Ethyl Hydroxymethyleneacetate, Sodium Salt

[58986-28-0]  · C5H7NaO3  · Ethyl Hydroxymethyleneacetate, Sodium Salt  · (MW 138.11)

(a three-carbon b-dicarbonyl building block)

Alternate Name: ethyl formylacetate, sodium salt.

Solubility: sol H2O and protic solvent; insol THF.

Preparative Methods: the material is usually prepared by the condensation of ethyl acetate and ethyl formate in the presence of a strong base such as Sodium Hydride, sodium alkoxide, or Sodium metal (eq 1).2-6

The condensation is accompanied by side reactions, and the white solid obtained is generally about 70% pure. Preparation under carbon monoxide pressure has been suggested to improve the yield and purity.6 The compound has also been prepared by the careful hydrolysis of ethyl b-chloroacrylate.7 The free acid (malonic semialdehyde) is easily oxidized in air,1 and the various parent esters8-10 are all subject to polymerization, although the t-butyl ester can be stored at -80 °C without deterioration for a month.10a

Handling, Storage, and Precautions: salts and free acid have limited stability1 and should be prepared as needed; use in a fume hood.

Synthons.

Because the parent compound and its salts are unstable, a number of synthons have been prepared and investigated. As suggested in the references above, the various esters increase in stability as the bulk of the alkyl group increases. The enolate salt has been trapped as ethyl b-trimethylsilyloxyacrylate11 and further elaborated as an equivalent of the sodium enolate. In similar manner, benzhydryl N-benzylaminoacrylate12 has been used in reactions typical of the enolate salt.

Reactions.

Perhaps the most frequent use of ethyl hydroxymethyleneacetate is for the preparation of various 4-pyrimidinols, wherein the reagent provides the three-carbon piece in the principal synthesis of pyrimidines (eq 2).6,13

The enolate has been used for the synthesis of variously b-substituted acrylates (1)11,14,15 which have applications as stable synthons of the enolate. They have also served as dienophiles in electrocyclic reactions.14

1,1-Dialkylhydrazines yield the corresponding hydrazones.16 The enolate can be alkylated on the central carbon to provide useful substituted building blocks. Condensation with acetone provides 4H-1,3-dioxin-4-ones, which have been brominated on C-6 (eq 3).9 Xanthate formation on the central carbon provides an entry to 5-thiopyrazoles (eq 4).17

Reaction of substituted t-butyl esters with cysteine or penicillamine esters proceeds to thiazolidinylacetate esters. Subsequent Mukaiyama-Ohno cyclization diastereoselectively provides penam-3-carboxylic acid derivatives (eq 5)8a,b Oxapenams have been similarly prepared.12

Related Reagents.

Diethyl Ethoxymethylenemalonate; Ethyl 3,3-Diethoxypropanoate; Ethyl 3-Ethoxyacrylate; Ethyl Ethoxymethyleneacetoacetate; Malondialdehyde; Methyl Diformylacetate; 2,2,6-Trimethyl-4H-1,3-dioxin-4-one.


1. Hayaishi, O.; Nishizuka, Y.; Tatibana, M.; Takeshita, M.; Kuno, S. JBC 1961, 236, 781.
2. Hauser, C. R.; Hudson, B. E. OR 1942, 1, 266.
3. Pechmann, H. CB 1892, 25, 1047.
4. De Combe, J. LA 1932, 18, 87.
5. Deustchel, W. HCA 1952, 35, 1587.
6. Northey, E.; Bischoff, C. U.S. Patent 2 394 255, 1946.
7. Pinner, A. LA 1875, 179, 74.
8. (a) Chiba, T.; Sakaki, J.; Kobayashi, S.; Furuya, T.; Inukai, N.; Kaneko, C. CPB 1989, 37, 877. (b) Chiba, T.; Sakaki, J.; Takahashi, T.; Aoki, K. JCS(P1) 1987.
9. Kaneko, C.; Sato, M. Jpn. Patent 62 205 075, 1987.
10. (a) Sato, M.; Yoneda, N.; Katagiri, N.; Watanabe, H.; Kaneko, C. S 1986, 672. (b) Sato, M.; Abe, Y.; Takayama, K.; Sekiguchi, K.; Kaneko, C.; Inoue, N.; Furuya, T.; Inukai, N. JHC 1991, 28, 241.
11. Foehlisch, B.; Giering, W. S 1980, 231.
12. Wolfe, S; Sterzycki, R. CJC 1987, 65, 26.
13. (a) The Pyrimidines; Brown, D. J., Ed.; Wiley: New York, 1962; p 34. (b) The Pyrimidines; Brown, D. J.; Ed.; Wiley: New York; 1970; Suppl. 1, p 25. (c) Brown, D. J., Ed. The Pyrimidines, Wiley: New York; 1985; Suppl. 2, p 34.
14. Ranganathan, S.; Ranganathan, D.; Mehrotra, A. S 1976, 620.
15. Blank, H.; Wolters, E.; Ullrich, F.; Kraus, H.; Marzolph, G.; Silber, G. Eur. Patent 388 744. 1990.
16. Yakimovich, S.; Zerova, I.; Starygina, N. ZOR 1977, 13, 1168.
17. Oya, E.; Sato, T.; Morimoto, K.; Yamamoto, S. Jpn. Pat. 62 004 273, 1987.

Gary D. Madding

Bristol-Myers Squibb Co., Evansville, IN, USA



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