77

Bergmann-Stern Azlactone
Synthesis

A. GENERAL DESCRIPTION OF THE REACTION

This reaction was first reported by Bergmann and Stern and others in 1926.1 It is the syn-
thesis of peptides by aminolysis of azlactones from α-amino acids or corresponding esters
and is generally known as the Bergmann-Stern azlactone synthesis.2 This reaction involves
the conversion of an acetylated amino acid and an aldehyde into an azlactone (also known as
5-oxazolone3 ) with an alkylidene side chain, the reaction of azlactone with the second amino
acid to form an acylated unsaturated dipeptide along with the opening of the azlactone ring,
the catalytic hydrogenation of the resulting N-acyl enamine, and final hydrolysis to give
dipeptide. In fact, the first unsaturated azlactone was prepared by Plöchl, who condensed
benzaldehyde with hippuric acid.4 It was Erlenmeyer who coined the word of azlactone to
describe the formed oxazolone and who initially showed the usefulness of these compounds
in formation of α-keto acids and α-amino acids.5 In comparison, the first saturated azlactone
was reported by Mohr and Geis in 1908 by heating N-benzoyl-α-aminoisobutyric acid with
acetic anhydride.6 In most cases, the azlactone is racemic even though the starting material
is optically active,7 and the partly optically active azlactone racemizes more rapidly than it
reacts with p-nitrophenol.8 It was Bergmann who realized the racemization of N-acyl or
benzoyl derivatives of α-amino acids in the presence of acetic anhydride, even in a catalytic
amount, and who developed the method of synthesizing peptide.9 This method has been
greatly improved, and its scope has been extended by gently heating α-amino acid with
trifluoroacetic anhydride to form 4-substituted-2-(trifluoromethyl)-6-oxazolone.10 Overall,

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

Copyright © 2010 John Wiley & Sons, Inc.

353
354 BERGMANN-STERN AZLACTONE SYNTHESIS

this reaction can be used to synthesize peptides containing tyrosine, arginine, histidine,
glutamic acid, and other amino acids.11 In addition, the formed azlactones can be converted
into α-keto acids and α-amino acids.5

B. GENERAL REACTION SCHEME

O
O
CO2H HN
Ar O H H2
+ Ar N CO2H
H2N R
N
O R
O
NH2
HN H
H H+ Ar N CO2H
Ar N CO2H
H2O O R
O R

C. PROPOSED MECHANISMS
 CITED EXPERIMENTAL EXAMPLES 355

D. MODIFICATION

This reaction has been modified to heat amino acid with trifluoroacetic anhydride to
form 4-substituted-2-(trifluoromethyl)-6-oxazolone,10 which can react with the succeeding
amino acid to form peptide. The azlactone with a saturated side chain can be prepared from
α-keto acid and subjected to the peptide synthesis.12

E. APPLICATIONS

This reaction has general application in the preparation of peptide. The azlactone itself
can be converted into α-keto acid or α-amino acid.5

F. RELATED REACTIONS

This reaction is related to the Erlenmeyer-Plöchl Azlactone Synthesis.

G. CITED EXPERIMENTAL EXAMPLES

O
Ph
Ph O O O CO2CH3
CO2CH3 H
H + N Ph
N N Ph
H2N N N
H H
O
Ph O Ph
Reference 13.

To a solution of 1.0 g azlactone (3.0 mmol) in 20 mL dry chloroform was added to a 5 mL

CHCl3 solution containing 0.64 g phenylalanine methyl ester hydrochloride (3.0 mmol)
and 0.30 g NEt3 (3.0 mmol). The reaction mixture was allowed to reflux for 8 h; then
the solvent was removed under reduced pressure. The residue was washed with water and
recrystallized from methanol-water and chloroform-petroleum ether to give methyl ester
of Ac-(dehydro-Phe)2 -L-Phe, m.p. 188–189◦ C. (Note: No yield was given in the original
reference.)

Reference 12.

A suspension of 3 g α-acetamino-α-hydroxyglutaric lactone in 60 mL acetic anhydride

was heated on a boiling water-bath until all the material dissolved; 10–15 min was required,
356 BERGMANN-STERN AZLACTONE SYNTHESIS

during which time the solution became orange-yellow. After removal of the excess acetic
anhydride in vacuo, the crude azlactone, a yellow viscous oil, was suspended in 30 mL
acetone and treated immediately with a solution of 1.12 g glycine in 15 mL normal sodium
hydroxide (1 N). The mixture, containing a trace of undissolved material, was shaken for
30 min, neutralized with 15 mL normal sulfuric acid (1 N), evaporated to dryness in vacuo,
and extracted thoroughly with cold 95% alcohol. The alcoholic solution was evaporated to
dryness; the residue was taken up in a small amount of water and decolorized with charcoal.
The aqueous solution was then evaporated to dryness, and the residue was washed with cold
alcohol. The 1.3 g of insoluble portion was recrystallized by suspension in hot alcohol with
dropwise additions of water until solution took place. On cooling, 0.7 g of the lactone of
α-acetamino-α-hydroxyglutarylglycine was separated from the solution.

Other references related to the Bergmann-Stern azlactone synthesis are cited in the
literature.14

H. REFERENCES

1. (a) Bergmann, M.; Stern, F. and Witte, C., Ann., 1926, 449, 271. (b) Bergmann, M.; Stern, F. and
Witte, C., Ann., 1926, 449, 277.
2. Steglich, W. and Hurnaus, R., Tetrahedron Lett., 1966, 383.
3. Fletcher, M. D. and Campbell, M. M., Chem. Rev., 1998, 98, 763.
4. Plöchl, J., Ber., 1883, 16, 2815.
5. (a) Erlenmeyer, E., Ber., 1900, 33, 2036. (b) Erlenmeyer, E., Ber., 1902, 35, 243.
6. Mohr, E. and Geis, T., Ber., 1908, 41,798.
7. Mohr, E. and Stroscheim, F., Ber., 1909, 42, 2521.
8. Goodman, M. and Levine, L., J. Am. Chem. Soc., 1964, 86, 2918.
9. (a) Bergmann, M. and Zervas, L., Biochem. J., 1928, 203, 280. (b) Bergmann, M. and Zervas, L.,
Hoppe-Seyler’s J. Physiol. Chem., 1928, 176, 154.
10. (a) Weygand, F.; Steglich, W. and Tanner, H., Ann., 1962, 658, 128. (b) Weygand, F. and Reiher,
M., Ber., 1955, 88, 26.
11. Sheehan, J. C. and Frank, V. S., J. Am. Chem. Soc., 1959, 71, 1856.
12. Shemin, D. and Herbst, R. M., J. Am. Chem. Soc., 1938, 60, 1951.
13. Pieroni, O.; Montagnoli, G.; Fissi, A.; Merlino, S. and Ciardellilc, F., J. Am. Chem. Soc., 1975,
97, 6820.
14. (a) Cooper, A. J. L.; Ginos, J. Z. and Meister, A., Chem. Rev., 1983, 83, 321. (b) Konno,
S. and Stammer, C. H., Int. J. Peptide Protein Res., 1978, 12, 222. (c) DeTar, D. F.; Sil-
verstein, R. and Rogers, F. F., J. Am. Chem. Soc., 1966, 88, 1024. (d) Greenstein, J. P. and
Winitz, M., Chemistry of the Amino Acids, Wiley; New York, 1961. (e) Pfleger, R. and Pelz,
J., Chem. Ber., 1957, 90, 1489. (f) Bergel, F. and Stock, J. A., Proc. Chem. Soc., 1957, 60.
(g) Stoll, A.; Hofmann, A.; Leemann, H. G.; Ott, H. and Schenk, H. R., Helv. Chim. Acta,
1956, 39, 1165. (h) Baltazzi, E., Quart. Rev. (London), 1956, 10, 235. (i) Springall, H. D.,
The Structural Chemistry of Proteins, Academic Press, New York, 1954, p. 29. (j) Archer, S.,
“Azlactone” in Amino Acids and Proteins, ed. Greenberg, D. M., Thomas, Springfield, IL., 1951,
p. 181. (k) Fruton, J. S., Advances in Protein Chemistry V, Academic Press, New York, 1949,
p. 15. (l) Cornforth, J. W. and Clarke, H. T., “Oxazoles and Oxazolones” in Chemistry of Pencillin,
ed. Clarke, H. T., Princeton University Press, Princeton, N.J., 1949, p. 783. (m) Dohefty, D. G.;
Tietzman, J. E., and Bergmann, M., J. Biol. Chem., 1943, 147, 617. (n) Dyer, E., J. Am. Chem.