Efficient preparation of 5-amino-4-cyano-N-(cyclopropylcarbamoyl)-3-aryl-2, 3-dihydrothiophene-2-carboxamide derivatives without using any other catalysts

Article abstract of DOI:10.1080/00397911.2012.721919

An efficient synthesis of 5-amino-4-cyano-N-(cyclopropylcarbamoyl)-3-aryl- 2,3-dihydrothiophene-2-carboxamide derivatives by the reaction of thiazolidine-2,4-dione, aromatic aldehydes, malononitrile, and cyclopropylamine has been reported. This reaction c

Full text of DOI:10.1080/00397911.2012.721919

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Efficient Preparation of 5-Amino-4-
cyano-N-(cyclopropylcarbamoyl)-3-
aryl-2,3-dihydrothiophene-2-
carboxamide Derivatives Without Using
Any Other Catalysts
Lijiu Gao a , Sheng Xia a , Nan Wu b , Shimin Tao a , Youjian Feng a &
Liangce Rong a
a Jiangsu Key Laboratory of Green Synthetic Chemistry for
Functional Materials , College of Chemistry and Chemical
Engineering, Jiangsu Normal University , Xuzhou , China
b Department of Aviation Oil and Material , Xuzhou Airforce College ,
Xuzhou , China
Published online: 26 Jun 2013.
To cite this article: Lijiu Gao , Sheng Xia , Nan Wu , Shimin Tao , Youjian Feng & Liangce Rong (2013):
Efficient Preparation of 5-Amino-4-cyano-N-(cyclopropylcarbamoyl)-3-aryl-2,3-dihydrothiophene-2-
carboxamide Derivatives Without Using Any Other Catalysts, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:19, 2590-2595
To link to this article: http://dx.doi.org/10.1080/00397911.2012.721919
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Synthetic Communications1, 43: 2590–2595, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.721919
EFFICIENT PREPARATION OF 5-AMINO-4-CYANO-
N-(CYCLOPROPYLCARBAMOYL)-3-ARYL-2,
3-DIHYDROTHIOPHENE-2-CARBOXAMIDE
DERIVATIVES WITHOUT USING ANY OTHER
CATALYSTS
Lijiu Gao,1 Sheng Xia,1 Nan Wu,2 Shimin Tao,1 Youjian Feng,1
and Liangce Rong1
1Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional
Materials, College of Chemistry and Chemical Engineering, Jiangsu Normal
University, Xuzhou, China
2Department of Aviation Oil and Material, Xuzhou Airforce College,
Xuzhou, China
GRAPHICAL ABSTRACT
Abstract An efficient synthesis of 5-amino-4-cyano-N-(cyclopropylcarbamoyl)-3-aryl-2,3-
dihydrothiophene-2-carboxamide derivatives by the reaction of thiazolidine-2,4-dione, aro-
matic aldehydes, malononitrile, and cyclopropylamine has been reported. This reaction
could be carried out smoothly without using any other catalysts in anhydrous ethanol.
The advantages of this procure were good yields, short reaction time, and mild reaction con-
ditions. Moreover, the purification process of products was very simple. The products could
be gained only as the reactants were cooled under room temperature, and the precipitate
could be brought out. These precipitate only need to filter out, without further purification.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Cyclopropylamine; 2,3-dihydrothiophene; multicomponent reactions; syn-
thesis; thiazolidine-2,4-dione
Received July 1, 2012.
Address correspondence to Liangce Rong, College of Chemistry and Chemical Engineering,
Jiangsu Normal University, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional
Materials, Xuzhou 221116, China. E-mail: lcrong2005@yahoo.com
2590

2,3-DIHYDROTHIOPHENE-2-CARBOXAMIDE
2591
INTRODUCTION
Multicomponent reactions (MCRs) have recently become one of the favored
methods to prepare organic compounds.[1] Among many kinds of multicomponent
reactions, four-component reactions are some of the most efficient and convenient
methods to achieve many valuable organic molecules. For example, the Ugi reac-
tion,[2] discovered more than 40 years ago, is without any doubt the most widely
exploited, not only to prepare peptide-like molecules, but also to achieve many dif-
ferent types of other biologically active targets. At the present time, many
four-component reactions[3] are used to obtain various compounds. In addition,
MCRs are useful approaches for the construction of diverse chemical libraries of
‘‘drug-like’’ molecules[4] (i.e., heterocyclic scaffolds compounds), and this has also
attracted much attention from chemists.
Thiophenes, which are used in medicinal chemistry and materials science, have
grown enormously during the past several years.[5] For example, thiophene is the
mother nucleus of several important pharmaceuticals such as reloxifen, duloxetine
(Cymbalta), tiotropium (Spiriva), and Cosopt (dorzolamide). Importantly, the
syntheses of the aforementioned drugs often use simple thiophenes as starting mate-
rials. The quest for these important molecules has been brought forth by modifi-
cation of classical methods and, more importantly, novel synthesis by highly
creative synthetic chemists. Similar attention has been drawn to the efficient syn-
thesis of thiophene-containing organic materials because of the importance of atom
economy and green chemistry. Recently, many novel thiophenes derivatives were
synthesized by different methods.[6] Herein, we report preparation of some novel
thiophene compounds by four-component reactions under catalyst-free conditions.
RESULTS AND DISCUSSION
Recently, some researchers have reported synthesizing thiophene derivatives by
four-component reactions from thiazolidine-2,4-dione, aromatic aldehyde, malono-
nitrile, and different organic amines.[7] However, in these reported methods, the reac-
tions were carried out in CH3CN, and the yields of products were very poor.
Moreover, the catalyst Et3N is required. Upon investigating, we found cyclopropy-
lamine has not been used in similar syntheses. In our research, we want to find other
useful methods to prepare new thiophene derivatives using cyclopropylamine as
starting reagent.
At the beginning of our research, we wanted to find the best reaction con-
ditions in which to carry out this synthesis. Thiazolidine-2,4-dione, 4-fluorobenzalde-
hyde, malononitrile, and cyclopropylamine were chosen as starting materials for the
model reaction under different solvents, such as H2O, CH3CN, CH3OH, EtOH, and
tetrahydrofuran (THF), and in solvent-free condition, without using any other cat-
alysts (Scheme 1). We found that in CH3CN (used in literature) the reaction could be
carried out, but the yield was very poor (only 25%). The reaction in water was such
also (only 18%). The desired product did not form under solvent-free conditions, and
only condensation products of 4-fluorobenzaldehyde and malononitrile could be
gained. Then, other solvents, such as CH3OH, anhydrous EtOH, and THF were
chosen to try this model reaction. Eventually, we found the reactions could operate

2592
L. GAO ET AL.
Scheme 1. Synthesis of 3-(4-fluorophenyl)-2,3-dihydrothiophene-2-carboxamide.
very well under anhydrous EtOH conditions. We thought that ethanol was a good
organic polar solvent, efficiently dissolving substances and reaction intermediates,
and so was beneficial to the formation of the products. The results of model reaction
are listed in Table 1.
To test the scope of the substrates under this optimizing condition, we used
different aromatic aldehydes 2 with either electron-withdrawing groups or
electron-donating groups to react with thiazolidine-2,4-dione 1, malononitrile 3,
and cyclopropylamine 4, and we found all the reactions could be carried out
smoothly with good yields (Scheme 2). The results of reactions showed that the
properties of substituted groups have no effect on these syntheses. Taking into
account these results, we reasoned these conditions were the perfect conditions for
this synthesis. In these reactions, cyclopropylamine behaves both as a base catalyst
and the reagent, so it did not require any other catalysts. Furthermore, the purifi-
cation of reactions was very simple. The products could be gained only as the reac-
tants were cooled under room temperature, and then the precipitate could be
brought out. These precipitates only need to be filtered out, without the need for
further purification. The results of reaction are summarized in Table 2.
According to the obtained product, the possible mechanism could be explained
by Scheme 3. First, 1 reacted with 2 or 2 reacted with 3 to give 6 and 7 respectively.
Then, 6 reacted with 3 and 7 reacted with 1 to give the same intermediate 8.
Table 1. Synthesis of 5b using different reaction conditions
Entry
Solventa
Time (h)
Yields (%)b
1
2
3
4
5
6
7
8
9
CH3CN
H2O (100 ꢀC)
—
2
2
2
2
2
2
1
2
3
25
18
0
50
CH3OH,
DMF (100 ꢀC)
THF
Trace
40
75
EtOH
EtOH
EtOH
89
90
Note. Reagents and conditions: thiazolidine-2,4-dione (1 mmol), 4-chlorobenzalde-
hyde (1 mmol), malononitrile (1 mmol), cyclopropylamine (1.2 mmol), and EtOH
(8 mL).
aUnless explicitly stated, the reaction was conducted under reflux conditions.
bIsolated products.

2,3-DIHYDROTHIOPHENE-2-CARBOXAMIDE
2593
Scheme 2. Synthesis of 3-aryl-2,3-dihydrothiophene-2-carboxamide.
Table 2. Results of synthesis of 3-aryl-2,3-dihydrothiophene-2-carboxamide
Entry
Ar
Product
Yields (%)
1
2
C6H5
4-FC6H4
5a
5b
5c
5d
5e
5f
85
89
90
82
83
91
84
80
81
87
92
3
4-ClC6H4
3-BrC6H4
4-BrC6H4
4
5
6
2,4-Cl2C6H3
3,4-Cl2C6H3
4-CH3C6H4
2-CH3OC6H4
4-CH3OC6H4
3,4-(CH3O)2C6H3
7
5g
5h
5i
8
9
10
11
5j
5k
Cyclopropylamine reacted with 8 and intermediate 9 could be gained. Intermediate 9
took place with ring opening to give 10. The intramolecular cyclization reaction of
intermediate 10 was taken place to give 11. At last, the product 5 was obtained by
the tautomerization of 11.
Scheme 3. Probable mechanisms of the reaction.

2594
L. GAO ET AL.
All the products were characterized by infrared (IR), 1H NMR, 13C NMR, and
high-resolution mass spectrometry (HRMS). The structures of the products could be
1
explained as follows, using example 5a: In H NMR shows a singlet at d 0.52 (2H),
multiple at d 0.64–0.69 (2H), and two doublets at d 2.63 (1H) due to the five aliphatic
hydrogen protons of cyclopropyl. A singlet at d 4.07 (1H) and a doublet at d 4.53
(1H) are two protons on the thiofuran ring. Multiple at d 7.28–7.31(3H) and triplet
at d 7.33 (2H) are five protons on the benzene ring. A singlet at d 7.21 of two protons
is the NH2 and the singlet at d 8.17 and 10.40 are due to the NH protons. In 13C
NMR, the chemical shifts of 16 carbon atoms show at 172.10, 162.15, 154.15,
141.90, 141.88, 129.17, 127.94, 127.89, 127.52, 118.64, 70.67, 55.62, 55.59, 22.78,
6.63, and 6.50. In HRMS spectrum, the calculated m=z for C16H16N4O2S [Mþ Na]
is 351.0892, and we found m=z is 351.0877.
CONCLUSION
In summary, we have developed a simple and efficient method for the synthesis
of 5-amino-4-cyano-N-(cyclopropylcarbamoyl)-3-aryl-2,3-dihydrothiophene-2-car-
boxamide derivatives via a one-pot, four-component reaction of thiazolidine-2,4-
dione, aromatic aldehydes, malononitrile, and cyclopropylamine without use of
any other catalysts. Eleven new compounds were successfully synthesized using
our reported method. The advantages of the present procedure are experimental
simplicity, good yields, and mild reaction conditions. In addition, the purification
of the products is very simple.
EXPERIMENTAL
All reagents were purchased from the Merck and Aldrich chemical companies
and used without further purification. Melting points were determined on an XT-5
microscopic melting-point apparatus and were uncorrected. IR spectra were
1
recorded on a Fourier transform (FT) Bruker Tensor 27 spectrometer. H NMR
spectra and 13C NMR spectra were obtained from solution in dimethylsulfoxide
(DMSO-d6) with Me4Si as internal standard using a Bruker-400 spectrometer.
HRMS spectra were obtained with a Bruker Micro-TOF-Q 134 instrument.
Thiazolidine-2,4-dione (1 mmol), aromatic aldehyde (1 mmol), malononitrile
(1 mmol), cyclopropylamine (1.2 mmol), and anhydrous EtOH (8 mL) were put in
a reaction flask and left at 75 ꢀC for about 2 h. After completing the reactions, the
mixture was cooled under room temperature. The precipitate could be brought
out, filtered, and dried, and 5 could be gained without further purification.
Complete experimental details are available online in the Supplemental
Material.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (NSFC)
(21172188), the Foundation of Xuzhou Normal University (10XLS02), and the
Priority Academic Program Development of Jiangsu Higher Education Institutions
for financial support.

2,3-DIHYDROTHIOPHENE-2-CARBOXAMIDE
2595
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