Org. Synth. 1960, 40, 21
DOI: 10.15227/orgsyn.040.0021
DIETHYL ACETAMIDOMALONATE
[Malonic acid, acetamido-, diethyl ester]
Submitted by Arthur J. Zambito and Eugene E. Howe
1.
Checked by John C. Sheehan and Alma M. Boston.
1. Procedure
A. Diethyl isonitrosomalonate. In a 500-ml. three-necked, round-bottomed flask, equipped with a mechanical stirrer and thermometer, is placed 50 g. (47.4 ml., 0.312 mole) of diethyl malonate. The flask is cooled in an ice bath, and a mixture of 57 ml. of glacial acetic acid and 81 ml. of water is added with stirring. With the temperature at about 5°, a total of 65 g. of sodium nitrite (Note 1) (0.944 mole) is added in portions over a period of 1.5 hours, the temperature being maintained around 5° during the addition. After all the sodium nitrite is added, the ice bath is removed, and the stirring is continued for 4 hours (Note 2). During this time, the temperature reaches a maximum of 34–38° within 2 hours and falls to about 29° by the end of the stirring period. Gases which escape during the reaction (mostly oxides of nitrogen) are led to the hood.
The reaction mixture is transferred to a 300-ml. separatory funnel and is extracted with two 50-ml. portions of ether. The combined ethereal solution of diethyl isonitrosomalonate is used in the next step immediately or, if desired, may be used after storage in a refrigerator overnight (Note 3).
B. Diethyl acetamidomalonate. The solution of diethyl isonitrosomalonate described above, 86 g. (0.842 mole) of acetic anhydride, and 225 ml. (3.95 moles) of glacial acetic acid are placed in a 1-l., three-necked, round-bottomed flask fitted with a mechanical stirrer, a thermometer, and a dropping funnel. With vigorous stirring 78.5 g. (1.20 moles) of zinc dust is added in small portions over a period of 1.5 hours in such a manner that the temperature of the reaction is maintained at 40–50°. The reaction is markedly exothermic during most of the zinc addition, and intermittent cooling (water bath) is required. After all the metal has been added, the mixture is stirred for an additional 30 minutes.
The reaction mixture is filtered with suction and the cake is washed thoroughly with two 200-ml. portions of glacial acetic acid (Note 4). The combined filtrate and washings are evaporated under reduced pressure on the steam bath until a thick oil, which generally partially crystallizes, remains. To purify the crude product, 100 ml. of water is added, and the flask is warmed on a steam bath until the solid melts. The mixture of water and oil is stirred rapidly in an ice bath, and diethyl acetamidomalonate crystallizes as a fine white product. After cooling in an ice bath for an additional hour, the product is collected by filtration, washed once with cold water, and dried in air at 50°. A second crop is obtained by concentrating the mother liquor under reduced pressure. The yield of diethyl acetamidomalonate, m.p. 95–97° (Note 5), is 52–53 g. (77–78%) based on malonic ester.
2. Notes
1.
Owing to the instability of
sodium nitrite solutions, the addition of the solid salt is preferred.
2.
Prolonging the stirring to 24 hours has no effect on the yield of
diethyl acetamidomalonate.
3.
No attempt has been made to purify
diethyl isonitrosomalonate. This product has been known to explode during distillation.
4.
The
zinc cake is very heavy and may be washed by slurrying on a
sintered-glass funnel or, if a standard
Büchner funnel is used, by removing and slurrying in a
beaker.
5.
The
diethyl acetamidomalonate obtained is of high purity. If a product of inferior quality is obtained, it may be recrystallized from hot water, using 2.5 cc. per g. Upon cooling, the product separates first as an oil. With rapid stirring, it is converted to fine white crystals which are easily washed with cold water.
Diethyl acetamidomalonate may be recrystallized in this manner with
97% recovery. The first crop amounts to
91% and the mother liquors may be concentrated to yield an additional
6%.
3. Discussion
Diethyl acetamidomalonate was first reported by Cherchez
2 in 1931, when in an attempt to carry out a carbon alkylation of
diethyl aminomalonate with
acetyl chloride he obtained a quantitative yield of
diethyl acetamidomalonate. This method of preparation, however, is not practical since
diethyl aminomalonate is unstable and is made in relatively poor yields.
Snyder and Smith
3 prepared
diethyl acetamidomalonate in
40% yield by reduction of
diethyl isonitrosomalonate in
ethanol over
palladium on charcoal followed by direct acetylation of
diethyl aminomalonate in the filtrate with
acetic anhydride. Ghosh and Dutta
4 used
zinc dust instead of
palladium. A modification using
Raney nickel is described by Akabori et al.
5 Shaw and Nolan
6 reported a
98% yield by conversion of
diethyl oximinomalonate-sodium acetate complex.
4. Use of Diethyl Acetamidomalonate
Diethyl acetamidomalonate is useful in the synthesis of α-amino acids by alkylation, as, for example, histidine and tryptophan.
This preparation is referenced from:
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
oxides of nitrogen
diethyl oximinomalonate-sodium acetate complex
ethanol (64-17-5)
acetic acid (64-19-7)
ether (60-29-7)
acetic anhydride (108-24-7)
acetyl chloride (75-36-5)
sodium nitrite (7632-00-0)
Raney nickel (7440-02-0)
zinc (7440-66-6)
palladium (7440-05-3)
diethyl malonate (105-53-3)
histidine (71-00-1)
tryptophan (73-22-3)
Diethyl acetamidomalonate,
Malonic acid, acetamido-, diethyl ester (1068-90-2)
diethyl isonitrosomalonate (6829-41-0)
diethyl aminomalonate (6829-40-9)
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