Organic Syntheses, CV 4, 515
Submitted by Barbara B. Kehm and Calvert W. Whitehead
1.
Checked by M. S. Newman and K. G. Ihrman.
1. Procedure
A.
N-n-Heptylurea. To a mixture of
24.1 g. (0.21 mole) of n-heptylamine (Note
1), 35 g. of cracked ice, and 150 ml. of ice-cold water is added
38 ml. of 5N hydrochloric acid (Note
2) with stirring. The mixture is heated on the
steam bath at 70–80°, and
14.3 g. (0.22 mole) of sodium cyanate is added portion-wise. After 2–4 hours of continued heating, two layers separate. The product crystallizes on standing overnight at room temperature. It is collected on a
Büchner funnel, washed with 100 ml. of cold water, and drained as dry as practical by suction. This solid is dissolved in
125 ml. of boiling ethyl acetate, and the resulting solution is cooled to room temperature. The white crystalline
N-n-heptylurea is filtered and dried on a porcelain plate at room temperature. A yield of
28.5–29.5 g. (
86–88%) of product melting at
110–111° is obtained (Note
3).
B.
3-n-Heptylureidomethylenemalononitrile. In a
250-ml. round-bottomed flask fitted with a heating mantle and a
reflux condenser are placed
28.5 g. (0.18 mole) of N-n-heptylurea,
11.9 g. (0.18 mole) of malononitrile (Note
4), and
26.7 g. (0.18 mole) of triethyl orthoformate (Note
4). The mixture is heated under reflux for 2 hours and then cooled in ice. The solid product is collected by suction filtration on a Büchner funnel. The filtrate is concentrated on the steam bath to incipient crystallization, cooled, and filtered. The two lots of tan solid,
41–42 g., thus obtained are dissolved in
75 ml. of 75% ethyl alcohol in a
250-ml. beaker,
2 g. of decolorizing carbon is added, and the mixture is boiled for 2–3 minutes with constant stirring (necessary to avoid vigorous bumping). The hot solution is filtered by gravity into a
250-ml. Erlenmeyer flask through
fluted filter paper. The flask is stoppered and cooled in the
refrigerator for 4 hours. The solid product is collected by suction filtration on a Büchner funnel and washed four times with 10-ml. portions of distilled water. The white crystalline
3-n-heptylureidomethylenemalononitrile is dried at 50° in a vacuum
oven. It melts at
130–132° and amounts to
33.8–34.8 g. (
80–83%) (Note
5).
C.
3-n-Heptyl-5-cyanocytosine. In a
250-ml. Erlenmeyer flask are placed
33.8 g. (0.145 mole) of 3-n-heptylureidomethylenemalononitrile and
70 ml. of methanol; then
8.5 g. (0.16 mole) of sodium methoxide (Note
6) is added carefully in small portions (Note
7). The resulting solution is allowed to stand at room temperature for 3 days in the stoppered flask. The contents of the flask are dissolved in 300 ml. of cold water in an
800-ml. beaker, and the solution is stirred as
11 ml. of glacial acetic acid is added. The precipitated solid is collected by suction filtration on a Büchner funnel and washed with three 40-ml. portions of distilled water. The undried product is dissolved in
600 ml. of hot ethyl alcohol; then the solution is filtered into a
1-l. flask by gravity through a
fluted filter paper, concentrated on the steam bath to 200 ml., and cooled in the
refrigerator for 4 hours. The
3-n-heptyl-5-cyanocytosine crystallizes in white needles, melts at
192–197° (Note
8), and amounts to
29.7–31.1 g. (
88–92%) (Note
9).
Recrystallization of 20 g. of this product from
230 ml. of hot ethyl alcohol affords
17.8 g. of fine colorless needles, m.p.
199.5–202.5°.
2. Notes
1.
n-Heptylamine is available from Sapon Laboratories, P. O. Box 599, Lynbrook, New York, and from Distillation Products Industries, Rochester 3, New York.
2. If excess acid is present, considerable foaming may occur on addition of
sodium cyanate.
3. The melting point for
N-n-heptylurea given in the literature
2 is
110–111°.
4. Commercially available reagents were employed.
6.
Sodium methoxide is available from Mathieson Chemical Corporation, Niagara Falls, New York. Alternatively, a solution prepared by dissolving
3.6 g. of sodium in
70 ml. of methanol may be used.
9. The submitters obtained comparable yields in all steps using
144.2 g. (1.25 moles) of heptylamine and correspondingly larger amounts of all reagents.
3. Discussion
The procedure described here has given equally good yields of other 3-alkyl-5-cyanocytosines and 3-cycloalkyl-5-cyanocytosines; however, it does not yield 3-aryl-5-cyanocytosines from arylureas.
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