Diketene1

[674-82-8]  · C4H4O2  · Diketene  · (MW 84.07)

(acetoacetylation reagent; acetylketene equivalent for heterocyclic synthesis)

Alternate Name: 4-methyleneoxetan-2-one.

Physical Data: mp -7.5 °C; bp 69-70 °C/100 mmHg; d 1.090 g cm-3.

Solubility: sol most organic solvents; immiscible H2O, hexane.

Form Supplied in: neat liquid.

Analysis of Reagent Purity: IR (2150 cm-1), NMR.

Preparative Method: via dimerization of ketene.2

Purification: vacuum distillation.

Handling, Storage, and Precautions: lachrymator; best stored as a solid (refrigerated) in plastic containers; avoid contamination; prepare for exothermic reactions. Handle in a fume hood.

Acetoacetylation Reagent.

Diketene is most commonly used as a reagent for the acetoacetylation of nucleophiles, including alcohols, phenols, amines, anilines, thiols, and carbanions. 4-Dimethylaminopyridine3 and tertiary amines are often the catalysts of choice, but sodium acetate, sulfuric acid, and a variety of other catalysts can also be used (eq 1). Amines can usually be acetoacetylated at 0-20 °C without any catalyst.

Alternate reagents for acetoacetylation include t-butyl acetoacetate4 and 2,2,6-Trimethyl-4H-1,3-dioxin-4-one (the diketene-acetone adduct). Both are prepared from diketene and are less reactive but easier to handle.

Acetoacetate esters are versatile synthetic intermediates; their chemistry is more thoroughly described elsewhere.1a,b Acetoacetate esters can be converted into g,d-unsaturated ketones (via Carroll rearrangement, eq 2),5 into a variety of heterocycles via diazotization/cyclization (eq 3)6 or the Hantzsch pyridine synthesis (eq 4),7 or in the direct synthesis of other heterocycles, as discussed below.

Preparation of Ketene.

Diketene is a convenient laboratory source of ketene. The dimer can be cracked at temperatures above 500 °C in a hot tube with a glowing filament (eq 5) to provide two molecules of ketene, free from the methylketene contaminant which is observed during the preparation of ketene by pyrolysis of acetone.8

Malonic Anhydride.

The ozonolysis of diketene provides malonic anhydride, which can be trapped with nucleophiles at low temperatures to afford malonate half-esters (eq 6).9

Preparation of 3-Methylenepropanoic Acids.

Grignard reagents, in the presence of specific transition metal catalysts, react with diketene to afford 3-substituted 3-butenoic acids (eq 7).10 The process has been optimized for large-scale synthesis of 3-aryl-3-butenoic acids.11

Acetoacetate Dianion Equivalent.

In the presence of Titanium(IV) Chloride, diketene reacts with aldehydes in a ring opening/condensation sequence to provide 4-substituted acetoacetate esters without the need for dianion formation (eq 8).12 Reaction with ketones requires the use of the corresponding acetals.13

Halogenated Acetones and Acetoacetic Acid Derivatives.

Diketene reacts with hydrogen chloride or chlorine to afford acetoacetyl chloride and 4-chloroacetoacetyl chloride, respectively.14 These compounds can be further chlorinated, initially at C-2, to provide other chlorinated materials (eq 9). This work is thoroughly described in the patent literature.1a Workup with alcohols provides chloroacetoacetate esters, while hydrolysis and decarboxylation can be used to prepare substituted acetone derivatives.15

Acetone Enolate Equivalent.

The careful hydrolysis of diketene with sodium hydroxide provides sodium acetoacetate which reacts with electrophiles at C-2 to form unstable b-keto acids; these decarboxylate on workup to provide substituted acetone derivatives (eq 10).16

b-Butyrolactone.

b-Butyrolactone, which is a valuable reagent for the preparation of b-hydroxybutyric acid derivatives and polymers, is easily prepared by reduction of diketene over ruthenium (eq 11).17 Enantioselective reduction processes have been developed.18 Caution: b-butyrolactone is a known carcinogen.

4-Substituted Acetoacetic Acid Derivatives: Radical, Carbene, and [2 + 2] Photocycloaddition.

Radical and carbene additions, and photochemical [2 + 2] reactions of diketene, all involve the exocyclic methylene group of the diketene molecule. Carbene19 and nitrene20 additions (eq 12), as well as photocycloaddition (eq 13),21 give spirocyclobutyrolactones. Ring opening these spirocyclic butyrolactones provides a synthesis of 4-substituted acetoacetates.

Likewise, radical addition to the double bond of diketene provides routes to substituted b-lactones and acetoacetic acid derivatives (eq 14).22

Preparation of Heterocycles.

Diketene is used extensively for the preparation of heterocycles. The products can often be predicted by viewing diketene as an acetylketene equivalent. A leading example is provided for each of several types of heterocyclization; many other substrates react analogously. The reader is referred to more detailed reviews for further discussion.1,23

Pyrone and Pyridone Formation via Acetoacetylation of an Active Methylene Group: Dehydroacetic Acid.

The fungicide dehydroacetic acid is prepared via the base-catalyzed dimerization of diketene (eq 15),1a,24 which is based upon the acetoacetylation of the activated methylene group of a ring-opened diketene molecule. Other 4-pyrones are similarly formed when diketene reacts with compounds containing active methylene groups.25

Likewise, diketene reacts with simple enamines to afford pyrones (eq 16).26 Enamides, however, more commonly provide pyridones upon treatment with diketene (eq 17).27 Because of the multiple functional groups normally present during heterocyclic synthesis with diketene, several different products can often be produced, depending on the reaction conditions.

6-Methyluracil.

The reaction of diketene with urea to afford 6-methyluracil (eq 18) is one of the classic heterocyclic syntheses which utilizes diketene;28 many analogous heterocycles can be prepared by reaction of bisnucleophilic species with diketene.

Preparation of Furanones (Butenolides) and Pyrrolidinones.

Diketene acetoacetylates a-hydroxy ketones29 and a-hydroxy acids,30 and a-amino ketones31 and acids,32 which undergo intramolecular condensation to afford five-membered heterocycles as shown (eqs 19 and 20).

b-Lactams.

The imidazole-promoted reaction of imines with diketene can be used to prepare b-lactams (eq 21).33

Related Reagents.

Acetoacetic Acid; Ethyl Acetoacetate; Ethyl 4-Chloroacetoacetate; Methyl Dilithioacetoacetate; b-Methyl-b-propiolactone; 2,2,6-Trimethyl-4H-1,3-dioxin-4-one.


1. (a) Clemens, R. J. CRV 1986, 86, 241. (b) Clemens, R. J.; Witzeman, J. S. In Acetic Acid and Derivatives; Dekker: 1993; p 173. (c) Boese, A. B., Jr. Ind. Eng. Chem. 1940, 32, 16. (d) Bormann, D. MOC 1968, 7, 53.
2. William, J. W.; Krynitsky, J. A. OSC 1955, 3, 508.
3. Nudelman, A.; Kelner, R.; Broida, N.; Gottlieb, H. E. S 1989, 387.
4. Lawesson, S. O.; Gronwall, S.; Sandberg, R. OS 1962, 42, 28.
5. (a) Caroll, M. F. JCS 1940, 704; 1941, 507. (b) Wilson, S. R.; Angelli, C. E. OS 1990, 68, 210.
6. (a) 1,2-Diazetidin-3-one synthesis; Lawton, G.; Moody, C. J.; Pearson, C. J. JCS(P1) 1987, 899. (b) Furan synthesis; Padwa, A.; Kinder, F. R. JOC 1993, 58, 21.
7. Hantzsch, A. LA 1882, 215, 1.
8. Andreades, S.; Carlson, H. D. OS 1965, 45, 50.
9. (a) Perrin, C. L.; Arrhenius, T. JACS 1978, 100, 5249. (b) Hurd, C. D.; Blanchard, C. A. JACS 1950, 72, 1461.
10. (a) Fujisawa, T.; Sato, T.; Goto, Y.; Kawashima, M.; Kawara, T. BCJ 1982, 55, 3555. (b) Abe, Y.; Sato, M.; Goto, H.; Sugawara, R.; Takahashi, E., Kato, T. CPB 1983, 31, 4346.
11. Itoh, K.; Harada, T.; Nagashima, H. BCJ 1991, 64, 3746.
12. Izawa, T.; Mukaiyama, T. CL 1978, 409; 1975, 161.
13. Ishikawa, T.; Yamato, M. CPB 1982, 30, 1594.
14. Hurd, C. D.; Abernethy, J. L. JACS 1940, 62, 1147.
15. Nollett, A. J. H.; Ladage, J. W.; Mijs, W. J. RTC 1975, 94, 59.
16. (a) Kaku, T.; Katsuura, K.; Sawaki, M. (Nippon Soda Company, Ltd.) U.S. Patent 4 335 184, 1982 (CA 1981, 94, 120 871). (b) Moulin, F. (Lonza, AG) Swiss Patent 647 495, 1985 (CA 1985, 102, 203 605).
17. Sixt, J. (Wacker Chemie GmbH) U.S. Patent 2 763 664, 1956 (CA 1957, 51, 5115).
18. Ohta, T.; Miyake, T.; Takaya, H. CC 1992, 1725.
19. Kato, T.; Katagiri, N. CPB 1973, 21, 729.
20. Kato, T.; Suzuki, Y.; Sato, M. CPB 1979, 27, 1181.
21. Kato, T.; Chiba, T.; Tsuchiya, S. CPB 1980, 28, 327; 1981, 29, 3715.
22. Dingwall, J. G.; Tuck, B. JCS(P1) 1986, 2081.
23. (a) Kato, T. ACR 1974, 7, 265. (b) Kato, T. Lect. Heterocycl. Chem., 1982, 6, 105.
24. Chick, F.; Wilsmore, N. T. M. JSC 1908, 93, 946.
25. Kato, T.; Yamamoto, Y.; Hozumi, T. CPB 1973, 21, 1840.
26. (a) Hünig, S.; Benzing, E.; Hübner, K. CB 1961, 94, 486. (b) Eiden, F.; Wanner, K. T. AP 1984, 317, 958.
27. Hörlein, G.; Kübel, B.; Studeneer, A.; Salbeck, G. LA 1979, 371.
28. (a) Gleason, A. H. (Standard Oil Development Corp.) U.S. Patent 2 174 239, 1939 (CA 1940, 34, 450). (b) Boese, A. B. (Carbide), U.S. Patent 2 138 756, 1938.
29. Lacey, R. N. JCS 1954, 822.
30. Bloomer, J. L.; Kappler, F. E. JOC 1974, 39, 113.
31. Kato, T.; Sato, M.; Yoshida, T. CPB 1971, 19, 292.
32. Schmidlin, T.; Tamm, C. HCA 1980, 63, 121.
33. Sasaki, A.; Goda, K.; Enomoto, M.; Sunagawa, M. CPB 1992, 40, 1094.

Robert J. Clemens

Eastman Chemical Company, Kingsport, TN, USA



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