Efficient synthesis of substituted thieno[3,2-e]indoles

Article abstract of DOI:10.1016/j.tet.2009.08.031

Efficient cyclization reactions of 5-aminobenzothiophene derivatives with internal and terminal acetylenes, giving 7- and 8-substituted thieno[3,2-e]indoles, are described. The reaction of 4-iodo-5-(methylsulfonamido)benzothiophene with terminal alkynes g

Full text of DOI:10.1016/j.tet.2009.08.031

Tetrahedron 65 (2009) 8497–8501
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of substituted thieno[3,2-e]indoles
*
Wim Van Snick, Wim Dehaen
Department of Chemistry, K.U. Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 June 2009
Received in revised form 11 August 2009
Accepted 11 August 2009
Available online 15 August 2009
Efficient cyclization reactions of 5-aminobenzothiophene derivatives with internal and terminal acety-
lenes, giving 7- and 8-substituted thieno[3,2-e]indoles, are described. The reaction of 4-iodo-5-(methyl-
sulfonamido)benzothiophene with terminal alkynes gave 7-substituted thienoindoles using general
Sonogashira reaction conditions. Reaction of 5-amino-4-iodobenzothiophene with internal acetylenes,
using Larock’s heterocyclization reaction conditions, gave 7,8-disubstituted thieno[3,2-e]indoles.
Ó 2009 Elsevier Ltd. All rights reserved.
R1
1. Introduction
I
R1
H
N
N
Ms
Pd(PPh3)4 , CuI
Ms
Few versatile methods exist for the synthesis of thieno[3,2-e]in-
doles. The Fischer indolization of 5-substituted benzothiophene
hydrazone,1 the photochemical cyclization of 2-[2-(2-thienyl)vinyl]-
1H-pyrroles,2 and the cyclocondensation of 3-oxoindole with 2-
thienylacetonitrile resulting in thienocarbazole3 are the most
important methods for the synthesis of thieno[3,2-e]indoles. The
need for harsh reaction conditions in these procedures is an impor-
tant drawback and leads to low yields and a restricted number of
possible substituents.
CO2Et
CO2Et
CO2Et
S
S
THF, iPr2NH
1
2
R1
N
R2
R1
R2
I
Pd(OAc)2
H2N
H
CO2Et
n-Bu4NCl
base, DMF
100 °C
S
S
4
5
R1, R2 = aryl, TMS, alkyl, alkoxy,...
In our preceding work we have reported the synthesis of
7-substituted thieno[3,2-e]indoles via the tetrabutylammonium
fluoride (TBAF) mediated cyclization of 5-acetamido-4-alky-
nylbenzothiophenes.4 This indole cyclization procedure requires
two steps, (a) coupling of terminal alkynes onto the benzothiophene
ring system via Sonogashira coupling and (b) the subsequent TBAF
cyclization reaction. Recently, Sakamoto and his co-workers have
reported a one-pot indole synthesis from 2-iodoanilines and ter-
minal alkynes using a palladium catalyst in the presence of TBAF.5
Also, theone-potsynthesisof methylsulfonyl-protected iodoanilines
with terminal acetylenes was reported.6–8 This reaction involves
a general Sonogashira coupling followed by ring formation to the
desired indole in one step, by addition of NH to the triple bond.7–9
In order to provide an efficient method for the synthesis of
7-substituted thienoindoles, we herein wish to report a one-pot
procedure for the synthesis of 7-substituted thieno[3,2-e]indoles
from 4-iodo-5-(methylsulfonamido)benzothiophene (1) and ter-
minal alkynes using a palladium catalyst under typical Sonogashira
reaction conditions7,8 (Scheme 1). We also wish to report that there
is no specific requirement for TBAFas cyclizing agent in this reaction.
Scheme 1. Synthesis of substituted thieno[3,2-e]indoles 2 and 5.
A convenient way of preparing 2,3-disubstituted indoles from 2-
iodoanilines and internal acetylenes has been reported by Larock
and co-workers.8,10 As a second part in this manuscript, we wish to
report the synthesis of 7,8-disubstituted thieno[3,2-e]indoles in
high yields via general Larock heterocyclization reaction conditions
from 5-amino-4-iodobenzothiophene (4) and internal alkynes. The
use of a specific base is crucial in this cyclization procedure.
2. Results and discussion
In ourprecedingwork we synthesized 7-substituted thieno[3,2-e]-
indoles through cyclization of 5-acetamido-4-alkynylbenzothio-
phenes in the presence of 3 equiv of tetrabutylammonium fluoride
(TBAF).4 The synthetic procedures for the preparation of ethyl-5-ace-
tamido-4-iodobenzothiophene-2-carboxylate (1a) and ethyl-4-iodo-
5-(methylsulfonamido)benzothiophene-2-carboxylate (1b) (Table 1)
were described therein.4
The reaction conditions for the alternative one-pot indole syn-
thesis from these amino-protected 4-iodobenzothiophenes (1a,b)
with phenylacetylene were examined as shown in Table 1. When
a mixture of benzothiophene (1a) and phenylacetylene is refluxed
* Corresponding author. Fax: þ32 16 327990.
E-mail address: wim.dehaen@chem.kuleuven.be (W. Dehaen).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.031

8498
W. Van Snick, W. Dehaen / Tetrahedron 65 (2009) 8497–8501
Table 1
trimethylsilylacetylene gave only 11% of the expected thienoindole
2f1, accompanied by the formation of the open Sonogashira pro-
duct, ethyl-5-(methylsulfonamido)-4-(trimethylsilylethynyl)benzoth-
iophene-2-carboxylate 2f2 in 61% yield. Finally, the cyclization
reaction of (1b) with electron deficient acetylenes, such as 2-
ethynylpyridine, gave no product under normal Sonogashira re-
action conditions. In accordance to literature we tried to use ZnBr2
under Negishi reaction conditions.11 We found that only on addi-
tion of a large excess of Hu¨nig’s base the expected product
7-(pyridin-2-yl)thienoindole 2g could be synthesized in an ac-
ceptable yield of 66%.
Next to the synthesis of 7-substituted thienoindoles, we ex-
plored the synthesis of 7,8-disubstituted thienoindoles. Using
Larock’s method for the synthesis of indoles, we tried different
bases (K2CO3, KOAc, Na2CO3, NaOAc) with or without PPh3 for the
coupling of 5-amino-4-iodobenzothiophene (4) with internal
alkynes. The coupling with tert-butyldimethyl(4-(tetrahydro-2H-
pyran-2-yloxy)-but-1-ynyl)silane (Table 3, entry 1) gave an
excellent result, when using Na2CO3 with 5 mol % of PPh3. It is
important to note that the yield highly depends on the choice of
base. Different alkynes were coupled as shown in Table 3. The
cyclization with 4-(pyridin-2-yl)but-3-yn-1-ol (entry 3) gave only
one isomer 5c in 85% yield. The coordination of the pyridine ring
in the palladium-complex intermediate resulting in one product
has recently been reported.12 In contrast, the coupling with 2-
(phenylethynyl)pyridine (entry 4) gave a mixture of both isomers
(5d1, 5d2). The cyclization with 2-(3-fluorophenyl)ethynyl-
trimethylsilane (entry 5) using NaOAc gave next to the desired
compound 5e1 the desilylated product ethyl-8-(3-fluorophenyl)-
6H-thieno[3,2-e]indole-2-carboxylate 5e2 in 34% yield. The use of
electron deficient alkynes, such as ethyl phenylpropiolate (entry
7), resulted in a complex mixture of products, from which it was
not possible to isolate the desired thienoindole. Analysis of the
structure of different isomers 5 has been established by 2D NMR
spectroscopy.
One-pot indole cyclization reaction of benzothiophenes 1 with phenylacetylene
EtO2C
S
EtO2C
S
EtO2C
Ph
S
+
I
Pd(PPh3)4 , CuI
Ph
Ph
N
R
N
NHR
THF, base
H
1a
R = Ac
1b R = SO2Me
2
3
Entry
Aryl iodide
Base conditionsa
Yieldb (%)
1
2
3
4
5
1a
1a
1b
1b
1b
A
B
A
B
C
3 (48)
3 (62)
3 (82)
3 (86)
2 (68)
a
Base conditions: (A) i-Pr2NH and TBAF (3 equiv) in one-pot, (B) i-Pr2NH/THF was
evaporated and TBAF (3 equiv)/THF was added, (C) i-Pr2NH (no TBAF).
b
All yields refer to isolated products.
in the presence of a palladium catalyst and 3 equiv of TBAF, ethyl-7-
phenyl-6H-thieno[3,2-e]indole-2-carboxylate 3 was obtained in
48% yield. The reaction of benzothiophene (1b) with phenyl-
acetylene in the presence of TBAF resulted in the same demesylated
compound 3 in 82% yield. Addition of TBAF to the evaporated re-
action mixture after completion of the Sonogashira coupling re-
action (Table 1, entries 2 and 4) gave in both cases thienoindole 3
with only slightly improved yields (62 and 86%, respectively). After
performing the reaction with benzothiophene (1b) under general
Sonogashira conditions without the use of TBAF as the cyclizing
agent (Table 1, entry 5), we obtained the methylsulfonyl-protected
thienoindole 2 in 68% yield.
Based on the above results, we next examined this thieno-
indole synthesis from (1b) with different terminal acetylenes, as
shown in Table 2. We previously reported that cyclization of ethyl-
5-acetamido-4-(4-hydroxybut-1-ynyl)benzothiophene-2-carboxy-
late (and analogous products) under TBAF reaction conditions
resulted in the formation of 7-vinylthienoindoles as byproducts.4
In contrast, the Sonogashira coupling reaction of (1b) with 2-(but-
3-ynyloxy)tetrahydro-2H-pyran or but-3-yn-1-ol (Table 2, entries
2 and 3) resulted in the formation of 7-substituted thienoindoles
2b and 2c in excellent yields (91% and 86%, respectively). The re-
action with propargyl alcohol (entry 4) gave a rather disappointing
result (31% yield), next to an excellent yield of 88% for the 7-(2-
hydroxy-2-propyl)thienoindole 2e. The indole synthesis using
Table 3
Thienoindole synthesis from ethyl-5-amino-4-iodobenzothiophene-2-carboxylate 4
R1
R2
R1
R2
I
N
H2N
H
CO2Et
CO2Et
Pd(OAc)2, n-Bu4NCl,
base, DMF, 100 °C
S
S
5
4
Entry R1
R2
Basea
Time Thienoindole 5,
(h)
yieldb (%)
Table 2
Thienoindole synthesis from ethyl-5-(methylsulfonamido)-4-iodobenzothiophene-
2-carboxylate 1b
1
2
3
4
5
6
7
TBDMS
Phenyl
2-Pyridinyl CH2CH2OH
2-Pyridinyl Phenyl
TMS
TMS
CH2CH2OTHP
CH2CH2OH
Na2CO3(þ) 18
Na2CO3 (þ) 18
Na2CO3 (þ) 16
5a, 91
5b1, 48 and 5b2,c 40
5c, 85
R
I
KOAc (ꢀ)
48
2
5d1, 36 and 5d2,c 38
H
R
3-Fluorophenyl NaOAc (ꢀ)
5e1, 43d
N
N
Ms
Pd(PPh3)4 , CuI
Ms
CO2Et
CO2Et
CH2CH2OH
CO2Et
Na2CO3 (þ) 17
5f, 71
Phenyl
d
d
5g, de
S
S
THF, iPr2NH
reflux
1b
2
a
b
c
All yields refer to isolated products.
(þ): 5 mol % of PPh3 is used; (ꢀ): no PPh3 used.
Yielda (%)
R1 and R2 interchanged.
Entry
Acetylene R¼
Phenyl
CH2CH2OTHP
CH2CH2OH
CH2OH
CMe2OH
TMS
Time (h)
d
2a, 68b
2b, 91
2c, 86
2d, 31
2e, 88
2f1, 11c
2g, 66d
Desilylated product (34%) formed, ethyl-8-(3-fluorophenyl)-6H-thieno[3,2-
1
2
3
4
5
6
7
24
18
19
18
20
22
17
e]indole-2-carboxylate 5e2.
e
Different base conditions were tried; no product obtained.
In conclusion, we have synthesized 7-substituted and 7,8-di-
substituted thieno[3,2-e]indoles by different procedures. One is the
one-pot cyclization of 5-(methylsulfonamido)-4-iodobenzothio-
phene with terminal acetylenes, using general Sonogashira re-
action conditions. 7,8-Disubstituted thieno[3,2-e]indoles were
synthesized by Larock’s heteroannulation reaction.
2-Pyridinyl
a
b
c
All yields refer to isolated products.
Pd(PPh3)4 (5 mol %) and CuI (10 mol %) were used.
Ethyl-5-(methylsulfonamido)-4-((trimethylsilyl)ethynyl)benzo[b]thiophene-2-
carboxylate 2f2 (61%) obtained.
d
Pd(PPh3)4 (10 mol %), ZnBr2 (3 equiv), and Hu¨nig’s base were used.

W. Van Snick, W. Dehaen / Tetrahedron 65 (2009) 8497–8501
8499
3. Experimental section
3.1. General
3.3.1. Ethyl-6-(methylsulfonyl)-7-phenyl-6H-thieno[3,2-e]indole-2-
carboxylate (2a). Obtained as a yellow solid; mp 206–208 ꢁC; IR:
2980, 1705 cmꢀ1
; d 1.44 (t, 3H,
1H NMR (300 MHz, CDCl3):
J¼7.3 Hz), 2.80 (s, 3H), 4.43 (q, 2H, J¼7.3 Hz), 7.04 (s, 1H), 7.47 (m,
Melting points (not corrected) were determined using a Reich-
ert Thermovar apparatus, using the product obtained from purifi-
cation by column chromatography. IR spectra were recorded using
a Bruker ALPHA-P spectrometer. NMR spectroscopy was performed
on commercial instruments (Bruker Avance 300 MHz and Bruker
3H), 7.60 (m, 2H), 7.80 (d, 1H, J¼9.1 Hz), 8.28 (d, 1H, J¼9.1 Hz), 8.33
(s, 1H); 13C NMR (75 MHz, CDCl3):
d 14.5, 40.4, 61.8, 111.3, 115.8,
119.2, 126.3, 127.9, 129.3, 130.5, 131.7, 134.8, 135.3, 139.4, 142.4,
162.8; HRMS (EI): m/z calcd for C20H17O4NS2 (Mþ): 399.0599;
found: 399.0609.
AMX 400 MHz) and chemical shifts (d) are reported in parts per
million (ppm) referenced to tetramethylsilane (1H) or the carbon
signal of deuterated solvents (13C). Mass spectra were run using
a HP5989A apparatus (CI and EI, 70 eV ionization energy) with
Apollo 300 data system, and a Kratos MS50TC instrument for exact
mass measurements (performed in the EI mode at a resolution of
10,000). For column chromatography 70–230 mesh silica 60 (E.M.
Merck) was used as the stationary phase. Chemicals received from
commercial sources were used without further purification. The
synthetic procedures for the preparation of ethyl-5-(acetamido)-4-
iodobenzothiophene-2-carboxylate (1a), ethyl-4-iodo-5-(methyl-
sulfonamido)benzothiophene-2-carboxylate (1b), ethyl-5-amino-
4-iodobenzothiophene-2-carboxylate (4), and ethyl-5-amino-4-
(phenylethynyl)benzo[b]thiophene-2-carboxylate were described
in our previous work.4
3.3.2. Ethyl-6-(methylsulfonyl)-7-(2-(tetrahydro-2H-pyran-2-yloxy)-
ethyl)-6H-thieno[3,2-e]indole-2-carboxylateꢀ1(2b). Obtained as a yel-
low solid; mp 44 ꢁC; IR: 2940, 1705 cm
;
1H NMR (300 MHz,
CDCl3):
d
1.44 (t, 3H, J¼7.3 Hz), 1.70 (m, 6H), 3.11 (s, 3H), 3.38 (t, 2H,
J¼6.4 Hz), 3.53 (m, 1H), 3.82 (m, 2H), 4.15 (m, 1H), 4.43 (q, 2H,
J¼7.3 Hz), 4.66 (m,1H), 6.90 (s,1H), 7.68 (d,1H, J¼9.1 Hz), 8.15 (d,1H,
J¼9.1 Hz), 8.27 (s, 1H); 13C NMR (75 MHz, CDCl3):
d 14.4, 19.7, 25.4,
29.4, 30.7, 41.3, 61.7, 62.6, 66.2, 99.1, 107.9, 114.3, 118.0, 125.6, 127.9,
131.2, 133.7, 134.2, 138.6, 139.3, 162.8; HRMS (EI): m/z calcd for
C21H25O6NS2 (Mþ): 451.1123; found: 451.1120.
3.3.3. Ethyl-7-(2-hydroxyethyl)-6-(methylsulfonyl)-6H-thieno[3,2-
e]indole-2-carboxylate (2c). Obtained as a solid; mp 155–156 ꢁC; IR:
3460, 2930, 1670 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 1.43 (t, 3H,
J¼7.3 Hz), 2.32 (br s, 1H), 3.09 (s, 3H), 3.32 (t, 2H, J¼6.4 Hz), 4.04 (t,
2H, J¼6.4 Hz), 4.40 (q, 2H, J¼7.3 Hz), 6.89 (s, 1H), 7.68 (d, 1H,
J¼9.1 Hz), 8.15 (d, 1H, J¼9.1 Hz), 8.27 (s, 1H); 13C NMR (75 MHz,
3.2. Ethyl-7-phenyl-6H-thieno[3,2-e]indole-2-carboxylate (3)
(Table 1, entry 1)4
CDCl3):
d 14.4, 32.3, 41.3, 61.8, 61.9, 108.7, 114.4, 118.3, 125.6, 127.9,
131.3, 133.9, 134.4, 139.0, 162.8; HRMS (EI): m/z calcd for
To a suspension of tetrakis(triphenylphosphine)palladium(0)
(11.6 mg, 1 mol %) and CuI (3.8 mg, 2 mol %) in 12 mL of THF/i-
Pr2NH 1:1 were added ethyl-4-iodo-5-acetamidobenzothiophene-
2-carboxylate (1a) (389 mg, 1 mmol), phenylacetylene (153 mg,
1.5 mmol), and TBAF (3 mL, 1 M solution in THF). The mixture was
stirred for 18 h at 60 ꢁC. After cooling, water (20 mL) was added.
The mixture was extracted with EtOAc (3ꢂ20 mL) and the com-
bined organic layers were washed with brine (20 mL) and dried
over MgSO4. The mixture was filtered, evaporated to dryness, and
the residue was purified by column chromatography on silica gel
using CH2Cl2 as eluent to afford 154 mg of ethyl-7-phenyl-6H-
thieno[3,2-e]indole-2-carboxylate (3). Obtained as a yellow solid;
C15H15O5NS2 (Mþ): 353.0392; found: 353.0397.
3.3.4. Ethyl-7-(hydroxymethyl)-6-(methylsulfonyl)-6H-thieno[3,2-
e]indole-2-carboxylate (2d). Obtained as a yellow-white solid; mp
165–166 ꢁC; IR: 3550, 2930, 1700 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
1.44 (t, 3H, J¼7.3 Hz), 2.83 (t, 1H, J¼6.4 Hz), 3.24 (s, 3H), 4.43 (q,
2H, J¼7.3 Hz), 4.97 (d, 2H, J¼6.4 Hz), 7.01 (s, 1H), 7.78 (d, 1H,
J¼9.1 Hz), 8.16 (d, 1H, J¼9.1 Hz), 8.30 (s, 1H); 13C NMR (75 MHz,
CDCl3): d 14.5, 41.6, 58.3, 61.9, 109.6, 114.0, 119.5, 127.8, 131.9, 135.0,
138.9, 139.9, 162.8; HRMS (EI): m/z calcd for C16H17O5NS2 (Mþ):
367.0548; found: 367.0540.
mp 199–201 ꢁC; IR: 3350, 2900, 1670 cmꢀ1
CDCl3):
;
1H NMR (300 MHz,
3.3.5. Ethyl-7-(2-hydroxypropan-2-yl)-6-(methylsulfonyl)-6H-
d
1.45 (t, 3H, J¼7.3 Hz), 4.43 (q, 2H, J¼7.3 Hz), 7.15 (s, 1H),
thieno[3,2-e]indole-2-carboxylate (2e). Obtained as a yꢀe1llow-white
7.35 (t, 1H, J¼7.3 Hz), 7.47 (t, 2H, J¼7.3 Hz), 7.53 (d, 1H, J¼9.1 Hz),
7.60 (d, 1H, J¼9.1 Hz), 7.71 (d, 2H, J¼7.3 Hz), 8.40 (s, 1H), 8.72 (br s,
solid; mp 110–112 ꢁC; IR: 3530, 2980, 2930, 1695 cm
;
1H NMR
(300 MHz, CDCl3):
d
1.44 (t, 3H, J¼7.3 Hz), 1.84 (s, 6H), 3.16 (s, 3H),
1H); 13C NMR (75 MHz, CDCl3):
d 14.6, 61.5, 99.1, 112.5, 116.5, 125.0,
4.43 (q, 2H, J¼7.3 Hz), 4.52 (s, 1H), 7.03 (s, 1H), 7.74 (d, 1H, J¼9.1 Hz),
125.3, 128.0, 128.6, 129.3, 131.9, 132.1, 132.9, 133.9, 136.6, 137.8,
163.4; HRMS (EI): m/z calcd for C19H15O2NS (Mþ): 321.0823; found
321.0824.
8.23 (d, 1H, J¼9.1 Hz), 8.29 (s, 1H); 13C NMR (75 MHz, CDCl3):
d 14.4,
31.3, 40.8, 61.7, 69.7, 108.4, 115.0, 119.3, 125.0, 127.6, 131.8, 134.9,
135.3, 139.0, 148.2, 162.7; HRMS (EI): m/z calcd for C17H19O5NS2
(Mþ): 381.0705; found: 381.0708.
3.3. Preparation of 7-substituted thieno[3,2-e]indoles 2:
typical procedure for the one-pot reaction of 4-iodo-5-
(methylsulfonamido)benzothiophene (1b) with external
acetylene
3.3.6. Ethyl-6-(methylsulfonyl)-7-(trimethylsilyl)-6H-thieno[3,2-
e]indole-2-carboxylate (2f1). Obtaiꢀn1ed as an off-white to gray solid;
mp 54–56 ꢁC; IR: 2955, 1705 cm
;
1H NMR (300 MHz, CDCl3):
d
0.46 (s, 9H), 1.45 (t, 3H, J¼7.3 Hz), 3.07 (s, 3H), 4.43 (q, 2H,
J¼7.3 Hz), 7.26 (s, 1H), 7.77 (d, 1H, J¼9.1 Hz), 8.16 (d, 1H, J¼9.1 Hz),
8.34 (s, 1H); 13C NMR (75 MHz, CDCl3):
0.4, 14.5, 40.9, 61.8, 113.8,
119.3, 119.4, 126.6, 127.9, 131.8, 134.9, 136.1, 138.6, 142.8, 162.8;
HRMS (EI): m/z calcd for C17H21O4NS2Si (Mþ): 395.0681; found:
395.0701.
To a suspension of tetrakis(triphenylphosphine)palladium(0)
(1 mol %) and CuI (2 mol %) in 10 mL of THF/i-Pr2NH 1:1 were added
ethyl-4-iodo-5-(methylsulfonamido)benzothiophene-2-carboxylate
(1b) (1 mmol) and acetylene (1.5 mmol). The mixture was refluxed
for the appropriate time indicated in Table 2. After cooling, EtOAc
and water (both 20 mL) were added. The mixture was extracted
with EtOAc (3ꢂ20 mL) and the combined organic layers were
washed with brine (20 mL) and dried over MgSO4. The mixture
was filtered, evaporated to dryness, and the residue was purified
by column chromatography to afford 2 (silica, eluent: CH2Cl2/EtOAc
mixtures).
d
3.3.7. Ethyl-5-(methylsulfonamido)-4-((trimethylsilyl)ethynyl)benzo-
[b]thiophene-2-carboxylate (2f2). A white solid; mp 145–146 ꢁC; IR:
3250, 2930, 2165, 1710 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 0.36
(s, 9H), 1.44 (t, 3H, J¼7.3 Hz), 3.01 (s, 3H), 4.43 (q, 2H, J¼7.3 Hz), 7.04
(br s, 1H), 7.74 (d, 1H, J¼9.1 Hz), 7.82 (d, 1H, J¼9.1 Hz), 8.15 (s, 1H);

8500
W. Van Snick, W. Dehaen / Tetrahedron 65 (2009) 8497–8501
13C NMR (75 MHz, CDCl3):
d
0.03, 14.4, 40.0, 62.1, 97.4, 108.0, 110.9,
J¼7.3 Hz), 2.15 (br s, 1H), 2.99 (t, 2H, J¼5.5 Hz), 3.92 (t, 2H,
J¼5.5 Hz), 4.31 (q, 2H, J¼7.3 Hz), 7.44 (m, 6H), 7.54 (d, 1H, J¼8.2 Hz),
120.5, 124.2, 129.5, 136.3, 136.4, 138.8, 140.1, 162.4; HRMS (EI): m/z
calcd for C17H21O4NS2Si (Mþ): 395.0681; found: 395.0671.
7.95 (s, 1H), 9.27 (br s, 1H); 13C NMR (75 MHz, CDCl3):
d 14.4, 28.8,
61.3, 62.6, 112.6, 115.6, 116.0, 122.5, 127.1, 128.6, 128.9, 130.8, 131.2,
131.7, 132.1, 134.2, 134.3, 136.9, 163.4.
3.4. Ethyl-6-(methylsulfonyl)-7-(pyridin-2-yl)-6H-thieno[3,2-
e]indole-2-carboxylate (2g)
3.5.4. Ethyl-8-(2-hydroxyethyl)-7-(pyridin-2-yl)-6H-thieno[3,2-e]in-
To a solution of ZnBr2 (168 mg, 0.75 mmol) in THF (3 mL) under
nitrogen atmosphere were added i-Pr2NEt (1 mL), ethyl-4-iodo-5-
(methylsulfonamido)benzo[b]thiophene-2-carboxylate (1b) (106 mg,
0.25 mmol), 2-ethynylpyridine (77.3 mg, 0.75 mmol), and tetrakis
(triphenylphosphine)palladium(0) (29 mg, 10 mol %). The mixture
was stirred for 17 h at 60 ꢁC. After cooling, water (20 mL) was added
and the mixture was extracted with CH2Cl2 (3ꢂ30 mL). The combined
organic layers were washed with brine (2ꢂ30 mL) and dried over
MgSO4. The mixture was filtered, evaporated to dryness, and the
residue was purified by column chromatography on silica gel using
CH2Cl2/EtOAc (90:10) as eluent to afford 65.8 mg of ethyl-6-(methyl-
sulfonyl)-7-(pyridin-2-yl)-6H-thieno[3,2-e]-indole-2-carboxylate 4g
as ayellow-white solid;mp 208–209 ꢁC; IR: 3020,1710 cmꢀ1; 1H NMR
dole-2-carboxylate (5c). Obtained as a white solid; mp 194–196 ꢁC;
IR: 3135, 2850, 1710 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 1.48 (t, 3H,
J¼7.3 Hz), 3.42 (t, 2H, J¼5.5 Hz), 4.34 (t, 2H, J 5.5 Hz), 4.47 (q, 2H,
J¼7.3 Hz), 6.61 (br s, 1H), 6.88 (d, 1H, J¼8.2 Hz), 6.97 (d, 1H,
J¼8.2 Hz), 7.02 (m, 1H), 7.51 (d, 1H, J¼8.2 Hz), 7.66 (t, 1H, J¼8.2 Hz),
8.17 (d, 1H, J¼4.6 Hz), 8.32 (s, 1H), 10.02 (br s, 1H); 13C NMR
(75 MHz, CDCl3):
d 14.6, 27.8, 61.6, 63.1, 112.8, 113.7, 116.4, 121.8,
122.4, 122.8, 127.6, 131.5, 132.6, 133.7, 134.2, 137.0, 137.1, 148.3, 150.3,
163.5; HRMS (EI): m/z calcd C20H18O3N2S for (Mþ): 366.1038;
found: 366.1057.
3.5.5. Ethyl-8-phenyl-7-(pyridin-2-yl)-6H-thieno[3,2-e]indole-2-car-
boxylate (5d1). Obtained as a yellowsolid; mp 167–170 ꢁC; IR: 3370,
(300 MHz, CDCl3):
d
1.44 (t, 3H, J¼7.3 Hz), 3.67 (s, 3H), 4.43 (q, 2H,
2920,1680 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
1.34 (t, 3H, J¼7.0 Hz),
J¼7.3 Hz), 7.16 (s,1H), 7.34 (dd,1H, J¼7.3, 5.0 Hz), 7.66 (d,1H, J¼7.3 Hz),
7.82 (m, 2H), 8.24 (d, 1H, J¼9.1 Hz), 8.33 (s,1H), 8.67 (d,1H, J¼4.6 Hz);
4.30 (t, 2H, J¼7.0 Hz), 7.08 (m,1H), 7.13 (d,1H, J¼8.2 Hz), 7.41 (dt,1H,
J¼8.2, 1.8 Hz), 7.55 (m, 7H), 7.64 (d, 1H, J¼8.2 Hz), 8.57 (d, 1H,
13C NMR (75 MHz, CDCl3):
d
14.4, 43.3, 61.7, 110.4, 115.0, 119.3, 123.2,
J¼4.8 Hz), 10.14 (br s, 1H); 13C NMR (100 MHz, CDCl3):
d 14.4, 61.3,
124.5, 124.9, 127.8, 131.8, 134.6, 135.0, 136.8, 138.6, 139.8, 148.6, 151.2,
162.8; HRMS (EI): m/z calcd for C19H16O4N2S2 (Mþ): 400.0551; found:
400.0570.
112.8, 117.7, 117.8, 121.1, 122.0, 124.8, 128.2, 128.4, 129.4, 130.9, 131.9,
132.1, 132.3, 132.6, 136.1, 136.4, 137.2, 149.3, 150.3, 163.1; HRMS (EI):
m/z calcd for C24H18O2N2S (Mþ): 398.1089; found: 398.1095.
3.5. Preparation of 7,8-disubstituted thieno[3,2-e]indoles 5:
typical procedure for the Larock heteroannulation reaction
of 5-amino-4-iodobenzothiophene (4) with internal acetylene
3.5.6. Ethyl-7-phenyl-8-(pyridin-2-yl)-6H-thieno[3,2-e]indole-2-car-
boxylate (5d2). Obtained as a yellow solid; mp 235–236 ꢁC; IR:
2950,1710 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
1.38 (t, 3H, J¼7.0 Hz),
4.34 (t, 2H, J¼7.0 Hz), 7.24 (m, 7H), 7.32 (d, 1H, J¼7.8 Hz), 7.41 (d, 1H,
J¼8.8 Hz), 7.58 (d, 1H, J¼8.8 Hz), 7.67 (dt, 1H, J¼7.8, 1.8 Hz), 8.08 (s,
1H), 8.82 (d, 1H, J¼4.5 Hz), 9.07 (br s, 1H); 13C NMR (100 MHz,
A mixture of Pd(OAc)2 (5 mol %), n-Bu4NCl (0.5 mmol), PPh3
(5 mol %), the appropriate base (see Table 3, 2.5 mmol), aryl iodide
(4) (174 mg, 0.5 mmol) and alkyne (2.5 mmol) in DMF (10 mL) was
purged with nitrogen and stirred for the appropriate time (as in-
dicated in Table 3) at 100 ꢁC. After cooling, water (40 mL) was
added and the mixture was extracted with EtOAc (3ꢂ20 mL). The
combined organic layers were washed with brine (20 mL) and dried
over MgSO4. The mixture was filtered, evaporated to dryness, and
the residue was purified by column chromatography to afford 5
(silica, eluent: CH2Cl2/EtOAc mixtures).
CDCl3):
d 14.5, 61.3, 112.5, 115.8, 117.0, 122.2, 123.4, 126.4, 128.1,
128.4,128.9,129.9,131.6,131.9,132.2,133.1,135.8,136.5,137.7,149.9,
155.5, 163.3; HRMS (EI): m/z calcd for C24H18O2N2S (Mþ): 398.1089;
found: 398.1086.
3.5.7. Ethyl-8-(3-fluorophenyl)-7-(trimethylsilyl)-6H-thieno[3,2-
e]indole-2-carboxylate (5e1). Obtaꢀin1ed as a yellow solid; mp 163–
167 ꢁC; IR: 3400, 2925, 1690 cm
;
1H NMR (300 MHz, CDCl3):
d
0.21 (s, 9H), 1.36 (t, 3H, J¼7.3 Hz), 4.32 (q, 2H, J¼7.3 Hz), 7.17 (m,
3.5.1. Ethyl-7-(tert-butyldimethylsilyl)-8-(2-(tetrahydro-2H-pyran-
2-yloxy)ethyl)-6H-thieno[3,2-e]indole-2-carboxylate (5a). Obtained
as an off-white solid; mp 143–145 ꢁC; 1H NMR (300 MHz, CDCl3):
2H), 7.27 (m, 1H), 7.44 (m, 1H), 7.55 (d, 1H, J¼9.1 Hz), 7.63 (d, 1H,
J¼9.1 Hz), 7.74 (s, 1H), 8.54 (br s, 1H); 13C NMR (75 MHz, CDCl3):
d
ꢀ0.5, 14.4, 53.6, 61.4, 112.6, 114.3, 114.6, 117.0, 117.8, 118.1, 123.3,
d
0.44 (s, 6H), 0.94 (s, 9H), 1.42 (t, 3H, J¼7.3 Hz), 1.68 (m, 6H), 3.45
126.7, 126.9, 128.3, 129.7, 129.9, 131.4, 132.5, 134.7, 134.9, 137.0,
139.4, 139.5, 161.1, 163.2, 164.4.
(m, 3H), 3.69 (m, 1H), 3.96 (m, 2H), 4.41 (q, 2H, J¼7.3 Hz), 4.69 (m,
1H), 7.48 (d, 1H, J¼9.1 Hz), 7.55 (d, 1H, J¼9.1 Hz), 8.40 (br s,1H), 8.60
(s, 1H); 13C NMR (75 MHz, CDCl3):
d
ꢀ4.9, 14.5, 17.9, 19.5, 25.6, 26.7,
3.5.8. Ethyl-8-(3-fluorophenyl)-6H-thieno[3,2-e]indole-2-carboxyl-
28.5, 30.7, 61.4, 62.0, 68.5, 99.0, 112.7, 116.5, 122.8, 123.6, 128.8,
131.5, 132.1, 132.7, 136.0, 136.6, 163.4; HRMS (EI): m/z calcd for
C26H37O4NSSi (Mþ): 487.2213; found: 487.2213.
ate (5e2). Obtained as a yellow solid; mp 222–223 ꢁC; IR: 3365,
2985, 1680 cmꢀ1 1H NMR (400 MHz, acetone-d6):
; d 1.41 (t, 3H,
J¼7.0 Hz), 4.40 (q, 2H, J¼7.3 Hz), 7.10 (dt, 1H, J¼8.3, 2.0 Hz), 7.51 (m,
2H), 7.67 (m, 3H), 7.76 (d, 1H, J¼7.8 Hz), 8.45 (s, 1H), 11.19 (br s, 1H);
3.5.2. Ethyl-8-(2-hydroxyethyl)-7-phenyl-6H-thieno[3,2-e]indole-2-
13C NMR (100 MHz, acetone-d6):
d 14.7, 61.9,100.2,100.3,112.4,112.6,
carboxylate (5b1). Obtained as a yellow-white solid; mp 87–91 ꢁC;
114.0, 114.1, 114.8, 115.0, 117.2, 121.8, 121.9, 125.5, 129.2, 131.8, 131.9,
132.7, 133.6, 135.4, 135.6, 135.7, 136.8, 137.3, 163.1, 163.3, 165.5; HRMS
(EI): m/z calcd for C19H14O2NSF (Mþ): 339.0729; found: 339.0731.
IR: 3360, 2925, 1680 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 1.42 (t, 3H,
J¼7.1 Hz), 1.67 (br s, 1H), 3.38 (t, 2H, J¼7.0 Hz), 4.02 (t, 2H, J¼6.8 Hz),
4.41 (q, 2H, J¼7.1 Hz), 7.38 (m, 1H), 7.47 (m, 3H), 7.62 (m, 3H), 8.48
(s, 1H), 8.49 (br s, 1H); 13C NMR (100 MHz, CDCl3):
d
14.5, 29.1, 61.6,
3.5.9. Ethyl-8-(2-hydroxyethyl)-7-(trimethylsilyl)-6H-thieno[3,2-
62.9, 110.4, 112.6, 116.6, 123.9, 128.2, 128.3, 128.6, 129.1, 131.7, 132.8,
133.0, 133.2, 136.0, 137.2, 163.4.
e]indole-2-carboxylate (5f). Obtained as a white solid; mp 155–
157 ꢁC; IR: 3500, 3290, 2950, 1690 cmꢀ1 1H NMR (300 MHz,
;
CDCl3):
d
0.42 (s, 9H), 1.41 (t, 3H, J¼7.3 Hz), 2.40 (br s, 1H), 3.35 (t,
3.5.3. Ethyl-7-(2-hydroxyethyl)-8-phenyl-6H-thieno[3,2-e]indole-2-
2H, J¼7.3 Hz), 3.93 (t, 2H, J¼7.3 Hz), 4.40 (q, 2H, J¼7.3 Hz), 7.49 (d,
carboxylate (5b2). Obtained as a yellow solid; mp 76–78 ꢁC; IR:
1H, J¼9.1), 7.55 (d, 1H, J¼9.1 Hz), 8.50 (s, 1H), 8.62 (br s, 1H); 13C
3320, 2925, 1700 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
1.34 (t, 2H,
NMR (75 MHz, CDCl3):
d
ꢀ0.3, 14.5, 30.9, 61.6, 63.1, 112.9, 116.6,

W. Van Snick, W. Dehaen / Tetrahedron 65 (2009) 8497–8501
8501
3. Rao, M. V. B.; Kumar, U. K. S.; Ila, H.; Junjappa, H. Tetrahedron 1999, 55,
11563.
4. Van Snick, W.; Nulens, W.; Jambon, S.; Dehaen, W. Synthesis 2009, 767.
5. (a) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T.; Yamanaka, H. Chem. Pharm.
Bull. 1988, 36, 1305; (b) Suzuki, N.; Yasaki, S.; Yasuhara, A.; Sakamoto, T. Chem.
Pharm. Bull. 2003, 51, 1170.
121.4,123.5, 128.5, 131.4, 132.6,134.8,135.9,136.8, 163.5; HRMS (EI):
m/z calcd for C18H23O3NSSi (Mþ): 361.1168; found: 361.1179.
Acknowledgements
6. Zhang, H.-C.; Ye, H.; Moretto, A. F.; Brumfield, K. K.; Maryanoff, B. E. Org. Lett.
2000, 2, 89.
The authors are grateful to the IWT [Institute for the Promotion of
Innovation through Science and Technology in Flanders (IWT-
Vlaanderen)] for a doctoral fellowship for W.V.S., the F.W.O. Vlaan-
deren and the University of Leuven are thanked for financial support.
´
7. Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
8. Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079.
9. Mu¨ ller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108,
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References and notes
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