Organic Syntheses, CV 6, 104
Submitted by Harry Heaney
1 and Steven V. Ley.
Checked by A. Brossi, E. E. Garcia, and R. P. Schwartz.
1. Procedure
A
500-ml. Erlenmeyer flask equipped with a
magnetic stirring bar is charged with
200 ml. of dimethyl sulfoxide (Note
1) and
26.0 g. (0.399 mole) of potassium hydroxide (Note
2). The mixture is stirred at room temperature for 5 minutes before
11.7 g. (0.100 mole) of indole (Note
3) is added. Stirring is continued for 45 minutes before
34.2 g. (0.200 mole) of benzyl bromide (Note
4) is added (Note
5). After being stirred for an additional 45 minutes the mixture is diluted with 200 ml. of water. The mixture is extracted with three
100-ml. portions of diethyl ether, and each
ether layer is washed with three 50-ml. portions of water. The combined
ether layers are dried over
calcium chloride, and the solvent is removed at slightly reduced pressure (Note
6). The excess
benzyl bromide is removed by distillation at approximately 15 mm., and the residue is distilled, yielding
17.5–18.4 g. (
85–89%) of
1-benzylindole, b.p.
133–138° (0.3 mm.). The distillate crystallizes upon cooling and scratching; recrystallization from
ethanol gives material melting at
42–43° (Note
7) and (Note
8).
2. Notes
1. The
dimethyl sulfoxide used was not rigorously dried but should not contain an appreciable amount of water.
3. A
commercial grade of indole is satisfactory.
4.
Reagent grade benzyl bromide was used without further purification.
5. Cooling with an
ice–water bath moderates the exothermic reaction.
6. The submitters used a
Büchi rotary evaporator (
water aspirator).
7. The submitters have obtained yields as high as
20 g. (
97%).
8.
1H NMR (CDCl
3): 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).
3. Discussion
Although the
N-alkylation of
pyrrole2 and
indole3 has been reported on many occasions, a generally applicable, simple, high yield procedure was not available. Many simple procedures give mixtures of products because of the ambident nature of the anions; however, alkylation at
nitrogen is usually predominant in strongly ionizing solvents. Recent methods include alkylations of
indole in
liquid ammonia,
4 N,N-dimethylformamide,
5 and
hexamethylphosphoric triamide.
6
The use of
dimethyl sulfoxide as a dipolar aprotic solvent is well known;
7 the present method can be regarded as a model procedure and has been applied to the preparation of a number of
N-n-alkyl pyrroles and
N-n-alkyl indoles.
8 The yield of
N-benzylindole is considerably higher than in previously reported preparations and is as good as that reported for the preparations of
N-methylindole in liquid
ammonia.
4 The present method is, however, less laborious and quicker. Very high yields are obtained using
n-alkyl halides and moderately good yields with secondary alkyl halides. The reactions may be compared with those recently reported for
pyrrylthallium9
The procedure has been much used for the alkylation of a variety of indoles,
10 including a modification using
sodium methoxide in the methylation of
tetrahydroalstonine.
11 The wide applicability of the method is indicated by the methylation of diarylamines such as
10,11-dihydro-5H-dibenzo[b,f]azepine.
12 An extension to the acylation of indoles has been reported using, for example,
acetic anhydride-KOH in
dimethyl sulfoxide.
13
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