G.-Z. Yang et al. / European Journal of Medicinal Chemistry 194 (2020) 112253
9
0
4.2.3.13. 2,3-dimethoxyquinolino[2 ,3’:3,4]pyrrolo[2,1-b]quinazolin-
1
33.1, 130.7, 130.4, 129.6, 128.7127.3, 126.7, 126.5, 121.3, 47.3, 21.8.
þ
ꢀ
1
HRMS (ESI): calcd for C19
13
H N
3
O, [MþNa] , 322.0956; found
11(13H)-one (10l). White solid, yield, 38%; m.p. 279.6e281.2 C; H
NMR (400 MHz, CDCl
3
22.0962.
3
)
d
8.44 (d, J ¼ 7.9 Hz, 1H, AreH), 8.28 (s, 1H,
AreH), 8.09 (d, J ¼ 8.2 Hz, 1H, AreH), 7.89e7.81 (m, 1H, AreH), 7.78
0
(s, 1H, AreH), 7.58 (d, J ¼ 1.6 Hz, 1H, AreH), 7.16 (s, 1H, AreH), 5.31
4
.2.3.7. 3-chloroquinolino[2 ,3’:3,4]pyrrolo[2,1-b]quinazolin-
1
3
ꢀ
1
(s, 2H, eCH
(
2
-), 4.08 (d, J ¼ 2.1 Hz, 6H, eOCH
3
); C NMR
1
1(13H)-one (10f). White solid, yield, 53%; m.p. 274.6e276.8 C; H
NMR (400 MHz, DMSO‑d 8.99 (s, 1H, AreH), 8.79 (s, 1H, AreH),
.27 (d, J ¼ 8.1 Hz, 2H, AreH), 8.21 (d, J ¼ 8.8 Hz, 1H, AreH),
100 MHz,CDCl ) d 160.7, 150.1, 149.7, 149.3, 148.4, 139.0, 134.7,
3
6
) d
1
33.2, 131.6, 129.8, 128.7, 128.1, 127.7, 126.8, 124.4, 122.5, 121.5, 57.0,
8
þ
55.3, 47.3. HRMS (ESI): calcd for C20
H
15
N
3
O
3
, [MþNa] , 368.1011;
7
2
.93e7.83 (m, 2H, AreH), 7.78 (dd, J ¼ 8.8, 2.2 Hz,1H, AreH), 5.30 (s,
13
found 368.1015.
2 3
H, eCH -); C NMR (100 MHz, CDCl ) d 160.5, 155.1, 151.2, 149.2,
1
34.7, 133.6, 131.1, 130.4, 129.9, 129.1, 128.8, 128.4, 127.7, 126.5,122.3,
0
þ
4.2.3.14. 2,3-difluoroquinolino[2 ,3’:3,4]pyrrolo[2,1-b]quinazolin-
121.5, 47.5. HRMS (ESI): calcd for C18
H10ClN
3
O, [MþNa] , 342.0410;
ꢀ
1
1(13H)-one (10m). White solid, yield, 41%; m.p. 277.6e279.9 C;
H NMR (400 MHz, CDCl ) d 8.53e8.35 (m, 2H, AreH), 8.24 (dd,
3
found 342.0416.
1
J ¼ 10.8, 7.8 Hz, 1H, AreH), 8.13 (d, J ¼ 8.4 Hz, 1H, AreH), 7.88 (t,
0
.2.3.8. 4-methoxyquinolino[2 ,3’:3,4]pyrrolo[2,1-b]quinazolin-
4
1
J ¼ 7.8 Hz, 1H, AreH), 7.57 (d, J ¼ 1.5 Hz, 2H, AreH), 5.37 (s, 2H,
ꢀ
1
1(13H)-one (10g). White solid, yield, 55%; m.p. 270.6e273.1 C; H
NMR (400 MHz, DMSO‑d 8.70 (s, 1H,AreH), 8.35e8.26 (m, 2H,
AreH), 7.99e7.90 (m, 2H, AreH), 7.58e7.54 (m, 2H, AreH), 7.32 (t,
13
eCH
2
-); C NMR (100 MHz, CDCl
3
)
d
158.8, 155.1, 149.8, 149.3,
6
) d
148.4, 139.0, 134.7, 133.2, 131.6, 129.8, 128.8, 128.1, 127.7, 126.8,
1
24.4, 122.5, 121.5, 57.0, 47.5. HRMS (ESI): calcd for C18
H
9
F
2
N
3
O,
1
3
J ¼ 4.5 Hz, 1H, AreH), 5.31 (s, 2H, eCH
2
-), 4.08 (s, 3H,-OCH
3
);
C
þ
[MþNa] , 344.0611; found 344.0615.
NMR (100 MHz, CDCl 160.7, 155.6, 152.1, 149.3, 148.4, 139.0,
3
) d
1
34.7,133.2,131.6, 129.8,128.7, 128.1, 127.7, 126.8, 124.4, 122.5,121.3,
0
4
.2.3.15. 3-(trifluoromethyl)quinolino[2 ,3’:3,4]pyrrolo[2,1-b]quina-
(10n). White solid, yield, 41%; m.p.
74.6e277.4 C; H NMR (400 MHz, DMSO‑d 8.98 (s, 1H), 8.60 (d,
þ
57.0, 47.3. HRMS (ESI): calcd for C19
H
13
N
3
O
2
, [MþNa] , 338.0905;
zolin-11(13H)-one
2
found 338.0910.
ꢀ
1
6
) d
J ¼ 8.5 Hz, 1H, AreH), 8.29 (dd, J ¼ 17.4, 7.5 Hz, 2H, AreH), 8.06 (t,
0
4
1
.2.3.9. 4-methylquinolino[2 ,3’:3,4]pyrrolo[2,1-b]quinazolin-
J ¼ 8.0 Hz, 1H, AreH), 8.01e7.89 (m, 2H, AreH), 7.66 (m, 1H, AreH),
ꢀ
1
13
1(13H)-one (10h). White solid, yield, 53%; m.p. 272.3e274.6 C; H
NMR (400 MHz, DMSO‑d 8.73 (s, 1H, AreH), 8.35e8.25 (m, 1H,
AreH), 7.96 (dt, J ¼ 25.5, 7.8 Hz, 3H, AreH), 7.76 (d, J ¼ 7.1 Hz, 1H,
AreH), 7.63 (m, 2H, AreH), 5.31 (s, 2H, eCH -), 2.87 (s, 3H, -CH3);
160.7, 152.9, 150.1, 149.4, 148.6, 138.9,
5.37 (s, 2H, eCH
2
-); C NMR (100 MHz, CDCl
3
)
d
160.5, 152.9, 151.8,
6
)
d
149.2, 148.4, 134.8, 131.6, 131.4, 129.9, 129.3, 128.9, 128.4, 127.8,
126.5, 124.1, 121.4, 47.3. HRMS (ESI): calcd for C19
[MþNa] , 410.0284; found 410.0292.
H
9
ClF
3
N
3
O,
þ
2
13
3
C NMR (100 MHz, CDCl ) d
0
1
34.4, 133.1, 131.7, 130.8, 129.3, 128.9, 127.4, 126.3, 125.9, 121.3, 47.2,
4.2.3.16. 1-(trifluoromethyl)quinolino[2 ,3’:3,4]pyrrolo[2,1-b]quina-
þ
18.5. HRMS (ESI): calcd for C19
H
13
N
3
O, [MþNa] , 322.0956; found
zolin-11(13H)-one
(10o). White yield,
m.p.270.6e272.1 C; 1H NMR (400 MHz, DMSO‑d
) d 8.92 (s, 1H,
6
solid,
39%;
ꢀ
3
22.0962.
AreH), 8.65 (s, 1H, AreH), 8.44 (d, J ¼ 8.6 Hz, 1H, AreH), 8.36e8.26
0
(m, 1H,AreH), 8.03 (d, J ¼ 8.9 Hz, 1H, AreH), 7.96 (d, J ¼ 6.4 Hz, 2H,
4
.2.3.10. 2-(trifluoromethyl)quinolino[2 ,3’:3,4]pyrrolo[2,1-b]quina-
13
2
AreH), 7.64 (m, 1H, AreH), 5.37 (s, 2H, eCH -); C NMR (100 MHz,
zolin-11(13H)-one
2
8
(10i). White
71.1e273.2 C; H NMR (400 MHz, DMSO‑d
.74 (s, 1H, AreH), 8.49 (d, J ¼ 8.9 Hz, 1H, AreH), 8.35e8.27 (m, 1H,
solid,
yield,
) d 8.98 (s, 1H, AreH),
42%;
m.p.
ꢀ
1
3
CDCl ) d 160.5, 152.0, 149.5, 149.1, 135.4, 134.7, 130.8, 129.0, 128.8,
6
1
C
28.4, 127.8, 127.1126.5, 124.8, 121.4, 47.5. HRMS (ESI): calcd for
þ
19
H
10
F
3
N
3
O, [MþNa] , 376.0674; found 376.0680.
AreH), 8.20e8.10 (m, 1H, AreH), 7.97 (d, J ¼ 6.1 Hz, 2H, AreH),
13
7
.84e7.68 (m, 1H, AreH), 5.38 (s, 2H, eCH
CDCl 160.5, 152.0, 149.2, 134.8, 133.1, 132.7, 130.7, 128.9, 127.9,
O,
2
-); C NMR (100 MHz,
4.2.4. Synthesis of luotonin A derivatives (10p)
3
) d
2 2
A solution of boron tribromide (5 mL, 5 mmol, 1.0 M) in CH Cl
was slowly added dropwise with a syringe to 10a (73 mg, 0.23 mmol)
1
27.67, 126.5,121.4, 47.3. HRMS (ESI): calcd for C19
H F
10 3
N
3
þ
[MþNa] , 376.0674; found 376.0680.
ꢀ
in CH Cl
2 2
under nitrogen at ꢂ78 C. After 5 min of completion, the
reaction solution was slowly returned to room temperature. After
stirring for 12 h, the mixture was heated to reflux for 30 min. Then,
the reaction solution was placed in an ice bath, and 5 mL of water
was slowly added thereto, stirred for 30 min, and the reaction so-
0
4
1
.2.3.11. 3-fluoroquinolino[2 ,3’:3,4]pyrrolo[2,1-b]quinazolin-
1(13H)-one (10j). White solid, yield, 42%; m.p. 270.2e272.3 C; H
ꢀ
1
NMR (400 MHz, CDCl
1
1
3
)
d
8.72e8.65 (m, 1H, AreH), 8.37 (dd, J ¼ 7.9,
.6 Hz, 1H, AreH), 8.23 (d, J ¼ 8.7 Hz, 1H, AreH), 8.06 (d, J ¼ 8.2 Hz,
2 2
lution was diluted with 50 mL of CH Cl , and the mixture was
H, AreH), 7.86e7.68 (m, 2H,AreH), 7.53 (ddd, J ¼ 8.1, 7.1, 1.2 Hz,1H,
13
adjusted to pH 11 with a NaOH (2N) solution to collect water. The
water layer was adjusted to pH 2 with concentrated hydrochloric
acid, and a solid was precipitated. The obtained precipitate was
collected by vacuum filtration, washed several times with water
AreH), 7.31 (dd, J ¼ 9.5, 8.0 Hz, 1H, AreH), 5.32 (s, 2H, eCH
2
-);
C
3
NMR (100 MHz, CDCl ) d 160.5,155.6,151.2,149.3,144.8,135.1,133.1,
1
30.8, 129.0, 128.8, 127.7, 126.5, 124.6, 122.5, 121.3, 47.3. HRMS (ESI):
þ
calcd for C18
H10FN
3
O, [MþNa] , 326.0706; found 326.0711.
(20 mL), and dried to give the compound 10p as a faint yellow solid.
0
0
4
1
.2.3.12. 1-fluoroquinolino[2 ,3’:3,4]pyrrolo[2,1-b]quinazolin-
4.2.4.1. 2-hydroxyquinolino[2 ,3’:3,4]pyrrolo[2,1-b]quinazolin-
ꢀ
1
ꢀ
1
1(13H)-one (10k). White solid, yield, 42%; m.p. 273.4e275.8 C; H
NMR (400 MHz, CDCl 8.53e8.38 (m, 2H, AreH), 8.18e8.06 (m,
H, AreH), 7.99 (dd, J ¼ 9.1, 5.9 Hz, 1H, AreH), 7.88 (td, J ¼ 8.3, 7.7,
11(13H)-one (10p). Faint yellow solid, yield, 40%; m.p. >300 C; H
NMR (400 MHz, DMSO‑d 10.55 (s, 1H, eOH), 8.48 (s, 1H, AreH),
3
)
d
6
) d
2
1
8.27 (d, J ¼ 7.9 Hz, 1H, AreH), 8.11 (d, J ¼ 9.0 Hz, 1H, AreH),
.6 Hz, 1H, AreH), 7.61 (t, J ¼ 7.4 Hz, 1H, AreH), 7.55e7.43 (m, 1H,
7.93e7.91 (m, 2H, AreH), 7.60e7.57 (m, 1H, AreH), 7.51e7.47 (m,
1
3
13
AreH), 5.36 (s, 2H, eCH
1
2
-); C NMR (100 MHz, CDCl
3
)
d
160.5,
1H, AreH), 7.33e7.32 (m, 1H, AreH), 5.27 (s, 2H, eCH
(100 MHz, CDCl
2
-); C NMR
58.2, 152.2, 149.2, 144.7, 135.0, 134.7, 131.6, 130.2, 125.2, 121.4,
3
)
d
160.7, 155.3, 151.1, 149.6, 137.1133.3, 133.1, 130.7,
1
C
19.5, 115.5, 114.2, 112.2, 111.9,107.75, 47.5. HRMS (ESI): calcd for
130.4, 129.6, 128.7, 127.3, 126.7, 126.5, 121.3, 47.3. HRMS (ESI): calcd
þ
þ
18
H10FN
3
O, [MþNa] , 326.0706; found 326.0711.
for C18H
11
N
3
O
2
, [MþH] , 301.0851; found 301.0855.