Organic Syntheses, CV 6, 618
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%.
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
The 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.
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