Organic Syntheses, CV 8, 493
Submitted by Jan Bergman and Peter Sand
1.
Checked by Cynthia A. Smith and Andrew S. Kende.
1. Procedure
A.
Ethyl N-(2-methyl-3-nitrophenyl)formimidate. A
1-L, one-necked, round-bottomed flask, fitted with a
Claisen condenser protected from moisture with a drying tube, is charged with
200 g (1.35 mol) of freshly distilled triethyl orthoformate,
1 g of p-toluenesulfonic acid and
152 g (1 mol) of 2-methyl-3-nitroaniline (Note
1) and (Note
2). The solution is heated to 120°C and all of the ethanol formed is continuously distilled off during ca. 1 hr. Fractional vacuum distillation of the residue gives at
156–158°C/6 mm, the imidate ester,
184 g (
88%), as a light-yellow, solidifying oil, mp
57–58°C.
B.
4-Nitroindole. To a solution of
22 g (0.15 mol) of diethyl oxalate in
50 mL of dry dimethylformamide in a
200-mL beaker is added, under cooling,
11 g (0.13 mol) of potassium ethoxide with vigorous stirring (Note
3) and (Note
4). The solution is immediately (within a few seconds) poured into a
250-mL flask containing a solution of
20.8 g (0.10 mol) of ethyl N-(2-methyl-3-nitrophenyl)formimidate in 75 mL of dry dimethyl sulfoxide (Note
5). The resulting deep-red solution is stirred for 1 hr at ca. 40°C (Note
6) and (Note
7). The solution is then transferred into a
1-L beaker and water is added under stirring at a rate that gives smooth precipitation of
4-nitroindole. The product is filtered off and dried, giving
16.3 g (ca.
100%) of a brownish-yellow solid, mp
195–201°C [sublimation (subl.)], which is sublimed at 170°C/0.5 mm giving
11.5 g (
71%) of yellow crystals, mp
204–205°C (subl.) (Note
8).
2. Notes
3.
Diethyl oxalate was purchased from Merck and Company, Inc., and was used without further purification.
Potassium ethoxide was purchased from Alfa Products, Johnson Mathey Co. or preferably was prepared from
potassium metal and
absolute ethanol.
6. At elevated temperatures (e.g., above 40°C) by-products are formed.
7. The reaction can be monitored by TLC (CH
2Cl
2). The spots were developed with an ethanolic solution of
p-dimethylaminobenzaldehyde/
HCl. The product gave a bright-red spot at
Rf 0.5, and the imidate ester gave a yellow spot at
Rf 0.6. Addition of small portions of
diethyl oxalate/
potassium ethoxide complex was continued if the starting material was not consumed after the initial reaction period.
3. Discussion
This procedure illustrates the synthesis of
4-nitroindoles; the present method can easily be extended to the 2-alkyl derivatives (using other
ortho esters), 5-, 6- and/or 7-substituted derivatives and 1-alkyl derivatives (from the corresponding
N-alkylanilides).
2,3 Other published preparations of
4-nitroindole (e.g.,
4) are of no practical value.
The mechanism of the formation of
4-nitroindole parallels the Reissert indole synthesis
5 and is discussed in
2 and
3.
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