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Erlenmeyer-Pl Ochl Azlactone Synthesis: A. General Description of The Reaction

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338 views

Erlenmeyer-Pl Ochl Azlactone Synthesis: A. General Description of The Reaction

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stwar
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217

Erlenmeyer-Plöchl
Azlactone Synthesis

A. GENERAL DESCRIPTION OF THE REACTION

The condensation between aromatic aldehydes and hippuric acid in the presence of
acetic anhydride was initially reported by Plöchl in 18831 and was studied extensively by
Erlenmeyer in 1892.2 In addition, Erlenmeyer corrected the original assigned structure of
a product containing a three-membered ring and coined the word azlactone for the formed
product.3 Therefore, this reaction is known as the Plöchl-Erlenmeyer reaction,4 Erlenmeyer-
Plöchl reaction,5 Erlenmeyer-Plöchl synthesis,6 Erlenmeyer-Plöchl oxazolone synthesis,7
Erlenmeyer-Plöchl method,8 Erlenmeyer synthesis,9 and Erlenmeyer azlactone synthesis.10
In detail, the Erlenmeyer-Plöchl azlactone synthesis is the preparation of azlactones (also
called oxazolones11 ) in a Z configuration (originally assigned to the E configuration)10b by
condensation of aromatic aldehydes with hippuric acid (the benzoyl glycine derivatives12 )
in the presence of acetic anhydride. The formed azlactones have found many applications in
organic synthesis, especially for α-ketos, α-amino acids2c,2d and peptides.13 This reaction
normally gives one product: the thermodynamically stable one;10b however, two products
are also formed in some cases.7 In addition, transacylation often occurs in this reaction,
especially when the reaction mixture is refluxed.5b,6 Thus the yields of desired products are
not very high, and extensive purification of crude azlactones should be avoided to generate
higher yields.5b

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang


Copyright © 2010 John Wiley & Sons, Inc.

997
998 ERLENMEYER-PLÖCHL AZLACTONE SYNTHESIS

B. GENERAL REACTION SCHEME

Ar
O Ac2O H
Ar CHO + N
Ar′ N CO2H
H Ar′ O
O

C. PROPOSED MECHANISMS

D. MODIFICATION

This reaction has been modified to occur in polyphosphoric acid (PPA) to form the
azlactones in the E configuration.10b

E. APPLICATIONS

This reaction has been used for the synthesis of α-keto, α-amino acids,2c,2d and
peptides.13

F. RELATED REACTIONS

This reaction is related to the Bergmann-Stern Azlactone Synthesis, Claisen Condensa-


tion, and Perkin Reaction.
REFERENCES 999

G. CITED EXPERIMENTAL EXAMPLES

Ar
NO2 O
NO2 H
NaOAc/Ac2O N
Ph CHO + N CO2H
H ∆ O
O

Reference 4b.

To a flask equipped with a condenser, were added 1.07 mmol ortho-nitrobenzoylglycine,


0.96 mmol benzaldehyde, 0.96 mmol fused NaOAc, and 3 mmol acetic anhydride. The
mixture was heated in a boiling water bath for 1 h. After cooling, 2 mL 95% ethanol was
added to the flask, and the mixture was left at 5◦ C for 4–6 h. The precipitate formed was
filtered and washed with cold ethanol, then with boiling water, and again with cold ethanol.
The dried precipitate was recrystallized to a constant melting point in acetic acid to give
57% product as yellow needles, m.p. 210◦ C.

H
O
PPA Ph
Ph CHO + N
Ph N CO2H ∆
H Ph O
O
Reference 10b.

To a sample of polyphosphoric acid prepared from 20 mL phosphoric acid and 32 g


phosphoric anhydride was added 5.3 g benzaldehyde (50 mmol) and 8.95 g hippuric acid
(50 mmol). The mixture was then heated on a steam bath (80–95◦ C) for 90 min and then
poured into water. The resultant solid product was collected and repeatedly washed with
water. Finally, 12.0 g 2-phenyl-4-phenylmethylene-2-oxazolin-5-one was recrystallized
from a mixture of benzene-Skellysolve B, in a yield of 90%, m.p. 146–147◦ C.

Other references related to the Erlenmeyer-Plöchel azlactone synthesis are cited in the
literature.14

H. REFERENCES

1. Plöchl, J., Ber., 1883, 16, 2815.


2. (a) Erlenmeyer, E., Ann., 1892, 271, 167. (b) Erlenmeyer, E., Ann., 1893, 275, 1. (c) Erlenmeyer,
E., Ber., 1900, 33, 2036. (d) Erlenmeyer, E., Ber., 1902, 35, 243. (e) Erlenmeyer, E., Ann., 1904,
337, 265.
3. Cooper, A. J. L.; Ginos, J. Z. and Meister, A., Chem. Rev., 1983, 83, 321.
4. (a) Ivanova, G., Tetrahedron, 1992, 48, 177. (b) Bassi, D. A.; Deulofeu, V. and Ortega, F. A. F.,
J. Am. Chem. Soc., 1953, 75, 171.
5. (a) Zavyalov, S. I.; Dorofeyeva, O. V. and Rumyantseva, Y. Y., Khim.-Farmatsevticheskii Zh.,
1993, 27, 76. (b) Bennett, E. L. and Niemann, C., J. Am. Chem. Soc., 1950, 72, 1803.
6. Bennett, E. L. and Hoerger, E., J. Am. Chem. Soc., 1952, 74, 5975.
1000 ERLENMEYER-PLÖCHL AZLACTONE SYNTHESIS

7. Pages, R. A. and Burger, A., J. Med. Chem., 1966, 9, 766.


8. Mosberg, H. I.; Sobczyk-Kojiro, K.; Subramanian, P.; Crippen, G. M.; Ramalingam, K. and
Woodard, R. W., J. Am. Chem. Soc., 1990, 112, 822.
9. (a) Yu, C. M.; Zhou, B. C.; Su, W. K. and Xu, Z. Y., Synth. Commun., 2006, 36, 3447.
(b) Chandrasekhar, S. and Karri, P., Tetrahedron Lett., 2006, 47, 5763. (c) Karade, N. N.; Shirodkar,
S. G.; Dhoot, B. M. and Waghmare, P. B., J. Chem. Res., 2005, 46. (d) Mogilaiah, K.; Prashanthi,
M. and Reddy, C. S., Indian J. Chem., Sect. B, 2003, 42B, 2126.
10. (a) Chandrasekhar, S. and Karri, P., Tetrahedron Lett., 2007, 48, 785. (b) Rao, Y. S., J. Org. Chem.,
1976, 41, 722. (c) Boekelheide, V. and Schramm, L. M., J. Org. Chem., 1949, 14, 298.
11. Kobayashi, S.; Bryant, L. L.; Tsukamoto, Y. and Saegusa, T., Macromolecules, 1986, 19, 1547.
12. Henze, H. R.; Whitney, W. B. and Eppright, M. A., J. Am. Chem. Soc., 1940, 62, 565.
13. (a) Leplawy, M. T.; Jones, D. S.; Kenner, G. W. and Sheppard, R. C., Tetrahedron, 1960, 11, 39.
(b) Bergmann, M.; Stern, F. and Witte, C., Ann., 1926, 449, 277.
14. (a) Palcut, M., J. Chem. Res., 2005, 766. (b) Schumacher, M.; Miesch, L. and Franck-Neumann,
M., Tetrahedron Lett., 2003, 44, 5393. (c) Konkel, J. T.; Fan, J. F.; Jayachandran, B. and Kirk, K.
L., J. Fluor. Chem., 2002, 115, 27. (d) Combs, A. P. and Armstrong, R. W., Tetrahedron Lett.,
1992, 33, 6419. (e) Cornforth, J.; Ming-Hui, D., J. Chem. Soc., Perkin Trans. I, 1991, 2183.
(f) Moriya, T.; Yoneda, N.; Miyoshi, M. and Matsumoto, K., J. Org. Chem., 1982, 47, 94.
(g) Kriby, G. W. and Varley, M. J., J. Chem. Soc., Chem. Commun., 1974, 833. (h) Steglich, W.,
Fortsch. Chem. Forsch., 1969, 12, 84. (i) Muxfeldt, H.; Behling, J.; Grethe, G. and Rogalski,
W., J. Am. Chem. Soc., 1967, 89, 4991. (j) Filler, R.; Rao, K. B. and Rao, Y. S., J. Org. Chem.,
1962, 27, 1110. (k) Crawford, M. and Little, W. T., J. Chem. Soc., 1959, 729. (l) Shaw, K. N.
F.; McMillan, A.; Gudmundson, A. G. and Armstrong, M. D., J. Org. Chem., 1958, 23, 1171.
(m) Stefanovic, G. and Stefanovic, M., J. Org. Chem., 1956, 21, 161. (n) Buckles, R. E.; Filler,
R. and Hilfman, L., J. Org. Chem., 1952, 17, 233. (o) Carter, H. E., Org. React., 1946, 3, 198.
(p) Raiford, L. C. and Buurman, C. H., J. Org. Chem., 1944, 9, 466. (q) Carter, H. E. and Risser,
W. C., J. Biol. Chem., 1941, 139, 255. (r) Plöchl, J., Ber., 1884, 17, 1616.

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