A green chemical approach: a straightforward one-pot synthesis of 2-aminothiophene derivatives via Gewald reaction in deep eutectic solvents

Article abstract of DOI:10.1007/s00706-016-1787-6

Abstract: The synergic effect of choline chloride/urea as a deep eutectic solvent was investigated in the synthesis of 2-aminothiophene derivatives via a three-component cyclocondensation of a ketone or an aldehyde with activated nitriles and elemental sulfur catalyzed by NaOH as cheap and highly accessible base. The advantages of this catalytic protocol are eco-friendly, easy to set up, reusability, and a simple separation and purification of products without using chromatography in high yields at short times. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-016-1787-6

Monatsh Chem
DOI 10.1007/s00706-016-1787-6
ORIGINAL PAPER
A green chemical approach: a straightforward one-pot synthesis
of 2-aminothiophene derivatives via Gewald reaction in deep
eutectic solvents
Ahmad Shaabani1 Seyyed Emad Hooshmand1 Hadi Afaridoun1
•
•
Received: 18 January 2016 / Accepted: 23 May 2016
Ó Springer-Verlag Wien 2016
Abstract The synergic effect of choline chloride/urea as a
deep eutectic solvent was investigated in the synthesis of
(ChCl), urea, and other hydrogen-bond donors such as
carboxylic acids, sugar, resorcinol, and glycerol [1–4].
DESs have similar characteristics to ionic liquids (ILs), but
they have some more advantages relative to ionic liquids.
For example, DESs are non-toxic, can be sourced from
renewable feed stocks, and have cheaper production pro-
cedure and lower cost of the raw materials [5, 6].
Heretofore, DESs have been used in various chemical
processing such as extraction [7], materials synthesis [8],
and organic transformations [9–15].
2-aminothiophene derivatives via
a three-component
cyclocondensation of a ketone or an aldehyde with acti-
vated nitriles and elemental sulfur catalyzed by NaOH as
cheap and highly accessible base. The advantages of this
catalytic protocol are eco-friendly, easy to set up,
reusability, and a simple separation and purification of
products without using chromatography in high yields at
short times.
Graphical abstract
Multicomponent reactions (MCRs), due to their pro-
ductivity, simple procedures, convergence, and facile
execution are one of the best tools in combinatorial
chemistry [16]. In this regard, the Gewald reaction has
been one of the most interesting MCRs, a reaction that
involves a one-pot cyclocondensation of ketones or alde-
hydes with activated nitrile derivatives and elemental
sulfur to obtain 2-aminothiophenes [17]. The applications
of Gewald three-component reaction have already been
rewarding for the pharmaceutical industry [18], for exam-
ple olanzepine (I) is an atypical antipsychotic drug used in
the treatment of schizophrenia [19] and tinoridine (II) is a
nonsteroidal basic anti-inflammatory drug with a potent
antiperoxidative properties (Fig. 1).
O
R
DES (1 cm3), 2-3 h
NC
R
+ S8
+
NaOH, 60 o
C
NH2
S
R: CN, COOEt
No chromatography or aqueous workup required
Keywords Gewald reaction Á
2-Aminothiophene derivatives Á Deep eutectic solvents Á
Multicomponent reactions Á Green chemistry
Introduction
Several protocols have been reported for the synthesis of
substituted 2-aminothiophenes [20–27]. To comply with
the principles of green chemistry, eco-friendly reaction
media such as water [28] and task-specific ionic liquids
[29] and, in addition, the alternative activation methodol-
ogy such as mechanochemical mixing [30, 31], ultrasonic
irradiation [32] and using solar thermal energy [33] have
been reported for the synthesis of substituted
2-aminothiophenes.
Deep eutectic solvents (DESs) have been recognized as
superior green, biorenewable, and biodegradable solvents.
The most common DESs are based on choline chloride
& Ahmad Shaabani
a-shaabani@sbu.ac.ir
1
As part of our continuing interest in applying green
medium in multicomponent reaction transformations
Faculty of Chemistry, Shahid Beheshti University, G. C.,
P. O. Box 19396-4716, Tehran, Iran
123

A. Shaabani et al.
The use of choline chloride/urea, besides reducing time,
causes the easy work-up without using any chromatogra-
phy or purification methods. Choline chloride/urea may
play a dual role in this reaction: as a solvent and as a co-
catalyst which in the latter case, it was activated carbonyl
and cyano groups via hydrogen bonding.
N
CO2Me
NH2
N
S
N
N
S
N
H
Mechanistically, the reaction may be rationalized as the
initial formation of conjugated electron-deficient hetero-
diene by a standard Knoevenogel condensation of the
malononitrile (1) and carbonyl compounds 2 to produce an
acrylonitrile [A], followed by a base catalyst which is then
thiolated at the c-methylene group with elemental sulfur 3
according to an SNX mechanism. The sulfurated compound
[B] undergoes ring closure via nucleophilic mercaptide
attack at the cyano carbon to provide intermediate [C].
I
II
Tinoridine ( )
Olanzepine ( )
Fig. 1 Examples of pharmaceutical agents containing 2-aminothio-
phene ring
[34–39], in this work we investigated the possibility of the
synthesis of substituted 2-aminothiophenes via Gewald
reaction in choline chloride-based deep eutectic solvents
(DESs).
Finally,
a
prototropic rearrangement affords the
2-aminothiophenes 4 (Scheme 1).
The choline chloride/urea can be recovered and reused
for second and third consecutive cycles without any sig-
nificant loss in catalytic activity in the synthesis of 4j (86,
78, and 65 %). The reaction mixture including choline
chloride/urea and product was dissolved in water and the
crude product was extracted with EtOAc. The choline
chloride/urea was recovered by evaporating the water at
60 °C under vacuum and was recycled for the next
reaction.
Results and discussion
To obtain the best conditions, the reaction of propi-
onaldehyde, malononitrile with elemental sulfur, as a
model reaction, was investigated in various DESs in the
presence of different organic and inorganic bases. As
indicated in Table 1, different hydrogen-bond donor such
as urea, citric acid, ethylene glycol, imidazole, resorcinol
and metal salts such as ZnCl2 and FeCl3 were examined in
the preparation of choline chloride-based DES systems.
The results show that the choline chloride/urea as a
prominent deep eutectic solvent is the best for the
requirements of excellent yield via a short reaction time.
Afterward, several organic and inorganic bases were
evaluated in this three-component reaction and the best
yields obtained in NaOH (0.1 cm3 of a 4 mol dm-3
aqueous solution) in choline chloride/urea at 60 °C.
To explore the versatility of the synergistic effect of DES
and base, different conditions were used. It is worth noting
that in the absence of bases, the desired product was
obtained in low yield (Table 1, entry 1). In addition, the
desired product 4b was obtained in 20 % yield using solid
NaOH (40 mol%) in DES (Table 1, entry 2). To verify the
efficiency of DES, the model reaction was carried out in the
absence of DES. The results show that the reaction yield is
considerably decreased (15 % yield; Table 1, entry 3).
Finally, the scope of this reaction was investigated using
different aldehydes or ketones, ethyl cyanoacetate or
malononitrile, and elemental sulfur. As indicated in
Table 2, various aldehydes and ketones such as linear and
cyclic were applied successfully in this reaction and
afforded the corresponding 2-aminothiophenes in good
yields. In addition, between activated nitriles derivatives,
malononitrile led to better yield relative to ethyl
cyanoacetate.
The results of our catalyst are compared with some recent
reports for the synthesis of 2-aminothiophenes with respect
to their yields, catalyst, solvent, and the times requiredfor the
reaction. As shown in Table 3, in the case of DES (choline
chloride:urea), the reaction yield is relatively increased at the
shorter reaction times using a cheapest base in a green sol-
vent and co-solvent. In addition, other methods often suffer
from some disadvantages, including expensive reagent or
catalyst, use of organic solvent, not easily recoverable, and
use of toxic metals. Moreover, we believe that the present
methodology offers several advantages such as straightfor-
ward and green procedure, environmentally friendly,
convenient and easy work-up aspects of the protocol over all
reported methodologies.
Conclusions
In summary, we have developed a straightforward and
environmentally friendly approach for the synthesis of
2-aminothiophenes via a three-component cascade Gewald
reaction in choline chloride/urea as a green solvent in the
presence of NaOH as an inexpensive base. The DES was
found to play a catalyst and reaction medium. The
advantages of this approach are eco-friendly, reusability,
and a simple separation and purification without column
chromatography with high yields in short reaction times.
123

Green chemical approach: a straightforward one-pot synthesis…
Table 1 The Gewald reaction [propionaldehyde (0.50 mmol), malononitrile (0.50 mmol), elemental sulfur (0.60 mmol) in DES were stirred for
2 h] in various DESs in the presence of different bases
O
CN
H
DES
Base, 60 oC
+
NC
CN
NH2
S8
S
4b
Entry
DESb
Base
Yield/%a
1
Choline chloride:urea (1:2)
Choline chloride:urea (1:2)
Without DESc
–
10
2
NaOH (40 mol%)
NaOH (40 mol%)
NaOH (0.05 cm3)d
NaOH (0.1 cm3)d
NaOH (0.1 cm3)e
NaOH (0.1 cm3)f
NaOH (0.1 cm3)
NaOH (0.1 cm3)
–
NaOH (0.1 cm3)
NaOH (0.1 cm3)
NaOH (0.1 cm3)
Et3N (40 mol%)
DABCO (40 mol%)
DIPEA (40 mol%)
DBU (40 mol%)e
DBU (40 mol%)
K2CO3 (40 mol%)
NaH (40 mol%)
20
3
15
4
Choline chloride:urea (1:2)
Choline chloride:urea (1:2)
Choline chloride:urea (1:2)
Choline chloride:urea (1:2)
Choline chloride:citric acid (1:1)
75
5
86
6
30
7
50
8
78
9
Choline chloride:ethylene glycol (1:2)
Choline chloride:imidazole (3:7)
Choline chloride:ZnCl2 (1:2)
Choline chloride:FeCl3 (1:3)
Choline chloride:urea:resorcinol (1:2:3)
Choline chloride:urea (1:2)
Choline chloride:urea (1:2)
Choline chloride:urea (1:2)
Choline chloride:urea (1:2)
Choline chloride:urea (1:2)
Choline chloride:urea (1:2)
Choline chloride:urea (1:2)
45
10
11
12
13
14
15
16
17
18
19
20
a
60
Trace
40
55
20
Trace
25
20
55
60
68
Isolated yield
b
c
d
e
f
ChCl: second component ratio in (mmol:mmol)
Using water as solvent
NaOH (4 mol dm-3 aqueous solution)
At room temperature
At 40 °C
To the best of our knowledge, this is the first report on the
synthesis of 2-aminothiophene derivation in DESs and
these new reaction conditions open an important alternative
to utilizing volatile organic solvents.
75.47 MHz. NMR spectra were obtained in DMSO-d6.
Elemental analyses were performed on an elementar
analysensysteme GmbH VarioEL CHNS mode. The
chemicals used were purchased from Merck and Fluka
Chemical Companies.
Experimental
Preparation of deep eutectic solvents (DESs)
Melting points were measured on an Electrothermal 9100
apparatus. IR spectra were recorded on a Shimadzu IR-470
spectrometer. 1H and 13C NMR spectra were recorded on a
BRUKER DRX-300 AVANCE spectrometer at 300.13 and
Deep eutectic solvents based on choline chloride were
prepared according to the literature [1–4]. Choline chlo-
ride and hydrogen-bond donors were mixed (as indicated
molar ratio in Table 1) and heated until a liquid appeared.
123

A. Shaabani et al.
O
R
Table 2 Diversity in the
synthesis of 2-aminothiophenes
in choline chloride:urea
cm3
DES
2-3 h
(1
),
60 o
NC
R
S8
+
+
C
NH2
NaOH,
S
R:
COOEt
CN,
1
2
3
4
Entry Carbonyl compound
Product
Yield /%a
M.p. /°C (Lit)
CN
O
1
4a
4b
80
86
107-110 (104-105 [21])
107-110 (105-106 [21])
H
NH2
CN
S
O
2
H
NH2
S
S
COOEt
O
3
4c
65
85
Yellow syrup
H
NH2
CN
O
4
4d
120-123 (120-121 [21])
H
NH2
S
CN
NH2
CN
O
5
4e
4f
73
82
68
88
114-115 (117-119 [21])
144-146 (145-146 [21])
90-93 (91 [25])
S
O
6
NH2
S
COOEt
NH2
O
7
4g
4h
S
CN
O
8
145-148 (146-147 [25])
NH2
S
COOEt
O
9
4i
4j
75
86
114-116 (115 [25])
123-125 (126 [25])
NH2
CN
S
O
10
NH2
S
O
CN
NH2
11
4k
84
107-110 (110 [25])
S
O
CN
12
4l
88
75
150-153
131-135
NH2
S
CN
NH2
O
13
4m
S
a Isolated yields
123

Green chemical approach: a straightforward one-pot synthesis…
Scheme 1
O
Cl
N
N
H
H N
R1
H
H
N
H
H
O
N
N
H
R2
O
N
S
N
H
N
H
S
S
S
S
S
N
R1
S
S
[B]
N
N
N
R2
N
R1
N
S
S
S
R1
R2
S
[A]
R2
H
S
R2
S
S
R1
S
3
B:
H
2O
S
S
S
S
S
S
N
N
HO
H
NH
S
R1
R2
H
N
R2
R1
O
H
-S7
S
N
R1
H
N
O
2
R2
[C]
H
O
H
N
H
Cl
N
NH2
N
N
R1
H
H
H
S
N
O
1
R2
4
N
Table 3 Comparison of the results for Gewald reaction using DES with reported method
Entry
Catalyst
Solvent
Time/h
T/°C
Yield/%
Ref.
1
2
3
4
5
6
7
L-Prolin
Nano ZnO
ZnO
DMF
S.F.
24
14
6
60
84
62
60
37
55
71
86
[20]
100
100
50
[21]
S.F.
[22]
Imidazole
KF-Alumina
EDDA
DMF
EtOH
BmimBF4
DES
12
4
[23]
Reflux
50
[25]
6
[26]
NaOH
2
60
This work
The obtained DESs were used without any further
purification.
solid product was separated by filtration and if necessary
the precipitate recrystallized from EtOH to afford the
corresponding pure product.
Typical procedure for the synthesis
of 2-aminothiophene derivatives
2-Amino-4,5,6,7-tetrahydro-6-propylbenzo[b]thiophene-3-
carbonitrile (4l, C12H16N2S)
Cream powder; m.p.: 150–153 °C; IR (KBr): vꢀ = 3429,
3332, 3253, 2924, 2851, 2220, 1644, 1570, 1450,
A mixture of 0.070 g 4-propylcyclohexanone (0.5 mmol),
0.030 g malononitrile (0.5 mmol), 0.019 g sulfur powder
(0.6 mmol), and 0.1 cm3 NaOH (4 mol dm-3 aqueous
solution) in 1 cm3 choline chloride/urea was stirred at
60 °C for 2–3 h. After completion of the reaction, indi-
cated by TLC monitoring, 5 cm3 water was added. The
869 cm-1 1H NMR (300 MHz, DMSO-d6): d = 0.84
;
(m, 3H), 1.22–1.28 (m, 7H), 1.42–1.52 (m, 4H), 3.09
(brs, 2H) ppm; 13C NMR (75 MHz, DMSO-d6): d = 13.8,
14.2, 14.4, 19.8, 24.3, 30.7, 32.5, 88.4, 115.1, 120.3, 131.2,
160.2 ppm.
123

A. Shaabani et al.
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(2016) Monatsh Chem 147:801
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Divers 15:41
17. Gewald K (1961) Angew Chem 73:114
2-Amino-5-butyl-4-methylthiophene-3-carbonitrile
(4m, C10H14N2S)
Dark powder; m.p.: 131–135 °C; IR (KBr): vꢀ = 3430,
3327, 3265, 2933, 2851, 2218, 1654, 1577, 1450,
1
869 cm-1; H NMR (300 MHz, DMSO-d6): d = 0.87 (m,
¨
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Xu X-Y, Zeng B-B (2010) Synlett 1351
3H), 1.22–1.25 (m, 4H), 1.30–1.45 (m, 5H), 3.11 (brs, 2H)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 12.1, 12.7, 14.8,
23.5, 24.1, 90.2, 115.7, 120.8, 132.0, 159.5 ppm.
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Acknowledgments We gratefully acknowledge financial support
from the National Science Foundation (INSF), Research Council of
Shahid Beheshti University and Catalyst Center of Excellence (CCE)
at Shahid Beheshti University.
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