An efficient synthesis of dihydrothiophene ureidoformamides by domino reactions of 1,3-thiazolidinedione under catalyst-free conditions

Article abstract of DOI:10.1039/c0gc00884b

An efficient synthesis of dihydrothiophene ureidoformamides by the domino reactions of aldehydes, malononitrile, amines and 1,3-thiazolidinedione in PEG 400/H₂O is studied. The reaction is free of catalysts and toxic solvents, of shorter reacti

Full text of DOI:10.1039/c0gc00884b

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PAPER
An efficient synthesis of dihydrothiophene ureidoformamides by domino
reactions of 1,3-thiazolidinedione under catalyst-free conditions†
Guo-ping Lu, Li-Yan Zeng and Chun Cai*
Received 6th December 2010, Accepted 24th January 2011
DOI: 10.1039/c0gc00884b
An efficient synthesis of dihydrothiophene ureidoformamides by the domino reactions of
aldehydes, malononitrile, amines and 1,3-thiazolidinedione in PEG 400/H2O is studied. The
reaction is free of catalysts and toxic solvents, of shorter reaction time and with ease of the
product isolation, making it more environmentally friendly and suitable for large-scale operations.
catalyst,8 but these protocols fail to meet the requirements of
Introduction
green chemistry due to long reaction time, low yields and the use
Green chemistry, which emphasizes the development of envi-
of toxic solvents and catalysts. Thus, we wish to explore a more
ronmentally benign chemical processes and technologies has
“green” and efficient process for the synthesis of these com-
attracted much attention in recent years.1 Domino reactions
pounds, obtaining more information about the mechanism of
defined as processes of two or more bond-forming reactions
the domino reactions and ascertaining its scope and limitation.
under identical conditions have emerged as a powerful tool to
Along this line, we describe here a facile, eco-friendly method for
achieve the goal of green chemistry.2 Because the subsequent
efficient synthesis of dihydrothiophene ureidoformamides from
transformation takes place at the functionalities obtained in
aldehydes, malononitrile, amines and 1,3-thiazolidinedione in
the former transformation in domino reactions, they allow the
PEG 400/H2O under catalyst-free conditions.
efficient synthesis of complex molecules from simple substrates
in an ecologically and economically favorable way. In addition,
the use of “green” solvents such as water,3 poly(ethylene glycol)4
Results and discussion
and glycerol5 is also considered advantageous as a medium for
Water as a cheap, safe and non-toxic solvent, is considered as the
preferential choice of medium for organic reactions in view of
economic and environmental problems.9 As a part of our interest
in using water as solvent for organic synthesis, we performed a
domino reaction of 1a, 2, 3 and 4a in water at 80 ◦C in the
absence of catalysts. First, a mixture of 1a and 2 was stirred for
10 min in water at 80 ◦C, then 3 and 4a were added and stirred
for additional 8 h at the same temperature. After the reaction
completed, a low yield (19%) of 5a was obtained (Table 1, entry
1). Several organic solvents, such as EtOH, CH3CN, acetone, n-
hexane, DMF, PEG 400 were applied to the reaction to further
explore the solvent effects on the reaction (Table 1, entries 2–7),
however, only EtOH and PEG 400 provided poor yields of the
desired product.
Based on these results, it was found that polar protic solvents
had a promotion effect on the reaction. Thus, the domino
reaction was carried out in PEG 400/H2O and EtOH/H2O to
improve the unsatisfactory results (Table 1, entries 8, 9), and
PEG 400/H2O gave the better yield (74%).
Further investigations indicated that 9a was the key interme-
diate to initiate the reaction. Only in PEG 400/H2O, 1a could
react with 2 completely to yield 9a under identical conditions,
preventing the reaction of 1a and 3 to form 10a which is the
reaction and workup relative to flammable, volatile or toxic
organic solvents.
The active methylene derivatives with both electrophilic and
nucleophilic sites, have proven to be valuable tools in the
synthesis of a wide variety of molecular systems, especially
complex heterocyclic scaffolds.6 A representative example of
such compounds is 1,3-thiazolidinedione, which is an important
synthetic intermediate in various synthetic transformations,
since thiazolidineone structures are widely present in a number
of biologically active and medicinal agents.7 Therefore, it will
be interesting and significant to apply 1,3-thiazolidinedione in
domino reactions for preparation of new and useful organic
compounds.
Recently, Sun et al. have reported the synthesis of di-
hydrothiophene ureidoformamides by domino reactions of
1,3-thiazolidinedione in acetonitrile using organic amines as
College of Chemical Engineering, Nanjing University of Science and
Technology, 200 Xiaoling Wei, Nanjing, 210094, China.
E-mail: c.cai@mail.njust.edu.cn; Fax: +86 25 84315030; Tel: +86 25
84315514
† Electronic supplementary information (ESI) available: Copies of NMR
spectra for the all compounds. See DOI: 10.1039/c0gc00884b
998 | Green Chem., 2011, 13, 998–1003
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Table 1 Solvent effects on the reactiona
Entry
T/◦C
Solvent (v/v)
Yield (%)b
1
2
3
4
5
6
7
8
9
80
H2O
EtOH
CH3CN
Acetone
n-Hexane
DMF
PEG 400
PEG 400/H2O(1 : 1)
EtOH/H2O(1 : 1)
19
23
Trace
Trace
Trace
Trace
43
Reflux
Reflux
Reflux
Reflux
80
80
80
74
57
80
a Reaction conditions: after 1a (2 mmol) and 2 (2.2 mmol) were stirred
for 10 min in solvent (4 ml), 3 (2 mmol) and 4a (2 mmol) were added
and stirred for additional 8 h. b Isolated yield.
main side prodcut in the reaction. The reasons for this could
be explained as follows. (1) The use of PEG 400 increases the
solubility of reactants, which leads to larger interfacial area,
lower mass transfer resistance.10 (2) The promoting effects of
water to the reaction could be attributed to its hydrophobic,
polarity and hydro-bonding effects.11 Hydrophobic effect: The
hydrophobic effect leads to high negative volume of activation
which means greater stabilization of activated complexes than
hydrophobic reactants in the reaction. Polarity effect: The high
polarity of water results in the more polar translated states
than initial states, so the reaction speed can be increased.
Hydrogen-bonding effect: Water could activate the reactants and
intermediate products by forming the hydrogen bonds with
the carbonyl oxygen and hydroxyl oxygen respectively (Scheme
1), making them easy to form corresponding products. It was
found that only polar protic solvents could give the desired
product, and the hydrogen-bonding effect is the main differ-
ence between polar protic solvents and other solvents, so the
hydrogen-bonding effect may be the key factor to promote the
reaction.
Scheme 1 A plausible mechanism for the formation of dihydrothio-
phene ureidoformamides from 1, 2, 3 and 4.
cyclohexane aldehyde 1e in place of aromatic aldehydes could
react with 2, 3 and 4, and the target products 7a–i could be
obtained (Table 4). Although the protocol could accept a wide
variety of aldehydes 1 and amines 4, we were unable to extend it
to other active methylene compounds including ethyl cyanocae-
tate, 3-cyanoacetylindole instead of malononitrile. Further, it
was noteworthy that the reaction of aldehydes 1, malononitrile
2, 1,3-thiazolidinedione 3 and diamines 4k–m could afford
the bis-dihydrothiophene ureidoformamido compounds 8a–d
(Table 5).
Encouraged by the remarkable results, we decided to use
various aromatic aldehydes and aromatic amines to ascertain
the scope and generality of the protocol, and a serious of
dihydrothiophene ureidoformamides 5a–h were prepared in
moderate to good yields (Table 2). The reaction was not affected
obviously by the characteristics of the substituent group on
aniline or benzaldehyde. In addition, 1-naphthaldehyde, 1-
naphthalenamine and aminopyridine were also applied to the
protocol successfully.
Efforts were also made to expand the scope of the method to
aliphatic amines, and the results were summarized in Table 3.
Various primary and secondary amines were employed, and af-
forded the desired products 6a–h. However, we failed to use other
amines including benzyl amine, formamide, aminoethanol, 5-
aminotetrazole in the protocol, due to the low nucleophilicity of
their amino groups.
The interesting and remarkable results obtained by the
protocol prompted us to explore more details about the reaction
mechanism. The continued research indicated the reaction of 9a
and 3 provided 10a as the final product in the absence of 4a, so
it could be concluded that amine 4 was a necessary reactant to
initiate the ring-opening reaction of thiozolidinedione structure
(Scheme 1). According to the above results, a plausible mecha-
nism for the formation of dihydrothiophene ureidoformamides
from 1, 2, 3 and 4 was illustrated in Scheme 1. First, 9 is formed
by the Knoevenagel condensation of 1 with 2. The second step
is the Michael addition of 3¢ which has better nucleophilic
character than 3, and 9 to yield the adduct A. Then, 4 attacks the
carbonyl group of thiazolidinedione in a ring-opening reaction
to give a sulfide anion B, which intramolecularly nucleophilically
attacks one of the cyano groups to form C.8 Finally, the product
is formed through an imine-enamine tautomerization process. If
there is no amine 4 in the reaction, the ring-opening reaction will
be inhibited, and 10 is produced from 9 and 3¢ as final product.
To further broaden the scope of the reaction, we also focused
on employing aliphatic aldehydes to the protocol. To our delight,
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Table 2 The reaction of aromatic aldehydes, malononitrile, 1,3-thiazolidinedione and aromatic aminesa
Aldehyde
Ar1
Amine
Ar2
Entry
1
4
Product
Yield (%)b
1
2
3
4
5
6
7
8
Ph
4-ClC6H4
4-MeOC6H4
1-Naphthyl
Ph
Ph
Ph
Ph
1a
1b
1c
1d
1a
1a
1a
1a
Ph
Ph
Ph
Ph
4a
4a
4a
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
5f
74
90
68
86
54
76
71
27
4-ClC6H4
4-MeC6H4
1-Naphthyl
2-Pyridyl
5g
5h
a Reaction conditions: after 1 (2 mmol) and 2 (2.2 mmol) were stirred for 10 min in PEG 400/H2O (4 ml v/v = 1 : 1) at 80 ◦C, 3 (2 mmol) and 4
(2 mmol) were added and stirred for additional 8 h at the same temperature. b Isolated yield.
Table 3 The reaction of aromatic aldehydes, malononitrile, 1,3-thiazolidinedione and aliphatic aminesa
Aldehyde
Entry
Ar1
1
4
Product
Yield (%)b
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
1a
1a
1a
1a
1b
1c
1d
1a
Piperidine
Morpholine
4f
4g
4h
4i
4i
4i
4i
4j
6a
6b
6c
6d
6e
6f
51
55
27
63
51
44
54
54
Diethylamine
Cyclohexylamine
Cyclohexylamine
Cyclohexylamine
Cyclohexylamine
Butylamine
4-ClC6H4
4-MeOC6H4
1-Naphthyl
Ph
6g
6h
a Reaction conditions: after 1 (2 mmol) and 2 (2.2 mmol) were stirred for 10 min in PEG 400/H2O (4 ml v/v = 1 : 1) at 80 ◦C, 3 (2 mmol) and 4
(2 mmol) were added and stirred for additional 6 h at the same temperature. b Isolated yield.
yields. The potential to apply the reaction in synthetic and
medicinal chemistry are also quite significant.
Conclusions
The domino reactions of aldehydes, malononitrile, amines and
1,3-thiazolidinedione for formation of dihydrothiophene ureid-
Experimental
oformamides in PEG 400/H2O under catalyst-free conditions
are reported. We have extended the scope of the previously
discovered tandem reactions of 1,3-thiazolidinedione, malonon-
itrile, aromatic aldehydes, and amines. The process provides an
opportunity to avoid toxic solvents and catalysts, and resource
consumption compare to the previous reaction systems. The
protocol is available for large-scale operations, owing to its
simple work-up procedure, shorter reaction time and higher
General procedure for the preparation of dihydrothiophene
ureidoformamides from aldehyde, malononitrile,
1,3-thiazolidinedione and amine
A mixture of aldehyde (2.0 mmol) and malononitrile (2.2 mmol)
in PEG 400/H2O (4.0 ml, v/v = 1 : 1) was stirred at 80 ◦C
for 10 min. Then amine (2.0 mmol) and 1,3-thiazolidinedione
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Table 4 The reaction of cyclohexanaldehyde, malononitrile, 1,3-
127.48, 128.72, 129.42, 129.60, 130.84, 134.38, 136.40, 137.91,
thiazolidinedione and aminesa
150.97, 162.80, 172.88. MS (ESI) m/z: 413 (M-H)-. Anal. calcd
for C23H18N4O2S: C, 66.65; H, 4.38; N, 13.52%, Found: C, 66.68;
H, 4.29; N, 13.74%.
5-Amino-4-cyano-N-(1-naphthylcarbamoyl)-3-phenyl-2,3-dih-
ydrothiophene-2-carboxamide 5g. Mp: 230–232 ◦C; white
1
solid; H NMR (500 MHz, DMSO-d6): d = 4.28 (s, 1H), 4.71
(s, 1H), 7.30–7.34 (m, 3H), 7.40–7.43 (m, 4H), 7.51–7.54 (m,
1H), 7.59–7.62 (m, 1H), 7.70–7.73 (m, 1H), 7.76 (d, 1H, J =
8.0 Hz), 7.99–8.01 (m, 2H), 8.09 (d, 1H, J = 6.5 Hz), 11.01 (br,
2H). 13C NMR (125 MHz, DMSO-d6): d = 52.03, 55.81, 70.93,
118.63, 118.76, 120.87, 125.03, 126.04, 126.28, 126.74, 127.21,
127.61, 128.03, 129.15, 129.25, 132.87, 134.09, 142.10, 151.51,
162.24, 173.60. MS (ESI) m/z: 413 (M-H)-. Anal. calcd for
C23H18N4O2S: C, 66.65; H, 4.38; N, 13.52%, Found: C, 66.71; H,
4.48; N, 13.77%.
Entry
4
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
Aniline
p-Chloroaniline
p-Toluidine
1-Naphthalenamine
Piperidine
Morpholine
Diethylamine
Cyclohexylamine
Butylamine
4a
4b
4c
4d
4f
7a
7b
7c
7d
7e
7f
7g
7h
7i
73
46
68
65
70
34
25
60
65
4g
4h
4i
4j
5-Amino-4-cyano-3-phenyl-N -(pyridin-2-ylcarbamoyl)-2,3-
dihydrothiophene-2-carboxamide 5h. Mp: 202–204 ◦C; white
solid; 1H NMR (500 MHz, DMSO-d6): d = 4.26 (s, 1H), 4.63 (s,
1H), 7.13–7.16 (m, 1H), 7.25 (s, 2H), 7.30–7.41 (m, 5H), 7.80–
7.83 (m, 1H), 7.91 (s, 1H), 8.33 (d, 1H, J = 4.0 Hz), 10.62 (br, 1H),
10.98 (br, 1H). 13C NMR (125 MHz, DMSO-d6): d = 51.84, 56.03,
70.82, 113.53, 118.68, 120.20, 127.60, 128.01, 129.22, 139.07,
142.00, 148.69, 150.89, 151.26, 162.08, 172.92. MS (ESI) m/z:
364 (M-H)-. Anal. calcd for C18H15N5O2S: C, 59.16; H, 4.14; N,
19.17%, Found: C, 59.29; H, 4.43; N, 18.88%.
a Reaction conditions: after 1e (2 mmol) and 2 (2.2 mmol) were stirred
for 10 min in PEG 400/H2O (4 ml v/v = 1 : 1) at 80 ◦C, 3 (2 mmol)
and 4 (2 mmol) were added and stirred for additional 4 h at the same
temperature. b Isolated yield.
Table 5 The
reaction
of
aldehydes,
malononitrile,
1,3-
thiazolidinedione and diaminesa
N-[(5-Amino-4-cyano-3-phenyl-2,3-dihydrothiophen-2-yl)car-
bonyl]morpholine-4-carboxamide 6b. Mp: 216–218 ◦C; white
1
solid; H NMR (500 MHz, DMSO-d6): d = 3.35 (d, 4H, J =
5.5 Hz), 3.54–3.56 (m, 4H), 4.42 (s, 1H), 4.60 (d, 1H, J = 2.5
Hz), 7.12 (s, 2H), 7.28–7.31 (m, 3H), 7.36–7.39 (m, 2H), 10.09
(s, 1H). 13C NMR (125 MHz, DMSO-d6): d = 45.13 51.48, 56.13,
66.30, 71.24, 118.88, 127.49, 127.88, 129.23, 142.75, 152.85,
162.20, 171.40. MS (ESI) m/z: 357 (M-H)-. Anal. calcd for
C17H18N4O3S: C, 56.97; H, 5.06; N, 15.63%, Found: C, 57.06; H,
5.28; N, 15.44%.
Entry
Aldehyde
Diamine
Time/h
Product
Yield (%)b
1
2
3
4
1a
1a
1a
1e
4k
4l
4m
4m
10
8
8
8a
8b
8c
8d
87
84
76
65
6
a Reaction conditions: after 1 (2 mmol) and 2 (2.2 mmol) were stirred
for 10 min in PEG 400/H2O (4 ml v/v = 1 : 1) at 80 ◦C, 3 (2 mmol) and
4 (1 mmol) were added and stirred for the period of time listed in Table
5 at the same temperature. b Isolated yield.
5-Amino-4-cyano-N-(cyclohexylcarbamoyl)-3-phenyl-2,3-dih-
ydrothiophene-2-carboxamide 6d. Mp: 228–230 ◦C; white
solid; 1H NMR (500 MHz, DMSO-d6): d = 1.25–1.35 (m, 5H),
1.54 (d, 1H, J = 12 Hz), 1.64 (d, 2H, J = 8.0 Hz), 1.81 (d, 2H, J =
5.0 Hz), 3.56 (s, 1H), 4.08 (s, 1H), 4.55 (d, 1H, J = 2.0 Hz), 7.20
(s, 2H), 7.29–7.39 (m, 5H), 8.17 (s, 1H), 10.43 (s, 1H). 13C NMR
(125 MHz, DMSO-d6): d = 24.62, 25.51, 32.70, 48.33, 51.99,
55.66, 70.89, 118. 64, 127.57, 127.96, 129.20, 141.99, 152.46,
162.19, 172.40. MS (ESI) m/z: 369 (M-H)-. Anal. calcd for
C19H22N4O2S: C, 61.60; H, 5.99; N, 15.12%, Found: C, 61.37; H,
5.83; N, 15.40%.
(2.0 mmol) were added and the reaction was stirred at the same
temperature for several hours monitored by TLC. After the
reaction completed, water (10 ml) was added to the mixture,
and the precipitate was separated by filtration and washed with
water. The crude product was recrystallized or washed with a
mixture of ethanol and n-hexane to give the pure product.
Data for unknown compounds
5-Amino-3-(4-chlorophenyl)-4-cyano-N-(cyclohexylcarbamo-
yl)-2,3-dihydrothiophene-2-carboxamide 6e. Mp: 240–242 ◦C;
white solid; 1H NMR (500 MHz, DMSO-d6): d = 1.19–1.32 (m,
5H), 1.52 (s, 1H), 1.63 (s, 2H), 1.80 (s, 2H), 3.55 (s, 1H), 4.03 (s,
1H), 4.55 (s, 1H), 7.26 (s, 2H), 7.34 (d, 2H, J = 7.5 Hz), 7.44 (d,
2H, J = 8.0 Hz), 8.16 (s, 1H), 10.44 (s, 1H). 13C NMR (125 MHz,
DMSO-d6): d = 24.62, 25.49, 32.70, 48.49, 51.20, 55.51, 70.51,
118.52, 129.15, 129.52, 132.54, 140.95, 152.47, 162.47, 172.27.
5-Amino-4-cyano-3-(naphthalen-1-yl)-N-(phenylcarbamoyl)-
2,3-dihydrothiophene-2-carboxamide 5d. Mp: 236–238 ◦C;
1
white solid, H NMR (500 MHz, DMSO-d6): d = 4.15 (s, 1H),
5.46 (s, 1H), 7.10–7.13 (m, 1H), 7.34–7.40 (m, 4H), 7.47 (d, 1H,
J = 7.0 Hz), 7.57–7.66 (m, 5H), 7.91–7.95 (m, 2H), 8.03 (d,
1H, J = 8.0 Hz). 13C NMR (125 MHz, DMSO-d6): d = 55.10,
69.25, 118.64, 120.31, 122.87, 124.35, 124.94, 126.08, 126.44,
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MS (ESI) m/z: 403 (M-H)-. Anal. calcd for C19H21ClN4O2S: C,
56.36; H, 5.23; N, 13.84%, Found: C, 56.44; H, 5.09; N, 13.68%.
for C19H21ClN4O2S: C, 56.36; H, 5.23; N, 13.84%, Found: C,
56.40; H, 5.37; N, 13.81%.
5-Amino-4-cyano-3-cyclohexyl-N-(p-tolylcarbamoyl)-2,3-dih-
ydrothiophene-2-carboxamide 7c. Mp: 216–218 ◦C; white solid;
1H NMR (500 MHz, DMSO-d6): d = 1.14–1.23 (m, 5H), 1.52
(s, 1H), 1.67–1.74 (m, 5H), 2.26 (s, 3H), 3.29 (s, 1H), 4.20 (s,
1H), 6.98 (s, 2H), 7.13 (d, 2H, J = 7.0 Hz), 7.41 (d, 2H, J =
7.0 Hz), 10.17 (s, 1H), 10.70 (s, 1H). 13C NMR (125 MHz,
DMSO-d6): d = 20.85, 26.25, 26.36, 26.47, 29.27, 29.57, 42.29,
50.80, 52.37, 52.80, 68.70, 119.37, 120.23, 133.30, 135.32, 151.00,
161.84, 173.57. MS (ESI) m/z: 383 (M-H)-. Anal. calcd for
C20H24N4O2S: C, 62.48; H, 6.29; N, 14.57%, Found: C, 62.37; H,
6.36; N, 14.82%.
5-Amino-4-cyano-N -(cyclohexylcarbamoyl)-3-(4-methoxy-
phenyl)-2,3-dihydrothiophene-2-carboxamide 6f. Mp: 224–226
◦C; white solid; 1H NMR (500 MHz, DMSO-d6): d = 1.19–1.35
(m, 5H), 1.53 (d, 1H, J = 12.5 Hz), 1.63 (s, 2H), 1.80 (d, 2H,
J = 5 Hz), 3.55 (s, 1H), 3.75 (s, 3H), 4.01 (s, 1H), 4.50 (d, 1H,
J = 2.0 Hz), 6.93 (d, 2H, J = 8.5 Hz), 7.17–7.22 (m, 4H), 8.17 (s,
1H), 10.44 (s, 1H). 13C NMR (125 MHz, DMSO-d6): d = 24.63,
25.49, 48.31, 51.40, 55.57, 55.88, 71.19, 114.56, 118.70, 128.69,
133.77, 152.45, 159.13, 161.85, 172.44. MS (ESI) m/z: 399 (M-
H)-. Anal. calcd for C20H24N4O3S: C, 59.98; H, 6.04; N, 13.99%,
Found: C, 60.02; H, 5.99; N, 13.87%.
5-Amino-4-cyano-3-cyclohexyl-N -(naphthalen-1-ylcarbam-
oyl)-2,3-dihydrothiophene-2-carboxamide 7d. Mp: 208–210 ◦C;
white solid; 1H NMR (500 MHz, DMSO-d6): d = 1.14–1.25 (m,
5H), 1.56 (s, 1H), 1.65 (d, 1H, J = 11.0 Hz), 1.74 (s, 4H), 3.38
(d, 1H, J = 2.5 Hz), 4.28 (s, 1H), 7.05 (s, 2H), 7.50–7.54 (m,
1H), 7.57–7.60 (m, 1H), 7.66–7.70 (m, 1H), 7.74 (d, 1H, J =
8.5 Hz), 7.95–7.99 (m, 2H), 8.10 (d, 1H, J = 7.5 Hz), 11.00 (br,
2H). 13C NMR (125 MHz, DMSO-d6): d = 26.28, 26.40, 26.50,
29.30, 29.50, 42.50, 50.51, 52.92, 68.68, 118.51, 119.46, 120.80,
124.97, 125.95, 126.26, 126.71, 127.19, 129.13, 132.85, 134.06,
151.50, 161.94, 174.39. MS (ESI) m/z: 419 (M-H)-. Anal. calcd
for C23H24N4O2S: C, 65.69; H, 5.75; N, 13.32%, Found: C, 65.77;
H, 6.03; N, 13.62%.
5-Amino-4-cyano-N-(cyclohexylcarbamoyl)-3-(naphthalen-1-
yl)-2,3-dihydrothiophene-2-carboxamide 6g. Mp: 238–240 ◦C;
white solid; H NMR (500 MHz, DMSO-d6): d = 1.22–1.31
1
(m, 5H), 1.54 (s, 1H), 1.67 (s, 2H), 1.85 (s, 2H), 3.57 (s, 1H),
4.04 (s, 1H), 5.39 (s, 1H), 7.36 (s, 2H), 7.44 (d, 1H, J = 7.0 Hz),
7.58–7.63 (m, 3H), 7.84 (d, 1H, J = 7.0 Hz), 7.93 (d, 1H, J = 7.5
Hz), 8.02 (d, 1H, J = 7.5 Hz), 8.19 (s, 1H), 10.47 (s, 1H). 13C
NMR (125 MHz, DMSO-d6): d = 24.69, 25.51, 32.69, 48.52,
55.05, 69.26, 118.61, 122.73, 124.93, 126.06, 126.41, 127.41,
128.67, 129.60, 130.84, 134.37, 136.41, 152.37, 162.81, 172.54.
MS (ESI) m/z: 419 (M-H)-. Anal. calcd for C23H24N4O2S: C,
65.69; H, 5.75; N, 13.32%, Found: C, 65.44; H, 5.68; N, 13.53%.
5-Amino-N-(butylcarbamoyl)-4-cyano-3-(naphthalen-1-yl)-2,
3-dihydrothiophene-2-carboxamide 6h. Mp: 228–230 ◦C; white
N -(5-Amino-4-cyano-3-cyclohexyl-2,3-dihydrothiophene-2-
carbonyl)piperidine-1-carboxamide 7e. Mp: 200–202 ◦C; white
solid; 1H NMR (500 MHz, DMSO-d6): d = 1.07–1.18 (m, 6H),
1.47–1.72 (m, 13H), 3.34 (s, 3H), 4.40 (s, 1H), 6.86 (s, 2H), 9.92
(s, 1H). 13C NMR (125 MHz, DMSO-d6): d = 24.24, 25.92,
26.27, 26.38, 26.49, 29.28, 29.71, 42.38, 45.58, 50.59, 51.92,
68.89, 119.56, 152.57, 161.99, 172.01. MS (ESI) m/z: 361 (M-
H)-. Anal. calcd for C18H26N4O2S: C, 59.64; H, 7.23; N, 15.46%,
Found: C, 59.74; H, 7.01; N, 15.65%.
1
solid; H NMR (500 MHz, DMSO-d6): d = 0.88–0.91 (s, 3H),
1.26–1.34 (m, 2H), 1.43–1.48 (m, 2H), 3.16 (d, 2H, J = 6.5 Hz),
4.10 (s, 1H), 4.56 (d, 1H, J = 2.5 Hz), 7.20 (s, 2H), 7.29–7.32 (m,
3H), 7.37–7.40 (m, 2H), 8.20 (br, 1H), 10.40 (s, 1H). 13C NMR
(125 MHz, DMSO-d6): d = 14.06, 19.97, 31.67, 39.15, 52.10,
55.66, 70.82, 118.65, 127.57, 127.97, 129.21, 141.99, 153.30,
162.19, 172.08. MS (ESI) m/z: 343 (M-H)-. Anal. calcd for
C17H20N4O2S: C, 59.28; H, 5.85; N, 16.27%, Found: C, 59.22; H,
5.69; N, 16.34%.
N -(5-Amino-4-cyano-3-cyclohexyl-2,3-dihydrothiophene-2-
carbonyl)morpholine-4-carboxamide 7f. Mp: 194–196 ◦C;
5-Amino-4-cyano-3-cyclohexyl-N-(phenylcarbamoyl)-2,3-dih-
ydrothiophene-2-carboxamide 7a. Mp: 226–228 ◦C; white
solid; 1H NMR (500 MHz, DMSO-d6): d = 1.08–1.24 (m, 5H),
1.52 (s, 1H), 1.64–1.75 (m, 5H), 3.30 (d, 1H, J = 13.5 Hz), 4.20
(s, 1H), 6.99 (s, 2H), 7.08–7.11 (m, 1H), 7.32–7.35 (m, 2H), 7.54
(d, 2H, J = 8.0 Hz), 10.23 (s, 1H), 10.72 (s, 1H). 13C NMR
(125 MHz, DMSO-d6): d = 26.25, 26.36, 26.47, 29.30, 29.57,
42.31, 50.41, 52.81, 68.73, 119.36, 120.25, 124.28, 129.39, 137.88,
151.05, 161.83, 173.61. MS (ESI) m/z: 369 (M-H)-. Anal. calcd
for C19H22N4O2S: C, 61.60; H, 5.99; N, 15.12%, Found: C, 61.42;
H, 5.88; N, 15.31%.
1
white solid; H NMR (500 MHz, DMSO-d6): d = 1.13–1.23
(m, 5H), 1.47 (s, 1H), 1.65–1.73 (m, 5H), 3.32 (d, 1H, J = 2.5
Hz), 3.37 (s, 4H), 3.57 (s, 4H), 4.39 (s, 1H), 6.87 (s, 2H), 10.01 (s,
1H). 13C NMR (125 MHz, DMSO-d6): d = 26.26, 26.38, 26.48,
29.35, 29.64, 42.45, 45.10, 50.70, 51.86, 66.34, 68.89, 119.57,
152.88, 161.96, 172.03. MS (ESI) m/z: 363 (M-H)-. Anal. calcd
for C17H24N4O3S: C, 56.02; H, 6.64; N, 15.37%, Found: C, 56.14;
H, 7.02; N, 15.18%.
5-Amino-4-cyano-3-cyclohexyl-N -(diethylcarbamoyl)-2,3-
dihydrothiophene-2-carboxamide 7g. Mp: 192–194 ◦C; white
solid; 1H NMR (500 MHz, DMSO-d6): d = 1.00–1.23 (m, 11H),
1.47 (br, 1H), 1.65–1.73 (m, 5H), 3.27–3.34 (m, 5H), 4.48 (s,
1H), 6.861 (s, 2H), 9.74 (s, 1H).13C NMR (125 MHz, DMSO-
d6): d = 13.98, 26.26, 26.36, 26.49, 29.31, 29.77, 41.62, 42.34,
50.79, 51.80, 68.89, 119.59, 152.81, 162.00, 172.40. MS (ESI)
m/z: 349 (M-H)-. Anal. calcd for C17H26N4O2S: C, 58.26; H,
7.48; N, 15.99%, Found: C, 58.14; H, 7.20; N, 15.92%.
5-Amino-N-(4-chlorophenylcarbamoyl)-4-cyano-3-cyclohexyl-
2,3-dihydrothiophene-2-carboxamide 7b. Mp: 220–222 ◦C;
1
white solid; H NMR (500 MHz, DMSO-d6): d = 1.16–1.24
(m, 5H), 1.52 (s, 1H), 1.63–1.74 (m, 5H), 3.28 (d, 1H, J = 2.5
Hz), 4.19 (s, 1H), 6.99 (s, 2H), 7.38 (d, 2H, J = 8.5 Hz), 7.59
(s, 2H, J = 8.5 Hz), 10.28 (s, 1H), 10.78 (s, 1H). 13C NMR
(125 MHz, DMSO-d6): d = 26.24, 26.35, 26.47, 29.32, 29.52,
42.30, 50.41, 52.77, 68.67, 119.37, 121.96, 127.95, 129.22, 136.91,
151.10, 161.84, 173.52. MS (ESI) m/z: 403 (M-H)-. Anal. calcd
N -(5-Amino-4-cyano-3-cyclohexyl-2,3-dihydrothiophene-2-
carbonyl)piperidine-1-carboxamide 7h. Mp: 224–226 ◦C; white
1002 | Green Chem., 2011, 13, 998–1003
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solid; 1H NMR (500 MHz, DMSO-d6): d = 1.01–1.34 (m, 10H),
1.48–1.54 (m, 2H), 1.64–1.80 (m, 9H), 3.21 (s, 1H), 3.54 (s, 1H),
4.09 (s, 1H), 6.94 (s, 2H), 8.13 (s, 1H), 10.39 (s, 1H). 13C NMR
(125 MHz, DMSO-d6): d = 19.01, 24.60, 25.59, 26.25, 26.34,
26.47, 29.20, 29.59, 32.66, 42.22, 48.28, 50.18, 52.82, 56.49,
68.76, 119.32, 152.49, 161.82, 173.25. MS (ESI) m/z: 375 (M-
H)-. Anal. calcd for C19H28N4O2S: C, 60.61; H, 7.50; N, 14.88%,
Found: C, 60.59; H, 7.26; N, 14.94%.
N,N¢-(Butane-1,4-diylbis(azanediyl))bis(oxomethylene)bis(5-
amino-4-cyano-3-cyclohexyl-2,3-dihydrothiophene-2-carbox-
amide) 8d. Mp: 210–212 ◦C; brown solid, 1H NMR (500 MHz,
DMSO-d6): d = 1.06–1.21 (m, 10H), 1.44 (s, 6H), 1.63–1.71 (m,
10H), 3.15 (s, 4H), 3.23 (s, 2H), 4.10 (s, 2H), 6.94 (s, 4H), 8.19
(s, 2H), 10.35 (br, 2H). 13C NMR (125 MHz, DMSO-d6): d =
26.26, 26.35, 26.47, 27.09, 27.90, 29.13, 29.62, 39.16, 42.14,
50.14, 52.83, 68.77, 119.34, 153.40, 161.83, 172.87. MS (ESI)
m/z: 641 (M-H)-. Anal. calcd for C30H42N8O4S2: C, 56.05; H,
6.59; N, 17.43%, Found: C, 56.13; H, 6.72; N, 17.66%.
5-Amino-N-(butylcarbamoyl)-4-cyano-3-cyclohexyl-2,3-dih-
ydrothiophene-2-carboxamide 7i. Mp: 198–200 ◦C; white solid;
1H NMR (500 MHz, DMSO-d6): d = 0.86–0.89 (t, 3H), 1.03–
1.31 (m, 10H), 1.41–1.48 (m, 3H), 1.63–1.73 (m, 5H), 3.15 (d,
2H, J = 6.5 Hz) 3.23 (s, 1H), 4.10 (s, 1H), 6.93 (s, 2H), 8.16 (s,
1H), 10.36 (s, 1H). 13C NMR (125 MHz, DMSO-d6): d = 14.03,
19.96, 26.27, 26.35, 26.47, 29.11, 29.63, 31.66, 39.11, 42.14,
50.10, 52.86, 68.74, 119.31, 153.35, 161.79, 172.96. MS (ESI)
m/z: 349 (M-H)-. Anal. calcd for C17H26N4O2S: C, 58.26; H,
7.48; N, 15.99%, Found: C, 58.19; H, 7.64; N, 16.12%.
References
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8a. Mp: 230–232 C; light brown solid, 1H NMR (500 MHz,
DMSO-d6): d = 4.18 (s, 2H), 4.61 (s, 2H), 7.25 (br, 4H), 7.34–7.40
(m, 10H), 7.52 (br, 4H), 10.26 (br, 2H), 10.77 (br, 2H). 13C NMR
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127.59, 128.01, 129.23, 133.83, 141.98, 151.04, 162.21, 172.75.
MS (ESI) m/z: 649 (M-H)-. Anal. calcd for C32H26N8O4S2: C,
59.06; H, 4.03; N, 17.22%, Found: C, 59.09; H, 4.27; N, 16.97%.
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amino-4-cyano-3-p◦henyl-2,3-dihydrothiophene-2-carboxamide)
8b. Mp: 206–208 C; light brown solid, 1H NMR (500 MHz,
DMSO-d6): d = 3.32 (s, 4H), 4.09 (s, 2H), 4.56 (s, 2H), 7.22
(s, 4H), 7.30–7.37 (m, 6H), 7.39 (d, 4H, J = 7.5 Hz), 8.33
(s, 2H), 10.47 (br, 2H). 13C NMR (125 MHz, DMSO-d6):
d = 39.62, 52.08, 55.67, 70.75, 118.71, 127.58, 127.99, 129.23,
141.95, 153.67, 162.24, 171.83. MS (ESI) m/z: 601 (M-H)-.
MS (ESI) m/z: 649 (M-H)-. Anal. calcd for C28H26N8O4S2:
C, 55.80; H, 4.35; N, 18.59%, Found: C, 55.59; H, 4.19; N,
18.47%.
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N ,N¢-(Butane-1,4-diylbis(azanediyl))bis(oxomethylene)bis-
(5-amino-4-cyano-3-phenyl-2,3-dihydrothiophene-2-carbox-
amide) 8c. Mp: 238–240 ◦C; brown solid, 1H NMR (500 MHz,
DMSO-d6): d = 1.47 (s, 4H), 3.18 (s, 4H), 4.09 (s, 2H), 4.57 (s,
2H), 7.22 (s, 4H), 7.31 (d, 6H, J = 7.0 Hz), 7.37–7.40 (m, 4H),
8.25 (s, 2H), 9.82 (br, 2H). 13C NMR (125 MHz, DMSO-d6): d =
27.13, 39.20, 52.06, 55.68, 70.25, 70.79, 118.70, 127.59, 127.98,
129.22, 141.97, 153.36, 162.25, 172.03. MS (ESI) m/z: 629 (M-
H)-. Anal. calcd for C30H30N8O4S2: C, 57.13; H, 4.79; N, 17.77%,
Found: C, 56.89; H, 4.77; N, 17.65%.
This journal is
The Royal Society of Chemistry 2011
Green Chem., 2011, 13, 998–1003 | 1003
©