Synthesis of novel quinoline analogues of nimesulide: An unusual observation

Article abstract of DOI:10.1002/jhet.618

Reduction of nimesulide followed by treating the N-acyl derivative of resulting arylamine with Vilsmeier-Haack reagent provided novel 2-chloro-3-formylquinoline derivatives. The construction of quinoline ring using Vilsmeier-Haack reagent afforded an unex

Full text of DOI:10.1002/jhet.618

May 2011
Synthesis of Novel Quinoline Analogues of Nimesulide: An
Unusual Observation
555
Lingam Venkata Reddy,a Mamatha Nakka,a Alishetty Suman,a
Soumen Ghosh,b Madeleine Helliwell,c Khagga Mukkanti,a
Alok Kumar Mukherjee,b and Sarbani Pald*
aCenter for Chemical Science and Technology, IST, JNTH University, Kukatpally,
Hyderabad 500085, India
bDepartment of Physics, Jadavpur University, Kolkata 700032, India
cDepartment of Chemistry, University of Manchester, Manchester M13 9PL, England
dDepartment of Chemistry, MNR Degree and PG College, Kukatpally, Hyderabad 500072, India
*E-mail: sarbani277@yahoo.com
Received March 10, 2010
DOI 10.1002/jhet.618
Published online 22 February 2011 in Wiley Online Library (wileyonlinelibrary.com).
Reduction of nimesulide followed by treating the N-acyl derivative of resulting arylamine with Vils-
meier-Haack reagent provided novel 2-chloro-3-formylquinoline derivatives. The construction of quino-
line ring using Vilsmeier-Haack reagent afforded an unexpected compound, N-(2-chloro-3-formyl-7-
phenoxy quinolin-6-yl)formamide, in addition to the expected product. The structure of this unexpected
quinoline derivative was established via single-crystal X-ray analysis and its formation could be
explained by an unprecedented N-S bond cleavage under Vilsmeier-Haack reaction conditions. The 2-
chloro-3-formylquinoline derivatives obtained were converted to a number of corresponding Schiff
bases with potential pharmacological importance.
J. Heterocyclic Chem., 48, 555 (2011)
INTRODUCTION
compounds, is of particular interest. For example, most
of the classical routes to quinoline e.g., Skraup, Doeb-
ner-von Miller, Combes and Conrad-Limpach syntheses
are based on this strategy. We anticipated that this strat-
egy would be beneficial in our study because the
required aniline component could be readily prepared.
However, to construct the quinoline ring possessing the
desired functional groups we opted for the Vilsmeier-
Haack cyclization of acetanilides leading to the 2-
chloro-3-formylquinoline derivatives [8,9]. Our interest
in 2-chloro-3-formylquinoline moiety stem from the fact
that it can be utilized for further [b]-annelation to afford
a wide variety of rings and for various functional group
inter conversions. Our synthesis of novel quinoline ana-
logues structurally related to nimesulide is shown in
Scheme 1.
Nimesulide, a preferential COX-2 inhibitor, is a non-
carboxylic acid nonsteroidal anti-inflammatory drug
(NSAID) that has been in clinical use for treatment of
pain for more than 20 years [1]. Several derivatives of
nimesulide have shown antiviral, anticancer [2] and
COX-2 inhibiting [3] properties. 2-Chloroquinoline
derivatives, on the other hand, have shown a range of
biological activities [4,5]. Thus combining nimesulide
with 2-chloroquinoline in a single molecule would pro-
vide new chemical entities of potential pharmacological
interest (Fig. 1). In continuation to our interest in the
synthesis and biological activity of nimesulide deriva-
tives [6], we decided to prepare a series of novel mole-
cules A for in vitro pharmacological studies. Herein, we
report for the first time the synthesis of a series of
hybrid molecules structurally related to both nimesulide
and 2-chloroquinoline.
RESULTS AND DISCUSSION
Although different methods have been reported [7]
for the construction of a quinoline ring, the approach of
employing an aromatic primary amine i.e., CACAN
unit as the nucleophilic nitrogen donating component
and an electrophilic three carbon unit, usually carbonyl
The nimesulide was converted to the corresponding
aromatic amine via reduction of its nitro group follow-
ing a known procedure [6]. The primary amine was then
converted to the corresponding N-acetyl derivative 1,
C
V
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556
L. V. Reddy, M. Nakka, A. Suman, S. Ghosh, M. Helliwell, K. Mukkanti, A. K. Mukherjee,
and S. Pal
Vol 48
twinned via a 180ꢀ rotation about the [100] direction
and the correct unit cell was found by the program
CELL_NOW [11] using 1023 reflections in the y angu-
lar range of 2.77–25.73ꢀ. Data were corrected for Lp
and absorption effects. The structure was solved by
direct methods and refined by full-matrix least-squares
technique on F2 using SHELXS-97 and SHELXL-97
[12]. Hydrogen atoms were located from difference Fou-
rier maps and refined without any restraint.
Figure 1. Design of novel molecules based on nimesulide and 2-
chloroquinolines.
An ORTEP diagram [13] of molecule 3 with atom
numbering scheme is shown in Figure 3. The bond dis-
tances and angles are consistent with the reported values
for other chloroquinoline derivatives [14–18]. The 2-
chloroquinoline ring is essentially planar with a maxi-
which upon treatment with the Vilsmeier-Haack reagent
(POCl3 /DMF) afforded the desired product 2 along
with another product 3 (Scheme 1). In a typical proce-
dure, compound 1 (1.0 equiv) in DMF (3.3 equiv) was
treated with POCl3 (6.6 equiv) under nitrogen at 110–
120ꢀC for 4 h. After usual workup and purification by
column chromatography two quinoline derivatives i.e.,
compounds 2 and 3 were isolated in 85% overall yield
(approximate ratio 1:1). Based on the analysis of their
spectral data (NMR, IR and MS) generated (for 1H
NMR, see Fig. 2), the compound 2 was identified as N-
(2-chloro-3-formyl-7-phenoxyquinolin-6-yl)methanesul-
fonamide and the compound 3 as N-(2-chloro-3-formyl-
7-phenoxy quinolin-6-yl)formamide. Since the formation
of compound 3 was unusual we decided to conduct fur-
ther studies on this reaction. To prepare compound 3 as
the sole product we carried out the reaction of 1 with
POCl3/DMF at room temperature and at a higher tem-
perature i.e., 140–145ꢀC in addition to that at 110–
120ꢀC as described earlier. The reaction did not proceed
at room temperature (or at other temperature below
100ꢀC), whereas both products i.e., 2 and 3, were iso-
lated in 1:1 ratio with 50% overall yield when the reac-
tion was conducted at 140–145ꢀC. Moreover, a tar like
material was isolated while conducting the reaction
140–145ꢀC thereby reducing the overall yield of com-
pounds 2 and 3. Thus the optimum temperature was
found to be 110–120ꢀC. In a separate study, the progress
of this reaction with time was closely monitored by
maintaining the reaction temperature at 110–120ꢀC. Ini-
tially, compound 2 was formed as indicated by TLC,
but subsequent formation of 3 was observed as the reac-
tion progressed further. Notably, the reaction did not
proceed further after completing 4 h when a mixture of
2 and 3 was formed in 1:1 ratio. This experiment though
remained inconclusive suggested that compound 3 was
perhaps formed via 2 instead of directly from 1.
˚
mum deviation of 0.024(1) A of C9 atom from the
least-squares plane through the remaining nonhydrogen
atoms. The dihedral angle between the planes of quino-
line [C1-C9, N1] and phenyl [C10-C15] rings is
77.7(1)ꢀ.
In the quinoline fragment of 3, the CAC bond lengths
(C5-C6, C2-C3, and C1-C9) and CAN bond distances
(C8-N1 and C7-N1) (Table 1) are shorter and the
remaining bond distances are longer than the mean
˚
value of aromatic C-C bond length of 1.387 A [19].
Such features are reported also for other quinoline con-
taining structures [20–25]. The formamide group is
planer and the planarity of the formamide group is pro-
vided by the delocalization of lone pair of O2 and N2
atoms, which results in
a shortening of C16-O2
˚
˚
[1.213(2) A] and N2-C16 [1.357(2) A] bond lengths
than the average values reported in the literature. The
extended conformation of the formamide group is estab-
lished by the torsion angles C1-C2-N2-C16 [170.8(2)ꢀ]
and C2-N2-C16-O2 [0.2(3)ꢀ].
Molecular packing of compound 3 is stabilized by
NAH. . .O and CAH. . .O hydrogen bonding. In com-
pound 3, a pair of intermolecular CAH. . .O hydrogen
bonds between centrosymmetrically related molecules
involving the quinoline C5 atom in the molecule at (x,
y, z) and formamide atom O2 in the molecule at (1-x, 1-
y, 2-z) generates an R2 (16) dimeric ring centred at (1= ,
2
2
1= , 1) [Fig. 4(a)]. Propagation of these R2 (16) rings
along the [010] direction forms a C(9) chain [Fig. 4(b)]
2
2
Scheme 1. Preparation of novel 2-chloro-3-formylquinoline derivatives
from nimesulide.
The compound 3 was characterized by spectral data
and its structure was confirmed unambiguously via sin-
gle-crystal X-ray analysis [10]. Intensity data of 3 were
collected at Daresbury Laboratory (station 9.8) using a
Bruker SMART CCD area detector using silicon mono-
˚
chromated synchrotron radiation (k ¼ 0.6945 A) at
150(2) K using u and x scan method. The crystal was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2011
Synthesis of Novel Quinoline Analogues of Nimesulide: An Unusual Observation
557
Figure 2. 1H NMR (300 MHz) of compound 2 and 3 in DMSO-d6.
via another type of intermolecular NAH. . .O hydrogen
bond between formamide N2 atom and aldehyde O3
atom (Table 2).
The generation of N-(2-chloro-3-formyl-7-phenoxy-
quinolin-6-yl) methanesulfonamide (2) can be explained
mechanistically by the well documented synthesis of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

558
L. V. Reddy, M. Nakka, A. Suman, S. Ghosh, M. Helliwell, K. Mukkanti, A. K. Mukherjee,
and S. Pal
Vol 48
Table 1
Selected geometric parameters (A, ꢀ) for 3.
˚
C1-C9
C2-C3
1.354(3)
1.379(2)
1.370(3)
1.362(2)
1.296(2)
1.743(2)
1.213(2)
1.357(2)
115.6(1)
170.8(2)
0.2(3)
C5-C6
C8-N1
C7-N1
C7-Cl1
O2-C16
N2-C16
N1-C7-Cl1
C1-C2-N2-C16
C2-N2-C16-O2
vides the intermediate possessing Me2N¼¼CHANHA
group. This moiety on subsequent hydrolysis could be
converted into a ANHCHO group. There is, however, no
direct evidence to support this pathway. To the best of
our knowledge, this is the first example of an NAS bond
cleavage under Vilsmeier-Haack reaction condition.
Generation of Schiff bases from 2-chloro-3-formyl-
quinoline has been a topic for studying not only nonlin-
ear optical phenomenon arising due to the extended con-
jugation within the molecules [16] but also for analgesic
properties [4]. In our effort to generate a library of mol-
ecules of potential pharmacological interest we decided
to prepare Schiff bases from 2 and 3. Accordingly, 3
was initially reacted with a variety of hydrazines
(Scheme 2) and the results are summarized in Table 3.
A number of Schiff bases 5a-f has been prepared
from 3 in good yields by using a variety of hydrazines
4a-f (Table 4) including hydrazinecarboxamide and
hydrazinecarbothioamide. The presence of both electron
donating (Entries 1, 4 and 5, Table 3) and withdrawing
groups (Entries 2 and 6, Table 3) on the phenyl ring of
hydrazine moiety was well tolerated. The formamide
group on the quinoline ring at C-6 was also well
Figure 3. An ORTEP view of molecule 3 with atom-labeling scheme.
Displacement ellipsoids are drawn at 40% probability level and the H-
atoms are shown as small spheres of arbitrary radii.
quinolines via Vilsmeier-Haack cyclization of acetani-
lides. However, the reason for the formation of N-(2-
chloro-3-formyl-7-phenoxy quinolin-6-yl)formamide (3)
as a side product in the same reaction is not clearly
understood. Perhaps the presence of excess of Vilsme-
ier-Haack reagent generated in situ was responsible for
this side product formation. Thus the interaction of
ANHSO2Me group of 2 through its nitrogen lone pair
with [Me2N¼¼CHACl]þ generated in situ from DMF
and POCl3 followed by the cleavage of NAS bond pro-
Figure 4. (a) Formation of R22 (16) dimeric ring in C17O3N2H11Cl. (3) [Symmetry code: (i) 1-x, 1-y, 2-z]. (b) Propagation of R22 (16) rings in
C17O3N2H11Cl (3) along the [010] direction. H-atoms not involved in the hydrogen bonding have been omitted for clarity. [Symmetry codes: (i) 1-
x, 1-y, 2-z; and (ii) 1þx, -1þy, z]
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Synthesis of Novel Quinoline Analogues of Nimesulide: An Unusual Observation
559
Table 2
Intermolecular contacts (A, ꢀ) for 3.
˚
DAH. . .A
DAH
H. . .A
D. . .A
DAH. . .A
Symmetry code
C5AH5. . .O2i
N2AH2N. . .O3ii
N2AH2N. . .O1
C3AH3. . .O2
0.97
0.82
0.82
0.95
2.33
2.29
2.25
2.30
3.183(2)
3.053(2)
2.614(2)
2.899(2)
147
155
107
120
1-x,1-y,2-z
1þx,-1þy,z
x, y, z
x, y, z
obtained was purified by column chromatography to give the
desired product.
tolerated. Schiff base was also generated from com-
pound 2 (Scheme 2) using hydrazines (4b, 4g, and 4h)
as shown in Table 4.
N-(2-Chloro-3-formyl-7-phenoxyquinolin-6-yl)methanesul-
fonamide (2). Light yellow powder; yield 55%; Rf 0.7
(CHCl3: EtOAc 9:1); mp 172–174ꢀC; 1H NMR (300 MHz,
DMSO-d6) d 10.3 (1H, s, CHO), 10.0 (1H, D2O exchange, s,
NH), 8.9 (1H, s, ArH), 8.3 (1H, s, ArH), 7.8–7.3 (5H, m,
ArH), 7.0 (1H, s, ArH), 3.2 (3H, s, SO2CH3); 13CNMR (75
MHz, DMSO-d6) d 189, 156, 154, 149, 147, 141, 131, 130,
126, 125, 124, 123, 121, 111, 40; MS (m/z, CI method) 377.1
(Mþ, 100), 379 (Mþ2, 33); IR (KBr, cmꢂ1) 3418 (NH), 3255,
2924, 1689, 1622, 1579, 1498.
Elemental Analysis found: C, 54.34; H, 3.40; N, 7.15
C17H13Cl N2O4S Requires: C, 54.19; H, 3.48; N, 7.43.
N-(2-Chloro-3-formyl-7-phenoxy quinolin-6-yl)formamide
(3). Off white solid; yield 45%; Rf 0.8 (CHCl3: EtOAc 9:1);
mp 206–208ꢀC; 1H NMR (300 MHz, DMSO-d6) d 10.5 (1H,
D2O exchange, s, NH), 10.2 (1H, s, CHO), 9.1 (1H, s,
NHCHO), 8.9 (1H, s, ArH), 8.5 (1H, s, ArH), 7.7–7.4 (5H, m,
ArH), 7.0 (1H, s, ArH); 13CNMR (75 MHz, DMSO-d6) d
189.7, 161.5, 154, 140.9, 131, 129.7, 126.4, 125.7, 122.8,
121.1, 119.3, 110.6; MS (m/z, CI method) 327.1 (Mþ, 100),
329 (Mþ2, 33); IR (KBr, cmꢂ1) 3330 (NH), 1699, 1682,
1620, 1580, 1526.
CONCLUSIONS
In conclusion, reduction of nimesulide followed by
treating the N-acyl derivative of resulting arylamine
with Vilsmeier-Haack reagent provided novel 2-chloro-
3-formylquinoline derivatives. The methanesulfonamide
group was found to be sensitive to the Vilsmeier-Haack
reagent as the construction of quinoline ring using this
reagent afforded an unusual product i.e., N-(2-chloro-3-
formyl-7-phenoxy quinolin-6-yl)formamide in addition
to the expected product, N-(2-chloro-3-formyl-7-phenox-
yquinolin-6-yl)methanesulfonamide. The structure of
this unexpected quinoline derivative was established
unambiguously via single-crystal X-ray analysis. Its for-
mation can be explained by an N-S bond cleavage under
Vilsmeier-Haack reaction conditions. The synthetic util-
ity of 2-chloro-3-formylquinoline derivatives has been
demonstrated by converting them into the corresponding
Schiff bases with potential pharmacological importance.
Elemental Analysis found: C, 62.38; H, 3.30; N, 8.89
C17H11ClN2O3 Requires: C, 62.49; H, 3.39; N, 8.57.
Preparation of Schiff bases (5 and 6). A solution of com-
pound 2 (3.8 g, 10.0 mmol) or 3 (3.3 g, 10.0 mmol) and an
appropriate hydrazine 4a–h (11.0 mmol) as indicated in Tables
3 and 4 in PEG 400 (10 mL) was stirred at room temperature
according to the time indicated in Tables 3 and 4. After com-
pletion of the reaction, as indicated by TLC, the mixture was
diluted by using ice cold water (25 mL) with vigorous stirring.
The solid separated was filtered, washed with ice cold water
and recrystallized from ethanol to afford the expected product
(5a–f or 6a–c).
[(2-Chloro-6-formamido-7-phenoxyquinolin-3-yl)methy-
lene]-N-(4-methoxyphenyl)hydrazinecarbothioamide (5a). Light
green crystalline solid; Rf 0.58 (CHCl3 : EtOAc 9:1); mp
118–120ꢀC; 1H NMR (300 MHz, DMSO-d6) d 10.50 (1H,
D2O exchangeable, NH), 9.05 (1H, s, NHCHO), 8.95 (1H, s,
ArH), 8.50 (1H, s, ArH), 7.60 (2H, t, J ¼ 7.7 Hz, ArH), 7.40
EXPERIMENTAL
Reactions were monitored by thin layer chromatography
(TLC) on silica gel plates (60 F254), visualizing with ultravio-
1
let light or iodine spray. H NMR spectra were determined in
a solvent as specified on a 300 MHz spectrometers. Proton
chemical shifts (d) are relative to tetramethylsilane (TMS, d ¼
0.00) as internal standard and expressed in ppm. Spin multi-
plicities are given as s (singlet), d (doublet) and m (multiplet)
as well as b (broad). Coupling constants (J) are given in hertz.
A
13C NMR spectrum was recorded in DMSO-d6 at 75 MHz.
Infrared spectra were recorded on a FT- IR spectrometer.
Melting points were determined by using melting point appara-
tus and are uncorrected. MS spectra were obtained on a JMS-
D 300 spectrometer.
Preparation of 2-Chloro-3-formylquinoline derivatives (2
and 3). A mixture of compound 1 (1.0 g, 3.0 mmol), DMF
(0.7 mL, 10 mmol) and POCl3 (2.0 mL, 20 mmol) was stirred
at 0–5ꢀC. After 0.5 h the temperature of the reaction mixture
was increased to 120ꢀC and maintained for 4 h. The mixture
was then cooled to room temperature, poured into crushed ice
(50 mL) and extracted with CHCl3 (3 ꢁ 25 mL). The organic
layers were collected, combined, washed with water, dried
over anhydrous Na2SO4 and concentrated. The brown solid
Scheme 2. Preparation of Schiff bases from 2 to 3.
Journal of Heterocyclic Chemistry
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560
L. V. Reddy, M. Nakka, A. Suman, S. Ghosh, M. Helliwell, K. Mukkanti, A. K. Mukherjee,
and S. Pal
Vol 48
Table 3
Preparation of Schiff bases from compound 3.a
Entry
Hydrazines (4)
Time (h)
3.0
1.
70
2.
4.0
83
3.
4.0
74
4.
3.0
76
5.
6.0
81
6.
6.0
60
a All the reactions were carried out using compound 3 (10.0 mmol) and 4 (11.0 mmol) in PEG 400 at room temperature.
(8H, m, ArH þ NH), 7.15 (2H, d, J ¼ 8.7 Hz, ArH), 6.90
(1H, s, ACH¼¼) 3.80 (3H, s, OCH3); IR (KBr, cmꢂ1) 3236
(NH), 1691 (C¼¼O); MS (m/z, CI method) 506 (Mþ, 100%).
Elemental Analysis found: C, 59.64; H, 3.90; N, 13.65
C25H20N5SO3Cl Requires: C, 59.34; H, 3.98; N, 13.84.
(300 MHz, DMSO-d6) d 12.5 (1H, s, D2O exchangeable, NH),
10.50 (1H, s, D2O exchangeable, NH), 9.10 (3H, m, NHCHO
þ ArH), 8.90 (1H, s, ArH), 8.60 (1H, s, ArH), 8.4 (1H, s,
ArH), 8.3 (1H, s, ArH), 7.60 (2H, m, ArH), 7.30 (3H, m,
ArH), 7.0 (1H, s, ACH¼¼); IR (KBr, cmꢂ1) 3267 (NH),
1691(C¼¼O); MS (m/z, CI method) 507 (Mþ,100%).
N-(2-Chloro-3-[(2-(2,4-dinitrophenyl)hydrazono)methyl]-
7-phenoxyquinolin-6-yl)formamide (5b). Orange crystalline
Elemental Analysis found: C, 54.74; H, 2.90; N, 16.35
C23H15N6O6Cl Requires: C, 54.50; H, 2.98; N, 16.58.
1
solid; Rf 0.62 (CHCl3: EtOAc 9:1); mp 268–270ꢀC; H NMR
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Synthesis of Novel Quinoline Analogues of Nimesulide: An Unusual Observation
561
Table 4
Preparation of Schiff bases from compound 2.a
Entry
1.
Hydrazines (4)
Time (h)
4.0
Products (6)
Yields (%)
68
2.
3.0
70
3.
4.0
74
a All the reactions were carried out using compound 2 (10.0 mmol) and 4 (11.0 mmol) in PEG 400 at room temperature.
NH), 10.50 (1H, s, D2O exchangeable, NH), 8.61 (4H, m, ArH
þ ANHCHO), 7.43 (9H, m, ArH), 6.98 (1H, s, ACH¼¼), 2.41
(3H, s, CH3); IR (KBr, cmꢂ1) 3294, 1705, 1584; MS (m/z, CI
method) 459 (Mþ100%).
N-(3-[(2-Benzoylhydrazono)methyl]-2-chloro-7-phenoxy-
quinolin-6-yl)formamide (5c). Cream colored crystalline
1
solid; Rf 0.53 (CHCl3: EtOAc 9:1); mp 218–216ꢀC; H NMR
(300 MHz, DMSO-d6) d 12.20 (1H, s, D2O exchangeable,
NH), 10.50 (1H, s, D2O exchangeable, NH), 9.10 (1H, s,
NHCHO), 8.80 (2H, d, J ¼ 8.8 Hz, ArH), 8.50 (1H, s, ArH),
8.0 (2H, m, ArH), 7.55 (5H, m, ArH), 7.20 (3H, m, ArH) 7.0
(1H, s, ACH¼¼); IR (KBr, cmꢂ1) 3360 (NH), 1708 (C¼¼O),
1661 (NHCHO), 1621, 1588, 1577; MS (m/z, CI method) 445
(Mþ, 100%).
Elemental Analysis found: C, 68.94; H, 4.05; N, 12.50
C25H19N4O3Cl Requires: C, 68.63; H, 4.17; N, 12.21.
N-(2-Chloro-3-[(2-(3-nitrobenzoyl)hydrazono)methyl]-7-
phenoxyquinolin-6-yl)formamide (5f). Pale yellow crystal-
line solid; Rf 0.62 (CHCl3 : EtOAc 9:1); mp 258–260ꢀC; 1H
NMR (300 MHz, DMSO-d6) d 12.50 (1H, s, D2O exchange-
able, NH), 10.40 (1H, bs, D2O exchangeable, NH), 8.86 (2H,
m, ArH), 8.45 (5H, m, ArH), 7.32 (5H, m, ArH), 7.16 (2H, m,
ArH); IR (KBr, cmꢂ1) 3318, 1695, 1527; MS (m/z, CI
method) 490 (Mþ, 100%).
Elemental Analysis found: C, 64.54; H, 3.90; N, 12.63
C24H17N4O3Cl Requires: C, 64.80; H, 3.85; N, 12.59.
N-(2-Chloro-3-[(2-(4-chlorobenzoyl)hydrazono)methyl]-7-
phenoxyquinolin-6-yl)formamide (5d). White crystalline
1
solid; Rf 0.58 (CHCl3: EtOAc 9:1); mp 298–300ꢀC; H NMR
Elemental Analysis found: C, 58.94; H, 3.10; N, 14.35
C24H16N5O5Cl Requires: C, 58.84; H, 3.29; N, 14.30.
N-(2-Chloro-3-[(2-(2,4-dinitrophenyl)hydrazono)methyl]-7-
phenoxyquinolin-6-yl)methanesulfonamide (6a). Light orange
crystalline solid; Rf 0.50 (CHCl3 : EtOAc 9:1); mp 244–
246ꢀC; 1H NMR (300 MHz, DMSO-d6) d 12.1 (1H, s, D2O
exchangeable, NH), 10.5 (1H, s, D2O exchangeable, NH), 8.95
(2H, m, ArH), 8.0 (1H, d, J ¼ 8.8 Hz, ArH), 7.90 (1H, d, J ¼
8.8 Hz, ArH), 7.6 (2H, m, ArH), 7.30 (3H, m, ArH), 7.0 (3H,
(300 MHz, DMSO-d6) d 12.20 (1H, s, D2O exchangeable,
NH), 10.50 (1H, s, D2O exchangeable, NH), 9.10 (1H, s, -
NHCHO), 8.90 (2H, m, ArH), 8.50 (1H, s, ArH), 8.0 (2H, d, J
¼ 8.7 Hz, ArH), 7.70 (2H, d, J ¼ 7.7 Hz, ArH), 7.60 (2H, t, J
¼ 7.7 Hz, ArH), 7.30 (3H, m, ArH), 7.0 (1H, s, ACH¼¼); IR
(KBr, cmꢂ1) 3396, 1704, 1659, 1592, 1524.9, 1491.8; MS (m/
z, CI method) 479 (Mþ, 100%).
Elemental Analysis found: C, 60.41; H, 3.35; N, 11.56
C24H16N4O3Cl2 Requires: C, 60.14; H, 3.36; N, 11.69.
N-(2-Chloro-3-[(2-(2-methylbenzoyl)hydrazono)methyl]-7-
phenoxyquinolin-6-yl)formamide (5e). Cream colored crys-
m, ArH þ ACH¼¼), 3.80 (3H, s, SO2CH3); IR (KBr, cmꢂ1
)
3382, 2923, 1616, 1643, 1589; MS (m/z, CI method) 557
(Mþ, 100%).
1
talline solid; Rf 0.65 (CHCl3: EtOAc 9:1); mp 242–244ꢀC; H
Elemental Analysis found: C, 49.66; H, 3.01; N, 15.01
C23H17ClN6O7S Requires: C, 49.60; H, 3.08; N, 15.09.
NMR (300 MHz, DMSO-d6) d 12.0 (1H, s, D2O exchangeable,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

562
L. V. Reddy, M. Nakka, A. Suman, S. Ghosh, M. Helliwell, K. Mukkanti, A. K. Mukherjee,
and S. Pal
Vol 48
[2] Karakuꢀs, S.; Ku¨c¸u¨kgu¨zel, S. G.; Ku¨c¸u¨kgu¨zel, I.; Clercq, E.
D.; Pannecouque, C.; Andrei, G.; Snoeck, R.; Sꢀahin, F.; Bayrak, O. F.
Eur J Med Chem 2009, 44, 3591.
N-(2-Chloro-3-[(2-(2-(2,3-dimethylphenylamino)benzoyl)hy-
drazono)methyl]-7-phenoxyquinolin-6-yl)methanesulfonamide
(6b). Light yellow solid; Rf 0.65 (CHCl3 : EtOAc 9:1); mp
202–204ꢀC; 1H NMR (300 MHz, DMSO-d6) d 12.3 (1H, s,
D2O exchangeable, NH), 10.5 (1H, s, D2O exchangeable, NH),
9.4 (1H, s, D2O exchangeable, NH), 9.0 (1H, s, ArH), 8.90
(2H, m, ArH), 8.50 (1H, s, ArH), 7.8 (1H, d, J ¼ 8.8 Hz,
ArH), 7.15 (11H, m, ArH þ ACH¼¼), 3.7 (3H, s, SO2CH3),
2.4 (3H, s, CH3) 2.2 (3H, s, CH3); IR (KBr, cmꢂ1) 2869,
1687, 1620, 1555; MS (m/z, CI method) 614 (Mþ, 100%).
Elemental Analysis found: C, 62.50; H, 4.65; N, 11.48
C32H28ClN5O4S Requires: C, 62.58; H, 4.60; N, 11.40.
´
[3] Michaux, C.; Charlier, C.; Julemont, F.; Leval, X. de;
´
Dogne, J.–M.; Pirotte, B.; Durant, F. Eur J Med Chem 2005, 40, 1316.
[4] Kidwai, M.; Negi, N. Monatshefte ffir Chemie 1997, 128, 85.
[5] Nagaraja, G. K.; Prakash, G. K.; Kumaraswamy, M. N.;
Vaidya, V. P.; Mahadevan, K. M. ARKIVOC 2006, xv, 160.
[6] Pericherla, S.; Mareddy, J.; Geetha, R. D. P.; Gollapudi, P.
V.; Pal, S. J Braz Chem Soc 2007, 18, 384.
´ ´
[7] Kouznetsov, V. V.; Mendez, L. Y. V.; Gomez, C. M. M.
Curr Org Chem 2005, 9, 141.
[8] Marson, C. M.; Giles, P. R. Synthesis using Vilsmeier
Reagents; CRC: Boca Raton, 1994.
N-(2-Chloro-3-[(2-(2-hydroxybenzoyl)hydrazono)methyl]-7-
phenoxyquinolin-6-yl)methanesulfonamide (6c). Cream col-
ored solid; Rf 0.62 (CHCl3 : EtOAc 9:1); mp 218–220ꢀC; 1H
NMR (300 MHz, DMSO-d6) d 10.5 (1H, s, D2O exchangeable,
NH), 9.9 (1H, s, D2O exchangeable, NH), 9.1 (2H, m, ArH),
8.90 (1H, s, ArH), 8.50 (1H, s, ArH), 8.2 (s, 1H, ArH), 7.87
(1H, d, J ¼ 8.8 Hz, ArH), 7.5 (2H, m, ArH), 7.30 (3H, m,
ArH), 7.15 (2H, d, J ¼ 8.8 Hz, ArH), 6.9 (1H, s, ACH¼¼), 3.8
(3H, s, SO2CH3); IR (KBr, cmꢂ1) 3377, 2923, 1678, 1605;
MS (m/z, CI method) 511 (Mþ, 100%).
[9] Meth-Cohn, O.; Taylor, D. L. Tetrahedron 1995, 51, 12869.
[10] Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication no.
CCDC 734903. Copies of available material can be obtained, free of
charge via www.ccdc.cam.ac.uk/data_request/cif, by e-mailing data_re-
quest@ccdc.cam.ac.uk, or contacting the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: Þ44
1223 336033.
¨
[11] Sheldrick, G. M. CELL_NOW, 2002; University of Gottin-
gen, Germany.
[12] Sheldrick, G. M. SHELXS 97 and SHELXL 97, 1997; Uni-
Elemental Analysis found: C, 56.49; H, 3.74; N, 10.90
C24H19ClN4O5S Requires: C, 56.42; H, 3.75; N, 10.97.
X-ray crystallographic study of N-(2-chloro-3-formyl-7-
phenoxy quinolin-6-yl)formamide (3). Molecular formula
C17O3N2H11Cl, M ¼ 326.7, triclinic, space group P-1, a ¼
¨
versity of Gottingen, Germany.
[13] Farrugia, L. J. J Appl Cryst 1997, 30, 565.
[14] Palani, K.; Ambalavanan, P.; Ponnuswamy, N. N. G.;
Yathirajan, H. S.; Prabhuswamy, B.; Raju, C. R.; Nagaraja, P.; Shashi-
kanth, S. Anal Sci 2004, 20, 403.
˚
5.3015(9), b ¼ 9.0196(19), c ¼ 15.454(4) A, a ¼ 99.011(4), b
3
ꢀ
˚
¼ 92.710(4), c ¼ 93.355(2) , V ¼ 727.4(4) A , Z ¼ 2, F(000)
¼ 336, T ¼ 150 (2)K, k ¼ 0.6945 A, Dc ¼ 1.492 Mg mꢂ3, l
˚
[15] Somvanshi, R. K.; Subashini, R.; Dhanasekaran, V.; Arul-
prakash, G.; Das, S.; Dey, S. J. Chem Crystallogr 2008, 38, 381.
[16] Kalkhambkar, R. G.; Kulkarni, G. M.; Hwang, W.-S.; Lee,
C.-S. Acta Cryst 2008, E64, 0258.
¼ 0.280 mmꢂ1, Final R1 ¼ 0.0540, WR2 ¼ 0.1219, S ¼ 1.100
for 2968 reflections; for 2578 observed reflections [I> 2r (I)]
R1 ꢂ¼3 0.0486, WR2 ¼ 0.1165, Dqmax/Dqmin ¼ 0.447/ꢂ0.456
˚
eA
[17] Rajendran, P.; Karavembu, R. Ind J Chem 2002, 41B, 222.
[18] Dutta, N. J.; Khunt, R. C.; Parikh, A. R. Ind J Chem 2002,
41B, 433.
Acknowledgment. S.P. thank M. N. Raju, the chairman of
M.N.R. Educational Trust for his constant encouragement. S.G.
thank Jadavpur University and Government of West Bengal for
the research fellowship.
[19] Bu¨rgi, H.-B.; Dunitz, J. D., Eds. Structure Correlation,
Vol. 2.; Weinheim, Verlag VCH: New York, 1994, p 771.
[20] Cheng, H.-M.; Zhu, D.-R.; Lu, W.; Xu, R.-H.; Shen, X. J.
Heterocyclic Chem 2010, 47, 210.
[21] Blackburn, A. C.; Dobson, A. J.; Gerkin, R. E. Acta Cryst
1996, C52, 409.
[22] Chiang, L. Y.; Swirczewski, J. W.; Kastrup, R.; Hsu, C. S.;
Upasani, R. B. J Am Chem Soc 1991, 113, 6574.
[23] Gdaniec, M.; Jaskolski, M.; Kosturkiewicz, Z. Polym J
Chem 1980, 54, 1539.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet