Microwave-assisted synthesis of 2-amino-thiophene-3-carboxylic derivatives under solvent-free conditions

Article abstract of DOI:10.1081/SCC-200057268

Under microwave irradiation and solvent-free conditions, cyanoacetates (cyanoacetamides) react with ketones and sulphur in the presence of a small amount of morpholine to give 2-amino-thiophene-3-carboxylic derivatives. In particular, tetrahydro-benzo[b]thiophene-3-carboxylic acid N-aryl amides were synthesized in high yields of 84-95%. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200057268

This article was downloaded by: [Fordham University]
On: 16 January 2013, At: 04:09
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
Microwave‐Assisted
Synthesis of
2‐Amino‐thiophene‐3‐Carboxylic
Derivatives Under Solvent‐Free
Conditions
Wei Huang a b , Jian Li a b , Jing Tang a , Hong Liu a
Jianhua Shen a & Hualiang Jiang a
,
a Drug Discovery and Design Center, State Key
Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Shanghai Institutes for Biological
Sciences, Chinese Academy of Sciences, Shanghai,
China
b Graduate School of the Chinese Academy of
Sciences, Shanghai, China
Version of record first published: 16 Aug 2006.
To cite this article: Wei Huang , Jian Li , Jing Tang , Hong Liu ,
Jianhua Shen & Hualiang Jiang (2005): Microwave‐Assisted Synthesis of
2‐Amino‐thiophene‐3‐Carboxylic Derivatives Under Solvent‐Free Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:10, 1351-1357
To link to this article: http://dx.doi.org/10.1081/SCC-200057268
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, 35: 1351–1357, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200057268
Microwave-Assisted Synthesis of
2-Amino-thiophene-3-Carboxylic
Derivatives Under Solvent-Free Conditions
Wei Huang and Jian Li
Drug Discovery and Design Center, State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica, Shanghai Institutes
for Biological Sciences, Chinese Academy of Sciences, Shanghai,
China and Graduate School of the Chinese Academy of Sciences,
Shanghai, China
Jing Tang, Hong Liu, Jianhua Shen, and Hualiang Jiang
Drug Discovery and Design Center, State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica, Shanghai Institutes
for Biological Sciences, Chinese Academy of Sciences,
Shanghai, China
Abstract: Under microwave irradiation and solvent-free conditions, cyanoacetates
(cyanoacetamides) react with ketones and sulphur in the presence of a small amount
of morpholine to give 2-amino-thiophene-3-carboxylic derivatives. In particular, tetra-
hydro-benzo[b]thiophene-3-carboxylic acid N-aryl amides were synthesized in high
yields of 84–95%.
Keywords: 2-Amino-thiophene-3-carboxylic derivatives, microwave irradiation
synthesis, solvent-free
Received in Japan November 22, 2004
Address correspondence to Hong Liu, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park,
Shanghai 201203, China. Tel.: þ86-21-50806600 ext. 5416; Fax: þ86-21-50807088;
E-mail: hliu@mail.shcnc.ac.cn
1351

1352
W. Huang et al.
INTRODUCTION
2-Amino-thiophene-3-carboxylic derivatives are known for their local anaes-
thetic activity.[1,2] Substituted 2-aminothiophenes have been used as starting
materials in the synthesis of thienopyrimidines[3–6] and thienoimidazoles,[7]
which display a variety of pharmacological activities, such as antimicrobial,[3]
antiinflammatory,[4] anxiolytic,[5] and psychotropic[6] activity. Accordingly,
developing more efficient, convenient, and environmentally friendly
methods for synthesizing 2-aminothiophenes is of significance.
2-Amino-thiophene-3-carboxylic derivatives were synthesized previously
by the Gewald method[8] from the reaction of ketones, cyanoacetates (cyano-
acetamides), and sulphur (Scheme 1). Gewald et al. used a simplified one-pot
procedure to synthesize these compounds instead of a two-step synthetic
method. However, the yields of some compounds, such as 2-amino-4-methy-
thiophene-3-carboxylic derivatives and tetrahydro-benzo[b]thiophene-3-
carboxylic acid N-aryl amides, synthesized in this way are comparatively
low. Moreover, this synthetic process needs long heating time and compli-
cated handling.
In the present communication, we report on an expeditious solvent-free
method to prepare 2-amino-thiophene-3-carboxylic derivatives, which used
microwave irradiation as the heating source and basic aluminum oxide as
solid support. The results indicate that this synthetic method is easy and the
yields of products are increased dramatically.
RESULTS AND DISCUSSION
Treated with basic aluminium oxide as solid support and morpholine as base
catalyst, ketones, cyanoacetates (cyanoacetamides), and sulphur were mixed
and placed in an open vessel, and then the mixture was subjected to
microwave irradiation for several minutes (Scheme 2). The purification of
the reaction mixture by flash chromatography resulted in the exclusive
isolation of 2-amino-thiophene 2a–q in good yields.
The reaction conditions were optimized by testing several parameters,
such as solid supports, power of microwave oven, and time of irradiation.
Solid supports such as various clays, aluminium oxides, and silica gel
have been widely used in microwave-assisted organic synthesis to enhance
substrates absorption of microwave energy. Using morpholine as base
Scheme 1.

Synthesis of 2-Amino-thiophene-3-Carboxylic Derivatives
1353
Scheme 2.
catalyst, we compared the reaction yields of basic aluminium oxide with silica
gel as solid supports during the synthesis of 2e. The result indicated that basic
aluminium oxide (87%) is more efficient than silica gel (59%). The reason of
this result is probably due to the basicity of aluminium oxide, which enhances
the catalytic effect of the base in the reaction.
Second, we evaluated the role of the base in the reaction. The reaction
was respectively performed on the two solid supports without morpholine.
Cyano-(4-methyl-cyclohexylidene)-acetic acid ethyl ester (1e) was obtained
as the product of the reaction on basic aluminium oxide, but no product was
determined on silica gel. This demonstrated the slight alkalinity of basic
aluminium oxide and its effect on this procedure. Morpholine as an inexpen-
sive and readily available secondary amine was used and found to be the most
suitable in this reaction conditions.
In addition, the employed power of microwave oven and the irradiation
time were investigated. When the power increased to 320 W, byproducts
were observed on TLC and the yield was reduced in the synthesis of 2e. No
target product was observed in the synthesis of 2f at 320 W for 5 min. We
compared the irradiation time of 5 min, 10 min, and 15 min at 160 W in the
synthesis of 2e, and the corresponding yields are 73%, 87%, and 61%,
respectively (Table 1).
Based on the studies described, the optimized condition of this procedure
is basic aluminium oxide as solid support, microwave irradiation at 160 W,
and reaction for 10 min. Compounds 2a–q were synthesized under these
conditions and the results are listed in Table 2.
Table 1. Procedure optimization of compound 2e under microwave irradiation and
solvent-free conditions
Solid support
Power (W)
Irradiation time (min)
Yield (%)
Silica gel
160
160
160
160
320
320
320
10
5
59
73
87
61
52
46
41
Basic Al2O3
Basic Al2O3
Basic Al2O3
Basic Al2O3
Basic Al2O3
Basic Al2O3
10
15
5
10
15

Table 2. Comparison of yields of 2-amino-thiophene-3-carboxylic derivatives 2a–q obtained under thermal and microwave conditions
Yield (%)
Thermal
conditionb
Microwave
condition
Compd.a
R
R0
X
2a
2b
2c
2d
2e
2f
CH3
CH3
COCH3
CO2Et
–OMe
–OEt
–OEt
31[8]
32[8]
45[8]
51[8]
70[9]
61[8]
21[10]
34[10]
32[10]
67[6]
—
51
80
77
73
87
71
93
93
95
91
85
86
84
84
86
–(CH2)3–
–(CH2)3–
–NHC6H4-o-Me
–OEt
–NH2
–CH2CH2CH(CH3)CH2–
–(CH2)4–
–(CH2)4–
2g
2h
2i
–NHC6H5
–(CH2)4–
–(CH2)4–
–NHC6H4-o-Me
–NHC6H4-p-Me
–NHC6H5
2j
–CH2CH2CH(CH3)CH2–
–CH2CH2CH(CH3)CH2–
–(CH2)4–
2k
2m
2n
2p
2q
–NHC6H4-p-Me
–NHC6H3-3-Cl-4-F
–NHC6H3-3-Cl-4-F
–NHC6H4-p-OCF3
–NHC6H4-p-OCF3
—
—
–CH2CH2CH(CH3)CH2–
–(CH2)4–
–CH2CH2CH(CH3)CH2–
—
—
aCompounds 2k–2q are new chemicals.
bTaken from references [6], [8], [9], [10].

Synthesis of 2-Amino-thiophene-3-Carboxylic Derivatives
1355
Compared with the Gewald method,[8] the yields of the present method
were greatly improved. In particular, the yields of tetrahydro-benzo[b]
thiophene-3-carboxylic acid N-aryl amides were increased from 21–67% to
84–95% (Table 2).
In conclusion, we have found an efficient method to prepare the title
compounds by solvent-free microwave-assisted reaction. This method is
also quite suitable for the synthesis of various tetrahydro-benzo[b]
thiophene-3-carboxylic acid N-aryl amides.
EXPERIMENTAL
Melting points were tested on a melting point apparatus (SGW X-4) and are
uncorrected. NMR spectra were obtained on a Bruker AMX-400 instrument
in CDCl3 or DMSO-d6. MS spectra were recorded on a MAT-95 spectrometer.
Microwave experiments were carried out in a domestic microwave oven
(Galanz WG800DSL20II-K6).
Synthesis of 2-amino-thiophene-3-carboxylic derivatives: general pro-
cedures are described as those of compound 2a.
5-Acetyl-2-amino-4-methyl-thiophene-3-carboxylic acid methyl ester
(2a). A one-neck 50-mL flask containing acetylacetone (0.3 g, 3 mmol),
methyl cyanoacetate (0.2 g, 2 mmol), sulphur (0.11 g, 3.4 mmol), basic
Al2O3 (0.2 g), and morpholine (0.2 g, 2.3 mmol) was placed into a
microwave oven and irradiated at the power of 160 W for 10 min. After
cooling, the residue was separated by column chromatography with silica
gel using petroleum ether/ethyl acetate (8/1) as eluting solution. The
product 2a (0.22 g, yield 51%) was obtained as a solid upon evaporation.
Mp 159–1618C. 1H NMR (400 MHz, DMSO-d6): d 2.33 (s, 3H), 2.58
(s, 3H), 3.73 (s, 3H), 7.98 (s, 2H). m/z (EI): 213 (Mþ), 166 (100%).
5-Amino-3-methyl-thiophene-2,4-dicarboxylic acid diethyl ester (2b).
Mp 106–1088C. 1H NMR (400 MHz, DMSO-d6): d 1.21 (t, 3H,
J ¼ 7.2 Hz), 1.26 (t, 3H, J ¼ 7.2 Hz), 2.58 (s, 3H), 4.12 (q, 2H, J ¼ 7.2 Hz),
4.21 (q, 2H, J ¼ 7.2 Hz), 7.90 (s, 2H). m/z (EI): 257 (Mþ), 211 (100%).
2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic acid ethyl
1
ester (2c). Mp 91–928C. H NMR (400 MHz, DMSO-d6): d 1.21 (t, 3H,
J ¼ 7.2 Hz), 2.19 (m, 2H), 2.59 (m, 2H), 2.69 (m, 2H), 4.11 (q, 2H,
J ¼ 7.2 Hz), 7.16 (s, 2H). m/z (EI): 211 (Mþ), 165 (100%).
2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic acid
1
o-tolyl-amide (2d). Mp 153–1558C. H NMR (400 MHz, DMSO-d6): d 2.23
(s, 3H), 2.31 (m, 2H), 2.67 (t, 2H, J ¼ 7.2 Hz), 2.96 (t, 2H, J ¼ 7.2 Hz),
7.02 (t, 1H, J ¼ 7.2 Hz), 7.12–7.20 (m, 2H), 7.16 (s, 2H), 7.79 (d, 1H,
J ¼ 7.2 Hz), 7.91 (s, 1H). m/z (EI): 272 (Mþ), 165 (100%).
2-Amino-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic
1
acid ethyl ester (2e). Mp 109–1108C. H NMR (400 MHz, CDCl3): d 1.03

1356
W. Huang et al.
(d, 3H, J ¼ 6.4 Hz), 1.32–1.36 (m, 1H), 1.35 (t, 3H, J ¼ 7.2 Hz), 1.84 (m, 2H),
2.16 (m, 1H), 2.59 (m, 2H), 2.88 (m, 1H), 4.24 (q, 2H, J ¼ 7.2 Hz). m/z (EI):
239 (Mþ), 193 (100%), 151, 125.
2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid amide
1
(2f). Mp 187–1898C. H NMR (400 MHz, CDCl3): d 1.81 (m, 4H), 2.54
(m, 2H), 2.63 (m, 2H). m/z (EI): 196 (Mþ), 179 (100%), 151.
2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid phenyl-
amide (2g). Mp 138–1408C. 1H NMR (400 MHz, DMSO-d6): d 1.66
(m, 2H), 1.74 (m, 2H), 2.47 (m, 2H), 2.62 (m, 2H), 6.48 (s, 2H), 6.99
(t, 1H, J ¼ 7.6 Hz), 7.25 (t, 2H, J ¼ 7.6 Hz), 7.58 (d, 2H, J ¼ 7.6 Hz), 8.91
(s, 1H). m/z (EI): 272 (Mþ), 179 (100%), 151.
2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid o-tolyl-
amide (2h). Mp 118–1208C. 1H NMR (400 MHz, DMSO-d6): d 1.71
(m, 4H), 2.21 (s, 3H), 2.47 (m, 2H), 2.73 (m, 2H), 6.65 (s, 2H), 7.03 (t, 1H,
J ¼ 7.6 Hz), 7.12–7.19 (s, 2H), 7.62 (d, 1H, J ¼ 7.6 Hz), 8.41 (s, 1H). m/z
(EI): 286 (Mþ), 179 (100%), 151,107, 91, 57.
2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid p-tolyl-
amide (2i). Mp 131–1348C. 1H NMR (400 MHz, DMSO-d6): d 1.64
(m, 2H), 1.72 (m, 2H), 2.23 (s, 3H), 2.47 (m, 2H), 2.62 (m, 2H), 6.48
(s, 2H), 7.06 (d, 2H, J ¼ 8.0 Hz), 7.47 (d, 2H, J ¼ 8.0 Hz), 8.82 (s, 1H).
m/z (EI): 286 (Mþ), 179 (100%), 151,107, 91, 56.
2-Amino-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic
1
acid phenyl-amide (2j). Mp 163–1658C. H NMR (400 MHz, DMSO-d6): d
1.01 (d, 3H, J ¼ 6.8 Hz), 1.24–1.30 (m, 1H), 1.75–1.84 (m, 2H), 2.10
(m, 1H), 2.52–2.72 (m, 3H), 6.52 (s, 2H), 6.99 (t, 1H, J ¼ 7.2 Hz), 7.25
(t, 2H, J ¼ 7.2 Hz), 7.58 (d, 2H, J ¼ 7.2 Hz), 8.91 (s, 1H). m/z (EI): 286
(Mþ), 193, 151, 57 (100%).
2-Amino-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic
1
acid p-tolyl-amide (2k). Mp 128–1308C. H NMR (400 MHz, DMSO-d6):
d 1.01 (d, 3H, J ¼ 6.8 Hz), 1.22–1.29 (m, 1H), 1.75–1.82 (m, 2H), 2.10
(m, 1H), 2.51–2.62 (m, 3H), 7.06 (d, 2H, J ¼ 8.0 Hz), 7.47 (d, 2H,
J ¼ 8.0 Hz), 8.81 (s, 1H). m/z (EI): 300 (Mþ), 193, 151, 56 (100%). m/z
(high-resolution EI-MS): 300.1293 (C17H20N2OSþ) calc. 300.1296.
2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid (3-
chloro-4-fluoro-phenyl)-amide (2m). Mp 99–1008C. 1H NMR (400 MHz,
CDCl3): d 1.82–1.87 (m, 4H), 2.58 (m, 2H), 2.75 (m, 2H), 6.04 (s, 2H),
7.09 (t, 1H, J ¼ 8.8 Hz), 7.32 (m, 1H), 7.49 (s, 1H), 7.72 (m, 1H). m/z (EI):
324 (Mþ), 177 (100%), 166. m/z (high-resolution EI-MS): 324.0498
(C15H14ClFN2OSþ) calc. 324.0499.
2-Amino-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic
acid (3-chloro-4-fluoro-phenyl)-amide (2n). Mp 184–1878C. 1H NMR
(400MHz, CDCl3): d 1.06 (d, 3H, J ¼ 6.8 Hz), 1.46–1.51 (m, 1H), 1.92–1.98
(m, 2H), 2.22 (m, 1H), 2.61–2.84 (m, 3H), 7.09 (t, 1H, J ¼ 8.8 Hz), 7.32
(m, 1H), 7.54 (s, 1H), 7.72 (m, 1H). m/z (EI): 338 (Mþ), 194 (100%), 151.
m/z (high-resolution EI-MS): 338.0638 (C16H16ClFN2OSþ) calc. 338.0656.

Synthesis of 2-Amino-thiophene-3-Carboxylic Derivatives
1357
2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid (4-
1
trifluoro-methoxy-phenyl)-amide (2p). Mp 124–1278C. H NMR (400MHz,
CDCl3): d 1.84–1.87 (m, 4H), 2.58 (m, 2H), 2.76 (m, 2H), 6.02 (s, 2H), 7.17
(d, 2H, J ¼ 8.0 Hz), 7.55 (d, 2H, J ¼ 8.0 Hz). m/z (EI): 356 (Mþ), 177, 166
(100%). m/z (high-resolution EI-MS): 356.0801 (C16H15F3N2O2Sþ) calc.
356.0806.
2-Amino-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic
acid (4-trifluoro-methoxy-phenyl)-amide (2q). Mp 153–1578C. 1H NMR
(400 MHz, CDCl3): d 1.07 (d, 3H, J ¼ 6.8 Hz), 1.42–1.49 (m, 1H), 1.91–
1.96 (m, 2H), 2.29 (m, 1H), 2.61–2.87 (m, 3H), 6.02 (s, 2H), 7.17 (d, 2H,
J ¼ 8.0 Hz), 7.55 (d, 2H, J ¼ 8.0 Hz). m/z (EI): 370 (Mþ), 194 (100%), 151.
m/z (high-resolution EI-MS): 370.0951 (C17H17F3N2O2Sþ) calc. 370.0963.
Cyano-(4-methyl-cyclohexylidene)-acetic acid ethyl ester (1e). 1H NMR
(400 MHz, CDCl3): d 0.95 (d, 3 H, J ¼ 6.8 Hz), 1.21–1.29 (m, 2H), 1.35
(t, 3H, J ¼ 7.2 Hz), 1.73 (m, 1H), 1.90–2.05 (m, 2H), 2.15 (dt, 1H, J ¼ 4.8,
12.8 Hz), 2.33 (dt, 1H, J ¼ 4.8, 12.8 Hz), 3.03 (m, 1H), 3.85 (m, 1H), 4.26
(q, 2H, J ¼ 7.2 Hz). m/z (EI): 207 (Mþ), 179 (100%), 162, 135.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of
China (Grants 20472094, 20372069, 20102007, and 29725203), the Qi
Ming Xing Foundation of Shanghai Ministry of Science and Technology
(Grant 03QD14065), and the 863 Hi-Tech Program of China (Grants
2003AA235030, 2002AA233061).
REFERENCES
1. Ramanathan, J. D.; Namboothiri, D. G.; Shan, G. F.; Radhakrishnan, A. V.;
Mehta, H. J.; Padhya, A. C. J. Indian Chem. Soc. 1978, 55 (8), 822–825.
2. Gadad, A. K.; Hemant, K.; Shishoo, C. J. Indian J. Chem. Sec. B 1994, 33 (3),
298–301.
3. Patil, C. D.; Sadana, G. S. J. Indian Chem. Soc. 1991, 68 (2), 169–171.
4. Manhas, M. S.; Sharma, S. D.; Amin, S. G. J. Med. Chem. 1972, 15 (1), 106–107.
5. Blackburn, T. P.; Davies, D. T.; Forbes, I. T.; Hayward, C. J.; Johnson, C. N.;
Martin, R. T.; Piper, D. C.; Thomas, D. R.; Thompson, M.; Upton, N.;
Ward, R. W. Bioorg. Med. Chem. Lett. 1995, 5 (22), 2589–2592.
6. Nakanishi, M.; Tahara, T.; Araki, K.; Shiroki, M.; Tsumagari, T.; Takigawa, Y.
J. Med. Chem. 1973, 16 (3), 214–219.
7. Johnson, C. N.; Martin, R. T.; Morgan, H. K.A.; Thompson, M. Synth. Commun.
1997, 27 (3), 473–482.
8. Gewald, K.; Elfriede, S.; Horst, B. Chem. Ber. 1966, 99, 94–100.
9. Monique, P.; Cuong, L. D.; Guy, N.; Francoise, B. L.; Francois, H. Eur. J. Med.
Chem. Chim. Ther. 1980, 15 (5), 413–418.
10. Marion, S.; Bohm, R.; Pech, R. Pharmazie 1984, 39 (1), 19–21.