Synthesis and antineoplastic activity of quinoline derivatives

Article abstract of DOI:10.1071/CH07419

Designed as a new series of molecules that contain the quinoline substructure, several 11H-indolo[3.2-c]quinoline derivatives were synthesized and subjected to biological evaluation. Several compounds were found to exhibit cytotoxic activity against the growth of colon (HTC-8), liver (BEL-7402), gastric (BCG-823), pulmonary gland (A549), and ovary (A2780) cancer cell lines. The structureactivity relationship of these compounds is discussed. CSIRO 2008.

Full text of DOI:10.1071/CH07419

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2008, 61, 531–536
Synthesis and Antineoplastic Activity of Quinoline
Derivatives
Qiang Zhou,A Jing Hou,A Huamin Li,A Li Cui,A Han Jia,A Bing Gong,A,B
and Lan HeA,C
AColleges of Chemistry and Resources Science and Technology, Beijing Normal University,
Beijing 100875, China.
BDepartment of Chemistry, University at Buffalo, State University of New York,
Buffalo, NY 14260, USA.
CCorresponding author. Email: helan1961@yahoo.com.cn
Designed as a new series of molecules that contain the quinoline substructure, several 11H-indolo[3.2-c]quinoline deriva-
tives were synthesized and subjected to biological evaluation. Several compounds were found to exhibit cytotoxic activity
against the growth of colon (HTC-8), liver (BEL-7402), gastric (BCG-823), pulmonary gland (A549), and ovary (A2780)
cancer cell lines. The structure–activity relationship of these compounds is discussed.
Manuscript received: 5 December 2007.
Final version: 29 April 2008.
Introduction
Compound 1a was synthesized using the conventional Kubo
method.[7] Various side chains were introduced onto position
6 of 1a (Scheme 1), which yielded the corresponding quino-
line derivatives 1b–d.[8] The 4-substituted compounds 2, 4,
6, and 8 were formed from the condensation of compounds
1a–d and the corresponding aniline derivatives based on known
procedures.[9] The cyclized 11H-indolo[3,2-c]quinoline deriva-
tives 3, 5, 7, and 9 were then obtained in acetic acid in the
presence of palladium(ii) acetate under reflux.[4]
In recent years there has been intense interest in the design
and analysis of inhibitors of epidermal growth factor recep-
tor (EGFR) with anti-tumour activities.[1] For example, com-
pound PD-153035 was reported to have a specific inhibitory
activity toward EGFR tyrosine kinase.[2] Compound ZD1839
was found to be effective for non-small-cell lung cancer and
was recently approved for clinical use in Japan.[3] Both com-
pounds contain the quinoline substructure. In 2003, He et al.
designed and synthesized a series of 11H-indolo[3.2-c]quinoline
derivatives (A) that exhibited high cytotoxic activity on HL-
60 and small-cell lung cancer[4] (Fig. 1). To further explore
the structure–activity relationship of compounds that contain
the quinoline substructure in detail, we synthesized a series of
new compounds that share the quinoline unit while having dif-
ferent substituted groups. Based on results from assays using
the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide] method,[5,6] several compounds were found to possess
cytotoxic activity against the growth of colon (HTC-8), liver
(BEL-7402), gastric (BCG-823), pulmonary gland (A549), and
ovary (A2780) cancer cell lines.
Results and Discussion
Table 1 shows the cytotoxic activities of the synthesized com-
pounds 2a–4d derived from 11H-indole[3,2-c]quinoline by
varying the substituents at the 4- and 6-positions.
Among the assayed compounds, the 6-methoxy derivatives
2 and 6-(3-morpholinopropoxy) derivatives 8 showed the high-
est cytotoxic activities, followed by the 6-(2-methoxyethoxy)
derivatives 6. 6-Hydroxy derivatives 4 exhibited no obvious
inhibitory activity. These results indicated that compounds
bearing methoxy and (3-morpholinopropoxy) groups at the
6-position had good activities.
The synthetic procedures for the preparation of 11H-
indole[3,2-c]quinoline derivatives are shown in Scheme 1.
The compounds bearing a 3-chloro-4-fluorophenyl amino
group at the 4-position (2a, 4a, 6a, 8a) exhibited higher
F
O
HN
N
Cl
HN
N
Br
HN
N
O
O
Z
O
O
N
N
Y
N
PD-153035
ZD1839
A
Fig. 1. Structures of quinoline derivatives.
© CSIRO 2008
10.1071/CH07419
0004-9425/08/070531

532
Q. Zhou et al.
HN
N
Cl
N
Cl
N
R1
R2
O
O
O
O
O
O
Pd(CH3COO)2
CH3COOH
H2N
PriOH
3
2
1a
R
1 ϭ Cl, R2 ϭ F
a
b
a R1 ϭ Cl,
R
2 ϭ F
R
1 ϭ Cl, R2 ϭ H
R
R
R
1 ϭ CϵCH, R2 ϭ H
b
c
d
1 ϭ CH3,
1 ϭ Cl,
R
2 ϭ H
2 ϭ H
R
R1
R2
R1
R2
Cl
HN
N
H2N
PriOH
HO
O
HO
O
DL-methioine
MeSO3H
1a
N
4
1b
a R1 ϭ Cl,
R
2 ϭ F
R
R
R
1 ϭ CϵCH, R2 ϭ H
b
c
d
1 ϭ CH3,
1 ϭ Cl,
R
2 ϭ H
2 ϭ H
R
R1
R2
HN
N
HO
Pd(CH3COO)2
CH3COOH
O
5
a R1 ϭ Cl, R2 ϭ H
R1
R2
R1
R2
HN
Cl
N
H2N
O
BrCH2CH2OCH3
K2CO3/DMF
O
O
O
1b
PriOH
O
N
O
6
1c
a R1 ϭ Cl,
R
2 ϭ F
R
R
R
1 ϭ CϵCH, R2 ϭ H
b
c
d
1 ϭ CH3,
1 ϭ Cl,
R
2 ϭ H
2 ϭ H
R
R1
R2
HN
O
Pd(CH3COO)2
CH3COOH
O
O
N
7
R
1 ϭ Cl, R2 ϭ F
a
Scheme 1.

Synthesis of Quinoline Derivatives
533
R1
R2
R1
R2
O
Cl
N
O
HN
N
C7H14ClNO
H2N
PriOH
N
O
O
N
O
O
1b
K2CO3/DMF
8
1d
R
1 ϭ Cl,
1 ϭ CH3, R2 ϭ H
1 ϭ Cl, 2 ϭ H
R2 ϭ F
a
b
c
R
R
R
R1
R2
O
HN
N
N
O
O
Pd(CH3COO)2
CH3COOH
9
R
1 ϭ Cl, R2 ϭ F
a
Scheme 1. (Continued)
Table 1. Inhibitory action of quinoline derivatives
Samples
IC50 [m]
HCT-8
BEL-7402
BCG-823
A549
A2780
2a
2b
2c
2d
3a
3b
4a
4b
4c
4d
5a
6a
6b
6c
6d
7a
8a
8b
8c
9a
2.07 × 10−6
4.27 × 10−6
5.69 × 10−6
4.14 × 10−6
1.70 × 10−6
2.47 × 10−6
>10 × 10−6
>10 × 10−6
>10 × 10−6
>10 × 10−6
3.00 × 10−6
4.43 × 10−6
>10 × 10−6
>10 × 10−6
4.70 × 10−6
2.09 × 10−6
1.70 × 10−6
2.87 × 10−6
1.99 × 10−6
4.27 × 10−6
1.78 × 10−6
3.51 × 10−6
5.22 × 10−6
>10 × 10−6
1.78 × 10−6
2.37 × 10−6
>10 × 10−6
>10 × 10−6
>10 × 10−6
>10 × 10−6
5.37 × 10−6
3.53 × 10−6
6.81 × 10−6
>10 × 10−6
>10 × 10−6
3.21 × 10−6
1.78 × 10−6
5.33 × 10−6
>10 × 10−6
4.61 × 10−6
0.64 × 10−6
2.21 × 10−6
3.35 × 10−6
>10 × 10−6
1.48 × 10−6
>10 × 10−6
1.59 × 10−6
>10 × 10−6
>10 × 10−6
>10 × 10−6
>10 × 10−6
3.08 × 10−6
>10 × 10−6
>10 × 10−6
3.14 × 10−6
2.96 × 10−6
1.03 × 10−6
2.45 × 10−6
2.53 × 10−6
2.49 × 10−6
3.27 × 10−6
2.49 × 10−6
>10 × 10−6
>10 × 10−6
1.18 × 10−6
3.12 × 10−6
>10 × 10−6
>10 × 10−6
>10 × 10−6
>10 × 10−6
5.32 × 10−6
2.02 × 10−6
6.74 × 10−6
>10 × 10−6
>10 × 10−6
5.44 × 10−6
1.24 × 10−6
4.11 × 10−6
4.39 × 10−6
3.56 × 10−6
0.42 × 10−6
1.58 × 10−6
1.51 × 10−6
6.38 × 10−6
<0.1 × 10−6
2.52 × 10−6
0.32 × 10−6
>10 × 10−6
>10 × 10−6
>10 × 10−6
4.01 × 10−6
4.64 × 10−6
>10 × 10−6
>10 × 10−6
7.55 × 10−6
2.95 × 10−6
0.28 × 10−6
2.87 × 10−6
3.40 × 10−6
2.85 × 10−6
anti-tumour activity (IC50 < 10−6 m) than those with a 4-(3-
chloroaniline) group (2d, 4d, 6d, 8c), which demonstrated that
the 3-chloro-4-fluorophenylamino group was a more effective
substituent that led to higher activities than the 3-chloroaniline
group.
Most of the examined compounds exhibited higher activities
on human ovarian cancer cell lines (A2780) than on the other
four cancer cell lines, which indicated that human ovarian cancer
cells were most sensitive to these compounds.
Compounds 3a, 3b, 5a, 7a, and 9a, which share the
indole substructure, showed high inhibitory activity. Among
them, compound 3a (9-chloro-8-fluoro-2,3-dimethoxy-11H-
indole[3,2-c]quinoline) had a prominent effect on the ovary cell
line (A2780) (IC50 < 0.1 × 10−6 m). These results demonstrate
that indole[3,2-c]quinoline derivatives have great potential for
developing new anti-tumour agents.
Conclusions
In summary, the type of substituents derived from aniline and
other groups at the 6-position of the assayed compounds had
obvious, and, in some cases, dramatic effects on their biological
activities. The revealed structure–activity relationship provides

534
Q. Zhou et al.
new insights on factors that determine the anti-tumour activities
of the corresponding compounds.
1H), 7.20 (m, 2H), 7.1 (s, 1H), 6.84 (d, J 4.8, 1H), 6.37 (s, 1H),
4.05 (s, 6H). δC (CDCl3, 125 MHz) 154.7, 152.2, 148.8, 148.6,
146.3, 146.2, 138.7, 123.9, 122.6, 120.3, 117.9, 114.4, 108.5,
101.7, 101.2, 56.3, 56.0. m/z 332.0 (M+, 63%), 334.1 (M+ + 2,
33), 108.7 (60), 75.0 (80), 63.0 (100). (Found: C 61.6, H 4.2,
N 8.3. Calc. for C17H14ClFN2O2: C 61.4, H 4.2, N 8.4%.)
Experimental
All melting points were taken on an X-4 melting point appara-
tus. 1H NMR spectra were carried out in CDCl3, CD3COCD3,
or (D6)DMSO on an Avance Bruker (500 MHz) spectrometer
(Bruker Biospin, Fällanden, Switzerland) using tetramethyl-
silane (TMS) as an internal standard. Mass spectra, infrared
absorption spectra, and elemental analysis were determined,
respectively, by Agilent HPLC MSD (Agilent, Santa Clara, CA,
USA), AVATAR-360FT-IR (Thermo Nicolet, Madison, USA),
and Perkin–Elmer 240-c (Perkin–Elmer, Massachusetts, USA)
machines.
N-(3-Ethynylphenyl)-6,7-dimethoxyquinolin-4-amine 2b
This compound was obtained in 89.7% yield by the general pro-
ceduredescribedinMethodA, mp221–223◦C. νmax (KBr)/cm−1
3249, 1659, 1582, 1508, 1438, 1274, 1255. δH ((D6)DMSO,
500 MHz) 8.33 (d, J 5.3, 1H), 7.63 (s, 1H), 7.41 (m, 3H), 7.27
(s, 1H), 7.22 (d, J 6.7, 1H), 6.90 (d, J 5.4, 1H), 4.21 (s, 1H),
3.93 (s, 3H), 3.91 (s, 3H). δC ((D6)DMSO, 125 MHz) 152.5,
148.9, 148.0, 146.7, 145.4, 141.5, 130.3, 127.0, 125.0, 123.2,
122.7, 114.5, 107.8, 101.9, 101.4, 83.7, 81.3, 56.4, 56.0. m/z
304.1 (M+, 60%), 83.8 (97), 65.9 (100). (Found: C 74.5, H 5.2,
N 9.3. Calc. for C19H16N2O2: C 75.0, H 5.3, N 9.2%.)
4-Chloro-7-methoxy-6-(2-methoxyethoxy)quinoline 1h
A stirred mixture of 4-chloro-7-methoxyquinolin-6-ol (0.5 g,
2.38 mmol), 1-bromo-2-methoxyethane (1.66 g, 11.9 mmol),
dimethylformamide (DMF, 31 mL), and K2CO3 (2.3 g,
16.7 mmol) was heated at 90◦C for 4.5 h. The reaction mix-
ture was cooled and extracted with ethyl acetate, the organic
layer was dried (Na2SO4), and the solvent concentrated under
vacuum. The product was purified through a silica gel column
using petroleum spirits/acetone (4:1) as eluent to give a white
solid (0.467 g, 73.2%), mp 89–91◦C. δH (CDCl3, 500 MHz) 8.61
(d, J 4.8, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.38 (d, J 4.8, 1H), 4.38
(t, J 4.6, 2H), 4.05 (s, 3H), 3.93 (t, J 4.7, 2H), 3.52 (s, 3H).
6,7-Dimethoxy-N-m-tolylquinolin-4-amine 2c
This compound was obtained in 51.2% yield by the gen-
eral procedure described in Method A, mp 225–226◦C. νmax
(KBr)/cm−1 3266, 1631, 1592, 1515, 1489, 1275, 1255. δH
(CDCl3, 500 MHz) 8.44 (d, J 5.3, 1H), 7.39 (s, 1H), 7.30 (m,
1H), 7.17 (s, 1H), 7.11 (m, 2H), 6.97 (m, 2H), 6.66 (s, 1H), 4.0
(s, 3H), 3.99 (s, 3H), 2.39 (s, 3H). δC (CDCl3, 125 MHz) 152.3,
149.1, 148.5, 146.6, 146.0, 140.5, 139.6, 129.4, 124.9, 122.7,
119.1, 114.6, 108.8, 102.8, 98.9, 56.1, 55.9, 21.4. m/z 294.2
(M+, 75%), 85.9 (100), 83.9 (95), 48.9 (86). (Found: C 73.0,
H 5.7, N 9.3. Calc. for C18H18N2O2: C 73.5, H 6.2, N 9.5%.)
4-Chloro-7-methoxy-6-(3-morpholinopropoxy)quinoline 1i
This compound was obtained in a similar manner as for the
preparation of 1h. Yield of the white product was 57.1 mg, mp
119–120◦C. δH (CDCl3, 500 MHz) 8.60 (d, J 4.8, 1H), 7.44 (s,
2H), 7.37 (d, J 4.8, 1H), 4.30 (t, J 6.5, 2H), 4.05 (s, 3H), 3.78
(m, 4H), 2.64 (m, 2H), 2.55 (m, 4H), 2.18 (t, J 6.6, 2H).
N-(3-Chlorophenyl)-6,7-dimethoxyquinolin-4-amine 2d
This compound was obtained in 91.5% yield by the general pro-
ceduredescribedinMethodA, mp209–210◦C. νmax (KBr)/cm−1
3601, 1625, 1576, 1510, 1360, 1258, 1213. δH ((D6)DMSO,
500 MHz) 8.34 (d, J 4.8, 1H), 7.6 (s, 1H), 7.41 (t, J 7.9, 1H), 7.33
(m, 2H), 7.28 (s, 1H), 7.13 (d, J 7.8, 1H), 6.97 (d, J 4.9, 1H), 3.93
(s, 3H), 3.91 (s, 3H). δC ((D6)DMSO, 125 MHz) 152.3, 148.9,
148.6, 146.2, 145.8, 143.2, 134.1, 131.4, 122.9, 121.0, 119.8,
114.9, 108.5, 102.6, 101.3, 56.3, 56.0. m/z 314.2 (M+, 10%),
316.2 (M+ + 2, 5), 84.0 (63), 66.0 (87), 47.9 (100). (Found: C
65.2, H 4.5, N 8.6. Calc. for C17H15ClN2O2: C 64.9, H 4.8, N
8.9%.)
General Procedure for the Preparation of
N-Phenylquinolin-4-amine Derivatives (Method A)
To a stirred mixture of the 6,7-substituted quinolines (1f or 1g) in
PriOH was added the appropriate aniline dissolved in PriOH that
contained two drops of conc. HCl.The mixture was refluxed, and
then cooled after completion of the reaction. Saturated NaHCO3
was added and the resulting white solid was collected by filtra-
tion. Compounds 2a–d, 4a–d, 6a–d, and 8a–c were prepared by
this method.
9-Chloro-8-fluoro-2,3-dimethoxy-11H-indolo
[3,2-c]quinoline 3a
This compound was obtained in 30.3% yield by the general pro-
ceduredescribedinMethodB, mp287–289◦C. νmax (KBr)/cm−1
3418, 1628, 1514, 1467, 1287. δH ((D6)DMSO, 500 MHz) 9.46
(s, 1H), 8.34 (d, J 9.6, 1H), 7.93 (s, 1H), 7.88 (d, J 6.1, 1H), 7.54
(s, 1H), 4.0 (s, 3H), 3.97 (s, 3H). δC ((D6)DMSO, 125 MHz)
154.0, 152.2, 152.1, 149.7, 142.3, 140.9, 139.6, 135.7, 121.7,
118.0, 113.4, 111.0, 107.8, 107.1, 101.7, 56.4, 56.2. m/z 330.0
(M+, 65%), 332.0 (M+ + 2, 25), 84.0 (73), 66.0 (100). (Found:
C 61.9, H 3.7, N 8.4. Calc. for C17H12ClFN2O2: C 61.7, H 3.7,
N 8.5%.)
General Procedure for the Preparation of
11H-Indolo[3,2-c]quinoline (Method B)
A stirred mixture of the appropriate N-phenylquinolin-4-amine
and palladium(ii) acetate in acetic acid was heated under reflux
in the presence of nitrogen until the reaction was complete. The
resulting solid was collected by filtration and purified by column
chromatography. Compounds 3a,b, 5a, 7a, and 9a were prepared
by this method.
N-(3-Chloro-4-fluorophenyl)-6,7-dimethoxyquinolin-
4-amine 2a
9-Chloro-2,3-dimethoxy-11H-indolo[3,2-c]quinoline 3b
This compound was obtained in 95.3% yield by the general pro-
ceduredescribedinMethodA, mp191–192◦C. νmax (KBr)/cm−1
3439, 3282, 2925, 1630, 1587, 1506, 1256, 1220, 999, 842, 801,
544. δH (CDCl3, 500 MHz) 8.46 (s, 1H), 7.42 (s, 1H), 7.36 (s,
This compound was obtained in 38.0% yield by the general pro-
ceduredescribedinMethodB, mp260–261◦C. νmax (KBr)/cm−1
1571, 1512, 1286, 1230. δH ((D6)DMSO, 500 MHz) 9.38 (s, 1H),
8.25 (d, J 8.3, 1H), 7.87 (s, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 7.33 (d,

Synthesis of Quinoline Derivatives
535
J 8.3, 1H), 3.99 (s, 3H), 3.94 (s, 3H). δC ((D6)DMSO, 125 MHz)
151.5, 149.4, 142.2, 141.9, 140.8, 139.7, 130.2, 121.8, 121.4,
121.1, 113.5, 111.8, 111.3, 109.0, 101.6, 56.3, 56.1. m/z 312.2
(M+, 50%), 314.4 (M+ + 2, 18), 149.2 (100), 83.9 (87), 65.9
(78). (Found: C 65.0, H 4.1, N 9.0. Calc. for C17H13ClN2O2:
C 65.3, H 4.2, N 9.0%.)
δC ((D6)DMSO, 125 MHz) 151.4, 147.3, 141.2, 140.7, 139.9,
130.2, 121.8, 121.4, 121.2, 113.2, 111.8, 108.6, 104.7, 56.2. m/z
298.9 (M+, 100%), 283.9 (35), 256.3 (40), 191.7 (30), 73.6 (15).
(Found: C 64.3, H 3.5, N 9.6. Calc. for C16H11ClN2O2: C 64.3,
H 3.7, N 9.4%.)
N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-
(2-methoxyethoxy)quinolin-4-amine 6a
4-(3-Chloro-4-fluoro-phenylamino)-7-methoxyquinolin-
6-ol 4a
This compound was obtained in 79.7% yield by the gen-
eral procedure described in Method A, mp 90–91◦C. νmax
(KBr)/cm−1 1633, 1594, 1515, 1503, 1471, 1250, 1229. δH
(CDCl3, 500 MHz) 8.46 (d, J 5.3, 1H), 7.38 (s, 1H), 7.34 (m,
1H), 7.21 (s, 1H), 7.19 (s, 1H), 7.16 (m, 1H), 6.83 (d, J 5.3, 1H),
6.59 (s, 1H), 4.27 (t, J 4.7, 2H), 4.0 (s, 3H), 3.86 (d, J 4.7, 2H),
3.48 (s, 3H). δC (CDCl3, 125 MHz) 155.8, 153.9, 152.7, 148.8,
148.4, 146.4, 146.2, 137.4, 124.3, 122.0, 117.4, 114.3, 109.0,
102.5, 100.8, 70.9, 68.6, 59.3, 56.0. m/z 376.2 (M+, 45%), 318.2
(49), 128.9 (40), 75.1 (38), 63.1 (42), 58.8 (100). (Found: C 60.8,
H 4.8, N 7.2. Calc. for C19H18ClFN2O3: C 60.6, H 4.8, N 7.4%.)
This compound was obtained in 35.5% yield by the general pro-
ceduredescribedinMethodA, mp241–242◦C. νmax (KBr)/cm−1
3041, 1728, 1587, 1503, 1279, 1223. δH ((D6)DMSO, 500 MHz)
8.34 (d, J 6.7, 1H), 7.81 (s, 1H), 7.69 (m, 1H), 7.57 (t, J 8.9, 1H),
7.46 (m, 1H), 7.35 (s, 1H), 6.75 (d, J 6.7, 1H), 3.9 (s, 3H).
δC ((D6)DMSO, 125 MHz) 155.2, 152.8, 148.1, 146.9, 145.7,
142.4, 138.1, 124.4, 123.2, 120.4, 118.0, 114.7, 106.0, 105.0,
101.4, 56.3. m/z319.1(M+ + 1, 54%), 108.7(70), 76.0(91), 53.0
(100). (Found: C 60.6, H 4.1, N 8.6. Calc. for C16H12ClFN2O2:
C 60.3, H 3.8, N 8.8%.)
4-(3-Ethynylphenylamino)-7-methoxyquinolin-6-ol 4b
N-(3-Ethynylphenyl)-7-methoxy-6-(2-methoxyethoxy)
quinolin-4-amine 6b
This compound was obtained in 85.0% yield by the gen-
eral procedure described in Method A, mp 251–252◦C. νmax
(KBr)/cm−1 3282, 3212, 2924, 2853, 1594, 1576, 1522, 1482.
δH ((D6)DMSO, 500 MHz) 8.33 (d, J 6.2, 1H), 7.75 (s, 1H), 7.46
(m, 3H), 7.34 (m, 2H), 6.83 (d, J 6.2, 1H), 4.24 (s, 1H), 3.99
(s, 3H). δC ((D6)DMSO, 125 MHz) 153.7, 149.9, 147.4, 143.5,
140.0, 130.5, 128.6, 126.4, 124.2, 123.4, 114.1, 104.9, 103.9,
100.9, 83.4, 81.8, 56.5. m/z 290.5 (M+, 25%), 100.1 (65), 84.2
(96), 66.0 (100), 46.2 (86). Found: C 74.4, H 4.9, N 9.6. Calc.
for C18H14N2O2: C 74.5, H 4.9, N 9.7%.)
This compound was obtained in 49.2% yield by the general pro-
cedure described in Method A, mp 88–89◦C. νmax (KBr)/cm−1
3479, 3246, 2930, 1626, 1574, 1506, 1451, 1357, 1254, 1216,
1132, 927, 856. δH (CDCl3, 500 MHz) 8.38 (d, J 5.4, 1H), 7.44
(s, 1H), 7.35 (m, 2H), 7.32–7.27 (m, 3H), 6.94 (d, J 5.3, 1H),
4.29 (t, J 4.6, 2H), 3.97 (s, 3H), 3.85 (t, J 3.8, 2H), 3.47 (s, 3H),
3.13 (s, 1H). δC (CDCl3, 125 MHz) 152.9, 148.5, 148.0, 146.3,
145.6, 140.6, 129.7, 127.6, 124.9, 123.5, 122.1, 114.5, 108.3,
102.9, 101.0, 83.0, 77.8, 70.9, 68.7, 59.3, 56.0. m/z 348.3 (M+,
30%), 254.2 (65), 229.2 (85), 75.2 (77), 63.2 (70), 59.2 (95),
45.2 (100). (Found: C 72.8, H 5.8, N 8.2. Calc. for C21H20N2O3:
C 72.4, H 5.8, N 8.0%.)
7-Methoxy-4-m-tolylaminoquinolin-6-ol 4c
This compound was obtained in 30.7% yield by the gen-
eral procedure described in Method A, mp 228–229◦C. νmax
(KBr)/cm−1 3227, 1604, 1589, 1525, 1506, 1286, 1261, 1219.
δH ((D6)DMSO, 500 MHz) 8.25 (d, J 5.4, 1H), 7.61 (s, 1H), 7.26
(m, 2H), 7.12 (m, 2H), 6.92 (d, J 7.5, 1H), 6.82 (d, J 5.5, 1H),
3.94 (s, 3H), 2.31 (s, 3H). δC ((D6)DMSO, 125 MHz) 152.0,
147.2, 147.1, 146.4, 144.5, 141.2, 139.1, 129.6, 124.5, 122.7,
119.3, 115.2, 107.5, 105.0, 101.5, 56.1, 21.5. m/z 282.3 (M+ + 2,
100%), 91.1 (40), 77.1 (55), 65.1 (60), 51.1 (32). (Found: C 72.4,
H 6.1, N 9.5. Calc. for C17H16N2O2: C 72.8, H 5.8, N 10.0%.)
7-Methoxy-6-(2-methoxyethoxy)-N-m-tolylquinolin-
4-amine 6c
This compound was obtained in 52.0% yield by the general pro-
ceduredescribedinMethodA, mp200–201◦C. νmax (KBr)/cm−1
3419, 2917, 2658, 1633, 1589, 1509, 1471, 1417, 1276, 1228,
1069, 863, 792. δH (CDCl3, 500 MHz) 8.42 (d, J 5.3, 1H), 7.39
(s, 1H), 7.31 (m, 1H), 7.26 (s, 1H), 7.13 (m, 2H), 6.9 (d, J 7.4,
1H), 6.95 (d, J 5.4, 1H), 4.32 (t, J 4.6, 2H), 4.0 (s, 3H), 3.88
(t, J 4.8, 2H), 3.50 (s, 3H), 2.4 (s, 3H). δC (CDCl3, 125 MHz)
152.8, 148.3, 148.0, 146.9, 140.2, 139.6, 129.4, 125.0, 122.7,
119.1, 114.2, 108.4, 102.3, 101.2, 70.9, 68.8, 59.3, 56.0, 21.5.
m/z 338.4 (M+, 15%), 219.3 (17), 91.2 (25), 77.2 (27), 65.2 (34),
59.2 (91), 45.2 (100). (Found: C 71.4, H 6.2, N 8.5. Calc. for
C20H22N2O3: C 71.0, H 6.6, N 8.3%.)
4-(3-Chlorophenylamino)-7-methoxyquinolin-6-ol 4d
This compound was obtained in 65.6% yield by the general pro-
ceduredescribedinMethodA, mp255–256◦C. νmax (KBr)/cm−1
3054, 1587, 1523, 1479, 1294, 1241. δH ((D6)DMSO, 500 MHz)
8.34 (d, J 5.6, 1H), 7.6 (s, 1H), 7.41 (t, J 8.0, 1H), 7.36 (s, 1H),
7.30 (m, 2H), 7.14 (d, J 7.9, 1H), 6.93 (d, J 5.6, 1H), 3.96 (s, 3H).
δC ((D6)DMSO, 125 MHz) 152.7, 147.1, 146.9, 146.1, 143.2,
142.9, 134.1, 131.4, 123.3, 121.2, 120.1, 115.3, 106.5, 105.0,
102.5, 56.3. m/z 301.2 (M+ + 1, 8%), 63.1 (60), 53.1 (35), 41.1
(100). (Found: C 64.2, H 4.7, N 9.0. Calc. for C16H13ClN2O2:
C 63.9, H 4.4, N 9.3%.)
N-(3-Chlorophenyl)-7-methoxy-6-(2-methoxyethoxy)
quinolin-4-amine 6d
This compound was obtained in 43.7% yield by the general pro-
cedure described in Method A, mp 81–82◦C. νmax (KBr)/cm−1
3288, 2930, 1625, 1579, 1505, 1479, 1356, 1256, 1208, 1095,
915, 857. δH (CDCl3, 500 MHz) 8.47 (d, J 5.3, 1H), 7.39 (s,
1H), 7.33 (t, J 8.0, 1H), 7.29 (m, 1H), 7.24 (s, 1H), 7.18 (dd,
J 6.7, 1.3, 1H), 7.12 (dd, J 6.9, 1.0, 1H), 7.0 (d, J 5.3, 1H),
4.29 (t, J 4.6, 2H), 3.99 (s, 3H), 3.86 (t, J 4.8, 2H), 3.49 (s,
3H). δC (CDCl3, 125 MHz) 152.8, 148.7, 148.6, 146.4, 145.4,
142.2, 135.2, 130.6, 123.6, 121.0, 119.1, 114.8, 108.9, 103.6,
101.0, 70.9, 68.7, 59.3, 56.0. m/z 358.3 (M+, 5%), 75.1 (35),
9-Chloro-3-methoxy-11H-indolo[3,2-c]quinolin-2-ol 5a
This compound was obtained in 65.3% yield by the general pro-
ceduredescribedinMethodB, mp280–281◦C. νmax (KBr)/cm−1
3082, 1701, 1608, 1529, 1458, 1296. δH ((D6)DMSO, 500 MHz)
9.39 (s, 1H), 8.27 (d, J 8.4, 1H), 7.72 (s, 1H), 7.67 (d, J 1.6,
1H), 7.53 (s, 1H), 7.33 (dd, J 8.4, 1.7, 1H), 3.98 (s, 1H).

536
Q. Zhou et al.
59.0 (99), 45.1 (100). (Found: C 63.4, H 5.2, N 8.0. Calc. for
C19H19ClN2O3: C 63.6, H 5.3, N 7.8%.)
7.20 (d, J 7.9, 1H), 7.11 (d, J 7.9, 1H), 7.0 (d, J 5.3, 1H), 4.1 (m,
2H), 3.94 (s, 3H), 3.7 (t, J 4.1, 4H), 2.5 (t, J 7.0, 2H), 2.4 (m, 4H),
2.05 (m, 2H). δC ((D6)DMSO, 125 MHz) 155.3, 153.2, 148.9,
140.6, 139.4, 135.7, 134.4, 131.9, 127.3, 125.4, 124.2, 112.2,
104.2, 100.4, 100.0, 67.2, 63.8, 56.8, 54.1, 51.6, 23.3. m/z 427.1
(M+, 30%), 429.4 (M+ + 2, 12), 127.9 (80), 100.2 (93), 96.7
(75), 69.8 (69), 55.8 (64), 41.4 (100). (Found: C 64.4, H 6.3, N
9.7. Calc. for C23H26ClN3O3: C 64.6, H 6.1, N 9.8%.)
9-Chloro-8-fluoro-3-methoxy-2-(2-methoxyethoxy)-
11H-indolo[3,2-c]quinoline 7a
This compound was obtained in 56.0% yield by the general pro-
ceduredescribedinMethodB, mp107–108◦C. νmax (KBr)/cm−1
3401, 1631, 1556, 1511, 1466, 1376, 1288. δH ((D6)DMSO,
500 MHz) 9.36 (s, 1H), 8.29 (d, J 9.6, 1H), 7.85 (s, 1H), 7.81 (d,
J 6.1, 1H), 7.50 (s, 1H), 4.28 (t, J 4.4, 2H), 3.95 (s, 3H), 3.81
(t, J 4.4, 2H), 3.38 (s, 3H). δC ((D6)DMSO, 125 MHz) 153.8,
151.9, 151.8, 148.5, 142.5, 141.7, 135.5, 132.0, 129.1, 113.5,
113.1, 111.2, 109.1, 107.5, 102.6, 70.6, 68.3, 58.8, 56.1. m/z
374.2 (M+, 47%), 376.4 (M+ + 2, 15), 316.0 (65), 58.9 (100).
(Found: C 60.5, H 4.1, N 7.9. Calc. for C19H16ClFN2O3: C 60.9,
H 4.3, N 7.5%.)
9-Chloro-8-fluoro-3-methoxy-2-(3-morpholinopropoxy)-
11H-indolo[3,2-c]quinoline 9a
This compound was obtained in 22.6% yield by the general pro-
cedure described in Method B, mp 189–190◦C. δH ((D6)DMSO,
500 MHz) 9.38 (s, 1H), 8.33 (d, J 9.6, 1H), 7.90 (s, 1H), 7.84 (d,
J 6.1, 1H), 7.53 (s, 1H), 4.22 (t, J 6.1, 2H), 3.9 (s, 3H), 3.61 (m,
4H), 2.56 (m, 2H), 2.47 (m, 4H), 2.06 (m, 2H). δC ((D6)DMSO,
125 MHz) 153.8, 151.6, 148.6, 142.8, 142.4, 141.5, 135.4, 121.9,
117.3, 113.5, 113.0, 111.3, 109.6, 107.6, 102.5, 67.2, 66.5,
56.1, 55.3, 53.7, 26.1. m/z 444.4 (M+ + 1, 45%), 301.3 (39),
128.3 (98), 97.3 (100). (Found: C 62.6, H 5.2, N 9.8. Calc. for
C23H23ClFN3O3: C 62.2, H 5.2, N 9.5%.)
N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-(3-
morpholinopropoxy)quinolin-4-amine 8a
This compound was obtained in 85.0% yield by the gen-
eral procedure described in Method A, mp 183–184◦C. νmax
(KBr)/cm−1 3340, 1625, 1582, 1531, 1500, 1354, 1247. δH
(CDCl3, 500 MHz) 8.41 (d, J 5.3, 1H), 7.39 (s, 1H), 7.37 (s, 1H),
7.20 (m, 3H), 6.82 (d, J 5.3, 1H), 4.22 (t, J 6.6, 2H), 4.01 (s, 3H),
3.74 (t, J 4.3, 4H), 2.59 (t, J 7.0, 2H), 2.51 (m, 4H), 2.13 (m, 2H).
δC (CDCl3, 125 MHz) 156.0, 153.0, 148.7, 147.1, 147.0, 137.0,
130.9, 128.8, 124.6, 122.3, 117.4, 114.2, 107.7, 102.2, 100.6,
67.5, 66.9, 56.1, 55.4, 53.7, 26.1. m/z 445.2 (M+, 64%), 447.4
(M+ + 2, 20), 56.1 (52), 100.0 (79), 42.1 (80), 69.9 (90), 128.0
(100). (Found: C 61.9, H 5.7, N 9.7. Calc. for C23H25ClFN3O3:
C 62.0, H 5.7, N 9.4%.)
Acknowledgements
This work was supported by the Research Fund for the Doctoram of Higher
Education of China Grant 20070027038 (to L.H.), the National Natural
Science Foundation of China Grant 20772012 (to L.H.), and the Beijing Nat-
ural Science Foundation of China Grant 2073024 (to L.H.); the Changjiang
ScholarProgramandtheCultivationFundoftheKeyScientificandTechnical
Innovation Project, Ministry of Education of China Grant 708009 (to B.G.),
National Science Foundation Grant CHE-0314577 (to B.G.), and Office of
Naval Research Grant N000140210519 (to B.G.).
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7-Methoxy-6-(3-morpholinopropoxy)-N-m-tolylquinolin-
4-amine 8b
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ceduredescribedinMethodA, mp198–199◦C. νmax (KBr)/cm−1
2948, 2851, 1623, 1578, 1507, 1487, 1356, 1274, 1210, 1116,
1066, 860. δH (CDCl3, 500 MHz) 8.30 (d, J 5.0, 1H), 7.32∼7.28
(m, 3H), 7.16 (m, 2H), 7.01 (d, J 7.5, 1H), 6.9 (d, J 5.3, 1H),
4.22 (t, J 6.6, 2H), 3.97 (s, 3H), 3.74 (t, J 4, 4H), 2.57 (t, J 7.1,
2H), 2.49 (m, 4H), 2.40 (s, 3H), 2.12 (t, J 6.9, 2H). δC (CDCl3,
125 MHz) 152.9, 148.5, 147.4, 146.8, 140.0, 139.7, 129.5, 125.3,
122.8, 119.2, 114.1, 107.4, 102.1, 100.7, 67.5, 67.0, 56.0, 55.4,
53.7, 26.2, 21.5. m/z 407.3 (M+, 55%), 280.1 (28), 128.2 (100),
100.1 (72), 70.0 (43), 56.0 (35). (Found: C 71.0, H 7.3, N 10.6.
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N-(3-Chlorophenyl)-7-methoxy-6-(3-
morpholinopropoxy)quinolin-4-amine 8c
This compound was obtained in 82.6% yield by the gen-
eral procedure described in Method A, mp 173–174◦C. νmax
(KBr)/cm−1 3391, 3035, 1607, 1590, 1511, 1465, 1275. δH
(CDCl3, 500 MHz) 8.44 (m, 1H), 7.35 (s, 1H), 7.29 (m, 3H),