CN103304516B - Method for preparing beta-aminoketone, ester and nitrile amide derivatives - Google Patents

Method for preparing beta-aminoketone, ester and nitrile amide derivatives Download PDF

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CN103304516B
CN103304516B CN201310182187.7A CN201310182187A CN103304516B CN 103304516 B CN103304516 B CN 103304516B CN 201310182187 A CN201310182187 A CN 201310182187A CN 103304516 B CN103304516 B CN 103304516B
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choline chloride
ester
nmr
amide derivatives
ionic liquid
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CN103304516A (en
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应安国
武承林
李嵘嵘
杭智军
杨圆
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Taizhou University
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Taizhou University
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Abstract

The invention discloses a method for preparing beta-aminoketone, ester and nitrile amide derivatives. The method comprises the steps of: by taking choline chloride functional ionic liquid as a catalyst, carrying out aza-Michael addition reaction on an amine substance and electron-deficient olefins at room temperature and normal pressure, so as to obtain the beta-aminoketone, ester, nitrile amide derivatives. The choline chloride functional ionic liquid can be repeatedly utilized for a plurality of times. The method is simple to operate, high in yield, good in reusability of a catalytic reaction system and mild in reaction condition, and has a good industrial prospect.

Description

A kind of method preparing beta-amino ketones, ester, nitrile and amide derivatives
Technical field
The present invention discloses a kind of efficient, green, prepare beta-amino ketones, ester, nitrile and amide derivatives with the Michael addition reaction that is catalyzer of choline chloride 60 functional ion liquid method.
Background technology
Beta-amino ketones, ester, nitrile and amide derivatives are widely used in fine chemistry industry and microbiotic field of medicaments as intermediate.General synthetic method comprises Mannich reaction and aza-Michael addition.By contrast, Michael addition is more suitable for preparing beta-amino ketones, ester, nitrile and amide derivatives.For many years, emerge in large numbers a lot of catalyzer, as: LiClO 4, Yb (OTf 3), Bi (NO 3), FeCl 3.6H 2o, CeCl 3.7H 2o, InCl 3, SmI 2with Cu (OTf) 2deng.Emerge a collection of novel catalystic converter system in recent years, beta-cyclodextrin, Bromodimethylsulfonium bromide, Boric acid in water, ZrOCl 2.8H 2o onmontmorillonite K10, Imidazolium-based polymer supported CuI, KF/Al 2o 3, [HP (HNCH 2cH 2) 3n] NO 3deng.But there is the use (1,2-ethylene dichloride and acetonitrile) reusing difference and some poisonous and harmful solvents requiring little or some catalyzer of the substrate range of choice of excessive response reagent or some catalyzer in these reaction systems.Therefore, develop efficient, green amine and grip altogether and add to electron deficient olefins and prepare beta-amino ketones, ester, nitrile and amide derivatives method not only there is important economic benefit, and also have good environmental and social benefits.
Summary of the invention
The object of the invention is to replace the method that traditional catalysis aza-Michael addition amine and electron deficient olefins prepare beta-amino ketones, ester, nitrile and amide derivatives, a kind of efficient, environmental friendliness is provided, under solvent-free gentleness (room temperature) reaction conditions, realizes aza-Michael addition.
The object of the invention is to realize in the following manner:
A kind of method that beta-amino ketones, ester, nitrile and amide derivatives are prepared in aza-Michael addition by amine substance and electron deficient olefins comprises the following steps: with choline chloride 60 functional ion liquid for catalyzer, under room temperature, normal pressure, amine substance and electron deficient olefins carry out aza-Michael addition reaction, obtain beta-amino ketones, ester, nitrile and amide derivatives; Wherein, described choline chloride 60 functional ion liquid has following structural formula I:
Wherein, X --for CH 3o -, CH 3cH 2o -, CH 3cH 2cH 2o -, CH 3(CH 3) CHO -, (CH 3) 3cO -, CH 3cH 2cH 2cH 2o -, CH 3cH 2cH 2cH 2cH 2o -, CH 3cH 2cH 2cH 2cH 2cH 2o -, CH 3cH 2cH 2cH 2cH 2cH 2cH 2o -, CH 3cH 2cH 2cH 2cH 2cH 2cH 2cH 2o -or CH 3cH 2cH 2cH 2cH 2cH 2cH 2cH 2cH 2o -.
The mol ratio of above-mentioned amine substance and electron deficient olefins is 1:1 ~ 1:2.Described choline chloride 60 functional ion liquid be 0.01 ~ 1:1 with the mol ratio of amine substance.
Amine substance can be morpholine, n-Butyl Amine 99, Tri N-Propyl Amine, pyrroles, N methyl piperazine, NEP, ethamine, imidazoles, 2 isopropyl imidazole, piperidines, diethylamine, hexahydroaniline or para-totuidine.Electron deficient olefins can be methyl acrylate, α-methacrylic acid ethyl ester, ethyl propenoate, n-butyl acrylate, Methyl Methacrylate, vinyl cyanide, methylene acetone, α, β-unsaturated cyclonene or acrylic acid amides.Reaction process of the present invention is without the need to any solvent.Reaction times can be 0.5 ~ 24 hour, is preferably 0.5 ~ 2 hour.
After above-mentioned reaction terminates, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product (after substrate is more than 1 mole, direct rectifying separation reaction solution), the 60 DEG C of vacuum-dryings of extracting phase (in rectifying tower reactor raffinate) choline chloride 60 functional ion liquid were reacted for next batch after 6 hours, and can repeatedly use.Confirm through experiment, ionic liquid reuses 8 times, does not find that reaction yield obviously declines.
The present invention utilizes the ionic liquid-catalyzed addition amine substance of gripping altogether of choline chloride 60 to electron deficient olefins, generates the method for beta-amino ketones, ester, nitrile and amide derivatives, specifically can be realized by following approach:
The preparation process of the functional ion liquid based on choline chloride 60 used in the present invention:
The metal-salt MX of the choline chloride 60 of precise and equimolar amount is carried out ion exchange reaction at temperature is 60 ~ 215 DEG C, reaction times is 12-24 hour, cold filtration, filtrate washed with diethylether, then underpressure distillation is except desolventizing, and under gained liquid 60 ~ 80 DEG C of conditions, vacuum-drying 5 ~ 10 hours, obtains light yellow transparent liquid, be functional ion liquid, its reaction equation is as follows:
Wherein, M is Na +, or K +; X is CH 3o -, CH 3cH 2o -, CH 3cH 2cH 2o -, CH 3(CH 3) CHO -, (CH 3) 3cO -, CH 3cH 2cH 2cH 2o -, CH 3cH 2cH 2cH 2cH 2o -, CH 3cH 2cH 2cH 2cH 2cH 2o -, CH 3cH 2cH 2cH 2cH 2cH 2cH 2o -, CH 3cH 2cH 2cH 2cH 2cH 2cH 2cH 2o -or CH 3cH 2cH 2cH 2cH 2cH 2cH 2cH 2cH 2o -.
Aza-Michael adduct preparation process is:
In the there-necked flask that magnetic stirring apparatus is housed, add Ammonia material, electron deficient olefins and ionic liquid.Wherein the mol ratio of Ammonia material and electron deficient olefins is 1:1-1:2, and the mol ratio of ionic liquid and Ammonia material is 0.01:1-1:1, and without the need to any solvent compartment normal temperature and pressure reaction 0.5-24 hour, thin-layer chromatography (TLC) follows the tracks of extent of reaction.After reaction terminates, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product (when substrate is more than 1 mole, can direct rectifying separation reaction solution), the 60 DEG C of vacuum-dryings of extracting phase (bottom product) choline chloride 60 functional ion liquid are for next batch reaction after 6 hours, and ionic liquid reuses 8 times, does not find that reaction yield obviously declines.
Choline chloride 60 (the HOC that the present invention uses 2h 4n (CH 3) 3 +cl -) functional ion liquid has special physicochemical characteristic and thermodynamic stability, dissolving power is strong, low volatility, molecular structure are adjustable, are successfully applied to catalyzed reaction of the present invention (as catalyzer), aftertreatment is simple, choline chloride 60 (HOC 2h 4n (CH 3) 3 +cl -) functional ion liquid can repeatedly use, and shows very excellent feature.Further, choline chloride 60 (HOC 2h 4n (CH 3) 3 +cl -) functional ion liquid preparation is simple, price is very cheap, and without any toxicity.
Compared with the prior art, the inventive method reaction conditions is gentle, simple to operate, yield is high, catalystic converter system reusability is good, environmental protection, and contriver utilizes the choline chloride 60 catalysis of functional ionic liquid carbonnitrogen bond Michael addition of degradable and environment friendly to have good industrial prospect.
Embodiment
Below with reference to embodiment, the present invention will be further described, and embodiments of the invention are only for illustration of technical scheme of the present invention, and non-limiting the present invention.
Embodiment 1
Morpholine (5mmol), methyl acrylate (5.5mmol), 1mmol ionic liquid [Ch] [OMe] are joined in 50mL single port bottle successively, stirring at room temperature 0.5 hour, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 96%, content 98%.
3-(1-Morpholinyl)-propionic acid methyl ester: 1H NMR(400MHz,CDCl 3)(ppm):3.66(s,3H,OCH 3),3.67-3.65(m,4H,morpholinyl),2.65(t,2H,J=6Hz,CH 2),2.48(t,2H,J=6Hz,CH 2),2.43-2.41(m,4H,morpholinyl); 13C NMR(100MHz,CDCl 3)(ppm):172.8,66.8,53.8,53.3,51.6,31.7.
Embodiment 2
Tri N-Propyl Amine (5mmol), methyl acrylate (10mmol), 5mmol ionic liquid [Ch] [OMe] are joined in 50mL single port bottle successively, stirring at room temperature 0.5 hour, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 91%, content 98%.
3-(1-Propylamine)-propionic acid methyl ester: 1H NMR(400MHz,CDCl 3)(ppm):3.63(s,3H,OCH 3),2.62(t,2H,J=6.4Hz,CH 2),2.45(t,2H,J=6.4Hz,CH 2),2.58(m,2H,CH 2),1.41(m,2H,CH 2),0.90(m,3H,CH 3); 13C NMR(100MHz,CDCl 3)(ppm):170.5,66.8,52.8,52.1,44.9,28.1,12.3.
Embodiment 3
Piperidines (5mmol), methyl acrylate (5.5mmol), 1mmol ionic liquid [Ch] [OMe] are joined in 50mL single port bottle successively, stirring at room temperature 0.5 hour, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 96%, content 99%.
3-(1-Piperidinyl)-propionic acid methyl ester: 1H NMR(400MHz,CDCl 3)(ppm):3.86(s,3H,OCH 3),2.86(t,2H,J=6Hz,CH 2),2.68(t,2H,J=6Hz,CH 2),1.80-1.75(m,4H,piperidinyl),1.61-1.44(m,4H,piperidiny),1.42-1.26(m,2H,piperidinyl); 13C NMR(100MHz,CDCl 3)(ppm):173.8,54.2,53.8,52.9,31.8,29.3,25.8,24.6,23.1.
Embodiment 4
2 isopropyl imidazole (5mmol), methyl acrylate (5.5mmol), 0.3mmol ionic liquid [Ch] [OMe] are joined in 50mL single port bottle successively, stirring at room temperature 2 hours, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 79%, content 96%.
3-(2-Isopropyl-1-imidazole)-propionic acid methyl ester: 1H NMR(400MHz,CDCl 3)(ppm):6.94(d,1H,J=1.2Hz,imidazole),6.81(d,1H,J=1.2Hz,imidazole),4.20(t,2H,J=7.2Hz,CH 2),3.71(s,3H,OCH 3),3.03(q,1H,J=7.2Hz,CH)2.76(t,2H,J=7.2Hz,CH 2),1.33(d,6H,2CH 3); 13C NMR(100MHz,CDCl 3)(ppm):170.9,152.4,127.4,118.3,52.0,40.6,35.6,25.7,21.8.
Embodiment 5
Morpholine (5mmol), ethyl propenoate (5.5mmol), 1mmol ionic liquid [Ch] [OEt] are joined in 50mL single port bottle successively, stirring at room temperature 1 hour, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 92%, content 98%.
3-(1-Morpholinyl)-propionic acid ethyl ester: 1H NMR(400MHz,CDCl 3)(ppm):4.15(q,2H,J=7.2Hz,OCH 2),3.7(m,4H,J=4.4Hz,morpholinyl),2.69(t,2H,J=7.6Hz,CH 2),2.50(t,2H,J=7.6Hz,CH 2),2.47(q,4H,J=4.4Hz,morpholinyl),1.27(t,3H,J=7.2Hz,CH 3); 13C NMR(100MHz,CDCl 3)(ppm):175.4,66.9,60.4,53.9,53.4,32.1,14.2.
Embodiment 6
Morpholine (5mmol), n-butyl acrylate (5.5mmol), 1mmol ionic liquid [Ch] [OEt] are joined in 50mL single port bottle successively, stirring at room temperature 1.5 hours, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 93%, content 96%.
3-(1-Morpholinyl)-propionic acid butyl ester: 1H NMR(400MHz,CDCl 3)(ppm):4.09(t,2H,J=8.4Hz,OCH 2),3.69(t,4H,J=4.4Hz,morpholinyl),2.68(t,2H,J=7.6Hz,CH 2),2.49(t,2H,J=7.6Hz,CH 2),1.65-1.58(m,2H,CH 2),0.94(t,3H,J=7.2Hz,CH 3); 13C NMR(100MHz,CDCl 3)(ppm):172.5,66.9,64.3,53.9,53.3,32.1,30.6,19.1,13.7.
Embodiment 7
Morpholine (5mmol), Methyl Methacrylate (5.5mmol), 1mmol ionic liquid [Ch] [OEt] are joined in 50mL single port bottle successively, stirring at room temperature 1 hour, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 95%, content 98%.
2-Methyl-3-(1-morpholinyl)-propionic acid methyl ester: 1H NMR(400MHz,CDCl 3)(ppm):3.69(s,3H,OCH 3),3.68-3.64(m,4H,morpholinyl),2.74-2.62(m,2H,morpholinyl),2.50-2.41(m,2H,morpholinyl),2.41-2.36(m,2H,CH 2),2.33-2.28(m,1H,CH),1.15(d,3H,J=6.8Hz,CH 3); 13C NMR(100MHz,CDCl 3)(ppm):176.4,67.0,62.0,53.7,51.6,37.5,15.5.
Embodiment 8
Morpholine (5mmol), vinyl cyanide (5.5mmol), 1mmol ionic liquid [Ch] [OEt] are joined in 50mL single port bottle successively, stirring at room temperature 1 hour, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 90%, content 97%.
3-(1-Morpholinyl)-propionitrile: 1H NMR(400MHz,CDCl 3)(ppm):3.72(t,4H,J=4.4Hz,morpholinyl),2.68(t,2H,J=7.2Hz,CH 2),2.53(t,2H,J=7.2Hz,CH 2),2.51(t,4H,J=4.4Hz,morpholinyl); 13C NMR(100MHz,CDCl 3)(ppm):118.5,66.5,53.4,52.9,15.6.
Embodiment 9
Morpholine (5mmol), acrylic acid amides (5.5mmol), 1mmol ionic liquid [Ch] [O (t-Bu)] are joined in 50mL single port bottle successively, stirring at room temperature 1 hour, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 95%, content 98%.
3-(1-Morpholinyl)-propanamide: 1H NMR(400MHz,CDCl 3)(ppm):7.84(br,1H,NH),6.06(br,1H,NH),3.73(s,4H,morpholinyl),2.64(t,2H,J=6Hz,CH 2),2.51(s,4H,morpholinyl),2.41(t,2H,J=6Hz,CH 2); 13C NMR(100MHz,CDCl 3)(ppm):175.0,66.7,54.1,52.9,31.6.
Embodiment 10
Imidazoles (5mmol), methyl acrylate (5.5mmol), 1mmol ionic liquid [Ch] [O (t-Bu)] are joined in 50mL single port bottle successively, stirring at room temperature 0.5 hour, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 95%, content 96%.
3-Imidazol-1-yl-propionic acid methyl ester: 1H NMR(400MHz,CDCl 3)(ppm):7.54(s,1H,imidazole),7.05(s,1H,imidazole),6.93(s,1H,imidazole),4.27(t,2H,J=6.6Hz,CH 2),3.70(s,3H,OCH 3),2.78(t,2H,J=6.6Hz,CH2); 13C NMR(100MHz,CDCl 3)(ppm):172.8,66.8,53.8,53.3,51.6,31.7.
Embodiment 11
Diethylamine (5mmol), methylene acetone (5.5mmol), 1mmol ionic liquid [Ch] [O (t-Bu)] are joined in 50mL single port bottle successively, stirring at room temperature 0.5 hour, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 90%, content 98%.
4-Diethyamino-1-yl-butan-2-one: 1H NMR(400MHz,CDCl 3)(ppm):2.76(m,4H,2CH 2),2.52(q,4H,J=7.2Hz,2CH 2),2.14(s,3H,CH 3),1.03(t,6H,J=7.2Hz,2CH 3); 13C NMR(100MHz,CDCl 3)(ppm):207.3,52.4,47.1,40.0,30.3,12.2.
Embodiment 12
By miaow N methyl piperazine (5mmol), α, β-unsaturated cyclonene (5.5mmol), 1mmol ionic liquid [Ch] [O (t-Bu)] join in 50mL single port bottle successively, stirring at room temperature 0.5 hour, TLC detects, and raw material disappears, and uses extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 93%, content 98%.
3-(1-Methylpiperazine)-6-yl-cyclohexan-1-one: 1H NMR(400MHz,CDCl 3)(ppm):2.88(m,4H),2.70(m,1H,CH),2.27(s,3H,CH 3),2.13(m,2H,CH 2),1.72(m,2H,CH 2),1.55(m,2H,CH 2),1.42(m,2H,CH 2); 13C NMR(100MHz,CDCl 3)(ppm):207.0,55.9,49.1,47.9,45.8,40.8,32.8,27.8,22.2.
Embodiment 13
By miaow N-base piperazine (5mmol), α, β-unsaturated cyclonene (5.5mmol), 1mmol ionic liquid [Ch] [O (t-Bu)] join in 50mL single port bottle successively, stirring at room temperature 0.5 hour, TLC detects, and raw material disappears, and uses extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 96%, content 98%.
3-(1-ethylpiperazine)-6-yl-cyclohexan-1-one: 1H NMR(400MHz,CDCl 3)(ppm):3.25(q,2H,J=7.2Hz,CH 2),2.85(m,4H),2.65(m,1H,CH),2.35(m,2H,CH 2),2.15(q,3H,J=7.2Hz,CH 3),2.08(m,2H,CH 2),1.69(m,2H,CH 2),1.52(m,2H,CH 2),1.40(m,2H,CH 2); 13C NMR(100MHz,CDCl 3)(ppm):206.8,56.7,50.2,48.7,40.3,32.5,21.8,11.5.
Embodiment 14
Hexahydroaniline (5mmol), methylene acetone (8.5mmol), 0.05mmol ionic liquid [Ch] [OPr] are joined in 50mL single port bottle successively, stirring at room temperature 0.5 hour, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 62%, content 96%.
4-Cyclohexylamine-1-yl-butan-2-one: 1H NMR(400MHz,CDCl 3)(ppm):2.73(m,4H,2CH 2),2.30(m,1H),2.12(s,3H,CH 3),1.90(m,1H),2.30(m,1H),1.73(m,1H),1.62(m,1H),1.14(m,1H),1.02(m,1H),; 13C NMR(100MHz,CDCl 3)(ppm):207.5,53.1,51.1,41.2,37.5,30.9,27.2,25.4.
Embodiment 15
4-monomethylaniline (5mmol), methyl acrylate (5.5mmol), 1mmol ionic liquid [Ch] [OPr] are joined in 50mL single port bottle successively, stirring at room temperature 1 hour, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 95%, content 98%.
3-(4-Methlphenyl)-propionic acid methyl ester: 1h NMR (400MHz, CDCl 3) (ppm): 6.79-6.73 (m, 2H, ArH), 6.59-6.56 (m, 2H, ArH), 1.73 (s, 3H, CH 3), 3.73 (s, 3H, OCH 3), 3.37 (t, 2H, J=6.4Hz, CH 2), 2.58 (t, 2H, J=6.4Hz, CH 2); 13c NMR (100MHz, CDCl 3) (ppm): 168.9,149.4,139.5,112.9,112.4,53.6,49.7,38.8,32.1. embodiment 16
Experimental installation is there-necked flask mainly, in order to stir fully, adopts mechanical stirring.Flask is placed in by the choline chloride 60 of precise with containing the enanthol solution of enanthol potassium (with choline chloride 60 etc. mole), flask is placed in oil bath, under high-speed stirring, 176 DEG C are reacted 24 hours, cold filtration, filtrate washed with diethylether, then underpressure distillation is except desolventizing, and gained liquid vacuum 80 DEG C of dryings 5 hours, obtain light yellow transparent liquid, yield 86%, purity is 95%.The ionic liquid prepared: 1h NMR (400M, D 2o): δ 3.95 (m, 2H), 3.46 (t, 2H, J=7.2Hz), 3.15 (s, 9H), 2.24 (t, 2H, J=7.2Hz), 1.96-1.71 (m, 10H), 0.88 (t, 3H, J=7.2Hz); 13c NMR (100M, D 2o): δ 67.52,56.01,53.85,54.05 .53.88,40.62,31.68,29.82,28.52,27.63,26.32,13.23.
Reaction formula is:
Embodiment 17
Experimental installation is there-necked flask mainly, in order to stir fully, adopts mechanical stirring.Flask is placed in by the choline chloride 60 of precise with containing the octanol solution of octanol potassium (with choline chloride 60 etc. mole), flask is placed in oil bath, under high-speed stirring, 184 DEG C are reacted 24 hours, cold filtration, filtrate washed with diethylether, then underpressure distillation is except desolventizing, and gained liquid vacuum 80 DEG C of dryings 5 hours, obtain light yellow transparent liquid, yield 83%, purity is 96%.The ionic liquid prepared: 1h NMR (400M, D 2o): δ 4.02 (m, 2H), 3.48 (t, 2H, J=4.8Hz), 3.18 (s, 9H), 2.31 (t, 2H, J=7.2Hz), 1.89-1.73 (m, 12H), 0.83 (t, 3H, J=7.2Hz); 13c NMR (100M, D 2o): δ 67.58,56.03,53.89,54.55 .54.03,40.68,31.75,30.06,29.38,28.63,27.63,26.33,13.35.
Reaction formula is:
Embodiment 18
Experimental installation is there-necked flask mainly, in order to stir fully, adopts mechanical stirring.Flask is placed in by the choline chloride 60 of precise with containing the nonyl alcohol solution of nonyl alcohol potassium (with choline chloride 60 etc. mole), flask is placed in oil bath, under high-speed stirring, 215 DEG C are reacted 24 hours, cold filtration, filtrate washed with diethylether, then underpressure distillation is except desolventizing, and gained liquid vacuum 80 DEG C of dryings 5 hours, obtain light yellow transparent liquid, yield 85%, purity is 96%.The ionic liquid prepared: 1h NMR (400M, D 2o): δ 4.05 (m, 2H), 3.50 (t, 2H, J=4.8Hz), 3.15 (s, 9H), 2.35 (t, 2H, J=7.2Hz), 1.92-1.68 (m, 14H), 0.91 (t, 3H, J=7.2Hz); 13c NMR (100M, D 2o): δ 67.51,56.11,53.85,55.12,54.03,41.05,31.68,30.73,29.78,29.14,28.65,27.22,26.39,14.08.
Reaction formula is:
Embodiment 19
Morpholine (5mmol), methyl acrylate (5.5mmol), 1mmol are joined in 50mL single port bottle according to the ionic liquid that embodiment 18 method prepares successively, stirring at room temperature 2 hours, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 88%, content 96%.Structure of title compound confirms: 1h NMR (400MHz, CDCl 3) (ppm): 3.66 (s, 3H, OCH 3), 3.67-3.65 (m, 4H, morpholinyl), 2.65 (t, 2H, J=6Hz, CH 2), 2.48 (t, 2H, J=6Hz, CH 2), 2.43-2.41 (m, 4H, morpholinyl); 13c NMR (100MHz, CDCl 3) (ppm): 172.8,66.8,53.8,53.3,51.6,31.7.
Embodiment 20
Morpholine (5mmol), methyl acrylate (5.5mmol), 1mmol are joined in 50mL single port bottle according to the ionic liquid that embodiment 17 method prepares successively, stirring at room temperature 1.5 hours, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 90%, content 98%.Products obtained therefrom NMR structure is with embodiment 19.
Embodiment 21
Morpholine (5mmol), methyl acrylate (5.5mmol), 1mmol are joined in 50mL single port bottle according to the ionic liquid that embodiment 16 method prepares successively, stirring at room temperature 1 hour, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 95%, content 98%.Products obtained therefrom NMR structure is with embodiment 19.
Embodiment 22
Extracting phase in morpholine (5mmol), methyl acrylate (5.5mmol), embodiment 1 is joined in 50mL single port bottle through the ionic liquid of 60 DEG C of vacuum-dryings after 6 hours successively, stirring at room temperature 0.5 hour, TLC detects, raw material disappears, use extracted with diethyl ether reaction solution, merge organic phase, column chromatography for separation obtains product, yield 93%, content 98%.Ionic liquid reuses 8 times, does not find that yield obviously declines, specifically in Table 1.NMR DATA Example 1.
Table 1
Described in embodiment 1-15,22, ionic liquid is respectively:
referred to as [Ch] [OMe],
referred to as [Ch] [OEt],
referred to as [Ch] [OPr],
referred to as [Ch] [O (t-Bu)].
Choline chloride 60 functional ion liquid [Ch] [OMe] preparation method: the choline chloride 60 of precise and the methanol solution that the moles of sodium methoxide such as to contain are placed in flask, flask is placed in oil bath, under high-speed stirring, 65 DEG C are reacted 12 hours, cold filtration, filtrate washed with diethylether, then underpressure distillation is except desolventizing, gained liquid vacuum 60 DEG C of dryings 5 hours, obtain light yellow transparent liquid.
Choline chloride 60 functional ion liquid [Ch] [OEt] preparation method: be placed in flask by the choline chloride 60 of precise with containing the ethanolic soln with the moles of sodium ethoxide such as choline chloride 60, flask is placed in oil bath, under high-speed stirring, 65 DEG C are reacted 12 hours, cold filtration, filtrate washed with diethylether, then underpressure distillation is except desolventizing, gained liquid vacuum 60 DEG C of dryings 5 hours, obtain light yellow transparent liquid.
Choline chloride 60 functional ion liquid [Ch] [OPr] preparation method: be placed in flask by the choline chloride 60 of precise with containing the n-propyl alcohol solution with mole n-propyl alcohol sodium such as choline chloride 60, flask is placed in oil bath, under high-speed stirring, 65 DEG C are reacted 12 hours, cold filtration, filtrate washed with diethylether, then underpressure distillation is except desolventizing, gained liquid vacuum 60 DEG C of dryings 5 hours, obtain light yellow transparent liquid.
Choline chloride 60 functional ion liquid [Ch] [O (t-Bu)] preparation method: be placed in flask by the choline chloride 60 of precise with containing the t-butanol solution with mole potassium tert.-butoxide such as choline chloride 60, flask is placed in oil bath, under high-speed stirring, 65 DEG C are reacted 12 hours, cold filtration, filtrate washed with diethylether, then underpressure distillation is except desolventizing, gained liquid vacuum 60 DEG C of dryings 5 hours, obtain light yellow transparent liquid.

Claims (6)

1. prepare the method for beta-amino ketones, ester, nitrile and amide derivatives for one kind, it is characterized in that, described method comprises with the functional ion liquid based on choline chloride 60 for catalyzer, under room temperature, normal pressure, amine substance and electron deficiency material carry out aza-Michael addition reaction, obtain beta-amino ketones, ester, nitrile and amide derivatives; Wherein, the described functional ion liquid based on choline chloride 60 has following structural formula I:
I
X-be CH 3o -, CH 3cH 2o -, CH 3cH 2cH 2o -, CH 3(CH 3) CHO -, (CH 3) 3cO -, CH 3cH 2cH 2cH 2o -, CH 3cH 2cH 2cH 2cH 2o -, CH 3cH 2cH 2cH 2cH 2cH 2o -, CH 3cH 2cH 2cH 2cH 2cH 2cH 2o -, CH 3cH 2cH 2cH 2cH 2cH 2cH 2cH 2o -or CH 3cH 2cH 2cH 2cH 2cH 2cH 2cH 2cH 2o -; Amine substance is morpholine, n-Butyl Amine 99, Tri N-Propyl Amine, ethamine, pyrroles, N methyl piperazine, NEP, imidazoles, 2 isopropyl imidazole, piperidines, diethylamine, hexahydroaniline or para-totuidine; Electron deficiency material is methyl acrylate, α-methacrylic acid ethyl ester, ethyl propenoate, n-butyl acrylate, Methyl Methacrylate, vinyl cyanide, methylene acetone, α, β-unsaturated cyclonene or acrylic acid amides, above-mentioned reaction process is without the need to any solvent.
2. the method for claim 1, is characterized in that, the mol ratio of described amine substance and electron deficiency material is 1:1 ~ 1:2.
3. the method for claim 1, is characterized in that, the described functional ion liquid based on choline chloride 60 be 0.01 ~ 1:1 with the mol ratio of amine substance.
4. the method for claim 1, is characterized in that, the reaction times is 0.5 ~ 24 hour.
5. the method for claim 1, is characterized in that, after reaction terminates, uses extracted with diethyl ether reaction solution, and merge organic phase, column chromatography for separation obtains product.
6. method as claimed in claim 5, it is characterized in that, the extracting phase that described extracted with diethyl ether reaction solution obtains was through 60 DEG C of vacuum-dryings 6 hours.
CN201310182187.7A 2013-05-15 2013-05-15 Method for preparing beta-aminoketone, ester and nitrile amide derivatives Expired - Fee Related CN103304516B (en)

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