Syntheses and evaluation of antioxidant activity of sydnonyl substituted thiazolidinone and thiazoline derivatives

Article abstract of DOI:10.1016/j.bmc.2004.06.033

3-Aryl-4-formylsydnone 4′-phenylthiosemicarbazones (3a-d) and 3-aryl-4-formylsydnone thiosemicarbazones (3e-h), which are precursors of 3-aryl-4-heterocyclic sydnones, are prepared by the condensation of 3-aryl-4-formylsydnones (1a-d) with 4′-phenylthiosemicarbazide (2a) and thiosemicarbazide (2b), respectively. The thiosemicarbazones 3 reacted with cyclic reagents such as ethyl chloroacetate (4a), ethyl 2-chloroacetoacetate (4b) and 2-bromoacetophenone (4c) to produce heterocyclic substituted sydnone derivatives 5-7 that possess 4-oxo-thiazolidine and thiazoline groups. The antioxidant activity of synthesized compounds 5a-7h was evaluated. Among these compounds, 4-methyl-2-[(3-arylsydnon-4-yl-methylene)hydrazono]-2,3-dihydro- thiazole-5-carboxylic acid ethyl ester (6e-h) and 4-phenyl-2-[(3-arylsydnon-4- yl-methylene)hydrazono]-2,3-dihydro-thiazoles (7e-h) exhibit the potent DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity, comparable to that of vitamin E.

Full text of DOI:10.1016/j.bmc.2004.06.033

Bioorganic & Medicinal Chemistry 12 (2004) 4633–4643
Syntheses and evaluation of antioxidant activity of
sydnonyl substituted thiazolidinone and thiazoline derivatives
Mei-Hsiu Shih* and Fang-Ying Ke
Department of Chemical Engineering, Southern Taiwan University of Technology, 1 Nan-Tai St. Yung-Kang, Tainan 710,
Taiwan, ROC
Received 26 May 2004; revised 25 June 2004; accepted 25 June 2004
Abstract—3-Aryl-4-formylsydnone 40-phenylthiosemicarbazones (3a–d) and 3-aryl-4-formylsydnone thiosemicarbazones (3e–h),
which are precursors of 3-aryl-4-heterocyclic sydnones, are prepared by the condensation of 3-aryl-4-formylsydnones (1a–d) with
40-phenylthiosemicarbazide (2a) and thiosemicarbazide (2b), respectively. The thiosemicarbazones 3 reacted with cyclic reagents
such as ethyl chloroacetate (4a), ethyl 2-chloroacetoacetate (4b) and 2-bromoacetophenone (4c) to produce heterocyclic substituted
sydnone derivatives 5–7 that possess 4-oxo-thiazolidine and thiazoline groups. The antioxidant activity of synthesized compounds
5a–7h was evaluated. Among these compounds, 4-methyl-2-[(3-arylsydnon-4-yl-methylene)hydrazono]-2,3-dihydro-thiazole-5-carb-
oxylic acid ethyl ester (6e–h) and 4-phenyl-2-[(3-arylsydnon-4-yl-methylene)hydrazono]-2,3-dihydro-thiazoles (7e–h) exhibit the
potent DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity, comparable to that of vitamin E.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
phenylthiosemicarbazones (3a–d) or 3-aryl-4-formyl-
sydnone thiosemicarbazones (3e–h) with cyclic reagents
such as ethyl chloroacetate (4a), ethyl 2-chloroacetoace-
tate 4b and 2-bromoacetophenone (4c). The scavenging
effects of all of the synthesized compounds on the DPPH
free radical are evaluated. Nowadays, antioxidants that
exhibit DPPH radical scavenging activity are increas-
ingly receiving attention. They have been reported to
have interesting anticancer, antiageing and anti-inflam-
matory activities. To the authorsÕ knowledge, no investi-
gation of the radical scavenging effects of synthesized
sydnone derivatives has yet been undertaken. Accord-
ingly, a study of the syntheses of new sydnone deriva-
tives with antioxidant activity would support the
development of new drugs and improve the treatment
of various diseases.
Several sydnone derivatives have associated with a
broad range of physiological activities, exhibiting anti-
microbial, anti-inflammatory, analgesic and antipyretic
properties.1–3 Hence, chemists have been enthusiastically
pursuing the syntheses of these derivatives.4–6 Thio-
semicarbazones have been reported to exhibit antituber-
culosis activity.7,8 Besides, thiazoles and their derivatives
exhibit various biological activities such as antimicro-
bial, anti-inflammatory, antiviral, antituberculosis and
cytotoxic activities, among others.9–18 Following reports
of these activities, this study seeks to synthesize a series
of novel thiazole derivatives that contain the sydnonyl
moiety, with the aim of obtaining new biologically active
compounds. In view of the continued interest in the
development of simpler and more convenient synthetic
routes for preparing heterocyclic systems,19–27 an effi-
cient and useful method is reported herein to synthesize
some new sydnonyl-substituted thiazolidinones and thi-
azolines by the reaction of 3-aryl-4-formylsydnone 40-
2. Results and discussion
2.1. Synthetic chemistry
Thiosemicarbazones exhibit various biological activities
and are widely used in medicine, especially in the treat-
ment of tuberculosis.7,8 Many compounds with a thio-
Keywords: 3-Aryl-4-formylsydnone thiosemicarbazones; Thiazolindi-
nones; Thiazolines; Antioxidant activity.
*
Corresponding author. Tel.: +886-6-2533131x3723; fax: +886-6-
2425741; e-mail: meihsius@mail.stut.edu.tw
semicarbazone
moiety
also exhibit biological
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.06.033

4634
M.-H. Shih, F.-Y. Ke / Bioorg. Med. Chem. 12 (2004) 4633–4643
activity.28 Accordingly, 3-aryl-4-formylsydnone 40-phen-
ylthiosemicarbazones (3a–d) and 3-aryl-4-formylsyd-
none thiosemicarbazones (3e–h) were synthesized in
good yields by the reactions of 3-aryl-4-formylsydnones
(1a–d) with 40-phenylthiosemicarbazide (2a) and thi-
osemicarbazide (2b), respectively (Scheme 1).
posed during reaction and/or workup, so in the reaction,
sodium acetate was used to scavenge the released hydro-
gen chloride that could cause the decomposition of syd-
nones. Acetic acid was used to catalyze the cyclization.
Increasing the amount of acetic acid accelerated the
reaction. Besides, acetic acid and sodium acetate form
a buffer system to maintain the pH value of the reaction
solution at 4.6–4.7 and avoid the decomposition of syd-
nones. Therefore, under optimal conditions, compounds
3a–d reacted with ethyl chloroacetate in ethanol solution
with a catalytic amount of acetic acid to yield the desired
products 5a–d. All these products were spectroscopically
characterized. Among the new products 5a–d, the or-
ange crystal 5c was analytically pure and suitable for
X-ray structure analyses. Figure 1 presents the mole-
cular structure of compound 5c.
Thiazolidine-4-ones are well known for their pharmaco-
logical activities. Several substituted thiazolidinones
have been found to possess hypnotic, anaesthetic, seda-
tive, anticonvulsant and microbiological activities.29–31
In view of the various physiological activities of thiazol-
idinone derivatives, many thiazolidinone derivatives
have been prepared. In this report, 3-aryl-4-formylsyd-
none 40-phenyl thiosemicarbazones (3a–d) were used to
react with ethyl chloroacetate (4a) in ethanol solution
that contained sodium acetate/acetic acid buffer system,
to produce 2-[(3-aryl-sydnon-4-ylmethylene)hydraz-
ono]-3-phenyl-thiazolidin-4-ones (5a–d) in high yields
(Scheme 2).
The pharmacological properties of thiazolines have been
studied. Thus, some thiazoline derivatives show interest-
ing anti-HIV or anticancer activities and can inhibit cell
division.32–34 This paper presents a convenient strategy
for synthesizing 4-methyl-5-ester-substituted thiazolines
6 and 4-phenyl-substituted thiazolines 7. Cyclic reagents
The sydnone ring is sensitive to acids such as hydrochlo-
ric acid, and sydnone compounds are sometimes decom-
S
H2N
N
H
N
H
S
H
Ar
N
yield: 80-90
yield: 71-80
%
N
H
N
H
2a
N
O
N
O
O
Ar
H
S
3a-3d
H
N
H2N
N
S
O
N
NH2
O
Ar
N
H
1a-1d
%
N
N H
N
2b
H
H
N
O
O
3e-3h
Scheme 1. 1a: Ar=C6H5; 1b: Ar=p-CH3C6H4; 1c: Ar=p-CH3OC6H4; 1d: Ar=p-C2H5OC6H4.
O
H
Cl
80
S
N
OC2H5
Ar
N
4a
, 40-45 h
N
N
O
o
C
N
O
O
5a-5d
O
O
C
O
H
OC2H5
CH3
S
CH3
80
OC2H5
N
Ar
S
H
N
Cl
N
N
N
Ar
4b
N
H
N
H
N
O
N
o
, 20-25 h
O
N
O
6a-6d
O
3a-3d
H
Br
S
N
Ar
N
N
O
N
N
4c
O
O
o
50 , 7-12 h
C
7a-7d
Scheme 2. 3a: Ar=C6H5; 3b: Ar=p-CH3C6H4; 3c: Ar=p-CH3OC6H4; 3d : Ar=p-C2H5OC6H4.

M.-H. Shih, F.-Y. Ke / Bioorg. Med. Chem. 12 (2004) 4633–4643
4635
Figure 1. Crystal structure of compound 5c.
such as ethyl 2-chloroacetoacetate (4b) and 2-bromoac-
etophenone (4c) were allowed to react with 3-aryl-4-
formylsydnone 40-phenylthiosemicarbazones (3a–d) in
buffer systems of sodium acetate and acetic acid, to pro-
duce the desired products 2-[(3-arylsydnon-4-ylmethyl-
ene)hydrazono]-4-methyl-3-phenyl-2,3-dihydro-thiazole-5-
carboxylic acid ethyl esters (6a–d) and 3,4-diphenyl-2-
[(3-arylsydnon-4-ylmethylene)hydrazono]-2,3-dihydro-
thiazoles (7a–d) in good yields, too (Scheme 2).
Figure 2. Crystal structure of compound 6b.
All the reactions of compounds 3a–d with reagents 4a–c
were initiated at room temperature and then heated un-
til completion. The reaction time and reaction tempera-
ture of these cyclic reagents 4a–c with compounds 3
imply that the order of their reactivities is 4c>4b>4a.
All these products were spectroscopically characterized.
Among these new thiazoline derivatives 6a–7d, the or-
ange crystals 6b and 7c were analytically pure and suit-
able for X-ray structure analyses. Figures 2 and 3 show
the molecular structures of compounds 6b and 7c. De-
tails of crystal data of compounds 5c, 6b and 7c are
given in Table 1.
Figure 3. Crystal structure of compound 7c.
Treatment of 3-aryl-4-formylsydnone thiosemicarba-
zones (3e–h) with reagents 4a–c in ethanol solution that
contains sodium acetate and acetic acid buffer systems
yielded the desired products 5e–h, 6e–h and 7e–h also
in good yields (Scheme 3). The reaction time, the reac-
tion temperature and the corresponding yields of the
reaction 3a–h with reagents 4a–c imply that compounds
3e–h are more reactive than compounds 3a–d, because
the steric effect of the phenyl group reduces the ability
of compounds 3a–d to undergo nucleophilic cyclization,
and the greater electron density on the NH2 in com-
pounds 3e–h than on the NH in compounds 3a–d in-
creases the ability of compounds 3e–h to undergo
nucleophilic cyclization.
tate and acetic acid in that order, but still, the starting
materials 3e–h were unavoidably decomposed. Many
tests established that sodium acetate and acetic acid
should be first added to the ice-cooled solution of syd-
none 3. Then, cyclic reagent 4c was slowly added to
the buffer solution and the mixture was stirred to precip-
itate the desired material. Consequently, under optimal
experimental conditions, compounds 3e–h reacted with
2-bromoacetophenone (4c) in ethanol to generate prod-
ucts 7e–h in high yields (Scheme 3).
2.2. Scavenging effect of antioxidant activity on DPPH
radical
Among the cyclic reagents 4a–c, 2-bromoacetophenone
(4c) is the most reactive compound with thiosemicarba-
zones 3. The reactions of 4c with 3e–h must be per-
formed in an ice-cooled system to prevent the
decomposition of sydnone compounds during the reac-
tion. The reactions were initially also controlled by the
successive addition of reagent 4c, sydnones, sodium ace-
The model of the scavenging of the stable DPPH radical
is extensively used to evaluate antioxidant activities in
less time than other methods. DPPH is a stable free rad-
ical that can accept an electron or hydrogen radical and
thus be converted into a stable, diamagnetic molecule.
DPPH has an odd electron and so has a strong absorp-
tion band at 517nm. When this electron becomes paired

4636
M.-H. Shih, F.-Y. Ke / Bioorg. Med. Chem. 12 (2004) 4633–4643
Table 1. Crystal data of compounds 5c, 6b and 7c
Compound
5c
6b
7c
Diffractometer
Formula
Rigaku AFC7S
C19H15N5O4S
409.42
Rigaku AFC7S
C23H21N5O4S
463.51
Rigaku AFC7S
C25H19N5O3S
469.52
Formula weight
Crystal system
Crystal colour, habit
Space group
Monoclinic
Orange, plate
Cc (#9)
Triclinic
Orange, prism
P1ꢀ(#2)
Orthorhombic
Red, prism
Pca21 (#29)
24.48(1)
˚
a (A)
24.775(4)
5.325(4)
14.157(6)
10.165(2)
12.394(2)
10.026(2)
90.97(1)
110.47(1)
73.86(1)
1132.2(3)
2
˚
b (A)
5.593(4)
16.52(1)
˚
c (A)
a (ꢁ)
b (ꢁ)
c (ꢁ)
97.17(2)
3
˚
V (A )
1853(1)
4
1.467
2262(2)
4
Z
Dcalc (gcmꢀ3
F0 0 0
)
1.360
484.00
1.378
976.00
848.00
l (MoKa) (cmꢀ1
)
2.131.831.82
0.20·0.60·0.80
293293293
x–2h
52.0
2087
Crystal size (mm)
Temperature (K)
Scan type
0.20·0.60·0.70
0.35·0.55·0.65
x–2h
52.0
x–2h
52.1
2592
2hmax (ꢁ)
Reflections measured
Unique reflections
No. observations [I>3.00r(I)]
No. variables
4722
4457 (Rint =0.017)
2035 (Rint =0.015)
1451
262
3218
298
1281
307
Residuals: R; Rw
GoF
0.039; 0.057
1.531.82
0.044; 0.064
1.82
0.060; 0.082
O
H
S
N
Cl
o
Ar
Ar
Ar
N
N
N
OC2H5
N
4a
N
O
N
O
, 27-35 h
C
80
H
O
5e-5h
O
O
O
H
OC2H5
CH3
S
CH3
OC2H5
N
S
H
Cl
4b
N
N
Ar
N
N
H
N
H
H
N
N
O
o
H
, 20-24 h
C
O
80
N
6e-6h
O
O
3e-3h
H
Br
S
N
N
O
N
4c
N
O
H
O
o
, 8-19 h
C
0
7e-7h
Scheme 3. 3e: Ar=C6H5; 3f: Ar=p-CH3C6H4; 3g: Ar=p-CH3OC6H4; 3h: Ar=p-C2H5OC6H4.
off, the absorption decreases stoichiometrically with
respect to the number of electrons taken up. Such a
change in the absorbance produced in this reaction has
been widely applied to test the capacity of numerous
molecules to act as free radical scavengers. The scaveng-
ing effect of the synthesized compounds 5a–7h on the
DPPH radical was evaluated according to the methods
of Shimada et al.,35 Leong and Shui36 and Braca
et al.37 Various concentrations of the test compound
in 1.5mL methanol were added to a 1.5mL (0.2mM)
solution of DPPH radical in methanol (final concentra-
tion of DPPH was 0.1mM). The mixture was shaken
vigorously and allowed to stand for 30min or more;
absorbance at 517nm was determined by a Hitachi U-
2001 spectrophotometer, and the percentage of activity
was calculated. Vitamin E was used as a reference com-
pound. All tests and analyses were undertaken on three
replicates and the results averaged. The tests reveal that
the reaction with DPPH is in a time-dependent fashion
and that the more the concentration of the tested com-
pound the higher the radical scavenging activity it is.
However, compounds 5a–h with 4-oxo-thiazolidine moi-
ety exhibited 50–60% radical scavenging activity after
standing 3h (10–20% in 30min) at a final concentration

M.-H. Shih, F.-Y. Ke / Bioorg. Med. Chem. 12 (2004) 4633–4643
4637
of 0.1mM. Compounds 6a–d and 7a–d with 3-phenyl-
100
80
60
40
20
0
2,3-dihydrothiazole moiety showed 10–15% and 0–5%
radical scavenging activity (in 30min incubation),
respectively. In contrast, compounds 6e–h and 7e–h with
2,3-dihydrothiazole moiety scavenge DPPH radical very
fast and the incubated time only takes 10min to reach
equilibrium. Compounds 6e–h and 7e–h exhibited very
good radical scavenging activity 90–98% at a final con-
centration of 0.1mM. The radical scavenging effects
for each of the compounds 5a–7h (0.1mM) incubated
30min with DPPH at 0.1mM concentration are shown
in Figure 4. The profiles of the scavenging effect of com-
pounds 6e–h and 7e–h on DPPH are comparable to that
of vitamin E, and are presented in Figures 5 and 6,
respectively. In this study, compounds 6e–h and 7e–h
exhibited strong activity, perhaps due to the presence
of the functional group N–H in the 2,3-dihydrothiazole
moiety, which can donate hydrogen atoms. After donat-
ing a hydrogen atom, compounds 6e–h and 7e–h with
2,3-dihydrothiazole moiety exist in radical form, and
the electron conjugation effect in the structure stabilizes
the radical so that it does not become involved in a
destructive biochemical reaction.
7e
7f
7g
7h
Vit. E
0.00
0.05
0.10
0.15
0.20
0.25
0.30
Concentration mM
Figure 6. Scavenging activity of compounds 7e–h on DPPH radical.
3. Conclusion
In summary, various biologically active compounds that
contain a thiazolindinone or thiazoline moiety have
been discovered or chemically synthesized. This work
describes an efficient method of obtaining sydnonyl-sub-
stituted thiazolindinones or thiazolines. Applying this
method to the cyclization of 3-aryl-4-formylsydnone
40-phenylthiosemicarbazones (3a–d) or 3-aryl-4-formyl-
sydnone thiosemicarbazones (3e–h) with ethyl chloroac-
etate (4a), ethyl 2-chloroacetoacetate (4b) and 2-
bromoacetophenone (4c) provides access to the target
compounds, such as thiazolidin-4-ones 5a–h, 4-methyl-
2,3-dihydro-thiazole-5-carboxylic acid ethyl esters 6a–h
and 4-phenyl-2,3-dihydro-thiazoles 7a–h. Among these,
compounds 6e–h, 7e–h exhibit a potent DPPH radical
scavenging activity, which is comparable to that of vita-
min E. The 2,3-dihydrothiazole moiety of compounds
6e–h and 7e–h plays an important role in the scavenging
radical activity.
100
90
80
70
60
50
40
30
20
10
0
5a-5d
5e-5h
6a-6d
6e-6h
7a-7d
7e-7h
Vit. E
Tested compounds
Figure 4. Scavenging activity of compounds 5a–7h (0.1mM) incubated
30min with DPPH at 0.1mM concentration.
100
80
4. Experimental
4.1. General
All melting points were determined on an England Elec-
trothermal Digital Melting Point apparatus and are
uncorrected. IR spectra were recorded on a MATT-
SON/SATELLITE 5000 FT-IR spectrophotometer.
Mass spectra were measured on a VG Quattro GC/
60
1
MS/MS/DS spectrometer. H NMR spectra were run
6e
6f
40
20
0
on a Bruker AMX-200 NMR spectrometer, using
TMS as an internal standard. 13C NMR spectra were
carried out with complete 1H decoupling and assign-
ments were made through additional DEPT experi-
ments. Elemental analyses were taken with a Heraeus
CHN-O-Rapid Analyzer or Elementar Vario EL-III An-
alyzer. X-ray spectra were performed on a Rigaku
AFC7S diffractometer. 3-Phenyl-4-formylsydnone (1a),
3-(4-methylphenyl)-4-formylsydnone (1b), 3-(4-methoxy-
phenyl)-4-formylsydnone (1c) and 3-(4-ethoxyphenyl)-4-
6g
6h
Vit E
0.00
0.05
0.10
0.15
0.20
0.25
0.30
Concentration mM
Figure 5. Scavenging activity of compounds 6e–h on DPPH radical.

4638
M.-H. Shih, F.-Y. Ke / Bioorg. Med. Chem. 12 (2004) 4633–4643
formylsydnone (1d) were prepared according to the liter-
ature.19
ide (2b, 287mg, 3.15mmol) was slowly added. The
mixed solution was heated at 45ꢁC for 2–3days and
then cooled. The precipitating solid was collected by fil-
tration and recrystallized from dichloromethane/ethanol
to afford 624mg (79%) of 3-phenyl-4-formylsydnone thio-
semicarbazone (3e) as yellow crystal. The chemical and
physical spectral characteristics of these products 3e–h
are given below.
4.2. Syntheses of 3-aryl-4-formylsydnone 40-phenyl thio-
semicarbazones (3a–d)
To a solution of 3-phenyl-4-formylsydnone (1a, 570mg,
3.0mmol) in absolute ethanol (20mL), 4-phenyl-
thiosemicarbazide (2a, 526mg, 3.15mmol) was slowly
added. The mixed solution was heated at 45ꢁC for 2–3
days and then cooled. The precipitating solid was
collected by filtration and recrystallized from dichloro-
methane/ethanol to afford 815mg (80%) of 3-phenyl-4-
formylsydnone 40-phenylthiosemicarbazone 3a as yellow
powder. The chemical and physical spectral characteris-
tics of these products 3a–d are given below.
4.3.1. 3-Phenyl-4-formylsydnone thiosemicarbazone (3e).
Yellow crystals from CH2Cl2/EtOH; yield 79%; mp 188–
190ꢁC; IR (KBr) 3406, 3262, 3154, 1737, 1599, 1521,
1
1263cmꢀ1; H NMR (DMSO-d6): d 6.33 (s, 1H), 7.91–
+
7.63(m, 6H), 8.28 (s, 1H), 11.50 (s, 1H); FABMS
m/z (%): 264 (M+ +H, 100), 263(M , 19); Anal. Calcd
+
for C10H9N5O2S: C, 45.62; H, 3.45; N, 26.60. Found:
C, 45.51; H, 3.47; N, 26.53.
4.2.1. 3-Phenyl-4-formylsydnone 40-phenylthiosemicar-
bazone (3a). Yellow powder from CH2Cl2/EtOH; yield
80%; mp 170–171ꢁC; IR (KBr) 3322, 3148, 2986, 1776,
4.3.2. 3-(4-Methylphenyl)-4-formylsydnone thiosemi-
carbazone (3f). Yellow powder from CH2Cl2/EtOH;
yield 71%; mp 190–192ꢁC; IR (KBr) 3430, 3310, 3178,
3040, 2998, 1755, 1605, 1539, 1263cmꢀ1; 1H NMR (DMSO-
d6): d 2.43 (s, 3H), 6.34 (s, 1H), 7.51(d, J=8.4Hz, 2H),
7.68 (d, J=8.4Hz, 2H), 7.72 (s, 1H), 8.29 (s, 1H),
11.47 (s, 1H); FABMS+ m/z (%): 278 (M+ +H, 100),
277 (M+, 17); Anal. Calcd for C11H11N5O2S: C, 47.64;
H, 4.00; N, 25.25. Found: C, 47.50; H, 4.11; N, 25.11.
1
1590, 1533, 1515, 1260, 1203cmꢀ1; H NMR (DMSO-
d6): d 7.14–7.89 (m, 11H), 8.66 (s, 1H), 11.93(s, 1H);
FABMS+ m/z (%): 340 (M+ +H, 100), 339 (M+, 17);
Anal. Calcd for C16H13N5O2S: C, 56.63; H, 3.86; N,
20.64. Found: C, 56.55; H, 3.84; N, 20.57.
4.2.2. 3-(4-Methylphenyl)-4-formylsydnone 40-phenyl-thio-
semicarbazone (3b). Yellow powder from CH2Cl2/EtOH;
yield 83%; mp 177–178ꢁC; IR (KBr) 3286, 3224, 1743,
4.3.3. 3-(4-Methoxyphenyl)-4-formylsydnone thiosemi-
carbazone (3g). Yellow powder from CH2Cl2/EtOH;
yield 80%; mp 197–198ꢁC; IR (KBr) 3422, 3346, 3166,
1
1599, 1543, 1515, 1257, 1194cmꢀ1; H NMR (DMSO-
d6): d 2.22 (s, 3H), 7.13–7.39 (m, 5H), 7.48 (d,
J=8.2Hz, 2H), 7.73(d, J=8.2Hz, 2H), 7.84 (s, 1H),
8.40 (s, 1H), 11.96(s, 1H); FABMS+ m/z (%): 354
(M+ +H, 100), 353 (M+, 18); Anal. Calcd for
C17H15N5O2S: C, 57.78; H, 4.28; N, 19.82. Found: C,
57.66; H, 4.29; N, 19.84.
3010, 2842, 1749, 1605, 1590, 1524, 1263cmꢀ1 1H
;
NMR (DMSO-d6): d 3.86 (s, 3H), 6.48 (s, 1H), 7.22
(d, J=9.1Hz, 2H), 7.73(s, 1H), 7.74 (d, J=9.1Hz,
2H), 8.32 (s, 1H), 11.49 (s, 1H); FABMS+ m/z (%):
294 (M+ +H, 100), 293(M +, 18); Anal. Calcd for
C11H11N5O3S: C, 45.05; H, 3.78; N, 23.88. Found: C,
44.85; H, 3.80; N, 23.80.
4.2.3. 3-(4-Methoxyphenyl)-4-formylsydnone 40-phenyl-
thiosemicarbazone (3c). Yellow needles from CH2Cl2/
EtOH; yield 90%; mp 176–177ꢁC; IR (KBr) 3292,
4.3.4. 3-(4-Ethoxyphenyl)-4-formylsydnone thiosemicar-
bazone (3h). Yellow needles from CH2Cl2/EtOH; yield
78%; mp 191–192ꢁC; IR (KBr) 3394, 3232, 3154, 2988,
3214, 3064, 1740, 1605, 1533, 1515, 1260, 1188cmꢀ1
;
1H NMR (DMSO-d6): d 3.69 (s, 3H), 7.18–7.40 (m,
7H), 7.79 (d, J=9.0Hz, 2H), 7.84 (s, 1H), 8.57 (s, 1H),
11.95 (s, 1H); FABMS+ m/z (%): 370 (M+ +H, 100),
369 (M+, 15); Anal. Calcd for C17H15N5O3S: C, 55.27;
H, 4.09; N, 18.96. Found: C, 55.25; H, 4.09; N, 18.99.
1
1734, 1593, 1527, 1254cmꢀ1; H NMR (DMSO-d6): d
1.36 (t, J=7.1Hz, 3H), 4.13 (q, J=7.1Hz, 2H), 6.47 (s,
1H), 7.20 (d, J=8.9Hz, 2H), 7.72 (d, J=8.9Hz, 2H),
+
7.73(s, 1H), 8.33(s, 1H), 11.47 (s, 1H); FABMS
m/z
(%): 308 (M+ +H, 100), 307 (M+, 25); Anal. Calcd for
C12H13N5O3S: C, 46.90; H, 4.26; N, 22.79. Found: C,
46.75; H, 4.26; N, 22.78.
4.2.4. 3-(4-Ethoxyphenyl)-4-formylsydnone 40-phenyl-thio-
semicarbazone (3d). Yellow needles from CH2Cl2/EtOH;
yield 82%; mp 176–177ꢁC; IR (KBr) 3294, 3214, 3064,
2988, 2932, 1740, 1596, 1533, 1515, 1257, 1185cmꢀ1
;
4.4. Syntheses of 2-[(3-arylsydnon-4-ylmethylene)
hydrazono]-3-phenyl-thiazolidin-4-ones (5a–d)
1H NMR (DMSO-d6): d 1.25 (t, J=7.0Hz, 3H), 3.90
(q, J=7.0Hz, 2H), 7.15–7.43(m, 7H), 7.76 (d,
J=9.0Hz, 2H), 7.83(s, 1H), 8.49 (s, 1H), 11.95 (s,
1H); FABMS+ m/z (%): 384 (M+ +H, 100), 383 (M+,
18); Anal. Calcd for C18H17N5O3S: C, 56.38; H, 4.47;
N, 18.27. Found: C, 56.25; H, 4.43; N, 18.32.
To a solution of ethyl chloroacetate (4a, 184mg,
1.50mmol) in absolute ethanol (5mL), were slowly
added
3-phenyl-4-formylsydnone
40-phenyl-
thiosemicarbazone (3a, 339mg, 1.00mmol) and sodium
acetate (246mg, 3.00mmol). Acetic acid (0.5mL) was
added to the above solution as a catalyst. The mixed
solution was heated to 80ꢁC for around 40h until the
reaction was completed. The system was then allowed
to attain room temperature. The precipitated solid was
collected by filtration and washed with ice-cold water
4.3. Syntheses of 3-aryl-4-formylsydnone thiosemicarba-
zones (3e–h)
To a solution of 3-phenyl-4-formylsydnone (1a, 570mg,
3.0mmol) in absolute ethanol (20mL), thiosemicarbaz-

M.-H. Shih, F.-Y. Ke / Bioorg. Med. Chem. 12 (2004) 4633–4643
4639
and cold ethanol. The collected solid was recrystallized
7.63(s, 1H), 7.69 (d,
J=9.0Hz, 2H); 13C NMR
from acetone/ethanol to yield 235mg (62%) of 2-[(3-phe-
nylsydnon-4-ylmethylene)hydrazono]-3-phenyl-thiazol-
idin-4-one (5a) as yellow powder. The chemical and
physical spectral characteristics of these products 5a–d
are given below.
(DMSO-d6): d 14.60, 32.53, 64.05, 105.37, 115.59,
125.99, 127.19, 128.30, 128.87, 129.22, 135.00, 142.84,
161.36, 164.66, 166.52, 172.18; FABMS+ m/z (%): 424
(M+ +H, 100), 423(M +, 10), 393 (M+–NO, 17), 365
(M+–NO–CO, 32); Anal. Calcd for C20H17N5O4S: C,
56.73; H, 4.05; N, 16.54. Found: C, 56.53; H, 4.08; N,
16.41.
4.4.1. 2-[(3-Phenylsydnon-4-ylmethylene)hydrazono]-3-
phenyl-thiazolidin-4-one (5a). Yellow powder from
CH3COCH3/EtOH; yield 62%; mp 210–211ꢁC; IR
4.5. Syntheses of 2-[(3-arylsydnon-4-ylmethylene)hydraz-
ono]-4-methyl-3-phenyl-2,3-dihydro-thiazole-5-carboxylic
acid ethyl ester (6a–d)
(KBr) 3058, 2974, 1764, 1721, 1607, 1547, 1241cmꢀ1
;
1H NMR (DMSO-d6): d 4.01 (s, 2H), 7.20–7.35 (m,
2H), 7.37–7.55 (m, 3H), 7.68 (s, 1H), 7.70–7.90 (m,
5H); 13C NMR (DMSO-d6): d 32.56, 105.39, 125.72,
128.33, 128.94, 129.28, 130.24, 132.65, 133.87, 135.00,
142.52, 164.95, 166.77, 172.24; FABMS+ m/z (%): 380
(M+ +H, 100), 379 (M+, 14), 349 (M+–NO, 21), 321
(M+–NO–CO, 27); Anal. Calcd for C18H13N5O3S: C,
56.99; H, 3.45; N, 18.46. Found: C, 57.00; H, 3.46; N,
18.47.
To a solution of ethyl 2-chloroacetoacetate (4b, 247mg,
1.50mmol) in absolute ethanol (4mL), 3-phenyl-4-form-
ylsydnone 40-phenylthiosemicarbazone (3a, 339mg,
1.00mmol) and sodium acetate (246mg, 3.00mmol)
were slowly added. Acetic acid (0.5mL) was added to
the above solution as a catalyst. The mixed solution
was heated at 80ꢁC for about 20h and then allowed to
attain room temperature. The precipitating solid was
collected by filtration and washed with ice-cold water
and cold ethanol. The collected solid was recrystallized
from acetone/ethanol to yield 211mg (47%) of 4-
methyl-3-phenyl-2-[(3-phenylsydnon-4-ylmethylene)hy-
drazono]-2,3-dihydro-thiazole-5-carboxylic acid ethyl
ester (6a) as yellow crystalline. The chemical and physi-
cal spectral characteristics of these products 6a–d are gi-
ven below.
4.4.2. 2-{[3-(4-Methylphenyl)sydnon-4-ylmethylene]-hy-
drazono}-3-phenyl-thiazolidin-4-one (5b). Yellow powder
from CH3COCH3/EtOH; yield 68%; mp 202–203ꢁC; IR
(KBr) 3057, 2980, 1761, 1717, 1606, 1547, 1243cmꢀ1; 1H
NMR (DMSO-d6): d 2.41 (s, 3H), 4.03 (s, 2H), 7.16–7.49
(m, 7H), 7.62 (s, 1H), 7.66 (d, J=8.3Hz, 2H); 13C NMR
(DMSO-d6): d 21.10, 32.53, 105.33, 125.41, 128.28,
128.85, 129.20, 130.54, 131.18, 134.99, 142.67, 142.89,
164.61, 166.60, 172.17; FABMS+ m/z (%): 394
(M+ +H, 100), 393 (M+, 15), 363 (M+–NO, 17), 335
(M+–NO–CO, 22); Anal. Calcd for C19H15N5O3S: C,
58.01; H, 3.84; N, 17.80. Found: C, 58.00; H, 3.98; N,
17.54.
4.5.1. 4-Methyl-3-phenyl-2-[(3-phenylsydnon-4-ylmethyl-
acid
ene)hydrazono]-2,3-dihydro-thiazole-5-carboxylic
ethyl ester (6a). Yellow crystals from CH3COCH3/
EtOH; yield 47%; mp 223–224ꢁC; IR (KBr) 3074,
2976, 1752, 1694, 1594, 1523, 1491, 1305, 1248cmꢀ1
;
1H NMR (DMSO-d6): d 1.30 (t, J=7.1Hz, 3H), 2.13
(s, 3H), 4.24 (q, J=7.1Hz, 2H), 7.30–7.60 (m, 6H),
7.62–7.82 (m, 5H); 13C NMR (DMSO-d6): d 13.86,
14.42, 60.91, 103.70, 106.07, 125.66, 128.70, 129.63,
129.87, 130.23, 132.39, 134.01, 135.84, 137.59, 147.38,
161.40, 164.86, 168.85; FABMS+ m/z (%): 450
(M+ +H, 100), 449 (M+, 32), 419 (M+–NO, 59); Anal.
Calcd for C22H19N5O4S: C, 58.79; H, 4.26; N, 15.58.
Found: C, 58.82; H, 4.39; N, 15.63.
4.4.3. 2-{[3-(4-Methoxyphenyl)sydnon-4-ylmethylene]-hy-
drazono}-3-phenyl-thiazolidin-4-one (5c). Orange crystals
from CH3COCH3/EtOH; yield 58%; mp 203–204ꢁC; IR
(KBr) 3054, 2977, 1757, 1717, 1610, 1550, 1252cmꢀ1; 1H
NMR (DMSO-d6): d 3.84 (s, 3H), 4.03 (s, 2H), 7.19 (d,
J=9.0Hz, 2H), 7.26–7.32 (m, 2H), 7.34–7.57 (m, 3H),
7.62 (s, 1H), 7.72 (d, J=9.0Hz, 2H); 13C NMR
(DMSO-d6): d 32.58, 56,05, 105.43, 115.30, 126.21,
127.24, 128.34, 128.94, 129.29, 135.04, 142.87, 162.12,
164.72, 166.60, 172.25; FABMS+ m/z (%): 410
(M+ +H, 100), 409 (M+, 14), 379 (M+–NO, 19), 351
(M+–NO–CO, 25); Anal. Calcd for C19H15N5O4S: C,
55.74; H, 3.69; N, 17.11. Found: C, 55.76; H, 3.73; N,
17.11. X-ray analytical data are listed in Table 1. Fur-
ther details have been deposited at the Cambridge Crys-
tallographic Data Center and allocated the deposition
number CCDC 216222.
4.5.2. 4-Methyl-3-phenyl-2-{[3-(4-methylphenyl)sydnon-
4-ylmethylene]hydrazono}-2,3-dihydro-thiazole-5-carb-
oxylic acid ethyl ester (6b). Orange crystals from
CH3COCH3/EtOH; yield 40%; mp 240–241ꢁC; IR
(KBr) 3074, 2975, 1762, 1707, 1601, 1523, 1492, 1304,
1
1260cmꢀ1; H NMR (DMSO-d6): d 1.28 (t, J=7.2Hz,
3H), 2.13 (s, 3H), 2.42 (s, 3H), 4.24 (q, J=7.2Hz, 2H),
7.30–7.56 (m, 8H), 7.63 (d, J=8.3Hz, 2H); 13C NMR
(DMSO-d6): d 13.97, 14.53, 21.14, 60.96, 103.67,
106.03, 125.40, 128.75, 129.68, 129.92, 130.60, 131.49,
135.92, 137.81, 142.75, 147.49, 161.49, 164.90, 168.67;
FABMS+ m/z (%): 464 (M+ +H, 100), 463(M +, 25),
433 (M+–NO, 47); Anal. Calcd for C23H21N5O4S: C,
59.60; H, 4.57; N, 15.11. Found: C, 59.65; H, 4.64; N,
15.15. X-ray analytical data are listed in Table 1. Fur-
ther details have been deposited at the Cambridge Crys-
tallographic Data Center and allocated the deposition
number CCDC 216223.
4.4.4. 2-{[3-(4-Ethoxyphenyl)sydnon-4-ylmethylene]-hy-
drazono}-3-phenyl-thiazolidin-4-one (5d). Yellow crystals
from CH3COCH3/EtOH; yield 52%; mp 204–205ꢁC;
IR (KBr) 3055, 2980, 1754, 1716, 1609, 1551,
1
1249cmꢀ1; H NMR (DMSO-d6): d 1.34 (t, J=7.1Hz,
3H), 4.04 (s, 2H), 4.11 (q, J=7.1Hz, 2H), 7.15 (d,
J=9.0Hz, 2H), 7.27–7.31 (m, 2H), 7.39–7.50 (m, 3H),

4640
M.-H. Shih, F.-Y. Ke / Bioorg. Med. Chem. 12 (2004) 4633–4643
4.5.3.
4-Methyl-3-phenyl-2-{[3-(4-methoxyphenyl)syd-
46); Anal. Calcd for C24H17N5O2S: C, 65.59; H, 3.90;
N, 15.93. Found: C, 65.52; H, 4.03; N, 15.96.
non-4-ylmethylene]hydrazono}-2,3-dihydro-thiazole-5-
carboxylic acid ethyl ester (6c). Orange crystals from
CH3COCH3/EtOH; yield 45%; mp 220–221ꢁC; IR
(KBr) 3068, 2978, 1761, 1693, 1593, 1522, 1493, 1303,
4.6.2. 3,4-Diphenyl-2-{[3-(4-methylphenyl)sydnon-4-yl-
methylene]hydrazono}-2,3-dihydro-thiazole (7b). Orange
crystals from CH3COCH3/EtOH; yield 48%; mp 241–
242ꢁC; IR (KBr) 3091, 1746, 1583, 1511, 1492,
1250cmꢀ1; H NMR (DMSO-d6): d 1.28 (t, J=7.1Hz,
1
3H), 2.14 (s, 3H), 3.85 (s, 3H), 4.24 (q, J=7.1Hz, 2H),
7.18 (d, J=9.1Hz, 2H), 7.25–7.60 (m, 6H), 7.69 (d,
J=9.1Hz, 2H); 13C NMR (DMSO-d6): d 13.95, 14.45,
56.00, 60.96, 103.67, 106.09, 115.30, 126.40, 127.18,
128.76, 129.69, 129.94, 135.92, 138.05, 147.47, 161.51,
162.04, 164.86, 168.62; FABMS+ m/z (%): 480
(M+ +H, 100), 479 (M+, 30), 449 (M+–NO, 40); Anal.
Calcd for C23H21N5O5S: C, 57.61; H, 4.41; N, 14.60.
Found: C, 57.66; H, 4.44; N, 14.63.
1
1260cmꢀ1; H NMR (DMSO-d6): d 2.42 (s, 3H), 6.64
(s, 1H), 7.05–7.40 (m, 10H), 7.48 (d, J=8.4Hz, 2H),
7.49 (s, 1H), 7.65 (d, J=8.4Hz, 2H); 13C NMR
(DMSO-d6): d 21.14, 102.61, 106.33, 125.42, 128.27,
128.39, 128.49, 128.67, 128.79, 129.10, 130.58, 130.63,
131.47, 135.94, 137.38, 139.87, 142.67, 164.90, 171.22;
FABMS+ m/z (%): 454 (M+ +H, 100), 453(M +, 29),
423(M +–NO, 66); Anal. Calcd for C25H19N5O2S: C,
66.21; H, 4.22; N, 15.44. Found: C, 66.15; H, 4.30; N,
15.43.
4.5.4. 4-Methyl-3-phenyl-2-{[3-(4-ethoxyphenyl)sydnon-
4-ylmethylene]hydrazono}-2,3-dihydro-thiazole-5-carb-
oxylic acid ethyl ester (6d). Yellow powder from
CH3COCH3/EtOH; yield 42%; mp 232-233 ꢁC; IR
(KBr) 3070, 2994, 1762, 1686, 1592, 1510, 1475, 1370,
4.6.3. 3,4-Diphenyl-2-{[3-(4-methoxyphenyl)sydnon-4-yl-
methylene]hydrazono}-2,3-dihydro-thiazole (7c). Orange-
red crystal from CH3COCH3/EtOH; yield 51%; mp
222–223ꢁC; IR (KBr) 3062, 1746, 1590, 1510, 1491,
1315 cmꢀ1; H NMR (DMSO-d6): d 1.28 (t, J=7.1Hz,
1
3H), 1.35 (t, J=7.0Hz, 3H), 2.15 (s, 3H), 4.12 (q,
J=7.0Hz, 2H), 4.24 (q, J=7.1Hz, 2H), 7.16 (d,
J=9.1Hz, 2H), 7.37–7.53 (m, 6H); 7.68 (d, J=9.1Hz,
2H); 13C NMR (DMSO-d6): d 13.91, 14.40, 14.59,
60.88, 64.01, 103.61, 106.03, 115.58, 126.15, 127.14,
128.72, 129.62, 129.87, 135.88, 138.08, 147.40, 161.30,
161.44, 164.73, 168.52; FABMS+ m/z (%): 494
(M+ +H, 100), 493(M +, 31), 463 (M+–NO, 41); Anal.
Calcd for C24H23N5O5S: C, 58.41; H, 4.70; N, 14.19.
Found: C, 58.57; H, 4.73; N, 14.22.
1
1259cmꢀ1; H NMR (DMSO-d6): d 3.86 (s, 3H), 6.66
(s, 1H), 7.01–7.46 (m, 12H), 7.51 (s, 1H), 7.72 (d,
J=8.9Hz, 2H); 13C NMR (DMSO-d6):
d 56.00,
102.56, 106.36, 115.25, 126.46, 127.18, 128.24, 128.38,
128.47, 128.64, 128.78, 129.08, 130.62, 136.11, 137.38,
139.84, 161.92, 164.89, 171.10; FABMS+ m/z (%): 470
(M+ +H, 100), 469 (M+, 37), 439 (M+–NO, 68); Anal.
Calcd for C25H19N5O3S: C, 63.95; H, 4.08; N, 14.92.
Found: C, 63.75; H, 4.16; N, 14.82. X-ray analytical
data are listed in Table 1. Further details have been
deposited at the Cambridge Crystallographic Data Cen-
ter and allocated the deposition number CCDC 216224.
4.6. Syntheses of 3,4-diphenyl-2-[(3-arylsydnon-4-yl-
methylene)hydrazono]-2,3-dihydro-thiazole (7a–d)
To a solution of 2-bromoacetophenone (4c, 219mg,
1.10mmol) in absolute ethanol (5mL), were slowly
4.6.4. 3,4-Diphenyl-2-{[3-(4-ethoxyphenyl)sydnon-4-yl-
methylene]hydrazono}-2,3-dihydro-thiazole (7d). Red
crystal from CH3COCH3/EtOH; yield 48%; mp 203–
204ꢁC; IR (KBr) 3063, 1752, 1590, 1512, 1491,
added
3-phenyl-4-formylsydnone
40-phenyl-
thiosemicarbazone (3a, 339mg, 1.00mmol) and sodium
acetate (246mg, 3.00mmol). Acetic acid (0.2mL) was
added to the above solution as a catalyst. The mixed
solution was heated at 50ꢁC for about 10h until the
reaction was completed. The system was then allowed
to attain room temperature. The precipitating solid
was collected by filtration and washed with ice-cold
water and cold ethanol. The collected solid was recrys-
tallized from acetone/ethanol to afford 250mg (57%)
of 3,4-diphenyl-2-[(3-phenylsydnon-4-ylmethylene)hy-
drazono]-2,3-dihydro-thiazole (7a) as orange powder.
The chemical and physical spectral characteristics of
these products 7a–d are given below.
1
1260cmꢀ1; H NMR (DMSO-d6): d 1.35 (t, J=7.0Hz,
3H), 4.12 (q, J=7.0Hz, 2H), 6.64 (s, 1H), 7.05–7.45
(m, 12H), 7.51 (s, 1H), 7.69 (d, J=8.9Hz, 2H); 13C
NMR (DMSO-d6): d 14.64, 64.04, 102.55, 106.35,
115.60, 126.28, 127.17, 128.24, 128.37, 128.47, 128.63,
128.77, 129.08, 130.62, 136.12, 137.37, 139.84, 161.20,
164.89, 171.08; FABMS+ m/z (%): 484 (M+ +H, 100),
483(M +, 35), 453 (M+–NO, 50); Anal. Calcd for
C26H21N5O3S: C, 64.58; H, 4.38; N, 14.48. Found: C,
64.42; H, 4.41; N, 14.43.
4.6.1. 3,4-Diphenyl-2-[(3-phenylsydnon-4-ylmethylene)-
hydrazono]-2,3-dihydro-thiazole (7a). Orange powder
from CH3COCH3/EtOH; yield 57%; mp 229–230ꢁC;
4.7. Syntheses of 2-[(3-arylsydnon-4-ylmethylene)hydraz-
ono]thiazolidin-4-ones (5e–h)
1
IR (KBr) 3052, 1747, 1588, 1512, 1490, 1258cmꢀ1; H
To a solution of ethyl chloroacetate (4a, 184mg,
1.50mmol) in absolute ethanol (5mL), 3-phenyl-4-form-
ylsydnone thiosemicarbazone (3e, 263mg, 1.00mmol)
and sodium acetate (246mg, 3.00mmol) were slowly
added. Acetic acid (150lL) was added to the above
solution as a catalyst. The mixed solution was heated
at 80ꢁC for about 35h until the reaction was completed.
NMR (DMSO-d6): d 6.62 (s, 1H), 7.05–7.40 (m, 10H),
7.52 (s, 1H), 7.60–7.85 (m, 5H); 13C NMR (DMSO-
d6): d 102.53, 106.28, 125.67, 128.24, 128.35, 128.47,
128.64, 128.75, 129.06, 130.17, 130.59, 132.34, 134.12,
135.67, 137.32, 139.85, 165.09, 171.19; FABMS+ m/z
(%): 440 (M+ +H, 100), 439 (M+, 33), 409 (M+–NO,

M.-H. Shih, F.-Y. Ke / Bioorg. Med. Chem. 12 (2004) 4633–4643
4641
The system was allowed to attain room temperature.
4.8. Syntheses of 4-methyl-2-[(3-arylsydnon-4-ylmethyl-
ene)hydrazono]-2,3-dihydro-thiazole-5-carboxylic acid
ethyl ester (6e–h)
The precipitating solid was collected by filtration and
washed with ice-cold water and cold ethanol. The col-
lected solid was recrystallized from acetone/ethanol to
afford 240mg (79%) of 2-[(3-phenyl-sydnon-4-ylmethyl-
ene)hydrazono]thiazolidin-4-one 5e as yellow needles.
The chemical and physical spectral characteristics of
these products 5e–h are given below.
To a solution of ethyl 2-chloroacetoacetate (4b, 247mg,
1.50mmol) in absolute ethanol (5mL), 3-phenyl-4-form-
ylsydnone thiosemicarbazone (3e, 263mg, 1.00mmol)
and sodium acetate (246mg, 3.00mmol) were slowly
added. Acetic acid (200lL) was added to the above
solution as a catalyst. The mixed solution was heated
at 80ꢁC for about 24h until the reaction was completed.
The system was then allowed to attain room tempera-
ture. The precipitating solid was collected by filtration
and washed with ice-cold water and cold ethanol. The
collected solid was recrystallized from dichlorometh-
ane/ethanol to afford 254mg (68%) of 4-methyl-2-[(3-
phenylsydnon-4-ylmethylene)hydrazono]-2,3-dihydro-
thiazole-5-carboxylic acid ethyl ester (6e) as yellow pow-
der. The chemical and physical spectral characteristics
of these products 6e–h are given below.
4.7.1. 2-[(3-Phenylsydnon-4-ylmethylene)hydrazono]-thi-
azolidin-4-one (5e). Yellow needles from CH3COCH3/
EtOH; yield 79%; mp 215–217ꢁC; IR (KBr) 2995,
2956, 2774, 1785, 1727, 1628, 1249cmꢀ1 1H NMR
;
(DMSO-d6): d 3.76 (s, 2H), 7.55–7.86 (m, 6H), 11.88
(s, 1H); 13C NMR (DMSO-d6): d 33.24, 105.33,
125.69, 130.12, 132.50, 134.10, 141.24, 165.29, 166.26,
174.12; FABMS+ m/z (%): 304 (M+ +H, 100), 303
(M+, 18), 273(M +–NO, 26), 245 (M+–NO–CO, 18);
Anal. Calcd for C12H9N5O3S: C, 47.52; H, 2.99; N,
23.09. Found: C, 47.70; H, 3.08; N, 22.90.
4.8.1. 4-Methyl-2-[(3-phenylsydnon-4-ylmethylene)-hy-
drazono]-2,3-dihydro-thiazole-5-carboxylic acid ethyl
ester (6e). Yellow powder from CH2Cl2/EtOH; yield
68%; mp 197–198ꢁC; IR (KBr) 3194, 3074, 2982, 2931,
4.7.2. 2-{[3-(4-Methylphenyl)sydnon-4-ylmethylene]hy-
drazono}thiazolidin-4-one (5f). Yellow needles from
CH3COCH3/EtOH; yield 72%; mp 226–227ꢁC; IR
(KBr) 2996, 2947, 2776, 1782, 1729, 1627, 1251cmꢀ1
;
1
1760, 1673, 1555, 1272cmꢀ1; H NMR (DMSO-d6): d
1H NMR (DMSO-d6): d 2.43 (s, 3H), 3.82 (s, 2H),
7.49 (d, J=8.4Hz, 2H), 7.68 (d, J=8.4Hz, 2H), 7.81
(s, 1H), 11.92 (s, 1H); 13C NMR (DMSO-d6): d 21.14,
33.29, 105.29, 125.41, 130.46, 131.47, 141.41, 142.75,
165.06, 166.24, 174.21; FABMS+ m/z (%): 318
(M+ +H, 100), 317 (M+, 20), 287 (M+–NO, 33), 259
(M+–NO–CO, 52); Anal. Calcd for C13H11N5O3S: C,
49.21; H, 3.49; N, 22.07; S, 10.10. Found: C, 49.13; H,
3.54; N, 22.08; S, 10.09.
1.27 (t, J=7.2Hz, 3H), 2.38 (s, 3H), 4.16 (q, J=7.2Hz,
+
2H), 7.57–7.83(m, 6H), 12.30 (s, 1H); FABMS
m/z
(%): 374 (M+ +H, 100), 373 (M+, 31), 343 (M+–NO,
28); Anal. Calcd for C16H15N5O4S: C, 51.47; H, 4.05;
N, 18.76; S, 8.60. Found: C, 51.28; H, 4.19; N, 18.56;
S, 8.47.
4.8.2. 4-Methyl-2-{[3-(4-methylphenyl)sydnon-4-ylmeth-
ylene]hydrazono}-2,3-dihydro-thiazole-5-carboxylic acid
ethyl ester (6f). Yellow powder from CH2Cl2/EtOH;
yield 55%; mp 186–188ꢁC; IR (KBr) 3171, 3049, 2984,
4.7.3. 2-{[3-(4-Methoxyphenyl)sydnon-4-ylmethylene]hy-
drazono}thiazolidin-4-one (5g). Yellow needles from
CH3COCH3/EtOH; yield 67%; mp 216–217ꢁC; IR
1
2927, 1759, 1704, 1580, 1267cmꢀ1; H NMR (DMSO-
d6): d 1.25 (t, J=7.2Hz, 3H), 2.38 (s, 3H), 2.45 (s,
3H), 4.17 (q, J=7.2Hz, 2H), 7.50 (d, J=8.2Hz, 2H),
7.63–7.67 (m, 3H), 12.29 (s, 1H); FABMS+ m/z (%):
388 (M+ +H, 100), 387 (M+, 25), 357 (M+–NO, 31);
Anal. Calcd for C17H17N5O4S: C, 52.70; H, 4.42; N,
18.08. Found: C, 52.59; H, 4.51; N, 18.07.
(KBr) 2988, 2945, 2767, 1783, 1723, 1626, 1252cmꢀ1
;
1H NMR (DMSO-d6): d 3.80 (s, 2H), 3.84 (s, 3H),
7.19 (d, J=9.0Hz, 2H), 7.72 (d, J=9.0Hz, 2H), 7.79
(s, 1H), 11.89 (s, 1H); 13C NMR (DMSO-d6): d 33.29,
56.05, 105.33, 115.18, 126.48, 127.21, 141.58, 162.03,
165.09, 166.17, 174.27; FABMS+ m/z (%): 334
(M+ +H, 100), 333 (M+, 19), 303 (M+–NO, 20), 275
(M+–NO–CO, 25); Anal. Calcd for C13H11N5O4S: C,
46.84; H, 3.33; N, 21.01. Found: C, 46.69; H, 3.46; N,
20.91.
4.8.3.
4-Methyl-2-{[3-(4-methoxyphenyl)sydnon-4-yl-
methylene]hydrazono}-2,3-dihydro-thiazole-5-carboxylic
acid ethyl ester (6g). Yellow needles from CH2Cl2/EtOH;
yield 62%; mp 191–192ꢁC; IR (KBr) 3160, 2930, 2908,
2841, 2821, 1756, 1701, 1578, 1256cmꢀ1 1H NMR
;
4.7.4. 2-{[3-(4-Ethoxyphenyl)sydnon-4-ylmethylene]hy-
drazono}thiazolidin-4-one (5h). Yellow needles from
CH3COCH3/EtOH; yield 82%; mp 223–224ꢁC; IR
(DMSO-d6): d 1.24 (t, J=7.2Hz, 3H), 2.39 (s, 3H),
3.86 (s, 3H), 4.16 (q, J=7.2Hz, 2H), 7.21 (d,
J=9.1Hz, 2H), 7.65 (s, 1H), 7.71 (d, J=9.1Hz, 2H),
12.28 (s, 1H); FABMS+ m/z (%): 404 (M+ +H, 100),
403(M +, 28), 373 (M+–NO, 32); Anal. Calcd for
C17H17N5O5S: C, 50.61; H, 4.25; N, 17.36. Found: C,
50.60; H, 4.33; N, 17.31.
(KBr) 2986, 2946, 2770, 1780, 1724, 1630, 1251cmꢀ1
;
1H NMR (DMSO-d6): d 1.34 (t, J=7.0Hz, 3H), 3.80
(s, 2H), 4.12 (q, J=7.0Hz, 2H), 7.17 (d, J=8.9Hz,
2H), 7.70 (d, J=8.9Hz, 2H), 7.79 (s, 1H), 11.90 (s,
1H); 13C NMR (DMSO-d6): d 14.64, 33.29, 64.10,
105.32, 115.56, 126.31, 127.21, 141.62, 161.33, 165.11,
166.29, 174.27; FABMS+ m/z (%): 348 (M+ +H, 100),
347 (M+, 18), 317 (M+–NO, 24); Anal. Calcd for
C14H13N5O4S: C, 48.41; H, 3.77; N, 20.16. Found: C,
48.20; H, 3.88; N, 19.94.
4.8.4. 4-Methyl-2-{[3-(4-ethoxyphenyl)sydnon-4-ylmeth-
ylene]hydrazono}-2,3-dihydro-thiazole-5-carboxylic acid
ethyl ester (6h). Yellow needles from CH2Cl2/EtOH;
yield 73%; mp 194–195ꢁC; IR (KBr) 3148, 2982, 2905,
1
1768, 1715, 1266 cmꢀ1; H NMR (DMSO-d6): d 1.24

4642
M.-H. Shih, F.-Y. Ke / Bioorg. Med. Chem. 12 (2004) 4633–4643
(t, J=7.2Hz, 3H), 1.36 (t, J=6.9Hz, 3H), 2.39 (s, 3H),
4.13(q, J=6.9Hz, 2H), 4.16 (q, J=7.2Hz, 2H), 7.19
(d, J=9.0Hz, 2H), 7.65 (s, 1H), 7.70 (d, J=9.0Hz,
2H), 12.29 (s, 1H); FABMS+ m/z (%): 418 (M+ +H,
100), 417 (M+, 26), 387 (M+–NO, 35); Anal. Calcd for
C18H19N5O5S: C, 51.79; H, 4.59; N, 16.78. Found: C,
51.62; H, 4.60; N, 16.70.
127.70, 128.72, 134.63, 150.55, 161.94, 165.14, 167.47;
FABMS+ m/z (%): 394 (M+ +H, 100), 393 (M+, 19),
363 (M+–NO, 34); Anal. Calcd for C19H15N5O3S: C,
58.01; H, 3.84; N, 17.80; S, 8.15. Found: C, 57.87; H,
3.90; N, 17.65; S, 8.16.
4.9.4. 4-Phenyl-2-{[3-(4-ethoxyphenyl)sydnon-4-ylmethyl-
ene]hydrazono}-2,3-dihydro-thiazole (7h). Yellow powder
from CH3COCH3/EtOH; yield 68%; mp 164–165ꢁC; IR
4.9. Syntheses of 4-phenyl-2-[(3-arylsydnon-4-ylmethyl-
ene)hydrazono]-2,3-dihydro-thiazoles (7e–h)
1
(KBr) 3192, 1721, 1556, 1244 cmꢀ1; H NMR (DMSO-
d6): d 1.38 (t, J=7.0Hz, 3H), 4.16 (q, J=7.0Hz, 2H),
7.21 (d, J=9.0Hz, 2H), 7.27 (s, 1H), 7.29–7.50 (m,
3H), 7.65 (s, 1H), 7.72 (d, J=9.0Hz, 2H), 7.76–7.90
(m, 2H), 12.13(s, 1H); 13C NMR (DMSO-d6): d 14.65,
64.11, 104.33, 105.88, 115.63, 125.65, 126.50, 127.04,
127.19, 127.73, 128.75, 134.64, 150.61, 161.23, 165.17,
167.50; FABMS+ m/z (%): 408 (M+ +H, 100), 407
(M+, 22), 377 (M+–NO, 31); Anal. Calcd for
C20H17N5O3S: C, 58.96; H, 4.21; N, 17.19; S, 7.90.
Found: C, 59.00; H, 4.28; N, 17.20; S, 7.95.
To an ice cooled solution of 3-phenyl-4-formylsydnone
thiosemicarbazone (3e, 263mg, 1.00mmol) in absolute
ethanol (5mL), sodium acetate (246mg, 3.00mmol)
was slowly added. Acetic acid (150lL) was added as a
catalyst. 2-Bromoacetophenone (4c, 209mg, 1.05mmol)
was slowly added to the above solution over 30min. The
mixed solution was stirred at 0ꢁC for about 15h until
the reaction was completed. The precipitating solid
was collected by filtration and washed with ice-cold
water and cold ethanol. The collected solid was recrys-
tallized from acetone/ethanol to yield 247mg (68%) of
4-phenyl-2-[(3-phenylsydnon-4-ylmethylene)hydrazono]-
2,3-dihydro-thiazole (7e) as yellow powder. The chemi-
cal and physical spectral characteristics of these prod-
ucts 7e–h are given below.
4.10. Scavenging effect on 1,1-diphenyl-2-picrylhydrazyl
(DPPH) radical35–37
The scavenging effect of the synthesized compounds 5a–
7h on the DPPH radical was evaluated according to the
methods of Shimada et al.,35 Leong and Shui36 and Braca
et al.37 Various concentrations of the test compound in
1.5mL methanol were added to a 1.5mL (0.2mM) solu-
tion of DPPH radical in methanol (final concentration
of DPPH was 0.1mM). The mixture was shaken vigor-
ously and allowed to stand for 30min; absorbance at
517nm was determined (Hitachi U-2001 spectropho-
tometer), and the percentage of activity was calculated.
Vitamin E was used as a reference compound. All tests
and analyses were undertaken on three replicates and
the results averaged.
4.9.1.
4-Phenyl-2-[(3-phenylsydnon-4-ylmethylene)hy-
drazono]-2,3-dihydro-thiazole (7e). Yellow powder from
CH3COCH3/EtOH; yield 68%; mp 165–166ꢁC; IR
(KBr) 3210, 1728, 1566, 1422, 1265cmꢀ1 1H NMR
;
(DMSO-d6): d 7.23–7.40 (m, 4H), 7.67–7.84 (m, 8H),
12.17 (s, 1H); 13C NMR (DMSO-d6): d 104.35, 105.89,
125.64, 125.69, 126.71, 127.74, 128.75, 130.18, 132.39,
134.19, 134.61, 150.58, 165.29, 167.47; FABMS+ m/z
(%): 364 (M+ +H, 100), 363 (M+, 28), 333 (M+–NO,
29); Anal. Calcd for C18H13N5O2S: C, 59.49; H, 3.61;
N, 19.27; S, 8.80. Found: C, 59.60; H, 3.68; N, 19.33;
S, 8.87.
Scavenging activity (%)={[(Ab+As)ꢀAm]/Ab}·100%;
Ab: absorbance of 0.1mM DPPH methanol solution
at 517nm; As: absorbance of various concentration
solution of test compound at 517nm; Am: absorbance
of mixture methanol solution at 517nm.
4.9.2. 4-Phenyl-2-{[3-(4-methylphenyl)sydnon-4-ylmethyl-
ene]hydrazono}-2,3-dihydro-thiazole (7f). Yellow powder
from CH3COCH3/EtOH; yield 65%; mp 167–168ꢁC; IR
(KBr) 3212, 1729, 1562, 1423, 1261cmꢀ1 1H NMR
;
(DMSO-d6): d 2.46 (s, 3H), 7.27 (s, 1H), 7.30–7.45 (m,
3H), 7.52 (d, J=8.4Hz, 2H), 7.65 (s, 1H), 7.69 (d,
J=8.4Hz, 2H), 7.72–7.80 (m, 2H), 12.13(s, 1H); 13C
NMR (DMSO-d6): d 21.15, 104.43, 105.89, 125.44,
125.64, 126.87, 127.73, 128.77, 130.55, 131.63, 134.65,
142.61, 150.58, 165.11, 167.50; FABMS+ m/mz (%):
378 (M+ +H, 100), 377 (M+, 31), 347 (M+–NO, 31);
Anal. Calcd for C19H15N5O2S: C, 60.47; H, 4.01; N,
18.56; S, 8.50. Found: C, 60.46; H, 4.07; N, 18.58; S,
8.53.
Acknowledgements
Financial support of this work by the National Science
Council of the Republic of China (NSC-93-2113-M-
218-001) and Southern Taiwan University of Technol-
ogy is highly appreciated.
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