152

Conrad-Limpach Quinoline
Synthesis

A. GENERAL DESCRIPTION OF THE REACTION

This reaction was first reported by Conrad and Limpach in 1887.1 It is the syn-
thesis of 4-quinolones, which often isomerize (or aromatize) to 4-hydroxyquinolines
through the thermal condensation of primary aromatic amines with the carbonyl group
of β-ketoesters followed by the cyclization of Schiff base intermediates (alkyl β-
arylaminocrotonates). Therefore, it is known as the Conrad-Limpach quinoline synthesis2
or Conrad-Limpach synthesis.3 However, during the condensation of primary aromatic
amines with β-ketoesters, the amino group might also react at the ester group of β-
ketoesters to form β-ketoacetamide intermediates (isomerize to ketoacetanilides), which
cyclize to 2-hydroxyquinolines; this type of conversion was initially discovered on Knorr
in 1886.4 Therefore, the Conrad-Limpach quinoline synthesis sometimes is also referred
to as Conrad-Limpach-Knorr quinolone synthesis,5 Conrad-Limpach-Knorr reaction,6 and
Knorr-Conrad-Limpach method.7 Nevertheless, there are still some distinctive differences
between these two reactions. For example, β-ketoesters are used in Conrad-Limpach quino-
line synthesis, whereas ethyl acetoacetate is mostly used in the Knorr Quinoline Synthesis,
in addition, higher temperature of condensation results in the Knorr product, whereas
moderate or lower temperatures lead to the Conrad-Limpach product.6 Furthermore, the
presence of iodine or an acidic catalyst is often necessary for the Conrad-Limpach quino-
line synthesis.6 In this reaction, the condensed intermediates have seldom been isolated and
characterized because, in most cases, these intermediates are viscous oils that are directly
subjected to thermal cyclization.8 During the cyclization, the protonated carbonyl group
will function as an electrophile, whereas the aromatic ring acts as a nucleophile;9 if an

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

Copyright © 2010 John Wiley & Sons, Inc.

692
 APPLICATIONS 693

electron-withdrawing group exists on the aromatic ring, such as a nitro group, then the
cyclization is difficult.6,7,10 Similarly, as a poor nucleophile, 3-aminopyridine is difficult
to react with β-ketoesters to form naphthyridine;9 it is surprising, however, that 2,6-
diaminopyridine reacts conveniently to afford naphthyridine even at room temperature,11
this is likely attributed to the distribution of an electron cloud to the pyridyl ring from the
two strong electron-donating amino groups.

B. GENERAL REACTION SCHEME

C. PROPOSED MECHANISMS

Displayed below is a general illustration of the reaction.

D. MODIFICATION

This reaction has been modified for the use of acetoacetonitriles12 and Meldrum’s acid13
instead of β-ketoesters to afford 4-hydroxyquinolines.

E. APPLICATIONS

This reaction is generally good for the synthesis of 4-hydroxyquinolines and 4-

quinolones.
694 CONRAD-LIMPACH QUINOLINE SYNTHESIS

F. RELATED REACTIONS

This reaction is related to the Camps Reaction, Combes Quinoline Synthesis, Doebner-
Miller Reaction, Gould-Jacobs Quinoline Synthesis, Niementowski Reaction and Skraup
Reaction.

G. CITED EXPERIMENTAL EXAMPLES

TBSO
NHCBZ

+ O O + HC(OMe)3
∆
MeO NH2 O O
OBn
NHCBZ
TBSO
NHCBZ TBSO
O
O
Ph2O
O
∆
MeO N
H O MeO N
OBn O H
OBn
Reference 13.

Meldrum’s acid (0.413 g, 2.87 mmol) was refluxed under nitrogen in 35 mL trimethyl
orthoformate for 2 h. O-Benzyl N-2-(5-amino-4-benzyloxy-3-methoxyphenyl)-2-(tert-
butyldimethylsilyloxy)ethyl carbamate (1.14 g, 2.39 mmol) dissolved in 15 mL trimethyl
orthoformate, was added to the solution of Meldrum’s acid, and the mixture was refluxed
for 4 h. The solvent was removed in vacuo and the residue was subjected to flash
chromatography (2:1 hexane/EtOAc) to give 1.00 g 5-[5-[2-(benzyloxycarbonylamino)-
1-(tert-butyldimethylsilyloxy)ethyl]-2-benzyloxy-3-methoxyphenylaminomethylene]-2,2-
dimethyl-1,3-dioxane-4,6-dione as a white solid, in a yield of 87%, m.p. 110–111◦ C after
recrystallization from EtOAc/hexanes.
To a solution of 100 mL diphenyl ether was added 1.09 g 1,3-dioxane-4,6-dione
(1.57 mmol). A stream of nitrogen was passed through the solution for 20 min and the
flask was then lowered into a large silicone oil bath preheated to 240◦ C. The temper-
ature of the bath dropped to 225◦ C and rose again to 240◦ C in 5–7 min. The solution
was stirred in the bath for a total of 18 min, then removed and allowed to cool. The
solvent was removed under vacuum (0.1 mmHg, 110◦ C). Flash chromatography (1:2
to 6:1 hexanes/EtOAc) gave 0.326 g O-benzyl N-2-(tert-butyldimethylsilyloxy)-2-[8-
benzyloxy-7-methoxy-4(1H)-quinolinon-5-yl]ethyl carbamate as a tan solid, in a yield of
35%. An analytical sample, m.p. 63–65◦ C, was obtained by recrystallization from EtOAc/
hexanes.
 REFERENCES 695

CO2Me

+ MeO2C CO2Me
NH2 ∆ N CO2Me
NO2 H
NO2
O

PPA
∆
N CO2Me
H
NO2
Reference 5.

An equal molar amount (0.02 mol) of o-nitroaniline and dimethyl acetylenedicarboxylate

was mixed in 100 mL anhydrous methanol and refluxed for 24–48 h. The reaction mixture
was cooled in ice, and the precipitated product was removed by filtration. Successive crystal
crops were obtained by concentration in vacuo of the mother liquors to give 95% of a Michael
Addition product, m.p. 130–131◦ C.
A paste, formed from intimately mixing 2–4 g Michael adduct with 20–30 g polyphos-
phoric acid, was heated with stirring at 140–180◦ C for 30 min. Considerable foaming
resulted, and the mixture turned progressively darker. After cooling to 100◦ C, the viscous
solution was poured into a mixture of chopped ice and water and scratched with a glass rod
to induce crystallization. If allowed to stand at ice bath temperatures for 5–10 h before filtra-
tion, the filterability of the product was improved. The solid, removed by vacuum filtration,
was air dried and recrystallized from methanol. The sample was purified by sublimation at
0.5 mmHg at 20◦ C under its melting point, the yield was 47%, m.p. 195◦ C.

Other references related to the Conrad-Limpach quinoline synthesis are cited in the
literature.14

H. REFERENCES

1. (a) Conrad, M. and Limpach, L., Ber., 1887, 20, 944. (b) Conrad, M. and Limpach, L., Ber., 1887,
20, 948.
2. Kulkarni, S. A.; Thakor, V. M. and Shah, R. C., J. Indian Chem. Soc., 1951, 28, 688.
3. (a) Egri, J.; Halmos, J. and Rakoczi, J., Acta Chim. Acad. Sci. Hungaricae, 1973, 78, 217.
(b) Steck, E. A.; Hallock, L. L.; Holland, A. J. and Fletcher, L. T., J. Am. Chem. Soc., 1948, 70,
1012.
4. (a) Knorr, L., Ann., 1886, 236, 69. (b) Knorr, L., Ann., 1888, 245, 357. (c) Knorr, L., Ann., 1888,
245, 378.
5. Heindel, N. D.; Bechara, I. S.; Lemke, T. F. and Fish, V. B., J. Org. Chem., 1967, 32, 4155.
6. Misani, F. and Bogert, M. T., J. Org. Chem., 1945, 10, 347.
7. Carmack, M. and Von, I., J. Am. Chem. Soc., 1946, 68, 1809.
8. Heindel, N. D.; Bechara, I. S.; Kennewell, P. D.; Molnar, J.; Ohnmacht, C. J.; Lemke, S. M. and
Lemke, T. F., J. Med. Chem., 1968, 11, 1218.
9. Hauser, C. R. and Reynolds, G. A., J. Org. Chem., 1950, 15, 1224.
10. Coffey, S.; Thomson, J. K. and Wilson, E. J., J. Chem. Soc., 1936, 856.
696 CONRAD-LIMPACH QUINOLINE SYNTHESIS

11. Hauser, C. R. and Weiss, M. J., J. Org. Chem., 1949, 14, 453.
12. Hauser, C. R. and Murray, J. G., J. Am. Chem. Soc., 1955, 77, 2851.
13. Walz, A. J. and Sundberg, R. J., J. Org. Chem., 2000, 65, 8001.
14. (a) Reddy, B. and Reddy, V., Synth. Commun., 1999, 29, 2789. (b) Ouar, M. E.; Knouzi, N.
and Hamelin, J., J. Chem. Res. (S), 1998, 92. (c) Cassis, R.; Tapia, R. and Valderrama, J. A.,
Synth. Commun,. 1985, 15, 125. (d) Moore, J. A. and Mitchell, T. D., J. Polym. Chem., 1980,
18, 3029. (e) Jones, G., “Quinolines”, in The Chemistry of Heterocyclic Compounds, ed. Jones,
G., John Wiley & Sons, New York, 1977, 32, Part 1, pp. 137–151. (f) Perche, J.-C. and Saint-
Ruf, G., J. Heterocycl. Chem. 1974, 11, 93. (g) Madhav, R.; Dufresne, R. and Southwick, P.,
J. Heterocycl. Chem., 1973, 10, 225. (h) Werner, W., Tetrahedron, 1969, 25, 255. (i) Heidel
N. D. and Ohnmacht C. J., J. Heterocycl. Chem., 1968, 5, 869. (j) Reitsema, R. H., Chem. Rev.,
1948, 43, 43. (k) Manske, R. H. F., Chem. Rev. 1942, 30, 113. (l) Limpach, L., Ber., 1931, 64,
970. (m) Conrad, M. and Limpach, L., Ber., 1891, 24, 2990.