Organic Syntheses, CV 7, 359
Submitted by Y. Oikawa, T. Yoshioka, K. Sugano, and Osamu Yonemitsu
1.
Checked by Michael J. Taschner, Hans P. Märki, and Clayton H. Heathcock.
1. Procedure
Into a
300-mL, round-bottomed flask equipped with a
dropping funnel and a
magnetic stirrer is placed a solution of
23.75 g (0.165 mol) of recrystallized Meldrum's acid (Note
1) in
65 mL of anhydrous dichloromethane. The flask and its contents are cooled in an
ice bath, and
32.5 mL (0.40 mol) of anhydrous pyridine (Note
2) is added with stirring under an
argon atmosphere over a 10-min period. To the resulting colorless clear solution is added a solution of
25.0 g (0.16 mol) of freshly distilled phenylacetyl chloride (Note
3) in
50 mL of anhydrous dichloromethane over a 2-hr period. After the addition is complete, the resulting orange, cloudy reaction mixture is stirred for 1 hr at 0°C, then for an additional 1 hr at room temperature. The reaction mixture is diluted with
35 mL of dichloromethane, and then poured into
100 mL of 2 N hydrochloric acid containing crushed ice. The organic phase is separated and the aqueous layer extracted twice with
25-mL portions of dichloromethane. The organic phase and the extracts are combined, washed twice with
25-mL portions of 2 N hydrochloric acid and
30 mL of saturated sodium chloride solution, and dried over anhydrous
sodium sulfate. The solvent is removed with a
rotary evaporator to yield an
acyl Meldrum's acid (Note
4) as a pale-yellow solid.
The solid
acyl Meldrum's acid, without purification, is refluxed in
250 mL of anhydrous methanol for 2.5 hr. The solvent is removed with a rotary evaporator, and the residual oil is distilled under reduced pressure to give
25.2 g (
82%) of
methyl phenylacetylacetate as a colorless liquid, bp
126–128°C/(0.6 mm).
2. Notes
3.
Phenylacetyl chloride is supplied by Wako Pure Industries, Ltd. (Japan) and the Aldrich Chemical Company, Inc. It is distilled before use, bp
95–96°C/(12 mm). The checkers found the distilled commercial material to be slightly pink. However, material of this quality gave a good yield of pure product.
4. The product,
2,2-dimethyl-5-phenylacetyl-1,3-dioxane-4,6-dione, is isolated in its enol form in
97% yield. If desired, it may be further purified by recrystallization from
ether–hexane to give pale-yellow prisms, mp
96–97°C (dec). The checkers recrystallized the material from
dichloromethanehexane and obtained
65% yield of material, mp
94–96°C (dec) and
7%, mp
84–90°C. The
1H NMR spectrum of this compound has absorptions at δ 1.65 (s, 6 H), 4.30 (s, 2 H), 7.20 (s, 5 H), and 15.0 (br s, 1 H).
3. Discussion
Because β-keto esters are among the most important intermediates in organic synthesis, many methods have been developed for their synthesis.
3 However, it is still desirable to have a general and practical method for preparation of β-keto esters of the general type RCOCH
2CO
2R', and thence by alkylation with alkyl halides compounds of the type RCOCHR''CO
2R'.
4 The available synthetic methods can be classified broadly in three categories: those involving acetoacetic esters,
5 those involving mixed malonic esters,
6 and those involving
malonic acid half esters.
7 The procedure described herein
8 may be classified as one of the malonic ester methods. The procedure consists of two simple steps and utilizes readily accessible starting materials. When the carboxylic acid chloride is not available, the carboxylic acid may be condensed with
Meldrum's acid in the presence of a condensing agent such as
ethyl phosphorocyanidate.
9
Methanolysis or ethanolysis of an
acyl Meldrum's acid is performed simply by refluxing in
methanol or
ethanol solution. The products are methyl or ethyl β-keto esters, and they can usually be purified by distillation. When a higher
ester (such as
benzyl, tert-butyl, or trichloroethyl) is required, it is easily prepared by refluxing the
acyl Meldrum's acid in
benzene containing about 3 equiv of the appropriate alcohol.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
ester
benzyl, tert-butyl, or trichloroethyl
acyl Meldrum's acid
ethanol (64-17-5)
hydrochloric acid (7647-01-0)
Benzene (71-43-2)
methanol (67-56-1)
ether (60-29-7)
acetonitrile (75-05-8)
sodium chloride (7647-14-5)
sodium sulfate (7757-82-6)
acetone (67-64-1)
pyridine (110-86-1)
dichloromethane (75-09-2)
Malonic acid (141-82-2)
phenylacetyl chloride (103-80-0)
hexane (110-54-3)
calcium hydride (7789-78-8)
CARBONYLDIIMIDAZOLE
argon (7440-37-1)
p-Nitrobenzyl alcohol (619-73-8)
Methyl phenylacetylacetate,
Benzenebutanoic acid, β-oxo-, methyl ester (37779-49-0)
2,2-dimethyl-1,3-dioxane-4,6-dione,
MELDRUM'S ACID (2033-24-1)
2,2-Dimethyl-5-phenylacetyl-1,3-dioxane-4,6-dione
dichloromethanehexane
ethyl phosphorocyanidate
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