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:
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. The compound has a number of useful and unusual properties. 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]

It is a stable chemical, unlike the parent compound 3-aminoacrolein,[6] and can be used as a comparably nontoxic precursor to 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 its vinamidines derivates[8] can be used as 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 (propiolic aldehyde) via a Reppe vinylation.[3]

Propynal is an inappropriate starting material for industrial synthesis, because of its 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. In the weakly alkaline medium, 3-dimethylaminoacrolein is formed, cleaving dimethylamine to form propanedial upon exposure to strong bases (such as sodium hydroxide).

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

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] and decompose at 110 °C. The products can be easily transformed with nucleophiles into the corresponding vinylogous amide acetals or amidines.[14]

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 to form 1,3-butadiene derivatives or with cyclopentadiene to an aminofulvene.

With guanidine, 3-dimethylaminoacrolein forms 2-aminopyrimidine.[4]

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

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

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]

Occasionally, the salt from the reaction of the Vilsmeier reagent and the vinyl ether is directly used for synthesis, such as for pyrazoles.[19]

When hydrazine hydrate is used, a pyrazole parent body is formed.

Reactions to vinamidinium salts

The reaction of 3-dimethylaminoacrolein with dimethylammonium tetrafluoroborate produces 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 salt (1,1,5,5-tetramethyl-1,5-diazapentadienium chloride) is also formed by the reaction of 3-dimethylaminoacrolein with dimethylamine hydrochloride.[21] The two-step reaction of dimethylamine and 70% perchloric acid with 3-dimethylaminoacrolein forms the same salt (referred to as 1,3-bis(dimethylamino)trimethinium perchlorate).[22]

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]

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]

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]

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 ethyl cyanoacetate[26] to 2-chloronicotinic acid ester or with cyanoacetic acid n-butyl ester to 2-chloronicotinic-n-butyl ester[27] in a Knoevenagel reaction.

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. ^ a b c "3-(Dimethylamino)acrolein 927-63-9 | TCI Deutschland GmbH". www.tcichemicals.com (in German). Retrieved 2018-01-14.
  2. ^ a b Sigma-Aldrich Co., product no. 305839.
  3. ^ 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 
  4. ^ 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 
  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. ^ 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
  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{{citation}}: CS1 maint: work parameter with ISBN (link)
  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 
This article is issued from Wikipedia. The text is available under Creative Commons Attribution-Share Alike 4.0 unless otherwise noted. Additional terms may apply for the media files.