Bis(trimethylsilyl) Malonate1

[18457-04-0]  · C9H20O4Si2  · Bis(trimethylsilyl) Malonate  · (MW 248.43)

(reagent useful in the synthesis of b-keto acids2-4 and methyl ketones3)

Physical Data: bp 63-66 °C/1 mmHg; d 0.974 g cm-3.

Preparative Method: commercially available; alternatively, it can be easily prepared from malonic acid by a number of silylation procedures.5

Handling, Storage, and Precautions: flammable liquid, moisture sensitive.

Synthetic Applications.

In the homologation of activated carboxylic acid derivatives to b-keto acids, bis(trimethylsilyl) malonate has been shown to be a useful alternative to conventional methods.4 However, despite the mild reaction conditions and generally high product yields, the reagent has seen limited use in organic synthesis.

The lithio derivative (1) adds smoothly to a variety of acid derivatives, including acid chlorides, mixed anhydrides, or HOBT esters, to provide b-keto acids following mild aqueous hydrolysis.2 Thus benzoylacetic acid was obtained in 92% yield upon treatment of (1) with Benzoyl Chloride (eq 1).

In the presence of lithium or magnesium salts, bis(trimethylsilyl) malonate can be acylated with acid chlorides under milder conditions.3 Metal complexation enhances the acidity of malonates such that tertiary amines can be used as bases.3b The reaction is less successful with other acylating agents. The b-keto acids can be isolated after a mild aqueous workup, or the corresponding methyl ketone can be obtained directly using more vigorous conditions (eq 2).

5-Acetyl-2-chloro-3-nitropyridine, an intermediate in the synthesis of analogs of the inotropic agent isomazole, was prepared from the corresponding acid chloride using this methodology (eq 3).6

The a-substituted b-keto acid (2), an intermediate useful in the synthesis of chiral 2-methyl-3-hydroxybutyrolactones, was obtained via the reaction of the anion derived from methyl bis(trimethylsilyl) malonate (eq 4).7

Related Reagents.

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

1. Schmidt, U.; Schwochau, M. M 1967, 98, 1492.
2. Barnick, J. W. F. K.; van der Baan, J. L.; Bickelhaupt, F. S 1979, 787.
3. (a) Rathke, M. W.; Nowak, M. A. SC 1985, 15, 1039. (b) Rathke, M. W.; Cowan, P. J. JOC 1985, 50, 2622.
4. For a review on the synthesis and uses of b-keto acids, see: Oshry, L.; Rosenfeld, S. M. OPP 1982, 14, 249.
5. (a) Palomo, C. S 1981, 809. (b) Hergott, H. H.; Simchen, G. S 1980, 626. (c) Rigo, B.; Fasseur, D.; Cauliez, P.; Couturier, D. TL 1989, 30, 3073.
6. (a) Barraclough, P.; Black, J. W.; Cambridge, D.; Collard, D.; Firmin, D.; Gerskowitch, V. P.; Glen, R. C.; Giles, H.; Hill, A. P.; Hull, R. A. D.; Iyer, R.; King, W. R.; Kneen, C. O.; Lindon, J. C.; Nobbs, M. S.; Randall, P.; Shah, G. P.; Smith, S.; Vine, S. J.; Whiting, M. V.; Williams, J. M. JMC 1990, 33, 2231. For a similar application, see: (b) Young, R.; Chang, C. K. JACS 1985, 107, 898.
7. Buisson, D.; Henrot, S.; Larcheveque, M.; Azerad, R. TL 1987, 28, 5033.

Gary L. Bolton

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

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