One-pot synthesis of new tetrasubstituted thiophenes and selenophenes

Article abstract of DOI:10.1016/j.tet.2009.10.021

In this work, we described the synthesis of new tetrasubstituted thiophenes and selenophenes achieved by an easy one-pot four-step procedure. Expected compounds were obtained in good yield from ketene dithioacetals.

Full text of DOI:10.1016/j.tet.2009.10.021

Tetrahedron 65 (2009) 10453–10458
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of new tetrasubstituted thiophenes and selenophenes
a
a
a
a
b
´
David Thomae , Enrico Perspicace , Dorothee Henryon , Zhanjie Xu , Serge Schneider ,
a
a,
c
*
´
Stephanie Hesse , Gilbert Kirsch , Pierre Seck
a
´
´
Laboratoire d’Ingenierie Moleculaire et Biochimie Pharmacologique, Institut Jean Barriol, FR CNRS 2843, 1 Boulevard Arago, 57070 Metz, France
b Laboratoire National de Sante´, Division de Toxicologie, Universite´ de Luxembourg, 162a, Avenue de la Fa¨ıencerie, L-1511 Luxembourg, Luxembourg
c Laboratoire de Chimie, Faculte´ des Sciences, de la Technologie et de la Communication, Universite´ du Luxembourg 162a, Avenue de la Fa¨ıencerie, L-1511 Luxembourg, Luxembourg
a r t i c l e i n f o
a b s t r a c t
Article history:
In this work, we described the synthesis of new tetrasubstituted thiophenes and selenophenes achieved
by an easy one-pot four-step procedure. Expected compounds were obtained in good yield from ketene
dithioacetals.
Received 8 June 2009
Received in revised form
27 September 2009
Accepted 6 October 2009
Available online 13 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Substituted 4-amino-3-cyanothiophenes
Substituted 4-amino-3-selenophenes
Ketene dithioacetals
1. Introduction
1) HNR1R2
NH2
DMF
CN
N
N
2) Na2Y
Thiophene is a major scaffold in heterocyclic chemistry, found in
many compounds.1 Moreover some of them have interesting
properties. It has been showed that they inhibit the growth of
Escherichia coli, Micrococcus luteus, and Aspergillus niger.2 N-(5-
Substituted)-thiophene-2-alkylsulfonamides are potent inhibitors
for 5-lipoxygenase.3 Thienopyridinones are good inhibitors of
R1
EWG
N
Y
3) X-CH2-EWG
4) K2CO3
MeS
SMe
R2
Y = S, Se
X = Cl, Br
NMDA (N-methyl-D
-aspartate) receptor.4 Also, 3-amino-2-nitro-
EWG= CN, CO2Et, Ac, NO2, Bz, p-Cl-C6H4-CO
benzo[b]thiophene was used as starting material for the prepara-
Scheme 1. Synthesis of 2,4,5-trisubstituted-1,3-thiazoles and selenazoles.
tion of dyes.5
One major field of investigation of our team is the synthesis
of heterocyclic compounds with potential biological activity.6
Recently, we described the preparation of 2,4,5-trisubstituted-1,3-
thiazoles and selenazoles from dimethyl cyanodithioimidocar-
bonate using a one-pot four-step procedure (Scheme 1).7
In this work, we extended these methods to access to new tet-
rasubstituted thiophenes and selenophenes from ketene
dithioacetals.
for the preparation of thiophenes and thieno-condensed systems,9
were prepared from malonitrile successfully reacted with a base, an
isothiocyanate, and an activated halide.9a,10 Few years ago, this
method was optimized using ketene N,S-acetals as intermediate
(Scheme 2).9a–c Another possibility to obtain thiophenes substituted
by a secondary amine is to realize an SNAr reaction on substituted
2-methylsulfanylthiophenes (Scheme 2).11,12
In this work, we propose an alternative route using ketene
dithioacetals as starting material. The first step of our strategy was
the preparation of ketene dithioacetals 1,2, respectively, from
malononitrile and 2,4-pentanedione. The expected compounds 1,2
were obtained easily in high yield as reported in literature
(Scheme 3).9
2. Results and discussion
Ketene dithioacetals are versatile starting materials for many
heterocyclic products.8–12 At the laboratory, these compounds, used
Inspired by the methodology we established recently to prepare
2,4,5-trisubstituted thiazoles from dimethyl cyanodithioimido-
carbonate (Scheme 1),7 we have presumed that compounds 3–8
* Corresponding author. Tel.: þ33 3 87 31 52 95; fax: þ33 3 87 31 58 01.
E-mail address: kirsch@univ-metz.fr (G. Kirsch).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.021

10454
D. Thomae et al. / Tetrahedron 65 (2009) 10453–10458
Table 1
NH2
CO2Et
NC
HSCH2CO2Et
DMF
NC
CN
Synthesis of substituted ethyl-2-thiophenecarboxylates 3–8, comparison of
Methods A and B
Ph
HN
Ph
S
N
H
SMe
K2CO3
Compound
Entry
Method A
28%
Method B
43%
NC
NH2
CO2Et
3
NC
NH2
O
N
O
NC
MeS
NH2
NH
S
O
Ph
Ph
N
S
S
O
NH2
CO2Et
NC
N
Δ
O
4
5
6
7
80%
40%
63%
17%
77%
50%
31%
90%
Scheme 2. Two examples of the synthesis of substituted 2-aminothiophenes in
S
literature.
NH2
CO2Et
NC
1) K2CO3
Z
Z
DMF
2) CS2
3) MeI (2 eq)
Z
Z
N
S
N
MeS
SMe
Bn
O
Ac
Me
1 Z = CN 92%
2 Z = Ac 85%
CO2Et
N
S
Scheme 3. Synthesis of ketene dithioacetals.
Ac
Me
CO2Et
Me
CO2Et
could be obtained directly from ketene dithioacetals 1–2. We used
a sequential procedure (Method A, Scheme 4). Compounds 1–2
were dissolved in DMF, then the secondary amine was added and
heated at 70 ꢀC for 75 min. After this time, ethyl thioglycolate and
potassium carbonate were successively added and heated for 3 h.
Expected compounds were obtained in yields ranging from 17% to
80% (Table 1). Ethyl thioglycolate may also be replaced by sodium
sulfide and ethyl bromoacetate (Method B, Scheme 4). After the
formation of the intermediate ketene N,S-acetals, sodium sulfide
was added to form the intermediate thiolate liberating 1 equiv of
methyl thiolate in the reaction media. The first equivalent of ethyl
bromoacetate was consumed by the methyl thiolate so that 2 equiv
of the activated halide were required. Finally, potassium carbonate
was added to perform the cyclization (Method B, Scheme 4).
Compounds 3–8 were obtained in better yields (31–90%) than using
Method A because sodium sulfide is more nucleophilic than ethyl
thioglycolate (Table 1).
N
S
Ac
N
S
8
19%
62%
Moreover sodium sulfide allowed us to extend this method to
activated halides like chloroacetonitrile, chloracetone, and
u-bromo-p-chloroacetophenone and diversify the substitution of
thiophenes in position 5 (Scheme 5).
1) HNR1R2
DMF
2) Na2S.9H2O
NC
NH2
EWG
NC
CN
R1
N
S
MeS
SMe
3) X-CH2-EWG
4) K2CO3
R2
Method A
9-17
1
Z
R
X = Cl, Br
1) HNR1R2
DMF
Z
Z
R1
CO2Et
N
S
MeS
SMe
1) HNR1R2
DMF
2) Na2S.9H2O
2) HSCH2CO2Et (1 eq)
K2CO3
R2
Ac
Me
EWG
Ac
Ac
1 Z= CN
2 Z= Ac
Z= CN, R=NH2
Z= Ac, R=CH3
R1
3-8
N
S
MeS
SMe
3) X-CH2-EWG
4) K2CO3
R2
Method B
2
18-25
Z
Z
S
X = Cl, Br
Z
Z
Z
Z
Na2S.9H2O
EWG = CN, Ac, p-Cl-C6H4-CO
HNR1R2
R1
R1
N
Na
N
SMe
DMF
75 min
70 °C
2 h
Scheme 5. One-pot four-step synthesis of polysubstituted thiophenes.
MeS
SMe
R2
MeSH
R2
70 °C
MeSH
MeS
Na
1 Z= CN
2 Z= Ac
Substituted 3-aminothiophenes 9–17 and substituted 3-methyl-
thiophenes 18–25 were synthesized, respectively, from 1 and 2 in
good yields. In all cases, the best results were obtained adding
2 equiv of the activated halide (Tables 2 and 3).
BrCH2CO2Et
2 eq
2h, 50 °C
In comparison with literature, this one-pot four-step procedure
presents some improvements and advantages. The yields that we
obtained are good and this method is one-step shorter than the
SNAr way. In terms of construction of the thiophene ring, this
strategy is elegant and effective. In the same reaction, substitution
on positions 2 and 5 was determined choosing the appropriate
secondary amine and activated halide. Moreover substitution on
positions 3 and 4 was determined choosing the appropriate ketene
Z
R
Z
Z
S
R1
N
K2CO3
CO2Et
R1
S
N
CO2Et
R2
1h, 50 °C
R2
Z= CN, R=NH2
Z= Ac, R=CH3
3-8
Scheme 4. Synthesis of substituted ethyl-2-thiophenecarboxylates 3–8.

D. Thomae et al. / Tetrahedron 65 (2009) 10453–10458
10455
Table 2
Synthesis of substituted 3-aminothiophenes 9–17
Compound
–NR1R2
Halide used X–CH2–EWG
Chloroacetonitrile (2 equiv)
Entry
Yield (%)
NC
NH2
CN
4-Morpholinyl-
1-Pyrrolidinyl-
4-Benzyl-1-piperazinyl-
9
10
11
74
74
63
R1
N
S
R2
NC
R1
NH2
Ac
4-Morpholinyl-
1-Pyrrolidinyl-
4-Benzyl-1-piperazinyl-
12
13
14
77
90
73
Chloroacetone (2 equiv)
N
S
R2
Cl
NH2
O
NC
R1
4-Morpholinyl-
1-Pyrrolidinyl-
4-Benzyl-1-piperazinyl-
15
16
17
60
80
71
N
u-Bromo-p-chloroacetophenone (2 equiv)
S
R2
Table 3
Synthesis of substituted 3-methylthiophenes 18–25
Compound
–NR1R2
Halide used X–CH2–EWG
Chloroacetonitrile (2 equiv)
Entry
Yield (%)
Ac
Me
CN
4-Morpholinyl-
1-Pyrrolidinyl-
1-Piperidinyl-
18
19
20
44
37
64
R1
N
S
R2
Ac
Me
Ac
4-Morpholinyl-
1-Pyrrolidinyl-
1-Piperidinyl-
21
22
23
55
67
65
R1
Chloroacetone (2 equiv)
N
S
R2
Cl
Me
Ac
R1
N
S
4-Morpholinyl-
1-Piperidinyl-
24
25
92
48
u
-Bromo-p-chloroacetophenone (2 equiv)
O
R2
dithioacetals as starting material. We extend this one-pot four-step
procedure using sodium selenide instead of sodium sulfide to ac-
cess to new tetrasubstituted selenophenes.
Compound 1 was heated at 70 ꢀC during 1 h with a secondary
amine to form the first intermediate (Scheme 6). Sodium selenide
was prepared freshly,13 filtered under an argon atmosphere, and
added to the reaction mixture at 70 ꢀC to form the intermediate
selenolate. After 20 min, the activated halide (2 equiv) was added
dropwise and stirred for two more hours. Cyclizationwas performed
byaddition of potassium carbonate (Scheme 6). Pouring the reaction
mixture in water gave the compounds 26–28 as solids in moderate
to good yields (Table 4). As for the preparation of thiophenes 3–17,
we had to use 2 equiv of activated halide to isolate tetrasubstituted
selenophenes 26–28. We tried to prepare substituted 3-methyl-
selenophenes from compound 2 using this one-pot four-step pro-
cedure but unfortunately the expected compounds could not be
isolated. But it was not really a surprise because in literature, the
synthesis of selenophenes from ketene N,S-acetal 3-[anilino(me-
thylsulfanyl)methylene]-2,4-pentanedione was unsuccessful.14
Table 4
Synthesis of substituted 3-aminoselenophenes 26–29
NC
CN
HNR1R2
DMF
NC
CN
Compound
Halide used X–CH2–EWG
Chloroacetone (2 equiv)
Yield (%)
88
NC
CN
Na2Se
R1
R1
N
Se
NC
NH2
Ac
Na
N
SMe
20 min
70 °C
75 min
70 °C
MeS
SMe
R2
MeSH
R2
MeSH
N
Se
26
MeS
Na
1
X-CH2-EWG
2 eq
2h, 70 °C
Cl
NC
NH2
O
u
-Bromo-p-chloroacetophenone
38
N
(2 equiv)
NH2
EWG
NC
NC
CN
Se EWG
Se
27
NC
K2CO3
R1
R1
N
N
Se
1h, 70 °C
R2
R2
NH2
CN
26-28
X= Cl, Br
EWG= CN, Ac, p-Cl-C6H4-CO
N
Se
N
Bn
Scheme 6. Synthesis of substituted 3-aminoselenophenes: one-pot four-step se-
quential procedure.
28
Chloroacetonitrile (2 equiv)
19

10456
D. Thomae et al. / Tetrahedron 65 (2009) 10453–10458
3. Conclusion
4.4. Synthesis of substituted 3-amino-4-cyanothiophenes
4.4.1. General Method.
Here we demonstrated that our sequential procedure is very
convenient for the synthesis of tetrasubstituted thiophenes and
trisubstituted 3-aminoselenophenes. We determined the condi-
tions to obtain expected compounds in good yields. This method is
shorter than the SNAr pathway. Another advantage is that ketene
dithioacetals 1 and 2 were the same starting material for the
preparation of all thiophenes and selenophenes.
4.4.1.1. Method A. 2-[Bis(methylsulfanyl)methylene]malononi-
trile or 3-[bis(methylsulfanyl)methylene]-2,4-pentanedione
1
2
(0.01 mol) was dissolved in DMF (15 mL). The secondary amine
(0.01 mol) wasadded and the mixturewas heated at 70 ꢀC for 75 min.
Then ethyl thioglycolate (0.01 mol) and potassium carbonate
(0.01 mol) were added and heated for 2 h at 70 ꢀC. The mixture was
poured onto water (100 mL) with good stirring. The precipitate was
filtered, washed with water, and dried at room temperature until
constant weight and purified by recrystallization in ethanol.
4. Experimental section
4.1. General
4.4.1.2. Method B. 2-[Bis(methylsulfanyl)methylene)malononi-
trile 1 or 3-[bis(methylsulfanyl]methylene]-2,4-pentanedione 2
(0.01 mol) was dissolved in DMF (15 mL). The secondary amine
(0.01 mol) was added and the mixture was heated at 70 ꢀC for
75 min. Then, Na2S$9H2O (0.01 mol) was added and heated for 2 h
at 70 ꢀC. The activated halide (0.02 mol) was added dropwise at
70 ꢀC. The mixture was heated at 70 ꢀC for 2 h and the potassium
carbonate was added (0.02 mol). The reaction was stirred at 70 ꢀC
for 90 min more. The mixture was poured onto water (100 mL)
with good stirring. When a precipitate appeared, it was filtered,
washed with water, and dried at room temperature until constant
weight. When a viscous mixture appeared, 25 mL of ether was
added and the precipitate was filtered, washed with water, and
dried at room temperature until constant weight. The isolated solid
was purified by recrystallization in ethanol or acetonitrile.
Melting points were determined on a Stuart SMP3 apparatus
and are uncorrected. IR spectra were performed on a Perkin–Elmer
FT-IR Baragon 1000PC equipped with a Graseby-Specac golden gate
and treated with the Spectrum (Perkin–Elmer) software version
5.3.1. 1H and 13C NMR spectra (
d in ppm) were recorded on an AC
Bruker 250 MHz spectrometer in CDCl3 or DMSO-d6. MS spectra
were recorded on an Agilent Technologies GC–MS instrument
equipped with a 7683 injector, 6890 N gas chromatograph and
a 5973 mass selective detector. The mass spectrometer was oper-
ated in EI mode at 70 eV and MS spectra were recorded from m/z 50
to 650. HMRS were collected on a Bruker MICROTOF-Q ESI/QqTOF
spectrometer.
4.2. Synthesis of 2-[bis(methylsulfanyl)methylene]-
malononitrile (1)
4.4.2. Ethyl 3-amino-4-cyano-5-(4-morpholinyl)-2-thiophenecarboxy-
late (3). Yield: 28% (Method A), 43% (Method B). Colorleꢁs1s solid; mp
0.2 mol of malononitrile was dissolved in DMF (240 mL). Po-
tassium carbonate (0.2 mol) was added and the solution was stirred
for 2 h at room temperature. Carbon disulfide was added dropwise
at 0 ꢀC. The reaction mixture was stirred at room temperature for
2 h. Methyl iodide (0.4 mol) was added dropwise at 0 ꢀC and the
reaction was stirred at room temperature for 3 h. The precipitate
was filtered and the solid was washed with water and dried at room
temperature until constant weight. The compound was used
without further purification for the synthesis of thiophenes and
selenophenes. Only a small portion of the solid was purified by
recrystallization in isopropanol.
133 ꢀC. IR: 3343 (s), 3312 (s), 2200 (s), 1655 (s) cm 1H NMR
.
(250 MHz, DMSO-d6):
2ꢂCH2), 3.71 (m, 4H, 2ꢂCH2), 4.12 (q, J¼7.2 Hz, 2H, CH2), 5.65 (s, 2H,
NH2). 13C NMR (62.5 MHz, DMSO-d6):
14.4, 49.6, 59.3, 65.0, 77.9,
d
1.20 (t, J¼7.5 Hz, 3H, CH3), 3.54 (m, 4H,
d
115.2, 135.1, 155.3, 162.7, 166.6. GC–MS (EI, 70 eV): m/z (%): 281
(100), 253 (33), 236 (20), 209 (36), 195 (14), 177 (18), 151 (9). HRMS
calcd for C12H16N3O3S [MþH]þ 282.0907, found 282.0894.
4.4.3. Ethyl 3-amino-4-cyano-5-(1-pyrrolidinyl)-2-thiophenecarboxy-
late (4). Yield: 80% (Method A), 77% (Method B). Colorless solid; mp
215 ꢀC. IR: 3421 (s), 3319 (s), 2199 (s), 1645 (s) cmꢁ1 1H NMR
.
15
Yield: 92%. Colorless solid; mp 82 ꢀC; mplit : 80–81 ꢀC. IR: 2176
(250 MHz, DMSO-d6):
2ꢂCH2), 3.59 (m, 4H, 2ꢂCH2), 4.19 (q, J¼7.5 Hz, 2H, CH2), 6.68 (s, 2H,
NH2). 13C NMR (62.5 MHz, DMSO-d6):
14.5, 25.2, 51.2, 59.0, 75.0,
d
1.27 (t, J¼7.5 Hz, 3H, CH3), 2.05 (m, 4H,
(s) cmꢁ1. 1H NMR (250 MHz, CDCl3):
d
2.75 (s, 6H, 2ꢂCH3). 13C NMR
(62.5 MHz, CDCl3):
d
19.3, 74.4, 112.7, 185.8.
d
115.9, 162.1, 162.7, 169.4, 170.5. GC–MS (EI, 70 eV): m/z (%): 265
(100), 237 (37), 220 (27), 193 (48). HRMS calcd for C12H16N3O2S
[MþH]þ 266.0958, found 266.0949.
4.3. Synthesis of 3-[bis(methylsulfanyl)methylene]-2,4-
pentanedione (2)
4.4.4. Ethyl
3-amino-5-(4-benzyl-1-piperazinyl)-4-cyano-2-thio-
0.2 mol of 2,4-pentanedione was dissolved in DMF (240 mL).
Potassium carbonate (0.2 mol) was added and the solution was
stirred for 2 h at room temperature. Carbon disulfide was added
dropwise at 0 ꢀC. The reaction mixture was stirred at room tem-
perature for 2 h. Methyl iodide (0.4 mol) was added dropwise at
0 ꢀC and the reaction was stirred at room temperature for 24 h. The
precipitate was filtered and the solid was washed with water and
dried at room temperature until constant weight. The compound
was used without further purification for the synthesis of thio-
phenes and selenophenes. Only a small portion of the solid was
purified by recrystallization in isopropanol.
phenecarboxylate (5). Yield: 40% (Method A), 50% (Method B). Col-
orless solid; mp 122 ꢀC. IR: 3440 (s), 3335 (s), 2196 (s), 1660 (s)
cmꢁ1. 1H NMR (250 MHz, CDCl3):
d
1.30 (t, J¼7.5 Hz, 3H, CH3), 2.60
(m, 4H, 2ꢂCH2), 3.54 (s, 2H, CH2), 3.63 (m, 3H), 3.83 (m, 1H), 4.23 (q,
J¼7.5 Hz, 2H, CH2), 5.81 (s, 2H, NH2), 7.37 (m, 5H, 5ꢂCH). 13C NMR
(62.5 MHz, DMSO-d6):
d 14.4, 49.8, 51.3, 59.2, 77.7, 115.3, 127.1,
128.4, 129.2, 137.4, 162.7, 166.1, 169.4, 175.3, 177.6. GC–MS (EI,
70 eV): m/z (%): 370 (100), 325 (11), 279 (19), 209 (13), 91 (90).
HRMS calcd for C19H23N4O2S [MþH]þ 371.1536, found 371.1515.
4.4.5. Ethyl 4-acetyl-3-methyl-5-(4-morpholinyl)-2-thiophenecarboxy-
late (6). Yield: 63% (Method A), 31% (Method B). Yellow solid; mp
137–138 ꢀC. IR: 2984 (s), 1698 (s), 1661 (s) cmꢁ1. 1H NMR (250 MHz,
16
Yield: 85%. Colorless solid; mp 61 ꢀC; mplit : 61 ꢀC. IR: 2176 (s)
cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
2.37 (s, 6H, 2ꢂCH3); 2.40 (s,
6H, 2ꢂCH3). 13C NMR (62.5 MHz, DMSO-d6):
d
18.5, 30.8, 144.5,
DMSO-d6):
d
1.35 (t, J¼7.2 Hz, 3H, CH3), 2.48 (s, 3H, CH3), 2.56 (s, 3H,
152.8, 197.6.
CH3), 3.08 (m, 4H, 2ꢂCH2), 3.84 (m, 4H, 2ꢂCH2), 4.28 (q, J¼7.2 Hz,

D. Thomae et al. / Tetrahedron 65 (2009) 10453–10458
10457
2H, CH2). 13C NMR (62.5 MHz, DMSO-d6):
d
14.7, 15.8, 29.7, 54.0,
28.4, 57.7, 83.7, 111.8, 116.9, 122.0, 127.1, 204.5. GC–MS (EI, 70 eV):
m/z (%): 235 (77), 220 (100), 192 (34), 167 (30), 70 (14). HRMS calcd
for C11H14N3OS [MþH]þ 236.0852, found 236.0862.
60.6, 66.0, 116.5, 129.8, 145.8, 162.4, 164.7, 198.4. GC–MS (EI, 70 eV):
m/z (%): 297 (100), 280 (57), 252 (25), 197 (26). HRMS calcd for
C14H20NO4S [MþH]þ 298.1108, found 298.1096.
4.4.13. 5-Acetyl-4-amino-2-(4-benzyl-1-piperazinyl)-3-thio-
4.4.6. Ethyl 4-acetyl-3-methyl-5-(1-pyrrolidinyl)-2-thiophenecarboxy-
phenecarbonitrile (14). Yield: 73%. Orange solid; mp 192 ꢀC. IR:
late (7). Yield: 17% (Method A), 90% (Method B). Pale brown solid;
3376 (s), 3288 (s), 3191 (s), 2195 (s), 1623 (s) cmꢁ1 1H NMR
.
mp 103–104 ꢀC. IR: 2962 (s), 1683 (s), 1646 (s) cmꢁ1
.
1H NMR
(250 MHz, DMSO-d6):
(s, 2H, CH2), 3.61 (m, 4H, 2ꢂCH2), 7.31 (m, 5H, 5ꢂCH), 7.47 (s, 2H,
NH2). 13C NMR (62.5 MHz, DMSO-d6):
49.9, 51.2, 60.3, 61.4, 77.6,
d
2.07 (s, 3H, CH3), 2.52 (m, 4H, 2ꢂCH2), 3.52
(250 MHz, DMSO-d6):
d
1.33 (t, J¼7.1 Hz, 3H, CH3), 2.00 (m, 4H,
2ꢂCH2), 2.51 (s, 3H, CH3), 2.60 (s, 3H, CH3), 3.21 (m, 4H, 2ꢂCH2), 4.26
d
(q, J¼7.1 Hz, 2H, CH2). 13C NMR (62.5 MHz, DMSO-d6):
d
14.5, 15.5,
114.8, 115.4, 127.1, 128.2, 128.9, 137.4, 157.0, 166.0. GC–MS (EI,
70 eV): m/z (%): 340 (100), 269 (14), 249 (21), 91 (100), 56 (19).
HRMS calcd for C18H21N4OS [MþH]þ 341.1431, found 341.1418.
25.8, 31.9, 53.0, 60.2, 109.3, 122.2, 145.9, 160.7, 162.9, 198.2. GC–MS
(EI, 70 eV): m/z (%): 281 (100), 266 (36), 238 (29), 197 (28), 70 (16).
HRMS calcd for C14H20NO3S [MþH]þ 282,1158, found 282.1157.
4.4.14. 4-Amino-5-(4-chlorobenzoyl)-2-(4-morpholinyl)-3-thio-
phenecarbonitrile (15). Yield: 60% (Method B). Yellow solid; mp
236 ꢀC. IR: 3371 (s), 3350 (s), 3233 (s), 2198 (s), 1650 (m), 1587 (s)
4.4.7. Ethyl 4-acetyl-3-methyl-5-(4-piperidinyl)-2-thiophenecarbox-
ylate (8). Yield: 19% (Method A), 62% (Method B). Yellow solid; mp
69–70 ꢀC. IR: 2938 (s), 1693 (s), 1667 (s) cmꢁ1. 1H NMR (250 MHz,
cmꢁ1
.
1H NMR (250 MHz, DMSO-d6):
d
3.58 (m, 4H, 2ꢂCH2), 3.70
DMSO-d6):
d
1.31 (t, J¼7.5 Hz, 3H, CH3), 1.63 (m, 4H, 2ꢂCH2), 1.71
(m, 4H, 2ꢂCH2), 7.51 (d, J¼8.3 Hz, 2H, 2ꢂCH), 7.61 (d, J¼8.3 Hz, 2H,
(m, 2H, CH2), 2.51 (s, 3H, CH3), 2.53 (s, 3H, CH3), 3.06 (m, 4H,
2ꢂCH), 7.96 (s, 2H, NH2). 13C NMR (62.5 MHz, DMSO-d6):
d 49.7,
2ꢂCH2), 4.26 (q, J¼7.5 Hz, 2H, CH2). 13C NMR (62.5 MHz, DMSO-d6):
65.0, 77.1, 93.5, 115.0, 128.6, 128.7, 135.2, 139.4, 159.1, 167.5, 182.6.
GC–MS (EI, 70 eV): m/z (%): 347 (100), 288 (34), 261 (15), 236 (8),
208 (5). HRMS calcd for C16H15N3O2SCl [MþH]þ 348.0568, found
348.0549.
d
14.4, 14.8, 23.5, 25.4, 29.2, 56.0, 60.5, 114.9, 128.4, 146.2, 162.7,
166.7, 198.7. GC–MS (EI, 70 eV): m/z (%): 295 (100), 278 (94), 250
(27), 205 (26), 82 (23). HRMS calcd for C15H22NO3S [MþH]þ
296.1315, found 296.1317.
4.4.15. 4-Amino-5-(4-chlorobenzoyl)-2-(1-pyrrolidinyl)-3-thio-
4.4.8. 3-Amino-5-(4-morpholinyl)-2,4-thiophenedicarbonitrile
phenecarbonitrile (16). Yield: 80% (Method B). Yellow solid; mp
(9). Yield: 74% (Method B). Colorless solid; mp 277 ꢀC. IR: 3414 (m),
231 ꢀC. IR: 3427 (m), 3269 (m), 2196 (s), 1555 (s) cmꢁ1 1H NMR
.
3339 (s), 3237 (s), 2200 (m), 2177 (s), 1643 (m) cmꢁ1
.
1H NMR
(250 MHz, DMSO-d6):
7.52 (d, J¼8.3 Hz, 2H, 2ꢂCH), 7.60 (d, J¼8.3 Hz, 2H, 2ꢂCH), 7.98 (s,
2H, NH2). 13C NMR (62.5 MHz, DMSO-d6):
21.6, 51.5, 75.5, 93.2,
d
1.96 (m, 4H, 2ꢂCH2), 3.55 (m, 4H, 2ꢂCH2),
(250 MHz, DMSO-d6):
d
3.51 (m, 4H, 2ꢂCH2), 3.71 (m, 4H, 2ꢂCH2),
6.64 (s, 2H, NH2). 13C NMR (250 MHz, DMSO-d6):
d
49.6, 60.5, 65.0,
d
77.7, 114.8, 115.4, 157.0, 166.4. GC–MS (EI, 70 eV): m/z (%): 234 (100),
176 (60). HRMS calcd for C10H11N4OS [MþH]þ 235.0648, found
235.0645.
115.5, 128.5, 128.6, 135.0, 139.7, 159.5, 163.4, 181.8. GC–MS (EI,
70 eV): m/z (%): 331 (100), 261 (15), 139 (21), 111 (20). HRMS calcd
for C16H15N3OSCl [MþH]þ 332.0619, found 332.0597.
4.4.9. 3-Amino-5-(1-pyrrolidinyl)-2,4-thiophenedicarbonitrile
(10). Yield: 74%. Colorless solid; mp 206 ꢀC. IR: 3387 (s), 3330 (s),
3225 (s), 2176 (s),1648 (m),1534 (s) cmꢁ1.1H NMR (250 MHz, DMSO-
4.4.16. 4-Amino-2-(4-benzyl-1-piperazinyl)-5-(4-chlorobenzoyl)-3-
thiophenecarbonitrile (17). Yield: 71%. Yellow crystal; mp 186 ꢀC. IR:
3387 (s), 3279 (s), 2202 (s), 1584 (s) cmꢁ1 1H NMR (250 MHz,
.
d6):
d
1.96 (m, 4H, 2ꢂCH2), 3.50 (m, 4H, 2ꢂCH2), 6.52 (s, 2H, NH2).13
C
DMSO-d6):
d
2.57 (m, 4H, 2ꢂCH2), 3.59 (s, 2H, CH2), 3.70 (m, 4H,
NMR (62.5 MHz, DMSO-d6):
d
25.2, 51.3, 74.5, 83.4,115.5,115.9,157.3,
2ꢂCH2), 7.38 (m, 5H, 5ꢂCH), 7.60 (d, J¼8.3 Hz, 2H, 2ꢂCH), 7.69 (d,
161.8. GC–MS (EI, 70 eV): m/z (%): 218 (100),190 (14),176 (22). HRMS
calcd for C10H11N4S [MþH]þ 219.0699, found 219.0689.
J¼8.3 Hz, 2H, 2ꢂCH), 8.05 (s, 2H, NH2). 13C NMR (62.5 MHz, DMSO-
d6):
d 50.0, 51.3, 61.3, 77.0, 93.4, 115.0, 127.1, 128.2, 128.5, 128.7,
128.9, 129.1, 135.2, 139.5, 159.2, 167.1, 182.5. GC–MS (EI, 70 eV): m/z
(%): 307 (100), 292 (10), 197 (12), 139 (23), 111 (25), 75 (13). HRMS
calcd for C23H22N4OSCl [MþH]þ 437.1197, found 437.1187.
4.4.10. 3-Amino-5-(4-benzyl-1-piperazinyl)-2,4-thiophenedicarboni-
trile (11). Yield: 63%. Brown solid; mp 181 ꢀC. IR: 3377 (s), 3335 (s),
3234 (s), 2182 (s), 1653 (s) cmꢁ1. 1H NMR (250 MHz, CDCl3):
d 2.47
(m, 4H, 2ꢂCH2), 3.31 (s, 2H, CH2), 3.55 (m, 4H, 2ꢂCH2), 6.61 (s, 2H,
4.4.17. 4-Acetyl-3-methyl-5-(4-morpholinyl)-2-thiophenecarboni-
NH2), 7.27 (m, 5H, 5ꢂCH). 13C NMR (62.5 MHz, CDCl3):
d
49.9, 51.2,
trile (18). Yield: 44%. Pale brown crystal; mp 148 ꢀC. IR: 2916 (s),
60.3, 61.4, 77.6, 114.8, 115.4, 127.1, 128.2, 128.9, 137.4, 157.0, 165.9.
GC–MS (EI, 70 eV): m/z (%): 323 (75), 232 (21), 91 (100), 56 (15).
HRMS calcd for C17H18N5S [MþH]þ 324.1277, found 324.1259.
2202 (s), 1656 (s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
2.37 (s, 3H,
CH3), 2.61 (s, 3H, CH3), 3.09 (m, 4H, 2ꢂCH2), 3.86 (m, 4H, 2ꢂCH2).
13C NMR (62.5 MHz, DMSO-d6):
18.8, 31.0, 51.5, 66.5, 103.5, 113.5.
d
135.0, 149.9, 159.5, 193.1. GC–MS (EI, 70 eV): m/z (%): 250 (100), 233
(71), 219 (14), 192 (35), 177 (50), 164 (39), 150 (45). HRMS calcd for
C12H15N2O2S [MþH]þ 251.0849, found 251.0846.
4.4.11. 5-Acetyl-4-amino-2-(4-morpholinyl)-3-thiophenecarbonitrile
(12). Yield: 77% (Method B). Colorless solid; mp 244 ꢀC (dec). IR:
3408 (s), 3305 (s), 2196 (s), 1595 (s) cmꢁ1 1H NMR (250 MHz,
.
DMSO-d6):
d
2.09 (s, 3H, CH3), 3.58 (m, 4H, 2ꢂCH2), 3.73 (m, 4H,
4.4.18. 4-Acetyl-3-methyl-5-(1-pyrrolidinyl)-2-thiophenecarbonitrile
2ꢂCH2), 7.47 (s, 2H, NH2). 13C NMR (62.5 MHz, DMSO-d6):
d
27.8,
(19). Yield: 37%. Brown crystal; mp 100–101 ꢀC. IR: 2919 (m), 2193
49.7, 65.0, 77.5, 115.1, 128.6, 130.8, 166.2, 186.3. GC–MS (EI, 70 eV):
m/z (%): 251 (100), 236 (87), 208 (15),193 (10),178 (37). HRMS calcd
for C11H14N3O2S [MþH]þ 252.0801, found 252.0802.
(s), 1662 (s), 1639 (s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
1.97 (m,
4H, 2ꢂCH2), 2.36 (s, 3H, CH3), 2.38 (s, 3H, CH3), 3.15 (m, 4H, 2ꢂCH2).
13C NMR (62.5 MHz, DMSO-d6):
17.1, 26.0, 31.3, 54.2, 115.6, 119.6,
d
143.2, 149.1, 162.3, 195.6. GC–MS (EI, 70 eV): m/z (%): 234 (100), 217
(33), 201 (13), 191 (53), 178 (20), 150 (46), 70 (42). HRMS calcd for
C12H15N2OS [MþH]þ 235.0900, found 235.0902.
4.4.12. 5-Acetyl-4-amino-2-(1-pyrrolidinyl)-3-thiophenecarbonitrile
(13). Yield: 90%. Orange solid; mp 254 ꢀC (dec). IR: 3375 (m), 3285
(m), 2949 (m), 2196 (s), 1586 (s), 1621 (s) cmꢁ1. 1H NMR (250 MHz,
DMSO-d6):
d
1.98 (m, 4H, 2ꢂCH2), 2.05 (s, 3H, CH3), 3.58 (m, 4H,
4.4.19. 4-Acetyl-3-methyl-5-(4-piperidinyl)-2-thiophenecarbonitrile
(20). Yield: 64%. Brown crystal; mp 118–119 ꢀC. IR: 2928 (s), 2200
2ꢂCH2), 7.54 (s, 2H, NH2). 13C NMR (62.5 MHz, DMSO-d6):
d
22.0,

10458
D. Thomae et al. / Tetrahedron 65 (2009) 10453–10458
(s), 1668 (s) cmꢁ1
.
1H NMR (250 MHz, DMSO-d6):
d
1.55 (m, 2H,
dried at room temperature until constant weight. The isolated solid
was purified by recrystallization in acetonitrile.
CH2), 1.68 (m, 4H, 2ꢂCH2), 2.31 (s, 3H, CH3), 2.45 (s, 3H, CH3), 3.00
(m, 4H, 2ꢂCH2). 13C NMR (62.5 MHz, DMSO-d6):
d
14.8, 23.3, 24.9,
No satisfying 13C NMR spectra were obtained for these three
compounds: due to their very low solubility, recording 13C NMR
spectra required long time accumulation and those products were
not stable in solution for a long time.
28.7, 56.0, 93.8, 114.7, 126.1, 150.2, 168.3, 196.6. GC–MS (EI, 70 eV):
m/z (%): 248 (80), 231 (100), 83 (23), 55 (14). HRMS calcd for
C13H17N2OS [MþH]þ 249.1056, found 249.1046.
4.5.1. 5-Acetyl-4-amino-2-(1-pyrrolidinyl)-3-selenophenecarboni-
4.4.20. 2,4-Diacetyl-3-methyl-5-(4-morpholinyl)-2-thiophene
trile (26). Yield: 88%. Brown solid; mp 279 ꢀC. IR: 3340 (s), 3270 (s),
(21). Yield: 55%. Pale brown crystal; mp 92–93 ꢀC. IR: 2971 (s),
3171 (s), 2955 (m), 2193 (s), 1623 (s), 1577 (s), 1540 (s) cmꢁ1 1H
.
1675 (s), 1642 (s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d 2.46 (s, 3H,
NMR (250 MHz, DMSO-d6):
d
2.01 (m, 7H, 2ꢂCH2þCH3), 3.57 (m,
CH3), 2.63 (s, 3H, CH3), 2.72 (s, 3H, CH3), 3.10 (m, 4H, 2ꢂCH2), 3.84
(m, 4H, 2ꢂCH2). 13C NMR (62.5 MHz, DMSO-d6):
d 16.4, 18.8, 26.9,
4H, 2ꢂCH2), 7.61 (s, 2H, NH2). GC–MS (EI, 70 eV): m/z (%): 283 (74),
268 (100), 240 (22). HRMS calcd for C11H14N3OSe [MþH]þ
284.0297, found 284.0280.
29.9, 31.4, 134.6, 139.1, 144.4, 155.3, 190.1, 195.7. GC–MS (EI, 70 eV):
m/z (%): 267 (100), 252 (67), 208 (27), 194 (49), 167 (33). HRMS
calcd for C13H18NO3S [MþH]þ 268.1002, found 268.0992.
4.5.2. 4-Amino-5-(4-chlorobenzoyl)-2-(1-piperidinyl)-3-selenophe-
necarbonitrile (27). Yield: 38%. Brown solid; mp 177 ꢀC. IR: 3397 (s),
4.4.21. 2,4-Diacetyl-3-methyl-5-(1-pyrrolidinyl)-2-thiophene
3260 (s), 2952 (m), 2194 (s), 1580 (s), 1538 (s) cmꢁ1 1H NMR
.
(22). Yield: 67%. Yellow crystal; mp 120–121 ꢀC. IR: 2969 (m), 1666
(m), 1621 (s) cmꢁ1 1H NMR (250 MHz, DMSO-d6):
. d 2.00 (m, 4H,
(250 MHz, DMSO-d6):
d
1.62 (m, 6H, 3ꢂCH2), 3.63 (m, 4H, 2ꢂCH2),
7.55 (m, 4H, 4ꢂCH), 7.97 (s, 2H, NH2). GC–MS (EI, 70 eV): m/z (%):
393 (100), 336 (8), 309 (15), 282 (14), 254 (11). HRMS calcd for
C17H17N3OSe [MþH]þ 394.0218, found 394.0195.
2ꢂCH2), 2.38 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.43 (s, 3H, CH3), 3.24
(m, 4H, 2ꢂCH2). 13C NMR (62.5 MHz, DMSO-d6):
d 16.2, 25.8, 29.7,
32.3, 53.4 120.7, 122.9, 144.5, 160.3, 189.4, 199.2. GC–MS (EI, 70 eV):
m/z (%): 251 (100), 236 (49), 208 (39), 167 (30), 70 (14). HRMS calcd
for C13H18NO2S [MþH]þ 252.1053, found 252.1049.
4.5.3. 3-Amino-5-(4-benzyl-1-piperazinyl)-2,4-selenophenedicarbo-
nitrile (28). Yield: 19%. Yellow solid; mp 158 ꢀC. IR: 3388 (s), 3328
(s), 3230 (s), 2172 (s), 1644 (s), 1550 (s), 1520 (s) cmꢁ1 1H NMR
.
4.4.22. 2,4-Diacetyl-3-methyl-5-(4-piperidinyl)-2-thiophene
(250 MHz, CDCl3):
d
2.60 (m, 4H, 2ꢂCH2), 3.63 (m, 6H,
(23). Yield: 65%. Colorless crystal; mp 112–113 ꢀC. IR: 2916 (m),
1686 (m), 1634 (s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d 1.53 (m,
2ꢂCH2þCH2), 4.79 (s, 2H, NH2), 7.30 (m, 5H, 5ꢂCH). GC–MS (EI,
70 eV): m/z (%): 371 (41), 280 (10), 262 (8). HRMS calcd for
C17H18N5Se [MþH]þ 372.0723, found 372.0696.
2H, CH2), 1.66 (m, 4H, 2ꢂCH2), 2.38 (s, 3H, CH3), 2.40 (s, 3H, CH3),
2.45 (s, 3H, CH3), 3.03 (m, 4H, 2ꢂCH2). 13C NMR (62.5 MHz, DMSO-
d6):
d 15.5, 23.5, 24.9, 29.9, 30.2, 56.5, 125.3, 128.6, 144.7, 166.4,
References and notes
190.3, 199.1. GC–MS (EI, 70 eV): m/z (%): 211 (52), 196 (100), 181
(12), 124 (15), 83 (14), 69 (4).
1. (a) Russell, R. K.; Press, J. B. In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. W. F., Padwa, A., Eds.; Pergamon: New York, NY,
1996; Vol. 2, pp 679–729; (b) Jesberger, M.; Davis, T. P.; Barner, L. Synthesis
2003, 1929; (c) The Chemistry of Heterocyclic Compounds: Thiophenes and its
Derivatives; Gronowitz, S., Ed.; Wiley: New York, NY, 1991; Vol. 44.
2. Morley, J. O.; Matthews, T. P. Org. Biomol. Chem. 2006, 4, 359.
3. Beers, S. A.; Malloy, E. A.; Wu, W.; Wachter, M.; Ansell, J.; Singer, M.; Steber, M.;
Barbone, A.; Kirchner, T.; Ritchie, D.; Argentieri, D. Bioorg. Med. Chem.1997, 5, 779.
4. Buschtaller, H.-P.; Siebert, C.; Steimetz, R.; Frank, A.; Berger, M.; Gottschlisich,
R.; Leibrock, J.; Krug, M.; Steinhilber, D.; Noe, C. J. Med. Chem. 2006, 49, 864.
5. Hallas, G.; Towns, A. D. Dyes Pigments 1997, 3, 219.
6. (a) Hesse, S.; Perspicace, E.; Kirsch, G. Tetrahedron Lett. 2007, 48, 5261; (b) Tho-
mae, D.; Kirsch, G.; Seck, P. Synthesis 2007,1027; (c) Seck, P.; Thomae, D.; Kirsch, G.
J. Heterocycl. Chem. 2008, 45, 853; (d) Thomae, D.; Kirsch, G.; Seck, P. Synthesis
2008, 1600; (e) Thomae, D.; Kirsch, G.; Seck, P. Synthesis 2007, 2153; (f) Thomae,
D.; Perspicace, E.; Hesse, S.; Kirsch, G.; Seck, P. Tetrahedron 2008, 64, 9309.
7. Thomae, D.; Perspicace, E.; Xu, Z.; Henryon, D.; Schneider, S.; Hesse, S.; Kirsch,
G.; Seck, P. Tetrahedron 2009, 65, 2982.
8. (a) Gupta, A. K.; Ila, H.; Junjappa, H. Tetrahedron Lett. 1988, 29, 6633; (b) Gupta,
A. K.; Ila, H.; Junjappa, H. Tetrahedron 1990, 46, 2561; (c) Gupta, A. K.; Ila, H.;
Junjappa, H. Tetrahedron 1990, 46, 3703; (d) Singh, O. M.; Junjappa, H.; Ila, H. J.
Chem. Soc., Perkin Trans. 1 1997, 3561; (e) Barun, O.; Patra, P. K.; Ila, H.; Junjappa,
H. Tetrahedron Lett. 1999, 40, 3797; (f) Kishore, K.; Reddy, K. R.; Suresh, J. R.; Ila,
H.; Junjappa, H. Tetrahedron 1999, 55, 7645; (g) Basveshwar Rao, M. V.; Syam
Kumar, U. K.; Junjappa, H. Tetrahedron 1999, 55, 11563; (h) Mehta, B. K.; Nandi,
S.; Ila, H.; Junjappa, H. Tetrahedron 1999, 55, 12843; (i) Barun, O.; Mohanta, P. K.;
Ila, H.; Junjappa, H. Synlett 2000, 653; (j) Kolb, M. Synthesis 1990, 171; (k) To-
minaga, Y. J. Heterocycl. Chem. 1989, 26, 1167; (l) Yokoyama, M.; Togo, H.; Kondo,
S. Sulfur Rep. 1990, 10, 23.
9. (a) Sommen, G.; Comel, A.; Kirsch, G. Tetrahedron 2003, 59, 1557; (b) Sommen,
G.; Comel, A.; Kirsch, G. Synlett 2001, 1731; (c) Sommen, G.; Comel, A.; Kirsch, G.
Synthesis 2003, 735; (d) Sommen, G.; Comel, A.; Kirsch, G. Tetrahedron Lett.
2002, 43, 257.
10. (a) Fishwick, B. R.; Rowles, D. K.; Stirling, C. J. M. J. Chem. Soc., Perkin Trans. 1
1986, 1171; (b) Gewald, K.; Hain, U.; Schmidt, M. J. Prakt. Chem. Leipzig 1986,
328, 459; (c) El-Kousy, S. M.; Mohareb, R. M.; Sherif, S. M. J. Chem. Res., Synop.
1993, 8, 312.
11. Rehwald, M.; Gewald, K.; Bo¨ttcher, G. Heterocycles 1997, 45, 493.
12. Gruner, M.; Bo¨ttcher, G.; Gewald, K. J. Heterocycl. Chem. 2008, 45, 1071.
13. Thomae, D.; Kirsch, G.; Seck, P. Synthesis 2008, 1600.
14. Sommen, G.; Comel, A.; Kirsch, G. Synlett 2003, 855.
15. Yu, S.-Y.; Cai, Y.-X. Synth. Commun. 2003, 33, 3989.
4.4.23. 3-Acetyl-5-(4-chlorobenzoyl)-4-methyl-2-(4-morpholinyl)-3-
thiophene (24). Yield: 92%. Yellow crystal; mp 188 ꢀC. IR: 2957 (s),
1662 (s), 1625 (s) cmꢁ1 1H NMR (250 MHz, CDCl3):
. d 2.22 (s, 3H,
CH3), 2.49 (s, 3H, CH3), 3.04 (m, 4H, 2ꢂCH2), 3.78 (m, 4H, 2ꢂCH2),
7.37 (d, J¼8.6 Hz, 2H, 2ꢂCH), 7.63 (d, J¼8.6 Hz, 2H, 2ꢂCH). 13C NMR
(62.5 MHz, CDCl3):
d 16.7, 29.8, 54.5, 66.1, 125.3, 128.6, 129.7, 130.0,
138.3, 138.4, 145.2, 165.9, 187.9, 198.5. GC–MS (EI, 70 eV): m/z (%):
363 (100), 348 (48), 304 (23), 263 (16), 139 (81), 111 (36). HRMS
calcd for C18H19NO3SCl [MþH]þ 364.0769, found 364.0760.
4.4.24. 3-Acetyl-5-(4-Chlorobenzoyl)-4-methyl-2-(4-piperidinyl)-3-
thiophene (25). Yield: 48%. Yellow solid; mp 137 ꢀC. IR: 2930 (s),
1666 (s), 1618 (s), 1585 (s) cmꢁ1 1H NMR (250 MHz, DMSO-d6):
.
d
1.50 (m, 2H, CH2), 1.61 (m, 4H, 2ꢂCH2), 2.16 (s, 3H, CH3), 2.43 (s,
3H, CH3), 3.05 (m, 4H, 2ꢂCH2), 7.53 (d, J¼8.5 Hz, 2H, 2ꢂCH), 7.64 (d,
J¼8.5 Hz, 2H, 2ꢂCH). 13C NMR (62.5 MHz, DMSO-d6):
d 16.0, 22.8,
24.7, 29.1, 55.1, 122.0, 127.0, 128.5, 130.0, 136.4, 138.9, 145.4, 166.9,
186.7, 197.9. GC–MS (EI, 70 eV): m/z (%): 361 (100), 346 (66), 318 (6).
HRMS calcd for C19H21NO2SCl [MþH]þ 362.0976, found 362.0961.
4.5. Synthesis of substituted 4-amino-3-cyanoselenophenes:
general procedure
2-[Bis(methylsulfanyl)methylene]malononitrile
1
(0.01 mol)
was dissolved in DMF (15 mL). The secondary amine (0.01 mol) was
added and the mixture was heated at 70 ꢀC for 75 min. Then, fresh
sodium selenide (0.01 mol) was added and heated for 20 min at
70 ꢀC. Activated halide (0.02–0.03 mol) was added dropwise at
70 ꢀC. The mixture was heated at 70 ꢀC for 2 h and the potassium
carbonate was added (0.01 mol). The reaction was stirred at 70 ꢀC
for 1 h more. The mixture was poured onto water (100 mL) with
good stirring. The precipitate was filtered, washed with water, and
16. El-Sayed, A. M.; El-Saghier, A. M. M.; Mohamed, M. A. A.; El-Shafei, A. K. Gazz.
Chim. Ital. 1997, 127, 605.