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S. Leyva, E. Leyva / Tetrahedron 63 (2007) 2093–2097
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4.1.2. Ethyl 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-
3-carboxylate (3). Compound 2 (5.30 g, 16.70 mmol) was
added to diphenyl ether (35 mL) and refluxed for 6 h. After
the solution was cooled, the resulting precipitate was filtered
off and recrystallized from EtOH to give 3.76 g (83%) of 3 as
a white solid, sublimation point: 279–280 ꢀC. 1H NMR
(CF3CO2D, d ppm): 9.10 (1H, s, vinyl H), 7.99 (1H, m, aro-
matic H), 4.43 (2H, q, CH2), 1.30 (3H, t, CH3); 13C NMR
(CF3CO2D, d ppm): 171.62 (C]O, ketone), 166.50
(C]O, ester), 153.00 and 108.19 (vinyl C), 152.30,
141.00, 130.30, 125.09, 119.46 and 113.82 (aromatic C),
60.34 (CH2), 17.04 (CH3); IR (cmꢁ1): broad band around
3000 (N–H, secondary amine), 2986 (C–H, aliphatic),
3082 (C–H, aromatic and vinylic), 1572 (C]C, alkene),
1497 (C]C, aromatic), 1717 (C]O, ester), 1298 and
1251 (C–O, ester), 1628 (C]O, ketone).
a bright brown solid, mp: 204–205 ꢀC. H NMR (CDCl3,
d ppm): 8.53 (1H, s, vinyl quinolone H), 8.30 (1H, dd, vinyl
uracil H), 7.37 (1H, s, aromatic H), 4.53 (4H, br q, 2CH2),
4.51 (1H, br s, NH), 1.66 (3H, br t, CH3), 1.53 (3H, br t,
CH3); 13C NMR (CDCl3, d ppm): 174.00 (C]O, ketone),
167.82 (C]O, ester), 153.70 and 152.52 (C]O, uracil),
144.00 and 93.08 (vinyl uracil C), 153.70 and 102.42 (vinyl
quinolone C), 149.26, 147.15, 128.54, 113.64, 112.90 and
112.66 (aromatic C), 63.99 and 56.09 (CH2), 18.78 and
17.09 (CH3); IR (cmꢁ1): 1743 (C]O, overtone uracil),
1654 and 1575 (C]O, uracil), 1483 (C–N), 1681 (C]O,
ester), 1318 (C–O, ester), 1608 (C]O, ketone), 1510
(C]C, aromatic); MS (EI, 70 eV) m/z 323 (22%), 322
(100%); exact mass for C18H15F3N4O5: 424.0995 amu,
observed: 424.0968 amu.
4.1.6. Ethyl 7-(2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-
ylamino)-1-ethyl-6,8-difluoroquinolone-3-carboxylate
(7b). A mixture of compound 5 (0.40 g, 1.24 mmol) and ura-
cil 6b (0.14 g, 1.29 mmol) in 3.5 mL of pyridine was heated
at 50 ꢀC for 5 h. Then, the mixture was cooled and water
(20 mL) was added. The residue was filtered, washed with
water, and dried. The solid was recrystallized from ethanol,
yielding 0.26 g of 7b (51%) as a sand color solid, mp: 206–
207 ꢀC. 1H NMR (CDCl3, d ppm): 8.52 (H, br s, vinyl quino-
lone H), 8.33 (2H, m, vinyl uracil H and aromatic H), 7.34
(1H, d, vinyl uracil H), 4.53 (4H, br q, 2CH2), 4.50 (1H, br
s, NH), 1.66 (3H, br t, CH3), 1.55 (3H, br t, CH3); 13C
NMR (CD3COCD3, d ppm): 174.00 (C]O, ketone),
167.80 (C]O, ester), 153.70 and 152.83 (C]O, uracil),
149.47 and 112.66 (vinyl uracil C), 153.70 and 102.42
(vinyl quinolone C), 146.23, 144.94, 142.59, 128.53,
113.63 and 112.90 (aromatic C), 63.98 and 55.99 (CH2),
18.78 and 17.09 (CH3); IR (cmꢁ1): 1653 and 1568 (C]O,
uracil), 1480 (C–N), 1678 (C]O, ester), 1321 (C–O, ester),
1608 (C]O, ketone), 1514 (C]C, aromatic); MS
(EI, 70 eV) m/z 323 (35%), 322 (100%), 294 (2%); exact
mass for C18H16F2N4O5: 406.1080 amu, observed:
406.1067 amu.
4.1.3. Ethyl 1-ethyl-6,7,8-trifluoroquinolone-3-carboxyl-
ate (4). A mixture of 3 (2.71 g, 10 mmol), K2CO3 (3.45 g,
24.96 mmol), EtI (50 mmol), and DMF (20 mL) was re-
fluxed with stirring. After 10 h, the precipitate of K2CO3
and KHCO3 was filtered off and washed with ethanol.
Then, the filtrate was cooled to yield 4 (1.58 g, 53%) as
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a white solid, mp: 201–202 ꢀC. H NMR (CDCl3, d ppm):
8.40 (1H, s, vinyl H), 8.20 (1H, m, aromatic H), 4.43 (4H,
q, 2CH2), 1.60 (3H, t, CH3), 1.48 (3H, t, CH3); 13C NMR
(CDCl3, d ppm): 171.36 (C]O, ketone), 165.05 (C]O,
ester), 151.12 and 109.79 (vinyl C), 146.16, 126.04,
125.84, 125.73, 110.87 and 110.16 (aromatic C), 61.31
and 53.42 (CH2), 16.14 and 14.44 (CH3); IR (cmꢁ1): 2986
(C–H, aliphatic), 3082 (C–H, aromatic and vinyl), 1680
(C]O, ester), 1323 (C–O, ester), 1611 (C]O, ketone),
1490 (C]C, aromatic), 1106 and 1100 (C–F); exact
mass for C14H12F3NO3Na+: 322.0667 amu, observed:
322.0647 amu.
4.1.4. Ethyl 7-azido-1-ethyl-6,8-difluoroquinolone-3-car-
boxylate (5). Compound 4 (0.53 g, 1.78 mmol) and sodium
azide (0.12 g, 1.85 mmol) were added to acetone/water
(2.5 mL/1 mL). The mixture was refluxed for 6 h and water
(5 mL) was added. The precipitate was filtered, washed with
water, and dried, yielding 0.47 g of 5 (83%) as a fine white
4.1.7. Ethyl 7-[N0-(2,4-dioxo-1,2,3,4-tetrahydro-pyrimi-
din-5-yl)-hydrazino]-1-ethyl-6,8-difluoroquinolone-3-
carboxylate (7c). A mixture of compound 5 (0.40 g,
1.24 mmol) and 5-aminouracil 6c (0.16 g, 1.29 mmol) in
3.5 mL of pyridine was heated at 50 ꢀC for 5 h. Then, the
mixture was cooled and water (15 mL) was added. The resi-
due was filtered, washed with water, and dried, yielding
0.29 g of 7c (56%) as a yellow crystalline solid, mp:
206–207 ꢀC. 1H NMR (CDCl3, d ppm): 8.52 (1H, br s, vinyl
quinolone), 8.30 (1H, dd, aromatic H), 7.37 (1H, br s, vinyl
uracil H), 4.53 (4H, br q, 2CH2), 4.50 (1H, br s, NH), 1.73
(1H, br s, NH), 1.66 (3H, br t, CH3), 1.55 (3H, br t, CH3);
13C NMR (CD3COCD3, d ppm): 180.00 (C]O, ketone),
165.11 (C]O, ester), 152.22 and 151.66 (C]O, uracil),
125.00 and 123.33 (vinyl uracil C), 152.22 and 109.87 (vinyl
quinolone C), 145.83, 145.00, 130.83, 120.83, 115.14 and
111.87 (aromatic C), 66.32 and 51.39 (CH2), 16.07 and
14.68 (CH3); IR (cmꢁ1): 1748 (C]O, overtone uracil),
1647 and 1567 (C]O, uracil), 1494 and 1480 (C–N),
1673 (C]O, ester), 1321 (C–O, ester), 1608 (C]O,
ketone), 1508 (C]C, aromatic); MS (EI, 70 eV) m/z 323
(40%), 322 (100%), 319 (18%); exact mass for
C18H17F2N5O5: 421.1198 amu, observed: 421.1171 amu.
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solid, mp: 203–204 ꢀC. H NMR (CDCl3, d ppm): 8.52
(1H, s, vinyl H), 8.30 (1H, dd, aromatic H), 4.51 (4H, br q,
2CH2), 1.66 (3H, br t, CH3), 1.52 (3H, br t, CH3); 13C
NMR (CDCl3, d ppm): 173.93 (C]O, ketone), 167.75
(C]O, ester), 153.60 and 102.36 (vinyl C), 164.00,
153.60, 128.56, 113.74, 112.88 and 112.78 (aromatic C),
63.92 and 55.82 (CH2), 18.70 and 17.05 (CH3); IR (cmꢁ1):
2123 (ꢁN]N+]N), 1684 (C]O, ester), 1323 (C–O, ester),
1608 (C]O, ketone), 1483 (C]C, aromatic), 1130 and 1111
(C–F); MS (EI, 70 eV) m/z 322 (100%), 317 (40%), 254
(6%); exact mass for C14H12F2N4O3Na+: 345.0775 amu,
observed: 345.0764 amu.
4.1.5. Ethyl 1-ethyl-7-(5-fluoro-2,6-dioxo-3,6-dihydro-
2H-pyrimidin-1-ylamino)-6,8-difluoroquinolone-3-car-
boxylate (7a). A mixture of compound 5 (0.40 g,
1.24 mmol) and 5-fluorouracil 6a (0.16 g, 1.29 mmol) in
3.5 mL of pyridine was heated at 50 ꢀC for 5 h. Then, the
mixture was cooled and water (20 mL) was added. The resi-
due was filtered, washed with water, and dried. The solid was
recrystallized from ethanol, yielding 0.28 g of 7a (54%) as