Org. Synth.1978,58, 79
DOI: 10.15227/orgsyn.058.0079
γ-KETOESTERS FROM ALDEHYDESVIA DIETHYL ACYLSUCCINATES:ETHYL 4-OXOHEXANOATE
[Hexanoic acid, 4-oxo-, ethyl ester]
Submitted by Pius A. Wehrli
1 and Vera Chu.
Checked by William B. Farnham and William A. Sheppard.
1. Procedure
A.Diethyl propionylsuccinate(1). A solution of412 g. (2.40 mole) ofdiethyl maleate(Note 1),278 g. (4.79 mole) of freshly distilledpropionaldehyde(Note 2), and1.2 g. (0.0048 mole) ofbenzoyl peroxide in anormal, 2-l. Pyrex flask is heated under reflux while undergoing irradiation with aUV lamp(Note 3). The initial reflux temperature is 60°. After 2 hours another1.2 g. ofbenzoyl 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 last1.2 g. ofbenzoyl peroxide is added. The reaction is continued for a total of 30 hours, at which time the pot temperature reaches 74.5°. Thereflux condenser is then replaced with a distillation head, and the excesspropionaldehyde (119 g.) is distilled under atmospheric pressure, b.p. 48–49°.Succinate1 is distilled under reduced pressure. The main fraction, b.p.145–151.5° (15–16 mm), provides417–449 g. (75–81%) of product having sufficient purity for use in the next step(Note 4).
B.Ethyl 4-oxohexanoate(2). A1-l., three-necked, round-bottomed flask equipped with amechanical stirrer,thermometer, andClaisen condenser connected to agas-measuring device(Note 5) is charged with276 g. (1.20 mole) ofsuccinate1 and74.1 g. (1.20 mole) ofboric acid(Note 6). The initially heterogeneous mixture is stirred and immersed in a 150°oil bath. Within 1 hour 36 g. of distillate (mainlyethanol) and approximately 2.3 l. of gas collect. As the temperature is raised to 170°, the rate ofcarbon 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 three500-ml. portions oftoluene. The combined organic layers are dried over anhydrousmagnesium sulfate, and the solvent is removed under reduced pressure. The product is distilled through a10-cm. Vigreux column, yielding156–162 g. (82–85%) ofethyl 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
succinate1 has the following
1H NMR spectra (CDCl
3), δ (multiplicity, number of protons, assignment): 1.0–1.45 (m, 9H, 3C
H3), 2.6–3.5 (m, 4H, 2C
H2), 3.9–4.4 (m, 5H, 2OC
H2CH
3 and C
H).
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 gradeboric 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 (CDCl
3), δ (multiplicity, coupling constant
J in Hz., number of protons, assignment): 1.05 (t,
J = 7, 3H, C
H3), 1.2 (t,
J = 7, 3H, C
H3), 2.4–2.9 (m, 6H, 3C
H2), 4.2 (q,
J = 7, 2H, OC
H2CH
3).
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 method
3 utilizes the free radical addition of
butyraldehyde to
methyl acrylate, but the reported yield is low (11%).
The present method
4 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.
4γ-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.
10This preparation is referenced from:
References and Notes
- Chemical Research Department, Hoffmann–La Roche Inc., Nutley, New Jersey 07110.
- T. M. Patrick, Jr.,J. Org. Chem.,17, 1009 (1952).
- E. C. Ladd, U. S. Pat. 2,577,133 (1951) [Chem. Abstr.,46, 6147h (1952)].
- P. A. Wehrli and V. Chu,J. Org. Chem.,38, 3436 (1973).
- R. H. Leonard,Ind. Eng. Chem.,48, 1330 (1956).
- H. A. Schuette and P. Sah,J. Am. Chem. Soc.,48, 3163 (1926).
- A. Müller and H. Wachs,Monatsh. Chem.,53, 420 (1929).
- N. R. Chakrabarty and S. K. Mitra,J. Chem. Soc., 1385 (1940).
- R. L. Frank, W. R. Schmitz, and B. Zeidman,Org. Synth.,Coll. Vol. 3, 328 (1955).
- U. Hengartner and V. Chu,Org. Synth.,Coll. Vol. 6, 774 (1988).
Appendix
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)
LEVULINIC ACID (123-76-2)
boric acid (10043-35-3)
benzoyl peroxide (94-36-0)
methyl acrylate (96-33-3)
magnesium sulfate (7487-88-9)
succinate
Ethyl 4-oxohexanoate,
Hexanoic acid, 4-oxo-, ethyl ester (3249-33-0)
Diethyl propionylsuccinate (4117-76-4)
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