Organic Syntheses, CV 5, 794
Submitted by H. Bredereck
1
Checked by Max Tishler, G. A. Stein, W. F. Jankowski, and J. ten Broeke.
1. Procedure
A
2-l. three-necked flask is equipped with a stirrer, a thermometer, an addition funnel, and a wide-bore reflux condenser (Note
1). A
second condenser set downward for distillation is connected to the top of the reflux condenser by means of a head provided with a thermometer well. The thermometer well should be positioned in the connecting head in such a manner that the
thermometer gives the temperature at the head of the reflux condenser.
Caution! The flask should be in a hood so that the carbon monoxide evolved cannot be a hazard.
The three-necked flask is charged with
750 ml. of formamide, 25 ml. of water, and
50 g. of ammonium chloride (Note
2). The mixture is heated to 180–190° in an
oil bath, and
400 g. (3.02 moles) of 4,4-dimethoxy-2-butanone (Note
3) is added dropwise with stirring over the course of 6 hours (Note
4). The flow of cooling water in the reflux condenser should be adjusted to a rate such that the
methanol and
methyl formate formed during the reaction distil out (Note
5). After all the acetal has been added, heating is continued for 1 hour (Note
6). The mixture is allowed to cool and is poured into
1 l. of 1N sodium hydroxide. The resultant solution is extracted with
chloroform in a
liquid-liquid extractor for 24 hours. The
chloroform is separated, dried over
sodium sulfate, and removed by distillation through a
short column on a
steam bath.
The residue is distilled under reduced pressure, and all the distillate boiling at 60–80°/15 mm. is collected (Note
7) and (Note
8). Pure
4-methylpyrimidine is obtained by redistillation through a short column at atmospheric pressure; b.p.
140–142°;
nD25 1.4936; weight
153–180 g. (
54–63%).
2. Notes
1. A wide-bore condenser is employed to prevent clogging of the tube by ammonium salts that may sublime from the reaction mixture (Note
5). A
Liebig condenser is most suitable because it can be cleaned from the top with a rod or wire during the reaction.
3.
4,4-Dimethoxy-2-butanone from Chemische Werke Huls, Huls, Germany, was used by the submitter. The checkers used
4,4-dimethoxy-2-butanone (practical grade) from Eastman Organic Chemicals Co., Rochester, New York; it was 95% pure by vapor-phase chromatography.
4. The checkers found that, during the course of the addition, the internal temperature fell from 190° to 140°.
5. The checkers found that, if the temperature at the head of the
reflux condenser is kept at 50–55°, no ammonium salts collect in the condenser and, therefore, there is no problem of clogging.
6. The checkers found that the temperature of the reaction mixture remains at 140° during the additional hour of heating.
7. It is advisable to carry out a vacuum distillation prior to the final distillation because the tarry residues obtained by distillation at atmospheric pressure retain a considerable amount of product.
8. The checkers collected their product at
50–70°/30 mm.
3. Discussion
4. Merits of the Preparation
The present one-step procedure for making
4-methylpyrimidine is simpler and easier than the three-step method used in the past. The present procedure and modifications of it have been used to make a variety of 4- and 4,6-substituted pyrimidines.
2,5
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved