May 2010
Quinolone Analogues 10: Synthesis of Antimalarial Quinolones having
Pyridyl Moiety in N1-Side Chain
661
Ethyl 7-chloro-6-fluoro-1,4-dihydro-1-[(Z)-1-methoxycar-
bonyl-2-(4- and 3-pyridyl)vinyl]-4-oxoquinoline-3-carboxy-
lates 6a,b. General procedure. A solution of compound 14
Compound 7b was obtained in 49% yield (3.10 g); mp 140–
ꢀ
ꢁ1
þ
141 ; IR: m 1725, 1690 cm ; ms: m/z 410 (M ); NMR (deu-
teriodimethyl sulfoxide): 8.65 (s, 1H, 2-H), 8.55 (d, J ¼ 2.0
Hz, 1H, pyridine 2-H), 8.53 (dd, J ¼ 4.5, 2.0 Hz, 1H, pyridine
6-H), 8.29 (s, 1H, vinylic H), 7.92 (dd, 9.0, 3.0 Hz, 1H, 5-H),
7.57 (ddd, J ¼ 9.0, 8.0, 3.0 Hz, 1H, 7-H), 7.50 (dd, J ¼ 9.0,
4.5 Hz, 1H, 8-H), 7.39 (ddd, J ¼ 8.0, 2.0, 2.0 Hz, 1H, pyridine
4-H), 7.33 (dd, J ¼ 8.0, 4.5 Hz, 1H, pyridine 5-H), 4.28 (dq,
J ¼ 11.0, 7.0 Hz, 1H, methylene CH), 4.24 (dq, J ¼ 11.0, 7.0
Hz, 1H, methylene CH), 4.22 (dq, J ¼ 11.0, 7.0 Hz, 1H, meth-
ylene CH), 4.17 (dq, J ¼ 11.0, 7.0 Hz, 1H, methylene CH),
(
5.0 g, 14.6 mmol), 4- or 3-pyridinecarbaldehyde (2.50 g, 23.4
mmol), and 1,8-diazabicyclo[5.4.0]-7-undecene (1.19 g, 7.80
mmol) in dry dioxane (100 mL) was refluxed with stirring for
10 h. Acetic acid (5 mL) was added to the solution, and the
solvent was evaporated in vacuo to give colorless crystals.
Recrystallization from dioxane/water afforded colorless needles
6
a or 6b.
Compound 6a was obtained in 55% yield (3.48 g); mp 226–
ꢀ
ꢁ1
þ
þ
2
27 ; IR: m 1730 cm ; ms: m/z 430 (M ), 432 (M þ 2);
1.23 (dd, J ¼ 7.0, 7.0 Hz, 3H, CH ), 1.22 (dd, J ¼ 7.0, 7.0
3
NMR (deuteriodimethyl sulfoxide): 8.65 (s, 1H, 2-H), 8.54 (d,
J ¼ 6.5 Hz, 2H, pyridine 2-H and 6-H), 8.24 (s, 1H, vinylic
H), 8.07 (d, J ¼ 9.0 Hz, 1H, 5-H), 7.81 (d, J ¼ 6.0 Hz, 1H, 8-
H), 7.12 (d, J ¼ 6.5 Hz, 2H, pyridine 3-H and 5-H), 4.18 (q,
J ¼ 7.0 Hz, 2H, CH ), 3.81 (s, 3H, CH ), 1.22 (t, J ¼ 7.0 Hz,
Hz, 3H, CH ). Anal. Calcd. for C H FN O : C, 64.39; H,
2 5
3
22 19
4.67; N, 6.83. Found: C, 64.16; H, 4.67; N, 6.90.
Compound 7c was obtained in 58% yield (3.73 g); mp 166–
ꢀ
ꢁ1
þ
167 ; IR: m 1700 cm ; ms: m/z 410 (M ); NMR (deuteriodi-
methyl sulfoxide): 8.56 (s, 1H, 2-H), 8.27 (ddd, J ¼ 5.0, 1.5,
0.5 Hz, 1H, pyridine 6-H), 8.24 (s, 1H, vinylic H), 7.99 (dd, J
¼ 9.0, 3.0 Hz, 1H, 5-H), 7.83 (ddd, 7.5, 7.5, 1.5 Hz, 1H, pyri-
dine 4-H), 7.69 (ddd, J ¼ 7.5, 1.0, 0.5 Hz, 1H, pyridine 3-H),
7.50 (ddd, J ¼ 9.0, 8.0, 3.0 Hz, 1H, 7-H), 7.41 (dd, J ¼ 9.0,
4.5 Hz, 1H, 8-H), 7.29 (ddd, J ¼ 7.5, 5.0, 1.0 Hz, 1H, pyridine
5-H), 4.30 (dq, J ¼ 10.5, 7.0 Hz, 1H, methylene CH), 4.25
(dq, J ¼ 10.5, 7.0 Hz, 1H, methylene CH), 4.17 (q, J ¼ 7.0
2
3
3
5
H, CH ). Anal. Calcd. for C H ClFN O ꢂ1/3H O [15]: C,
3
21 16
2
5
2
7.74; H, 3.85; N, 6.41. Found: C, 57.79; H, 3.81; N, 6.36.
Compound 6b was obtained in 61% yield (3.82 g); mp 214–
ꢀ
ꢁ1
þ
þ
2
2
15 ; IR: m 1735, 1720 cm ; ms: m/z 430 (M ), 432 (M
); NMR (deuteriodimethyl sulfoxide): (isomer A) [14] 8.66
þ
(
s, 1H, 2-H), 8.29 (s, 1H, vinylic H), 8.08 (d, J ¼ 9.0 Hz, 1H,
5
-H), 7.81 (d, J ¼ 6.0, Hz, 1H, 8-H), 7.41 (ddd, J ¼ 4.0, 2.0,
.0 Hz, 1H, pyridine 4-H), 7.34 (dd, J ¼ 8.0, 4.0 Hz, 1H, pyri-
2
dine 5-H), 8.57–8.52 (m, 2H, pyridine 2-H and 6-H), 4.21 (dq,
Hz, 2H, CH
J ¼ 7.0 Hz, 3H, CH
64.39; H, 4.67; N, 6.83. Found: C, 64.00; H, 4.69; N, 6.85.
-Chloro-6-fluoro-1,4-dihydro-1-[(Z)-1-methoxycarbonyl-
2
), 1.23 (dd, J ¼ 7.0, 7.0 Hz, 3H, CH
3
), 1.22 (t,
3
). Anal. Calcd. for C22
H19FN O : C,
2 5
J ¼ 11.0, 7.0 Hz, 1H, methylene CH), 4.17 (dq, J ¼ 11.0, 7.0
7
Hz, 1H, methylene CH), 3.81 (s, 3H, CH
3
), 1.23 (dd, J ¼ 7.0,
2
8
(
-(4- and 3-pyridyl)vinyl]-4-oxoquinoline-3-carboxylic acids
a,b. General procedure. A solution of compound 6a or 6b
1.0 g, 2.33 mmol) in concentrated sulfuric acid (0.4 mL),
water (1.0 mL), and acetic acid (40 mL) was refluxed with
stirring for 2 h. The solvent was evaporated in vacuo to give
an oily product, which was dissolved in ethanol (10 mL) and
then neutralized with sodium hydrogen carbonate to afford
crystals. The crystals were collected by suction, and then
recrystallization from N,N-dimethylformamide/ethanol/water
provided yellow needles 8a or 8b.
7
1
6
4
.0 Hz, 3H, CH ); (isomer B) [14] 8.60 (s, 1H, 2-H), 8.22 (s,
3
H, vinylic H), 8.08 (d, J ¼ 9.0 Hz, 1H, 5-H), 7.73 (d, J ¼
.0 Hz, 1H, 8-H), 7.41 (ddd, J ¼ 4.0, 2.0, 2.0 Hz, 1H, pyridine
-H), 7.33 (dd, J ¼ 8.0, 4.0 Hz, 1H, pyridine 5-H), 8.57–8.52
(
m, 2H, pyridine 2-H and 6-H), 4.20 (dq, J ¼ 11.0, 7.0 Hz,
1
H, methylene CH), 4.16 (dq, J ¼ 11.0, 7.0 Hz, 1H, methyl-
ene CH), 3.81 (s, 3H, CH
), 1.23 (dd, J ¼ 7.0, 7.0 Hz, 3H,
CH ). The 5-H, pyridine 4-H, ester methyl proton signals of
3
3
the above isomers A and B were observed in the same mag-
netic field. Anal. Calcd. for C H ClFN O ꢂ1/2H O [15]: C,
2
1
16
2
5
2
Compound 8a was obtained in 87% yield (810 mg); mp
ꢀ
5
7.35; H, 3.90; N, 6.37. Found: C, 57.39; H, 3.75; N, 6.42.
Methyl 1-[(Z)-1-ethoxycarbonyl-2-(4-, 3-, and 2-pyridyl)-
ꢁ1
þ
þ
2
2
44–245 ; IR: m 1740 cm ; ms: m/z 402 (M ), 404 (M
þ
); NMR (deuteriodimethyl sulfoxide): 14.23 (brs, 1H,
vinyl]-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylates
7
COOH), 9.05, 8.90 [14] (s, 1H, 2-H), 8.52 (d, J ¼ 6.0 Hz, 2H,
pyridine 2-H and 6-H), 8.28 (s, 1H, vinylic H), 8.25 (d, J ¼
a–c. General procedure. A solution of compound 15 (5.0 g,
5.6 mmol), 4-, 3-, or 2-pyridinecarbaldehyde (2.50 g, 23.4
1
9
6
.0 Hz, 1H, 5-H), 8.07 (d, J ¼ 6.0 Hz, 1H, 8-H), 7.09 (d, J ¼
3
mmol), and 1,8-diazabicyclo[5.4.0]-7-undecene (1.19 g, 7.80
mmol) in dry dioxane (100 mL) was refluxed with stirring for 10
h. Acetic acid (5 mL) was added to the solution, and the solvent
was evaporated in vacuo to give colorless crystals. Recrystalliza-
tion from dioxane/water afforded colorless needles 7a, 7b, or 7c.
Compound 7a [16] was obtained in 59% yield (3.75 g); mp
.0 Hz, 2H, pyridine 3-H and 5-H), 3.80 (s, 3H, CH
12ClFN O [15]: C, 56.16; H, 3.08; N,
ꢂ1/5H
.89. Found: C, 56.08; H, 3.07; N, 6.93.
Compound 8b was obtained in 51% yield (470 mg); mp
). Anal.
Calcd. for C19
H
2
O
5
2
6
ꢀ
ꢁ1
þ
þ
2
2
16–217 ; IR: m 1725 cm ; ms: m/z 402 (M ), 404 (M
þ
); NMR (deuteriodimethyl sulfoxide): 14.22 (brs, 1H,
ꢀ
ꢁ1
þ
2
26–227 ; IR: m 1725 cm ; ms: m/z 410 (M ); NMR (deuter-
COOH), 9.06 (s, 1H, 2-H), 8.60 (s, 1H, pyridine 2-H), 8.55
dd, J ¼ 3.6, 1.0 Hz, 1H, pyridine 6-H), 8.34 (s, 1H, vinylic
H), 8.26 (dd, 9.1, 1.0 Hz, 1H, 5-H), 8.08 (dd, J ¼ 4.0, 1.0 Hz,
iodimethyl sulfoxide): 8.63 (s, 1H, 2-H), 8.54 (d, J ¼ 6.0 Hz,
(
2
9
7
H, pyridine 2-H and 6-H), 8.25 (s, 1H, vinylic H), 7.92 (dd,
.3, 3.0 Hz, 1H, 5-H), 7.58 (ddd, 9.0, 8.0, 3.0 Hz, 1H, 7-H),
.50 (dd, J ¼ 9.0, 4.5 Hz, 1H, 8-H), 7.11 (d, J ¼ 6.0 Hz, 2H,
1
H, 8-H), 7.34 (dd, J ¼ 5.0, 1.0 Hz, 1H, pyridine 4-H), 7.30
(dd, J ¼ 5.0, 3.6 Hz, 1H, pyridine 5-H), 3.82 (s, 3H, CH ).
3
pyridine 3-H and 5-H), 4.28 (dq, J ¼ 11.0, 7.0 Hz, 1H, meth-
ylene CH), 4.24 (dq, J ¼ 11.0, 7.0 Hz, 1H, methylene CH),
Anal. Calcd. for C H ClFN O ꢂ1/3H O [15]: C, 55.83; H,
19
12
2
5
2
3.12; N, 6.85. Found: C, 55.83; H, 3.11; N, 6.96.
4
.18 (q, J ¼ 7.0 Hz, 2H, CH ), 1.22 (dd, J ¼ 7.0, 7.0 Hz, 3H,
1-[(Z)-1-Ethoxycarbonyl-2-(4-, 3-, and 2-pyridyl)vinyl]-6-
fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acids 9a–c.
General procedure. A solution of compound 7a, 7b, or 7c
(1.0 g, 2.44 mmol) in concentrated sulfuric acid (0.4 mL),
2
CH ), 1.21 (t, J ¼ 7.0 Hz, 3H, CH ). Anal. Calcd. for
3
3
C
4
22
H
.67; N, 6.86.
19FN
2
O
5
: C, 64.39; H, 4.67; N, 6.83. Found: C, 64.39; H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet