3-Dimethylaminoacrolein
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Names | |
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Preferred IUPAC name
(2E)-3-(Dimethylamino)prop-2-enal | |
Other names
3-Dimethylaminopropenal
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Identifiers | |
3D model (JSmol)
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ChemSpider | |
ECHA InfoCard | 100.011.962 |
EC Number |
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PubChem CID
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UNII | |
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Properties | |
C5H9NO | |
Molar mass | 99.133 g·mol−1 |
Appearance | Clear, faintly yellow[1] to dark brown liquid[2] |
Density | 0.99 g·cm−3 at 25°C[1] |
Boiling point | *91 °C at 0.1 kPa[1] |
Soluble[3] | |
Solubility in methanol,[4] 1,2-dichloroethane[5] | Soluble |
Hazards | |
GHS labelling: | |
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Danger | |
H314 | |
P260, P264, P280, P301+P330+P331, P303+P361+P353, P304+P340, P305+P351+P338, P310, P321, P363, P405, P501 | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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3-Dimethylaminoacrolein is an organic compound with the formula Me2NC(H)=CHCHO. It is a pale yellow water-soluble liquid. The compound has a number of useful and unusual properties, e.g. it "causes a reversal of the hypnotic effect of morphine in mice" and has a "stimulating effect in humans".[3]
It is a stable and comparably nontoxic precursor for the genotoxic, mutagenic, and potentially carcinogenic malondialdehyde.[6] The compound can be thought of as vinylogous dimethylformamide (DMF) and combines the functionalities of an unsaturated aldehyde and an enamine. Therefore, 3-dimethylaminoacrolein and vinamidines derived therefrom (composed of vinylogous amidines) or vinamidinium salts (substituted 1,5-diazapentadienes)[7] can be used as reactive molecular building blocks for the formation of nitrogen-containing heterocycles, such as pyridines, pyrimidines, pyrroles or pyrazoles.[8]
Preparation[edit]
3-Dimethylaminoacrolein is obtained by the addition of dimethylamine to the triple bond of propynal (propargyl aldehyde) via a Reppe vinylation.[3]
![Synthese of Dimethylaminoacrolein from propynal.](http://upload.wikimedia.org/wikipedia/commons/thumb/c/c3/3-Dimethylaminoacrolein_Synthese_aus_Propargylaldehyd.svg/400px-3-Dimethylaminoacrolein_Synthese_aus_Propargylaldehyd.svg.png)
Propynal is however an inappropriate starting material for industrial synthesis because of its tendency to explode.[9] Vinyl ethers (such as ethyl vinyl ether) are more suited.[10] They react with phosgene and dimethylformamide (which forms in-situ the Vilsmeier reagent) in 68% yield to 3-ethoxypropenylidene dimethylammonium chloride, an enol ether iminium salt. In the weakly alkaline medium, 3-dimethylaminoacrolein is formed therefrom, which cleaves dimethylamine to form propanedial upon exposure to strong bases (such as sodium hydroxide).
![Synthesis of dimethylaminoacrolein as described by Arnold.](http://upload.wikimedia.org/wikipedia/commons/thumb/4/42/3-Dimethylaminoacrolein_Synthese_nach_Z._Arnold.svg/400px-3-Dimethylaminoacrolein_Synthese_nach_Z._Arnold.svg.png)
In an alternative route, isobutyl vinyl ether reacts with the iminium chloride derived from DMF and phosgene. The conversion can be implemented in a continuous process.[4] The iminium salt yields 3-dimethylaminoacrolein in dilute sodium hydroxide solution in 86% yield.[11]
![Synthesis of 3-dimethylaminoacrolein via isobutylvinylether.](http://upload.wikimedia.org/wikipedia/commons/thumb/4/4a/3-Dimethylaminoacrolein_Synthese_mit_Isobutylvinylether.svg/600px-3-Dimethylaminoacrolein_Synthese_mit_Isobutylvinylether.svg.png)
Instead of phosgene, the iminium salt can also be prepared via an inorganic acid chloride, such as phosphoryl trichloride or an organic acid chloride, such as oxalyl chloride.
Use[edit]
Reactions with 3-dimethylaminoacrolein[edit]
3-Dimethylaminoacrolein can be used to introduce unsaturated and reactive C3 groups into CH-acidic and nucleophilic compounds.
The activated aldehyde group of 3-dimethylaminoacrolein reacts quantitatively with dialkyl sulfates such as dimethyl sulfate. The products are reactive but unstable[12] decompose at 110 °C back into the starting materials. The products can be easily transformed with nucleophiles such as alkoxides or amines into the corresponding vinylogous amide acetals or amidines.[13]
![Reaktionen vinyloger Amidine nach Bredereck](http://upload.wikimedia.org/wikipedia/commons/thumb/7/7a/Reaktionen_vinyloger_Amidine.svg/500px-Reaktionen_vinyloger_Amidine.svg.png)
The stable 3-dimethylaminoacrolein dimethyl acetal is obtained by reaction with sodium methoxide in 62% yield. 3-Dimethylaminoacrolein can be reacted with CH-acidic compounds (such as malononitrile) to 1,3-butadiene derivatives or with cyclopentadiene to an aminofulvene.
With guanidine, 3-dimethylaminoacrolein forms almost quantitatively 2-aminopyrimidine.[4]
![Synthese von 2-Aminopyrimidin aus 3-Dimethylaminoacrolein](http://upload.wikimedia.org/wikipedia/commons/thumb/2/2c/Synthese_von_2-Aminopyrimidin.svg/500px-Synthese_von_2-Aminopyrimidin.svg.png)
The amidine formed with 2-naphthylamine and the dimethyl sulfate adduct can be cyclized with sodium methoxide to give benzo[f]quinoline (1-azaphenanthrene).[14]
![Synthese von Benzo[f]chinolin mit 3-Dimethylaminoacrolein](http://upload.wikimedia.org/wikipedia/commons/thumb/6/68/Synthese_von_1-Azaphenanthren.svg/400px-Synthese_von_1-Azaphenanthren.svg.png)
N-methylpyrrole forms the 3-(2-N-methylpyrrole)propenal with 3-dimethylaminoacrolein and POCl3 in 49% yield.[15]
![Synthese von substituiertem Pyrrol](http://upload.wikimedia.org/wikipedia/commons/thumb/f/f8/Synthese_von_substituiertem_Pyrrol.svg/400px-Synthese_von_substituiertem_Pyrrol.svg.png)
Similarly, the preparation of an intermediate for the cholesterol lowering drug fluvastatin via the reaction of a fluoroaryl-substituted N-isopropylindole with 3-dimethylaminoacrolein and POCl3 proceeds similarly.[16][17]
![Synthese einer Fluvastatin-Zwischenstufe mit 3-Dimethylaminoacrolein](http://upload.wikimedia.org/wikipedia/commons/thumb/1/19/Fluvastatin-Zwischenstufe.svg/500px-Fluvastatin-Zwischenstufe.svg.png)
Occasionally, the iminium salt from the reaction of the Vilsmeier reagent and the vinyl ether (a precursor of 3-dimethylaminopropenal) is directly used for synthesis, e. g. for pyrazoles.[18]
![Pyrazolsynthese mit 3-Dimethylaminoacrolein](http://upload.wikimedia.org/wikipedia/commons/thumb/f/fe/Synthese_von_Pyrazol.svg/500px-Synthese_von_Pyrazol.svg.png)
When hydrazine hydrate is used, a pyrazole parent body is formed in 84% yield.
Reactions to vinamidinium salts[edit]
The reaction of 3-dimethylaminoacrolein with dimethylammonium tetrafluoroborate produces virtually quantitatively the vinamidinium salt 3-dimethylaminoacrolein dimethyliminium tetrafluoroborate, which crystallizes better as the perchlorate salt. The salt reacts also with cyclopentadiene in the presence of sodium amide in liquid ammonia to give the aminofulvene derivative.[19]
The same vinamidinium salt 1,1,5,5-tetramethyl-1,5-diazapentadienium chloride is also formed in the reaction of 3-dimethylaminoacrolein with dimethylamine hydrochloride in 70% yield.[20] The two-step reaction of dimethylamine and 70% perchloric acid with 3-dimethylaminoacrolein forms the same iminium salt (herein referred to as 1,3-bis(dimethylamino)trimethinium perchlorate).[21]
![Synthese des 1,3-Bis(dimethylamino)trimethinium perchlorats](http://upload.wikimedia.org/wikipedia/commons/thumb/f/fc/Bildung_von_1%2C1%2C5%2C5-Tetramethyl-1%2C5-diazapentadieniumperchlorat.svg/500px-Bildung_von_1%2C1%2C5%2C5-Tetramethyl-1%2C5-diazapentadieniumperchlorat.svg.png)
Lactones (e.g. γ-butyrolactone) or cyclic ketones (such as cyclopentanone) form with the vinylamidinium salt of 3-dimethylaminoacrolein and dimethylamine hydrochloride the corresponding dienaminones in 91% and 88% yield.[22]
![Reaktion von 3-Dimethylaminoacrolein mit gamma-Butyrolacton](http://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Dienaminon_mit_gamma-Butyrolacton.svg/500px-Dienaminon_mit_gamma-Butyrolacton.svg.png)
The vinamidinium salt 1,1,5,5-tetramethyl-1,5-diazapentadienium chloride reacts with heterocycles bearing CH-acidic groups to form the corresponding dienamines which can be cyclized with bases to form fused heteroaromatics, such as carbazoles, benzofurans or benzothiophenes.[7]
![Synthese von Carbazolen und Benzothiophenen](http://upload.wikimedia.org/wikipedia/commons/thumb/d/dd/Carbazol%2BBenzothiophen-Synthese.svg/400px-Carbazol%2BBenzothiophen-Synthese.svg.png)
N-alkylpyrroles are obtained in good yield (86%) in the reaction of the vinamidinium salt with glycine esters,[23] substituted thiophenes (up to 87%) in the reaction with mercaptoacetic acid esters.[24]
![Synthese von Thiophenen und Pyrrolen](http://upload.wikimedia.org/wikipedia/commons/thumb/3/32/Thiophen%2BPyrrol-Synthese.svg/400px-Thiophen%2BPyrrol-Synthese.svg.png)
The use of 3-dimethylaminoacrolein for the synthesis of 2-chloronicotinic acid (2-CNA) is of industrial interest as an important starting material for agrochemicals and pharmaceuticals. For this purpose, 3-dimethylaminoacrolein is reacted with cyanessigsäureethylester[25] to 2-chlornicotinsäureethylester or with cyanoacetic acid n-butyl ester to 2-Chlornicotinsäure-n-butyl ester[26] in a Knoevenagel reaction.
![Synthese von 2-Chlornicotinsäure mit 3-Dimethylaminoacrolein](http://upload.wikimedia.org/wikipedia/commons/thumb/b/b8/2-Chlornicotins%C3%A4ure_mit_3-Dimethylaminoacrolein.svg/500px-2-Chlornicotins%C3%A4ure_mit_3-Dimethylaminoacrolein.svg.png)
The resulting esters of 2-chloropyridine carboxylic acid can be hydrolyzed smoothly to 2-chloronicotinic acid.
Other reactions[edit]
It reacts weakly alkaline and gives with iron(III) chloride a deep red color.
Related compounds[edit]
- (Z)-β-Aminoacrolein (H2NCH=CHCHO, CAS# 25186-34-9)[27]
- (E)3-(N-Phenyl-N-methyl)aminoacrolein (PhNHCH=CHCHO, CAS# 14189-82-3)
References[edit]
- ^ a b c "3-(Dimethylamino)acrolein 927-63-9 | TCI Deutschland GmbH". www.tcichemicals.com (in German). Retrieved 2018-01-14.
- ^ a b Sigma-Aldrich Co., product no. 305839.
- ^ a b c d DE 944852, F. Wille, "Verfahren zur Herstellung von Derivaten des 3-Amino-acroleins", published 1956-06-28, assigned to Badische Anilin- & Soda-Fabrik AG
- ^ a b c DE 2424373, M. Decker, W. Schönleben, H. Toussaint, H. Hoffmann, "Verfahren zur Herstellung von Derivaten des Malondialdehyds", published 1975-12-11, assigned to BASF AG
- ^ US 5780622, D. Dolphin, R. Boyle, "Methods of synthesizing 5,15-diarylbenzochlorine-7-one", published 1998-07-14, assigned to The University of British Columbia
- ^ L.J. Niederhofer; J.S. Daniels; C.A. Rouzer; R.E. Greene; L.J. Marnett (2003), "Malondialdehyde, a product of lipid peroxidation, is mutagenic in human cells", J. Biol. Chem., vol. 278, no. 33, pp. 31426–31433, doi:10.1074/jbc.M212549200, PMID 12775726
- ^ a b D. Lloyd; H. McNab (1976), "Vinamidine and Vinamidinium-Salze – Beispiele für stabilisierte Push-Pull-Alkene", Angew. Chem., vol. 88, no. 15, pp. 496–504, doi:10.1002/ange.19760881503
- ^ S. Makhseed; H.M.E. Hassaneen; M.H. Elnagdi (2007), "Studies with 2-(Arylhydrazono)aldehydes: Synthesis and Chemical Reactivity of Mesoxalaldehyde 2-Arylhydrazones and of Ethyl 2-Arylhydrazono-3-oxopropionates" (PDF), Z. Naturforsch., vol. 62b, pp. 529–536
- ^ P. Perlmutter (2001), "Propargyl Aldehyde", E-EROS Encyclopedia of Reagents for Organic Synthesis, doi:10.1002/047084289X.rp262m, ISBN 0471936235
- ^ Z. Arnold; F. Sorm (1958), "Synthetische Reaktionen von Dimethylformamid. I. Allgemeine Synthese von β-Dialdehyden", Collect. Czech. Chem. Commun. (in German), vol. 23, no. 3, pp. 452–461, doi:10.1135/cccc19580452
- ^ DE 19825200, D. Golsch, M. Keil, H. Isak, "Verfahren zur Herstellung von 3-Aminoacroleinderivaten", published 1999-11-18, assigned to BASF AG
- ^ H. Bredereck; F. Effenberger; G. Simchen (1963), "Säureamid-Reaktionen, XXXII. Über Säureamid-Dialkylsulfat-Komplexe", Chem. Ber. (in German), vol. 96, no. 5, pp. 1350–1355, doi:10.1002/cber.19630960526
- ^ H. Bredereck; F. Effenberger; D. Zeyfang (1965), "Synthese und Reaktionen vinyloger Amidacetale und Amidine", Angew. Chem. (in German), vol. 77, no. 5, p. 219, Bibcode:1965AngCh..77..219B, doi:10.1002/ange.19650770511
- ^ C. Jutz; C. Jutz; R.M. Wagner (1972), "Die synchrone Sechs-Elektronen-Cyclisierung von Hexatrien-Systemen als neues Syntheseprinzip zur Darstellung von Aromaten und Heteroaromaten", Angew. Chem. (in German), vol. 84, no. 7, pp. 299–302, Bibcode:1972AngCh..84..299J, doi:10.1002/ange.19720840714
- ^ F.W. Ulrich; E. Breitmeier (1983), "Vinyloge Vilsmeier-Formylierung mit 3-(N,N-Dimethylamino)-acroleinen", Synthesis (in German), vol. 1983, no. 8, pp. 641–645, doi:10.1055/s-1983-30457, S2CID 95436195
- ^ D. Sriram; P. Yogeeswari (2010), Medicinal Chemistry (2nd ed.), Delhi: Pearson, p. 364, ISBN 978-81-317-3144-4
- ^ J.T. Zacharia; T. Tanaka; M. Hagashi (2010), "Facile and highly enenatioselective synthesis of (+)- and (−)-fluvastatin and their analogues", J. Org. Chem., vol. 75, no. 22, pp. 7514–7518, doi:10.1021/jo101542y, PMID 20939538
- ^ EP 0731094, H.-J. Wroblowsky, R. Lantzsch, "Verfahren zur Herstellung von Pyrazolen", published 1996-09-11, assigned to Bayer AG
- ^ Z. Arnold; J. Zemlicka (1960), "Reaktionen der Formamidinium-salze und ihrer Vinyloge mit Carbanionen", Collect. Czech. Chem. Commun. (in German), vol. 25, no. 5, pp. 1302–1307, doi:10.1135/cccc19601302
- ^ V. Nair; C.S. Cooper (1981), "Chemistry of 1,5-diazapentadienium (vinamidinium) salts: alkylation reactions to multifunctional dienamines and dienaminones", J. Org. Chem., vol. 46, no. 23, pp. 4759–4765, doi:10.1021/jo00336a027
- ^ Z. Arnold; D. Dvorak; M. Havranek (1996), "Convenient preparation of 1,3-Bis(dimethylamino)trimethinium perchlorate, tetrafluoroborate and hexafluorophosphate", Collect. Czech. Chem. Commun., vol. 61, no. 11, pp. 1637–1641, doi:10.1135/cccc19961637
- ^ V. Nair; C.S. Cooper (1980), "Selective alkylation reactions with vinamidinium salts", Tetrahedron Lett., vol. 21, no. 33, pp. 3155–3158, doi:10.1016/S0040-4039(00)77433-8
- ^ M.T. Wright; D.G. Carroll; T.M. Smith; S.Q. Smith (2010), "Synthesis of alkylpyrroles by use of a vinamidinium salt", Tetrahedron Lett., vol. 51, no. 31, pp. 4150–4152, doi:10.1016/j.tetlet.2010.06.009
- ^ R.T. Clemens; S.Q. Smith (2005), "The application of vinamidinium salts to the synthesis of 2,4-disubstituted thiophenes", Tetrahedron Lett., vol. 46, no. 8, pp. 1319–1320, doi:10.1016/j.tetlet.2004.12.113
- ^ EP 0372654, L. Schröder, "Preparation of 2-chloropyridine 3-carboxylic acid esters", published 1990-06-13, assigned to Shell Internationale Research Maatschappij B.V.
- ^ WO 0007989, D. Golsch, M. Keil, H. Isak, H. Mayer, "Verfahren zur Herstellung von 2-Halogennikotinsäurederivaten und 2-Halogennikotinsäure-n-butylester als Zwischenprodukt", published 2000-02-17, assigned to BASF AG
- ^ Randolph P. Thummel (2001). "(Z)-β-Aminoacrolein". e-EROS Encyclopedia of Reagents for Organic Synthesis. doi:10.1002/047084289X.ra087. ISBN 0471936235.