Org. Synth. 1956, 36, 28
DOI: 10.15227/orgsyn.036.0028
β-ETHYL-β-METHYLGLUTARIC ACID
[Glutaric acid, 3-ethyl-3-methyl-]
Submitted by H. H. Farmer and Norman Rabjohn
1.
Checked by Melvin S. Newman and Robert Harper.
1. Procedure
A. α,α'-Dicyano-β-ethyl-β-methylglutarimide. In a 2-l. round-bottomed flask are placed 452 g. (4.0 moles) of ethyl cyanoacetate, 144 g. (2.0 moles) of methyl ethyl ketone, 2 g. of ammonium acetate, and 800 ml. of 95% ethanol which contains 80 g. (4.7 moles) of anhydrous ammonia (Note 1) and (Note 2). The flask is stoppered and placed in a refrigerator.
After about 12 hours, the ammonium salt of the imide which has precipitated is removed by filtration (Note 3), washed on a Büchner funnel with about 200 ml. of ether and air-dried. It is dissolved in the minimum amount (about 800 ml.) of boiling water, and the solution is made acid to Congo red paper with concentrated hydrochloric acid. The free imide precipitates immediately and forms a white slurry which is cooled in an ice bath. The imide is collected on a Büchner funnel and dried at 100° in an oven, or in a vacuum desiccator. The yield is 266–287 g. (65–70%), m.p. 187–191° (Note 4).
B. β-Ethyl-β-methylglutaric acid. A mixture of 280 g. (1.36 moles) of α,α'-dicyano-β-ethyl-β-methylglutarimide (Note 5) and 1.35 l. of 65% (by weight) sulfuric acid is heated under reflux in a 5-l. round-bottomed flask for 8–10 hours (Note 6). The mixture is allowed to cool, and the precipitate is removed by filtration on a sintered glass (or other suitable type) filter. The crude β-ethyl-β-methylglutaric acid is recrystallized from water (Note 7). The yield of product is 174–191 g. (73–80%), m.p. 78–80°.
2. Notes
1.
The
ethyl cyanoacetate and methyl ethyl ketone were Eastman Kodak Company white label grade chemicals and were used without further purification. Commercial absolute
ethanol was found to give a slightly better yield of the ammonium salt of the imide.
2.
It is convenient to pass gaseous
ammonia into the
ethanol. It is advisable to carry out the preparation and manipulation of the
ammonia solution in a
hood.
3.
The mother liquor is returned to the refrigerator and a second and a third crop of crystals may be collected after 24 and 48 hours. The first crop of crystals usually comprises 95% of the total yield.
4.
In taking the melting point of this compound there was still some solid remaining at 200°. The crude imide is satisfactory for conversion to
β-ethyl-β-methylglutaric acid and need not be dried before hydrolysis.
5.
Although the ammonium salt of the imide may be hydrolyzed to the acid, the free imide appears to give better results.
6.
The large flask is used because considerable foaming occurs during the first 2–3 hours of reaction.
7.
A ratio of 3 ml. of water to 1 g. of acid gives satisfactory results. The use of activated
carbon during the recrystallization is recommended.
3. Discussion
α,α'-Dicyano-β-ethyl-β-methylglutarimide apparently has been prepared only from the condensation of
methyl ethyl ketone,
ethyl cyanoacetate, and
ammonia.
2,3,4,5,6
β-Ethyl-β-methylglutaric acid has been prepared by the acid hydrolysis of
α,α'-dicyano-β-ethyl-β-methylglutarimide,
2,3,4,5,6 3-cyano-4-ethyl-6-imino-2-keto-4-methylpiperidine-5-carboxamide or the
diimide of β-ethyl-β-methylpropane-α,α,α',α'-tetracarboxylic acid;
7 by the oxidation of
β-ethyl-β-methyl-δ-valerolactone with
chromic acid;
8 and by the reaction of
sodium hypobromite on
1,4-dimethyl-1-ethyl-3,5-cyclohexanedione.
9
The present procedure is essentially that of Guareschi
2 as detailed by Vogel.
4
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
diimide of β-ethyl-β-methylpropane-α,α,α',α'-tetracarboxylic acid
ethanol (64-17-5)
sulfuric acid (7664-93-9)
hydrochloric acid (7647-01-0)
ammonia (7664-41-7)
ether (60-29-7)
ammonium acetate (631-61-8)
carbon (7782-42-5)
chromic acid (7738-94-5)
Ethyl cyanoacetate (105-56-6)
sodium hypobromite
methyl ethyl ketone (78-93-3)
β-Ethyl-β-methylglutaric acid,
Glutaric acid, 3-ethyl-3-methyl- (5345-01-7)
3-cyano-4-ethyl-6-imino-2-keto-4-methylpiperidine-5-carboxamide
β-ethyl-β-methyl-δ-valerolactone
1,4-dimethyl-1-ethyl-3,5-cyclohexanedione
α,α'-Dicyano-β-ethyl-β-methylglutarimide
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