3-Dimethylaminoacrolein

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3-Dimethylaminoacrolein
3-Dimethylaminoacrolein Struktur.svg
Names
Preferred IUPAC name
(2E)-3-(Dimethylamino)prop-2-enal
Other names
3-Dimethylaminopropenal
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.011.962 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 213-157-7
PubChem CID
UNII
  • InChI=1S/C5H9NO/c1-6(2)4-3-5-7/h3-5H,1-2H3/b4-3+
    Key: RRLMPLDPCKRASL-ONEGZZNKSA-N
  • CN(C)/C=C/C=O
Properties
C5H9NO
Molar mass 99.133 g·mol−1
AppearanceClear, 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]
  • 133–144 °C [3]
  • 270–273 °C [2]
Soluble [3]
Solubility in methanol, [4] 1,2-dichloroethane [5] Soluble
Hazards
GHS labelling:
GHS-pictogram-acid.svg
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).

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. For instance, when used on mice given morphine, it can reverse the hypnotic effect of the drug, while the compound has a more stimulating effect on human subjects. [3]

Contents

It is a stable chemical, unlike the parent compound 3-aminoacrolein  [ ru ], [6] and can be used as a comparably nontoxic precursor for the genotoxic, mutagenic, and potentially carcinogenic malondialdehyde. [7] 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 there from (composed of vinylogous amidines) or vinamidinium salts (substituted 1,5-diazapentadienes) [8] can be used as reactive molecular building blocks for the formation of nitrogen-containing heterocycles, such as pyridines, pyrimidines, pyrroles or pyrazoles. [9]

Preparation

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. 3-Dimethylaminoacrolein Synthese aus Propargylaldehyd.svg
Synthese of Dimethylaminoacrolein from propynal.

Propynal is however an inappropriate starting material for industrial synthesis because of high explosion risk. [10] Vinyl ethers (such as ethyl vinyl ether) are more suited. [11] 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. 3-Dimethylaminoacrolein Synthese nach Z. Arnold.svg
Synthesis of dimethylaminoacrolein as described by Arnold.

In an alternative route, isobutyl vinyl ether reacts with the Vilsmeier reagent. The conversion can be implemented in a continuous process. [4] That process gives 3-dimethylaminoacrolein in dilute sodium hydroxide solution in 86% yield. [12]

Synthesis of 3-dimethylaminoacrolein via isobutylvinylether. 3-Dimethylaminoacrolein Synthese mit Isobutylvinylether.svg
Synthesis of 3-dimethylaminoacrolein via isobutylvinylether.

Instead of phosgene, the Vilsmeier reagent can also be prepared via phosphoryl trichloride or oxalyl chloride.

Use

Reactions with 3-dimethylaminoacrolein

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 [13] 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. [14]

Reaktionen vinyloger Amidine nach Bredereck Reaktionen vinyloger Amidine.svg
Reaktionen vinyloger Amidine nach Bredereck

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 Synthese von 2-Aminopyrimidin.svg
Synthese von 2-Aminopyrimidin aus 3-Dimethylaminoacrolein

The amidine formed with 2-naphthylamine and the dimethyl sulfate adduct can be cyclized with sodium methoxide to give benzo[f]quinoline (1-azaphenanthrene). [15]

Synthese von Benzo[f]chinolin mit 3-Dimethylaminoacrolein Synthese von 1-Azaphenanthren.svg
Synthese von Benzo[f]chinolin mit 3-Dimethylaminoacrolein

N-methylpyrrole forms the 3-(2-N-methylpyrrole)propenal with 3-dimethylaminoacrolein and POCl3 in 49% yield. [16]

Synthese von substituiertem Pyrrol Synthese von substituiertem Pyrrol.svg
Synthese von substituiertem Pyrrol

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. [17] [18]

Synthese einer Fluvastatin-Zwischenstufe mit 3-Dimethylaminoacrolein Fluvastatin-Zwischenstufe.svg
Synthese einer Fluvastatin-Zwischenstufe mit 3-Dimethylaminoacrolein

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. [19]

Pyrazolsynthese mit 3-Dimethylaminoacrolein Synthese von Pyrazol.svg
Pyrazolsynthese mit 3-Dimethylaminoacrolein

When hydrazine hydrate is used, a pyrazole parent body is formed in 84% yield.

Reactions to vinamidinium salts

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. [20]

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. [21] 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). [22]

Synthese des 1,3-Bis(dimethylamino)trimethinium perchlorats Bildung von 1,1,5,5-Tetramethyl-1,5-diazapentadieniumperchlorat.svg
Synthese des 1,3-Bis(dimethylamino)trimethinium perchlorats

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. [23]

Reaktion von 3-Dimethylaminoacrolein mit gamma-Butyrolacton Dienaminon mit gamma-Butyrolacton.svg
Reaktion von 3-Dimethylaminoacrolein mit gamma-Butyrolacton

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. [8]

Synthese von Carbazolen und Benzothiophenen Carbazol+Benzothiophen-Synthese.svg
Synthese von Carbazolen und Benzothiophenen

N-alkylpyrroles are obtained in good yield (86%) in the reaction of the vinamidinium salt with glycine esters, [24] substituted thiophenes (up to 87%) in the reaction with mercaptoacetic acid esters. [25]

Synthese von Thiophenen und Pyrrolen Thiophen+Pyrrol-Synthese.svg
Synthese von Thiophenen und Pyrrolen

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 [26] to 2-chlornicotinsäureethylester or with cyanoacetic acid n-butyl ester to 2-Chlornicotinsäure-n-butyl ester [27] in a Knoevenagel reaction.

Synthese von 2-Chlornicotinsaure mit 3-Dimethylaminoacrolein 2-Chlornicotinsaure mit 3-Dimethylaminoacrolein.svg
Synthese von 2-Chlornicotinsäure mit 3-Dimethylaminoacrolein

The resulting esters of 2-chloropyridine carboxylic acid can be hydrolyzed smoothly to 2-chloronicotinic acid.

Other reactions

It is weakly alkaline and turns deep red when reacted with iron(III) chloride.

References

  1. 1 2 3 "3-(Dimethylamino)acrolein 927-63-9 | TCI Deutschland GmbH". www.tcichemicals.com (in German). Retrieved 2018-01-14.
  2. 1 2 Sigma-Aldrich Co., product no. 305839.
  3. 1 2 3 4 DE 944852,F. Wille,"Verfahren zur Herstellung von Derivaten des 3-Amino-acroleins",published 1956-06-28, assigned to Badische Anilin- & Soda-Fabrik AG
  4. 1 2 3 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
  5. ↑ 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
  6. ↑ Thummel, Randolph P. (2001). "(Z)-β-Aminoacrolein". Encyclopedia of Reagents for Organic Synthesis . doi:10.1002/047084289X.ra087. ISBN   0-471-93623-5.
  7. ↑ 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
  8. 1 2 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
  9. ↑ 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
  10. ↑ P. Perlmutter (2001), "Propargyl Aldehyde", E-EROS Encyclopedia of Reagents for Organic Synthesis, doi:10.1002/047084289X.rp262m, ISBN   0471936235
  11. ↑ 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
  12. ↑ DE 19825200,D. Golsch, M. Keil, H. Isak,"Verfahren zur Herstellung von 3-Aminoacroleinderivaten",published 1999-11-18, assigned to BASF AG
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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
  16. ↑ 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
  17. ↑ D. Sriram; P. Yogeeswari (2010), Medicinal Chemistry (2nd ed.), Delhi: Pearson, p. 364, ISBN   978-81-317-3144-4
  18. ↑ 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
  19. ↑ EP 0731094,H.-J. Wroblowsky, R. Lantzsch,"Verfahren zur Herstellung von Pyrazolen",published 1996-09-11, assigned to Bayer AG
  20. ↑ 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
  21. ↑ 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
  22. ↑ 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
  23. ↑ 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
  24. ↑ 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
  25. ↑ 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
  26. ↑ EP 0372654,L. Schröder,"Preparation of 2-chloropyridine 3-carboxylic acid esters",published 1990-06-13, assigned to Shell Internationale Research Maatschappij B.V.
  27. ↑ 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
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