One-pot synthesis of 5-arylidene-2-imino-4-thiazolidinones under microwave irradiation

Article abstract of DOI:10.3390/11080597

A rapid and easy solvent free one-pot synthesis of 5-arylidene-2-imino-4- thiazolidinones by condensation of the thioureas with chloroacetic acid and an aldehyde under microwave-irradiation is described.

Full text of DOI:10.3390/11080597

Molecules 2006, 11, 597-602
molecules
ISSN 1420-3049
http://www.mdpi.org
Communication
One-Pot Synthesis of 5-Arylidene-2-Imino-4-Thiazolidinones
under Microwave Irradiation
Souad Kasmi-Mir 1,*, Ayada Djafri 3, Ludovic Paquin 2,†, Jack Hamelin 2 and Mustapha
Rahmouni 1,‡
1
Laboratoire Synthèse et Catalyse, LSCT, Université Ibn Khaldoun, Tiaret, Algeria; E-mail:
‡rahmouni@mail.univ-tiaret.dz
2
ICMV, UMR 6226, Université de Rennes 1, Campus de Beaulieu, Bt10A 35042-Rennes, France;
E-mail: †ludovic.paquin@univ-rennes1.fr
3
Laboratoire Synthèse Organique Appliquée, Université Essénia, Oran, Algeria; Fax : (+213) 41 41
91 84.
* Author to whom correspondence should be addressed: E-mail: kasmi@mail.univ-tiaret.dz
Received: 2 June 2006; in revised form: 24 July 2006/ Accepted: 25 July 2006 / Published: 10 August
2006
Abstract: A rapid and easy solvent free one-pot synthesis of 5-arylidene-2-imino-4-
thiazolidinones by condensation of the thioureas with chloroacetic acid and an aldehyde
under microwave-irradiation is described.
Keywords: 5-Arylidene-2-imino-4-thiazolidinones; one-pot synthesis, microwave-
irradiation.
Introduction
4-Thiazolidinone derivatives constitute an important class of heterocyclic compounds for their
potential pharmaceutical applications [1-8]. Consequently, a large number of synthetic protocols
leading to these compounds have been reported in the literature [9]. Recently, 5-arylidene-2-imino-4-
thiazolidinones [10] were synthesized by the reaction of 2-imino-4-thiazolidinones and appropriate
aldehydes under basic conditions in ethanol at reflux for about 24 hours. The 2-imino-thiazolidinones
in turn were obtained by condensation of thiourea with chloroacetyl chloride in the presence of

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Molecules 2006, 11
triethylamine in CHCl3 at room temperature. We have previously reported the synthesis of
iminothiazolines [11] by Hantzsch cyclisation using microwave-irradiation. In similar fashion and
following the same strategy, we describe herein the one-pot three component solvent-free reaction of
the thioureas 1a,a’, chloroacetic acid and an appropriate aldehydes 2a-e under microwave-irradiation
according to Scheme 1. Yields and reaction conditions are given in Table 1.
Scheme 1. Synthesis of 5-arylidene-2-imino-4-thiazolidinones 3a-e, 4a-e.
R2
Ph
S
S
MW
N
+
+
R2CHO
ClCH2COOH
N
R1HN
NHPh
O
-HCl, H2O
R1
2
1a,a'
3 a-e, R1 = Ph
4 a-e, R1 = 4-Methylpyridin-2-yl
O
O
R2 =
(a)
(e)
OMe
N
N
Me
Me
Me
Me
(b)
(c)
(d)
Table 1. Yields and reaction conditions used for the microwave syntheses of 3a-e and 4a-e
Compounds 3
R1
Time (min)
Yields(%)(a)
3a
Ph
20
15
20
20
20
20
20
10
10
15
89
64
73
71
75(b)
79
68
77
74
61
3b
Ph
3c
Ph
3d
Ph
3e, 3e’
Ph
4a
4-methylpyridin-2-yl
4-methylpyridin-2-yl
4-methylpyridin-2-yl
4-methylpyridin-2-yl
4-methylpyridin-2-yl
4b
4c
4d
4e
(a) Isolated product yields
(b) 3:1 mixture of isomers 3e/3e’
The structures of all new compounds 3a-e, 4a-e were established by analysis of their 1H- and 13C-
NMR and mass spectra. The Z configuration of the exocyclic C=C bond was assigned on the basis of
1H-NMR spectroscopy, according to literature data for analogous 4-thiazolidinones [3,10,12]. The
methine proton deshielded by the adjacent C=O was detected at 7.76-8.30 ppm, except for 3d and 4d.
In the case of the reaction with aldehyde 2e a 3:1 mixture of two isomers 3e and 3e’ was obtained.
When the synthesis was performed in EtOH at reflux, the major and the most stable isomer 3e was
obtained. The 13C-NMR spectra of all compounds were characterized by the presence of the rhodanine
C2 C=N at 150.99-154.90 ppm and C=O at the rhodanine C4 at 165.20-167.25 ppm.

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Molecules 2006, 11
Conclusions
A solvent-free synthesis coupled with focused microwave irradiation appears to be a simple, fast
and high yielding method for the preparation of 5-arylidene-2-imino-4-thiazolidinones.
Acknowledgements
We thank Mr Pierre Guenot, responsible for the CRMPO and his group for mass spectrometry
Experimental
General
1
Melting points were determined on a Koffler melting point apparatus and are uncorrected. H-
NMR spectra were recorded on a Bruker ARX 200 (1H at 200 MHz) or Bruker AC 300P (1H and 13C at
300 and 75 MHz, respectively) spectrometers. Chemical shifts are expressed in parts per million
downfield from tetramethylsilane used as an internal standard. The mass spectra were recorded on a
Varian MAT 311 at a ionizing potential of 70eV at the “Centre de Mesures Physiques de l’Ouest”
(CRMPO, Rennes). Reactions under microwaves were performed in a PROLABO Synthewave 402
(2.45 GHz) microwave reactor with a single focused system. All solvents and reagents were purchased
from Acros Organics and Aldrich Chemical and used without further purification.
Preparation of Thioureas 1a,a’
A mixture of the appropriate amine (0.1 mol) and phenylisothiocyanate (0.12 mol) was stirred in
CH2Cl2 at room temperature for 24 h. The crude product was concentrated under vacuum and
1
recrystallized from ethanol. 1.3-diphenylthiourea (1a): 93% yield; beige crystals; mp = 157°C; H-
NMR (CDCl3/CF3COOH): δ 10.00 (bs, 2H, NH), 7.47 (m, 10H); 13C-NMR (CDCl3/CF3COOH) δ:
178.89 (C=S), 137.23, 129.12, 126.65, 124.79. 1-(4-methylpyridin-2yl)-3-phenylthiourea (1a’): 94%
yield; beige crystals; mp = 160°C; 1H-NMR (CDCl3) δ: 13.91 (bs, 1H, NH), 9.72 (bs, 1H, NH), 8.07 (d,
1H, J=5.16Hz), 7.36 (m, 5H), 6.82 (d, 1H, J=6Hz), 6.80 (s, 1H); 13C-NMR (CDCl3) δ: 178.73
(C=S), 153.5 (C=N), 150.59, 150.09, 138.38, 128.73, 126.19, 125.02, 119.82, 112.72, 21.33 (CH3).
General procedure for the preparation of 5-arylidene-2-imino-4-thiazolidinones 3a-e, 4a-e.
The appropriate thiourea 1a-a’ (3 mmol), chloroacetic acid (3.6 mmol) and the aldehyde 2 (3 mmol)
were placed successively in a cylindrical quartz tube (Ø = 1.5cm). Then the tube was introduced into
®
the Synthwave 402 Prolabo microwave reactor and irradiated at 90-110°C for 10-20 min. The
microwave is monitored by a computer which allows the temperature of the reaction mixture to be
adjusted. After, cooling down to room temperature; the mixture was extracted with CH2Cl2. After
elimination of the solvent under vacuum, the residue was purified by recrystallisation from

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Molecules 2006, 11
EtOH/water. Reaction times and yields are listed in Table 1, while microwave power settings and
reaction temperatures are given under each entry.
5-Benzylidene-3-phenyl-2-(phenylimino)thiazolidin-4-one (3a): 50W (110°C); yellow solid; mp =
1
13
216°C; H-NMR (CDCl3) δ: 7.88 (s, 1H, CH=C5rhod), 7.6-7.04 (m, 15H); C-NMR (CDCl3) δ: 166.6
(C=O), 151.05 (C=N), 148.23, 134.77 (CH=C5rhod), 134.51, 133.73, 133.28, 132.73, 131.58, 130.35,
129.46, 128.13, 127.36, 124.96, 121.37; 121.15 (C5rhod); HRMS, m/z found 356.0982 (calc. for
C22H16N2OS: 356.09834)
5-(4-Methoxybenzylidene)-3-phenyl-2-(phenylimino)thiazoldin-4-one (3b): 50W (90°C); yellow
1
powder; mp = 204°C; H-NMR (CDCl3) δ: 7.8 (s, 1H, CH=C5rhod), 7.32 (m, 10H), 7.04 (d, 2H, J=
7.3Hz), 6.9 (d, 2H, J=8.76Hz), 3.8 (s, 3H, CH3O); 13C-NMR (CDCl3) δ: 166.70 (C=O), 160.99, 151.36
(C=N), 148.49, 134.89 (CH=C5), 133.80, 133.12, 132.03, 129.29, 128.92, 127.12, 126.39, 124.88,
121.22, 121.27, 118.35 (C5rhod), 114.77 (C5rhod), 55.46 (CH3)2); HRMS, m/z found 386.1072 (calc.
for C23H19N3O2S: 386.10890)
5-(4-(Dimethylamino)benzylidene)-3-phenyl-2-(phenylimino)thiazolidin-4-one (3c): 50W (110°C);
yellow crystals; mp = 208°C; 1H-NMR (CDCl3) δ: 7.82 (s, 1H, CH=C5rhod), 7.58 -7.06 (m, 10H),
7.03 (d, 2H, J =8.03Hz), 6.76 (d, 2H, J=8.8Hz ), 3.02 (s, 6H, (CH3)2); 13C-NMR (CDCl3) δ: 167.03
(C=O), 151.92 (C=N), 151.15, 148.76, 135.19 (CH=C5rhod), 134.51, 132.72, 132 .46, 129.29, 128.72,
128.26, 127.50, 124.65, 121.35, 114.58 (C5rhod), 112.01, 40.06 (CH3)2); HRMS, m/z found 399.1406
(calc. for C2H21N3OS: 399.1053).
5-(3-(4(Dimethylamino)phenyl)allylidene)-3-phenyl-2-(phenylimino)thiazolidin-4-one (3d): 30W
1
(110°C); purple crystals; mp = 246°C; H-NMR (CDCl3) δ: 7.62-7.47 (m, 10H), 7.39 (d, 2H, J=
7.61Hz), 7.20 (1H, dd, J=6Hz, J=2Hz), 7.02 (d, 2H, J=7.57Hz), 6.78 (d, 1H, J=3Hz), 6.57 (d, 1H, J=
3.4Hz), 3.06 (s, 6H, (CH3)2); 13C-NMR (CDCl3) δ: 166.06 (C=O), 151.54 (C=N), 48.60, 142.96,
134.98 (CH =C5), 134.77, 132.37, 131.31, 129.24, 129.20, 128.76, 128.09, 124.74, 121.25, 119.07
(C5rhod); 112.74, 40.68 (CH3)2); HRMS, m/z found 425.1567 (calc. for C26H23N3OS 425.15618).
5-((Benzo[d][1,3]dioxol-6-yl)methylene)-3-phenyl-2-(phenylimino)thiazolidin-4-one (3e, 3e’): 50W
(110°C); a 3:1 mixture of 3e/3e’; yellow solid; mp = 218°C, after crystallisation with EtOH/water; 1H-
NMR (CDCl3) δ: 7.90 (s, 1H, CH=C5rhod), 7.76 (s, 1H, CH=C5rhod), 7.57-6. 85 (m, 20H), 7.3 (s, 1H),
7.18 (d, 1H, J=8.0Hz), 7.10 (d, 1H, J = 8.2Hz), 7.03 (d, 1H, J = 8.3Hz), 7.01 (s, 1H), 6.02 (s, 2H,
13
CH2), 6.01 (s, 2H, CH2); C-NMR (CDCl3) δ: 167.22 (C=O), 166.58 (C=O), 151.54 (C=N), 150.99
(C=N), 149.91, 149.20, 148.78, 148.40, 148.65, 148.38, 148.33, 148.30, 134.87, 134.80 (CH=C5rhod),
132.80, 131.42, 129.93, 129.34, 129.31, 129.22, 128.90, 126.15 , 127.51, 126.83 , 126.13, 124.90,
121.12, 119.04 (C5rhod), 119.02 (C5rhod), 109.80, 109.24, 109.20, 109.16, 109.10, 108.98, 102.02 (CH2),
101.80 (CH2). Isomer 3e is obtained in 80% yield after reflux in EtOH for 5 hours; yellow solid; mp =
1
265°C; H-NMR (CDCl3) δ: 7.76 (s, 1H, CH=C5rhod), 7.60-6.86 (m, 10H), 7.00 (s, 1H), 7.03 (d, 1H,
J=8.4Hz), 6.86 (d, 1H, J=8.07Hz), 6.01 (s, 2H, CH2); 13C-NMR (CDCl3) δ: 166.58 (C=O), 150.99 (C=

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Molecules 2006, 11
N), 149.20, 148.65, 148.38, 148.31, 134.81 (CH=C5rhod), 131.43, 129.93, 129.31, 128.90, 126.14,
124.90, 121.12, 119.02 (C5rhod), 109.20, 109.16, 108.98, 101.79 (CH2); HRMS, m/z found 400.0889
(calc. for C23H16N2O3S: 400.08816).
5-Benzylidene-3-(4-methylpyridin-2-yl)-2-(phenylimino)thiazolidin-4-one (4a): 50W (110°C); yellow
1
solid; mp>260°C; H-NMR (CDCl3/CF3COOH) δ: 8.45 (d, 1H, J=6.7Hz), 8.17 (s, 1H, CH=C5rhod),
13
7.60 (s, 1H), 7.53 (m, 10H), 7.46 (d, 1H, J=5.7Hz), 2.70 (s, 3H, CH3); C-NMR (CDCl3) δ: 167.25
(C=O), 160.58, 153.05 (C=N), 148.75, 148.20, 139.10, 138.90, 135.90 (CH=C5rhod), 132.09, 130.58,
129.90, 129.56, 127.84, 122.96, 118.61 (C5rhod), 117.00, 116.9, 112.42, 22.54 (CH3); HRMS, m/z
found 371.1083 (calc. for C22H17N3OS: 371.10923).
5-(4-Methoxybenzylidene)-3-(4-methyl-3-(4-methylpyridin-2-yl)-2-(phenylimino)thiazolidin-4-one (4b):
50W (90°C); yellow powder; mp = 207°C; 1H-NMR (CDCl3/CF3COOH) δ: 8.28 (d, 1H, J = 5.76Hz),
7.95 (s, 1H, CH=C5rhod), 7.9 (m, 5H), 7.3 (d, 2H, J=8.3Hz), 7.23 (d, 1H, J=5.6Hz), 7.19 (s, 1H), 6.97
13
(d, 2H, J=8.3Hz), 3.85 (s, 3H, CH3pyridine), 2.54 (s, 3H, CH3O); C-NMR (CDCl3) δ: 165.63 (C=O),
160.18, 154. 06 (C=N), 139.53, 136.14 (CH=C5rhod), 133.72, 132.52, 129.68, 127.89, 125.16, 122.42,
121.27, 118.53 (C5rhod), 117.45, 115.01, 113.63, 109.81, 55.51 (CH3O), 22.26 (CH3pyridine); HRMS,
m/z found 401.1213 (calc. for C23H19N3O2S: 401.11980).
5-(4-(Dimethylaminobenzylidene)-3-(4-methylpyridin-2-yl)-2-(phenylimino)thiazolidin-4one
(4c):
30W (90°C); red crystals; mp = 230°C; 1H-NMR (CDCl3/CF3COOH) δ: 8.45 (d, 1H, J=5.74Hz), 7.96
(s, 1H, CH=C5rhod), 7.62 (s, 1H), 7.58-7.50 (m, 5H), 7. 47 (d, 1H, J=4.12Hz), 7.33 (d, 2H, J=5.33Hz),
7.26 (d, 2H, J=5.43Hz), 3.10 (s, 6H (CH3)2), 2.35 (s, 3H, CH3pyridine); 13C-NMR (CDCl3/CF3COOH) δ:
165.20 (C=O), 159.65, 153.99 (C=N), 146.33, 139.67, 134.33 (CH=C5rhod), 133.21, 132.28, 130.20,
129.90, 129. 62, 127.77, 122.51, 118.72 (C5rhod), 118.63, 117.22, 113.41, 44.52 (CH3)2), 22.52 (CH3);
HRMS, m/z = 414.1501 found (calc. for C24H22N4OS: 414.15143).
5-(3-(4-(Dimethylamino)phenyl)allylidene)-3-(4-methylpyridin-2-yl)-2-(phenylimino)thiazolidin-4-one
1
(4d): 30W (90°C); red crystals; mp> 260°C; H-NMR (CDCl3) δ: 8.43 (d, 1H, J =5.74Hz), 7.58 (d,
1H, J=5.21Hz), 7.53 (t, 1H, J=3.91Hz), 7.47 (m, 5H), 7.04 (s, 1H), 6.94 (d, 2H, J=6.28Hz), 6.90 (d,
1H, J=3.23Hz), 6.83 (d, 1H, J=3.83Hz), 6.74 (d, 2H, J=8.7Hz), 3.08 (s, 6H, (CH3)2, 2.34 (s, 3H,
CH3pyridine); 13C-NMR (CDCl3) δ: 165.96 (C=O), 158.01, 153.25 (C=N), 151.25, 149.28, 146.33,
143.34, 135.63, 133.59, 129.30, 129.05, 128.4, 124.10, 122.15, 121.2, 118.78 (C5rhod), 112.03, 40.23
(CH3)2), 20.79 (CH3pyridine); HRMS, m/z found 440.1657 (calc. for C26H24N4OS: 440.16708).
5-((Benzo[d][1,3]dioxol-6-yl)methylene)-3-(4-methylpyridin-2yl)-2-(phenylimino)thiazolidin-4-one
(4e): 50W (90°C); yellow powder; mp = 217°C; 1H-NMR (CDCl3/CF3COOH) δ: 8.40 (d, 1H, J=
5.97Hz), 8.3 (s, 1H, CH=C5rhod), 7.86 (s, 1H), 7.5 (d, 1H, J=3Hz), 7.20 (m, 8H), 6.04 (s, 2H, CH2),
2.53 (s, 3 H); 13C-NMR (CDCl3) δ: 165.50 (C=O), 160.67, 154.9 (C=N), 150.15, 148.64, 141.07,
135.08 (CH=C5rhod), 133.67, 129.52, 127.98, 127.92, 127.13, 127.04, 122.22, 118.81 (C5rhod), 117.77,
116.44, 113.94, 108.99, 102.06, 22.26 (CH3); HRMS, m/z found 415.099 (calc. for C23H17N3O3S:
415.09906)

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Molecules 2006, 11
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