10
E. Martín-Encinas et al. / European Journal of Medicinal Chemistry 195 (2020) 112292
chromatography using an elution of 20e80% ethyl acetate - hexane
to afford products 8 or 10.
CH), 4.83 (s, 1H, NH), 6.33 (d, 3JHH ¼ 4.8 Hz, 1H, CHarom), 6.82e7.47
13
1
(m, 14H, Harom), 7.85e7.89 (m, 1H, CHarom) ppm. C { H} NMR
6
.1.5.1.1. 7-Phenyl-5-tosyl-5,6,6a,7,12,12a-hexahydroquinolino
3 3 2
(75 MHz, CDCl ) d: 21.7 (CH ), 40.0 (CH), 48.6 (CH ), 48.7 (CH), 53.2
[
4,3-b][1,5]naphthyridine (8a). The general procedure was followed
(CH), 123.9 (CH), 124.1 (CH), 125.2 (CH), 125.7 (CH), 127.1 (2 CH),
128.1 (CH), 128.4 (CH), 128.5 (C), 128.9 (C), 129.3 (2 CH), 129.6 (C),
129.9 (CH), 129.9 (CH), 133.8 (C), 135.8 (C), 136.0 (C), 137.8 (CH),
using aldimine 4a and BF3$Et
(
2
O (2 mmol, 0.25 mL) affording 0.284
88%) of a white solid identified as 8a, mp 190e191 C (ethyl ace-
ꢀ
1
tate/hexane).
H
NMR (400 MHz, CDCl
3
)
d
:
1.90 (dddd,
138.4 (CH), 138.8 (C), 139.9 (C), 144.1 (C) ppm. HRMS (EI) calculated
3
3
3
3
þ
J
HH ¼ 11.3 Hz, JHH ¼ 11.3 Hz, JHH ¼ 10.7 Hz, JHH ¼ 4.2 Hz, 1H, CH),
for C28
H N
24 3
BrO
2
S [M] 545.0773; found 545.0742. Purity 95.10%
3
3
2
3
4
6
H
{
(
(
.34 (s, 3H, CH
3
), 3.36 (dd, JHH ¼ 14.0 Hz, JHH ¼ 11.3 Hz, 1H, CH
2
),
(EtOH/Heptane ¼ 10/90, Rt ¼ 7.20 min).
3
3
.85 (d, JHH ¼ 11.0 Hz, 1H, CH
2
), 3.98 (d, JHH ¼ 10.7 Hz, 1H, CH),
6.1.5.1.5. 7-Phenyl-5-tosyl-6a,7,12,12a-tetrahydroquinolino[4,3-b]
[1,5]naphthyridin-6(5H)-one (9). The general procedure was fol-
3
3
.05 (dd, JHH ¼ 14.0 Hz, JHH ¼ 4.2 Hz, 1H, Harom), 4.22 (s, 1H, NH),
3
4
.94e7.38 (m, 14H, Harom), 7.95 (dd, JHH ¼ 4.2 Hz, JHH ¼ 1.8 Hz, 1H,
lowed using aldimine 5 and BF3$Et
2
O (2 mmol, 0.25 mL) affording
3
4
13
ꢀ
arom), 7.99 (dd, JHH ¼ 8.6 Hz, JHH ¼ 2.0 Hz, 1H, Harom) ppm.
C
0.456 g (95%) of a white solid identified as 9, mp 270e271 C (ethyl
1
1
H} NMR (75 MHz, CDCl
3
)
d
: 21.7 (CH
3
), 41.5 (CH), 48.6 (CH
2
), 51.6
acetate/hexane). H NMR (400 MHz, CDCl
3
)
d
: 2.39 (s, 3H, CH
3
), 3.06
3
3
3
CH), 53.3 (CH), 122.2 (CH), 122.8 (CH), 124.5 (CH), 125.1 (CH), 125.4
CH), 127.2 (3 CH), 128.2 (C), 128.9 (2 CH), 129.2 (2 CH), 129.6 (C),
29.8 (2 CH), 136.0 (C), 136.3 (C), 140.7 (CH), 140.8 (C), 142.0 (C),
(dd, JHH ¼ 12.0 Hz, JHH ¼ 9.0 Hz, 1H, CH
2
), 4.32 (d, JHH ¼ 9.0 Hz,
3
1H, CH
2
), 4.36 (d, JHH ¼ 12.0 Hz,1H, CH), 6.71 (s,1H, NH), 6.97e7.89
1
3
1
1
3 3
(m, 16H, Harom) ppm. C { H} NMR (75 MHz, CDCl ) d: 21.1 (CH ),
1
43.8 (C), 145.1 (C) ppm. HRMS (EI) calculated for C28
H
25
N
3
O
2
S
45.4 (CH), 48.7 (CH), 51.75 (CH), 121.9 (CH), 122.2 (CH), 123.6 (CH),
123.9 (CH), 125.7 (CH), 126.4 (CH), 127.4 (CH), 127.9 (2 CH), 128.0 (2
CH), 129.1 (2 CH), 129.8 (2 CH), 132.0 (C), 132.8 (C), 136.1 (C), 139.4
þ
[
M] 467.1667; found 467.1666. Purity 96.00% (EtOH/Heptane ¼ 10/
0, Rt ¼ 7.30 min).
.1.5.1.2. 9-Methoxy-7-phenyl-5-tosyl-5,6,6a,7,12,12a-hexahy-
droquinolino[1,2-b][1,5]naphthyridine (8b). The general procedure
was followed using aldimine 4b and BF3$Et O (2 mmol, 0.25 mL)
affording, 0.422 g (85%) of a white solid identified as 8b, mp
9
6
(C), 140.0 (CH), 144.6 (C), 145.1 (C), 145.3 (C), 170.5 (CO) ppm. HRMS
þ
(EI) calculated for C28
33
H N
3
O
3
S [M] 467.1667; found 481.1461.
2
Purity 98.40% (EtOH/Heptane ¼ 10/90, Rt ¼ 8.05 min).
ꢀ
1
2
35e236 C (ethyl acetate/hexane). H NMR (400 MHz, CDCl
3
)
d:
6.1.6. Synthesis of quinolino[4,3-b][1,5]naphthyridines 10 and
quinolino[4,3-b][1,5]naphthyridin-6(5H)-one 11
6.1.6.1. General procedure A. To a solution of the corresponding
.75 (dddd, 3
J
HH ¼ 11.0 Hz,
3
J
HH ¼ 11.0 Hz,
3
J
HH ¼ 11.0 Hz,
1
3
3
J
HH ¼ 4.0 Hz, 1H, CH), 2.25 (s, 3H, CH
3
), 3.26 (dd, JHH ¼ 14.0 Hz,
3JHH ¼ 11.0 Hz, 1H, CH
), 3.38 (s, 3H, OCH
), 3.65 (d, JHH ¼ 11.0 Hz,
3
naphthyridine derivative (1 mmol) in toluene (20 mL) MnO
2
2
3
3
3
1
H, CH
2
), 3.85 (d, JHH ¼ 11.0 Hz, 1H, CH), 4.08 (dd, JHH ¼ 14.0 Hz,
(4 mmol, 0.347 g) was added and the reaction was refluxed for 24 h.
The reaction mixture was filtered on celite, washed with
dichloromethane (2 ꢂ 10 mL), and dried over anhydrous MgSO4.
The solvent was removed under vacuum afforing an oil that was
purified by silica gel flash column chromatography using an elution
of 20e80% ethyl acetate - hexane to afford products 10 and 11.
General procedure B. To a solution of the corresponding alde-
3
3
J
HH ¼ 4.0 Hz, 1H, Harom), 6.37 (d,
J
HH ¼ 7.8 Hz, 1H, CHarom),
3
6
.86e7.26 (m, 14H, Harom), 7.90 (d, JHH ¼ 9.10 Hz, 1H, CHarom) ppm.
1
3
1
C { H} NMR (75 MHz, CDCl
3
)
d
: 21.7 (CH
3
), 40.9 (CH), 48.7 (CH
2
),
5
1
(
1
1.2 (CH), 53.1 (OCH
25.4 (CH), 126.8 (CH), 127.2 (2 CH), 128.2 (CH), 128.3 (2 CH), 129.1
2 CH), 129.4 (2 CH), 129.8 (CH and C), 134.5 (C), 136.0 (C), 136.4 (C),
41.4 (C), 142.0 (C), 143.7 (C), 157.3 (C) ppm. HRMS (EI) calculated
3
), 54.1 (CH), 109.4 (CH), 124.8 (CH), 125.1 (CH),
hyde 12 (1 mmol, 0.389 g) in CHCl
aminopyridine (1 mmol) was added in presence of molecular
sieves (4 Å). Then, BF3$Et O was added and the reaction was
3
(20 mL), the corresponding 3-
þ
27 3 3
H N O S [M] 497.1773; found 497.1769. Purity 98.60%
for C29
EtOH/Heptane ¼ 10/90, Rt ¼ 6.90 min).
.1.5.1.3. 9-Bromo-7-phenyl-5-tosyl-5,6,6a,7,12,12a-hexahy-
droquinolino[4,3-b][1,5] naphthyridine (8c). The general procedure
was followed using aldimine 4c and BF3$Et O (2 mmol, 0.25 mL)
affording 0.465 g (85%) of a white solid identified as 8c, mp
(
2
6
refluxed for 12 h. The reaction mixture was washed with 2M
aqueous solution of NaOH (50 mL) and water (50 mL), extracted
with dichloromethane (2 ꢂ 25 mL), and dried over anhydrous
MgSO4. The solvent was removed under vacuum afforing an oil that
was purified by silica gel flash column chromatography using an
elution of 20e80% ethyl acetate - hexane to afford products 10.
6.1.6.1.1. 7-Phenyl-5-tosyl-5,6-dihydroquinolino[4,3-b][1,5]naph-
thyridine (10a). The general procedure A was followed using
naphthyridine 8a 0.463 g (99%) of a white solid identified as 10a,
2
ꢀ
1
2
38e239 C (ethyl acetate/hexane). H NMR (400 MHz, CDCl ) d:
3
.85 (dddd, 3
J
HH ¼ 11.0 Hz,
3
J
HH ¼ 11.0 Hz,
3
J
HH ¼ 10.0 Hz,
1
3
3
J
J
HH ¼ 4.7 Hz, 1H, CH), 2.37 (s, 3H, CH
3
), 3.35 (dd, JHH ¼ 14.0 Hz,
3
3
HH ¼ 11.0 Hz, 1H, CH
2
), 3.81 (d, JHH ¼ 11.0 Hz, 1H, CH
2
), 3.98 (d,
3JHH ¼ 10.0 Hz, 1H, CH), 4.10 (dd, JHH ¼ 14.0 Hz, JHH ¼ 4.7 Hz, 1H,
3
3
3
ꢀ
H
arom), 4.25 (s, 1H, NH), 6.86 (d,
J
HH ¼ 9.0 Hz, 1H, CHarom),
mp 193e194 C (ethyl acetate/hexane). When the procedure B was
3
6
.94e7.39 (m, 14H, Harom), 8.00 (d, JHH ¼ 8.4 Hz, 1H, CHarom) ppm.
followed using aldimine 13a and BF3$Et
0.393 g (85%) of compound 10a were obtained. H NMR (400 MHz,
2
O (2 mmol, 0.25 mL),
1
3
1
1
C { H} NMR (75 MHz, CDCl
3
)
d
: 21.7 (CH
3
), 41.2 (CH), 48.4 (CH
2
),
3
51.2 (CH), 53.4 (CH), 124.5 (CH), 125.1 (CH), 125.4 (CH), 125.9 (CH),
CDCl
3
)
d
: 1.90 (s, 3H, CH
3
), 4.93 (s, 2H, CH
2
), 6.66 (d, JHH ¼ 7.8 Hz,
3
126.5 (CH), 127.2 (3 CH), 128.4 (CH), 128.7 (2 CH), 129.0 (C), 129.3 (2
1H, CH), 6.97 (d, JHH ¼ 8.5 Hz, 1H, CH), 7.36e7.65 (m, 8H, CH), 7.81
3
3
3
CH), 129.8 (2 CH), 129.9 (C), 135.9 (C), 136.3 (C), 140.3 (C), 141.2 (C),
(dd, JHH ¼ 14.0 Hz, JHH ¼ 8.0 Hz, 1H, CH), 7.81 (dd, JHH ¼ 8.2 Hz,
3 4
4
1
43.8 (C), 145.7 (C) ppm. HRMS (EI) calculated for C28
H
24BrN
545.0773; found 545.0742. Purity 96.60% (EtOH/
Heptane ¼ 10/90, Rt ¼ 6.80 min).
.1.5.1.4. 11-Bromo-7-phenyl-5-tosyl-5,6,6a,7,12,12a-hexahy-
droquinolino[4,3-b][1,5] naphthyridine (8d). The general procedure
was followed using aldimine 4b and BF3$Et O (2 mmol, 0.25 mL)
affording 0.386 g (70%) of a white solid identified as 8d, mp
3
O
2
S
J
HH ¼ 1.6 Hz,1H, CH), 8.30 (dd, JHH ¼ 8.2 Hz, JHH ¼ 2.0 Hz,1H, CH),
3 4 13 1
þ
[M]
8.30 (dd, JHH ¼ 4.2 Hz, JHH ¼ 1.8 Hz, 1H, CH) ppm. C { H} NMR
(75 MHz, CDCl : 21.1 (CH ), 48.1 (CH ), 124.0 (CH), 126.4 (CH),
3
)
d
3
2
6
126.5 (C), 121.1 (2 CH), 128.0 (2 CH), 128.7 (2 CH), 128.8 (2 CH), 129.2
(CH), 130.2 (2 CH), 130.8 (C), 131.1 (CH), 133.7 (C), 134.5 (C), 137.0
2
(CH), 138.4 (C), 141.6 (C), 143.2 (C), 143.7 (C), 145.2 (C), 150.3 (C),
þ
21 3 2
150.8 (CH) ppm. HRMS (EI) calculated for C28H N O S [M]
ꢀ
1
2
01e202 C (ethyl acetate/hexane). H NMR (400 MHz, CDCl
3
)
d:
463.1354; found 463.1363. Purity 97.00% (EtOH/Heptane ¼ 10/90,
.84 (dddd, 3
J
HH ¼ 11.2 Hz,
3
J
HH ¼ 11.5 Hz,
3
J
HH ¼ 10.5 Hz,
Rt ¼ 6.35 min).
1
3
3
J
J
HH ¼ 5.0 Hz, 1H, CH), 2.29 (s, 3H, CH
3
), 3.23 (dd, JHH ¼ 13.8 Hz,
6.1.6.1.2. 9-Methoxy-7-phenyl-5-tosyl-5,6-dihydroquinolino[4,3-
b][1,5]naphthyridine (10b). The general procedure A was followed
using naphthyridine 9b 0.493 g (99%) of a white solid identified as
3
3
HH ¼ 11.2 Hz, 1H, CH
2
), 3.60 (d, JHH ¼ 11.2 Hz, 1H, CH
2
), 3.84 (dd,
3JHH ¼ 13.5 Hz, JHH ¼ 5.0 Hz, 1H, Harom), 3.83 (d, JHH ¼ 10.5 Hz, 1H,
3
3