Acetoacetic Acid1

[541-50-4]  · C4H6O3  · Acetoacetic Acid  · (MW 102.09)

(acetone enolate equivalent in alkylations,2 carbonyl additions,3 conjugate additions,4 and diazonium ion coupling reactions5)

Alternate Name: 3-oxobutanoic acid.

Physical Data: mp 36-37 °C; pKa 3.58; enol content: carbon tetrachloride (35 °C), 49%; DMSO-d6 (35 °C), 10.8%; D2O (0 °C), <2%.6

Solubility: sol H2O, alcohol.

Preparative Methods: traditionally prepared by base hydrolysis of Ethyl Acetoacetate.3,7 A high yield synthesis by acid hydrolysis of Diketene is also reported.6

Handling, Storage, and Precautions: acetoacetic acid is extremely hygroscopic but can be stored under vacuum in a freezer for several weeks with little change. It decomposes rapidly to acetone and carbon dioxide when heated above the melting point. Use in a fume hood.

Functionalization of the active methylene group in acetoacetic acid by reaction with electrophiles and subsequent in situ decarboxylation provides a convenient one-step synthesis of a-substituted acetone derivatives.

Alkylations.

Dilithio acetoacetate can be generated from acetoacetic acid and n-Butyllithium at 0 °C and then alkylated to give an adduct which decarboxylates at room temperature to give a-alkylated acetone (eq 1).2

Addition and Condensation Reactions.

Acetoacetic acid reacts with aliphatic aldehydes in the presence of Pyridine to give a,b-unsaturated methyl ketones in good yields (eq 2).3,8 Aromatic aldehydes are generally less reactive under these conditions and give mixtures of b-ketols and enones. Exclusive formation of b-ketol is observed when the phenyl ring bears a strong electron withdrawing substituent (eq 2).3,8 Although ketones generally do not condense with acetoacetic acid, the corresponding enamine derivatives can be used as ketone equivalents and, in this case, the condensation proceeds without an added base.9

The addition of acetoacetic acid to an imine double bond and subsequent decarboxylation can be used in the preparation of a-acetonylated piperidine10-12 and pyrrolidine derivatives (eq 3).13 Base catalyzed 1,4-addition of acetoacetic acid to a,b-unsaturated ketones provides b-acetonyl ketones in good yield (eq 4).14,15

Diazonium Coupling Reactions.

Coupling of arenediazonium salts with acetoacetic acid provides a useful preparation of pyruvaldehyde monohydrazones (eq 5).16-18 Symmetrical acetylformazan derivatives are produced via the coupling of two equivalents of diazonium salts.19 Sequential treatment of acetoacetic acid with two different arenediazonium salts results in unsymmetrical acetylformazan derivatives.20

Related Reagents.

Acetone; Acetone Cyclohexylimine; Acetone Hydrazone; Ethyl Acetoacetate; Ethyl 4-Chloroacetoacetate; Ethyl Lithio(trimethylsilyl)acetate; Ethyl 4-(Triphenylphosphoranylidene)acetoacetate; Methyl Dilithioacetoacetate; 2,2,6-Trimethyl-4H-1,3-dioxin-4-one.


1. For a general account of synthesis and uses of b-keto acids, see Oshry, L.; Rosenfeld, S. M. OPP 1982, 14, 251.
2. Kjonaas, R. A.; Patel, D. D. TL 1984, 25, 5467.
3. Grayson, D. H.; Tuite, M. R. J. JCS(P1) 1986, 2137.
4. Fujii, M.; Terao, Y.; Sekiya, M. CPB 1974, 22, 2675.
5. (a) Parmerter, S. M. OR 1959, 10, 1. (b) Phillips, R. R. OR 1959, 10, 143.
6. Grande, K. D.; Rosenfeld, S. M. JOC 1980, 45, 1626.
7. Krueger, R. C. JACS 1952, 74, 5536.
8. Schopf, C.; Thierfelder, K. LA 1935, 518, 127.
9. Kumagaya, N.; Suzuki, K.; Sekiya, M. CPB 1973, 21, 1601.
10. Quick, J; Oterson, R. S 1976, 745.
11. Schopf, C.; Braun, F.; Burkhardt, K.; Dummer, G.; Muller, H. LA 1959, 626, 123.
12. Wisse, J. H.; De Klonia, H.; Visser, B. J. RTC 1964, 83, 1265.
13. Baxter, G.; Melville, J. C.; Robins, D. J. SL 1991, 359.
14. Yasuda, M. CL 1975, 89.
15. Fujii, M.; Terao, Y.; Sekiya, M. CPB 1974, 22, 2675.
16. Japp, F. R.; Klingemann, F. LA 1888, 247, 217.
17. Reynolds, G. A.; VanAllen, J. A. OS 1952, 32, 84.
18. (a) González, A. SC 1988, 18, 1225. (b) González, A. SC 1991, 21, 669.
19. Bamberger, E.; Lorenzen, J. CB 1892, 25, 3539.
20. Shmelev, L. V.; Lipunova, G. N.; Sulim, O. P.; Bednyagina, N. P. ZOB 1986, 56, 2393 (CA 1987, 107, 58913u).

Shridhar G. Hegde

Monsanto Company, St. Louis, MO, USA



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