Convenient synthesis of 2-aminothiophene derivatives by acceleration of gewald reaction under ultrasonic aqueous conditions

Article abstract of DOI:10.1080/00397910903219435

Under ultrasound irradiation and in the presence of H₂O/Et ₂NH, ethyl cyanoacetate or malononitrile can combine with-methylene carbonyl compounds and elemental sulfur to efficiently yield 2-aminothiophene derivatives within a few minutes. Products are easily obtained by simple filtration because of their spontaneous precipitation in the reaction mixtures. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903219435

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Convenient Synthesis of 2-
Aminothiophene Derivatives by
Acceleration of Gewald Reaction Under
Ultrasonic Aqueous Conditions
Mohammad M. Mojtahedi a , M. Saeed Abaee a , Peyman Mahmoodi b
& Mehdi Adib b
a Chemistry and Chemical Engineering Research Center of Iran,
Tehran, Iran
b School of Chemistry, University of Tehran, Tehran, Iran
Version of record first published: 17 Jun 2010.
To cite this article: Mohammad M. Mojtahedi , M. Saeed Abaee , Peyman Mahmoodi & Mehdi Adib
(2010): Convenient Synthesis of 2-Aminothiophene Derivatives by Acceleration of Gewald Reaction
Under Ultrasonic Aqueous Conditions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:14, 2067-2074
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Synthetic Communications1, 40: 2067–2074, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903219435
CONVENIENT SYNTHESIS OF 2-AMINOTHIOPHENE
DERIVATIVES BY ACCELERATION OF GEWALD
REACTION UNDER ULTRASONIC AQUEOUS
CONDITIONS
Mohammad M. Mojtahedi,1 M. Saeed Abaee,1
Peyman Mahmoodi,2 and Mehdi Adib2
1Chemistry and Chemical Engineering Research Center of Iran, Tehran, Iran
2School of Chemistry, University of Tehran, Tehran, Iran
Under ultrasound irradiation and in the presence of H2O/Et2NH, ethyl cyanoacetate or
malononitrile can combine with a-methylene carbonyl compounds and elemental sulfur to
efficiently yield 2-aminothiophene derivatives within a few minutes. Products are easily
obtained by simple filtration because of their spontaneous precipitation in the reaction
mixtures.
Keywords: 2-Aminothiophenes; aqueous conditions; Gewald reaction; ultrasound irradiation
In the past decade, several books,[1] reviews,[2] and papers[3] have been published that
emphasize the extensive applications of ultrasonic irradiation in various types of
organic transformations. Consequently, many protocols have been developed to
carry out chemical reactions in shorter time periods and especially under more envir-
onmentally friendly conditions.[4] In another green chemistry front, multicomponent
reactions (MCRs)[5] have increasingly gained popularity in synthetic organic chem-
istry[6] in recent years because they offer one-pot combinations of more than two
reactants in one step, allowing direct access to complex target molecules. In this con-
text, the one-pot cyclocondensation of ketones or aldehydes and b-substituted acet-
onitrile derivatives with elemental sulfur, known as the Gewald reaction,[7] has been
one of the most well-studied MCRs in recent years. The reaction affords formation
of 2-aminothiophenes with diverse pharmaceutical,[8] agrochemical,[9] and dye[10]
properties. In addition, there are several natural products[11] and biologically active
compounds[12] in which the 2-aminothiophene moiety serves as the basic structural
framework. To extend the scope of the reaction, many alterations have been made
to the original Gewald’s base-catalyzed, two-component combination of a-mercapto
ketones with cyanoacetate[13] by varying the components[14] and the conditions.[15]
The usual long reaction time periods required in most of the published procedures
Received April 18, 2009.
Address correspondence to Mohammad M. Mojtahedi, Chemistry and Chemical Engineering
Research Center of Iran, P. O. Box 14335-186, Tehran, Iran. E-mail: abaee@ccerci.ac.ir
2067

2068
M. M. MOJTAHEDI ET AL.
Scheme 1. Ultrasound-mediated Gewald reactions in water.
are dramatically decreased by the use of microwave irradiation in combination with
the use of additional reagents and catalysts.[16] In the present work, ultrasound
irradiation is employed to conduct various Gewald reactions under inexpensive
and environmentally friendly H2O=Et2NH conditions (Scheme 1). The reaction
times have been considerably decreased to a few minutes and, because of the high
polarity of the medium, products precipitate spontaneously, which allows their
solvent-free separation from the reaction mixtures.
First, an equimolar mixture of 1-butanal 1a, ethyl cyanoacetate 2a, and sulfur
was sonicated under various sets of conditions. The best results were obtained in the
presence of H2O=Et2NH, leading to sole formation of ethyl 2-amino-5-ethylthio-
phene-3-carboxylate 3aa within 5 min (Table 1, entry 1). The solid product precipi-
tated by itself and was easily separated by simple filtration. A possible simultaneous
thermal activation was excluded by conducting a temperature-controlled experiment.
As a result, when a water bath was used to maintain the reaction temperature at
25 ꢀ 1 ꢁC, a similar yield was obtained for 3aa after the same time period. Alterna-
tively, in the absence of irradiation, the same mixture gave only low quantities of 3aa
after several hours, illustrating the crucial role of the sonication in the reaction.
These observations suggest that the ultrasonic irradiation can significantly assist
the reaction, presumably by providing the required energy of the transition state,
as previously proposed by others.[17]
Reaction of 3-methylbutanal 1b with 2a proceeded equally well, leading to
formation of 3ba after 5 min of sonication (entry 2). Under the same conditions,
cyclic ketones also gave their respective products in good yields (entries 3–6). The
generality of the procedure was further shown by subjecting malononitrile to
reaction with cyclic ketones, giving 3db, 3eb, and 3fb in excellent yields (entries 7–9).
Based on these observations, a mechanistic pathway as depicted in Scheme 2
can be proposed in which an a-b-unsaturated nitrile intermediate is formed via a
Knoevenagel condensation.[8a,18] This intermediate further adds to S8 to form the
thiophene structure after a ring-closure process, followed by an aromatization
rearrangement.
In summary, we have furnished a rapid and efficient method for the prep-
aration of substituted 2-aminothiophenes via condensation of carbonyl compounds
with elemental sulfur and ethyl cyanoacetate or malononitrile under ultrasonic
irradiation. The H2O=Et2NH medium is inexpensive, no extra additive or catalyst
is required, and the conditions are environmentally safe and green. We can reach

ULTRASOUND-ACCELERATED GEWALD REACTIONS
2069
Table 1. Ultrasound-promoted Gewald reactions
Entry
1
Substrate
Product
Time (Min.)
Yield (%)a
1a þ 2a
5
91
2
1b þ 2a
5
89
3
4
5
6
7
8
1c þ 2a
1d þ 2a
1e þ 2a
1 g þ 2a
1d þ 2b
1e þ 2b
5
5
7
3
5
8
96
97
88
87
96
90
9
1f þ 2b
8
87
aIsolated yields.
a better conclusion by comparing the performance of the present work with some
other reports available in the literature as illustrated in Table 2.
EXPERIMENTAL
Reactions were monitored by thin-layer chromatography (TLC) and gas chro-
matography (GC). Fourier transform–infrared (FT-IR) spectra were recorded using

2070
M. M. MOJTAHEDI ET AL.
Scheme 2. The proposed mechanism.
KBr disks on a Bruker Vector-22 IR spectrometer, and absorptions are reported as
wave numbers (cmꢂ1). NMR spectra were obtained on a FT-NMR Bruker DRX-300
Avance spectrometer at 300.13 and 75.47 MHz as CDCl3 solutions, and the chemical
shifts are expressed as d units with Me4Si as the internal standard. Mass spectra were
obtained on a Finnigan Mat 8430 apparatus at ionization potential of 70 eV.
Elemental analysis was performed for compound 3ba using a Thermo Finnigan
Flash EA 1112 instrument. Aldehydes were purified using standard procedures prior
to use. All other chemicals and reagents were purchased from commercial sources
and were used without further purification. Sonication was performed using a
Sartorius Ultrasonic homogenizer Labsonic P 230-V=50-Hz instrument with a
frequency of 24 KHz and nominal power of 460 W=cm2. In all reactions, the tip of
the sonotrode was located in the same position just under the liquid surface in order
to obtain optimal sonication and reproducible results.
Typical Procedure for the Synthesis of 3aa
A mixture of 1a (360 mg, 5 mmol), 2a (565 mg, 5 mmol), and sulfur (160 mg,
5 mmol) in H2O (1 mL) and Et2NH (0.3 mL) was sonicated in a 10-mL test tube
for an appropriate length of time (as indicated in Table 1) until TLC showed com-
plete disappearance of the starting materials. In temperature-controlled experiments,
reactions were performed in a water bath at 25 ꢀ 1 ꢁC. The product precipitated
upon completion of the reaction. The pure product was obtained by recrystallization
of the precipitates using an EtOAc=hexane mixture. Products were identified based
on their melting points and spectral characteristics.
Table 2. Ultrasound-mediated Gewald reaction in comparison with some other methods
Energy type
Solvent requirement
Reference
Ultrasonic
Thermal
Thermal
H2O
MeOH, Et2O
Present work
Gutschow et al.[14b]
¨
EDDA,a Et2O
Hu et al.[15a]
Microwave
Microwave
Electrochemical
Toluene, MeOH, CH2Cl2, DMF
EtOH, CH2Cl2
MeCN
Hoener et al.[16b]
Sridhar et al.[16c]
Feroci et al.[15d]
aEthylenediammonium diacetate.

ULTRASOUND-ACCELERATED GEWALD REACTIONS
2071
Data
Ethyl
2-Amino-5-ethylthiophene-3-carboxylate
(3aa). Mp
73 ꢁC
(reported mp. 73 ꢁC)[16c]; H NMR (CDCl3) d 6.64 (s, 1H), 5.84 (s, 2H), 4.25 (q,
2H, J ¼ 7.1 Hz), 2.60 (q, 2H, J ¼ 7.5 Hz), 1.33 (t, 3H, J ¼ 7.1 Hz), 1.22 (t, 3H,
J ¼ 7.5 Hz); 13C NMR (CDCl3) d 165.5, 161.2, 128.5, 120.6, 106.2, 59.6, 23.0, 15.4,
14.5; IR (KBr) 3407, 3305, 1660, 1254 cmꢂ1; MS m=z (%) 200 (Mþ, 25), 199 (100),
184 (80), 138 (86).
1
Ethyl 2-Amino-5-isopropylthiophene-3-carboxylate (3ba). Mp 68 ꢁC;1H
NMR (CDCl3) d 6.63 (s, 1H), 5.80 (s, 2H), 4.25 (q, 2H, J ¼ 7.1 Hz), 2.95–2.86 (m,
1H), 1.34 (t, 3H, J ¼ 7.1 Hz), 1.24 (d, 6H, J ¼ 6.8 Hz); 13C NMR (CDCl3) d 165.5,
161.0, 134.2, 119.1, 106.0, 59.6, 29.5, 24.1, 14.6; IR (KBr) 3441, 3334, 1677,
1590 cmꢂ1; MS m=z (%) 213 (Mþ, 35), 198 (100), 152 (40). Calcd. for C10H15NO2S:
C, 56.31; H, 7.09. Found: C, 56.44; H, 7.12.
Ethyl 2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate
(3ca). Mp 90 ꢁC (reported mp. 89–90 ꢁC);15c 1H NMR (CDCl3) d 5.83 (s, 2H),
4.25 (q, 2H, J ¼ 7.1 Hz), 2.85–2.80 (m, 2H), 2.74–2.69 (m, 2H), 2.36–2.26 (m, 2H),
1.33 (t, 3H, J ¼ 7.1 Hz); 13C NMR (CDCl3) d 166.2, 165.8, 142.7, 121.4, 103.0,
59.4, 30.8, 28.9, 27.2, 14.4; IR (KBr) 3414, 3294, 1624, 1287 cmꢂ1; MS m=z (%)
211 (Mþ, 100), 165 (70), 137 (15).
Ethyl
2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate
(3da). Mp 113 ꢁC (reported mp. 115 ꢁC)[15c]; H NMR (CDCl3) d 6.01 (s, 2H),
4.25 (q, 2H, J ¼ 7.2 Hz), 2.71–2.69 (m, 2H), 2.48–2.46 (m, 2H), 1.75–1.73 (m, 4H),
1.33 (t, 3H, J ¼ 7.2 Hz); 13C NMR (CDCl3) d 166.6, 161.9, 132.4, 117.5, 105.5,
59.4, 27.0, 24.5, 23.3, 22.9, 14.5; IR (KBr) 3405, 3299, 1647, 1274 cmꢂ1; MS m=z
(%) 225 (Mþ, 100), 223 (90), 179 (51), 151 (24).
1
Ethyl 2-Amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbox-
1
ylate (3ea). Mp 87 ꢁC (reported mp 89 ꢁC)[16c]; H NMR (CDCl3) d 5.74 (s, 2H),
4.28 (q, 2H, J ¼ 7.2 Hz), 3.00–2.96 (m, 2H), 2.60–2.56 (m, 2H), 1.82–1.78 (m, 2H),
1.68–1.62 (m, 4H), 1.35 (t, 3H, J ¼ 7.2 Hz); 13C NMR (CDCl3) d 166.0, 159.7,
137.9, 121.4, 107.6, 59.6, 32.2, 28.7, 28.6, 27.8, 27.0, 14.5; IR (KBr) 3398, 3301,
1651, 1277 cmꢂ1; MS m=z (%) 239 (Mþ, 9), 193 (8), 83 (100).
Ethyl 2-Amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-car-
boxylate (3ga).[8c] Mp 99 ꢁC; 1H NMR (CDCl3) d 6.18 (s, 2H), 4.22 (q, 2H,
J ¼ 7 Hz), 3.37 (s, 2H), 2.82 (m, 2H), 2.67 (m, 2H), 2.43 (s, 3H), 1.30 (t, 3H, J ¼ 7 Hz);
13C NMR (CDCl3) d 165.9, 162.4, 130.5, 113.9, 104.9, 59.5, 53.1, 52.3, 45.2, 27.1,
14.4; IR (KBr) 3394, 3262, 1667 cmꢂ1
.
2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (3db). Mp
1
145 ꢁC (reported mp. 146–147 ꢁC)[15c]; H NMR (CDCl3) d 4.71 (s, 2H), 2.48–2.46
(m, 4H), 1.79 (m, 4H); 13C NMR (CDCl3) d 160.1, 132.3, 120.6, 115.6, 88.5, 24.5,
24.1, 23.4, 22.1; IR (KBr) 3445, 3328, 2196, 1521 cmꢂ1; MS m=z (%) 178 (Mþ,
85), 150(100).
2-Amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbonitrile
1
(3eb). Mp 125 ꢁC (reported mp. 126 ꢁC)[16c]; H NMR (CDCl3) d 4.26 (s, 2H),

2072
M. M. MOJTAHEDI ET AL.
2.65–2.57 (m, 4H), 1.83–1.79 (m, 2H), 1.67–1.63(m, 4H); 13C NMR (CDCl3) d 157.7,
136.9, 123.9, 115.9, 92.0, 31.9, 29.4, 29.2, 28.1, 27.2; IR (KBr) 3443, 3310, 2203 cmꢂ1
MS m=z (%) 192 (Mþ, 100), 164 (35), 138 (25).
;
2-Amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophene-3-carbonitrile
(3fb). Mp 107 ꢁC (reported mp. 110 ꢁC)[16c] 1H NMR (CDCl3) d 4.69 (s, 2H),
;
2.64–2.58 (m, 4H), 1.64–1.59 (m, 4H), 1.41–1.26 (m, 4H); 13C NMR (CDCl3) d
159.2, 135.1, 122.7, 115.8, 90.0, 31.5, 29.8, 26.1, 26.0, 25.8, 25.5; IR (KBr) 3428,
3334, 2194, 1619 cmꢂ1; MS m=z (%) 206 (Mþ, 100), 178 (85), 163 (25).
ACKNOWLEDGMENT
Partial financial support by the Ministry of Science, Research, and Technology
of Iran is greatly appreciated.
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