Improved synthesis of dihydrothiophenes derivatives under ultrasound irradiation

Article abstract of DOI:10.1002/jhet.662

Figure represented. A series of dihydrothiphenes derivatives were synthesized via the four-component reaction of aldehyde, malononitrile, 1,3-thiazolidinedione, and piperidine at room temperature under ultrasound irradiation. Compared with the conventiona

Full text of DOI:10.1002/jhet.662

896
Improved Synthesis of Dihydrothiophenes Derivatives Under
Ultrasound Irradiation
Vol 48
Da-Qing Shi,a* Yi Zou,b Yu Hu,a and Hui Wub
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical
Engineering and Materials Science, Soochow University, Suzhou 215123, People’s Republic of
China
bSchool of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou 221116,
People’s Republic of China
*E-mail: dqshi@suda.edu.cn
Received July 24, 2010
DOI 10.1002/jhet.662
Published online 19 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
A series of dihydrothiphenes derivatives were synthesized via the four-component reaction of alde-
hyde, malononitrile, 1,3-thiazolidinedione, and piperidine at room temperature under ultrasound irradia-
tion. Compared with the conventional methods, the remarkable advantages of this method are
operational simplicity, higher yield, and shorter reaction time.
J. Heterocyclic Chem., 48, 896 (2011).
INTRODUCTION
Sulfur-containing heterocyclic compounds are wide-
spread in nature, and their applications to biologically
active pharmaceuticals [8], agrochemicals [9], and
functional materials are becoming more and more im-
portant. The development of new efficient methods to
synthesize S-heterocycles with structural diversity is
one major interest of modern synthetic organic chem-
ists. Among a large variety of sulfur-containing heter-
ocyclic compounds, the dihydrothiophene moiety has
been found in various natural products, biologically
active compounds, and synthetic intermediates [10,11],
whose preparation often required lengthy steps and
suffered from drawbacks, as well as lower yields
[12,13].
Currently, multicomponent reactions are being rapidly
developed because using a ‘‘one-pot’’ methodology
makes the synthesis simpler and more environmentally
friendly [1]. They allow the creation of several bonds in
a single operation and are attracting increasing attention
as one of the most powerful emerging synthetic tools
for the creation of molecular diversity and complexity
[2].
The efficient high-throughput synthesis of organic
compounds is one of the most important objectives in
modern drug discovery. Organic reactions should be
rapid and facile, and the target products should be easily
separated and purified in high yields. Therefore, there is
much interest in the implementation of new synthetic
strategies such as microwave assisted, ultrasonic irradia-
tion, and supercritical fluids, which find application as
methods to achieve these goals [3].
Recently, Sun et al. [14] have reported the synthesis
of dihydrothiophenes under stirring in the presence of
acetonitrile. Nevertheless, this method possesses some
weaknesses: (a) long reaction time of up to 48 h, (b)
dramatically low yield and (c) utilization of toxic sol-
vent-acetonitrile. Therefore, it is urgent to further de-
velop an efficient and convenient method to construct
such scaffold. As part of our current studies on the de-
velopment of new routs to heterocyclic systems [15], we
herein would like to report an ultrasound assisted one-
pot procedure for the preparation of dihydrothiophene
derivatives by four-component reaction (Scheme 1),
which has the advantage of excellent yields and short
reaction time.
Recently published comprehensive books [4] and
articles [5] indicate chemical applications of ultrasounds.
Ultrasonic activation, based on cavitation effects leading
to mass transfer improvement, is a green powerful syn-
thetic approach in organic chemistry, offering a versatile
and facile pathway for a large variety of syntheses [6].
After several decades of research, it is discovered that a
large number of organic reactions can be carried out
under ultrasonic irradiation in high yields, short reaction
time, and mild conditions [7].
C
V
2011 HeteroCorporation

July 2011
Improved Synthesis of Dihydrothiophenes Derivatives Under Ultrasound Irradiation
897
Scheme 1. One-pot four-component reaction of aldehydes, malononitrile, 1,3-thiazolidinedione, and piperidine under ultrasonic irradiation.
RESULTS AND DISCUSSION
perature in ethanol under ultrasound irradiation. The
results are summarized in Table 2. It was observed that
the yields of the products decreased under conventional
conditions (Table 2, entries 1–8). Thus, ultrasonic irradi-
ation was found to have beneficial effect on the synthe-
sis of dihydrothiophene derivatives which was superior
to the traditional method with respect to yield, reaction
time, simplicity, and safety.
The choice of an appropriate reaction medium is of
crucial importance for the successful organic synthesis.
To achieve suitable conditions, we investigated the reac-
tion of piperidine 1, 1,3-thiazolidinedione 2, 4-methyl-
benzaldehyde 3a and malononitrile
conditions.
4 in different
To study the effect of solvent on this synthesis, we
first performed five experiments in water, acetonitrile,
ethanol, methanol, and THF under stirring condition.
However, they all afforded a lower yield at longer reac-
tion time. Then, we have studied the sonochemical
effect on model reaction by using different solvents. In
all cases, the experimental results show that the reaction
times are strikingly shorter and the yields of the prod-
ucts are higher under sonication and ethanol was the
best choice of solvent and the use of ultrasound radia-
tion in ethanol increased the yield of the reaction to
81% and decreased the reaction time to 1 h (Table 1,
entry 3). Therefore, ultrasound irradiation exhibited sev-
eral advantages over the classical methods by reducing
the reaction time and improving the reaction yields. The
reason may be the phenomenon of cavitation produced
by ultrasound [16].
To test the scope of the substrates, we used different
aromatic aldehyde with either electron with-drawing
groups or electron-donating groups (Table 2, entries 9–
13), which was not used in the literature and heterocy-
clic aldehyde (Table 2, entries 14,15) can also be carried
out smoothly. The results were excellent in terms of
yields and product purity using ethanol as solvent (Table
2). According to the reported literature [14], in this reac-
tion piperidine behaves both as a base catalyst and as a
nucleophile. First, the arylidenemalononitrile 6 are likely
formed via initial condensation of aromatic aldehyde
with malononitrile, which is catalyzed by piperidine.
Table 2
Results of one-pot four-component reactions.a
To further improve the yield of the reaction, we tried
to perform the reaction in higher temperature under
ultrasound irradiation. However, it showed no substan-
tial improvement for this reaction. With our optimized
the conditions, we performed the reaction at room tem-
Yieldb
(%)
Product (Lit.[14])
m.p. (ꢀC)
(Lit.[14])
Entry
R
1
2
3
4
5
6
7
8
9
4-CH3C6H4
C6H5
4-HOC6H4
4-CH3OC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
3,4-(CH3O)2C6H3
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
81(31) 200–202(202–204)
70(41) 223–224(220–222)
67(32) 230–232(230–233)
65(48) 211–213(210–212)
94(43) 216–218(220–222)
73(35) 300–301(299–301)
69(49) 219–220(220–222)
87(27) 200–202(209–211)
Table 1
Optimization for the synthesis of 5a.
With USa
Without USb
60
77
64
94
70
69
53
197–199
223–224
206–208
219–220
215–217
227–228
209–210
Yieldc
(%)
Time
(h)
Yieldc
(%)
10 3-ClC6H4
11 2-ClC6H4
Time
(h)
Entry
Solvent
Water
12 3,4-Cl2C6H3
13 3,4-OCH2OC6H3
14 thiophene-2-yl
15 pyridine-3-yl
1
2
3
4
5
3
54
50
81
67
72
33
48
27
29
30
33
31
38
33
40
Acetonitrile
Ethanol
Methanol
THF
2
1
1
1.5
a
Reaction conditions: aldehyde (2 mmol), malononitrile (2 mmol),
1,3-thiazolidinedione (2 mmol), piperidine (2.5 mmol), ethanol (2 mL)
at room temperature under ultrasound irradiation and the ultrasonic
power 250 W, irradiation frequency 40 kHz.
a Reaction under ultrasonic waves at room temperature.
b Reaction under stirring condition at room temperature.
cYields of isolated products.
b
Yields of isolated products.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

898
D.-Q. Shi, Y. Zou, Y. Hu, and H. Wu
Vol 48
Scheme 2. Proposed reaction mechanism.
area in the cleaner; the surface of reactants is slightly lower
than the level of the water.
The second step is a Michael addition of the carbanion
of 1,3-thiazolidinedione to arylidenemalononitrile 6 to
yield adduct 7. Then, piperidine attacks the carbonyl
group of thiazolidinedione to open its ring and cause the
formation of a sulfide anion 8, which in turn intramolec-
ularly attacks one of the two cyano group to form a sul-
fur-containing 5-membered ring intermediate 9. Finally
the dihydrothiophene 5 was produced through imine-
enamine tautomerization (Scheme 2). When aniline and
other piperidine derivatives were used as substrate
instead of piperidine, unfortunately, we could not get
the expected product.
General procedure for the synthesis of dihydrothiophene
derivatives 5 is represented as follows. A 50 mL flask was
charged with the aldehyde (2 mmol), malononitrile (0.132 g, 2
mmol), 1,3-thiazolidinedione (0.234 g, 2 mmol), and piperidine
(0.213 g, 2.5 mmol) in ethanol (2 mL). The mixture was soni-
cated in the water bath of an ultrasonic cleaner under an air
conditions at 25–30ꢀC for 1 h (monitored by TLC). After the
completion of the reaction, the resulting precipitate was filtered
and washed with ethanol to afford the pure product as solid in
good to excellent yields. The authenticity of the products was
1
established by their IR, H NMR, HRMS.
N-(5-Amino-4-cyano-3-(p-tolyl)-2,3-dihydrothiophene-2-car-
bonyl)piperidine-1-carboxamide (5a). White powder; m.p.
200–202ꢀC (lit.[14] m.p. 202–204ꢀC); IR (KBr, cmꢁ1): 3412,
3324, 3217, 3081, 2926, 2175, 1675, 1626, 1474, 1346, 1242,
In summary, we have found a facile and efficient
method for the one-pot four-component synthesis of
dihydrothiophene derivatives in ethanol under ultrasound
irradiation. The present procedure avoided the use of
poisonous organic solvent during the reaction, and
showed a short reaction time and good yields.
1
1021, 810, 739, 651; H NMR (300 MHz, DMSO-d6): d (ppm)
1.42 (d, J ¼ 3.6 Hz, 4H, 2 ꢂ CH2), 1.51 (d, J ¼ 4.2 Hz, 2H,
CH2), 2.27 (s, 3H, CH3), 3.28–3.30 (m, 4H, 2 ꢂ CH2), 4.36
(d, J ¼ 2.1 Hz, 1H, CH), 4.54 (d, J ¼ 3.0 Hz, 1H, CH), 7.07
(s, 2H, NH2), 7.15 (s, 4H, ArH), 9.98 (s, 1H, NH); HRMS cal-
culated for C19H23N4O2S [M
371.1554.
þ
H]: 371.1536, found:
EXPERIMENTAL
N-(5-Amino-4-cyano-3-phenyl-2,3-dihydrothiophene-2-car-
bonyl)piperidine-1-carboxamide (5b). White powder; m.p.
223–224ꢀC (lit.[14] m.p. 220–222ꢀC); IR (KBr, cmꢁ1): 3400,
3307, 3193, 2941, 2855, 2195, 1690, 1654, 1585, 1492, 1379,
1246, 1025, 749, 696; 1H NMR (300 MHz, DMSO-d6): d
(ppm) 1.43 (d, J ¼ 3.3 Hz, 4H, 2 ꢂ CH2), 1.51 (d, J ¼ 3.6
Hz, 2H, CH2), 3.29–3.31 (m, 4H, 2 ꢂ CH2), 4.39 (s, 1H, CH),
4.58 (d, J ¼ 2.7 Hz, 1H, CH), 7.11 (s, 2H, NH2), 7.26–7.38
(m, 5H, ArH), 10.00 (s, 1H, NH); HRMS calculated for
C18H20N4O2SNa [M þ Na]: 379.1199, found: 379.1198.
All reagents were purchased from commercial sources and
used without further purification. Ultrasonication was per-
formed in a KQ-250E medical ultrasound cleaner with a fre-
quency of 40 KHz and an output power of 250 W (Builtin
heating, 30–110ꢀC thermostatically adjustable). Melting points
are uncorrected. IR spectra were recorded on Varian F-1000
spectrometer in KBr with absorptions in cmꢁ1 1H NMR was
.
determined on Varian Invoa-300/400 MHz spectrometer in
DMSO-d6 solution. J values are in Hz. Chemical shifts are
expressed in ppm downfield from internal standard TMS.
HRMS data were obtained using Bruker micrOTOF-Q instru-
ment. The reaction flask was located at the maximum energy
N-(5-Amino-4-cyano-3-(4-hydroxyphenyl)-2,3-dihydrothio-
phene-2-carbonyl)piperidine-1-carboxamide (5c). White pow-
der; m.p. 230–232ꢀC (lit.[14] m.p. 230–233ꢀC); IR (KBr,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Improved Synthesis of Dihydrothiophenes Derivatives Under Ultrasound Irradiation
899
cmꢁ1): 3402, 3301, 3196, 2941, 2857, 2192, 1657, 1651, 1511,
3214, 2940, 2856, 2177, 1667, 1577, 1514, 1463, 1351, 1238,
1141, 1025, 741, 654; 1H NMR (300 MHz, DMSO-d6): d
(ppm) 1.43 (d, J ¼ 3.3 Hz, 4H, 2 ꢂ CH2), 1.52 (d, J ¼ 3.3
Hz, 2H, CH2), 3.29 (s, 4H, 2 ꢂ CH2), 3.72 (s, 6H, 2 ꢂ
OCH3), 4.36 (s, 1H, CH), 4.54 (d, J ¼ 3.0 Hz, 1H, CH), 6.77
(d, J ¼ 8.4 Hz, 1H, ArH), 6.86 (d, J ¼ 1.5 Hz, 1H, ArH),
6.92 (d, J ¼ 8.4 Hz, 1H, ArH), 7.06 (s, 2H, NH2), 9.96 (s, 1H,
NH); HRMS calculated for C20H24N4O4SNa [MþNa]:
439.1410, found: 439.1422.
1
1374, 1252, 1032, 819, 729; H NMR (300 MHz, DMSO-d6):
d (ppm) 1.42 (s, 4H, 2 ꢂ CH2), 1.51 (s, 2H, CH2), 3.29 (s,
4H, 2 ꢂ CH2), 4.31 (s, 1H, CH), 4.48 (s, 1H, CH), 6.72 (d, J
¼ 7.8 Hz, 2H, ArH and NH2), 7.04 (s, 4H, ArH), 9.39 (s, 1H,
OH), 9.98 (s, 1H, NH); HRMS calculated for C18H20N4O3SNa
[M þ Na]: 395.1148, found: 395.1157.
N-(5-Amino-4-cyano-3-(4-methoxyphenyl)-2,3-dihydrothio-
phene-2-carbonyl)piperidine-1-carboxamide (5d). White pow-
der; m.p. 211–213ꢀC (lit.[14] m.p. 210–212ꢀC); IR (KBr, cmꢁ1):
3404, 3312, 3201, 2930, 2858, 2175, 1676, 1626, 1472, 1345,
1244, 1031, 825, 653; 1H NMR (300 MHz, DMSO-d6): d (ppm)
1.42 (s, 4H, 2 ꢂ CH2), 1.50 (s, 2H, CH2), 3.28 (s, 4H, 2 ꢂ CH2),
3.72 (s, 3H, OCH3), 4.34 (s, 1H, CH), 4.54 (d, J ¼ 2.7 Hz, 1H,
CH), 6.91 (d, J ¼ 8.4 Hz, 2H, ArH), 7.07 (s, 2H, NH2), 7.18 (d, J
¼ 8.4 Hz, 2H, ArH), 9.98 (s, 1H, NH); HRMS calculated for
C19H22N4O3SNa [M þ Na]: 409.1305, found: 409.1316.
N-(5-Amino-3-(3-chlorophenyl)-4-cyano-2,3-dihydrothiophene-
2-carbonyl)piperidine-1-carboxamide (5j). White powder; m.p.
223–224ꢀC; IR (KBr, cmꢁ1): 3412, 3326, 3231, 2940, 2856,
1
2177, 1699, 1577, 1471, 1362, 1241, 1025, 896, 790, 652; H
NMR (300 MHz, DMSO-d6): d (ppm) 1.44 (s, 4H, 2 ꢂ CH2),
1.51–1.52 (m, 2H, CH2), 3.30 (s, 4H, 2 ꢂ CH2), 4.40 (s, 1H,
CH), 4.59 (d, J ¼ 2.1 Hz, 1H, CH), 7.19 (s, 2H, NH2), 7.25–
7.42 (m, 4H, ArH), 10.00 (s, 1H, NH); HRMS calculated for
C18H20N4O2S35Cl [MþH]: 391.0990, found: 391.0989.
N-(5-Amino-4-cyano-3-(4-fluorophenyl)-2,3-dihydrothiophene-
2-carbonyl)piperidine-1-carboxamide (5e). Yellow powder; m.p.
216–218ꢀC (lit.[14] m.p. 220–222ꢀC); IR (KBr, cmꢁ1): 3397,
3302, 3195, 2936, 2852, 2193, 1653, 1581, 1504, 1378, 1237,
N-(5-Amino-3-(2-chlorophenyl)-4-cyano-2,3-dihydrothio-
phene-2-carbonyl)piperidine-1-carboxamide (5k). White pow-
der; m.p. 206–208ꢀC; IR (KBr, cmꢁ1): 3412, 3316, 3211, 2942,
2855, 2188, 1656, 1583, 1496, 1368, 1241, 1031, 897, 755, 650;
1H NMR (300 MHz, DMSO-d6): d (ppm) 1.44 (s, 4H, 2 ꢂ
CH2), 1.52 (d, J ¼ 3.9 Hz, 2H, CH2), 3.31 (s, 4H, 2 ꢂ CH2),
4.28 (s, 1H, CH), 4.97 (s, 1H, CH), 7.28 (s, 2H, NH2), 7.31–
7.52 (m, 4H, ArH), 10.08 (s, 1H, NH); HRMS calculated for
C18H19N4O2S35ClNa [MþNa]: 413.0809, found: 413.0804.
N-(5-Amino-4-cyano-3-(3,4-dichlorophenyl)-2,3-dihydrothio-
phene-2-carbonyl)piperidine-1-carboxamide (5l). White pow-
der; m.p. 219–220ꢀC; IR (KBr, cmꢁ1): 3417, 3334, 3229,
2941, 2182, 1667, 1581, 1468, 1352, 1241, 1023, 893, 821,
739, 649; 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.44 (s,
4H, 2 ꢂ CH2), 1.52 (s, 2H, CH2), 3.32 (s, 4H, 2 ꢂ CH2), 4.41
(s, 1H, CH), 4.62 (s, 1H, CH), 7.26 (s, 2H, NH2), 7.32 (d, J ¼
8.4 Hz, 1H, ArH), 7.51–7.67 (m, 2H, ArH), 10.03 (s, 1H,
NH); HRMS calculated for C18H18N4O2S35Cl2Na [MþNa]:
447.0420, found: 447.0407.
1
1019, 823, 726; H NMR (400 MHz, DMSO-d6): d (ppm) 1.44
(s, 4H, 2 ꢂ CH2), 1.52 (s, 2H, CH2), 3.31 (s, 4H, 2 ꢂ CH2),
4.37 (s, 1H, CH), 4.60 (s, 1H, CH), 7.17 (s, 2H, NH2), 7.22
(d, J ¼ 8.4 Hz, 2H, ArH), 7.32–7.35 (m, 2H, ArH), 10.03 (s,
1H, NH); HRMS calculated for C18H19N4O2SFNa [MþNa]:
397.1105, found: 397.1127.
N-(5-Amino-3-(4-chlorophenyl)-4-cyano-2,3-dihydrothiophene-
2-carbonyl)piperidine-1-carboxamide (5f). Yellow powder; m.p.
300–301ꢀC (lit.[14] m.p. 299–301ꢀC); IR (KBr, cmꢁ1): 3406,
3310, 3219, 2930, 2858, 2175, 1676, 1577, 1478, 1345, 1242,
1
1017, 817, 652; H NMR (300 MHz, DMSO-d6): d (ppm) 1.42
(s, 4H, 2 ꢂ CH2), 1.51 (s, 2H, CH2), 3.28 (s, 4H, 2 ꢂ CH2),
4.37 (s, 1H, CH), 4.59 (d, J ¼ 2.1 Hz, 1H, CH), 7.16 (s, 2H,
NH2), 7.31 (d, J ¼ 8.1 Hz, 2H, ArH), 7.43 (d, J ¼ 8.4 Hz,
2H, ArH), 10.00 (s, 1H, NH); HRMS calculated for
C18H20N4O2S35Cl [MþH]: 391.0990, found: 391.0989.
N-(5-Amino-3-(4-bromophenyl)-4-cyano-2,3-dihydrothiophene-
2-carbonyl)piperidine-1-carboxamide (5g). White powder; m.p.
219–220ꢀC (lit.[14] m.p. 220–222ꢀC); IR (KBr, cmꢁ1): 3406,
3313, 3218, 2933, 2857, 2174, 1675, 1578, 1480, 1347, 1242,
N-(5-Amino-3-(benzo[d][1,3]dioxol-5-yl)-4-cyano-2,3-dihy-
drothiophene-2-carbonyl)piperidine-1-carboxamide (5m). Light
yellow powder; m.p. 215–217ꢀC; IR (KBr, cmꢁ1): 3434, 3337,
3223, 2927, 2176, 1699, 1572, 1495, 1355, 1235, 1035, 924,
1
1
1011, 815, 652; H NMR (300 MHz, DMSO-d6): d (ppm) 1.44
815, 742, 655; H NMR (300 MHz, DMSO-d6): d (ppm) 1.42
(s, 4H, 2 ꢂ CH2), 1.53 (s, 2H, CH2), 3.31 (s, 4H, 2 ꢂ CH2),
4.39 (s, 1H, CH), 4.58 (s, 1H, CH), 7.18 (s, 2H, NH2), 7.26
(d, J ¼ 7.6 Hz, 2H, ArH), 7.57 (d, J ¼ 7.2 Hz, 2H, ArH),
10.02 (s, 1H, NH); HRMS calculated for C18H19N4O2S79BrNa
[MþNa]: 457.0304, found: 457.0303.
(s, 4H, 2 ꢂ CH2), 1.51 (s, 2H, CH2), 3.30 (s, 4H, 2 ꢂ CH2),
4.34 (s, 1H, CH), 4,52 (d, J ¼ 2.7 Hz, 1H, CH), 6.00 (s, 2H,
CH2), 6.74 (dd, J1 ¼ 7.8 Hz, J2 ¼ 1.2 Hz, 1H, ArH), 6.82–
6.89 (m, 2H, ArH), 7.11 (s, 2H, NH2), 10.00 (s, 1H, NH);
HRMS calculated for C19H20N4O4SNa [MþNa]: 423.1097,
found: 423.1094.
N-(5-Amino-4-cyano-3-(4-nitrophenyl)-2,3-dihydrothiophene-
2-carbonyl)piperidine-1-carboxamide (5h). Deep yellow pow-
der; m.p. 208–210ꢀC (lit.[14] m.p. 209–211ꢀC); IR (KBr,
cmꢁ1): 3422, 3314, 3211, 2938, 2857, 2180, 1697, 1569, 1518,
1348, 1247, 1016, 855, 741, 697; 1H NMR (400 MHz,
DMSO-d6): d (ppm) 1.44 (s, 4H, 2 ꢂ CH2), 1.51 (s, 2H, CH2),
3.21 (s, 4H, 2 ꢂ CH2), 4.45 (s, 1H, CH), 4.74 (d, J ¼ 2.1 Hz,
1H, CH), 7.28 (s, 2H, NH2), 7.59 (d, J ¼ 8.7 Hz, 2H, ArH),
8.25 (d, J ¼ 8.7 Hz, 2H, ArH), 10.06 (s, 1H, NH); HRMS cal-
culated for C18H19N5O4SNa [MþNa]: 424.1050, found:
424.1048.
N-(5’-Amino-4’-cyano-2’,3’-dihydro-[2,3’-bithiophene]-2’-
carbonyl)piperidine-1-carboxamide (5n). White powder; m.p.
227–228ꢀC; IR (KBr, cmꢁ1): 3404, 3298, 3225, 2937, 2857,
1
2180, 1670, 1572, 1472, 1351, 1232, 1026, 849, 710; H NMR
(300 MHz, DMSO-d6): d (ppm) 1.45 (d, J ¼ 3.3 Hz, 4H, 2 ꢂ
CH2), 1.52 (s, 2H, CH2), 3.32 (s, 4H, 2 ꢂ CH2), 4.46 (s, 1H,
CH), 4.89 (s, 1H, CH), 6.96–7.00 (m, 2H, ArH), 7.17 (s, 2H,
NH2), 7.42 (d, J ¼ 4.8 Hz, 1H, ArH), 10.06 (s, 1H, NH);
HRMS calculated for C16H18N4O2S2Na [MþNa]: 385.0763,
found: 385.0744.
N-(5-Amino-4-cyano-3-(3,4-dimethoxyphenyl)-2,3-dihydro-
thiophene-2-carbonyl)piperidine-1-carboxamide (5i). Light
yellow powder; m.p. 197–199ꢀC; IR (KBr, cmꢁ1): 3383, 3314,
N-(5-Amino-4-cyano-3-(pyridin-3-yl)-2,3-dihydrothiophene-
2-carbonyl)piperidine-1-carboxamide (5o). White powder;
m.p. 209–210ꢀC; IR (KBr, cmꢁ1): 3350, 3301, 3241, 2940,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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D.-Q. Shi, Y. Zou, Y. Hu, and H. Wu
Vol 48
[7] Ji, S. J.; Shen, Z. L.; Gu, D. G.; Huang, X. Y. Ultrason
Sonochem 2005, 12, 161.
2857, 2179, 1661, 1573, 1497, 1357, 1245, 1025, 814, 742,
1
654; H NMR (400 MHz, DMSO-d6): d (ppm) 1.38 (s, 4H, 2
[8] Imada, I. U.S. Pat.4,362,740, 1982.
ꢂ CH2), 1.47 (s, 2H, CH2), 3.26 (s, 4H, 2 ꢂ CH2), 4.38 (s,
1H, CH), 4.58 (s, 1H, CH), 7.17 (s, 2H, NH2), 7.34–7.37 (m,
1H, ArH), 7.65–7.67 (m, 1H, ArH), 8.46 (d, J ¼ 2.4 Hz, 2H,
ArH), 9.98 (s, 1H, NH); HRMS calculated for
C17H19N5O2SNa [MþNa]: 380.1152 found: 380.1132.
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Acknowledgment. We acknowledge the financial support from
the Foundation of Key Laboratory of Organic Synthesis of
Jiangsu Province (No. KJS0812). We are also grateful to the Ana-
lytical and Testing Center of Soochow University for supports in
IR, 1H NMR, and HRMS analyses.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet