Checked by Christina M. J. Fox and James D. White.
1. Procedure
A.
Ethyl α-(hydroxymethyl)acrylate. (See (Note
1)). A
1000-mL, four-necked, round-bottomed flask is fitted with
mechanical stirrer,
250-mL equalizing funnel,
condenser, and
thermometer.
Paraformaldehyde (48 g,
1.6 mol), 1 N phosphoric acid (4 mL), and water (110 mL) are heated at 90°C for 1.5 hr to form a clear aqueous
formaldehyde solution. This solution is cooled to room temperature.
Triethyl phosphonoacetate (89.6 g, 0.4 mol) is added to the flask and the solution is stirred at room temperature at 1000 rpm. A solution of
potassium carbonate (60.7 g, 0.44 mol) in water (60 mL) is added at room temperature (first slowly: 10 mL in 10 min) and then more rapidly (40 min). The temperature reaches 35–40°C and must be maintained at this level (with a
water bath if necessary). Stirring is continued for 5 min at 40°C after the end of the addition; then the mixture (liquid–liquid heterogenous mixture) must be cooled rapidly to room temperature using an
ice bath (Note
2) while
diethyl ether (200 mL) and
brine (150 mL) are added. After decantation, the mixture is extracted with
ether (three 100-mL portions). The combined organic layers are washed with
brine (two 100-mL portions) (Note
3) and dried over
magnesium sulfate; the solvents are evaporated under reduced pressure and the remaining oil is distilled to give a fraction at
65–70°C (1 mm) that weighs
38.5–41.6 g (
74–80%),
nD20 1.4494. The hydroxy ester is of high purity as shown by GLC analysis (
25-m silica capillary OV-1 column) and spectral data (Note
4) and (Note
5).
2. Notes
1. All manipulations should be carried out in a
well-ventilated hood. The preparation requires the use of
formaldehyde solution and gives rise to ethyl acrylate as a secondary product, the amount of which increases if the addition of the carbonate solution, is too rapid and the temperature rises to 45°C. A freshly opened supply of
paraformaldehyde purchased from Aldrich Chemical Company, Inc. was used by the checkers. The use of commercial
formaldehyde solutions that now contain up to
15% methanol leads to the formation of several by-products that cannot be separated by distillation from the α-(hydroxymethyl)acrylate.
2. This experimental procedure must be followed carefully to avoid partial decomposition of
ethyl α-(hydroxymethyl) acrylate. The reaction is stopped rapidly after the addition of the carbonate solution (5 min) to prevent formation of high molecular weight by-products which result from transesterification and Michael addition, both of which occur in the basic medium. However, about 25% of the product is lost. Addition of
diethyl ether during cooling minimizes side reactions.
3. Treatment with brine allows total elimination of base in the organic layer and prevents any side reaction during the distillation.
4. The spectral properties of
ethyl α-(hydroxymethyl) acrylate are as follows:
1H NMR (CCl
4) δ: 4.20 (2 H, CH
2-OH), 5.80 and 6.15 (2 H, CH
2=);
13C NMR (CDCl
3) δ: 60.9 (CH
2OH), 124.8 (CH
2=C), 140.2 (CH
2=C), 166.5 (COOEt).
5. α-(Bromomethyl)-, α-(chloromethyl)-, α-(iodomethyl)-, and α-(fluoromethyl)acrylates are easily obtained from the α-(hydroxymethyl)acrylate
2 as illustrated in the following procedure.
A
500-mL, four-necked, round-bottomed flask is fitted with a mechanical stirrer, a
100-mL pressure-equalizing addition funnel, a
reflux condenser capped with a drying tube (silica gel), and a thermometer (range −90° to +60°C). The flask is charged with a stirred solution of
ethyl α-(hydroxymethyl)acrylate (33.84 g, 0.26 mol) in dry
ether (250 mL) at −10°C.
Phosphorus tribromide (34 g, 11.5 mL, 0.12 mol) is added slowly (15 min). The temperature is allowed to rise to 20°C and stirring is continued for 3 hr. Water (150 mL) is added at −10°C and the mixture is extracted with
technical-grade hexane (three 50-mL portions). The organic phase is washed twice with a saturated
sodium chloride solution (50 mL) and dried over
magnesium sulfate. The solvents are removed with a
rotary evaporator under reduced pressure, and the remaining oil is distilled to give
ethyl α-(bromomethyl)acrylate, bp
85–87°C (20 mm), which weighs
43.8 g (
87%),
nD20 1.4502. The ester is of high purity as shown by GLC analysis on a capillary OV-1 column, and spectral data.
The spectral properties of
ethyl α-(bromomethyl)acrylate are as follows:
1H NMR (CCl
4) δ: 4.15 (2 H, CH
2Br), 5.90 and 6.22 (2 H, H
2C=);
13C NMR (CDCl
3) δ: 29.2 (CH
2Br), 126.5 (CH
2=C), 137.8 (CH
2=C), 164.5 (COOEt).
3. Discussion
Ethyl α-(bromomethyl)acrylate has been used extensively for the synthesis of α-methylene lactones from ketones and aldehydes,
7 and α-methylene lactams, which are known for their cytotoxic activity,
7,8,9 from imines.
8
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