Ethyl Ethoxymethyleneacetoacetate

[3788-94-1]  · C9H14O4  · Ethyl Ethoxymethyleneacetoacetate  · (MW 186.21)

(mono-, bi-, and trifunctional three-carbon electrophile in carbonyl reactions, cyclizations;1 b-keto ester equivalent)

Physical Data: bp 265-266 °C, 149-151 °C/16 mmHg; d 1.067 g cm-3; n20D 1.472-1.473.

Form Supplied in: colorless, viscous liquid.

Preparative Methods: obtained by heating Ethyl Acetoacetate with Triethyl Orthoformate in Acetic Anhydride.2a,b

Handling, Storage, and Precautions: may be kept for a few weeks at 0 °C in the dark with addition of hydroquinone. The enol ether hydrolyses slowly in contact with water. Use in a fume hood.

Cyclization with Amino Nucleophiles.

Ethyl ethoxymethyleneacetoacetate (1) has three types of carbonyl groups, the labile ethoxy group (a masked aldehyde) being the most reactive. It will be substituted first by nucleophiles such as amino compounds. Amidines give aminomethylene derivatives, which cyclize to a substituted pyrimidine ring with a bridgehead nitrogen. 2-Aminopyridines condense with (1), the intermediates yielding 3-acetyl-4-keto-4H-pyrido[1,2-a]pyrimidine (eq 1).1a 5-Amino-4-cyanopyrazole and (1) cyclocondense to 6-ethoxycarbonyl-3-cyano-7-methylpyrazolo[1,5-a]pyrimidine.1b In a modified Gould-Jacobs reaction of amino heterocycles and (1), cyclization takes place at a carbon atom: 1-substituted 5-aminopyrazoles give 5-acetyl-1H-pyrazolo[3,4-b]pyridine derivatives.3a,b Similarly, acetyl-substituted isoxazolo[4,5-b]pyridines,3c thieno[2,3-b]pyridines,4 thieno[3,2-b]pyridines,4 5H-[1]benzopyrano[3,4-b]pyridinones,5a and 3H-pyrano[3,2-f]quinoline5b are obtained from 5-aminoisoxazole, 2- or 3-aminothiophene derivatives, 3-aminocoumarin, and 6-aminocoumarin, respectively. 1,1,1-Tris(aminomethyl)ethane and (1) condense to form a hexadentate ligand for CoIII and FeIII.6

Reaction with Carbon Nucleophiles.

Compounds with acidic protons such as acetoacetate7a or malodinitrile7b behave as nucleophiles towards (1). 2-Methylpyridinium salts8 and (1) give 1-alkyl-2-allylidenedihydropyridines (eq 2).

Dimethylsulfoxonium ylides as nucleophiles and (1) yield 4-ethoxycarbonyl-1,3-dimethylthiabenzene 1-oxide9a or a carbonylvinyl-stabilized sulfur ylide.9b

Related Reagents.

3-Butyn-2-one; Diethyl Ethoxymethylenemalonate; Ethyl Acetoacetate; Ethyl 3-Ethoxyacrylate; Ethyl Ethoxymethylenecyanoacetate.

1. (a) Antaki, H. JACS 1958, 80, 3066. (b) Sunthankar, S. V.; Vaidya, S. D. IJC(B) 1977, 15B, 349.
2. (a) Claisen, L. LA 1897, 297, 1. (b) Yasuda, H. YZ 1959, 79, 836 (CA 1960, 54, 1493f).
3. (a) Denzel, T.; Höhn, H. AP 1976, 309, 486. (b) Lynch, B. A.; Khan, M. A.; Chia-Teo, H.; Pedrotti, F. CJC 1988, 66, 420. (c) Denzel, T.; Höhn, H. AP 1972, 305, 833.
4. Khan M. A.; Guarconi, A. E. JHC 1977, 14, 807.
5. (a) Khan M. A.; Gemal, A. L. JHC 1977, 14, 1009. (b) Khan M. A.; Gemal, A. L. JHC 1978, 15, 159.
6. Flückinger, J.-R.; Schläpfer, C. W. HCA 1978, 61, 1765.
7. (a) Urushibara, Y. BCJ 1930, 5, 109. (b) Schmidt, H.-W.; Junek, H. LA 1979, 2005.
8. Kakehi, A.; Ito, S.; Funahashi, T.; Ogasawara, N. CL 1975, 919; BCJ 1976, 49, 2250.
9. (a) Tamura, Y.; Miyamoto, T.; Taniguchi, H.; Sumoto, K.; Ikeda, M. TL 1973, 20, 1729. (b) Watanabe, M.; Kinoshita, T.; Furukawa, S. CPB 1975, 23, 82.

Roswitha M. Böhme

University of Bonn, Germany

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