CN101712584A - Method for synthesizing alpha, beta, gamma, delta-unsaturated carbonyl compound - Google Patents
Method for synthesizing alpha, beta, gamma, delta-unsaturated carbonyl compound Download PDFInfo
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Abstract
The invention discloses a method for synthesizing an alpha, beta, gamma, delta-unsaturated carbonyl compound. The alpha, beta-unsaturated aldehyde reacts with a 1,3-diketone compound by the catalysis of natural amino acid to prepare the alpha, beta, gamma, delta-unsaturated carbonyl compound; and the natural amino acid is selected from L-lysine, L-proline, L-tryptophan, L-arginine or L-asparagine. The alpha, beta, gamma, delta-unsaturated carbonyl compound is synthesized by the Knoevenagel reaction of the alpha, beta-unsaturated aldehyde and the 1,3-diketone compound through adopting the natural amino acid as a catalyst, therefore, the invention has the advantages of good catalytic activity, low cost, safety, no poison, no pollution to the environment, and the like; the reaction can be smoothly carried out at room temperature without high temperature, and has mild condition, simple operation and high yield; and the method has high universality and wide application prospect, and is suitable for the synthesis of various alpha, beta, gamma, delta-unsaturated carbonyl compounds.
Description
Technical field
The present invention relates to a kind of synthetic method of compound, particularly α, beta, gamma, the synthetic method of δ-beta-unsaturated carbonyl compounds.
Background technology
Knoevenagel (Borneo camphor Wen Gaier) reaction is the classics reaction that forms carbon-carbon double bond in the organic synthesis, is subjected to people for a long time and pays much attention to, and is used widely in synthetic fields such as many important compound such as spices, medicine, superpolymer.At present, study maximum Knoevenagel reaction and be the reaction between aldehydes or ketones and the active methylene compound, and α, the Knoevenagel repercussion study of beta-unsaturated aldehyde and active methylene compound is less, and because α, the activity of beta-unsaturated aldehyde is lower, and existing method majority exists that yield is low, reaction conditions violent as requires problem such as high temperature.In addition, relevant 1, the report of the Knoevenagel reaction of 3-dione compounds is also less, mainly is because 1, the 3-dione compounds trends towards forming stable cyclenes alcohol compound, thereby makes its activity in the Knoevenagel reaction low than other active methylene compound.Current research report shows, with 1, the 3-dione compounds is that the Knoevenagel reaction of substrate exists deficiencies such as long reaction time, yield are low.But, α, beta-unsaturated aldehyde and 1, the Knoevenagel reaction of 3-dione compounds can make important α, beta, gamma, δ-beta-unsaturated carbonyl compounds, it is Diels-Alder (Di Ersi-Alder) reaction and 1, the general synthon and the good substrates of 4-addition reaction.Therefore, study a kind of reaction conditions gentleness and the high α of yield, beta-unsaturated aldehyde and 1, the Knoevenagel reaction of 3-dione compounds has important use and is worth.
In the Knoevenagel of aldehydes or ketones and active methylene compound reaction, catalyzer commonly used has alkali, zeolite, clay, double-deck oxyhydroxide (LDHs), hydrotalcite, ionic liquid, Lewis acid as TiCl
4, ZnCl
2, CeCl
37H
2O/NaI and HClO
4-SiO
2Deng.The Knoevenagel reaction report that with amino acid is catalyzer is less, and most proline(Pro) that adopts.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of α, β, γ, the synthetic method of δ-beta-unsaturated carbonyl compounds is a catalyzer with the natural amino acid, utilize α, beta-unsaturated aldehyde and 1, the Knoevenagel reaction of 3-dione compounds is synthesized, and has reaction conditions gentleness, simple to operate, advantages such as yield is high, cost is low, environmentally safe.
For reaching this purpose, the present invention adopts following technical scheme:
α, beta, gamma, the synthetic method of δ-beta-unsaturated carbonyl compounds, with α, beta-unsaturated aldehyde and 1, the 3-dione compounds reacts under natural amino acid catalysis, makes α, beta, gamma, δ-beta-unsaturated carbonyl compounds; Described natural amino acid is L-Methionin, L-proline(Pro), L-tryptophane, L-arginine or altheine.
Further, described natural amino acid is L-Methionin or L-proline(Pro);
Further, described natural amino acid is a L-Methionin;
Further, described be reflected at solvent-free or have under the solvent condition carry out, described solvent is dimethyl sulfoxide (DMSO) or N, dinethylformamide;
Further, described being reflected under the solvent condition carried out, and described solvent is a dimethyl sulfoxide (DMSO);
Further, described natural amino acid and α, the mol ratio of beta-unsaturated aldehyde is 0.2: 1;
Further, the described temperature that is reflected at is to carry out under 15～35 ℃ of conditions.
Beneficial effect of the present invention is: the present invention utilizes α, beta-unsaturated aldehyde and 1, the synthetic α of Knoevenagel reaction between the 3-dione compounds, β, γ, δ-beta-unsaturated carbonyl compounds has been avoided use metal or other toxic reagent, changing with the natural amino acid is catalyzer, has good, the advantages such as cost is low, safety non-toxic, environmentally safe of catalytic activity; Reaction need not high temperature, at room temperature can carry out mild condition, simple to operate and yield is high smoothly; The inventive method highly versatile is applicable to various α, beta-unsaturated aldehyde and various 1, and the Knoevenagel reaction between the 3-dione compounds, promptly various α, beta, gamma, δ-beta-unsaturated carbonyl compounds synthetic, application prospect is very wide.
Embodiment
In order to make the purpose, technical solutions and advantages of the present invention clearer, below the preferred embodiments of the present invention are described in detail.
In a preferred embodiment, raw material and reagent are commercially available product and without being further purified, adopt tlc (GF254 silica-gel plate) monitoring reaction process in the reaction, flash column chromatography (200～300 order silica gel) purification of target product, gained target product adopt the X-4 micro-fusing point instrument of type (digital display) measure fusing point (mp) (temperature is not proofreaied and correct), Bruker AV-300 type nmr determination proton nmr spectra (
1HNMR) (is interior mark with tetramethylsilane) and carbon-13 nmr spectra (
13CNMR) (is interior mark with deuterochloroform), Varian 7.0T type electro-spray ionization fourier transform ion cyclotron resonance mass spectrometer (ICR) (ESI-FTICR-MS) are measured high resolution mass spectrum (HRMS).Compare for ease of the result, in the preferred embodiment " room temperature " all be controlled at 25 ± 1 ℃.
In research work, solvent, catalyst levels and catalyst type have been investigated at first respectively to α, beta-unsaturated aldehyde and 1, the influence of the Knoevenagel reaction of 3-dione compounds.
1, the influence of solvent
With phenylacrolein and methyl ethyl diketone is model substrates, is catalyzer with the L-proline(Pro), has investigated solvent to α, beta-unsaturated aldehyde and 1, the influence of the Knoevenagel reaction of 3-dione compounds.Higher in order to ensure product yield, excessive phenylacrolein (mol ratio of phenylacrolein and methyl ethyl diketone is 3: 1) and long reaction times (24 hours) are adopted in reaction.The results are shown in Table 1.
Table 1 solvent is to the influence of the Knoevenagel reaction of phenylacrolein and methyl ethyl diketone
A: the product yield behind the flash column chromatography purifying.
As shown in Table 1, solvent has remarkably influenced to the Knoevenagel reaction of phenylacrolein and methyl ethyl diketone: when solvent was water, product yield extremely low (26%) may be because phenylacrolein and all water-fast cause of methyl ethyl diketone; When solvent is tetrahydrofuran (THF) (THF) or methylene dichloride, product yield lower (being respectively 31% and 48%); When solvent is N, dinethylformamide (DMF) or when not adding solvent, product yield medium (being respectively 58% and 60%); When solvent is dimethyl sulfoxide (DMSO) (DMSO), product yield the highest (97%).
2, the influence of catalyst levels
With phenylacrolein and methyl ethyl diketone is model substrates, is catalyzer with the L-proline(Pro), is solvent with DMSO, and stirring reaction is 1 hour under the room temperature, has investigated catalyst levels to α, beta-unsaturated aldehyde and 1, the influence of the Knoevenagel reaction of 3-dione compounds.The results are shown in Table 2.
Table 2 catalyst levels is to the influence of the Knoevenagel reaction of phenylacrolein and methyl ethyl diketone
A: the product yield behind the flash column chromatography purifying.
As shown in Table 2, when catalyst levels is 0.2mmol, promptly the mol ratio of catalyzer and phenylacrolein is 0.2: 1 o'clock, excellent catalytic effect, and product yield height (89%), continuing increases catalyst levels, and product yield does not have bigger variation.
3, the influence of catalyst type
With phenylacrolein and methyl ethyl diketone is model substrates, is catalyzer with the natural amino acid, is solvent with DMSO, and stirring reaction is 1 hour under the room temperature, has investigated the amino acid type to α, beta-unsaturated aldehyde and 1, the influence of the Knoevenagel reaction of 3-dione compounds; Simultaneously, in order to investigate amino acid whose katalysis, carried out blank assay.The results are shown in Table 3.
Table 3 amino acid type is to the influence of the Knoevenagel reaction of phenylacrolein and methyl ethyl diketone
A: the product yield behind the flash column chromatography purifying.
As shown in Table 3, when not adding amino acid, product yield is extremely low in reaction, and only 7%; When adding amino acid in the reaction, partial amino-acid demonstrates good catalytic activity, and wherein the catalytic activity of L-Methionin is best, product yield the highest (93%); The L-proline(Pro) takes second place, and product yield is 89%; The arginic better catalytic activity of L-tryptophane and L-, product yield higher (being respectively 72% and 64%).As if because of L-Methionin and L-arginine are basic aminoacids, above-mentioned reaction result points out amino acid whose basicity that catalytic activity is had considerable influence, but the L-Histidine that is similarly basic aminoacids does not provide analog result, and its product yield only is 6%; And the product yield that contains the L-tryptophane of indole ring in the structure is higher than the L-Histidine that contains imidazole ring in the structure far away, and well-known, the alkalescence of indole ring is weaker than imidazole ring, therefore, in general, amino acid whose basicity is not the principal element that influences catalytic activity.In addition, result of study shows that the very approaching altheine of structure has extremely different catalytic activitys with L-glutaminate, and product yield is respectively 58% and 8%; The catalytic activity of L-methionine(Met), L-halfcystine and L-tryptophane is close, and product yield is 33%～35%, and other amino acid whose poor catalytic activity, product yield low (≤15%).
Comprehensive above-mentioned result of study, α, beta-unsaturated aldehyde and 1, the optimal conditions of the Knoevenagel reaction of 3-dione compounds is: with L-Methionin is catalyzer, is solvent with DMSO, L-Methionin and α, the mol ratio of beta-unsaturated aldehyde is 0.2: 1.Under this optimal conditions, select dissimilar α, beta-unsaturated aldehyde and 1,3-dione compounds carry out the Knoevenagel reaction, with the versatility of verification method.
Embodiment 1～32, α, beta-unsaturated aldehyde and 1, the Knoevenagel reaction of 3-dione compounds
To containing α, beta-unsaturated aldehyde (1mmol), 1, add L-Methionin (0.2mmol) in the reaction system of 3-dione compounds (1mmol) and DMSO (2mL), stirring reaction under the room temperature adopts the tlc monitoring reaction to finishing, and adds methylene dichloride (20mL) dilute reaction solution, after water (10ml * 2) washing, underpressure distillation removes and desolvates, and the gained crude product promptly gets target product with flash column chromatography (moving phase is the mixed solution of ethyl acetate and sherwood oil) purifying.Concrete raw material, reaction times and product yield see Table 4.Product structure is used
1HNMR,
13CNMR and HRMS identify that the spectroscopic data of known compound is consistent with bibliographical information, and the spectroscopic data of new compound sees Table 4.
Table 4 α, beta-unsaturated aldehyde and 1, the Knoevenage reaction of 3-dione compounds
A: the product yield behind the flash column chromatography purifying;
B: because of the new carbon-carbon double bond (C that forms
2=C
3) and the total recovery of the Z/E isomer that produces, the mol ratio of Z/E isomer is respectively 2.1 (embodiment 2 and 8), 2.2 (embodiment 13 and 18) and 3.2 (embodiment 24);
C: new compound, its spectroscopic data is as follows:
(4E)-and ethyl (2-p-nitrophenyl formyl radical-5-phenyl)-2,4-pentadienoic acid ethyl ester (p6): yellow solid; Mp 94-98 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=8.33 (2H, d, J=8.6Hz, p-NO
2Ph), 8.04 (2H, d, J=8.6Hz, p-NO
2Ph), 7.79 (1H, d, J=11.7Hz, R
3CH=CR
4R
5), 7.41 (2H, d, J=1.9Hz, Ph), 7.34-7.33 (3H, m, Ph), 7.14 (1H, d, J=15.4Hz, PhCH=), 6.90 (1H, dd, J
1=11.8Hz, J
2=15.3Hz, PhCH=CH-CH), 4.18 (2H, q, J=7.1Hz, OCH
2), 1.13 (3 H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=192.7,164.7,150.3,146.1,145.8,142.1,135.1,130.1,129.8,129.6,128.8,127.8,123.8,122.3,61.4,13.9; HRMS-ESI:m/z[M+Na]
+C
20H
17NO
5The Na theoretical value is 374.0999, and measured value is 374.100l.
(4E)-and ethyl (2-p-nitrophenyl formyl radical-5-p-methoxyphenyl)-2,4-pentadienoic acid ethyl ester (p11): yellow solid; Mp143-145 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=8.32 (2H, d, J=8.1Hz, p-NO
2Ph), 8.02 (2H, d, J=8.2Hz, p-NO
2Ph), 7.78 (1H, d, J=11.8Hz, R
3CH=CR
4R
5), 7.38 (2H, d, J=8.2Hz, p-OCH
3Ph), 7.10 (1H, d, J=15.3Hz, PhCH=), 6.87-6.77 (3H, m, p-OCH
3Ph and PhCH=CH-CH), 4.17 (2H, q, J=6.9Hz, OCH
2), 3.82 (3H, s, OCH
3), 1.12 (3H, t, J=7.0Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=192.9,165.0,161.4,150.3,147.0,145.9,142.5,129.8,129.6,128.1,123.8,123.6,120.4,114.4,61.3,55.4,14.0; HRMS-ESI:m/z[M+Na]
+C
21H
19NO
6The Na theoretical value is 404.1105, and measured value is 404.1107.
3-[(E)-and 3-p-methylphenyl-2-propenylidene] pentane-2,4-diketone (p12): yellow solid; Mp 79-81 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.40 (2H, d, J=7.9Hz, p-CH
3Ph), 7.23-7.14 (3H, m, R
3CH=CR
4R
5And p-CH
3Ph), 7.09-7.06 (2H, m, p-CH
3PhCH=and p-CH
3PhCH=CH-CH), 2.42 (3H, s, COCH
3), 2.41 (3H, s, COCH
3), 2.37 (3H, s, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=203.1,197.1,145.3,143.4,140.8,140.4,132.7,129.6,127.8,122.4,31.7,26.3,21.4; .HRMS-ESI:m/z[M+Na]
+C
15H
16O
2The Na theoretical value is 251.1043, and measured value is 251.1047.
(2E, 4E)-ethyl (2-ethanoyl-5-p-methylphenyl)-2,4-pentadienoic acid ethyl ester (p13a): yellow oil;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.47 (1H, d, J=11.6Hz, R
3CH=CR
4R
5), 7.40 (2H, d, J=7.9Hz, p-CH
3Ph), 7.30 (1H, dd, J
1=11.6Hz, J
2=15.0Hz, p-CH
3PhCH=CH-CH), 7.17 (2H, d, J=7.8Hz, p-CH
3Ph), 7.04 (1H, d, J=15.2Hz, p-CH
3PhCH=), 4.29 (2H, q, J=7.1Hz, OCH
2), 2.46 (3H, s, PhCH
3), 2.36 (3H, s, COCH
3), 1.35 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=200.5,165.5,145.9,145.7,140.3,132.9,131.0,129.5,127.9,122.6,61.1,31.2,21.4,14.2; HRMS-ESI:m/z[M+Na]
+C
16H
18O
3The Na theoretical value is 281.1148, and measured value is 281.1153.
(2Z, 4E)-ethyl (2-ethanoyl-5-p-methylphenyl)-2,4-pentadienoic acid ethyl ester (p13b): yellow oil;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.44 (1H, d, J=12.0Hz, R
3CH=CR
1R
2), 7.40 (2H, d, J=7.9Hz, p-CH
3Ph), 7.34-7.23 (1H, m, p-CH
3PhCH=CH-CH), 7.18 (2H, d, J=7.6Hz, p-CH
3Ph), 7.08 (1H, d, J=15.2Hz, p-CH
3PhCH=), 4.39 (2H, q, J=7.0Hz, OCH
2), 2.40 (3H, s, PhCH
3), 2.37 (3H, s, COCH
3), 1.40 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=195.6,166.4,146.0,145.2,140.4,132.9,131.7,129.6,127.8,122.7,61.2,28.0,21.4,14.2; HRMS-ESI:m/z[M+Na]
+C
16H
18O
3The Na theoretical value is 281.1148, and measured value is 281.1151.
Diethyl-2-[(E)-3-p-methylphenyl-2-propenylidene] propanedioic acid (p14): yellow solid; Mp 61-66 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.53 (1H, d, J=11.5Hz, R
3CH=CR
4R
5), 7.40 (2H, d, J=7.8Hz, p-CH
3Ph), 7.34-7.22 (1H, m, p-CH
3PhCH=CH-CH), 7.18 (2H, d, J=7.2Hz, p-CH
3Ph), 7.02 (1H, d, J=15.4Hz, p-CH
3PhCH=), 4.37 (2H, q, J=7.1Hz, OCH
2), 4.28 (2H, q, J=7.0Hz, OCH
2), 2.37 (3H, s, p-CH
3PhCH
3), 1.38 (3H, t, J=7.1Hz, CH
3), 1.33 (3H, t, J=7.0Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=165.4,164.8,145.6,144.7,140.2,132.9,129.5,127.8,124.2,122.3,61.2,21.4,14.2; HRMS:m/z[M+Na]
+C
17H
20O
4The Na theoretical value is 311.1254, and measured value is 311.1255.
(4E)-and ethyl (2-benzoyl-5-p-methylphenyl)-2,4-pentadienoic acid ethyl ester (p15): yellow solid; Mp 71-75 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.91 (2H, d, J=8.0Hz, Ph), 7.70 (1H, d, J=11.7Hz, R
3CH=CR
4R
5), 7.59-7.45 (3H, m, Ph), 7.28 (2H, d, J=8.1Hz, p-CH
3Ph), 7.11 (2H, d, J=7.7Hz, p-CH
3Ph), 7.02 (1H, d, J=15.4Hz, p-CH
3PhCH=), 6.78 (1H, dd, J
1=11.8Hz, J
2=15.1Hz, p-CH
3PhCH=CH-CH), 4.18 (2H, q, J=7.1Hz, OCH
2), 2.32 (3H, s, p-CH
3PhCH
3), 1.13 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=194.4,165.2,144.4,144.1,140.0,137.2,133.5,132.7,130.6,129.5,129.1,128.6,127.6,121.9,61.0,21.4,13.9; HRMS-ESI:m/z[M+Na]
+C
21H
20O
3The Na theoretical value is 343.1305, and measured value is 343.1307.
(4E)-and ethyl (2-p-nitrophenyl formyl radical-5-p-methylphenyl)-2,4-pentadienoic acid ethyl ester (p16): yellow solid; Mp 131-134 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=8.32 (2H, d, J=8.5Hz, p-NO
2Ph), 8.03 (2H, d, J=8.4Hz, p-NO
2Ph), 7.78 (1H, d, J=11.7Hz, R
3CH=CR
4R
5), 7.32 (2H, d, J=7.8Hz, p-CH
3Ph), 7.13 (2H, d, J=7.3Hz, p-CH
3Ph), 7.09 (1H, p-CH
3PhCH=), 6.87 (1H, dd, J
1=11.9Hz, J
2=14.9Hz, p-CH
3PhCH=CH-CH), 4.17 (2H, q, J=7.0Hz, OCH
2), 2.34 (3H, s, p-CH
3PhCH
3), 1.12 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=192.8,164.8,150.2,146.6,146.0,142.2,140.6,132.4,129.7,129.6,128.8,127.8,123.8,121.4,61.3,21.4,13.9; HRMS-ESI:m/z[M+Na]
+C
21H
19NO
5The Na theoretical value is 388.1155, and measured value is 388.1148.
3-[(E)-and 3-(4-rubigan)-2-propenylidene) pentane-2,4-diketone (p17): yellow solid; Mp 80-83 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.43 (2H, d, J=8.2Hz, p-ClPh), 7.35 (2H, d, J=8.1Hz, p-ClPh), 7.22-6.98 (3H, m, p-ClPhCH=CH-CH), 2.42 (6H, s, 2COCH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=202.9,197.1,143.3,142.5,141.6,135.7,133.8,129.1,128.9,123.8,31.7,26.3; HRMS-ESI:m/z[M+Na]
+C
14H
13ClO
2The Na theoretical value is 271.0496, and measured value is 271.0493.
(2E, 4E)-ethyl (2-ethanoyl-5-rubigan)-2,4-pentadienoic acid ethyl ester (p18a): yellow solid; Mp 50-53 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.46-7.42 (3H, d, p-ClPh and R
3CH=CR
4R
5), 7.32 (2H, d, J=8.1Hz, p-ClPh), 7.27-7.23 (1H, p-ClPhCH=CH-CH), 7.00 (1H, d, J=15.2Hz, p-ClPhCH=C), 4.30 (2H, q, J=7.0Hz, OCH
2), 2.46 (3H, s, COCH
3), 1.35 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=202.3,165.2,144.7,143.9,135.6,134.1,132.2,129.1,129.0,124.0,61.2,31.2,14.2; HRMS-ESI:m/z[M+Na]
+C
15H
15ClO
3The Na theoretical value is 301.0602, and measured value is 301.0606.
(2Z, 4E)-ethyl (2-ethanoyl-5-rubigan)-2,4-pentadienoic acid ethyl ester (p18b): yellow solid; Mp 81-83 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.43 (2H, d, J=8.3Hz, p-ClPh), 7.42 (1H, d, J=11.6Hz, R
3CH=CR
4R
5), 7.35 (2H, d, J=8.1Hz, p-ClPh), 7.30-7.23 (1H, m, p-ClPhCH=CH-CH), 7.04 (1H, d, J=15.0Hz, p-ClPhCH=C), 4.40 (2H, q, J=7.1Hz, OCH
2), 2.40 (3H, s, COCH
3), 1.41 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=195.5,166.2,144.3,144.1,135.7,134.1,132.7,129.1,128.9,124.1,61.3,28.0,14.2; HRMS-ESI:m/z[M+Na]
+C
15H
15ClO
3The Na theoretical value is 301.0602, and measured value is 301.0599.
Diethyl-2-[(E)-3-rubigan-2-propenylidene] propanedioic acid (p19): white solid; Mp 75-76 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.50 (1H, d, J=11.5Hz, R
3CH=CR
4R
5), 7.43 (2H, d, J=8.4Hz, p-ClPh), 7.34 (2H, d, J=8.4Hz, p-ClPh), 7.23 (1H, dd, J=11.6Hz, J
2=15.3Hz, p-ClPhCH=CH-CH), 6.98 (1H, d, J=15.4Hz, p-ClPhCH=C), 4.37 (2H, q, J=7.1Hz, OCH
2), 4.28 (2H, q, J=7.1Hz, OCH
2), 1.38 (3H, t, J=7.1Hz, CH
3), 1.33 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=165.1,164.5,144.7,142.8,135.5,134.0,129.0,128.8,125.4,123.7,61.3,14.1; HRMS-ESI:m/z[M+Na]
+C
16H
17ClO
4The Na theoretical value is 331.0708, and measured value is 331.0708.
(4E)-and ethyl (2-benzoyl-5-rubigan)-2,4-pentadienoic acid ethyl ester (p21): yellow solid; Mp 99-102 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.90 (2H, d, J=7.8Hz, Ph), 7.68 (1H, d, J=11.6Hz, R
3CH=CR
4R
5), 7.62-7.58 (1H, m, Ph), 7.51-7.46 (2H, m, Ph), 7.32-7.28 (4H, m, p-ClPh), 6.99 (1H, d, J=15.4Hz, p-ClPhCH=C), 6.83-6.78 (1H, m, p-ClPhCH=CH-CH), 4.18 (2H, q, J=7.1Hz, OCH
2), 1.13 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=194.1,165.0,143.5,142.2,137.2,135.4,134.0,133.6,131.9,129.1,129.0,128.7,128.7,123.4,61.2,13.9; HRMS-ESI:m/z[M+Na]
+C
20H
17ClO
3The Na theoretical value is 363.0758, and measured value is 363.0753.
(4E)-and ethyl (2-p-nitrophenyl formyl radical-5-rubigan)-2,4-pentadienoic acid ethyl ester (p22): yellow solid; Mp 151-153 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=8.33 (2H, d, J=8.5Hz, p-NO
2Ph), 8.03 (2H, d, J=8.5Hz, p-NO
2Ph), 7.76 (1H, d, J=11.6Hz, R
3CH=CR
4R
5), 7.36 (2H, d, J=8.4Hz, p-ClPh), 7.30 (2H, d, J=8.4Hz, p-ClPh), 7.08 (1H, d, J=15.4Hz, p-ClPhCH=), 6.87 (1H, dd, J
1=11.7Hz, J
2=15.1Hz, p-ClPhCH=CH-CH), 4.18 (2H, q, J=7.1Hz, OCH
2), 1.13 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=192.6,164.6,150.4,145.8,144.2,142.0,136.0,133.7,130.2,129.8,129.1,129.0,123.9,122.9,61.5,13.9; HRMS:m/z[M+Na]
+C
20H
16ClNO
5The Na theoretical value is 408.0609, and measured value is 408.0607.
3-[(E)-3-is to fluorophenyl-2-propenylidene] pentane-2,4-diketone (p23): yellow solid; Mp 101-102 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.50 (2H, d, J=5.7Hz, p-FPh), 7.22-7.19 (1H, m, p-FPhCH=CH-CH), 7.15-7.10 (2H, m, R
3CH=CR
4R
5And p-FPhCH=), 7.06 (2H, d, J=5.8Hz, p-FPh), 2.42 (6H, s, 2OCH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=203.0,197.2,163.6 (d, J=250.0Hz), 143.6,142.9,141.4,131.7,129.7 (d, J=8.3Hz), 123.2,116.1 (d, J=21.8Hz), 31.8,26.4; HRMS-ESI:m/z[M+Na]
+C
14H
13FO
2The Na theoretical value is 255.0792, and measured value is 255.0794.
(2E, 4E)-ethyl (2-ethanoyl-5-is to fluorophenyl)-2,4-pentadienoic acid ethyl ester (p24a): yellow oil;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.45-7.41 (3H, m, p-FPh and R
3CH=CR
4R
5), 7.24 (1H, dd, J
1=12.0Hz, J
2=15.0Hz, p-FPhCH=CH-CH), 7.09-7.00 (3H, m, p-FPh and p-FPhCH=), 4.30 (2H, q, J=7.1Hz, OCH
2), 2.46 (3H, s, COCH
3), 1.35 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=200.3,165.3,163.6 (d, J=249.8Hz), 145.1,144.2,131.9,131.8,129.7 (d, J=8.0Hz), 123.3,116.0 (d, J=21.8Hz), 61.2,31.2,14.2; HRMS-ESI:m/z[M+Na]
+C
15H
15FO
3The Na theoretical value is 285.0897, and measured value is 285.0898.
(2Z, 4E)-ethyl (2-ethanoyl-5-is to fluorophenyl)-2,4-pentadienoic acid ethyl ester (p24b): yellow solid; Mp 39-41 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.52-7.41 (3H, m, p-FPh and R
3CH=CR
4R
5), 7.25 (1H, dd, J
1=15.2Hz, J
2=10.1Hz, p-FPhCH=CH-CH), 7.10-7.04 (3H, m, p-FPh and p-FPhCH=), 4.40 (2H, q, J=7.1Hz, OCH
2), 2.41 (3H, s, COCH
3), 1.41 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=195.6,166.3,163.6 (d, J=250.0Hz), 144.7,144.4,132.3,131.9,129.6 (d, J=8.3Hz), 123.4,116.1 (d, J=21.8Hz), 61.3,28.1,14.3.HRMS-ESI:m/z[M+Na]
+C
15H
15FO
3The Na theoretical value is 285.0897, and measured value is 285.0898.
Diethyl-2-[(E)-3-is to fluorophenyl-2-propenylidene] propanedioic acid (p25): white solid; Mp 63-65 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.52-7.45 (3H, m, p-FPh and R
3CH=CR
4R
5), 7.19 (1H, dd, J
1=11.6Hz, J
2=15.3Hz, p-FPhCH=CH-CH), 7.09-6.97 (3H, m, p-FPh and p-FPhCH=), 4.37 (2H, q, J=7.1Hz, OCH
2), 4.28 (2H, q, J=7.1Hz, OCH
2), 1.38 (3H, t, J=7.1Hz, CH
3), 1.33 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=165.3,164.7,163.5 (d, J=249.6Hz), 145.0,143.1,131.8,129.5 (d, J=8.2Hz), 125.0,123.0,115.9 (d, J=21.8Hz), 61.3,14.2; HRMS-ESI:m/z[M+Na]
+C
16H
17FO
4The Na theoretical value is 315.1003, and measured value is 315.1005.
(4E)-and ethyl (2-benzoyl-5-is to fluorophenyl)-2,4-pentadienoic acid ethyl ester (p26): white solid; Mp 107-108 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=7.91 (2H, d, J=7.2Hz, Ph), 7.70-7.66 (1H, m, Ph), 7.59 (1H, d, J=7.2Hz, R
3CH=CR
4R
5), 7.48 (2H, dd, J
1=7.2Hz, J
2=7.3Hz, Ph), 7.35 (2H, d, J=5.4Hz, p-FPh), 7.02-6.97 (3H, m, p-FPh and p-FPhCH=), 6.78-6.73 (1H, m, p-FPhCH=CH-CH), 4.18 (2H, q, J=7.1Hz, OCH
2), 1.13 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=194.2,165.0,163.3 (d, J=250.3Hz), 143.8,142.5,137.1,133.6,131.7,131.3,129.4 (d, J=8.2Hz), 129.1,128.6,122.6,115.8 (d, J=21.8Hz), 61.1,13.9; HRMS-ESI:m/z[M+Na]
+C
20H
17FO
3The Na theoretical value is 347.1054, and measured value is 347.1051.
(4E)-and ethyl (2-p-nitrophenyl formyl radical-5-is to fluorophenyl)-2,4-pentadienoic acid ethyl ester (p27): yellow solid; Mp 121-123 ℃;
1HNMR (300MHz, CDCl
3): δ (ppm)=8.32 (2H, d, J=8.1Hz, p-NO
2Ph), 8.03 (2H, d, J=8.0Hz, p-NO
2Ph), 7.76 (1H, d, J=11.7Hz, R
3CH=CR
4R
5), 7.44-7.39 (2H, m, p-FPh), 7.13-7.00 (3H, m, p-FPh and p-FPhCH=), 6.83 (1H, dd, J
1=12.0Hz, J
2=15.0Hz), 4.18 (2H, q, J=7.0Hz, OCH
2), 1.13 (3H, t, J=7.0Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=192.7,164.7,163.7 (d, J=250.3Hz), 150.4,146.1,144.4,142.1,131.5,129.8,129.7,123.9,122.2,116.2,115.9,61.4,14.0; HRMS-ESI:m/z[M+Na]
+C
20H
16FNO
5The Na theoretical value is 392.0905, and measured value is 392.0907.
(4E)-and ethyl (2-p-nitrophenyl formyl radical)-2,4-Sorbic Acid ethyl ester (p32): this product is two kinds of mixture of isomers, and wherein the data of the isomer of large percentage are as follows: yellow oil;
1HNMR (300MHz, CDCl
3): δ (ppm)=8.31 (2H, d, J=8.5Hz, p-NO
2Ph), 8.01 (2H, d, J=8.6Hz, p-NO
2Ph), 7.58 (1H, d, J=11.6Hz, R
3CH=CR
4R
5), 6.43 (1H, dd, J
1=7.1Hz, J
2=19.7Hz, CH
3CH=CH-CH), 6.37-6.15 (1H, m, CH
3CH=), 4.16 (2H, q, J=7.2Hz, OCH
2), 1.86 (3H, d, J=6.7Hz, CH
3), 1.11 (3H, t, J=7.1Hz, CH
3);
13CNMR (75MHz, CDCl
3): δ (ppm)=192.8,164.8,149.0,147.8,146.1,145.8,141.9,129.8,126.5,123.8,61.3,19.1,13.9; HRMS:m/z[M+Na]
+C
15H
15NO
5The Na theoretical value is 312.0842, and measured value is 312.0837.
As shown in Table 4: 1. dissimilar α, beta-unsaturated aldehyde and 1, the Knoevenagel reaction of 3-dione compounds all can be carried out smoothly and obtain α, beta, gamma, δ-beta-unsaturated carbonyl compounds, yield is higher than 33%; 2. to aromatic alpha, beta-unsaturated aldehyde (embodiment 1～27) is analyzed, find: electronic effect is to aromatic alpha, beta-unsaturated aldehyde and 1, the Knoevenagel reaction of 3-dione compounds has remarkably influenced, when the hydrogen atom on the aromatic nucleus is not substituted or is replaced by donor residues, product yield higher (embodiment 1～16); And when being replaced by electron withdrawing group, product yield lower (embodiment 17～27); Infer that its major cause is: reaction product is α, β, γ, δ-beta-unsaturated carbonyl compounds can be in two positions and 1, further reaction takes place in the 3-dione compounds, be respectively beta carbon and δ-carbon atom, when deriving from aromatic alpha, when having electron withdrawing group to exist in the substituent R of beta-unsaturated aldehyde, beta carbon and δ-carbon atom are reduced by the cloud density that influences of this electron withdrawing group, and positive polarity increases, be beneficial to 1, active methyne in the 3-dione compounds is initiated nucleophilic attack, thereby causes side reaction to take place, and product yield reduces; In addition, data presentation in the table, product yield to fluorine phenylacrolein (embodiment 23～27) all is lower than chlorocinnamaldehyde (embodiment 17～22), and it is well-known, the electron-withdrawing power of fluorine atom is better than the chlorine atom, therefore can further infer: substituent electron-withdrawing power is strong more on the aromatic nucleus, and product yield is low more; 3. to aliphatic alpha, beta-unsaturated aldehyde (embodiment 28～32) is analyzed, find: the product yield of crotonic aldehyde and methyl ethyl diketone (embodiment 28), methyl aceto acetate (embodiment 29) or diethyl malonate (embodiment 30) reaction is higher, and it is lower with the product yield of ethyl benzoylacetate (embodiment 31) reaction, it is less sterically hindered that its reason may be that the δ-carbon atom of products therefrom has, be easy to continue reaction and generate by product, thereby make himself yield reduction with ethyl benzoylacetate; In addition, the reaction of crotonic aldehyde and p-nitrophenyl malonaldehydic acid ethyl ester (embodiment 32), because of reacting incomplete, product yield is lower equally, and spectroscopic data shows that this product is two kinds of mixture of isomers, once attempted in the research to separate these two kinds of isomer with column chromatography but fail, from the NMR data, the ratio of these two kinds of isomer is about 3.3: 1; 4. to 1,3-dione compounds (embodiment 1～32) is analyzed, and finds: except have strong electron-withdrawing group to the fluorine phenylacrolein (embodiment 23), methyl ethyl diketone and most of α, during the beta-unsaturated aldehyde reaction, product yield is higher, and (embodiment 1,7,12,17); Equally, diethyl malonate and most α, during the beta-unsaturated aldehyde reaction, product yield is also higher, and (embodiment 3,9,19), but when reacting to methyl phenylacrolein (embodiment 14) or to fluorine phenylacrolein (embodiment 25), product yield is relatively low, mainly comes from reaction not exclusively, but discover that further the prolongation reaction times can not be improved product yield; Isopropylidene malonate and phenylacrolein (embodiment 4) or low to the product yield of chlorocinnamaldehyde (embodiment 20) reaction mainly come from unstable products; The product yield of methyl aceto acetate and phenylacrolein (embodiment 2) or p-met hoxycinnamic aldehyde (embodiment 8) reaction is higher, but with to methyl phenylacrolein (embodiment 13), to chlorocinnamaldehyde (embodiment 18) or lower to the product yield of fluorine phenylacrolein (embodiment 24) reaction; And, methyl aceto acetate and α, the reaction product of beta-unsaturated aldehyde is because of the new carbon-carbon double bond (C that forms
2=C
3) and have two kinds of isomer of Z, E, and the ratio of Z isomer always is higher than E isomer; Ethyl benzoylacetate and all α, the reaction of beta-unsaturated aldehyde has the quantity by product that more or less to generate (embodiment 5,10,15,21,26); P-nitrophenyl malonaldehydic acid ethyl ester and phenylacrolein (embodiment 6), p-met hoxycinnamic aldehyde (embodiment 11) or can react completely to methyl phenylacrolein (embodiment 16), but with can not react completely to chlorocinnamaldehyde (embodiment 22) or to fluorine phenylacrolein (embodiment 27).
Explanation is at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by invention has been described with reference to the preferred embodiments of the present invention, but those of ordinary skill in the art is to be understood that, can make various changes to it in the form and details, and the spirit and scope of the present invention that do not depart from appended claims and limited.
Claims (7)
1. α, beta, gamma, the synthetic method of δ-beta-unsaturated carbonyl compounds is characterized in that: with α, beta-unsaturated aldehyde and 1, the 3-dione compounds reacts under natural amino acid catalysis, makes α, beta, gamma, δ-beta-unsaturated carbonyl compounds; Described natural amino acid is L-Methionin, L-proline(Pro), L-tryptophane, L-arginine or altheine.
2. α according to claim 1, beta, gamma, the synthetic method of δ-beta-unsaturated carbonyl compounds is characterized in that: described natural amino acid is L-Methionin or L-proline(Pro).
3. α according to claim 2, beta, gamma, the synthetic method of δ-beta-unsaturated carbonyl compounds is characterized in that: described natural amino acid is a L-Methionin.
4. α according to claim 1, beta, gamma, the synthetic method of δ-beta-unsaturated carbonyl compounds is characterized in that: described be reflected at solvent-free or have under the solvent condition carry out, described solvent is dimethyl sulfoxide (DMSO) or N, dinethylformamide.
5. α according to claim 4, beta, gamma, the synthetic method of δ-beta-unsaturated carbonyl compounds is characterized in that: described being reflected under the solvent condition carried out, and described solvent is a dimethyl sulfoxide (DMSO).
6. according to the described α of the arbitrary claim of claim 1 to 5, beta, gamma, the synthetic method of δ-beta-unsaturated carbonyl compounds is characterized in that: described natural amino acid and α, the mol ratio of beta-unsaturated aldehyde is 0.2: 1.
7. α according to claim 6, beta, gamma, the synthetic method of δ-beta-unsaturated carbonyl compounds is characterized in that: the described temperature that is reflected at is to carry out under 15～35 ℃ of conditions.
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