Diethyl Malonate1

(1; R1 = R2 = Et)

[105-53-3]  · C7H12O4  · Diethyl Malonate  · (MW 160.17) (2; R1 = R2 = Me)

[108-59-8]  · C5H8O4  · Dimethyl Malonate  · (MW 132.12) (3; R1 = R2 = t-Bu)

[541-16-2]  · C11H20O4  · Diethyl Malonate  · (MW 216.28) (4; R1 = t-Bu, R2 = Me)

[42726-73-8]  · C8H14O4  · t-Butyl Methyl Malonate  · (MW 174.20) (5; R1 = t-Bu, R2 = Et)

[32864-38-3]  · C9H16O4  · t-Butyl Ethyl Malonate  · (MW 188.22) (6; R1 = R2 = Bn)

[15014-25-2]  · C17H16O4  · Dibenzyl Malonate  · (MW 284.31) (7; R1 = Bn, R2 = Me)

[52267-39-7]  · C11H12O4  · Benzyl Methyl Malonate  · (MW 208.21) (8; R1 = Bn, R2 = Et)

[42998-51-6]  · C12H14O4  · Benzyl Ethyl Malonate  · (MW 222.24)

(two- or three-carbon nucleophiles in enolate or enol alkylation, conjugate addition, and various condensation reactions1)

Physical Data: (1) mp -50 °C; bp 199 °C; d20 1.055 g cm-3; nD20 1.4143; dipole moment 1.57 D. (2) mp -62 °C; bp 181 °C; d20 1.154 g cm-3; nD20 1.4140; dipole moment 2.39 D. (3) bp 112-115 °C/31 mmHg; d20 0.965 g cm-3. (4) bp 80 °C/11 mmHg; d20 1.030 g cm-3. (5) bp 83-85/8 mmHg; d20 1.001 g cm-3. (6) bp 188 °C/0.2 mmHg; d20 1.158 g cm-3. (7) bp 125 °C/0.5 mmHg; d20 1.150 g cm-3. (8) bp 138-139 °C; d20 1.087 g cm-3.

Solubility: (1) and (2) sparingly sol water; miscible in all proportions with ether and alcohol.

Form Supplied in: dimethyl and diethyl malonates are colorless liquids with a minimum assay of 99% (GC) which are widely available.

Preparative Methods: dibenzyl malonate is prepared by refluxing malonic acid with benzyl alcohol with catalytic amount of sulfuric acid.2 Di-t-butyl malonate is usually obtained from malonic acid and isobutene with catalytic amount of sulfuric acid.3 t-Butyl methyl and t-butyl ethyl malonates can be obtained through reaction of methyl and ethyl malonyl chlorides with t-butyl alcohol, e.g. over activated alumina as a catalyst.4a Unsymmetrical methyl, ethyl, and benzyl malonates may be prepared by reaction of the corresponding monoalkyl malonates with alkyl chloroformates.4b

Handling, Storage, and Precautions: no specific health hazard if handled with the usual precaution.

Introduction.

The principal synthetic utility of the malonate esters may be summarized as follows:1

  • 1) the acidity of the methylene group (pKa &AApprox; 13) is such that metal salts can be easily formed with the metal alkoxides. The resulting carbanions undergo acylation, alkylation,5 aldol,6 and Michael reactions;7
  • 2) the possibility of hydrolyzing and subsequently decarboxylating only one of the ester functions;
  • 3) the usual reactions of the ester functions.

    In many syntheses reported in the literature, malonates react at both the methylene group and the ester functions, which make them very useful reagents, especially in the formation of heterocycles.

    The main feature of di-t-butyl, dibenzyl, and the t-butyl and benzyl alkyl malonates is that the t-butyl ester and benzyl ester groups can easily be cleaved by hydrolysis/decarboxylation or by hydrogenolysis/decarboxylation, respectively. Selective removal of t-butyl and benzyl esters may also be accomplished with Iodotrimethylsilane.8 Cleavage and decarboxylation of dimethyl, diethyl, and unsymmetrical methyl and ethyl malonates can be effected by SN2 attack on the methyl or ethyl ester carbon with strong nucleophilic anions such as chloride, iodide, cyanide, alkylthiolates, and phenylselenate.9

    Acylation.

    Acylation of diethyl malonate followed by partial hydrolysis and decarboxylation is one of the methods used for synthesizing b-keto esters.10 Nevertheless, further malonate derivatives such as Meldrum's acid (2,2-Dimethyl-1,3-dioxane-4,6-dione),11a and mixed malonates such as t-butyl ethyl malonate11b or potassium ethyl malonate,11c can also be advantageously used. The latter allows the synthesis of b-keto esters in high purity without the partial hydrolysis step so that they can be used without isolation in subsequent transformations to, for example, quinolone moieties (eq 1).11c

    Acylation of dibenzyl malonate12a or di-t-butyl malonate12b followed by hydrogenolysis/decarboxylation (eq 2) or hydrolysis/decarboxylation (eq 3) of the acylmalonates yields methyl ketones.

    A similar synthesis of methyl 7-(2-hydroxy-5-oxo-1-cyclopentenyl)heptanoate has been reported (eq 4).13 Condensation of orthoformates with malonates affords alkoxymethylene malonates which are widely used for heterocyclic synthesis.

    Alkylation.

    1,5 Both a-hydrogens can be replaced by alkyl substituents (eq 5).14

    Mono- and dialkyl malonates can be further modified by partial hydrolysis and decarboxylation of an ester function,9,14 or by reduction of both ester functions with Lithium Aluminum Hydride to give 2-substituted 1,3-propanediols (eq 6).15 A useful synthesis of primary a-methylene alcohols involves LiAlH4 reduction of the sodium salts formed from a-alkyl malonates (eq 7).16 Cyclocondensation with N-ethylaniline affords a 4-hydroxy carbostyril (eq 8).17

    a,a-Dialkylation of malonates with dihaloalkanes and intramolecular a-alkylation with a-(o-haloalkyl)malonates provides effective approaches for construction of carbocyclic rings containing 3-21 carbon atoms.18 Alkylation of sodio diethyl malonate with chiral 2,3-epoxybutane affords enantiomerically pure (>99% ee) cis-b,g-dimethyl-g-butyrolactone (eq 9).19 Although a-alkylation of malonate carbanions with tertiary alkyl halides cannot usually be effected in practically useful yields owing to competing elimination, t-butylation of diethyl malonate could be accomplished in 56% yield under Lewis acidic conditions (BF3, CS2/ClCH2CH2Cl, D, 18 h), presumably via an SN1-type mechanism involving the t-butyl carbenium ion (eq 10).20

    An important advance in the potential applications of malonate chemistry is the development of efficient procedures for a-allylation of malonate anions with allylic esters and lactones as well as vinyl epoxides (e.g. cyclopentadiene monoepoxide) by means of Pd0 catalysts (eq 11).21,22

    Less economically attractive, but still quite useful, are the allyl coupling reactions that occur between p-allylpalladium complexes and malonate anions. The former Pd0-catalyzed allylations usually occur with retention of the C-O bond stereochemistry as a consequence of the two configurational inversions which occur during the formation of the p-allylpalladium intermediate and its subsequent displacement by the malonate group. It should be noted that mixtures of allylic isomers are often formed from unsymmetrical allylic esters owing to malonate attack at both C-1 and C-3 of the p-allylpalladium intermediate.

    a-Alkylation of malonate esters by monosubstituted alkenes and isobutene occurs in the simultaneous presence of Manganese(III) Acetate (limiting stoichiometric oxidant) and catalytic amounts of Copper(II) Acetate. The resulting a-alkenylmalonates (40-70% based on MnIII) undergo hydrolysis and decarboxylation to g,d-unsaturated carboxylic acids.23 a-Arylation of a-alkylmalonate diesters may be accomplished by means of coupling reactions with aryllead triacetates [ArPb(OAc)3].24 However, the unsubstituted parent malonates do not undergo arylation under the same conditions.

    Knoevenagel Reactions.

    Such reactions6 with aldehydes or ketones are frequently followed by cyclocondensation at one of the ester functions (eq 12).25 When reacted with acetaldehyde, diethyl ethylidenemalonate is obtained which in turn can be ozonolyzed to diethyl oxomalonate (eq 13), a versatile reagent for organic synthesis.26

    Michael Reaction.

    The Michael addition7 to activated double bonds such as those of a,b-unsaturated carbonyl compounds is frequently described in the literature. Followed by a ring-closing Claisen condensation and a subsequent decarboxylation, this sequence leads to the formation of 1,3-cyclohexanedione derivatives (eq 14).27 They can further be aromatized to substituted resorcinols,28 reduced to 5-substituted 2-cyclohexenones,29 or involved in cyclocondensation reactions.27

    In the case of b,b-bis(trifluoromethyl)acrylic esters as starting material, an anti-Michael addition followed by a fluoride elimination has been reported (eq 15).30

    Other Reactions.

    A further reaction at the central methylene group is nitrosation with Sodium Nitrite, giving oximinomalonates which are subsequently reduced to the corresponding 2-aminomalonates (eq 16).31

    Usual reactions at the ester functions include, for example, transesterification to mixed malonates like benzyl ethyl malonate2 or base-catalyzed cyclocondensation with ureas, thioureas, guanidines, or amidines yielding the corresponding 2-substituted pyrimidines.32

    Related Reagents.

    Bis(trimethylsilyl) Malonate; Diethyl Ethoxymethylenemalonate; Diethyl Ethylidenemalonate; Diethyl Methylenemalonate; Diethyl Oxomalonate; 2,2-Dimethyl-1,3-dioxane-4,6-dione; Diethyl Ethoxymagnesiomalonate; Ethyl Malonate; Ethyl Trimethylsilyl Malonate; Magnesium Ethyl Malonate; Manganese(III) Acetate; Tetrakis(triphenylphosphine)palladium(0).


    1. (a) Ullmann's Encyclopedia of Industrial Chemistry, 5th ed.; VCH: Weinheim, 1990; Vol. A16, pp 63-75. (b) Hughes, D. W. In Kirk-Othmer Encyclopedia of Chemical Technology, 3rd ed.; Wiley: New York, 1976; Vol. 14, pp 794-804. (c) House, H. O. Modern Synthetic Reactions; Benjamin: Menlo Park, CA, 1972. (d) Stowell, J. C. Carbanions in Organic Synthesis; Wiley: New York, 1979; pp 192-197. (e) FF 1967, 1, 627, 887, 1069, 1251, 1268. (f) Henecka, H. Chemie der Beta-Dicarbonyl Verbindungen; Springer: Berlin, 1950.
    2. Baker, B. R.; Schaub, R. E.; Querry, M. V.; Williams, J. A. JOC 1952, 17, 77.
    3. MacCloskey, A. L.; Fonken, G. S.; Kluiber, R. W.; Johnson, W. S. OSC 1963, 4, 261.
    4. (a) Nagasawa, K.; Yoshitake, S.; Amiya, T.; Ito, K. SC 1990, 20, 2033. (b) Gutman, A. L.; Boltanski, A. TL 1985, 26, 1573.
    5. Cope, A. C.; Holmes, H. L.; House, H. O. OR 1957, 9, 107.
    6. (a) Tietze, L. F.; Beifuss, U. COS 1991, 2, 341. (b) Tietze, L. F.; Beifuss, U. OS 1993, 71, 167. (c) Lehnert, W. TL 1970, 4723.
    7. (a) Jung, M. E. COS 1991, 4, 1. (b) Bergman, E. D.; Ginsburg, D.; Pappo, R. OR 1959, 10, 179.
    8. (a) Groutas, W. C.; Felker, D. S 1980, 861. (b) Jung, M. E. JACS 1977, 99, 968. (c) Ho, T.-L.; Olah, G. A. AG(E) 1976, 749; S 1977, 917.
    9. (a) Krapcho, A. P. S 1982, 805, 893. (b) McMurry, J. OR 1976, 24, 187.
    10. Pollet, P. L. J. Chem. Educ. 1983, 60, 244.
    11. (a) Oikawa, Y.; Sugano, K.; Yonemitsu, O. JOC 1978, 43, 2087. (b) Pichat, L.; Beaucourt, J. P. S 1973, 537. (c) Clay, R. J.; Collom, T. A.; Karrick, G. L.; Wemple, J. S 1993, 3, 290.
    12. (a) Bowman, R. E. JCS 1950, 325. (b) Fonken, G. S.; Johnson, W. S. JACS 1952, 74, 831.
    13. Naora, H.; Ohnuki, T.; Nakamura, A. BCJ 1988, 61, 993.
    14. Bhagwat, S. S.; Gude, C.; Boswell, C.; Contardo, N.; Cohen, D. S.; Dotson, R.; Mathis, J.; Lee, W.; Furness, P.; Zoganas, H. JMC 1992, 35, 4373.
    15. Rastetter, W. H.; Phillion, D. P. JOC 1981, 46, 3204.
    16. (a) Marshall, J. A.; Anderson, N. H.; Hochstetter, A. R. JOC 1967, 32, 113. (b) Corey, E. J.; Helquist, P. TL 1975, 4091.
    17. Stadlbauer, W.; Laschober, R.; Lutschounig, H.; Schindler, G.; Kappe, T. M 1992, 123, 617.
    18. (a) Casadei, M. A.; Galli, C.; Mandolini, L. JACS 1984, 106, 1051. (b) Knipe, A. C.; Stirling, C. J. JCS(B) 1968, 67. (c) Ref. 1c, pp 541-543.
    19. Hedenström, E.; Högberg, H. E.; Wassgren, A. B.; Bergström, G.; Lötqvist, J.; Hansson, B.; Anderbrant, O. T 1992, 48, 3139.
    20. Boldt, P.; Militzer, H.; Thielecke, W.; Schulz, L. LA 1968, 718, 101.
    21. (a) Trost, B. M.; Verhoeven, T. R. JACS 1980, 102, 4730. (b) Trost, B. M. JOM 1986, 300, 263; Chemtracts-Org. Chem. 1988, 1, 415.
    22. Heck, R. F. Palladium Reagents in Organic Synthesis; Academic: New York, 1985; pp 130-154.
    23. Nikishin, G. I.; Vinogradov, M. G.; Fedorova, T. M. CC 1973, 693.
    24. Pinhey, J. T.; Rowe, B. A. TL 1980, 21, 965.
    25. Ivanov, I. C.; Karagiosov, S. K.; Simeonov, M. F. LA 1992, 203.
    26. Jung, M. E.; Shishido, K.; Davis, L. H. JOC 1982, 47, 891.
    27. Kesten, S. J.; Degnan, M. J.; Hung, J.; McNamara, D. J.; Ortwine, D. F.; Uhlendorf, S. E.; Werbel, L. M. JMC 1992, 35, 3429.
    28. Kotnis, A. S. TL 1991, 32, 3441.
    29. Hataba, H. M.; Sayed, M. A. Egypt. J. Chem. 1989, 32, 195.
    30. Martin, V.; Molines, H.; Wackselman, C. JOC 1992, 57, 5530.
    31. May, D. A., Jr.; Lash, T. D. JOC 1992, 57, 4820.
    32. Brown, D. J. The Chemistry of Heterocyclic Compounds: The Pyrimidines, Weissberger, A., Ed.; Interscience: New York, 1962; Suppl. I, 1970; Suppl. II, 1985.

    Gérard Romeder

    Lonza, Basel, Switzerland



    Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.