Organic reactions in ionic liquids; ionic liquid-accelerated three-component reaction: A rapid one-pot synthesis of 3-alkyl-5-[(Z)-arylmethylidene]-1,3-thiazolidine-2,4-diones

Article abstract of DOI:10.1055/s-2003-40980

A rapid one-pot synthesis of 3-alkyl-5-[(Z)-arylmethylidene]-1,3-thiazolidine-2,4-diones is described that occurs in recyclable ionic liquid [bmim]PF₆ (1-butyl-3-methylimidazolium hexafluorophosphate). Significant rate enhancement and good selectivity have been observed.

Full text of DOI:10.1055/s-2003-40980

PAPER
1891
Organic Reactions in Ionic Liquids; Ionic Liquid-Accelerated Three-Compo-
nent Reaction: A Rapid One-Pot Synthesis of 3-Alkyl-5-[(Z)-arylmethylidene]-
1,3-thiazolidine-2,4-diones
O
ne-Pot Synthesis
e
of 3-Alkyl
-
-5-[(
Z
)-a
H
rylmethylidene]-1
o
,3-thiazolidin
n
e-2,4-dione
s
g Yang,b Zhen-Chu Chen,*a,b Song-Ying Chen,b Qin-Guo Zhengc
a
Ningbo Institute of Technology, Zhejiang University, Ningbo, 315104, P. R. China
E-mail: zhenchuc@mail.hz.zj.cn
b
c
Department of Chemistry, Zhejiang University (XiXi Campus), HangZhou, 310028, P. R. China
Pharmaceutical Sciences Research Institute, Aston University, Aston Triangle, Birmingham B4 7ET, UK
Received 9 April 2003; revised 23 May 2003
great promise as an attractive alternative to conventional
solvents. They offer an eco-friendly reaction medium for
a variety of organic transformations, as they are non-vol-
atile, recyclable, non-explosive, easy to handle and ther-
mally robust. To date, some of the more important
reactions have been carried out and investigated in ionic
liquids.4 As part of a program to investigate the range of
organic reactions possible in ionic liquids,5 we have made
an attempt to provide a convenient and rapid synthesis of
3-alkyl-5-arylmethylidene-1,3-thiazolidine-2,4-diones by
ionic liquid-accelerated three-component reaction.
Abstract: A rapid one-pot synthesis of 3-alkyl-5-[(Z)-arylme-
thylidene]-1,3-thiazolidine-2,4-diones is described that occurs in
recyclable ionic liquid [bmim]PF6 (1-butyl-3-methylimidazolium
hexafluorophosphate). Significant rate enhancement and good se-
lectivity have been observed.
Key words: three-component reaction, 1,3-thiazolidine-2,4-di-
ones, ionic liquid
Combinatorial chemistry has gained importance as a tool
for the synthesis of a wide variety of useful compounds in-
cluding pharmaceuticals.1 In this context, the multiple
component condensation (MCC) approach is especially
appealing due to the fact that products are formed in a sin-
gle step and diversity can be achieved simply by varying
the reacting components. 3-Alkyl-5-arylmethylidene-1,3-
thiazolidine-2,4-diones are an important class of synthetic
intermediates in organic synthesis and many of these com-
pounds display biological and pharmaceutical activities,
such as anticonvulsant, antithelmintic, antitubercular,
insecticidal, bactericidal, fungicidal, etc.2 Generally, 3-
alkyl-5-arylmethylidene-1,3-thiazolidine-2,4-diones were
prepared by the alkylation of 5-arylmethylidene-1,3-thia-
zolidine-2,4-diones or the condensation of 3-alkyl-1,3-
thiazolidine-2,4-diones with aromatic aldehydes in re-
fluxing DMF or toluene.3 These methods require first the
preparation of the intermediates, 5-arylmethylidene-1,3-
thiazolidine-2,4-diones or 3-alkyl-1,3-thiazolidine-2,4-
diones and give low total yields. To the best of our know-
ledge, there is no report in the literature on the synthesis
of 3-alkyl-5-arylmethylidene-1,3-thiazolidine-2,4-diones
in a one-pot operation with an aromatic aldehyde, 1,3-
thiazolidine-2,4-dione and an alkyl halide. In addition, the
use of harmful organic solvents is undesirable from the
view of present environmental consciousness. Hence, the
development of rapid and eco-friendly synthesis of 3-
alkyl-5-arylmethylidene-1,3-thiazolidine-2,4-diones is a
challenging task.
First, we investigated the three-component reaction of
benzaldehyde (1a) and 1,3-thiazolidine-2,4-dione (2) with
methyl iodide (3a) (Scheme 1). The results are presented
in Table 1.
O
NH
C6H5CHO
+
CH3I
+
S
O
1a
2
3a
O
H
Et3N
N
CH3
S
C6H5
O
(Z)-4a
Scheme 1
We found that in the presence of Et3N, the reaction of
benzaldehyde (1a) and 1,3-thiazolidine-2,4-dione (2) and
methyl iodide (3a) in 1-n-butyl-3-methylimidazolium
hexafluorophosphate ([bmim]PF6) ionic liquid resulted in
the formation of 3-methyl-5[(Z)-phenylmethylidene]-1,3-
thiazolidine-2,4-dione (4a) in 83% yield. The reaction
proceeded smoothly at room temperature and was com-
Room temperature ionic liquids, especially those based on
the 1-n-alkyl-3-methylimidazolium cation, have shown
Synthesis 2003, No. 12, Print: 02 09 2003. Web: 30 07 2003.
Art Id.1437-210X,E;2003,0,12,1891,1894,ftx,en;F03203SS.pdf.
DOI: 10.1055/s-2003-40980
© Georg Thieme Verlag Stuttgart · New York

1892
D.-H. Yang et al.
PAPER
Table 1 Three-Component Reaction of 1a, 2 and 3a in Different
Solvents to Form 4aa
thiazolidine-2,4-dione (2) and alkyl halides 3 occurred
easily in [bmim]PF6 in the presence of Et3N to form the
corresponding 3-alkyl-5-[(Z)-arylmethylidene]-1,3-thiaz-
olidine-2,4-diones 4. The results are summarized in
Table 2. In fact, simple stirring of a mixture of aldehydes
1, 1,3-thiazolidine-2,4-dione (2), alkyl halides 3 and Et3N
in [bmim]PF6 at room temperature for methyl iodide (3a)
or at 60 °C for other alkyl halides (3b–e) for 2–4 hours
gave, after extraction with diethyl ether, the desired
3-alkyl-5-[(Z)-arylmethylidene]-1,3-thiazolidine-2,4-di-
ones 4 in good yields and the reaction was found to be
generally applicable. Different aromatic aldehydes con-
taining electron-withdrawing substituent, such as nitro
group, or electron-releasing substituent, such as methoxy
group reacted successfully. Several alkyl halides contain-
ing chloro group, bromo group or iodo group succeeded
Solvent
[bmim]PF6
[bmim]PF6
DMF
Time (h)
Temp (°C)
Yield (%)b
2
8
25
25
25
25
25
83
10c
40
26
13
10
10
10
MeCN
toluene
a All the reactions were run with benzaldehyde (1a; 0.053 g, 0.5
mmol), 1,3-thiazolidine-2,4-dione (2; 0.059 g, 0.5 mmol), and MeI
(3a; 0.085 g, 0.6 mmol) in different solvents (2 mL) using Et3N (0.061
g, 0.6 mmol) as a base.
b Isolated yields based on 1,3-thiazolidine-2,4-dione (2).
c Using K2CO3 as a base.
O
pleted within 2 hours. When the Et3N was replaced by
K2CO3, the yield of 4a was only 10% even after a long re-
action period of 8 hours. Furthermore, we have performed
the reactions in other solvents such as DMF, MeCN and
toluene to compare the efficiency of the ionic liquid. The
yields of 4a were 40%, 26%, and 13%, respectively, even
after a reaction period of 10 hours. It is obvious that the
ionic liquid [bmim]PF6 can truly accelerate the three-
component reaction of benzaldehyde (1a) and 1,3-thiazo-
lidine-2,4-dione (2) with methyl iodide (3a) to form 3-me-
thyl-5-[(Z)-phenylmethylidene]-1,3-thiazolidine-2,4-
dione (4a) which was characterized by 1H NMR, IR, and
melting point, which were in good accordance with the lit-
erature data.2c
NH
ArCHO
RX
+
+
S
O
1
2
3
O
H
Et3N
N
R
[bmim]PF6
S
Ar
Then, the scope of the reactions of different aromatic al-
dehydes 1 with 1,3-thiazolidine-2,4-dione (2) and various
alkyl halides 3 was investigated (Scheme 2). We found
that the three-component reaction of aldehydes 1 with 1,3-
O
(Z)-4
Scheme 2
Table 2 Reaction of Aromatic Aldehydes 1, with 1,3-Thiazolidine-2,4-dione (2) and Alkyl Halides 3 in [bmim]PF6
Entrya
ArCHO
RX
Product
4a
Temp (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
PhCHO (1a)
MeI (3a)
25
25
25
60
60
60
60
60
60
2
2
2
3
3
3
4
3
3
83
81
62
85
84
70
68
79
75
4-MeOC6H4CHO (1b)
4-NO2C6H4CHO (1c)
PhCHO (1a)
MeI (3a)
4b
MeI (3a)
4c
PhCH2Cl (3b)
PhCH2Cl (3b)
PhCH2Cl (3b)
4-NO2C6H4CH2Cl (3c)
Me(CH2)2CH2Br (3d)
Me2CHI (3e)
4d
4-MeOC6H4CHO (1b)
4-NO2C6H4CHO (1c)
PhCHO (1a)
4e
4f
4g
PhCHO (1a)
4h
PhCHO (1a)
4i
a All reactions were run with aldehydes 1 (0.5 mmol), 1,3-thiazolidine-2,4-dione (2; 0.5 mmol), alkyl halides 3 (0.6 mmol) and Et3N (0.6 mmol)
in [bmim]PF6 (2 mL).
b Isolated yields based on 1,3-thiazolidine-2,4-dione (2).
Synthesis 2003, No. 12, 1891–1894 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 3-Alkyl-5-[(Z)-arylmethylidene]-1,3-thiazolidine-2,4-diones
1893
n-hexane, 1: 4) to give 4a (0.091 g, 83%) as a pale yellow solid; mp
for primary and secondary alkyl halides especially. The Z
or E configuration of all the products was determined by
125–128 °C (Lit.3e mp 130 °C).
the prospective method to calculate the chemical shifts of IR (KBr): 3017, 2925, 1742, 1672 cm–1.
1H NMR (CDCl3): = 7.93 (1 H, s, ArCH=), 7.50–7.54 (5 H, m,
ArH), 3.28 (3 H, s, NCH3).
the protons on variously substituted olefins. Sohda et al.
have reported the calculated value of the methine protons
of Z products in 1H NMR spectra to be 7.90 ppm, which is
consistent with our tested value, and the value of E-prod-
ucts to be 7.42 ppm. In addition, the Z-products are more
stable than the E-types.6
5-[(Z)-(4-Methoxyphenyl)methylidene]-3-methyl-1,3-thiazoli-
dine-2,4-dione (4b)
Mp: 145–147 °C.
IR (KBr): 3025, 2950, 1735, 1681 cm–1.
1H NMR (CDCl3): = 7.88 (1 H, s, ArCH=), 7.27–7.49 (2 H, m,
ArH), 6.99–7.02 (2 H, m, ArH), 3.88 (3 H, s, OCH3), 3.25 (3 H, s,
NCH3).
The ionic liquid can be typically recovered by extracting
out the product first, then washing the residue with water
followed by vacuum drying. The recovered ionic liquid
can be reused with no appreciable decrease in yield. The
results are summarized in Table 3.
Anal. Calcd for C12H11NO3S: C, 57.83; H, 4.42; N, 5.62. Found: C,
57.84; H, 4.40; N, 5.66.
Table 3 Results Obtained Using Recycled Ionic Liquid [bmim]PF6
3-Methyl-5-[(Z)-(4-nitrophenyl)methylidene]-1,3-thiazolidine-
2,4-dione (4c)
Mp 180–185 °C.
IR (KBr): 3080, 1706, 1670, 1599 cm–1.
1H NMR (CDCl3): = 8.22–8.25 (2 H, s, ArH), 7.89 (1 H, s,
Entrya
Product
4a
Cycle
Yield (%)b
1
2
3
4
1
2
3
4
83
83
82
84
4a
ArCH=), 7.76–7.81 (2 H, m, ArH), 4.25 (3 H, s, NCH3).
4a
Anal. Calcd for C11H8N2O4S: C, 50.00; H, 3.03; N, 10.60. Found:
C, 50.03; H, 3.34; N, 10.55.
4a
a All reactions were run with benzaldehyde (1a; 0.053 g, 0.5 mmol),
1,3-thiazolidine-2,4-dione (2; 0.059 g, 0.5 mmol), and CH3I (3a;
0.085 g, 0.6 mmol) in presence of Et3N (0.061 g, 0.6 mmol) in
[bmim]PF6 (2 ml) at 25 °C.
3-Benzyl-5-[(Z)-phenylmethylidene]-1,3-thiazolidine-2,4-dione
(4d)
Mp 133–134 °C (Lit.3d mp 132.5–134.0 °C).
IR: 3035, 1730, 1684, 1604 cm–1.
1H NMR (CDCl3): = 7.93 (1 H, s, ArCH=), 7.28–7.52 (10 H, m,
b Isolated yields based on 1,3-thiazolidine-2,4-dione
ArH), 4.92 (2 H, s, NCH2).
Under the same conditions, the reaction of rhodanine (2-
thioxo-1,3-thiazolidine-4-one) with benzaldehyde (1a)
and MeI (3a) was also investigated. But the expected
product, 3-methyl-5-[(Z)-phenylmethylidene]-2-thioxo-
1,3-thiazolidine-4-one was not observed.
3-Benzyl-5-[(Z)-(4-methoxyphenyl)methylidene]-1,3-thiazoli-
dine-2,4-dione (4e)
Mp 144–146 °C.
IR (KBr): 3011, 2932, 1736,1673 cm–1.
1H NMR (CDCl3): = 7.87 (1 H, s, ArCH=), 6.98–7.48 (9 H, m,
In conclusion, we have provided a convenient and rapid
synthesis of 3-alkyl-5-[(Z)-arylmethylidene]-1,3-thiazoli-
dine-2,4-diones 4 by ionic liquid accelerated three-com-
ponent reaction. The simple operation combined with
easy recovery and reuse of the reaction media
([bmim]PF6), makes this process economic and environ-
mentally benign.
ArH), 4.91(2 H, s, NCH2), 3.76 (3 H, s, OCH3).
Anal. Calcd for C18H15NO3S: C, 66.46; H, 4.62; N, 4.31. Found: C,
66.49; H, 4.62; N, 4.33.
3-Benzyl-5-[(Z)-(4-nitrophenyl)methylidene]-1,3-thiazolidine-
2,4-dione (4f)
Mp 204–207 °C.
IR (KBr): 3153, 1720, 1698, 1601 cm–1.
Melting points are uncorrected. IR spectra were recorded as KBr
pellets on Vector-22 IR spectrophotometer. 1H NMR spectra were
recorded on Bruker (400 MHz) spectrometer using TMS as an inter-
nal standard. Elemental analyses were performed on Carlo Erba EA
1106 instrument.
1H NMR (CDCl3): = 8.26–8.30 (2 H, m, ArH), 7.91 (1 H, s,
ArCH=), 7.18–7.69 (7 H, m, ArH), 4.96 (2 H, s, NCH2).
Anal. Calcd for C17H12N2O4S: C, 60.00; H, 3.53; N, 8.24: Found: C,
60.11; H, 3.57; N, 8.19.
3-(4-Nitrobenzyl)-5-[(Z)-phenylmethylidene]-1,3-thiazolidine-
2,4-dione (4g)
Mp 188–190 °C.
IR (KBr): 3081, 1741, 1683 cm–1.
1H NMR (CDCl3): = 8.20 (2 H, d, J = 8.8 Hz, ArH), 7.99 (1 H, s,
ArCH=), 7.56–7.64 (7 H, m, ArH), 4.98 (2 H, s, NCH2).
3-Methyl-5-[(Z)-phenylmethylidene]-1,3-thiazolidine-2,4-dione
(4a); Typical Procedure
Benzaldehyde (1a; 0.053 g, 0.5 mmol), 1,3-thiazolidine-2,4-dione
(2; 0.059 g, 0.5 mmol), MeI (3a; 0.085 g, 0.6 mmol) and Et3N
(0.061 g, 0.6 mmol) were added to [bmim]PF6 (2 ml).The resulting
mixture was stirred at 25 °C for 2 h. Then the reaction mixture was
extracted with Et2O (4 × 15 mL). The remaining ionic liquid sus-
pension was washed with H2O, and reused after drying in vacuum.
The combined Et2O solution was evaporated under reduced pres-
sure. The crude product was purified by preparative TLC (EtOAC–
Anal. Calcd for C17H12N2O4S: C, 60.00; H, 3.53; N, 8.24. Found: C,
59.95; H, 3.55; N, 8.27.
Synthesis 2003, No. 12, 1891–1894 © Thieme Stuttgart · New York

1894
D.-H. Yang et al.
PAPER
3-Butyl-5-[(Z)-phenylmethylidene]-1,3-thiazolidine-2,4-dione
(4h)
Mp 80–82 °C.
IR (KBr): 3035, 2960, 2874, 1745, 1675, 1605 cm–1.
1H NMR (CDCl3): = 7.91 (1 H, s, ArCH=), 7.28–7.55 (5 H, m,
ArH), 3.76–3.79 (2 H, t, J = 7.2 Hz, NCH2), 1.66–1.77 (2 H, m,
CH2CH2CH2), 1.36–1.41 (2 H, m, CH2CH3), 0.95–0.99 (3 H, t, J =
7.2 Hz, CH3).
(2) (a) Singh, S. P.; Parmar, S. S.; Raman, K.; Stenberg, V. I.
Chem. Rev. 1981, 81, 175. (b) Grant, E. B.; Guiadeen, D.;
Baum, E. Z.; Foleno, B. D. Bioorg. Med. Chem. Lett. 2000,
10, 2179. (c) Giles, R. G.; Lewis, N. J.; Quick, J. K.; Sasse,
M. J.; Urquhart, M. W. J.; Youssef, L. Tetrahedron 2000, 56,
4531. (d) Albuquer, J. F. C.; Andrade, A. M. C.; Barros, L.
M.; Nascimento, M. R.; Ximenes, E. A.; Galdino, S. L.;
Pitta, I. R.; Perrissin, M. Ann. Pharm. Fr. 1999, 57, 385;
Chem. Abstr. 2000, 132, 333. (e) Amorim, E. L. C.;
Branedao, S. S. F.; Cavalcanti, C. O. M.; Galdino, S. L.;
Pitta, I. R.; Luu, D. C. Ann. Pharm. Fr. 1992, 50, 103; Chem.
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Anal. Calcd for C14H15NO2S: C, 64.37; H, 5.75; N, 5.36: Found: C,
64.39; H, 5.75; N, 5.37.
3-Isopropyl-5-[(Z)-phenylmethylidene]-1,3-thiazolidine-2,4-di-
one (4i)
Mp 68–70 °C.
IR (KBr): 2980, 1740, 1686 cm–1.
1H NMR (CDCl3): = 7.87 (1 H, s, ArCH=), 7.49–7.51 (5 H, m,
ArH), 4.66–4.73 (1 H, m, NCH), 1.49–1.51 (6 H, d, J = 5.2 Hz,
CH3).
(3) (a) Lo, C.-P.; Shropshire, E. Y. J. Am. Chem. Soc. 1957, 79,
999. (b) Bradsher, C. K.; Brown, F. C.; Sinclair, E. F. J. Am.
Chem. Soc. 1956, 78, 6189. (c) Vasil’eva, V. N.;
Gur’yanova, E. N. Zh. Fiz. Khim. 1954, 28, 1319; Chem.
Abstr. 1956, 50, 308. (d) Vladzimirskaya, E. V. Zh. Obshch.
Khim. 1959, 29, 2795; Chem. Abstr. 1960, 54, 16997.
(e) Vladzimirs’ka, O. V. Zh. Obshch. Khim. 1962, 32, 2019;
Chem. Abstr. 1963, 58, 9055. (f) Singh, H.; Singh, P.; Deep,
K. Chem. Ind. (London) 1981, 252. (g) Barret, G. C.
Tetrahedron 1980, 36, 2023.
Anal. Calcd for C13H13NO2S: C, 63.16; H, 5.26; N, 5.67. Found: C,
63.15; H, 5.27; N, 5.70.
(4) (a) Gordon, C. M. Appl. Catal. A 2001, 222, 101.
(b) Sheldon, R. A. Chem. Commun. 2001, 2399.
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Synthesis 2003, No. 12, 1891–1894 © Thieme Stuttgart · New York