A solvent-free protocol for the green synthesis of arylalkylidene rhodanines in a task-specific ionic liquid

Article abstract of DOI:10.1139/V10-011

2-Hydroxyethylammonium formate acts as a task-specific ionic liquid (TSIL) for the Knoevenagel condensation of carbonyl compounds with rhodanine to afford arylalkylidene rhodanines under solvent-free conditions and in good-to-excellent yields. Additionally, compared with those in organic solvents, the yields obtained in the presence of our ionic liquid (IL) were significantly increased. The detailed mechanism of the catalytic effect of TSIL is also reported for the first time.

Full text of DOI:10.1139/V10-011

514
A solvent-free protocol for the green synthesis of
arylalkylidene rhodanines in a task-specific ionic
liquid
Abdolhamid Alizadeh, Mohammad M. Khodaei, and Ali Eshghi
Abstract: 2-Hydroxyethylammonium formate acts as a task-specific ionic liquid (TSIL) for the Knoevenagel condensation of
carbonyl compounds with rhodanine to afford arylalkylidene rhodanines under solvent-free conditions and in good-to-excellent
yields. Additionally, compared with those in organic solvents, the yields obtained in the presence of our ionic liquid (IL)
were significantly increased. The detailed mechanism of the catalytic effect of TSIL is also reported for the first time.
Key words: 2-Hydroxyethylammonium formate, task-specific ionic liquids (TSILs), Knoevenagel condensation, arylalkylidene
rhodanines.
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Resume : Dans des conditions n’impliquant aucun solvant, le formiate de 2-hydroxyethylammonium agit comme liquide
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ionique pour une tache specifique (LITS) pour la condensation de Knoevenagel des composes carbonyles avec la rhoda-
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nine qui conduit aux arylalkylidenes de rhodanine avec des rendements allant de bons a excellents. De plus, par comparai-
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son avec les rendements obtenus dans des solvants organiques, ceux obtenus en presence de notre liquide ionique sont
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nettement plus eleves. On propose pour la premiere fois un mecanisme detaille de l’effet catalytique du LITS.
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Mots-cles : formiate de 2-hydroxyethylammonium, liquide ionique pour une tache specifique (LITS), condensation de
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Knoevenagel, arylalkylidenes de rhodanine.
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[Traduit par la Redaction]
Fig. 1. Biologically active compounds bearing a 5-arylalkylidene
rhodanine moiety.
Introduction
Rhodanine derivatives, especially arylalkylidene rhodanines
(I) (Fig. 1), have proven to be attractive compounds because
of their outstanding biological activities and have undergone
rapid development as anticonvulsant, antibacterial, and anti-
diabetic agents.1 A series of arylalkylidene rhodanines have
also been reported as Hepatitis C Virus (HCV) protease
inhibitors (II)2 (Fig. 1) or as novel inhibitors of UDP N-
acetylmuramate/L-alanine ligase (III) (Fig. 1).3
For the preparation of 5-arylalkylidene rhodanines, vari-
ous methods have been developed from acyclic building
blocks or by functionalization of the thiazolone core.4 In the
second case, the Knoevenagel condensation of aldehydes at
the nucleophilic C-5 position of rhodanine leads to the de-
sired arylalkylidene rhodanine adducts. This reaction has
been performed using sodium acetate in refluxing glacial ace-
tic acid5a or piperidinium benzoate in refluxing toluene.5b Re-
cently, Lee and Sim reported the synthesis of 5-arylalkylidene
rhodanines by heating the reactants suspended in toluene at
110 8C for 3 days.6 Also, Sing et al. reported the condensa-
tion of rhodanine with an aldehyde by heating in anhydrous
EtOH for 6 h at 80 8C.7
solid inorganic support (Al2O3 or montmorillonite KSF
clay)8,9 but without control of the reaction temperature. Re-
cently, Zhou et al. reported the use of MW and tetrabuty-
lammonium bromide (TBAB) as phase-transfer catalyst in
water.10 In addition, despite their promising biological fea-
tures, the synthesis of ketone derivatives of arylalkylidene
rhodanine adducts has not been subjected to detailed investi-
gations, and only a 60-year-old study of Brown and co-
workers has reported the Knoevenagel condensation reaction
of rhodanine with ketones in the presence of ammonium hy-
droxide and ammonium chloride in refluxing ethanol.11 Sim-
ilar to most conventional chemical transformations, all of
the above-mentioned procedures involve harsh reaction con-
ditions, large quantities of toxic solvents, long reaction
The use of microwave irradiation (MW) as a clean and
operationally simple technique has also been employed with
Received 15 October 2009. Accepted 4 January 2010. Published on the NRC Research Press Web site at canjchem.nrc.ca on 29 April
2010.
A. Alizadeh,1 M.M. Khodaei,2 and A. Eshghi. Faculty of Chemistry and Nanoscience & Nanotechnology Research Center (NNRC),
Razi University, Kermanshah 67149, Iran.
1Corresponding author (e-mail: ahalizadeh2@hotmail.com).
2Corresponding author (e-mail: mmkhoda@razi.ac.ir).
Can. J. Chem. 88: 514–518 (2010)
doi:10.1139/V10-011
Published by NRC Research Press

Alizadeh et al.
515
Scheme 1. TSIL-catalyzed synthesis of 5-arylalkylidene rhoda-
nines.
catalyst at room temperature (Table 1, entry 1). Further in-
crease in the reaction temperature did not result in a de-
crease in the reaction time or in an increase in the yield.
Also, using 2 mmol of aldehyde (and 1 mmol of rhodanine)
showed no change in the final product structure, and again,
5-benzylidene-2-thioxothiazolidine-4-one (Table 1, entry 1)
was obtained as the final product.
Thus, under this optimized mild condition, various struc-
turally diverse aromatic aldehydes and ketones were tested
with rhodanine, and the corresponding results are listed in
Tables 1 and 2.
As shown in Table 1, the aryl aldehydes bearing electron-
releasing and electron-withdrawing groups are effective for
the aforementioned reaction and gave the desired products
in excellent yields in the reaction time ranging from 1 to
6 min. For instance, aryl aldehydes such as 4-nitrobenzalde-
hyde and 4-fluorobenzaldehyde required relatively short re-
action times (Table 1, entries 4 and 6), and in contrast, aryl
aldehydes with electron-releasing groups required nearly
longer reaction times (Table 1, entries 11 and 13).
In examining the scope and generality of the developed
protocol as well as the influence of structural variation of
carbonyl compounds on their reactivity toward rhodanine
enolate, we studied the Knoevenagel condensation reaction
of rhodanine with ketones in the conditions similar to that
of aldehydes. It was found that the reaction proceeds in a
similar fashion to that of aryl aldehydes except that ketones
undergo nucleophilic attack of rhodanine enolate more
slowly with relatively low yields. Entries 1–4 in Table 2
show that both cyclic and acyclic ketones can react with rho-
danine enolate. In contrast, any effort to obtain Knoevenagel
condensation adducts from the reaction of rhodanine enolate
with benzophenone, benzamide, and 2,4-dimethyl-3-pentanone
(diisopropylketone) was unsuccessful. We believe that ben-
zophenone and benzamide do not participate in the conden-
sation, presumably because of the resonance of the carbonyl
moiety with the phenyl groups and nitrogen lone-pair elec-
trons. Also, diisopropylketone has a steric hindrance around
the carbonyl group, and hence, it does not react with rhoda-
nine. The results are listed in Table 2.
times, and unsatisfactory yields. Therefore, facile and green
routes to arylalkylidene rhodanines would be of great inter-
est.
Currently, ionic liquids (ILs) are being used as green sol-
vents for laboratory as well as industrial use because of their
desirable properties, such as good solvating ability, variable
polarity, negligible vapor pressure, and ease of recyclabil-
ity.12 A literature survey revealed that ILs have not been uti-
lized extensively for the Knoevenagel condensation of
aldehydes or ketones with rhodanine, and only a study by
Liu and co-workers utilizing a functionalized imidazolium-
based IL has been reported.13
While considering ILs as reaction media and their use in
industrial processes, one major concern is cost. The cost of
the IL would be directly dependent on the price of the cati-
ons and anions that are used for their production.11 Thus, the
popular ILs incorporating expensive cations, such as alkyl
methyl imidazolium and dialkyl imidazolium, are likely to
remain expensive. Similarly, the anions that are frequently
used in ILs, such as tetraflouro borate and hexaflouro phos-
phate, are also expensive. This indicates that there is a need
to develop and explore simple and cost-effective ILs.
Herein, we wish to report for the first time, a solvent-free
and green procedure for the Knoevenagel condensation of ar-
omatic aldehydes and ketones with rhodanine promoted with
a low cost and task-specific IL (2-hydroxyethylammonium
formate)14 as an effective catalyst and reaction medium
(Scheme 1).
A control experiment was also allowed to proceed under
the developed conditions utilizing 1 mL of TSIL, 1 mmol
of p-methylbenzaldehye, and 1 mmol of acetophenone to
evaluate the chemoselectivity of the TSIL. It was found that
in the presence of 1 mL of the IL, rhodanine only reacts
with p-methylbenzaldehye, which leads to the formation of
4-methylbenzylidene rhodanine as the final product, and no
adduct was obtained from the condensation of rhodanine
with ketone (Scheme 2).
To our knowledge, literature only shows one recent publi-
cation15 related with the application of this new potential IL,
but no further information is available about its application
in chemical processes and organic syntheses. This IL can
easily be synthesized from commercially available low cost
chemicals (ethanolamine and formic acid) and has high con-
ductivity and powerful solvating ability. Also, its low melt-
ing point (–82 8C) makes it an appropriate solvent for low
temperature chemical transformations.
The obtained results allow us to propose a tentative mech-
anism for the TSIL-catalyzed Knoevenagel condensation re-
action of aldehydes and ketones with rhodanine as depicted
in Scheme 3. The structure of the IL used in this study
(2-hydroxyethylammonium formate) has a specific feature
bearing both acidic and basic sites. We believe that the
acidic part of the IL (ammonium moiety) protonates the
oxygen of the carbonyl group; this is a very suitable condi-
tion in nucleophilic additions to carbonyl compounds. On
the other hand, rhodanine is a CH-acidic nucleophile and
the anionic part of the IL (formate anion) is basic and easily
deprotonates rhodanine at the C-5 position and causes the
Results and discussion
Our investigations on the Knoevenagel condensation reac-
tion of rhodanine with carbonyl compounds began with the
optimization of reaction conditions. Initially, the reaction of
1 mmol benzaldehyde with 1 mmol rhodanine in acetonitrile
was tested in the absence of IL at room temperature. The re-
actants remained unchanged even after stirring for 20 h.
Upon addition of only 1 mL of IL, condensation occurred
and the reaction lead to the desired product immediately
after only 2 min in 94% yield without using any solvent or
Published by NRC Research Press

516
Can. J. Chem. Vol. 88, 2010
Table 1. TSIL-catalyzed reaction of rhodanine with aromatic aldehydes.
Mp (8C)
Entry
1
2
3
4
5
6
7
8
Ar
C6H5
Time (min)
Found
205
221
251
255
232
226
230.5
230
275c
230
Reported
20416
22016
25116
25016
23216
22617
23117
23116
—
22916
27018
19216
22218
—
Yield (%)a,b
2
2
2
1
2
1
1
1
3
2
3
4
6
1
94
95
96
98
96
98
97
95
92
95
90
94
91
98
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
4-FC6H4
4-BrC6H4
2,4-ClC6H3
2,4-MeOC6H3
2-Furyl
4-N(Me)2C6H4
2-ClC6H4
2-OHC6H4
Cinammyl
9
10
11
12
13
14
272
191
223
227c
Note: Reaction conditions: aldehyde (1 mmol), rhodanine (1 mmol), ionic liquid (1 mL), and RT.
aThe products were characterized by comparison of their spectroscopic and physical data with those
reported in the literature.
bYields refer to pure isolated products.
cNew compounds.
Table 2. TSIL-catalyzed reaction of rhodanine with ketones.
Mp (8C)
Time
Entry
R1
R2
(min)
20
15
70
Found
175
195
167
205
Reported
17311
Yield (%)a
87
90
92
1
2
3
4
5
6
7
(–CH2–)5
(–CH2–)4
C6H5
4ClC6H4
C6H5
(–CH2–)5
(–CH2–)4
CH3
CH3
C6H5
i-Pro
19511
16611
20411
72
90
NRb
NR
NR
i-Pro
C6H5
NH2
Note: Reaction conditions: ketone (1 mmol), rhodanine (1 mmol), ionic liquid (1 mL), and RT.
aYields refer to pure isolated products.
bNR: No reaction.
formation of nucleophilic rhodanine enolate. Subsequently,
this enolate attacks the protonated aldehyde or ketone and
gives an intermediate alcohol. Eventually, protonation of
this alcohol, followed by a dehydration process, gives the
desired products, recovered catalyst, and water as the only
byproduct of the reaction.
The ionic liquid was recovered and reutilized four times
without the addition of extra ionic liquid; the results are
shown in Fig. 2.
friendly, solvent-free, and reagentless protocol for the prepa-
ration of a series of arylalkylidene rhodanine derivatives us-
ing 2-hydroxyethylammonium formate as a task-specific
ionic liquid. The ease of preparation of the IL from com-
mercially available low cost starting materials, its high con-
ductivity, powerful solvating ability, and low melting point
make it an appropriate solvent for room temperature reac-
tions. Furthermore, this method is applicable to both elec-
tron-rich as well as electron-deficient aldehydes. In all
cases, the reaction proceeds smoothly under very mild con-
In conclusion, we have described a general, environment-
Published by NRC Research Press

Alizadeh et al.
517
Scheme 2. Comparison of the reactions of rhodanine with benzal-
dehyde and acetophenone in the presence of TSIL.
yields obtained in the presence of this TSIL are significantly
increased. We believe that the low cost and the experimental
simplicity of the method gives this green ionic-liquid-cata-
lyzed procedure great potential, and it may find potential ap-
plications in synthetic organic chemistry, and more
importantly, it can compliment the existing chemical strat-
egies.
Experimental
All chemicals (ethanolamine, formic acid, rhodanine, al-
dehydes, and ketones) were reagent-grade materials, and
they were used without further purification. Throughout all
experiments, distilled water was used, and all the experi-
ments were done at room temperature. 1H and 13C NMR
spectra were recorded on a Bruker spectrometer operating at
200 and 50 MHz, respectively. Melting points were meas-
ured on a BI Branstead Electrothermal 9200 instrument and
are uncorrected. FTIR spectra were recorded on a Rayleigh
Wqf-510 spectrometer using a drop casting technique on
KBr plates and are reported in wavenumbers (cm–1).
Scheme 3. Representative mechanism of TSIL-promoted Knoeve-
nagel condensation reaction of aldehydes and ketones with rhoda-
nine.
Synthesis of arylalkylidene rhodanines: general
procedure
Rhodanine (1 mmol) and 2-hydroxyethylammonium for-
mate (1 mL) were mixed together and stirred at room tem-
perature for 2 min after which 1 mmol of aromatic
aldehyde or ketone was added to the reaction mixture. After
completion of the reaction (monitored by TLC), a mixture of
water and ethanol (50:50 v/v) was added to the reaction
flask, and the obtained precipitates were easily filtered lead-
ing to the final pure products while no extra purification was
needed. Evaporating the water of the filtrate gave the pure
IL, which could be reused for further reactions. Selected
characterization data for some of the arylalkylidene rhoda-
nines prepared are given below.
5-Phenyl-2-thioxothiazolidin-4-one
1
Yellow powder, mp 205 8C (lit.16 mp 204 8C). H NMR
(DMSO-d6, 200 MHz) d (ppm): 7.51–7.85 (m, 5H, Har), 7.68
(s, 1H, vinyl), 13.87 (s, 1H, NH). 13C NMR (DMSO-d6,
50 MHz) d (ppm): 125.9, 127.4, 129.8, 130.8, 131.1, 131.9,
169.8, 196.1.
5-(4-Methylbenzyliden)-2-thioxothiazolidin-4-one
1
Yellow powder, mp 221 8C (lit.16 mp 220 8C). H NMR
Fig. 2. Successive trials by using the recoverable TSIL.
(DMSO-d6, 200 MHz) d (ppm): 2.40 (s, 3H, CH3), 7.40 (d,
2H, Har), 7.53 (d, 2H, Har), 7.65 (s, 1H, vinyl), 13.88 (s, 1H,
NH). 13C NMR (DMSO-d6, 50 MHz) d (ppm): 21.5, 124.7,
130.4, 130.6, 130.9, 132.1, 141.5, 169.9, 196.1.
5-(2,4-Dimethoxybenzyliden)-2-thioxothiazolidin-4-one
Orange powder, mp 275 8C. IR (KBr) n (cm–1): 3452,
1707, 1621, 1564, 1445, 1117. 1H NMR (DMSO-d6,
200 MHz) d (ppm): 3.86 (s, 3H, OCH3), 3.91 (s, 3H,
OCH3), 6.70–6.75 (m, 2H, Har), 7.33 (d, 1H, Har), 7.74 (s,
1H, vinyl), 13.72 (s, 1H, NH). 13C NMR (DMSO-d6,
50 MHz) d (ppm): 55.7, 55.9, 98.7, 106.5, 115.5, 123.0,
126.7, 130.6, 159.7, 162.7, 163.2, 199.1. Anal. calcd. for
C12H11NO3S2: C, 51.23%; H, 3.94%; N, 4.98%; S, 22.79%.
Found: C, 48.2%; H, 5.0%; N, 6.6%; S, 19.1%.
ditions without introducing any acid, base, or metal catalyst,
and water is the only byproduct of the reaction. Compared
with those obtained using traditional organic solvents, the
Published by NRC Research Press

518
Can. J. Chem. Vol. 88, 2010
(5) (a) Cutshall, N. S.; O’Day, C.; Prezhdo, M. Bioorg. Med.
Chem. Lett. 2005, 15 (14), 3374. doi:10.1016/j.bmcl.2005.
05.034. PMID:15961311.; (b) Lohray, B. B.; Bhushan, V.;
Rao, P. B.; Madhavan, G. R.; Murali, N.; Rao, K. N.; Reddy,
K. A.; Rajesh, B. M.; Reddy, P. G.; Chakrabarti, R.; Rajago-
palan, R. Bioorg. Med. Chem. Lett. 1997, 7 (7), 785. doi:10.
1016/S0960-894X(97)00118-2.
(6) Lee, C. L.; Sim, M. M. Tetrahedron Lett. 2000, 41 (30),
5729. doi:10.1016/S0040-4039(00)00866-2.
(7) Sing, W. T.; Lee, C. L.; Yeo, S. L.; Lim, S. P.; Sim, M. M.
Bioorg. Med. Chem. Lett. 2001, 11 (2), 91. doi:10.1016/
S0960-894X(00)00610-7. PMID:11206478.
5-[(E)-3-Phenylallylidene]-2-thioxothiazolidin-4-one
Orange powder, mp 227 8C. IR (KBr) n (cm–1): 3458,
1691, 1624, 1573, 1448, 1150. 1H NMR (DMSO-d6,
200 MHz) d (ppm): 7.01 (m, 1H, vinyl), 7.31 (d, 1H, vinyl),
7.40–7.47 (m, 5H, Har), 7.67 (d, 1H, vinyl), 13.64 (s, 1H,
NH). 13C NMR (DMSO-d6, 50 MHz) d (ppm): 124.6, 128.0,
128.9, 129.8, 130.8, 132.9, 136.4, 145.5, 169.6, 196.2. Anal.
calcd. for C12H9NOS2: C, 58.27%; H, 3.67%; N, 5.66%; S,
25.93%. Found: C, 58.2%; H, 4.1%; N, 6.1%; S, 24.1%.
Supplementary data
(8) (a) Zhang, L. Chem. J. Chin. Univ. 1994, 15, 1647; (b) Bou-
grin, K.; Soufiaoui, M. N. J. Chem. 1998, 22, 809.
(9) Bourahla, K.; Derdour, A.; Rahmouni, M.; Carreaux, F.; Ba-
zureau, J. P. Tetrahedron Lett. 2007, 48 (33), 5785. doi:10.
1016/j.tetlet.2007.06.078.
Supplementary data for this article are available on the
journal Web site (canjchem.nrc.ca).
Acknowledgment
Financial support for this work by Razi University is
hereby appreciated.
(10) Zhou, J. F.; Zhu, F. X.; Song, Y. Z.; Zhu, Y. L. Arkivoc
2006, iv, 175.
(11) Brown, F. C.; Bradsher, C. K.; McCallum, S. G.; Potter, M.
J. Org. Chem. 1950, 15 (1), 174. doi:10.1021/jo01147a028.
(12) Wasserscheid, P.; Welton, T., Eds. Ionic Liquids in Synth-
esis; Wiley-VCH Verlag GmbH & Co. KGaA, 2003. doi:10.
1002/3527600701.fmatter_indsub.
(13) Gong, K.; He, Z. W.; Xu, Y.; Fang, D.; Liu, Z. L. Monatsh.
Chem. 2008, 139 (8), 913. doi:10.1007/s00706-008-0871-y.
(14) Bicak, N. J. Mol. Liq. 2005, 116 (1), 15. doi:10.1016/j.
molliq.2004.03.006.
References
(1) (a) Ohishi, Y.; Mukai, T.; Nagahara, M.; Yajima, M.; Kaji-
kawa, N.; Miyahara, K.; Takano, T. Chem. Pharm. Bull.
(Tokyo) 1990, 38 (7), 1911. PMID:2125247.; (b) Momose,
Y.; Meguro, K.; Ikeda, H.; Hatanaka, C.; Oi, S.; Sohda, T.
Chem. Pharm. Bull. (Tokyo) 1991, 39 (6), 1440. PMID:
1934164.
(2) Sudo, K.; Matsumoto, Y.; Matsushima, M.; Fujiwara, M.;
Konno, K.; Shimotohno, K.; Shigeta, S.; Yokota, T. Bio-
chem. Biophys. Res. Commun. 1997, 238 (2), 643. doi:10.
1006/bbrc.1997.7358. PMID:9299567.
(3) Sim, M. M.; Ng, S. B.; Buss, A. D.; Crasta, S. C.; Goh, K.
L.; Lee, S. K. Bioorg. Med. Chem. Lett. 2002, 12 (4), 697.
doi:10.1016/S0960-894X(01)00832-0. PMID:11844704.
(4) (a) Brown, F. C. Chem. Rev. 1961, 61 (5), 463. doi:10.1021/
cr60213a002.; (b) Singh, S. P.; Parmar, S. S.; Raman, K. V.;
Stenberg, I. Chem. Rev. 1981, 81 (2), 175. doi:10.1021/
cr00042a003.
(15) Sharma, Y. O.; Degani, M. S. J. Mol. Catal. Chem. 2007,
277 (1-2), 215. doi:10.1016/j.molcata.2007.07.053.
(16) Luo, J.; Li, Y.; Zhou, M. J. Chem. Int. 2006, 8, 17.
´
´
(17) Sortino, M.; Delgado, P.; Juarez, S.; Quiroga, J.; Abonıa, R.;
Insuasty, B.; Nogueras, M.; Rodero, L.; Garibotto, F. M.;
Enriz, R. D.; Zacchino, S. A. Bioorg. Med. Chem. 2007, 15
(1), 484. doi:10.1016/j.bmc.2006.09.038. PMID:17049255.
(18) Zhou, J. F.; Zhu, F. X.; Song, Y. Z.; Zhu, Y. Arkivoc 2006,
xiv, 175.
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