Convenient synthesis of 5-arylidene-2-imino-4-thiazolidinone derivatives using microwave irradiation

Article abstract of DOI:10.1055/s-0033-1341108

A concise approach for the preparation of 5-arylidene-2-imino-4- thiazolidinone derivatives is described. Structurally diverse amines, isothiocyanates, aldehydes, and chloroacetyl chloride were combined under microwave irradiation to afford new 5-arylidene-2-imino-4-thiazolidinone derivatives. The one-pot synthesis involves the in situ formation of a thiourea followed by reaction with chloroacetyl chloride and an aldehyde to generate the target compounds. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341108

LETTER
▌1257
lCettoernvenient Synthesis of 5-Arylidene-2-imino-4-thiazolidinone Derivatives
Using Microwave Irradiation
5-Arylidene-2-imino-4-thiazolidinone Derivatives
Manal Sarkis, Diem-Ngan Tran, Maria Chiara Dasso Lang, Christiane Garbay, Emmanuelle Braud*
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, Université Paris Descartes, PRES Sorbonne Paris
Cité, 45 rue des Saints-Pères, 75006 Paris, France
Fax +33(1)42864082; E-mail: emmanuelle.braud@parisdescartes.fr
Received: 07.02.2014; Accepted after revision: 13.03.2014
O
O
Abstract: A concise approach for the preparation of 5-arylidene-2-
imino-4-thiazolidinone derivatives is described. Structurally di-
verse amines, isothiocyanates, aldehydes, and chloroacetyl chloride
were combined under microwave irradiation to afford new 5-aryli-
dene-2-imino-4-thiazolidinone derivatives. The one-pot synthesis
involves the in situ formation of a thiourea followed by reaction
with chloroacetyl chloride and an aldehyde to generate the target
compounds.
R1
N
R1
N
N
S
S
R3
N
R2
R2
R1
I
II
OMe
Key words: 5-arylidene-2-imino-4-thiazolidinone, thiourea, mi-
crowave irradiation, multicomponent reaction, Knoevenagel con-
densation
O
O
HO
N
N
S
N
O
S
N
The thiazolidin-4-one scaffold is found in a large number
of heterocyclic compounds with a wide variety of biolog-
ical properties.1,2 In particular, 5-arylidene-2-imino-4-thi-
azolidinone derivatives I have been identified as
antimicrobial,3–5 anti-inflammatory,5–7 antibacterial,8–10
antihypertensive,11 antithrombotic,12,13 and anticancer
agents14,15 (Figure 1). Finally, ponesimod, which is a se-
lective agonist of the S1P1 receptor, has completed phase
II trials for multiple sclerosis treatment.16–18 Only a few
NO2
COOH
IIb
OMe
IIa
Figure 1 Structures of 5-arylidene-2-iminothiazolidin-4-one deriva-
tives
compounds of type II bearing identical substituents on the ally followed (Scheme 1).21,22 Both synthetic pathways
imino group and at position 3 of the thiazolidin-4-one ring involve initial formation of the 2-iminothiazolidinone
have been described in the literature. For example, thia- core followed by a Knoevenagel condensation. In the first
zolidinone IIa has been reported to exhibit bacterial anti- procedure (A), the 2-iminothiazolidinone ring is obtained
biofilm activity,19 and derivative IIb was identified as an by cyclization of a thiourea in the presence of an α-halo-
inhibitor of PTPMT1 phosphatase activity20 (Figure 1).
acetic acid derivative. In this step, the nature of R1 and R2,
the α-haloacetic acid derivative and the reaction condi-
tions are crucial for the regioselectivity of the cyclization.
Synthesis of 5-arylidene-2-iminothiazolidin-4-one deriv-
atives has been widely explored and two routes are gener-
O
O
R1
R2
O
O
O
S
R1
R2
N
N
Cl
R1
R2
N
N
R3CHO
Y
R2NCS
+
N
H
N
+
R3
S
S
H
N
R2
N
R1
R3
S
S
N
R2
N
R1
A
R1NH2
I
O
B
O
R1
R1
O
O
N
R3CHO
R2NCS
R1
Cl
N
Cl
Cl
N
H
R3
S
N
R2
S
N
R2
I
Scheme 1 Classical synthetic pathways to 5-arylidene-2-iminothiazolidin-4-one derivatives
SYNLETT 2014, 25, 1257–1262
Advanced online publication: 03.04.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1341108; Art ID: ST-2014-D0104-L
© Georg Thieme Verlag Stuttgart · New York

1258
M. Sarkis et al.
LETTER
In case B, the condensation between a primary amine and To this end, the reaction conditions of a model reaction
chloroacetyl chloride leads to the formation of the corre- were tested using 4-methoxybenzylamine and its corre-
sponding amide derivative which can react with an iso- sponding isothiocyanate, chloroacetyl chloride, and 4-me-
thiocyanate to afford the 2-iminothiazolidinone ring. In thoxybenzaldehyde as the starting materials (Scheme 2).
2006, Kasmi-Mir et al. reported an attractive microwave
Ethanol was chosen as the solvent and sodium acetate as
synthesis of 5-arylidene-2-imino-4-thiazolidinones using
the base for the Knoevenagel condensation. To avoid re-
a three-component reaction between N,N′-diarylthioureas,
action between the amine and chloroacetyl chloride, we
chloroacetic acid, and aldehydes under solvent-free con-
decided to achieve initial preparation of the thiourea inter-
ditions.23 This strategy was also used by Abdel-Aziz et
mediate. For this model reaction, formation of the thio-
al.24 However, in both cases, this approach was applied
urea starting from 4-methoxybenzylamine and its
only to a very limited number of arylthioureas that were
corresponding isothiocyanate was complete within 20
either prepared by the authors or were commercially
minutes at room temperature which allowed the subse-
available.
quent addition of sodium acetate, chloroacetyl chloride,
Herein, we report a convenient method for the synthesis of and 4-methoxybenzaldehyde in the reaction vial.
5-arylidene-2-imino-4-thiazolidinones of type II bearing
In a first trial, the suspension was heated at 120 °C for 15
minutes under microwave irradiation, when thiazolidi-
none 1 was obtained in 39% yield (Table 1, entry 1).
diversely substituted alkyl chains R1 and R2, using micro-
wave irradiation. This sequential reaction, which utilizes
readily available starting materials, is achieved in one-pot,
Increasing the reaction time to 20 and 30 minutes resulted
reduces significantly the reaction time as well as solvent
in only a slight increase in yield [Table 1, entries 2 (45%)
and reagent use.
and 3 (43%), respectively]. In these cases, the 3-(4-me-
thoxybenzyl)-2-(4-methoxybenzylimino)-thiazolidin-4-
Table 1 Optimization of the Reaction Conditionsa
Entry
Heating conditions
Solvent
Time
Temp (°C)
Base (1.5 equiv)
Yield (%)b
1
2
MW
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
THF
15 min
20 min
30 min
20 min
20 min
20 min
20 min
20 min
20 min
7 h
120
120
120
120
120
120
80
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
–
39
45
43
48c
37d
35e
41
34
36
23
30f
31g
16
27
41
32
–
MW
3
MW
4
MW
5
MW
6
MW
7
MW
8
MW
110
150
reflux
120
120
120
120
120
120
120
9
MW
10
11
12
13
14
15
16
17
conventional heating
MW
MW
MW
MW
MW
MW
MW
20 min
20 min
20 min
20 min
20 min
20 min
20 min
NaOAc
NaOAc
NaOAc
NaOAc
dioxane
–
a 4-Methoxybenzylisothiocyanate (0.5 mmol), 4-methoxybenzylamine (0.5 mmol), chloroacetyl chloride (0.75 mmol), and 4-methoxybenz-
aldehyde (0.5 mmol).
b Isolated yield.
c Conditions: 2 equiv of 4-methoxybenzaldehyde.
d In the presence of molecular sieves.
e In the presence of MgSO4.
f In the presence of 2 equiv of NaOAc.
g In the presence of 2.5 equiv of NaOAc.
Synlett 2014, 25, 1257–1262
© Georg Thieme Verlag Stuttgart · New York

LETTER
5-Arylidene-2-imino-4-thiazolidinone Derivatives
1259
OMe
O
NH2
NCS
Cl
MeO
base
MW
CHO
S
Cl
O
EtOH
N
N
+
N
H
H
r.t., 20 min
MeO
OMe
N
various conditions
S
OMe
OMe
OMe
MeO
1
Scheme 2 Model reaction for the preparation of 5-benzylidene-2-iminothiazolidin-4-one 1
one intermediate and unreacted aldehyde were observed tries 7–9) with the yield varying from 34–45% (Table 1,
at the end of the reaction. This indicated that the Knoeve- entry 2) at elevated temperatures. In addition, the reaction
nagel condensation was the limiting step of the reaction. was conducted under classical heating conditions. After
All the following reactions were then performed for 20 refluxing for seven hours, the desired compound 1 was
minutes. An excess of 4-methoxybenzaldehyde (2 equiv) isolated in 23% yield (Table 1, entry 10). Thus, the opti-
was used which afforded product 1 with a comparable mal reaction time and temperature were set at 20 minutes
yield (48%, Table 1, entry 4). The use of molecular sieves and 120 °C (Table 1, entry 2). The effect of the base was
or MgSO4 to trap water released from Knoevenagel con- then examined. Increasing amounts of NaOAc decreased
densation also did not increase the yield (Table 1, entries the yield (Table 1, entries 11 and 12) as well as the ab-
5 and 6).The temperature was then screened (Table 1, en- sence of a base. Other solvents such as methanol, THF, or
Table 2 Synthesis of 2-Iminothiazolidin-4-ones 2–13 Using Different Aldehydes
OMe
OMe
OMe
O
NaOAc, EtOH
Cl
+
O
+
RCHO
+
Cl
MW, 30 W, 120 °C, 20 min
N
N
H2N
SCN
S
R
OMe
2–13
Product
Aldehyde
Yield (%)a
2
3
4-MeSC6H4
4-MeC6H4
55
46
37
39
29
28
48
47
28
30
42
51
4
Ph
5
4-O2NC6H4
4-HO2CC6H4
4-MeO2SC6H4
3,4-Cl2C6H3
3-MeOC6H4
3-O2NC6H4
2-MeOC6H4
1-naphthyl
5-phenyl-2-furyl
6
7
8
9
10
11
12
13
a Isolated yield.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1257–1262

1260
M. Sarkis et al.
LETTER
O
O
O
O
OMe
OMe
O
N
N
N
N
O
F
S
S
S
S
N
N
N
N
MeS
MeO
MeO
MeO
F
OMe
16, 57%
17, 48%
O
O
MeO
14, 34%
15, 52%
O
O
F
F
O
I
N
N
N
S
N
S
O
S
O
N
N
I
MeS
18, 25%
19, 22%
20, 46%
O
O
O
O
N
N
N
N
S
N
S
N
O
S
N
N
MeO
MeS
MeS
21, 29%
22, 32%
23, 34%
Figure 2 Structures and yields of 2-iminothiazolidinones 14–23
dioxane were used (Table 1, entries 14–16). In the case of drawing groups at position 3 afforded compounds 18 and
methanol, the 27% yield may be due to a higher solubility 19 in lower yields. The multicomponent reaction could
of the product in this solvent. Finally, solvent-free condi- also be applied to alkylamines and their corresponding
tions did not lead to the formation of the expected thi- isothiocyanates to afford compounds 20–23 with yields
azolidinone 1 (Table 1, entry 17).
between 29% and 46%. It is to be noted that microwave
irradiation was also used to allow a rapid and complete
formation of the thiourea for the preparation of com-
pounds 18–20 and 23.
The scope of the multicomponent reaction was then ex-
tended to a variety of substituted aldehydes using the op-
timized conditions.25 As described in Table 2, a subseries
of new 5-arylidene-2-iminothiazolidin-4-one derivatives Finally, all 5-arylidene-thiazolidinones 1–23 were ob-
(compounds 2–13) was synthesized. The presence of oth- tained as a single isomer. The formation of the thermody-
er electron-donating substituents at position 4 of the phe- namically stable Z isomer was confirmed by the chemical
nyl moiety was also well tolerated and afforded shift of the methine proton, which was comparable to re-
thiazolidinones 2 and 3 in 55% and 46% yields, respec- ported data for analogous derivatives.26–29
tively.
In summary, we have described the synthesis of new 5-ar-
Yields decreased when substituents with electron-with- ylidene-2-iminothiazolidin-4-one derivatives using a one-
drawing properties were introduced (compounds 5–7) pot sequential reaction. Microwave irradiation has been
while product 8 with two chlorine substituents was isolat- used, leading to shorter reaction times and higher yields.
ed in a better yield (48%). In the case of substituents at the This strategy gives an easy access to a series of structural-
meta position of the phenyl ring (compounds 9 and 10), a ly diverse thiazolidinone compounds. Moreover, it af-
similar profile was observed. Finally, the multicomponent fords, under simple conditions, access to quantities
reaction could also be applied to other aryl aldehydes such sufficient (50–130 mg) for preliminary evaluation on a
as 1-naphthaldehyde and 5-phenyl-2-furaldehyde which panel of biological tests. Finally, this approach could be
afforded compounds 12 and 13 in 42% and 51% yields, extended to the preparation of other 5-arylidene-2-imino-
respectively.
thiazolidin-4-ones.
Different amines and their corresponding isothiocyanates
were then tested in the presence of 4-methoxybenzalde-
hyde, 5-phenyl-2-furaldehyde, or 4-methylthiobenzalde-
hyde. Ten new compounds were obtained with yields
between 22% and 57% (Figure 2). In the case of the ben-
zylamines/isothiocyanates, the presence of electron-with-
Acknowledgment
The authors would like to thank the research group of Dr Christine
Gravier-Pelletier for allowing us to use their CEM microwave ap-
paratus and especially Dr Laurent Le Corre for helpful discussions.
Synlett 2014, 25, 1257–1262
© Georg Thieme Verlag Stuttgart · New York

LETTER
5-Arylidene-2-imino-4-thiazolidinone Derivatives
1261
This work has benefited from the facilities and expertise of the
Small Molecule Mass Spectrometry platform of IMAGIF (Centre
de Recherche de Gif - http://www.imagif.cnrs.fr/).
(24) Abdel Aziz, H. A.; El-Zahabi, H. S. A.; Dawood, K. M. Eur.
J. Med. Chem. 2010, 45, 2427.
(25) Optimized Procedure for the Synthesis of 5-Arylidene-2-
aryliminothiazolidin-4-ones
In a 10 mL reaction vial, the amine (0.5 mmol) was added to
a solution of isothiocyanate (0.5 mmol) in absolute EtOH (1
mL). The formation of the thiourea was achieved either at r.t.
or by irradiating the reaction mixture for the duration
indicated for each compound at a maximum power of 90 W
and 120 °C. Anhydrous NaOAc (61.5 mg, 1.5 equiv),
chloroacetyl chloride (59.7 μL, 1.5 equiv), and aldehyde
(1 equiv) were added successively. The reaction mixture
was then irradiated for 20 min at a maximum power of 30 W
and 120 °C. The precipitate was filtered and dissolved in
CH2Cl2. The organic phase was washed with H2O and brine,
dried over Na2SO4, and concentrated in vacuo. Either
crystallization from EtOH or purification by flash
chromatography afforded the corresponding 5-arylidene-2-
aryliminothiazolidin-4-ones.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
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(29) Selected Analytical Data
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Compound 1: pale yellow solid (106 mg, 45%); mp 143–
145 °C. 1H NMR (250 MHz, CDCl3): δ = 3.81 (s, 3 H, CH3),
3.84 (s, 3 H, CH3), 3.88 (s, 3 H, CH3), 4.60 (s, 2 H, CH2),
5.04 (s, 2 H, CH2), 6.84 (d, 2 H, J = 6.2 Hz, ArH), 6.91 (d, 2
H, J = 6.5 Hz, ArH), 7.00 (d, 2 H, J = 6.5 Hz, ArH), 7.26 (d,
2 H, J = 6.2 Hz, ArH), 7.47 (d, 2 H, J = 6.5 Hz, ArH), 7.51
(d, 2 H, J = 6.5 Hz, ArH), 7.73 (s, 1 H, C=CH). 13C NMR (63
MHz, CDCl3): δ = 45.5, 55.2, 55.3, 55.4, 55.8, 113.7 (2 C),
113.8 (2 C), 114.5 (2 C), 118.8, 126.6, 128.6 (2 C), 128.8,
130.0, 130.5 (2 C), 131.3, 131.8 (2 C), 149.0, 158.6, 159.2,
160.7, 166.9. IR: ν = 2951, 2829, 1697, 1644, 1615, 1599,
1509, 1468, 1443, 1426, 1380, 1338, 1297, 1249, 1173,
1163, 1117, 1106, 1032 cm–1. ESI-HRMS: m/z calcd for
C27H27N2O4S [M + H]+: 475.1692; found: 475.1707.
Compound 2: yellow solid (134 mg, 55%); mp 169–170 °C.
1H NMR (250 MHz, CDCl3): δ = 2.54 (s, 3 H, CH3), 3.81 (s,
3 H, CH3), 3.84 (s, 3 H, CH3), 4.61 (s, 2 H, CH2), 5.05 (s, 2
H, CH2), 6.84 (d, 2 H, J = 6.5 Hz, ArH), 6.91 (d, 2 H, J = 6.5
Hz, ArH), 7.25–7.33 (m, 4 H, ArH), 7.47 (d, 2 H, J = 8.0 Hz,
ArH), 7.71 (s, 1 H, C=CH). 13C NMR (63 MHz, DMSO-d6):
δ = 16.5, 47.1, 56.7, 56.8, 57.2, 115.1 (2 C), 115.3 (2 C),
121.8, 127.4 (2 C), 130.0 (2 C), 130.1, 131.0, 131.7 (2 C),
131.8, 131.9 (2 C), 132.5, 143.0, 150.2, 160.1, 160.6, 168.1.
IR: ν = 2840, 1698, 1646, 1610, 1585, 1513, 1497, 1467,
1423, 1403, 1380, 1331, 1295, 1248, 1171, 1162, 1092,
1072, 1041, 1030 cm–1. ESI-HRMS: m/z calcd for
C27H27N2O3S2 [M + H]+: 491.1463; found: 491.1440.
Compound 13: yellow solid (130 mg, 51%); mp 141–
143 °C. 1H NMR (250 MHz, CDCl3): δ = 3.81 (s, 3 H,
OCH3), 3.84 (s, 3 H, OCH3), 4.66 (s, 2 H, C=NCH2), 5.05 (s,
2 H, NCH2), 6.84–6.94 (m, 6 H, ArH), 7.29–7.55 (m, 8 H,
ArH and C=CH), 7.78 (d, 2 H, J = 6.8 Hz, ArH). 13C NMR
(63 MHz, CDCl3): δ = 45.5, 55.2, 55.3, 55.5, 108.3, 113.7 (2
C), 113.8 (2 C), 116.2, 118.3, 119.0, 124.3 (2 C), 128.5,
128.7 (2 C), 128.9 (2 C), 129.0, 129.6, 130.3, 130.4 (2 C),
131.4, 149.7, 156.9, 158.7, 159.1, 166.4. IR: ν = 2924, 2851,
1728, 1697, 1678, 1647, 1608, 1510, 1439, 1415, 1379,
1328, 1289, 1244, 1163, 1110, 1088, 1029 cm–1. ESI-
HRMS: m/z calcd for C30H27N2O4S [M + H]+: 511.1685;
found: 511.1694.
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Rahmouni, M. Molecules 2006, 11, 597.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1257–1262

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LETTER
Compound 21: yellow solid (52 mg, 29%); mp 68 °C. 1H
NMR (250 MHz, CDCl3): δ = 0.94–1.01 (m, 6 H, 2 × CH3),
1.34–1.49 (m, 4 H, 2 × CH2), 1.63–1.74 (m, 4 H, 2 × CH2),
2.54 (s, 3 H, SCH3), 3.42 (t, 2 H, J = 6.8 Hz, C=NCH2), 3.87
(t, 2 H, J = 7.2 Hz, NCH2), 7.30 (d, 2 H, J = 8.5 Hz, Har), 7.47
(d, 2 H, J = 8.5 Hz, Har), 7.66 (s, 1 H, C=CH). 13C NMR (63
MHz, CDCl3): δ = 13.7, 13.9, 15.1, 20.0, 20.5, 29.5, 32.8,
42.8, 52.9, 120.9, 126.0 (2 C), 128.6, 130.2 (2 C), 130.6,
141.1, 147.3, 166.9. IR: ν = 2952, 2851, 2817, 1706, 1641,
1602, 1586, 1490, 1429, 1381, 1295, 1261, 1198, 1116,
1090, 1009 cm–1. ESI-HRMS: m/z calcd for C19H27N2OS2
[M + H]+: 363.1559; found: 363.1559.
Synlett 2014, 25, 1257–1262
© Georg Thieme Verlag Stuttgart · New York

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