Solvent-free synthesis of 2-aminothiophene-3-carbonitrile derivatives using high-speed vibration milling

Article abstract of DOI:10.3184/174751914X14034491855728

The solvent-free synthesis of 2-aminothiophene-3-carbonitrile derivatives by high-speed vibration milling using the inexpensive and environmentally friendly Et2NH as a catalyst was studied. The reaction conditions were optimised and the derivatives were obtained in good yield. This method has advantages in terms of short reaction time and facile conditions.

Full text of DOI:10.3184/174751914X14034491855728

450 RESEARCH PAPER
VOL. 38 JULY, 450–452
JOURNAL OF CHEMICAL RESEARCH 2014
Solvent-free synthesis of 2-aminothiophene-3-carbonitrile derivatives using
high-speed vibration milling
Fang Xu, Yujin Li*, Fengshuang Xu, Qing Ye, Liang Han, Jianrong Gao and Wubin Yu
Zhengjiang University of Technology, Hangzhou, Zhejiang 310014, P.R. China
The solvent-free synthesis of 2-aminothiophene-3-carbonitrile derivatives by high-speed vibration milling using the inexpensive
and environmentally friendly Et NH as a catalyst was studied. The reaction conditions were optimised and the derivatives were
2
obtained in good yield. This method has advantages in terms of short reaction time and facile conditions.
Keywords: solvent-free synthesis, high-speed vibration milling, 2-aminothiophene
High-speed vibration milling (HSVM) is a mechanical
technique which is widely used for the grinding of minerals into
a fine grain, and in the preparation or modification of inorganic
carbonitrile by the reaction of cyclohexanone and malononitrile
in the presence of elemental sulfur and base. The reaction was
conducted under HSVM, with a vibrational frequency of 30 Hz
for 30 minutes.
1,2
3
solids, in materials science and in the pharmaceutical
4
industry. Recently, the technique of HSVM was applied
In order to find the most effective catalyst, different common
organic and inorganic bases were examined. As shown in
Table 1, most of the bases improved the Gewald reaction to
produce 2-aminothiophene-3-carbonitrile. The product 4a was
obtained in moderate yield in the presence of inorganic bases
such as Na CO , KF, K CO , and NaHCO . The yield of 4a
successfully in solvent-free reactions in organic synthesis
5
such as the functionalisation of fullerenes, the Knoevenagel
6
7
reaction, the aldol condensation, Heck-type cross-coupling
8
9
reactions and Horner–Wadsworth–Emmons reaction.
10,11
The Gewald reaction
has been a well-studied multi-
2
3
2
3
3
component reaction. It involves the reaction of a ketone with an
activated nitrile in the presence of elemental sulfur to construct
a poly-substituted 2-aminothiophene. Many methods have been
examined to optimise the reaction conditions for the Gewald
reduced to 32% and 28% in the presence of NaOH and KOH
and the by-products increased. The yield of 4a was improved
to 74% when the organic base Et NH was employed (Table 1,
2
entry 9).
12
reaction. Madabhushi had used microwave to synthesis target
In further experiments, we found that the yield of 4a was
13
product with KF-alumina as catalyst and Mohammad had
improved to 84% catalysed by 0.1 equiv. of Et NH. When
2
realised this reaction under ultrasound irradiation with Et NH
as catalyst. Yi Hu increased the speed of the reaction with the
ionic liquids as a new catalyst.
However, the application of HSVM to the Gewald reaction
has not been reported. The one-pot cyclo-condensation of
a variety of ketones and malononitrile with elemental sulfur
has been used employing high-speed vibration milling
we investigated the ratio of the reactants, the yield of 4a was
slightly increased to 88% with 1.2 equiv. of elemental sulfur.
To further optimise the reaction conditions, we have carried
out this Gewald reaction at different vibration frequencies
and reaction times. It was found that the vibration frequency
had an effect on this reaction (Table 2). As shown in Table 2,
higher vibration frequency of the vibration mill certainly
accelerated the reaction. It is easy to understand that the faster
milling vibration produces the higher energy, and therefore
local pressure is applied to the reaction system. Furthermore, it
was found that the best reaction time was vibration for 20 min
2
14
with Et NH as the catalyst. The reaction times have been
2
considerably decreased and the product was purified by a short
column chromatography. Initial research was focused on the
synthesis of 2-amino-4,5,6,7-tetrahydrobenzo[b]-thiophene-3-
Table 1 Different catalysts on synthesis of 4a
NC
CN
O
CN
Base
+ NC
+
CN
S
8
NH2
HSVM
S
1a
2
3
4a
5
Entrya
Base
Product
Yield/%
1
2
3
4
5
6
7
8
9
KOH
4a
4a
4a
4a
4a
4a
4a
4a
4a
5
28
32
43
54
56
60
63
71
74
20
NaOH
K CO
2
3
DBU
KF
Piperidine
Na CO
2
3
Et N
3
Et NH
2
1
0
CH COOH
3
aThe reaction: Cyclohexanone (0.0981 g, 1.0 mmol), malononitrile (0.0660 g, 1.0 mmol), elemental
sulfur (0.0320 g, 1.0 mmol) was vigorously shaken with different bases by HSVM with 30 Hz for 30 min.
*
Correspondent. E-mail: lyjzjut@zjut.edu.cn
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JOURNAL OF CHEMICAL RESEARCH 2014 451
Table 2 The effect on the reaction of 1a, 2 and sulfur
O
CN
Base
+ NC
+
CN
S
8
NH2
S
HSVM
1a
2
3
4a
Entry
1:2:3
Et NH/mmol
Vibration time/min Speed/s-1
Yield/%
2
1
2
3
4
5
6
7
8
9
1:1:1
1:1:1
1:1:1
1.0
0.2
0.1
0.05
0.1
0.1
0.1
0.1
0.1
0.1
0.1
30
30
30
30
30
30
30
20
15
30
20
30
30
30
30
30
30
30
30
30
20
20
74
82
84
40
84
88
88
88
79
83
83
1:1:1
1.2:1:1
1:1:1.2
1:1:1.5
1:1:1.2
1:1:1.2
1:1:1.2
1:1:1.2
10
11
in 88% yield. The result indicated that the Gewald reaction
Cyclohexanone and substituted cyclohexanones gave excellent
yields but the reaction of 2-methylcyclohexanone and
4-tertbutylcyclohexanone gave lower yields of 43% and 52%
proceeded in good yield in the presence of 0.1 equiv. Et NH
2
under HSVM conditions.
The reaction conditions using a vibration frequency (30 Hz),
t
due to the steric hindrance of the ortho- substituent and Bu-
reaction time (20 min) and 0.1 equiv. Et NH as catalyst and
substituent (Table 3, entry 5, 9). Other cyclic ketones also gave
the corresponding product in moderate yields of 42–61%.
In conclusion, we have developed a green and comparatively
convenient way for the synthesis of 2-aminothiophene-3-
carbonitrile derivatives by HSVM. The notable advantages of
this strategy are its short reaction time, clean conditions and
2
starting material mole ratio 1:1:1.2 were selected from the
above results, for investigating the Gewald reaction with
different cyclic ketone 1 and malononitrile with sulfur.
As shown in Table 3, the cyclic ketone gave the corresponding
2
-aminothiophene-3-carbonitrile derivative in good yield.
Table 3 Synthesis of 2-aminothiophene-3-carbonitrile derivatives
NC
NH2
O
CN
Et NH
2
+
S8
+
S
n=1,2,3,4
R
CN
HSVM
n
R=CH ,CH CH ,C(CH )
R
3
2
3
3 3
n
1a
2
3
4a
Entrya
Substrate
n
R
Product
Yield/%
1
2
3
4
1a
1b
1c
1d
2
1
3
4
H
4a
4b
4c
4d
88
42
61
52
H
H
H
CN
5
1e
2
2-Methyl
4e
43
NH2
S
CN
6
7
1f
2
2
4-Methyl
4-Ethyl
81
94
4
f
NH2
S
CN
1g
NH2
4g
S
CN
4h
NH2
52
8
1h
2
4-t-Bu
S
aThe reaction: Cyclic ketone (1.0 mmol), malononitrile (0.0660 g, 1.0 mmol), elemental sulfur (0.0384 g,
.2 mmol) was vigorously shaken with Et NH (0.1 mmol) by HSVM with 30 Hz for 20 min.
1
2
JCR1402550_FINAL.indd 451
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452 JOURNAL OF CHEMICAL RESEARCH 2014
inexpensive catalyst. We believe that this method has provided
a better way to synthesise 2-aminothiophenes and will be
an improvement over the existing methods for other organic
reactions.
2-Amino-4,5,6,7-tetrahydro-6-methyl-benzo[b]thiophene-3-
carbonitrile (4f): Yield 81%; m.p. 117–118 °C; H NMR (500 MHz,
1
CDCl ): δ (ppm) 4.59 (s, 2H, NH ), 2.62–2.46 (m, 3H), 2.18–2.12 (m, 1H),
3
2
1
(
.96–1.85 (m, 2H), 1.44–1.34 (s, 1H), 1.07 (d, J=6.5 Hz, 3H); HRMS
+
ESI-TOF) m/z calcd for C H N S [M+H] 193.0794; found 193.0794.
10 13 2
Experimental
2-Amino-6-ethyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-
1
carbonitrile (4g): Yield 94%; m.p. 109–110 °C; H NMR (500 MHz,
CDCl ): δ (ppm) 4.59 (s, 2H, NH ), 2.63–2.58 (m, 2H), 2.51–2.12 (m,
All chemicals were purchased from commercial vendors and were
used as received without further purification. The H NMR spectra
were recorded at 500 MHz in CDCl using TMS as internal standard
with a Bruker AM 500 spectrometer. The GC-MS was taken on Varian
1
3
2
2
H), 1.95–1.64 (m, 2H), 1.48–1.34 (m, 3H), 0.96 (t, J=7.5 Hz, 3H);
3
+
HRMS (ESI-TOF) m/z calcd for C H N S [M+H] 207.0950; found
11 15
2
2
07.0950.
(GC431-MS210). The HSVM was achieved with Retsch MM301
2
-Amino-6-(1,1-dimethylethyl)-4,5,6,7-tetrahydro-benzo[b]
(
Retsch GmbH, Haan, Germany) equipment.
1
thiophene-3-carbonitrile (4h): Yield 52%; m.p. 150–151; H NMR
(500 MHz, CDCl ): δ (ppm) 4.60 (s, 2H, NH ), 2.68–2.53 (m, 2H),
General procedure
3
2
Cyclohexanone (0.0981 g, 1.0 mmol), malononitrile (0.0660 g,
2.46–2.26 (m, 2H), 2.03–1.28 (m, 3H), 0.93 (s, 9H); HRMS (ESI-TOF)
+
1.0 mmol), elemental sulfur (0.0384 g, 1.2 mmoL) was vigorously
m/z calcd for C H N S [M+H] 235.1261; found 235.1263.
13
19
2
shaken by HSVM for a designated time.
The product was purified by chromatography on silica gel and eluted
using CH Cl as the eluent to afford the desired product 2-amino-5,6-
dihydro-4H-cyclopenta[b]-thiophene-3-carbonitrile as colourless
solid.
We gratefully acknowledge financial support from the Natural
Science Foundation of China (21176223), the Key Innovation
Team of Science and Technology in Zhejiang Province
2
2
(2010R50018) and the National Natural Science Foundation of
2
-Amino-4,5,6,7-tetrahydrobenzo[b]-thiophene-3-carbonitrile (4a):
Zhejiang (LY13B020016).
21
1
Yield 88%; m.p. 146–147 °C (lit. 145 °C); H NMR (500 MHz, CDCl ):
3
δ (ppm) 4.61 (s, 2H, NH ), 2.52–2.50 (m, 4H), 1.85–1.77 (m, 4H);
2
Received 25 March 2014; accepted 8 June 2014
Paper 1402550 doi: 10.3184/174751914X14034491855728
Published online: 12 July 2014
+
HRMS (ESI-TOF) m/z calcd for C H N S [M+H] 179.0637; found
9
11
2
179.0637.
2
-Amino-5,6-dihydro-4H-cyclopenta[b]-thiophene-3-carbonitrile
1
(
4b): Yield 42%; m.p. 159–160 °C; H NMR (500 MHz, CDCl ): δ
3
References
(
(
ppm) 4.69 (s, 2H, NH ), 2.78–2.69 (m, 4H), 2.40–2.34 (s, 2H); HRMS
2
+
1
G. Kaupp, M.R. Naimi-Jamal, H. Ren and H. Zoz, Res. Signpost. Kerala,
003, 83.
ESI-TOF) m/z calcd for C H N S [M+H] 165.0482; found 165.0481.
8
9
2
2
2
-Amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-
2
3
S. Kipp, V. Sepelak and K.D. Becker, Chem Unsere Zeit., 2005, 39, 384.
V.P. Balema, K.W. Dennis and V.K. Pecharsky, Chem. Commun., 2000, 17,
1665.
21
1
carbonitrile (4c): Yield 61%; m.p. 125–126 °C (lit. 125 °C), H NMR
500 MHz, CDCl ): δ (ppm) 4.49 (s, 2H, NH ), 2.63–2.59 (m, 4H),
(
3
2
1
.85–1.81 (m, 2H), 1.68–1.63 (m, 4H); HRMS (ESI-TOF) m/z calcd for
4
5
6
T.P. Shakhtshneider and V.V. Boldyrev, Mol. Solid State, 1999, 3, 271.
K. Komatsu, Top. Curr. Chem., 2005, 254, 185.
G. Kaupp, M.R. Naimi-Jamal and J. Schmeyers, Tetrahedron, 2003, 59,
3753.
B. Rodriguez, A. Bruckmann and C. Bolm, Chem. Eur. J., 2007, 13, 4710.
E. Tullberg, F. Schacher, D. Peters and T. Frejd, Synthesis, 2006, 7, 1183.
A. Baron, J. Martinez and F. Lamaty, Tetrahedron Lett., 2010, 51, 6246.
+
C H N S [M+H] 193.0792; found 193.0794.
10
13
2
2
-Amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophene-3-
21
1
carbonitrile (4d): Yield 52%; m.p. 108–109 °C (lit. 107 °C); H NMR
500 MHz,CDCl ): δ (ppm) 4.56 (s, 2H, NH ), 2.65–2.61 (m, 4H),
7
8
9
(
3
2
1.69–1.59 (m, 4H), 1.45–1.38 (m, 4H); HRMS (ESI-TOF) m/z calcd for
+
C H N S [M+H] 207.0950; found 207.0950.
10 K. Gewald, Chem. Heterocycl. Compd, 1976, 12, 1077.
11 R.W. Sabnis, Sulfur Rep., 1994, 16, 1.
12 M. Sridhar, R.M. Rao, N.H.K. Baba and R.M. Kumbhare, Tetrahedron
Lett., 2007, 48, 3171.
11
15
2
2
-Amino-4,5,6,7-tetrahydro-4-methyl-benzo[b]thiophene-
1
3
-carbonitrile (4e): Yield 43%; m.p. 126–128 °C;
H NMR
(500 MHz,CDCl ): δ (ppm) 4.60 (s, 2H, NH ), 2.85–2.79 (m, 1H),
3
2
13
M.M. Mojtahedi, M.S. Abaee, P. Mahmoodi and M. Adib, Synth. Commun.,
010, 40, 2067.
2
.53–2.43 (m, 2H), 1.90–1.73 (m, 3H), 1.57–1.54 (m, 1H), 1.28 (d,
2
+
J=7 Hz, 3H); HRMS (ESI-TOF) m/z calcd for C H N S [M+H]
10
13
2
14 Y. Hu, Z.C. Chen, Z.G. Le and Q.G. Zheng, Synth. Commun., 2004, 34,
193.0793; found 193.0794.
3801.
JCR1402550_FINAL.indd 452
10/07/2014 11:39:10

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