Org. Synth. 1962, 42, 41
DOI: 10.15227/orgsyn.042.0041
DIETHYL β-KETOPIMELATE
[Pimelic acid, β-oxo-, diethyl ester]
Submitted by Maya Guha and D. Nasipuri
1.
Checked by William G. Dauben and Richard Ellis.
1. Procedure
A. Diethyl α-acetyl-β-ketopimelate. In a 2-l. three-necked flask equipped with a mercury-sealed Hershberg stirrer, a dropping funnel, and a reflux condenser protected with a calcium chloride tube are placed 11.5 g. (0.5 g. atom) of finely powdered sodium (Note 1) and 500 ml. of dry ether. The flask is placed in an ice bath, and 65.0 g. (63.5 ml., 0.5 mole) of freshly distilled ethyl acetoacetate in 150 ml. of dry ether is slowly added from the dropping funnel with stirring (approximate time for addition is 30–40 minutes). The mixture is stirred overnight, then it is cooled in an ice bath, and 89.0 g. (0.5 mole) of γ-carbethoxybutyryl chloride (Note 2) in 200 ml. of dry ether is added gradually over the course of 1 hour. The reaction is first stirred overnight at room temperature, then gently refluxed by heating in a water bath for 30 minutes. The mixture is cooled in an ice bath, and a cold solution of 20 ml. of concentrated sulfuric acid in 300 ml. of water is added cautiously with vigorous stirring. The stirring is continued until two clear layers form when the stirring is stopped. The ethereal layer is separated and the aqueous layer extracted once with 100 ml. of ether. The two organic layers are combined, washed once with water, and dried over anhydrous sodium sulfate. After removal of the sodium sulfate by filtration, the solvent is removed by heating the ethereal solution on a water bath held at about 50–60°. The residual light-brown liquid is transferred to a 150 ml. Claisen flask and distilled under reduced pressure. The fraction boiling at 142–147°/0.4 mm. or 158–162°/2.5 mm. is collected (Note 3). The yield is 84–91 g. (61–66%), nD28 1.4649–1.4655.
B. Diethyl β-ketopimelate. In a 250-ml. distillation flask fitted with an inlet tube reaching near the bottom of the flask and a soda-lime drying tube on the side-arm is placed a solution of 50 g. (0.18 mole) of diethyl α-acetyl-β-ketopimelate in 75 ml. of dry ether. The solution is cooled by placing the flask in an ice-salt bath, and then a slow stream of ammonia gas is passed through the inlet tube. The solution becomes turbid during the first few minutes and soon becomes clear again. The gas stream is continued for 45–50 minutes, and the yellow liquid is allowed to stand at room temperature overnight with due protection from atmospheric moisture. Most of the ether is then removed by passing a stream of dry air through the solution, and the residue is transferred to a separatory funnel with the aid of 50 ml. of ether. The ethereal solution is washed with three 70-ml. portions of cold 3N hydrochloric acid, each extraction being shaken vigorously for 10 minutes. The ethereal layer is set aside, and the acid washings are extracted twice with 50-ml. portions of ether. The combined ethereal extracts are washed once with water and dried over anhydrous sodium sulfate. After removal of the sodium sulfate by filtration, the solvent is removed by heating the solution on a water bath. The residue is transferred to a Claisen flask with a short Vigreux column, and the fraction boiling at 130–132°/0.5 mm. or 120–121°/0.2 mm. is collected (Note 4) and (Note 5). The yield is 21–25 g. (50–59%), nD28 1.4400, nD31.5 1.4376, nD36.5 1.4338.
2. Notes
1.
Clean pieces of
sodium are melted under
xylene and powdered by vigorous shaking. When cold, the
xylene is decanted and the
sodium powder is washed by decantation with a few milliliters of dry
ether and then washed into the reaction flask with dry
ether.
2.
The
γ-carbethoxybutyryl chloride (b.p.
100–101°/5–6 mm. or
108–110°/15 mm.) was prepared by the method of Bachmann, Kushner, and Stevenson.
23.
The distillate contains mostly C-acyl ester with a little of O-acyl ester. Separation of these two esters by means of a carbonate solution in which only the C-acyl ester is soluble
3,4 is possible. This separation is unnecessary in the present procedure for the O-acyl derivative gives rise to
ethyl acetoacetate during decomposition with
ammonia. This low-boiling ester is removed during the distillation of
diethyl β-ketopimelate.
4.
A small fore-run, b.p.
60–80°/5 mm., is collected which gives a positive test with
ferric chloride reagent. Presumably this fraction consists mostly of
ethyl acetoacetate.
5.
The checkers used an
18-in. Vigreux column with a heated jacket and observed a boiling point of 126–128°/2 mm.
3. Discussion
The described method of preparing
diethyl β-ketopimelate is a modification of that described by Bouveault
5 and is essentially the same as that reported by Bardhan and Nasipuri.
6 This ester has also been prepared by condensation of
γ-carbethoxybutyryl chloride with
ethoxymagnesiummalonic ester and cleavage of the resulting acylated malonic ester by
β-naphthalenesulfonic acid7 or by acetic or propionic acids containing a trace of concentrated
sulfuric acid.
84. Merits of Preparation
The present method offers a more convenient synthesis with appreciably higher yields of
diethyl β-ketopimelate. It is reported to be useful for the preparation of
dimethyl β-ketoadipate3,9 and
diethyl β-ketosuberate.
4This preparation is referenced from:
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
Ethoxymagnesiummalonic ester
sulfuric acid (7664-93-9)
hydrochloric acid (7647-01-0)
ammonia (7664-41-7)
ether (60-29-7)
sodium sulfate (7757-82-6)
β-naphthalenesulfonic acid (120-18-3)
sodium (13966-32-0)
ferric chloride (7705-08-0)
xylene (106-42-3)
Ethyl acetoacetate (141-97-9)
Diethyl β-ketopimelate,
Pimelic acid, β-oxo-, diethyl ester (40420-22-2)
γ-carbethoxybutyryl chloride (5205-39-0)
Diethyl α-acetyl-β-ketopimelate (61983-62-8)
dimethyl β-ketoadipate
diethyl β-ketosuberate
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