Base-catalyzed condensation of thioglycolic ester with β- chloropyrrolecarbaldehyde: One-pot approach to substituted thieno[2,3-b]pyrroles

Article abstract of DOI:10.1002/jhet.525

A simple methodology has been developed for the synthesis of thieno[2,3-b]pyrroles from N-aryl-diformylated-pyrroles by base catalyzed condensation with thioglycolic ester.

Full text of DOI:10.1002/jhet.525

218
Base-Catalyzed Condensation of Thioglycolic Ester with
b-Chloropyrrolecarbaldehyde: One-Pot Approach to Substituted
Thieno[2,3-b]pyrroles
Vol 48
Gopa Barman and Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
*E-mail: jkray@chem.iitkgp.ernet.in
Received February 18, 2010
DOI 10.1002/jhet.525
Published online 7 October 2010 in Wiley Online Library (wileyonlinelibrary.com).
A simple methodology has been developed for the synthesis of thieno[2,3-b]pyrroles from N-aryl-
diformylated-pyrroles by base catalyzed condensation with thioglycolic ester.
J. Heterocyclic Chem., 48, 218 (2011).
INTRODUCTION
of pharmacological importance. However, the existing
methods for the synthesis of thienopyrroles are laborious
and have a number of limitations.
Bioisosterism represents one approach used by the me-
dicinal chemist for the rational modification of lead com-
pounds into safer and more clinically effective agents.
The concept of bioisosterism is often considered to be
qualitative and intuitive [1]. With the structure–activity
relationships around the indole core evaluated, bioisos-
teric replacement of the indole arene ring with thiophene
afforded a series of analogous thienopyrroles [2].
Whittamore et al. [4], Venable et al. [5], and
Krayushkin et al. [6] have synthesized thienopyrroles by
the condensation of the corresponding thiophenalde-
hydes with esters. Paulmier and coworkers [7] have syn-
thesized thieno[3,2-b]pyrrole derivatives via palladium-
catalyzed cyclization.
Herein, we use the N-phenyl-chloropyrroledicarboxal-
dehydes as starting materials, which are prepared from
c-lactam carboxylic acid derivatives [8]. The N-aryl-
diformylated-pyrroles have a range of electrophilic center
and a range of sterically encumbered heteroaryl pyrroles
that can be synthesized from their reaction with nucleo-
philes. Clemens et al. [9] and Owton et al. [10] have used
methyl thioglycolate for the construction of thiophene
rings. Olesen et al. [11] have synthesized thieno[2,3-
b]indole from methyl 1-benzylthieno[2,3-b]indole-car-
boxylate via debenzylation with aluminium trichloride in
toluene and followed by decarboxylation. Herein, we
wish to synthesize thienopyrroles by reaction with methyl
thioglycolate with N-aryl-diformylated-pyrroles.
The heteroarylpyrroles are less stable than their sim-
ple pyrrole counterparts and, in general, classical meth-
ods are not applicable to their synthesis so their prepara-
tion was of very challenging to us. The condensation of
thioglycolic ester with b-chloropyrrolecarbaldehyde in
basic medium makes our methodology different from
other previous literature methodology.
Blair et al. [3a] have shown that thiophene replace-
ment of the annulated benzene ring in derivatives of pir-
oxicam, amphetamine, had no effect on activity. Many
thieno-fused bicyclic compounds such as thienopyri-
dines, thienopyrimidines, and thienopyrroles have been
recently prepared and tested for their biological proper-
ties. Among them, thienopyrroles are important from
both theoretical and synthetic points of view, as they are
isosteric with indole with their six p electrons. They are
biologically active as PLA2 inhibitors, MCP-1 inhibi-
tors, glycogen phosphorylase inhibitors, gonadotropin-
releasing hormone antagonists, and antiviral agents [3b].
Moreover, the variable position of the heteroatom in
thienopyrrole derivative increases the chance of suitable
binding in a biological system.
RESULTS AND DISCUSSION
The synthesis of thienopyrroles has attracted much
attention from organic chemists mainly because they are
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2010 HeteroCorporation

January 2011 Base-Catalyzed Condensation of Thioglycolic Ester with b-Chloropyrrolecarbaldehyde:
One-Pot Approach to Substituted Thieno[2,3-b]pyrroles
219
Scheme 1
Scheme 2
The
N-aryl-5-chloro-3-aryl/heteroaryl-pyrrole-2,4-
dicarbaldehyde derivatives on treatment with thiogly-
colic ester and triethylamine in dry pyridine solution
generates the head-to-head thienopyrrole derivatives in
good yield (Scheme 1; Table 1).
using Waters LCT mass spectrometer. All reagents and sol-
vents are obtained from commercial suppliers.
Chromatographic purification was done with either 60–120
or 100–200 mesh silica gels (SRL). Petroleum ether refers to
the fraction boiling in the range 60–80ꢀC. Tetrahydrofuran
was freshly distilled over sodium–bezophenone.
However, the mechanism of the reaction is uncertain,
and we were unable to isolate any intermediates,
although a plausible mechanism may be written as
depicted in Scheme 2 [12].
General procedure for the synthesis of thieno[2,3-b]pyr-
role derivatives (2). To a flask containing N-aryl-diformy-
lated-pyrrole 1 (1 mmol) and methyl thioglycolate (2 mmol) in
dry pyridine (3–5 mL) at OꢀC, triethylamine (2 mmol) was
added dropwise. The reaction mixture was gradually allowed
to attain the room temperature (25–30ꢀC) and then stirred for
additional 30 min at 45–50ꢀC. Then, it was cooled to 10–15ꢀC
and 6 mL of 50% KOH (aq.) solution was added to it and
stirred at that temperature for 20 min. The reaction mixture
was then poured into ice cold water and extracted with
CH2Cl2. The combined organic layer was repeatedly washed
with 10% HCl solution and brine. After drying the organic
layer with Na2SO4, the solvent was evaporated under reduced
pressure. The product thus obtained was purified by silica gel
(60–120 mesh) column chromatography [petroleum ether (60–
80ꢀC)–ethylacetate 20:1)].
CONCLUSIONS
In conclusion, we say that we have developed a new
preparation method based on the use of active methyl-
ene thiol compounds and pyrrole-chloroaldehyde. The
experimental simplicity of the reaction opens up new
opportunities for the use of this reaction in synthetic and
industrial processes.
EXPERIMENTAL
1H-NMR spectra were recorded in CDCl3 with TMS as the
internal standard on a BRUKER-AC 200 and 400 MHz spec-
trometer. Chemical shifts are reported in ppm. Data are
reported as follows: chemical shifts, multiplicity (s, singlet; d,
doublet; t, triplet; q, quartet; br, broad; m, multiplet), and cou-
pling constant (Hz).
13C-NMR (50 MHz) and 13C-NMR (100 MHz) spectra were
recorded on a BRUKER-AC 200 and 400 MHz spectrometer
with complete proton decoupling. IR spectra were recorded on
a Perkin-Elmer 883 and Shimadzu FTIR-8300 infrared spec-
trometers. EIMS (70 ev) spectra were taken using a VG Auto
spec M mass spectrometer and ESI-MS spectra were taken
Methyl-6-(3,4-dichloro-phenyl)-5-formyl-4-phenyl-6H-thieno
[2,3-b]pyrrole-2-carboxylate (2a). Light yellow viscous semi-
1
solid; H-NMR (CDCl3, 200 MHz) d: 3.90 (s, 3H), 7.51–7.63
(m, 7H), 7.93 (s, 1H), 8.10 (s, 1H), 9.7 (s, 1H). 13C-NMR
(CDCl3, 50 MHz) d: 52.40, 114.34, 125.60, 126.72 (2C),
128.84, 129.01 (2C), 129.70 (2C), 129.84, 130.12 (2C),
131.47, 131.99, 132.72, 133.89, 135.62, 136.48, 162.89,
179.95. ESI-MS Cal for C21H13NO3Cl2S [M], [M þ Hþ] ¼
431.104 found 430.0994 (35Cl, 35Cl), 432.0977 (37Cl, 35Cl).
Anal. Calcd. for C21H13NO3Cl2S: C, 58.62; H, 3.05; N, 3.26%;
Found: C, 58.46; H, 3.13; N, 3.41%.
Table 1
Synthesis of N-aryl-thienopyrrole derivatives (2) from N-aryl-diformylated-pyrroles (1).
Substrate
Ar
Products
Yield (%)
N-aryl-diformylated-pyrrole
N-aryl-thienopyrrole
1a
1b
1c
1d
1e
1f
R1 ¼ H, R3 ¼ R2 ¼ Cl
Phenyl
Phenyl
Phenyl
2-Thienyl
Phenyl
Phenyl
2a
2b
2c
2d
2e
2f
61
60
52
58
90
87
R1 ¼ R3 ¼ H, R2 ¼ Br
R1 ¼ H, R3 ¼ R2 ¼ F
R1 ¼ Cl, R2 ¼ F, R3 ¼ H
R1 ¼ R3 ¼ R2 ¼ H
R1 ¼ R3 ¼ H, R2 ¼ Cl
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

220
G. Barman and J. K. Ray
Vol 48
6.97 (d, J ¼ 8.6 Hz, 1H), 7.42–7.50 (m, 8H), 7.81 (d, J ¼ 8.8
Hz, 1H), 9.67 (s, 1H). 13C-NMR (CDCl3, 50 MHz) d: 52.54,
122.64, 124.53, 126.89 (2C), 128.72, 128.94 (2C), 129.44,
129.54, 129.67, 130.04 (2C), 131.00, 131.34, 132.88 (2C),
133.92, 137.71, 162.86, 179.89. Anal. Calcd. for
C21H14ClNO3S: C, 63.72; H, 3.56; N, 3.54%; Found: C, 63.54;
H, 3.83; N, 3.77%.
Methyl-6-(4-bromo-phenyl)-5-formyl-4-phenyl-6H-thieno
[2,3-b]pyrrole-2-carboxylate (2b). Light yellow viscous
dense liquid; 1H-NMR (CDCl3, 200 MHz) d: 3.89 (s, 3H),
7.37 (dd, J ¼ 1.5, 6.6 Hz, 2H), 7.50–7.53 (m, 3H), 7.58–7.68
(m, 4H), 7.93 (s,1H), 9.71 (s, 1H). 13C-NMR (CDCl3, 100
MHz) d: 52.36, 122.34, 125.53, 126.90 (2C), 128.78, 128.94
(2C), 129.44, 129.54, 129.67, 130.04 (2C), 131.00, 131.34,
132.56 (2C), 133.92, 137.61, 162.86, 179.91. Anal. Calcd. for
C21H14BrNO3S: C, 57.28; H, 3.20; N, 3.18%; Found: C,
57.54; H, 3.63; N, 3.47%.
Acknowledgments. Financial support from DST and CSIR
(New Delhi) is gratefully acknowledged.
Methyl-6-(3,4-difluoro-phenyl)-5-formyl-4-phenyl-6H-thieno
[2,3-b]pyrrole-2-carboxylate (2c). Light yellow viscous semi-
solid; H-NMR (CDCl3, 400 MHz) d: 3.93 (s, 3H), 7.29–7.37
1
REFERENCES AND NOTES
(m, 2H), 7.47–7.55 (m, 4H), 7.60 (d, J ¼ 6.8 Hz, 2H) 7.93 (s,
1H), 9.7 (s, 1H). 13C-NMR (CDCl3, 100 MHz) d: 52.41,
115.45, 115.65, 117.78, 117.96, 121.80, 121.83, 125.54,
128.78, 128.87, 128.99 (2C), 129.49, 129.59, 130.02 (2C),
130.83, 131.18, 132.65, 133.96, 162.80, 179.87. Anal. Calcd.
for C21H13F2NO3S: C, 63.47; H, 3.30; N, 3.52%; Found: C,
63.66; H, 3.57; N, 3.28%.
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(CDCl3, 400 MHz) d: 3.88 (s, 3H), 7.47–7.54 (m, 8H), 7.63
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet