Preparation of thieno[2,3-b]pyrroles starting from ketene-N,S-acetals

Article abstract of DOI:10.1016/S0040-4020(03)00054-1

Thieno[2,3-b]pyrroles 4 can easily be synthesised in two different ways by using phenyl isothiocyanate and activated methylene compounds. The priority of the formation of the thiophene or pyrrole ring is investigated.

Full text of DOI:10.1016/S0040-4020(03)00054-1

Tetrahedron 59 (2003) 1557–1564
Preparation of thieno[2,3-b]pyrroles starting from
ketene-N,S-acetals
*
Geoffroy Sommen, Alain Comel and Gilbert Kirsch
´ ´ ´
Laboratoire d’Ingenierie Moleculaire et Biochimie Pharmacologique, Faculte des Sciences, Universit de Metz, Ile du Saulcy,
57045 Metz Cedex, France
Received 11 October 2002; revised 9 December 2002; accepted 3 January 2003
Abstract—Thieno[2,3-b]pyrroles 4 can easily be synthesised in two different ways by using phenyl isothiocyanate and activated methylene
compounds. The priority of the formation of the thiophene or pyrrole ring is investigated. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Potassium carbonate has been used as the base in order to
obtain the intermediate ketene aminothioacetals. The
addition of two or more equivalents of alkyl bromoacetate,
chloroacetonitrile, chloracetone or a-bromoacetophenone
leads only to the thiophenes 2 in moderate to good yields
(Scheme 1 and Table 1).
Many thieno-fused bicyclic compounds have been recently
prepared and tested for their biological properties, among
them nitrogen containing heterocyclic systems such as
thienopyridines1, thienopyrimidines2 and thienopyrroles3,4
as well as more complex structures.5,6
Condensation of the intermediate salt ketene-N,S-acetal
with the halide currently leads to the corresponding
aminothioacetal which smoothly undergoes a Dieckmann
or Thorpe–Ziegler cyclisation in basic medium at room
temperature. Formation of the pyrrole fused ring was
achieved by prolonged reflux of 2 in acetone for 4–5 days
in the presence of 1.5 equiv. of an alkyl bromoacetate.12
Blair et al.4 have reviewed some cases for which the
thiophene replacement of the annulated benzene ring in
some biologically active compounds maintains the activity
but modifies the selectivity of these bioisosteres. These
observations led them to investigate the activity of
thienopyrroles, bioisosteric analogues of tryptamine
derivatives.
Generally described synthetic access required appropriate
thiophenes obtained after multi-step synthesis. Due to the
interesting biological properties of thienopyrroles, we
decided to develop new preparation methods based on the
use of methylene active compounds and isothiocyanates.
2. Results and discussion
We have recently reported a one-pot method7 for the
preparation of aminothiophenes 2, precursors of thieno[2,3-
b]pyrroles 4.
The first step is the condensation of activated methylene
compounds with alkyl or aryl isothiocyanates in a basic
medium, which is well documented in the literature.8–11
Keywords: thieno[2,3-b]pyrroles; ketene-N,S-acetals; thieno-fused bicyclic
compounds.
*
Corresponding author. Tel.: þ33-387315295; fax: þ33-387315333;
Scheme 1. Preparation of thiophenes 2: Method A.
e-mail: kirsch@sciences.univ-metz.fr
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00054-1

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G. Sommen et al. / Tetrahedron 59 (2003) 1557–1564
Table 1. One-pot method for the preparation of thiophenes 2 from 1,3-
diketones or related compounds and phenyl isothiocyanate (Method A)
Table 2. Preparation of pyrroles 3 starting from 1
Entry
Starting compound
Product
Yield (%)
81
Entry
Starting compound
Product
Yield (%)
47
3a
2a
2b
2c
71
34
3b
3c
43
98
2d
46
3d
10
2e
19
34
2h
formation of the N-phenyl S-methyl ketene-N,S-acetals 1,
obtained in one-pot from methylene active compounds,
phenyl isothiocyanate and methyl iodide under the pre-
viously used basic conditions (K2CO3/DMF). These com-
pounds were easily obtained in yields around 90% in all
cases. In a second step, the ability of thioglycolate to react
with compounds 1, which is poorly related in the
literature,14 was therefore investigated (Scheme 2).
2i
94
30
82
99
82
2j
2k
2l
Although two steps are required for the preparation of the
thiophenes 2 the yields for the two steps, in some cases,
have been increased by a factor 2 to 3 (Tables 2 and 3).
On the other hand, thiophenes 2f,g could be obtained by this
way in moderate yields when our one step method
completely failed.
2m
We must note that in some cases our previous one step
method remains attractive (see 2b) and is the only easy way
we currently have to introduce a substituent at the 2-position
different from the carbethoxy group, which can be achieved
in moderate (2f, 2g) to excellent yields (almost quantitative
for 2l).
We have also shown13 that the preparation of these
aminothiophenes 2 can be achieved in two steps with
good yields when the one-pot method failed or gave the
expected products in low yields. The first step consists in the
In a last step, we decided to investigate which of the
thiophene or pyrrole rings should be prepared first in order
to optimize this method (Scheme 3).
Starting from intermediates 1, the corresponding 2-phenyl-
amino-thiophenes 2 and 2-methylsulfanylpyrroles 3 have
been obtained in moderate to good yields (10–98%)
(Table 4).
We have already described7 the preparation of thieno[2,3-
b]pyrroles 4 from thiophenes 2 but the replacement of a
methylsulfanyl group with a thiol on substituted pyrroles
have not been related in the literature.
We have established that this strategy could be applied to
Scheme 2. Preparation of thiophenes 2: Method B.

G. Sommen et al. / Tetrahedron 59 (2003) 1557–1564
1559
Table 3. Comparison of the two methods for the preparation of thiophenes 2 starting from 1
Entry
Starting Compound
Product 1
Yield (%)
Product 2
Yield (%)
Method A
47
Method B
79
a
96
b
c
58
98
97
71
34
46
21
88
62
d
e
f
91
80
87
19
64
32
28
–
–
g
ketene aminothioacetal 1. Although the ketene aminothio-
acetals moiety is still present in the pyrrole 2 skeleton, it was
not obvious that a nucleophilic aromatic substitution
reaction with thioglycolates was still feasible.
preparation method chosen (4a,c) but for another case
(4d), we were not able to continue the synthesis from the
pyrrole 3d even when we did not encounter major problems
to prepare thiophenes 2d and to finally obtain thieno[2,3-
b]pyrroles 4d.
According to the results we report here, we clearly show that
the methylsulfanyl group of some pyrroles can act as a
leaving group in the presence of thioglycolate and lead to
the expected thienopyrroles 4 (Table 4).
In fact, it should be stressed that a thiol must react to
replace the methylsulfanyl group from the pyrroles 3
even when a halide is required to obtain the compounds 4
from the thiophenes 2. As a consequence, it becomes
much more interesting to implement on account of the
higher reliability of the latter, whether it is commercial or
not.
Nevertheless, it is currently not possible to predict whether
the thiophene or pyrrole ring has to be synthesized first. In
some cases, it appears to be independent from the
Scheme 3.

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G. Sommen et al. / Tetrahedron 59 (2003) 1557–1564
Table 4. Comparative study for the preparation of thieno[2,3-b]pyrroles 4
Entry
Yield (%)
79a
Entry
Yield (%)
73
81
72
61
36b
43
26
59
92a
Scheme 4. Preparation of thieno[2,3-b]pyrroles 4e–h.
the best way to prepare these bicyclic compounds is the
formation of the appropriate thiophenes, in one or two steps,
prior to the pyrrole. The one-pot condensation with the
appropriate halides followed by a Dieckman-type cyclisa-
tion allows to readily obtain the expected products in good
yields.12
98
62a
10
43
32
3. Experimental
3.1. General
1
NMR spectra were recorded at 250 and 62.5 MHz for H
–
and 13C, respectively on a Bruker AC 250 spectrometer. IR
spectra were recorded on a Mattson FTIR galaxy 3000
spectrophotometer using samples as KBr plates. Melting
points were recorded on a Stuart Scientific SMP3 capillary
melting point apparatus and were uncorrected. Elemental
analysis were recorded on a Carlo Erba 1106 analyzer.
a
Method B.
Method A.
b
Finally, we want to report the preparation of thieno[2,3-
b]pyrroles 4e–g (see Scheme 4) obtained from thiophenes
2f, 2g and 2j by treatment with ethyl bromacetate under the
same conditions described for the preparation of compounds
4 from thiophenes 2. Obviously, the use of our one-pot
method to prepare the thiophene ring prior to the pyrrole one
is required for the preparation of these bicyclic compounds.
3.2. General procedure for the preparation of 1 and 2
(Method A)
A 100 mL three-necked round-bottom flask equipped with a
magnetic stirrer, condenser and septum was charged with a
solution of 1,3-diketone (10.0 mmol, 1 equiv.) in DMF
(30 mL). Dried potassium carbonate (10.0 mmol, 1 equiv.)
was added and the mixture was stirred for 1 h at room
temperature. Phenyl isothiocyanate (10.0 mmol, 1 equiv.)
was then added dropwise and the mixture was stirred for 2 h
at room temperature before adding the appropriate halide
(methyl iodide for 1, ethyl bromacetate for 2a–g,
chloracetonitrile for 2h, chloracetone for 2i–k or a-broma-
cetophenone for 2l,m)(10.0 mmol, 1 equiv.) and dried
potassium carbonate (10.0 mmol, 1 equiv., not needed for
1). The reaction was quenched with 100 mL of water after
having stirred for 4 h at room temperature. The crude
product precipitated and was purified by filtration followed
by crystallisation in ethanol.
Compound 4h, isomer of 4e, has been prepared from
thiophenes 2a following the same method with chloraceto-
nitrile instead of bromacetate. This example clearly shows
that our strategy allows to choose the position of all the
desired substituents on the thieno[2,3-b]pyrrole framework,
which demonstrates the generality and reliability of our
method.
To sum up, we have developed a new synthetic pathway for
the preparation of thieno[2,3-b]pyrroles.
Therefore, we have shown that, except for some rare cases,

G. Sommen et al. / Tetrahedron 59 (2003) 1557–1564
1561
3.2.1. 2-Acetyl-3-hydroxy-N-phenyl-but-2-enimidothioic
acid methyl ester (1a). Mp: 728C (ethanol); IR (KBr): 1597
(KBr): 1495, 1602 cm21; 1H NMR (DMSO): d 1.14 (t, 3H,
J¼7.3 Hz), 4.13 (q, 2H, J¼7.3 Hz), 6.95–7.47 (m, 15H),
11.19 (sl, 1H); 13C NMR (DMSO): d 14.0, 60.6, 110.2,
119.0, 120.2(2C), 124.7(2C), 126.8, 127.2(2C), 127.4(2C),
128.1, 128.3(4C), 129.7, 130.4, 134.6, 139.5, 148.3, 155.9,
163.0, 194.7; Anal. calcd for C26H21NO3S: C 73.04; H 4.95;
N 3.28. Found: C 73.00; H 5.02; N 3.32.
1
(L) cm21; H NMR (CDCl3): d 2.12 (s, 6H), 2.50 (s, 3H),
6.69–7.39 (m, 5H), 15.04 (sl, 1H); 13C NMR (CDCl3): d
14.3(2C), 23.8, 111.6, 120.6(2C), 123.9, 128.8(2C), 149.6,
164.8, 190.3(2C); Anal. calcd for C13H15NO2S: C 62.62; H
6.06; N 5.62. Found: C 62.74; H 6.20; N 5.58.
3.2.2. 2-(Methylsulfanyl-phenylamino-methylene)-1,3-
diphenyl-propane-1,3-dione (1b). Mp: 978C (ethanol); IR
(KBr): 1654 cm21; 1H NMR (CDCl3): d 1.92 (s, 3H), 7.13–
7.57 (m, 15H), 13.41 (sl, 1H); 13C NMR (CDCl3): d 17.3,
112.2, 123.5, 125.8, 127.9(8C), 128.8(2C), 129.5(2C),
131.3(2C), 139.4, 140.8, 166.2, 187(2C); Anal. calcd for
C23H19NO2S: C 73.97; H 5.13; N 3.75. Found: C 74.00; H
5.12; N 3.80.
3.2.9. 3-Hydroxy-5-phenylamino-thiophene-2,4-dicar-
boxylic acid diethyl ester (2c). Mp: 968C (ethanol); IR
(KBr): 2982, 2932, 1733, 1663, 1596, 1577, 1234, 1189,
1151, 1030 cm21 1H NMR (CDCl3): d 1.10 (t, 3H,
;
J¼7.2 Hz), 1.22 (t, 3H, J¼7.2 Hz), 3.96 (q, 2H,
J¼7.2 Hz), 4.22 (q, 2H, J¼7.2 Hz), 7.14–7.55 (m, 5H);
13C NMR (CDCl3): d 14.0(2C), 60.0, 60.3, 98.3, 120.2(2C),
123.2, 124.8, 128.8(2C), 138.8, 161.7, 163.6, 165.3, 165.8;
Anal. calcd for C16H17NO5S: C 57.30; H 5.11; N 4.18.
Found: C 57.20; H 5.12; N 4.20.
3.2.3. 2-(Methylsulfanyl-phenylamino-methylene)-malo-
nic acid diethyl ester (1c). Mp: 568C (ethanol); IR (KBr):
1715(L) cm21; 1H NMR (CDCl3): d 1.31 (t, 6H, J¼7.2 Hz),
1.95 (s, 3H), 4.25 (q, 4H, J¼7.2 Hz), 7.22–7.33 (m, 5H),
10.61 (sl, 1H); 13C NMR (CDCl3): d 13.6, 13.8, 16.0, 60.3,
61.8, 101.7, 123.2(2C), 124.9, 129.2(2C), 139.1, 159.3,
166.5(2C); Anal. calcd for C15H19NO4S: C 58.23; H 6.19; N
4.53. Found: C 58.34; H 6.41; N 4.68.
3.2.10. 3-Methyl-5-phenylamino-thiophene-2,4-dicar-
boxylic acid diethyl ester (2d). Mp: 1198C (ethanol); IR
(KBr): 2984, 1693, 1656, 1593, 1560, 1521, 1250, 1230,
1
1195 cm21; H NMR (CDCl3): d 1.34 (t, 3H, J¼7.2 Hz),
1.41 (t, 3H, J¼7.2 Hz), 2.77 (s, 3H), 4.27 (q, 2H, J¼7.2 Hz),
4.35 (q, 2H, J¼7.2 Hz), 7.11–7.44 (m, 5H), 10.60 (sl, 1H);
13C NMR (CDCl3): d 14.0, 14.1, 15.7, 60.2, 108.6, 109.0,
119.5(2C), 124.0, 129.4(2C), 139.7, 147.2, 162.0, 162.5,
166.6; Anal. calcd for C17H19NO4S: C 61.24; H 5.74; N
4.20. Found: C 61.25; H 5.70; N 4.17.
3.2.4. 2-(Methylsulfanyl-phenylamino-methylene)-malo-
nonitrile (1e). Mp: 1698C (ethanol); IR (KBr): 2196,
1
2182 cm21; H NMR (CDCl3): d 2.71 (s, 3H), 7.25–7.46
(m, 5H), 8.09 (sl, 1H); 13C NMR (CDCl3): d 16.8, 114.1,
114.4, 124.3, 127.7(2C), 128.2, 129.8(2C), 137.1, 172.4;
Anal. calcd for C11H9N3S: C 61.37; H 4.21; N 19.52. Found:
C 61.22; H 4.29; N 19.46.
3.2.11. 3-Amino-4-cyano-5-phenylamino-thiophene-2-
carboxylic acid ethyl ester (2e). Mp: 2198C (ethanol); IR
(KBr): 1720, 2200, 3420 cm21; 1H NMR (CDCl3): d 1.29 (t,
3H, J¼7.2 Hz), 4.25 (q, 2H, J¼7.2 Hz), 5.79 (sl, 2H), 7.38
(m, 5H); 13C NMR (CDCl3): d 14.6(CH3), 60.1(CH2), 80.0,
89.4, 113.6(CN), 120.5, 125.6(2C), 129.9(2C), 138.8, 152.8,
161.9(CO2), 162.0; Anal. calcd for C14H13N3O2S: C 58.52;
H 4.56; N 14.62. Found: C 58.60; H 4.50; N 14.72.
3.2.5. 2-Benzoyl-3-methylsulfanyl-3-phenylamino-
acrylonitrile (1f). Mp: 1328C (ethanol); IR (KBr): 2195,
1591 cm21; 1H NMR (CDCl3): d 2.33 (s, 3H), 7.34–7.88 (m,
10H), 13.95 (sl, 1H); 13C NMR (CDCl3): d 17.3, 85.5, 119.8,
124.6(2C), 127.3, 127.8(2C), 128.1(2C), 129.3(2C), 131.6,
137.1, 138.1, 172.7, 191.5; Anal. calcd for C17H14N2OS: C
69.36; H 4.79; N 9.52. Found: C 69.53; H 4.74; N 9.46.
3.2.12. 3-Amino-4-benzoyl-5-phenylamino-thiophene-2-
carboxylic acid ethyl ester (2f). Mp: 2328C (ethanol); IR
;
(KBr): 1665, 1619, 1417, 1330, 1285cm21 1H NMR
3.2.6. 2-Cyano-3-methylsulfanyl-3-phenylamino-acrylic
acid ethyl ester (1g). Mp: 868C (ethanol); IR (KBr):
(CDCl3): d 1.04 (t, 3H, J¼7.1 Hz), 3.98 (q, 2H, J¼7.1 Hz),
7.22–7.59 (m, 5H); 13C NMR (CDCl3): d 14.1, 60.1, 118.1,
118.2, 127.8, 128.0, 129.0(2C), 129.3(2C), 129.4(2C),
129.6(2C), 130.4, 137.0, 139.6, 159.8, 161.3(CO2),
187.3(CO); Anal. calcd for C20H18N2O3S: C 65.55; H
4.95; N 7.64. Found: C 65.40; H 5.11; N 7.52.
2203, 1658 cm21 1H NMR (CDCl3): d 1.35 (t, 3H,
;
J¼7.2 Hz), 2.24 (s, 3H), 4.25 (q, 2H, J¼7.2 Hz), 7.26–
7.41 (m, 5H), 11.52 (sl, 1H); 13C NMR (CDCl3): d 14.2,
17.2, 61.2, 117.4, 124.8(2C), 127.1(2C), 129.3, 129.4,
137.6, 167.7, 170.1; Anal. calcd for C13H14N2O2S: C 59.52;
H 5.38; N 10.68. Found: C 59.61; H 5.49; N 10.89.
3.2.13. 3-Amino-5-phenylamino-thiophene-2,4-dicar-
boxylic acid diethyl ester (2g). Mp: 1408C (ethanol); IR
(KBr): 3507, 3379, 2977, 1696, 1664, 1596, 1569, 1505,
3.2.7. 4-Acetyl-3-methyl-5-phenylamino-thiophene-2-
carboxylic acid ethyl ester (2a). Mp: 1258C (ethanol); IR
(KBr): 1680, 1700, 2990 cm21; 1H NMR (CDCl3): d 1.34 (t,
3H, J¼7.1 Hz), 2.58 (s, 3H), 2.82 (s, 3H), 4.28 (q, 2H,
J¼7.1 Hz), 7.35–7.42 (m, 5H), 12.1 (s, 1H); 13C NMR
(CDCl3): d 14.3, 16.5, 31.3, 60.5, 108.9, 119.2, 120.5,
124.7(2C), 129.5(2C), 139.6, 145.8, 162.7, 163.4, 195.7;
Anal. calcd for C16H17NO3S: C 63.34; H 5.65; N 4.62.
Found: C 63.47; H 5.46; N 4.61.
1
1288, 1252, 1030 cm21; H NMR (CDCl3): d 1.18 (t, 3H,
J¼7.1 Hz), 1.32 (t, 3H, J¼7.2 Hz), 4.09 (q, 2H, J¼7.1 Hz),
4.34 (q, 2H, J¼7.2 Hz), 7.24–7.45 (m, 5H), 10.05 (s, 1H);
13C NMR (CDCl3): d 13.4(CH3), 13.6(CH3), 58.3(CH2),
59.5(CH2), 96.8, 101.0, 119.6(2C), 123.9, 128.6(2C), 138.3,
147.4, 162.0(CO2), 163.1, 164.1(CO2); Anal. calcd for
C16H18N2O4S: C 57.47; H 5.43; N 8.38. Found: C 57.55; H
5.29; N 8.45.
3.2.8. 4-Benzoyl-3-phenyl-5-phenylamino-thiophene-2-
carboxylic acid ethyl ester (2b). Mp: 2228C (ethanol); IR
3.2.14. 4-Acetyl-3-methyl-5-phenylamino-thiophene-2-
carbonitrile (2h). Mp: 868C (ethanol); IR (KBr): 3292,

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G. Sommen et al. / Tetrahedron 59 (2003) 1557–1564
1
2201, 1621, 1590, 1548, 1519 cm21; H NMR (DMSO): d
2.56 (s, 3H), 2.61 (s, 3H), 7.23–7.43 (m, 5H), 12.10 (sl, 1H);
13C NMR (DMSO): d 18.2, 30.9, 115.0, 117.3, 121.2(2C),
125.8, 130.0(2C), 130.1, 139.5, 150.2, 163.5, 194.9; Anal.
calcd for C14H12N2OS: C 65.60; H 4.72; N 10.93. Found: C
65.78; H 4.50; N 11.13.
product precipitated and was purified by filtration followed
by crystallisation in ethanol.
3.4. General procedure for the preparation of pyrroles 3
A 100 mL three-necked round-bottom flask equipped with a
magnetic stirrer, condenser and septum was charged with a
solution of aminothioacetals 1 (10.0 mmol, 1 equiv.) in
acetone (30 mL). Dried potassium carbonate (10.0 mmol,
1 equiv.) and ethyl bromoacetate (or chloroacetonitrile)
(10.0 mmol, 1 equiv.) was added. The reaction was
quenched with 100 mL of water after having stirred 4–5
days in refluxing acetone. The crude product when
precipated was purified by filtration followed by crystal-
lisation in ethanol, when it was an oil the aqueous phase was
washed 3£ with dichloromethane and dried over mag-
nesium sulfate and evaporated.
3.2.15. 1-(5-Acetyl-4-methyl-2-phenylamino-thiophen-3-
yl)-ethanone (2i). Mp: 1158C (ethanol); IR (KBr): 3180,
;
1650, 1614, 1533, 1485, 1399, 1218 cm21 1H NMR
(CDCl3): d 2.45 (s, 3H), 2.59 (s, 3H), 2.80 (s, 3H), 7.16–
7.45 (m, 5H), 11.99 (sl, 1H); 13C NMR (CDCl3): d 17.3,
30.4, 31.6, 119.9, 120.0, 120.8(2C), 125.1, 129.6(2C),
139.5, 144.6, 163.3, 190.2, 196.5; Anal. calcd for
C15H15NO2S: C 65.91; H 5.53; N 5.12. Found: C 66.17; H
5.65; N 5.21.
3.2.16. 5-Acetyl-4-hydroxy-2-phenylamino-thiophene-3-
carboxylic acid ethyl ester (2j). Mp: 1098C (ethanol); IR
(KBr): 1549, 1587, 1665 cm21;1H NMR (CDCl3): d 1.41 (t,
3H, J¼7.2 Hz), 2.26 (s, 3H), 4.42 (q, 2H, J¼7.2 Hz), 7.13–
7.59 (m, 5H), 10.89 (sl, 1H); 13C NMR (CDCl3): d 14.4,
30.3, 60.4, 106.2, 121.6(2C), 124.9, 129.2(2C), 138.4,
145.2, 151.0, 152.2, 165.9, 180.5; Anal. calcd for
C15H15NO4S: C 59.00; H 4.95; N 4.59. Found: C 59.13; H
4.97; N 4.62.
3.4.1. 4-Acetyl-3-methyl-5-methylsulfanyl-1-phenyl-1H-
pyrrole-2-carboxylic acid ethyl ester (3a). Yellow oil; 1H
NMR (CDCl3): d 1.00 (t, 3H, J¼7.2 Hz), 2.08 (s, 3H), 2.53
(s, 3H), 2.73 (s, 3H), 4.04 (q, 2H, J¼7.2 Hz), 7.20–7.46 (m,
5H); 13C NMR (CDCl3): d 12.3, 13.8, 20.6, 31.3, 60.2,
120.0(2C), 123.0, 123.9, 128.3, 128.4(2C), 128.5, 128.8,
150.8, 160.9, 196.5; Anal. calcd for C17H19NO3S: C 64.33;
H 6.03; N 4.41. Found: C 64.30; H 6.12; N 4.50.
3.2.17. 5-Acetyl-4-amino-2-phenylamino-thiophene-3-
carbonitrile (2k). Mp: 2128C (ethanol); IR (KBr): 3379,
3266, 3191, 2204, 1588 cm21; 1H NMR (CDCl3): d 2.07 (s,
3H), 7.18–7.57 (m, 5H), 10.44 (sl, 1H); 13C NMR (DMSO):
d 028.0, 113.8, 114.8, 121.9(2C), 124.2, 125.6, 129.7(2C),
140.2, 155.1, 163.2, 186.9; Anal. calcd for C13H11N3OS: C
60.68; H 4.31; N 16.33. Found: C 60.79; H 4.32; N 16.31.
3.4.2. 4-Benzoyl-5-methylsulfanyl-1,3-diphenyl-1H-pyr-
role-2-carboxylic acid ethyl ester (3b). Mp: 1078C
1
(ethanol); IR (KBr): 1706, 1652 cm21; H NMR (CDCl3):
d 0.76 (t, 3H, J¼7.3 Hz), 2.06 (s, 3H), 3.89 (q, 2H,
J¼7.3 Hz), 7.11–7.51 (m, 15H); 13C NMR (CDCl3): d 13.1,
20.2, 60.2, 123.9, 127.0, 127.2(2C), 127.8(2C), 128.2(2C),
128.4(2C), 128.6, 129.6(2C), 130.0(2C), 132.6, 133.3,
138.1, 138.5, 160.1, 193.2; Anal. calcd for C27H23NO3S:
C 73.44; H 5.25; N 3.17. Found: C 73.45; H 5.25; N 3.15.
3.2.18. 1-(5-Benzoyl-4-methyl-2-phenylamino-thiophen-
3-yl)-ethanone (2l). Mp: 1108C (ethanol); IR (KBr): 1621,
1600 cm21; 1H NMR (CDCl3): d 2.56 (s, 3H), 2.58 (s, 3H),
7.16–7.72 (m, 5H), 12.10 (sl, 1H); 13C NMR (CDCl3): d
18.5, 31.5, 120.7(2C), 125.1(2C), 128.2, 128.4(2C),
128.6(2C), 129.6, 131.8, 132.8, 139.5, 140.6, 144.9, 164.5,
196.3, 199.4; Anal. calcd for C20H17NO2S: C 71.62; H 5.11;
N 4.18. Found: C 71.69; H 5.09; N 4.25.
3.4.3. 3-Hydroxy-5-methylsulfanyl-1-phenyl-1H-pyr-
role-2,4-dicarboxylic acid diethyl ester (3c). Yellow oil;
1
IR (NaCl): 1738, 1687 cm21; H NMR (CDCl3): d 1.20 (t,
3H, J¼7.2 Hz), 1.34 (t, 3H, J¼7.2 Hz), 1.80 (s, 3H), 3.27 (s,
1H), 4.10 (q, 2H, J¼7.2 Hz), 4.30 (q, 2H, J¼ 7.2 Hz), 7.00–
7.34 (m, 5H); 13C NMR (CDCl3): d 13.8, 13.9, 16.4, 60.7,
62.2, 119.3(2C), 124.2, 128.0, 128.7(2C), 129.5, 129.7,
147.9, 159.9, 167.7, 169.8; Anal. calcd for C17H19NO5S: C
58.44; H 5.48; N 4.01. Found: C 58.55; H 5.50; N 4.00.
3.2.19. 4-Amino-5-benzoyl-2-phenylamino-thiophene-3-
carbonitrile (2m). Mp: 2678C (ethanol); IR (KBr): 3420,
;
2207, 1624 cm21 1H NMR (DMSO): d 7.18–7.56 (m,
10H), 8.05 (sl, 2H), 10.57 (sl, 1H); 13C NMR (DMSO): d
80.5, 94.0, 113.7, 122.3(2C), 125.9, 127.0(2C), 128.7(2C),
129.8(2C), 130.8, 139.9, 141.0, 157.7, 165.2, 184.8; Anal.
calcd for C18H13N3OS: C 67.69; H 4.10; N 13.16. Found: C
67.67; H 3.94; N 12.98.
3.4.4. 4-Acetyl-3-hydroxy-5-methylsulfanyl-1-phenyl-
1H-pyrrole-2-carboxylic acid ethyl ester (3d). Mp: 768C
(ethanol); IR (KBr): 1757, 1693 cm21; 1H NMR (CDCl3): d
1.27 (t, 3H, J¼7.2 Hz), 2.25 (s, 3H), 2.47 (s, 3H), 4.26 (q,
2H, J¼7.2 Hz), 4.52 (s, 1H), 6.78–7.19 (m, 5H); 13C NMR
(CDCl3): d 13.7, 14.0, 17.5, 66.0, 119.4, 120.0, 119.8(2C),
123.1, 123.8, 128.1(2C), 128.8, 150.8, 167.9, 195.6; Anal.
calcd for C16H17NO4S: C 60.17; H 5.37; N 4.39. Found: C
60.36; H 5.15; N 4.49.
3.3. General procedure for the preparation of thiophenes
2 (Method B) from 1
A 100 mL three-necked round-bottom flask equipped with a
magnetic stirrer, condenser and septum was charged with a
solution of the aminothioacetals 1 (10.0 mmol, 1 equiv.) in
ehanol (30 mL). Dried potassium carbonate (10.0 mmol,
1 equiv.) and ethylthioglycolate (10.0 mmol, 1 equiv.) was
added. The reaction was quenched with 100 mL of water
after having stirred 6 h in refluxing ethanol. The crude
3.5. General procedure for the preparation of thieno[2,3-
b]pyrroles 4
Formation of the pyrrole fused ring. Alkyl bromoacetate (or
chloroacetonitrile) (15.0 mmol, 1.5 equiv.) was added to a
stirred solution of thiophenes 2 (10.0 mmol, 1 equiv.) in

G. Sommen et al. / Tetrahedron 59 (2003) 1557–1564
1563
30 mL of dry acetone and dried potassium carbonate
(10.0 mmol, 1 equiv.). The reaction mixture was heated at
reflux for 5 days before quenching in 100 mL of water. The
crude product precipitated and was purified by filtration
followed by crystallisation in ethanol.
3.5.5. 2-Cyano-3,4-dimethyl-6-phenyl-6H-thieno[2,3-
b]pyrrole-5-carboxylic acid ethyl ester (4e). Mp: 1258C
(ethanol); IR (KBr): 2201, 1635 cm21; 1H NMR (CDCl3): d
1.35 (t, 3H, J¼7.2 Hz), 2.55 (s, 3H), 2.60 (s, 3H), 4.35 (q,
2H, J¼7.2 Hz), 7.19–7.45 (m, 5H); 13C NMR (CDCl3): d
18.7, 60.1, 108.4, 115.0, 116.2, 117.2, 120.9, 121.0, 125.3,
125.8(2C), 129.9(2C), 133.4, 135.1, 139.0, 150.8,
166.7(CO2).; Anal. calcd for C18H16N2O2S: C 66.64; H
4.97; N 8.64. Found: C 66.54; H 4.86; N 8.70.
Formation of the thiophene fused ring. A 100 mL three-
necked round-bottom flask equipped with a magnetic stirrer,
condenser and septum was charged with a solution of the
pyrroles 3 (10.0 mmol, 1 equiv.) in ehanol (30 mL). Dried
potassium carbonate (10.0 mmol, 1 equiv.) and ethylthio-
glycolate (10.0 mmol, 1 equiv.) was added. The reaction
was quenched with 100 mL of water after having stirred 6 h
in refluxing ethanol. The crude product precipitated and
was purified by filtration followed by crystallisation in
ethanol.
3.5.6. 2-Acetyl-3,4-dimethyl-6-phenyl-6H-thieno[2,3-
b]pyrrole-5-carboxylic acid ethyl ester (4f). Mp:
;
1468C(ethanol); IR (KBr): 1730, 1629 cm21 1H NMR
(CDCl3): d 1.18 (t, 3H, J¼7.2 Hz), 1.74 (s, 3H), 2.41 (s,
3H), 2.51 (s, 3H), 4.16 (s, 2H, J¼7.2 Hz), 7.05–7.42 (m,
5H); 13C NMR (CDCl3): d 13.8, 22.9, 28.2, 28.5, 60.5,
114.4(2C), 121.3, 127.2, 129.4(2C), 132.4, 139.4, 139.7,
140.1, 153.3, 167.0, 168.2, 188.4; Anal. calcd for
C19H19NO3S: C 66.84; H 5.61; N 4.10. Found: C 66.78; H
5.55; N 4.12.
3.5.1. 3,4-Dimethyl-6-phenyl-6H-thieno[2,3-b]pyrrole-
2,5-dicarboxylic acid diethyl ester (4a). Mp: 1278C
(ethanol); IR (KBr): 2985, 2974, 1697(L), 1597, 1505,
1
1369, 1268, 1238, 1159, 1111 cm21; H NMR (CDCl3): d
1.08 (t, 3H, J¼7.2 Hz), 1.33 (t, 3H, J¼7.2 Hz), 2.71 (s, 3H),
2.83 (s, 3H), 4.14 (q, 2H, J¼7.2 Hz), 4.16 (q, 2H,
J¼7.2 Hz), 7.30–7.34 (m, 5H); 13C NMR (CDCl3): d
11.7, 13.8, 14.3, 14.5, 60.1, 60.5, 120.3, 124.8, 125.0, 126.1,
127.5(2C), 128.9(2C), 130.7, 139.7, 139.9, 143.5, 161.1,
163.1; Anal. calcd for C20H21NO4S: C 64.67; H 5.70; N
3.77. Found: C 64.84; H 5.58; N 3.90.
3.5.7. 2-Benzoyl-3,4-dimethyl-6-phenyl-6H-thieno[2,3-
b]pyrrole-5-carboxylic acid ethyl ester (4g). Mp:
1558C(ethanol); IR (KBr): 2982, 1720, 1628, 1597, 1499,
1446, 1272, 1135, 1031 cm21; 1H NMR (CDCl3): d 1.10 (t,
3H, J¼7.2 Hz), 2.64 (s, 3H), 2.72 (s, 3H), 4.16 (q, 2H,
J¼7.2 Hz), 7.29–7.75 (m, 10H); 13C NMR (CDCl3): d 13.8,
14.1, 15.9, 60.2, 120.9, 125.4(2C), 127.9, 128.2(2C),
128.4(2C), 128.7(2C), 128.9, 129.0, 129.2, 129.7, 131.7,
133.6, 140.3, 142.4, 162.0, 191.4; Anal. calcd for
C24H21NO3S: C 71.44; H 5.25; N 3.47. Found: C 71.40; H
5.30; N 3.55.
3.5.2. 3,4,6-Triphenyl-6H-thieno[2,3-b]pyrrole-2,5-
dicarboxylic acid diethyl ester (4b). Mp: 1568C (ethanol);
1
IR (KBr): 1706, 1651, 1596, 1492, 1237, 1150 cm21; H
NMR (CDCl3): d 0.81 (t, 3H, J¼7.2 Hz), 1.14 (t, 3H,
J¼7.2 Hz), 3.95 (q, 2H, J¼7.2 Hz); 4.14 (q, 2H, J¼7.2 Hz),
6.97–7.54 (m, 15H); 13C NMR (CDCl3): d 13.4, 13.9, 60.3,
60.7, 119.1, 124.8(2C), 125.4(2C), 126.5(2C), 126.7,
126.9(2C), 127.1(2C), 128.2(2C), 129.1(2C), 129.4, 129.9,
130.6, 133.6, 138.4, 139.1, 140.2, 148.5, 161.2, 163.4; Anal.
calcd for C30H25NO4S: C 72.71; H 5.08; N 2.83. Found: C
72.72; H 5.06; N 2.72.
3.5.8. 5-Cyano-3,4-dimethyl-6-phenyl-6H-thieno[2,3-
b]pyrrole-2-carboxylic acid ethyl ester (4h). Mp:
1158C(ethanol); IR (KBr): 2202, 1696, 1530 cm21 1H
;
NMR (CDCl3): d 1.34 (t, 3H, J¼7.2 Hz), 2.58 (s, 3H), 2.82
(s, 3H), 4.29 (q, 2H, J¼7.2 Hz), 7.14–7.44 (m, 5H); 13C
NMR (CDCl3): d 18.5, 60.2, 108.0(CN), 115.4, 115.9,
117.8, 121.0, 121.1, 125.0, 125.8(2C), 130.0(2C), 132.9,
135.1, 139.2, 148.8, 164.7(CO2); Anal. calcd for
C18H16N2O2S: C 66.64; H 4.97; N 8.64. Found: C 66.48;
H 4.95; N 8.62.
3.5.3. 3,4-Dihydroxy-6-phenyl-6H-thieno[2,3-b]pyrrole-
2,5-dicarboxylic acid diethyl ester (4c). Orange oil; IR
(KBr): 2982, 1739, 1629, 1593, 1211, 1029 cm21; 1H NMR
(CDCl3): d 1.21 (t, 3H, J¼7.2 Hz), 1.32 (t, 3H, J¼7.2 Hz),
4.09 (q, 2H, J¼7.2 Hz), 4.27 (q, 2H, J¼7.2 Hz), 6.97–7.44
(m, 5H); 13C NMR (CDCl3): d 13.8, 13.9, 60.6, 62.2,
119.3(2C), 120.6, 124.2, 128.9(2C), 133.6, 140.0, 147.9,
160.0, 162.1, 162.2, 167.7, 169.8; Anal. calcd for
C18H17NO6S: C 57.59; H 4.56; N 3.73. Found: C 57.40; H
4.50; N 3.60.
References
1. Campos, P. J.; Anon, E.; Carmen Malo, M.; Rodriguez, M. A.
Tetrahedron 1999, 55, 14079.
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1065.
3.5.4. 4-Hydroxy-3-methyl-6-phenyl-6H-thieno[2,3-
b]pyrrole-2,5-dicarboxylic acid diethyl ester (4d). Yellow
oil; IR (KBr): 2982, 2930, 1720, 1628, 1597, 1368, 1272,
;
1135, 1031 cm21 1H NMR (CDCl3): d 1.10 (t, 3H,
J¼7.2 Hz), 1.28 (t, 3H, J¼7.2 Hz), 2.81 (s, 3H), 4.13 (q,
2H, J¼7.2 Hz), 4.27 (q, 2H, J¼7.2 Hz), 4.88 (s, 1H), 7.33–
7.46 (m, 5H); 13C NMR (CDCl3): d 13.8, 14.2, 14.4, 60.3,
60.7, 125.4(2C), 128.0, 129.2(2C), 139.2, 147.8, 160.5,
161.1, 162.5, 168.7, 170.2; Anal. calcd for C19H19NO5S:
C 61.11; H 5.13; N 3.75. Found: C 61.22; H 5.04; N
3.80.
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