Organic Syntheses, Coll. Vol. 3, p.495 (1955); Vol. 21, p.60 (1941).
A. Diethyl sec.-butylmalonate
. To 700 ml. of absolute ethanol
in a 2-l. three-necked round-bottomed flask
equipped with a long, wide-bore reflux condenser
is added 35 g. (1.52 gram atoms) of sodium
cut in pieces of suitable size. When all the sodium
has reacted, the flask is placed on a steam cone and fitted with a mercury-sealed stirrer
, a dropping funnel
, and a reflux condenser bearing a calcium chloride tube (Note 1)
. The flask is heated, and 250 g. (1.56 moles) of diethyl malonate
is added in a steady stream with stirring. After the ester addition, 210 g. (1.53 moles) of sec-butyl bromide
is added at such a rate that the heat of reaction causes refluxing. The mixture is then stirred and refluxed for 48 hours. At the end of this time, the reflux condenser is exchanged for a downward condenser and the ethanol
is removed by distillation (Note 2)
. The residue is treated with 200 ml. of water, shaken, and allowed to stand until the ester layer separates. The ester layer is separated from the aqueous layer and distilled from a 500-ml. two-necked flask
fitted with a well-wrapped 18-in. Vigreux column
. The fraction boiling at 110–120°/18–20 mm.
is diethyl sec-butylmalonate
, and it amounts to 274–278 g.
B. α-Bromo-β-methylvaleric acid
. In a 2-l. three-necked round-bottomed flask equipped with a stirrer and dropping funnel and placed on a steam cone, 250 g. of technical potassium hydroxide
is dissolved in 200 ml. of water. To the hot solution, 250 g. (1.16 moles) of diethyl sec-butylmalonate
is added in a steady stream with vigorous stirring (Note 3)
. A tube connected to a vacuum line assists in the removal of ethanol
. The mixture is stirred and heated for 5 hours (Note 4)
, and then the contents of the flask are transferred to a beaker
fitted with a stirrer and surrounded by an ice bath
. The cooling is hastened by the addition of 50 g. of ice, and, when the temperature reaches 15°, technical hydrochloric acid
is added at such a rate that the temperature does not rise above 20°. After the addition of about 250 ml. of acid, the monopotassium salt separates, necessitating stirring by hand until solution again occurs. When the solution is acid to Congo red (Note 5)
it is transferred to a separatory funnel (Note 6)
The sec-butylmalonic acid
is extracted with three 200-ml. portions of ether
, and the combined extracts are dried over calcium chloride
overnight. The ether
solution is then decanted into a 2-l. three-necked flask fitted with a mercury-sealed stirrer, reflux condenser, and dropping funnel. Five milliliters of bromine
is added at one time, and the solution is stirred until decolorized (Note 7)
. Then 50 ml. more bromine
is added dropwise at such a rate that the ether refluxes gently. When all the bromine
has been added, 200 ml. of water is added through the dropping funnel dropwise so as to produce no foaming or violent reaction.
layer containing the bromomalonic acid
is separated from the aqueous layer, and the ether
is removed by distillation from a steam cone. The residual liquid is decarboxylated by refluxing for 5 hours in a 500-ml. round-bottomed flask
on an oil bath
heated to 130°. The bromo acid is then separated from the small amount of water and distilled. The material distilling at 125–140°/18–20 mm.
is α-bromo-β-methylvaleric acid (Note 8)
. The yield is 150.5 g.
. One hundred and fifty grams (0.77 mole) of α-bromo-β-methylvaleric acid
is added to 645 ml. of technical ammonium hydroxide
(sp. gr. 0.90) in a 1.5-l. round-bottomed flask
. A stopper
is wired in, and the flask is allowed to stand at room temperature for a week (Note 9)
. The stopper is removed and the mixture heated on a steam cone overnight to remove ammonia
. The aqueous solution is concentrated under reduced pressure until bumping becomes violent (about 300 ml.). The mixture is then cooled to 15° and the crystals are collected on a filter. The crystals are washed with 40 ml. of ethanol
and dried. The filtrate is again concentrated to about 150 ml., and a second crop of crystals is obtained. This second crop is washed with 25 ml. of water and then with 25 ml. of 95% ethanol
. The yield of crude product is 65 g.
is recrystallized by dissolving it in 850 ml. of water heated to 95° on a steam cone. The solution is decolorized by treatment with a gram of Norit
for 30 minutes and is then filtered hot. To the hot solution is added 425 ml. of 95% ethanol
. and the flask is placed in an ice chest
overnight. The yield of pure product is 38 g.
An additional crop of 12 g.
may be obtained by concentrating the mother liquors from the recrystallization to about 100 ml. and adding an equal volume of ethanol
. This second crop is washed with 10 ml. of cold water and 10 ml. of cold ethanol
. The total yield is 50 g.
). The product decomposes at 278–280°
in a sealed evacuated capillary (Note 10)
The submitters carried out the preparation on a run ten times this size, using a 12-l. round-bottomed flask
. After the sodium
had reacted, the flask was fitted with a stopper containing the stirrer and two angle tubes connected respectively to a reflux condenser and a dropping funnel. The time allowed for the various reactions to take place was the same as for the smaller run. The percentage yields of the various products were practically identical.
On a run ten times this size, the submitters distilled the ethanol
into another 12-l. flask connected by means of an adapter
and fitted with the wide-bore reflux condenser originally used. The sodium
necessary for a second run was added to the second flask as the ethanol
distilled into it; on the large run this took 4–6 hours.
The ester is added quite slowly at first, until the reaction gets under way, and then more rapidly.
Water is added if necessary to keep the mass from solidifying.
About 400 ml. of acid is required.
For a run ten times this size, the solution is transferred to a 12-l. round-bottomed flask fitted with a stopper containing a large stop-cock
which barely pierces the stopper and a glass tube which reaches to the bottom of the flask. A flask so fitted can be used as a large separatory funnel. The stopper is wired when the flask is upturned.
It is important that the first 5-ml. portion react completely; otherwise the bromination will not go smoothly and the solution may foam out of the condenser.
.If the decarboxylation was not complete it will be finished here. Occasionally it is some time before a good water pump
will maintain constant pressure.
On a larger run, the submitters allowed 350 g. of the bromoacid
and 1.5 l. of ammonium hydroxide
in a 3-l. flask
to stand for a week. The contents of four such flasks, including any solid material, were combined in a 12-l. round-bottomed flask and heated on a steam cone overnight.
The product obtained in this manner has the calculated amount of amino nitrogen.
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