Org. Synth. 1971, 51, 100
DOI: 10.15227/orgsyn.051.0100
ETHYL PYRROLE-2-CARBOXYLATE
[1H-Pyrrole-2-carboxylic acid, ethyl ester]
Submitted by Denis M. Bailey, Robert E. Johnson, and Noel F. Albertson
1.
Checked by A. Brossi and P. Wehrli.
1. Procedure
A. 2-Pyrrolyl trichloromethyl ketone. A 3-l., three-necked, round-bottomed flask equipped with a sealed mechanical stirrer, a dropping funnel, and an efficient reflux condenser with a calcium chloride drying tube is charged with 225 g. (1.23 moles) of trichloroacetyl chloride and 200 ml. of anhydrous diethyl ether. The solution is stirred while 77 g. (1.2 moles) of freshly distilled pyrrole in 640 ml. of anhydrous ether is added over 3 hours (Note 1); the heat of reaction causes the mixture to reflux. Following the addition, the mixture is stirred for 1 hour before 100 g. (0.724 mole) of potassium carbonate in 300 ml. of water is slowly added through the dropping funnel (Note 2). The layers are separated, and the organic phase is dried with magnesium sulfate, treated with 6 g. of Norit, and filtered. The solvent is removed by distillation on a steam bath, and the residue is dissolved in 225 ml. of hexane. The dark solution is cooled on ice to induce crystallation. The tan solid is collected and washed with 100 ml. of cold hexane, giving 189–196 g. (77–80%) of the ketone, m.p. 73–75° (Note 3).
B. Ethyl pyrrole-2-carboxylate. A 1-l., three-necked, round-bottomed flask equipped with a sealed mechanical stirrer and powder funnel is charged with 1.0 g. (0. 44 g.-atom) of sodium and 300 ml. of anhydrous ethanol. When the sodium is dissolved, 75 g. (0.35 mole) of 2-pyrrolyl trichloromethyl ketone is added portionwise over a 10-minute period (Note 4). Once the addition is complete, the solution is stirred for 30 minutes, then concentrated to dryness using a rotary evaporator. The oily residue is partitioned between 200 ml. of ether and 25 ml. of 3 N hydrochloric acid. The ether layer is separated, and the aqueous layer is washed once with 100 ml. of ether. The combined ether solutions are washed once with 25 ml. of saturated sodium hydrogen carbonate solution, dried with magnesium sulfate, and concentrated by distillation. The residue is fractionated at reduced pressure, giving 44.0–44.5 g. (91–92%) of ethyl pyrrole-2-carboxylate as a pale yellow oil, b.p. 125–128° (25 mm.) (Note 5). The yield based on pyrrole is 70–74%. Upon standing at room temperature the product crystallizes, m.p. 40–42°.
2. Notes
1.
If the addition time is shortened to 1 hour, the yield is decreased by about 5%.
2.
Excessive frothing will occur if the
potassium carbonate solution is added too fast.
3.
A similar run on a scale 3.3 times as large with a 3-hour addition time gave the ketone in 74% yield.
4.
The solution becomes warm during the addition, and the final color of the solution is reddish-brown.
5.
A similar run on a scale three times as large gave the ester in
96% yield.
3. Discussion
Pyrrole-2-carboxylic acid esters have been prepared from
ethyl chloroformate and
pyrrolylmagnesium bromide2 or
pyrrolyllithium,
3 by hydrolysis and decarboxylation of
dimethyl pyrrole-1,2-dicarboxylate followed by re-esterification of the 2-acid
4 and by oxidation of
pyrrole-2-carboxaldehyde followed by esterification with
diazomethane.
4
Methods of acylating
pyrrole similar to the present, using
oxalyl chloride,
5 trifluoroacetic anhydride,
6 carbamic acid chloride,
7 and
trichloroacetyl chloride,
8 have been reported. In the last preparation, it was necessary to separate the product from highly colored by-products with alumina chromatography.
2-Pyrrolyl trichloromethyl ketone has also been prepared by the reaction of pyrrolylmagnesium halide with
trichloroacetyl chloride.
9The present procedure provides a facile and versatile synthesis, on large scale, of a variety of pyrrole-2-carboxylic acid derivatives without necessitating the use of moisture-sensitive organometallic reagents. The use of alcohols other than ethanol in the alcoholysis reaction provides virtually any desired ester. Ammonia or aliphatic amines readily give amides in high yields, and aqueous base can be used to give the free acid.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
ethanol (64-17-5)
potassium carbonate (584-08-7)
hydrochloric acid (7647-01-0)
ammonia (7664-41-7)
ether,
diethyl ether (60-29-7)
sodium hydrogen carbonate (144-55-8)
sodium (13966-32-0)
ethyl chloroformate (541-41-3)
Pyrrole (109-97-7)
magnesium sulfate (7487-88-9)
Diazomethane (334-88-3)
carbamic acid chloride
oxalyl chloride (79-37-8)
hexane (110-54-3)
Pyrrole-2-carboxaldehyde (1003-29-8)
trifluoroacetic anhydride (407-25-0)
trichloroacetyl chloride (76-02-8)
Ethyl pyrrole-2-carboxylate,
1H-Pyrrole-2-carboxylic acid, ethyl ester (2199-43-1)
2-pyrrolyl trichloromethyl ketone (35302-72-8)
Pyrrole-2-carboxylic acid (634-97-9)
pyrrolylmagnesium bromide
pyrrolyllithium
dimethyl pyrrole-1,2-dicarboxylate
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