A Publication
of Reliable Methods
for the Preparation
of Organic Compounds
Annual Volume
Org. Synth. 1974, 54, 60
DOI: 10.15227/orgsyn.054.0060
[1H-Indole, 1-(phenylmethyl)-]
Submitted by George M. Rubottom1 and John C. Chabala2.
Checked by R. E. Ireland and James E. Kleckner.
1. Procedure
Caution! Hexamethylphosphoric triamide (HMPA) vapors have been reported to cause cancer in rats.3 All operations with hexamethylphosphoric triamide should be performed in a good hood, and care should be taken to keep the liquid off the skin.
A 100-ml., three-necked flask fitted with a reflux condenser, a magnetic stirring bar, and a gas-inlet tube is charged with 2.34 g. (0.0200 mole) of indole (Note 1) and 15 ml. of hexamethylphosphoric triamide (Note 2) under a static atmosphere of argon. The flask is cooled to 0° with an ice bath, and 0.53 g. (0.022 mole) of sodium hydride is added to the stirred solution over a period of 10 minutes (Note 3). The resulting slurry is stirred for 5 hours at room temperature (Note 4) then cooled to 0° (ice bath) before 2.53 g. (2.30 ml., 0.0200 mole) of benzyl chloride (Note 5) is added as rapidly as possible to the stirred mixture. The mixture is stirred for 8–15 hours (overnight), during which time the ice in the ice bath melts, and the temperature of the reaction flask gradually rises to room temperature. The mixture is then diluted with 15 ml. of water and extracted with three 25-ml. portions of diethyl ether. The combined ethereal extracts are washed with two 40-ml. portions of water and dried with anhydrous magnesium sulfate. After filtration the solvent is removed at reduced pressure, and 4.4 g. of crude 1-benzylindole is obtained as a liquid. After bulb-to-bulb distillation of this material in a Kügelrohr oven [120–130° (0.0025 mm.)], crystallization of the distillate from 15 ml. of hot ethanol affords 3.46–3.61 g. (83–87%) of 1-benzylindole. A second crop of 0.17–0.26 g. (4–6%) is obtained on concentration of the mother liquors to 6 ml. The total yield of 1-benzylindole, m.p. 43–44°, is 3.72–3.78 g. (90–91%) (Note 6) and (Note 7).
2. Notes
1. Commercial indole (Matheson, Coleman and Bell) was used with no further purification.
2. Commercial HMPA (Aldrich) was stored over Linde 4 A Molecular Sieves and used without further purification.
3. A batch of 0.93 g. of a 57% sodium hydride dispersion in mineral oil is washed with hexane to remove the mineral oil immediately prior to use. The slow addition in the cold minimizes the small amount of foaming caused by hydrogen evolution.
4. This stirring time insures complete formation of sodium indolide.
5. Commercial benzyl chloride (Matheson, Coleman and Bell) was used without further purification.
6. The recrystallized product has 1H NMR absorptions (CDCl3) at δ 5.21 (s, 2H), 6.52 (d, J = 3.4 Hz., 1H), 7.0–7.4 (m, 9H), and 7.5–7.7 (m, 1H).
7. 1-Benzylindole colors significantly in contact with air at room temperature (ca. 1 week), but keeps indefinitely under argon.
3. Discussion
Generally, the alkylation of sodium indolide, generated from indole and sodium amide in liquid ammonia, has been used for the preparation of N-alkylindoles.4,5,6,7,8,9,10,11,12 The drawback to this method is the use of liquid ammonia. The procedure outlined here13 overcomes this problem and affords pure N-alkylindoles in excellent yields. Further, the use of the hexamethylphosphoric triamidesodium hydride system affords conditions leading to the formation of the N-alkylindoles with little or no side reaction leading to C-alkylated products.13,14 Table I illustrates the generality of the method.


Yield of N-Alkylindole, %

b.p. or m.p.



b.p. 73–75°/2.4 mm. (Ref. 15, b.p. 70–75/2 mm.)



b.p. 83–86°/0.6 mm. (Ref. 16, b.p. 82–85°/0.7 mm.)



b.p. 72–73°/0.12 mm. (Ref. 7, b.p. 114–116°/6 mm.)



m.p. 43–44° (Ref. 6, m.p. 44°)

References and Notes
  1. Department of Chemistry, University of Puerto Rico, Rio Piedras, Puerto Rico 00931. [Present address: Department of Chemistry, University of Idaho, Moscow, Idaho 83843.]
  2. Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065.
  3. J. A. Zapp, Science, 190, 422 (1975).
  4. K. T. Potts and J. E. Saxton, J. Chem. Soc., 2641 (1954).
  5. K. T. Potts and J. E. Saxton, Org. Synth., Coll. Vol. 5, 769 (1973).
  6. H. Plieninger, Chem. Ber., 87, 127 (1954).
  7. M. Nakazaki and S. Isoe, Nippon Kagaku Zasshi, 76, 1159 (1955); Chem. Abstr., 51, 17877.
  8. M. Nakazaki, Bull. Chem. Soc. Jpn., 32, 838 (1959).
  9. N. I. Grineva, V. L. Sadovskaya and V. N. Ufimtsev, Zh. Obshch. Khim., 33, 552 (1963).
  10. M. Julia and P. Manoury, Bull. Soc. Chim. Fr., 1946 (1964).
  11. S. Yamada, Chem. Pharm. Bull. (Tokyo), 13, 88 (1965).
  12. A. H. Jackson and A. E. Smith, Tetrahedron, 21, 989 (1965).
  13. Essentially the procedure outlined in G. M. Rubottom and J. C. Chabala, Synthesis, 566 (1972).
  14. B. Cardillo, G. Casnati, A. Pochini, and R. Ricca, Tetrahedron, 23, 3771 (1967).
  15. L. Marion and C. W. Oldfield, Can. J. Res. B, 25, 1 (1947).
  16. A. P. Gray, H. Kraus, and D. E. Heitmeier, J. Org. Chem., 25, 1939 (1960).

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

ethanol (64-17-5)

ammonia (7664-41-7)

diethyl ether (60-29-7)

hydrogen (1333-74-0)

benzyl chloride (100-44-7)

magnesium sulfate (7487-88-9)

sodium amide (7782-92-5)

sodium hydride (7646-69-7)

Indole (120-72-9)

hexane (110-54-3)

argon (7440-37-1)

hexamethylphosphoric triamide (680-31-9)

1H-Indole, 1-(phenylmethyl)- (3377-71-7)