Efficient three-component Gewald reactions under Et3N/H 2O conditions

Article abstract of DOI:10.1080/17415993.2013.860141

In a medium consisting of triethylamine and water, methylene ketones undergo room temperature Gewald reactions with elemental sulfur and ethyl cyanoacetate (or malononitrile) to yield 2 aminothiophene derivatives efficiently within short time periods. Because of the high polarity of the medium, products precipitate in the reaction mixtures spontaneously. This makes isolation of the products easy by simple filtration and avoids cumbersome chromatographic separations. Mechanistic studies suggest that the reactions proceed via a Knoevenagel condensation pathway(equation presented). 2013

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Efficient three-component Gewald
reactions under Et N/H O conditions
3
2
a
a
M. Saeed Abaee & Somayeh Cheraghi
a
Department of Organic Chemistry and Natural Products,
Chemistry and Chemical Engineering Research Center of Iran,
Pajouhesh Blvd, 17th Km Tehran-Karaj Highway, P.O. Box
14335-186, Tehran, Iran
Published online: 15 Nov 2013.
To cite this article: M. Saeed Abaee & Somayeh Cheraghi (2014) Efficient three-component
Gewald reactions under Et N/H O conditions, Journal of Sulfur Chemistry, 35:3, 261-269, DOI:
3
2
10.1080/17415993.2013.860141
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Journal of Sulfur Chemistry, 2014
Vol. 35, No. 3, 261–269, http://dx.doi.org/10.1080/17415993.2013.860141
Efficient three-component Gewald reactions under Et N/H O
3
2
conditions
∗
M. Saeed Abaee and Somayeh Cheraghi
Department of Organic Chemistry and Natural Products, Chemistry and Chemical Engineering Research
Center of Iran, Pajouhesh Blvd, 17th Km Tehran-Karaj Highway, P.O. Box 14335-186, Tehran, Iran
(Received 23 July 2013; accepted 24 October 2013)
In a medium consisting of triethylamine and water, α-methylene ketones undergo room temperature Gewald
reactions with elemental sulfur and ethyl cyanoacetate (or malononitrile) to yield 2-aminothiophene deriva-
tives efficiently within short time periods. Because of the high polarity of the medium, products precipitate
in the reaction mixtures spontaneously. This makes isolation of the products easy by simple filtration and
avoids cumbersome chromatographic separations. Mechanistic studies suggest that the reactions proceed
via a Knoevenagel condensation pathway.
Keywords: Gewald reaction; aqueous conditions; three-component reaction; thiophene; Knoevenagel
condensation
1
.
Introduction
Althoughwateristhemostabundantchemicalonourplanet, itsusehasbeenneglectedasamedium
or a solvent in organic chemistry for many decades. This ignorance has been the result of the belief
that water destroys many organic reagents and chemicals and is only safe to be used in workup
procedures. This opinion was widespread until Grieco [1,2] and Breslow [3,4] demonstrated
that aqueous media can cause Diels-Alder cycloadditions to proceed with extraordinary rate
and selectivity enhancement. Since then, an overwhelming number of papers,[5–7] reviews,[8,9]
and books [10,11] have been released discussing various synthetic reactions in water and more
publications are expected to come.
Another green chemistry front that has witnessed remarkable development and found numerous
applications in synthetic organic chemistry in recent decades has been multi-component reactions
(
MCRs).[12,13] The MCRs allow combination of more than two reactants in one-pot operations
and allow direct access to complex molecules and chemical libraries.[14,15] In this regard, the
∗
Corresponding author. Email: abaee@ccerci.ac.ir
©
2013 Taylor & Francis

2
62 M.S. Abaee and S. Cheraghi
Gewald reaction has been one of the most interesting MCRs; a reaction that involves a one-
pot cyclocondensation of ketones or aldehydes with β-substituted derivatives of acetonitrile and
elemental sulfur.[16,17] The products of the reaction are derivatives of 2-aminothiophene that
have diverse pharmaceutical,[18,19] agrochemical,[20] and dye [21] properties. Moreover, many
synthetic or natural products [22] and biologically active molecules [23] are known to have the
2
-aminothiophene backbone in their structures.
The original Gewald reaction is a two-component process that combines α-mercapto ketones
with cyanoacetate under basic conditions.[24] The scope of the reaction is extended drastically
by adopting multi-component modes [25–27] and altering the conditions.[28–31] Despite these
developments, even some of newer reports still involve the use of relatively harsh conditions or
require organic solvents during the reaction or workup stage. In the framework of our studies on
the chemistry of heterocyclic systems [32–34] and in continuation of our previous investigations
on the development of synthetic methods in aqueous media,[35,36] we would like to herein report
an efficient protocol for Gewald reactions of several ketones with malononitrile derivatives and
sulfur using triethylamine (Et3N) under aqueous conditions (Scheme 1). As far as we know, this
is one of the most inexpensive and environmentally friendly procedures offered so far for the
Gewald reaction. The reaction times are shorter and due to high polarity of the medium, products
precipitate spontaneously so that expensive and time-consuming chromatographic separations are
avoided.
Scheme 1. Three-component Gewald reactions under H2O/Et3N conditions.
2
. Results and discussion
We first optimized the conditions for the reaction of 1a (1.0 mmol) with 2b (1.0 mmol) and sulfur
1.0 mmol) to produce 3ab (Table 1). Entry 1 shows that the best results are obtained when
(
both water (0.3 mL) and Et3N (1.0 mmol) are present in the mixture. In the absence of water, a
dramatic rate decrease is observed illustrating the crucial role of the aqueous medium (Entry 2).
The case gets even worst when Et3N is omitted from the reaction mixture (Entry 3). Variation
of the amounts of water (Entries 4 and 5) and the amine (Entries 6 and 7) lowers the yield of
3
ab suggesting that the optimum conditions are observed when 0.3 mL and 1.0 mmol of these
two components of the medium are used, respectively. Reactions conducted in the presence of
other amines (Entries 8–11) show that Et3N is the most effective amine under our experimental
conditions. The superiority of Et3N coincides with both the basicity and the solubility of this amine
in comparison with those of other amines in water.[37] Et3N has a relatively higher basicity and
remainspartiallyundissolvedinthemixtureundertheoptimizedconditionsandisalwaysavailable
for more effective deprotonation of the starting materials. Therefore, Et3N leads to the highest

Journal of Sulfur Chemistry 263
Table 1. Optimization of the conditions for aqueous-mediated
Gewald reactions.
Entry
H2O (mL)
Amine (mmol)
Yield (%)a,b
1
2
3
4
5
6
7
8
9
0.3
0.0
0.3
0.1
0.5
0.3
0.3
0.3
0.3
0.3
0.3
Et3N (1.0)
Et3N (1.0)
Et3N (0.0)
Et3N (1.0)
Et3N (1.0)
Et3N (0.7)
Et3N (3.0)
DABCO (1.0)
Morpholine (1.0)
Et2NH (1.0)
HexylNH2 (1.0)
95
30
–
78
77
47
80
83
75
47
9
10
1
1
a
Reaction times, 7 h.
Isolated yield.
b
conversion of the reactants to 3ab. In addition, when the amine of choice is Et3N, spontaneous
precipitation of the products is observed.
We next applied the optimum conditions to the reactions of various ketones with malononitrile
derivatives and sulfur (Table 2). Cyclohexanone (Entries 1 and 2) and cyclopentanone (Entries 3
and 4) showed similar reactivities when subjected to the optimized conditions. As a result, high
yields of the respective products were obtained within 6–7 h. Heavier cycloalkanones gave slightly
lower yields of their products (Entries 5–7), perhaps due to their lower reactivities associated with
their higher molecular weights. Due to our interests in the chemistry of thiopyran-4-one [33,35]
and its other heterocyclic analogues,[38,39] we then applied the conditions to 1e (Entries 8 and 9),
1
f (Entries 10 and 11), and 1g (Entry 12) ketones. These ketones, especially 1g, underwent the
reactions more rapidly and gave high yields of their respective products in shorter time periods. To
further demonstrate the generality of the method, we finally applied the conditions to an acyclic
ketone (Entry 13) and an aliphatic aldehyde (Entry 14), where again high amounts of products
3
hb and 3ib were obtained. In each case, formation of a single product was observed which
precipitated from the reaction mixture and was separated by a simple filtration.
The mechanistic rationale for the efficiency of aqueous-mediated reactions is due to either
hydrophobic interactions of the reactants in water [40] or to the hydrogen-bonded [41] activation
of organic functional groups by H2O molecules. Consequently, we then decided to study the
mechanism of this water-mediated Gewald reaction. We designed several parallel experiments
for the reaction of 1e with 2b and sulfur as summarized in Table 3. For meaningful conclusions,
workup procedures were performed (after 2.5 h) before reactants had completely consumed. In
the presence of optimum amounts of water and Et3N only 45% of 3eb was obtained (Entry 1).
As expected, omission of water considerably decreased the yield (Entry 2). In the presence of
solutions of NaCl (Entry 3) or LiCl (Entry 4), an ascending pattern in the yields was observed.
This increase in the rate that is more obvious at higher concentrations of the two salts (Entries 5
and 6), is consistent with the “salt-out” [42] effect. In contrast, rates decreased when the reaction
was conducted in the presence of guanidinium chloride (GnCl) (Entries 7 and 8) or LiClO4
(Entries 9 and 10) solutions. These results suggest that the hydrogen-bonded association of the
reactants with water does not have a major role in the catalysis of the reaction. On the other
hand, these results can be rationalized by proposing an effective hydrophobic interaction of the
starting organic molecules with water to force the reactants toward a Gewald reaction, as proposed
by others to explain similar observations.[43,44] As a result of these observations, it can also be
understood why a less soluble amine like Et3N would behave better under the conditions governed
by hydrophobic forces.

2
64 M.S. Abaee and S. Cheraghi
Table 2. Gewald reactions of various carbonyl compounds under the optimized conditions.
Entry
Reactants
Product
Time (h)
Yield (%)a
1
1a + 2a
6
89
2
3
4
1a + 2b
1b + 2a
1b + 2b
7
6
7
95
90
95
5
6
1c + 2a
1c + 2b
7
7
80
75
7
8
9
1d + 2a
1e + 2a
1e + 2b
1f + 2a
7
4
4
5
76
98
97
1
0
77
(
Continued)

Journal of Sulfur Chemistry 265
Table 2. Continued.
Entry Reactants
Product
Time (h)
Yield (%)a
1
1
1f + 2b
1g + 2b
5
98
12
2
94
1
1
3
4
7
3
82
86
+
+
aIsolated yield.
Table 3. Effect of different additives on the syn-
thesis of 3eb under aqueous conditions.
Entry
Additive
Water
Yield (%)a,b
1
2
3
4
5
6
7
8
9
45
15
51
47
63
55
23
10
18
5
–
NaCl (aq, 1.5 M)
LiCl (aq, 1.5 M)
NaCl (aq, 3.0 M)
LiCl (aq, 3.0 M)
GnCl (aq, 1.5 M)
GnCl (aq, 3.0 M)
LiClO4 (aq, 1.5 M)
LiClO4 (aq, 3.0 M)
10
a
All reactions conducted in the presence of Et3N (1 mmol).
Isolated yield.
b
Based on these observations, a mechanism can be proposed for the process (Figure 1), where
an α,β-unsaturated nitrile intermediate is formed via a Knoevenagel condensation.[45] Then, the
Knoevenagel intermediate I adds to S8, a ring closure process occurs, and the final aromatization
rearrangement takes place to produce the thiophene skeleton. To support this mechanism, the
intermediate I was prepared separately (for reactants 1a,f and 2b) and subjected to the same
reaction conditions with S8. The result was the formation of products 3ab and 3fb in comparable
yields and time periods indicated in Table 2.
3
. Conclusion
We have reported a general and efficient protocol for the preparation of various 2-aminothiophene
derivatives by the Gewald reactions of different ketones with malononitrile derivatives and sulfur

2
66 M.S. Abaee and S. Cheraghi
Figure 1. The proposed mechanism.
at room temperature. Reactions takes place using an environmentally friendly medium consisted of
water and Et3N. Preparation of single products in high yields within relatively short time periods,
ease of operation, the absence of harmful organic solvent, and no special handling requirements
makes this protocol an attractive addition to the present literature archive. This conclusion is
further supported by comparison of the results of the present work with those of other recent
studies. As shown in Table 4, the Et3N/H2O method (Entry 1) offers higher yields of the products
in relatively shorter time periods under fairly inexpensive conditions and by using a one-pot
operation.
4
.
Experimental
Reactions were monitored by TLC. FT-IR spectra were recorded using KBr disks on a Bruker
−
1
Vector-22 infrared spectrometer and absorptions were reported as wave numbers (cm ). NMR
TM
spectra were obtained on a FT-NMR Bruker Ultra Shield (500 MHz) as CDCl3 or DMSO-d6
solutions and the chemical shifts were expressed as δ units with Me4Si as the internal standard.
Mass spectra were obtained on a Finnigan Mat 8430 apparatus at ionization potential of 70 eV.
Elemental analyses were performed by a Thermo Finnigan Flash EA 1112 instrument. Com-
pound 1e was prepared using available methods.[48] All other chemicals were purchased from
commercial sources and were freshly used after being purified by standard procedures.
4
.1. Typical procedure
A mixture of 1a (311 μL, 3 mmol), 2a (198 mg, 3 mmol), and sulfur (96 mg, 3 mmol) in H2O
(
0.9 mL) and Et3N (418 μL, 3.0 mmol) was stirred at room temperature for 6 h until TLC showed
complete disappearance of the starting materials. The product, which precipitated at the end of
the reaction, was separated by filtration. The pure product was obtained by recrystallization of
Table 4. Comparison of the present method with some other recent-related procedures.
Entry
Conditions
Time
Reference
1
2
3
4
5
6
Et3N, H2O, rt
2–7 h
This work
[46]
[31]
[28]
[30]
◦
(i) NH4OAc, AcOH, benzene, reflux; (ii) S, Et2NH, MeOH (abs), 35–40 C
(i) MeCO2NH4, MeCO2H, benzene, reflux, (ii) S8, Et2NH, EtOH, 50 C
Imidazole, DMF, 60 C
nano ZnO, 100 C
17–42 h
>24 h
10–17 h
6 h
◦
◦
◦
KF-alumina, MW
6 min
[47]

Journal of Sulfur Chemistry 267
the precipitates using EtOAc/hexane mixture. Product 3aa was obtained in 89% yield (475 mg).
The product was identified based on its physical and spectral characteristics.
4
.2. Selected spectral data
4
.2.1. 2-Amino-5,7-dihydro-4H-thieno[2,3-c]thiopyran-3-carbonitrile (3ea)
◦
1
Light brown solid, mp: 205–207 C [49]; H NMR (500 MHz, DMSO-d6) δ 2.58–2.61 (t, J = 5.81,
1
3
1
1.45 Hz, 2H), 2.84–2.86 (t, J = 5.74, 11.59 Hz, 2H), 3.53 (s, 2H), 7.05 (s, 2H) ppm; C NMR
−1
(
125 MHz, DMSO-d6) δ 24.5, 25.4, 26.9, 84.6, 114.0, 116.6, 131.8, 163.0 ppm; (KBr, cm )
−
1
+
3
4
415, 3317, 3207, 2885, 2196, 1622, 1519, 1411 cm ; MS (70 eV): m/z 196 (M ), 168, 150, 60,
5, 29, 27; Anal. Calcd for C8H8N2S2: C, 48.95; H, 4.11. Found: C, 49.03; H, 4.22.
4
.2.2. Ethyl 2-amino-5,7-dihydro-4H-thieno[2,3-c]thiopyran-3-carboxylate (3eb)
◦
1
Orange solid, mp: 86–89 C [49]; H NMR (500 MHz, CDCl3) δ 1.34–1.37 (t, J = 7.13, 14.26 Hz,
3
4
H), 2.88–2.90 (t, J = 5.94, 11.79 Hz, 2H), 3.03–3.05 (t, J = 5.84, 11.80 Hz, 2H), 3.59 (s, 2H),
13
.27–4.21 (q, J = 7.09, 14.23, 21.32 Hz, 2H), 6.05 (s, 2H) ppm; C NMR (125 MHz, CDCl3)
−
1
δ 14.9, 25.4, 26.6, 29.1, 60.0, 106.5, 114.0, 132.7, 161.6, 166.2 ppm; (KBr, cm ) 3412, 3304,
−
1
+
2
978, 2943, 2895, 1651, 1568, 1483, 1018 cm ; MS (70 eV): m/z 243 (M ), 197, 170, 45, 29,
2
7; Anal. Calcd for C10H13NO2S2: C, 49.36; H, 5.38. Found: C, 49.43; H, 5.54.
4
.2.3. Ethyl 2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (3fb)
◦
1
Yellow solid, mp: 117–118 C [50]; H NMR (500 MHz, CDCl3) δ 1.33–1.36 (t, J = 7.12,
1
4.23 Hz, 3H), 2.82–2.84 (m, 2H), 3.91–3.93 (t, J = 5.59, 11.19 Hz, 2H), 4.25–4.30 (q, J = 7.11,
13
1
4.22, 21.34 Hz, 2H), 4.56–4.57 (t, J = 3.32, 10.69 Hz, 2H), 6.11 (s, 2H) ppm; C NMR
(
125 MHz, CDCl3) δ 14.8, 28.1, 59.9, 65.0, 65.3, 105.7, 115.0, 130.7, 162.8, 166.3 ppm. (KBr,
−
+
1
−1
cm ) 3433, 3325, 2945, 2902, 2846, 1654, 1587, 1265, 1083, 1018 cm ; MS (70 eV): m/z 229
2
+1
+
(
M
), 228 (M ), 227 (M ), 198, 124, 125, 29; Anal. Calcd for C10H13NO3S: C, 52.85; H, 5.77.
Found: C, 52.63; H, 5.80.
4
.2.4. Ethyl 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (3gb)
◦
1
White solid, mp:119–120 C [51]; H NMR (500 MHz, CDCl3) δ 1.35–1.37 (t, J = 7.14, 14.23 Hz,
3
3
H), 1.66 (s, 1.3H), 2.75–2.77 (m, 2H), 3.08–3.11 (t, J = 5.84, 11.67 Hz, 2H), 3.8 (t, J = 1.8,
13
.58 Hz, 2H), 4.27–4.31 (q, J = 7.1, 14.23, 21.34 Hz, 2H), 6.02 (s, 2H) ppm; C NMR (125 MHz,
CDCl3) δ 14.9, 28.7, 43.9, 44.8, 59. 9, 106.2, 117.2, 131.7, 162.3, 166.4 ppm. MS (70 eV): m/z
+
2
26 (M ), 197, 179, 125, 43, 29, 27; Anal. Calcd for C10H14N2O2S: C, 53.08; H, 6.24. Found:
C, 53.33; H, 6.40.
Acknowledgement
Authors would like to thank the Analytical Chemistry Department for conducting some of the analysis experiments.
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