Organic Syntheses, Coll. Vol. 5, p.769 (1973); Vol. 40, p.68 (1960).
1-METHYLINDOLE
[Indole, 1-methyl-]
Submitted by K. T. Potts and J. E. Saxton1.
Checked by W. E. Parham, Wayland E. Noland, and Bryce A. Cunningham.
1. Procedure
Caution! Ammonia gas is an extreme irritant and can cause serious burns to the eyes, etc. It is necessary to carry out the entire reaction under a well-ventilated hood.
In a 1-l. three-necked flask fitted with a motor stirrer (Note 1), gas inlet tube, dropping funnel, and a wide-bore soda-lime tube are placed 400–500 ml. of liquid ammonia and 0.1 g. of ferric nitrate nonahydrate (Note 2).
In small portions, just sufficient to maintain the blue color, 5.0 g. (0.22 gram atom) of clean, metallic sodium is added with vigorous stirring. After dissolution is complete (Note 3), a solution of 23.4 g. (0.20 mole) of indole (Note 4) in 50 ml. of anhydrous ether is added slowly and then, after an additional 10 minutes, a solution of 31.2 g. (0.22 mole) of methyl iodide in an equal volume of anhydrous ether is added dropwise. Stirring is continued for a further 15 minutes. The ammonia is allowed to evaporate (Note 5), 100 ml. of water is added, followed by 100 ml. of ether. The ether layer is separated, the aqueous phase extracted with an additional 20 ml. of ether, and the combined ether extracts washed with three 15 ml.-portions of water (Note 6) and dried over anhydrous sodium sulfate. The solvent is removed at atmospheric pressure, and the crude oil (n18.5°D 1.6078) is purified by distillation under reduced pressure. 1-Methylindole is obtained as a colorless oil, b.p. 133°/26 mm., n18.5°D 1.6082. In several runs the yield is 22.3–24.9 g. (85–95%).
2. Notes
1. Any sealed mechanical stirrer may be used. Those of the Hershberg2 type were found particularly efficient during the formation of the sodium amide.
2. It was found most advantageous to run in the liquid ammonia from the commercial cylinder, laid on the floor with the foot raised slightly, and connected to the gas inlet tube with rubber tubing approximately 1 cm. in diameter. The large excess of liquid ammonia used obviates the need of a dry iceacetone cooling bath and permits a reasonably rapid formation of sodium amide.
3. This occurs when the blue color has disappeared. The formation of the light gray sodium amide is usually complete within 20 minutes and may be observed by washing a portion of the outside of the flask with a little alcohol.
4. A commercial grade of indole is satisfactory.
5. The checkers removed the ammonia by distillation (water aspirator).
6. The checkers extracted with two 50-ml. portions of ether and three 50-ml. portions of water.
3. Discussion
1-Methylindole has been prepared from the as-methylphenylhydrazone of pyruvic acid,3 by the action of sodium amide or sodium hydride on indole followed by methyl iodide at elevated temperatures,4,5 by treatment of indole with methyl p-toluenesulfonate and anhydrous sodium carbonate in boiling xylene,6 and by the action of methyl sulfate on indole previously treated with sodium amide in liquid ammonia.7 The present method is essentially that of Potts and Saxton.8
1-Methylindole has also been prepared by lithium aluminum hydride reduction of 1-methylindoxyl.9 Compounds giving rise to NH absorption in the infrared (indole, skatole) can be completely removed10 by refluxing the crude 1-methylindole over sodium for 2 days and then distilling the unreacted 1-methylindole from the sodio derivatives and tarry decomposition products.
This preparation is referenced from:
References and Notes
  1. Department of Organic Chemistry, University of Adelaide, Adelaide, South Australia.
  2. E. B. Hershberg, Ind. Eng. Chem., Anal. Ed., 8, 313 (1936).
  3. E. Fischer and O. Hess, Ber., 17, 559a (1884).
  4. R. Weissgerber, Ber., 43, 3522 (1910).
  5. A. P. Gray, J. Am. Chem. Soc., 75, 1253 (1953).
  6. D. A. Shirley and P. A. Roussel, J. Am. Chem. Soc., 75, 375 (1953).
  7. H. Plieninger, Ber., 87, 127 (1954).
  8. K. T. Potts and J. E. Saxton, J. Chem. Soc., 2641 (1954).
  9. P. L. Julian and H. C. Printy, J. Am. Chem. Soc., 71, 3206 (1949).
  10. W. E. Noland, W. C. Kuryla, and R. F. Lange, J. Am. Chem. Soc., 81, 6015 (1959).

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

as-methylphenylhydrazone of pyruvic acid

1-methylindoxyl

ammonia (7664-41-7)

ether (60-29-7)

sodium carbonate (497-19-8)

sodium sulfate (7757-82-6)

sodium (13966-32-0)

xylene (106-42-3)

Methyl iodide (74-88-4)

methyl sulfate (75-93-4)

sodium amide (7782-92-5)

lithium aluminum hydride (16853-85-3)

sodium hydride (7646-69-7)

Indole (120-72-9)

1-Methylindole,
Indole, 1-methyl- (603-76-9)

skatole (83-34-1)

ferric nitrate nonahydrate (7782-61-8)

Methyl p-toluenesulfonate (80-48-8)

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