Palladium-catalyzed regioselective aerobic oxidative cyclization via C-H activation in chloroquine analogues: Synthesis and cytotoxic study

Article abstract of DOI:10.1007/s00706-015-1474-z

The intramolecular regioselective aerobic oxidative cyclization via two types of discrete C-H activation in 7-chloroquinoline analogues is described. All the synthesized compounds are screened against three human cancer cell lines (CCRF-CEM, HT29, and MCF

Full text of DOI:10.1007/s00706-015-1474-z

Monatsh Chem
DOI 10.1007/s00706-015-1474-z
ORIGINAL PAPER
Palladium-catalyzed regioselective aerobic oxidative cyclization
via C–H activation in chloroquine analogues: synthesis
and cytotoxic study
1
2,3,4
2
1
Gopal Senthil Kumar
•
Mohamed Ashraf Ali
•
Tan Soo Choon
•
Karnam Jayarampillai Rajendra Prasad
Received: 10 December 2014 / Accepted: 6 April 2015
Ó Springer-Verlag Wien 2015
Abstract The intramolecular regioselective aerobic
oxidative cyclization via two types of discrete C–H acti-
vation in 7-chloroquinoline analogues is described. All the
synthesized compounds are screened against three human
cancer cell lines (CCRF-CEM, HT29, and MCF7) for their
anticancer activities. Among them, chloroquine analogues
with naphthalene ring either substituted/fused form
enhance remarkable cytotoxic activity against human
breast adenocarcinoma cancer cell line (MCF-7) which
outranged positive control doxorubicin. Similarly,
Graphical abstract
Keywords Chloroquine analogues Á
Intramolecular oxidative cyclization Á S Ar reaction Á
N
3
-chloro-7H,12H-pyrazolo[5,4-b]quinolino[3,2-c]indole
Regioselective Á Cytotoxicity
has possessed significant activity against all the tested cell
lines and outranged activity against CCRF-CEM cell line.
Introduction
Transition metal-catalyzed carbon–carbon (C–C) bond
formation is one of the raising areas with great interest in
synthetic organic chemistry owing to its region-controlled
bond formation in the oxidative coupling reactions [1–8].
Generally, bond formation between two unactivated
2
2
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-015-1474-z) contains supplementary
material, which is available to authorized users.
(hetero)arenes C(sp )–C(sp ) with Pd-catalyzed C–H acti-
vation provides a highly attractive strategy for an ideal
chemical synthesis [9]. The intramolecular oxidative cou-
2
pling of two C(sp )–H bonds has emerged as an efficient and
&
Karnam Jayarampillai Rajendra Prasad
prasad_125@yahoo.com
atom economic approach to construct C–C bond, thereby
rendering superior sustainability and environmental com-
patibility. The development of such C–H activation/
arylation reactions, particularly with broad scope, high
functional group tolerance, and mild reaction conditions
represents an area of significant current interest [10–14].
Quinoline-containing compounds have long been studied
for treatment of malaria beginning with quinine [15]. In
continuation, the best compound that found for potent
antimalarial activity is chloroquine which was discovered in
the 1940s [16]. In the last two decades, a number of new
1
2
3
Department of Chemistry, Bharathiar University,
Coimbatore 641046, India
Institute for Research in Molecular Medicine, Universiti
Sains Malaysia, 11800 Minden, Penang, Malaysia
New Drug Discovery Research, Department of Medicinal
Chemistry, Alwar Pharmacy College, Alwar,
Rajasthan 301030, India
4
New Drug Discovery Research, Department of Medicinal
Chemistry, Sunrise University, Alwar, Rajasthan 301030,
India
123

G. Senthil Kumar et al.
potent quinolines that overcome chloroquine resistance
have been reported [17–19]. Most of the compounds contain
the 7-chloroquinoline nucleus of chloroquine and vary in the
length of basic amine side chain [20–22]. Recently several
clinical trials have been made repurposing use of chloro-
quine as anticancer agent due to their therapeutic efficacy
and lower cost [23]. A few literatures have reported that the
repositioning 4-amino basic side chain of chloroquine sig-
nificantly increased the anticancer activity [24, 25].
temperature to 120 °C to furnish the target aminoquinoline
compound as a single product with no need of additional
purification other than recrystallization from methanol.
After obtaining the aminoquinolines as potential pre-
cursors, we subsequently extended the reaction scope to the
intramolecular C–H activation field disclosing the direct
aryl–heteroaryl C–C bond formation through C–H activa-
tion sequences. Previous report suggested the Buchwald–
Hartwig amination followed by an intramolecular arylation
reaction but have never distinguished the regioselectivity
of arylation [39]. To test our hypothesis, we first examined
the reaction of 7-chloro-4-[N-(9-ethyl-9H-carbazol-3-
In recent years, natural and synthetic compounds with
the indoloquinoline ring system have attracted growing
interest due to their large spectrum of biological activities
[
26]. Recent studies on the biological effects and DNA
yl)amino]quinoline (3c) using 5 mol % of Pd(OAc) with
2
binding properties of other naturals and synthetic indolo-
quinolines have confirmed their remarkable biological
potency with promising antiproliferative activities towards
various cancer cells in some cases [27–29].
Cs CO as a base and tetrabutylammonium bromide as an
2
3
additive in presence of air to yield a single detectable
regioisomeric product with the new C–C bond installed in
7-chloro-4-aminoquinoline which was angular product 4c
0
Based on the above biological importance of 7-chloro-
quinoline scaffolds and indoloquinoline compounds, herein
we have described the reaction of various aromatic/
heteroaromatic amines with 4,7-dichloroquinoline to afford
instead of linear product 4c (Scheme 2). The formation of
the angular product 4c was unambiguously confirmed on
the basis of spectral data.
The IR spectrum of the compound showed absorption
-
band at 3140 cm for NH group. H NMR of the com-
1
1
7
-chloroquinoline compounds (analogues of chloroquine)
which subsequently undergo Pd(OAc) -catalyzed oxidative
2
pound exhibited a doublet at d = 8.27 ppm (J = 1.0 Hz)
for C –H proton of the quinoline ring. A triplet at 1.38 ppm
coupling reaction to give the stable angular products in
regioselective manner. The biological significance of this
synthesized compound was evaluated on the basis of
in vitro cytotoxicity against three human cancer cell lines.
8
(J = 7.5 Hz) and a quartet at 4.50 ppm (J = 7.0 Hz) was
corresponding to the N -attached methyl and methylene
9
protons, respectively. The disappearance of a doublet of
0
C –H in quinoline ring and a singlet of C –H in carbazole
3
4
ring has confirmed the C–C bond formation occurs at C4-
carbon of the carbazole and C3-carbon of quinoline rings to
give angular product 4c. The other possible isomeric linear
Results and discussion
0
Nucleophilic displacement (S Ar reaction) of halogen
N
product 4c is ruled out. The observed regioselectivity
atom at the C-4 position of quinolines by various amine
compounds has traditionally been fashioned to acquire
makes this reaction a potentially valuable curiosity for
palladium-mediated oxidative coupling reaction. Next, all
the aminoquinolines were examined for this aerobic
oxidative coupling reaction. As our expectation, com-
pounds 3d and 3f gave the respective angular product as
the only product instead of other possibility of linear
products in regioselective manner (Scheme 3).
4
-aminoquinoline family [30–32]. Synthetic procedures
involved S Ar reaction in most previous reports have
N
demonstrated at elevated temperature or in the presence of
phenol, with or without iodide, anhydrous K CO and
2
3
microwave irradiation [33–38]. Focus on microwave
reactions reported for the amination of chloroquinolines
have several disadvantages such as requiring organic sol-
vent, need of extraction and chromatographic purification
process that involve generation of waste from organic
Based on the results observed from our present investi-
gation and literature data ([40], and references therein), the
following mechanism has been proposed for the formation
of compound 4a (Scheme 4). Initially, 7-chloro-(N-phenyl-
amino)quinoline containing aryl ring undergoes C–H acti-
solvents. For the present work, initially, the S Ar amina-
N
tion reaction of 4,7-dichloroquinoline with aromatic and
heteroaromatic amines afforded the corresponding
vation at ortho position with Pd(OAc) in presence of base
2
followed by deprotonation to give o-palladation interme-
diate A. Then the second C–H activation occurs at
heteroaryl ring to afford intermediate B. Subsequently the
intermediate B undergoes reductive elimination to afford
the final product 3-chloro-11H-indolo[3,2-c]quinoline (4a)
with generating Pd(0) in presence of TBAB which was used
to avoid palladium black generation [41]. Open air as ter-
minal oxidant to oxidize Pd(0) with acetic acid regenerates
7
-chloro-4-aminoquinoline compounds under catalyst-free,
solvent-free microwave irradiation at 120 °C (Scheme 1).
In a typical experiment, 1 equiv. of 4,7-dichloroquinoline
was treated with 1.2 equiv. of amine compounds in a sealed
microwave vessel and kept at 90 °C for a minute in a Bio-
tage microwave oven to get homogeneous reaction mixture.
Then the reaction was prolonged for 10 min with the raise of
1
23

Palladium-catalyzed regioselective aerobic…
Scheme 1
Scheme 2
catalytically active palladium(II)acetate with liberation of
hydrogen peroxide. The similar mechanism was also
applicable to the formation of other derivatives 4b–4f.
activity against MCF7 cancer cell line with IC50 value of
25.40 ± 0.82 lM which is outranged to the standard drug
doxorubicin (28.09 ± 3.72 lM) and moderate activity
against CCRF-CEM and weak activity against HT29 can-
cer cell lines with the IC50 values of 69.66 ± 1.19 and
In vitro cytotoxicity
104.46 ± 4.23 lM, respectively. Both the compounds 3a
All the synthesized and characterized compounds were
then subjected to cytotoxic evaluation against CCRF-CEM,
HT29, and MCF7 cancer cell lines. The results were
summarized in Table 1. Doxorubicin, a clinically used
antitumor agent was also evaluated for positive control.
The anticancer potency of these compounds was indicated
by its IC50 value. In general, all the cyclization precursors
and 3b are simple aromatic amine-substituted compounds
in which compound 3b showed remarkable activity as
compared to compound 3a which may be due to higher
electron density of 1-naphthylamine than simple aniline.
It was observed that the presence of heteroaromatic
amine skeleton did not influence the activity profile in the
panel of intermediate compounds as compared with the
simple amine-substituted compounds. The next set of
(
i.e., intermediate compounds 3a–3g) showed moderate to
weak cytotoxicity in all the three cancer cell lines. Among
them, the compound 3b (in which quinoline 4-position
holds naphthylamine moiety) selectively showed excellent
compounds is Pd(OAc) -catalyzed cyclized products, i.e.,
2
various quinoline-fused indoles 4a–4f. Among them com-
pound 4f showed strong activity against CCRF-CEM and
123

G. Senthil Kumar et al.
Table 1 In vitro cytotoxicity/lM
which promoted two types of discrete C–H activation in
7-chloro-4-aminoquinoline compounds. The aminoquino-
Compound
CCRF-CEM
HT29
MCF7
lines were developed from a simple catalyst-free and
solvent-free microwave irradiation method. The synthe-
sized compounds have showed potent activity against
MCF7 cell line among the tested three human cancer cell
lines.
3
3
3
3
3
3
3
4
4
4
4
4
4
a
b
d
e
c
f
76.25 ± 4.87
69.66 ± 1.19
67.52 ± 1.99
87.00 ± 3.59
60.00 ± 3.99
61.24 ± 5.44
82.73 ± 6.30
90.72 ± 1.83
67.49 ± 1.23
84.41 ± 3.19
62.27 ± 2.76
42.86 ± 0.79
36.61 ± 1.61
39.12 ± 0.32
99.99 ± 0.52
80.36 ± 3.81
104.64 ± 4.23
87.97 ± 3.69
102.27 ± 6.66
104.99 ± 8.36
48.39 ± 12.79
37.39 ± 3.97
88.23 ± 5.72
93.76 ± 1.00
93.12 ± 2.96
85.03 ± 7.89
62.58 ± 1.85
26.20 ± 1.10
13.65 ± 2.11
100.00 ± 8.36
83.88 ± 1.48
25.40 ± 0.82
88.89 ± 4.40
78.07 ± 7.99
92.30 ± 1.21
89.08 ± 0.75
91.43 ± 6.46
89.50 ± 3.11
27.82 ± 1.14
80.61 ± 0.54
71.48 ± 0.31
37.56 ± 1.96
36.82 ± 2.80
28.09 ± 3.72
100.00 ± 2.78
g
a
b
d
e
c
f
Experimental
Melting points were determined on a Mettler FP 51 appa-
ratus (Mettler Instruments, Switzerland). A Nicolet Avatar
Model FT-IR spectrophotometer was used to record the IR
-
1
1
13
spectra (4000–400 cm ). H NMR and C NMR spectra
1
were recorded on Bruker AV 500 [500 MHz ( H) and
1
3
25 MHz ( C)] and Bruker AV 400 [400 MHz ( H) and
1
1
DOX
1
00 MHz ( C)] spectrometers using tetramethylsilane
3
1
DMSO
(
TMS) as an internal reference. The chemical shifts are
expressed in parts per million (ppm). Coupling constants
J) are reported in hertz (Hz). The terms s, d, t, dd refer to
(
MCF7 cancer cell lines with the IC50 value of 36.61 ± 1.61
and 36.82 ± 2.80 lM, respectively, which is better than the
standard drug (39.12 ± 0.32 and 28.09 ± 3.72 lM) and
showed moderate activity against HT29 cell line. Com-
pound 4c is the next active compound in this series, which
displayed good cytotoxicity against CCRF-CEM and MCF7
cancer cell lines with the IC50 value of 42.86 ± 0.79 and
singlet, doublet, triplet, and doublet of doublet, respec-
tively, bs refers to a broad singlet. Mass spectra (MS) were
recorded on an Auto Spec EI?Shimadzu QP 2010 PLUS
GC–MS and Perkin Elmer Clarus 600 (EI) mass spec-
trometer. Microanalyses were performed on a Vario EL III
model CHNS analyzer (Vario, Germany) at the Department
of Chemistry, Bharathiar University. Palladium(II) acetate
was purchased from Sigma Aldrich. Unless otherwise
specified, other reagents were obtained from commercial
suppliers. When known compounds had to be prepared
according to the literature procedures, pertinent references
are given. The purity of the products was tested by TLC
with plates coated with silica gel-G using petroleum ether
and ethyl acetate in the ratio of 50:50 as developing sol-
vents. Columns packed with activated silica gel (60–120
mesh) were used to purify the product.
3
7.56 ± 1.96 lM, respectively, which is quite comparable
with the standard drug, also showed moderate activity
against HT29 cell line, same as compound 4f. Very inter-
estingly, compound 4b which is benzoindoloquinoline
derived from the intermediate compound 3b, displayed
selectively strong cytotoxicity in MCF7 cancer cell line
which outranged the standard drug with the IC50 value of
2
7.82 ± 1.14 lM and showed moderate activity against
CCRF-CEM and weak activity against HT29 cancer cell
line. From these results, we observed that most of the
compounds are selectively active against MCF7 cancer cell
lines. Furthermore compound 4f which is indoloquinoline
fused with pyrazole ring enhances the activity profile
towards all the three cell lines. In general, mostly all the
compounds showed weak activity against HT29 cancer cell
line. By comparing the intermediate and the final cyclized
compounds, the cyclized compounds showed superior
activity than the intermediates.
General procedure for the synthesis of 7-chloro-4-
aryl amino-substituted quinoline compounds
A mixture of 4,7-dichloroquinoline (1, 1.2 mmol) and the
respective aryl/heteroaryl amino compounds (2a–2g,
1.0 mol) was mixed thoroughly with the use of glass rod in
a microwave vessel and subjected to microwave irradiation
(
Biotage microwave oven, 120 °C, 2 bar pressure) for
1
0 min. The progress of the reaction was monitored by
Conclusion
thin-layer chromatography. After completion of the reac-
tion, the reaction mixture was cooled and washed with
aqueous methanol. The crude product obtained was dried
and recrystallized from methanol to afford pure 4-ary-
lamino substituted quinoline compounds 3a–3g.
This paper describes a new palladium-catalyzed reaction
for the highly regioselective intramolecular oxidative
coupling using Cs CO as a base under aerobic condition,
2
3
1
23

Palladium-catalyzed regioselective aerobic…
Scheme 3
Scheme 4
7
-Chloro-N-phenylquinolin-4-amine (3a, C H ClN )
1
(DMSO-d , 500 MHz): d = 6.78 (d, J = 7.0 Hz, 1H, C –
5
11
2
6
3
0
H), 7.45 (t, J = 7.5 Hz, 1H, C –H), 7.50 (d, J = 7.5 Hz,
4
Yield: 0.244 g (96 %); whitish yellow solid; m.p.:
1
[
-
1
0
0
0
0
300 °C; IR (KBr): mꢀ = 3105, 1599 cm
;
H NMR
2H, C –, C –H), 7.59 (t, J = 7.0 Hz, 2H, C –, C –H),
2
6
3
5
123

G. Senthil Kumar et al.
0
C –H), 9.04 (d, J = 2.5 Hz, 1H, C –H), 11.36 (s, 1H,
5 2
7
.88 (dd, J = 9.0 Hz, 2.0 Hz, 1H, C –H), 8.19 (d,
6
1
3
J = 2.0 Hz, 1H, C –H), 8.52 (d, J = 7.0 Hz, 1H, C –H),
8
NH), 14.81 (bs, 1H, iminol) ppm; C NMR (DMSO-d6,
125 MHz): d = 101.39, 109.68, 116.75, 120.02, 126.62,
128.08, 128.15, 128.65, 129.30, 130.45, 131.37, 131.51,
139.00, 139.74, 144.48, 146.57, 148.75, 155.43 ppm; GC–
2
8
.90 (d, J = 9.5 Hz, 1H, C –H), 11.22 (s, 1H, NH), 14.79
5
1
3
(
bs, 1H, iminol) ppm; C NMR (DMSO-d , 125 MHz):
6
d = 100.72, 116.42, 119.73, 125.93, 126.63, 127.82,
1
?
28.10, 130.46, 137.44, 138.85, 139.60, 143.88,
?
55.36 ppm; GC–MS (EI): m/z (%) = 254.20 ([M ], 100).
MS (EI): m/z (%) = 305.23 ([M ], 100).
1
7-Chloro-N-(8-quinolinyl)quinolin-4-amine
7
-Chloro-N-(1-naphthalenyl)quinolin-4-amine
(3e, C H ClN )
12
1
8
3
(
3b, C H ClN )
1
Yield: 0.290 g (95 %); brown solid; m.p.: [300 °C; IR
9
13
2
-1 1
;
Yield: 0.296 g (97 %); brown solid; m.p.: [300 °C; IR
(KBr): mꢀ = 3342, 1590 cm
H NMR (DMSO-d6,
-
1
1
(
KBr): mꢀ = 3229, 1584 cm
;
H NMR (DMSO-d6,
500 MHz): d = 6.31 (d, J = 7.0 Hz, 1H, C –H), 7.70
3
0
5
00 MHz): d = 6.19 (d, J = 7.0 Hz, 1H, C –H), 7.58 (t,
(dd, J = 4.5 Hz, 8.5 Hz, 1H, C –H), 7.83 (t, J = 7.5 Hz,
3
3
0
0
0
1H, C –H), 7.92 (d, J = 9.5 Hz, 1H, C –H), 7.99 (d,
6
0
J = 7.5 Hz, 1H, C –H), 7.65 (t, J = 7.5 Hz, 1H, C –H),
7
6
5
0
0
7
.68–7.74 (m, J = 7.0 Hz, 2H, C –, C –H), 7.88 (d,
3
J = 7.5 Hz, 1H, C –H), 8.18 (dd, J = 8.0 Hz, 1.0 Hz,
6
2
0
J = 8.0 Hz, 1H, C –H), 7.94 (dd, J = 9.0 Hz, 2.0 Hz, 1H,
6
1H, C –H), 8.25 (s, 1H, C –H), 8.40 (d, J = 7.0 Hz, 1H,
4
8
0
0
0
C –H), 8.12 (d, J = 9.5 Hz, 2H, C –, C –H), 8.24 (d,
4
C –H), 8.61 (d, J = 8.5 Hz, 1H, C –H), 8.92 (dd,
2 5
5
8
0
J = 2.0 Hz, 1H, C –H), 8.40 (d, J = 7.0 Hz, 1H, C –H),
8
J = 9.0 Hz, 1.0 Hz, 1H, C –H), 9.04 (d, J = 9.0 Hz,
7
2
0
13
9
.06 (d, J = 9.5 Hz, 1H, C –H), 11.54 (s, 1H, NH), 14.89
5
1H, C –H), 11.52 (s, 1H, NH), 14.92 (bs, 1H, iminol)
2
1
bs, 1H, iminol) ppm; C NMR (DMSO-d , 125 MHz):
3
(
ppm;
C NMR (DMSO-d , 125 MHz): d = 101.93,
6
6
d = 101.12, 116.21, 119.62, 123.03, 125.72, 126.73,
108.99, 116.12, 120.62, 125.88, 127.64, 128.33, 128.69,
129.72, 130.65, 131.84, 132.59, 139.39, 139.95,
143.88, 146.25, 148.81, 154.48 ppm; GC–MS (EI):
1
26.92, 127.48, 127.78, 127.87, 129.14, 129.38, 129.47,
1
33.33, 134.80, 138.92, 139.48, 143.60, 156.95 ppm; GC–
?
MS (EI): m/z (%) = 304.15 ([M ], 100).
?
m/z (%) = 305.21 ([M ], 100).
N-(7-Chloro-4-quinolinyl)-9-ethyl-9H-carbazol-3-amine
7-Chloro-N-(1H-indazol-6-yl)quinolin-4-amine
(
3c, C H ClN )
2
(3f, C H ClN )
16 11
3
18
3
4
Yield: 0.357 g (96 %); yellow solid; m.p.: [300 °C; IR
Yield: 0.277 g (94 %); yellow solid; m.p.: [300 °C; IR
-
1
1
-1 1
(
KBr): mꢀ = 3325, 1570 cm
;
H NMR (DMSO-d6,
(KBr): mꢀ = 3387, 3182, 1597 cm ; H NMR (DMSO-d ,
6
5
00 MHz): d = 1.33 (t, J = 7.5 Hz, 3H, –N–CH –CH ),
500 MHz): d = 6.84 (d, J = 7.0 Hz, 1H, C –H), 7.21 (dd,
2
3
3
0 0
J = 8.5 Hz, 2.0 Hz, 1H, C –H), 7.67 (s, 1H, C –H), 7.88
5 3
4
.56 (q, J = 6.5 Hz, 2H, –N–CH –CH ), 6.71 (d,
2
3
0
J = 7.0 Hz, 1H, C –H), 7.24 (t, J = 7.5 Hz, 1H, C –H),
3
(dd, J = 9.0 Hz, 2.0 Hz, 1H, C –H), 7.94 (d, J = 8.5 Hz,
6
7
0
0
0
7
.50–7.53 (m, 2H, C –, C –H), 7.68 (d, J = 8.5 Hz, 1H,
1
1H, C –H), 8.17 (s, 1H, C –H), 8.19 (d, J = 2.5 Hz, 1H,
8
6
4
0
0
0
C –H), 7.81 (d, J = 8.5 Hz, 1H, C –H), 7.88 (dd,
5
C –H), 8.50 (d, J = 7.0 Hz, 1H, C –H), 8.94 (d,
2
8
7
J = 8.0 Hz, 1.0 Hz, 1H, C –H), 8.12 (s, 1H, C –H), 8.19
6
J = 9.5 Hz, 1H, C –H), 11.37 (s, 1H, N–H), 13.37 (s,
5
13
1H, N’–H), 14.86 (bs, 1H, iminol) ppm; C NMR
4
0
(
d, J = 8.0 Hz, 1H, C –H), 8.27 (d, J = 1.0 Hz, 1H, C –
2
8
H), 8.45 (d, J = 7.0 Hz, 1H, C –H), 8.87 (d, J = 9.0 Hz,
2
(DMSO-d6, 125 MHz): d = 100.98, 116.46, 118.76,
119.68, 121.54, 122.58, 126.74, 127.77, 130.58, 133.74,
135.39, 138.82, 139.58, 143.79, 145.62, 155.64 ppm; GC–
1
H, C –H), 11.24 (s, 1H, NH), 14.63 (bs, 1H, iminol) ppm;
5
1
3
C NMR (DMSO-d , 125 MHz): d = 14.24, 37.68,
6
?
1
1
1
1
00.65, 110.00, 110.86, 116.14, 118.47, 119.64, 121.25,
22.25, 123.44, 124.13, 126.36, 126.96, 127.97, 128.44,
34.34, 138.82, 139.06, 139.54, 140.66, 143.72,
MS (EI): m/z (%) = 294.24 ([M ], 100).
7-Chloro-N-(5-isoquinolinyl)quinolin-4-amine
(
3g, C H ClN )
18 12
?
3
56.17 ppm; GC–MS (EI): m/z (%) = 371.27 ([M ], 100).
Yield: 0.287 g (94 %); yellow solid; m.p.: [300 °C; IR
-
1
1
7
-Chloro-N-(3-quinolinyl)quinolin-4-amine
(KBr): mꢀ = 3329, 1591 cm
;
H NMR (DMSO-d6,
(
3d, C H ClN )
18 12 3
500 MHz): d = 6.83 (d, J = 7.0 Hz, 1H, C –H), 7.44 (d,
3
0 0
J = 8.0 Hz, 1H, C –H), 7.74–7.82 (m, 2H, C –, C –H),
6 8 6
Yield: 0.297 g (97 %); brown solid; m.p.: [300 °C; IR
-
1
1
0
(
KBr): mꢀ = 3285, 1573 cm
;
H NMR (DMSO-d6,
7.87 (t, J = 7.5 Hz, 1H, C –H), 8.07 (s, 1H, C –H), 8.18
8
7
0
(d, J = 5.0 Hz, 1H, C –H), 8.26 (d, J = 7.0 Hz, 1H, C –
4 2
5
00 MHz): d = 7.04 (d, J = 7.0 Hz, 1H, C –H), 7.71 (t,
3
0
0
0
J = 7.5 Hz, 1H, C –H), 7.84 (t, J = 7.5 Hz, 1H, C –H),
6
H), 8.43 (d, J = 8.0 Hz, 1H, C –H), 8.91 (s, 1H, C –H),
5
7
1
0
7
.94 (dd, J = 9.0 Hz, 2.0 Hz, 1H, C –H), 8.08 (d,
6
9.33 (d, J = 4.5 Hz, 1H, C –H), 10.23 (s, 1H, NH) ppm;
3
13
0
0
J = 8.0 Hz, 1H, C –H), 8.12 (d, J = 8.5 Hz, 1H, C –
5
C NMR (DMSO-d , 125 MHz): d = 102.80, 115.23,
118.26, 119.99, 121.23, 125.01, 125.82, 127.12, 128.65,
8
6
0
H), 8.19 (s, 1H, C –H), 8.53 (d, J = 2.5 Hz, 1H, C –H),
8
4
8
.60 (d, J = 7.0 Hz, 1H, C –H), 8.91 (d, J = 8.0 Hz, 1H,
2
128.98, 130.15, 133.39, 136.51, 139.61, 149.51, 152.06,
1
23

Palladium-catalyzed regioselective aerobic…
1
52.96, 158.66 ppm; GC–MS (EI): m/z (%) = 305.21
500 MHz): d = 1.38 (t, J = 7.5 Hz, 3H, –N–CH CH ),
4.50 (q, J = 7.0 Hz, 2H, –N–CH CH ), 7.23 (t,
2 3
2
3
?
[M ], 100).
(
J = 7.5 Hz, 1H, C –H), 7.50–7.55 (m, 2H, C –H, NH),
8
9
General procedure for the synthesis of quinolino-
fused indole compounds
7.67 (d, J = 8.5 Hz, 1H, C –H), 7.81 (d, J = 8.5 Hz, 1H,
12
C –H), 7.88–7.91 (m, 2H, C –, C –H), 8.14–8.22 (m, 2H,
1
3
7
10
C –, C –H), 8.27 (d, J = 1.0 Hz, 1H, C –H), 8.69 (d,
2
6
4
1
3
A mixture of an appropriate 7-chloro-4-amino-substituted
J = 9.0 Hz, 1H, C –H) ppm;
1
C
NMR (CDCl3,
compound (3a–3f, 1.0 mmol) with TBAB (1.5 mmol) and
3
Cs CO (1.5 mmol) in 10 cm anhydrous DMF was taken
125 MHz): d = 19.28, 30.92, 121.88, 122.09, 124.66,
125.19, 126.05, 126.49, 126.87, 127.31, 127.42, 127.60,
127.66, 129.43, 131.01, 131.74, 133.90, 134.41, 141.31,
143.94, 147.07, 147.56 ppm; GC–MS (EI): m/
2
3
in round-bottom flask and subsequently 5 mol% of
Pd(OAc) was added. The whole contents were placed in a
2
?
heating mantle at 120 °C under open air condition for 3 h.
After completion of the reaction, the reaction mixture was
cooled, diluted with water, and extracted with ethyl acetate.
The combined organic extracts were washed with aqueous
z (%) = 369.29 ([M ], 100).
3-Chloro-13H-pyrrolo[3,2-c]bisquinoline
(
4d, C H ClN )
3
1
8
10
Yield: 0.243 g (80 %); brown solid; m.p.: 233–235 °C; IR
1
N HCl and dried over anhydrous sodium sulfate. The
-
1
1
(
KBr): mꢀ = 3198, 1588 cm
;
H NMR (DMSO-d6,
solvent was distilled off under vacuum and the crude
product subjected to column chromatography over silica
gel using petroleum ether:ethyl acetate (85:15) as an eluent
to afford the corresponding indolo-fused quinoline 4a–4f.
5
00 MHz): d = 7.58–7.96 (m, 5H, C –, C –, C –, C –,
2
7
8
9
C –H), 8.01 (d, J = 8.5 Hz, 1H, C –H), 8.27 (s, 1H, C –
1
0
1
4
H), 8.56 (s, 1H, C –H), 8.97 (s, 1H, C –H), 9.45 (s, 1H,
6
12
1
3
NH) ppm; C NMR (DMSO-d , 125 MHz): d = 115.45,
6
3
-Chloro-11H-indolo[3,2-c]quinoline (4a, C H ClN )
1
118.92, 121.58, 123.57, 125.99, 126.87, 127.60, 128.32,
128.74, 129.18, 129.84, 131.32, 133.29, 135.98, 139.77,
141.36, 147.96, 153.43 ppm; GC–MS (EI): m/
5
9
2
Yield: 0.205 g (81 %); yellow solid; m.p.: 216–218 °C; IR
-
1
1
(
KBr): mꢀ = 3167, 1567 cm
;
H
NMR (CDCl3,
?
4
1
3
8
00 MHz): d = 7.19 (t, J = 7.6 Hz, 1H, C –H), 7.26 (s,
z (%) = 303.25 ([M ], 100).
8
H, NH), 7.30 (t, J = 7.6 Hz, 1H, C –H), 7.40–7.45 (m,
9
3-Chloro-13H-pyrido[7,6-b]quinolino[3,2-c]indole
H, C –, C –, C –H), 7.89 (d, J = 8.4 Hz, 1H, C –H),
6
7
10
2
(
4e, C H ClN )
3
1
8
10
.01 (d, J = 1.0 Hz, 1H, C –H), 8.53 (d, J = 7.6 Hz, 1H,
4
Yield: 0.252 g (83 %); brown solid; m.p.: 227–229 °C; IR
1
3
C –H) ppm; C NMR (CDCl , 100 MHz): d = 114.56,
1
3
-1
1
(
KBr): mꢀ = 3233, 1591 cm
;
H
NMR (CDCl3,
1
18.22, 121.42, 123.00, 125.16, 126.26, 129.05, 129.92,
4
00 MHz): d = 7.23–7.53 (m, 5H, C –, C –, C –, C –H,
2
7
8
9
1
35.50, 139.56, 147.89, 149.74, 151.99 ppm; GC–MS (EI):
NH), 7.95 (dd, J = 6.8 Hz, 4.4 Hz, 1H, C –H), 8.03 (d,
10
?
m/z (%) = 252.22 ([M ], 100).
J = 1.6 Hz, 1H, C –H), 8.06 (s, 1H, C –H), 8.45 (d,
4
6
3
-Chloro-13H-benzo[g]indolo[3,2-c]quinoline
J = 7.6 Hz, 1H, C –H), 8.87 (dd, J = 4.0 Hz, 1.6 Hz, 1H,
1
1
3
(
4b, C H ClN )
2
C –H) ppm; C NMR (CDCl , 100 MHz): d = 119.55,
1
9
11
11
3
Yield: 0.260 g (86 %); brown solid; m.p.: 228–230 °C; IR
120.42, 122.61, 124.71, 125.19, 125.84, 127.35, 128.06,
128.69, 132.45, 135.11, 135.47, 135.94, 136.24, 137.79,
142.52, 146.69, 153.90 ppm; GC–MS (EI): m/
-
1
1
(
KBr): mꢀ = 3210, 1586 cm
;
H
NMR (CDCl3,
5
1
3
7
00 MHz): d = 7.28 (t, J = 7.5 Hz, 1H, C –H), 7.34 (s,
1
0
?
H, NH), 7.45 (t, J = 7.5 Hz, 1H, C –H), 7.58–7.65 (m,
1
z (%) = 303.24 ([M ], 100).
1
H, C –, C –, C –H), 7.78 (d, J = 8.0 Hz, 1H, C –H),
12
6
9
8
3-Chloro-7H,12H-pyrazolo[5,4-b]quinolino[3,2-c]indole
.84 (d, J = 8.0 Hz, 1H, C –H), 8.24 (d, J = 2.0 Hz, 1H,
7
(
4f, C H ClN )
4
1
6
9
C –H), 8.40 (d, J = 7.0 Hz, 1H, C –H), 9.06 (d,
4
2
Yield: 0.246 g (84 %); yellow solid; m.p.: 207–209 °C; IR
1
3
J = 9.5 Hz, 1H, C –H) ppm;
1
C
NMR (CDCl3,
-1
1
(
KBr): mꢀ = 3267, 1594 cm
;
H
NMR (CDCl3,
1
1
1
1
25 MHz): d = 117.63, 119.37, 122.94, 124.61, 125.53,
26.44, 126.98, 127.35, 127.60, 127.82, 129.64, 129.92,
4
00 MHz): d = 7.23–7.53 (m, 5H, C –, C –, C –, C –
6
9
10
11
H, N –H), 7.95 (d, J = 8.8 Hz, 1H, C –H), 8.03 (d,
1
2
2
31.17, 132.85, 134.55, 139.71, 140.43, 144.03,
?
55.38 ppm; GC–MS (EI): m/z (%) = 302.30 ([M ], 100).
J = 1.6 Hz, 1H, C –H), 8.45 (d, J = 7.6 Hz, 1H, C –H),
4
1
1
3
1
1.76 (s, 1H, N –H) ppm; C NMR (CDCl , 100 MHz):
7
3
3
-Chloro-11-ethyl-14H-indolo[5,4-b]quinolino[3,2-c]in-
d = 108.96, 109.60, 117.61, 119.31, 120.74, 121.37,
122.55, 123.74, 123.99, 126.05, 126.47, 138.44, 140.70,
141.98, 143.67, 148.15 ppm; GC–MS (EI): m/
dole (4c, C H ClN )
3
2
3
16
Yield: 0.303 g (82 %); yellow solid; m.p.: 246–248 °C; IR
-
1
1
?
(
KBr): mꢀ = 3140, 1569 cm
;
H
NMR (CDCl3,
z (%) = 292.11 ([M ], 100).
123

G. Senthil Kumar et al.
In vitro cytotoxicity
10. Hung TQ, Thang NN, Hoang DH, Dang TT, Villinger A, Langer
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2
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bance at 490 nm with wells containing medium mixed with
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calculated as OD value of cells treated with the test com-
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Acknowledgments Our sincere thanks go to VIT-SIF Lab, SAS,
Chemistry division, VIT University, Vellore, and the SAIF, IIT
Madras, Chennai for providing access to their NMR spectral facilities.
Dr. K. J. Rajendra Prasad is grateful to UGC-BSR for the one-time
research grant.
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