Multicomponent synthesis of new primaquine thiazolidinone derivatives

Article abstract of DOI:10.1055/s-0031-1289580

Primaquine thiazolidinone derivatives, potentially useful as antimalarial agents, were synthesized in good yields by multicomponent reactions of primaquine diphosphate, mercaptoacetic acid, and an optionally substituted benzaldehyde or cyclohexanone for t

Full text of DOI:10.1055/s-0031-1289580

3866
PAPER
Multicomponent Synthesis of New Primaquine Thiazolidinone Derivatives
T
hiazolidinon
a
P
rimaquin
t
e
H
ete
r
rocycle
s
ícia D. Neuenfeldt,a Bruna B. Drawanz,a Anna Caroline C. Aguiar,b,c Flávio Figueiredo Jr.,b
Antoniana U. Krettli,b,c Wilson Cunico*a
a
Núcleo de Química Aplicada, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, UFPel,
Campus Universitário s/no, 96010-900, Pelotas, RS, Brazil
Fax +55(53)32757454; E-mail: wjcunico@yahoo.com.br
Centro de Pesquisas René Rachou-Fiocruz, Laboratório de Malária, Av. Augusto de Lima 1715, 30190-002 Belo Horizonte, MG, Brazil
b
c
Universidade Federal de Minas Gerais, Programa de Pós Graduação em Medicina Molecular, Faculdade de Medicina,
Av. Alfredo Balena, 30130-100 Belo Horizonte, MG, Brazil
Received 3 September 2011; revised 26 September 2011
MeO
Abstract: Primaquine thiazolidinone derivatives, potentially useful
as antimalarial agents, were synthesized in good yields by multi-
component reactions of primaquine diphosphate, mercaptoacetic
N
HN
acid, and an optionally substituted benzaldehyde or cyclohexanone
N
for two to four hours. All the products were characterized by 1H and
H
13C NMR spectroscopy and by LC-MS.
O
O
Key words: heterocycles, multicomponent reactions, cycloconden-
Figure 1 Structure of bulaquine
sations, antimalarials
ample, as antimicrobials,10 anti-inflammatory agents,11
tuberculostatic agents,12 or anti-HIV agents.13 We recent-
Malaria is one of the most devastating of human diseases
ly reported a synthesis of thiazolidinones by cycloconden-
sation of an aldehyde or ketone with mercaptoacetic acid
and phenylhydrazine or 2,4-dinitrophenylhydrazine as the
amino fragment.14 Our research group has also been
studying unconventional methods for the synthesis of thi-
azolidinones by using ultrasound irradiation to reduce re-
action times.15 Thiazolidinones have also been
synthesized by means of microwave irradiation16 or ionic
liquid-phase catalysis.17 Recently, Pratap and co-
workers18 described an efficient synthesis of such hetero-
cycles by biocatalysis with Saccharomyces cerevisiae
(baker’s yeast).
Solomon and co-workers19 reported the use of thiazolidi-
none and thiazinanone chloroquine analogues as antima-
larial agents that exhibit superior in vitro activity against
P. falciparum compared with the standard drug chloro-
quine. In the present work, therefore, our aim was to ex-
plore primaquine as an amino precursor for the synthesis
of thiazolidinone primaquine derivatives, potentially use-
ful as antimalarial agents.
and accounts for more than 800,000 human deaths each
year, largely among children under five years of age. In
Brazil, the disease is endemic in the Amazon region, caus-
ing over 500,000 cases annually.1 Among the five species
of parasites known to infect humans,2 Plasmodium vivax
is the most common and P. falciparum the most deadly.
The disease is a consequence of invasion by the parasite,
which replicates within red blood cells following an
asymptomatic replicative stage inside hepatocytes. Be-
cause of the impact of malaria on human health, there is a
pressing need to develop new antimalarial drug therapies.3
The high rate of mutation of the parasites, which can lead
to the development of drug resistance, means that effec-
tive drugs with known or new mechanisms of action are
urgently needed.4
Primaquine (PQ), which was synthesized in 1946, is the
most representative member of the family of 8-amino-
quinolines that are effective against the liver stages of all
malarial parasites. Because PQ is rather toxic, several new
compounds have been prepared by modification of the ter-
minal amino group of PQ.5 Bulaquine (Figure 1) is a po-
tent new antimalarial PQ analogue that is currently
undergoing Phase II clinical trials. Unlike other PQ ana-
logues, bulaquine has no free amino group and, as a result,
causes less hemolysis than PQ in individuals who are de-
ficient in glucose-6-phosphate hydrogenase.6,7
The target compounds were prepared as outlined in
Scheme 1. In our first attempt to obtain the primaquine
thiazolidinone derivatives 5j, a mixture of primaquine
diphosphate (1; one equivalent), N,N-diisopropylethyl-
amine (DIPEA; two equivalents), 4-nitrobenzaldehyde
(2j; two equivalents), and an excess of mercaptoacetic
acid (3) was heated at 110 °C for 16 h overnight, as report-
ed in the literature (Scheme 1).12 However, when this cy-
clocondensation reaction was carried out overnight, it
produced large amounts of insoluble impurities and gave
very low yields of products (< 20%). When the reaction
was monitored every hour by thin-layer chromatography
The heterocycle thiazolidinone is a five-membered ring
that is widely used in medicinal chemistry.8,9 Its deriva-
tives show a diverse range of biological activities, for ex-
SYNTHESIS 2011, No. 23, pp 3866–3870
x
x.
x
x
.
2
0
1
1
Advanced online publication: 27.10.2011
DOI: 10.1055/s-0031-1289580; Art ID: M85911SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Thiazolidinone Primaquine Heterocycles
3867
MeO
MeO
MeO
CHO
O
N
N
⋅2H3PO4
HN
N
HN
+
N
S
R
NH2
HN
N
R
1
2a–p
R
5a–p
4a–p
Scheme 1 Reagents and conditions: DIPEA, HSCH2CO2H (3), toluene, 110 °C, Dean–Stark distillation, 2–4 h.
(TLC) using hexane/ethyl acetate (3:1) as eluent, product To gain further insight into the nature of the reaction, we
5j was observed to be formed in three hours.
used the cyclohexanone 2q as the carbonyl precursor in
the one-pot reaction with primaquine (1) and mercapto-
acetic acid (3) to give the spirothiazolidinone 5q in a good
yield (Scheme 2).
We therefore prepared the 3-[4-(6-methoxyquinolin-8-
ylamino)pentyl]-2-aryl-1,3-thiazolidin-4-ones 5a–p by a
one-pot multicomponent reaction of primaquine diphos-
phate (1), DIPEA, benzaldehyde 2a–p, and an excess of
mercaptoacetic acid (3) in refluxing toluene for two to
four hours while monitoring the reaction by TLC
(Scheme 1). The desired heterocycles were obtained in
moderate-to-good yields (37–89%) after purification of
the crude product by column chromatography on silica gel
(Table 1). Similar yields were obtained by adding the
mercaptoacetic acid to a mixture of primaquine diphos-
phate, DIPEA, and the benzaldehyde that had previously
been refluxed for one hour, and then refluxing the result-
ant mixture for an additional three hours or more. To our
surprise, when 2-formylbenzonitrile was used as the alde-
hyde, the product 5 (R = 2-CN) was not obtained and, in-
stead, a complex mixture of products was formed.
MeO
MeO
O
O
N
N
⋅2H3PO4
HN
+
N
S
HN
NH2
80%
1
2q
5q
Scheme 2 Reagents and conditions: DIPEA, HSCH2CO2H (3),
toluene, 110 °C, Dean–Stark distillation, 3 h.
The analytical and spectral data (1H and 13C NMR) for all
the compounds were in full agreement with the proposed
structures (Figure 2). We used two-dimensional NMR
techniques (HMBQ, HMQC and COSY) to help us assign
the signals of the compounds correctly. As expected, the
presence of two asymmetric carbons in the primaquine
thiazolidinone derivatives 5a–p resulted in the formation
of a pair of diastereoisomers that were clearly observed in
a 1:1 proportion in the NMR spectra. The H2 hydrogen
(the CH of the thiazolidinone ring) appears as a singlet (or
a doublet with a small coupling constant) at 5.38–5.97
ppm for each of the diastereoisomers. The appearances of
the aromatic signals having the relative integrations ex-
pected for the quinoline ring or the benzaldehyde residue
were as expected from the structures of the compounds.
Table 1 Yields and LC-MS of Compounds 5a–p
Product R
Yielda Time LC-MS (m/z)
(%) (h)
(%)
5a
5b
5c
5d
5e
5f
H
86
44
89
89
66
70
52
59
37
52
4
2
2
3
3
3
2
3
4
3
2
4
2
3
4
3
444.2 [M + 23]+ (100)
462.5 [M + 23]+ (100)
462.5 [M + 23]+ (100)
462.5 [M + 23]+ (100)
478.3 [M + 23]+ (100)
478.5 [M + 23]+ (100)
478.3 [M + 23]+ (100)
489.5 [M + 23]+ (100)
489.5 [M + 23]+ (100)
489.5 [M + 23]+ (100), 462.5 (40%)
474.6 [M + 23]+ (100)
474.4 [M + 23]+ (100)
474.3 [M + 23]+ (100)
469.3 [M + 23]+ (100)
469.3 [M + 23]+ (100)
458.5 [M + 23]+ (100), 436.6 (83%)
2-F
3-F
4-F
2-Cl
3-Cl
4-Cl
2-NO2
3-NO2
4-NO2
1
The H NMR spectrum showed hydrogen signals for the
methylene group of the thiazolidinone ring overlapping
other aliphatic signals; the corresponding signals in the
13C NMR could, however, be clearly observed at 31–33
ppm.
5g
5h
5i
The racemic primaquine spirothiazolidinone derivative
5q is characterized by an absence of hydrogen at the 2-po-
sition of the thiazolidine ring. Its 13C NMR spectrum ex-
hibited peaks at d = 170.1, 73.2, and 33.2 ppm,
corresponding to the C4 (C=O), C2 (quaternary), and C5
(CH2) carbon atoms of the thiazolidinone ring, respective-
ly.
5j
5k
5l
2-OMe 72
3-OMe 88
4-OMe 87
5m
5n
5o
5p
3-CN
4-CN
4-Me
41
87
89
In conclusion, seventeen new primaquine thiazolidinone
derivatives were readily synthesized in moderate-to-good
yields by a one-pot cyclocondensation reaction. The syn-
thesized compounds are good starting points for develop-
a Yield of pure compound after chromatography.
Synthesis 2011, No. 23, 3866–3870 © Thieme Stuttgart · New York

3868
P. D. Neuenfeldt et al.
PAPER
3.83 (ddd, 2J = 15.1 Hz, 4J = 5.0 Hz, 4J = 1.5 Hz, 2 H, H-16a), 3.89
(s, 6 H, H-1), 5.85 and 5.90 (2d, 4J = 1.7 Hz, 2 H, H-17), 5.95 (br s,
2 H, H-9), 6.23 (2d, 4J = 2.3 Hz, 2 H, H-3), 6.35 (d, 4J = 2.3 Hz, 2
H, H-7), 7.15 (m, 6 H, Ph), 7.23 (m, 2 H, Ph), 7.31 (ddd, 3J = 8.0 Hz,
3J = 4.3 Hz, 5J = 1.0 Hz, 2 H, H-5), 7.92 (d, 3J = 8.0 Hz, 2 H, H-4),
8.53 (m, 2 H, H-6).
ing new lead antimalarials, and a biological study is
ongoing. There is an urgent need to identify new antima-
larials to replace primaquine, and they would be especial-
ly useful if they were also active against the blood stages
of the deadly P. falciparum parasite.
13C NMR (100 MHz, CDCl3): d = 20.7 and 20.8 (C11), 23.7 (C13),
29.9 (C16), 33.7 and 33.9 (C12), 43.1 and 43.2 (C14), 47.7 and 47.9
(C10), 55.4 (C1), 57.1 and 57.2 (C17), 91.8, 91.9, 96.9, 97.0, 116.2,
116.4, 122.0, 124.8, 124.9, 127.0, 127.1, 128.1, 128.2, 130.1, 130.7,
130.8, 134.8, 134.9, 135.5, 144.4, 145.0, 145.1 (aryl), 159.6 (C2),
160.5 (d, 1JC–F = 250 Hz, C20), 171.5 (C15).
Unless otherwise indicated, all common reagents and solvents were
used as obtained from commercial suppliers without further purifi-
1
cation. H and 13C NMR spectra were recorded on a Bruker DRX
400 spectrometer (1H at 400.14 MHz and 13C at 100.61 MHz) or
with a Bruker Avance 500 spectrometer (1H at 500.13 MHz and 13
C
at 125.75 MHz) in CDCl3 or DMSO-d6 containing TMS as an inter-
nal standard. The low-resolution LC-MS analyses were performed
on a Micromass ZMD instrument using 1:1 CHCl3–MeOH as the
mobile phase at a flux of 0.3 mL/min. These analyses used electro-
spray ionization in the positive-ion mode, and the samples were in-
troduced by the standard direct-insertion probe method.
2-(3-Fluorophenyl)-3-{4-[(6-methoxyquinolin-8-yl)amino]pen-
tyl}-1,3-thiazolidin-4-one (5c)
3
1H NMR (500 MHz, DMSO-d6): d = 1.16 (d, J = 6.4 Hz, 6 H, H-
11), 1.40 (m, 8 H, H-12 and H-13), 2.62 (m, 2 H, H-14b), 3.53 (m,
4 H, H-10 and H-14a), 3.64 (2d, 2J = 15.6 Hz, 2 H, H-16b), 3.81 (s,
2
4
6 H, H-1), 3.88 (2dd, J = 15.6 Hz, J = 4.9 Hz, 2 H, H-16a), 5.76
and 5.83 (2s, 2 H, H-17), 6.06 (t, 3J = 9.8 Hz, 2 H, H-9), 6.20 (s, 2
H, H-3), 6.47 (d, 4J = 1.9 Hz, 2 H, H-7), 7.14 (m, 6 H, Ph), 7.35 (m,
Primaquine Thiazolidinone Analogues 5a–q: General Proce-
dure
3
3
A soln of primaquine diphosphate (1; 2.275 g, 5 mmol), DIPEA
(1.292 g, 1.74 mL, 10 mmol), benzaldehyde 2a–p (0.435–0.466 g,
10 mmol) or cyclohexanone 2q (0.490 g, 10 mmol), and
HSCH2CO2H (3; 1.380 g, 1.05 ml, 15 mmol) in toluene (50 mL)
was refluxed with a Dean–Stark trap for 2–4 until the reagents were
completely consumed (TLC). The organic layer was then washed
with sat. aq NaHCO3 (3 × 50 mL), dried (MgSO4), and concentrated
to give a crude product that was purified by column chromatogra-
phy [silica gel 60 (0.2–0.5 mm), hexane–EtOAc (7:3)] to give an oil
(Rf = 0.1). The generic structures and atom-numbering of com-
pounds 5 are given in Figure 2.
2 H, Ph), 7.42 (dd, J = 7.8 Hz, J = 3.9 Hz, 2 H, H-5), 8.07 (d,
3J = 8.2 Hz, 2 H, H-4), 8.53 (d, 3J = 4.0 Hz, 2 H, H-6).
13C NMR (125 MHz, DMSO-d6): d = 9.9 and 20.1 (C11), 22.9 and
23.1 (C13), 31.8 (C16), 32.6 and 32.9 (C12), 42.2 (C14), 46.8
(C10), 55.0 (C1), 61.1 and 61.2 (C17), 91.7, 91.8, 96.1, 96.3, 113.5,
113.7, 115.5, 115.6, 122.1, 122.8, 129.6, 130.8, 130.9, 134.5, 134.8,
143.4, 143.5, 144.3, 144.5, 144.6 (aryl), 159.0 (C2), 162.3 (d,
1JC–F = 243.7 Hz, C22), 170.7 (C15).
2-(4-Fluorophenyl)-3-{4-[(6-methoxyquinolin-8-yl)amino]pen-
tyl}-1,3-thiazolidin-4-one (5d)
1H NMR (500 MHz, CDCl3): d = 1.26 (2d, 3J = 5.8 Hz, 6 H, H-11),
1.50 (m, 8 H, H-12 and H-13), 2.65 (m, 2 H, H-14b), 3.60 (m, 2 H,
H-14a), 3.78 (m, 6 H, H-10 and H-16), 3.89 (s, 6 H, H-1), 5.45 and
1
3
4
1
3
4
3a
2
MeO
3a
2
MeO
5
6
5
6
4
5.56 (2s, 2 H, H-17), 5.93 (br s, 2 H, H-9), 6.22 (2d, J = 2.9 Hz,
7
9
O
7
9
4J = 1.9 Hz, 2 H, H-3), 6.35 (d, 4J = 1.9 Hz, 2 H, H-7), 6.93 (m, 4 H,
Ph), 7.16 (m, 4 H, Ph), 7.33 (m, 2 H, H-5), 7.93 (m, 2 H, H-4), 8.54
(m, 2 H, H-6).
O
8a
10
N
8
16
S
N
8a
10
8
16
S
15
15
HN
13
HN
13
N
14
12
N
17
18
14
12
17
18
13C NMR (125 MHz, CDCl3): d = 20.6 and 20.8 (C11), 23.2 (C13),
33.0 and 33.2 (C16), 33.6 (C12), 42.8 (C14), 47.4 and 47.7 (C10),
55.9 (C1), 62.8 (C17), 91.8, 91.9, 96.8, 97.0, 115.8, 116.2, 116.3,
121.9, 128.9, 129.1, 130.0, 134.8, 134.9, 135.4, 144.3, 144.9, 145.0
(aryl), 159.5 (C2), 165.4 (C23), 171.0 and 171.1 (C15).
19
21
11
20
R
11
19
21
20
24
22
5q
5a–p
22
23
Figure 2 Primaquine thiazolidinone derivatives 5a–q
2-(2-Chlorophenyl)-3-{4-[(6-methoxyquinolin-8-yl)amino]pen-
tyl}-1,3-thiazolidin-4-one (5e)
3-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-2-phenyl-1,3-thi-
azolidin-4-one (5a)
1H NMR (500 MHz, CDCl3): d = 1.30 (2d, 3J = 5.8 Hz, 6 H, H-11),
1.65 (m, 8 H, H-12 and H-13), 2.70 (m, 2 H, H-14b), 3.63 (m, 2 H,
H-14a), 3.65 (2d, 2J = 15.6 Hz, 2 H, H-16b), 3.74 (dd, 2J = 16.6 Hz,
4J = 5.8 Hz, 2 H, H-16a), 3.83 (m, 2 H, H-10), 3.89 (s, 6 H, H-1),
5.97 (d, 3J = 8.0 Hz, 2 H, H-9), 6.02 and 6.06 (2s, 2 H, H-17), 6.23
(2d, 4J = 1.9 Hz, 2 H, H-3), 6.35 (d, 4J = 1.9 Hz, 2 H, H-7), 7.20 (m,
6 H, Ph), 7.31 (m, 2 H, Ph), 7.33 (m, 2 H, H-5), 7.92 (dd, 3J = 7.8
Hz, 4J = 1.9 Hz, 2 H, H-4), 8.53 (m, 2 H, H-6).
1H NMR (400 MHz, CDCl3): d = 1.24 (2d, 3J = 6.6 Hz, 6 H, H-11),
1.58 (m, 8 H, H-12 and H-13), 2.70 (m, 2 H, H-14b), 3.70 (m, 8 H,
H-10, H-14a, and H-16), 3.89 (s, 6 H, H-1), 5.48 and 5.59 (2s, 2 H,
H-17), 5.95 (s, 2 H, H-9), 6.23 (2d, 4J = 2.2 Hz, 4J = 2.5 Hz, 2 H, H-
3), 6.34 (d, 4J = 2.0 Hz, 2 H, H-7), 7.32 (m, 12 H, Ph and H-5), 7.92
(d, 3J = 8.0 Hz, 2 H, H-4,), 8.53 (d, 3J = 4.2, 2 H, H-6).
13C NMR (100 MHz, CDCl3): d = 20.4 and 20.6 (C11), 23.1 and
23.2 (C13), 32.8 and 32.9 (C16), 33.2 and 33.6 (C12), 42.6 and 42.7
(C14), 47.5 and 47.6 (C10), 55.2 (C1), 63.3 and 63.4 (C17), 91.6,
91.7, 96.7, 96.9, 121.9, 127.0, 128.9, 129.1, 129.8, 129.9, 134.7,
134.8, 153.3, 139.2, 139.3, 144.2, 144.3 (aryl), 159.4 and 159.5
(C2), 171.1 and 171.2 (C15).
13C NMR (125 MHz, CDCl3): d = 20.5 and 20.6 (C11), 23.5 (C13),
32.3 (C16), 33.5 and 33.7 (C12), 43.0 and 43.1 (C14), 47.5 and 47.7
(C10), 55.2 (C1), 59.6 (C17), 91.7, 96.6, 96.7, 121.8, 127.5, 129.7,
129.9, 130.2, 132.8, 134.7, 135.3, 144.2, 144.8, 144.9 (aryl), 159.4
(C2), 171.7 (C15).
2-(2-Fluorophenyl)-3-{4-[(6-methoxyquinolin-8-yl)amino]pen-
tyl}-1,3-thiazolidin-4-one (5b)
2-(3-Chlorophenyl)-3-{4-[(6-methoxyquinolin-8-yl)amino]pen-
tyl}-1,3-thiazolidin-4-one (5f)
1H NMR (400 MHz, CDCl3): d = 1.25 (m, 6 H, H-11), 1.60 (m, 8 H,
H-12 and H-13), 2.74 (m, 2 H, H-14b), 3.53 (m, 2 H, H-14a), 3.68
1H NMR (500 MHz, CDCl3): d = 1.26 (2d, 3J = 5.8 Hz, 6 H, H-11),
1.60 (m, 8 H, H-12 and H-13), 2.68 (m, 2 H, H-14b), 3.63 (m, 4 H,
H-10 and H-14a), 3.74 (m, 2 H, H-16b), 3.83 (m, 2 H, H-16a), 3.89
2
4
(dd, J = 15.4 Hz, J = 3.2 Hz, 2 H, H-16b), 3.79 (m, 2 H, H-10),
Synthesis 2011, No. 23, 3866–3870 © Thieme Stuttgart · New York

PAPER
Thiazolidinone Primaquine Heterocycles
3869
(s, 6 H, H-1), 5.39 and 5.53 (2s, 2 H, H-17), 5.94 (br s, 2 H, H-9),
6.25 (2d, 4J = 2.9 Hz, 4J = 1.9 Hz, 2 H, H-3), 6.35 (d, 4J = 2.9 Hz, 2
H, H-7), 7.03 (m, 2 H, Ph), 7.20 (m, 6 H, Ph), 7.32 (dd, 3J = 7.8 Hz,
13C NMR (100 MHz, CDCl3): d = 20.9 and 21.0 (C11), 22.9 and
23.3 (C13), 32.9 and 33.0 (C16), 33.1 and 33.4 (C12), 42.6 and 43.2
(C14), 47.0 and 47.8 (C10), 55.4 (C1), 62.3 and 62.4 (C17), 92.0,
92.1, 96.9, 97.1, 122.1, 124.3, 124.4, 127.7, 127.8, 128.6, 130.1,
130.2, 133.5, 134.1, 134.2, 135.4, 144.5, 144.9, 146.6, 146.8, 148.1,
148.2 (aryl), 159.5 (C2), 171.2 and 171.3 (C15).
3
3J = 3.9 Hz, 2 H, H-5), 7.93 (d, J = 7.8 Hz, 2 H, H-4), 8.52 (d,
3J = 3.9 Hz, 2 H, H-6).
13C NMR (125 MHz, CDCl3): d = 20.4 and 20.6 (C11), 23.5 (C13),
32.5 (C16), 33.5 and 33.8 (C12), 42.9 (C14), 47.6 and 47.7 (C10),
55.4 (C1), 59.1 (C17), 91.9, 96.0, 96.1, 121.2, 127.6, 129.7, 129.8,
130.1, 132.3, 134.8, 135.3, 144.0, 144.7, 144.9 (aryl), 159.2 (C2),
171.3 (C15).
2-(2-Methoxyphenyl)-3-{4-[(6-methoxyquinolin-8-yl)ami-
no]pentyl}-1,3-thiazolidin-4-one (5k)
1H NMR (500 MHz, CDCl3): d = 1.26 (2d, 3J = 6.8 Hz, 6 H, H-11),
1.80 (m, 8 H, H-12 and H-13), 2.71 (m, 2 H, H-14b), 3.60 (m, 4 H,
H-10 and H-14a), 3.74 (m, 4 H, H-16), 3.76 and 3.81 (2s, 6 H, H-
24), 3.88 (s, 6 H, H-1), 5.96 (m, 4 H, H-9 and H-17), 6.24 (m, 2 H,
H-3), 6.33 (s, 2 H, H-7), 6.87 (m, 4 H, Ph), 7.06 (2d, 3J = 6.8 Hz, 2
H, Ph), 7.25 (m, 2 H, Ph), 7.30 (dd, 3J = 7.8, 3J = 3.9, 2H, H-5), 7.92
(d, 3J = 8.8 Hz, 2 H, H-4), 8.52 (2d, 3J = 3.9 Hz, 2 H, H-6).
2-(4-Chlorophenyl)-3-{4-[(6-methoxyquinolin-8-yl)amino]pen-
tyl}-1,3-thiazolidin-4-one (5g)
1H NMR (500 MHz, CDCl3): d = 1.15 (2d, 3J = 5.8 Hz, 6 H, H-11),
1.48 (m, 8 H, H-12 and H-13), 2.69 (m, 2 H, H-14b), 3.73 (m, 8 H,
H-16, H-10, and H-14a), 3.87 (s, 6 H, H-1), 5.44 and 5.55 (2s, 2 H,
H-16), 5.93 (br s, 2 H, H-9), 6.23 and 6.26 (2d, 4J = 1.9 Hz, 2 H, H-
3), 6.33 (d, 4J = 1.9 Hz, 2 H, H-7), 7.30 (m, 4 H, Ph), 7.44 (m, 2 H,
Ph), 7.61 (m, 2 H, Ph), 7.91 (m, 2 H, H-5), 8.05 (d, 3J = 8.0 Hz, 2 H,
H-4), 8.53 (d, 3J = 4 Hz, 2 H, H-6).
13C NMR (125 MHz, CDCl3): d = 20.6 (C11), 23.6 and 23.8 (C13),
32.8 (C16), 33.8 (C12), 43.0 and 43.1 (C14), 47.7 and 47.9 (C10),
55.2 (C24), 55.5 (C1), 57.8 and 57.9 (C17), 91.7, 96.7, 96.8, 111.0,
120.9, 121.9, 126.7, 127.6, 129.8, 129.9, 134.8, 135.4, 144.3, 145.0
(aryl), 156.9 and 159.5 (C2), 171.9 (C15).
13C NMR (125 MHz, CDCl3): d = 20.6 and 20.8 (C11), 23.1 (C13),
32.9 and 33.0 (C16), 33.6 (C12), 42.5 (C14), 47.7 (C10), 55.3 (C1),
62.7 (C17), 91.8, 91.9, 95.8, 96.8, 97.0, 121.9, 128.4, 128.2, 129.3,
134.8, 137.7, 144.4, 145.0 (aryl), 159.5 (C2), 171.0 (C15).
2-(3-Methoxyphenyl)-3-{4-[(6-methoxyquinolin-8-yl)ami-
no]pentyl}-1,3-thiazolidin-4-one (5l)
1H NMR (400 MHz, CDCl3): d = 1.26 (2d, 3J = 6.3 Hz, 6 H, H-11),
1.75 (m, 8 H, H-12 and H-13), 2.75 (m, 2 H, H-14b), 3.58 (m, 4 H,
H-10 and H-14a), 3.68 (m, 2 H, H-16b), 3.74 and 3.78 (2s, 6 H, H-
24), 3.80 (m, 2 H, H-16a), 3.90 (s, 6 H, H-1), 5.47 and 5.58 (2d,
J = 1.7 Hz, 2 H, H-17), 5.96 (d, 3J = 8.8 Hz, 2 H, H-9), 6.24 and 6.26
(2d, J = 2.2 Hz, 2 H, H-3), 6.35 (2d, 4J = 2.2 Hz, 2 H, H-7), 6.76 (m,
4 H, Ph), 6.82 (m, 2 H, Ph), 7.20 (m, 2 H, Ph), 7.31 (dd, 3J = 8.3 Hz,
3J = 4.2 Hz, 2 H, H-5), 7.93 (dd, 3J = 8.3 Hz, 4J = 1.5 Hz, 2 H, H-4),
8.55 (m, 2 H, H-6).
3-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-2-(2-nitrophe-
nyl)-1,3-thiazolidin-4-one (5h)
1H NMR (500 MHz, CDCl3): d = 1.27 (2d, 3J = 5.8 Hz, 6 H, H-11),
1.66 (m, 8 H, H-12 and H-13), 2.62 (m, 2 H, H-14b), 3.58 (m, 2 H,
H-14a), 3.59 (d, 2J = 15.6 Hz, 2 H, H-17b), 3.68 (d, 2J = 15.6 Hz, 2
H, H-17a), 3.82 (m, 2 H, H-10), 3.83 (s, 6 H, H-1), 6.08 (br s, 2 H,
H-9), 6.21 (m, 4 H, H-3 and H-17), 6.47 (d, 4J = 1.9 Hz, 2 H, H-7),
7.33 (m, 6 H, Ph), 7.42 (m, 2 H, Ph), 7.63 (m, 2 H, H-5), 7.91 (d,
3J = 7.8 Hz, 2 H, H-4), 8.04 (2d, 3J = 6.8 Hz, 2 H, Ph), 8.51 (m, 2 H,
H-6).
13C NMR (100 MHz, CDCl3): d = 20.6 and 20.8 (C11), 23.4 and
23.6 (C13), 33.1 (C16), 33.4 and 33.9 (C12), 42.9 and 43.0 (C14),
47.8 and 47.9 (C10), 55.4 (C24), 55.1 (C1), 63.4 and 63.5 (C17),
91.9, 92.0, 96.9, 97.1, 112.3, 112.4, 114.8, 114.9, 119.3, 122.0,
130.1, 130.2, 130.3, 134.9, 135.5, 135.5, 141.2, 144.5, 145.1 (aryl),
159.6 and 160.3 (C2), 171.4 (C15).
13C NMR (125 MHz, CDCl3): d = 20.7 (C11), 23.6 (C13), 31.8
(C16), 33.6 and 33.9 (C12), 43.5 (C14), 47.4 and 47.9 (C10), 55.2
(C1), 58.6 (C17), 91.8, 91.9, 96.7, 96.8, 121.9, 125.9, 126.2, 129.2,
129.3, 129.9, 134.4, 134.7, 134.8, 135.3, 136.6, 144.4, 144.9 (aryl),
159.4 (C2), 172.3 (C15).
2-(4-Methoxyphenyl)-3-{4-[(6-methoxyquinolin-8-yl)ami-
no]pentyl}-1,3-thiazolidin-4-one (5m)
3-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-2-(3-nitrophe-
nyl)-1,3-thiazolidin-4-one (5i)
1H NMR (400 MHz, CDCl3): d = 1.16 (d, 3J = 6.3 Hz, 6 H, H-11),
1.45 (m, 8 H, H-12 and H-13), 2.58 (m, 2 H, H-14b) 3.50 (m, 4 H,
H-10 and H-14a), 3.65 (m, 2 H, H-16b), 3.71 and 3.72 (2s, 6 H, H-
24) 3.78 (m, 2 H, H-16a), 3.82 (s, 6 H, H-1), 5.67 and 5.75 (2s, 2 H,
H-17) 6.08 (t, 3J = 9.3 Hz, 2 H, H-9), 6.20 (d, 4J = 2.5 Hz, 2 H, H-
3), 6.47 (d, 4J = 2.0 Hz, 2 H, H-7), 6.86 (2d, 3J = 8.5 Hz, 3J = 8.3 Hz,
1H NMR (500 MHz, CDCl3): d = 1.25 (2d, 3J = 6.8 Hz, 6 H, H-11),
1.60 (m, 8 H, H-12 and H-13), 2.71 (m, 2 H, H-14b), 3.57 (m, 4 H,
H-10 and H-14a), 3.74 (m, 2 H, H-16b), 3.80 (m, 2 H, H-16a), 3.89
(2s, 6 H, H-1), 5.50 and 5.65 (s, 1 H, H-17), 5.89 (br s, 2 H, H-9),
6.18 and 6.21 (2d, 4J = 1.9 Hz, 2 H, H-3), 6.34 (2d, 4J = 2.9 Hz, 2
H, H-7), 7.32 (m, 2 H, Ph), 7.43 (m, 4 H, Ph), 7.94 (m, 2 H, H-5),
8.02 (m, 2 H, Ph), 8.05 (m, 3J = 8.8 Hz, 2 H, H-4), 8.53 (s, 2 H, H-6).
3
3
4 H, Ph), 7.23 (2d, J = 8.5 Hz, J = 8.3 Hz, 4 H, Ph), 7.43 (dd,
3J = 8.3 Hz, 3J = 4.3 Hz, 2 H, H-5), 8.07 (d, 3J = 8.0 Hz, 2 H, H-4),
8.53 (2d, 3J = 3.8 Hz, 2 H, H-6).
13C NMR (125 MHz, CDCl3): d = 20.7 and 20.9 (C11), 23.0 and
23.2 (C13), 32.9 (C16), 33.7 (C12), 42.8 and 43.1 (C14), 47.3 and
47.6 (C10), 55.2 and 55.3 (C1), 62.4 (C17), 91.8, 91.9, 96.7, 97.0,
122.0, 123.9, 124.0, 130.0, 130.1, 132.6, 132.7, 134.9, 135.9, 141.9,
144.4 (aryl), 159.4 (C2), 171.1 and 171.2 (C15).
13C NMR (100 MHz, DMSO-d6): d = 19.9 and 20.0 (C11), 22.8 and
22.9 (C13), 32.0 (C16), 32.6 and 32.8 (C12), 41.8 and 41.9 (C14),
46.8 (C10), 54.9 and 55.1 (C1), 61.6 and 61.7 (C17), 91.6, 91.7,
96.0, 96.2, 114.0, 114.1, 122.0, 128.4, 128.5, 129.5, 131.5, 134.5,
134.7, 144.2, 144.4, 144.6 (aryl), 158.9 and 159.4 (C2), 170.3 and
170.4 (C15).
3-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-2-(4-nitrophe-
nyl)-1,3-thiazolidin-4-one (5j)
3-(3-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-4-oxo-1,3-thi-
azolidin-2-yl)benzonitrile (5n)
1H NMR (400 MHz, CDCl3): d = 1.25 (m, 6 H, H-11), 1.60 (m, 8 H,
H-12 and H-13), 2.65 (m, 2 H, H-14b), 3.57 (m, 4 H, H-10 and H-
14a), 3.68 (m, 2 H, H-16b), 3.82 (m, 2 H, H-16a), 3.87 and 3.90 (2s,
6 H, H-1), 5.50 and 5.62 (2d, 4J = 1.2 Hz, 2 H, H-17), 6.11 and 6.22
1H NMR (500 MHz, CDCl3): d = 1.27 (2d, 3J = 6.4 Hz, 6 H, H-11),
1.60 (m, 8 H, H-12 and H-13), 2.67 (m, 2 H, H-14b) 3.57 (m, 4 H,
H-10 and H-14a), 3.72 (m, 2 H, H-16b), 3.79 (m, 2 H, H-16a), 3.91
(s, 6 H, H-1), 5.38 and 5.57 (2s, 2 H, H-17) 5.93 (br s, 2 H, H-9),
6.21 and 6.26 (2d, 4J = 2.9 Hz, 2 H, H-3), 6.37 (d, 4J = 1.9 Hz, 2 H,
4
(2d, 4J = 2.5 Hz, 2 H, H-3), 6.34 (2d, J = 2.5 Hz, 2 H, H-7), 7.32
(m, 4 H, Ph), 7.35 (m, 2 H, H-5), 7.97 (m, 2 H, Ph), 8.08 (d, 3J = 8.8
Hz, 2 H, H-4), 8.55 (2dd, 3J = 4.2 Hz, 4J = 1.5 Hz, 2 H, H-6).
Synthesis 2011, No. 23, 3866–3870 © Thieme Stuttgart · New York

3870
P. D. Neuenfeldt et al.
PAPER
H-7), 7.36 (m, 8 H, Ph), 7.51 (dd, 3J = 8.0 Hz, 3J = 4.0 Hz, 2 H, H-
5), 7.96 (d, 3J = 8.1 Hz, 2 H, H-4), 8.56 (m, 2 H, H-6).
121.9, 129.4, 134.4, 134.6, 144.1, 144.6 (aryl), 158.9 (C2), 170.1
(C15).
13C NMR (125 MHz, CDCl3): d = 20.6 and 20.9 (C11), 22.8 and
23.3 (C13), 32.6 (C16), 32.8 and 33.7 (C12), 42.7 and 42.9 (C14),
47.4 and 47.5 (C10), 55.3 (C1), 62.3 and 62.4 (C17), 91.9, 92.0,
96.8, 97.1, 113.3, 118.0, 122.0, 122.1, 129.9, 130.0, 130.4, 130.5,
131.1, 131.2, 132.6, 134.9, 135.3, 141.3, 141.4, 144.4, 144.5, 144.8,
145.0 (aryl and C24), 159.5 (C2), 171.1 and 171.2 (C15).
Acknowledgment
The authors thank CNPq (Projects 575746/2008-4 and 305314/
2009-2) for their financial support of the research. We also thank
UFPel and CAPES.
4-(3-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-4-oxo-1,3-thi-
azolidin-2-yl)benzonitrile (5o)
References
1H NMR (500 MHz, CDCl3): d = 1.25 (2d, 3J = 6.4 Hz, 6 H, H-11),
1.58 (m, 8 H, H-12 and H-13), 2.64 (m, 2 H, H-14b) 3.66 (m, 4 H,
H-10 and H-14a), 3.73 (m, 2 H, H-16b), 3.83 (m, 2 H, H-16a), 3.91
(s, 6 H, H-1), 5.46 and 5.58 (2s, 2 H, H-17) 5.92 (br s, 2 H, H-9),
6.16 and 6.25 (2s, 2 H, H-3), 6.38 (d, 4J = 2.9 Hz, 2 H, H-7), 7.21
(m, 4 H, Ph), 7.37 (m, 4 H, Ph), 7.54 (dd, 3J = 8.0 Hz, 3J = 4.0 Hz,
2 H, H-5), 7.98 (d, 3J = 7.8 Hz, 2 H, H-4), 8.55 (d, 3J = 4.0 Hz, 2 H,
H-6).
13C NMR (125 MHz, CDCl3): d = 20.7 and 20.9 (C11), 22.9 and
23.2 (C13), 32.8 and 32.9 (C16), 33.1 and 33.4 (C12), 42.6 and 43.1
(C14), 47.0 and 47.7 (C10), 55.3 (C1), 62.5 (C17), 91.9, 96.8, 97.0,
112.8, 112.9, 118.2, 122.0, 127.5, 130.0, 132.7, 132.9, 134.9, 135.3,
144.4, 144.6, 144.8, 144.9 (aryl and C24), 159.5 (C2), 171.1 and
171.2 (C15).
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3-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-2-(4-methylphe-
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1H NMR (400 MHz, CDCl3): d = 1.25 (2d, 3J = 6.3 Hz, 6 H, H-11),
1.55 (m, 8 H, H-12 and H-13), 2.30 and 2.32 (2s, 6 H, H-24), 2.68
(m, 2 H, H-14b), 3.57 (m, 2 H, H-14a), 3.65 (m, 2 H, H-10), 3.66
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4
2 H, H-16a), 3.89 (s, 6 H, H-1), 5.46 and 5.57 (2d, J = 1.7 Hz,
J = 1.5 Hz, 2 H, H-17), 5.94 (d, 3J = 8.3 Hz, 2 H, H-9), 6.21 and 6.24
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8 H, Ph), 7.32 (ddd, 3J = 8.3 Hz, 3J = 4.0 Hz, 4J = 1.2 Hz, 2 H, H-5),
7.93 (dt, 3J = 8.3 Hz, 4J = 1.7 Hz, 2 H, H-4), 8.54 (2dd, 3J = 4.0 Hz,
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13C NMR (100 MHz, CDCl3): d = 20.7 and 20.8 (C11), 21.3 (C24),
23.3 and 23.4 (C13), 33.2 (C16), 33.4 and 33.8 (C12), 42.7 and 42.8
(C14), 47.7 and 47.9 (C10), 55.4 (C1), 63.4 and 63.5 (C17), 91.9,
96.9, 97.1, 122.0, 127.1, 129.8, 129.9, 130.1, 134.9, 135.0, 135.5,
136.4, 139.3, 144.5, 145.0, 145.1 (aryl), 159.6 (C2), 171.3 and
171.4 (C15).
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4-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-1-thia-4-aza-
spiro[4.5]decan-3-one (5q)
1H NMR (400 MHz, DMSO-d6): d = 1.21 (d, 3J = 6.4 Hz, 3 H, H-
11), 1.58 (m, 14 H, cyclohexane, H-12 and H-13), 3.41 (m, 5 H, H-
10, H-14 and H-16), 3.82 (s, 3 H, H-1), 6.10 (s, 1 H, H-9), 6.29 (d,
4
4J = 2.3 Hz, 1 H, H-3), 6.46 (d, J = 2.3 Hz, 1 H, H-7), 7.40 (dd,
3J = 8.1 Hz, 3J = 4.4 Hz, 1 H, H-5), 8.05 (d, 3J = 8.2 Hz, 1 H, H-4),
8.53 (d, 3J = 4.0 Hz, 1 H, H-6).
13C NMR (100 MHz, DMSO-d6): d = 20.3 (C11), 23.0 (C20 and
C21), 23.5 (C22), 25.8 (C13), 30.2 (C12), 33.2 (C16), 37.2 (C18
and C19), 41.2 (C14), 46.8 (C10), 54.8 (C1), 73.2 (C17), 91.7, 95.9,
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Synthesis 2011, No. 23, 3866–3870 © Thieme Stuttgart · New York