CN101314574A - Process for synthesizing acylations enamine - Google Patents
Process for synthesizing acylations enamine Download PDFInfo
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- CN101314574A CN101314574A CNA2008100635856A CN200810063585A CN101314574A CN 101314574 A CN101314574 A CN 101314574A CN A2008100635856 A CNA2008100635856 A CN A2008100635856A CN 200810063585 A CN200810063585 A CN 200810063585A CN 101314574 A CN101314574 A CN 101314574A
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- phenyl
- naphthyl
- aryl
- dicarbonyl compound
- bromophenyl
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Abstract
The invention relates to a synthetic method of acylated enamine, which comprises the steps as follows: mixing dicarbonyl compound and amine compound, and adding pure water (6-10mL/5mmol dicarbonyl compound) as a solvent; adding 0.005-0.015 equivalent weight of phosphotungstic acid as a catalyst to the mixture, and stirring and reacting at 5-60 DEG C for 2-12 hours, wherein the mole ratio of dicarbonyl compound to amine compound to catalyst of 1:1.1:(0.005-0.015); extracting the reaction solution with ethyl acetate after the reaction is finished; mixing the organic layers, separating and removing the water layer; sequentially washing the organic layer with a saturated sodium carbonate solution and a saturated sodium chloride solution, drying by anhydrous magnesium sulfate, filtering, removing the solvent under the reduced pressure to obtain a coarse product; and separating by the column chromatography to obtain the purified product of acylated enamine.
Description
Technical field
The present invention relates to a kind of synthetic method of acylated enamine, particularly a kind ofly in pure water, make dicarbonyl compound and aminated compounds condensation obtain the synthetic method of acylated enamine by catalysis of phosphotungstic acid.
Background technology
The method of existing preparation acylated enamine has: dicarbonyl compound and aminated compounds azeotropic dehydration (as Synthesis 1983,902) etc. in the aromaticity solvent.The defective that these class methods exist is: the use of organic solvent brings environment unfriendly (its volatility causes topsoil, and inflammableness causes potential safety hazard); Long reaction time; Productive rate is not high.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, provide a kind of and in pure water, make dicarbonyl compound and aminated compounds condensation get the synthetic method of acylated enamine by catalysis of phosphotungstic acid.
In order to solve the problems of the technologies described above, the present invention is achieved by the following technical solutions.
A kind of synthetic method of acylated enamine may further comprise the steps:
(1) dicarbonyl compound is mixed with aminated compounds, add pure water as solvent, the pure water solvent of every 5mmol dicarbonyl compound correspondence 6～10mL; Add 0.005～0.015 equivalent phospho-wolframic acid as catalyzer in said mixture, stirring reaction is 2～12 hours under 5 ℃～60 ℃ temperature; The mol ratio of dicarbonyl compound, aminated compounds and catalyzer is 1: 1.1: 0.005～1: 1.1: 0.015;
Its reaction formula is as follows:
R in the reaction formula (1)
1Be alkyl or aryl, R
2Be alkyl, aryl or alkoxyl group, R
3Be hydrogen, alkyl or halogen group, R
4Be alkyl or aryl;
(2) question response finishes, and with ethyl acetate above-mentioned reaction solution is extracted, and merges organic layer, and separatory is abandoned water layer; Organic layer is washed successively with saturated sodium carbonate solution, saturated nacl aqueous solution, use anhydrous magnesium sulfate drying then, filter, the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain the pure product of acylated enamine.
As a kind of improvement, R in the raw material dicarbonyl compound in the described reaction formula (1)
1During for aryl, described aryl is substituted-phenyl, naphthyl or benzyl; Wherein substituted-phenyl be p-methoxyphenyl, p-methylphenyl, phenyl, to fluorophenyl, adjacent fluorophenyl, rubigan, Chloro-O-Phenyl, to bromophenyl, o-bromophenyl, right-(trifluoromethyl) phenyl, right-(N, the N dimethylamine base) phenyl, o-methyl-phenyl-, an aminomethyl phenyl or 3,4-3,5-dimethylphenyl, naphthyl are Alpha-Naphthyl or betanaphthyl.
As a kind of improvement, R in the raw material dicarbonyl compound in the described reaction formula (1)
2During for aryl, described aryl is substituted-phenyl, naphthyl or benzyl; Wherein substituted-phenyl be p-methoxyphenyl, p-methylphenyl, phenyl, to fluorophenyl, adjacent fluorophenyl, rubigan, Chloro-O-Phenyl, to bromophenyl, o-bromophenyl, right-(trifluoromethyl) phenyl, right-(N, the N dimethylamine base) phenyl, o-methyl-phenyl-, an aminomethyl phenyl or 3,4-3,5-dimethylphenyl, naphthyl are Alpha-Naphthyl or betanaphthyl.
As a kind of improvement, substituent R in the raw material aminated compounds in the described reaction formula (1)
4During for aryl, described aryl is substituted-phenyl, naphthyl or benzyl; Wherein substituted-phenyl be p-methoxyphenyl, p-methylphenyl, phenyl, to fluorophenyl, adjacent fluorophenyl, rubigan, Chloro-O-Phenyl, to bromophenyl, o-bromophenyl, right-(trifluoromethyl) phenyl, right-(N, the N dimethylamine base) phenyl, o-methyl-phenyl-, an aminomethyl phenyl or 3,4-3,5-dimethylphenyl, naphthyl are Alpha-Naphthyl or betanaphthyl.
The invention has the beneficial effects as follows: products made thereby of the present invention is a class important biological material, has important effect the synthetic of medicine with in using; This synthetic method mild condition, productive rate is higher; Make solvent with pure water, environmental friendliness; Reaction raw materials is easy to get, and is easy and simple to handle, is applicable to prepared in laboratory and industrial-scale production.
Embodiment
Embodiment 1
Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.025mmol, stir and reacted 12 hours to add 0.005 equivalent phospho-wolframic acid with aminated compounds 2a by 72mg) 25 ℃ (being room temperature).Reaction finishes, and the reaction solution ethyl acetate extraction merges organic layer, and separatory is abandoned water layer; Organic layer washs successively with saturated sodium carbonate solution, saturated nacl aqueous solution, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (630mg, 72%).
Attached: 3a:
1H NMR (CDCl
3): d 2.289 (s, 3H, CH
3), 2.294 (s, 3H, CH
3), 6.00 (s, 1H, CH), 7.37-7.42 (m, 4H, Ph).
13C NMR (CDCl
3): d 12.62,13.70,107.57,125.99,129.34,133.04,138.74,139.60,149.56.MS (ESI) m/z 208 ([M+H]
+).
Embodiment 2
Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.05mmol, stir and reacted 12 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2a by 114mg) 25 ℃ (being room temperature).Reaction finishes, and the reaction solution ethyl acetate extraction merges organic layer, and separatory is abandoned water layer; Organic layer washs successively with saturated sodium carbonate solution, saturated nacl aqueous solution, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (788mg, 90%).
Embodiment 3
Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.075mmol, stir and reacted 12 hours to add 0.015 equivalent phospho-wolframic acid with aminated compounds 2a by 216mg) 25 ℃ (being room temperature).Reaction finishes, and the reaction solution ethyl acetate extraction merges organic layer, and separatory is abandoned water layer; Organic layer washs successively with saturated sodium carbonate solution, saturated nacl aqueous solution, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (788mg, 90%).
Embodiment 4
Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.05mmol, stir and reacted 6 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2a by 114mg) 25 ℃ (being room temperature).Reaction finishes, and the reaction solution ethyl acetate extraction merges organic layer, and separatory is abandoned water layer; Organic layer washs successively with saturated sodium carbonate solution, saturated nacl aqueous solution, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (718mg, 82%).
Embodiment 5
Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.05mmol, stir and reacted 2 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2a by 114mg) 25 ℃ (being room temperature).Reaction finishes, and the reaction solution ethyl acetate extraction merges organic layer, and separatory is abandoned water layer; Organic layer washs successively with saturated sodium carbonate solution, saturated nacl aqueous solution, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (569mg, 65%).
Embodiment 6
Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.025mmol, 72mg) reacted 12 hours to add 0.005 equivalent phospho-wolframic acid with aminated compounds 2a by 5 ℃ of stirrings.Reaction finishes, and the reaction solution ethyl acetate extraction merges organic layer, and separatory is abandoned water layer; Organic layer washs successively with saturated sodium carbonate solution, saturated nacl aqueous solution, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (516mg, 59%).
Embodiment 7
Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.05mmol, 114mg) reacted 4 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2a by 40 ℃ of stirrings.Reaction finishes, the cooling reaction solution, and the reaction solution ethyl acetate extraction merges organic layer, and separatory is abandoned water layer; Organic layer washs successively with saturated sodium carbonate solution, saturated nacl aqueous solution, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (788mg, 90%).
Embodiment 8
Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.05mmol, 114mg) reacted 2 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2a by 60 ℃ of stirrings.Reaction finishes, the cooling reaction solution, and the reaction solution ethyl acetate extraction merges organic layer, and separatory is abandoned water layer; Organic layer washs successively with saturated sodium carbonate solution, saturated nacl aqueous solution, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (796mg, 91%).
Embodiment 9
Dicarbonyl compound 1b (5mmol, 650mg) (5.5mmol, 589mg) in pure water (8ml), (0.05mmol, stir and reacted 12 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2b by 114mg) 25 ℃ (being room temperature).Reaction finishes, and the reaction solution ethyl acetate extraction merges organic layer, and separatory is abandoned water layer; Organic layer washs successively with saturated sodium carbonate solution, saturated nacl aqueous solution, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain yellow oily liquid 3b (925mg, 89%).
Attached: 3b:
1H NMR (CDCl
3): d 1.25-1.28 (t, J=7.0Hz, 3H, CH
3), 1.92 (s, 3H, CH
3), 4.09-4.13 (q, J=7.1Hz, 2H, CH
2), 4.43-4.44 (d, J=6.4Hz, 2H, CH
2), 4.55 (s, 1H, CH), 7.26-7.36 (m, 5H, Ph), 8.96 (s, 1H, NH).
13C NMR (CDCl
3): d 14.83,19.54,47.00,58.57,83.45,126.92,127.54,128.98,138.98,161.97,170.79.MS (ESI) m/z 220 ([M+H]
+).
Embodiment 10
Dicarbonyl compound 1b (5mmol, 650mg) (5.5mmol, 589mg) in pure water (10ml), (0.05mmol, stir and reacted 12 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2b by 114mg) 25 ℃ (being room temperature).Reaction finishes, and the reaction solution ethyl acetate extraction merges organic layer, and separatory is abandoned water layer; Organic layer washs successively with saturated sodium carbonate solution, saturated nacl aqueous solution, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain yellow oily liquid 3b (925mg, 89%).
At last, it is also to be noted that what more than enumerate only is specific embodiments of the invention.Obviously, the invention is not restricted to above embodiment, many distortion can also be arranged.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought protection scope of the present invention.
Claims (4)
1, a kind of synthetic method of acylated enamine may further comprise the steps:
(1) dicarbonyl compound is mixed with aminated compounds, add pure water as solvent, the pure water solvent of every 5mmol dicarbonyl compound correspondence 6～10mL; Add 0.005～0.015 equivalent phospho-wolframic acid as catalyzer in said mixture, stirring reaction is 2～12 hours under 5 ℃～60 ℃ temperature; The mol ratio of dicarbonyl compound, aminated compounds and catalyzer is 1: 1.1: 0.005～1: 1.1: 0.015;
Its reaction formula is as follows:
R in the reaction formula (1)
1Be alkyl or aryl, R
2Be alkyl, aryl or alkoxyl group, R
3Be hydrogen, alkyl or halogen group, R
4Be alkyl or aryl;
(2) question response finishes, and with ethyl acetate above-mentioned reaction solution is extracted, and merges organic layer, and separatory is abandoned water layer; Organic layer is washed successively with saturated sodium carbonate solution, saturated nacl aqueous solution, use anhydrous magnesium sulfate drying then, filter, the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain the pure product of acylated enamine.
2, according to the synthetic method of the described acylated enamine of claim 1, it is characterized in that R in the raw material dicarbonyl compound in the described reaction formula (1)
1During for aryl, described aryl is substituted-phenyl, naphthyl or benzyl; Wherein substituted-phenyl be p-methoxyphenyl, p-methylphenyl, phenyl, to fluorophenyl, adjacent fluorophenyl, rubigan, Chloro-O-Phenyl, to bromophenyl, o-bromophenyl, right-(trifluoromethyl) phenyl, right-(N, the N dimethylamine base) phenyl, o-methyl-phenyl-, an aminomethyl phenyl or 3,4-3,5-dimethylphenyl, naphthyl are Alpha-Naphthyl or betanaphthyl.
3, according to the synthetic method of the described acylated enamine of claim 1, it is characterized in that R in the raw material dicarbonyl compound in the described reaction formula (1)
2During for aryl, described aryl is substituted-phenyl, naphthyl or benzyl; Wherein substituted-phenyl be p-methoxyphenyl, p-methylphenyl, phenyl, to fluorophenyl, adjacent fluorophenyl, rubigan, Chloro-O-Phenyl, to bromophenyl, o-bromophenyl, right-(trifluoromethyl) phenyl, right-(N, the N dimethylamine base) phenyl, o-methyl-phenyl-, an aminomethyl phenyl or 3,4-3,5-dimethylphenyl, naphthyl are Alpha-Naphthyl or betanaphthyl.
4, according to the synthetic method of the described acylated enamine of claim 1, it is characterized in that substituent R in the raw material aminated compounds in the described reaction formula (1)
4During for aryl, described aryl is substituted-phenyl, naphthyl or benzyl; Wherein substituted-phenyl be p-methoxyphenyl, p-methylphenyl, phenyl, to fluorophenyl, adjacent fluorophenyl, rubigan, Chloro-O-Phenyl, to bromophenyl, o-bromophenyl, right-(trifluoromethyl) phenyl, right-(N, the N dimethylamine base) phenyl, o-methyl-phenyl-, an aminomethyl phenyl or 3,4-3,5-dimethylphenyl, naphthyl are Alpha-Naphthyl or betanaphthyl.
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| CN2008100635856A CN101314574B (en) | 2008-06-27 | 2008-06-27 | Process for synthesizing acylations enamine |
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| CN2008100635856A CN101314574B (en) | 2008-06-27 | 2008-06-27 | Process for synthesizing acylations enamine |
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| CN101314574B CN101314574B (en) | 2012-04-04 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023116940A1 (en) * | 2021-12-22 | 2023-06-29 | 苏州大学 | MODIFICATION METHOD FOR PRECURSOR OF β-KETOIMINE LIGAND, AND PRODUCT THEREOF |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023116940A1 (en) * | 2021-12-22 | 2023-06-29 | 苏州大学 | MODIFICATION METHOD FOR PRECURSOR OF β-KETOIMINE LIGAND, AND PRODUCT THEREOF |
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