[5394-63-8]  · C7H10O3  · 2,2,6-Trimethyl-4H-1,3-dioxin-4-one  · (MW 142.17)

(acetylketene equivalent, used for acetoacetylation and cycloaddition reactions; can be functionalized to provide substituted acylketenes; diketene equivalent)

Alternate Name: diketene-acetone adduct.

Physical Data: mp 12-13 °C; bp 65-67 °C/0.2 mmHg; d 1.088 g cm-3.

Solubility: miscible with most organic solvents.

Form Supplied in: neat liquid; 95% (major impurity acetone).

Analysis of Reagent Purity: GC (keep injector port 200-225 °C); NMR.

Preparative Methods: the diketene-acetone adduct (1) is one of a series of 1,3-dioxin-4-ones which can be prepared by the reaction of diketene with an aldehyde or ketone in the presence of an acidic catalyst2 or a quaternary ammonium salt (eq 1).3 An alternate preparatory method is the reaction of a b-keto acid with acetone.4

Purification: high-vacuum distillation at temperatures below 80 °C.

Handling, Storage, and Precautions: generally nonhazardous; anticipate release of acetone upon heating over 80 °C; will also produce CO2 if heated in presence of water; extremely good solvent: will dissolve some plastic tubing. Use in a fume hood.

Chemical Transformations: Acetylketene Generation.

Dioxinone (1) generates acetylketene (2) and acetone upon heating at temperatures around 120 °C,5 via a retro Diels-Alder reaction. The acetylketene thus produced reacts in situ with nucleophiles, including alcohols, amines, and thiols, to provide acetoacetic acid derivatives, e.g. (3) (eq 2).6 The diketene-acetone adduct is thus a convenient, safe, and nonlachrymatory alternative to diketene. In practice, dioxinone (1) is often added to a solution of the nucleophile in xylene at 110 °C and the acetone is removed by evaporation or distillation; no catalyst is required. Most of these acetoacetylation reactions are complete within 20 min at 120 °C if the acetone is removed efficiently, although polymeric nucleophiles may require higher reaction temperatures or longer times. Changing the substituents at C-2 will alter the temperature at which the acetylketene is liberated (see below). Irradiation at 254 nm will also provide acetylketene from (1).7 Nucleophilic ring opening can also be effected with base (Potassium Carbonate, MeOH).8

Virtually every synthetic transformation which utilizes dioxinone (1) ultimately involves the generation of an acylketene or a b-keto ester, often following elaboration of the dioxinone nucleus.

Preparation of Heterocycles.

Dioxinone (1), as an acetylketene equivalent, reacts with a wide variety of functional groups in a manner analogous to diketene9 to provide heterocycles. For example, heating dioxinone (1) in the presence of electron-rich alkenes, such as enamines or enol ethers, will provide the corresponding pyrone derivative (4) via a [4 + 2] cycloaddition reaction, as illustrated in the preparation of 2,6-dideoxy sugar (5) (eq 3).10,11

DeMayo Reactions.

The [2 + 2] photocycloaddition of alkenes to dioxinone (1) (eq 4), followed by reduction and then cyclization of the resultant retro-aldol product, affords cyclohexenones (6).12

Synthesis of Modified Dioxinones.

Many dioxinones are modified prior to acylketene generation, either at C-5 or on the C-6 methyl group, to enhance the synthetic utility.1 Thus dioxinone (1) can be halogenated13 at C-5 or on the 6-methyl group14 prior to further synthetic elaboration (eqs 5 and 6). The latter bromomethyl dioxinone (7) is readily converted into a Wittig15 or Horner-Emmons reagent.14

An alternate approach to modification of dioxinone (1) on the C-6 methyl group is via deprotonation (eq 7),16 sometimes accompanied by silyl enol ether formation (eq 8).

The resulting elaborated dioxinones have been used to effect ring closure of large rings via intramolecular ketene trappings,16 methoxide-mediated ring openings to the b-keto esters,16c,17 and in intramolecular photocycloaddition reactions (eq 9),18 thereby demonstrating the synthetic utility and versatility of the diketene-acetone adduct (1). Both (R)- and (S)-2-t-butyl dioxinones are enantiopure acetoacetate derivatives that are useful for asymmetric synthesis.

Related Reagents.

Acetoacetic Acid; (R)-2-t-Butyl-6-methyl-4H-1,3-dioxin-4-one; Diketene; Ethyl Acetoacetate; Ethyl 4-Chloroacetoacetate; Ethyl 3-Hydroxybutanoate; Ethyl 4-(Triphenylphosphoranylidene)acetoacetate; Methyl Dilithioacetoacetate.

1. (a) FF 1967, 1, 256; 1982, 10, 424. (b) Kaneko, C.; Sato, M.; Sakaki, J.; Abe, Y. JHC 1990, 27, 25.
2. Carroll, M. F.; Bader, A. R. JACS 1952, 74, 6305; 1953, 75, 5400.
3. Dehmlow, E. V.; Shamout, A. R. LA 1982, 1753.
4. Sato, M.; Ogasawanra, H.; Oi, K.; Kato, T. CPB 1983, 31, 1896.
5. Clemens, R. J.; Witzeman, J. S. JACS 1989, 111, 2186.
6. Clemens, R. J.; Hyatt, J. A. JOC 1985, 50, 2431.
7. Sato, M.; Ogasawara, H.; Takayama, K.; Kaneko, C. H 1987, 26, 2611.
8. Sato, M.; Sakaki, J.; Sugita, J.; Yasuda, S.; Sakoda, H.; Kaneko, C. T 1991, 47, 5689.
9. Clemens, R. J. CRV 1986, 86, 241.
10. Sato, M.; Ogasawara, H.; Kato, T. CPB 1984, 32, 2602.
11. Coleman, R. S.; Fraser, J. R. JOC 1993, 58, 385.
12. Baldwin, S. W.; Wilkinson, J. M. JACS 1980, 102, 3634.
13. Clemens, R. J. U.S. Patents 4 582 913 and 4 633 013, 1986.
14. Boeckman, R. K., Jr.; Thomas, A. J. JOC 1982, 47, 2823.
15. Bodurow, C.; Carr, M. A.; Moore, L. L. OPP 1990, 22, 109.
16. (a) Petasis, N. A.; Patane, M. A. CC 1990, 836. (b) Sugita, Y.; Sakaki, J.; Sato, M.; Kaneko, C. JCSPI 1992, 2855. (c) Lichtenthaler, F. W.; Dinges, J.; Fukuda, Y. AG(E) 1991, 30, 1339.
17. Sato, M.; Sugita, Y.; Abiko, Y.; Kaneko, C. TA 1992, 3, 1157.
18. Winkler, J. D.; Hey, J. P.; Hannon, F. J. H 1987, 25, 55.

Robert J. Clemens

Eastman Chemical Company, Kingsport, TN, USA

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