Synthesis of Novel Ethyl (substituted)phenyl-4-oxothiazolidin-3-yl)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-Carboxylates as Potential Anticancer Agents

Article abstract of DOI:10.1002/jhet.2212

A series of ethyl (substituted)phenyl-4-oxothiazolidin-3-yl)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylates (7a, 7b, 7c, 7d, 7e, 7f, 7g) has been prepared from reactions between aminoquinolones 6 with arenealdehydes and mercaptoacetic acid. The critical intermediates, 6a and 6b, were obtained from appropriate amines by a sequence of steps involving (i) reaction with diethylethoxymethylenemalonate, (ii) thermal cyclization in diphenyl ether, (iii) ethylation and (iv) Pd/C catalyzed reduction. New compounds 7a, 7b, 7c, 7d, 7e, 7f, 7g were fully identified and characterized by NMR (¹H and ¹³C) and specifically for 7d by X-ray crystallography. Compounds 7b, 7c, 7d, 7e, 7f were found not to exhibit activity at 10 uM concentrations against gastric ascitis (AGP-01), gastric adenocarcinoma kind intestinal (ACP-02), colon (HCT-116) and murine melanome (B16F10) cancer cells. However, none exhibited cytotoxicity against normal cells human fibroblast (MRC-5), murine fibroblast (NIH3T3) and normal human melanocyte (Melan-A).

Full text of DOI:10.1002/jhet.2212

Month 2014 Synthesis of Novel Ethyl (substituted)phenyl-4-oxothiazolidin-3-yl)-1-ethyl-
4-oxo-1,4-dihydroquinoline-3-Carboxylates as Potential Anticancer Agents
Victor Facchinetti,a,b Felipe A. Guimarães,a Marcus Vinícius N. de Souza,b Claudia Regina B. Gomes,b
e
a
Maria Cecília B. V. de Souza,a James L. Wardell,c,d Solange M. S. V. Wardell, and Thatyana R. A. Vasconcelos
*
aUniversidade Federal Fluminense, Instituto de Química, Programa de Pós-Graduação em Química, Outeiro de São João
Batista, s/nº, Centro, Niterói, 24020-141, RJ, Brazil
bFundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos – Farmanguinhos, Rua Sizenando Nabuco 100,
Manguinhos, Rio de Janeiro, 21041-250, RJ, Brazil
cFundação Oswaldo Cruz, Centro de Desenvolvimento Tecnológico em Saúde (CDTS) – Casa Amarela, Av. Brasil, 4365,
Manguinhos, Rio de Janeiro, 21040-900, RJ, Brazil
dUniversity of Aberdeen, Department of Chemistry, Aberdeen, AB24 3UE, Scotland
eCHEMSOL, 1 Harcourt Road, Aberdeen, AB15 5NY, Scotland
*
E-mail: gqothatyana@vm.uff.br
Additional Supporting Information may be found in the online version of this article.
Received January 22, 2013
DOI 10.1002/jhet.2212
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A series of ethyl (substituted)phenyl-4-oxothiazolidin-3-yl)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylates
(7a–g) has been prepared from reactions between aminoquinolones 6 with arenealdehydes and mercaptoacetic
acid. The critical intermediates, 6a and 6b, were obtained from appropriate amines by a sequence of steps involving
(i) reaction with diethylethoxymethylenemalonate, (ii) thermal cyclization in diphenyl ether, (iii) ethylation and (iv)
Pd/C catalyzed reduction. New compounds 7a–g were fully identified and characterized by NMR (1H and 13C) and
specifically for 7d by X-ray crystallography. Compounds 7b–f were found not to exhibit activity at 10 uM concen-
trations against gastric ascitis (AGP-01), gastric adenocarcinoma kind intestinal (ACP-02), colon (HCT-116) and
murine melanome (B16F10) cancer cells. However, none exhibited cytotoxicity against normal cells human
fibroblast (MRC-5), murine fibroblast (NIH3T3) and normal human melanocyte (Melan-A).
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
Cancer still remains threat to men’s health,
attention lately because of their chemical properties and
diverse biological activities [5]. The thiazolidinone core is a
very versatile scaffold, which can be easily modified at
positions 2-, 3- and 5- of the heterocyclic ring allowing the
synthesis of a large number of derivatives [6]. This core has
also been reported as an important pharmacophore with a
wide range of biological activities, such as antimicrobial
[7,8], antiviral [9], antiprotozoal [10], analgesic [11],
antitubercular [12], anticancer [13] and anticonvulsant [14].
Thiazolidinones are obtained through various synthetic proce-
dures from primary amines or hydrazines in one- or two-step
reactions with aldehydes or ketones and mercaptoacetic acid
[5]. Such reactions proceed through an initial imine formation,
which undergoes attack by the sulfur nucleophile, followed by
intramolecular cyclization and elimination of water. N,N′-
dicyclohexylcarbodiimide can promote dehydration but
a
representing the leading cause of death in economically
developed countries and the second in developing
countries [1,2]. In 2008, 7.6 million people died from
cancer, around 13% of all deaths worldwide. It is projected
a continuous rise in the number of cases, with an expectation
of 13 million deaths in 2030 [3]. In the last years, many
efforts have been made to develop new strategies for finding
effective ways of treating this disease, which include an
increase in the understanding of the biological process
involved in cancer survival and also the search for more
selective and potent chemotherapeutic agents [4].
In this context, thiazolidinones represent an important class
of heterocyclic compounds that have attracted special
© 2014 HeteroCorporation

V. Facchinetti, F. A. Guimarães, M. V. N. deSouza, C. R. B. Gomes, M. C. B. V. deSouza,
J. L. Wardell, S. M. S. V. Wardelf, and T. R. A. Vasconcelos
Vol 000
Scheme 1. Synthesis of 4-thiazolidinones from α-haloacetic and α-mercaptoacetic acids.
azeotropic distillation is the most common protocol applied
for water removal. 4-Thiazolidinones can also be prepared
through cyclization reactions of imines, thiosemicarbazides,
thiourea and thioamides with α-haloacetic and α-mercap-
toacetic acids [15] as shown in Scheme 1. These reactions
have also been carried out using microwave and ultrasound
irradiation [16,17]. Our research group has a vast experience
on the synthesis of 1,3-thiazolidin-4-ones from amines
through cyclization with aldehydes and thioglycolic acid in
one-pot conditions [12,17–19].
The quinolone scaffold has also been widely explored
because of its various pharmacological activities [20–23].
Indeed, there are a considerable number of quinolone-
based molecules in the market as anti-infective agents,
and others are currently being studied for their potential
activity as antitumoral [24], antiviral [25], anti-ischemic
[26], antiparasitic [27] and anxiolytic [28] agents.
Recently, our research group has published a review article
highlighting recent developments on potentially active
quinolones against cancer and tuberculosis [22].
laboratory. Quinolones 4a–b were obtained through the
classic Gould–Jacobs procedure [20,29]. The procedure
consists of treating anilines with diethylethoxy-
1
methylenemalonate 2 to give the enamines 3, which were
thermally cyclized in diphenyl ether. N-Ethylation of
quinolones 4 was achieved using ethyl bromide and
K2CO3 in DMF. Key intermediates 6a and 6b were
obtained in moderate to good yields (60–70%) by Pd/C
catalyzed reduction of 5. This type of reduction in the
presence of Pd/C is unprecedented for this system. It is
noteworthy that the previously reported nitro group
reduction of quinolones 5a–b employing the classic
methodology with iron and aqueous ammonium chloride
0.05 M [33,34] was tested and found to be a poor option
The most common protocols for the synthesis of
quinolones include the Gould–Jacobs reaction [29] and
the Grohe–Heitzer cycloacylation [30].
Thus, in continuation of our efforts on the synthesis of some
pharmacologically important heterocycles [12,17–19,24,31],
a novel series of ethyl aryl-4-oxothiazolidin-3-yl)-1-ethyl-
4-oxo-1,4-dihydroquinoline-3-carboxylates was designed
(Fig. 1), synthesized (Scheme 2) and evaluated against
three human cancer cell lines.
RESULTS AND DISCUSSION
The target compounds 7a–g were synthesized as shown
Figure 1. A design for synthesis of ethyl aryl-4-oxothiazolidin-3-yl)-1-
in Scheme 2, following procedures used previously in our
ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylates.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Novel Ethyl (substituted)phenyl-4-oxothiazolidin-3-yl)-1-ethyl-4-oxo-
1,4-dihydroquinoline-3-Carboxylates
Scheme 2. Synthesis of ethyl (substituted)phenyl-4-oxothiazolidin-3-yl)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylates 7a–g.
because of the partial solubility in water of the respective
aminoquinolone 6a–b. This fact has made the isolation
and purification of the desired amine difficult, leading to
low yields (15–20%) after tedious work up. Ethyl
(substitutedphenyl)-4-oxothiazolidin-3-yl)-1-ethyl-4-oxo-
1,4-dihydroquinoline-3-carboxylate derivatives 7a–g
were obtained from reactions of amines 6, arenealdehydes
and mercaptoacetic acid (1:1:3) in one-pot under reflux in
toluene using a Dean–Stark trap (Scheme 2). The molar
ratio of 1:1:3 of amine, arenealdehyde and mercaptoacetic
acid was determined to be optimal leading to 35–56%
yields of pure products (Table 1).
Two-dimensional NMR techniques (COSY, heteronuclear
single-quantum correlation and heteronuclear multiple-bond
correlation) were used to identify the signals for the new
compounds. As an example, the 1H NMR spectrum of
compound 7b exhibits a singlet at 8.62 ppm for H2, a broad
singlet at 6.74 ppm for H2′, and a double doublet at 4.12 ppm
(J = 15.7; 1.4 Hz) and a doublet at 3.94 ppm (J = 15.7 Hz), re-
spectively, for the diastereotopic hydrogens, H5′a and H5′b.
Methylenic hydrogens (NCH2CH3) are identified as a quartet
at 4.33ppm (J = 7.1 Hz) (Fig. 2). In addition, phenyl signals
were assigned. The 13C NMR spectrum exhibits signals at
148.8, 62.4 and 32.5 ppm for C2, C2′ and C5′, respectively.
The three carbonyl groups could be identified in the 13C
NMR spectrum by the peaks at 172.1 ppm (C4), 170.8 ppm
(C4′) and 164.4 ppm (CO2Et) (Fig. 3).
Characterization was achieved in all cases from NMR
and IR spectral and ESI-MS data, and in the case of 7d
additionally by a single crystal structure determination.
Table 1
Yields and selected physical properties of compounds 7a–g.
Substance
Ra
Yield (%)
P.F. (°C)
ESI-MS m/z %
7a
7b
7c
7d
7e
7f
3-NO2
4-CN
3-Br
H
3-Br
4-CN
H
56
52
41
40
37
43
35
111–112
145–147
193–195
104–105
184–185 (d)
134–136
97–100
468.3 ([M + H]+; 100)
448.3 ([M + H]+; 100)
501.1 ([M + H]+; 100), based on 79Br
423.3 ([M + H]+; 100)
501.1 ([M + H]+; 100), based on 79Br
448.2 ([M + H]+; 100)
7g
423.2 ([M + H]+; 100)
aQuinolones 7a–d bear the thiazolidinone moiety at position 6.
Quinolones 7e–g bear the thiazolidinone moiety at position 7.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. Facchinetti, F. A. Guimarães, M. V. N. deSouza, C. R. B. Gomes, M. C. B. V. deSouza,
J. L. Wardell, S. M. S. V. Wardelf, and T. R. A. Vasconcelos
Vol 000
Figure 2. 1H NMR spectrum of compound 7b (500.00 MHz, DMSO-d6).
Recrystallization of 7d from moist EtOH led to the
isolation of the mixed solvate, [(7d)2·(H2O)2(EtOH)],
the structure of which was determined by X-ray
crystallography form data collected at 120 K [35–37].
The asymmetric unit of [(7d)2·(H2O)2(EtOH)], consists
of a single molecule of 7d and a single disordered
water molecule [occupancy ratio = 60:40] and a half
molecule of the EtOH solvate disordered equally over
two symmetry related sites. Figure 4a shows the atom
arrangements and numbering scheme for the
molecule 7d in [(7d)2·(H2O)2(EtOH). Bond lengths
and angles in 7d are in the expected regions and are
not discussed further.
The oxothiazolidinyl ring has an envelope shape with a
flap at the sulfur atom. Overall, the molecule of 7d is far
from planar, see Figure 4b. The phenyl ring, [C1–C6], is
nearly orthogonal to both the 4-oxo-1,4-dihydroquinolinyl,
and oxothiazolidinyl rings are shown by the angles
Figure 3. 13C NMR spectrum of compound 7b (125.00 MHz, DMSO-d6).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Novel Ethyl (substituted)phenyl-4-oxothiazolidin-3-yl)-1-ethyl-4-oxo-
1,4-dihydroquinoline-3-Carboxylates
Figure 4. (a) Atom arrangements and numbering scheme for the molecule of 7d in the mixed solvate [(7d)2·(H2O)2(EtOH)]; (b) view of the molecule of
7d looking down the plane of the 4-oxo-1,4-dihydroquinolinyl moiety.
between the best planes of 88.52(3) and 82.76(4)°,
respectively, through the rings. The angles between
the planes through the 4-oxo-1,4-dihydroquinolinyl and
oxothiazolidinyl rings is 46.26(5)°. Of interest, the
carbonyl group at C16 and that in the CO2Et group at
C17 have a cis-arrangement, and this appear suitably sited
for 7d to act as a chelating ligand. Direct links between
the molecules involve weak C–H–O and C–H–π hydro-
gen bonds and by π–π stacking arrangements. While the
disorder involving the solvate molecules complicates the
discussion of the intermolecular interactions, it is
apparent that molecules of 7d are linked indirectly via
the solvate molecules, utilizing strong O–H–O hydrogen
bonds [35].
Compounds 7b–f were evaluated in vitro for their
anticancer activities against gastric ascitis (AGP-01),
gastric adenocarcinoma kind intestinal (ACP-02), colon
(HCT-116) and murine melanome (B16F10) cancer cells.
None of these derivatives exhibited activity at 10 uM
concentration. In addition, none of these compounds
exhibited cytotoxicity against the normal cells human
fibroblast (MRC-5), murine fibroblast (NIH3T3) and
normal human melanocyte (Melan-A), in spite of the lack
of anticancer activity. Title compounds will be evaluated
on their antibacterial activity.
CONCLUSION
A series of new ethyl (substituted)phenyl-4-oxothia-
zolidin-3-yl)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-car-
boxylate derivatives has been synthesized in moderate
yields from commercially available materials. The com-
pounds were generally characterized from spectroscopic
data and specifically for 7d, as the mixed solvate, [(7d)
2·(H2O)2(EtOH)], by X-ray diffraction. Compounds 7b–f
were not cytotoxic to normal cells. Despite the lack of
anticancer activity, the quinolone core is known to pos-
sess antibacterial activity; therefore, these structures are
also potential antibacterials.
EXPERIMENTAL
General.
All reagents and solvents were used as obtained
from commercial suppliers without further purification.
Melting points were determined on a Fisatom 430 instrument
and are uncorrected. Infrared (IR) spectra were recorded
on a Perkin-Elmer 1420 spectrometer in potassium bromide
disks. Hydrogenation reactions were performed on a Berghof
BR-300 reactor. Mass spectra (ESI-MS) were recorded on a
ZQ-4000 single quadrupole mass spectrometer. NMR spectra
were recorded on Bruker Avance 500 or on Varian Unity
300 e 500 spectrometers in deuterated dimethyl sulfoxide.
The progress of the reactions was monitored by thin-layer
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. Facchinetti, F. A. Guimarães, M. V. N. deSouza, C. R. B. Gomes, M. C. B. V. deSouza,
J. L. Wardell, S. M. S. V. Wardelf, and T. R. A. Vasconcelos
Vol 000
chromatography with F254 silica gel precoated sheets (Merck),
using chloroform/methanol (9:1) mixture as eluent, and
visualized under UV light. All the chemicals were purchased
and used without further purification.
General procedure for the synthesis of ethyl (substituted)
Ethyl 6-(2-(3-bromophenyl)-4-oxothiazolidin-3-yl)-1-ethyl-4-
oxo-1,4-dihydroquinoline-3-carboxylate (7c). This compound
was obtained as yellow powder; yield: 41%; mp: 193–195 °C; IR
(KBr): C═O 1722, C═O 1682, C═O 1611 cmÀ1 1H NMR
;
(500.00MHz, DMSO-d6) δ (ppm): 8.64 (s, 1H, H2), 8.13 (s, 1H,),
7.80 (s, 2H), 7.66 (s, 1H); 7.45 (d, 1H, J = 7.8 Hz), 7.41 (d, 1H,
J = 7.9Hz, H4″), 7.25 (dd, 1H, J = 7.9Hz, H5″), 6.66 (br, 1H,
H2′), 4.35 (q, 2H, J = 7.0 Hz, OCH2CH3), 4.20 (q, 2H, J = 7.1 Hz,
OCH2CH3), 4.13 (d, 1H, J = 15.5Hz, H5′b), 3.92 (d, 1H,
J = 15.7 Hz, H5′a), 1.31 (t, 3H, J = 7.1 Hz, NCH2CH3), 1.27
(t, 3H, J=7.1Hz, OCH2CH3); 13C NMR (125.0 MHz, DMSO-d6)
δ (ppm): 172.2 (C4), 170.8 (C4′), 164.5 (COOEt), 148.9 (C2),
142.8 (C1″), 136.6 (C8a), 134.2 (C6), 131.5 (Ph), 131.0 (Ph),
129.7 (Ph), 129.6 (Ph), 128.6 (C4a), 126.0 (Ph), 122.4 (C5),
121.9 (Ph), 118.1 (C8), 110.0 (C3), 62.3 (C2′), 59.8 (OCH2CH3),
48.0 (NCH2CH3), 32.6 (C5″), 14.4 (OCH2CH3), 14.3
(NCH2CH3); ESI-MS (m/z; %): 501.1 ([M + H]+; 100), based
on 79Br.
phenyl-4-oxothiazolidin-3-yl)-1-ethyl-4-oxo-1,4-dihydroquinoline-
3-carboxylate derivatives (7a–g). The quinolone derivatives 4
were prepared by treating the appropriate aniline (50 mmol) with
diethyl ethoxymethylenemalonate (50 mmol) under reflux in
ethanol (10 mL) for 20 h to obtain the enamine derivatives, which
were cyclized in refluxing diphenyl ether for 1 h. The quinolones
4 (4mmol) were ethylated using ethyl bromide (40 mmol) and
K2CO3 (10mmol) in DMF (15mL) at 50°C for 24h leading to
compounds 5. Key intermediates 6 were obtained after catalytic
hydrogenation of ethylquinolones 5 (4mmol) with Pd/C 10%
(220mg) in a Paar reactor under 6 atm H2 pressure in toluene
(150 mL) after 6 h. A solution of an arenealdehyde (0.78 mmol) and
6-aminoquinolone (6a or 6b) (0.78 mmol) in toluene (30 mL) was
reflux for 6 h under Dean–Stark conditions. Mercaptoacetic acid
(2.34 mmol) was added, and the mixture refluxed for 16 h. The
reaction mixture was washed with an aqueous saturated solution of
KHCO3 (5 × 50 mL), dried over Na2SO4 and evaporated to obtain a
solid, that was either washed with ethyl ether (for 7b, 7f and 7g) or
recrystallized from ethyl ether : ethyl acetate (1:1) (for 7a and 7e) or
Ethyl 1-ethyl-4-oxo-6-(4-oxo-2-phenylthiazolidin-3-yl)-1,4-
dihydroquinoline-3-carboxylate (7d).
obtained as yellow powder; yield: 40%; mp: 104–105 °C; IR
(KBr): C═O 1726, C═O 1690, C═O 1611 cmÀ1 1H NMR
This compound was
;
(500.00 MHz, DMSO-d6) δ (ppm): 8.62 (s, 1H, H2), 8.11
(d, 1H, J = 1.6 Hz, H5), 7.79 (dd, 1H, J = 9.3, 2.0 Hz, H7),
7.76 (d, 1H, J = 9.2 Hz, H8), 7.41 (d, 2H, J = 7.5 Hz, H2″),
7.28 (dd, 2H, J = 7.5 Hz, H3″), 7.21 (t, 1H, J = 7.3 Hz, H4″),
6.64 (br, 1H, H2′), 4.33 (q, 2H, J = 7.0 Hz, NCH2CH3), 4.20
(q, 2H, J = 7.1 Hz, OCH2CH3), 4.07 (d, 1H, J = 15.9 Hz, H5′
b), 3.93 (d, 1H, J = 15.7 Hz, H5′a), 1.30 (t, 3H, J = 7.1 Hz,
NCH2CH3), 1.26 (t, 3H, J = 7.1 Hz, OCH2CH3); 13C NMR
(125.0 MHz, DMSO-d6) δ (ppm): 172.2 (C4), 171.0 (C4′),
164.5 (COOEt), 148.9 (C2), 139.8 (C1″), 136.5 (C8a), 134.5
(C6), 129.8 (C7), 128.8 (Ph), 128.6 (C4a), 128.5 (Ph), 127.0
(Ph), 122.5 (C5), 118.0 (C8), 109.9 (C3), 63.3 (C2′), 59.8
(OCH2CH3), 48.0 (NCH2CH3), 32.7 (C5″), 14.4 (OCH2CH3),
14.3 (NCH2CH3); ESI-MS (m/z; %): 423.3 ([M + H]+; 100).
Ethyl 7-(2-(3-bromophenyl)-4-oxothiazolidin-3-yl)-1-ethyl-4-
from methanol/water (8:2) (for 7c and 7d).
Ethyl 1-ethyl-6-(2-(3-nitrophenyl)-4-oxothiazolidin-3-yl)-4-oxo-
1,4-dihydroquinoline-3-carboxylate (7a).
This compound was
obtained as yellow powder; yield: 56%; mp: 111–112 °C; IR
(KBr): C═O 1722, C═O 1693, C═O 1609, Nitro 1530, Nitro
1352cmÀ1 1H NMR (500.00 MHz, DMSO-d6) δ (ppm): 8.61
;
(s, 1H, H2); 8.29 (dd, 1H, J=2.0Hz, H2″), 8.15 (d, 1H, J=2.3Hz,
H5), 8.08 (ddd, 1H, J= 8.2; 2.3; 0.9 Hz, H4″), 7.98–7.94 (m, 1H,
H6″), 7.81 (dd, 1H, J= 9.1; 2.5 Hz, H7), 7.78 (d, 1H, J=9.0Hz,
H8), 7.61 (dd, 1H, J=8.0Hz, H5″), 6.85 (br, 1H, H2′), 4.33 (q,
2H, J=7.1Hz, NCH2CH3), 4.20 (q, 2H, J=7.0Hz, OCH2CH3),
4.5 (dd, 1H, J= 15.7; 1.4 Hz, H5′a), 3.96 (d, 1H, J= 15.8 Hz, H5′
b), 1.31 (t, 3H, J=7.1Hz, NCH2CH3), 1.27 (t, 3H, J=7.1Hz,
OCH2CH3); 13C NMR (125.0 MHz, DMSO-d6) δ (ppm): 171.8
(C4), 170.5 (C4′), 164.1 (COOEt), 148.5 (C2), 147.5 (3″), 142.1
(C1″), 136.4 (C8a), 133.7 (C6), 133.2 (Ph), 130.2 (Ph), 129.3
(C7), 128.2 (C4a), 123.2 (Ph), 122.1 (C5), 121.3 (Ph), 118.0
(C8), 109.7 (C3), 61.7 (C2′), 59.4 (OCH2CH3), 47.6
(NCH2CH3), 32.2 (C5′), 14.0 (OCH2CH3), 13.9 (NCH2CH3);
oxo-1,4-dihydroquinoline-3-carboxylate (7e).
This compound
was obtained as yellow powder; yield: 37%; mp: 184–185 °C (d);
1
IR (KBr): C═O 1719, C═O 1690, C═O 1603cmÀ1; H NMR
(500.00MHz, DMSO-d6) δ (ppm): 8.64 (s, 1H, H2), 8.14 (d, 1H,
J = 8.7Hz, H6), 7.71 (s, 2H, H8 and H2″), 7.53 (d, 1H, J = 8.3 Hz,
H5), 7,47 (d, 1H, J = 7.6 Hz, H4″), 7.41 (d, 1H, J = 7.8 Hz, H6″),
7.24 (dd, 1H, J = 7.8 Hz, H5″), 6.78 (br, 1H, H2′), 4.38–4.25
(m, 2H, NCH2CH3), 4.20 (q, 2H, J = 7,0 Hz, OCH2CH3), 4.13
(d, 1H, J= 15.9 Hz, H5′b), 3.97 (d, 1H, J= 15.9 Hz, H5′a), 1.27–
1.23 (m, 6H, NCH2CH3 e OCH2CH3); 13C NMR (125.0 MHz,
DMSO-d6) δ (ppm): 172.2 (C4), 171.0 (C4′), 164.6 (COOEt),
149.6 (C2), 142.6 (C1″), 141.3 (Ph), 138.8 (8a), 131.7 (Ph), 131.1
(Ph), 129.9 (Ph), 127.2 (C5), 126.1 (Ph), 126.1 (Ph), 122.0 (Ph),
121.6 (C6), 113.0 (C8), 110.4 (C3), 62.1 (C2′), 59.9 (OCH2CH3),
48.1 (NCH2CH3), 32.9 (C5″), 14.4 (OCH2CH3), 14.3 (NCH2CH3);
ESI/MS (m/z; %): 501.1 ([M + H]+; 100), based on 79Br.
ESI-MS (m/z; %): 468.3 ([M + H]+; 100).
Ethyl 1-ethyl-6-(2-(4-cyanophenyl)-4-oxothiazolidin-3-yl)-4-
oxo-1,4-dihydroquinoline-3-carboxylate (7b).
This compound
was obtained as yellow powder; yield: 52%; mp 145–147 °C; IR
1
(KBr): CN 2226, C═O 1698, C═O 1683, C═O 1608 cmÀ1; H
NMR (500.00 MHz, DMSO-d6) δ (ppm): 8.62 (s, 1H, H2), 8.14
(d, 1H, J = 2.5Hz, H5), 7.81 (dd, 1H, J = 9.2; 2.5 Hz, H7), 7.78–
7.74 (m, 3H, 3″ and H8), 7.67–7.63 (m, 2H, 2″);, 6.75 (bs, 1H,
H2′), 4.33 (q, 2H, J = 7.1 Hz, NCH2CH3), 4.20 (q, 2H, J = 7.1 Hz,
OCH2CH3), 4.12 (dd, 1H, J = 15.7; 1.4 Hz, H5′a), 3.94 (d, 1H,
J = 15.7Hz, H5′b), 1.31 (t, 3H, J = 7.1 Hz, NCH2CH3); 1.26
(t, 3H, J = 7.1 Hz, OCH2CH3); 13C NMR (125.0 MHz, DMSO-d6)
δ (ppm): 172.1 (C4), 170.8 (C4′), 164.4 (CO2Et), 148.8 (C2),
145.5 (C1″), 136.6 (C8a), 134.1 (C6), 132.8 (C3″), 129.5 (C7),
128.5 (C4a), 127.8 (2″), 122.2 (C5), 118.2 (CN), 118.0 (C8),
111.2 (C4″), 110.1 (C3), 62.4 (C2′), 59.7 (OCH2CH3), 47.9
(NCH2CH3), 32.5 (C5′), 14.3 (OCH2CH3), 14.2 (NCH2CH3);
ESI-MS (m/z; %): 448.2 ([M + H]+; 100).
Ethyl 7-(2-(4-cyanophenyl)-4-oxothiazolidin-3-yl)-1-ethyl-4-
oxo-1,4-dihydroquinoline-3-carboxylate (7f).
was obtained as yellow powder; yield: 43%, mp: 134–136 °C; IR
(KBr): CN 2227, C═O 1705, C═O 1612 cmÀ1 1H NMR
This compound
;
(300.00MHz, DMSO-d6) δ (ppm): 8.62 (s, 1H, H2), 8.14 (d, 1H,
J=8.7Hz, H5), 7.78–7.72 (m, 3H, H8 and H3″), 7.69–7.64
(m, 2H, H2″), 7.50 (dd, 1H, J=8.8, 1.8Hz, H6), 6.86 (br, 1H,
H2′), 4.38–4.23 (m, 2H, NCH2CH3), 4.19 (q, 2H, J=7.1Hz,
OCH2CH3), 4.12 (dd, 1H, J= 15.9, 1.2 Hz, H5′b), 3.97 (d, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Novel Ethyl (substituted)phenyl-4-oxothiazolidin-3-yl)-1-ethyl-4-oxo-
1,4-dihydroquinoline-3-Carboxylates
[16] Gouvêa, D. P.; Bareno, V. D. O.; Bosenbecker, J.; Drawanz,
B. B.; Neuenfeldt, P. D.; Siqueira, G. M.; Cunico, W. Ultrason Sonochem
2012, 19, 1127.
[17] Cunico, W.; Vellasco, W. T., Jr.; Moreth, M.; Gomes, C. R. B. Lett
Org Chem 2008, 5, 342.
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C. R. B.; Wardell, S. M. S. V.; Flores, A. F. C.; Cunico, W. Tetrahedron Lett
2010, 51, 3106.
[19] Cunico, W.; Capri, L. R.; Gomes, C. R. B.; Sizilio, R. H.; Wardell,
S. M. S. V. Synthesis 2006, 20, 3405.
[20] Canuto, C. V. B. S.; Gomes, C. R. B.; Marques, I. P.; Faro,
L. V.; Santos, F. C.; Frugulhetti, I. C. P. P.; Souza, T. M. L.; Cunha,
A. C.; Romeiro, G. A.; Ferreira, V. F.; Souza, M. C. B. V. Lett Drug Des
Discov 2007, 4, 404.
[21] Lucero, B. D.; Gomes, C. R. B.; Frugulhetti, I. C. P. P.; Faro,
L. V.; Souza, M. C. B. V.; Souza, T. M. L.; Ferreira, V. F. Bioorg Med
Chem Lett 2006, 16, 1010.
J = 15.9 Hz, H5′a), 1.25 (t, 3H, NCH2CH3) , 1.24 (t, 3H,
OCH2CH3); 13C NMR (75.0 MHz, DMSO-d6) δ (ppm): 172.3
(C4), 171.0 (C4′), 164.6 (COOEt), 149.6 (C2), 145.4 (C1″),
141.2 (Ph), 138.8 (C8a) , 132.9 (C3″), 127.9 (C2″), 126.7 (C5),
126.1 (Ph), 121.4 (C6), 118.4 (CN), 113.0 (C8), 111.4 (C4″),
110.5 (C3), 62.3 (C2′), 59.9 (OCH2CH3), 48.2 (NCH2CH3),
32.9 (C5′), 14.4 (OCH2CH3), 14.2 (NCH2CH3); ESI/MS (m/z):
448.2 ([M + H]+; 100).
Ethyl 1-ethyl-4-oxo-7-(4-oxo-2-phenylthiazolidin-3-yl)-1,4-
dihydroquinoline-3-carboxylate (7 g).
This compound was
obtained as yellow powder; yield: 35%, mp: 98–101 °C; IR (KBr):
C═O 1720, C═O 1692, C═O 1605 cmÀ1; 1H NMR (500.00 MHz,
DMSO-d6) δ (ppm): 8.62 (s, 1H, H2), 8.12 (d, 1H, J=8.7Hz, H5),
7.70 (s, 1H, H8), 7.51 (dd, 1H, J=8.8, 1.2Hz, H6), 7.45 (d, 2H,
J=7.4Hz, H2″), 7.28 (t, 2H, J=7.5Hz, H3″), 7.21 (t, 1H,
J=7.3Hz, H4″), 6.78 (br, 1H, H2′), 4.36–4.17 (m, 2H, NCH2CH3),
4.19 (q, 2H, J=7.1Hz, OCH2CH3), 4.09 (d, 1H, J= 15.7 Hz, H5′
b), 3.97 (d, 1H, J= 15.9 Hz, H5′a), 1.25 (t, 3H, J=7.1Hz,
NCH2CH3), 1.22 (t, 3H, J=7.2Hz, OCH2CH3); 13C NMR
(125,0 MHz, DMSO-d6) δ (ppm): 172.1 (C4), 171.0 (C4′), 164.5
(COOEt), 149.4 (C2), 141.5 (Ph), 139.6 (Ph), 138.7 (C8a), 128.8
(Ph), 128.6, 127.0 (C5), 125.9 (Ph), 121.6 (C6), 112.9 (C8), 110.3
(C3), 63.0 (C2′), 59.7 (OCH2CH3), 48.0 (NCH2CH3), 32.9 (C5′),
14.3 (OCH2CH3), 14.2 (NCH2CH3); ESI/MS (m/z): 423.2
([M + H]+; 100).
[22] Facchinetti, V.; Gomes, C. R. B.; Souza, M. V. N.; Vasconcelos,
T. R. A. Mini Rev Med Chem 2012, 12, 866.
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L. V.; de Moraes, M. O.; Filho, J. D. B. M.; de Souza, A. M. T.; de Carvalho,
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Chang, D. J.; Kwon, D. Y.; Li, F.; Suh, Y. G. Bioorg Med Chem 2007,
15, 6517.
Acknowledgments. The authors thank FAPERJ and CAPES for
financial support. The authors also thank the NCS service, based
at the University of Southampton, England for the data collection
for [(7d)2·(H2O)2(EtOH)].
[27] Bajohr, L. L.; Ma, L.; Platte, C.; Liesenfeld, O.; Tietze,
L. F.; Gross, U.; Bohne, W. Antimicrob Agents Chemother 2010,
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and PLATON in the calculation of the molecular geometry. The
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Journal of Heterocyclic Chemistry
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V. Facchinetti, F. A. Guimarães, M. V. N. deSouza, C. R. B. Gomes, M. C. B. V. deSouza,
J. L. Wardell, S. M. S. V. Wardelf, and T. R. A. Vasconcelos
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[37] Crystal data collected at 120(2)K, colourless crystal:
0.4 × 0.24 × 0.2 mm; Formula: C24H26.5N2O5.5; M = 463.03; triclinic, P-1;
a = 10.8717(3) Å, α = 66.040(2)°, b = 11.0038(3) Å, β = 86.422(2)°,
c = 11.2648(3) Å, γ = 67.0520(10)°, Z = 2, V = 1126.63(3) Å3, 51915 inde-
pendent reflections [R(int) = 0.0412], 4307 observed reflections [I > 2 s
(I)]: date/restrainsts/parameters 5191/0/330; R1 = 0.042; largest diff. peak
and hole 0.36 andÀ0.41 e.ÅÀ1. Atomic coordinates, bond lengths, angles
and thermal parameters have been deposited at the Cambridge Crystallo-
graphic Data Centre, deposition number 911296.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet