Green synthesis of 5-benzylidene rhodanine derivatives catalyzed by 1-butyl-3-methyl imidazolium hydroxide in water

Article abstract of DOI:10.1007/s00706-008-0871-y

A basic functionalized ionic liquid, 1-butyl-3-methyl imidazolium hydroxide ([bmim][OH]), catalyzed the Knoevenagel condensation of rhodanine with aromatic aldehydes. It proceeded smoothly in water to afford the 5-benzylidene rhodamine derivatives in high yields at room temperature. This new method offers several advantages, such as excellent yields, short reaction times, and simple procedure. The catalyst can be reused at least 5 times without significant loss of activity.

Full text of DOI:10.1007/s00706-008-0871-y

Monatsh Chem 139, 913–915 (2008)
DOI 10.1007/s00706-008-0871-y
Printed in The Netherlands
Green synthesis of 5-benzylidene rhodanine derivatives
catalyzed by 1-butyl-3-methyl imidazolium hydroxide in water
Kai Gong, Zhi-Wei He, Ying Xu, Dong Fang, Zu-liang Liu
School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, P.R. China
Received 25 November 2007; Accepted 12 December 2007; Published online 18 February 2008
# Springer-Verlag 2008
Abstract A basic functionalized ionic liquid, 1-butyl-
3-methyl imidazolium hydroxide ([bmim][OH]), cata-
lyzed the Knoevenagel condensation of rhodanine
with aromatic aldehydes. It proceeded smoothly in
water to afford the 5-benzylidene rhodamine deriva-
tives in high yields at room temperature. This new
method offers several advantages, such as excellent
yields, short reaction times, and simple procedure.
The catalyst can be reused at least 5 times without
significant loss of activity.
to both the solvent emission and catalytic recycling
problem [2]. Moreover, the low cost of water, along
with its non-toxic nature, renders it as attractive me-
dium for chemical synthesis. Reactions in aqueous
media offer many advantages, such as simple opera-
tion and high efficiency in many organic reactions
that involve water soluble substrates and reagents
[3]. These advantages become even more attractive
if such reactions can be conducted using ionic
liquids in aqueous media.
Rhodanine derivatives have shown a wide range
of pharmacological activities, which include anti-
convulsant, antibacterial, antiviral, and antidiabetic
effects [4]. Additionally, rhodanine-based molecules
have been popular as small molecule inhibitors of
numerous targets such as HCV protease [5], aldose
reductase [6], ꢀ-lactamase [7], JNK-stimulating
phosphatase-1 (JSP-1) [8], etc. Rhodanine and some
of its derivatives have higher sensitivity and selectiv-
ity for the analysis of certain noble metal ions [9].
Thus, the synthesis of rhodanine derivatives current-
ly is of much importance. It is well known that
5-benzylidene rhodanine derivatives are generally
prepared by reacting aromatic aldehydes with rhoda-
nine in organic solvents (i.e., ethanol, acetic acid)
and in the presence of base (i.e., NaOAc, NH4OAc)
[10]. Conventional approaches for the synthesis of
these compounds often involve long reaction times,
harsh reaction conditions, unsatisfactory yields, and
environmentally unfavorable solvents. Recently, mi-
crowave irradiation has been used in this reaction to
Keywords Aromatic aldehyde; Rhodanine; Benzylidenerho-
damine; Ionic liquid.
Introduction
Ionic liquids have attracted extensive research inter-
est in recent years as environmental benign solvents
due to their favorable properties, like non-inflam-
mability, negligible vapor pressure, reusability, and
high thermal stability [1]. They have also been re-
ferred to as ‘‘designer solvents’’ as their physical and
chemical properties could be adjusted by a careful
choice of cation and anion. Apart from this they
exhibit acidic or basic properties. Combining these
unique properties of ionic liquids they are emerging
as ‘‘green reaction media’’. The use of ionic liquids
as reactions medium may offer a convenient solution
Correspondence: Zu-liang Liu, School of Chemical Engineer-
ing, Nanjing University of Science and Technology, Nanjing
210094, P.R. China. E-mail: liuzl@mail.njust.edu.cn

914
K. Gong et al.
decrease reaction times and increase yields [11].
Thus, the development of a new procedure for the
synthesis of 5-benzylidene rhodanine derivatives
would be highly desirable. In continuation of our
work on development of benign procedures using
functionalized ionic liquid [12], we would like to
report an efficient method for the synthesis of 5-
benzylidene rhodanine derivatives in the presence
of basic ionic liquid [bmim][OH] as catalyst. To our
knowledge, synthesis of 5-benzylidene rhodanine
derivatives catalyzed by [bmim][OH] have not been
reported. Herein, we describe a simple and straight-
forward procedure for synthesis of 5-benzylidene rho-
danine derivatives via the condensation of aromatic
aldehydes with rhodamine catalyzed by [bmim][OH]
in aqueous media under mild conditions.
The catalyst plays a crucial role in the success
of the reaction in terms of the rate and the yields.
Taking the benzaldehyde reacted with 2 as an exam-
ple, the reaction could be carried out in the absence
of the catalyst when the mixture was stirred at room
temperature for 12 h, but the product was obtained in
very poor yield (15%). We have tested some cata-
lysts such as tetramethylammonium hydroxide and
tetrabutylammonium hydroxide, the yields of the
two basic catalysts were 72% and 75%, respectively,
showing that [bmim][OH] was the best catalyst for
this reaction.
Compare with traditional solvents, ionic liquids
are easily reused, which is superior to the conven-
tional solvents and catalysts. Hence, we decided to
study the catalytic activity of the recycled reaction
system of [bmim][OH]=H2O in the synthesis of 3a.
After the separation of products, the catalyst-con-
taining aqueous medium was reused in the next run
without further purification. As shown in Table 2, the
reaction medium can be recycled at least five times
without significant decrease of the yields, the yields
ranged from 86% to 81%.
Results and discussion
The Knoevenagel condensation of the C-5 active
methylene of rhodanine with aromatic aldehydes
proceeded smoothly in the presence of 10 mol% of
basic ionic liquid [bmim][OH] at room temperature
and the results are summarized in Table 1. It shows
that the aromatic aldehydes having different substitu-
ents, such as fluoro, chloro, nitro, methyl, methoxy,
methyl, etc. were converted to the corresponding
products in high yields. However, the aromatic alde-
hydes with electron-withdrawing groups, such as
fluoro, chloro or nitro proceeded at faster rates than
those with electron-donating groups, such as me-
thoxy, methyl, etc.
In conclusion, we have developed a simple and
effective method for the synthesis of 5-benzylidene
rhodamine derivatives by the Knoevenagel conden-
sation of various aromatic aldehydes with rhodanine
in the presence of [bmim][OH] at room temperature.
The catalyst can be reused at least five times with-
out significant loss of activity. Furthermore, water
was chosen as the solvent, which is cheap and
benign.
Table 1 Synthesis of 5-benzylidene rhodanine derivativesa
Entry
Ar
Time=min
Comp.
Yield=%b
mp=ꢀC
mp=ꢀC [Ref.]
1
2
3
4
5
6
7
8
H
2-Cl
4-Cl
60
30
30
30
30
30
20
10
90
90
90
90
30
3a
3b
3c
3d
3e
3f
3g
3h
3i
86
91
95
92
96
90
96
98
80
87
81
88
91
203–204
180–181
230–231
232–233
221–222
230–231
263–264
255–256
224–225
250–251
185–186
273–274
230–231
205 [4c]
181–182 [13]
229–230 [13]
233–234 [13]
219 [4c]
2,4-Cl2
4-F
4-Br
3-NO2
4-NO2
4-CH3
4-CH3O
4-OH
4-(CH3)2N
2-fruyl
230 [4c]
263–265 [13]
255–256 [11]
221–223 [13]
249–250 [13]
184–185 [11]
170–271 [13]
228–229 [13]
9
10
11
12
13
3j
3k
3l
3m
a
Reaction conditions: aldehyde (5 mmol), rhodanine (5 mmol), [bmim][OH] (0.5 mmol), H2O (2 cm3) as solvent, rt
Isolated yield
b

Green synthesis of 5-benzylidene rhodanine derivatives
915
Table 2 Reusing of the ionic liquid [bmim][OH]=H2O for
synthesis of 3aa
to get the crude products, which were purified by recrystalli-
zation from ethanol. The ionic liquid remained in the aqueous
phase and reused in subsequent reaction without further puri-
fication. All products are known compounds, which were
characterized by IR and 1H NMR spectral data and their mps
compared with literature reports.
Entry
Run
Yield=%b
1
2
3
4
5
6
fresh
86
87
84
82
83
81
1
2
3
4
5
Acknowledgements
We are grateful to Nanjing University of Science and
Technology for financial support.
a
Reaction conditions: benzaldehyde (5 mmol), rhodanine
(5 mmol), [bmim][OH] (0.5 mmol), H2O (2 cm3) as solvent,
rt, reaction time, 60 min
References
b
Isolated yield
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1
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General procedure for the preparation of 5-benzylidene
rhodanine derivatives
A mixture of 5 mmol of the aromatic aldehyde, 5 mmol rho-
danine, 0.5mmol [bmim][OH] and 2 cm3 H2O in a flask was
stirred at room temperature for the appropriate time (reaction
were monitored by TLC). The reaction mixtures were filtered