Org. Synth. 1987, 65, 146
DOI: 10.15227/orgsyn.065.0146
4-NITROINDOLE
[Indole, 4-nitro-]
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
1.
2-Methyl-3-nitroaniline and
triethyl orthoformate were purchased from Fluka AG.
2.
Trimethyl orthoformate is not suitable for this preparation because of side-product formation.
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.
4.
The
diethyl oxalate/
potassium ethoxide complex can also be prepared by adding the oxalic ester to an ethanolic solution of
potassium ethoxide and evaporating the solvent. However, this complex is less active and is difficult to store.
5.
Dimethyl sulfoxide (DMSO) prevents precipitation of intermediate salts, which can also be achieved by using a larger volume of
dimethylformamide (DMF) (ca. 200 mL). Attempts to prepare the
diethyl oxalate/
potassium ethoxide complex in DMSO have not been successful (i.e., it is not active).
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.
8.
Crude
4-nitroindole can also be purified by recrystallization from
methanol,
ethanol, or
acetonitrile giving brownish-yellow crystals, mp
204–206°C.
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.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
4-nitroindoles
ethanol (64-17-5)
HCl (7647-01-0)
methanol (67-56-1)
acetonitrile (75-05-8)
potassium (7440-09-7)
triethyl orthoformate (122-51-0)
potassium ethoxide (917-58-8)
dimethylformamide (68-12-2)
diethyl oxalate (95-92-1)
dimethyl sulfoxide (67-68-5)
p-Dimethylaminobenzaldehyde (100-10-7)
p-toluenesulfonic acid (104-15-4)
trimethyl orthoformate (149-73-5)
4-Nitroindole,
Indole, 4-nitro- (4769-97-5)
2-methyl-3-nitroaniline (603-83-8)
Ethyl N-(2-methyl-3-nitrophenyl)formimidate (115118-93-9)
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