Org. Synth. 1978, 58, 79
DOI: 10.15227/orgsyn.058.0079
[Hexanoic acid, 4-oxo-, ethyl ester]
Submitted by Pius A. Wehrli1 and Vera Chu.
Checked by William B. Farnham and William A. Sheppard.
1. Procedure
A. Diethyl propionylsuccinate (1). A solution of 412 g. (2.40 mole) of diethyl maleate (Note 1), 278 g. (4.79 mole) of freshly distilled propionaldehyde (Note 2), and 1.2 g. (0.0048 mole) of benzoyl peroxide in a normal, 2-l. Pyrex flask is heated under reflux while undergoing irradiation with a UV lamp (Note 3). The initial reflux temperature is 60°. After 2 hours another 1.2 g. of benzoyl peroxide is added. Strong reflux and irradiation are maintained throughout the entire reaction period. After 18 hours of reflux, the internal pot temperature reaches 68°, at which point the last 1.2 g. of benzoyl peroxide is added. The reaction is continued for a total of 30 hours, at which time the pot temperature reaches 74.5°. The reflux condenser is then replaced with a distillation head, and the excess propionaldehyde (119 g.) is distilled under atmospheric pressure, b.p. 48–49°. Succinate 1 is distilled under reduced pressure. The main fraction, b.p. 145–151.5° (15–16 mm), provides 417–449 g. (75–81%) of product having sufficient purity for use in the next step (Note 4).
B. Ethyl 4-oxohexanoate (2). A 1-l., three-necked, round-bottomed flask equipped with a mechanical stirrer, thermometer, and Claisen condenser connected to a gas-measuring device (Note 5) is charged with 276 g. (1.20 mole) of succinate 1 and 74.1 g. (1.20 mole) of boric acid (Note 6). The initially heterogeneous mixture is stirred and immersed in a 150° oil bath. Within 1 hour 36 g. of distillate (mainly ethanol) and approximately 2.3 l. of gas collect. As the temperature is raised to 170°, the rate of carbon dioxide evolution increases, a total of 24.9 l. of gas being collected after 1.5 hours. At this time gas evolution has almost ceased, and the reaction mixture has a clear, light-yellow appearance. The contents of the flask are cooled to room temperature, poured onto 1.5 l. of ice, and extracted with three 500-ml. portions of toluene. The combined organic layers are dried over anhydrous magnesium sulfate, and the solvent is removed under reduced pressure. The product is distilled through a 10-cm. Vigreux column, yielding 156–162 g. (82–85%) of ethyl 4-oxohexanoate, b.p. 109–112° (18 mm.). GC analysis indicates the material to be 99.2% pure (Note 7).
2. Notes
1. Diethyl maleate, practical grade, available from Eastman Organic Chemicals, was used without further purification.
2. Propionaldehyde was obtained from Aldrich Chemical Company, Inc., and must be distilled before use.
3. The checkers used a 275-W. General Electric sunlamp. The submitters used a 140-W. Hanovia Ultraviolet Quartz lamp of a type no longer available.
4. The succinate 1 has the following 1H NMR spectra (CDCl3), δ (multiplicity, number of protons, assignment): 1.0–1.45 (m, 9H, 3CH3), 2.6–3.5 (m, 4H, 2CH2), 3.9–4.4 (m, 5H, 2OCH2CH3 and CH).
5. As a gas-measuring device, the submitters used an inverted, calibrated, 10-l. bottle, filled with saturated sodium chloride, resting in an enamel bucket big enough to hold the volume to be displaced. The checkers used a gas meter. However, the rate of gas evolution can be estimated by using a simple gas bubbler.
6. Reagent grade boric acid, available from Aldrich Chemical Company, Inc., was used.
7. GC analysis was performed on a Hewlett-Packard Model 5720 with dual flame detector; column 1.85 m. × 0.313 cm. outer diameter, stainless steel; 10% UCW-98 on Diatoport 5, programmed at 30° per minute from 50–250°. The purity was calculated by an area comparison. Ester 2 has the following 1H NMR spectrum (CDCl3), δ (multiplicity, coupling constant J in Hz., number of protons, assignment): 1.05 (t, J = 7, 3H, CH3), 1.2 (t, J = 7, 3H, CH3), 2.4–2.9 (m, 6H, 3CH2), 4.2 (q, J = 7, 2H, OCH2CH3).
3. Discussion
γ-Ketoesters, notably 5-substituted ethyl levulinates, have been prepared via radical addition of aldehydes to diethyl maleate to give acylated diethyl succinates.2 These intermediates in turn had to be saponified,2 decarboxylated,2 and reesterified to give the corresponding 4-oxocarboxylates. A more direct method3 utilizes the free radical addition of butyraldehyde to methyl acrylate, but the reported yield is low (11%).
The present method4 is simple, versatile, and efficient in contrast to earlier methods, which were multistep or preparatively unsatisfactory. Various 5-substituted 4-oxocarboxylates can be prepared by this procedure.4
γ-Ketoesters, in general, and levulinic acid or esters, in particular, have extensive utility.5 For example, they can serve as central intermediates for γ-butyrolactones,6 1,4-diols,7 thiophenes,8 pyrrolidones,9 and 2-alkyl-1,3-cyclopentanediones.10
This preparation is referenced from:

References and Notes
  1. Chemical Research Department, Hoffmann–La Roche Inc., Nutley, New Jersey 07110.
  2. T. M. Patrick, Jr., J. Org. Chem., 17, 1009 (1952).
  3. E. C. Ladd, U. S. Pat. 2,577,133 (1951) [Chem. Abstr., 46, 6147h (1952)].
  4. P. A. Wehrli and V. Chu, J. Org. Chem., 38, 3436 (1973).
  5. R. H. Leonard, Ind. Eng. Chem., 48, 1330 (1956).
  6. H. A. Schuette and P. Sah, J. Am. Chem. Soc., 48, 3163 (1926).
  7. A. Müller and H. Wachs, Monatsh. Chem., 53, 420 (1929).
  8. N. R. Chakrabarty and S. K. Mitra, J. Chem. Soc., 1385 (1940).
  9. R. L. Frank, W. R. Schmitz, and B. Zeidman, Org. Synth., Coll. Vol. 3, 328 (1955).
  10. U. Hengartner and V. Chu, Org. Synth., Coll. Vol. 6, 774 (1988).

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

ethanol (64-17-5)

sodium chloride (7647-14-5)

Propionaldehyde (123-38-6)

carbon dioxide (124-38-9)

toluene (108-88-3)

butyraldehyde (123-72-8)

diethyl maleate (141-05-9)


boric acid (10043-35-3)

benzoyl peroxide (94-36-0)

methyl acrylate (96-33-3)

magnesium sulfate (7487-88-9)


Ethyl 4-oxohexanoate,
Hexanoic acid, 4-oxo-, ethyl ester (3249-33-0)

Diethyl propionylsuccinate (4117-76-4)