Organic Syntheses, CV 6, 936
Submitted by R. C. Cookson
1, S. S. Gupte, I. D. R. Stevens, and C. T. Watts.
Checked by Y. Chao and R. Breslow.
1. Procedure
Caution!
Benzene has been identified as a carcinogen; OSHA has issued emergency standards on its use. All procedures involving
benzene should be carried out in a
well-ventilated hood, and glove protection is required.
A.
Ethyl hydrazinecarboxylate. To
100 g. (96.9 ml., 2.00 moles) of 100% hydrazine hydrate, contained in a 1-l., round-bottomed flask, is added
236 g. (243 ml., 2.00 moles) of diethyl carbonate (Note
1). The flask is fitted with a
calcium chloride-containing drying tube and shaken vigorously, mixing the two liquids. After about 5 minutes, the milky emulsion becomes warm, and shaking is continued until a clear solution is obtained (approximately 20 minutes). The flask is equipped with a
reflux condenser fitted with a calcium chloride-containing drying tube and heated on a
steam bath for 3.5 hours. The reaction mixture is transferred to a
500-ml., round-bottomed flask and is distilled through a
15-cm. Vigreux column under reduced pressure, yielding
161–176 g. (
77–85%) of a colorless liquid collected at
102–103° (18 mm.) or
117–118° (40 mm.) (Note
2),
n22D 1.4495; IR cm
−1 1640, 1725, 3350. The product, which may crystallize on standing, m.p.
45–47°, need not be purified for the next step.
B.
4-Phenyl-1-carbethoxysemicarbazide. A
1-l., three-necked, round-bottomed flask equipped with a
liquid-sealed mechanical stirrer (Note
3), a
constant-pressure dropping funnel, and a reflux condenser fitted with a
drying tube containing silica gel is charged with a solution of
52 g. (0.50 mole) of ethyl hydrazinecarboxylate in 550 ml. of dry benzene (Note
4). After the solution is cooled with an
ice bath, stirring is begun and
59.7 g. (54.5 ml., 0.501 mole) of phenyl isocyanate is added dropwise to the solution over a 45-minute period. After about one-half of the isocyanate has been added, a white precipitate of the product appears, and the reaction mixture becomes progressively thicker. After addition is complete the ice bath is removed; the mixture is stirred at room temperature for 2 hours, then heated under reflux for 2 hours. The suspension is allowed to cool to room temperature, and
4-phenyl-1-carbethoxysemicarbazide is isolated by suction filtration, washed with
500 ml. of benzene, and dried in a
vacuum desiccator, yielding
108 g. (
97%) of
4-phenyl-1-carbethoxysemicarbazide, m.p.
151–152°. The product is not further purified for use in the next step, but may be recrystallized from
ethyl acetate to yield white crystals, m.p.
154–155°; IR cm.
−1 1645, 1687, 1797, and 3300 (Note
6).
C.
4-Phenylurazole. A
250-ml. Erlenmeyer flask is charged with
100 ml. of aqueous 4 M potassium hydroxide and
44.6 g. (0.200 mole) of 4-phenyl-1-carbethoxysemicarbazide. The suspension is warmed on a steam bath, the flask being swirled occasionally to wash the solid off the sides. After 1.5 hours most of the solid has dissolved, and the hot solution is filtered. After cooling to room temperature, the solution is acidified with concentrated
hydrochloric acid (about 33 ml. is required). The mixture is again cooled to room temperature and the precipitated
4-phenylurazole is isolated by suction filtration. The mother liquor is evaporated to dryness on a
rotary evaporator, and the residue is extracted twice with
100-ml. portions of boiling absolute ethanol (Note
7). The
ethanol solutions are combined, filtered, and evaporated to dryness on a rotary evaporator, and the additional
4-phenylurazole recovered is combined with that obtained above. The product is crystallized from
95% ethanol (about 80 ml.), yielding
30.0–33.5 g. (
85–95%) of
4-phenylurazole, m.p.
209–210°; IR cm.
−1 1685 and 3120 (Note
8),(Note
9), and (Note
10).
D.
4-Phenyl-1,2,4-triazoline-3,5-dione. A
100-ml., three-necked, round-bottomed flask equipped with a dropping funnel, a
gas-inlet tube, a calcium chloride-containing drying tube, and a
magnetic stirrer is flushed with
oxygen-free nitrogen (Note
11) and charged with
12 ml. of ethyl acetate (Note
12) and
4.4 g. (0.025 mole) of 4-phenylurazole (Note
13). The stirrer is started, and
2.5 g. (2.8 ml., 0.023 mole) of tert-butyl hypochlorite (Note
14) and (Note
15) is added to the flask over a period of approximately 20 minutes, the reaction mixture being maintained close to room temperature with a
cold-water bath (Note
16) and (Note
17). After the addition is complete, the resulting suspension is stirred for 40 minutes at room temperature. The reaction mixture is transferred to a 100-ml., round-bottomed flask, and the solvent is removed on a rotary evaporator, keeping the temperature below 40°. The last traces of solvent are removed with a
high-vacuum pump (about 0.1 mm.). The product is sublimed (Note
18) onto an ice-cooled cold finger under vacuum (100° at 0.1 mm.), yielding
2.7–2.8 g. (
62–64%) of the triazoline as carmine-red crystals which decompose (
165–175°) before melting; IR cm.
−1 1760 and 1780; UV (dioxane) nm (ε) 247 (2300), 310 (1020), and 532 (171) (Note
19) and (Note
20).
2. Notes
2. A forerun of approximately 100 ml., boiling below 80° (18 mm.), containing
ethanol, water, and unreacted starting materials, is also collected.
3. An
efficient stirrer should be employed, since the reaction mixture becomes quite viscous. If efficient mixing is not maintained a violent reaction can occur. This is especially important when using aliphatic isocyanates.
4.
British Drug Houses Ltd. or Amend Drug & Chemical Co., Inc., reagent grade benzene, dried over
sodium wire, is adequate.
5.
British Drug Houses Ltd. or Matheson Laboratory reagent grade phenyl isocyanate was used without further purification. When using other isocyanates, care should be taken to ensure their purity as the yield is greatly dependent upon this, commercially available
4-nitrophenyl isocyanate being a case in point.
11. A gentle stream of
nitrogen is maintained through the apparatus during the entire reaction.
Hydrogen chloride is evolved and adequate precautions should be taken to prevent exposure to the gas.
13. The
4-phenylurazole should be ground with a
pestle and mortar before use.
15. An excess of
tert-butyl hypochlorite should not be used, as it cannot be removed and interferes with the sublimation of the product.
16. When preparing the 4-(4-nitrophenyl)- and 4-benzalamino- analogs, the reaction mixture should be maintained at 0–5°.
17. As soon as the first drop of hypochlorite is added, the reaction mixture becomes red in color, with the color deepening as the addition proceeds.
18. The impure material has a limited stability and should be sublimed as quickly as possible. The scale of the reaction should not be greatly increased unless an efficient large subliming apparatus is available. The submitters report similar yields on experiments four times this scale.
19. The product has a shelf life of several months if stored in the dark in a
refrigerator.
20. This method has been used to prepare 4-methyl- [sublimed at 50° (0.1 mm.), 85%, m.p. 104°], 4-
tert-butyl- [50° (0.1 mm.). 80%, m.p. 119°], 4-(4-nitrophenyl)- [100° (0.1 mm.), 25%, m.p. 130°], and
4-benzalamino-1,2,4-triazoline-3,5-dione [
100° (0.1 mm.),
75%].
3. Discussion
Ethyl hydrazinecarboxylate has been prepared from
hydrazine hydrate and
ethyl N-tricarboxylate in good yield.
4 The method described here is comparable in efficiency, but has the added advantage that both starting materials are commercially available.
In common with other azodicarboxylic acid derivatives,
4-phenyl-1,2,4-triazoline-3,5-dione has many uses. It undergoes Diels-Alder reactions with most dienes
10,11,12,13 and is, in fact, the most reactive dienophile so far reported.
14,15 As with the formation of all Diels-Alder adducts the reaction is reversible, and in the case of the adduct with
3β-acetoxy-17-cyano-5,14,16-androstatriene, the reverse reaction can be made to proceed under especially mild conditions.
13 An instance has also been reported of the dione photochemically catalyzing other retro Diels-Alder reactions.
16 Along with the proved use of azodicarboxylic ester,
17,18 the dione should be potentially important in the preparation of strained ring compounds.
4-Phenyl-1,2,4-triazoline-3,5-dione also undergoes "addition-abstraction" reactions (
e.g., with
acetone16). As would be expected for such a species, it will oxidize alcohols to the corresponding aldehydes or ketones.
19 This oxidation is especially mild (room temperature in
benzene,
chlorobenzene or
ethyl acetate) and is, as such, a valuable method of oxidizing or preparing compounds sensitive to acid, base, or heat.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
dinitrogen tetroxide
Ethyl N-tricarboxylate
oxygen-free nitrogen
ethanol (64-17-5)
hydrogen chloride,
hydrochloric acid (7647-01-0)
Benzene (71-43-2)
ethyl acetate (141-78-6)
methanol (67-56-1)
nitric acid (7697-37-2)
silver nitrate (7761-88-8)
nitrogen (7727-37-9)
aniline hydrochloride (142-04-1)
benzaldehyde (100-52-7)
iodine (7553-56-2)
acetone (67-64-1)
chlorobenzene (108-90-7)
potassium hydroxide (1310-58-3)
sodium wire (13966-32-0)
sodium ethoxide (141-52-6)
hydrazine hydrate (7803-57-8)
phenyl isocyanate (103-71-9)
dioxane (5703-46-8)
diethyl carbonate (105-58-8)
Ethyl hydrazinecarboxylate (4114-31-2)
urazole (3232-84-6)
4-Phenyl-1,2,4-triazoline-3,5-dione,
4-Phenylurazole (15988-11-1)
4-Phenyl-1-carbethoxysemicarbazide
4-nitrophenyl isocyanate (100-28-7)
4-(4-nitrophenyl)-1-carbethoxysemicarbazide
4-nitrophenylurea
4-(4-nitrophenyl)urazole,
4-(4-Nitrophenyl)-1,2,4-triazoline-3,5-dione
4-Benzalaminourazole,
4-benzalamino-1,2,4-triazoline-3,5-dione
4-aminourazole
biurea (110-21-4)
3β-acetoxy-17-cyano-5,14,16-androstatriene
lead dioxide
tert-Butyl hypochlorite (507-40-4)
4-tert-Butyl-1-carbethoxysemicarbazide
4-tert-butylurazole
3H-1,2,4-Triazole-3,5(4H)-dione, 4-phenyl- (4233-33-4)
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