Submitted by Emily F. M. Stephenson
Checked by C. F. H. Allen, C. V. Wilson, and Jean V. Crawford.
1. Procedure
A.
o-Hydrazinobenzoic acid hydrochloride. In a
2-l. beaker, provided with a
stirrer and a
low-temperature thermometer, and cooled in an
ice-salt bath, are placed
42 g. (0.31 mole) of anthranilic acid and 300 ml. of water. The stirrer is started, and
340 ml. of concentrated hydrochloric acid (sp. gr. 1.18) is added in one portion; the
anthranilic acid dissolves, and its hydrochloride begins to separate almost immediately. After the mixture has been cooled to 0°, a solution of
21.6 g. (0.31 mole) of technical sodium nitrite in 210 ml. of water is added from a
dropping funnel, the tip of which extends below the surface of the suspension, at such a rate that the temperature never rises above 3°. The addition requires about 30 minutes; stirring is continued for 15 minutes longer, and at the end of this period a positive test with starch-iodide paper should be obtained (Note
1). The clear brown solution is then diluted with 150 ml. of ice water.
In a
12-l. flask, equipped with a low-temperature thermometer and surrounded by an ice-salt bath, a solution of
sulfurous acid is prepared by saturating 2.4 l. of water at 0–5° with
sulfur dioxide from a cylinder. A brisk stream of the gas is continued (Note
2) while the cold diazonium salt solution is added in about 150-ml. portions over a 30-minute period and the temperature is maintained at 5–10°; the reaction mixture assumes a dark orange color (Note
3). The cooling bath is removed, but
sulfur dioxide is passed into the mixture for an additional 30 minutes. After the mixture has been allowed to stand for 12 hours at room temperature,
3 l. of concentrated hydrochloric acid (sp. gr. 1.18) is added; the
o-hydrazinobenzoic acid hydrochloride separates at once. The mixture is chilled to 0–5° and filtered through a precooled
Büchner funnel; the product is washed with two
50-ml. portions of ice-cold dilute (1:1) hydrochloric acid. The yield is
50–51 g. (
86–88%); the salt melts at
194–195° with decomposition (Note
4) and is suitable for the next step without further purification (Note
5).
B.
Indazolone. In a
2-l. round-bottomed flask to which a
reflux condenser is attached are placed
47.1 g. (0.25 mole) of o-hydrazinobenzoic acid hydrochloride, 1.25 l. of water, and
12.5 ml. of concentrated hydrochloric acid (sp. gr. 1.18). The mixture is refluxed for 30 minutes. The resulting pale yellow solution is transferred in two portions to a
23-cm. evaporating dish and concentrated on the
steam bath to about one-fourth its original volume. The
indazolone separates at an early stage of the evaporation but redissolves as the concentration of acid increases.
Sodium carbonate is added to the warm solution in small portions until the acid is neutralized (Note
6), and the suspension is allowed to stand for 2 hours. The nearly colorless
indazolone is removed by filtration, washed with two 25-ml. portions of cold water, and air-dried. The yield of product, m.p.
246–249°, is
30–33 g. (
90–98%) (Note
7).
C.
3-Chloroindazole. In a
200-ml. flask connected by a glass joint to an
air condenser protected by a drying tube are placed
26.8 g. (0.2 mole) of dry indazolone and
15.8 g. (16 ml., 0.2 mole) of dry pyridine (Note
8);
46.1 g. (27.6 ml., 0.3 mole) of phosphorus oxychloride is then added, with shaking, over a 10-minute period. Heat is evolved, and acid fumes are generated. The mixture is heated with occasional shaking in an
oil bath, which is maintained at 128–130° for 1 hour and at 130–140° for 4 hours. The clear brown solution is then cooled to 70° and poured, with hand stirring, upon 500 g. of cracked ice. This mixture is allowed to stand for 24 hours. The pale buff solid is removed, washed on the filter, first with
100 ml. of 0.5 N hydrochloric acid and then with 40 ml. of cold water, and air-dried (Note
9). The
3-chloroindazole is crystallized from
3 l. of 20% ethanol. The yield is
21–22.5 g. (
68–74%) of material melting at
148–148.5° (Note
10).
D.
Indazole. In a
300-ml. flask are placed
15.3 g. (0.1 mole) of 3-chloroindazole,
18.6 g. (0.15 mole) of red phosphorus, and
100 ml. of constant-boiling hydriodic acid (sp. gr. 1.7) (Note
11). The mixture is refluxed for 24 hours (Note
12), cooled, and filtered through a
sintered-glass funnel (Note
13) to remove the
phosphorus; the flask and the solid are washed with two 20-ml. portions of water. The clear filtrate is transferred to a
300-ml. Claisen flask and concentrated to about 40 ml. by heating in a
water bath at a reduced pressure. The residue is washed into a
250-ml. beaker with 70–80 ml. of hot water, and the clear solution is cooled in an
ice bath and made strongly alkaline with concentrated
ammonium hydroxide (about 80 ml. is required). The next day, the
indazole is collected and dried; the white solid melts at
143–145° (Note
14).
The product is added to
75 ml. of benzene, and the suspension is boiled until the frothing has ceased, the
benzene lost being replaced (Note
15); the resulting suspension is filtered to remove the insoluble material. The clear filtrate is heated to boiling, diluted with
25 ml. of petroleum ether (b.p.
70–90°), and allowed to cool slowly. The yield of white product, m.p.
145–146.5°, is
9.7–10.2 g. (
82–86%). The over-all yield from
anthranilic acid is
43–55%.
2. Notes
1. If the starch-iodide test is negative at this point a little solid
sodium nitrite may be added.
2. This operation should be carried out in a
hood or out-of-doors.
4. The melting point varies with the rate of heating. The values given were obtained with a bath preheated to 180°.
5. The free acid may be obtained by treatment of a solution of the hydrochloride with a concentrated aqueous solution of
sodium acetate. The powdered
hydrochloride (18.9 g., 0.1 mole) is dissolved in 567 ml. of water, and
sodium acetate solution (8.2 g. [0.1 mole] of anhydrous sodium acetate in 30 ml. of water) is added.
o-Hydrazinobenzoic acid separates at once; the mixture is chilled, and the light-tan acid is removed by filtration, washed with two 25-ml. portions of water, and air-dried. The yield is
13.1 g. (
86%); m.p.
248–250°. If a purer acid is required, the crude material may be recrystallized from
ethanol (50 ml. per g.); the pale tan product then melts at
250–251.5°.
7. The
indazolone may be purified further by recrystallization from
methanol (24 ml. per g.), with filtration of the hot solution through a layer of Norit. It separates as white needles, m.p.
250–252°; the recovery is about
50%. An additional
10% of material (m.p.
246–248°) may be obtained by dilution of the filtrate with 2 volumes of water.
The submitter reports that the described method of purification gives a better product than is obtained by solution in dilute
sodium hydroxide and reprecipitation with acid.
8. The submitter reports that
dimethylaniline can be used but that it is less desirable because a small amount of a green by-product is formed.
9. The crude
chloroindazole, m.p.
143–145°, is difficult to dry. Small quantities may be crystallized satisfactorily from water (250 ml. per g.). The submitter reports that a good product can be obtained by steam distillation but that even with superheated steam the distillation is very slow.
10. In a run 2.5 times this size, the checkers dissolved the crude product in
190 ml. of ethanol and diluted the hot filtrate with 260 ml. of water; the
chloroindazole was obtained in
80% yield.
11. It is essential to use acid of this concentration.
12. This reaction time ensures complete conversion of the
chloroindazole.
13. As an alternative procedure, the mixture may be diluted with 70 ml. of water and filtered through S & S No. 596 filter paper.
14. The crude
indazole is so difficult to dry that the weight at this stage is not significant.
15. This operation is carried out in an open flask in the hood and at a point remote from flames; the
indazole is dried by the steam distillation of the water with the
benzene.
3. Discussion
Indazole has been obtained in a variety of ways which are of no preparative value. The elimination of the amino group from aminoindazoles, first utilized by Witt,
4 by the action of
ethanol or
sodium stannite on the diazonium compounds appears to be the only other useful procedure.
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