A new method for the preparation of 5-acylidene and 5-imino substituted rhodanine derivatives and their antioxidant and antimicrobial activities

Article abstract of DOI:10.1016/j.tet.2015.04.069

Versatile syntheses of 5-imino or 5-acylidene substituted 1,3-thiazolidin-4-one derivatives are reported from α-dioxothiazole systems and phosphoranes via Wittig reactions. Antimicrobial and antioxidant activity of the compounds were evaluated. 5-Carbonyl

Full text of DOI:10.1016/j.tet.2015.04.069

Tetrahedron xxx (2015) 1e12
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A new method for the preparation of 5-acylidene and 5-imino
substituted rhodanine derivatives and their antioxidant and
antimicrobial activities
a
,
b
a
b
€
*
€
€
S¸ evket Hakan Ungoren , Sevil Albayrak , Ahmet Gunay , Lutfiye Yurtseven ,
a
€
Nurgul Yurttas¸
a Department of Chemistry, Faculty of Arts and Sciences, Bozok University, Yozgat, Turkey
b Department of Biology, Faculty of Sciences, Erciyes University, Kayseri, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Versatile syntheses of 5-imino or 5-acylidene substituted 1,3-thiazolidin-4-one derivatives are reported
Received 8 February 2015
Received in revised form 8 April 2015
Accepted 20 April 2015
Available online xxx
from
a-dioxothiazole systems and phosphoranes via Wittig reactions. Antimicrobial and antioxidant
activity of the compounds were evaluated. 5-Carbonylmethylene substituted 2-thioxo-1,3-thiazolidines
have better antioxidant properties than the 5-arylimino substituted ones. The % inhibition value of the
compound 3 (90.8%) was near to that of standard BHT (93.6%) at the same concentration. Compounds 5
and 15, which have the alkyliden-amide group at the C-5 position of the 1,3-thiazolidine ring showed the
highest antimicrobial activities among the synthesized compounds.
Keywords:
Rhodanines
Wittig reaction
Chalcones
Ó 2015 Published by Elsevier Ltd.
Perimidines
Antioxidant activity
Antimicrobial activity
1. Introduction
2-Thioxo-1,3-thiazolidin-4-one, commonly named as rhoda-
nine,1 is privileged scaffold2 that shows multiple biological activi-
ties3 by means of selective affinity towards various enzymes such as
aldose reductase,4
b
-lactamase,5 HCV NS3 protease,6 histidine
decarboxylase,7 N-acetyltransferase8 and histone acetyltransfer-
ase.9 The 1,3-thioazolidin-4-one skeleton is also a pharmacophore
for treatment of type 2 diabetes and is found in the structure of
some drugs like Epalrestat, Pioglitazone, Rosiglitazone,
Ciglitazone.3
Moreover, there is an important application of 5-acylidene
substituted rhodanines as dye sensitizer,10 and also 5-arylimino
substituted derivatives of rhodanine framework are very in-
teresting structures as optical materials.11 Thus, rhodanine struc-
tures have become useful for the development of not only bioactive,
but also optoelectronic materials.
A short time ago, the synthesis of some 5-imino substituted
rhodanines was revealed from the reaction of the corresponding
thiazolidines and aryl nitroso compounds.11 On the other hand,
only two methods are known about the preparation of 5-acylidene
rhodanines. The first one is well known and it based on the
Knoevenagel reaction of 2-thioxo/oxo/imino substituted rhodanine
derivatives with aldehydes.1,12 The second method is the cyclization
of thioureas or dithiocarbamic acids with dialkylacetylene dicar-
boxylates (DAADs).13 The second method is not used commonly
because of the limited availability of DAADs.
Considering the importance of thiazolidine compounds, we can
report that a new generalized protocol about the preparation of 5-
* Corresponding author. Tel.: þ90 354 242 1021; fax: þ90 354 242 1022; e-mail
€
€
address: hungoren@erciyes.edu.tr (S¸ .H. Ungoren).
http://dx.doi.org/10.1016/j.tet.2015.04.069
0040-4020/Ó 2015 Published by Elsevier Ltd.
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S¸ .H. Ungoren et al. / Tetrahedron xxx (2015) 1e12
2
acylidene and 5-arylimino substituted rhodanine derivatives is able
to provide rich sources of valuable chemical materials.
analyses,13d the olefinic proton signal is observed at
this study, the same compound (20) showed a signal at
d
7.00 ppm. In
7.01 ppm
d
In this study, we propose a new useful method for synthesis of
5-acylidene and 5-imino rhodanine series by rection of 1,3-
in CDCl3 due to the olefinic proton in Z-form. Thus, we have clearly
proved the structures of the synthesized compounds in Z-
geometry.
Before performing biological studies of the novel rhodanine
derivatives, two chalcone analogues of 5-acylidene rhodanines
were synthesized from 13 with aldehydes for structural diversity of
5-acylidene rhodanines. Therefore, structureeactivity relationship
of antibacterial and antioxidant properties of the new rhodanine
derivatives would be better understood.
The condensation reactions occurred in presence of BF3 as cat-
alyst, in moderate yields, (Table 2). The chalcone derivatives (33,
34) were purified by column chromatography, and their spectro-
scopic data were correspond with proposed structures.
thiazolidine-4,5-diones (
reagents. The chemical behavior of the Wittig reagents towards
dioxothiazole derivatives has not been investigated previously,
however, the Wittig reactions of similar structures such as
dioxoimidazole,
-dioxofurane were reported earlier.14
a-dioxothiazole derivatives) with Wittig
a
-
a
-
a
In addition to our synthesis study, we have investigated anti-
bacterial and antioxidant properties of the newly synthesized
rhodanine analogues.
2. Results and discussion
2.1. Synthesis
2.2. In vitro antioxidant activity
First, 3-aryl-2-thioxo-1,3-thiazolidine-4,5-diones (A, B) were
prepared from corresponding ammonium dithiocarbamates with
oxalyl chloride at reflux condition in benzene.15 2-Arylimino
substituted 1,3-thiazolidinedione analogues (C, D) were synthe-
sized with similar pathway as second-type of starting materials in
MeCN (as shown Scheme 1).16,13a
The inhibitory effects of some of the synthesized compounds
(1e20, 33, 34) on DPPH radical are presented as % inhibition in
Table 3. Statistical differences among the DPPH scavenger activities
of the compounds were important (p<0.05). DPPH radical scav-
enging activity of the synthesized compounds was detected to be
good to moderate as compared to the standard BHA. % Inhibition
value of the compound 3 (90.8%) was near to that of standard BHT
(93.6%) at the same concentration. It appears that compounds 3, 13,
14, 4, 1, 11 and 17 were found to be a significant scavenger of the
DPPH radical (90.8%, 82.1%, 81.2%, 71.2%, 71.2%, 55.9% and 54.4%,
respectively) when compared to BHT. The other compounds except
for 20 were showed moderate inhibitory effect and inhibition rates
in the range of 42.2e11.6%. Compound 20 was exhibited the
weakest inhibitory effect with 6.1%.
The study reveals that the sulfur atom attached on C-2 atom of
1,3-thiazolidine skeleton increases the antioxidant potential of the
rhodanine derivatives, compared to effect of nitrogen atom at-
tached on the same point. 5-Carbonylmethylen substituted 1,3-
thiazolidines have much more antioxidant properties from the 5-
arylimino substituted ones, generally. Moreover, in the event that
there are methyl, methylene and methine groups attached to car-
bonyl group of 1,3-thiazolidine analogues, the protons of these
groups provide additional antioxidant activity by transferring the
protons to oxidizing agent.
2.3. Antimicrobial activity
Scheme 1. Preparations of 1,3-thiazolidine-4,5-dione structures as substrates (AeD).
Subsequently, heating a benzene solution of compounds AeD
with various methylenephosphoranes leads to the regioselectively
formation of 1,3-thiazolidine-5-ylidene derivatives at good yields
as shown Table 1. Also, iminophosphoranes are reacted on the
SeC]O group, but not NeC]O group of the substrates, similarly.
The alkylidene substituted products were isolated in Z-form.
The antimicrobial activity of compounds 1e34 against four-
teen microorganisms determined by agar diffusion method was
investigated. The results revealed that most of the synthesized
rhodanine compounds (2e7, 13e18) showed significant anti-
bacterial activities (Table 4). Among the tested rhodanine
compounds, 4, 5, 14 and 15 had the strongest antibacterial
activity.
In the 13C NMR spectra of AeD, SeC]O signals of
a-dioxoti-
hiazole derivatives were observed in the range of 178e190 ppm. In
the 13C NMR spectrum of the Wittig reaction products, these signals
were disappeared and new signals, which belong to substituted
group of the products were appeared. For example, 16 resonances
were seen in the 13C NMR spectra of 29, and signals of a methyl
group and two carbonyl group (acetyl and amide) were observed at
30.7, 196.7, 153.0 ppm, respectively. The other carbon signals are
convenient for the proposed structure.
Validation studies for the proposed method were performed by
using reported spectroscopic data of compounds 2717 and 20.13a,d
These compounds can be prepared from the reaction of dimethy-
lacetylene dicarboxylate with corresponding thiourea derivatives
in methanol. According to published 1H NMR data of the compound
20, which is formed in Z-geometry, and also supported with X-ray
As clearly seen in Table 4, among the Gram (ꢀ) bacteria tested,
the most sensitive bacteria were Aeromonas hydrophila, Klebsiella
pneumoniae and Pseudomonas aeruginosa while the most resistant
bacteria were Escherichia coli, Salmonella typhimurium, Proteus
mirabilis and Yersinia enterocolitica. Amongst the tested five Gram
(þ) bacteria the most sensitive bacteria were Bacillus cereus, Bacillus
subtilis, Listeria monocytogenes and Staphylococcus aureus while
none of the tested compounds had inhibitory activity against My-
cobacterium smegmatis. 2 exhibited inhibitory activity against only
S. aureus (7.0 mm) while 7 showed inhibitory activity against B.
cereus (9.0 mm). All other compounds did not show antibacterial
activity against the bacteria tested. Only 5, 15 and 18 had an in-
hibitory effect on Candida albicans with inhibition zones of 11.0,
12.5 and 7.5, respectively. Compound 18 did not exhibit any activity
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S¸ .H. Ungoren et al. / Tetrahedron xxx (2015) 1e12
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Table 1
5-Acylidene substituted thiazolidines (product no: 1e32) prepared using Wittig/aza-Wittig reactions
No
Subs
Reagent
Product
Time (min)
Yield (%)
Mp (ꢁC)
No
Subs
Reagent
Product
Time (min)
Yield (%)a
Mp (ꢁC)
1
A
10
17
B
10
82 (EtOH)
168ꢀ169
61 (MeOH)
175ꢀ176
2
A
10
18
B
10
78 (MeOH)
127ꢀ128
61 (2-PrOH)
195ꢀ196
3
A
10
19
B
10
65 (EtOH)
191ꢀ192
69 (MeOH)
158ꢀ159
4
A
10
20
C
30
76 (MeCN)
185ꢀ186
90 (n-Hex.)
126ꢀ127b
5
A
180
21
D
15
63 (MeCN)
261ꢀ262
76 (EtOAc)
201ꢀ202
(continued on next page)
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S¸ .H. Ungoren et al. / Tetrahedron xxx (2015) 1e12
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Table 1 (continued )
No
Subs
Reagent
Product
Time (min)
Yield (%)
Mp (ꢁC)
No
Subs
Reagent
Product
Time (min)
Yield (%)a
Mp (ꢁC)
6
A
10
22
D
10
68 (EtOH)
187ꢀ188
77 (MeCN)
172ꢀ173
7
8
9
A
A
A
10
23
24
25
D
D
D
10
86 (MeCN)
138ꢀ139
77 (EtOAc)
229ꢀ230
10
10
73 (2-PrOH)
146ꢀ147
81 (EtOAc)
232ꢀ233
20
30
82 (n-Hex.)
128ꢀ129
83 (MeCN)
198ꢀ199
10
A
10
26
D
15
88 (2-PrOH)
170ꢀ171
73 (DMF)
225ꢀ226
11
B
10
27
D
10
82 (MeOH)
150ꢀ151
87 (MeCN)
215ꢀ216c
12
B
10
28
D
10
88 (2-PrOH)
121ꢀ122
81 (MeCN)
179ꢀ180
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S¸ .H. Ungoren et al. / Tetrahedron xxx (2015) 1e12
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Table 1 (continued )
No
Subs
Reagent
Product
Time (min)
Yield (%)
Mp (ꢁC)
No
Subs
Reagent
Product
Time (min)
Yield (%)a
Mp (ꢁC)
13
B
10
29
D
10
61 (MeOH)
206ꢀ207
89 (MeCN)
203ꢀ204
14
B
10
30
D
20
76 (2-PrOH)
187ꢀ188
83 (Xylene)
193ꢀ194
15
B
60
31
D
60
75 (Toluene)
242ꢀ243
54 (DMF)
307ꢀ308
10
15
16
B
79 (MeOH)
125ꢀ126
32
D
88 (MeCN)
239ꢀ240
a
Isolated yield.
b
c
Lit.13d Mp: 128e130 ꢁC.
Lit.13a Mp: 215e218 ꢁC.
against bacterial strains and Aspergillus parasiticus while it had
inhibitory effect on C. albicans (7.5 mm). Antifungal activities of
Natamycin as positive control against C. albicans (24.0 mm) was
higher than that of rhodanine compounds tested.
moderate antifungal activity against C. albicans with MIC of
2.5e5.0 mg mLꢀ1 (except for 5, MIC¼0.31 mg/mL).
A rough order of antimicrobial activity of substituted rhodanine
analogues is outlined in Fig.1. The highest antimicrobial activities of
the new rhodanine series were observed in case of the compounds
5 and 15, which have the alkyliden-amide group at the C-5 position
of the 1,3-thiazolidine ring.
The MICs (minimum inhibitory concentrations) of the com-
pounds against these microorganisms are summarized in Table 5 (a
smaller MIC value corresponds to higher activity). As shown in
Table 5, 15 exhibited the highest antibacterial activity against A.
hydrophila, K. pneumonia, P. aeruginosa and B. cereus with an MIC as
low as 0.63 mg/mL 14 exhibited excellent activity against Morga-
nella morganii and P. aeruginosa with MIC of 0.63 mg mLꢀ1. Com-
pound 5 exhibited the most potent antibacterial activity with MIC
of 0.63 mg mLꢀ1 against B. subtilis and MIC of 0.16 mg/mL against L.
monocytogenes. The best antibacterial activity was observed for 4
against L. monocytogenes (MIC¼0.08 mg/mL). Among the synthe-
sized compounds, 2, 3, 4, 5, 13 and 14 exhibited moderate activity
with MIC of 2.5e5.0 mg mLꢀ1 against S. aureus. 15 and 18 exhibited
3. Conclusions
We have described stereo- and regioselective method for simple
synthesis of 5-acylidene and 5-imino substituted rhodanine
framework. The generalized procedure gave 32 samples in total,
and is a new route to these potentially bioactive materials. Our
investigation reveals that 5-acylidene rhodanines having an amide
group attached to alkylidene moiety can be candidates for broad-
spectrum antibiotics.
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S¸ .H. Ungoren et al. / Tetrahedron xxx (2015) 1e12
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Table 2
Synthesis and experimental data of chalcone derivatives of 5-acylidene rhodanines
No
Subst.
Reagent
Product
t (min)
Yield (%)
Mp (ꢁC)
33
30
66
172ꢀ173
34
30
48
191ꢀ192
4. Experimental
The agar well diffusion method19 was used for the de-
termination of antibacterial activity of synthesized rhodanine
compounds against fifteen microorganism including five Gram (þ),
eight Gram (ꢀ) bacterial strains, one yeast and one fungal strain. A.
hydrophila ATCC7965, B. cereus RSKK 863, B. subtilis ATCC 6633, E.
coli ATCC 25922, K. pneumoniae ATCC 27736, L. monocytogenes 1/2B,
M. smegmatis RUT, M. morganii, P. mirabilis BC 3624, P. aeruginosa
ATCC 27853, S. typhimurium NRRLE 4463, S. aureus ATCC 25923, Y.
enterocolitica ATCC 1501 were used to determine antibacterial ac-
tivity. As for antifungal activity, standard strain of C. albicans ATCC
10231 and A. parasiticus DSM 577 were used. Tetracycline (10 mg/
mL, Sigma T3258-T6) and Natamycin (30 mg mLꢀ1, Delvocid DMS)
were used as positive control. All the synthesized rhodanine com-
pounds were dissolved to prepare a stock solution of 10 mg mLꢀ1
using DMSO. The bacterial culture strains and fungal spore sus-
Melting points were measured on an Electro thermal 9100 ap-
paratus and uncorrected. Elemental analyses for C, H and N were
carried out using a LECO-932 CHNSeO Elemental Analyzer. 1H and
13C NMR spectra were measured with Bruker Advance 400 spec-
trometer using CDCl3 or DMSOꢀd6 solvents. The IR spectra were
obtained with ATR method using a Shimadzu 8400 and Perkin
Elmer Spectrum Two Model FTIR spectrometer. The progress of
reactions was monitored by thin layer chromatography (TLC) on
silica gel GF254 using CHCl3 as mobile phase.
The antioxidant activity of the synthesized compounds was
evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical
scavenging method.18 All the synthesized rhodanine compounds
were dissolved to prepare a stock solution of 1 mg/mL using di-
methyl sulfoxide (DMSO). Fifty microliter solutions of compounds
were added to 1 mL of a 0.1 mM solution of DPPH in methanol. After
2 h, absorbance values were measured at 517 nm. Butylated hy-
droxyl anisole (BHA) was used as the standard. The percentage
inhibition activity was calculated by means of a Formula: % Anti-
pensions were adjusted to give
a final concentration of
106ꢀ107 cfu mLꢀ1. About 25 mL of media (Mueller Hinton Agar,
Malt Extract Agar and Patoto Dextrose Agar for bacteria, yeast and
mold, respectively) were poured into Petri plates (9 cm in diameter)
and inoculated with respective test organism. Wells (6 mm) were
_
oxidant activity (% Inhibition)¼100ꢂ(1- OD of test compound/OD
made with cork borer on the solid agar and loaded with 50
mL of the
of control compound).
test compounds. Y. enterocolitica, C. albicans and A. parasiticus were
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S¸ .H. Ungoren et al. / Tetrahedron xxx (2015) 1e12
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Table 3
In vitro antioxidant activity of some of the compounds (No: 1e20, 33, 34)
No
% Inhibition
*
No
% Inhibition
*
1
3
5
7
71.2ꢃ0.8d
90.8ꢃ0.3b
12.1ꢃ0.4n
20.8ꢃ0.2k
13.8ꢃ2.2m
55.9ꢃ0.6e
82.1ꢃ0.6c
13.9ꢃ0.7m
54.4ꢃ0.2e
41.5ꢃ1.3g
14.8ꢃ0.4m
93.6ꢃ0.1a
2
4
6
21.1ꢃ0.4k
71.2ꢃ0.4d
33.3ꢃ0.9i
16.8ꢃ1.8l
11.6ꢃ0.3n
42.2ꢃ0.5g
81.2ꢃ0.3c
21.3ꢃ0.4k
26.3ꢃ0.2j
6.1ꢃ0.1o
8
9
10
12
14
16
18
20
34
11
13
15
17
19
33
BHT
37.3ꢃ0.8h
(*) In each column, means of three independent experiments (ꢃ SD) with different superscript letters are significantly different (p<0.05).
Table 4
In vitro antimicrobial activity of newly synthesized compounds (2e7, 13e15, 18)
Microorganisms
Rhodanine compounds (10 mg/mL)
Tetracycline
(10 mg/mL)
Gram (ꢀ)
2
3
d
4
5
6
7
13
d
14
15
18
A. hydrophila
E. coli
d
d
d
d
d
d
d
d
13.0ꢃ1.4
11.0ꢃ0.0
9.5ꢃ0.7
d
d
d
d
d
d
d
d
10.5ꢃ0.7
12.0ꢃ1.4
25.0ꢃ0.0
26.0ꢃ0.0
25.0ꢃ0.0
18.0ꢃ0.0
21.0ꢃ0.0
23.0ꢃ0.0
18.0ꢃ0.0
29.0ꢃ0.0
d
10.0ꢃ0.0a
d
d
d
d
d
d
K. pneumoniae
M. morganii
P. mirabilis
P. aeruginosa
S. typhimurium
Y. enterocolitica
Gram (þ)
13.0ꢃ1.4
10.5ꢃ0.7
9.5ꢃ0.7
d
d
8.0ꢃ0.0
d
11.0ꢃ0.0
10.0ꢃ0.0
d
11.5ꢃ0.7
11.5ꢃ0.7
d
d
d
d
d
d
d
d
7.5ꢃ0.7
d
13.5ꢃ0.7
10.0ꢃ0.0
d
9.0ꢃ1.4
d
d
11.0ꢃ0.0
d
12.5ꢃ0.7
d
d
d
d
d
d
d
d
d
d
B. cereus
B. subtilis
L. monocytogenes
M. smegmatis
S. aureus
d
d
9.5ꢃ0.7
10.0ꢃ0.0
12.0ꢃ0.0
d
12.0ꢃ1.4
10.5ꢃ0.7
10.0ꢃ0.0
d
7.0ꢃ0.0
9.0ꢃ0.0
d
9.0ꢃ0.0
8.0ꢃ0.0
9.0ꢃ0.0
d
9.5ꢃ0.7
12.5ꢃ0.7
12.5ꢃ0.7
d
33.0ꢃ0.0
30.0ꢃ0.0
27.0ꢃ0.0
17.0ꢃ0.0
22.0ꢃ0.0
Natamisin
(30 mg mLꢀ1)
24.0ꢃ0.0
d
d
d
d
d
d
d
d
d
d
d
d
7.0ꢃ0.0
d
7.0ꢃ0.0
d
d
7.0ꢃ0.0
9.0ꢃ0.0
11.5ꢃ0.7
11.0ꢃ0.0
9.0ꢃ0.0
7.75ꢃ0.4
d
Yeast
C. albicans
11.0ꢃ0.0
12.5ꢃ0.7
7.5ꢃ0.7
d: No inhibition.
a
Inhibition zones include diameter of hole (6 mm). Sample amount 50 mL.
incubated at 27 ꢁC while other microorganisms were incubated at
35 ꢁC for 28ꢀ48 h. The average diameter of the inhibition zone
surrounding the wells was measured as mm.
Same procedure was conducted for Tetracycline and Nata-
mycin. MICs values of test compounds were determined by col-
orimetric assay using Resazurin Sodium Salt (RSS). A change in
color from blue to pink pointed out the growth of bacteria, and
the MIC was defined as the lowest concentration of the com-
pound that prevented this change in color. The lowest concen-
tration at, which there was no visible growth was taken as the
minimal inhibitory concentration (MIC) and expressed in mg
The in vitro minimum inhibitory concentrations (MICs) of the
synthesized rhodanine compounds were determined using
microdilution assay in 96ꢀwell plates according to the methods
recommended by Sarker et al.20 The compounds were dissolved in
DMSO to obtain a concentration of 10 mg mLꢀ1. Then this solution
was added to the first two wells on a micro-titer plate and twofold
dilutions were done in (Mueller Hinton Broth, Malt Extract Broth
and Patoto Dextrose Broth for bacteria, yeast and mold, respectively
from well two. The final range was from 0.078 to 5.000 mg/mL.
Each well was inoculated with the microbial suspensions
(106ꢀ107 cfu mLꢀ1) and incubated at 35 ꢁC for 28 h.
mlꢀ1
.
Statistical analysis: Data from the experiments were subjected to
analysis of variance (ANOVA) using SPSS (2001) for Windows.21
Percentage data were transformed using arcsine Ox before
ANOVA. Means were separated at the 5% significance level by the
least significant difference (LSD) test.
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Table 5
MIC values (mg mLꢀ1) for the rhodanine compounds (2e7, 13e15, 18)
Microorganisms
Tetracycline
g mLꢀ1
Rhodanine derivatives
Gram (ꢀ)
m
2
3
d
4
2.5
d
5
2.5
d
6
7
13
d
d
2.5
d
d
d
d
d
14
1.25
d
15
0.63
d
18
A. hydrophila
E. coli
<7.8
<7.8
<7.8
31.3
31.3
15.6
62.5
15.6
d
d
d
d
d
d
d
d
2.5
d
d
d
d
2.5
d
d
d
d
d
d
d
d
d
d
d
K. pneumoniae
M. morganii
P. mirabilis
P. aeruginosa
S. typhimurium
Y. enterocolitica
Gram (þ)
1.25
d
10.0
d
1.25
2.5
d
2.5
0.63
d
0.63
1.25
d
d
d
1.25
d
0.31
d
0.63
d
0.63
d
0.63
d
d
d
d
d
d
B. cereus
B. subtilis
L. monocytogenes
M. smegmatis
S. aureus
62.5
7.8
62.5
125
d
d
d
d
5.0
d
2.5
1.25
0.63
0.16
d
5.0
d
d
d
d
2.5
d
d
d
d
d
2.5
2.5
2.5
d
0.63
1.25
1.25
d
d
10.0
0.08
d
d
10.0
d
2.5
d
15.6
2.5
2.5
2.5
2.5
2.5
d
Yeast
C. albicans
Natamycin
0.0625
0.31
2.5
5.0
d: No inhibition.
cyclohexane and recrystallized from corresponding solvent (see
Table 1) to give pure compounds 1e32.
5. Methyl (2Z)-(5-oxo-3-phenyl-2-thioxo-1,3-thiazolidin-4-
ylidene)acetate (1)
Yellow crystals; mp 168ꢀ169 ꢁC; yield 0.229 g 82%; IR (ATR):
ymax¼1723 (COOMe), 1699 (NC]O), 1610 (C]C), 1346 (C]S) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d (ppm) 7.48e7.25 (m, 5H, AreH), 6.92
(s, 1H, C]CH), 3.91 (s, 3H, OMe); 13C NMR (100 MHz, CDCl3):
(ppm) 195.7 (C]S), 166.2 (COOMe), 165.7 (NeC]O), 142.4, 130.0,
129.7, 128.2 (AreC), 134.1, 117.0 (C]CH), 53.0 (OMe); Anal. Calcd for
12H9NO3S2 (279.3 g/mol): C, 51.60; H, 3.25; N, 5.01; S, 22.96.
d
Fig. 1. Order of antimicrobial activity of substituted rhodanine analogues.
C
Found: C, 51.71; H, 3.23; N, 4.91; S, 22.83%.
4.1. General procedure for the preparation of substrates AeD
6. Ethyl (2Z)-(5-oxo-3-phenyl-2-thioxo-1,3-thiazolidin-4-
ylidene)acetate (2)
A solution of dry ammonium aryldithiocarbamates or thioureas
(1 mmol) and oxalyl chloride (1.1 mmol) in 30 mL dry benzene (for
C and D in 30 mL CH3CN) were stirred for 10 min, and then refluxed
for 30 min. After removal of the solvents, the residues were treated
with 15 mL n-hexane to give pure AeD.
Yellow crystals; mp 127ꢀ128 ꢁC; yield 0.228 g 78%; IR (ATR):
ymax¼1717 (COOEt), 1682 (NC]O), 1610 (C]C), 1350 (C]S) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d (ppm) 7.48e7.25 (m, 5H, AreH), 6.91
(s, 1H, C]CH), 4.36 (q, J¼7.12 Hz, 2H, OCH2), 1.40 (t, J¼7.12 Hz, 3H,
4.1.1. 3-Phenyl-2-(phenylimino)-1,3-thiazolidine-4,5-dione
(C). Yellow crystals, mp 168ꢀ169 ꢁC; recrystallized from cyclo-
hexane, yield 0.212 g 75%; IR (ATR): ymax¼3061 (AreH), 1770, 1748,
Me); 13C NMR (100 MHz, CDCl3):
d
(ppm) 195.9 (C]C), 166.3
(COOEt), 165.2 (NeC]O), 142.1, 130.0, 129.6, 128.2 (AreC), 134.1,
117.6 (C]CH), 62.3 (OCH2), 14.2 (Me); Anal. Calcd for C13H11NO3S2
(293.4 g/mol): C, 53.22; H, 3.78; N, 4.77; S, 21.86. Found: C, 53.41; H,
3.71; N, 4.61; S, 21.99%.
1728 (C]O),1644 (C]N) cmꢀ1; 1H NMR (400 MHz, CDCl3):
7.66e6.92 (m, 10H, AreH); 13C NMR (100 MHz, CDCl3):
d
(ppm)
(ppm)
d
179.9 (SeC]O), 157.1 (NeC]O), 146.3 (C]N), 145.2, 133.3, 129.7,
129.5, 129.4, 127.4, 126.1, 120.6 (C]C); Anal. Calcd for C15H10N2O2S
(282.3 g/mol): C, 63.81; H, 3.57; N, 9.92; S, 11.36. Found: C, 63.99; H,
3.65; N, 10.10; S, 11.48%.
7. (4Z)-4-(2-Oxopropylidene)-3-phenyl-2-thioxo-1,3-
thiazolidin-5-one (3)
Yellow crystals; mp 192ꢀ193 ꢁC; yield 0.171 g 65%; IR (ATR):
4.1.2. [1,3]Thiazolo[3,2-a]perimidine-9,10-dione (D). Red crystals,
mp 208ꢀ209 ꢁC, Lit13a mp 207e209, recrystallized from CH3CN,
yield 0.228 g 90%; IR (ATR): ymax¼1751, 1705 (C]O) cmꢀ1; 1H NMR
ymax¼1709 (MeC]O), 1668 (NC]O), 1346 (C]S) cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d (ppm) 7.80e7.24 (m, 5H, AreH), 7.05 (s, 1H, C]
CH), 2.51 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d (ppm) 198.0
(400 MHz, CDCl3):
(100 MHz, CDCl3):
d
(ppm) 8.63e7.17 (m, 6H, AreH); 13C NMR
(MeC]O), 196.6 (C]S), 167.1 (NeC]O), 140.3, 130.0, 129.6, 128.2
(AreC), 134.1, 120.6 (C]CH), 31.0 (Me); Anal. Calcd for C12H9NO2S2
(263.3 g/mol): C, 54.73; H, 3.44; N, 5.32; S, 24.35. Found: C, 54.60;
H, 3.47; N, 5.39; S, 24.42%.
d
(ppm) 178.0 (SeC]O), 153.8 (NeC]O), 145.2
(C]N), 136.9, 133.6, 130.0, 128.3, 127.6, 126.5, 126.3, 126.6, 118.6,
111.9 (C]C); Anal. Calcd for C13H6N2O2S (254.3 g/mol): C, 61.41; H,
2.38; N, 11.02; S, 12.61. Found: C, 61.52; H, 2.38; N, 10.91; S, 12.88%.
4.1.3. General procedure for the preparation of compounds
1e32. The solution of compounds AeD (1 mmol) and corre-
sponding Wittig reagents (1 mmol) in 30 mL dry toluene (in 30 mL
xylene for 5,15, 31) were refluxed for optimized time. After removal
of the solvent, the residues were washed with hot 10 mL
8. Ethyl (4Z)-3-oxo-4-(5-oxo-3-phenyl-2-thioxo-1,3-
thiazolidin-4-ylidene)butanoate (4)
Orange crystals; mp 185ꢀ186 ꢁC; yield 0.255 g 76%; IR (ATR):
ymax¼1710 (EtC]O), 1642 (NC]O), 1620 (C]C), 1341 (C]S) cmꢀ1
;
€
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9
1H NMR (400 MHz, CDCl3):
d
(ppm) 12.27 (s, 1H, enoleOH),
(312.4 g/mol): C, 61.51; H, 3.87; N, 8.97; S, 20.53. Found: C, 61.65; H,
3.76; N, 8.83; S, 20.60%.
7.59e7.24 (m, 5H, AreH), 7.00 (s, 1H, ring]CH), 5.52 (s, 1H, C]
CHCOOEt), 4.29 (q, J¼7.12 Hz, 2H, OCH2), 1.35 (t, J¼7.12 Hz, 3H, Me);
13C NMR (100 MHz, CDCl3):
d (ppm) 195.3 (C]S),172.1 (O]CeCH2),
14. 4-[(4-Methoxyphenyl)imino]-3-phenyl-2-thioxo-1,3-
thiazolidin-5-one (10)
167.0 (COOEt), 165.2 (NC]O), 134.5, 132.5, 129.2, 128.3, 123.8, 99.2
(C]C), 61.2 (OCH2),14.2 (Me); Anal. Calcd for C15H13NO4S2 (335.4 g/
mol): C, 53.72; H, 3.91; N, 4.18; S, 19.12. Found: C, 53.90; H, 3.98; N,
4.26; S, 19.02%.
Yellow crystals; mp 170ꢀ171 ꢁC; yield 0.288 g 88%; IR (ATR):
ymax¼1730 (C]O), 1613 (C]N), 1343 (C]S) cmꢀ1
;
1H NMR
(400 MHz, CDCl3):
d (ppm) 7.59e7.03 (m, 9H, AreH), 3.89 (s, 3H,
9. 3-(5-Oxo-3-phenyl-2-thioxo-1,3-thiazolidin-4-ylidene)pyr-
rolidine-2,5-dione (5)
OCH3); 13C NMR (100 MHz, CDCl3):
d (ppm) 192.1 (C]S), 162.0
(NeC]O), 146.0 (C]N), 160.3, 140.5, 134.1, 130.0, 129.7, 124.6, 114.9
(C]C ve C]N), 55.6 (CH3). Anal. Calcd for C16H12N2O2S2 (328.4 g/
mol): C, 58.52; H, 3.68; N, 8.53; S, 19.53. Found: C, 58.60; H, 3.61; N,
8.58; S, 19.42%.
Orange crystals; mp 261ꢀ262 ꢁC; yield 0.191 g 63%; IR (ATR):
ymax¼3162 (NH), 1776, 1758, 1721, 1694, 1683, 1644 (C]O), 1620
(C]C), 1345 (C]S) cmꢀ1; 1H NMR (400 MHz, DMSOꢀd6):
d (ppm)
12.10 (s, 1H, NH), 7.58e7.36 (m, 5H, AreH), 3.66 (s, 2H, CH2); 13C
15. Methyl (2Z)-[3-(4-methylphenyl)-5-oxo-2-thioxo-1,3-
thiazolidin-4-ylidene]acetate (11)
NMR (100 MHz, DMSO-d6):
d (ppm) 175.8 (C]S), 171.1 (CH2C]O),
170.9 (NHC]O), 166.6 (AreNeC]O), 135.1, 130.1, 129.8, 129.5,
129.1, 127.1 (C]C), 36.5 (CH2); Anal. Calcd for C13H8N2O3S2
(304.3 g/mol): C, 51.30; H, 2.65; N, 9.20; S, 21.07. Found: C, 51.45; H,
2.72; N, 9.33; S, 21.16%.
Yellow crystals; mp 150ꢀ151 ꢁC; yield 0.240 g 82%; IR (ATR):
ymax¼1729 (COOMe), 1698 (NC]O), 1609 (C]C), 1348 (C]S) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d (ppm) 7.37e7.13 (m, 4H, AreH), 6.91
(s, 1H, C]CH), 3.91 (s, 3H, OMe), 2.45 (s, 3H, PhMe); 13C NMR
(100 MHz, CDCl3): (ppm) 195.9 (C]S), 166.3 (COOMe), 165.7
10. 3-Phenyl-4-({4-[phenyldiazenyl]phenyl}imino)-2-thioxo-
1,3-thiazolidin-5-one (6)
d
(NeC]O), 142.5, 131.4, 130.4, 127.9 (AreC), 140.22, 117.0 (C]CH),
53.0 (OMe), 21.4 (Ar-CH3). Anal. Calcd for C13H11NO3S2 (293.4 g/
mol): C, 53.22; H, 3.78; N, 4.77; S, 21.86. Found: C, 53.28; H, 3.91; N,
4.86; S, 21.71%.
Yellow crystals; mp 188ꢀ189 ꢁC; yield 0.273 g 68%; IR (ATR):
ymax¼1738 (C]O), 1615 (C]N), 1343 (C]S) cmꢀ1
;
1H NMR
(400 MHz, DMSOꢀd6):
d
(ppm) 8.08e7.44 (m, 14H, AreH); 13C NMR
(100 MHz, DMSOꢀd6):
d (ppm) 193.7 (C]S), 160.9 (C]O), 154.0,
16. Ethyl (2Z)-[3-(4-methylphenyl)-5-oxo-2-thioxo-1,3-
thiazolidin-4-ylidene]acetate (12)
152.4,151.4,151.0,135.1,132.3,130.2,130.0,129.9,129.0,124.9,123.1,
121.8 (C]C and C]N); Anal. Calcd for C21H14N4OS2 (402.5 g/mol):
C, 62.67; H, 3.51; N, 13.92; S, 15.93. Found: C, 62.83; H, 3.62; N,
13.98; S, 15.63%.
Yellow crystals; mp 121ꢀ122 ꢁC; yield 0.270 g 88%; IR (ATR):
ymax¼1720 (COOEt), 1685 (NC]O), 1613 (C]C), 1356 (C]S) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d (ppm) 7.71e7.13 (m, 4H, AreH), 6.91
11. 4-[(4-Bromophenyl)imino]-3-phenyl-2-thioxo-1,3-
thiazolidin-5-one (7)
(s, 1H, C]CH), 4.36 (q, J¼7.12 Hz, 2H, OCH2), 1.38 (t, J¼7.12 Hz, 3H,
Me), 2.44 (s, 3H, Ph-CH3); 13C NMR (100 MHz, CDCl3):
d
(ppm) 196.0
(C]C), 166.3 (COOEt), 165.2 (NeC]O), 142.1, 140.2, 130.3, 127.9
(AreC), 131.4, 117.6 (C]CH), 62.2 (OCH2), 21.4 (CH2eCH3), 14.2 (Ar-
CH3). Anal. Calcd for C14H13NO3S2 (307.4 g/mol): C, 54.70; H, 4.26;
N, 4.56; S, 20.86. Found: C, 54.78; H, 4.38; N, 4.48; S, 20.94%.
Yellow crystals; mp 138ꢀ139 ꢁC; yield 0.324 g 86%; IR (ATR):
ymax¼1726 (C]O), 1658 (C]N), 1344 (C]S) cmꢀ1
;
1H NMR
(400 MHz, CDCl3):
d
(ppm) 7.69e7.14 (m, 9H, AreH); 13C NMR
(100 MHz, CDCl3):
d (ppm) 190.9 (C]S), 161.4 (C]O), 151.3 (C]N),
147.2, 133.8, 132.9, 130.2, 129.8, 128.2, 122.6, 122.1 (C]C, arom.);
Anal. Calcd for C15H9BrN2OS2 (377.3 g/mol): C, 47.75; H, 2.40; N,
7.43; S, 17.00. Found: C, 47.87; H, 2.38; N, 7.63; S, 17.16%.
17. (4Z)-3-(4-Methylphenyl)-4-(2-oxopropylidene)-2-thioxo-
1,3-thiazolidin-5-one (13)
Yellow crystals; mp 206ꢀ207 ꢁC; yield 0.169 g 61%; IR (ATR):
12. 3-Phenyl-4-(phenylimino)-2-thioxo-1,3-thiazolidin-5-one
(8)
ymax¼1711 (MeC]O), 1667 (NC]O), 1350 (C]S) cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d (ppm) 7.37e7.12 (m, 4H, AreH), 7.23 (s, 1H, C]
CH), 2.50 (s, 3H, ArCH3), 2.45 (s, 3H, COCH3); 13C NMR (100 MHz,
CDCl3): (ppm) 198.1 (MeC]O), 196.6 (C]S), 167.2 (NeC]O),
Yellow crystals; mp 146ꢀ147 ꢁC; yield 0.244 g 73%; IR (ATR):
d
ymax¼1737 (C]O), 1666 (C]N), 1342 (C]S) cmꢀ1
;
1H NMR
140.3, 131.4, 130.3, 127.9 (AreC), 140.2, 120.5 (C]CH), 31.0 (COCH3),
21.4 (ArCH3). Anal. Calcd for C13H11NO2S2 (277.4 g/mol): C, 56.29; H,
4.00; N, 5.05; S, 23.12. Found: C, 56.38; H, 4.12; N, 4.91; S, 23.28%.
(400 MHz, CDCl3):
d
(ppm) 7.87e7.01 (m, 10H, AreH); 13C NMR
(100 MHz, CDCl3): d (ppm) 191.8 (C]S), 161.5 (NeC]O), 157.5 (C]
N), 150.7, 148.5, 130.10, 129.8, 129.30, 120.90, (C]C ve C]N). Anal.
Calcd for C15H10N2OS2 (298.4 g/mol): C, 60.38; H, 3.38; N, 9.39; S,
21.49. Found: C, 60.52; H, 3.30; N, 9.46; S, 21.61%.
18. Ethyl (4Z)-4-[3-(4-methylphenyl)-5-oxo-2-thioxo-1,3-
thiazolidin-4-ylidene]-3-oxobutanoate (14)
13. 4-[(4-Methylphenyl)imino]-3-phenyl-2-thioxo-1,3-
thiazolidin-5-one (9)
Orange crystals; mp 187ꢀ188 ꢁC; yield 0.265 g 76%; IR (ATR):
ymax¼1712 (EtC]O), 1651 (NC]O), 1619 (C]C), 1356 (C]S) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
(ppm) 12.27 (s, 1H, enolꢀOH),
Yellow crystals; mp 128ꢀ129 ꢁC; yield 0.256 g 82%; IR (ATR):
7.37e7.12 (m, 4H, AreH), 7.00 (s, 1H, C]CH), 5.51 (s, 1H, C]
CHCOOEt), 4.29 (q, J¼7.12 Hz, 2H, OCH2), 3.75 (s, 2H, CH2, keto
form), 2.44 (s, 3H, PhCH3), 1.35 (t, J¼7.12 Hz, 3H, CH3); 13C NMR
ymax¼1738 (C]O), 1615 (C]N), 1342 (C]S) cmꢀ1
;
1H NMR
(400 MHz, CDCl3):
d (ppm) 7.61e7.21 (m, 9H, AreH), 2.43 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3):
d
(ppm) 192.1 (C]S), 161.7 (NC]
(100 MHz, CDCl3): d (ppm) 195.5 (C]S), 172.1 (O]CeCH2), 167.1
O), 148.9 (C]N), 145.6, 139.1, 134.0, 130.3, 130.0, 129.8, 129.7, 128.2,
121.6 (C]C ve C]N), 21.3 (CH3). Anal. Calcd for C16H12N2OS2
(COOEt), 165.2 (NeC]O), 140.1, 132.5, 131.8, 130.3, 127.9, 123.7, 99.1
(C]C), 61.2 (OCH2), 21.4 (PhCH3),14.2 (CH3). Anal. Calcd for
€
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S¸ .H. Ungoren et al. / Tetrahedron xxx (2015) 1e12
10
C15H13NO4S2 (335.4 g/mol): C, 53.72; H, 3.91; N, 4.18; S, 19.12.
Found: C, 53.76; H, 3.96; N, 4.22; S, 19.14%.
24. Methyl (2Z)-[5-oxo-3-phenyl-2-(phenylimino)-1,3-
thiazolidin-4-ylidene]acetate (20)
Yellow crystals; mp 126ꢀ127 ꢁC; yield 0.304 g 90%; IR (ATR):
19. 3-[3-(4-Methylphenyl)-5-oxo-2-thioxo-1,3-thiazolidin-4-
ylidene]pyrrolidine-2,5-dione (15)
ymax¼1728, 1698, 1651 (C]O, C]N) cmꢀ1
;
1H NMR (400 MHz,
CDCl3):
d (ppm) 7.58e6.94 (m, 10H, AreH), 7.01 (s, 1H, CH), 3.84 (s,
3H, OCH3); 13C NMR (100 MHz, CDCl3):
d (ppm) 166.4 (C]O, ester),
Green crystals; mp 242ꢀ243 ꢁC; yield 0.238 g 75%; IR (ATR):
164.6 (NC]O), 151.7, 147.4, 141.5, 134.0, 129.4, 129.3, 129.2, 127.9,
125.3, 120.9, 116.5 (C]C and C]N), 52.6 (OCH3); Anal. Calcd. For
18H14N2O3S (338.4 g/mol): C, 63.89; H, 4.17; N, 8.28; S, 9.48.
ymax¼3153 (NH), 1759, 1705, 1686 (C]O), 1343 (C]S) cmꢀ1
;
1H
NMR (400 MHz, DMSOꢀd6):
d (ppm) 12.10 (s,1H, NH), 7.92e7.17 (m,
C
4H, AreH), 3.43 (s, 2H, CH2), 2.50 (s, 3H, CH3); 13C NMR (100 MHz,
(ppm) 176.0 (C]S), 171.1 (CH2C]O), 170.9 (NHC]O),
Found: C, 63.72; H, 4.13; N, 8.36; S, 9.57%.
DMSOꢀd6):
d
166.6 (ArNeC]O), 139.8, 134.5, 130.8, 128.8, 126.2, 120.3 (C]C),
36.6 (CH2), 21.3 (ArCH3). Anal. Calcd for C14H10N2O3S2 (318.4 g/
mol): C, 52.82; H, 3.17; N, 8.80; S, 20.14. Found: C, 52.87; H, 3.18; N,
8.78; S, 20.17%.
25. 9-(Phenylimino)[1,3]thiazolo[3,2-a]perimidin-10(9H)-one
(21)
Orange solid; mp 201ꢀ202 ꢁC; yield 0.250 g 76%; IR (ATR):
ymax¼1717 (C]O), 1626 (C]N) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
d
(ppm) 8.78e7.22 (m, 11H, AreH); 13C NMR (100 MHz, CDCl3):
20. 3-(4-Methylphenyl)-4-(phenylimino)-2-thioxo-1,3-
thiazolidin-5-one (16)
(ppm) 158.4 (N]CeS), 148.8 (C]O), 148.6 (C]NeAr),148.1, 137.8,
133.9, 131.1, 129.8, 128.2, 127.8, 127.6, 125.5, 125.4,121.0, 120.4,118.7,
111.7 (C]C, arom.); Anal. Calcd. For C19H11N3OS (329 g/mol): C,
69.28; H, 3.37; N, 12.76; S, 9.74 Found: C, 69.43; H, 3.31; N, 12.95; S,
9.92%.
Yellow crystals; mp 125ꢀ126 ꢁC; yield 0.302 g 79%; IR (ATR):
ymax¼1740 (C]O), 1667 (C]N), 1346 (C]S) cmꢀ1
;
1H NMR
(400 MHz, CDCl3):
d (ppm) 7.70e7.19 (m, 9H, AreH), 2.46 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3):
d (ppm) 192.0 (C]S), 161.6 (NC]
26. 9-[(4-Methylphenyl)imino][1,3]thiazolo[3,2-a]perimidin-
10(9H)-one (22)
O), 150.8 (C]N), 148.5, 140.4, 130.4, 129.7, 129.3, 128.3, 127.8, 120.9,
(C]C and C]N), 21.4 (ArCH3). Anal. Calcd for C16H12N2OS2 (312.4 g/
mol): C, 61.51; H, 3.87; N, 8.97; S, 20.53. Found: C, 61.68; H, 3.85; N,
8.92; S, 20.47%.
Orange solid; mp 172ꢀ173 ꢁC; yield 0.264 g 77%; IR (ATR):
ymax¼1714 (C]O), 1626 (C]N) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
(ppm) 8.75e7.21 (m, 10H, AreH), 2.43 (s, 3H, Me); 13C NMR
21. 3-(4-Methylphenyl)-4-(1-naphthylimino)-2-thioxo-1,3-
thiazolidin-5-one (17)
(100 MHz, CDCl3): d (ppm) 158.5 (N]CeS), 148.9 (C]O), 146.5 (C]
NeAr), 146.0, 138.3, 137.9, 133.9, 131.1, 130.3, 128.2, 127.6, 125.4,
125.3, 120.9, 120.8, 118.7, 111.6, (C]C, arom.), 21.3 (Me); Anal. Calcd.
For C20H13N3OS (343 g/mol): C, 69.95; H, 3.82; N, 12.24; S, 9.34
Found: C, 69.82; H, 3.89; N, 12.36; S, 9.25%.
Red crystals; mp 175ꢀ176 ꢁC; yield 0.220 g 61%; IR (ATR):
ymax¼1733 (C]O), 1697 (C]N), 1347 (C]S) cmꢀ1
;
1H NMR
(400 MHz, CDCl3):
d (ppm) 8.23e7.16 (m, 11H, AreH), 2.48 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3):
d (ppm) 192.2 (C]S), 161.3 (NC]
27. 9-[(4-Methoxyphenyl)imino][1,3]thiazolo[3,2-a]peri-
midin-10(9H)-one (23)
O), 151.5 (C]N), 145.6, 140.4, 134.2, 131.3, 130.5, 128.7, 127.9, 127.8,
127.7, 127.3, 126.8, 125.4, 123.3, 113.0 (C]C and C]N), 21.4 (ArCH3).
Anal. Calcd for C20H14N2OS2 (362.5 g/mol): C, 66.27; H, 3.89; N,
7.73; S, 17.69. Found: C, 66.41; H, 3.86; N, 7.80; S, 17.81%.
Orange solid; mp 229ꢀ230 ꢁC; yield 0.276 g 77%; IR (ATR):
ymax¼1728 (C]O), 1626 (C]N) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
(ppm) 8.76e6.99 (m, 10H, AreH), 3.89 (s, 3H, OMe); 13C NMR
(100 MHz, CDCl3): d (ppm) 158.8 (N]CeS), 149.1 (C]O), 143.8 (C]
22. 3-(4-Methylphenyl)-4-[(4-methylphenyl)imino]-2-thioxo-
1,3-thiazolidin-5-one (18)
NeAr), 159.7, 140.8, 138.0, 133.9, 131.2, 128.2, 127.6, 125.3, 125.2,
123.7, 120.7, 118.8, 114.9, 111.6 (C]C, arom.), 55.6 (OMe); Anal.
Calcd. For C20H13N3O2S (359 g/mol): C, 66.84; H, 3.65; N, 11.69; S,
8.92 Found: C, 66.71; H, 3.67; N, 11.48; S, 9.12%.
Yellow crystals; mp 195ꢀ196 ꢁC; yield 0.199 g 61%; IR (ATR):
ymax¼1737 (C]O), 1659 (C]N), 1343 (C]S) cmꢀ1
;
1H NMR
(400 MHz, CDCl3):
d (ppm) 7.58e7.19 (m, 8H, AreH), 2.46 (s, 3H,
28. 9-[(4-Bromophenyl)imino][1,3]thiazolo[3,2-a]perimidin-
10(9H)-one (24)
ArCH3), 2.43 (s, 3H, ArCH3); 13C NMR (100 MHz, CDCl3):
d (ppm)
192.3 (C]S), 161.8 (NC]O), 145.6, 140.3, 139.0, 131.3, 130.4, 130.3,
127.9,121.6,119.8 (C]C and C]N), 21.4, 21.3 (2ꢂArCH3). Anal. Calcd
for C17H14N2OS2 (326.4 g/mol): C, 62.55; H, 4.32; N, 8.58; S, 19.65.
Found: C, C, 62.21; H, 4.53; N, 8.38; S, 19.54%.
Orange solid; mp 232ꢀ233 ꢁC; yield 0.330 g 81%; IR (ATR):
ymax¼1716 (C]O), 1619 (C]N) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
d
(ppm) 8.77e7.14 (m, 10H, AreH); 13C NMR (100 MHz, CDCl3):
(ppm) 158.1 (N]CeS), 148.0 (C]O), 147.7 (C]NeAr), 137.8, 133.8,
23. 4-[(4-Bromophenyl)imino]-3-(4-methylphenyl)-2-thioxo-
1,3-thiazolidin-5-one (19)
133.0, 131.1, 128.3, 127.6, 125.7, 125.6, 122.1, 121.3, 121.2, 118.6, 111.8,
(C]C, arom.); Anal. Calcd. For C19H10BrN3OS (408 g/mol): C, 55.89;
H, 2.47; N, 10.29; S, 7.85 Found: C, 55.68; H, 2.47; N, 10.18; S, 7.62%.
Orange crystals; mp 158ꢀ159 ꢁC; yield 0.269 g 69%; IR (ATR):
ymax¼1739 (C]O), 1659 (C]N), 1334 (C]S) cmꢀ1
;
1H NMR
29. 9-(1-Naphthylimino)[1,3]thiazolo[3,2-a]perimidin-
10(9H)-one (25)
(400 MHz, CDCl3):
d (ppm) 7.64e7.12 (m, 8H, AreH), 2.46 (s, 3H,
ArCH3); 13C NMR (100 MHz, CDCl3):
d (ppm) 191.0 (C]S), 161.5 (C]
O), 151.4 (C]N), 147.2, 140.5, 133.0, 131.1, 130.5, 127.8, 122.6, 122.1,
(C]C, arom.), 21.4 (ArCH3). Anal. Calcd. For C16H11BrN2OS2 (391.3 g/
mol): C, 49.11; H, 2.83; N, 7.16; S, 16.39. Found: C, 49.23; H, 2.80; N,
7.37; S, 16.51%.
Orange solid; mp 198ꢀ199 ꢁC; yield 0.315 g 83%; FTꢀIR (ATR):
ymax¼1717 (C]O), 1626 (C]N) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
d
(ppm) 8.80e7.22 (m, 13H, AreH); 13C NMR (100 MHz, CDCl3):
(ppm) 158.4 (N]CeS), 148.8 (C]O), 148.5 (C]NeAr), 137.8,
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11
133.8, 131.1, 129.8, 128.2, 127.8, 127.6, 125.5, 125.4, 121.0, 120.4, 111.7
(C]C, arom.); Anal. Calcd. For C23H13N3OS (408 g/mol): C, 72.80; H,
3.45; N, 11.07; S, 8.45 Found: C, 72.99; H, 3.42; N, 11.01; S, 8.49%.
(CH3); Anal. Calcd. For C19H14N2O4S (366 g/mol): C, 62.28; H, 3.85;
N, 7.65; S, 8.75 Found: C, 62.32; H, 3.71; N, 7.44; S, 8.58%.
35. 3-(10-Oxo[1,3]thiazolo[3,2-a]perimidin-9(10H)-ylidene)
pyrrolidine-2,5-dione (31)
30. 9-(4-Phenyldiazenylphenylimino)[1,3]thiazolo[3,2-a]peri-
midin-10(9H)-one (26)
Red solid; mp 307ꢀ308 ꢁC; yield 0.181 g 54%; IR (ATR):
Red solid; mp 225ꢀ226 ꢁC; yield 0.317 g 73%; IR (ATR):
ymax¼3176 (NH), 1764, 1694, (C]O), 1625 (C]N) cmꢀ1
;
1H NMR
ymax¼1732 (C]O), 1625 (C]N) cmꢀ1
;
1H NMR (400 MHz, DMSO-
(400 MHz, DMSOꢀd6):
d (ppm) 11.98 (s, 1H, NH), 8.51e7.18 (m, 6H,
d6):
d
(ppm) 8.59e7.24 (m, 15H, AreH); 13C NMR (100 MHz,
AreH), 3.78 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6):
d (ppm)
Pyridineꢀd5):
d (ppm) 159.8 (N]CeS), 151.7 (C]O), 150.6 (C]
175.9, 170.9, 153.0 (NHC]O), 162.7, 138.9, 134.1, 132.2, 128.9, 128.5,
128.0, 125.1, 119.8, 118.4, 110.3 (C]C and C]N), 39.1 (CH2); Anal.
Calcd. For C17H9N3O3S (335 g/mol): C, 60.89; H, 2.71; N, 12.53; S,
9.56 Found: C, 60.96; H, 2.66; N, 12.39; S, 9.59%.
NeAr), 154.3, 153.4, 152.7, 152.1, 140.0, 137.3, 136.3, 135.6, 133.2,
133.1, 131.0, 130.0, 129.1, 126.8, 126.7, 126.4, 124,7, 124.2, 122.6,
122.3, 120.4, 112.7 (C]C, arom.); Anal. Calcd. For C25H15N5OS
(433 g/mol): C, 69.27; H, 3.49; N, 16.16; S, 7.40 Found: C, 69.12; H,
3.43; N, 16.32; S, 7.43%.
36. (9Z)-9-(2-Oxo-2-phenylethylidene)[1,3]thiazolo[3,2-a]
perimidin-10(9H)-one (32)
31. Methyl (2Z)-(10-oxo[1,3]thiazolo[3,2-a]perimidin-9(10H)-
ylidene)acetate (27)
Brown solid; mp 239ꢀ240 ꢁC; yield 0.313 g 88%; IR (ATR):
ymax¼1700, 1638 (C]O), 1624 (C]N) cmꢀ1
;
1H NMR (400 MHz,
Red solid; mp 215ꢀ216 ꢁC; yield 0.270 g 87%; IR (ATR):
CDCl3): d
(ppm) 8.71e7.32 (m, 11H, AreH), 7.24 (s, 1H, CH); 13C NMR
ymax¼1709 (COOMe), 1688 (NC]O), 1628 (C]N) cmꢀ1
;
1H NMR
(100 MHz, CDCl3):
d (ppm) 188.6 (PhC]O), 162.4 (NC]O), 153.3,
(400 MHz, CDCl3): d (ppm) 8.59e7.23 (m, 6H, AreH), 7.05 (s,1H, C]
CH), 3.91 (s, 3H, OMe); 13C NMR (100 MHz, CDCl3):
d (ppm) 166.6
140.9, 138.4, 136.7, 134.0, 133.9, 131.6, 129.1, 128.6, 128.4, 127.4,
125.3, 125.2, 120.9, 118.3, 117.7, 111.5 (C]C and C]N); Anal. Calcd.
For C21H12N2O2S (356 g/mol): C, 70.77; H, 3.39; N, 7.86; S, 9.00
Found: C, 71.00; H, 3.35; N, 7.93; S, 9.11%.
(MeC]O), 140.3 (NC]O), 161.5, 138.2, 133.8, 131.5, 128.3, 127.3,
125.3, 125.0, 120.6, 118.2, 116.5, 111.3, 100.0 (C]C and C]N), 52.7
(OMe); Anal. Calcd. For C16H10N2O3S (310 g/mol): C, 61.93; H, 3.25;
N, 9.03; S, 10.33 Found: C, 62.16; H, 3.29; N, 9.22; S, 10.06%.
37. General procedure for the preparation of chalcone de-
rivatives 33 and 34
32. Ethyl (2Z)-(10-oxo[1,3]thiazolo[3,2-a]perimidin-9(10H)-
ylidene)acetate (28)
To solution of compound 13 (0.263 g, 1 mmol) and corre-
sponding aldehyde (1.1 mmol) in 3 mL dioxane was added (0.185 g,
1.3 mmol) BF3$(C2H5)2O, then the solution was stirred at 50 ꢁC for
30 min. After addition of 5 mL water, the residue was subjected to
column chromatography on silica gel 60 Hf254; elution with CHCl3
afforded the product.
Red solid; mp 179ꢀ180 ꢁC; yield 0.262 g 81%; IR (ATR):
ymax¼1710 (COOEt), 1680 (NC]O), 1625 (C]N) cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d (ppm) 8.62e7.24 (m, 6H, AreH), 7.06 (s,1H, C]
CH), 4.37 (q, J¼7.1 Hz, 2H, OCH2), 1.40 (t, J¼7.1 Hz, 3H, CH3); 13C
NMR (100 MHz, CDCl3):
d (ppm) 166.1 (MeC]O), 139.9 (NeC]O),
161.6, 139.9, 138.3, 133.9, 131.5, 128.3, 127.3, 125.2, 125.0, 120.6,
118.2, 117.1, 111.3 (C]C and C]N), 61.9 (OCH2), 14.2 (CH3); Anal.
Calcd. For C17H12N2O3S (324 g/mol): C, 62.95; H, 3.73; N, 8.64; S,
9.89 Found: C, 62.82; H, 3.80; N, 8.78; S, 10.11%.
38. (5Z)-5-[(3E)-4-(4-Methoxyphenyl)-2-oxobut-3-en-1-
ylidene]-3-(4-methylphenyl)-2-thioxo-1,3-thiazolidin-4-one
(33)
33. (9Z)-9-(2-Oxopropylidene)[1,3]thiazolo[3,2-a]perimidin-
10(9H)-one (29)
Red crystals; mp 172ꢀ173 ꢁC; yield 0.253 g 66%; IR (ATR):
ymax¼1728, 1694, 1646 (C]O, C]N), 1345 (C]S) cmꢀ1
;
1H NMR
(400 MHz, CDCl3):
d
(ppm) 7.81 (d, J¼15.89 Hz, 1H,]CH), 7.62e6.96
Redꢀbrown needles; mp 203ꢀ204 ꢁC; yield 0.262 g 89%; IR
(m, 8H, AreH), 7.58 (s, 1H,]CH), 6.94 (d, J¼15.89 Hz, 1H,]CH), 3.89
(ATR): ymax¼1710 (C]O), 1626 (C]N) cmꢀ1
;
1H NMR (400 MHz,
d (ppm) 8.52e7.16 (m, 6H, AreH), 7.37 (s, 1H, C]CH), 2.49
(s, 3H, OCH3), 2.45 (s, 3H, PhꢀCH3); 13C NMR (100 MHz, CDCl3):
CDCl3):
d
(ppm) 189.9 (C]O, keton), 187.1 (C]S), 167.4 (NC]O), 162.6,
(s, 3H, Me); 13C NMR (100 MHz, CDCl3):
d (ppm) 196.7 (MeC]O),
146.1, 140.5, 140.1, 131.6, 130.8, 130.3, 128.0, 126.8, 124.0, 120.6, 114.7
(C]C), 55.5 (ArOCH3), 21.4 (ArCH3); Anal. Calcd. For C21H17NO3S2
(395.5 g/mol): C, 63.77; H, 4.33; N, 3.54; S,16.22. Found: C, 63.98; H,
4.33; N, 3.48; S, 16.02%.
153.0 (NC]O), 162.1, 138.4, 138.2, 133.7, 131.3, 128.2, 127.3, 125.2,
125.0, 120.8, 120.8, 118.1, 111.3 (C]C and C]N), 30.7 (Me); Anal.
Calcd. For C16H10N2O2S (294 g/mol): C, 65.29; H, 3.42; N, 9.52; S,
10.89 Found: C, 65.46; H, 3.42; N, 9.41; S, 10.97%.
34. Ethyl (4Z)-3-oxo-4-(10-oxo[1,3]thiazolo[3,2-a]perimidin-
9(10H)-ylidene)butanoate (30)
39. (5Z)-5-[(3E)-4-(2-Chlorophenyl)-2-oxobut-3-en-1-
ylidene]-3-(4-methylphenyl)-2-thioxo-1,3-thiazolidin-4-one
(34)
Red solid; mp 193ꢀ194 ꢁC; yield 0.304 g 83%; IR (ATR):
ymax¼1714 (C]O), 1626 (C]N) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
Orange crystals; mp 191ꢀ192 ꢁC; yield 0.186 g 48%; IR (ATR):
d
(ppm) 12.37 (s, 1H, OH), 8.77e7.20 (m, 6H, AreH), 7.09 (d,
ymax¼1724, 1696, 1637 (C]O, C]N), 1345 (C]S) cmꢀ1
;
1H NMR
J¼1.8 Hz, 1H, C]CHC]O), 5.45 (s, 1H, enol’s C]CH), 4.28 (q,
(400 MHz, CDCl3):
d
(ppm) 8.25 (d, J¼16.1 Hz, 1H,]CH), 7.75e6.93
J¼7.1 Hz, 2H, CH2), 1.35 (t, J¼7.2 Hz, 3H, Me); 13C NMR (100 MHz,
(m, 8H, AreH), 7.62 (s, 1H,]CH), 6.94 (d, J¼15.5 Hz, 1H,¼CH), 2.46
CDCl3):
d
(ppm) 172.3 (EtOC]O), 165.9 (CeOH), 152.2 (NC]O),
(s, 3H, Ph-CH3); 13C NMR (100 MHz, CDCl3):
d
(ppm) 198.5 (C]O,
162.7, 138.4, 138.5, 134.0, 131.8, 129.6, 128.3, 127.3, 125.0, 124.5,
123.1, 120.0, 118.4, 110.9, 97.4 (C]C and C]N), 61.0 (OCH2), 14.2
keton), 187.3 (C]S), 167.2 (NC]O), 141.7, 141.5, 140.2, 136.0, 132.3,
132.1, 131.5, 130.5, 130.3, 128.3, 127.9, 127.8, 127.3, 119.7 (C]C), 21.4
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S¸ .H. Ungoren et al. / Tetrahedron xxx (2015) 1e12
12
8. Szewczuk, L. M.; Saldanha, S. A.; Ganguly, S.; Bowers, E. M.; Javoroncov, M.;
Karanam, B.; Culhane, J. C.; Holbert, M. A.; Klein, D. C.; Abagyan, R.; Cole, P. A. J.
Med. Chem. 2007, 50, 5330e5338.
(ArCH3); Anal. Calcd. For C20H14ClNO2S2 (400 g/mol): C, 60.07; H,
3.53; N, 3.50; S, 16.04. Found: C, 60.12; H, 3.51; N, 3.53; S, 16.13%.
9. Furdas, S. D.; Shekfeh, S.; Kannan, S.; Sippl, W.; Jung, M. Med. Chem. Commun.
2012, 3, 305e311.
10. Mishra, A.; Fischer, M. K. R.; Bauerle, P. Angew. Chem., Int. Ed. 2009, 48,
2474e2499.
Acknowledgements
This work was financially supported by Erciyes University Re-
search Fund, Project No: FYL-2012-4163 and Bozok University Re-
search Fund, Project No: 2013FEF/A89 and 2013FBE/T54.
11. Delower, M.; Bhuiyan, H.; Teshome, A.; Gainsford, G. J.; Ashraf, M.; Clays, K.;
Asselberghs, I.; Kay, A. J. Opt. Mater. 2010, 32, 669e672.
12. Ramkumar, K.; Yarovenko, V. N.; Nikita, A. S.; Zavarzin, I.; Krayushkin, M. M.;
Kovalenko, L. V.; Esqueda, A.; Odde, S.; Neamati, N. Molecules 2010, 15,
3958e3992.
Supplementary data
13. (a) Liu, C. K.; Chen, H. H.; Lee, L. C.; Chern, J. W. Arch. Pharmacol. 1979, 312,
776e780; (b) Rahnema, M.; Bigdeli, M. R.; Kazemizadeh, A. R.; Ramazani, A.
Phosphorus, Sulfur and Silicon. 2007, 182, 1683e1688; (c) Wade, J. J. J. Org. Chem.
1979, 44, 1816e1819; (d) Alizadeh, A.; Rostamnia, S.; Zohreh, N.; Hosseinpour,
R. Tetrahedron Lett. 2009, 50, 1533e1535; (e) Choudhary, G.; Peddinti, R. K.
Tetrahedron Lett. 2014, 55, 5597e5600.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.04.069.
€
€
€
€
14. (a) Sac¸ macı, M.; Ungoren, S¸ . H.; Akc¸ amur, Y.; Arıcı, C.; Ulku, D. Heteroat. Chem.
References and notes
€
€
2005, 16, 235e241; (b) Sac¸ macı, M.; Ungoren, S¸ . H.; Akc¸ amur, Y. Amino Acids
_
€
€
2006, 31, 397e401; (c) Koca, I.; Sac¸ macı, M.; Yılmaz, F.; Ungoren, S¸ . H. J. Het-
€
_
1. Hajibabaei, K. Synlett 2014, 2083e2084.
2. Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14,
347e361.
€
€
erocycl. Chem. 2013, 51, 212e218; (d) Ungoren, S¸ . H.; Kani, I.; Gunay, A. Tetra-
hedron Lett. 2012, 53, 4758e4762.
15. Ritter, W. Tetrahedron Lett. 1967, 46, 4593e4596.
3. Tomasic, T.; Masic, L. P. Curr. Med. Chem. 2009, 16, 1596e1629.
4. (a) Maccari, R.; Ottana, R.; Curinga, C.; Vigorita, M. G.; Rakowitz, D.; Steindl, T.;
Langer, T. Bioorg. Med. Chem. 2005, 13, 2809e2823; (b) Kador, P. F.; Kinoshita, J.
H.; Sharpless, N. E. J. Med. Chem. 1985, 28, 841e849.
5. Grant, E. B.; Guiadeen, D.; Baum, E. Z.; Foleno, B. D.; Jin, H.; Montenegro, D. A.;
Nelson, E. A.; Bush, K.; Hlasta, D. J. Bioorg. Med. Chem. Lett. 2000, 10, 2179e2182.
6. Sign, W. T.; Lee, C. L.; Yeo, S. L.; Lim, S. P.; Sim, M. M. Bioorg. Med. Chem. Lett.
2001, 11, 91e94.
16. Ulrich, H.; Sayigh, A. A. R. J. Org. Chem. 1965, 30, 2781e2783.
17. Acheson, R. M.; Wallis, J. D. J. Chem. Soc., Perkin Trans. 1 1981, 2, 415e422.
18. Lee, S. K.; Mbwambo, Z. H.; Chung, H.; Luyengi, L.; Gamez, E. J.; Mehta, R. G.;
Kinghorn, A. D.; Pezzuto, J. M. Comb. Chem. High Throughput Screening 1988, 1,
35e46.
€
ꢀ
19. Ozyanık, M.; Demirci, S.; Bektas¸ , H.; Demirbas¸ , N.; Demirbas¸ , A.; Karaoglu, S¸ . A.
Turk. J. Chem. 2012, 36, 233e246.
20. Sarker, S. D.; Nahar, L.; Kumarasamy, Y. Methods 2007, 42, 321e324.
21. SPSS Version 10.0., 2001. SPSS Inc, 233 S. Wacker Drive, Chicago, Illiois.
7. Free, C. A.; Majchrowicz, E.; Hess, S. M. Biochem. Pharmacol. 1971, 20,
1421e1428.
€
€
Please cite this article in press as: Ungoren, S¸ . H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.069