Ethyl Malonate1

(R = Et)

[1071-46-1]  · C5H8O4  · Ethyl Malonate  · (MW 132.13) (R = Me)

[16695-14-0]  · C4H6O4  · Methyl Malonate  · (MW 118.10) (R = t-Bu)

[40052-13-9]  · C7H12O4  · t-Butyl Malonate  · (MW 160.19) (R = Bn)

[40204-26-0]  · C10H10O4  · Benzyl Malonate  · (MW 194.20)

(synthesis of b-keto esters2,3 and esters4)

Physical Data: R = Et, bp 110 °C/0.05 mmHg, d 1.189 g cm-3. R = Me, bp 80 °C/0.15 mmHg, d 1.128 g cm-3. R = t-Bu, bp 90 °C/2 mmHg. R = Bn, mp 49-52 °C.

Preparative Methods: ethyl malonate is commercially available, or it may be easily prepared1 by acidification of the potassium salt of ethyl malonate, which is also commercially available or is readily obtained from Diethyl Malonate.1 Methyl and t-butyl malonates can be obtained from Meldrum's acid (2,2-Dimethyl-1,3-dioxane-4,6-dione) by treatment with the appropriate alcohol.5,6 Methyl malonate has also been prepared from dimethyl malonate or from potassium methyl malonate.7 Benzyl malonate has been prepared from Malonyl Chloride and benzyl alcohol,8a or from dibenzyl malonate.8c,d

Ethyl malonate (1) has been most widely utilized in the efficient one-step synthesis of b-keto esters.3,9,10 Two different approaches have been taken in this regard, both of which take advantage of the facile decarboxylation which occurs when a C-acyl derivative of (1) is subjected to a mild acidic hydrolysis. In the first procedure, treatment of (1) with n-Butyllithium (2 equiv) results in the formation of the dianion (2), which readily undergoes C-acylation with various acid chlorides to provide b-keto esters in excellent yields following mild acidic workup (eq 1).3a This methodology has been applied in the synthesis of a variety of b-keto esters.9 A related procedure involving a milder preparation of a dianion of (1) has also recently been reported.10

In a different approach, the neutral magnesium salt of methyl malonate (3), prepared from Mg(OEt)2 and methyl malonate (2 equiv), adds smoothly to a variety of acylimidazoles, which are themselves obtained by prior derivatization of a carboxylic acid with N,N-Carbonyldiimidazole (CDI) (eq 2).3b The b-keto ester is again obtained in a single step upon a mild acidic workup.

The corresponding magnesium salts of other malonate half-esters have been prepared and utilized extensively. The mildness and versatility of this procedure have made it the method of choice for the preparation of b-keto esters, as demonstrated by the numerous recent synthetic applications which have been reported.11 For example, homologation of the acid (4) to keto ester (6), an important intermediate in the synthesis of thienamycin, was accomplished in 86% yield with the magnesium salt of p-nitrobenzyl malonate (5) (eq 3).11a This methodology has also been applied in the synthesis of b-keto esters from amino acids.12

In a one-step alternative to the classical malonic ester synthesis, the dianion (2) has been alkylated with a number of alkyl halides. Subsequent decarboxylation leads to various esters in moderate yield (eq 4).4

Ethyl malonate has been used in the preparation of cinnamic and acrylic acid derivatives under modified Doebner/Knoevenagel conditions.13 Ethyl 2,4-pentadienoate has been prepared in a one-pot, high yielding application of this procedure (eq 5).13a

An intermolecular carbolactonization of alkenes with (1) in the presence of Manganese(III) Acetate has been employed in the preparation of various g-lactones in good yields (eq 6).14

Activated derivatives of (1), such as the corresponding acid chloride or 1-Hydroxybenzotriazole ester, have been utilized in the preparation of various mixed malonate esters or amides by reaction with alcohols or amines, respectively.8d,15

Chiral monosubstituted16 and disubstituted17 derivatives of (1) are useful intermediates for the preparation of chiral synthons which have been applied in the synthesis of sesquiterpenes containing a quaternary chiral center (eq 7).17a

Related Reagents.

Bis(trimethylsilyl) Malonate; Diethyl Ethoxymagnesiomalonate; Diethyl Malonate; Ethyl 3,3-Diethoxyacrylate; Ethyl Trimethylsilyl Malonate; Magnesium Ethyl Malonate; Methyl Magnesium Carbonate; Malonic Acid; Methyl Cyanoformate.

1. Strube, R. E. OSC 1963, 4, 417.
2. For a review of the preparation of b-keto esters from malonates, see: Pollet, P. J. Chem. Educ. 1983, 60, 244.
3. (a) Wierenga, W.; Skulnick, H. I. OSC 1990, 7, 213. (b) Brooks, D. W.; Lu, L. D.-L.; Masamune, S. AG(E) 1979, 18, 72.
4. McMurry, J. E.; Musser, J. H. JOC 1975, 40, 2556.
5. Brooks, D. W.; Castro de Lee, N.; Peevey, R. TL 1984, 25, 4623.
6. Junek, H.; Ziegler, E.; Herzog, U.; Kroboth, H. S. S 1976, 332.
7. (a) Grakauskas, V.; Guest, A. M. JOC 1978, 43, 3485. (b) Hutchinson, C. R.; Nakane, M.; Gollman, H.; Knutson, P. L. OSC 1990, 7, 323. (c) Rigo, B.; Fasseur, D.; Cauliez, P.; Couturier, D. TL 1989, 30, 3073.
8. (a) Fritsch, W.; Stache, U.; Ruschig, H. LA 1966, 699, 195. (b) Chaudhry, I. A.; Clezy, P. S.; Mirza, A. H. AJC 1980, 33, 1095. (c) Valasinas, A.; Levy, E. S.; Frydman, B. JOC 1974, 39, 2872. (d) English, A. R.; Girard, D.; Jasys, V. J.; Martingano, R. J.; Kellog, M. S. JMC 1990, 33, 344.
9. (a) Chu, D. T. W.; Maleczka, R. E., Jr.; Nordeen, C. W. JHC 1988, 25, 927. (b) Buhlmann, P.; Badertscher, M.; Simon, W. T 1993, 49, 595. (c) Domagala, J. M.; Heifetz, C. L.; Hutt, M. P.; Mich, T. F.; Nichols, J. B.; Solomon, M.; Worth, D. F. JMC 1988, 31, 991. (d) Williard, P. G.; de Laszlo, S. E. JOC 1984, 49, 3489. (e) Wenkert, E.; Guo, M.; Pizzo, F.; Ramachandran, K. HCA 1987, 70, 1429.
10. Clay, R. J.; Collom, T. A.; Karrick, G. L.; Wemple, J. S 1993, 290.
11. (a) Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard, F. A. JACS 1980, 102, 6161. (b) Fetter, J.; Lempert, K.; Gizur, T.; Nyitrai, J.; Kajtar-Peredy, M.; Simig, G.; Hornyak, G.; Doleschall, G. JCS(P1) 1986, 221. (c) Nagao, Y.; Abe, T.; Shimizu, H.; Kumagai, T.; Inoue, Y. H 1992, 33, 523. (d) Neyer, G.; Achatz, J.; Danzer, B.; Ugi, I. H 1990, 30, 863. (e) Nagao, Y.; Nagase, Y.; Kumagai, T.; Kuramoto, Y.; Kobayashi, S.; Inoue, Y.; Taga, T.; Ikeda, H. JOC 1992, 57, 4238. (f) Chen, C. Crich, D. TL 1992, 33, 1945. (g) Batty, D.; Crich, D. JCS(P1) 1991, 2894. (h) Schmidt, U.; Zah, M.; Lieberknecht, A. CC 1991, 1002. (i) Barco, A.; Benetti, S.; Pollini, G. P.; Baraldi, P. G.; Gandolfi, C. JOC 1980, 45, 4776. (j) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Polo, E.; Simoni, D. JOC 1985, 50, 23. (k) Herbert, R. B.; Knagg, E.; Organ, H. M.; Pasupathy, V.; Towlson, D. E. H 1987, 25, 409. (l) Schroeder, M. C.; Kiely, J. S.; Laborde, E.; Johnson, D. R.; Szotek, D. L.; Domagala, J. M.; Stickney, T. M.; Michel, A.; Kampf, J. W. JHC 1992, 29, 1481. (m) Suto, M. J.; Turner, W. R.; Kampf, J. W. JHC 1992, 29, 1441. (n) Rapoport, H.; Luly, J. R. JACS 1983, 105, 2859. (o) Brower, P. L.; Butler, D. E.; Deering, C. F.; Le, T. V.; Millar, A.; Nanninga, T. N.; Roth, B. D. TL 1992, 33, 2279. (p) Gasparski, C. M.; Ghosh, A.; Miller, M. J. JOC 1992, 57, 3546. (q) McCarthy, N.; McKervey, M. A.; Ye, T.; McCann, M.; Murphy, E.; Doyle, M. P. TL 1992, 33, 5983.
12. (a) Hamada, Y.; Hayashi, K.; Shioiri, T. TL 1991, 32, 931. (b) Tamura, N.; Iwama, T.; Itoh, K. CPB 1992, 40, 381. (c) Nishi, T.; Saito, F.; Nagahori, H.; Kataoka, M.; Morisawa, Y.; Yabe, Y.; Sakurai, M.; Higashida, S.; Shoji, M.; Matsushita, Y.; Iijima, Y.; Ohizumi, K.; Koike, H. CPB 1990, 38, 103. (d) Hashiguchi, S.; Kawada, A.; Natsugari, H. S 1992, 403.
13. (a) Waegell, B.; Rodriguez, J. S 1988, 534. (b) Breuer, S. W.; Dillingham, K. A. JCR(S) 1992, 414. (c) Prager, R. H.; Tsopelas, C. AJC 1992, 45, 1771. (d) Yang, Z.; Liu, H. B.; Lee, C. M.; Chang, H. M.; Wong, H. N. C. JOC 1992, 57, 7248.
14. (a) Corey, E. J.; Gross, A. W. TL 1985, 26, 4291. (b) Kurosawa, K.; Fujimoto, N.; Nishino, H. BCJ 1986, 59, 3161.
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16. Gutman, A. L.; Shapira, M.; Boltanski, A. JOC 1992, 57, 1063.
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Gary L. Bolton

Parke-Davis/Warner-Lambert Company, Ann Arbor, MI, USA

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