PAPER
Synthesis of Novel Covalently Linked Flavoquinolones
2319
7.21 (d, 1 H, H-6, J = 8.20 Hz), 7.27 (s, 1 H, H-8), 8.43 (d, 1 H, H-
5, J = 8.23 Hz), 8.47 (s, 1 H, H-2).
MS: m/z (%) = 470 (M+, 28), 283 (23), 228 (100), 215 (11), 187
(55).
Anal. Calcd for C25H22N6O4: C, 63.82; H, 4.71; N, 17.86. Found: C,
63.79; H, 4.59; N, 17.89.
Ethyl 1-Ethyl-7-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-
3-carboxylate (11b)
Yield: 3.74 g (72%); mp 122 °C (Lit.21 mp 120.8–121.6 °C).
1-Ethyl-N-(10-hexylisoalloxazinyl)-7-methyl-4-oxo-1,4-dihy-
droquinoline-3-carboxamide (14a)
Yield: 0.061 g (29%); mp 189 °C.
1H NMR (CDCl3, 300 MHz): d = 1.45 (t, 3 H, CH2CH3, J = 7.20
Hz), 1.54 (t, 3 H, CH2CH3, J = 7.33 Hz), 2.68 (s, 3 H, 7-CH3), 3.99
(q, 2 H, CH2CH3, J = 7.23 Hz), 4.08 (q, 2 H, CH2CH3, J = 7.33 Hz),
7.14 (d, 1 H, H-6, J = 8.20 Hz), 8.04 (d, 1 H, H-5, J = 8.12 Hz), 8.19
(s, 1 H, H-2).
IR (KBr): 3422, 2921, 2828, 1709, 1657, 1610, 1581, 1547, 1451,
1510, 1406, 1287, 1248, 1092, 957, 885, 774 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.20 (t, 3 H, CH2CH3, J = 7.09
Hz), 1.34–1.75 [m, 8 H, (CH2)4], 2.59 (s, 3 H, CH3), 3.27 (q, 2 H,
CH2CH2NH, J = 6.89 Hz), 4.19 (q, 2 H, 1-CH2, J = 7.10 Hz), 4.70
(t, 2 H, N10CH2, J = 6.73 Hz), 7.15 (t, 1 H, H-7¢, J = 8.19 Hz), 7.28
(d, 1 H, H-9¢, J = 8.65 Hz), 7.46 (s, 1 H, H-8), 7.73 (t, 1 H, H-8¢, J =
8.20 Hz)), 8.12 (d, 1 H, H-6, J = 8.95 Hz), 8.21 (d, 1 H, H-5,
J = 8.35 Hz), 8.38 (d, 1 H, H-9¢, J = 7.43 Hz), 8.73 (s, 1 H, H-2).
1-Ethyl-7-methyl-4-oxo-1,4-dihydroquinoline/1,4-dihy-
dro[1,8]naphthyridine-3-carboxylic Acids (12); General Proce-
dure
A mixture of compound 11 (5 mmol) and aq 1 M NaOH (6 mL) in
THF (60 mL) was heated to reflux and maintained at reflux for 8 h.
The THF was removed on the rotary evaporator at reduced pressure.
H2O was added to the residue and the mixture was filtered. The fil-
trate was acidified with aq 6 M HCl and the precipitate was collect-
ed, washed and dried. The product was recrystallized from DMF.
MS: m/z (%) = 526 (M+, 21), 339 (12), 228 (77), 215 (100), 187
(45).
Anal. Calcd for C29H30N6O4: C, 66.14; H, 5.74; N, 15.96. Found: C,
66.21; H, 5.69; N, 15.89.
1-Ethyl-7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic
Acid (12a)
1-Ethyl-N-(10-dodecylisoalloxazinyl)-7-methyl-4-oxo-1,4-dihy-
droquinoline-3-carboxamide (15a)
Yield: 0.081 g (33%); mp 185 °C.
Yield: 1.097 g (95%); mp 280 °C (Lit.20 mp 280–282 °C).
IR (KBr): 3047, 2926, 1712, 1660, 1620, 1525, 1466, 1378, 1244,
976, 801, 685 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.37 (t, 3 H, CH2CH3, J = 7.10
Hz), 2.63 (s, 3 H, 7-CH3), 4.45 (q, 2 H, CH2CH3, J = 7.11 Hz), 6.59
(d, 1 H, H-6, J = 8.25 Hz), 7.31 (d, 1 H, H-5, J = 8.25 Hz), 7.62 (s,
1 H, H-8), 8.88 (s, 1 H, H-2), 13.91 (s, 1 H, CO2H).
IR (KBr): 3425, 2958, 2885, 1712, 1675, 1645, 1614, 1580, 1547,
1500, 1421, 1285, 1248, 1093, 957, 778 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.37 (t, 3 H, CH2CH3, J = 6.95
Hz), 1.40–1.65 [m, 20 H, (CH2)10], 2.60 (s, 3 H, CH3), 3.17 (q, 2 H,
CH2CH2NH, J = 7.00 Hz), 4.39 (q, 2 H, 1-CH2, J = 6.96 Hz), 4.69
(t, 2 H, N10CH2, J = 6.79 Hz), 7.25 (t, 1 H, H-7¢, J = 8.09 Hz), 7.29
(d, 1 H, H-9¢, J = 8.75 Hz), 7.38 (s, 1 H, H-8), 7.62 (t, 1 H, H-8¢,
J = 8.09 Hz), 8.19 (d, 1 H, H-6, J = 8.15 Hz), 8.20 (d, 1 H, H-5,
J = 8.36 Hz), 8.29 (d, 1 H, H-6¢, J = 7.44 Hz), 8.74 (s, 1 H, H-2).
1-Ethyl-7-methyl-4-oxo-1,4-dihydro[1,8]naphthylridine-3-
carboxylic Acid (12b)
Yield: 1.055 g (91%); mp 232 °C (Lit.17 mp 226.8–230.2 °C).
IR (KBr): 3045, 2924, 2362, 1714, 1627, 1519, 1474, 1442, 1353,
1295, 1228, 1130, 972, 805 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.55 (t, 3 H, CH2CH3, J = 7.04
Hz), 2.74 (s, 3 H, 7-CH3), 4.61 (q, 2 H, CH2CH3, J = 7.08 Hz), 7.39
(d, 1 H, H-6, J = 8.19 Hz), 8.68 (d, 1 H, H-5, J = 8.22 Hz), 8.90 (s,
1 H, H-2), 14.67 (s, 1 H, CO2H).
MS: m/z (%) = 610 (M+, 38), 423 (18), 228 (18), 215 (55), 187
(100).
Anal. Calcd for C35H42N6O4: C, 68.83; H, 6.93; N, 13.76. Found: C,
68.81; H, 7.01; N, 13.89.
1-Ethyl-N-(10-ethylisoalloxazinyl)-7-methyl-4-oxo-1,4-dihy-
dro[1,8]naphthyridine-3-carboxamide (13b)
Yield: 0.062 g (33%); mp 230 °C (dec.).
Flavoquinolones 13–15; General Procedure
Ethyl chloroformate (1.1 g, 0.96 mL, 10.1 mmol) was added in
small portions to a solution of anhyd Et3N (0.2 mL) and 12 (0.2
mmol) in anhyd CHCl3 (50 mL) maintaining the temperature at
0 °C. The CHCl3–MeOH (1:1) solution of flavin 6 (0.2 mmol) was
added dropwise to the above mixture at 0 °C. The mixture was
stirred for 30 min at r.t. The solvent was removed under reduced
pressure and the residue was redissolved in MeOH (15 mL) and pu-
rified by preparative TLC using MeOH as mobile phase.
IR (KBr): d = 3449, 2926, 1710, 1657, 1614, 1580, 1546, 1459,
1504, 1406, 1281, 1244, 1092, 774 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.25 (t, 3 H, CH2CH3, J = 6.91
Hz), 2.66 (s, 3 H, 7-CH3), 3.66 (q, 2 H, CH2CH2NH, J = 6.71 Hz),
4.17 (q, 2 H, 1-CH2, J = 6.91 Hz), 4.88 (t, 2 H, N10CH2, J = 6.73 Hz),
5.17 (br s, 1 H, NH), 7.68 (t, 1 H, H-7¢, J = 8.14 Hz), 7.99 (t, 1 H,
H-8¢, J = 8.15 Hz), 8.17 (d, 1 H, J = 7.44 Hz), 8.33 (d, 1 H, J = 7.91
Hz), 8.48 (br s, 1 H, N3¢H), 8.65 (d, 1 H , J = 7.93 Hz), 8.90 (s, 1 H,
H-2).
1-Ethyl-N-(10-ethylisoalloxazinyl)-7-methyl-4-oxo-1,4-dihy-
droquinoline-3-carboxamide (13a)
Yield: 0.055 g (30%); mp 198 °C.
MS: m/z (%) = 471 (M+, 28), 284 (20), 228 (12), 215 (49), 187
(100).
IR (KBr): 3425, 2927, 1708, 1669, 1656, 1614, 1580, 1546, 1459,
1500, 1406, 1285, 1248, 1092, 957, 774 cm–1.
Anal. Calcd for C24H21N7O4: C, 61.14; H, 4.49; N, 20.80. Found: C,
61.21; H, 4.29; N, 20.89.
1H NMR (CDCl3, 300 MHz): d = 1.13 (t, 3 H, CH2CH3, J = 6.99
Hz), 2.58 (s, 3 H, CH3), 3.57 (q, 2 H, CH2CH2NH, J = 6.71 Hz), 3.99
(q, 2 H, 1-CH2, J = 7.01 Hz), 4.79 (t, 2 H, N10CH2, J = 6.73 Hz), 7.05
(t, 1 H, H-7¢, J = 8.11 Hz), 7.28 (d, 1 H, H-9¢, J = 8.65 Hz), 7.42 (s,
1 H, H-8), 7.63 (t, 1 H, H-8¢, J = 8.11 Hz), 8.04 (d, 1 H, H-6, J = 8.95
Hz), 8.19 (d, 1 H, H-5, J = 8.35 Hz), 8.28 (d, 1 H, H-9¢, J = 7.43
Hz), 8.63 (s, 1 H, H-2).
1-Ethyl-N-(10-hexylisoalloxazinyl)-7-methyl-4-oxo-1,4-dihy-
dro[1,8]naphthyridin-3-carboxamide (14b)
Yield: 0.078 g (37%); mp 202–204 °C.
IR (KBr): 3432, 2926, 2918, 2362, 1714, 1670, 1550, 1458, 1102,
725, 669 cm–1.
Synthesis 2005, No. 14, 2315–2320 © Thieme Stuttgart · New York