Organic reactions in ionic liquids: Gewald synthesis of 2-aminothiophenes catalyzed by ethylenediammonium diacetate

Article abstract of DOI:10.1081/SCC-200032526

Ionic liquids based on 1-butyl-3-methylimidazolium tetrafluoroborate (BmimBF₄) and 1-butyl-3-methylimidazolium hexafluorophosphate (BmimPF₆) were used as reusable alternatives to volatile organic solvents (VOCs) for ethylenediammonium diacetate (EDDA) catalyzed Gewald synthesis of 2-aminothiophenes. Significant rate enhancement and improvement of the yield were observed. The ionic liquids containing catalyst EDDA were recycled several times with no decreases in yields and reaction rates.

Full text of DOI:10.1081/SCC-200032526

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Organic Reactions in Ionic
Liquids: Gewald Synthesis of
2‐Aminothiophenes Catalyzed
by Ethylenediammonium
Diacetate
a b
a b
b
Yi Hu
, Zhen‐Chu Chen
, Zhang‐Gao Le &
c
Qin‐Guo Zheng
a
Ningbo Institute of Technology, Zhejiang
University, Ningbo, 315104, P.R. China
b
Department of Chemistry, Zhejiang University (Xi
Xi Campus), Hangzhou, 310028, P.R. China
c
Pharmaceutical Science Research Institute, Aston
University, Aston Triangle, Birmingham, B4 7ET, UK
Published online: 19 Apr 2010.
To cite this article: Yi Hu , Zhen‐Chu Chen , Zhang‐Gao Le & Qin‐Guo Zheng
2004) Organic Reactions in Ionic Liquids: Gewald Synthesis of 2‐Aminothiophenes
(
Catalyzed by Ethylenediammonium Diacetate, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:20, 3801-3806, DOI: 10.1081/SCC-200032526
To link to this article: http://dx.doi.org/10.1081/SCC-200032526
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SYNTHETIC COMMUNICATIONS
Vol. 34, No. 20, pp. 3801–3806, 2004
Organic Reactions in Ionic Liquids: Gewald
Synthesis of 2-Aminothiophenes Catalyzed
by Ethylenediammonium Diacetate
1
Yi Hu, Zhen-Chu Chen,
,2
1,2,*
2
Zhang-Gao Le, and
3
Qin-Guo Zheng
1
Ningbo Institute of Technology, Zhejiang University,
Ningbo, 315104, P.R. China
2
Department of Chemistry, Zhejiang University (Xi Xi Campus),
Hangzhou, 310028, P.R. China
3
Pharmaceutical Science Research Institute, Aston University,
Aston Triangle, Birmingham, B4 7ET, UK
ABSTRACT
Ionic liquids based on 1-butyl-3-methylimidazolium tetrafluoroborate
(
(
(
BmimBF
BmimPF
VOCs) for ethylenediammonium diacetate (EDDA) catalyzed Gewald
4
)
and 1-butyl-3-methylimidazolium hexafluorophosphate
6
) were used as reusable alternatives to volatile organic solvents
synthesis of 2-aminothiophenes. Significant rate enhancement and
improvement of the yield were observed. The ionic liquids containing
*
Correspondence: Zhen-Chu Chen, Ningbo Institute of Technology, Zhejiang
University, Ningbo 315104, P.R. China; E-mail: humi1@sohu.com.
3
801
DOI: 10.1081/SCC-200032526
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3
802
Hu et al.
catalyst EDDA were recycled several times with no decreases in yields
and reaction rates.
Key Words: 2-Aminothiophene; Gewald reaction; Ionic liquids;
Knoevenagel condensation.
2-Aminothiophenes derivatives are important intermediates for pharmaceu-
[1,2]
ticals, dyes, conducting polymers, agriculture, and other related materials.
The most elegant and simple version of the Gewald reaction, involving three-
component condensation of a ketone, aldehyde, or b-dicarbonyl compound,
an active nitrile, and elemental sulfur in the presence of base (Sch. 1), is the
most well-established route to the synthesis of 2-aminothiophenes containing
[
2]
electron-withdrawing groups in the 3-position. The Gewald-thiophene syn-
thetic procedures usually require 0.5–1.0 molar equivalents of organic amines
such as Et N, Et NH, diisopropylethylamine (DIPEA), morpholine, piper-
3
2
[
2,3]
idine, etc.,
of this synthesis have been developed recently, including heterogenous cata-
and the use of volatile organic solvent. Many modifications
[4]
[1a]
[5]
[6]
lysis, Lewis acid catalysis, solid support, microwave irradiation, etc.
However, these conditions indispensably need the use of organic base
and volatile organic solvent, yet usually need long reaction times and some-
times give low yields. Therefore, the improvement on Gewald synthesis of
2
-aminothiophenes is still a challenge in organic synthesis.
In recent years, room-temperature ionic liquids (RTILs) have attracted
[7]
increasing interest as green and reusable reaction media. Our recent research
has revealed that the ionic liquids 1-butyl-3-methylimidazolium tetrafluorobo-
rate (BmimBF ) and 1-butyl-3-methylimidazolium hexafluorophosphate
4
(
ammonium diacetate (EDDA)-catalyzed Knoevenagel condensation between
BmimPF ) could be used as recyclable reaction medium for ethylenedi-
6
[8]
aldehydes or ketones with active methylene compounds. It is known that
[2,4]
the Knoevenagel condensation is a key step in the Gewald reaction.
Herein, we wish to report our preliminary results on the application of
Scheme 1.

Organic Reactions in Ionic Liquids
3803
EDDA as a reusable catalyst in the Gewald 2-aminothiophenes synthesis using
ionic liquids as recyclable reaction medium.
For this study, BmimBF and BmimPF were synthesized according to
4
6
[
9]
the procedures reported in the literature. The results are summarized in
1
Table 1. All products were characterized by H-NMR, IR, and melting
points that were consistent with the literature data. As delineated in Table 1,
different carbonyl compounds were examined and found to be generally
applicable. The ionic liquid BmimPF gave the same excellent results as
6
BmimBF . Moreover, the ionic liquid containing catalyst EDDA could be
4
typically recovered and reused with no appreciable decrease in yields and
reaction rates. To investigate the catalytic influence of EDDA in detail, we
separately carried out the reaction of cyclohexanone and malononitrile with
EDDA (first step). The Knoevanagel condensation product was isolated and
cyclized to 2-aminothiophenes by elemental sulfur in the presence of the
catalyst under the same experimental conditions (second step). We found
that the first step of the reaction is completed in 2 h and could hardly take
place in the absence of catalyst. The second step of the reaction proceeded
smoothly in the presence of catalyst, whereas, in the absence of catalyst, reac-
tion was very slow and never attained completion. From the rate of reaction of
both the steps, it can be concluded that the EDDA not only catalyzed the con-
densation step but also functioned as an effective catalyst in the cyclization
step. We believe our method exhibited pronounced rate accelerations and
[
3]
gave high yields. For example, the literature reported 4c was obtained in
4
ment, 4c was obtained in 61% yield using 20 mol% EDDA as the base after 8 h
7% yield after 24 h using Et NH as the base at 708C in t-BuOH. In our experi-
2
[
4]
at 508C in BmimBF . The literature reported 4a was obtained in 61% yield
4
after 8 h using Calcined Mg-Al Hydrotalcite as the base at 608C in EtOH,
while 4a was obtained in 71% yield after 6 h using our method.
In conclusion, we demonstrated that the one-pot Gewald synthesis of
2
BmimBF or BmimPF catalyzed by EDDA. The present method has many
-aminothiophenes can effectively be performed in the ionic liquids
4
6
obvious advantages compared to those reported in the literature, including
being environmentally more benign, the generality, the shorter reaction
times, the higher yields, and the potential for recycling of ionic liquids and
catalyst EDDA.
EXPERIMENTAL
Melting points were determined on digital melting point apparatus and
were not corrected. Infrared spectra were recorded using KBr pellets on a
1
VECTOR-22 Infrared Spectrophotometer. H-NMR spectra were recorded

Table 1. Gewald Synthesis of 2-Aminothiophenes in BmimBF
4
Catalyzed by EDDA.
a
Entry
R
1
R
2
X
Time/h
Yield/%
Mp /8C
Lit.mp/8C
[
2a]
1
2
3
4
5
6
7
8
9
4a
4a
4b
4c
4d
4e
4e
4e
4e
CH
CH
CH
3
3
3
CH
CH
CH
3
3
3
CN
CN
CO
6
6
8
8
6
3
3
3
3
4
6
71
139–140
139–140
89–90
141–142
b
69
[
2a]
2
C
2
H
5
5
5
65
61
59
89
91–92
108–109
[
2a]
CH3
H
CO C H
2
CO C H
2
106–107
44–45
2
5
2
[
2a]
CH
— (CH
3
CO
CN
CN
CN
CN
2
C
2
H
46
147–148
[
2a]
2
)
4
—
146–147
146–147
146–147
146–147
113–114
89–90
c
— (CH ) —
87
2
2
2
4
4
4
d
— (CH
— (CH
)
)
—
—
88
b
87
[
[
2a]
2a]
1
0 4f
— (CH ) —
2
CO C H
2
84
65
115
91
4
2
5
1
1 4g
— (CH
2
)
3
—
CO
2
C
2
H
5
a
Melting points were uncorrected.
b
BmimPF
6
was used as solvent.
Second and third recycling of BmimBF containing the catalyst EDDA.
c–d
4

Organic Reactions in Ionic Liquids
3805
on a BRUKER-400 MHz spectrometer using CDCl as the solvent, with tri-
3
methylsilane (TMS) as an internal standard. All materials are commercially
available and were used without further purification.
General Procedure for the Gewald Reaction
Carbonyl compound (2 mmol), malononitrile, or ethyl cyanoacetate
2 mmol) and sulfur (2 mmol) were added in ionic liquid BmimBF4 or
(
BmimPF (2 mL). The reaction mixture was stirred for 3–8 h at 508C. Reac-
6
tion was monitored by thin-layer chromatography (TLC). After the reaction,
the resulting mixture was extracted with Et O (3 Â 10 ml). The combined
2
ethereal solution was evaporated to give the crude product, which was puri-
fied by recrystallization or preparative TLC (silica gel). After isolation of the
product, the remainder of the ionic liquids containing catalyst EDDA was dried
for 2 h under vacuum at 508C. The next run was performed under identical
reaction conditions.
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Received in Japan May 10, 2004