Alkylation of aryl 3-oxopropanedithioate and 3-amino-1-aryl-3-thioxo-1-propanones as an effective tool for the construction of differently substituted thiophenes and annulated thiophenes

Article abstract of DOI:10.1016/j.tet.2008.04.036

The alkylation of aryl 3-oxopropanedithioate with α-haloketones under different reaction conditions afforded substituted aryl[2-(methylsulfanyl)-4-phenyl-3-thienyl]methanones and [3-aryl-5-(methylsulfanyl)-2-thienyl](phenyl)methanones. The same strategy w

Full text of DOI:10.1016/j.tet.2008.04.036

Tetrahedron 64 (2008) 5944–5948
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Alkylation of aryl 3-oxopropanedithioate and 3-amino-1-aryl-3-thioxo-1-
propanones as an effective tool for the construction of differently substituted
thiophenes and annulated thiophenes
Reichel Samuel, Prakash Chandran, S. Retnamma, K.A. Sasikala, N.K. Sreedevi,
,
E.R. Anabha y, C.V. Asokan z
*
School of Chemical Sciences, Mahatma Gandhi University, Kottayam, Kerala, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The alkylation of aryl 3-oxopropanedithioate with a-haloketones under different reaction conditions af-
Received 20 November 2007
Received in revised form 9 April 2008
Accepted 10 April 2008
forded substituted aryl[2-(methylsulfanyl)-4-phenyl-3-thienyl]methanones and[3-aryl-5-(methylsulfanyl)-
2-thienyl](phenyl)methanones. The same strategy was extended to 3-amino-1-aryl-3-thioxo-1-propanones
to afford aryl[2-amino-4-phenyl-3-thienyl]methanones and ethyl 3-phenyl-5-piperidino-2-thiophene
carboxylate.
Available online 12 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Alkylation
Aryl-3-oxopropanedithioate
b-Oxothioamides
1,3-Oxathiole
Thiophene
1. Introduction
investigations on the alkylations of aryl 3-oxopropanedithioates
with a-haloketones yielding differently substituted thiophenes are
explained in this paper.
The synthesis of thiophenes and annulated thiophenes1,2 are of
special interest due to their potential use as pharmaceuticals,3–5
conjugated polymers,6,7 organic conductors,8–10 semiconduc-
tors,11,12 light emitting devices,13 etc. A general strategy employing
alkylation of an intermediate dimetaloketene dithioacetal is used
for the synthesis of alkylthiothiophenes or thienothiophenes.12,14–19
We envisioned that the difficulties involved in the selective se-
quential alkylations of the intermediate dimetaloketene dithio-
O
S
R3
O
O
R2
R1
S
O
Br
R1
R3
R3
R1
SCH3
O
O
NaH, toluene
48 h
H3CS
S
R2
2
R2
1
3
acetals could be circumvented by the use of
in the above reaction. Earlier report from this laboratory has de-
scribed similar alkylation reactions of -oxothioamides with
-haloketones for the synthesis of functionalized thiophenes.20 In
a recent preliminary report, we have explained the alkylations of
aryl 3-oxopropanedithioates with -haloketones such as phenacyl
b-oxodithiocarboxylates
Scheme 1. Synthesis of 1-aryl-2-(5-alkyl/aryl-1,3-oxathiol-2-yliden)-1-ethanones 3.
b
2. Results and discussion
a
In an earlier report, the formation of 1-aryl-2-(5-aryl-1,3-oxa-
thiol-2-yliden)-1-ethanones 2 from aryl 3-oxopropanedithioates
1a–e21–25 is described by the cyclizations of intermediate ketene
dithioacetals in the presence of sodium hydride.21 We envisioned
that the intermediate ketene dithioacetal 2 could be isolated from
the reaction, conducting the alkylation in the presence of mild base
like potassium carbonate. So the alkylation of 4-(methylphenyl) 3-
oxopropanedithioate 1a with phenacyl bromide was carried out in
the presence of potassium carbonate in acetone at room tempera-
ture, yielding 1-(methylphenyl)-3-(methylsulfanyl)-3-{[oxo(phe-
nyl)ethyl]sulfanyl}-2-propen-1-one 2a in 94% yield. However, on
a
bromide and bromo acetone in the presence of sodium hydride in
toluene yielding 1,3-oxathiole derivatives (Scheme 1).21 Further
* Corresponding author. Fax: þ91 481 2731009.
E-mail address: anabhaer@rediffmail.com (E.R. Anabha).
Present address: Research Associate, Organic Chemistry Division, NIST (for-
y
merly RRL), Thiruvananthapuram. Tel.: þ91 471 2515257; fax: þ91 471 2491712.
z
The work was carried out under the guidance of Dr. C. V. Asokan (Late), Reader,
School of Chemical Sciences, Mahatma Gandhi University, Kottayam 686560, Kerala,
India.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.036

R. Samuel et al. / Tetrahedron 64 (2008) 5944–5948
5945
O
Ph
Ph
R1
O
S
O
O
S
Br
AcOH
Ph
R1
O
SCH3
R1
120 °C
SCH3
K2CO3
Acetone
SCH3
S
4a: R1=4-CH3C6H4 (91%)
2a: R1=4-CH3C6H4 (94%)
1a-c
4b: R1=C6H5 (90%)
2b: R1=C6H5 (95%)
4c: R1=4-CH3OC6H4 (85%)
2c: R1=4-CH3OC6H4 (97%)
Scheme 2. Synthesis of aryl[2-(methylsulfanyl)-4-phenyl-3-thienyl]methanones 4.
O
R2
SCH3
heating a solution of 2a in dichloromethane, it underwent ther-
mally induced cyclization affording (4-methylphenyl)[2-(methyl-
sulfanyl)-4-phenyl-3-thienyl]methanone 4a. The reaction was
applicable to other aryl 3-oxopropanedithioates 1a–c. In order to
improve the yield of the reaction the intermediate ketene
dithioacetals 2a–c were collected by filtration and a solution of 2 in
acetic acid was heated at 120 ꢀC. As expected 2a–c were exclusively
transformed into aryl[2-(methylsulfanyl)-4-phenyl-3-thienyl]me-
thanones 4a–c (Scheme 2). However, these thermal cyclizations are
O
R1
S
Br
R3
R3
R1
SCH3
NaOH
EtOH, rt., 48h
R2
S
O
1
6
6a:R1= 4-ClC6H4, R2= H, R3=Ph (67%)
6b:R1= C6H5, R2= H, R3=Ph (71%)
6c:R1, R2=
6d:R1, R2=
, R3=Ph (62%)
, R3=Ph (78%)
limited to 3-oxopropanedithioates, having no substituents at the
carbon atom.
a-
The mechanism of the reaction is explained by a thermally
induced intramolecular cyclization of the intermediate ketene
dithioacetal 2. Due to the presence of vinylic alkylsulfanyl groups,
6e:R1= CH3, R2= H, R3=Ph (76%)
6f:R1= C6H5, R2= H, R3=CH3 (79%)
the a-carbon atom of a ketene dithioacetal can act as a nucleophile
under suitable reaction conditions. In an earlier report, we have
described such a reactivity of aroyl ketene dithioacetals under
Vilsmeier–Haack reaction conditions to afford 2-aroyl-3,3-bis(al-
kylsulfanyl)acrylaldehydes.26 The addition of ketene dithioacetal
moiety to the benzoyl group under thermal condition followed by
the elimination of a water molecule from the intermediate 5 results
in the formation of functionalized thiophenes 4 (Scheme 3).
6g:R1= 4-ClC6H4, R2= H, R3=CH3 (70%)
6h:R1, R2= , R3=CH3 (84%)
Scheme 4. Synthesis of [3-aryl-5-(methylsulfanyl)-2-thienyl](phenyl)methanones
6a–e and 1-[3-aryl-5-(methylsulfanyl)-2-thienyl]-1-ethanones 6f–h.
within 30 min to afford [2-morpholino-4-(4-nitrophenyl)-3-thie-
nyl](phenyl) methanone 9a in 55% yield. The reaction was
applicable to differently substituted 3-oxopropanethioamides
(Scheme 5). However, the intermediate 8d underwent an aldol type
intramolecular cyclization reaction to afford ethyl 3-phenyl-5-
piperidino-2-thiophene carboxylate 10a in 60% yield. Their de-
rivatives are used as P38 MAP kinase inhibitors in the treatment of
inflammatory diseases.28
H3CS
H
H3CS
R1
O
SCH3
S
O
S
H+
R1
S
Ph
R1
-H2O
O
H
Ph
H
OH
Ph
O
2
5
4
Scheme 3. Mechanism for the formation of aryl[2-(methylsulfanyl)-4-phenyl-3-thi-
enyl]methanones 4 from 1-aryl-3-(methylsulfanyl)-3-{[oxo(phenyl)ethyl]sulfanyl}-2-
propen-1-ones 2.
O
Next, the intermediate ketene dithioacetal 2, with an intention
to cyclize them via an intramolecular aldol type reaction, yielding
aryl[5-(methylsulfanyl)-3-phenyl-2-thienyl] methanones 6, was
treated with sodium hydroxide in ethanol for 48 h. The reactions of
S
Ph
N
O
N
R1
S
Br
R1
N
O
X
X
K2CO3
Acetone
O
Ph
S
OEt
Ph
b
-oxodithiocarboxylates with a-haloketones like phenacyl bromide
9a: R1= 4-NO2C6H4, X = O (55%)
9b: R1= C6H5, X = O (60%)
9c: R1= C6H5, X = O (67%)
or bromo acetone in the presence of sodium hydroxide in ethanol
also resulted in alkylation followed by intramolecular aldol type
reaction to afford aryl[5-(methylsulfanyl)-3-phenyl-2-thienyl]
methanones 6a–e (Scheme 4).
7a X = O
7b X = CH2
10a (60%)
Scheme 5. Synthesis of aryl[2-amino-4-phenyl-3-thienyl]methanones 9a–c and [5-
amino-3-phenyl-2-thienyl](phenyl)methanone 10a.
As a continuation to these studies, 3-morpholino-1-phenyl-3-
thioxo-1-propanone 7a, which was synthesized by refluxing
methyl 3-oxo-3-phenylpropanedithioate 1a with morpholine,27
was alkylated with 2-bromo-1-(4-nitrophenyl)-1-ethanone in the
presence of potassium carbonate in acetone at room temperature.
The reaction was complete within an hour yielding a product
mixture. The intermediate ketene-N,S-acetal being heat sensitive
could not be separated from the reaction mixture by column
chromatography. Considering the thermally induced cyclization
reaction to afford functionalized thiophenes 5, we decided to
conduct the alkylation reaction in the presence of potassium
carbonate in acetone at 60 ꢀC. The reaction was complete
O
N
Ph
O
S
O
EtO
8d
In conclusion, we have demonstrated the alkylation of 3-oxo-
propanedithiocarboxylates and 3-oxopropanethioamides as an

5946
R. Samuel et al. / Tetrahedron 64 (2008) 5944–5948
effective tool for the construction of differently substituted
thiophenes.
3.3. General procedure for the synthesis of (aryl)[2-
(methylsulfanyl)-4-phenyl-3-thienyl] methanones (4)
The appropriate 1-aryl-3-(methylsulfanyl)-3-{[oxo(phenyl)-
ethyl]sulfanyl}-2-propen-1-ones 3a–c (5 mmol) were taken in
20 mL glacial acetic acid and refluxed at 120 ꢀC for 2 h. The reaction
mixture was cooled, poured into ice-cold water and extracted using
dichloromethane. The organic layer was dried over anhydrous
sodium sulfate and the solvent was removed under vacuum. The
residue was passed through a silica gel column using hexane and
ethylacetate (20:1) as eluent. The solid products obtained were
recrystallized from methanol.
3. Experimental procedure
3.1. General
Melting points were uncorrected and were obtained on a Buchi-
530 melting point apparatus. Infrared spectra were recorded with
a Shimadzu IR 470 spectrometer and are given as cmꢁ1 1H NMR
.
spectra were recorded in CDCl3 on a Jeol GSX 400 (400 MHz) or
a Bruker WM 300 (300 MHz) or Bruker WM 200 (200 MHz) spec-
trometer using TMS as internal standard and CDCl3 as solvent.
Coupling constants J are given in hertz. 13C NMR spectra were
recorded on a GSX 400 (100.00 MHz) or Brucker WM 300
(75.47 MHz) or Bruker WM 200 (22.64 MHz) spectrometer using
CDCl3 as solvent. Electron impact mass spectra (EIMS) were
obtained on a Finnigen-Mat 312 instrument or a Schimadzu model
GC–MS 5050 instrument. CHN analyses were done on an Elementar
Vario EL III Carlo Erba 1108 instrument. All reagents were com-
mercially available and were purified before use.
3.3.1. (4-Methylphenyl)[2-(methylsulfanyl)-4-phenyl-3-
thienyl]methanone (4a)
Yield: 91%, yellow crystalline solid, mp: 163–164 ꢀC. Anal. Calcd
for C19H16O2S: C, 70.33; H, 4.97. Found: C, 70.60; H, 4.99. IR (cmꢁ1
)
nmax 1620, 1490, 1440, 1390, 990; 1H NMR (200 MHz, CDCl3)
(s, 3H, CH3), 2.65 (s, 3H, SCH3), 6.8–7.7 (m, 10H, C-5 and ArH); 13C
NMR (22.64 MHz, CDCl3) 18.7, 20.1, 126.7, 128.1, 128.5, 128.8, 131.1,
d 2.25
d
131.8, 135.4, 136.7, 137.1, 145.3, 146.7, 187.6; MS (EI): m/z (%) 324
(Mþ, 13), 248 (7.4), 227 (100), 212 (97.5), 173 (13.4), 136 (15.9).
3.2. General procedure for the synthesis of 1-aryl-3-
(methylsulfanyl)-3-{[oxo(phenyl)ethyl]sulfanyl}-2-
propen-1-ones (2)
3.3.2. [2-(Methylsulfanyl)-4-phenyl-3-thienyl](phenyl)
methanone (4b)
Yield: 90%, yellow crystalline solid, mp: 77–78 ꢀC. Anal. Calcd for
C
18H14OS2: C, 69.64; H, 4.55. Found: C, 69.89; H, 4.56. IR (cmꢁ1
)
nmax
2.63 (s, 3H,
SCH3), 7.03 (s, 1H, C-5), 7.11–7.15 (m, 5H, ArH), 7.25–7.29 (m, 2H,
ArH), 7.53–7.56 (m, 3H, ArH); 13C NMR (22.64 MHz, CDCl3)
18.9,
To a suspension of potassium carbonate (1.05 g, 5 mmol) in
acetone (15 mL), 3-oxo-3-arylpropanedithiocarboxylate 1 (5 mmol)
was added and the mixture was stirred for 5 min. To this reaction
mixture, phenacyl bromide (0.96 g, 5 mmol) was added and further
stirred at room temperature for 30 min. It was poured into ice-cold
water; the solid separated was filtered and recrystallized from
chloroform.
1620, 1520, 1400, 1285, 715; 1H NMR (300 MHz, CDCl3)
d
d
127, 127.3, 127.8, 128.5,128.8,131.27, 134.6,136.9,145.7, 146.9,188.2;
MS (EI): m/z (%) 310 (Mþ, 100), 234 (14.2), 233 (28.5), 158 (17.6), 105
(38.8).
3.3.3. (4-Methoxyphenyl)[2-(methylsulfanyl)-4-phenyl-3-
thienyl]methanone (4c)
3.2.1. 1-(4-Methylphenyl)-3-(methylsulfanyl)-3-
{[oxo(phenyl)ethyl]sulfanyl}-2-propen-1-one (2a)
Yield: 94%, white crystalline solid, mp: 110–112 ꢀC. Anal. Calcd
Yield: 85%, yellow crystalline solid, mp: 80–82 ꢀC. Anal. Calcd for
C
19H16O2S2: C, 67.03; H, 4.74. Found: C, 67.31; H, 4.76. IR (cmꢁ1
)
nmax
2916, 2843.07, 1608.45, 1498.94, 1395.6, 1280.14, 1243.56, 1170.63,
1036.88, 866.54, 824.02; 1H NMR (300 MHz, CDCl3)
2.54 (s, 3H,
for C19H18O2S2: C, 66.63; H, 5.30. Found: C, 66.82; H, 5.32. IR (cmꢁ1
)
nmax 1690, 1610, 1490, 1240, 756; 1H NMR (300 MHz, CDCl3)
d
2.40
d
(s, 3H, CH3), 2.55 (s, 3H, SCH3), 4.40 (s, 2H, CH2), 7.05 (s, 1H, vinylic),
7.12–7.32 (m, 2H, ArH), 7.45–7.58 (m, 2H, ArH), 7.60–7.72 (m, 1H,
ArH), 7.8 (d, 2H, J¼8 Hz, ArH), 8.00 (d, 2H, J¼8 Hz, ArH); MS (EI):
m/z (%) 324 (Mþꢁ18, 36), 323 (40), 309 (5), 295 (47), 119 (80), 105
(100), 91 (72), 77 (94).
SCH3), 3.72 (s, 3H, OCH3), 6.55 (d, 2H, J¼9 Hz, ArH), 6.91 (t, 1H, C-5),
7.00 (d, 2H, J¼8 Hz, ArH), 7.07 (t, 2H, J¼8 Hz, ArH), 7.33 (t, 1H,
J¼9 Hz, ArH), 7.47 (d, 2H, J¼9 Hz, ArH); 13C NMR (22.64 MHz, CDCl3)
d
19.2, 54.8, 113.2, 127.5, 129.2, 130.2, 131.6, 131.8, 135.5, 137.5, 145.8,
146.9, 159.0, 163.2, 188.4; MS (EI): m/z (%) 340 (Mþ, 66), 263 (23),
216 (12), 173 (8), 145 (11), 105 (58), 77 (100).
3.2.2. 3-(Methylsulfanyl)-3-{[oxo(phenyl)ethyl]sulfanyl}-1-phenyl-
2-propen-1-one (2b)
3.4. General procedure for the synthesis of [3-aryl-5-
(methylsulfanyl)-2-thienyl](phenyl)methanones (6a–e) and
1-[3-aryl-5-(methylsulfanyl)-2-thienyl]-1-ethanones (6f–h)
Yield: 95%, white crystalline solid, mp: 108–110 ꢀC. Anal. Calcd
for C18H16O2S2: C, 65.82; H, 4.91. Found: C, 65.61; H, 4.94. IR (cmꢁ1
)
nmax 1680, 1620, 1610, 1485, 1230, 1200, 750; 1H NMR (200 MHz,
CDCl3) 2.53 (s, 3H, SCH3), 4.44 (s, 2H, CH2), 7.03 (s, 1H, vinylic),
d
To a well stirred suspension of sodium hydroxide (0.8 g,
7.30–7.72 (m, 6H, ArH), 7.87 (d, 2H, J¼8 Hz, ArH), 7.99 (d, 2H,
20 mmol) in ethanol (15 mL), the dithiocarboxylate 1 (5 mmol) was
added and stirred for 15 min. To this mixture, appropriate a-halo-
J¼8 Hz, ArH); 13C NMR (22.64 MHz, CDCl3)
d
15.4, 39.0, 111.2, 127.8,
128.5, 128.8, 129.0, 133.7, 138.9, 162.9, 185.8, 193.1; MS (EI): m/z (%)
310 (Mþꢁ18, 100), 233 (35), 77 (17).
ketone (5 mmol) was added and was stirred at room temperature
for 48 h. It was then poured into ice-cold water (50 mL) and the
precipitated solid was filtered, dissolved in chloroform (25 mL),
dried over anhydrous sodium sulfate and concentrated to get the
crude product. The functionalized thiophenes thus obtained were
purified by recrystallization from hexane–ethylacetate (5:1).
3.2.3. 1-(4-Methoxyphenyl)-3-(methylsulfanyl)-3-{[oxo-
(phenyl)ethyl]sulfanyl}-2-propen-1-one (2c)
Yield: 97%, white crystalline solid, mp: 101–102 ꢀC. Anal. Calcd
for C19H18O3S2: C, 63.66; H, 5.06. Found: C, 63.85; H, 5.09. IR (cmꢁ1
)
nmax 1680, 1600, 1470, 1230, 790; 1H NMR (300 MHz, CDCl3)
d
2.54
3.4.1. [3-(4-Chlorophenyl)-5-(methylsulfanyl)-2-
thienyl](phenyl)methanone (6a)
(s, 3H, SCH3), 3.87 (s, 3H, OCH3), 4.48 (s, 2H, CH2), 6.64–7.26 (m, 6H,
vinylic and ArH), 7.48–7.58 (m, 2H, ArH), 7.85–7.90 (m, 1H, ArH),
7.98–7.99 (m, 1H, ArH); MS (EI): m/z (%) 340 (Mþꢁ18, 13), 339 (16),
311 (10), 135 (45), 105 (46), 77 (56).
Yield: 67%, yellow crystalline solid, mp: 82–83 ꢀC. Anal. Calcd for
C
18H13ClOS2: C, 62.69; H, 3.80; Cl, 10.28. Found: C, 62.88; H, 3.83; Cl,
10.31. IR (cmꢁ1
)
nmax 2887, 2356, 1713, 1613, 1545, 1476, 1383, 1264,

R. Samuel et al. / Tetrahedron 64 (2008) 5944–5948
5947
1076, 946 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
¼2.62 (s, 3H, SCH3),
12.59. IR (cmꢁ1 nmax 1620, 1520, 1480, 1360, 1260, 1080 cmꢁ1 1H
) ;
6.96 (s, 1H, H-4), 7.07–7.14 (m, 5H, ArH), 7.29 (d, 2H, J¼9 Hz, ArH),
NMR (300 MHz, CDCl3) d 2.1 (s, 3H, CH3), 2.6 (s, 3H, SCH3), 6.81 (s,
7.55 (d, 2H, J¼9 Hz, ArH); 13C NMR (75.46 MHz, CDCl3)
d¼19.6,
1H, H-4), 7.29 (d, 2H, J¼9 Hz, ArH), 7.42 (d, 2H, J¼9 Hz, ArH); 13C
104.8, 127.9, 128.2, 129.5, 129.6, 130.4, 132.2, 133.86, 133.9, 136.7,
137.7, 137.7, 146.1, 146.6, 188.3; MS (EI): m/z (%) 346 (Mþþ2, 21), 344
(Mþ, 48), 267 (22), 232 (10), 105 (50), 77 (100).
NMR (100.40 MHz, CDCl3) d 18.96, 29.00, 128.57, 129.74, 130.26,
134.47, 138.49, 145.95, 147.60, 190.16; MS (EI): m/z (%) 286 (Mþþ2,
29), 284 (Mþ, 74), 269 (100), 234 (32.1), 182 (7.6), 146 (8.6).
3.4.2. [5-(Methylsulfanyl)-3-phenyl-2-thienyl](phenyl)-
methanone (6b)
3.4.8. [3-(Methylsulfanyl)-4,5,6,7-tetrahydro-2-benzothiophen-1-
yl]-1-ethanone (6h)
Yield: 71%, yellow crystalline solid, mp: 89–90 ꢀC. Anal. Calcd for
Yield: 84%, yellow crystalline solid, mp: 74–76 ꢀC. Anal. Calcd for
C
18H14OS2: C, 69.64; H, 4.55. Found: C, 69.91; H, 4.52. IR (cmꢁ1
)
nmax
C
11H14OS2: C, 58.37; H, 6.23. Found: C, 58.40; H 6.22. IR (cmꢁ1); nmax
1620, 1563, 1526, 1395, 1264, 1170, 1095, 1064, 1015 cmꢁ1; 1H NMR
1640, 1510, 1410, 1380, 1350, 1315, 1260, 1160, 1140, 980 cmꢁ1
NMR (300 MHz, CDCl3) 1.74–1.80 (m, 4H, CH2), 2.46 (s, 3H, CH3),
2.55 (s, 3H, SCH3), 2.56 (br s, 2H, CH2), 3.0 (br s, 2H, CH2); 13C NMR
;
1H
(300 MHz, CDCl3)
d
2.64 (s, 3H, SCH3), 7.03 (s, 1H, H-4), 7.11–7.14 (m,
d
6H, ArH), 7.27(br s, 2H, ArH), 7.54 (d, 2H, J¼8 Hz, ArH); 13C NMR
(75.46 MHz, CDCl3)
d
19.7, 127.5, 127.7, 127.8, 128.0, 129.2, 129.6,
(100.40 MHz, CDCl3) d 18.6, 22.35, 22.72, 25.55, 28.07, 29.43, 134.37,
131.9, 135.42, 136.8, 137.7, 146.2, 147.4, 188.7; MS (EI): m/z (%) 310
(Mþ, 90), 263 (12), 233 (40),190 (13),158 (24),146 (19),114 (18),105
(59), 77 (100).
139.19, 140.07, 146.43, 189.35; MS (EI): m/z (%) 226 (Mþ, 14), 225
(94), 210 (100), 182 (15), 167 (12).
3.5. General procedure for the synthesis of 4-aryl-2-
dialkylamino-3-thienyl(phenyl) methanone 9 and ethyl
3-phenyl-5-piperidino-2-thiophene carboxylate 10
3.4.3. [3-(Methylsulfanyl)-4,5-dihydronaphtho[1,2-c]thiophen-1-
yl](phenyl)methanone (6c)
Yield: 62%, yellow crystalline solid, mp: 78–79 ꢀC. Anal. Calcd for
C
20H16OS2: C, 71.39; H, 4.79. Found: C, 71.65; H 4.81. IR (cmꢁ1
)
nmax
2.53 (s,
3H, SCH3), 2.8 (t, 2H, J¼7.2 Hz, CH2), 2.92 (t, 2H, J¼7.2 Hz, CH2),
6.86–7.80 (m, 9H, ArH); 13C NMR (100.40 MHz, CDCl3)
19.96,
The appropriate b-oxothioamides 7 (2 mmol), prepared by
2916, 1641, 1593, 1423 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
refluxing phenyl 3-oxopropanedithioate with secondary amines,8
were stirred with anhydrous potassium carbonate (3 g, 20 mmol) in
dry acetone (30 mL) at reflux temperature for 10 min. The reaction
d
24.41, 30.16, 96.19, 105.49, 127.98, 128.12, 128.22, 129.99, 137.64,
141.67, 189.23; MS (EI): m/z (%) 336 (Mþ, 55), 259 (29), 216 (20), 105
(60), 77 (100).
mixture was cooled and a-haloketone (2 mmol) was added; then
refluxed for 30 min. In order to remove potassium carbonate, the
reaction mixture was filtered through a small column and the fil-
trate was evaporated to get the crude product, which was further
purified by column chromatography using hexane–ethylacetate
(9:1) as the eluent.
3.4.4. [3-(Methylsulfanyl)-4,5,6,7-tetrahydro-2-benzothiophen-1-
yl](phenyl)methanone (6d)
Yield: 78%, yellow crystalline solid, mp: 69–70 ꢀC. Anal. Calcd for
C
16H16OS2: C, 66.63; H, 5.59. Found: C, 66.68; H 5.60. IR (cmꢁ1
)
nmax
3.5.1. [2-Morpholino-4-(4-nitrophenyl)-3-thienyl](phenyl)
methanone (9a)
1620, 1565, 1505, 1405, 1380, 1320 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.7–1.85 (m, 4H, CH2), 2.55 (s, 3H, SCH3), 2.60 (t, 2H, J¼7 Hz, CH2),
Yield: 55%, yellow crystalline solid, mp: 170–172 ꢀC. Anal. Calcd
for C21H18N2O4S: C, 63.94; H, 4.60; N, 7.10. Found: C, 64.11; H, 4.62;
3.0 (t, 2H, J¼7 Hz, CH2), 7.45 (t, 2H, J¼8 Hz, ArH), 7.54 (t, 1H, J¼8 Hz,
ArH), 7.77 (d, 2H, J¼8 Hz, ArH); 13C NMR (100.40 MHz, CDCl3)
N, 7.15. IR (cmꢁ1
)
nmax 1640, 1510, 1449, 1410, 1372, 1341, 1264, 1201,
d
18.56, 22.35, 22.67, 25.30, 28.23, 128.17, 128.49, 131.51, 132.36,
1142,1109, 1027, 986, 937, 901, 852, 738; 1H (300 MHz, CDCl3)
d
2.99
138.82, 140.66, 142.22, 148.33, 187.99; MS (EI): m/z (%) 288 (Mþ,
(t, 4H, J¼6 Hz, NCH2), 3.45 (t, 4H, J¼5 Hz, OCH2), 6.93 (s, 1H, C-5),
7.35–7.44 (m, 4H, ArH), 7.5–7.58 (t, 1H, J¼8 Hz, ArH), 7.82 (d, 2H,
100), 240 (39), 211 (8), 106 (51), 77 (47).
ArH), 8.07 (d, 2H, J¼8 Hz, ArH); 13C NMR (75 MHz, CDCl3)
d 54.6,
3.4.5. [3-Methyl-5-(methylsulfanyl)-2-thienyl](phenyl)-
methanone (6e)
66.6, 94.2, 105, 116, 126.5, 128.2, 1287, 129, 133.7, 138.3, 140.3, 147.1,
162, 193; MS (EI): m/z (%) 394 (Mþ, 7), 364 (8), 149 (12), 105 (21), 91
(32), 71 (61), 57 (100).
Yield: 76%, dark brown oil. Anal. Calcd for C13H12OS2: C, 62.87; H,
4.87. Found: C, 62.94; H 4.89. IR (cmꢁ1
)
nmax 1620, 1570, 1515, 1440,
1395, 1330, 1310, 1270, 1180, 1140, 1080, 1020 cmꢁ1 1H NMR
(300 MHz, CDCl3) 2.41 (s, 3H, CH3), 2.55 (s, 3H, SCH3), 6.83 (s,1H, H-
;
3.5.2. [2-Morpholino-4-phenyl-3-thienyl](phenyl) methanone (9b)
Yield: 60%, yellow crystalline solid, mp: 128–130 ꢀC. Anal. Calcd
for C21H19NO2S: C, 72.18; H, 5.48; N, 4.01. Found: C, 72.31; H, 5.51;
d
4), 7.46 (t, 2H, J¼8 Hz, ArH), 7.54 (t, 1H, J¼8 Hz, ArH), 7.78 (d, 2H,
J¼8 Hz, ArH); 13C NMR (100.40 MHz, CDCl3)
d
16.83, 19.23, 128.12,
N, 4.02. IR (cmꢁ1
631; 1H NMR (300 MHz, CDCl3)
)
nmax 1590, 1466, 1368, 1299, 1115, 915, 872, 755,
3.32 (t, 4H, J¼6 Hz, NCH2), 3.85 (t,
128.49,128.70,131.75,134.22,139.95,146.64,146.70,188.20;MS (EI):
d
m/z (%) 248 (Mþ, 100), 200 (43), 171 (39), 128 (6), 105 (27), 77 (42).
4H, J¼5 Hz, OCH2), 6.16 (s, 1H, C-5), 6.95–7.19 (m, 8H, ArH), 7.39 (d,
2H, J¼8 Hz, ArH); 13C NMR (75 MHz, CDCl3)
d 49.8, 66.3, 108.8,
3.4.6. 1-[5-(Methylsulfanyl)-3-phenyl-2-thienyl]-1-ethanone (6f)
123.5, 127.7, 127.9, 128.1, 129.5, 129.4, 131.4, 136.9, 139.6, 150.3,
164.2, 189.0; MS (EI): m/z (%) 349 (Mþ, 100), 348 (41), 290 (17), 272
(15), 77 (12).
Yield: 79%, yellow crystalline solid, mp: 86–87 ꢀC. Anal. Calcd for
C
13H12OS2: C, 62.87; H, 4.87. Found: C, 62.93; H, 4.90. IR (cmꢁ1
)
nmax
1.99 (s,
3H, CH3), 2.56 (s, 3H, SCH3), 6.79 (s, 1H, H-4), 7.31 (m, 5H, ArH); 13
NMR (75.46 MHz, CDCl3) 19.08, 29.11, 128.70, 129.90, 130.02,
1630, 1540, 1400, 1270 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d
C
3.5.3. Phenyl(4-phenyl-2-piperidino-3-thienyl) methanone (9c)
Yield: 67%, yellow crystalline solid, mp: 108–110 ꢀC. Anal. Calcd
for C22H21NOS: C, 76.04; H, 6.09; N, 4.03. Found: C, 76.29; H, 6.12; N,
d
130.37, 134.59, 134.67, 138.65, 146.07, 147.72, 190.33; MS (EI): m/z
(%) 248 (Mþ, 80), 233 (100), 218 (5), 190 (14), 158 (20).
4.05. IR (cmꢁ1
)
nmax 1657, 1595, 1528, 1498, 1446, 1384, 1263, 1199,
1168, 1116, 1070, 1025, 980, 922, 850; 1H (300 MHz, CDCl3)
d
1.23–
3.4.7. 1-[3-(4-Chlorophenyl)-5-(methylsulfanyl)-2-thienyl]-1-
ethanone (6g)
1.37 (m, 6H, CH2), 3.2 (t, 4H, J¼5.5 Hz, NCH2), 6.75 (s, 1H, C-5), 7.18–
7.39 (m, 5H, ArH), 7.36 (t, 2H, J¼8 Hz, ArH), 7.48 (t, 1H, J¼8 Hz, ArH),
Yield: 70%, yellow crystalline solid, mp: 70–72 ꢀC. Anal. Calcd for
7.86 (d, 2H, J¼8 Hz, ArH); 13C NMR (75 MHz, CDCl3)
d 14.5, 21.5, 56,
C
13H11ClOS2: C, 55.21; H, 3.92, Cl, 12.54. Found: C, 55.32; H 3.94; Cl,
113, 125.7, 127.4, 128.2, 128.4, 128.5, 128.7, 129.9, 130.2, 133.0, 137.0,

5948
R. Samuel et al. / Tetrahedron 64 (2008) 5944–5948
138.4, 142.0, 162.9, 194.5; MS (EI): m/z (%) 347 (Mþ, 36), 330 (41),
187 (16), 134 (14), 115 (31), 105 (49), 91 (25), 77 (100).
4. Luker, T. J.; Beaton, H. G.; Whiting, M.; Kete, A.; Cheshire, D. R. Tetrahedron Lett.
2000, 41, 7731.
5. Holmes, J. M.; Lee, G. C. M.; Wijino, M.; Weinkam, R.; Wheeler, L. A.; Garst, M. E.
J. Med. Chem. 1994, 37, 1646.
6. Roncali, J. Chem. Rev. 1997, 97, 173.
3.5.4. Ethyl 3-phenyl-5-piperidino-2-thiophene carboxylate (10a)
Yield: 60%, yellow crystalline solid, mp: 132–134 ꢀC. Anal. Calcd
for C18H21NO2S: C, 68.54; H, 6.71; N, 4.44. Found: C, 68.81; H, 6.75;
7. Schopf, G.; Kossemehl, G. Adv. Polym. Sci. 1997, 129, 1.
8. Kiani, M. S.; Mitchell, G. R. Synth. Met. 1992, 46, 293.
9. Dimitrakopoulos, C. D.; Malenfant, P. R. L. Adv. Mater. 2002, 14, 99.
10. Wolf, J. J.; Wortmann, R. Adv. Phys. Org. Chem. 1999, 32, 121.
11. Morrison, J. J.; Murray, M. M.; Li, X. C.; Holmes, A. B.; Morratti, S. C.; Friend, R. H.;
Sirringhaus, H. Synth. Met. 1999, 102, 987.
12. Li, X. C.; Sirringhaus, H.; Garrier, F.; Holmes, A. B.; Morratti, S. C.; Feeder, N.;
Clegg, W.; Teat, S. J.; Friend, R. H. J. Am. Chem. Soc. 1998, 120, 2206.
13. Greenham, N. C.; Morratti, S. C.; Bradley, D. D. C.; Friend, R. H.; Holmes, A. B.
Nature (London) 1993, 365, 628.
14. Lee, S. B.; Hong, J.-I. Tetrahedron Lett. 1995, 36, 8439.
15. Mashraqui, S. H.; Hariharasubrahmanian, H.; Kumar, S. Synthesis 1999, 2030.
16. Prim, D.; Joseph, D.; Kirsch, G. Liebigs. Ann. Chem. 1996, 239.
17. Prim, D.; Kirsch, G. Synth. Commun. 1995, 2449.
18. Augustine, M.; Rudorf, W. D.; Schimdt, U. Tetrahedron 1976, 32, 3055.
19. Dalgard, L.; Jensen, L.; Lawesson, S. O. Tetrahedron 1974, 39, 93.
20. Suma, S.; Ushakumari, N. K.; Asokan, C. V. Phosphorus, Sulfur, Silicon Relat. Elem.
1997, 131, 161.
N, 4.42. IR (cmꢁ1
755, 632; 1H NMR (300 MHz, CDCl3)
) nmax 1654, 1466, 1380, 1288, 1121, 900, 851, 806,
d
1.1 (t, 3H, J¼7 Hz, CH3), 1.42–
1.58 (m, 6H, CH2), 3.2 (t, 4H, J¼5.5 Hz, NCH2), 4.2 (q, 2H, J¼7 Hz,
OCH2), 5.99 (s, 1H, C-5), 7.3–7.5 (m, 5H, ArH); 13C NMR (75 MHz,
CDCl3)
d 14.68, 23.99, 25.34, 51.1, 60.4, 108.2, 110, 127.9, 128, 129.4,
137, 150.8, 162.7, 162.9; MS (EI): m/z (%) 315 (Mþ, 58), 287 (13), 270
(14), 243 (100), 128 (22), 115 (51), 81 (9), 69 (61).
Acknowledgements
R.S. thanks UGC, P.C. thanks Prof. Wim Dehaen and Prof. Erick
van der Eycken, KU, Leuven and E.R.A. thanks the CSIR, New Delhi
for the award of research fellowships. We thank the Directors of
CDRI Lucknow and the Department of Chemistry, Madurai Kamaraj
University for providing spectral and analytical data.
21. Samuel, R.; Asokan, C. V.; Chandran, P.; Suma, S.; Retnamma, S.; Anabha, E. R.
Tetrahedron Lett. 2007, 48, 8376.
22. Voss, J. Synthesis of Thiolesters and Thiolactones. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1990; Vol. 6,
p 435.
23. Nair, S. K.; Samuel, R.; Asokan, C. V. Synthesis 2001, 573.
24. Ramdas, S. R.; Srinivasan, P. S.; Ramachandran, J.; Sastry, V. V. S. K. Synthesis
1983, 605.
References and notes
25. Singh, G.; Bhattacharjee, S. S.; Ila, H.; Junjappa, H. Synthesis 1982, 693.
26. Anabha, E. R.; Asokan, C. V. Synthesis 2006, 151.
1. Bohlmann, F.; Zdero, C. Thiophenes and its Derivatives; Gronowitz, S., Ed.; John
Wiley and Sons: New York, NY, 1985; Part 1, pp 261–323.
27. Viswakarma, J. N.; Apparao, S.; Ila, H.; Junjappa, H. Ind. J. Chem. 1985, 24B, 466.
28. Gill, A. L.; Woodhead, S.; Carr, M. Chem. Abstr. 2004, 141, 366122h (PCT Int.
Appl. WO 89,929, 2004).
2. Gronowitz, S. Thiophenes and its Derivatives; Gronowitz, S., Ed.; John Wiley and
Sons: New York, NY, 1985; Part 1, pp 42–59.
3. Pinto, I. L.; Jarvest, R. L.; Serafinowska, H. T. Tetrahedron Lett. 2000, 41, 1597.