3-Dimethylaminoacrolein

3-Dimethylaminoacrolein
Names
Preferred IUPAC name
(2E)-3-(Dimethylamino)prop-2-enal
Other names
3-Dimethylaminopropenal
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.011.962
EC Number
  • 213-157-7
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
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]
  • 133–144 °C[3]
  • 270–273 °C[2]
Soluble[3]
Solubility in methanol,[4] 1,2-dichloroethane[5] Soluble
Hazards
GHS labelling:
GHS05: Corrosive
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).
Infobox references

3-Dimethylaminoacrolein is an organic compound with the formula Me2NC(H)=CHCHO. It is a pale yellow, water-soluble liquid. A push-pull alkene, it has chemical similarities to malondialdehyde and dimethylformamide.

Pharmacology

3-Dimethylaminoacrolein is a stimulant in humans and animals. It reverses the hypnotic effect of morphine in mice.[3]

Preparation

The simplest notional synthesis of 3-dimethylaminoacrolein is a Reppe hydroamination:[3]

Synthese of Dimethylaminoacrolein from propynal.
Synthese of Dimethylaminoacrolein from propynal.

However, propynal is too explosive to make this procedure viable.[6][7]

Instead, 3-dimethylaminoacrolein typically arises from Vilsmeier formylation of a vinyl ether, which gives an enoliminium chloride. Weak bases then cleave the enoliminium cation and recover 3-dimethylaminoacrolein. (Strong bases decompose the product; see § Chemical properties).

For example, in the following reaction sequence,[4] a mixture of phosgene and dimethylformamide forms the Vilsmeier reagent, which then attacks isobutyl vinyl ether. Quenching with dilute NaOH gives the 3-dimethylaminoacrolein:[8]

Synthesis of 3-dimethylaminoacrolein via isobutylvinylether.

Chemical properties

3-Dimethylaminoacrolein is weakly alkaline and forms a deep red complex with iron(III) chloride. It is much more stable than its notional parent, 3-aminoacrolein.[7] As a tertiary amine, it cannot tautomerize to the corresponding imine without developing formal charges.

For organic synthesis, it resembles a vinylogous dimethylformamide, combining the unsaturated aldehyde and enamine functionalities. Applications generally fall into two categories: as a less toxic malondialdehyde substitute or as a (reversibly)-quenched enoliminium cation.

An excess of strong aqueous base hydrolyzes 3-dimethylaminoacrolein to malondial[9] through an addition-elimination sequence. Malondial is relatively toxic,[10] and 3-dimethylaminoacrolein is an appealing substitute in heterocycle syntheses. For example, it condenses with guanidine to form 2-aminopyrimidine:[4]

Synthese von 2-Aminopyrimidin aus 3-Dimethylaminoacrolein

A more elaborate reaction sequence converts 2-naphthylamine to 1-azaphenanthrene.[11]

3-Dimethylaminoacrolein is not interchangeable with malondial, however, because the carbonyl equivalents are differentially activated. Vilsmeier conditions only cause a single addition to N-methylpyrrole:[12]

Synthese von substituiertem Pyrrol

Another similar electrophilic arene alkenylation occurs in fluvastatin synthesis.[13][14]

3-dimethylaminoacrolein has been investigated for the industrial synthesis of 2-chloronicotinic acid (2-CNA):[15][16]

Synthese von 2-Chlornicotinsäure mit 3-Dimethylaminoacrolein

The nitrogen heteroatom's electron-richness extends through the π system, so that the aldehyde is an unusually competent nucleophile. Sulfate diesters alkylate the compound at the aldehyde oxygen,[17] giving an electrophilic cation susceptible to Knoevenagel- or aldol-like addition:[18]

Reaktionen vinyloger Amidine nach Bredereck

Reaction with an (non-quaternary) ammonium salt gives instead a hemiaminal cation, which can then dehydrate to a vinamidinium cation (discussed further in § Vinamidinium salts).[19]

In some reaction sequences, 3-dimethylaminoacrolein is not isolated, but rather the salt from Vilsmeier attack on the vinyl ether is used directly:[20]

Pyrazolsynthese mit 3-Dimethylaminoacrolein
Pyrazolsynthese mit 3-Dimethylaminoacrolein

Vinamidinium salts

Dimethylammonium salts (chloride,[21] tetrafluoroborate,[19] perchlorate)[22] react with 3-dimethylaminoacrolein to give a vinamidinium cation:

Synthese des 1,3-Bis(dimethylamino)trimethinium perchlorats
Synthese des 1,3-Bis(dimethylamino)trimethinium perchlorats

The resulting salts also resemble malondial. Thus, they add to cyclopentadienide[19] and α to lactones...[23]

Reaktion von 3-Dimethylaminoacrolein mit gamma-Butyrolacton
Reaktion von 3-Dimethylaminoacrolein mit gamma-Butyrolacton

...and form a wide variety of heterocycles.[24][25][26]

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. ↑ P. Perlmutter (2001), "Propargyl Aldehyde", E-EROS Encyclopedia of Reagents for Organic Synthesis, doi:10.1002/047084289X.rp262m, ISBN 0471936235
  7. 1 2 Thummel, Randolph P. (2001). "(Z)-β-Aminoacrolein". Encyclopedia of Reagents for Organic Synthesis. doi:10.1002/047084289X.ra087. ISBN 0-471-93623-5.
  8. ↑ DE 19825200, D. Golsch, M. Keil, H. Isak, "Verfahren zur Herstellung von 3-Aminoacroleinderivaten", published 1999-11-18, assigned to BASF AG
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ D. Sriram; P. Yogeeswari (2010), Medicinal Chemistry (2nd ed.), Delhi: Pearson, p. 364, ISBN 978-81-317-3144-4
  14. ↑ 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
  15. ↑ EP 0372654, L. Schröder, "Preparation of 2-chloropyridine 3-carboxylic acid esters", published 1990-06-13, assigned to Shell Internationale Research Maatschappij B.V.
  16. ↑ 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
  17. ↑ 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
  18. ↑ 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
  19. 1 2 3 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
  20. ↑ EP 0731094, H.-J. Wroblowsky, R. Lantzsch, "Verfahren zur Herstellung von Pyrazolen", published 1996-09-11, assigned to Bayer AG
  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. ↑ Lloyd, Douglas; McNab, Hamish (1976). "Vinamidines and vinamidinium salts: Examples of stabilized push-pull alkenes". Angew. Chem. 88 (15) (International ed.): 496–504. doi:10.1002/anie.197604591.
  25. ↑ 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
  26. ↑ 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
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