Cyclization
Phenacyl 3-(Ethoxycarbonyl)-4-oxo-1,4-dihydroquinoline-8-carboxylate (4)
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Method A. Benzoate 2 (2 g, 4.7 mmol) was added to diphenyl ether (20 g) heated to 245 °C. After
45 min the starting substance was not detectable. The reaction mixture was then poured into cyclo-
hexane (100 ml), cooled to room temperature, and the solid was collected (1.50 g). Crystallization
from acetone and ethyl acetate afforded 1.02 g (57%) of quinolone 4, m.p. 193–197 °C. For
C21H17NO6 (379.4) calculated: 66.49% C, 4.52% H, 3.69% N; found: 66.11% C, 4.64% H, 3.42% N.
1H NMR spectrum: 1.32 t, 3 H, J = 7.1 (CH3); 4.28 q, 2 H, J = 7.1 (CH2); 5.94 s, 2 H (CH2CO);
7.63–7.68 m, 3 H (2 × H-3′, H-4′); 7.78 t, 1 H, J = 7.1 (H-6); 8.10 d, 2 H, J = 7.1 (2 × H-2′);
8.56–8.59 m, 2 H (H-5, H-7); 8.71 s, 1 H (H-2); 12.1 bs, 1 H (NH).
Method B. A solution of phenacyl bromide (1.17 g, 5.92 mmol) in dimethylformamide (5 ml) was
added dropwise to a mixture of compound 8 (1.66 g, 6.35 mmol), anhydrous potassium carbonate
(1.0 g, 7.24 mmol) and dimethylformamide (30 ml) whereby the temperature of the mixture rose by
5 °C. After stirring for 2 h the mixture was poured into ice-cold water (200 ml). The formed precipi-
tate was filtered off, washed with water and dried to give the product (0.82 g; 36%). The identity
with the compound obtained by method A was confirmed by TLC and melting point measurement.
4-Oxo-8-[(phenacyloxy)carbonyl]-1,4-dihydroquinoline-3-carboxylic Acid (6)
Compound 4 (0.5 g, 1.32 mmol) was added to concentrated sulfuric acid (20 g). After heating at 105 °C
for 20 min, no starting compound was detected by TLC. The reaction mixture was then poured into
an ice–water mixture (150 g) and the separated white precipitate was collected and washed with
water to neutral reaction of the washings. The crude substance was dried (0.46 g) and recrystallized
to give 0.29 g (62%) of acid 6, m.p. 252–254 °C. For C19H13NO6 (351.3) calculated: 64.96% C,
3.73% H, 3.99% N; found: 64.67% C, 3.70% H, 3.82% N. 1H NMR spectrum: 5.98 s, 2 H (CH2);
7.65–7.78 m, 4 H (2 × H-3′, H-4′, H-6); 8.11 dd, 2 H, J = 1.3 and 7.9 (2 × H-2′); 8.58 d. 2 H, J = 7.9
(H-5, H-7); 8.71 s, 1 H (H-2).
2-{[2,2-Di(ethoxycarbonyl)vinyl]amino}benzoic Acid (7)
A mixture of anthranilic acid (6.85 g, 0.05 mol), diethyl (ethoxymethylidene)malonate (10.85 g, 0.05
mol) and ethanol (50 ml) was refluxed for 3.5 h. After this time no anthranilic acid could be detected
by TLC. The solution was concentrated to about one half, the same volume of hexane was added, and
the mixture was set aside at 5 °C. Isolation and drying afforded 11.8 g (77%) of acid 7, m.p. 156–158.5 °C
1
(reported8 m.p. 156–157 °C). H NMR spectrum: 1.30 2 × t, 6 H, J = 7.3 (2 × CH3); 4.19 q, 2 H, J = 7.3
(CH2); 4.28 q, 2 H, J = 7.3 (CH2); 7.25 dt, 1 H, 1J = 1.3, 2J = 7.0 (H-5); 7.64–7.72 m, 2 H (H-3,
H-4); 8.04 dd, 1 H, J = 7.0 and 1.3 (H-6); 8.55 d, 1 H, J = 13.6 (CH); 12.52 d, 1 H, J = 13.6 (NH).
IR spectrum: 1 714, 1 680 (CO), 1 637, 1 608 (C=C).
3-(Ethoxycarbonyl)-4-oxo-1,4-dihydroquinoline-8-carboxylic Acid (8)
Acid 7 (2.0 g, 3.5 mmol) was added to simmering (250 °C) diphenyl ether (20 g), and the mixture
was heated to the boil for 30 min. After this time the starting substance was no longer detected
(TLC). The solution was poured into cyclohexane (100 ml) and cooled to room temperature. The
separated precipitate was filtered off, washed with cyclohexane and dried to give 1.24 g of crude
quinolone 8. Recrystallization from acetic acid afforded 0.56 g (33%) of the product, m.p. 237–239 °C.
For C13H11NO5 (261.2) calculated: 59.76% C, 4.25% H, 5.36% N; found: 59.58% C, 4.30% H, 5.16% N.
1H NMR spectrum: 1.32 t, 3 H, J = 7.1 (CH3); 4.27 q, 2 H, J = 7.1 (CH2); 7.56 t, 1 H, J = 8.0 (H-6);
8.41 dd, 1 H, J = 1.5 and 8.0 (H-5); 8.48 dd, 1 H, J = 1.5 and 8.0 (H-7); 8.76 d, 1 H, J = 7.0 (H-2);
12.38 d, 1 H, J = 7.0 (NH). IR spectrum: 3 271 (NH), 3 083 (ArH), 1 723 (CO), 1 616, 1 570 (C=C).
Collect. Czech. Chem. Commun. (Vol. 63) (1998)