Effect of heterocyclic ring system on formation of dimeric quinolones under catalyst-free conditions: a green approach

Article abstract of DOI:10.1007/s11164-017-3032-2

The intermediate-dependent green and efficient synthesis of dimeric quinolones 4a–l and 7a–l by the Knoevenagel condensation followed by Michael-type addition of 4-hydroxy-1-methylquinolin-2(1H)-one 1a, b to indole-3-aldehydes 2a–f and aromatic aldehydes

Full text of DOI:10.1007/s11164-017-3032-2

Res Chem Intermed
DOI 10.1007/s11164-017-3032-2
Effect of heterocyclic ring system on formation
of dimeric quinolones under catalyst-free conditions:
a green approach
1
,2
2
•
Bandi Madhu
C. H. Venkata Ramana Reddy
•
B. Raja sekar
2
2
•
P. K. Dubey
Received: 8 May 2017 / Accepted: 3 July 2017
Ó Springer Science+Business Media B.V. 2017
Abstract The intermediate-dependent green and efficient synthesis of dimeric
quinolones 4a–l and 7a–l by the Knoevenagel condensation followed by Michael-
type addition of 4-hydroxy-1-methylquinolin-2(1H)-one 1a, b to indole-3-aldehydes
2
a–f and aromatic aldehydes 5a–l in water through the condensed compound 3a–l
under catalyst-free conditions is described. This reaction was found to be envi-
ronmentally friendly, has easy-workup and shorter reaction times giving good yields
of the product without the need for its isolation using column chromatography.
Keywords Dimeric quinolones Á Knoevenagel condensation Á Michael
addition Á Quinine Á Luotonin
Introduction
Quinoline and quinolone [1] derivatives have received considerable attention
because of their pharmological [2] importance and numerous biological activities
[
3]. Many of these derivatives are used in a large number of medicinal and
pharmaceutical preparations. Some of these quinoline derivatives are known for
their antimicrobial [4], antifungal [5], anticancer [6], anti-HIV [7], anti-oxidant [8],
enzyme inhibitory [9] and cytotoxic activities [10]. The quinoline ring system also
occurs in natural products [11], mainly in alkaloids [12]. Quinine is a quinoline-
based alkaloid isolated from the bark of cinchona tree [13] and is used for the
treatment of malaria. Luotonin [14] is a cytotoxic alkaloid isolated from peganum
&
Bandi Madhu
madhubandi2@gmail.com
1
2
Jawaharlal Nehru Technological University, Kakinada, Kakinada, A.P., India
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad College of
Engineering, Kukatpally, Hyderabad, T.S. 500 085, India
123

B. Madhu et al.
nigellastrum Bunge. This plant is used as a Chinese traditional medicine for the
treatment of rheumatism and inflammation. Quinarcine [15] is an acridine-based
alkaloid which has been used as an antimalarial agent. Kynurenic acid [16] is a
product of quinoline used for the normal metabolism of amino acids and shows
neuroactive activity. Especially, antimalarial drugs consist of amino quinoline
skeletons (primaquine) extensively used for the treatment of malaria. Pieraquine
was the first bis-quinoline-based antimalarial drug and was synthesized in the 1960s
from 4-amino quinoline [17].
Indoles are nitrogen-containing heterocyclic compounds widely distributed in
nature. Many of these derivatives possess a number of important biological and
pharmacological activities [18]. Also, a large number of natural and synthetic
indoles have been found in agricultural chemicals [19]. Especially, indolylmethanes
and their derivatives are widely recognized as chemical and bioactive metabolites of
marine and terrestrial origin [20]. These newly 3-substituted indoles have been
prepared by the condensation of indole with carbonyl compounds [21]. If the indole
ring system is coupled with other biologically active heterocycles like quinolines
and quinolones, the resulting dimeric system is expected to show an increased
spectrum of biological activity [22]. Recently, Guo et al. [23].reported the one-pot
synthesis of iro- catalyzed bis-indolylmethanes in THF as solvent. Vaghei et al. [24]
reported the efficient synthesis of di-, tri- and tetra-bis indolylmethanes under
thermal conditions with CTAB as a catalyst. Ramachandiran et al. [25] reported
palladium-catalyzed synthesis of indolylmethanes in the presence of Cu(OAc)2
under solvent-free conditions. However, some of the above reported methods suffer
from a few drawbacks, such as the toxic catalyst, low yields, lack of cost-effective
reagents and prolonged reaction conditions. Hence, to overcome these, a new
protocol for the Knoevengel condensation in water has been improved based on
green chemistry principles [26] and follows a single way which is indole
condensation with carbonyl compounds without catalyst.
1
23

Effect of heterocyclic ring system on formation of…
Keeping the above results in our mind and in continuation of our earlier work
27], we here report the green and eco-friendly synthesis of indolylmethanes and its
[
comparison study with dimeric quinolones in good yield by condensation of
different indole-3-carbaldehydes and aromatic aldehydes with quinolones under
green condition, without the need of a catalyst and column chromatography.
Experimental
Materials and methods
Melting points are uncorrected and were determined in open capillary tubes in a
sulfuric acid bath. TLC was run on silica gel-G and visualization was carried out
using iodine or UV light. IR spectra were recorded using a Perkin-Elmer 1000
1
instrument in KBr pellets. H NMR spectra were recorded in DMSO-d using TMS
6
as internal standard using a 400-MHz spectrometer. Mass spectra were recorded
onan Agilent-LCMS instrument under CI conditions and given by Q ? 1 values
only. The chemical and solvents were purchased either from from Aldrich or Avra
laboratories (India) without further purification. Products were purified by
recrystallization from ethanol.
General procedure for preparation of 3 from 1 and 2 by step-wise method
A mixture of 1 (10 mmol) and 2 (10 mmol) and water (5 ml) was stirred at room
temperature for 30 min. At the end of this period, a pale yellow-colored solid was
separated from the reaction mixture which was collected by filtration. The isolated
solid was washed with hot water (10 ml 9 3), dried, and recrystallized from ethanol
to obtain pure 3.
General procedure for preparation of 4 from 1 and 3 by step-wise method
A mixture of 1 (10 mmol) and 3 (10 mmol) and water (5 ml) was refluxed at 100 °C
for 30 min. At the end of this period, an orange-colored solid was separated from
the reaction mixture which was collected by filtration. The isolated solid was
washed with hot water (10 ml 9 3), dried, and recrystallized from ethanol to obtain
pure 4.
General procedure for preparation of 4 from 1 and 2 by one-pot method
A mixture of 1 (20 mmol) and 2 (10 mmol) and water (5 ml) was refluxed at 100 °C
1 h. At the end of this period, an orange-colored solid was separated from the
reaction mixture which was collected by filtration. The isolated solid was washed
with hot water (10 ml 9 3), dried, and recrystallized from ethanol to obtain pure 4.
123

B. Madhu et al.
General procedure for preparation of 7 from 1 and 5
A mixture of 1 (20 mmol), 5 (10 mmol) and water (5 ml) was refluxed at 100 °C for
–2 h. The reaction was monitored by checking TLC for the disappearance of the
1
starting material i.e. 1. At the end of this period, a colorless solid was separated
from the reaction mixture and was collected by filtration. The crude product was
then washed with water (10 ml) and dried. It was recrystallized from ethanol to
obtain pure 7.
Spectral data
3
a: 3-((1H-indol-3-yl) methylene)-1-methylquinoline-2,4(1H,3H)-dione
Pale yellow solid, Yield: 86%, Time: 30 min; M.P.: 210–212 °C; IR (KBr):
-
1
414 cm (–NH group, broad and medium), 1660 cm (–CO– group, sharp),
-1
3
1
3
-
1
1
649 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 3.76 (s,
6
H, N–CH ), 5.68 (s, 1H, –CH–Ar), 6.84–8.25 (m, 9H, four aryl protons of
3
quinoline ring plus five protons of the indole ring), 11.01 (s, 1H, –NH, and D O
2
1
3
exchangeable); C NMR (100 MHz; DMSO-d ): d 29.59, 55.38, 110.46, 111.80,
6
C
1
1
7
13.64, 115.42, 117.71, 118.06, 123.39, 124.49, 125.25, 127.62, 133.80, 135.47,
?
37.48, 152.03, 160.50. m/z (M ?1): 303.3 Anal. Calcd for C H N O (302.1): C,
5.48; H, 4.67; N, 9.27; Found: C, 75.44; H, 4.64; N, 9.31.
1
9 14 2 2
3
b: 1-methyl-3-((5-nitro-1H-indol-3-yl) methylene)quinoline-2,4(1H,3H)-dione
Pale yellow solid, Yield: 91%, Time: 30 min; M.P.: 216–218 °C; IR (KBr):
-
425 cm (–NH group, broad and medium), 1658 cm (–CO– group, sharp),
1
-1
3
1
3
-
1
1
641 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 3.81 (s,
6
H, N–CH ), 5.73 (s, 1H, –CH–Ar), 6.81–8.34 (m, 8H, four aryl protons of
3
quinoline ring plus four protons of the indole ring), 11.05 (s, 1H, –NH, and D O
2
1
3
exchangeable); C NMR (100 MHz; DMSO-d ): d 28.46, 55.29, 110.51, 111.75,
6
C
1
1
6
13.58, 115.33, 117.64, 118.12, 123.45, 124.53, 125.19, 127.70, 133.76, 135.54,
?
37.31, 152.10, 160.58. m/z (M ?1): 348.6 Anal. Calcd for C H N O (347.0): C,
1
9 13 3 4
5.70; H, 3.77; N, 12.10; Found: C, 65.74; H, 3.73; N, 12.06.
c: 3-((5-chloro-1H-indol-3-yl)methylene)-1-methylquinoline-2,4(1H,3H)-dione
3
Pale yellow solid, Yield: 89%, Time: 30 min; M.P.: 209–211 °C; IR (KBr):
-
438 cm (–NH group, broad and medium), 1662 cm (–CO– group, sharp),
1
-1
3
1
3
-
1
1
639 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 3.75 (s,
6
H, N–CH ), 5.69 (s, 1H, –CH–Ar), 6.78–8.31 (m, 8H, four aryl protons of
3
quinoline ring plus four protons of the indole ring), 11.12 (s, 1H, –NH, and D O
2
1
3
exchangeable); C NMR (100 MHz; DMSO-d ): d 28.52, 55.30, 110.58, 111.81,
6
C
1
13.60, 115.28, 117.59, 118.15, 123.37, 124.41, 125.25, 127.67, 133.80, 135.48,
?
37.36, 152.06, 160.41. m/z (M ?1): 337.5 Anal. Calcd for C H ClN O (336.0):
1
C, 67.76; H, 3.89; N, 8.32; Found: C, 67.80; H, 3.85; N, 8.36.
1
9
13
2 2
1
23

Effect of heterocyclic ring system on formation of…
3
d: 3-((5-bromo-1H-indol-3-yl)methylene)-1-methylquinoline-2,4(1H,3H)-dione
Pale yellow solid, Yield: 87%, Time: 30 min; M.P.: 206–208 °C; IR (KBr):
-
429 cm (–NH group, broad and medium), 1653 cm (–CO– group, sharp),
1
-1
3
1
3
-
1
1
627 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 3.65 (s,
6
H, N–CH ), 5.53 (s, 1H, –CH–Ar), 6.71–8.29 (m, 8H, four aryl protons of
3
quinoline ring plus four protons of the indole ring), 11.03 (s, 1H, –NH, and D O
2
1
3
exchangeable); C NMR (100 MHz; DMSO-d ): d 28.39, 55.42, 110.34, 111.76,
6
C
1
13.57, 115.21, 117.45, 118.09, 123.28, 124.33, 125.18, 127.53, 133.74, 135.30,
?
37.24, 152.12, 160.31. m/z (M ?1): 381.6 Anal. Calcd for C H BrN O (380.2):
1
1
9
13
2 2
C, 59.86; H, 3.44; N, 7.35; Found: C, 59.82; H, 3.48; N, 7.38.
e: 3-((5-methoxy-1H-indol-3-yl)methylene)-1-methylquinoline-2,4(1H,3H)-dione
Pale yellow solid, Yield: 76%, Time: 30 min; M.P.: 218–220 °C; IR (KBr):
3
-
1
-1
3
1
3
420 cm (–NH group, broad and medium), 1641 cm (–CO– group, sharp),
-
1
1
618 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 3.20 (s,
6
H, –OCH ), 3.59 (s, 3H, N–CH ), 5.66 (s, 1H, –CH–Ar), 6.75–8.31 (m, 8H, four
3
3
aryl protons of quinoline ring plus four protons of the indole ring), 11.14 (s, 1H, –
1
3
NH, and D O exchangeable); C NMR (100 MHz; DMSO-d ): d 29.19, 31.26,
2
6
C
5
5.51, 110.28, 111.65, 113.50, 115.32, 117.53, 118.11, 123.39, 124.41, 125.22,
?
27.56, 133.68, 135.15, 137.30, 152.23, 160.45. m/z (M ?1): 333.4 Anal. Calcd for
1
C H N O (332.1): C, 72.28; H, 4.85; N, 8.43; Found: C, 72.24; H, 4.89; N, 8.47.
2
0 16 2 3
3
f: 1-methyl-3-((5-methyl-1H-indol-3-yl)methylene)quinoline-2,4(1H,3H)-dione
Pale yellow solid, Yield: 74%, Time: 30 min; M.P.: 216–218 °C; IR (KBr):
-
431 cm (–NH group, broad and medium), 1648 cm (–CO– group, sharp),
1
-1
3
1
3
-
1
1
626 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 3.11 (s,
6
H, –CH ), 3.63 (s, 3H, N–CH ), 5.48 (s, 1H, –CH–Ar), 6.80–8.49 (m, 8H, four aryl
3
3
protons of quinoline ring plus four protons of the indole ring), 11.02 (s, 1H, –NH,
1
3
and D O exchangeable); C NMR (100 MHz; DMSO-d ): d 29.03, 31.56, 55.61,
2
6
C
1
1
7
10.39, 111.43, 113.60, 115.41, 117.50, 120.37, 124.03, 124.25, 125.38, 134.16,
?
37.66, 153.05, 160.38. m/z (M ?1): 317.0 Anal. Calcd for C H N O (316.1): C,
5.93; H, 5.10; N, 8.86; Found: C, 75.97; H, 5.14; N, 8.89.
2
0 16 2 2
3
g: 3-((1H-indol-3-yl)methylene)-1-ethylquinoline-2,4(1H,3H)-dione
Pale yellow solid, Yield: 85%, Time: 30 min; M.P.: 212–214 °C; IR (KBr):
-
425 cm (–NH group, broad and medium), 1656 cm (–CO– group, sharp),
1
-1
3
1
6
9
1
2
1
-
1
1
641 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 1.92 (t,
6
H, –(N–CH ) ), 4.25 (q, 4H, (–N–CH ) ), 5.98 (s, 1H, –CH–Ar), 6.76–8.37 (m,
2 2
3
2
H, four aryl protons of quinoline ring plus five protons of the indole ring), 11.16 (s,
1
3
H, –NH, and D O exchangeable); C NMR (100 MHz; DMSO-d ): d 13.41,
2
6
C
9.50, 55.26, 110.10, 111.72, 113.55, 115.31, 117.68, 118.23, 123.47, 124.53,
?
25.39, 127.62, 133.87, 135.43, 137.22, 152.13, 160.47. m/z (M ?1): 317.5 Anal.
123

B. Madhu et al.
Calcd for C H N O (316.1): C, 75.93; H, 5.10; N, 8.86; Found: C, 75.97; H, 5.14;
2
0 16 2 2
N, 8.89.
h: 1-ethyl-3-((5-nitro-1H-indol-3-yl)methylene)quinoline-2,4(1H,3H)-dione
Pale yellow solid, Yield: 91%, Time: 30 min; M.P.: 215–217 °C; IR (KBr):
3
-
1
-1
3
1
6
8
1
2
1
418 cm (–NH group, broad and medium), 1667 cm (–CO– group, sharp),
-
1
1
638 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 1.86 (t,
6
H, –(N–CH ) ), 4.32 (q, 4H, (–N–CH ) ), 5.86 (s, 1H, –CH–Ar), 6.71–8.43 (m,
H, four aryl protons of quinoline ring plus five protons of the indole ring), 11.23 (s,
3
2
2 2
1
3
H, –NH, and D O exchangeable); C NMR (100 MHz; DMSO-d ): d 13.34,
8.48, 55.13, 110.18, 111.67, 113.42, 115.53, 117.37, 118.41, 123.50, 124.62,
?
25.33, 127.70, 133.72, 135.39, 137.18, 152.06, 160.34. m/z (M ?1): 362.4 Anal.
2
6
C
Calcd for C H N O (361.1): C, 66.48; H, 4.18; N, 11.63; Found: C, 66.45; H,
2
0 15 3 4
4
.15; N, 11.67.
3
i: 3-((5-chloro-1H-indol-3-yl)methylene)-1-ethylquinoline-2,4(1H,3H)-dione
Pale yellow solid, Yield: 86%, Time: 30 min; M.P.: 209–211 °C; IR (KBr):
-
420 cm (–NH group, broad and medium), 1671 cm (–CO– group, sharp),
1
-1
3
1
6
8
1
2
1
-
1
1
628 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 1.67 (t,
6
H, –(N–CH ) ), 4.40 (q, 4H, (–N–CH ) ), 5.91 (s, 1H, –CH–Ar), 6.65–8.39 (m,
H, four aryl protons of quinoline ring plus five protons of the indole ring), 11.12 (s,
3
2
2 2
1
3
H, –NH, and D O exchangeable); C NMR (100 MHz; DMSO-d ): d 13.29,
2
6
C
8.37, 55.21, 110.34, 111.52, 113.38, 115.46, 117.35, 118.58, 123.12, 124.37,
?
25.69, 127.63, 133.54, 135.08, 137.23, 152.14, 160.40. m/z (M ?1): 351.3 Anal.
Calcd for C H ClN O (350.0): C, 68.48; H, 4.31; N, 7.99; Found: C, 68.45; H,
2
0
15
2 2
4
.34; N, 7.96.
3
j: 3-((5-bromo-1H-indol-3-yl)methylene)-1-ethylquinoline-2,4(1H,3H)-dione
Pale yellow solid, Yield: 85%, Time: 30 min; M.P.: 213–215 °C; IR (KBr):
-
431 cm (–NH group, broad and medium), 1671 cm (–CO– group, sharp),
1
-1
3
1
6
8
1
2
1
-
1
1
632 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 1.88 (t,
6
H, –(N–CH ) ), 4.51 (q, 4H, (–N–CH ) ), 5.83 (s, 1H, –CH–Ar), 6.57–8.48 (m,
H, four aryl protons of quinoline ring plus five protons of the indole ring), 11.05 (s,
3
2
2 2
1
3
H, –NH, and D O exchangeable); C NMR (100 MHz; DMSO-d ): d 13.18,
2
6
C
8.42, 55.33, 110.49, 111.67, 113.03, 115.51, 117.28, 118.45, 123.18, 124.00,
?
25.57, 127.74, 133.22, 135.11, 137.31, 152.29, 160.08. m/z (M ?1): 395.7 Anal.
Calcd for C H BrN O (394.1): C, 60.78; H, 3.83; N, 7.09; Found: C, 60.74; H,
2 2
2
0
15
3
.87; N, 7.05.
3
k: 1-ethyl-3-((5-methoxy-1H-indol-3-yl)methylene)quinoline-2,4(1H,3H)-dione
Pale yellow solid, Yield: 74%, Time: 30 min; M.P.: 231–234 °C; IR (KBr):
-
427 cm (–NH group, broad and medium), 1663 cm (–CO– group, sharp),
1
-1
3
1
23

Effect of heterocyclic ring system on formation of…
-
1
1
1
628 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 1.77 (t,
6
6
Ar), 6.44–8.61 (m, 8H, four aryl protons of quinoline ring plus five protons of the
H, –(N–CH ) ), 3.15 (s, 3H, –OCH ), 4.64 (q, 4H, (–N–CH ) ), 5.59 (s, 1H, –CH–
3
2
3
2 2
1
3
indole ring), 11.21 (s, 1H, –NH, and D O exchangeable); C NMR (100 MHz;
2
DMSO-d ): d 13.06, 28.17, 31.58, 55.39, 110.35, 111.60, 113.12, 115.47, 117.35,
6
C
1
z (M ?1): 345.5 Anal. Calcd for C H N O (346.1): C, 72.82; H, 5.24; N, 8.09;
18.53, 123.26, 124.09, 125.61, 127.82, 133.19, 135.07, 137.28, 152.14, 160.15. m/
?
2
1 18 2 3
Found: C, 72.86; H, 5.21; N, 8.05.
l: 1-ethyl-3-((5-methyl-1H-indol-3-yl)methylene)quinoline-2,4(1H,3H)-dione
Pale yellow solid, Yield: 71%, Time: 30 min; M.P.: 228–230 °C; IR (KBr):
3
-
1
-1
3
1
6
422 cm (–NH group, broad and medium), 1658 cm (–CO– group, sharp),
-
1
1
620 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 1.65 (t,
6
H, –(N–CH ) ), 3.02 (s, 3H, –CH ), 4.57 (q, 4H, (–N–CH ) ), 5.60 (s, 1H, –CH–
3
2
3
2 2
Ar), 6.31–8.59 (m, 8H, four aryl protons of quinoline ring plus five protons of the
1
3
indole ring), 11.17 (s, 1H, –NH, and D O exchangeable); C NMR (100 MHz;
2
DMSO-d ): d 13.06, 28.01, 31.62, 55.41, 110.27, 111.56, 113.04, 115.41, 117.29,
6
C
1
z (M ?1): 331.2 Anal. Calcd for C H N O (330.1): C, 76.34; H, 5.49; N, 8.48;
18.48, 123.35, 124.11, 125.65, 127.75, 133.30, 135.24, 137.28, 152.01, 160.28. m/
?
2
1 18 2 2
Found: C, 76.38; H, 5.45; N, 8.51.
0
4
a: 3,3 -((1H-indol-3-yl)methylene)bis(4-hydroxy-1-methylquinolin-2(1H)-one)
-
1
White solid, Yield: 90%, Time: 60 min; M.P.: 292–294 °C; IR (KBr): 3276 cm
(
–NH group, broad and medium), 2578 (–OH group, broad and medium),
-
630 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 3.65
1
1
1
6
(
D O exchangeable)12.97 (s, 2H, –OH, D O exchangeable); C NMR (100 MHz;
s, 6H, –(CH ) ), 6.40 (s, 1H, –CH), 6.72–8.14 (m, 13H, Ar–H), 10.87 (s, 1H, –NH,
1
3 2
3
2
2
DMSO-d ): d 25.32, 51.14, 110.69, 112.01, 115.81, 118.15, 118.80, 121.20,
6
C
?
23.20, 124.08, 127.17, 131.96, 136.83, 138.52, 158.83. m/z (M ?1): 478.7 Anal.
1
Calcd for C H N O (477.17): C, 72.94; H, 4.85; N, 8.80; Found: C, 72.90; H,
2
9 23 3 4
4
.89; N, 8.83.
0
4
one)
b: 3,3 -((5-nitro-1H-indol-3-yl)methylene)bis(4-hydroxy-1-methylquinolin-2(1H)-
-
1
White solid, Yield: 91%, Time: 60 min; M.P.: 289–291 °C; IR (KBr): 3356 cm
(
–NH group, broad and medium), 2581 (–OH group, broad and medium),
-
626 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 3.79
1
1
1
6
(
D O exchangeable)12.59 (s, 2H, –OH, D O exchangeable); C NMR (100 MHz;
s, 6H, –(CH ) ), 6.43 (s, 1H, –CH), 6.85–8.23 (m, 12H, Ar–H), 11.57 (s, 1H, –NH,
3 2
1
3
2
2
DMSO-d ): d 27.44, 51.04, 100.65, 110.25, 110.62, 112.57, 115.71, 123.19,
6
C
?
24.05, 124.78, 127.42, 131.94, 132.06, 138.51, 152.97. m/z (M ?1): 523.2 Anal.
1
Calcd for C H N O (522.15): C, 66.66; H, 4.24; N, 10.72; Found: C, 66.62; H,
2
9 22 4 6
4
.28; N, 10.76.
123

B. Madhu et al.
0
4
c: 3,3 -((5-chloro-1H-indol-3-yl)methylene)bis(4-hydroxy-1-methylquinolin-
(1H)-one)
2
-
1
White solid, Yield: 84%, Time: 60 min; M.P.: 282–284 °C; IR (KBr): 3346 cm
(
–NH group, broad and medium), 2539 (–OH group, broad and medium),
-
647 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 3.64
1
1
1
6
(
D O exchangeable)12.27 (s, 2H, –OH, D O exchangeable); C NMR (100 MHz;
s, 6H, –(CH ) ), 6.71 (s, 1H, –CH), 6.90–8.55 (m, 12H, Ar–H), 11.06 (s, 1H, –NH,
3 2
1
3
2
2
DMSO-d ): d 27.38, 51.27, 100.21, 105.32, 110.42, 110.79, 113.83, 115.20,
6
C
?
24.01, 125.07, 127.38, 131.52, 132.06, 135.74, 139.81, 153.47. m/z (M ?1): 512.6
1
Anal. Calcd for C H ClN O (511.13): C, 68.04; H, 4.33; N, 8.21; Found: C,
29
22
3 4
6
8.01; H, 4.37; N, 8.24.
0
4
d: 3,3 -((5-bromo-1H-indol-3-yl)methylene)bis(4-hydroxy-1-methylquinolin-
(1H)-one)
2
-
1
White solid, Yield: 83%, Time: 60 min; M.P.: 279–281 °C; IR (KBr): 3339 cm
(
–NH group, broad and medium), 2528 (–OH group, broad and medium),
-
637 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 3.89
1
1
1
6
(
D O exchangeable)12.40 (s, 2H, –OH, D O exchangeable); C NMR (100 MHz;
s, 6H, –(CH ) ), 6.30 (s, 1H, –CH), 6.74–8.23 (m, 12H, Ar–H), 10.86 (s, 1H, –NH,
3 2
1
3
2
2
DMSO-d ): d 27.23, 53.02, 100.07, 106.27, 110.18, 110.27, 115.74, 118.50,
6
C
?
24.05, 125.36, 127.49, 131.25, 135.13, 139.63, 140.58, 153.85. m/z (M ?1): 556.3
1
Anal. Calcd for C H BrN O (555.08): C, 62.60; H, 3.99; N, 7.55; Found: C,
2
9
22
3 4
6
2.64; H, 3.95; N, 7.51.
0
4
e: 3,3 -((5-methoxy-1H-indol-3-yl)methylene)bis(4-hydroxy-1-methylquinolin-
(1H)one)
2
-
1
White solid, Yield: 81%, Time: 60 min; M.P.: 296–298 °C; IR (KBr): 3412 cm
(
–NH group, broad and medium), 2569 (–OH group, broad and medium),
1
629 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 3.18
-
1
1
6
(
H), 11.03 (s, 1H, –NH, D O exchangeable)12.74 (s, 2H, –OH, D O exchangeable);
s, 3H, –OCH ), 3.90 (s, 6H, –(CH ) ), 6.22 (s, 1H, –CH), 6.63–8.45 (m, 12H, Ar–
3 3 2
2
2
1
3
C NMR (100 MHz; DMSO-d ): d 28.79, 31.44, 55.04, 100.65, 110.25, 110.62,
6
C
1
1
11.94, 112.58, 115.70, 117.16, 117.48, 123.18, 124.04, 124.79, 127.42, 131.93,
?
32.06, 138.50, 152.97. m/z (M ?1): 508.2 Anal. Calcd for C H N O (507.18):
3
0 25 3 5
C, 70.99; H, 4.96; N, 8.28; Found: C, 70.95; H, 4.92; N, 8.24.
0
4
one)
f: 3,3 -((5-methyl-1H-indol-3-yl)methylene)bis(4-hydroxy-1-methylquinolin-2(1H)-
-
1
White solid, Yield: 81%, Time: 60 min; M.P.: 297–299 °C; IR (KBr): 3411 cm
(
–NH group, broad and medium), 2552 (–OH group, broad and medium),
-
629 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 3.01
1
1
1
6
(
s, 3H, –CH ), 3.82 (s, 6H, –(CH ) ), 6.19 (s, 1H, –CH), 6.59–8.37 (m, 12H, Ar–H),
3 3 2
1
23

Effect of heterocyclic ring system on formation of…
1
3
1
0.84 (s, 1H, –NH, D O exchangeable)12.60 (s, 2H, –OH, D O exchangeable);
2
C
2
NMR (100 MHz; DMSO-d ): dC 28.61, 31.15, 55.21, 110.94, 112.47, 114.01,
6
1
1
7
15.29, 115.82, 116.70, 117.32, 123.28, 124.17, 126.33, 128.05, 132.15, 138.60,
?
40.11, 140.31, 153.61. m/z (M ?1): 492.3 Anal. Calcd for C H N O (491.1): C,
3.30; H, 5.13; N, 8.55; Found: C, 73.34; H, 5.17; N, 8.51.
3
0 25 3 4
0
4
g: 3,3 -((1H-indol-3-yl)methylene)bis(1-ethyl-4-hydroxyquinolin-2(1H)-one)
-
1
White solid, Yield: 89%, Time: 60 min; M.P.: 290–292 °C; IR (KBr): 3333 cm
(
–NH group, broad and medium), 2558 (–OH group, broad and medium),
1
626 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 1.70
-
1
1
6
(
t, 6H, –(N–CH ) ), 4.16 (q, 4H, (–N–CH ) ), 6.25 (s, 1H, –CH), 6.62–8.21 (m,
3H, Ar–H), 11.03 (s, 1H, –NH, D O exchangeable)12.74 (s, 2H, –OH, D O
2 2
3 2 2 2
1
1
3
exchangeable); C NMR (100 MHz; DMSO-d ): d 13.37, 27.29, 56.21, 110.66,
6
C
1
12.03, 115.54, 118.11, 118.72, 121.20, 123.09, 123.98, 124.50, 127.09, 132.08,
?
36.86, 137.38, 153.30. m/z (M -1): 504.2 Anal. Calcd for C H N O (505.20):
1
C, 73.65; H, 5.38; N, 8.31; Found: C, 73.62; H, 5.35; N, 8.35.
3
1 27 3 4
0
4
one)
h: 3,3 -((5-nitro-1H-indol-3-yl)methylene)bis(1-ethyl-4-hydroxyquinolin-2(1H)-
-
1
White solid, Yield: 91%, Time: 60 min; M.P.: 273–275 °C; IR (KBr): 3341 cm
(
–NH group, broad and medium), 2553 (–OH group, broad and medium),
-
632 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 1.74
1
1
1
6
(
t, 6H, –(N–CH ) ), 4.25 (q, 4H, (–N–CH ) ), 6.30 (s, 1H, –CH), 6.59–8.18 (m,
3 2 2 2
1
2H, Ar–H), 11.14 (s, 1H, –NH, D O exchangeable)12.81 (s, 2H, –OH, D O
2 2
1
3
exchangeable); C NMR (100 MHz; DMSO-d ): d 13.48, 27.36, 56.37, 110.57,
6
C
1
1
6
12.31, 115.46, 118.65, 121.19, 123.27, 123.88, 124.46, 127.71, 132.23, 136.78,
?
37.09, 153.44. m/z (M -1): 549.7 Anal. Calcd for C H N O (550.19): C,
7.63; H, 4.76; N, 10.18; Found: C, 67.67; H, 4.73; N, 10.14.
3
1 26 4 6
0
4
one)
i: 3,3 -((5-chloro-1H-indol-3-yl)methylene)bis(1-ethyl-4-hydroxyquinolin-2(1H)-
-
1
White solid, Yield: 87%, Time: 60 min; M.P.: 260–262 °C; IR (KBr): 3352 cm
(
–NH group, broad and medium), 2560 (–OH group, broad and medium),
-
645 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 1.63
1
1
1
6
(
t, 6H, –(N–CH ) ), 4.16 (q, 4H, (–N–CH ) ), 6.44 (s, 1H, –CH), 6.71–8.40 (m,
3 2 2 2
1
2H, Ar–H), 11.29 (s, 1H, –NH, D O exchangeable)12.39 (s, 2H, –OH, D O
2 2
1
3
exchangeable); C NMR (100 MHz; DMSO-d ): d 13.22, 27.29, 56.09, 110.83,
6
C
1
1
6
12.74, 115.61, 118.47, 121.21, 123.35, 123.92, 124.58, 127.80, 132.41, 136.59,
?
37.16, 153.50. m/z (M -1): 540.5 Anal. Calcd for C H ClN O (539.16): C,
8.95; H, 4.85; N, 7.78; Found: C, 68.91; H, 4.89; N, 7.74.
3
1
26
3 4
123

B. Madhu et al.
0
j: 3,3 -((5-bromo-1H-indol-3-yl)methylene)bis(1-ethyl-4-hydroxyquinolin-2(1H)-
4
one)
-
1
White solid, Yield: 85%, Time: 60 min; M.P.: 257–259 °C; IR (KBr): 3348 cm
(
–NH group, broad and medium), 2557 (–OH group, broad and medium),
-
641 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 1.48
1
1
1
6
(
t, 6H, –(N–CH ) ), 4.36 (q, 4H, (–N–CH ) ), 6.35 (s, 1H, –CH), 6.64–8.37 (m,
3 2 2 2
1
2H, Ar–H), 11.06 (s, 1H, –NH, D O exchangeable)12.47 (s, 2H, –OH, D O
2 2
1
3
exchangeable); C NMR (100 MHz; DMSO-d ): d 13.78, 27.26, 56.14, 110.75,
6
C
1
1
6
12.69, 115.77, 118.56, 121.31, 123.40, 123.83, 124.66, 127.74, 132.81, 136.72,
?
37.09, 153.67. m/z (M -1): 582.6 Anal. Calcd for C H BrN O (583.11): C,
3.71; H, 4.48; N, 7.19; Found: C, 63.74; H, 4.44; N, 7.16.
3
1
26
3 4
0
4
k: 3,3 -((5-methoxy-1H-indol-3-yl)methylene)bis(1-ethyl-4-hydroxyquinolin-
(1H)-one)
2
-
1
White solid, Yield: 84%, Time: 60 min; M.P.: 291–293 °C; IR (KBr): 3353 cm
(
–NH group, broad and medium), 2542 (–OH group, broad and medium),
1
637 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 1.42
-
1
1
6
(
CH), 6.58–8.24 (m, 12H, Ar–H), 11.15 (s, 1H, –NH, D O exchangeable)12.31 (s,
t, 6H, –(N–CH ) ), 3.28 (s, 3H, –OCH ), 4.51 (q, 4H, (–N–CH ) ), 6.40 (s, 1H, –
3 2 3 2 2
2
1
3
2
3
1
H, –OH, D O exchangeable); C NMR (100 MHz; DMSO-d ): d 13.78, 28.65,
2
6
C
1.79, 56.38, 110.67, 112.72, 115.50, 118.83, 121.22, 123.13, 123.44, 124.34,
?
27.56, 132.19, 136.25, 137.13, 153.82. m/z (M ?1): 536.4 Anal. Calcd for
C H N O (535.2): C, 71.76; H, 5.46; N, 7.85; Found: C, 71.72; H, 5.49; N, 7.81.
3
2
29 3 5
0
4
one)
l: 3,3 -((5-methyl-1H-indol-3-yl)methylene)bis(1-ethyl-4-hydroxyquinolin-2(1H)-
-
1
White solid, Yield: 82%, Time: 60 min; M.P.: 288–290 °C; IR (KBr): 3326 cm
(
–NH group, broad and medium), 2535 (–OH group, broad and medium),
-
629 cm (–CO– group, sharp); H-NMR (DMSO d /TMS, 400 MHZ): d 1.54
1
1
1
6
(
t, 6H, –(N–CH ) ), 3.35 (s, 3H, –CH ), 4.29 (q, 4H, (–N–CH ) ), 6.38 (s, 1H, –CH),
.41–8.65 (m, 12H, Ar–H), 11.01 (s, 1H, –NH, D O exchangeable)12.63 (s, 2H, –
2
3 2 3 2 2
6
1
3
OH, D O exchangeable); C NMR (100 MHz; DMSO-d ): d 13.28, 28.91, 31.35,
2
6
C
5
6.10, 110.54, 112.36, 115.62, 118.79, 121.34, 123.19, 123.55, 124.41, 127.67,
?
32.23, 136.40, 137.25, 154.07. m/z (M ?1): 520.2 Anal. Calcd for C H N O
519.5): C, 73.97; H, 5.63; N, 8.09; Found: C, 73.95; H, 5.67; N, 8.06.
1
3
2
29
3
4
(
0
a: 3,3 -(phenylmethylene) bis (4-hydroxy-1-methylquinolin-2(1H)-one)
7
White solid, Yield: 91% Time: 60 min; M.P.: 287–289 °C; IR (KBr): 2970 (–OH
-
1
1
group, broad), 1627 cm
4
(–CO– group, sharp); H-NMR (DMSO d /TMS,
6
00 MHZ): d 3.72 (s, 6H, –(CH ) ), 6.28 (s, 1H, –CH), 7.06–8.07 (m, 13H, Ar–
3
2
1
3
H), 12.60 (s, 2H, –OH, D O exchangeable); C NMR (100 MHz; DMSO-d ): d
2
6
C
1
8.88, 55.36, 115.71, 117.26, 123.12, 123.99, 126.02, 126.57, 128.43, 131.97,
1
23

Effect of heterocyclic ring system on formation of…
?
37.99, 138.51, 160.87. m/z (M ?1): 439. Anal. Calcd for C H N O (438.47): C,
1
2
7 22 2 4
7
3.96; H, 5.06; N, 6.39; Found: C, 73.84; H, 5.03; N, 6.28.
0
b: 3,3 -((3-chlorophenyl) methylene) bis (4-hydroxy-1-methylquinolin-2(1H)-one)
7
White solid, Yield: 84% Time: 90 min; M.P.: 190–192 °C; IR (KBr): 2975 (–OH
-
1
1
group, broad), 1673 cm
4
(–CO– group, sharp); H-NMR (DMSO d /TMS,
6
00 MHZ): d 3.83 (s, 6H, –(CH ) ), 6.46 (s, 1H, –CH), 7.41–8.72 (m, 12H, Ar–
3
2
1
3
H), 12.13 (s, 2H, –OH, D O exchangeable); C NMR (100 MHz; DMSO-d ): d
2
6
C
1
8.19, 55.28, 115.63, 117.26, 123.28, 123.72, 126.38, 126.75, 128.18, 131.82,
?
37.37, 137.81, 138.01, 138.28, 160.46. m/z (M ?1): 473. Anal. Calcd for
1
C H ClN O (472.95): C, 68.54; H, 4.49; N, 5.96; Found: C, 68.52; H, 4.48; N,
2
7
21
2 4
5
.94.
0
7
c: 3,3 -((4-chlorophenyl) methylene) bis (4-hydroxy-1-methylquinolin-2(1H)-one)
White solid, Yield: 83% Time: 90 min; M.P.: 174–175 °C; IR (KBr): 2979 (–OH
-
1
1
group, broad), 1683 cm
4
(–CO– group, sharp); H-NMR (DMSO d /TMS,
6
00 MHZ): d 3.48 (s, 6H, –(CH ) ), 6.96 (s, 1H, –CH), 7.23–8.61 (m, 12H, Ar–
3
2
1
3
H), 12.36 (s, 2H, –OH, D O exchangeable); C NMR (100 MHz; DMSO-d ): d
2
6
C
1
8.62, 55.31, 115.81, 117.26, 123.62, 123.83, 126.36, 126.71, 128.76, 131.28,
?
37.51, 138.76, 160.69. m/z (M ?1): 473. Anal. Calcd for C H ClN O (472.92):
1
C, 68.57; H, 4.48; N, 5.92; Found: C, 68.53; H, 4.45; N, 5.98.
2
7
21
2 4
0
7
one)
d: 3,3 -((2-hydroxyphenyl) methylene) bis (4-hydroxy-1-methylquinolin-2(1H)-
White solid, Yield: 72% Time: 120 min; M.P.: 220–222 °C; IR (KBr): 2972 (–OH
group, broad), 2968 (–OH group, broad), 1638, cm (–CO– group, sharp); H-NMR
-
1
1
(
(
DMSO d /TMS, 400 MHZ): d 3.79 (s, 6H, –(CH ) ), 6.35 (s, 1H, –CH), 7.12–8.32
6
3 2
m, 12H, Ar–H), 12.16 (s, 1H, –OH, D O exchangeable); 12.38 (s, 2H, –OH, D O
1
2
2
3
exchangeable); C NMR (100 MHz; DMSO-d ): d 18.71, 55.24, 115.62, 117.51,
6
C
1
z (M ?1): 455. Anal. Calcd for C H N O (454.47): C, 71.35; H, 4.88; N, 6.16;
23.24, 123.83, 126.11, 126.72, 128.24, 131.95, 137.14, 138.63, 160.69. m/
?
2
7 22 2 5
Found: C, 71.28; H, 4.91; N, 6.18.
0
7
e: 3,3 -((4-hydroxyphenyl) methylene) bis (4-hydroxy-1-methylquinolin-2(1H)-one)
White solid, Yield: 76% Time: 120 min; M.P.: 209–211 °C; IR (KBr): 2985 (–OH
group, broad), 2925 (–OH group, broad), 1664, cm (–CO– group, sharp); H-NMR
-
1
1
(
(
DMSO d /TMS, 400 MHZ): d 3.68 (s, 6H, –(CH ) ), 6.29 (s, 1H, –CH), 7.20–8.44
6
3 2
m, 12H, Ar–H), 12.23 (s, 1H, –OH, D O exchangeable); 12.40 (s, 2H, –OH, D O
1
2
2
3
exchangeable); C NMR (100 MHz; DMSO-d ): d 18.71, 55.42, 115.62, 117.47,
6
C
1
z (M ?1): 455. Anal. Calcd for C H N O (454.47): C, 71.31; H, 4.83; N, 6.13;
23.11, 123.92, 126.24, 126.39, 128.82, 131.73, 137.61, 138.83, 160.75. m/
?
2
7 22 2 5
Found: C, 71.22; H, 4.94; N, 6.16.
123

B. Madhu et al.
0
7
f: 3,3 -((3-nitrophenyl) methylene) bis (4-hydroxy-1-methylquinolin-2(1H)-one)
White solid, Yield: 85% Time: 60 min; M.P.: 296–298 °C; IR (KBr): 2986 (–OH
-
1
1
group, broad), 1679 cm
(–CO– group, sharp); H-NMR (DMSO d /TMS,
6
4
Aromatic hydrogens), 12.62 (s, 2H, –OH, D O exchangeable);
00 MHZ): d 3.82 (s, 6H, –(CH ) ), 6.46 (s, 1H, –CH), 7.82–8.49 (m, 12H,
3
2
1
3
C NMR
2
(
100 MHz; DMSO-d ): d 18.31, 55.36, 115.52, 117.29, 123.38, 123.91, 126.71,
6
C
?
26.79, 128.38, 131.57, 137.35, 137.62, 138.29, 138.58, 160.59. m/z (M ?1): 484.2
1
Anal. Calcd for C H N O (483.43): C, 67.02; H, 4.31; N, 8.69; Found: C, 67.03;
H, 4.32; N, 8.61.
2
7 21 3 6
0
7
g: 3,3 -((4-nitrophenyl) methylene) bis (4-hydroxy-1-methylquinolin-2(1H)-one)
White solid, Yield: 85% Time: 60 min; M.P.: 293–294 °C; IR (KBr): 2991 (–OH
-
1
1
group, broad), 1685 cm
4
(–CO– group, sharp); H-NMR (DMSO d /TMS,
6
00 MHZ): d 3.87 (s, 6H, –(CH ) ), 6.63 (s, 1H, –CH), 7.92–8.41 (m, 12H, Ar–
3
2
1
3
H), 12.83 (s, 2H, –OH, D O exchangeable); C NMR d (100 MHz; DMSO-d ):
2
C
6
1
8.27, 55.31, 115.46, 117.69, 123.26, 123.71, 126.53, 126.77, 128.81, 131.68,
?
37.19, 138.81, 160.93. m/z (M ?1): 484.2 Anal. Calcd for C H N O (483.49):
1
C, 67.02; H, 4.36; N, 8.64; Found: C, 67.01; H, 4.32; N, 8.63.
2
7 21 3 6
0
7
one)
h: 3,3 -((4-methoxyphenyl) methylene) bis (4-hydroxy-1-methylquinolin-2(1H)-
White solid, Yield: 75% Time: 120 min; M.P.: 237–238 °C; IR (KBr): 2976 (–OH
-
1
1
group, broad), 1672 cm
(–CO– group, sharp); H-NMR (DMSO d /TMS,
6
4
7
00 MHZ): d 3.51 (s, 6H, –(CH ) ), 3.83 (s, 3H, –OCH ), 6.84 (s, 1H, –CH),
3
2
3
13
.58–8.72 (m, 12H, Ar–H), 12.91 (s, 2H, –OH, D O exchangeable); C NMR
2
(
100 MHz; DMSO-d ): dC 18.11, 42.26, 55.42, 115.61, 117.72, 123.51, 123.85,
6
?
26.53, 126.79, 128.67, 131.73, 137.27, 138.66, 160.58. m/z (M ?1): 469.3 Anal.
1
Calcd for C H N O (468.50): C, 71.78; H, 5.16; N, 5.98; Found: C, 71.76; H,
2
8 24 2 5
5
.19; N, 5.95.
0
7
one)
i: 3,3 -((3,4-dimethoxyphenyl)methylene)bis(4-hydroxy-1-methylquinolin-2(1H)-
White solid, Yield: 79% Time: 120 min; M.P.: 239–241 °C; IR (KBr): 2974 (–OH
-
1
1
group, broad), 1676 cm
4
(–CO– group, sharp); H-NMR (DMSO d /TMS,
6
00 MHZ): d 3.46 (s, 6H, –(CH ) ), 3.68 (s, 3H, –OCH ), 3.81 (s, 3H, –OCH ),
3
2
3
3
6
.81 (s, 1H, –CH), 7.46–8.69 (m, 11H, Ar–H), 12.86 (s, 2H, –OH, D O
1
2
3
exchangeable); C NMR (100 MHz; DMSO-d ): d 18.25, 40.35, 42.34, 55.51,
6
C
1
1
5
15.73, 117.65, 123.58, 123.77, 126.60, 126.91, 128.56, 131.59, 137.17, 138.64,
?
60.28. m/z (M ?1): 499.2 Anal. Calcd for C H N O (498.10): C, 69.87; H,
.26; N, 5.62; Found: C, 69.85; H, 5.29; N, 5.66.
2
9 26 2 6
1
23

Effect of heterocyclic ring system on formation of…
0
7
j: 3,3 -((3-ethoxy-4-methoxyphenyl)methylene)bis(4-hydroxy-1-methylquinolin-
(1H)-one)
2
White solid, Yield: 71% Time: 120 min; M.P.: 240–242 °C; IR (KBr): 2982 (–OH
-
1
1
group, broad), 1678 cm
(–CO– group, sharp); H-NMR (DMSO d /TMS,
6
4
2
2
4
1
00 MHZ): d 3.43 (s, 6H, –(CH ) ), 3.74 (s, 3H, –CH ), 3.61 (q, 2H, -OCH ),
3
2
3
2
.81 (t, 3H, –CH –CH ), 6.74 (s, 1H, –CH), 7.31–8.62 (m, 11H, Ar–H), 12.91 (s,
1
2
3
3
H, –OH, D O exchangeable); C NMR (100 MHz; DMSO-d ): d 18.23, 33.61,
2
6
C
2.32, 45.63, 55.34, 115.57, 117.78, 123.36, 123.75, 126.44, 126.82, 128.53,
?
31.39, 137.31, 138.48, 160.48. m/z (M ?1): 513 Anal. Calcd for C H N O
3
0
28
2
6
(
512.55): C, 70.30; H, 5.51; N, 5.47; Found: C, 70.34; H, 5.56; N, 5.44.
0
7
k: 3,3 -(furan-2-ylmethylene) bis (4-hydroxy-1-methylquinolin-2(1H)-one)
White solid, Yield: 82% Time: 90 min; M.P.: 242–243 °C; IR (KBr): 2973 (–OH
-
1
1
group, broad), 1689 cm
4
(–CO– group, sharp); H-NMR (DMSO d /TMS,
6
00 MHZ): d 3.52 (s, 6H, –(CH ) ), 6.83 (s, 1H, –CH), 7.63–8.89 (m, 11H, Ar–
3
2
1
3
H), 12.13 (s, 2H, –OH, D O exchangeable); C-NMR (100 MHz; DMSO-d ): d
2
6
C
2
1
7
0.89, 56.45, 119.64, 121.17, 124.33, 125.24, 128.62, 129.51, 132.84, 137.93,
?
39.73, 160.72. m/z (M ?1): 429.3 Anal. Calcd for C H N O (428.44): C,
0.08; H, 4.71; N, 6.54; Found: C, 70.04; H, 4.76; N, 6.58.
2
5 20 2 5
0
7
l: 3,3 -(phenylmethylene)bis(1-ethyl-4-hydroxyquinolin-2(1H)-one)
White solid, Yield: 90% Time: 60 min; M.P.: 289–290 °C; IR (KBr): 2968 (–OH
-
1
1
group, broad), 1618 cm
(–CO– group, sharp); H-NMR (DMSO d /TMS,
6
4
7
00 MHZ): d 3.61 (t, 6H, –(CH ) ), 4.12 (q, 4H, (–N–CH ) ), 6.31 (s, 1H, –CH),
3
2
2 2
13
.12–8.24 (m, 13H, Ar–H), 12.58 (s, 2H, –OH, D O exchangeable); C NMR
2
(
100 MHz; DMSO-d ): dC 13.89, 18.75, 55.23, 115.57, 117.26, 123.34, 123.87,
6
?
26.16, 126.64, 128.39, 131.88, 137.73, 138.41, 160.72. m/z (M ?1): 467.4 Anal.
1
Calcd for C H N O (466.1): C, 74.66; H, 5.62; N, 6.00; Found: C, 74.62; H, 5.66;
N, 6.04.
2
9 26 2 4
Results and discussion
As illustrated in Scheme 1, initially one mole of 4-hydroxy-1-methylquinolin-
2
R = H) to form
(1H)-one 1a (i.e. 1 , R = CH ) was reacted with indole-3-carbaldehyde 2a (i.e. 2,
1
3
a
methylquinoline-2,4(1H,3H)-dione 3a (i.e. 3, R = CH , R = H) in water at room
condensed compound 3-((1H-indol-3-yl)methylene)-1-
2
1
3
2
temperature for 30 min. The structure of a was assigned on the basis of its spectral
properties-IR, NMR and Mass. Thus, its IR (KBr) spectrum showed a broad,
-
medium absorption at 3414 cm due to the presence of an indole-NH group and a
1
-
strong, sharp absorptions at 1660 and 1649 cm due to the presence of an amide
1
1
carbonyl group and a carbonyl group at the 4-position. Its H NMR, in DMSO-d ,
6
showed signals at d 3.76 (s, 3H, N–CH ), 5.68 (s, 1H, –CH–Ar), 6.84–8.25 (m, 9H,
3
123

B. Madhu et al.
Scheme 1 Step-wise and one pot synthesis of 4(a–l)
four aryl protons of quinoline ring plus five protons of the indole ring), 1and 1.01 (s,
H, –NH, and D O exchangeable). Its LC–MS spectrum, when recorded in the
1
2
Q ? 1 mode, showed the molecular ion peak at m/z 303 corresponding to a
molecular mass of 302.
Later, 3a was reacted with another mole of 1a in water under refluxing
0
conditions for 30 min. to form 3,3 -((1H-indol-3-yl)methylene)bis(4-hydroxy-1-
methylquinolin-2(1H)-one) 4a in good yields. The structure of the product was
assigned on the basis of its spectral properties-IR, NMR and Mass. Thus, its IR
-
KBr) spectrum showed a broad, medium absorption at 3276 cm due to the
1
(
presence of an indole-NH group, broad and medium absorption at 2578 cm
due to the presence of an OH group and a strong, sharp absorption at 1630 cm
-
1
-
1
1
due to the presence of an amide carbonyl group. Its H NMR, in DMSO-d ,
6
showed signals at d 3.65 (s, 6H, N–CH ), 6.40 (s, 1H, –CH–Ar), 6.72–8.14 (m,
3
1
3H, four aryl protons of quinoline ring plus five protons of the indole ring),
0.87 (s, 1H, –NH, and D O exchangeable), and 12.97 (s, 2H, –OH, and D O
1
2
2
exchangeable). Its LC–MS spectrum, when recorded in the Q ? 1 mode, showed
the molecular ion peak at m/z 478 corresponding to a molecular mass of 477.
In an alternative method, 4a could also be prepared in a one-pot method. Thus, a
mixture of 1a (1 mM) and 2a (2 mM) was refluxed in water for 1 h resulting in the
isolation of 4a in excellent yield and of good purity. The structure of 4a was
confirmed by comparison with an authentic sample which was prepared in the above
stepwise method. The reaction of 1a with 2a in a one-pot method was examined by
carrying out a series of experiments in the presence of different organic and green
solvents at different temperatures (Table 1). It was found from these experiments
that the formation of 4a refluxing in water for 1 h, unlike in other solvents such as a
1
23

Effect of heterocyclic ring system on formation of…
Table 1 Effect of solvent and
temperature on formation of 4a
Entry
Solvent
Temp.
Time (min)
Yield of 4a
in a one-pot method
1
2
3
4
5
6
7
8
9
Water
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
60
60
60
60
60
60
60
60
60
60
90
85
85
81
78
81
76
71
68
62
Ethanol
Methanol
PEG-600
Glycerol
Ethylene glycol
Acetic acid
1,4-dioxan
THF
1
0
DMF
ethanol, methanol, PEG-600, glycerol, ethylene glycol, acetic acid, 1,4-dioxan,
THF, and DMF, gave reasonably high yields (90%) of the product 4a and in good
purity (Table 1, entry-1).
This above model reaction was (compound 3 preparation) performed in water by
using different types of electron withdrawing and donating indole aldehydes 2a–f, 3
was found in good yield (Table 2) in the presence of a heterocyclic ring system
having an electron-withdrawing groups (i.e. 5-NO , 5-Cl, 5-Br). But after further
2
reaction (i.e. compound 4 preparation), 4 was found in good yield when the
heterocyclic ring system having both electron-withdrawing (i.e. NO , Cl, Br) and
2
electron-donating groups (i.e. 5-CH , 5-OCH ).
3
3
Table 2 Synthesis of 3a–l and 4a–l in water
Entry 1a, b (R
1
)
2a–f
(
Product Yield
obtained 3a–l 3a–l
Product Yield
obtained 4a–l 4a–l
M.P (°C) M.P (°C)
3a–l 4a–l
R
2
)
1
2
3
4
5
–CH
–CH
–CH
–CH
–CH
3
3
3
3
3
H
3a
3b
3c
3d
3e
86
91
89
87
76
4a
4b
4c
4d
4e
90
91
84
83
81
210–212 292–294
216–218 289–291
209–211 282–284
206–208 279–281
218–220 296–298
5-NO
5-Cl
5-Br
5-
2
OCH
3
6
7
8
9
1
1
–CH
–CH
–CH
–CH
–CH
–CH
3
2
2
2
2
2
5-CH
3
3f
74
85
91
86
85
74
4f
81
89
91
87
85
84
216–218 297–299
212–214 290–292
215–217 273–275
209–211 260–262
213–215 257–259
231–234 291–293
CH
3
H
3g
3h
3i
4g
4h
4i
CH
CH
CH
CH
3
3
3
3
5-NO
5-Cl
5-Br
5-
2
0
1
3j
4j
3k
4k
OCH
3
12
–CH
2
CH
3
5-CH
3
3l
71
4l
82
228–230 288–290
123

B. Madhu et al.
Table 3 The effect of solvent
for synthesis of compound 7a
Entry
Solvent
Temp (°C)
Time (min.)
Yield 7a
(Ref. 27)
1
2
3
4
5
6
7
H
2
O
100
100
100
100
100
100
RT
60
60
91
83
79
80
82
70
–
Ethylene glycol
Glycerol
90
Acetic acid
PEG-600
DMF
90
120
90
H
2
O
120
After the synthesis of 4a–l continuing our efforts to carry out the same reaction
by taking one mole of 4-hydroxy-1-methylquinolin-2(1H)-one 1a (i.e. 1,
R = CH ) with different types of aromatic aldehydes (i.e. benzaldehyde 5a)
1
3
(
(
instead of 2a) in water at room temperature, no product formation was observed
Table 3, entry 1). But the same reaction was performed in water under refluxing
conditions for 1 h instead of intermediate compound 6a the reaction was found to
1
be 3,3 -(arylmethylene)-bis-(4-hydroxy-1-methylquinolin-2(1H)-one) 7a in good
yield (91%), the structure having been established on the basis of spectral and
analytical data. We checked the reaction every 10 min by using thin layer
chromatography. The TLC did not show any intermediate spot of 6a, showing only
the spots corresponding to the 1a, 5a and 7a compounds. Based on the above
results, the intermediate 6a is highly unstable and rapidly reacts with another mole
of N-methylquinolone 1a to form the dimeric compound 7a.
Table 4 Optimization of the reaction conditions (effect of catalyst) (Ref. 27)
1
00
8
0
6
0
Catlyst S.NO
YIELD
4
0
2
0
0
1
2
Catlyst S.NO
3
4
5
6
7
Entry
Catalyst
Solvent
Temp (°C)
Yield (7a)
1
2
3
4
5
6
7
No catalyst
H
H
H
H
H
H
H
2
2
2
2
2
2
2
O
O
O
O
O
O
O
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
91
85
80
80
72
87
86
InCl
ZnCl
FeCl
Acetic acid
SnCl
L-Proline
3
2
3
2
1
23

Effect of heterocyclic ring system on formation of…
Scheme 2 Synthesis of 7(a–l)
Initially, this transformation was carried out in water under refluxing conditions
for 1–2 h in the absence of a catalyst, and 7a was found in good yield (91%). The
reaction conditions were optimized for the above reaction to increase the yield and
in order to find the best catalyst and solvent. Thus, the above reaction was carried
out in water by using series of catalysts like InCl , L-Proline, SnCl , ZnCl , FeCl ,
3
2
2
3
and even the protic acid like acetic acid. But, unfortunately, in the presence of the
catalyst the reaction produced some unreacted starting materials (1a and 5a). Due to
that reason, in the presence of the catalyst the reaction produced low yields of 7a.
However, water at 90 °C without a catalyst proved to the best condition. All these
results are summarized in Tables 3 and 4 (Scheme 2).
Encouraged by these results, we tested the reaction by using different types of
electron-donating and -withdrawing benzaldehyde derivatives to form 7a–l under
optimized conditions to better understand the generality of this method. In these
reactions, electron-withdrawing benzaldehyde derivatives gave reasonably better
yields. All these results were summarized in Table 5.
Intermediate-dependent reaction pathway
Based on the above two reactions, a plausible mechanism has been proposed for the
formation of 4 and 7. Initially, one mole of N-methyl quinolone 1 reacts with one
mole of indole aldehyde 2 in the presence of water to form intermediate compound
3. This compound further reacts with one mole of N-methyl quinolone 1 under
refluxing condition to form the final bis-compound. But in the presence of
123

B. Madhu et al.
Table 5 Synthesis of 7a–l from
a, b and 5a–l (Ref. 27)
Entry 1a, b
5a–k
7a–o Yield (%) M.P (°C)
1
1
2
–CH
–CH
3
7a
91
287–289
3
7b
84
190–192
3
–CH
3
7c
83
174–175
4
5
–CH
–CH
3
3
7d
7e
72
76
220–222
209–211
6
7
–CH
–CH
3
3
7f
85
85
296–298
293–294
7g
8
9
1
–CH
–CH
–CH
3
3
3
7h
7i
75
79
71
237–238
239–241
240–242
0
7j
1
1
1
2
–CH
–CH
3
2
7k
7l
82
90
242–243
289–290
–CH
3
benzaldehyde, the reaction pathway is completely opposite to the first one. In this
case, one mole of benzaldehyde 5 in the presence of one mole of N-methyl
quinolone 1 reacts to give the final bis-compound without any intermediate 6.
Maybe this can happen because the resulting intermediate 6 was highly reactive and
rapidly reacts with another mole of N-methyl quinolone 1 to gave the stable dimeric
compound 7.
1
23

Effect of heterocyclic ring system on formation of…
Conclusions
In summary, we have developed a facile, efficient and green step-wise, one-pot
synthesis of dimeric quinolones 4a–l and 7a–l by the Knoevenagel condensation
followed by Michael-type addition. The effect of heterocyclic (indole ring) and
aromatic ring systems on typical intermediate formation can be clearly seen. This
reaction was found to be environmentally friendly, has easy-workup and shorter
reaction times giving good yields of the product without the need for its isolation
using column chromatography.
Acknowledgements Authors are very thankful to the authorities of Jawaharlal Nehru Technological
University Hyderabad for providing laboratory facilities and financial support.
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23