Organic Syntheses, CV 7, 210
Submitted by K. Ramarajan, K. Ramalingam, D. J. O'Donnell, and K. D. Berlin
1.
Checked by H. S. Shou, E. Tsou, R. A. Hayes, and Orville L. Chapman.
1. Procedure
Caution! Ethyl α-(bromomethyl) acrylate is a potent vesicant and lachrymator and should be handled with care. All operations should be carried out in an efficiently ventilated hood in order to avoid contact.
A.
α-(Bromomethyl)acrylic acid. A
500-mL, three-necked, round-bottomed flask is equipped with a
magnetic stirrer,
fraction collector,
cold-finger condenser, and
two thermometers. Into the flask are placed
55.0 g (0.25 mol) of diethyl bis(hydroxymethyl)malonate (Note
1) and
142 mL (1.25 mol) of 47–49% hydrobromic acid (Note
2). The mixture is then heated and the temperature of the liquid maintained between 85 and 90°C. A mixture of
ethyl bromide and water distills during the course of 1.5–2 hr. The residue is then boiled for 10 hr, maintaining the temperature between 85–90°C (Note
3). At the end of this period, the mixture is concentrated on a
rotary evaporator at 65–70°C (10–15 mm). About 100 mL of water is removed. The residue is cooled in the
refrigerator overnight. Crystals of
α-(bromomethyl)acrylic acid are filtered in the cold (Note
4) to give, after drying (Note
5),
17.9 g (
43%) of acid, mp
71–73°C (Note
6).
B.
Ethyl α-(bromomethyl)acrylate. In a
nitrogen-flushed, 1-L, round-bottomed flask equipped with a magnetic stirrer,
Dean-Stark trap, and condenser are placed
42.0 g (0.25 mol) of α-(bromomethyl)acrylic acid and
300 mL of benzene. Approximately 50 mL of a binary azeotrope of
benzene and water is distilled (Note
7). The Dean-Stark trap is removed and
100 mL of absolute ethanol (Note
8) and
1 mL of concentrated sulfuric acid are added slowly. The contents of the flask are boiled in a
nitrogen atmosphere for 36 hr, the condensate being passed through 100 g of molecular sieves (Linde 3A) before being returned to the flask. About
125 mL of a mixture of benzene and ethanol is removed from the reaction mixture by distillation (at 67°C). Then
100 mL of benzene is added and another
125 mL of benzene-ethanol mixture distilled (67–75°C). The residue is poured into 200 mL of water and neutralized with solid
sodium bicarbonate (ca. 10–15 g) until
CO2 evolution ceases. The resulting solution is extracted with three
75-mL portions of ether, and the combined extracts are dried over anhydrous
sodium sulfate for 3 hr. The
ether is removed under reduced pressure in a rotary evaporator, and crude ester distilled to give a fraction at
39–40°C (0.9 mm) that weighs
33–34 g (
71%). The ester is of high purity, as evidenced by spectral analysis (Note
9).
2. Notes
1. The checkers prepared this ester on a 0.7-mol scale by a modification of the previously published method.
2 The modification was effected as follows. The ethereal extract from the
formaldehyde-diethyl malonate reaction, after drying over
sodium sulfate for 3 hr, was concentrated in a rotary evaporator and the residue was stored in a refrigerator overnight. The crude ester was obtained as white crystals, mp
47–50°C; yield
85.6%. The checkers found that the ester prepared in this manner gave superior yields of the
acrylic acid.
5. The compound was air-dried for 3 days at room temperature.
6. The product was almost pure. It could be recrystallized from
Skelly-solve-B (bp
60–80°C) and further purified by sublimation, mp
73–75°C (Anal. calcd. for C
4H
5BrO
2: C, 29.12; H, 3.05. Found: C, 29.07; H, 3.10). IR (KBr) cm
−1: 1689 (C=O), 1626 (C=CH
2),
1H NMR (CDCl
3) δ: 4.18 (s, 2 H, H
a), 6.09 (s, 1 H, H
b), 6.49 (s, 1 H, H
c).
7. There was only about 1 mL of water in the distillate.
9. The spectral properties of
ethyl α-(bromomethyl)acrylate are as follows:
1H NMR (CDCl
3) δ: 1.26–1.40 (t, 3 H, H
a), 4.16–4.38 (quintet, 2 H, H
b), 4.19 (s, 2 H, H
c), 5.96 (s, 1 H, H
D), 6.32 (s, 1 H, H
e).
3. Discussion
The procedure described here is a modification of that of Ferris.
3 The overall yield has been increased from
17 to 30% by making changes as indicated in (Note
2) and (Note
3). In addition, the number of stages in the preparation of
ethyl α-(bromomethyl)acrylate from
diethyl malonate has been reduced from four to three.
Ethyl α-(bromomethyl)acrylate has proved to be an excellent reagent for conversion of aldehydes and ketones, both acyclic and cyclic, into the corresponding α-methylene-γ-butyrolactone derivatives
4,5,6,7,8,9 in a Reformatsky type reaction. The yield was excellent in the case of several
spiro α-methylene-γ-butyrolactones.
10 Synthetic α-methylene-γ-butyrolactone derivatives have been shown to possess antitumor activity.
5,6,7,11,12,13 Ethyl α-(bromomethyl)acrylate has also proven of value in the synthesis of alkylated products of
enol ethers of cyclohexane-1,3-dione.
14
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