Sc(OTf)3 catalyzed synthesis of novel 6-phenyl-6H-chromeno[4,3-b]quinolines and evaluation of their cytotoxicity

Article abstract of DOI:10.1134/S1070363216070318

Novel 6-phenyl-6H-chromeno[4,3-b]quinoline derivatives have been prepared by reaction of 4-chloro-2-phenyl-2H-chromene-3-carbaldehyde with various aromatic amines using 5 mol % of Sc(OTf)3 in acetonitile. This is the first example of one-pot synthesis of

Full text of DOI:10.1134/S1070363216070318

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 7, pp. 1730–1734. © Pleiades Publishing, Ltd., 2016.
Sc(OTf)3 Catalyzed Synthesis
of Novel 6-Phenyl-6H-chromeno[4,3-b]quinolines
and Evaluation of Their Cytotoxicity1
Y. Jayaprakash Raoa,b, E. Pravardhan Reddya, G. Thirupathia,
E. Yadaiah gouda, M. Sowjanyac, and Y. Hemasrid
a Department of Chemistry, Osmania University, Hyderabad, Telangana, 500007 India
e-mail: pravardhan1@gmail.com; yjprou@yahoo.com
b Department Chemistry, Telangana University, Nizamabad, 503322 India
c Center for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007 India
d Department of Chemistry, Nizam College, Osmania University, 500001 India
Received March 21, 2016
Abstract—Novel 6-phenyl-6H-chromeno[4,3-b]quinoline derivatives have been prepared by reaction of
4-chloro-2-phenyl-2H-chromene-3-carbaldehyde with various aromatic amines using 5 mol % of Sc(OTf)3 in
acetonitile. This is the first example of one-pot synthesis of 6-phenyl-6H-chromeno[4,3-b]quinoline from
4-chloro-2-phenyl-2H-chromene-3-carbaldehyde at ambient temperature. Preliminary evaluation of cytotoxic
activity of these chromeno[4,3-b]quinoline derivatives has been carried out. Some products exhibited anti
cancer activity against two carcinoma cell lines A549 and B-16.
Keywords: 6-phenyl-6H-chromeno[4,3-b]quinoline, Sc(OTf)3, anti cancer
DOI: 10.1134/S1070363216070318
INTRODUCTION
RESULTS AND DISCUSSION
Most of Lewis acids decompose in presence of
water [1], whereas Sc(OTf)3 is stable and acts as a
Lewis acid catalyst in water solutions. Its catalytic
activity could be higher than that of [Ln(OTf)3] [2].
6-Phenyl-6H-chromeno[4, 3-b]quinoline (3a) was
synthesized previously from (E)-3-(2-nitrobenzyl-
idene)-2-phenylchroman-4-one using TiCl2 as a catalyst
[8]. We developed the synthetic approach to 6-phenyl-
6H-chromeno[4, 3-b]quinoline (3) from 4-chloro-2-
phenyl-2H-chromene-3-carbaldehyde (1) and anilines
(2) under Sc(OTf)3 catalysis (Scheme 1). The starting
material 1 was prepared from 2-phenylchroman-4-one
under Vilsmeier–Haack reaction conditions [9]. It
reacted with aromatic amines [10] in CH3CN under
Sc(OTf)3 catalysis at room temperature to give 3 with
high yields (Table 1). The products were characterized
by FT-IR, 1H and 13C NMR and mass spectroscopy.
Chromenes are oxygen containing heterocycles that
exhibit distinctive pharmaceutical activities such as
antimicrobial [3], anticancer [4], antioxidant, and anti-
inflammatory [5]. Quinoline derivatives also found
vast applications as pharmaceuticals [6]. A combina-
tion of chromene with quinoline in one molecule, for
example 6, 6-dimethyl-6H-chromeno[4, 3-b]quinoline
[7], has been studied and it demonstrated promising
bioactivity. Herein, we report the synthesis of 6-phe-
nyl-6H-chromeno[4, 3-b]quinolines from 4-chloro-2-
phenyl-2H-chromene-3-carbaldehyde and aniline and
its derivatives by using Sc(OTf)3 as a catalyst and
evaluation of their anticancer activity.
In all cases chromeno[4,3-b]quinoline was found to
be the major product. Among several solvents, ethanol,
tetrahydrofuran, toluene, benzene, dichloromethane,
and CH3CN, the latter one was found to be the most
efficient. Reaction of compound 1 with 2 in the presence
of 5 mol % of BF3.OEt2, Ln(OTf)3 or Sc(OTf)3 gave 3a
in 52%, 76%, and 95% yields respectively (Table 2).
1 The text was submitted by the authors in English.
1730

Sc(OTf)3 CATALYZED SYNTHESIS
1731
Scheme 1. Synthesis of 6-phenyl-6H-chromeno [4,3-b]quinoline from 4-chloro-2-phenyl-2H-chromene-3-carbaldehyde.
NH2
O
5 mol % Sc(OTf)3
O
R
R
+
room temperature,
CH3CN
CHO
N
Cl
2
1
3
Cytotoxicity. Some chromeno[4, 3-b]quinoline homo-
logous were subjected to insemination cytotoxicity to
human alveolar epithelial cell line (A549) and mouse
macrophage cell (B-16). Cytotoxicity of test com-
pounds in cells was determined by MTT [3-(4,5-di-
methylthaizol-2-yl)-2, 5-diphenyl tetrazolium bromide]
assay.
column chromatography on silica gel (EtOAc–hexane)
to give the pure product.
6-Phenyl-6H-chromeno[4,3-b]quinoline (3a). Yield
98%, white solid, mp 184–186°C. IR spectrum, ν, cm–1:
3035 (Ar, C–H), 2923 (=C–H), 1723 (C=C), 1028
1
(C–O). H NMR spectrum, δ, ppm: 8.52 d.d (1H,
Ar-H, J = 7.8, 1.6 Hz), 8.14 d (1H, Ar-H, J = 8.5 Hz),
7.50–7.72 m (1H, Ar-H), 7.62 d (1H, Ar-H, J =
8.1 Hz), 7.49–7.40 m (7H, Ar-H), 7.45–7.26 m (1H, Ar-H),
7.19–7.14 m (1H, Ar-H), 7.04 d.d (1H, Ar-H, J =
8.1, 0.9 Hz), 6.34 s (1H, =CH). 13C NMR spectrum, δ,
ppm: 156.5, 148.9, 148.1, 138.7, 132.9, 132.0, 129.8,
129.3, 128.9, 128.8, 128.5, 128.2, 127.8, 127.5, 126.2,
In general, majority of the tested compounds de-
monstrated moderate to strong cytotoxicity to the
above two cell lines. The product 3c demonstrated
most potent cytotoxicity to A549 (IC50 0.19 μg/mL)
(Table 3) and 3f exhibited the strongest cytotoxicity to
B-16 cell and significant cytotoxicity to A549cell lin.
Both compounds 3c and 3f (Table 3) contain the
methoxy substituent on the quinoline ring, which
indicated its influence on cytotoxicity.
Table 1. Effect of catalyst on the reaction of chloroaldehyde
(1) and aniline (2a)
EXPERIMENTAL
All chemicals were purchased from Aldrich and
Merk. Melting points were measured in open capillary
tubes. IR spectra were recorded as KBr pellets with a
NH2
O
1
Sc(OTf)3
Shimadzu FT-IR-8400s spectrophotometer. H NMR
1
+
(400 MHz) and 13C NMR (100 MHz) spectra were
measured with a Bruker Avance II 400 spectrometer
using TMS as the internal standard in CDCl3 solutions.
Mass spectra were measured with a Hewlett-Packard
1100 LC/MSD spectrometer.
room temperature,
CH3CN
N
2a
3a
Molecular
mass, mol %
Time, Yieldb
Entry
Acid
Solventa
h
6
6
3
1
4
6
of 3, %
Synthesis of 6-phenyl-6H-chromeno[4,3-b]quino-
lines (3a–3i). To a solution of 4-chloro-2-phenyl-2H-
chromene-3-carbaldehyde (1) (1 equiv.) and Sc(OTf)3
(5 mol %) in dry CH3CN under argon at room
temperature was added slowly a solution of aromatic
amine 2 (1.5 equiv.) through a syringe pump over
30 min. The mixture was stirred for 30 min. Progress
of the reaction was monitored by TLC. Upon
completion of the process the solvent was removed
under reduced pressure and the residue subjected to
1
2
3
4
5
6
BF3·OEt2
BF3·OEt2
Ln(OTf)3
Sc(OTf)3
Sc(OTf)3
AlCl3
5
5
5
5
5
5
CH3CN
Toluene
CH3CN
CH3CN
Water
52
Traces
76
95
10
CH3CN
10
a
All the reactions were carried out using 1 (1.0 mmol) and 2a
(1.5 mmol). b Isolated yield.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 7 2016

1732
Y. JAYAPRAKASH RAO et al.
Table 2. Synthesis of 6-phenyl-6H-chromeno[4,3-b]quinoline (3) from 1 (see Scheme 1)
Compound
Yielda,
%
Compound
Yielda,
%
Entry
1
Product 3
Entry
6
Product 3
2
2
2a; R = H
81
2f;
81
R = 3-OMe
O
O
N
OMe
N
3f
3a
2
2b;
80
7
2g;
81
R = 2-Me,
3Br, 5-Cl
R = 3NO2
Cl
Br
O
O
NO2
N
N
Me
3g
3b
3
2c;
78
8
2h;
80
R = 3-OMe,
4-Me
R = 3-Me
Me
O
O
OMe
Me
N
N
3h
3c
4
2d;
83
9
2i;
78
R = 3-Cl
R = 4-Cl
Cl
O
O
Cl
N
N
3i
3d
5
2e;
R = 3-Br
79
10 2j;
R = 4-Br
81
Br
O
O
Cl
N
N
3j
3e
a Yield refers to pure product after column chromatography.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 7 2016

Sc(OTf)3 CATALYZED SYNTHESIS
1733
Table 3. Cytotoxicity of novel polycyclic quinoline analogs 3
125.6, 123.2, 122.6, 117.7, 80.3. C22H15NO. MS (ESI):
m/z 310 [M + H] +.
Cytotoxicity to carcinoma cells
1C50a, μM
Entry Compound 3
10-Bromo-8-chloro-11-methyl-6-phenyl-6H-chro-
meno[4,3-b]quinoline (3b). Yield 81%, white solid,
mp 195–196°C. IR spectrum, ν, cm–1: 3025 (Ar, C–H),
A549
18.76
22.42
0.19
B-16
11.45
12.43
8.47
1
2
3a
3b
3c
3d
3e
3f
1
2974 (=C–H), 1704 (C=C), 1019 (C–O). H NMR
spectrum, δ, ppm: 8.60 d (1H, Ar-H, J = 2.5 Hz), 8.07
d (1H, Ar-H, J = 8.9 Hz), 7.67–7.62 m (2H, Ar-H),
7.45 d.d (1H, Ar-H, J = 8.6, 2.5 Hz), 7.41 s (1H, Ar-
H), 7.31 d (2H, Ar-H, J = 8.1 Hz), 7.25 d (2H, Ar-H,
J = 7.9 Hz), 6.92 d (1H, J = 8.6 Hz), 6.32 s (1H, =CH,
2.40 s (3H, CH3). 13C NMR spectrum, δ, ppm: 156.6,
149.1, 138.2, 132.4, 132.2, 132.0, 130.8, 130.6, 129.5,
129.1, 128.9, 128.1, 128.0, 126.4, 125.6, 122.7, 117.7,
80.2, 10.0. C23H15BrClNO. MS (ESI): m/z 438 [M + H]+.
3
4
9.58
35.70
12.00
1.90
5
14.02
3.20
6
7
3g
3h
3i
No activity
11.36
20.36
11.26
<0.1
7.69
8
11.30
12.42
7.32
9
10-Methoxy-9-methyl-6-phenyl-6H-chromeno-
[4,3-b]quinoline (3c). Yield 82%, white solid, mp 203–
205°C. IR spectrum, ν, cm–1: 3025 (Ar, C–H), 2929
(=C–H), 1724 (C=C), 1035 (C–O). 1H NMR spectrum,
δ, ppm: 8.58 d (1H, Ar-H, J = 2.5 Hz), 8.04 d (1H, Ar-
H, J = 9.2 Hz), 7.42–7.39 m (2H, Ar-H), 7.38–7.31 m
(3H, Ar-H), 7.24 d (2H, Ar-H, J = 7.9 Hz), 6.94 d (1H,
J = 2.7 Hz), 6.90 d (1H, J = 8.6 Hz), 6.31 s (1H, =CH),
3.88 s(3H, OCH3), 2.40 s (3H, CH3). 13C NMR
spectrum, δ, ppm: 159.6, 148.1, 137.2, 132.1, 132.1,
132.8, 130.0, 129.6, 129.4, 129.0, 128.6, 128.3, 128.1,
126.2, 125.4, 122.4, 117.7, 80.8, 56.8 15.2.
C24H19NO2. MS (ESI): m/z 354 [M + H] +
10
3j
Doxorubicin (control)
<0.1
a
The IC50 value corresponded to the compound concentration
causing 50%mortality in carcinoma after 72 h incubation. The
data is a mean value of three repeated experiments.
130.6, 129.5, 129.1, 128.9, 128.1, 128.0, 126.4, 125.6,
122.78, 117.7, 80.2. C22H14BrNO. MS (ESI): m/z 389
[M + H] +.
10-Methoxy-6-phenyl-6H-chromeno[4,3-b]quino-
line (3f). Yield 81%, white solid, mp 184–186°C. IR
spectrum, ν, cm–1: 3037 (Ar, C–H), 2977 (=C–H),
1778 (C=C), 1029 (C–O). 1H NMR spectrum, δ, ppm:
8.86 d (1H, Ar-H, J = 7.9, Hz), 8.12 d (1H, Ar-H, J =
7.5 Hz), 7.80-7.72 m (1H, Ar-H), 7.52 d (1H, Ar-H,
J = 8.3 Hz), 7.49–7.30 m (6H, Ar-H), 7.25-7.16 m (1H,
Ar-H), 7.06–6.94 m (1H, Ar-H), 6.64 d.d (1H, Ar-H,
J = 8.9, 1.1 Hz), 6.44 s (1H, =CH), 3.83 s (3H, OCH3).
13C NMR spectrum, δ, ppm: 57.6, 156.1, 146.6, 144.2,
138.8, 131.6, 131.4, 130.7, 128.8, 128.8, 128.5, 128.3,
125.1, 123.4, 122.6, 122.5, 117.6, 105.39, 80.3, 55.5.
C22H17NO2. MS (ESI): m/z 340 [M + H].
10-Chloro-6-phenyl-6H-chromeno[4,3-b]quino-
line (3d). Yield 81%, white solid, mp 172–174°C. IR
spectrum, ν, cm–1: 3063 (Ar, C–H), 2945 (=C–H),
1743 (C=C), 1023 (C–O).1H NMR spectrum, δ, ppm:
8.54 d (1H, Ar-H, J = 6.9 Hz), 8.15 s (1H, Ar-H), 7.63
d.d (2H, Ar-H, J = 12.0, 3.0 Hz), 7.51–7.35 m (7H,
Ar-H, 7.19 d (1H, Ar-H, J = 7.5 Hz), 7.07 t (1H,
Ar-H, J = 12.2 Hz), 6.34 s (1H, =CH). 13C NMR spec-
trum, δ, ppm: 158.6, 149.6, 149.1, 139.7, 134.9, 134.0,
131.8, 131.2, 129.0, 128.7, 128.4, 128.1, 127.9, 127.6,
126.3, 125.8, 123.4, 122.9, 118.7, 81.3. C22H14ClNO.
MS (ESI): m/z 344 [M + H] +.
10-Nitro-6-phenyl-6H-chromeno[4,3-b]quinoline
(3g). Yield 76%, white solid, mp 224–226°C. IR spec-
trum, ν, cm–1: 3047 (Ar, C–H), 2943 (=C–H), 1706
(C=C), 1082 (C–O). 1H NMR spectrum, δ, ppm: 8.94 d
(1H, Ar-H, J = 7.9 Hz), 8.35 s (1H, Ar-H), 7.93 d (2H,
Ar-H, J = 9.0 Hz), 7.56–7.45 m (6H, Ar-H), 7.19–7.10
m (2H, Ar-H), 7.06 t (1H, Ar-H, J = 11.2 Hz), 6.54 s
(1H, =CH). 13C NMR spectrum, δ, ppm: 161.6, 155.6,
150.1, 140.7, 137.0, 135.1, 133.2, 133.0, 130.0, 129.7,
10-Bromo-6-phenyl-6H-chromeno[4,3-b]quino-
line (3e). Yield 85%, white solid, mp 204–206°C. IR
spectrum, ν, cm–1: 3085 (Ar, C–H), 2966 (=C–H),
1752 (C=C), 1074 (C–O).1H NMR spectrum, δ, ppm:
8.62 d (1H, Ar-H, J =7.2 Hz), 8.23 s (1H, Ar-H), 7.80
d (2H, Ar-H, J = 12.0 Hz), 7.72–7.52 m (7H, Ar-H),
7.23 d (1H, Ar-H, J = 7.6 Hz), 7.10 t (1H, Ar-H, J =
12.5 Hz), 6.89 s (1H, =CH). 13C NMR spectrum, δ,
ppm: δ 156.6, 149.1, 138.2, 132.4, 132.2, 132.0, 130.8,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 7 2016

1734
Y. JAYAPRAKASH RAO et al.
128.9, 128.5, 127.6, 127.3, 126.2, 125.4, 123.2, 122.4,
carbaldehyde with aromatic amines. Some of the pro-
ducts (3c and 3f) demonstrated cytotoxicity against
two carcinoma cell lines.
119.8, 82.5. C22H14N2O3. MS (ESI): m/z 355 [M + H] +.
10-Methyl-6-phenyl-6H-chromeno[4,3-b]quino-
line (3h). Yield 83%, white solid, mp 164–166°C. IR
spectrum, ν, cm–1: 3087 (Ar, C–H), 2912 (=C–H), 1743
(C=C), 1020 (C–O). 1H NMR spectrum, δ, ppm: 8.46 d
(1H, Ar-H, J = 7.2, Hz), 8.09 d (1H, Ar-H, J = 8.2 Hz),
7.50-7.42 m (1H, Ar-H), 7.35 s (1H, Ar-H), 7.29–7.18
m (6H, Ar-H), 7.15–7.09 m (1H, Ar-H), 7.04–6.84 m
(1H, Ar-H), 6.34 d (1H, Ar-H, J = 7.8 Hz), 6.24 s (1H,
ACKNOWLEDGMENTS
The authors are thankful to the Head, Department
of Chemistry,Osmania University, Center for
Chemical Biology, CSIR-Indian Institute of Chemical
Technology for providing laboratory facilities and the
authors are also thankful to the Director, Central
Facilities for Research and Development (CFRD),
Osmania University for providing IR and NMR
spectral analysis. Financial support from UGC, New
Delhi for one of the authors EP is gratefully
acknowledged.
13
=CH), 2.79 s (3H, CH3). C NMR spectrum, δ, ppm:
157.5, 156.8, 145.5, 143.3, 139.6, 132.0, 131.6, 130.8,
129.9, 129.7, 128.5, 128.2, 125.3, 123.2, 122.3, 122.2,
117.8, 105.49, 80.6, 25.6. C22H17NO. MS (ESI): m/z
324 [M + H].
9-Chloro-6-phenyl-6H-chromeno[4,3-b]quinoline
(3i). Yield 86%, white solid, mp 202–204°C. IR spec-
trum, ν, cm–1: 3045 (Ar, C–H), 2941 (=C–H), 1713
(C=C), 1098 (C–O). 1H NMR spectrum, δ, ppm: 8.45 d
(1H, Ar-H, J = 6.8 Hz), 8.23 s (1H, Ar-H), 7.63 d.d
(2H, Ar-H, J = 11.1, 4.2 Hz), 7.51–7.35 m (7H,
Ar-H, 7.19 s (1H, Ar-H), 7.08 d (1H, Ar-H, J =
11.2 Hz), 6.54 s (1H, =CH). 13C NMR spectrum, δ,
ppm: 157.9, 149.8, 149.2, 139.4, 134.2, 133.2, 131.9,
131.0, 129.2, 128.9, 128.5, 128.2, 127.4, 127.3, 126.2,
124.8, 123.6, 121.8, 117.6, 80.2. C22H14ClNO. MS
(ESI): m/z 344 [M + H] +.
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