L. Paloque et al. / European Journal of Medicinal Chemistry 54 (2012) 75e86
83
solution in ethanol) were then added. The mixture was stirred and
heated under reflux for 24 h. After disappearance of 3 (monitored
by TLC), the mixture was poured into water and extracted with
ethyl acetate. The organic layer was washed with water, dried over
(200 MHz, CDCl
3
)
d
: 7.89e7.97 (m, 1H), 8.23 (d, J ¼ 9.0 Hz, 1H),
8.50e8.60 (m, 2H), 9.18 (d, J ¼ 9.0 Hz, 1H), 10.23 (d, J ¼ 0.8 Hz, 1H).
13
C NMR (50 MHz, CDCl : 120.0 (CH), 122.8 (C), 126.8 (CH), 128.5
3
) d
(CH), 133.7 (CH), 137.3 (CH), 145.6 (C), 147.9 (C), 153.2 (C), 192.7 (C).
2 4
anhydrous Na SO and evaporated. The crude residue was purified
by chromatography on a silica gel column, eluting with ethyl
acetate.
4.1.21. Preparation of 2-chloro-8-nitroquinoline 30 [40] and
2-chloro-5-nitroquinoline 31 [41]
ꢁ
Compound 23 was obtained as a yellow solid in 35% yield; mp
Pure H
HNO
stirred at rt for 1 h. After the reaction mixture was poured into
water, the solution was neutralized with Na CO and extracted
twice with dichloromethane. The organic layer was washed with
water, dried over anhydrous Na SO and evaporated in vacuo.
2
SO
4
was added onto 1 equiv of 29 at 0 C. 3 equiv of 65%
ꢁ
1
1
7
(
74 C. H NMR (200 MHz, DMSO-d
6
)
d
: 2.90 (d, J ¼ 4.2 Hz, 3H),
3
were then added dropwise and the reaction mixture was
.83e7.91 (m, 1H), 8.30 (d, J ¼ 8.6 Hz, 1H), 8.37e8.41 (m, 2H), 8.51
13
d, J ¼ 4.2 Hz, 1H), 8.77 (d, J ¼ 8.6 Hz, 1H). C NMR (50 MHz, DMSO-
: 26.8 (CH ), 120.9 (CH), 125.3 (CH), 127.7 (CH), 129.8 (C), 132.8
CH), 137.4 (C), 139.1 (CH), 148.1 (C), 152.5 (C), 164.2 (C). Anal. Calcd
for C11 : C, 57.14; H, 3.92; N, 18.17. Found: C, 57.32; H, 4.00; N,
2
3
d
6
)
d
3
(
2
4
H
9
N
3
O
3
Compound 30 was obtained, after purification by column
chromatography (eluent: cyclohexaneeethyl acetate 8:2), as
18.32.
ꢁ
ꢁ
1
a white solid in 54% yield; mp 152 C, Lit: 149 C [40]. H NMR
(200 MHz, CDCl
: 7.52e7.56 (d, J ¼ 8.6 Hz, 1H), 7.60e7.68 (m, 1H),
8.02e8.11 (m, 2H), 8.20 (d, J ¼ 8.6 Hz, 1H). C NMR (50 MHz, CDCl
: 124.6 (CH), 124.9 (CH), 125.8 (CH), 127.6 (C), 131.8 (CH), 138.6
(CH), 139.0 (C), 147.3 (C), 153.6 (C).
4
2
.1.19. Preparation of N-isopropyl-8-nitroquinoline-2-carboxamide
4 and [(8-nitroquinolin-2-yl)-pyrrolidin-1-yl]methanone 25
To a solution of 1 equiv of 8-nitro-2-trichloromethylquinoline 3
3
) d
13
3
)
d
in dioxane (30 mL), 15 equiv of appropriate amine were added. The
mixture was stirred and heated under reflux for 4 h.
After disappearance of 3 (monitored by TLC), the mixture was
poured into water and extracted with ethyl acetate. The organic
Compound 31 was obtained, after purification by column
chromatography (eluent: cyclohexaneeethyl acetate 8:2), as a pale
ꢁ
ꢁ
1
yellow solid in 14% yield; mp 134 C, Lit: 133e134 C [41]. H NMR
(200 MHz, CDCl
: 7.63 (d, J ¼ 9.2 Hz, 1H), 7.80e7.88 (m, 1H), 8.34
(d, J ¼ 8.5 Hz,1H), 8.40 (dd, J ¼ 1.1 and 7.7 Hz,1H), 8.99 (d, J ¼ 9.2 Hz,
layer was washed with water, dried over anhydrous Na
2
SO
4
and
3
) d
evaporated. The crude residue was purified by chromatography on
a silica gel (eluent: ethyl acetate) to give the corresponding amide
13
3
1H). C NMR (50 MHz, CDCl ) d: 119.9 (C), 124.9 (CH), 125.4 (CH),
2
4 and 25.
128.8 (CH), 134.9 (CH), 135.5 (CH), 145.4 (C), 148.0 (C), 152.5 (C).
Compound 24 was obtained as an orange solid in 56% yield; mp
ꢁ
1
1
29 C. H NMR (200 MHz, CDCl
.23e4.40 (m, 1H), 7.71 (dd, J ¼ 1.3 and 8.3 Hz, 1H), 7.96 (br s, 1H),
.12 (dd, J ¼ 1.3 and 8.3 Hz, 1H), 8.19 (dd, J ¼ 1.3 and 7.4 Hz, 1H),
.40e8.50 (m, 2H). 13C NMR (50 MHz, CDCl
: 22.6 (CH *2), 41.7
3
)
d
: 1.32 (d, J ¼ 6.6 Hz, 6 H),
4.1.22. Preparation of 8-nitroquinolin-2-amine 32 [40]
4
8
8
1 equiv of 30 was put in a sealed reactor. 15 mL of a 0.5 M
solution of ammonia in dioxane were injected. The reaction
ꢁ
3
)
d
3
mixture was then stirred at 110 C for 48 h before the solvent was
(
(
CH), 120.6 (CH), 125.0 (CH), 126.5 (CH), 129.8 (C), 132.3 (CH), 137.8
CH), 147.8 (C), 152.0 (C), 162.3 (C). The quaternary carbon atom
evaporated.
Compound 32 was obtained, after purification by column
chromatography (eluent: dichloromethaneeethyl acetate 1:1), as
a crystalline brown solid in 11% yield; mp 160 C. H NMR
(200 MHz, CDCl
: 5.20 (br s, 2H), 6.80 (d, J ¼ 8.9 Hz, 1H),
7.21e7.28 (m, 2H), 7.75e7.80 (m, 1H); 7.86e7.93 (m, 1H). C NMR
(50 MHz, CDCl : 124.5 (CH), 124.9 (CH), 125.8 (CH), 127.6 (C),
bearing the nitro group was not observed under these experimental
conditions. Anal. Calcd for C13 : C, 60.22; H, 5.05; N, 16.21.
Found: C, 60.07; H, 5.18; N, 15.89.
Compound 25 was obtained as a brown solid in 78% yield; mp
ꢁ
1
13
H N
3
O
3
3
) d
1
3
ꢁ
1
1
29 C. H NMR (200 MHz, CDCl
J ¼ 6.2 Hz, 2H), 4.00 (t, J ¼ 6.7 Hz, 2H), 7.67 (dd, J ¼ 7.9 and 7.9 Hz,
H), 8.07 (d, J ¼ 7.8 Hz, 2H), 8.24 (d, J ¼ 8.6 Hz, 1H), 8.35 (d,
3
)
d: 1.91e2.03 (m, 4H), 3.73 (t,
3
) d
131.8 (CH), 138.7 (CH), 138.9 (C), 147.2 (C), 153.5 (C). MS (þESI):
þ
1
190.38 (M þ H ). Calcd for C
9 7 3 2
H N O : 189.05.
13
J ¼ 8.6 Hz, 1H). C NMR (50 MHz, CDCl
3 2 2
) d: 23.8 (CH ), 26.9 (CH ),
4
7.6 (CH
2
), 49.5 (CH
2
), 123.3 (CH), 123.9 (CH), 126.3 (CH), 128.9 (C),
4.1.23. Preparation of 5-nitroquinolin-2-ol 33 [42]
1
31.7 (CH), 136.8 (CH), 137.7 (C), 148.4 (C), 155.4 (C), 164.3 (C). Anal.
Compound 33 was prepared as described previously [42] and
was obtained, after purification by column chromatography
Calcd for C14
4
H
13
N
3
O
3
: C, 61.99; H, 4.83; N, 15.49. Found: C, 62.10; H,
ꢁ
.99; N, 15.40.
(eluent: ethyl acetate), as a beige solid in 87% yield; mp 302 C, Lit:
ꢁ
1
3
02 C. H NMR (200 MHz, DMSO-d
7.63e7.75 (m, 2H), 7.85e7.90 (m, 1H), 8.25 (d, J ¼ 10.1 Hz, 1H).
NMR (50 MHz, DMSO-d : 111.7 (C), 118.7 (CH), 121.2 (CH), 125.5
6
)
d
: 6.76 (d, J ¼ 10.1 Hz, 1H),
13
4
5
.1.20. Preparation of 8-nitroquinoline-2-carbaldehyde 27 [35] and
-nitro-quinoline-2-carbaldehyde 28 [39]
C
6
) d
ꢁ
Pure H
HNO
stirred at rt for 1 h. After the reaction mixture was poured into
water, the solution was neutralized with Na CO and extracted
twice with dichloromethane. The organic layer was washed with
water, dried over anhydrous Na SO and evaporated in vacuo.
Compound 27 was obtained, after purification by column
chromatography (eluent: dichloromethaneeethyl acetate 8:2), as
a beige solid in 40% yield; mp 154 C, Lit: 152 C [35]. H NMR
2
SO
4
was added onto 1 equiv of 26 at 0 C. 3 equiv of 65%
(CH), 130.3 (CH), 134.4 (CH), 140.4 (C), 146.5 (C), 161.0 (C).
3
were then added dropwise and the reaction mixture was
4.1.24. Preparation of the 8-nitroquinoline 35 [43] and
2
3
5-nitroquinoline 36 [41]
ꢁ
Pure H
HNO
stirred at rt for 1 h. The reaction mixture was successively poured
into water, neutralized with Na CO and extracted twice with
dichloromethane. The organic layer was washed with water, dried
over anhydrous Na SO and evaporated in vacuo.
Compound 35 was obtained as a pale yellow solid in 34% yield;
2
SO
4
was added onto 1 equiv of 34 at 0 C. 3 equiv of 65%
2
4
3
were then added dropwise and the reaction mixture was
2
3
ꢁ
ꢁ
1
(
(
(
200 MHz, CDCl
m, 1H), 10.19 (s, 1H). C NMR (50 MHz, CDCl
CH), 127.9 (CH), 130.5 (C), 131.8 (CH), 137.7 (CH), 139.0 (C),146.8 (C),
53.9 (C), 192.9 (CH).
3
)
d
: 7.74e7.82 (m,1H), 8.11e8.18 (m, 3H), 8.43e8.47
2
4
13
3
) d: 119.0 (CH), 124.5
ꢁ
ꢁ
1
mp 90 C, Lit: 89e90 C [43]. H NMR (200 MHz, CDCl
3
) d: 7.53e7.66
1
(m, 2H), 8.04 (d, J ¼ 8.0 Hz, 2H), 8.27 (dd, J ¼ 1.6 and 8.4 Hz, 1H),
1
3
Compound 28 was obtained, after purification by column
chromatography (eluent: dichloromethaneeethyl acetate 8:2), as
a beige solid in 35% yield; mp 167 C, Lit: 168 C [39]. H NMR
9.70 (dd, J ¼ 1.7 and 4.2 Hz, 1H). C NMR (50 MHz, CDCl
3
) d: 122.8
(CH), 123.8 (CH), 125.3 (CH), 129.0 (C), 132.0 (CH), 136.1 (CH), 139.5
(C), 148.2 (C), 152.6 (CH).
ꢁ
ꢁ
1