Org. Synth. 1947, 27, 35
DOI: 10.15227/orgsyn.027.0035
ETHYL α-ISOPROPYLACETOACETATE
[Isovaleric acid, α-acetyl, ethyl ester]
Submitted by Joe T. Adams, Robert Levine, and Charles R. Hauser.
Checked by H. R. Snyder and John Mirza.
1. Procedure
This reaction should be carried out under a well-ventilated hood (Note 1).
A mixture of 30.0 g. (0.5 mole) of anhydrous isopropyl alcohol and 65.0 g. (0.5 mole) of freshly distilled ethyl acetoacetate is placed in a 500-ml. round-bottomed three-necked flask equipped with a mercury-sealed stirrer, a gas inlet tube terminating about 1 cm. above the surface of the liquid, a gas outlet tube connected with a calcium chloride drying tube, and a thermometer (Note 2). The gas inlet tube is connected to a source of boron fluorides (Note 3), and an ice bath is applied to the reaction flask; when the temperature of the stirred mixture has fallen to approximately 0° the stream of boron fluoride is started and adjusted so that the temperature of the mixture does not exceed 7°. The addition of boron fluoride is continued until the mixture is saturated and for 15 minutes thereafter (Note 4). The reaction mixture then is stirred at 28° for 2.5 hours (Note 5), at the end of which period it is poured slowly into a stirred mixture of 130 g. of hydrated sodium acetate, 100 ml. of water, and 200 g. of crushed ice. The beaker containing the resulting mixture is allowed to stand in an ice bath for 2 hours with occasional stirring.
The mixture is poured into a 1-l. separatory funnel. The beaker is rinsed with 300 ml. of ether, and this portion of solvent is shaken with the mixture in the separatory funnel. The phases are separated, and the aqueous solution is extracted twice with 100-ml. portions of ether. The combined ether solutions are washed with saturated aqueous bicarbonate solution until carbon dioxide no longer forms. The solution is transferred to an Erlenmeyer flask and dried over about 25 g. of anhydrous sodium sulfate for 12 hours, after which it is decanted into another Erlenmeyer flask and dried over about 10 g. of Drierite for 6 hours.
A 125-ml. modified Claisen flask is arranged for distillation, but with a dropping funnel fitted in the neck intended for the ebullator tube. Portions of the dried ether solution are introduced into the flask through the funnel while the flask is heated on the steam bath for continuous removal of the solvent. After all the ether solution and the ether washings from the last drying agent have been concentrated, the dropping funnel is replaced by an ebullator tube and distillation under diminished pressure is begun cautiously. Fractions are collected at 60–96°/20 mm. and at 96–98°/20 mm. The first fraction is redistilled to give an additional quantity of material boiling at 96–98°/20 mm. (Note 6). The combined product weighs 52–58 g. (60–67%) (Note 7).
2. Notes
1.
Although no definite data are available concerning the toxicity of
boron fluoride, users should exercise caution and avoid breathing the fumes. The toxic effects of
hydrogen fluoride and alkali fluorides are well known.
Boron fluoride reacts with moisture in the air, forming white fumes of
fluoboric acid and
boric acid which cause a choking sensation when breathed.
2.
The entire apparatus is dried in an
oven at about 100° just before use.
3.
Commercial
boron fluoride from a tank is passed through a saturated solution of
boric oxide in concentrated
sulfuric acid.
4.
The time required for saturation varies from 1 to 2 hours, depending upon the rate of addition. As the saturation point is approached, the fuming at the end of the exit tube increases rather sharply; the mixture is considered to be saturated when the fuming appears to have become constant.
5.
The temperature and time at this point are critical and must be controlled carefully.
6.
If the fractionation is conducted with a
30-cm. Vigreux column the redistillation of the fore-run is unnecessary.
7.
By the same method
ethyl α-cyclohexylacetoacetate (b.p.
146–148°/20 mm.) has been prepared in
34% yield from
cyclohexanol and
acetoacetic ester, and
ethyl α-tert-butylacetoacetate (b.p.
101–102°/20 mm.) In
10–14% yield from
tert-butyl alcohol and
acetoacetic ester.
3. Discussion
The above procedure is based on that described by Adams, Abramovitch, and Hauser.
1 Ethyl α-isopropylacetoacetate has also been prepared by Hauser and Breslow
2 by the reaction of
ethyl acetoacetate with
isopropyl ether in the presence of
boron trifluoride, by Bischoff
3 by the alkylation of the
sodium derivative of ethyl acetoacetate with
isopropyl bromide, and by Renfrow
4 by the alkylation of
ethyl acetoacetate with
isopropyl bromide using
potassium tert-amyloxide as the condensing agent.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
acetoacetic ester
sodium derivative of ethyl acetoacetate
fluoboric acid
Drierite
potassium tert-amyloxide
boric oxide
sulfuric acid (7664-93-9)
ether (60-29-7)
sodium acetate (127-09-3)
Cyclohexanol (108-93-0)
Isopropyl bromide (75-26-3)
sodium sulfate (7757-82-6)
carbon dioxide (124-38-9)
hydrogen fluoride (7664-39-3)
isopropyl alcohol (67-63-0)
Ethyl acetoacetate (141-97-9)
boric acid (10043-35-3)
boron fluoride,
boron trifluoride (7637-07-2)
isopropyl ether (108-20-3)
Ethyl α-isopropylacetoacetate,
Isovaleric acid, α-acetyl, ethyl ester (1522-46-9)
ethyl α-cyclohexylacetoacetate
tert-butyl alcohol (75-65-0)
ethyl α-tert-butylacetoacetate
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