Org. Synth. 1985, 63, 198
DOI: 10.15227/orgsyn.063.0198
[Benzenebutanoic acid, β-oxo-, methyl ester]
Submitted by Y. Oikawa, T. Yoshioka, K. Sugano, and Osamu Yonemitsu1.
Checked by Michael J. Taschner, Hans P. Märki, and Clayton H. Heathcock.
1. Procedure
Into a 300-mL, round-bottomed flask equipped with a dropping funnel and a magnetic stirrer is placed a solution of 23.75 g (0.165 mol) of recrystallized Meldrum's acid (Note 1) in 65 mL of anhydrous dichloromethane. The flask and its contents are cooled in an ice bath, and 32.5 mL (0.40 mol) of anhydrous pyridine (Note 2) is added with stirring under an argon atmosphere over a 10-min period. To the resulting colorless clear solution is added a solution of 25.0 g (0.16 mol) of freshly distilled phenylacetyl chloride (Note 3) in 50 mL of anhydrous dichloromethane over a 2-hr period. After the addition is complete, the resulting orange, cloudy reaction mixture is stirred for 1 hr at 0°C, then for an additional 1 hr at room temperature. The reaction mixture is diluted with 35 mL of dichloromethane, and then poured into 100 mL of 2 N hydrochloric acid containing crushed ice. The organic phase is separated and the aqueous layer extracted twice with 25-mL portions of dichloromethane. The organic phase and the extracts are combined, washed twice with 25-mL portions of 2 N hydrochloric acid and 30 mL of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent is removed with a rotary evaporator to yield an acyl Meldrum's acid (Note 4) as a pale-yellow solid.
The solid acyl Meldrum's acid, without purification, is refluxed in 250 mL of anhydrous methanol for 2.5 hr. The solvent is removed with a rotary evaporator, and the residual oil is distilled under reduced pressure to give 25.2 g (82%) of methyl phenylacetylacetate as a colorless liquid, bp 126–128°C/(0.6 mm).
2. Notes
1. Meldrum's acid, 2,2-dimethyl-1,3-dioxane-4,6-dione, is available from the Aldrich Chemical Company, Inc. It may also be prepared from malonic acid and acetone.2 It is used in this preparation after recrystallization from acetone or from acetonehexane. The checkers found that a final product of significantly lower purity is obtained if the Meldrum's acid is not recrystallized.
2. The checkers used pyridine that had been distilled from calcium hydride.
3. Phenylacetyl chloride is supplied by Wako Pure Industries, Ltd. (Japan) and the Aldrich Chemical Company, Inc. It is distilled before use, bp 95–96°C/(12 mm). The checkers found the distilled commercial material to be slightly pink. However, material of this quality gave a good yield of pure product.
4. The product, 2,2-dimethyl-5-phenylacetyl-1,3-dioxane-4,6-dione, is isolated in its enol form in 97% yield. If desired, it may be further purified by recrystallization from etherhexane to give pale-yellow prisms, mp 96–97°C (dec). The checkers recrystallized the material from dichloromethanehexane and obtained 65% yield of material, mp 94–96°C (dec) and 7%, mp 84–90°C. The 1H NMR spectrum of this compound has absorptions at δ 1.65 (s, 6 H), 4.30 (s, 2 H), 7.20 (s, 5 H), and 15.0 (br s, 1 H).
3. Discussion
Because β-keto esters are among the most important intermediates in organic synthesis, many methods have been developed for their synthesis.3 However, it is still desirable to have a general and practical method for preparation of β-keto esters of the general type RCOCH2CO2R', and thence by alkylation with alkyl halides compounds of the type RCOCHR''CO2R'.4 The available synthetic methods can be classified broadly in three categories: those involving acetoacetic esters,5 those involving mixed malonic esters,6 and those involving malonic acid half esters.7 The procedure described herein8 may be classified as one of the malonic ester methods. The procedure consists of two simple steps and utilizes readily accessible starting materials. When the carboxylic acid chloride is not available, the carboxylic acid may be condensed with Meldrum's acid in the presence of a condensing agent such as ethyl phosphorocyanidate.9
Methanolysis or ethanolysis of an acyl Meldrum's acid is performed simply by refluxing in methanol or ethanol solution. The products are methyl or ethyl β-keto esters, and they can usually be purified by distillation. When a higher ester (such as benzyl, tert-butyl, or trichloroethyl) is required, it is easily prepared by refluxing the acyl Meldrum's acid in benzene containing about 3 equiv of the appropriate alcohol.
Recently, Melillo and co-workers applied this Meldrum's acid method with some modifications to the synthesis of thienamycin. A carboxylic acid was treated with carbonyldiimidazole, followed by treatment with Meldrum's acid to give an acyl Meldrum's acid, which was converted to a β-keto p-nitrobenzyl ester by refluxing in acetonitrile containing p-nitrobenzyl alcohol.10

References and Notes
  1. Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060, Japan.
  2. Davidson, D.; Bernhard, S. A. J. Am. Chem. Soc. 1948, 70, 3426.
  3. For reviews, see Hauser, C. R.; Hudson, B. E. Org. React. 1942, 1, 266; House, H. O. "Modern Synthetic Reactions," 2nd ed.; W. A. Benjamin: Menlo Park, CA, 1972, p. 734.
  4. Durst, H. D.; Liebeskind, L. J. Org. Chem. 1974, 39, 3271; Brändström, A.; Junggren, U. Acta Chem. Scand. 1969, 23, 2204.
  5. Shriner, R. L.; Schmidt, A. G.; Roll, L. J. Org. Synth., Coll. Vol. II 1943, 266; Guha, M.; Nasipuri, D. Org. Synth., Coll. Vol. V 1973, 384; Viscontini, M.; Merckling, N. Helv. Chim. Acta 1952, 35, 2280.
  6. Breslow, D. S.; Baumgarten, E.; Hauser, C. R. J. Am. Chem. Soc. 1944, 66, 1286; Taylor, E. C.; McKillop, A. Tetrahedron 1967, 23, 897; Bowman, R. E.; Fordham, W. D. J. Chem. Soc. 1951, 2758; Pichat, L.; Beaucourt, J.-P. Synthesis 1973, 537.
  7. Ireland, R. E.; Marshall, J. A. J. Am. Chem. Soc. 1959, 81, 2907; Bram, G.; Vilkas, M. Bull. Soc. Chim. Fr. 1964, 945; Pollet, P.; Gelin, S. Synthesis 1978, 142; Brooks, D. W.; Lu, L. D.-L.; Masamune, S. Angew. Chem. Int. Ed. Engl. 1979, 18, 72.
  8. Oikawa, Y.: Sugano, K.; Yonemitsu, O. J. Org. Chem. 1978, 43, 2087.
  9. Shioiri, T.; Yokoyama, Y.; Kasai, Y.; Yamada, S. Tetrahedron 1976, 32, 2211; Takamizawa, A.; Sato, Y.; Tanaka, S. Yakugaku Zasshi 1965, 85, 298; Chem. Abstr. 1965, 63, 9940h.
  10. Melillo, D. G.; Shinkai, I.; Liu, T.; Ryan, K.; Sletzinger, M. Tetrahedron Lett. 1980, 21, 2783.

Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)


benzyl, tert-butyl, or trichloroethyl

acyl Meldrum's acid

ethanol (64-17-5)

hydrochloric acid (7647-01-0)

Benzene (71-43-2)

methanol (67-56-1)

ether (60-29-7)

acetonitrile (75-05-8)

sodium chloride (7647-14-5)

sodium sulfate (7757-82-6)

acetone (67-64-1)

pyridine (110-86-1)

dichloromethane (75-09-2)

Malonic acid (141-82-2)

phenylacetyl chloride (103-80-0)

hexane (110-54-3)

argon (7440-37-1)

calcium hydride (7789-78-8)


p-Nitrobenzyl alcohol (619-73-8)

Methyl phenylacetylacetate,
Benzenebutanoic acid, β-oxo-, methyl ester (37779-49-0)

MELDRUM'S ACID (2033-24-1)



ethyl phosphorocyanidate