Organic Syntheses, Coll. Vol. 5, p.88 (1973); Vol. 42, p.19 (1962).
A solution of 24.3 g. (0.125 mole) of piperazine hexahydrate
in 50 ml. of absolute ethanol
, contained in a 250-ml. Erlenmeyer flask
, is warmed in a bath at 65° as there is dissolved in the solution, by swirling, 22.1 g. (0.125 mole) of piperazine dihydrochloride monohydrate (Note 1)
. As warming in the bath at 65° is continued, there is added during 5 minutes, with vigorous swirling or stirring, 15.8 g. (14.3 ml., 0.125 mole) of recently distilled benzyl chloride
. The separation of white needles commences almost immediately. After the solution has been stirred for an additional 25 minutes at 65°, it is cooled, and the unstirred solution is kept in an ice bath
for about 30 minutes. The crystals of piperazine dihydrochloride monohydrate
are collected by suction filtration, washed with three 10-ml. portions of ice-cold absolute ethanol
, and then dried. Recovery of the dihydrochloride is 21.5–22.0 g.
) (Note 2)
The combined filtrate and washings from the piperazine dihydrochloride
are cooled in an ice bath and treated with 25 ml. of absolute ethanol
saturated at 0° with dry hydrogen chloride (Note 3)
. After the solution has been well mixed, it is cooled for 10–15 minutes in an ice bath. The precipitated white plates of 1-benzylpiperazine dihydrochloride
are collected by suction filtration, washed with dry benzene
, and dried. The product, which melts at about 280° with decomposition, after sintering at about 254° (Note 4)
, amounts to 29.0–29.5 g.
). A solution of this salt in 50 ml. of water is made alkaline (pH > 12) with about 60 ml. of 5N sodium hydroxide
, then extracted twelve times with 20-ml. portions (Note 5)
. The combined extracts are dried over anhydrous sodium sulfate
, and the pale-brown oil (Note 6)
remaining after removal of solvent is distilled at reduced pressure in a Claisen flask
. The yield of pure 1-benzylpiperazine
, b.p. 122–124°/2.5 mm.
1.5440–1.5450, is 14.3–16.5 g.
Piperazine dihydrochloride monohydrate
, which is recovered almost quantitatively in this procedure, may be purchased from K and K Laboratories, Jamaica 33, New York, or from L. Light and Co., Ltd., Poyle, Colnbrook, Bucks, England. It may be readily prepared in essentially quantitative yield from the free base by the following procedure.
A brisk stream of hydrogen chloride
gas is passed for 5–8 minutes into a solution of 24.3 g. (0.125 mole) of piperazine hexahydrate
in 50 ml. of absolute ethanol
contained in a 250-ml. Erlenmeyer flask. A wide gas-inlet tube (about 10 mm.) is used to avoid clogging, and the flask is cooled in an ice bath to keep the temperature at about 25°. After the gas stream has been discontinued, the contents of the flask are cooled to about 0°, and the crystalline product is collected by suction filtration and washed with two 25-ml. portions of ice-cold absolute ethanol
. The yield is about 22 g.
The melting point has been reported as 253° by Baltzly and co-workers.2
The checkers found continuous extraction with chloroform
to be convenient.
4. Merits of Preparation
The benzyl group, easily removed by hydrogenolysis, is an ideal blocking group for the preparation of 1-monosubstituted, and of 1,4-unsymmetrically disubstituted, piperazines.
Published methods for preparation of 1-benzylpiperazine
involve either fractionation of mixtures of piperazine
and its 1-benzyl- and 1,4-dibenzyl derivatives or the use of 1-carbethoxypiperazine
as an intermediate. The procedure here described is simple; it yields, in 30 minutes, pure 1-benzylpiperazine dihydrochloride
, stable to storage, from readily available starting materials, and free of any disubstituted compound.
This preparation is referenced from:
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