Microwave accelerated Gewald reaction: synthesis of 2-aminothiophenes

Article abstract of DOI:10.1016/j.tetlet.2007.03.052

Microwave-promoted synthesis of 2-aminothiophenes by multicomponent reactions of a ketone with an active nitrile and elemental sulfur under KF-alumina catalysis is described.

Full text of DOI:10.1016/j.tetlet.2007.03.052

Tetrahedron Letters 48 (2007) 3171–3172
Microwave accelerated Gewald reaction: synthesis of
2-aminothiophenesI
Madabhushi Sridhar,* Rayankula Mallikarjuna Rao, Nanduri H. K. Baba and
Ravindra M. Kumbhare
Fluoroorganic Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 15 February 2007; revised 2 March 2007; accepted 8 March 2007
Available online 12 March 2007
Abstract—Microwave-promoted synthesis of 2-aminothiophenes by multicomponent reactions of a ketone with an active nitrile and
elemental sulfur under KF-alumina catalysis is described.
ꢀ 2007 Elsevier Ltd. All rights reserved.
R1
R2
X
Substituted 2-aminothiophenes are important interme-
diates in the synthesis of a variety of agrochemicals, dyes
and pharmacologically active compounds.1 The most
convergent and well-established classical approach for
the preparation of 2-aminothiophenes is Gewald’s meth-
od,2 which involves multicomponent condensation of a
ketone with an activated nitrile and elemental sulfur in
the presence of morpholine as a catalyst.
KF-Alumina
microwave
3.5-8 min.
NH2
S
R1
R2
O
X
55-92%
S
+
+
CN
R1
R2
X
X= CN or COOEt
KF-Alumina
ethanol, reflux
3.5-7h
NH2
S
Heterogeneous organic reactions using reagents immo-
bilized on porous solid supports have often been proved
to be advantageous over conventional solution phase
reactions because of good dispersion of active reagent
sites, better selectivity and easier work-up. One such re-
agent is KF immobilized on alumina (or KF-alumina).3
The application of KF-alumina to a wide range of or-
ganic reactions has provided more convenient and effi-
cient methods in organic syntheses.4 Its benefits arise
from the strongly basic nature of KF/Al2O3, which
has allowed it to replace organic bases in a number of
reactions.5
48-91%
Scheme 1.
In the present study, a variety of ketones were reacted
with ethyl cyanoacetate (or malononitrile) and elemental
sulfur in the presence of KF-alumina as catalyst. This
reaction was studied both under microwave irradiation
as well as conventional heating conditions by refluxing
in ethanol (Table 1). In both the cases, the reaction pro-
ceeded well producing 2-aminothiophene derivatives in
moderate to good yields.
The high efficacy and ease of product isolation
prompted us to investigate the Gewald reaction but
replacing the organic base with KF-alumina and using
microwave irradiation for heating (Scheme 1).
The general procedure is as follows: cyclohexanone
(0.98 g, 1.0 mmol), ethyl cyanoacetate (1.13 g, 1.0
mmol), sulfur (0.32 g, 1.0 mmol), KF-alumina (1:1
w/w, 0.2 g) and 1.5 ml of dry ethanol were mixed and
placed in a 10 ml pressure tube. The mixture was sub-
jected to microwave irradiation (CEM Discover,
100 W, 250 psi, 100 ꢁC) for 3.5 min and then diluted
with dichloromethane (5 ml) and filtered. The solid
was rinsed/triturated with dichloromethane (2 · 2.5 ml)
Keywords: 2-Aminothiophene; KF-alumina catalysis; Microwave-
assisted synthesis.
q IICT Communication No. 070216.
*
Corresponding author. Tel.: +91 40 2719 3630; fax: +91 40 2716
0387; e-mail: smiict@gmail.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.052

3172
M. Sridhar et al. / Tetrahedron Letters 48 (2007) 3171–3172
Table 1.
Entry
Ketone
X
Reaction conditions
Melting point (ꢁC)
R1
R2
Microwavea
Conventionala
Yield (%) (Reaction time, min)
Yield (%) (Reaction time, h)
1
2
COOEt
CN
56 (6.0)
57 (8.0)
52 (7.0)
55 (5.5)
91b
151
O
3
4
COOEt
CN
91 (6.0)
92 (6.0)
89 (3.5)
91 (3.5)
115b
147b
O
O
5
6
COOEt
CN
85 (6.0)
86 (6.0)
75 (3.5)
81 (3.5)
89
126
7
8
COOEt
CN
58 (7.0)
62 (5.5)
55 (4.0)
60 (4.0)
81
110
O
9
10
11
12
13
14
15
16
CH3
CH3
CH3
CH3
Ph
Ph
H
H
CH3
CH3
COOEt
COOEt
H
H
CH3
Et
CH3
CH3
COOEt
CN
COOEt
CN
57 (3.5)
61 (3.5)
58 (3.5)
58 (3.5)
61 (7.5)
66 (7.5)
62 (6.0)
55 (6.0)
53 (4.0)
56 (4.0)
50 (4.0)
55 (4.0)
55 (4.0)
61 (4.0)
55 (4.0)
48 (4.0)
92b
142b
108b
151
98b
142
46b
73b
COOEt
COOEt
a Isolated yields. All the products gave satisfactory 1H NMR, mass and IR spectra.
b These values were identical with the literature report.2
and the combined extracts were concentrated and
purified by normal chromatography to afford the corre-
Acknowledgement
sponding 2-aminothiophene as a pale yellow solid
(2.04 g, 91%, mp 115 ꢁC). The product gave satisfactory
IR, 1H NMR and mass spectral data. In the case of con-
ventional heating, the reactants, as above in 15 ml etha-
nol, were heated at reflux for 6 h. When the reaction was
complete (TLC), ethanol was removed by evaporation
and the reaction mixture was diluted with 10 ml of
dichloromethane and filtered. After evaporation of the
solvent, the mixture was purified by normal column
chromatography to give the desired product in 89%
yield (mp 115 ꢁC). 1H NMR (CDCl3, 300 MHz): 1.4
(t, J = 7.5, Hz, 3H), 1.8 (m, 4H), 2.5 (m, 2H), 2.7 (m,
2H), 4.25 (q, J = 7.0, Hz, 2H), 5.95 (br s, 1H); exact
mass C11H15NO2SNa (+Na): 248.0730 (calcd:
248.0721).
We are grateful to Dr. J. S. Yadav, Director, IICT, for
his constant encouragement and support.
References and notes
1. Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J.
Heterocycl. Chem. 1999, 36, 333–345.
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94–100.
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Hooper, J. W.; Laishes, B. A. Can. J. Chem. 1970, 48, 3064–
3075; Villemin, D.; Ricard, M. Tetrahedron Lett. 1984, 25,
1059–1060.
4. Blass, B. E. Tetrahedron 2002, 58, 9301–9320.
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C. L.; Portlock, D. E. Tetrahedron Lett. 2001, 42, 1611–
1613; Rissafi, B.; El Louzi, A.; Loupy, A.; Petit, A.;
In conclusion, the present study is the first application of
KF-alumina as a base for the preparation of 2-aminothi-
ophenes by microwave accelerated multi-component
condensation. This method offers an efficient and conve-
nient modification to the Gewald reaction as it could be
carried out with very short reaction times under micro-
wave irradiation. Alternatively, the present reaction also
proceeds well under conventional heating by refluxing in
ethanol.
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