7.61(m,1H),7.55–7.53(m,2H),7.50–7.41(m,5H),3.54(s,3H).
13 C NMR (100 MHz, deuterated chloroform CDCl) 3 )δ189.9,164.4,136.5,134.9,133.9,133.8133.3,129.3(2C),129.1(2C),128.9(2C),128.8,128.4(2C),52.8.
Through calculation: compounds of formula (I) (C 17 H 13 BrO 3 ) Yield of 80%, melting point: 92-94 ℃.
Example 8:
adding the above formula of benzoic acid (II), chloroalkyne compound (III), and trifluoro-boric acid diethyl ether (BF) into toluene 3 ·Et 2 O), and then stirring and sealing at 40 ℃ for 2 hours. After the reaction system was cooled to 0 ℃, potassium carbonate and methyl iodide were added, and the reaction was continued for 12 hours.
Wherein the molar ratio of the benzoic acid (II) to the chloroalkyne compound (III) is 1:1.2; benzoic acid (II) and boron trifluoride diethyl etherate (BF) 3 ·Et 2 O) is 1:0.2; the ratio of benzoic acid (II) to toluene was 1mmol:4mL; the molar ratio of the benzoic acid (II) to the potassium carbonate is 1:2; the molar ratio of the benzoic acid (II) to the methyl iodide is 1:20.
After the reaction is finished, adding a mixed solution of ethyl acetate and saturated saline in equal volume ratio into a reaction system, carrying out oscillation extraction for 3 times, collecting an organic layer, drying, rotationally evaporating and concentrating to obtain a crude product, carrying out 300-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:20, thus obtaining the white solidThe target product of the body is a compound (C) 17 H 13 ClO 3 )。
For the compound (C) of formula (I) obtained in this example 17 H 13 ClO 3 ) Nuclear magnetic resonance analysis was performed, with the following results: 1 h NMR (400 MHz, deuterated chloroform CDCl) 3 )δ8.02–7.99(m,2H),7.64–7.61(m,1H),7.54–7.51(m,2H),7.49–7.40(m,5H),3.54(s,3H).
13 C NMR (100 MHz, deuterated chloroform CDCl) 3 )δ189.4,164.9,140.5,134.0,133.8,133.5,132.9,129.3(2C),129.2(2C),128.9(3C),128.3(2C),52.6.
Through calculation: compounds of formula (I) (C 17 H 13 ClO 3 ) Yield of 84%, melting point: 74-76 ℃.
In summary, the invention takes the alpha-keto acid compound and the halogenated alkyne compound as raw materials to prepare the beta-halogenated olefine acid ester under the condition of one-pot method, and the method has the advantages of high reaction yield, simple operation, high atom economy, good functional group compatibility and wide substrate application range, and provides a brand-new route for preparing the beta-halogenated olefine acid ester derivative.
It should be noted that, not described in detail, the present invention is well known to those skilled in the art.
The above embodiments are only for further illustrating the embodiments of the present invention, but the present invention is not limited to the above embodiments, and all the equivalent changes and modifications made in the above embodiments are included in the scope of the present invention according to the technical spirit of the present invention.

Claims (4)

1. The preparation method of the beta-halogenated olefine acid ester derivative is characterized by comprising the following steps of:
step A, sequentially adding an alpha-keto acid compound shown in a formula (II), a halogenated alkyne compound shown in a formula (III) and a catalyst into an organic solvent, and reacting at a certain temperature;
step B, continuously adding alkali and halohydrocarbon into a reaction system, reacting at a certain temperature, and purifying through post-treatment to obtain the beta-halogenated olefine acid ester derivative (I), wherein the reaction structural formula is shown as follows;
wherein R is 1 、R 2 Independently selected from any one of phenyl, C1-C6 alkyl; r is R 3 Independently selected from any one of halogen fluorine, chlorine, bromine and iodine;
in step a, the organic solvent is toluene;
in the step A, boron trifluoride diethyl etherate is used as a catalyst;
in step B, the base is potassium carbonate;
in step B, the halogenated hydrocarbon is methyl iodide.
2. The process for producing a β -haloenoate derivative according to claim 1, wherein in step a, the molar ratio of the α -keto acid compound (II) to the haloalkyne compound (III) is 1 (1-3); the molar ratio of the alpha-keto acid compound (II) to the catalyst is 1 (0.05-1); the dosage ratio of the alpha-keto acid compound (II) to the organic solvent is 1mmol (2-15) mL.
3. The process for producing a β -haloenoate derivative according to claim 1, wherein in step B, the molar ratio of the α -keto acid compound (II) to the base is 1 (0.5-3); the ratio of the alpha-keto acid compound (II) to the halogenated hydrocarbon is 1 (5-15).
4. The process for producing a β -haloenoate derivative according to claim 1, wherein in step B, the eluent used for column chromatography purification is a mixed solvent of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is (50-100): 1.
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Highly Stereoselective Gold-Catalyzed Coupling of Diazo Reagents and Fluorinated Enol Silyl Ethers to Tetrasubstituted Alkenes;Fu-Min Liao 等;《Communication》;2459-2463 *

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