Organic reactions in ionic liquids: Ionic liquid promoted Knoevenagel condensation of aromatic aldehydes with (2-thio)barbituric acid

Article abstract of DOI:10.1081/SCC-200043210

The Knoevenagel condensation of aromatic aldehydes with (2-thio)barbituric acid proceeded efficiently in reusable ionic liquids, EAN, BmimBF₄, and BmimPF₆ at room temperature in the absence of any catalyst with high yields.

Full text of DOI:10.1081/SCC-200043210

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Organic Reactions in
Ionic Liquids: Ionic Liquid
Promoted Knoevenagel
Condensation of
Aromatic Aldehydes with
(2‐Thio)Barbituric Acid
Yi Hu a b , Zhen‐Chu Chen a b , Zhang‐Gao Le a b c
Qin‐Guo Zheng d
&
a Ningbo Institute of Technology, Zhejiang
University, Ningbo, P. R. China
b Department of Chemistry, Zhejiang University (Xi
Xi Campus), Hangzhou, 310028, P. R. China
c Department of Applied Chemistry, East China
Institute of Technology, Fuzhou, P. R. China
d Pharmaceutical Science Research Institute, Aston
University, Aston Triangle, Birmingham, United
Kingdom
Version of record first published: 10 Jan 2011.
To cite this article: Yi Hu , Zhen‐Chu Chen , Zhang‐Gao Le & Qin‐Guo Zheng (2004):
Organic Reactions in Ionic Liquids: Ionic Liquid Promoted Knoevenagel Condensation
of Aromatic Aldehydes with (2‐Thio)Barbituric Acid, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:24, 4521-4529

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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 24, pp. 4521–4529, 2004
Organic Reactions in Ionic Liquids: Ionic
Liquid Promoted Knoevenagel
Condensation of Aromatic Aldehydes with
(2-Thio)Barbituric Acid
1,2,3
Yi Hu,1,2 Zhen-Chu Chen,1,2, Zhang-Gao Le,
*
and Qin-Guo Zheng4
1Ningbo Institute of Technology, Zhejiang University,
Ningbo, P. R. China
2Department of Chemistry, Zhejiang University (Xi Xi Campus),
Hangzhou, P. R. China
3Department of Applied Chemistry, East China Institute of
Technology, Fuzhou, P. R. China
4Pharmaceutical Science Research Institute, Aston University,
Aston Triangle, Birmingham, United Kingdom
ABSTRACT
The Knoevenagel condensation of aromatic aldehydes with (2-thio)barbi-
turic acid proceeded efficiently in reusable ionic liquids, EAN, BmimBF4,
*
Correspondence: Zhen-Chu Chen, Department of Chemistry, Zhejiang University (Xi
Xi Campus), Hangzhou 310028, P. R. China; E-mail: humi1@sohu.com.
4521
DOI: 10.1081/SCC-200043210
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4522
Hu et al.
and BmimPF6 at room temperature in the absence of any catalyst with
high yields.
Key Words: Aromatic aldehyde; Ionic liquids; Knoevenagel conden-
sation; (2-thio)barbituric acid.
The derivatives of the barbituric acid have been widely used as a sedative,
hypnotic, anesthetic, anticonvulsant, antiosteoporosis, as well as an antitumor
agent.[1] Arylidene (2-thio)barbituric acids are useful intermediates in
synthesis of benzylbarbituric derivatives,[2] heterocyclic compounds,[1a]
oxadeazaflavines,[3] and unsymmetrical disulfides.[4] Additionally, some of
them have been recently studied as nonlinear optical materials[5] and dyes.[6]
Generally, arylidene (2-thio)barbituric acids were synthesized by the Knoe-
venagel condensation of (2-thio)barbituric acids with aromatic aldehydes using
various acid or base as catalyst in organic solvents.[1,7] Usually, the yields
obtained are not satisfactory due to the formation of disubstituted condensation
products accompanying the desired monosubstituted condensation products.[1,8]
To achieve formation of only one (mono) condensation product, various efficient
methods have been developed, such as adsorption on Al2O3-KF,[9] microwave
irradiation,[10] infrared irradiation,[11] phase transfer catalysis.[12] However,
these methods usually need to use catalysts, volatile organic solvents for
product extraction from the solid reaction mixture, and sometimes long reaction
times are needed and only modest yields obtained. Additionally, Jursic reported
this condensation reaction could be performed in the absence of catalyst in
methanol, but a large volume of environmentally unfriendly methanol was
used and long reaction times were required when applied to the less reactive aro-
matic aldehydes.[1b] Therefore, preparation of arylidene (2-thio)barbituric acids
using a facile and efficient method with environmentally benign technologies
is still very interesting in organic synthesis.
In recent years, ionic liquids (ILs) have emerged as potential “greener”
alternatives to volatile organic solvents[13] and they have been used as
environmentally benign media for many important organic reactions.[14]
Recently, we have reported an effective Knoevenagel condensation catalyzed
by ethylenediammonium diacetate in ionic liquids [Bmim]BF4 and
[Bmim]PF6 ([Bmim] ¼ 1-butyl-3-methyl imidazolium).[15] In continuation
of our interest in using ionic liquids as a recyclable, eco-friendly reaction
medium in the Knoevenagel condensation, we found that the Knoevenagel
reaction of aromatic aldehydes with (2-thio)barbituric acid could occur in

Organic Reactions in Ionic Liquids
4523
ionic liquid [Bmim]BF4, [Bmim]PF6, and ethylammonium nitrate (EAN) in
the absence of catalyst.[16] In fact, simple stirring of a mixture of aromatic
aldehyde 1 and (2-thio)barbituric acid 2 in ionic liquid for an appropriate
time at room temperature gave, after directly filtering, the desired arylidene
(2-thio)barbituric acid 3 in high yield with practical purity (Sch. 1). The
1
results are summarized in Table 1. The products were characterized by H
NMR and IR, consistent with the literature data. It should be noted that
none of the products could be melted without decomposition.
As can be seen from the Table 1, the tested ionic liquids, [Bmim]BF4,
[Bmim]PF6, and EAN, were all efficient for this reaction, which proceeded
relatively slowly when performed in [Bmim]PF6. The reaction was found to
be general and applicable to the aromatic aldehydes bearing various substitu-
ents such as nitro, chloro, methyl, methoxyl, hydroxyl, N,N0-dimethylamino.
Aromatic aldehydes bearing electron-donating groups reacted much more
easily compared with those containing electron-withdrawing groups, the
same as described in the literature.[1b] The reaction of 2-furancarboxaldehyde
(Entry 13,14) and the aromatic a,b-unsaturated aldehyde, cinnamic aldehyde
(Entry 16,29) with (2-thio)barbituric acid also could be completed in short
times. Disappointedly, as simple as this reaction is, we can’t obtain satisfac-
tory results when applied to aliphatic aldehydes and ketones under the same
reaction conditions. In addition, the ionic liquid could be typically recovered
and reused with no appreciable decrease in yields and reaction rates (Entry
4-5, 25–26).
In order to compare with previous reported procedures, some literature
data[1b,10–12] are summarized in Table 2.
In conclusion, we have demonstrated that the Knoevenagel condensation
between aromatic aldehydes with (2-thio)barbituric acid could be effectively
performed at room temperature in the ionic liquids [Bmim]BF4, [Bmim]PF6,
and EAN. The present method has many obvious advantages compared to
previous methods, including no need for the use of any catalyst, being
Scheme 1.

4524
Hu et al.

Organic Reactions in Ionic Liquids
4525

4526
Hu et al.
Table 2. Knoevenagel condensation of aromatic aldehydes with (2-thio)barbituric
acids under different reaction conditions.
Yields (%)
Yields (%)
This
work
This
work
Product
Literature
Product
Literature
3d
3j
98
83
73,[10a] 81,[11] 79[12a]
68,[10a] 62,[11] 84,[12b] 75[10b]
3f
3l
96
98
86,[10a] 81[1b]
98[12b]
1bYield for reaction in methanol at r.t. for 5 days.
10aYield for reaction under microwave irradiation catalyzed by Montmorillonite KSF.
10bYield for reaction under microwave irradiation catalyzed by Montmorillonite KSF
and NaCl.
11Yield for reaction under infrared irradiation for 45 min.
12aYield for reaction catalyzed by CTMAB at r.t. for 0.5 h in water.
12bYield for reaction catalyzed by TEBA at 708C for 2 h in water.
environmentally more benign, ease of product isolation, simplicity of method-
ology, high yield, and generality. We have shown that ionic liquids play a dual
role as solvent and promoter in this reaction, resulting in a simpler system—a
good example of green chemistry.
EXPERIMENTAL
Melting points were determined on digital melting point apparatus and
were not corrected. Infrared spectra were recorded on a VECTOR-22 Infrared
Spectrophotometer. 1H NMR spectra were recorded on a BRUKER-400 MHz
spectrometer using DMSO-d6 as the solvent with TMS as an internal standard.
The ionic liquid [Bmim]PF6 and [Bmim]BF4 was synthesized as lit;[18]
ethylammonium nitrate (EAN) was synthesized according to the literature.[19]
All other materials are commercially available and were used without further
purification.
General Procedure for the Preparation of 3a–3q
Aromatic aldehyde 1 (1 mmol), (2-thio)barbituric acid 2 (1 mmol) were
added in ionic liquid [Bmim]BF4, [Bmim]PF6, or EAN (2 mL). The reaction
mixture was stirred at room temperature for an appropriate time; reaction
was monitored by TLC. Upon completion of the reaction, after filtering the

Organic Reactions in Ionic Liquids
4527
solid directly from the reaction mixture and washing with water, gave the
desired product 3 in high yields with essential purity. After isolation of the
product, the remainder of the ionic liquids ENA was dried for 4 h under
vacuum at 508C. The next run was performed under identical reaction
conditions.
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Received in Japan July 1, 2004