Synthesis of highly functionalized thiophenes by three-component and one-pot reaction

Article abstract of DOI:10.1080/17415993.2012.662981

Reaction between ethyl 2-cyano-3-arylacrylate and dialkyl acetylenedicarboxylates in the presence of KSCN at room temperature provided a simple and efficient one-pot route for the synthesis of highly functionalized thiophenes. The reaction is characterized by mild conditions, short reaction time and tolerance to various functional groups.

Full text of DOI:10.1080/17415993.2012.662981

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Synthesis of highly functionalized
thiophenes by three-component and
one-pot reaction
Alireza Hassanabadi a & Mohammad R. Hosseini-Tabatabaei a
a Department of Chemistry, Islamic Azad University, Zahedan
Branch, P.O. Box 98135-978, Zahedan, Iran
Published online: 21 Mar 2012.
To cite this article: Alireza Hassanabadi & Mohammad R. Hosseini-Tabatabaei (2012) Synthesis
of highly functionalized thiophenes by three-component and one-pot reaction, Journal of Sulfur
Chemistry, 33:3, 273-277, DOI: 10.1080/17415993.2012.662981
To link to this article: http://dx.doi.org/10.1080/17415993.2012.662981
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Journal of Sulfur Chemistry
Vol. 33, No. 3, June 2012, 273–277
Synthesis of highly functionalized thiophenes by
three-component and one-pot reaction
Alireza Hassanabadi* and Mohammad R. Hosseini-Tabatabaei
Department of Chemistry, Islamic Azad University, Zahedan Branch, P.O. Box 98135-978, Zahedan, Iran
(Received 25 December 2011; final version received 30 January 2012)
Reaction between ethyl 2-cyano-3-arylacrylate and dialkyl acetylenedicarboxylates in the presence of
KSCN at room temperature provided a simple and efficient one-pot route for the synthesis of highly func-
tionalized thiophenes. The reaction is characterized by mild conditions, short reaction time and tolerance
to various functional groups.
O
CO2R
Ar
CO2R
NC
Ar
KSCN
OEt
EtO
+
CH3CN, r.t.,6h
CO2R
S
O
CO2R
Keywords: three-component reaction; highly functionalized thiophene; ethyl 2-cyano-3-arylacrylate;
dialkyl acetylenedicarboxylate; anionic nucleophile
1. Introduction
Thiophenes are an important class of heterocyclic system, abundantly present as substructures
in various natural products (1) and pharmaceuticals (2). They are useful intermediates in the
preparation of novel conducting polymers (3), nonlinear optical materials (4) and for isosteric
replacement for phenyl group in medicinal chemistry (5). Diazathiophenes, derived from the
coupling of 2-aminothiophenes with various heterocycles, are highly colored brilliant shade dyes
(6) and arylthiophenes are agonist allosteric enhancer at A1 adenosine receptor (7, 8). Tri- and
tetra-substituted thiophenes are often prepared via the Gewald reaction (9).
Recently, a practical and high-yield two-step procedure was developed for the synthesis of ethyl
3-aminothiophene-2-carboxylate by the reaction of mercaptoacetic acid and 2-chloroacrylonitrile
followed by esterification (10). The reaction of alkylnitrile (RCH2CN) with ethyl formate
followed by ring closure upon reaction with ethyl thioglycolate leads to the formation of
*Corresponding author: E-mail: ar_hasanabadi@yahoo.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2012 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2012.662981
http://www.tandfonline.com

274 A. Hassanabadi and M.R. Hosseini-Tabatabaei
functionalized 3-aminothiophenes (11). The reaction of dialkyl acetylenedicarboxylates with
arylidenemalononitriles in the presence of KSCN in MeCN led to a mixture of dialkyl
(3E)-4-aryl-3-(arylideneamino)-5,5-dicyanocyclopenta-1,3-diene-1,2-dicarboxylates and dialkyl
4-aryl-5-cyanothiophene-2,3-dicarboxylates (12).
As a part of our current study on the development of new routes in organic synthesis (13–16), we
report here an efficient one-pot synthesis of highly functionalized thiophenes employing readily
available starting materials.
2. Results and discussion
Treatment of dialkyl acetylenedicarboxylates 1 and ethyl 2-cyano-3-arylacrylate 2 in the presence
of KSCN in acetonitrile for 6 h at room temperature afforded highly functionalized thiophenes 3
in 30–50% yield after purification (Scheme 1).
O
CO2R
Ar
CO2R
NC
Ar
KSCN
OEt
EtO
+
CH3CN, r.t.,6h
CO2R
S
O
CO2R
3
1
2
*
Ar
R
%Yield
3
a
b
c
phenyl
phenyl
Me
Et
42
43
p-CH3-phenyl
p-CH3-phenyl
p-Cl-phenyl
Me
50
47
39
40
d
e
Et
Me
Et
p-Cl-phenyl
f
g
p-NO2-phenyl
p-NO2-phenyl
Me
Et
32
30
h
*
yields
Isolated
Scheme 1. The synthesis routes to thiophenes 3.
The structures of compounds 3a–3h were deduced from their elemental analyses and IR, 1H
1
NMR, 13C NMR and mass spectra. The H NMR spectrum of compound 3a was simple and
exhibited two sharp singlets at 3.75 and 3.90 ppm for methoxycarbonyl groups and a triplet at
δ = 1.18 ppm (J = 7 Hz) and a quartet at δ = 4.20 ppm (J = 7 Hz) for ethyl protons and aromatic
protons at δ = 7.06–7.64 ppm. The 13C NMR spectrum of compound 3a showed 15 distinct
resonances in agreement with the proposed structure. The mass spectrum of 3a displayed the
molecular ion peak at m/z = 348. The IR spectrum of compound 3a also supported the suggested
structure, exhibiting strong absorption bands at 1727 and 1716 cm−1 for the carbonyl groups.
A plausible mechanism for the formation of compound 3 is proposed in Scheme 2. It is con-
ceivable that the reaction involves the initial formation of anionic intermediate 4 from SCN− and
1 which reacts with 2 to produce 5. Cyclization of this intermediate followed by loss of CN− and
HCN leads to 3.

Journal of Sulfur Chemistry 275
CN
S
CN
S
CO2R
Ar
RO2C
RO2C
CO2R
_
_
2
KCN
HCN
CN
_
KSCN
1
3
+
+
CN
CO2Et
_
CO2R
K
S
CO2Et
RO2C
Ar
+
K
4
5
6
Scheme 2. Proposed mechanism for 3.
In conclusion, we have described the use of KSCN as an anionic nucleophile in a reaction involv-
ing ethyl 2-cyano-3-arylacrylate and dialkyl acetylenedicarboxylates as a simple and efficient
route for the synthesis of highly functionalized thiophenes. The advantages of the reported method
are: inexpensive and easily available starting materials; simple and neutral reaction conditions;
the formation of a single product; and a simple work-up process.
3. Experimental
All melting points are uncorrected. Elemental analyses were performed using a Heraeus CHN-
O-Rapid analyzer. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer
operating at an ionization potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470
spectrometer.1H and 13C NMR spectra were recorded on Bruker DRX-500 Avance spectrometer
in CDCl3 solution using TMS as an internal standard. The chemicals used in this work were
purchased from Fluka (Buchs, Switzerland) and were used without further purification.
3.1. General procedure
To a magnetically stirred solution of ethyl 2-cyano-3-arylacrylate (2 mmol) and dialkyl
acetylenedicarboxylates (2 mmol) in acetonitrile (10 ml) was added KSCN at room temperature.
The reaction mixture was stirred for 6 h. The solvent was removed and the residue was purified
by silica gel column chromatography using hexane–ethyl acetate (4:1) as eluent. The solvent was
removed under reduced pressure to afford the product.
3.1.1. 5-Ethyl 2,3-dimethyl-4-phenylthiophene-2,3,5-tricarboxylate (3a)
Whitepowder;yield:42%;m.p. 148–150 ◦C. IR:1727, 1716, 1594, 1541. Electronionizationmass
spectrometry (EI-MS): 348 (M+, 11), 73 (30), 77 (100). Anal. Calcd for C17H16O6S: C, 58.61; H,
4.63%. Found: C, 58.48; H, 4.50%. 1H NMR: δ = 1.18 (3H, t, 3JHH = 7.1 Hz, CH3), 3.75 (3H, s,
OCH3), 3.90 (3H, s, OCH3), 4.20 (2H, q, 3JHH = 7.1 Hz, OCH2), 7.06–7.64 (5H, m, aromatic).
13C NMR: δ = 14.4 (CH3), 52.9 (OCH3), 53.2 (OCH3), 64.3 (OCH2), 112.5, 128.2, 128.8 and
=
129.5 (aromatic), 129.9 (C), 130.8 (C), 138.7 (C), 150.5 (C), 160.1, 164.4 and 166.2 (3C O).
3.1.2. Triethyl 4-phenylthiophene-2,3,5-tricarboxylate (3b)
White powder; yield: 43%; m.p. 134–136 ◦C. IR: 1729, 1715, 1590, 1543. EI-MS: 376 (M+, 8),
73 (30), 77 (100).Anal. Calcd for C19H20O6S: C, 60.62; H, 5.36%. Found: C, 60.71; H, 5.43%. 1H
NMR: δ = 1.14–1.37 (9H, m, 3CH3), 4.18–4.45 (6H, m, 3OCH2), 7.09–7.57 (5H, m, aromatic).
13C NMR: δ = 13.8, 14.1 and 14.3 (3CH3), 62.4, 62.8 and 64.1 (3OCH2), 112.7, 128.1, 128.7 and
=
129.9 (aromatic), 130.1 (C), 130.7 (C), 138.5 (C), 150.3 (C), 160.0, 164.3 and 165.9 (3C O).

276 A. Hassanabadi and M.R. Hosseini-Tabatabaei
3.1.3. 5-Ethyl 2,3-dimethyl-4-(4-methylphenyl)thiophene-2,3,5-tricarboxylate (3c)
White powder; yield: 50%; m.p. 131–133 ◦C. IR: 1730, 1719, 1592, 1537. EI-MS: 362 (M+, 10),
73 (50), 91(100). Anal. Calcd for C18H18O6S: C, 59.66; H, 5.01%. Found: C, 59.52; H, 5.09%. 1H
NMR: δ = 1.13 (3H, t, 3JHH = 7.1 Hz, CH3), 2.46 (3H, s, CH3), 3.79 (3H, s, OCH3), 3.88 (3H,
s, OCH3), 4.32 (2H, q, 3JHH = 7.1 Hz, OCH2), 7.21 (2H, d, 3JHH = 7.8 Hz, aromatic), 7.52 (2H,
d, 3JHH = 7.8 Hz, aromatic). 13C NMR: δ = 14.4 and 21.5 (2CH3), 53.0 (OCH3), 53.1 (OCH3),
64.7 (OCH2), 112.9, 128.4, 128.9 and 129.8 (aromatic), 129.8 (C), 130.6 (C), 138.5 (C), 150.8
=
(C), 160.2, 164.5 and 166.0 (3C O).
3.1.4. Triethyl 4-(4-methylphenyl)thiophene-2,3,5-tricarboxylate (3d)
White powder; yield: 47%; m.p. 152–154 ◦C. IR: 1726, 1717, 1591, 1541. EI-MS: 390 (M+, 5),
73 (40), 91 (100). Anal. Calcd for C20H22O6S: C, 61.52; H, 5.68%. Found: C, 61.65; H, 5.45%.
1H NMR: δ = 1.15 (3H, s, CH3), 1.35–1.42 (6H, m, 2CH3), 2.42 (3H, s, CH3), 4.15–4.41 (6H,
m, 3OCH2), 7.24 (2H, d, 3JHH = 7.8 Hz, aromatic), 7.50 (2H, d, 3JHH = 7.8 Hz, aromatic). 13
C
NMR: δ = 13.8, 14.1, 14.3 and 21.3 (4CH3), 62.1, 62.5 and 64.3 (3OCH2), 112.2, 128.4, 129.1
=
and 130.1 (aromatic), 130.2 (C), 130.9 (C), 138.7 (C), 150.5 (C), 160.3, 164.6 and 165.8 (3C O).
3.1.5. 5-Ethyl 2,3-dimethyl-4-(4-clorophenyl)thiophene-2,3,5-tricarboxylate (3e)
White powder; yield: 39%; m.p. 148–150 ◦C. IR: 1730, 1716, 1592, 1523. EI-MS: 382 (M+, 4), 73
(28), 111 (100).Anal. Calcd for C17H15ClO6S: C, 53.34; H, 3.95%. Found: C, 53.50; H, 3.76%. 1H
NMR: δ = 1.15 (3H, t, 3JHH = 7.1 Hz, CH3), 3.78 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.23 (2H,
3
3
3
q, JHH = 7.1 Hz, OCH2), 7.35 (2H, d, JHH = 7.8 Hz, aromatic), 7.49 (2H, d, JHH = 7.8 Hz,
aromatic). 13C NMR: δ = 14.1 (CH3), 53.2 (OCH3), 53.3 (OCH3), 64.4 (OCH2), 112.6, 129.3,
129.5 and 129.8 (aromatic), 135.7 (C), 136.5 (C), 138.6 (C), 148.7 (C), 159.9, 164.1 and 165.7
=
(3C O).
3.1.6. Triethyl 4-(4-clorophenyl)thiophene-2,3,5-tricarboxylate (3f)
White powder; yield: 40%; m.p. 154–156 ◦C. IR: 1729, 1718, 1593, 1522. EI-MS: 410 (M+, 7), 73
(24), 111 (100). Anal. Calcd for C19H19ClO6S: C, 55.54; H, 4.66%. Found: C, 55.41; H, 5.53%.
1H NMR: δ = 1.12–1.42 (9H, m, 3CH3), 4.13–4.47 (6H, m, 3OCH2), 7.45 (2H, d, 3JHH = 7.8 Hz,
3
aromatic), 7.58 (2H, d, JHH = 7.8 Hz, aromatic). 13C NMR: δ = 13.6, 14.0 and 14.2 (3CH3),
62.6, 63.1 and 64.2 (3OCH2), 111.8, 129.3, 129.5 and 129.8 (aromatic), 134.6 (C), 142.1 (C),
=
143.8 (C), 152.1 (C), 158.6, 162.1 and 165.4 (3C O).
3.1.7. 5-Ethyl 2,3-dimethyl-4-(4-nitrophenyl)thiophene-2,3,5-tricarboxylate (3g)
Yellow powder; yield: 32%; m.p. 165–167 ◦C. IR: 1737, 1725, 1594, 1522. EI-MS: 393 (M+,
5), 73 (40), 122 (100). Anal. Calcd for C17H15NO8S: C, 51.91; H, 3.84; N, 3.56%. Found: C,
52.10; H, 3.96; N, 3.40%. 1H NMR: δ = 1.13 (3H, t, 3JHH = 7.1 Hz, CH3), 3.81 (3H, s, OCH3),
3.92 (3H, s, OCH3), 4.43 (2H, q, 3JHH = 7.1 Hz, OCH2), 7.62 (2H, d, 3JHH = 7.8 Hz, aromatic),
8.27 (2H, d, 3JHH = 7.8, aromatic). 13C NMR: δ = 13.7 (CH3), 53.4 (OCH3), 53.5 (OCH3), 64.5
(OCH2), 112.4, 124.2, 127.1 and 129.6 (aromatic), 136.6 (C), 137.1 (C), 147.6 (C), 148.8 (C),
=
159.5, 163.6 and 165.3 (3C O).

Journal of Sulfur Chemistry 277
3.1.8. Triethyl 4-(4-nitrophenyl)thiophene-2,3,5-tricarboxylate (3h)
Yellow powder; yield: 30%; m.p. 159–161 ◦C. IR: 1735, 1724, 1592, 1524. EI-MS: 421 (M+, 5),
73 (43), 122 (100). Anal. Calcd for C19H19NO8S: C, 54.15; H, 4.54; N, 3.32%. Found: C, 54.23;
H, 4.45; N, 3.50%.1H NMR: δ = 1.14–1.46 (9H, m, 3CH3), 4.15–4.48 (6H, m, 3OCH2), 7.60
3
3
(2H, d, JHH = 7.8 Hz, aromatic), 8.31 (2H, d, JHH = 7.8 Hz, aromatic). 13C NMR: δ = 13.6,
14.2 and 14.5 (3CH3), 62.9, 63.4 and 64.4 (3OCH2), 112.2, 124.2, 127.3 and 129.7 (aromatic),
=
136.5 (C), 136.7 (C), 147.4 (C), 148.3 (C), 159.5, 163.7 and 165.1 (3C O).
Acknowledgement
We gratefully acknowledge financial support from the Research Council of Islamic Azad University of Zahedan of Iran.
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