Synthesis of 2-aminothiophenes on ionic liquid phase support using the Gewald reaction

Article abstract of DOI:10.1080/00397910600588819

The first report of the use of task-specific ionic liquid as soluble support for the Gewald synthesis of 2-aminothiophenes is reported in this article. This synthetic method is simple and efficient, and the products are obtained in good to excellent yields with high purities, without the need for chromatographic purification. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600588819

This article was downloaded by: [Dalhousie University]
On: 08 January 2013, At: 23:10
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of 2‐Aminothiophenes on Ionic
Liquid Phase Support using the Gewald
Reaction
Yi Hu a , Ping Wei a , He Huang a , Shi‐Qing Han a & Ping‐Kai Ouyang a
a College of Life Science and Pharmaceutical Engineering, Nanjing University
of Technology, Nanjing, China
Version of record first published: 21 Aug 2006.
To cite this article: Yi Hu , Ping Wei , He Huang , Shi‐Qing Han & Ping‐Kai Ouyang (2006): Synthesis of
2‐Aminothiophenes on Ionic Liquid Phase Support using the Gewald Reaction, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:11, 1543-1548
To link to this article: http://dx.doi.org/10.1080/00397910600588819
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

Synthetic Communicationsw, 36: 1543–1548, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600588819
Synthesis of 2-Aminothiophenes on Ionic
Liquid Phase Support using the
Gewald Reaction
Yi Hu, Ping Wei, He Huang,
Shi-Qing Han, and Ping-Kai Ouyang
College of Life Science and Pharmaceutical Engineering,
Nanjing University of Technology, Nanjing, China
Abstract: The first report of the use of task-specific ionic liquid as soluble support for
the Gewald synthesis of 2-aminothiophenes is reported in this article. This synthetic
method is simple and efficient, and the products are obtained in good to excellent
yields with high purities, without the need for chromatographic purification.
Keywords: 2-Aminothiophene, Gewald synthesis, ionic liquids, soluble support
2-Aminothiophene derivatives are very important intermediates for pharma-
ceuticals, dyes, conducting polymers, agriculture, and other related
materials.[1,2] The most common version of the Gewald reaction, involving
multicomponent condensation of ketones or aldehydes, cyanoacetate,
and elemental sulfur, is the most well-established route to the synthesis
of 2-aminothiophenes containing electron-withdrawing groups in the
3-position and has attracted increasing interest since it was originally
published in 1961 by Gewald.[2] Generally, Gewald–thiophene synthetic pro-
cedures require long reaction times for the condensation step and the resulting
products require laborious purification.[2,3] Many modifications of this
reaction have been developed recently, such as using solid support,[4]
Received in China October 17, 2005
Address correspondence to Yi Hu, College of Life Science and Pharmaceutical
Engineering, Nanjing University of Technology, Nanjing 210009, China. E-mail:
amit-129@163.com
1543

1544
Y. Hu et al.
microwave irradiation combined with insoluble polymer support[5] or soluble
polymer support,[6] heterogeneous catalysis,[7] and Lewis acid catalysis.[1a]
However, some of these methods are limited by low loading capacity; diffi-
culty of monitoring the reaction progress and configuration of polymer-
bound products; use of large excess of reagents, expensive catalyst, or toxic
volatile organic solvent; tedious workup; long reaction times; and
sometimes low yields. Therefore, the improvement of Gewald synthesis of
2-aminothiophenes using a facile and efficient method with environmentally
benign technologies is still very interesting in organic synthesis.
Recently, much attention has been focused on the use of ionic liquids (IL)
as green reaction media; numerous chemical reactions can be carried out in
ionic liquids.[8] More recently, IL formulations have been expanded to
include ions with structurally and functionally complex side chains—the so
called “task-specific ionic liquids” (TSIL).[9] One of the most elegant appli-
cations of functionalized IL has been pioneered by Bazureau et al., who
used TSIL as supports for organic synthesis in an approach analogous to
solid-phase synthesis, called ionic liquid-phase organic synthesis
(IoLiPOS).[10] It has recently been extended by Miao and Chan who has
shown it to be compatible with the Suzuki coupling and oligopeptides
synthesis.[11] With these facts in mind, and in continuation of our interest in
using IL as an ecofriendly medium in condensation reactions,[12] we report
herein the new synthesis of 2-aminothiophenes using the IL as a soluble
support for the Gewald reaction (Scheme 1).
As shown in Scheme 1, the reaction of 1 with a minor excess of cyano-
acetic acid (1.2 equiv.) in the presence of dicyclohexyl carbodiimide (DCC)
and a catalytic amount of 4-dimethylamino pyridine (DMAP) in dry MeCN
produced the functionalized IL phase bond 2 through ester linkage. The disap-
pearance of absorption for the hydroxyl group at 3598 cm21 of 1 and the
Scheme 1. Reagents and conditions: (i) DCC (1 equiv.), DMAP (5%), cyanoacetic
acid (1.2 equiv.), MeCN, rt, 12 h; (ii) ketone or aldehyde (1 equiv.), S8 (1 equiv.),
EDDA (0.1 equiv.), 50 8C; (iii) EtONa (0.5 equiv.), EtOH, rt, 6 h.

2-Aminothiophene on Ionic Liquid Phase Support
1545
appearance of ester carbonyl and cyano at 1745 and 2200cm21 in the IR
spectrum are clear evidence of the formation of 2. Then Gewald reactions
were carried out under solvent-free conditions catalyzed by ethylenediammo-
nium diacetate (EDDA).[12a] The completion of the reaction was evidenced
by the disappearance of cyano group and the appearance of amino group at
3413 and 3310cm21 in the IR spectrum of the products—the IL phase bond
intermediates 3. Treatment of 3 with NaOEt in ethanol resulted in a very
efficient cleavage from IL support to provide the corresponding products 4
with high purity without the need for chromatographic purification. Compared
to the conventional liquid synthesis methods, the IL phase bond intermediates
were easily isolated and purified by simple filtration and washing with Et2O
to remove the minor unreacted materials and neutral by-product. Compared to
the polymer-support methods, the most obvious advantages are the much
higher loading capacity of the TSIL and no need for the use of a large excess
of reagents, 1H NMR and IR could be used readily to analyze the configuration
of IL phase bond intermediates and products without detaching material from
the ionic liquid-phase support in each step of the sequences in contrast to
insoluble polymers as solid supports. Significantly, the three components
were added in equivalent portions in the reaction, to allow standard analytical
methods (1H NMR, TLC) to be used conveniently to monitor reaction progress.
To establish the scope of this reaction, various ketones, aldehydes, and
1,3-dicarbonyl compounds were investigated. The results were summarized
1
in Table 1; all the products were characterized by H NMR, IR, and melting
points, which were consistent with the literature data. As delineated in
Table 1, our method was found to be generally applicable; all the products
were obtained in good to excellent yields. Moreover, the IL phase 1
([2-hydemim][BF4]) could be typically recovered and reused with no
appreciable decrease in yields and reaction rates after the workup as
described in the literature.[10b]
Table 1. Synthesis of 2-aminothiophenes using ionic liquid as soluble support
Entry
Product
R1
R2
Time (h)
Yield (%)
1
2
4a
4b
4c
4d
4e
4f
CH3
CH3
CH3
6
6
6
6
5
5
3
3
3
5
75
77
70
69
68
67
91
89a
88b
83
CH3CH2
CH3
CH3
H
3
CO2C2H5
CO2CH3
CH3
4
5
6
H
CH3CH2
7
4g
4g
4g
4h
—(CH2)4—
—(CH2)4—
—(CH2)4—
—(CH2)3—
8
9
10
a,bSecond and third recycling of 1.

1546
Y. Hu et al.
In summary, we have successfully performed the Gewald reaction using
ionic liquid as support. The use of this novel IL phase offers many advantages
compared to previously reported methods including environmental friend-
liness, much higher loading capacity, easy isolation and purification of the
products, shorter reaction times, higher yields, no need for use of large
excess of reagents, compatibility with automatic manipulation, use of
standard analytical methods (IR, NMR, TLC) to monitor reaction progress,
and the recyclability of the soluble support.
EXPERIMENTAL
For this study, the functionalized ionic liquid 1-(2-hydroxylethyl)-3-methyli-
midazolium tetrafluorobate ([2-hydemim][BF4]) 1 was prepared according to
the literature.[10] Melting points were determined on a digital melting-point
apparatus and were not corrected. Infrared spectra were recorded using KBr
1
pellets on a Vector-22 infrared spectrophotometer. H NMR spectra were
recorded on a Bruker 400-MHz spectrometer using CDCl3 as the solvent
with TMS as an internal standard. All materials are commercially available
and were used without further purification.
IL-Supported Cyanoacetic Ester 2
Cyanoacetic acid (12 mmol), and DCC (10 mmol), DMAP (0.5 mmol) were
added to a solution of [2-hydemim][BF4] 1 (10 mmol) in MeCN (50 ml).
After vigorous stirring at rt for 12 h, the insoluble N,N0-dicyclohexylurea
(DCHU) was removed by filtration. The filtrate was concentrated under
reduced pressure, and the resulting crude product was washed successively
with dry Et2O (2 ꢀ 15 ml) and dried under vacuum to give the IL-supported
cyanoacetic ester 2 in almost quantitative yield (99%). Pale yellow viscous
liquid: IR (neat): 3170, 2200, 1745, 1578, 1453, 1170, 1072, 833 cm21
;
1H NMR: d ¼ 8.22 (br s, 1H), 7.28 (t, 1H, J ¼ 1.6 Hz), 7.20 (t, 1H,
J ¼1.6 Hz), 4.05 (t, 2H, J ¼ 4.8 Hz), 3.70 (s, 3H), 3.67 (t, 2H, J ¼ 4.8 Hz),
3.40 (s, 2H).
General Procedure for the Synthesis of 2-Aminothiophenes
Carbonyl compound (5 mmol), S8 (5 mmol), and EDDA (0.5 mmol) were
added to 2 (5 mmol). The reaction mixture was stirred under solvent-free
conditions for 3–6 h at 50 8C. The resulting mixture was filtered and
washed with dry Et2O (3 ꢀ 10 ml) and then dried under vacuum to give the
IL-supported 2-aminothiophene 3. The resulting 3 was added to a solution
of EtONa (2.5 mmol) in ethanol (50 ml); the mixture was stirred at rt for

2-Aminothiophene on Ionic Liquid Phase Support
1547
6 h. Upon completion of the reaction, the ethanol was removed under vacuum,
and the expected product 4 was extracted with Et2O (4 ꢀ 20 ml). The
combined ethereal solution was evaporated to give the product 4 with high
purity without the need for further chromatographic purification. The
reaction progress of the Gewald and the following cleavage reactions could
1
be easily monitored by IR, TLC, or H NMR.
ACKNOWLEDGMENTS
This work is supported by the National Natural Sciences Foundation of China
(No. 20336010), and the State Key Basic Research and Development Project
of China (No. 2003CB716004).
REFERENCES
1. (a) Lutjens, H.; Zickgraf, A.; Figler, H.; Linden, J.; Olsson, R. A.; Scammells, P. J.
J. Med. Chem. 2003, 46, 1870; (b) Pinto, I. L.; Jarvest, R. L.; Serafinowska, H. T.
Tetrahedron Lett. 2000, 41, 1597; (c) Ogawa, K.; Radke, K. R.; Rothstein, S. D.;
Rasmussen, S. C.T. J. Org. Chem. 2001, 66, 9067.
2. (a) Gewald, K. Angew. Chem. 1961, 73, 114; (b) Gewald, K.; Schinke, E.;
Bottcher, H. Chem. Ber. 1966, 99, 94; (c) Sabnis, R. W.; Rangnekar, D. W.;
Sonawane, N. D. J. Heterocycl. Chem. 1999, 36, 333.
3. (a) Koike, K.; Jia, Z.; Nikaido, T.; Liu, Y.; Guo, D. Org. Lett. 1999, 1, 197;
(b) Mckibben, B. P.; Cartwright, C. H.; Castelhano, A. L. Tetrahedron Lett.
1999, 40, 5471.
4. Castanedo, G. M.; Sutherlin, D. P. Tetrahedron Lett. 2001, 42, 7181.
5. Hoener, A. P.F.; Henkel, B.; Gauvin, J. C. Synlett. 2003, 63.
6. (a) Zhang, H. Q.; Yang, G. C.; Chen, J. N.; Chen, Z. X. Synthesis. 2004, 3055;
(b) Zhang, H. Q.; Yang, G. C.; Chen, J. N.; Chen, Z. X. J. Chem. Res. Synop.
2004, 3055.
7. Rajagopal, R.; Jyothi, T. M.; Daniel, T.; Srinivasan, K. V.; Rao, B. S. Synth.
Commun. 2001, 31, 3113.
8. (a) Welton, T. Chem. Rev. 1999, 99, 2071; (b) Wasserscheid, P.; Keim, W. Angew.
Chem. Int. Edit. 2000, 39, 3772; (c) Sheldon, R. Chem. Commun. 2001, 2399;
(d) Jairton, D.; Robeerto, F.; Paulo, A. Z. S. Chem. Rev. 2002, 102, 3667;
(e) Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S. M. S. Tetrahedron 2005, 61,
1015; (f) Wasserscheid, P., Welton, T., Eds.; Ionic Liquids in Synthesis;
Wiley–VCH: Weinheim, 2003.
9. Davis; Jr, J. H. Chem. Lett. 2004, 33, 1072.
10. (a) Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron, Lett. 2000, 41, 7351;
(b) Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron, Lett. 2001, 42, 6097;
(c) Fraga-Dubreuil, J.; Famelart, M.-H.; Bazureau, J. P. Org. Proc. Res. Dev.
2002, 6, 374; (d) Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron. 2003, 59,
6121; (e) Hakkou, H.; Eynde, J. J.V.; Hamelin, J.; Bazureau, J. P. Tetrahedron
2004, 60, 3745; (f) Yi, F. P.; Peng, Y. Q.; Song, G. H. Tetrahedron, Lett. 2005,
46, 3931; (g) de Kort, M.; Tuin, A. W.; Kuiper, S.; Overkleeft, H. S.; van der
Marel, G. A.; Buijsman, R. C. Tetrahedron, Lett. 2004, 45, 2171.

1548
Y. Hu et al.
11. (a) Miao, W.; Chan, T. H. Org. Lett. 2003, 5, 5003; (b) Chan, W. T.H. J. Org.
Chem. 2005, 70, 3251.
12. (a) Hu, Y.; Chen, Z. C.; Le, Z. G.; Zheng, Q. G. Synth. Commun. 2004, 34,
3801; (b) Hu, Y.; Chen, Z. C.; Le, Z. G.; Zheng, Q. G. Synth. Commun. 2004,
34, 4521; (c) Hu, Y.; Chen, J.; Chen, Z. C.; Le, Z. G. Synth.Commun. 2005, 35,
771.