365

Knorr Quinoline Synthesis

A. GENERAL DESCRIPTION OF THE REACTION

This reaction was first reported by Knorr in 1886.1 It is the synthesis of 2-

hydroxyquinolines via the cyclization and dehydration of an anilide intermediate condensed
from β-ketoesters and anilines at a relatively high temperature. Right after this report,
Conrad and Limpach also reported a similar reaction between anilines and β-ketoesters
but at low temperatures, which resulted in the formation of 4-hydroxyquinolines from
the intermediate of alkyl crotonate.2 Thus this reaction is known as the Knorr synthesis,3
Knorr-Limpach method,4 Knorr cyclization,5 Conrad-Limpach-Knorr reaction,6 or Knorr
quinoline synthesis.7 It has been reported that the formation of an alkyl crotonate interme-
diate is favored at moderate or low temperature in the presence of iodine or an acid catalyst,
whereas intermediate anilide is formed at high temperatures.6b

B. GENERAL REACTION SCHEME

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

Copyright © 2010 John Wiley & Sons, Inc.

1638
 CITED EXPERIMENTAL EXAMPLES 1639

C. PROPOSED MECHANISMS

The mechanism is illustrated by the reaction between aniline and ethyl β-ketoester.

D. MODIFICATION

N/A

E. APPLICATIONS

This reaction has general application in the preparation of 2-hydroxyquinoline

derivatives.

F. RELATED REACTIONS

This reaction is related to the Conrad-Limpach Quinoline Synthesis, Doebner-von Miller

Quinoline Synthesis, and Gould-Jacobs Quinoline Synthesis.

G. CITED EXPERIMENTAL EXAMPLES

CF3
O O ZnCl2
+ Et
O CF3 EtOH, ∆
H2N N 82% O N N
H H H
Reference 8.
1640 KNORR QUINOLINE SYNTHESIS

To a flame-dried, 100-mL, round-bottomed flask containing 210 mg aminotetrahy-

droquinoline (1.19 mmol) and 20 mL ethanol at room temperature was added 190 µL
ethyl-4,4,4-trifluoroacetoacetate (1.31 mmol, 1.10 eq.) and 244 mg ZnCl2 (1.79 mmol,
1.50 eq.). The reaction mixture was heated to reflux for 6 h, at which time TLC analysis
indicated complete consumption of the starting material. The reaction mixture was cooled to
room temperature, and the solvent was removed under reduced pressure. Dichloromethane
(20 mL) was added, and the organic phase was washed with saturated NaHCO3 (2 × 10 mL)
and brine (10 mL), then dried over Na2 SO4 and concentrated under reduced pressure. The
residue was purified by flash chromatography (CH2 Cl2 /MeOH, 15:1) to give 24.4 mg 4-
ethyl-1,2,3,4-tetrahydro-6-(trifluoromethyl)-8-pyridono[5,6-g]quinoline as a yellow solid,
in a yield of 82%, Rf = 0.37 (CH2 Cl2 /MeOH, 9:1). Recrystallization from EtOAc provided
an analytically pure sample as yellow needles, m.p. 264–265◦ C.

H2N OMe HO N OMe

a) CH3COCH2CO2Et, ∆

OMe b) H2SO4, ∆
OMe
Br Br
Reference 6b.

To 20 mL ethyl acetoacetate heated to 160–165◦ C was added 5.5 g 4-amino-6-

bromoveratrole over 3 min. After continuing the heating for an additional 30 min, the
excess ethyl acetoacetate was distilled off under reduced pressure, and the residue was
washed with light petroleum ether, leaving a thick oil in an apparently quantitative yield.
This thick oil was mixed with 8 mL concentrated H2 SO4 , and the mixture was heated for
2 min at 60–70◦ C. The mixture immediately solidified, which was thrown into water. The
solid was filtered out and crystallized from a mixture of chloroform and alcohol to give 60%
2-hydroxy-5-bromo-6,7-dimethoxylepidine as long white needles, m.p. 274–276◦ C (dec.).

Other references related to the Knorr quinoline synthesis are cited in the literature.9

H. REFERENCES

1. Knorr, L., Ann., 1886, 236, 69.

2. (a) Conrad, M. and Limpach, L., Ber., 1887, 20, 944. (b) Conrad, M. and Limpach, L., Ber., 1887,
20, 948.
3. (a) Outt, P. E.; Ares, J. J.; Roberts, G. E.; Wang, X. D.; Cupps, T. L. and Wireko, F. C., J. Org.
Chem., 1998, 63, 5762. (b) Curran, D. P. and Kuo, S.-C., J. Org. Chem., 1984, 49, 2063.
4. (a) Nasr, M.; Zayed, A. and Nabih, I., Pharmazie, 1978, 33, 424. (b) Dudley, K. H. and McKee,
R. L., J. Org. Chem., 1967, 32, 3210. (c) Benson, R. E. and Hamilton, C. S., J. Am. Chem. Soc.,
1946, 68, 2644.
5. (a) Hamann, L. G.; Higuchi, R. I.; Zhi, L.; Edwards, J. P.; Wang, X.-N.; Marschke, K. B.; Kong,
J. W.; Farmer, L. J. and Jones, T. K., J. Med. Chem., 1998, 41, 623. (b) Lopez-Alvarado, P.;
Avendano, C. and Menendez, J. C., Synthesis, 1998, 186.
6. (a) Yoshikawa, T., Yakugaku Zasshi, 1961, 81, 1323. (b) Misani, F. and Bogert, M. T., J. Org.
Chem., 1945, 10, 347. (c) Misani, F. and Bogert, M. T., J. Org. Chem., 1945, 10, 458.
7. (a) Tikotikar, N. L.; Navalgund, I. M.; Munavalli, S. N.; Kulkarni, S. N. and Nargund, K. S.,
J. Karnatak Univ., 1956, 1, 43. (b) Seide, O, Ber., 1925, 58B, 352.
 REFERENCES 1641

8. Hamann, L. G.; Mani, N. S.; Davis, R. L.; Wang, X.-N.; Marschke, K. B. and Jones, T. K., J. Med.
Chem., 1999, 42, 210.
9. (a) Hodgkinson, A. J. and Staskum, B., J. Org. Chem., 1969, 34, 1709. (b) Hauser, C. R. and
Reynolds, G. A., Org. Syn. Coll., 1955, 3, 593. (c) Hauser, C. R. and Reynolds, G. A., J. Am.
Chem. Soc., 1948, 70, 2402. (d) Kaslow, C. E. and Stayner, R. D., J. Am. Chem. Soc., 1948, 70,
3350. (e) Bergstrom, F. W., Chem. Rev., 1944, 35, 77. (f) Bergstrom, F. W., Chem. Rev., 1944,
35, 157. (g) Manske, R. H. F, Chem. Rev., 1942, 30, 113. (h) Ainley, A. D. and King, H., Proc.
Roy. Soc. (London), 1938, B125, 84. (i) Coffey, S.; Thompson, J. K. and Wilson, F. J., J. Chem.
Soc., 1936, 856. (j) Monti, L. and Cirelli, V., Gazz. Chim. Ital., 1936, 66, 723. (k) Knorr, L., Ann.,
1888, 245, 357. (l) Knorr, L., Ann., 1888, 245, 378.