RESEARCH IN THE CHEMISTRY OF CARBAZOLE DERIVATIVES

48. Synthesis of 9-Carbazolylacetic Acids

V. P. Lopatinskii, I. P. Zherebtsov

(Presented by the scientific-methodological seminar of the Chemical-Technological Faculty)

9-Carbazolylacetic acid and its derivatives with various substituents in the nucleus are of interest as plant-growth regulators, since it is known that N-phenylglycines are physiologically active substances [1].

Of particular interest in this respect are 9-carbazolylacetic acids containing chlorine in the nucleus, since, as a rule, the physiological activity of N-phenylglycines and their analogs—aryloxyacetic acids—increases sharply when halogens, especially chlorine, are present in the nucleus [1].

The known method for preparing 9-carbazolylacetic acid consists in saponification of its ethyl ester, obtained by boiling a large excess of ethyl chloroacetate with potassium carbazole [2, 3]. In addition to being multistage and involving a large consumption of ethyl chloroacetate, this method is not applicable to carbazoles chlorinated in the nucleus because of their instability upon fusion with caustic potash, and therefore cannot serve as a general method for the synthesis of 9-carbazolylacetic acids.

Considering the reaction of carbazole with chloroacetic acid or its derivatives as nucleophilic substitution of chlorine by the carbazole anion, it was to be expected that the reaction could proceed not only with potassium carbazole, but also with the carbazole anion. It is known [4] that carbazole and its halogen-substituted derivatives are ionized under the action of alkalis in solvents with sufficient proton-acceptor activity; moreover, under these conditions further transformations of the anions formed are possible, for example their interaction with ethylene oxide.

Using these facts, we hoped to carry out the synthesis of 9-carbazolylacetic acids by the action of haloacetic acids on carbazole or its substituted derivatives in proton-acceptor solvents in the presence of caustic alkalis, which was the aim of the present work.

Experiments showed that the reaction between carbazole and chloroacetic acid proceeds successfully upon brief heating of the mixture of reagents with alkali in dimethylformamide. The reaction forming carbazolylacetic acid also occurs with bromoacetic acid, but the yield in this case does not increase appreciably. Caustic potash and caustic soda can be successfully used as bases, and in both cases the yields are approximately the same.

The method of charging the reagents is important, since dimethylformamide reacts with alkali and chloroacetic acid at elevated—

temperature. Therefore, in order to obtain better yields, the following order of charging the reagents should be observed: alkali is introduced into dimethylformamide and immediately thereafter 25% of the total amount of chloroacetic acid. The remaining acid is introduced in three portions over the course of half an hour. It was also found that the yield of 9-carbazolylacetic acid can be increased by carrying out the reaction with an excess of carbazole. This manner of conducting the reaction makes it possible to consume the chloroacetic acid more completely, which is important, since its regeneration is difficult, whereas regeneration of unreacted carbazole is accomplished by simple filtration. The reaction product is isolated by pouring the reaction mixture into water, filtering off the unreacted carbazole, and acidifying the filtrate with a mineral acid.

This route to the synthesis of 9-carbazolylacetic acid proves especially interesting because it makes it possible to work with mixtures of carbazole with other substances, for example with anthracene, even with crude enriched anthracene, which makes it possible to dispense with preliminary isolation of carbazole from such mixtures.

Extension of the reaction to chloro- and nitro-substituted carbazoles showed that in these cases as well the corresponding 9-carbazolylacetic acids can be obtained in satisfactory yields.

The substances obtained were identified from elemental-analysis data and also (for 9-carbazolylacetic acid) from the UV absorption spectrum published earlier [3].

Tests of other solvents as media for carrying out the reaction—acetone, methyl ethyl ketone, dimethyl ether of diethylene glycol, morpholine—gave poorer results.

Experimental Part

Starting materials. “Pure” carbazole was a reagent of the Kharkov Coke-Chemical Plant. Crude anthracene was from the Kemerovo Coke-Chemical Plant.

3,6-Dichlorocarbazole was synthesized by the procedure described in [5], mp 202–203°C.

3-Nitrocarbazole was synthesized by the procedure described in [6], mp 213°C.

Chloroacetic acid and dimethylformamide were reagents of “pure” grade.

9-Carbazolylacetic Acid

Method a. Synthesis with an excess of chloroacetic acid.

5 g (0.03 M) of carbazole is dissolved in 30 ml of dimethylformamide (heated to 80°C); with stirring, 7.1 g (0.126 M) of powdered caustic potash and 3.52 g (0.037 M) of chloroacetic acid are introduced in equal portions 4 times over half an hour. The mixture is poured into 300 ml of water, the precipitated carbazole is filtered off, and the filtrate is acidified with concentrated hydrochloric acid (Congo test). A precipitate forms, which is filtered off and dried. The yield of 9-carbazolylacetic acid with mp 201–202°C is 3.14 g (46.6% of the theoretical amount calculated on carbazole and 37.4% calculated on the acid).

Analyses, %: N, found: 6.42; C₁₄H₁₁O₂N; calculated: 6.22.

Method b. Synthesis with an excess of carbazole

Under the above conditions, from 45 g (0.27 M) of carbazole, 10.5 g (0.11 M) of chloroacetic acid, and 63.9 g (1.14 M) of powdered cau-

potassium hydroxide in 220 ml of dimethylformamide, 12.71 g of 9-carbazolylacetic acid was obtained (yield 21% based on the carbazole charged and 51% based on chloroacetic acid).

The yield based on the carbazole that reacted is close to 100% in both cases.

Method c. Use of an artificial mixture of carbazole with anthracene

A mixture containing 5 g of carbazole and 5 g of anthracene is dissolved in 30 ml of dimethylformamide heated to 80°C; with stirring, 7.1 g of potassium hydroxide and 3.52 g of chloroacetic acid are introduced in four equal portions over half an hour. After the treatment described above, 2.82 g of 9-carbazolylacetic acid is obtained (40.6% calculated on the carbazole introduced).

Method d. Use of crude enriched anthracene

23.3 g of a mixture obtained by treating crude coke-chemical anthracene with benzene and containing about 40% carbazole is dissolved in 60 ml of dimethylformamide heated to 80°C, and, with stirring, 13.45 g of potassium hydroxide is charged, followed by 6.45 g of chloroacetic acid in four equal portions over half an hour. The usual treatment gives 5.08 g of 9-carbazolylacetic acid (40% based on the carbazole contained in the mixture), m.p. 198–200°C. Purification by dissolving in alkali and reprecipitation with acid raises the m.p. to 201°C. From the dried residue of the mixture (18.95 g) and 2.62 g of chloroacetic acid in the presence of 5.25 g of potassium hydroxide in 30 ml of dimethylformamide, 3.72 g of 9-carbazolylacetic acid and 15.1 g of residue are obtained; the latter is again treated with 1.01 g of chloroacetic acid and 4.12 g of potassium hydroxide, giving 1.37 g of 9-carbazolylacetic acid and 13.76 g of residue, which, after recrystallization from acetone, gives 8.9 g of anthracene, m.p. 211–212°C.

The total yield of 9-carbazolylacetic acid reaches 80%, calculated on the carbazole content in the initial enriched anthracene.

9-Carbazolylacetic acid is a white, finely crystalline substance, very poorly soluble in water. It dissolves well in alcohols and acetic acid, and in aqueous solutions of alkalis and ammonia. From xylene or ethyl acetate it crystallizes as fine needles, m.p. 201–202°C. According to the literature, 9-carbazolylacetic acid melts at 215°C [2], 216°C [3]. However, by repeated crystallization from various solvents we were unable to obtain a substance with an m.p. higher than 201–202°C. Nevertheless, the UV spectrum of this substance coincides completely with the published spectrum [3], where the authors used a preparation with m.p. 216°C. Nitrogen analysis also gives a quite satisfactory result.

3,6-Dichloro-9-carbazolylacetic acid

20 g (0.086 M) of 3,6-dichlorocarbazole is dissolved in 60 ml of dimethylformamide heated to 80°C; with stirring, 14.1 g (0.25 M) of powdered potassium hydroxide and 10 g (0.106 M) of chloroacetic acid are added. The mixture is stirred for half an hour and poured into 600 ml of water; the precipitate that separates is filtered off and dried. The yield of 3,6-dichloro-9-carbazolylacetic acid, m.p. 215–217°C, is 10.2 g (40.8% of theoretical, calculated on 3,6-dichlorocarbazole). After recrystallization from acetic acid, m.p. 230–232°C (yield 30% of theoretical).

Analyses, %: found: N 4.89; Cl 24.27; C₁₄H₉O₂NCl₂; calculated: N 4.75; Cl 24.13.

3-Nitro-9-carbazolylacetic acid

5 g (0.0236 M) of 3-nitrocarbazole, 5 g (0.053 M) of chloroacetic acid, and 50 ml of dimethylformamide are boiled under a reflux condenser for one hour, after which the mixture is worked up as described above. The yield of 3-nitro-9-carbazolylacetic acid with m.p. 229–232°C (with decomposition) is 1.6 g (25.7% of theoretical, calculated on 3-nitrocarbazole). 3-Nitro-9-carbazolylacetic acid crystallizes from acetic acid in the form of yellow needles with m.p. 231–232°C, which dissolve in aqueous alkali solutions with formation of a yellow-colored solution. Analyses, % found: N 10.17; $\mathrm{C}_{14}\mathrm{H}_{10}\mathrm{O}_{4}\mathrm{N}_{2}$, calculated: N 10.37.

Conclusions

1. A new method has been developed for the synthesis of 9-carbazolylacetic acid by the interaction of carbazole with haloacetic acids in the presence of alkali in dimethylformamide.
2. The method has been extended to substituted carbazoles.

Literature

1. N. N. Mel’nikov, Yu. A. Baskakov. Chemistry of Herbicides and Plant Growth Regulators. Goskhimizdat, 1962.
2. German patent 255304; Frdl. 11, 171.
3. S. I. Omel’chenko, Z. V. Pushkareva, S. G. Bogomolov. ZhOKh, 27, 3220, 1957.
4. V. P. Lopatinskii, I. P. Zherebtsov. Proceedings of Tomsk State University, in press.
5. V. P. Lopatinskii, I. P. Zherebtsov, S. K. Vereshchagina. Methods for Obtaining Chemical Reagents and Preparations, 11, 56, 1964.
6. R. Eikhman, V. Lukashevich, E. Sigaeva. POKh, 6, 93, 1939.