Malonic Acid1

[141-82-2]  · C3H4O4  · Malonic Acid  · (MW 104.07)

(useful reagent for synthesis of cinnamic and acrylic acid derivatives via the Doebner modification2 of the Knoevenagel condensation3)

Alternate Name: 1,3-propanedioic acid.

Physical Data: mp 135-137 °C; d 1.619 g cm-3; pKa (H2O) 2.38 and 5.69.1a

Solubility: very sol H2O; sol Et2O, EtOH; insol benzene; moderately sol pyridine.

Form Supplied in: white powder; widely available.

Preparative Method: can be prepared from chloroacetic acid;1c a number of monosubstituted derivatives are also commercially available.

Handling, Storage, and Precautions: strong irritant; LD50 1310 mg/kg (rat).1a

Synthetic Applications.

Malonic acid has been widely used in the Knoevenagel condensation with aldehydes and some ketones.3 The alkylidene or arylidene malonic acid derivatives can be obtained when ethanolic ammonia or acetic acid is the reaction solvent (eq 1).4 The Doebner modification, in which pyridine is used as the solvent, generally results in condensation with decarboxylation to provide cinnamic or acrylic acid derivatives.2,5 Other amines, such as piperidine, or amine salts, such as piperidinium acetate, have also been used to catalyze the reaction. 2,3-Dimethoxycinnamic acid has been prepared in good yield under these conditions (eq 2).5c The trans-a,b-unsaturated acids are generally obtained. The Doebner conditions are usually the method of choice for the preparation of cinnamic acid derivatives, in comparison with other classical synthetic procedures.2

Yields are generally high, and the reaction is usually not complicated by side reactions, such as the Michael addition of a second malonic acid molecule to the product.3 Monosubstituted malonic acid derivatives also undergo condensation with aldehydes to provide a-alkylcinnamic acids, but the synthetic utility is limited due to steric problems.3

The condensation sometimes proceeds inefficiently with aliphatic aldehydes, resulting in low yields or mixtures of the a,b- and b,g-unsaturated acids. For these reasons, a number of modified or improved Knoevenagel/Doebner procedures for the synthesis of acrylic acid derivatives have been reported.6 One such modification, in which acrolein is added dropwise to malonic acid in pyridine at 60 °C, provides trans-2,4-pentadienoic acid in a higher and more reproducible yield than earlier procedures (eq 3).5a The conditions can also be modified to provide trans-b,g-unsaturated acids exclusively in moderate yield.6a

The final step in the synthesis of strychnine (2) has been accomplished by treatment of the aldehyde (1) with malonic acid.7 Knoevenagel condensation under these conditions is accompanied by decarboxylation and cyclization to form the final two rings (eq 4).7

Efforts to effect asymmetric decarboxylation of disubstituted malonic acids have met with some success. Thus enzyme-mediated decarboxylation of prochiral a-methyl-a-phenylmalonic acid led to (R)-a-methylphenylacetic acid methyl ester in high yield with 98% ee after esterification (eq 5).8

1. (a) Hughes, D. W. In Kirk-Othmer Encyclopedia of Chemical Technology, 3rd ed.; Wiley: New York, 1981; Vol. 14, pp 794-810. (b) COS 1991, 2, 356. (c) Weiner, N. OSC 1943, 2, 376.
2. Johnson, J. R. OR 1942, 1, 226.
3. (a) Jones, G. OR 1967, 15, 204. (b) Mundy, B. P.; Ellerd, M. G. Name Reactions and Reagents in Organic Synthesis; Wiley: New York, 1988; p 120. (c) Tietze, L. F.; Beifuss, U. COS 1991, 2, 341.
4. Yoshida, Y.; Nagai, S.; Oda, N.; Sakakibara, J. S 1986, 1026.
5. (a) Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. OSC 1988, 6, 95. (b) Allen, C. F. H.; VanAllan, J. OSC 1955, 3, 783. (c) Koo, J.; Fish, M. S.; Walker, G. N.; Blake, J. OSC 1963, 4, 327. (d) Wiley, R. H.; Smith, N. R. OSC 1963, 4, 731. (e) Rajagopalan, S.; Raman, P. V. A. OSC 1955, 3, 425.
6. (a) Ragoussis, N. TL 1987, 28, 93. (b) Kingsbury, C. A.; Max, G. JOC 1978, 43, 3131. (c) Lee, C. K.; Shim, J. Y. OPP 1990, 22, 94. (d) Vinczer, P.; Novak, L.; Szantay, C. OPP 1991, 23, 441. (e) Thomas, A. F.; Rey, F. SC 1991, 21, 327.
7. (a) Anet, F. A. L.; Robinson, R. CI(L) 1953, 245. (b) Magnus, P.; Giles, M.; Bonnert, R.; Kim, C. S.; McQuire, L.; Merritt, A.; Vicker, N. JACS 1992, 114, 4403.
8. Miyamoto, K.; Ohta, H. JACS 1990, 112, 4077.

Gary L. Bolton

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

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