Nucleophilic substitution reactions of 1,4-naphthoquinone and biologic properties of novel S-, S,S-, N-, and N,S-substituted 1,4-naphthoquinone derivatives

Article abstract of DOI:10.1007/s00044-013-0806-y

A novel series of S-, S,S-, N- and N,S-substituted 1,4-naphthoquinone derivatives were synthesized and evaluated for their antibacterial and antifungal activity. Among the synthesized compounds especially 10a and 11b have been discovered as an antibacterial or antifungal agents, and 15f is the most effective compound against M. luteum as potent antifungal. The structures of the novel products were characterized by micro analysis, UV/Vis, ¹H NMR, ¹³C NMR, and MS. The electrochemical properties of some of the novel 1,4-naphthoquinone derivatives were also investigated by cyclic voltammetry. Springer Science+Business Media 2013.

Full text of DOI:10.1007/s00044-013-0806-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:2140–2149
DOI 10.1007/s00044-013-0806-y
ORIGINAL RESEARCH
Nucleophilic substitution reactions of 1,4-naphthoquinone
and biologic properties of novel S-, S,S-, N-, and N,S-substituted
1,4-naphthoquinone derivatives
•
Cemil Ibis Amac Fatih Tuyun Hakan Bahar Sibel Sahinler Ayla
•
•
•
•
•
•
Maryna V. Stasevych Rostyslav Ya. Musyanovych Olena Komarovska-Porokhnyavets
Volodymyr Novikov
Received: 26 December 2012 / Accepted: 24 September 2013 / Published online: 10 October 2013
Ó Springer Science+Business Media New York 2013
Abstract A novel series of S-, S,S-, N- and N,S-substi-
tuted 1,4-naphthoquinone derivatives were synthesized and
evaluated for their antibacterial and antifungal activity.
Among the synthesized compounds especially 10a and 11b
have been discovered as an antibacterial or antifungal
agents, and 15f is the most effective compound against M.
luteum as potent antifungal. The structures of the novel
products were characterized by micro analysis, UV/Vis, 1H
NMR, 13C NMR, and MS. The electrochemical properties
of some of the novel 1,4-naphthoquinone derivatives were
also investigated by cyclic voltammetry.
naphthoquinone have also many biological responses such
as anti-inflammatory, antiallergic, antipruritic, and anti-
cancer activities (Huang et al., 1998; Verma, 2006;
Ngampong et al., 2003). The quinone structure undergoes
redox cycling to generate reactive oxygen species that can
destroy the tumor cells (Huang et al., 2000). Because of
this important feature the electrochemistry of quinonoid
structures have also been widely studied as an example of a
simple two-step cathodic reduction (Guin et al., 2011; Kim
et al., 2001; Pedersen et al., 1998).
In continuation of our previous work for the synthesis of
biologically active quinones, we carried out the reactions
of 2,3-dichloro-1,4-naphthoquinone 1 with sulfur or amine
nucleophiles as biologic active agents and characterization
of them with spectral methods.
Keywords 1,4-Naphthoquinone ꢀ Amines ꢀ Thiols ꢀ
Antibacterial activity ꢀ Antifungal activity
Introduction
Result and discussion
Quinone structure is widespread in nature and synthetic
compounds (Lien et al., 2002; Ibis et al., 2011; Oku et al.,
2002; Ibis et al., 2013a). 1,4-Naphthoquinone is an
important example of quinonoid structure and used from
pharmaceuticals to dyes. The derivatives of 1,4-
The novel 2,3-di(thio)substituted compounds 3a–d were
obtained by the reaction of 2,3-dichloro-1,4-naphthoqui-
none 1 and thiol compounds 2a–d in ethanol with sodium
carbonate. In the mass spectrum of the compounds 3a and
3b, the molecular ion peaks were observed at m/z (%) 485
(100) [M?Na]? and 513 [M?H]?, respectively. The car-
bon atom signals of carbonyl groups of compound 3c were
observed at 182.31 ppm as one peak only. The IR spectrum
of compound 3d showed characteristic carbonyl group’s
band at 1,665 cm-1 (Scheme 1).
C. Ibis (&) ꢀ H. Bahar ꢀ S. S. Ayla
Department of Chemistry, Engineering Faculty, Istanbul
University, Istanbul, Turkey
e-mail: ibiscml@istanbul.edu.tr
A. F. Tuyun
Department of Chemical Engineering, Engineering &
Architecture Faculty, Beykent University, Istanbul, Turkey
The novel compounds 7, 8 and known compound 6 (Ibis
and Sahinler Ayla, 2011) were synthesized by the reaction
of 2,3-dichloro-1,4-naphthoquinone 1 and the mixture of
thiol compounds 4 and 5 in dimethylformamide with
sodium carbonate. The compound 6 was synthesized before
by our group (Ibis and Sahinler Ayla, 2011). In the IR
M. V. Stasevych ꢀ R. Ya. Musyanovych ꢀ
O. Komarovska-Porokhnyavets ꢀ V. Novikov
Department of Technology of Biologically Active Substances,
Pharmacy and Biotechnology, National University
‘‘Lviv Polytechnic’’, Lviv, Ukraine
123

Med Chem Res (2014) 23:2140–2149
2141
R1
2, 3, 12
a
O
O
O
O
H3CO
CH3
CH3
S
S
O
O
Cl
6
OH
O
b
O
O
O
S
CH3
S
O
Cl
H3CS
S
CH3
Cl
c
d
O
O
O
HO
SH
8
7
H3C
O
4
DMF
Na2CO3
CH3
H3C
O
SH
O
H3C
O
5
O
O
R1SH
2
SR1
SR1
Cl
Cl
e
f
H3C
O
EtOH
Na2CO3
O
O
O
H3C
1
O
3
EtOH
Na2CO3
NucH
9
Nuc
9, 10, 11
a
O
O
Nuc
Cl
Nuc
OCH2CH3
HO
N
N
O
O
b
10
11
N
N
CH3
O
O
R1SH
2
O
N
N
N
O2N
c
d
10d
SR1
CH2Cl2
Na2CO3
O
O
N
12
O
Scheme 1 Synthesis of novel naphthoquinone derivatives
spectra of compounds 7 and 8, the quinone carbonyl
group’s band was observed at 1,670 and 1,664 cm-1, while
the ester carbonyl group’s band was observed at 1,732 and
1,720 cm-1, respectively.
ethanol solution of sodium carbonate. The molecular ion
peak of compounds 10c was identified at m/z 397 [M]? in
the positive ion mode for ESI technique.
The ethoxy-amino-substituted compound 11b was
obtained by the reaction of 2,3-dichloro-1,4-naphthoquinone
1 and compound 9b in ethanol with sodium carbonate. In the
1H NMR spectrum of compound 11b, protons of methylene
group (–O–CH2–) were observed as a multiplet at 4.28 ppm.
The compound 10d was synthesized before by our
group (Ibis et al., 2013a). The monoaminosubstituted
compound 10d (Ibis et al., 2013a) was treated with
The N-substituted compound 10a was obtained by the
reaction of 2,3-dichloro-1,4-naphthoquinone 1 and com-
pound 9a in ethanol solution of sodium carbonate. The IR
spectrum the compound 10a showed broad band at
3,256 cm-1 for the OH stretching. The N-substituted
compound 10c was synthesized from the reaction of 2,3-
dichloro-1,4-naphthoquinone 1 and compound 9c in
123

2142
Med Chem Res (2014) 23:2140–2149
aliphatic thiols, and the N,S-substituted compounds 12e
and 12f were obtained. The molecular ion peak of com-
pounds 12e and 12f was identified at m/z (%) 441 (100)
[M?Na]? and 460 [M?H]? in the positive ion mode for
ESI technique, respectively (Scheme 2).
Committee for Clinical Laboratory Standard, 1998) with a
view to developing therapeutic agents having broad spec-
trum in antifungal activity. Antibacterial activity of syn-
thesized compounds was elucidated against Escherichia
coli B-906, Staphylococcus aureus 209-P, and Mycobac-
terium luteum B-917 by the diffusion method and serial
dilution method as shown in Tables 1 and 2. Their activi-
ties were compared with those of the known antibacterial
agent vancomycin and the antifungal agent nystatin.
Afterward, we have further synthesized and screened
compounds of 10a and 10c antibacterial activity by the
diffusion method as shown Table 1 on the basis of struc-
ture–activity relationship of antifungal activity of the
(hetero) cyclic quinone derivatives.
The N,S-substituted compounds 15a–g were synthesized by
the reactions of 2-chloro-3-((perchlorophenyl)thio)naphtha-
lene-1,4-dione 13 (Ibis et al., 2013b) and amine compounds
14a–g in dichloromethane solution of sodium carbonate. The
target compounds were designed regarding the related nucle-
ophile compound’s biologic activity properties such as mor-
pholine, thiomorpholine, methylor butyl esters, andpiperazine.
(Levin et al., 2006; Milczarska et al., 2005; Olma et al., 2012;
Ojima et al., 1997). It is also known that the sulfur or nitrogen
containing naphthoquinone derivatives show important activ-
ity properties (Perez-Sacau et al., 2007, Corral et al., 2006).
The molecular ion peak of compounds 15a and 15b was
identified at m/z (%) 524 (100) [M]? and 540 [M]? in the
positive ion mode for ESI technique, respectively. In the
1H NMR spectrum of compounds 15c and 15d, protons of
piperidine and pyrrolidine were observed as a multiplet at
3.99 and 3.60 ppm. In the 13C NMR spectrum of com-
pound 15e, the carbon atoms of the carbonyl groups were
gave signals at 180.48, 178.91 ppm. In the IR spectra of
compounds 15f and 15g, the quinone carbonyl group’s
band was observed at 1,662 and 1,654 cm-1, while the
ester carbonyl group’s band was observed at 1,736 and
1,666 cm-1, respectively.
The test-culture E. coli appeared not to be sensitive to
any compounds except that 10a. The S. aureus was
moderately sensitive to compound 10a by the diffusion
method, whereas compound 3c is nearly sensitive. The M.
luteum strain was sensitive to compounds 3c, 10a, and 15f
at a concentration of 0.5 % (diameter of the inhibition
zone was 11.0, 28.7, and 10.7 mm, respectively). Com-
parison of antibacterial activity with antibacterial drug
vancomycin (at 0.1 % concentration) showed that 3c (at
0.1 % concentration), 10a (at 0.5 % concentration), and
15f (at 0.5 % concentration) had good activity against M.
luteum.
The test-cultures C. tenuis and A. niger appeared not to
be sensitive to 15a–g except that 15g for A. niger. Anti-
fungal activity against C. tenuis was observed for 10c and
11b at concentration of 0.5 % (d = 15.7 and 20.0 mm,
respectively). C. tenuis was sensitive to compounds 3a, 3b,
and 3d at a concentration of 0.5 % (diameter of the inhi-
bition zone was 11.7, 7.0, and 7.4 mm, respectively).
Compounds 3b, 8, and 10a have no antifungal activity
against A. niger at 0.5 and 0.1 % evaluated concentrations
Biological study
The novel naphthoquinone derivatives were evaluated for
their antifungal activity against fungi Candida tenuis VKM
Y-70 and Aspergillus niger F-1119 by the diffusion method
(Murray et al., 1995) and serial dilution method (National
Cl
Cl
Cl
Cl
Cl
Cl
NucH
O
O
Cl
Cl
14
S
S
Cl
Cl
CH2Cl2
Na2CO3
Cl
Nuc
O
O
13
15
a
14, 15
d
e
f
g
b
c
S
S
CH3
O
O
CH3
Nuc
N
N
F
N
O
N
N
S
N
O
O
Scheme 2 Novel N,S- and S,S- substituted naphthoquinone compounds
123

Med Chem Res (2014) 23:2140–2149
2143
Table 1 Antibacterial and antifungal activities of compounds by
diffusion method
Table 2 Antibacterial and antifungal activities of compounds by
serial dilution method
Compounds Concentration Inhibition diameter of microorganism
(%)
Compounds Antibacterial activity
Antifungal activity
growth (mm)
MIC (lg/mL)
MIC (lg/mL)
Antibacterial activity
Antifungal
activity
E. coli S. aureus M. luteum C. tenuis A. niger
3a
?
?
?
62.5
500.0
?
250.0
?
E. coli S.
M.
aureus luteum tenuis niger
C.
A.
3b
?
?
?
3c
?
250.0
?
125.0
500.0
?
500.0
500.0
?
3a
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.1
0
0
0
0
7.0
0
11.7
7.4
7.0
0
7.4
0
3d
?
?
6
?
?
?
3b
0
0
0
0
8
?
?
?
?
?
0
0
0
0
10a
10c
11b
12e
12f
15a
15b
15c
15d
15e
15f
15g
500.0
?
62.5
?
31.2
?
125.0
31.2
62.5
?
125.0
31.2
31.2
500.0
62.5
?
3c
0
8.7
0
11.0
8.7
0
0
6.0
0
0
0
?
62.5
?
125.0
250.0
125.0
?
3d
0
0
7.4
0
6.0
0
?
0
0
0
?
?
?
6
0
0
0
0
6.0
0
?
?
?
0
0
0
0
?
?
?
125.0
?
?
8
0
0
6.0
0
0
0
?
?
?
?
0
0
0
0
?
?
?
?
?
10a
10c
11b
12e
12f
15a
15b
15c
15d
15e
15f
15g
8.0
6.0
0
20.7
11.4
0
28.7
16.0
0
0
0
?
?
125.0
15.6
125.0
?
?
0
0
?
250.0
?
62.5
?
?
15.7 13.7
8.5
20.0 19.0
?
?
0
0
0
0
?: Growth of microorganisms
0
0
7.4
0
0
0
12.4
0
8.0
8.4
0
0
0
12.6
0
by the diffusion method. Compounds 10c, 12e and 12f
were found to exhibit low antifungal activity against A.
niger on comparison with antifungal drug nystatin evalu-
ated by diffusion method. Compound 11b has good anti-
fungal activity against A. niger at 0.5 % concentration by
the diffusion method.
0
0
0
0
0
0
0
9.0
7.0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
The biological results of the compounds were classified
as follows: The antibacterial activity was considered as
significant when the MIC was 100 lg/mL or less; moder-
ate, when the MIC was 100–500 lg/mL; weak, when the
MIC was 500–1,000 lg/mL; and inactive, when the MIC
was above 1,000 lg/mL. Evaluation of the antibacterial
activity of synthesized compounds showed that 10a has
MIC (minimum inhibition concentration) 31.2 lg/mL
for M. luteum, but 15f was the most potent with
MIC = 15.6 lg/mL for M. luteum (Table 2).
Notable activity for 10c was observed against C. tenuis
fungi at 31.2 lg/mL concentration. Evaluations of anti-
fungal activity of compounds 3a, 11b, and 15f showed
MIC = 62.5 lg/mL against test-culture C. tenuis. MIC of
10a and 15b was observed at 125.0 lg/mL against test-
culture C. tenuis (Table 2). Notable activity for 10c and
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
10.7
6.0
0
0
0
0
0
0
0
0
0
0
6.0
0
0
0
0
0
Ca
14.0
15.0
18.0
19.0 20.0
a
Vancomycin was used as a control in the tests of antibacterial
activity, and nystatin was used in the tests of antifungal activity of the
synthesized compounds
123

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Med Chem Res (2014) 23:2140–2149
11b was observed against A. niger fungi at 31.2 lg/mL
concentrations. Evaluations of antifungal activity of com-
pounds 12f showed MIC = 62.5 lg/mL against test-cul-
ture A. niger. MIC of 10a and 3a was observed at 125.0 and
250.0 lg/mL against test-culture A. niger, respectively.
In conclusion, compounds especially 10a and 11b have
been discovered as an antibacterial or antifungal agents.
Synthesized compounds have been employed to prepare
new antifungal agents with low MICs against S. aureus, M.
luteum bacteria, and C. tenuis and A. niger fungi in com-
parison with controls. The some compounds (3a–b, 6, 8,
and 15a–d) did not show any significant antifungal and
antibacterial activity against fungi and bacteria species.
Among the tested compounds, 15f, 10c, and 11b are the
most effective compounds against C. tenuis as potent
antifungal. 15f is the most effective compound against M.
luteum as potent antifungal.
Table 3 Half-wave potentials (for the 1st wave) and electrochemical
data for some of the novel naphthoquinone derivatives (10-3 M) in
DMF/TBAP 0.1 M, t = 100 mV s-1
Compound Ep (Ic) (V) Ep (IIc) (V) DEap1 (mV) E1b,1/2 (V)
1
-0.246
-0.356
-0.145
-0.499
-0.460
-0.421
-0.398
-0.599
-0.390
-0.433
-1.052
-0.937
-0.786
-1.154
-1.154
-0.765
–
211
76
75
82
72
–
-0.1405
8
-0.318
3b
10a
10c
15a
15b
15c
15e
15f
a
-0.107
-0.458
-0.424
–
–
–
–
–
–
-1.074
–
–
–
–
–
DEp1 = Epa1 - Epc1
b
E1,1/2 = (Epa1 ? Epc1)/2
Electrochemical study
galvanostat. A glassy carbon disk was used as a working
electrode. The surface of the working electrode was polished
with alumina before each run. A platinum wire served as the
counter electrode. The reference electrode was an Ag/AgCl
electrode. Electrochemical grade tetrabutylammonium per-
chlorate (TBAP) in extra pure DMF was employed as the
supporting electrolyte at a concentration of 0.10 M. Prior to
each run, solutions were purged with nitrogen. Measurements
were taken over a potential range between 1 and -2 V with a
Some of the novel naphthoquinone derivatives were stud-
ied by cyclic voltammetry in aprotic media (DMF) using
tetrabutylammonium perchlorate (0.10 M) as supporting
electrolyte at 100 mV s-1 on glassy carbon electrode. The
electrochemical parameters, including cathodic peak
potentials (Epc1 and Epc2), the half-wave peak potentials
(E1,1/2), and the difference between the first oxidation and
reduction processes (DEp), are given at Table 3.
The cyclic voltammogram of compound 10c showed in
Fig. 1. The first and second peaks in Fig. 1 correspond to
semiquinone (Q/Q-) and dianion (Q-/Q2-) pairs, respec-
tively (Fig. 1).
step rate of 0.1 V s-1
.
Products were isolated by column chromatography on
silica gel (Fluka silica gel 60, particle size 63–200 lm).
Thin-layer chromatography (TLC) was performed on
Merck silica gel plates (60F254), and detection was
carried out with ultraviolet light (254 nm). All chemi-
cals were reagent grade and used without further
purification.
Experimental
General methods
General procedures
Melting points were measured using a Buchi B-540 melt-
ing point apparatus and are uncorrected. Elemental analy-
ses were performed on a Thermo Finnigan Flash EA 1112
elemental analyzer. Infrared (IR) spectra were recorded in
KBr pellets in Nujol mulls on a Perkin Elmer Precisely
Spectrum One FTIR spectrometer. UV spectra were
recorded in CHCl3 on the UV–Vis spectrophotometer TU-
1901. 1H NMR (500 MHz) and 13C NMR (125 MHz)
spectra were recorded in CDCl3 on a Varian Unity INOVA
spectrometer. Mass spectra were obtained on a Thermo
Finnigan LCQ Advantage MAX LC/MS/MS spectrometer
using ESI technique.
General procedure 1: synthesis of disulfanyl derivatives
of 1,4-naphthoquinones
Potassium carbonate (1.52 g) was dissolved in ethanol
(65 mL). 2,3-Dichloro-1,4-naphthoquinone (1) and thiol
(2) were added to the solution, respectively. Without
heating, the mixture was stirred for 6–8 h. The color of
the solution changed quickly, and the extent of the
reaction was monitored by TLC. After the reaction
mixture was filtered, filtrate was extracted in a Soxhlet
extractor with dichloromethane. After recovery of the
solvent, the crude product was purified by column
chromatography.
Cyclic voltammetry measurements were performed in a
conventional three-electrode cell using a computer controlled
system of a Gamry Reference 600 Model potentiostat/
123

Med Chem Res (2014) 23:2140–2149
2145
Fig. 1 Cyclic voltammogram
of compound 10c in
DMF ? 0.1 M TBAP on glassy
carbon electrode at 0.1 V s-1
kmax (nm) (loge): 280 (5.08), 477 (3.92). 1H NMR
(499.74 MHz, CDCl3): d 2.42–2.72 (m, 6H, –S–CH3),
7.13–7.18 (dd, 8H, Harom), 7.78–7.81 (m, 4H, Harom), 7.93–
7.95 (m, 2H, Harom). 13C NMR (125.66 MHz, CDCl3): d
15.20 (–CH3), 127.30, 127.37, 127.70 129.81, 132.51, 139.46
(Carom, CHarom), 182.31 (C=O). MS [? ESI]: m/z 466 [M]?.
Anal. Calcd. for C24H18O2S4 (M, 466.66): C, 61.77; H, 3.89;
S, 27.48 %. Found: C, 61.65; H, 3.75; S, 28.11 %.
2,3-Bis((4-methoxybenzyl)thio)naphthalene-1,4-dione (3a)
was synthesized by the reaction of 1 (1 g, 4.38 mmol) and
2a (0.68 g, 4.38 mmol) by using general procedure
1
Orange solid. M.p.: 194–195 °C. Yield: 0.65 g
(38.69 %). Rf : 0.9 with CHCl3 as an eluent. IR (KBr, cm-1):
t 2,925(C–H), 1,655(C=O), 1,592 (C=C). UV–Vis (CHCl3)
1
kmax (nm) (loge): 252 (4.84), 276 (4.93), 443 (3.88). H
NMR (499.74 MHz, CDCl3): d 3.38 (s, 6H, O–CH3),
4.39(s, 4H, –S–CH2), 6.79 (d, 4H, Harom), 7.15(d, 4H,
H
arom). 7.78–7.84(m, 2H, Harom) 7.90–7.99(m, 2H, Harom).
2,3-Bis((2-(4-methyl-2-oxocyclohexyl)propan-2-yl)thio)
13C NMR (125.66 MHz, CDCl3): d 40.23 (–S–CH3), 55.26
(O–CH3), 158.66, 147.16, 134.05, 132.66, 130.43, 126.64,
114.10 (Carom, CHarom), 178.77 (C=O). MS [?ESI]: m/z
485 [M?Na]?. Anal. Calcd. for C26H22O4S2 (M, 462.58):
C, 67.51; H, 4.79; S, 13.86 %. Found: C, 67.15; H, 4.20; S,
14.30 %.
naphthalene-1,4-dione (3d) was synthesized by the
reaction of
1 (1 g, 4.38 mmol) and 2d (0.82 g,
4.38 mmol) by using general procedure 1 Red solid. M.
p.: 114–114.6 °C. Yield: 0.76 g (42 %). Rf: 0.6 with
CHCl3 as an eluent. IR (KBr, cm-1): t 2,925(C–H),
1,665(C=O), 1,589 (C=C). UV–Vis (CHCl3) kmax (nm)
(loge): 262 (5.06); 1H NMR (499.74 MHz, CDCl3): d
1.17–1.25 (m, 6H, CH-CH3), 1.73 (s, 12H, C-CH3),
1.87–2.37(m, 16H, –CH–CH2), 7.43–8.16 (m, 4H, Harom).
13C NMR (125.66 MHz, CDCl3): d 26.93, 28.09, 33.38,
36.31, 37.65 (–CH2), 55.74, 63.76 (O=C–CH2), 120.96,
128.59, 130.43, 131.85, 132.84, 136.66, 137.00, 146.03
(Carom, CHarom), 182.86, 207.99 (C=O). MS [-ESI]: m/z
526 [M-H]-. Anal. Calcd. for C30H38O4S2 (M, 526.75):
C, 68.40; H, 7.27; S, 12.17 %. Found: C, 68.66; H, 7.57;
S, 12.70 %.
2,3-Bis((2,5-dichlorophenyl)thio)naphthalene-1,4-dione (3b)
was synthesized by the reaction of 1 (1 g, 4.38 mmol) and 2b
(0.79 g, 4.38 mmol) by using general procedure 1 Orange
solid. M.p.: 88–89 °C. Yield: 0.72 g (40.26 %). Rf: 0.85
with CHCl3 as an eluent. IR (KBr, cm-1): t 2,919(C–H),
1,661(C=O), 1,593 (C=C). UV–Vis (CHCl3) kmax (nm)
(loge): 260 (4.87), 438 (3.99); 1H NMR (499.74 MHz,
CDCl3): d 7.14–7.18 (dd, 4H, Harom), 7.26 (s, 2H Harom),
7.64–7.68 (m, 2H, Harom), 7.94–7.96 (m, 2H, Harom). 13C
NMR (125.66 MHz, CDCl3): d 145.64, 133.14, 132.78,
132.06, 131.28, 131.13, 129.93, 128.37, 126.46 (Carom
,
General procedure 2: for the reactions of mixture of two
thiols with 1,4-naphthoquinones
CHarom), 176.79 (C=O). MS [?ESI]: m/z 513 [M?H]?.
Anal. Calcd. for C22H10O2S2Cl4 (M, 512.26): C, 51.58; H,
1.97; S, 12.52 %. Found: C, 51.28; H, 1.55; S, 13.50 %.
2,3-Dichloro-1,4-naphthoquinone was dissolved in DMF as
reaction media (50 mL). Subsequently, the mixture of two
thiols (4 and 5) and Na2CO3 (1.52 g) were added to the
solution, respectively. Without heating, the mixture was
stirred for 4–6 h. The color of the solution changed
quickly, and the extent of the reaction was monitored by
TLC. The reaction mixture was extracted in a Soxhlet
extractor with dichloromethane. After recovery of the
2,3-Bis((4-(methylthio)phenyl)thio)naphthalene-1,4-dione
(3c) was synthesized by the reaction of 1 (1 g, 4.38 mmol)
and 2c (0.69 g, 4.38 mmol) by using general procedure
1
Red solid. M.p.: 80–81 °C. Yield: 0.54 g (31.99 %).
Rf: 0.75 with CHCl3 as an eluent. IR (KBr, cm-1): t
2,921(C–H), 1,662(C=O), 1,590 (C=C). UV–Vis (CHCl3)
123

2146
Med Chem Res (2014) 23:2140–2149
solvent, the crude product was purified by column
chromatography.
(1) amine (9) was added to the solution, respectively.
Without heating, the mixture was stirred for 4–6 h. The
color of the solution changed quickly, and the extent of the
reaction was monitored by TLC. The reaction mixture was
extracted in a Soxhlet extractor with dichloromethane.
After recovery of the solvent, the crude product was puri-
fied by column chromatography.
Dibutyl 3,30-((1,4-dioxo-1,4-dihydronaphthalene-2,3-diyl)bis
(sulfanediyl))dipropanoate (6) (Ibis and Sahinler Ayla, 2011),
butyl 3-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)thio)
propanoate (7), and butyl 3-((3-((4-hydroxyphenyl)thio)-1,4-
dioxo-1,4-dihydronaphthalen-2-yl)thio)propanoate (8) were
synthesized by the reaction of 1 (2 g, 8.76 mmol) and the
mixture of 4 (0.35 g, 2.19 mmol)and 5 (1.43 g, 8.76 mmol) by
using general procedure 2 6 (Ibis and Sahinler Ayla, 2011):
Red oil; Yield 0.25 g (6 %); Rf: 0.24 with CHCl3 as an
eluent; IR (KBr, cm-1): 2,959, 2,933, 2,873 (C–H), 1,659
(quinone C=O), 1,734 (ester C=O), 1,591 (C=C); MS
(?ESI): m/z 479 (M ? H)?; C24H30O6S2 (M, 478.62).
Calcd. C, 60.23; H, 6.32; S, 13.40. Found C, 60.12; H, 6.15;
S, 12.90 %.
2-Chloro-3-(4-(2-hydroxyethyl)piperazin-1-yl)naphthalene-
1,4-dione (10a) was synthesized by the reaction of 1 (1 g,
4.38 mmol) and 9a (0.566 g, 4.38 mmol) by using general
procedure 3 Orange solid. M.p.: 225.2–225.8 °C. Yield:
0.51 g (32.6 %). Rf: 0.8 with CHCl3 as an eluent. IR (KBr,
cm-1): t 3,256 (O–H), 2,924 (C–Harom), 1,676 (C=O),
1,553 (C=C), 1,445 (C–N). UV–Vis (CHCl3) kmax (nm)
(loge): 249 (4.49), 275 (4.45), 478 (3.64). 1H NMR
(499.74 MHz, CDCl3): d 1.2 (s, 1H, O–H), 2.48–2.69 (m,
10H, –N–CH2), 3.56–3.57(m, 2H, –CH2), 7.78–7.80 (m,
2H, Hquinone). 7.91–7.94 (m, 2H, Hquinone). 13C NMR
(125.66 MHz, CDCl3): d 51.16, 54.30, 58.58, 60.55 (–CH2),
121.56, 126.41, 131.61, 132.07 (Carom, CHarom), 150.92
(=C–N), 177.82, 181.72 (C=O). MS [?ESI]: m/z 321
[M?H]?. Anal. Calcd. for C16H17ClO3N2 (M, 320.77): C,
59.91; H, 5.34; N, 8.73 %. Found: C, 59.65; H, 5.67; N,
8.49 %.
7: Red oil; Yield 0.20 g (7 %); Rf: 0.4 with CHCl3 as an
eluent. IR (KBr, cm-1): 2,959, 2,932, 2872 (C–H), 1670
(quinone, C=O), 1,732 (ester C=O); UV–Vis (CHCl3) kmax
(nm) (loge): 263 (4.94), 431 (l4.02). 1H NMR (499.74 MHz,
CDCl3):d 0.85(m, 3H, –CH3), 1.18–1.56 (m, 4H, –CH2), 3.55
(t, J = 7.3 Hz, 2H, –SCH2), 4.03 (t, J = 6.8 Hz, 2H,
–OCH2), 2.69(t, J = 6.8 Hz, 2H, –C=O–CH2), 8.01–8.09(m,
2H, CHnapht), 7.68 (m, 2H, CHnapht). 13C NMR (125.66 MHz,
CDCl3): d 12.67 (–CH3); 29.58, 28.69, 18.10 (–CH2); 63.87
(–OCH2); 34.54 (–SCH2); 126.27, 131.56, 132.93 (CHnapht
,
2-Chloro-3-(4-(4-nitrophenyl)piperazin-1-yl)naphthalene-
1,4-dione (10c) was synthesized by the reaction of 1 (1 g,
4.38 mmol) and 9c (0.91 g, 4.38 mmol) by using general
procedure 3 Brown solid. M.p.: 219–220 °C. Yield:
1.20 g (69 %). Rf : 0.68 with CHCl3 as an eluent IR (KBr):
t (cm-1) 3,110, 3,059 (C–Harom), 2,920, 2,844 (C–Haliph),
1,589, 1,557 (C=C), 1,678, 1,631 (C=O). UV–Vis (CHCl3)
Cnapht), 147.25 (–C–S), 174.04 (–C–Cl), 170.30 (–O–C=O),
178.76 (quinone C=O). MS (-ESI): m/z 352 [M]-. Anal.
Calcd. for C17H17ClO4S (M, 352.83): C, 57.87; H, 4.86; S,
9.09 %. Found: C, 57.80; H, 4.45; S, 10.05 %.
8: Red solid; M.p.: 114–115 °C; Yield 0.40 g (11 %); Rf:
0.10 with CHCl3 as an eluent. IR (KBr, cm-1): 3,404 (–OH),
2,956, 2,931, 2,873 (C–H), 1,664 (quinone C=O), 1,720
(ester C=O); UV–Vis (CHCl3) kmax (nm) (loge): 256 (4.48),
443 (3.59). 1H NMR (499.74 MHz, CDCl3): d 0.83 (m, 3H,
–CH3), 1.18–1.57 (m, 4H, –CH2), 3.44 (t, J = 7.3 Hz, 2H,
–SCH2), 4.01 (t, J = 6.8 Hz, 2H, –OCH2), 2.65 (t,
J = 7.3 Hz, 2H, –C=O–CH2), 5.72 (s, 1H, –OH), 6.67–7.99
(m, 8H, CHnapht, CHarom). 13C NMR (125.66 MHz, CDCl3):
12.68 (–CH3); 28.96, 18.10 (–CH2); 63.95 (–OCH2); 34.53
(–SCH2); 115.29, 115.31, 122.75, 126.02, 126.06, 131.74,
1
kmax (nm) (loge): 284 (4.39), 394 (4.39), 485 (3.51). H
NMR (499.74 MHz, CDCl3): d 3.55 (t, 4H, J = 4.88,
N–CH2), 3.71 (t, 4H, J = 5.86, N–CH2–), 6.75–6.85 (m,
4H, CHarom), 7.59–7.69 (m, 2H, CHarom), 8.06–8.15 (m,
2H, CHarom). 13C NMR (125.66 MHz, CDCl3): d 49.59,
47.10 (N–CH2–), 152.99, 133.01, 131.20, 129.99, 130.54,
126.84, 124.96, 112.19 (Carom), 111.38 (=C–Cl), 153.74 (=
C–S), 180.80, 177.00 (C=O). MS [ESI]: m/z 397 [M]?.
Anal. Calcd. for C20H16ClN3O4 (M, 397.812): C, 60.38; H,
4.05; N, 10.56 %. Found: C, 60.75; H, 4.39; N, 10.12 %.
131.94, 132.56, 132.77, 132.82, 132.88 (CHnapht, Cnapht
,
CHarom, Carom), 147.90 (–C–S), 170.73 (–O–C=O), 178.63,
177.30 (quinone C=O). MS (?ESI): m/z 442 (M)?;
C23H22O5S2 (M, 442.55). Hesaplanan C, 62.42; H, 5.01; S,
14.49. Bulunan C, 62.22; H, 5.10; S, 13.60 %.
2-Ethoxy-3-(ethyl(pyridin-4-ylmethyl)amino)naphthalene-
1,4-dione (11b) was synthesized by the reaction of 1 (1 g,
4.38 mmol) and 9b (0.60 g, 4.38 mmol) by using general
procedure 3. Red solid. M.p.: 128–129 °C. Yield: 0.45 g
(28.12 %). Rf: 0.85 with CHCl3 as an eluent. IR (KBr,
cm-1): t 2,925(C–Harom), 1,680(C=O), 1,603 (N–H), 1,575
(C=C UV–Vis (CHCl3) kmax (nm) (loge): 244 (4.85), 276
(5.13), 471 (4.18). 1H NMR (499.74 MHz, CDCl3): d
1.18–1.21 (m, 6H, –CH3), 3.29(s 2H, N–CH2–CH), 3.73–3.76
General procedure 3: for amination of 1,4-
naphthoquinones
Sodium carbonate (1.52 g) was dissolved in ethanol as
reaction media (50 mL). 2,3-Dichloro-1,4-naphthoquinone
123

Med Chem Res (2014) 23:2140–2149
2147
(m, 2H, N–CH2–CH3), 4.27–4.28 (q, 2H, O–CH2),
7.39–7.41 (d, 2H, Harom) 7.70–7.82 (m, 4H, Harom) 7.95–
7.96 (d, 2H, Harom).13C NMR (125.66 MHz, CDCl3): d 17.21,
16.21 (–CH3), 39.61, 38.79, 69.80 (–CH2), 148.04, 135.59,
3,064 (C–Harom), 2,961, 2,924, 2,853 (C–Haliph), 1,591,
1,557 (C=C), 1,729, 1,667 (C=O). UV–Vis (CHCl3) kmax
1
(nm) (loge): 250 (4.06), 300 (4.01), 517 (3.26). H NMR
(499.74 MHz, CDCl3): d = 0.84 (t, 3H, J = 7.32, CH3),
1.26 (m, 2H, O–CH2–CH2), 1.54 (m, 2H, CH2–CH3), 1.85
(t, 4H, J = 5.86, CH2piper), 2.51 (t, 2H, J = 7.32, (C=O)–
CH2–), 3.06 (t, 2H, J = 7.32, S–CH2), 3.55 (t, 4H, J =
5.86, CH2piper), 3.94 (s, 4H, O–CH2–CH2–O), 3.96 (t, 2H,
J = 6.83, O–CH2), 7.55–7.62 (m, 2H, CHarom), 7.92–7.94
(dd, 1H, CHarom), 7.99–8.00 (dd, 1H, CHarom). 13C NMR
(125.66 MHz, CDCl3): d 12.67 (CH3), 18.10, 28.41 (CH2),
28.70 ((C=O)–CH2–), 34.00 (S–CH2), 34.98, 49.80, 125.64
(CH2piper), 63.66 (O–CH2), 64.64 (O–CH2–CH2–O), 132.67,
131.88, 125.31, 123.03 (Carom), 105.83 (=C–S), 154.16
(=C–N), 180.81, 180.76, 170.70 (C=O). MS [ESI]: m/z 460
[M?H]?. Anal. Calcd. for C24H29NO6S (M, 459.555): C,
62.73; H, 6.36; N, 3.05; S, 6.98 %. Found: C, 62.55; H,
5.92; N, 2.84; S, 6.18 %.
134.63, 133.28, 132.80, 131.28, 127.18, 126.49 (Carom
,
CHarom), 180.92 (C=O). MS [?ESI]: m/z 339 [M?2H]?.
Anal. Calcd. for C20H20O3N2 (M, 336.38): C, 71.41; H, 5.99;
N, 8.33 %. Found: C, 71.15; H, 5.47; N, 7.84 %.
General procedure 4: for the synthesis of sulfanyl
derivatives of 2-amino-1,4-naphthoquinones
Potassium carbonate (1.52 g) was dissolved in dichloro-
methane as reaction media (50 mL). 2-Chloro-3-(1,4-di-
oxa-8-azaspiro[4.5]decan-8-yl)naphthalene-1,4-dione (10d)
(Ibis et al., 2013a) and thiol (2) were added to the solution,
respectively. Without heating, the mixture was stirred for
6–8 h. The color of the solution changed quickly, and the
extent of the reaction was monitored by TLC. After the
reaction mixture was filtered, filtrate was extracted in a
Soxhlet extractor with dichloromethane. After recovery of
the solvent, the crude product was purified by column
chromatography.
General procedure 5: for the reactions of 2-sulfanyl-1,4-
naphthoquinones with nucleophiles
Potassium carbonate (1.52 g) was dissolved in dichloro-
methane as reaction media (50 mL). 2-Sulfanyl-3-chloro-
1,4-naphthoquinone (13) (Ibis et al., 2013b) and nucleo-
phile (14) were added to the solution, respectively.
Without heating, the mixture was stirred for 6–8 h. The
color of the solution changed quickly, and the extent of
the reaction was monitored by TLC. After the reaction
mixture was filtered, filtrate was extracted in a Soxhlet
extractor with dichloromethane. After recovery of the
solvent, the crude product was purified by column
chromatography.
Methyl 3-((1,4-dioxo-3-(1,4-dioxa-8-azaspiro[4.5]decan-8-
yl)-1,4-dihydronaphthalen-2-yl)thio)propanoate (12e) was
synthesized by the reaction of 10d (Ibis et al., 2013a)
(0.26 g, 0.78 mmol) and 2e (0.09 mL, 0.86 mmol) by using
general procedure 4 Dark red oil. Yield: 0.28 g (85 %).
Rf : 0.18 with CHCl3 as an eluent. IR (KBr): t (cm-1
)
3,057 (C–Harom), 2,962, 2,826 (C–Haliph), 1,591, 1,538 (C=
C), 1,737, 1,667 (C=O). UV–Vis (CHCl3) kmax (nm) (loge):
1
287 (3.66), 517 (2.94). H NMR (499.74 MHz, CDCl3): d
1.86 (t, 4H, J = 5.86, CH2piper), 2.52 (t, 2H, J = 7.32,
(C=O)–CH2–), 3.06 (t, 2H, J = 7.32, S–CH2), 3.55 (t,
4H, J = 5.86, CH2piper), 3.57 (s, 3H, O–CH3), 3.95 (s,
4H, O–CH2–CH2–O), 7.56–7.63 (m, 2H, CHarom),
7.92–7.94 (dd, 1H, CHarom), 7.99–8.01 (dd, 1H, CHarom).
13C NMR (125.66 MHz, CDCl3): d 29.63 ((C=O)–CH2–
), 36.20 (S–CH2), 51.11 (O–CH3), 35.01, 51.18, 126.56
(CH2piper), 64.64 (O–CH2–CH2–O), 133.09, 132.38,
126.88, 124.03 (Carom), 107.06 (=C–S), 155.56 (=C–N),
182.01, 172.32 (C=O). MS [ESI]: m/z 441 [M?Na]?.
Anal. Calcd. for C21H23NO6S (M, 417.475): C, 60.42; H,
5.55; N, 3.36; S, 7.68 %. Found: C, 60.46; H, 5.74; N,
3.15; S, 7.40 %.
2-Morpholino-3-((perchlorophenyl)thio)naphthalene-1,4-
dione (15a) was synthesized by the reaction of 13 (Ibis
et al., 2013b) (0.36 g, 0.76 mmol) and 14a (0.13 g,
1.52 mmol) by using general procedure 5 Brown solid.
M.p.: 196.5–198 °C. Yield: 0.32 g (80 %). Rf : 0.15 with
petroleum ether: CHCl3/2:1. 0.15. IR (KBr): t (cm-1
)
2,970, 2,898, 2,847 (C–Haliph), 1,588, 1,525 (C=C), 1,655
(C=O). UV–Vis (CHCl3) kmax (nm) (loge): 284 (5.42), 519
(4.64). 1H NMR (499.74 MHz, CDCl3): d 3.56 (t, 4H,
N–CH2morph), 3.82 (t, 4H, O–CH2morph), 7.55–7.61 (m, 2H,
CHarom), 7.81–7.83 (d, 1H, CHarom), 7.93–7.95 (d, 1H,
CHarom). 13C NMR (125.66 MHz, CDCl3): d 51.79
(O–CH2), 66.65 (N–CH2), 135.20, 133.06, 132.99, 132.66,
132.24, 131.18, 131.15, 130.80, 124.26 (Carom), 125.66
(=C–S), 151.61 (=C–N), 180.46, 178.95 (C=O). MS [ESI]:
m/z 524 [M]?. Anal. Calcd. For C20H12Cl5NO3S (M,
523.644): C, 45.87; H, 2.31; N, 2.67; S, 6.12 %. Found: C,
45.51; H, 2.14; N, 2.59; S, 6.22 %.
Butyl 3-((1,4-dioxo-3-(1,4-dioxa-8-azaspiro[4.5]decan-8-
yl)-1,4-dihydronaphthalen-2-yl)thio)propanoate (12f) was
synthesized by the reaction of 10d (Ibis et al., 2013a)
(0.27 g, 0.79 mmol) and 2f (0.15 mL, 0.87 mmol) by using
general procedure 4 Dark red oil. Yield: 0.32 g (86 %).
Rf : 0.29 with CHCl3 as an eluent. IR (KBr): t (cm-1
)
123

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Med Chem Res (2014) 23:2140–2149
2-((Perchlorophenyl)thio)-3-thiomorpholinonaphthalene-
1,4-dione (15b) was synthesized by the reaction of 13
(Ibis et al., 2013b) (0.36 g, 0.76 mmol) and 14b (0.16 g,
1.52 mmol) by using general procedure 5 Black solid.
M.p: 191–192.5 °C. Yield: 0.37 g (90 %). Rf : 0.35 with
Petroleum ether: CHCl3/2:1. IR (KBr): t (cm-1) 2,958,
2,907, 2,847 (C–Haliph), 1,587, 1,525 (C=C), 1,657 (C=O).
UV–Vis (CHCl3) kmax (nm) (loge): 247 (4.86), 287 (4.67),
153.85 (=C–N), 180.83, 178.82 (C=O). MS [ESI]: m/z 522
[M]?. Anal. Calcd. for C21H14Cl5NO2S (M, 521.671): C,
48.35; H, 2.70; N, 2.68; S, 6.15 %. Found: C, 48.53; H,
2.93; N, 2.83; S, 5.26 %.
2-(4-(4-Fluorophenyl)piperazin-1-yl)-3-((perchlorophenyl)
thio)naphthalene-1,4-dione (15e) was synthesized by the
reaction of 13 (Ibis et al., 2013b) (0.35 g, 0.74 mmol) and
14e (0.27 g, 1.48 mmol) by using general procedure
1
514 (4.00). H NMR (499.74 MHz, CDCl3): d 2.80 (t, 4H,
S–CH2thiomorph), 3.68 (t, 4H, N–CH2thiomorph), 7.56–7.61
(dd, 1H, CHarom), 7.80–7.81 (dd, 1H, CHarom), 7.93–7.95
(d, 2H, CHarom). 13C NMR (125.66 MHz, CDCl3): d 27.37
(S–CH2thiomorph), 53.62 (CH2thiomorph), 135.31, 132.92,
132.77, 132.37, 131.18, 131.08, 130.83, 127.03 (Carom),
125.80 (=C–S), 152.48 (=C–N), 180.33, 179.11 (C=O). MS
[ESI]: m/z 540 [M]?. Anal. Calcd. for C20H12Cl5NO3S (M,
539.710): C, 44.51; H, 2.24; N, 2.60; S, 11.88 %. Found:
C, 45.38; H, 2.86; N, 2.21; S, 10.40 %.
5
Black solid. M.p.: 168–170 °C. Yield: 0.35 g (78 %).
Rf : 0.60 with CHCl3 as an eluentIR (KBr): t (cm-1) 3056
(C–Harom), 2958, 2923, 2825 (C–Haliph), 1547, 1509 (C=C),
1666 (C=O). UV–Vis (CHCl3) kmax (nm) (loge): 256 (5.03),
1
287 (4.77), 517 (3.99). H NMR (499.74 MHz, CDCl3):
d 2.91–2.95 (m, 4H, CH2piperazine), 2.99–3.13 (m, 4H,
CH2piperazine), 6.49–6.70 (m, 4H, CHarom), 6.72–6.92 (m, 4H,
CHarom). 13C NMR (125.66 MHz, CDCl3): d 49.66, 44.60
(CH2piperazine), 159.77, 157.30, 155.39, 147.17, 135.21,
133.18, 131.15, 130.82, 118.08, 118.02, 117.35, 117.17, 116.
76, 116.70, 114.64, 124.26 (Carom), 125.79 (=C–S), 152.00
(=C–N), 180.48, 178.91 (C=O). MS [ESI]: m/z 617 [M?H]?.
Anal. Calcd. for C26H16Cl5FN2O2S (M, 615.758): C, 50.63;
H, 2.61; N, 4.54; S, 5.20 %. Found: C, 51.05; H, 2.74; N,
4.07; S, 5.86 %.
2-((Perchlorophenyl)thio)-3-(pyrrolidin-1-yl)naphthalene-
1,4-dione (15c) was synthesized by the reaction of 13 (Ibis
et al., 2013b) (0.33 g, 0.70 mmol) and 14c (0.099 g,
1.40 mmol) by using general procedure 5 Brown solid. M.
p.: 176–177.5 °C. Yield: 0.29 g (83 %). Rf : 0.37 with
Petroleum ether: CHCl3/2:1. IR (KBr): t (cm-1) 2,962,
2,924, 2,853 (C–Haliph), 1,512 (C=C), 1,670, 1,618 (C=O).
UV–Vis (CHCl3) kmax (nm) (loge): 249 (4.19), 283 (4.18),
493 (3.38). 1H NMR (499.74 MHz, CDCl3): d 1.91 (m, 4H,
N–CH2–CH2pyrrolidine), 3.99 (t, 4H, N–CH2pyrrolidine),
7.45–7.55 (dd, 1H, CHarom), 7.76–7.78 (dd, 1H, CHarom),
7.85–7.87 (m, 2H, CHarom). 13C NMR (125.66 MHz,
CDCl3): d 24.61 (N–CH2–CH2pyrrolidine), 54.11 (N–CH2pyr-
rolidine), 134.99, 134.87, 133.12, 132.07, 131.04, 130.71,
124.87, 104.40 (Carom), 125.16 (=C–S), 156.71 (=C–N),
182.91, 178.16 (C=O). MS [ESI]: m/z 508 [M]?. Anal. Calcd.
for C20H12Cl5NO2S (M, 507.645): C, 47.32; H, 2.38; N, 2.76;
S, 6.32 %. Found: C, 47.67; H, 2.50; N, 3.09; S, 5.46 %.
Methyl 3-((1,4-dioxo-3-((perchlorophenyl)thio)-1,4-dihydro-
naphthalen-2-yl)thio)propanoate (15f) was synthesized bythe
reaction of 13 (Ibis et al., 2013b) (0.33 g, 0.69 mmol) and 14f
(0.092 g, 0.76 mmol) by using general procedure 5 Red
solid. M.p.: 184–185.5 °C. Yield: 0.28 g (72 %). Rf : 0.62
with CHCl3 as an eluent. IR (KBr): t (cm-1) 3069 (C–Harom),
2983, 2955, 2929 (C–Haliph), 1593 (C=C), 1736, 1662
(C=O). UV–Vis (CHCl3) kmax (nm) (loge): 249 (5.14), 450
(3.85). 1H NMR (499.74 MHz, CDCl3): d 2.67 (t, 2H, J =
7.32, (C=O)–CH2–), 2.96 (t, 2H, J = 7.32, S–CH2), 3.63 (s,
3H, O–CH3), 7.61–7.64 (m, 2H, CHarom), 7.95–7.99 (m, 2H,
CHarom). 13C NMR (125.66 MHz, CDCl3): d 26.84 ((C=O)–
CH2–), 32.88 (S–CH2), 50.87 (O–CH3), 137.06, 135.65,
134.35, 132.73, 132.60, 131.99, 131.28, 125.62 (Carom),
125.45, 157.00 (=C–S), 181.64, 177.87, 171.09 (C=O). Anal.
Calcd. for C20H11Cl5O4S2 (M, 556.694): C, 43.15; H, 1.99;
S, 11.52 %. Found: C, 43.67; H, 1.74; S, 11.85 %.
2-((Perchlorophenyl)thio)-3-(piperidin-1-yl)naphthalene-
1,4-dione (15d) was synthesized by the reaction of 13 (Ibis
et al., 2013b) (0.37 g, 0.78 mmol) and 14d (0.133 g,
1.56 mmol) by using general procedure 5 Purple solid.
M.p.: 160.5–162 °C. Yield: 0.36 g (88 %). Rf : 0.87 with
CHCl3 as an eluent. IR (KBr): t (cm-1) 2927, 2,849
(C–Haliph), 1,588, 1,540 (C=C), 1663 (C=O). UV–Vis
(CHCl3) kmax (nm) (loge): 246 (4.30), 526 (3.38). 1H NMR
(499.74 MHz, CDCl3): d 1.65 (m, 2H, CH2piperidine), 1.74
(m, 4H, CH2piperidine), 3.60 (t, 4H, CH2piperidine), 7.50–7.54
(m, 1H, CHarom), 7.76–7.80 (m, 1H, CHarom), 7.88–7.91
(m, 2H, CHarom). 13C NMR (125.66 MHz, CDCl3): d 23.15
(N–CH2–CH2–CH2piperidine), 26.08 (N–CH2–CH2piperidine),
53.45 (N–CH2piperidine), 135.30, 133.84, 132.83, 132.24,
131.83, 130.99, 125.47, 120.93 (Carom), 125.68 (=C–S),
Butyl 3-((1,4-dioxo-3-((perchlorophenyl)thio)-1,4-dihydro-
naphthalen-2-yl)thio)propanoate (15g) was synthesized by
the reaction of 13(Ibis et al., 2013b) (0.36 g, 0.76 mmol) and
14g (0.14 g, 0.84 mmol) by using general procedure 5 Red
oil. Yield: 0.38 g (83 %). Rf : 0.6 with CHCl3 as an eluentIR
(KBr): t (cm-1) 3072 (C–Harom), 2961, 2927, 2870
(C–Haliph), 1591, 1491 (C=C), 1666, 1654 (C=O). UV–Vis
(CHCl3) kmax (nm) (loge): 244 (4.53), 444 (3.45). 1H NMR
(499.74 MHz, CDCl3): d 0.84 (t, 3H, J = 7.32, CH3), 1.30
(m, 2H, O–CH2–CH2), 1.53 (m, 2H, CH2–CH3), 2.60 (t, 2H,
123

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Acknowledgments The financial support from TUBITAK for Uk-
raine–Turkey agreement gratefully acknowledged (Project No.
109T617) and from State Agency on Science, Innovations and In-
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