RESEARCH IN THE CHEMISTRY OF CARBAZOLE DERIVATIVES

62. SYNTHESIS OF 9-OXYMETHYL AND 9-(2-HYDROXY)PROPYL DERIVATIVES OF 3-CHLORO- AND 3,6-DICHLOROCARBAZOLES

E. E. SIROTKINA, V. P. LOPATINSKII, N. G. KOZHINA, A. N. EGOROVA

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

In connection with the expansion of the search for physiologically active compounds in the series of substituted carbazoles, we have investigated methods for obtaining 9-oxymethyl and 9-(2-hydroxy)propyl derivatives of 3-chloro- and 3,6-dichlorocarbazoles.

The starting 3-chloro- and 3,6-dichlorocarbazoles were obtained by methods developed earlier [1, 2, 3]. For the synthesis of 9-oxymethyl derivatives, we used the previously studied method of the reaction of carbazole with paraformaldehyde, which led to good yields of 9-oxymethylcarbazole [4]. Since under these conditions it was not possible to obtain high yields of 3-chloro- and 3,6-dichloro-9-oxymethylcarbazoles, we studied the influence of the principal factors on the process of oxymethylation of 3,6-dichlorocarbazole. The results of these studies are summarized in Table 1 and showed that the reaction time should not exceed 15 min at 78–80°C; the optimal molar ratios of the reagents are 1 : (2.5–3); the best catalyst is potassium carbonate in an amount of 60% (mol.) relative to 3,6-dichlorocarbazole; and ethanol and isopropanol are equally suitable as solvents. Under the indicated optimal conditions, a yield of 3,6-dichloro-9-oxymethylcarbazole of more than 80% can be achieved. Under these same conditions, 3-chloro-9-oxymethylcarbazole is also obtained in a yield of more than 80%.

For the synthesis of 9-(2-hydroxy)propyl derivatives of chlorocarbazoles, the previously developed method of introducing an oxypropyl group by means of propylene oxide [5, 6] was used. Refinement of the optimal conditions for obtaining 3,6-dichloro-9-(2-hydroxy)propylcarbazole (Table 2) showed that, for the synthesis of the product in a yield of more than 90%, the required molar ratio of 3,6-dichlorocarbazole to propylene oxide is 1 : (3–3.5), with an equimolar ratio of 3,6-dichlorocarbazole to caustic potash, and the synthesis should be carried out for 3 hours with continuous stirring at 50°C in acetone, which is taken in an amount of 1.5 ml per 1 g of starting substance.

Under these same conditions, a high yield (more than 90%) of 3-chloro-9-(2-hydroxy)propylcarbazole is achieved.

Experimental Part

3-Chloro-9-oxymethylcarbazole

A flask equipped with a reflux condenser and containing 6 g (0.03 mole) of 3-chlorocarbazole, 1 g of potassium carbonate, 1.8 g (0.06 mole) of paraformaldehyde, and 70 ml of ethyl alcohol is heated on a boiling...

Effect of conditions on the oxymethylation of 3,6-dichlorocarbazole

Table 1

Table 2

Effect of conditions on the oxypropylation of 3,6-dichlorocarbazole

water bath for 30 min. After completion of the reaction, the contents of the flask are cooled and poured into cold water; a solid reaction product separates. It is filtered off, washed with water, dried, and recrystallized from a mixture of benzene and n-hexane (in a ratio of 1 : 2). This gives 6.9 g (87%) of colorless crystalline needles with m.p. 112°C, readily soluble in aliphatic alcohols, acetone, chloroform, and aromatic hydrocarbons, and less readily soluble in aliphatic hydrocarbons. It is readily hydrolyzed on heating in aqueous solutions.

Found, %: N 6.08; OH 6.98. C₁₃H₁₀NOCl.
Calculated, %: N 6.04; OH 7.34.

3,6-Dichloro-9-oxymethylcarbazole

By the method described above, from 2.36 g (0.01 mol) of 3,6-dichlorocarbazole, 0.8 g (0.006 mol) of potassium carbonate, 0.9 g (0.03 mol) of paraformaldehyde, and 30 ml of ethyl alcohol, with heating for 15 min, 2.53 g (95%) of crude product with m.p. 145—149°C was obtained. Recrystallization from a mixture of benzene and n-hexane (2 : 1) gave 2.3 g of colorless needles with m.p. 147—148°C, readily soluble in the solvents listed above. The substance is readily hydrolyzed on heating in aqueous solutions.

Found, %: N 4.94; 4.9; OH 6.46. C₁₃H₉NOCl₂.
Calculated, %: N 5.24; OH 6.36.

3,6-Dichloro-9-(2-oxy)propylcarbazole

A three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and thermometer, and containing 7 g (0.029 mol) of 3,6-dichlorocarbazole, 1.4 g (0.024 mol) of caustic potassium, and 9.5 ml of acetone, is heated to 40°C and, with the stirrer operating, 6 ml (0.086 mol) of freshly distilled propylene oxide is added from the dropping funnel. The temperature is then raised to 50°C and maintained at this temperature for three hours. After completion of the reaction, the contents of the flask are cooled and poured into cold water. The precipitate that forms is filtered off, washed to neutral reaction, dried, and recrystallized from ethyl alcohol. This gives 7.7 g (91.5%) of colorless crystalline needles with m.p. 134—134.5°C.

Found, %: N 4.77; 4.78; OH 5.62. C₁₅H₁₃NOCl₂.
Calculated, %: N 4.76; OH 5.76.

On heating with acetyl chloride, 3,6-dichloro-9-(2-acetoxy)propylcarbazole is obtained as colorless needles with m.p. 76–77°C. Heating with chloroacetyl chloride gives 3,6-dichloro-9-(2-chloroacetoxy)propylcarbazole as colorless crystals with m.p. 117–118°C.

3-Chloro-9-(2-hydroxy)propylcarbazole

By the method described above, from 7.8 g of 3-chlorocarbazole, 1.4 g of caustic potash, and 6.5 ml of propylene oxide in 10 ml of acetone, heating at 50°C for 3 hours gives 10 g (90.5%) of 3-chloro-9-(2-hydroxy)propylcarbazole as colorless needles from ethanol, with m.p. 120.5°C.

Found, %: N 5.48; OH 6.6. C₁₅H₁₄NOCl.
Calculated, %: N 5.4; OH 6.5.

On heating with acetyl chloride, 3-chloro-9-(2-acetoxy)propylcarbazole was obtained, m.p. 87–88°C.

Conclusion

The influence of the principal factors on the reactions of 3-chloro- and 3,6-dichlorocarbazoles with paraformaldehyde and propylene oxide has been investigated, and conditions have been determined for obtaining the 9-hydroxymethyl and 9-(2-hydroxy)propyl derivatives of the indicated chlorocarbazoles in high yields.

REFERENCES

1. V. P. Lopatinskii, I. P. Zherebtsov. Methods for the Preparation of Chemical Reagents and Preparations, IREA, issue 11, 102, 1964.
2. V. P. Lopatinskii, I. P. Zherebtsov, S. K. Vereshchagina. Methods for the Preparation of Chemical Reagents and Preparations, IREA, issue 11, 56, 1964.
3. V. P. Lopatinskii, I. P. Zherebtsov, E. E. Sirotkina, S. K. Vereshchagina. Izv. TPI, 136, 11, 1965.
4. V. P. Lopatinskii, E. E. Sirotkina. Izv. TPI, 111, 107, 1961.
5. V. P. Lopatinskii, E. E. Sirotkina. Author’s certificate 182161; B. I. No. 11, 1966.
6. V. P. Lopatinskii, E. E. Sirotkina, N. A. Musorina. Izv. TPI, 148, 64, 1967.