A Publication
of Reliable Methods
for the Preparation
of Organic Compounds
Annual Volume
Org. Synth. 1967, 47, 101
DOI: 10.15227/orgsyn.047.0101
Submitted by G. E. VandenBerg1, J. B. Harrison2, H. E. Carter2, and B. J. Magerlein1.
Checked by William G. Dauben, Noel Vietmeyer, and Steven A. Schmidt.
1. Procedure
A mixture of 537 g. (3 moles) of hippuric acid (Note 1) and 1.6 l. (17 moles) of acetic anhydride is prepared in a 3-l. three-necked, round-bottomed flask fitted with a sealed stirrer, a reflux condenser with a drying tube, a thermometer, and a nitrogen inlet tube (Note 2).
In a nitrogen atmosphere the reaction mixture is heated to 80° on a water bath over a period of 40 minutes with stirring. The solids slowly dissolve, and a yellow-orange solution results (Note 3). The reaction mixture is cooled to 5°, and the reflux condenser is turned downward for distillation. The condenser is cooled with a circulating fluid maintained at −20° to −40° (Note 4). The receiver is immersed in dry ice and acetone. At 1–3 mm. pressure, 1.5 l. of distillate is collected while the distillation flask is kept in a water bath maintained at 50° (Note 5). A capillary tube is used to bubble nitrogen through the reaction mixture to ensure good agitation. The distillation residue is dissolved in 1 l. of t-butanol, the solution scratched to encourage crystallization, and it is refrigerated overnight. The crystals are collected by filtration (Note 2). The filter cake is washed with a minimum volume of t-butanol and then with Skellysolve B (Note 6) or hexane. The moist cake is slurried with Skellysolve B or hexane under a nitrogen atmosphere (Note 7), filtered, and dried to constant weight under vacuum at ambient temperature. The yield of light buff to yellow crystals, m.p. 89–92°, is 320–328 g. (66–68%).
2. Notes
1. The checkers ran the reaction on one-fifth scale.
2. Exposure to air produces a pink to red product of lower melting point and purity.
3. Temperature control is important in order to obtain a high yield of light-colored product. Prolonged heating at 80° is to be avoided.
4. Acetone, cooled by passing through a copper coil placed in a dry ice-acetone bath, may be circulated through the condenser. If a temperature lower than −40° is used, the distillate will freeze in the condenser.
5. This distillate should be collected within about 1 hour, as longer distillation time diminishes the yield.
6. A saturated hydrocarbon fraction, b.p. 60–71°, available from, the Skelly Oil Company, Kansas City, Missouri.
7. Alternatively, the moist cake may be recrystallized by dissolving in hot t-butanol (about 800 ml.) and diluting with Skellysolve B. The yield is then about 40–50% and the melting point about the same as that of the reslurried product.
3. Discussion
This procedure is a modification of the original method of preparation of 2-phenyl-5-oxazolone3 which has since appeared in the literature in various forms.4,5,6 In addition to the use of acetic anhydride, the cyclization of hippuric acid to 2-phenyl-5-oxazolone has been described using phosphorus tribromide7 and N,N'-dicyclohexylcarbodiimide.8.
4. Merits of the Preparation
This procedure offers a reproducible method for the preparation of 2-phenyl-5-oxazolone, which is not commercially available. It illustrates that strict attention to detail often smooths out an erratic procedure. 2-Phenyl-5-oxazolone is, of course, an important intermediate in the synthesis of α-amino acids and related materials.6

References and Notes
  1. Research Laboratories, The Upjohn Company, Kalamazoo, Michigan.
  2. University of Illinois, Urbana, Illinois.
  3. J. W. Cornforth, in H. T. Clarke, J. R. Johnson, and R. Robinson, "Chemistry of Penicillin," Princeton University Press, Princeton, New Jersey, 1949, p. 778.
  4. M. M. Shemyakin, S. I. Lur'e, and E. I. Rodionovskaya, Zh. Obshch. Khim. 19, 769 (1949) [C.A., 44, 1096 (1950)].
  5. H. E. Carter, J. B. Harrison, and D. Shapiro, J. Am. Chem. Soc., 75, 4705 (1953).
  6. J. M. Stewart and D. W. Woolley, J. Am. Chem. Soc., 78, 5336 (1956).
  7. J. H. Hunter, J. W. Hinman, and H. E. Carter, in H. T. Clarke, J. R. Johnson, and R. Robinson, "Chemistry of Penicillin," Princeton University Press, Princeton, 1949, p. 915.
  8. I. T. Strukov, Zh. Obshch. Khim, 29, 2359 (1959) [C.A., 54, 9889 (1960)].

Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

acetic anhydride (108-24-7)

phosphorus tribromide (7789-60-8)

nitrogen (7727-37-9)

acetone (67-64-1)

Hippuric acid (495-69-2)

hexane (110-54-3)

t-butanol (75-65-0)

N,N'-dicyclohexylcarbodiimide (538-75-0)

2-Phenyl-2-oxazolin-5-one (1199-01-5)