Improved modular synthesis of thieno[3,2-b]pyrroles and thieno[2,3-b]pyrroles

Article abstract of DOI:10.1016/j.tetlet.2009.01.109

A convenient modular synthesis for the construction of densely functionalized thieno[3,2-b]pyrroles, allosteric inhibitors of the Hepatitis C virus NS5B polymerase, is described. The route allows the introduction of substituents in positions 4, 5, and 6 o

Full text of DOI:10.1016/j.tetlet.2009.01.109

Tetrahedron Letters 50 (2009) 1625–1628
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Improved modular synthesis of thieno[3,2-b]pyrroles and thieno[2,3-b]pyrroles
*
Savina Malancona , Josè I. Martin Hernando, Barbara Attenni, Jesus M. Ontoria, Frank Narjes
Department of Medicinal Chemistry, IRBM-MRL Rome, Via Pontina, Km 30.600, 00040 Pomezia, Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient modular synthesis for the construction of densely functionalized thieno[3,2-b]pyrroles,
allosteric inhibitors of the Hepatitis C virus NS5B polymerase, is described. The route allows the introduc-
tion of substituents in positions 4, 5, and 6 of the thienopyrrole scaffold and can also be applied to the
regioisomeric thieno[2,3-b]pyrrole core.
Received 18 December 2008
Accepted 20 January 2009
Available online 23 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The Hepatitis C virus (HCV) is the principal etiological agent of
chronic hepatitis C infection, affecting 170 million people world-
wide.1 If untreated, more than 60% of these individuals will devel-
op chronic liver disease that leads to chronic hepatitis, liver
cirrhosis, and hepatocellular carcinoma. The current therapy, pegy-
N
N
O
O
1
N
O
N
6
HO
2
S
HO
3
lated
a-interferon (IFN) alone or in combination with ribavirin, is
O
2
1
poorly tolerated. Additionally, it is of limited efficacy in patients in-
fected with HCV genotype 1, which accounts for about 70% of the
infections in the western world. Thus, new treatment regimens
are needed. The NS5B RNA-dependent RNA polymerase plays a
central role in virus replication and is considered an attractive tar-
get for drug discovery efforts. In recent years, several non-nucleo-
side inhibitors (NNIs) that bind to different areas of the enzyme
have been disclosed.2
IC50 = 0.058 µM
EC50 = 2.9 µM
IC50 = 0.059 µM
EC50 = 1.5 µM
Figure 1.
NO2
Indole-N-acetamides have been identified by us and others as
potent allosteric inhibitors of HCV polymerase.3 Essential features
for binding of the indole scaffold to NS5B are the cyclohexyl group
at C-3, the carboxylic acid at C-6, and an aryl group at C-2.The acet-
amide moiety was found to confer cell-based activity.3a
Parallel to the work in the indole series, the replacement of the
indole core system with bioisosteric structures was explored. In
this context, thieno[3,2-b]pyrroles were identified as equipotent
inhibitors of HCV polymerase (Fig. 1).4 In scheme 1, the synthetic
pathway to 2 is reported. Starting from thiophene 3, intermediate
4 was prepared according to a published procedure.5
HO2C
MeO2C
Ph
S
S
3
4
H
H
N
N
Ph
Ph
MeO2C
2
MeO2C
S
S
6
5
Scheme 1. Classical approach to 2.4
The cyclohexyl moiety was introduced by condensation with
cyclohexanone6 followed by reduction with triethylsilane7 to give
6. Alkylation of the indole nitrogen and basic hydrolysis of the
methyl ester furnished compound 2. SAR studies around the thie-
no[3,2-b]pyrrole structure were then initiated to improve potency
and physicochemical properties. We knew from the work around
the indole series that substitution at C-2 and N-1 is crucial for
cell-based activity.3a Since our approach to prepare 2 introduces
the aryl substituent early on, it was not deemed suitable for the
rapid exploration of SAR. Other synthetic routes to build up the thi-
enopyrrole system are known, but are generally characterized by
low yields and difficult access to the starting materials.8 To ad-
vance our studies, we postulated a different synthetic route that
is shown in scheme 2. Here, the aryl residue is introduced near
the end by Pd-mediated cross-coupling performed on key interme-
diate 8, which is prepared by manipulation of 9. We reasoned that
intermediate 9 should be accessible from thiophene 10 via a palla-
dium-catalyzed ring-closure with concomitant installation of the
cyclohexyl group, chemistry which has been widely applied for
the construction of indoles.9
* Corresponding author. Tel.: +39 06 91093336; fax: +39 06 91093756.
E-mail address: savina_malancona@merck.com (S. Malancona).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.109

1626
S. Malancona et al. / Tetrahedron Letters 50 (2009) 1625–1628
R1
Ac
N
R1
NHAc
a
O
15a saturated
15b unsaturated
O
N
X
Ar
EtO2C
EtO2C
Br
N
Br
S
S
HO
route a
R2O
S
13a
S
8
O
O
7
b
route b
EtO2C
Xd
c
H
N
NHAc
H
N
NHR3
Br
EtO2C
S
TMS
S
R2O
R2O
16
17
S
S
9
O
O
Scheme 4. Reagents and conditions: (a) LiCl or nBu4NCl, Na2CO3 or KOAc, Pd(AcO)2
or Pd2(dba)3, DMF, 100 °C; (b) Me3SiCCH, CuI, PdCl2(PPh3)2, TEA, THF, rt, 80%; (c) 1-
cyclohexenyl triflate, Cs2CO3, Pd(PPh3)4, MeCN, rt, 80%; (d) TFA, Et3SiH then HCl
(3 N), reflux.
10
Scheme 2. Retrosynthetic analysis.
To put this idea into practice, commercial ethyl thiophene-
2-carboxylate was nitrated giving a 1:1 mixture of the two
regioisomers, ethyl 4-nitrothiophene-2-carboxylate and ethyl 5-
nitrothiophene-2-carboxylate. The mixture was reduced with Fe
in Ac2O/AcOH10 to generate the acetylated amino derivatives
12a. This one-pot method of reduction–protection was preferred
since it avoided substantial degradation of the aminothiophene.
Decomposition also occurred when the nitro-intermediate was
reduced by hydrogenation over Pd/C. After bromination, the mix-
ture of the two regioisomers could be conveniently separated by
flash chromatography on silica gel (Scheme 3). We submitted reg-
ioisomer 13a first to the classical one-pot Pd-catalyzed heteroann-
ulation11 of internal alkynes (Scheme 4, route a), using either
cyclohexyl- or cyclohexenyl acetylene. Although this approach
has been reported to work extremely well in the synthesis of func-
tionalized indole systems, in our case at best only traces of 15a or b
were observed. Instead, it was possible to obtain 15b by a stepwise
process via the Sonogashira coupling of trimethylsilylacetylene fol-
lowed by Pd-catalyzed cyclization of 16 in the presence of cyclo-
hexenyl triflate (Scheme 4, route b).12
Despite numerous attempts further elaboration of 15b was
unsuccessful. The reduction of the double bond in the cyclohexenyl
ring using palladium under hydrogen atmosphere or the TFA/tri-
ethylsilane7 system failed or led to unidentified side products. Re-
moval of the acetyl group in both basic and acidic conditions gave
no reaction or led to decomposition under more forcing conditions.
Bromination gave the product contaminated with various side
products, probably due to the presence of the double bond.
To overcome these problems, we further remodeled the syn-
thetic pathway. The acetyl substituent was exchanged for protect-
ing groups, which can be cleaved under milder conditions. The
trifluoroacetyl intermediate 12b was prepared similar to 12a (Fe
in TFAA/TFA) and 12c was prepared from 12a in a two-step proce-
dure (Scheme 3). After bromination and separation of the regioi-
somers compounds 13b,c were submitted to the Sonogashira
coupling to give 20b,c (Scheme 5).
Different conditions for the cyclization to the pyrrole ring were
screened,9 including Pd(II) and Cu(I)-catalyzed methods, as well as
base and TBAF-mediated cyclizations. As the results in Table 1
show, most of the conditions did not give the desired product 21,
with the exceptions of the palladium-catalyzed cyclization in the
presence of cyclohexenyl triflate, and the TBAF-catalyzed cycliza-
tion. When the palladium-catalyzed cyclization procedure was ap-
plied to indole synthesis, it furnished exclusively the silylated
product. In our case with 20b the main product was 21d, but also
the desilylated product was isolated. On the contrary, in the Boc-
protected case 20c only the desilylated product was recovered.
Considering the yields better results were obtained in the Boc-pro-
tected case (compare entries 7 and 8), where on a small scale 21e
was obtained in 64% yield. Unfortunately, the yield dropped to
around 15% on multigram scale. This led us to prefer the TBAF-
mediated route, which gave the best results in terms of yield and
ease of purification when the cyclization was performed under
microwave irradiation, leading directly to the deprotected thieno-
pyrrole 21b (R = X = Y = H).
Next, the cyclohexyl moiety was introduced under basic condi-
tions, and the double bond was reduced by hydrogenation over
Pd(OH)2 at high pressure (Scheme 6). These conditions caused also
the hydrolysis of the ethyl ester. This drawback turned out to be
useful since we could install a t-butyl ester,13 which allowed for
a more convenient deprotection to obtain the final compounds.
In the case of the methyl ester, we had observed cleavage of the
acetamide moiety in some cases. Bromination and alkylation final-
ly gave the desired intermediate 23. This was used to introduce
diversity via palladium-catalyzed cross-coupling reaction. A vari-
ety of boronic acids were tested with good results as reported in
Table 2.
NHR
a, b
e
EtO2C
EtO2C
S
S
As a further extension of this work, we were interested if this
chemistry would also be applicable to the regioisomeric thie-
no[2,3-b]pyrrole (Scheme 7). Having in hand intermediate 14c,
12 a
12 b
12 c
11
c, d
NHR
Br
ratio 1 / 1
Br
a: R = Ac
b: R = COCF3
c: R = Boc
R
N
+
NHR
EtO2C
EtO2C
NHR
S
S
Y
a
b
13b
13c
14 a
14 b
14 c
EtO2C
13 a
13 b
13 c
EtO2C
S
S
X
TMS
20b
20c
21a-e
Scheme 3. Reagents and conditions: (a) HNO3, H2SO4, À10 °C, 96%; (b) Fe, Ac2O,
AcOH, 80 °C (77% for 12a); Fe, TFAA, TFA (52% for 12b); (c) BOC2O, TEA, DCM; (d)
Hydrazine, EtOH, 96% over two steps; (e) NBS, DCM, rt, 80%.
Scheme 5. Reagents and conditions: (a) Me3SiCCH, CuI, PdCl2(PPh3)2, TEA, THF,
50 °C, 89%; (b) see Table 1.

S. Malancona et al. / Tetrahedron Letters 50 (2009) 1625–1628
1627
Table 2
R1
24
Ar
Ya (%)
H
N
O
N
Br
21b
a
10
60
HO2C
c, d, e
S
a, b
t-BuO2C
S
Cl
22
23
R1
b
c
Cl
N
23 a-f
24 a-f
R1:
O
N
Ar
O
f, g, h
30
40
HO2C
23 g-k
24 g-k
S
R1:
CHO
OMe
N
24
Scheme 6. Reagents and conditions: (a) cyclohexanone, NaOEt/EtOH, reflux, then
water; (b) H2, P = 45 psi, Pd(OH)2, MeOH/AcOEt, 45% over two steps; (c) 2-tBu-1,3-
diisopropylisourea, THF, reflux; (d) NBS, DCM, 0 °C, 40% over two steps; (e)
ClCH2CON(Me)2, NaH, DMF, rt, 92%; (f) ArB(OH)2, PdCl2(dppf)2, Na2CO3, DME, 80 °C;
(g) DCM/TFA, rt; (h) RP-HPLC.
d
O
e
f
12
66
20
10
20
53
10
we performed the Sonogashira coupling to introduce the phenyl-
acetylene group. The 3-bromo isomer 14c was less reactive than
the corresponding isomer 13c and as a matter of fact that did not
react under the conditions applied to isomer 13c. Switching to
Pd(PhCN)2Cl2/P(t-Bu)3, with the electron-rich, sterically demand-
ing phosphine, developed by Fu,14 allowed the reaction to take
place. In contrast to the reaction of arylbromides, which undergo
the Sonogashira coupling at room temperature, we had to reflux
the reaction to achieve complete conversion in high yield. The
cyclization to the pyrrole was carried out through Pd-catalyzed
heteroannulation of internal alkynes in acceptable yield. Further
elaborations gave compound 28.
In summary, we have developed a suitable synthesis of thie-
no[3,2-b]pyrroles, which allowed us to further extend our SAR
studies. This method is highly flexible and allows the investigation
of positions 4, 5, and 6 of the thienopyrrole nucleus, and might also
be used for the construction of combinatorial libraries around this
core. We could also show that the same chemistry can be applied
to the thieno[2,3-b]pyrrole scaffold.
OMe
N
g
h
i
OMe
OBn
j
CHO
OMe
k
Supplementary data
Cl
Yield calculated from compounds 23 to 24 in a three steps sequence.
Supplementary data contains experimental details of the syn-
thesis and characterization of compounds. Supplementary data
a
Table 1
Entry
20
21
R
X
Y
Conditions yield
1
2
3
4
5
6
b
b
b
b
b
b
a
b
b
b
c
COCF3
H
H
H
COCF3
COCF3
H
H
H
H
H
H
H
H
H
H
TMS
TMS
CuI, DMF, 100 °C;9b 0%
KOtBu, tBuOH, reflux;9c 0%
NaOEt, EtOH, reflux;9c 0%
nBu4F, THF, 120 °C;9d 78%
Pd2(dba)3, K2CO3, DMSO, 40 °C;12 0%
Pd (PPh3)4, K2CO3, THF, reflux;12 0%
c
7
8
b
d
COCF3
TMSa
Cyclohexenyl triflate, Pd(PPh3)4, Cs2CO3, MeCN, rt;11 30%
c
c
e
Boc
H
H
H
Cyclohexenyl triflate, Pd(PPh3)4, Cs2CO3, MeCN, rt;11 64%
9
b
H
nBu4F, THF, 120 °C;9d 70%
a
10% of desilylated product was recovered.

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S. Malancona et al. / Tetrahedron Letters 50 (2009) 1625–1628
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S
S
EtO2C
NHBoc
Br
EtO2C
NHBoc
3. (a) Harper, S.; Avolio, S.; Pacini, B.; Di Filippo, M.; Altamura, S.; Tomei, L.;
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b
14c
25
Ph
H
Boc
S
N
S
N
EtO2C
Ph
c,d
EtO2C
Ph
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N
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HO2C
Ph
28
Scheme 7. Reagents and conditions: (a) Me3SiCCH, CuI, PdCl2(PhCN)2, P(tBu)3,
DIPEA, dioxane, rt, 96%; (b) K2CO3, Pd2(dba)3, P(tBu)3, THF, 80 °C, 66%; (c)
cyclohexanone, H3PO4, AcOH, Ac2O, 80 °C; (d) Et3SiH, TFA, rt, 58% over two steps;
(e) NaOH, THF/MeOH, reflux, 54%; (f) ClCH2CON(Me)2, NaH, DMF, rt, then RP-HPLC,
27%.
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.01.109.
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BBr3 gave low yields.
References and notes
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