A novel synthesis of some 2-imino-4-thiazolidinone derivatives

Article abstract of DOI:10.1002/jhet.5570440106

(Chemical Equation Presented) An efficient and simple route is presented to the synthesis of some iminothiazolidinone derivatives. α-Chloro amide derivatives undergo coupling reaction with isothiocyanate in the presence of a mild base, followed by nucleophilic substitution of chlorine by the sulfur atom of isothiocyanate.

Full text of DOI:10.1002/jhet.5570440106

Jan-Feb 2007
35
A Novel Synthesis of Some 2-Imino-4-thiazolidinone Derivatives
Firouz Matloubi Moghaddam* and Leila Hojabri
Department of Chemistry, Sharif University of Technology, P. O. Box 11365-9516 Tehran, Iran
Received December 27, 2005
Ar'
N
O
H
Cl
Ar
N
Ar'N=C=S
N
S
Cl
Ar
Cl
Ar NH2
,
K2CO3
CH3CN , rt
O
O
3
46-64%
2
1
An efficient and simple route is presented to the synthesis of some iminothiazolidinone derivatives. α–
Chloro amide derivatives undergo coupling reaction with isothiocyanate in the presence of a mild base,
followed by nucleophilic substitution of chlorine by the sulfur atom of isothiocyanate.
J. Heterocyclic Chem., 44, 35 (2007).
INTRODUCTION
with α–halo esters or acids in the presence of an inorganic
base (i.e. NaOAc) and in a polar solvent such as ethanol
or acetic acid (Scheme 1, Eq. 1) [11].
There has been considerable interest in the chemistry of the
4–thiazolidinone ring system, with regard to their wide array
of uses as pharmacologically active heterocyclic compounds.
They are known to possess a wide range of diverse biological
activities such as anti cancer activities [1-5].
Scheme 1. The reported routes to the synthesis of Iminothiazolidinone
derivatives
Some imino derivatives of thiazolidinone have
also shown to be strong anti-inflammatory [6],
antiviral [7], antimicrobial [8], and anti hepatic [9]
agents but they have not been investigated in
medicinal chemistry extensively, which may be due
to the lack of efficient synthetic methods for these
compounds. Some medicinally relevant iminothia-
zolidinones have been presented in Figure 1. On the
other hand, the development of simple synthetic
routes for widely used organic compounds from
readily available reagents is one of the major tasks
in organic synthesis [10].
COOR
R3
eq.1
Hal
O
S
NR2
+
NR1
NR2
R3
CN
CN
S
S
eq.2
NR1
HNR2
NHR1
R3
R3
O
O
O
eq.3
, CH3Cl
R3
H
Also, there are some other routes to prepare these
compounds. The reactions of thiourea with gem-dicyano
epoxide (Scheme 1, Eq. 2) or an aldehyde in the presence
of choloform (Scheme 1, Eq. 3) are among other typical
procedures [12].
R3
N
R2
N
S
S
NH
NR1
O
N
H
S
N
R
O
HO
O
CH3SO3H
N
R1
N+
H
N
-
OEt
H
O
R'
O
Figure 1. Two examples of medicinal iminothiazolidinones (inhibitor of
HCV replication) Darbufelon (anti inflammatory).
Figure 2. Enhanced regioselectivity by using the Heteroaryl ring
In the present work we wish to report a simple and regio-
selective synthesis of 2-imino-4-thiazolidinone derivatives.
For unsymmetrical thiourea (R1, R2), both of the two
possible regioisomeric iminothiazolidinone products are
formed. The regioselectivity is influenced by electronic
factor that predispose electron withdrawing substituent to
maintain conjugative stabilization with the imine's
nitrogen [11f].
RESULTS AND DISCUSSION
The common strategy to construct iminothiazolidinone
derivatives is the condensation of thiourea derivatives

36
F. M. Moghaddam and L. Hojabri
Vol 44
Scheme 2
3
Ar
Ar'
Ar'
N
O
a
b
c
d
e
f
Ph
4-NO2Ph
H
Cl
Ar
2,4-dimethoxy Ph 4-NO2Ph
3-acetoxy Ph
4-Cl Ph
N
Ar'N=C=S
N
S
Cl
Ar
Cl
Ar NH2
4-NO2Ph
4-NO2Ph
4-NO2Ph
4-NO2Ph
4-NO2Ph
4-Tolyl
K2CO3, CH3CN, rt
O
O
2-Tolyl
3(a-h)
1
2
3-methoxy Ph
1- naphtyl
1- naphtyl
g
h
In the absence of electronic properties between R1 and
R2 groups, the reaction of thiourea with α–halo acids or
esters proceeds with minimal regioselectivity.
Recently, some iminothiazoldinone derivatives have
been synthesized with high regioselectivity using a hetero
aryl methyl thiourea instead of aryl methyl thiourea in the
absence of NaOAc. It has been suggested that potential
hydrogen bond between the protonated heterocycle and
the reacting carbonyl ester drives the proximal thiourea
nitrogen to cyclize (Figure 2) [11f].
methodology different aromatic amides 2 were used
(Table 1).
We have not established the mechanism of the reaction,
however a possible mechanism is proposed in scheme 3.
The first step involves the addition of amide derivatives 2
to isothiocyanate in the presence of base; subsequent
cyclization takes place by nucleophilic substitution of
chlorine by the sulphure atom of isothiocyanate.
Scheme 3. Proposed Mechanism
Ar'
Here in we report an efficient and new method for the
regioisomer preparation of iminothizolidinone derivatives.
The reaction of aromatic amines 1 with choloro acetyl
choloride afforded the corresponding amide derivatives 2.
N
-
N
S
Ar'
Ar
N
S
N
Cl
Ar
Ar'
O
3
O
Then the compound
2 reacted smoothly with
N
S
-
N
isothiocyanates in the presence of a weak base such as
K2CO3 in CH3CN to produce iminothiazolidinones 3
(Scheme 2).
S
Ar'
-
Ar
Cl
S
N
O
Ar
Ar'
N
N
In a typical procedure amide 2 (1 mmol) was reacted
with isothiocyanate (1 mmol) at room temperature in the
presence of K2CO3 in acetonitrile, which took about 15
hours. After conventional work up, the product was
purified by simple crystallization from suitable solvent in
good yield. To demonstrate the generality of this
N
Cl
Ar
O
O
4
Considering the fact that isothiocyanate is an ambident
nucleophile, two different final structures of the
heterocycles could be considered, thiohydantion 4 or
Table 1
Physical and Analytical Data of Compound 3(a-h).
Ar'
N
H
Ar
N
Ar'N=C=S
N
S
Ar
Cl
K2CO3, CH3CN, rt
O
O
2
3
Entry
Product
Time
(h)
M.P (◦C)
Yield[a]
(%)
Elemental analysis
found (%)
calc (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
14
18
17
17
15
18
14
24
178-180
164-166
177-179
207-209
209-211
181-183
197-200
186-188
53
58
42
49
53
40
64
46
C, 57.4; H, 3.7; N, 13.5
C, 54.7; H, 4.2; N, 11.1
C, 57.4; H, 3.9; N, 11.6
C, 51.9; H, 3.0; N, 12.0
C, 58.7; H, 4.1; N, 12.8 C, 58.70; H, 4.00; N, 12.84
C, 56.1; H, 4.0; N, 12.1 C, 55.97; H, 3.82; N, 12.24
C, 62.3; H, 3.8; N, 11.3 C, 62.81; H, 3.61; N, 11.56
C, 57.50; H, 3.54; N, 13.41
C, 54.68; H, 4.05; N, 11.25
C, 57.46; H, 3.69; N, 11.82
C, 51.80; H, 2.90; N, 12.08
3g
3h
C, 72.0; H, 4.8; N, 7.9
C, 72.26; H, 4.85; N, 8.43
[a] Isolated yield.

Jan-Feb 2007
A Novel Synthesis of Some 2-Imino 4-Thiazolidinone Derivatives
37
residue was purified by column chromatography using
petroleum ether/ethyl acetate (2-4:1), and the product was
recrystallized from chloroform.
iminothiazolidinone 3. Spectroscopic data reveals that
chlorine atom has been substituted by the nucleophile and
cyclization has taken place. Two structures, thiohydantion
4 or iminothiazolidinone 3 are both consistent with these
features.
2-[(4-Nitrophenyl)imino]-3-phenyl-1,3-thiazolan-4-one
(3a). Yellow crystal (chloroform), mp 178-180°; ir (KBr)
1
(νmax/cm-1): 861, 1154, 1336, 1508, 1585, 1638, 1738 H nmr: δ
It is not evident from the classical spectroscopic data
4.07 (2H, s, CH2), 7.05 (2H, d, J=8.6Hz, CH), 7.39 (2H, d,
J=7.6Hz, CH), 7.50 (1H, t, J=7.4Hz, CH), 7.57 (2H, t, J=7.6Hz,
CH), 8.26 (2H, d, J=8.6Hz, CH), 13C nmr: δ 33.53 (CH2), 122.10
(2CH), 125.60 (2CH), 128.39 (2CH), 129.81 (CH), 129.97
(2CH), 134.73 (C), 144.99 (C), 154.51 (C),156.97(C), 171.45
(C). Anal. Calcd. for C15H11N3O3S: C, 57.50; H, 3.54; N, 13.41.
Found: 57.4; H, 3.7; N, 13.5.
1
(elemental analysis, HNMR, 13CNMR, and IR) which
compound is exactly produced. Therefore, more attempts
have been made to assure the structural assignment. Using
X-Ray single crystal analysis of 3d reveals that compound
3 is formed and the imino geometry for 3 is also
established (Figure 3) [13].
In conclusion, the presented method is a complementary
procedure along with the previously reported methods.
Most of these methods have been based on using thiourea
as a starting material but they have been limited by
unsymmetrical thiourea, due to the formation of two
regioisomers. However, in the current study only one of
the two possible isomers is obtained.
3-(2,4-Dimethoxyphenyl)-2-[(4-nitrophenyl)imino]-1,3-
thiazolan-4-one (3b). Pale yellow crystal (chloroform), mp
164-166°; ir (KBr) (νmax/cm-1): 869, 1038, 1115, 1181, 1346,
1
1515, 1585, 1646, 1738 H nmr: δ 3.88 (3H, s, OCH3), 3.91(3H,
s, OCH3), 4.03 (2H, AB quarted, J= 17.0 Hz, CH2), 6.61(1H, s,
CH), 6.62 (1H, d, J=8.5Hz, CH), 7.03 (2H, d, J=8.5Hz, CH),
7.18(1H, d, J=8.5Hz, CH), 8.24(2H, d, J=8.5Hz, CH) 13C nmr: δ
33.39 (CH2), 56.02 (OCH3), 56.34 (OCH3), 100.35 (CH), 105.54
(CH), 116.13 (C),122.19 (2CH), 125.51 (2CH), 130.58 (CH),
144.84 (C), 155.00 (C), 156.16(C), 156.81(C), 162.31 (C),
171.48 (C). Anal. Calcd. for C17H15N3O5S: C, 54.68; H, 4.05; N,
11.25. Found: C, 54.7; H, 4.2; N, 11.1.
EXPERIMENTAL
3-(3-Acethylphenyl)-2-[(4-nitrophenyl)imino]-1,3-thiazolan-
4-one (3c). Yellow crystal (chloroform), mp 177-179°; ir (KBr)
X-ray structure was recorded with a Brucker SMART 1000
1
(νmax/cm-1): 861, 1154, 1338, 1508, 1585, 1638, 1738 H nmr: δ
2.69 (3H, s, CH3), 4.13 (2H, s, CH2), 7.08 (2H, d, J=8.5Hz, CH),
7.64 (1H, d, J=7.8Hz, CH), 7.71 (1H, t, J=7.8Hz, CH), 8.04 (1H,
s, CH), 8.09 (1H, d, J=7.8Hz, CH), 8.25 (2H, d, J=8.5Hz, CH),
13C nmr: δ 26.95(CH3), 33.46 (CH2), 121.99 (2CH), 125.54
(2CH), 128.33 (CH), 129.44 (CH), 130.11 (CH), 132.88 (CH),
135.32 (C), 138.90 (C), 145.16 (C), 154.06 (C),156.53(C),
171.03 (C), 196.87 (C). Anal. Calcd. for C17H13N3O4S: C, 57.46;
H, 3.69; N, 11.82. Found: C, 57.4; H, 3.9; N, 11.6.
3-(4-Chlorophenyl)-2-[(4-nitrophenyl)imino]-1,3-thiazolan-
4-one (3d). Yellow crystal (chloroform), mp 207-209°; ir (KBr)
1
(νmax/cm-1): 896, 1156, 1195, 1335, 1505, 1579, 1622, 1728, H
nmr: δ 4.10 (2H, s, CH2), 7.07 (2H, d, J=8.8Hz, CH), 7.37 (2H,
d, J=8.6Hz, CH), 7.55 (2H, d, J=8.6Hz, CH), 8.25 (2H, d,
J=8.8Hz, CH) 13C nmr: δ 38.22 (CH2), 126.76 (2CH), 130.41
(2CH), 134.45 (2CH), 134.98 (2CH), 137.77 (C), 140.54 (C),
149.91 (C), 158.86 (C), 161.34 (C), 175.86 (C). Anal. Calcd. for
C15H10N3O3ClS: C, 51.80; H, 2.90; N, 12.08. Found: C, 51.9; H,
3.0; N, 12.0.
3-(2-Methylphenyl)-2-[(4-nitrophenyl)imino]-1,3-thiazolan-4-
one (3e). Pale yellow crystal (chloroform), mp 209-211°; ir
(KBr) (νmax/cm-1): 789, 862, 1112, 1290, 1344, 1511, 1586,
1645, 1734, 1H nmr: δ 2.33 (3H, s, CH3), 4.13 (2H, s, CH2), 7.06
(2H, d, J=8.8Hz, CH), 7.28 (1H, d, J=7.4Hz, CH), 7.40-7.47
(3H, m, CH), 8.24 (2H, d, J=8.8Hz, CH) 13C nmr: δ22.89 (CH3),
38.31 (CH2), 126.83 (CH), 130.33 (CH), 132.58 (CH), 133.64
(CH), 135.28 (CH), 136.61 (CH), 138.64 (C), 141.11 (C),
149.81 (C), 175.84 (C). Anal. Calcd. for C16H13N3O3S: C, 58.70;
H, 4.00; N, 12.84. Found: C, 58.7; H, 4.1; N, 12.8.
Figure 3. Crystal structure of compound 3d.
CCD area detector by XRSC, Moscow, Russia. Elemental
analysis were preformed by analytical laboratory of Research
Institute of Petroleum Industry (RIPI), Tehran, Iran. IR spectra
were recorded as KBr pellets on a Nicolet spectrometer (Magna
550). Melting points were measured on a Büchi B540 apparatus.
1H and 13C NMR are recorded (CDCl3 solution) with a Brucker
DRX-500 ADVANCE spectrometer. The α–chloro amides (2)
were prepared according to the known method [14].
General Procedure for Preparation of Compounds (3a-h).
To a stirred solution of amide derivatives (2a-h) (1 mmol) and
potassium carbonate (1.5 mmol) in acetonitrile (5 ml) was added
isothiocyanate (1 mmol) during about 5 minutes. The reaction
mixture was further stirred at room temperature for the required
time. The solvent was removed under reduced pressure and the
3-(3-Methoxyphenyl)-2-[(4-nitrophenyl)imino]-1,3-thiazolan-
4-one (3f). Yellow crystal (chloroform), mp 181-183°; ir (KBr)
(νmax/cm-1): 856, 1109, 1290, 1312, 1337, 1507, 1577, 1618,
1736 1H nmr: δ 3.88 (3H, s, OCH3), 4.09 (2H, s, CH2), 6.94 (1H,
s, CH), 6.99 (1H, d, J=7.9Hz, CH), 7.05(1H, d, J=8.4Hz, CH),
7.07(2H, d, J=8.9Hz, CH), 7.49(1H, dd, J=7.9Hz, J=8.4Hz CH),

38
F. M. Moghaddam and L. Hojabri
Vol 44
8.24(2H, d, J=8.9Hz, CH) 13C nmr: δ 33.52 (CH2), 56.63
(OCH3), 114.45 (CH), 115.39 (CH), 120.51 (CH), 122.10
(2CH), 125.59 (2CH), 130.68 (CH), 135.66 (C), 144.99 (C),
154.49 (C), 156.85 (C), 160.77 (C), 171.35 (C). Anal. Calcd. for
C16H13N3O4S: C, 55.97; H, 3.82; N, 12.24. Found: C, 56.1; H,
4.0; N, 12.1.
3-(1-Naphthyl)-2-[(4-nitrophenyl)imino]-1,3-thiazolan-4-
one (3g). Yellow crystal (chloroform), mp 197-200°; ir (KBr)
(νmax/cm-1): 777, 861, 1115, 1161, 1354, 1515, 1584, 1646, 1738
1H nmr: δ 4.25 (2H, AB quarted, J= 17.3 Hz, CH2), 7.01 (2H, d,
J=8.8Hz, CH), 7.56 (1H, d, J=7.1Hz, CH), 7.60-7.72 (4H, m,
CH), 8.00 (1H, d, J=8.0Hz, CH), 8.05 (1H, d, J=8.2Hz, CH),
8.21 (2H, d, J=8.8Hz, CH) 13C nmr: δ 38.49 (CH2), 126.75
(2CH), 126.84 (CH), 130.28 (2CH), 130.81 (CH), 131.94 (CH),
132.19 (CH), 132.71 (CH), 134.15 (CH), 134.57 (C), 135.71
(CH), 136.19 (C), 139.80 (C), 149.79 (C), 159.11 (C), 161.26
(C), 176.22 (C). Anal. Calcd. for C19H13N3O3S: C, 62.81; H,
3.61; N, 11.56. Found: C, 62.3; H, 3.8; N, 11.3.
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2-[(4-Methylphenyl)imino]-3-(1-naphthyl)-1,3-thiazolan-4-
one (3h). Pale yellow crystal (chloroform), mp 186-188°; ir
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M. Deshpande, D. Whitehouse, J. Lemm, Patent Cooperation Treaty
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1
(KBr) (νmax/cm-1): 777,1161, 1361, 1508, 1631, 1731 H nmr: δ
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New York, 1995.
2.36 (3H, s, CH3), 4.14 (2H, AB quarted, J= 17.0 Hz, CH2), 6.75
(2H, d, J=7.9Hz, CH), 7.1 (2H, d, J=7.9Hz, CH), 7.52-8.0 (7H,
m, CH), 13C nmr: δ 26.22(CH3), 38.32 (CH2), 125.92 (2CH),
127.32 (CH), 130.88 (CH), 131.78 (CH), 132.27 (CH), 132.49
(CH), 134.03 (CH), 134.83 (C), 134.94 (2CH), 135.37 (CH),
136.90 (C), 139.40 (C), 139.86 (C), 150.73 (C), 159.63 (C),
176.85 (C). Anal. Calcd. for C20H16N2OS: C, 72.26; H, 4.85; N,
8.43. Found: C, 72.0; H, 4.8; N, 7.9.
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[13] Full crystallographic data have been deposited to the
Cambridge Crystallographic Data Center (CCDC 265765). Copies of the
data can be obtained free of charge via the internet at
http://www.ccdc.cam.ac.uk.
REFERENCES
*
Correspondence: F. Matloubi Moghaddam, Sharif University
of Technology, Department of Chemistry, PO Box 11365- 9516, Tehran,
Iran; E-mail: matloubi@sharif.edu
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