2,2-Dimethyl-1,3-dioxane-4,6-dione1

[2033-24-1]  · C6H8O4  · 2,2-Dimethyl-1,3-dioxane-4,6-dione  · (MW 144.12)

(substitute for malonic esters as a two- or three-carbon nucleophile)

Alternate Name: Meldrum's acid.

Physical Data: mp 94-95 °C (dec); pKa 4.8 in water, 7.3 in DMSO.2

Form Supplied in: colorless crystals; commercially available.

Purification: recrystallization from acetone and water.

Introduction.

Meldrum's acid (1) is not just a simple substitute for malonic esters but rather a unique reagent in its own right for the following reasons. Firstly, the acidity of Meldrum's acid is comparable to that of acetic acid,2 and its stable enolate anion (2) is susceptible to the attack of various electrophiles even under nearly neutral conditions. Arnett2a has shown that the anomalously high acidity of (1) relative to dimethyl malonate and dimedone is the result of restricted rotation of the ester bonds in the bislactone structure. Subsequently, Houk2c and Wiberg2d have completed computational studies that provide an explanation of the acidity enhancement of (1), i.e. loss of a proton from the (E) rotamer (3) is easier than from the (Z) rotamer (4). Secondly, Meldrum's acid is susceptible to nucleophilic attack at the carbonyl groups, which results in ring cleavage, forming acetone and malonic acid derivatives (eq 1). Among the reactions of Meldrum's acid derivatives, the four described in the following sections have been the most frequently used for organic synthesis.1b

Ring Opening Reactions Initiated by Nucleophiles.

Under solvolytic conditions, Meldrum's acid derivatives generally form malonyl monoesters (eq 1). When ethanolysis is conducted in the presence of pyridine and Copper powder, subsequent decarboxylation occurs, giving monocarboxylates (eq 2)3. Amines cleave the dioxane ring in a similar manner, giving amides. In the reaction shown in eq 3, the 5-alkyl intermediate formed via Michael addition of (1) to the a,b-unsaturated ketone undergoes intramolecular attack by the amine nitrogen to form a tetrahydropyridone ring.4 b-Keto esters can be readily prepared by the reaction of 5-acyl Meldrum's acids with alcohols (eq 4).5 This reaction has been the most widely used application of Meldrum's acid, and it figures as a key step in many organic syntheses.1b Steps in the syntheses of tricyclic bimane,6 a thiol analytical agent for proteins, and didemnin,7 a cytotoxic cyclic peptide, are representative examples, which are illustrated in eqs 5 and 6, respectively. A chiral dienophile has been prepared by this method (eq 7).8

Conjugate Addition.

5-Methylene Meldrum's acids, which are easily prepared by a variety of methods1 (in particular by the Knoevenagel reaction of (1) with carbonyl compounds), undergo conjugate additions with various nucleophiles, such as hydride (eq 8),9 organometallic reagents (eq 9),10 and phenols (eq 10).11 Polyacylated alkenes are susceptible to conjugate addition of enolates, leading to a variety of products (eq 11).12 Analogously, homoconjugate addition of nucleophiles to spiro-cyclopropyl derivatives takes place resulting in cyclopropyl ring opening (eq 12).13

Cycloaddition.

The C=C double bond of 5-methylene Meldrum's acid is usually an active dienophile (eq 13),14 but the derivatives also act as reactive heterodienes both in inter- (eq 14)15 and intramolecular (eqs 15 and 16)16,17 Diels-Alder reactions.

Pyrolysis.

5-Methylene Meldrum's acid loses acetone and carbon dioxide at elevated temperatures giving methyleneketenes which further lose carbon monoxide thereby generating alkylidenecarbenes (eq 17).1b A wide variety of reactive species such as benzyne, cyclohexyne and hydroxyacetylene has been detected.18 Various heterocycles (eq 18)19 have been synthesized by intramolecular trapping of these chemical species.1b

Other Applications.

Recently, the applications of Meldrum's acid have been extended to the syntheses of a macrocyclic b-keto lactone (eq 19),20 4-pyridyl-substituted heterocycles (eq 20),21 and 2-substituted indoles (eq 21).22 The structures of Meldrum acid derivatives23 and the kinetics of nitrosation of (1)24 have been studied by NMR and X-ray methods.

Related Reagents.

Diethyl Malonate; 6,6-Dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione; Diethyl Ethoxymagnesiomalonate; Ethyl Malonate; Ethyl Trimethylsilyl Malonate; Magnesium Ethyl Malonate; Malonic Acid.


1. (a) McNab, H. CSR 1978, 7, 345. (b) Chen, B.-C. H 1991, 32, 529.
2. (a) Arnett, E. M.; Harrelson, J. A. JACS 1987, 109, 809. (b) Bausch, M. J.; Gaudalupe-Fasano, C.; Gostowski, R.; Selmarten, D.; Vaugh, A. JOC 1991, 56, 5640; cf. Bordwell, F. G. ACR 1988, 21, 456. (c) Wang, X.; Houk, K. N. JACS 1988, 110, 1870. (d) Wiberg, K. B.; Laidig, K. E. JACS 1988, 110, 1872.
3. Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. TL 1978, 1759; cf. Schreiber, S. L.; Kelley, S. E.; Porco, J. A.; Sammakia, T.; Suh, E. M. JACS 1988, 110, 6210.
4. Svelik, J.; Goljer, I.; Turecek, F. JCS(P1) 1990, 1315; cf. (a) Pettit, G. R.; Herald, D. L.; Singh, S. B.; Thornton, T. J.; Mullaney, J. T. JACS 1991, 113, 6692. (b) Patino, N.; Frérot, E.; Galeotti, N.; Poncet, J.; Coste, J.; Dufour, M.-N.; Jouin, P. T 1992, 48, 4115.
5. (a) Oikawa, Y.; Sugano, K.; Yonemitsu, O. JOC 1978, 43, 2087. (b) Oikawa, Y.; Yoshioka, T.; Sugano, K.; Yonemitsu, O. OSC 1990, 7, 359.
6. Marciano, D.; Baud'huin, M.; Zinger, B.; Goldberg, I.; Kosower, E. M. JACS 1990, 112, 7320.
7. Hamada, Y.; Kondo, Y.; Shibata, M.; Shioiri, T. JACS 1989, 111, 669.
8. Katagiri, N.; Haneda, T.; Hayasaka, E.; Watanabe, N.; Kaneko, C. JOC 1988, 53, 226.
9. Wright, A. D.; Haslego, M. L.; Smith, F. X. TL 1979, 2325.
10. Huang, X.; Chan, C.-C.; Wu, Q.-L. TL 1982, 23, 75.
11. Nair, V. SC 1987, 17, 723.
12. Wilson, R. M.; Hengge, A. C.; Ataei, A.; Ho, D. M. JACS 1991, 113, 7240.
13. Singh, R. K.; Danishefsky, S. OSC 1990, 7, 411.
14. Bell, V. L.; Holmes, A. B.; Hsu, S.-Y.; Mock, G. A.; Raphael, R. A. JCS(P1) 1986, 1507.
15. Bitter, J.; Leitich, J.; Partale, H.; Polansky, O. E.; Reimer, W.; Ritter-Thomas, U.; Schlamann, B.; Stilkerieg, B. CB 1980, 113, 1020.
16. (a) Tietze, L. F.; Bärtels, C. LA 1991, 155. (b) Tietze, L. F.; Beifuss, U.; Lokos, M.; Rischer, M.; Gohrt, A.; Scheldrich, G. M. AG(E) 1990, 29, 527.
17. Takano, S.; Sugihara, T.; Satoh, S.; Ogasawara, K. JACS 1988, 110, 6467.
18. For example: (a) Tseng, J.; McKee, M. L.; Shevlin, P. B. JACS 1987, 109, 5474. (b) Wentrup, C.; Lorencak, P. JACS 1988, 110, 1880.
19. Hunter, G. A.; McNab, H. CC 1990, 375.
20. Lermer, L.; Neeland, E. G.; Ounsworth, J. P.; Sims, R. J.; Tischler, S. A.; Weiler, L. CJC 1992, 70, 1427.
21. Henning, H.-G.; Stemplinger, G.; Rothe, K. LA 1992, 813.
22. Hirao, K.; Mohri, K.; Yonemitsu, O.; Tabata, M.; Sohma, J. TL 1992, 33, 1459.
23. Blake, A. J.; McNab,. H.; Monahan, L. C. JCS(P2) 1991, 2003.
24. Beloso, P. H.; Roy, P.; Williams, D. L. H. JCS(P2) 1991, 17.

Osamu Yonemitsu & Ken-ichi Hirao

Hokkaido University, Sapporo, Japan



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