Synthesis and characterization of new thiazolidin-4-one derivatives

Article abstract of DOI:10.1080/10426500802203053

The synthesis of some new functionalized thiazolidin-4-one derivatives has been described. The N-substituted-thiosemicarbazides 3a-3i were obtained though the reaction of alkylamines 2a-2i, carbon disulfide, and hydrazine hydrate. The condensation reaction between 3a-3i and 4-amino-2-methanesulfanylpyrimidine-5- carboxaldehyde 1 afforded the thiosemicarbazones 4a-4i. The corresponding thiazolidin-4-ones 5a-5i were prepared by cyclization of 4a-4i with ethyl bromoacetate. The structures of the final products were confirmed by IR, 1H NMR, ¹3C NMR, and HRMS.

Full text of DOI:10.1080/10426500802203053

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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Synthesis and Characterization
of New Thiazolidin-4-one
Derivatives
Bao Xiang Hu a , Zhen Lu Shen a , Jun Lu a , Xin Quan
Hu a , Wei Min Mo a , Nan Sun a & Dong Xu a
a College of Chemical Engineering and Materials
Science , Zhejiang University of Technology ,
Hangzhou, Zhejiang, China
Published online: 04 Feb 2009.
To cite this article: Bao Xiang Hu , Zhen Lu Shen , Jun Lu , Xin Quan Hu , Wei Min
Mo , Nan Sun & Dong Xu (2009) Synthesis and Characterization of New Thiazolidin-4-
one Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 184:2,
523-535, DOI: 10.1080/10426500802203053
To link to this article: http://dx.doi.org/10.1080/10426500802203053
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Phosphorus, Sulfur, and Silicon, 184:523–535, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802203053
Synthesis and Characterization of New Thiazolidin-4-one
Derivatives
Bao Xiang Hu, Zhen Lu Shen, Jun Lu, Xin Quan Hu,
Wei Min Mo, Nan Sun, and Dong Xu
College of Chemical Engineering and Materials Science, Zhejiang
University of Technology, Hangzhou, Zhejiang, China
The synthesis of some new functionalized thiazolidin-4-one derivatives has been
described. The N-substituted-thiosemicarbazides 3a-3i were obtained though the
reaction of alkylamines 2a–2i, carbon disulfide, and hydrazine hydrate. The
condensation reaction between 3a–3i and 4-amino-2-methanesulfanylpyrimidine-
5-carboxaldehyde 1 afforded the thiosemicarbazones 4a–4i. The corresponding
thiazolidin-4-ones 5a–5i were prepared by cyclization of 4a–4i with ethyl bro-
moacetate. The structures of the final products were confirmed by IR, 1 H NMR,
13 C NMR, and HRMS.
Keywords 4-Amino-2-methanesulfanylpyrimidine-5-carboxaldehyde; thiazolidin-4-
ones; thiosemicarbazides; thiosemicarbazones
INTRODUCTION
Thiazolidin-4-one derivatives have received much attention due to their
widespread application in the chemotherapeutic field. They display a
wide variety of biological activities such as antimicobial, antiinflamma-
tory, anti–Toxoplasma gondii, and anti-HIV, etc.1–8 Several synthesis
methods for thiazolidin-4-ones have been developed.9,10 The most im-
portant one of them is the cyclization of thiosemicarbazones, which are
also of biological interest due to their large spectrum of activity.11–13
Pyrimidine heterocycles are structural elements that frequently
impart biological activity. However, to our knowledge there is no
data describing compounds containing the two heterocyclic moieties,
Received 11 March 2008; accepted 14 May 2008.
We are grateful to the Natural Science Foundation of Zhejiang Province (Y406380)
for financial support.
Address correspondence to Zhen Lu Shen, College of Chemical Engineering and Ma-
terials Science, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, China.
E-mail: zhenlushen@zjut.edu.cn
523

524
B. X. Hu et al.
thiazolidin-4-one and pyrimidine. As a part of our research program
aimed at synthesizing druglike heterocycles, we became interested in
the substituted thiazolidin-4-one containing pyrimidine.
RESULTS AND DISCUSSION
4-Amino-2-methanesulfanylpyrimidine-5-carboxaldehyde 1, which was
prepared by selective oxidation of (4-amino-2-methanesulfanyl
pyrimidin-5-yl)methanol using our recently reported method,14 was
selected as the starting material in this work. The N-substituted-
thiosemicarbazides 3a–3i were prepared in a similar method according
to the literature.15,16 In the presence of triethylamine, alkylamines 2a–
2i conveniently react with carbon disulfide to form the intermediate
triethylammonium dithiocarbamates, which further reacted with hy-
drazine hydrate to yield 3a–3i. The thiosemicarbazones 4a–4i were
synthesized by condensation of 3a–3i with 1. The target products,
thiazolidin-4-ones 5a–5i, were synthesized from 4a–4i by cyclization
with ethyl 2-bromoacetate using basic conditions (Scheme 1). Their
structures were confirmed by IR, 1H NMR, 13C NMR, and HRMS.
In the procedure for synthesis of N-substituted-thiosemicarbazides3,
we tested two methods. One method involved the dropwise addition of
carbon disulfide into the mixture of alkylamines and triethylamine with
stirring, the other was to add the alkylamines dropwise into the mix-
tures of carbon disulfide and triethylamine. For all the compounds 3a–i,
with the exception of 3h, essentially the same results were obtained.
In the preparation of 3h, the two methods showed different results:
The addition of carbon disulfide yielded the desired product and 1,3-
dibenzylthiourea (ca. 1:1), whereas the alternate method involving the
addition of benzylamine smoothly formed the crude product.
According to the literature,3 chloroacetic acid, bromoacetic acid,
and ethyl 2-bromoacetate could be used in the cyclization reaction of
thiosemicarbazones 4a–4i to form thiazolidin-4-ones 5a–5i. Our exper-
imental results showed that ethyl bromoacetate was suitable for this
reaction and resulted in the best selectivity of desired products. The
IR spectra of compounds 5a–5i showed the disappearance of the strong
–1
C S band at 1224–1271 cm and a new band at 1715–1728 cm−1
attributed to the carbonyl group of thiazolidin-4-one. The 1H NMR
spectra showed that the signal due to C N N H (δ > 11.14 ppm), dis-
appeared and a new singlet at δ 3.94–4.12 ppm attributed to the CH2
of the thiazolidin-4-one ring appeared. It is noteworthy that the two
protons of amino group on pyrimidine heterocycle are exhibited as two
singlets, though they are shown as a broad singlet before the cyclization

New Thiazolidin-4-one Derivatives
525
S
S
NH2NH2 H2O
R
R
NH2
CS2
O
Et3N
+
+
R-NH2
N
S
N
N
NHEt3
H
H
H
2a-2h
3a-3h
a: R = Me
b: R = Et
c: R = n-Pr
d: R = i-Pr
e: R = n-Bu
f: R = t-Bu
H
H
N
H
H
H
N
N
N
AcOH
EtOH
N1
2
6
H
N1
2
6
N
R
5
4
5
4
H2N
R
+
3
N
3
S
S
g: R = cyclohexyl
h: R = benzyl
S
NH2
S
N
NH2
1
3a-3h
4a-4h
H
H
R
H
N
H
N
N
AcONa
EtOH
N
N
N
R
N1
2
6
3
N
N
3
2
S1
5
4
O
4
+ BrCH2COOC2H5
5
S
S
N
NH2
S
NH2
4a-4h
5a-5h
H
S
S
S
N
NHEt3
NH2NH2 H2O
NH2
NH
NH
NH
NH
NH2
Et3N
CS2
+
+
NH2
NH2
S
S
S
N
H
NHEt3
2i
3i
H2N
NH2
N
H
N
S
H
S
S
N
O
N
N
N
NH
NH
N
N
N
1
BrCH2COOC2H5
AcONa, EtOH
N
N
S
S
N
AcOH,EtOH
N
N
S
S
N
N
H
O
N
S
N
H
H2N
NH2
5i
4i
SCHEME 1
reaction. The 13C NMR spectra revealed new peaks at δ 31.89–32.41
ppm and δ169.13–171.65 ppm, which were due to the CH2 and O C
carbons of thiazolidin-4-one ring respectively. In the preparation of 5f,
1
the assignment of H NMR, 13C NMR, and HRMS showed that a 1:1
stable adduct of 5f and solvent ethanol was formed, but the ethanol
could not be removed by azeotropic distillation with toluene.

526
B. X. Hu et al.
EXPERIMENTAL
Melting points were measured using a CRC-1 melting point in-
strument and are uncorrected. The purities of thiosemicarbazones
and thiazolidin-4-ones were determined by HPLC (VARIAN Prostar)
equipped with a C18 column. FT-IR spectra were recorded on a Nicolet
instrument, Avetar 370. 1H NMR and 13C NMR spectra were obtained
on a Varian PLUS-400 spectrometer. d6-DMSO was used as the solvent
with tetramethylsilane (TMS) as the internal standard. Mass spectra
(MS) were recorded on a Bruker esquire 3000 plus instrument. High
resolution mass spectra (HRMS) were recorded on a Bruker Apex III
(7.0 Tesla) FTICR mass spectrometer. All reagents were obtained from
commercial sources and used as received. The reactions were monitored
by HPLC.
4-Amino-2-methanesulfanylpyrimidine-5-carboxaldehyde (1)
It was obtained as described in the literature.14 White powder, mp
182–184◦C.
4-Methylthiosemicarbazide (3a)
To a mixture of CS2 (45.6 g, 0.6 mol) and triethylamine (65.5 g, 0.65
mol), methylamine (38.8 g, 40%, 0.5 mol) was added dropwise with
stirring at a temperature lower than 20◦C. The reaction mixture was
stirred for additional 3 h, and then 150 mL H2O and hydrazine hydrate
(29.4 g, 85%, 0.5 mol) was added to the mixture. The obtained mixture
was refluxed for 24 h, and the hydrogen sulfide released from the re-
action system and was absorbed with 30% NaOH solution. Then the
reaction mixture was concentrated to about 100 mL, and the residue
was cooled to 0–3◦C with stirring. After filtration, ice-cold water wash-
ing, and drying with P2O5, the title product was obtained. Yield: 74%.
White crystals, mp 134–135◦C.
4-Ethylthiosemicarbazide (3b)
The procedure was the same as described for 1a. Yield: 76%. White
crystals, mp 81–83◦C.
4-Propylthiosemicarbazide (3c)
To a mixture of CS2 (45.6 g, 0.6 mol), 20 mL H2O, and triethylamine
(65.5 g, 0.65 mol), propylamine (29.5 g, 0.5 mol) was added dropwise

New Thiazolidin-4-one Derivatives
527
with stirring at temperature of 15–20◦C. Then the reaction procedure
was similar as described for 3a. The obtained reaction mixture was
concentrated to about 100 mL, and the lower layer of the residue was
separated. After being solidified, it was recrystallized from cyclohexane
to give 3c. Yield: 58%. White crystals, mp 53–54◦C.
4-iso-Propylthiosemicarbazide (3d)
The reaction procedure was similar as described for 3c. After concen-
tration of the obtained reaction mixture to about 120 mL, the residue
was cooled to room temperature. The precipitate was filtered off, cold
water washed, dried, and recrystallized from ethanol to give 3d. Yield:
63%. White crystals, mp 82–83◦C.
4-Butylthiosemicarbazide (3e)
The procedure was the same as described for 3c. Yield: 65%. White
crystals, mp 65–66◦C.
4-tert-Butylthiosemicarbazide (3f)
The reaction procedure was the same as described for 3d except that a
portion of product was precipitated in the course of reflux. Yield: 63%.
White crystals, mp 142–143◦C.
4-Cyclohexylthiosemicarbazide (3g)
The reaction procedure was the same as described for 3d. Yield: 61%.
White crystals, mp 147–148◦C.
4-Benzylthiosemicarbazide (3h)
The reaction procedure was the same as described for 3d. Yield: 76%.
White crystals, mp 127–128◦C.
1,6-Hexanebis(thiosemicarbazide) (3i)
To a mixture of CS2 (45.6 g, 0.6 mol), 20 mL H2O, and triethylamine
(65.5 g, 0.65 mol), 1,6-hexanediamine (29.1 g, 0.25 mol) was added
dropwise with stirring. The reaction temperature was maintained blow
20◦C. Then 150 mL H2O was added to the mixture. After stirring
overnight, hydrazine hydrate (29.4 g, 85%, 0.5 mol) was added. The

528
B. X. Hu et al.
obtained mixture was refluxed for 24 h and then concentrated to about
120 mL. The precipitate was filtered off, cold water washed, dried, and
recrystallized from ethanol to give 3i. Yield: 64%. White crystals, mp
144–145◦C.
General Procedure for the Synthesis of 4a–4i
To a solution of 4-amino-2-methanesulfanylpyrimidine-5-carboxalde-
hyde 1 (2 mmol) in ethanol (20 mL), N-substituted-thiosemicarbazides
3a–3h (2 mmol) was added. After addition of several drops of acetic
acid, the mixture was refluxed for 8–14 h until 1 could not be detected
by HPLC. Then the reaction mixture was partially concentrated and
cooled. The resulting precipitate was collected by filtration, washed
with ethanol, and dried. When 4i was the target product, 2 mmol of 1
and 1 mmol 3i was used.
1-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)-4-methyl
thiosemicarbazide (4a)
Yield: 86%. White powder, mp > 350◦C. IR νmax (KBr)/cm−1 3394,
3274, 3152, 3009, 1637, 1578, 1546, 1525, 1391, 1262, 1186, 1096, 1042,
1
957, 784, 526. H NMR (DMSO-d6)δ 2.47 (s, 3H, S CH3), 3.00 (d, 3H,
J = 4.4 Hz, NH CH3), 7.75 (br, s, 2H, -NH2), 8.06 (s, 1H, N CH ), 8.08
(s, 1H, pyri-H), 8.46 (s,1H, CH3 NH ), 11.28 (s, 1H, C N NH ). 13C
NMR (DMSO-d6)δ 13.44 (S CH3), 31.22 (NH-CH3), 105.85 (pyri-C-5),
142.83 (N CH ), 158.46 and 158.55 (pyri-C-4 and pyri-C-6), 170.68
(pyri-C-2), 176.99 (S C ). MS (ESI) m/z 257.2 (M + H+).
1-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)-4-ethy-
lthiosemicarbazide (4b)
Yield: 85%. White powder, mp > 350◦C. IR νmax (KBr)/cm−1 3404,
3315, 3143, 2997, 2930, 1637, 1572, 1531, 1363, 1241, 958, 776, 537. 1H
NMR (DMSO-d6)δ 1.13 (t, 3H,J = 7.2 Hz, -CH3), 2.47 (s, 3H, S-CH3),
3.58 (p, 2H, J = 6.8 Hz, CH3-CH2-), 7.75 (br, s, 2H, -NH2), 8.06 (s, 1H,
N CH ), 8.09 (s, 1H, pyri-H), 8.53 (s,1H, CH2 NH ), 11.18 (s, 1H,
C N NH ). 13C NMR (DMSO-d6)δ 13.37 (S CH3), 14.72 (-CH3), 38.53
(CH3 CH2 ), 105.85 (pyri-C-5), 142.82 (N CH ), 158.44 and 158.56
(pyri-C-4 and pyri-C-6), 170.64 (pyri-C-2), 175.94 (S=C ). MS (ESI)
m/z 271.4 (M + H+).
1-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)-4-pro-
pylthiosemicarbazide (4c)
Yield: 86%. Pale yellow crystals, mp 234–236◦C. IR νmax (KBr)/cm−1
3396, 3276, 3141, 2998, 2961, 2930, 2870, 1633, 1569, 1537, 1365, 1227,

New Thiazolidin-4-one Derivatives
529
1085, 961, 783. 1H NMR (DMSO-d6)δ 0.87 (t, 3H,J = 7.2 Hz, -CH3), 1.53-
1.63 (m, 2H, CH3 CH2 ), 2.47 (s, 3H, S CH3), 3.49 (q, 2H, J = 6.4 Hz,
NH CH2 ), 7.76 (br, s, 2H, NH2), 8.06 (s, 1H, N CH ), 8.09 (s, 1H,
pyri-H), 8.53 (s,1H, CH2 NH ), 11.19 (s, 1H, C N NH ). 13C NMR
(DMSO-d6)δ 11.12 ( CH3), 13.25 (S CH3), 22.11 (CH3 CH2 ), 45.35
(NH CH2 ), 105.82 (pyri-C-5), 142.65 (N CH-), 158.35 and 158.41
(pyri-C-4 and pyri-C-6), 170.55 (pyri-C-2), 176.33 (S C ). MS (ESI)
m/z 285.3 (M + H+).
1-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)-4-iso-
propylthiosemicarbazide (4d)
Yield: 86%. Pale yellow crystals, mp > 350◦C. IR νmax (KBr)/cm−1
3387, 3277, 3129, 2962, 2930, 2869, 1634, 1572, 1516, 1464, 1370, 1300,
1241, 1154, 968, 785, 763. 1H NMR (DMSO-d6)δ 1.20 (d, 6H, J = 6.4 Hz,
2CH3-), 2.46 (s, 3H, S-CH3), 4.47-4.56 (m, H, NH-CH-), 7.77 (br, s, 2H, -
NH2), 8.06 (s, 1H, N=CH ), 8.11 (s, 1H, pyri-H), 8.13 (s,1H, CH NH ),
11.14 (s, 1H, C=N NH ). 13C NMR (DMSO-d6)δ 13.38 (S CH3), 21.85
(2CH3 ), 46.02 (NH CH ), 106.01 (pyri-C-5), 142.60 (N CH ), 158.31
and 158.54 (pyri-C-4 and pyri-C-6), 170.62 (pyri-C-2), 175.43 (S=C-).
MS (ESI) m/z 285.3 (M + H+).
1-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)-4-butyl-
thiosemicarbazide (4e)
Yield: 86%. Pale yellow crystals, mp > 350◦C. IR νmax (KBr)/cm−1
3404, 3280, 3140, 2999, 2927, 2865, 1634, 1565, 1529, 1365, 1239,
1
1086, 963, 783. H NMR (DMSO-d6)δ 0.91 (t, 3H,J = 7.2 Hz, -CH3),
1.25–1.35 (m, 2H, CH3-CH2-), 1.51–1.58 (m, 2H, CH3 CH2 CH2 ),
2.47 (s, 3H, S-CH3), 3.53 (q, 2H, J = 6.8 Hz, NH-CH2-), 7.79 (br, s,
2H, -NH2), 8.06 (s, 1H, N CH ), 8.09 (s, 1H, pyri-H), 8.51 (s,1H,
CH2 NH ), 11.19 (s, 1H, C N NH ). 13C NMR (DMSO-d6)δ 13.44
(S CH3), 13.91 ( CH3), 19.71 (CH3 CH2 ), 31.20 (CH3 CH2 CH ),
43.57 (NH CH2 ), 105.91 (pyri-C-5), 142.77 (N CH ), 158.49 (pyri-C-
4 and pyri-C-6), 170.70 (pyri-C-2), 176.20 (S C ). MS (ESI) m/z 299.4
(M + H+).
1-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)-4-tert-
butylthiosemicarbazide (4f)
Yield: 82%. Yellow powder, mp > 350◦C. IR νmax (KBr)/cm−1 3372,
3279, 3128, 2971, 1633, 1571, 1524, 1371, 1264, 1191, 1075, 966, 787. 1H
NMR (DMSO-d6)δ 1.52 (s, 9H, 3CH3-), 2.46 (s, 3H, S-CH3), 7.39 (s, 1H,
C-NH-), 7.77 (br, s, 2H, -NH2), 8.05 (s, 1H, N CH ), 8.15 (s, 1H, pyri-H),
11.18 (s, 1H, C N NH ). 13C NMR (DMSO-d6)δ 13.79 (S CH3), 29.20

530
B. X. Hu et al.
(3CH3 ), 53.34 (NH C ), 106.74 (pyri-C-5), 141.69 (N CH ), 158.22
and 159.33 (pyri-C-4 and pyri-C-6), 171.00 (pyri-C-2), 175.89 (S C ).
MS (ESI) m/z 299.3 (M + H+).
1-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)-4-cyclo-
hexylthiosemicarbazide (4g)
Yield: 85%. White powder, mp > 350◦C. IR νmax (KBr)/cm−1 3413,
3389, 3277, 3142, 2996, 2927, 2851, 1631, 1568, 1513, 1370, 1270,
1
1225, 1189, 1151, 967, 784. H NMR (DMSO-d6)δ 1.10–1.16 (m, 1H,
cyclohexyl-4-Ha), 1.22–1.31 (m, 2H, cyclohexyl-2-Ha, and cyclohexyl-
6-Ha), 1.35–1.44 (m, 2H, cyclohexyl-3-Ha and cyclohexyl-5-Ha), 1.60–
1.63 (m, 1H, cyclohexyl-4-Hb), 1.71–1.74 (m, 2H, cyclohexyl-3-Hb and
cyclohexyl-5-Hb), 1.85–1.87 (m, 2H, cyclohexyl-2-Hb and cyclohexyl-6-
Hb), 2.46 (s, 3H, S-CH3), 4.16–4.18 (m, 1H, cyclohexyl-1-H), 7.78 (br,
s, 2H, NH2), 8.06 (s, 1H, N CH ), 8.08 (s, 1H, CH-NH-), 8.11 (s,
1H, pyri-H), 11.15 (s, 1H, C N NH ). 13C NMR (DMSO-d6)δ 13.41
(S CH3), 25.09 (cyclohexyl-C-3 and cyclohexyl-C-5), 25.27 (cyclohexyl-
C-4), 31.78 (cyclohexyl-C-2 and cyclohexyl-C-6), 53.23 (cyclohexyl-C-1),
106.04 (pyri-C-5), 142.56 (N CH ), 158.29 and 158.56 (pyri-C-4 and
pyri-C-6), 170.64 (pyri-C-2), 175.41 (S C ). MS (ESI) m/z 325.4 (M +
H+).
1-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)-4-benzy-
lthiosemicarbazide (4h)
Yield: 85%. White powder, mp > 350◦C. IR νmax (KBr)/cm−1 3401,
3368, 3275, 3135, 2992, 2820, 1629, 1560, 1526, 1458, 1367, 1301, 1230,
1
1118, 1074, 967, 736. H NMR (DMSO-d6)δ 2.47 (s, 3H, S-CH3), 4.85
(d, 2H, J = 6.0 Hz, NH-CH2-), 7.21-7.35 (m, 5H, phenyl-H), 7.79 (br,
s, 2H, NH2), 8.05 (s, 1H, N CH ), 8.06 (s, 1H, pyri-H), 9.07 (s,1H,
CH2 NH ), 11.39 (s, 1H, C N NH ). 13C NMR (DMSO-d6)δ 13.33 (S-
CH3), 46.81 (NH-CH2-), 105.75 (pyri-C-5), 126.65 (Phenyl-4-C), 126.92
(Phenyl-2-C and Phenyl-6-C), 128.17 (Phenyl-3-C and Phenyl-5-C),
139.45 (Phenyl-1-C), 143.34 (N CH ), 158.41 and 158.69 (pyri-C-4 and
pyri-C-6), 170.73 (pyri-C-2), 176.89 (S C ). MS (ESI) m/z 333.4 (M +
H+).
N,N ꢀ-(Hexane-1,6-diyl)bis(2-((4-amino-2-(methylthio)
pyrimidin-5-yl)methylene)hydrazinecarbothioamide) (4i)
Yield: 87%. Pale yellow powder, mp 246–249◦C. IR νmax (KBr)/cm−1
3555, 3276, 3168, 2927, 2855, 1618, 1575, 1525, 1457, 1364, 1299,
1242, 1200, 1107, 959, 783. 1H NMR (DMSO-d6)δ 1.32 (s, 4H,
2NH CH2 CH2 CH2 ), 1.59 (s, 4H, 2NH CH2 CH2 ), 2.47 (s, 6H,

New Thiazolidin-4-one Derivatives
531
S-CH3), 3.54 (q, 4H, J = 6.4 Hz, 2NH CH2 ), 7.78 (br, s, 4H,
2NH2-), 8.06 (s, 2H, 2N CH ), 8.09 (s, 2H, 2pyri-H), 8.53 (s,2H,
2CH2-NH-), 11.19 (s, 2H, 2C N NH ). 13C NMR (DMSO-d6)δ 13.38
(2S CH3), 26.28 (2NH CH2 CH2 CH2 ), 29.03 (2NH CH2 CH2 ),
43.78 (2NH CH2 ), 105.88 (2pyri-C-5), 142.78 (2N CH ), 158.44
(2pyri-C-4 and 2pyri-C-6), 170.62 (2pyri-C-2), 176.13 (2S C ). MS
(ESI) m/z 567.3 (M + H+).
General Procedure for the Synthesis of 5a–5i
To a mixture of thiosemicarbazones 4a–4h (1 mmol), sodium acetate
(1 mmol) in ethanol (20 mL) was added ethyl 2-bromoacetate (1.1 mol).
The reaction was refluxed for 4–16 h until the thiosemicarbazones 4a–
4h were completely converted to the product. Then the reaction mixture
was partially concentrated and cooled. The product was collected by
filtration and was recrystallized from ethanol. When 5i was the target
product, 0.5 mmol of 4i was needed.
2-(2-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)
hydrazono)-3-methylthiazolidin-4-one (5a)
Yield: 72%. Off-white powder, mp 275–277◦C. IR νmax (KBr)/cm−1
3389, 3285, 2928, 1727, 1635, 1560, 1571, 1515, 1364, 1313, 1265, 1198,
1120, 786, 646, 502. 1H NMR (DMSO-d6)δ 2.51 (s, 3H, S-CH3), 3.16 (s,
3H, -CH3), 4.02 (s, 2H, thiazoli-CH2-), 8.16 (br, s, 1H, NH), 8.42 (s, 1H,
N CH ), 8.56 (s, 1H, pyri-H), 8.72 (br, s, 1H, -NH). 13C NMR (DMSO-
d6)δ 13.38 (S-CH3), 29.35 (NH CH3), 32.40 (thiazoli-C-5), 106.00 (pyri-
C-5), 156.24 (N CH ), 158.03 (thiazoli-C-2), 159.64 (pyri-C-4), 164.09
(pyri-C-6), 170.83 (thiazoli-C-4), 172.01 (pyri-C-2). HRMS (ESI) m/z
297.0588 (M + H+), calcd. for C10H12N6OS2+ H+ = 297.05868.
2-(2-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)
hydrazono)-3-ethylthiazolidin-4-one (5b)
Yield: 71%. Pale yellow powder, mp 223–224◦C. IR νmax (KBr)/cm−1
3410, 3279, 2927,1723, 1620, 1566, 1518, 1451, 1368, 1338, 1262, 1195,
1
1128, 1049, 945, 785, 639. H NMR (DMSO-d6) δ 1.18 (t, 3H, J = 6.4
Hz, -CH3), 2.48 (s, 3H, S-CH3), 3.75 (q, 2H, J = 7.2 Hz, CH3 CH2 ),
4.02 (s, 2H, thiazoli-CH2- ), 7.92 (br, s, 1H, NH), 8.35 (s, 2H, N CH
and NH), 8.56 (s, 1H, pyri-H). 13C NMR (DMSO-d6)δ 12.26 ( CH3),
13.38 (S CH3), 32.41 (thiazoli-C-5), 37.79 (N CH2 ), 106.00 (pyri-C-
5), 156.18 (N CH ), 157.90 (thiazoli-C-2), 159.63 (pyri-C-4), 163.35
(pyri-C-6), 170.73 (thiazoli-C-4), 171.74 (pyri-C-2). HRMS (ESI) m/z
311.0740 (M + H+), calcd. for C11H14N6OS2+ H+ = 311.07433.

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B. X. Hu et al.
2-(2-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)
hydrazono)-3-propylthiazolidin-4-one (5c)
Yield: 65%. Pale yellow powder, mp 212–214◦C. IR νmax (KBr)/cm−1
3336, 3271, 3112, 2961, 2928, 1721, 1632, 1562, 1372, 1268, 1195, 1133,
1
1068, 964, 786. H NMR (DMSO-d6)δ 0.88 (t, 3H, J = 7.2 Hz, -CH3),
1.60–1.67 (m, 2H, CH3 CH2 ), 2.51 (s, 3H, S CH3), 3.67 (t, 2H, J = 7.2
Hz, N CH2 ), 4.04 (s, 2H, thiazoli-CH2- ), 8.11 (br, s, 1H, NH), 8.41
(s, 1H, N CH ), 8.56 (s, 1H, pyri-H), 8.64 (br, s, 1H, NH). 13C NMR
(DMSO-d6)δ 10.96 ( CH3), 13.32 (S CH3), 19.90 (CH3 CH2 ), 32.31
(thiazoli-C-5), 44.21 (N CH2 ), 106.04 (pyri-C-5), 155.49 (thiazoli-C-2),
155.56 (N CH ), 159.65 (pyri-C-4), 164.09 (pyri-C-6), 169.13 (thiazoli-
C-4), 171.97 (pyri-C-2). HRMS (ESI) m/z 325.0897 (M + H+), calcd. for
C12H16N6OS2+ H+ = 325.08998.
2-(2-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)
hydrazono)-3-isopropylthiazolidin-4-one (5d)
Yield: 65%. Pale yellow powder, mp 194–196◦C. IR νmax (KBr)/cm−1
3353, 3277, 3134, 2965, 2927, 1721, 1630, 1603, 1560, 1382, 1358, 1270,
1
1195, 1122, 1068, 963, 787, 644, 575, 503. H NMR (DMSO-d6)δ 1.43
(d, 6H, J = 7.2 Hz, 2CH3-), 2.48 (s, 3H, S-CH3), 3.97 (s, 2H, thiazoli-
CH2- ), 4.67-4.74 (m, 1H, N-CH-), 7.93 (br, s, 1H, NH), 8.28 (s, 2H,
N CH and NH), 8.56 (s, 1H, pyri-H), 13C NMR (DMSO-d6)δ 13.41
(S-CH3), 18.60 (2CH3-), 32.21 (thiazoli-C-5), 47.28 (N CH ), 106.00
(pyri-C-5), 156.36 (N CH ), 159.18 (pyri-C-4), 159.61 (thiazoli-C-2),
163.25 (pyri-C-6), 171.55 (thiazoli-C-4), 171.95 (pyri-C-2). HRMS (ESI)
m/z 325.0891 (M + H+), calcd. for C12H16N6OS2+ H+ = 325.08998.
2-(2-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)
hydrazono)-3-butylthiazolidin-4-one (5e)
Yield: 69%. White solid, mp 190–192◦C. IR νmax (KBr)/cm−1 3348,
3144, 2957, 2927, 1719, 1641, 1605, 1561, 1522, 1376, 1270, 1191,
1131, 1068, 969, 785, 571. 1H NMR (DMSO-d6)δ 0.89 (t, 3H, J =
7.2 Hz, -CH3), 1.25–1.34 (m, 2H, CH3 CH2 ), 1.57-1.64 (m, 2H,
CH3 CH2 CH2 ), 2.48 (s, 3H, S CH3), 3.71 (t, 2H, J = 7.6 Hz,
NH CH2 ), 4.03 (s, 2H, thiazoli-CH2- ), 7.92 (br, s, 1H, -NH), 8.35
(br, s, 1H, NH), 8.36 (s, 1H, N CH ), 8.55 (s, 1H, pyri-H), 13C NMR
(DMSO-d6)δ 13.37 (S CH3), 13.52 ( CH3), 19.40 (CH3 CH2 ), 28.69
(CH3 CH2 CH2 ), 32.27 (thiazoli-C-5), 42.43 (N CH2 ), 105.98 (pyri-
C-5), 156.46 (N CH ), 159.21 (pyri-C-4), 159.62 (thiazoli-C-2), 163.28
(pyri-C-6), 171.61 (thiazoli-C-4), 171.99 (pyri-C-2). HRMS (ESI) m/z
339.1056 (M + H+), calcd. for C13H18N6OS2+ H+ = 339.10563.

New Thiazolidin-4-one Derivatives
533
Adduct of 2-(2-((4-Amino-2-(methylthio)pyrimidin-
5-yl)methylene)hydrazono)-3-tert-butylthiazolidin-4-one
and ethanol (5f)
Yield: 64%. Pale yellow powder, mp 108–112◦C. IR νmax (KBr)/cm−1
3327, 3136, 2962, 2928, 1716, 1635, 1532, 1454, 1365, 1300, 1265, 1212,
1
1151, 1031, 967, 785, 602, 509. H NMR (DMSO-d6)δ 1.21 (t, 3H,J =
7.2 Hz, ethanol-CH3), 1.38 (s, 9H, 3CH3 ), 2.46 (s, 3H, S CH3), 3.94 (s,
2H, thiazoli-CH2-), 4.14 (q, 2H, J = 6.8 Hz, ethanol-CH2), 5.94 (s, 1H,
ethanol-OH), 8.11 (br, s, 1H, NH), 8.17 (br, s, 1H, NH), 8.26 (s, 1H,
N CH ), 8.31 (s, 1H, pyri-H), 13C NMR (DMSO-d6)δ 13.27 (S CH3),
13.95 (ethanol-CH3), 28.35 (3CH3 ), 31.89 (thiazoli-C-5), 53.37 (N-C-),
61.29 (ethanol-CH2-), 107.12 (pyri-C-5), 150.19 (N CH ), 157.65
(thiazoli-C-2), 157.81 (pyri-C-4), 159.43 (pyri-C-6), 169.73 (pyri-C-2),
169.84 (thiazoli-C-4). HRMS (ESI) m/z 385.1476 (M + H+), calcd. for
C15H24N6O2S2+ H+ = 385.14749.
2-(2-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)
hydrazono)-3-cyclohexylthiazolidin-4-one (5g)
Yield: 68%. White solid, mp 241–242◦C. IR νmax (KBr)/cm−1 3361,
3116, 2924, 2857, 1717, 1636, 1560, 1557, 1521, 1381, 1270, 1194, 1144,
1067, 968, 787, 545. 1H NMR (DMSO-d6)δ 1.12–1.19 (m, 1H, cyclohexyl-
4-Ha), 1.27-1.35 (m, 2H, cyclohexyl-2-Ha, and cyclohexyl-6-Ha), 1.62–
1.64 (m, 3H, cyclohexyl-3-Ha, cyclohexyl-4-Hb and cyclohexyl-5-Ha),
1.81–1.83 (m, 2H, cyclohexyl-3-Hb and cyclohexyl-5-Hb), 2.28–2.35 (m,
2H, cyclohexyl-2-Hb and cyclohexyl-6-Hb), 2.49 (s, 3H, S-CH3), 3.98 (s,
2H, thiazoli-CH2-), 4.28–4.33 (m, 1H, cyclohexyl-1-H), 7.95 (br, s, 1H,
NH), 8.38 (s, 2H, N CH and NH), 8.58 (s, 1H, pyri-H). 13C NMR
(DMSO-d6)δ 13.32 (S CH3), 24.79 (cyclohexyl-C-4), 25.53 (cyclohexyl-
C-3 and cyclohexyl-C-5), 27.83 (cyclohexyl-C-2 and cyclohexyl-C-6),
32.06 (thiazoli-C-5), 55.27 (cyclohexyl-C-1), 105.97 (pyri-C-5), 156.26
(N CH ), 158.91 (thiazoli-C-2), 159.56 (pyri-C-4), 163.40 (pyri-C-6),
171.36 (thiazoli-C-4), 171.96 (pyri-C-2). HRMS (ESI) m/z 365.1205 (M
+ H+), calcd. for C15H26N6OS2+ H+ = 365.12128.
2-(2-((4-Amino-2-(methylthio)pyrimidin-5-yl)methylene)
hydrazono)-3-benzylthiazolidin-4-one (5h)
Yield: 71%. White solid, mp 227–228◦C. IR νmax (KBr)/cm−1 3356,
3167, 2923, 1715, 1647, 1563, 1521, 1374, 1270, 1181, 1063, 966, 783,
1
697, 541, 501. H NMR (DMSO-d6)δ 2.48 (s, 3H, S CH3), 4.13 (s, 2H,
thiazoli-CH2-), 4.91 (s, 2H, N CH2 ), 7.29-7.36 (m, 5H, phenyl-H), 7.96
(br, s, 1H, -NH), 8.36 (s, 1H, N CH ), 8.42 (br, s, 1H, NH), 8.53 (s,
1H, pyri-H), 13C NMR (DMSO-d6)δ 13.83 (S CH3), 32.79 (thiazoli-C-5),

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B. X. Hu et al.
46.25 (N CH2 ), 106.37 (pyri-C-5), 128.01 (Phenyl-C-4, Phenyl-C-2
and Phenyl-C-6), 128.96 (Phenyl-C-3 and Phenyl-C-5), 136.23 (Phenyl-
C-1), 157.19 (N=CH-), 159.38 (thiazoli-C-2), 160.10 (pyri-C-4), 163.64
(pyri-C-6), 171.92 (thiazoli-C-4), 172.60 (pyri-C-2). HRMS (ESI) m/z
373.0902 (M + H+), calcd. for C16H16N6OS2+ H+ = 373.08998.
3,3 ꢀ-(Hexane-1,6-diyl)bis(2-(((4-amino-2-(methylthio)
pyrimidin-5-yl)methylene)hydrazono)thiazolidin-4-one) (5i)
Yield: 70%. Pale yellow powder, mp 273–276◦C. IR νmax (KBr)/cm−1
3395, 3348, 2923, 1718, 1637, 1560, 1376, 1320, 1260, 1178, 1151, 1060,
1
785. H NMR (DMSO-d6)δ 1.33 (s, 4H, 2N CH2 CH2 CH2 ), 1.63 (s,
4H, 2N CH2 CH2 ), 2.53 (s, 6H, 2S CH3), 3.71 (m, 4H, 2N CH2),
4.04 (s, 4H, 2thiazoli-CH2- ), 8.20 (s, 2H, NH), 8.41 (s, 1H, N CH ),
8.53 (s, 1H, pyri-H), 8.81 (s, 2H, NH). 13C NMR (DMSO-d6)δ 13.88
(2S CH3), 26.04 (2NH CH2 CH2 CH2 ), 26.76 (2NH CH2 CH2 ),
32.94 (thiazoli-C-5), 43.11 (2NH CH2 ), 106.59 (pyri-C-5), 154.54
(thiazoli-C-2), 155.71 (N CH ), 160.25 (pyri-C-4), 165.04 (pyri-C-6),
168.72 (thiazoli-C-4), 172.53 (pyri-C-2). HRMS (ESI) m/z 647.1554 (M
+ H+), calcd. for C24H30N12O2S2+ H+ = 647.15703.
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