A facile synthetic route towards substituted thieno[3,2-e]indoles

Article abstract of DOI:10.1055/s-0028-1083366

A number of substituted thieno[3,2-e]indoles have been prepared in high yields via a tetrabutylammonium fluoride mediated cyclization of 5-acetamido-4-ethynylbenzothiophenes, which, in turn, are easily accessible from the corresponding 4-iodoben- zothioph

Full text of DOI:10.1055/s-0028-1083366

PAPER
767
A Facile Synthetic Route towards Substituted Thieno[3,2-e]indoles
A
Facile Synthetic
Rout
i
e
towar
m
ds Substituted Thieno[3,2
V
-
e
]indoles an Snick, Wienand Nulens, Sarah Jambon, Wim Dehaen*
Department of Chemistry, K. U. Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax +32(16)327990; E-mail: wim.dehaen@chem.kuleuven.be
Received 28 August 2008; revised 10 November 2008
EtO2C
EtO2C
S
Abstract: A number of substituted thieno[3,2-e]indoles have been
prepared in high yields via a tetrabutylammonium fluoride mediat-
ed cyclization of 5-acetamido-4-ethynylbenzothiophenes, which, in
turn, are easily accessible from the corresponding 4-iodoben-
zothiophenes. This method presents a viable alternative to the tradi-
tionally used Fischer indolization procedures.
R
TBAF
THF
S
R
47–94%
N
NHAc
H
R = Ph, TMS, alkoxy, alkyl
Key words: thienoindoles, palladium, cyclizations, fused-ring sys-
tems, tetrabutylammonium fluoride
Scheme 1
Ethyl 5-nitrobenzo[b]thiophene-2-carboxylate (1) was
conveniently prepared by the condensation of 2-chloro-4-
nitrobenzaldehyde with ethyl 2-sulfanylacetate.9 After re-
duction of the nitro group using hydrogen and palladium
on carbon,10 the iodination reaction of ethyl 5-aminoben-
zo[b]thiophene-2-carboxylate (2) proceeded selectively
in the 4-position using iodine monochloride and sodium
hydrogen carbonate as a base giving ethyl 5-amino-4-io-
dobenzo[b]thiophene-2-carboxylate (3) (Scheme 2).11 All
of these reactions proceeded in nearly quantitative yield.
Few versatile methods exist for the synthesis of
thieno[3,2-e]indoles. Among these, the Fischer indoliza-
tion of a 5-substituted benzothiophene hydrazone,1 the
photochemical cyclization of 2-[2-(2-thienyl)vinyl]-1H-
pyrroles,2 and the cyclocondensation of a 3-oxoindole
with 2-thienylacetonitrile to give a thienocarbazole3 are
the most important. These procedures have significant
drawbacks, however, such as vigorous reaction condi-
tions, which lead to low yields and restrict the number of
possible substituents. Hence, in general, they are of limit-
ed applicability.
CO2Et
CO2Et
H2, Pd/C
EtOH
98%
In this manuscript, we will discuss a new, high-yielding
procedure for the synthesis of thieno[3,2-e]indoles using
readily available starting materials. The key step is the
synthesis of 5-amino-4-ethynylbenzothiophenes by a
Sonogashira coupling reaction of 5-amino-4-iodoben-
zothiophene with external acetylenes. Based on the avail-
able literature of indolization reactions,4 the 5-amino-4-
ethynylbenzothiophene should easily be cyclized to the
thienoindole. Cyclizing agents such as copper(I) iodide in
N,N-dimethylformamide,5 copper(II) salts,6 and potassi-
um hydride or potassium tert-butoxide in N-methylpyrro-
lidin-2-one,7 among others, have been employed with
varying success. The use of tetrabutylammonium fluoride
in tetrahydrofuran, however, proved to be a very success-
ful method (Scheme 1). Moreover, it seems to be a partic-
ularly soft and easy method, as there is no need for dry
conditions.8
S
S
O2N
H2N
2
1
I
CO2Et
ICl, NaHCO3
CH2Cl2
S
97%
H2N
3
Scheme 2
In the second step, a number of 5-amino-4-ethynylben-
zothiophenes 4a–d were prepared in high yields (89–
97%) using a general Sonogashira approach (Scheme 3,
equation 1 and Table 1).
In order to perform the ring closure using tetrabutylam-
monium fluoride as a cyclizing agent, conversion of the
free amine function 4 into an amide was required. Acety-
lation turned out to be the easiest method, using either
acetyl chloride or acetic anhydride in dichloromethane,
the latter requiring slightly longer reaction times
(Scheme 3, equation 1). Even though this procedure
worked well for the phenylethynyl- and (trimethylsi-
lyl)ethynyl-substituted benzothiophenes 4a,b (98% and
94% yields, respectively), problems were encountered
with those acetylenes containing alcohol functional
groups 4c,d (Table 2). As could be expected, the propar-
gyl alcohol group in 4c was acetylated together with the
amine, leading to the doubly acetylated product 5cc
Hence, thienoindoles are easily synthesized in three steps,
requiring little or no purification. The first step involves
the iodination of 5-aminobenzothiophene 2 (Scheme 2).
The second step is the Sonogashira coupling reaction of
this 4-iodobenzothiophene derivative. Finally, the in-
dolization can proceed with tetrabutylammonium fluoride
as the cyclizing agent (Scheme 1).
SYNTHESIS 2009, No. 5, pp 0767–0774
x
x
.
x
x
.2
0
0
9
Advanced online publication: 11.02.2009
DOI: 10.1055/s-0028-1083366; Art ID: T15008SS
© Georg Thieme Verlag Stuttgart · New York

768
W. Van Snick et al.
PAPER
R
R
H
Pd(PPh3)4, CuI
AcCl, Et3N
CH2Cl2
N
H2N
THF, i-Pr2NH
Ac
(1)
3
+
R
CO2Et
CO2Et
69–98%
89–97%
S
S
5
4
X
R
H
Pd(PPh3)4, CuI
THF, i-Pr2NH
AcCl, Et3N
CH2Cl2
N
Ac
(2)
2
5
CO2Et
44–95%
89%
S
6
X = H
ICl
NaHCO3
CH2Cl2
91%
7
X = I
Scheme 3
(Figure 1). This was not observed with the 1-hydroxy-1- To obtain the propargyl alcohol derivative, we then decid-
methylethyl group (CMe2OH) in 4d, probably due to ster- ed to reverse our protocol and introduce the acetyl group
ic effects. An alternative approach to the direct acetylation before the Sonogashira coupling reaction (Scheme 3,
of the propargyl alcohol derivative 4c was also consid- equation 2). Fearing that the iodination reaction might
ered, using sodium bisulfate supported on silica gel cata- proceed too slowly on an acetanilide, we first tried to
lyst.12 In this case, an N-monoacetylated product 5c was acetylate the 4-iodo derivative 3. This reaction turned out
acquired in 69% yield.
to be difficult to control, however, leading to a mixture of
products containing a doubly acetylated product 8, next to
the desired acetanilide 7 (Figure 1). We then tried to iodi-
nate the acetanilide derivative 6, which was easily pre-
pared by acetylation of 2. While considerably slower than
the iodination reaction with the free amine, this reaction
afforded the N-protected iodobenzothiophene 7 in high
yield (91%) (Scheme 3, equation 2). The subsequent
Sonogashira coupling reactions proceeded uneventfully
towards the acetylene substituted benzothiophenes 5. For
ease of work, we decided to use this protocol as a general
method for the synthesis of all other acetylenes 5a–i
(Table 1, entries 6–14).
Table 1 Sonogashira Cross-Coupling Reaction
EtO2C
EtO2C
R2
R2
Pd(PPh3)4, CuI
THF, i-Pr2NH
S
S
I
NHR1
NHR1
R1 = H
1 = Ac
4
5
R
R
1 = H
1 = Ac
3
7
R
Entry
1
Aryl iodide R2
Product
4a
Yielda (%)
3
3
3
3
3
7
7
7
7
7
7
7
7
7
Ph
97
2
TMS
4b
4c
94
Table 2 Acetylation of 5-Amino-4-ethynylbenzothiophenes 4
3
CH2OH
CMe2OH
CO2Et
89
Entry Substrate
R
Conditionsa Product Yieldb (%)
4
4d
4e
95
1
2
3
4
5
6
4a
4b
4c
4c
4d
4d
Ph
A
A
B
C
B
C
5a
5b
5cc
5c
98
94
85c
69
69
69
5
–
TMS
6
Ph
5a
94, 97b
86, 91b
44
CH2OH
CH2OH
CMe2OH
CMe2OH
7
TMS
5b
5c
8
CH2OH
CMe2OH
(CH2)2OH
CH2OTHP
CMe2OTHP
(CH2)2OTHP
Bu
5d
9
5d
5e
86
5d
10
11
12
13
14
90
a Conditions A: AcCl, Et3N, CH2Cl2; B: Ac2O, pyridine, CH2Cl2; C:
Ac2O, NaHSO4–silica gel, CH2Cl2.
5f
81
a All yields refer to isolated products.
c Doubly acetylated product 5cc.
5g
95
5h
5i
73
When using ethyl propynoate in the Sonogashira coupling
with 5-amino-4-iodobenzothiophene 3, no coupled prod-
uct could be detected, despite complete consumption of
the starting materials (Table 1, entry 5). Other attempts to
create the Sonogashira coupled product by varying the
82
a All yields refer to isolated products.
b 1 mol% of PdCl2(PPh3)2 was used as a catalyst.
Synthesis 2009, No. 5, 767–774 © Thieme Stuttgart · New York

PAPER
A Facile Synthetic Route towards Substituted Thieno[3,2-e]indoles
769
temperature and the amount of catalyst used also failed. starting materials could be noted. While ring closure of
We then decided to try a Negishi cross-coupling on the N- butynol derivative 5e was successful, the yield was con-
acetyl-protected iodobenzothiophene 7, but to our sur- siderably lower compared to the hex-1-yne compound 5i
prise a Michael-type adduct 9 was acquired in 45% yield (53% vs 88%). However, about 40% (based on 1H NMR)
(Figure 1). In an ultimate effort we used the N-mesyl-pro- of ethyl 7-vinyl-6H-thieno[3,2-e]indole-2-carboxylate
tected iodobenzothiophene 10, which has been reported to (11j) had also been formed (Figure 1). This dehydration
yield better results in this type of reaction,13 but this also reaction has been reported before under conditions similar
was to no avail. Based on mass spectrometry, the product to ours, and has been attributed to the electron-withdraw-
seemed to be present in the reaction mixture, but turned ing properties of an N-sulfonyl substituent.14 In another
out to be unstable during purification.
case, using analogous products and reaction conditions
but without tetrabutylammonium fluoride, no dehydration
was observed.15 This leads us to conclude that the forma-
tion of vinylindoles is mediated by tetrabutylammonium
fluoride, regardless of the nature of the other substituents.
When protecting the alcohol groups as the tetrahydro-2H-
pyran-2-yl ethers 5f–h, treatment with tetrabutylammoni-
um fluoride gave the corresponding indoles in moderate to
high yields. In the case of 5h, again about 40% of a 7-vi-
nylindole derivative 11j was obtained. The tetrahydro-
2H-pyran-2-yl-protected thienoindole 11g seemed to de-
grade during column chromatography purification, lead-
ing to a lower yield (57%). Moreover, compound 11g
could not be fully characterized, due to its instability.
OAc
I
CO2Et
Ac
S
N
H
N
Ac
Ac
8
Ac
CO2Et
S
5cc
EtO2C
I
CO2Et
S
N
I
CO2Et
9
S
HN
In conclusion, an easy and versatile procedure for the syn-
thesis of thieno[3,2-e]indoles has been developed, with
most reaction steps requiring little or no purification.
Ms
HN
10
CO2Et
S
11j
Table 3 Tetrabutylammonium Fluoride Mediated Cyclization
R
Figure 1
R
TBAF
Finally, ring closure of acetylenes 4a and 4b to the indoles
was first attempted with the classical Castro reaction, us-
ing an excess of copper(I) iodide in refluxing N,N-di-
methylformamide. The 2-phenylthienoindole 11a was
thus prepared in 70% yield, but in the case of the trimeth-
ylsilyl-protected acetylene 4b we could only note the
complete decomposition of the starting material. We then
tried Knochel’s method,7 first using potassium tert-butox-
ide in N-methylpyrrolidin-2-one, but in this case even the
phenylethynyl derivative 4a failed to produce any indole,
though some starting material was recovered. Moreover,
when using potassium hydride we had to witness the com-
plete decomposition of the starting compound. Most prob-
ably the ester function is too sensitive to survive these
reaction conditions.
H
THF
HN
N
reflux
Ac
CO2Et
CO2Et
S
S
5
11
Entry Substrate R
Equiv Time Product
TBAF (h)
Yielda
(%)
1
2
5a
5a
5b
5c
5d
5e
5f
Ph
Ph
2.5
3
18
18
2
11a
11a
11b
–
60b
89
94c
–
3
TMS
3
4
CH2OH
3
18
18
18
18
18
18
18
5
CMe2OH
(CH2)2OH
CH2OTHP
CMe2OTHP
(CH2)2OTHP
Bu
3
–
–
6
3
11e + 11j 53d
At this stage, ring closure of the 5-acetamido-4-ethynyl-
benzothiophenes 5 was investigated using tetrabutylam-
monium fluoride as the cyclizing agent (Table 3).8 A first
attempt using phenylacetylene 5a and 2.5 equivalents of
tetrabutylammonium fluoride led to an incomplete reac-
tion. Increasing the amount of tetrabutylammonium fluo-
ride to three equivalents, however, resulted in the
7
3
11f
91
57
8
5g
5h
5i
3
11g
9
3
11h + 11j 47d
11i 88
10
3
formation of the desired thienoindole 11a in a satisfying a All yields refer to isolated products.
b 20% of starting product was recovered.
89% yield. Similar results were obtained with most other
compounds.
c Product is ethyl 6H-thieno[3,2-e]indole-2-carboxylate (R = H).
d In addition to the yield of isolated product (11e or 11h), about 40%
of ethyl 7-vinyl-6H-thieno[3,2-e]indole-2-carboxylate (11j, R =
CH=CH2) was obtained (as estimated by 1H NMR).
Again, the propargylic alcohol groups proved to be prob-
lematic. In both cases 5c,d, only decomposition of the
Synthesis 2009, No. 5, 767–774 © Thieme Stuttgart · New York

770
W. Van Snick et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 1.42 (t, J = 7.3 Hz, 3 H, CH3),
4.41 (m, 4 H, NH2, CO2CH2), 6.93 (d, J = 8.2 Hz, 1 H), 7.38 (m, 3
H), 7.59 (m, 3 H), 8.16 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.4, 61.6, 83.6, 102.2, 106.0,
116.6, 123.1, 123.5, 128.5, 129.3, 131.6, 132.4, 134.8, 140.2, 142.2,
146.2, 162.9.
These procedures can easily be scaled up (up to 20 mmol
with only marginally lower yields). Research to convert
the Sonogashira coupling–tetrabutylammonium fluoride
cyclization into a one-pot procedure is currently ongoing.
Due to the general applicability of the method devised, a
number of substituted thienoindoles are currently being
investigated in a structure–activity relationship study.
HRMS (EI): m/z [M]+ calcd for C19H15NO2S: 321.0823; found:
321.0813.
Melting points (not corrected) were determined using a Reichert
Thermovar apparatus. IR spectra were recorded using a Bruker
ALPHA-P spectrophotometer. NMR spectroscopy was performed
on commercial instruments (Bruker Avance 300 MHz, Bruker
AMX 400 MHz or Bruker Avance II+ 600 MHz) and referenced to
TMS (1H) or the carbon signal of deuterated solvents (13C). Mass
spectra were run using a HP5989A apparatus (CI and EI, 70 eV ion-
ization energy) with Apollo 300 data system, and a Kratos MS50TC
instrument for exact mass measurements (performed in the EI mode
at a resolution of 10000). 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 following products were prepared accord-
ing to the literature: ethyl 5-nitrobenzo[b]thiophene-2-carboxylate
(1),9 and ethyl 5-aminobenzo[b]thiophene-2-carboxylate (2).10
Ethyl 5-Amino-4-[(trimethylsilyl)ethynyl]benzo[b]thiophene-2-
carboxylate (4b)
Yield: 94%; mp 104 °C.
IR: 3480, 3390, 2980, 2140, 1710 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.32 (s, 9 H, SiCH3), 1.42 (t,
J = 7.3 Hz, 3 H, CH3), 4.40 (m, J = 7.3 Hz, 4 H, NH2, CO2CH2),
6.88 (d, J = 9.1 Hz, 1 H), 7.55 (d, J = 9.1 Hz, 1 H), 8.07 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 0.0, 14.1, 61.4, 99.0, 102.8, 104.6,
116.2, 123.4, 129.1, 132.0, 134.4, 140.2, 146.6, 162.7.
HRMS (EI): m/z [M]+ calcd for C16H19NO2SSi: 317.0906; found:
317.0876.
Ethyl 5-Amino-4-(3-hydroxyprop-1-ynyl)benzo[b]thiophene-2-
carboxylate (4c)
Yield: 89%; mp 151 °C.
IR: 3450, 3410, 3320, 2920, 2220, 1690 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.42 (t, J = 7.3 Hz, 3 H, CH3),
1.89 (s, 1 H, OH), 4.35 (s, 2 H, NH2), 4.40 (q, J = 7.3 Hz, 2 H,
CO2CH2), 4.67 (s, 2 H, CH2OH), 6.88 (d, J = 9.1 Hz, 1 H), 7.57 (d,
J = 9.1 Hz, 1 H), 8.07 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.4, 51.9, 61.6, 80.1, 97.2, 116.6,
123.7, 128.5, 129.1, 132.3, 134.9, 140.6, 146.6, 162.9.
HRMS (EI): m/z [M]+ calcd for C14H13NO3S: 275.0616; found:
275.0621.
Ethyl 5-Amino-4-iodobenzo[b]thiophene-2-carboxylate (3)
To a stirred soln of ethyl 5-aminobenzo[b]thiophene-2-carboxylate
(2, 10.4 g, 46.8 mmol) and NaHCO3 (7.9 g, 93.7 mmol) in CH2Cl2
(350 mL) was added dropwise a soln of ICl (8.4 g, 51.5 mmol) in
CH2Cl2 (70 mL). The mixture was stirred at r.t. for 2 h. The resulting
mixture was washed with sat. Na2S2O3 (200 mL) and extracted with
CH2Cl2 (3 × 200 mL). The combined organic layers were washed
with sat. NaHCO3 and brine (both 200 mL) and dried (MgSO4). The
mixture was filtered and evaporated to dryness to afford 3 as a
brownish solid; yield: 15.8 g (97%); mp 157 °C. The product was
used without further purification.
IR: 3400, 3300, 3180, 2990, 1710 cm–1.
Ethyl 5-Amino-4-(3-hydroxy-3-methylbut-1-ynyl)ben-
zo[b]thiophene-2-carboxylate (4d)
Yield: 95%; mp 103 °C.
IR: 3440, 3320, 3190, 2980, 2220, 1670 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.42 (t, J = 7.3 Hz, 3 H, CH3),
1.72 [s, 6 H, C(CH3)2], 2.15 (s, 1 H, OH), 4.30 (s, 2 H, NH2), 4.40
(q, J = 7.3 Hz, 2 H, CO2CH2), 6.89 (d, J = 8.2 Hz, 1 H), 7.55 (d,
J = 8.2 Hz, 1 H), 8.03 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 1.42 (t, J = 7.3 Hz, 3 H, CH3),
4.26 (s, 2 H, NH2), 4.41 (q, J = 7.3 Hz, 2 H, CO2CH2), 6.90 (d,
J = 9.1 Hz, 1 H), 7.56 (d, J = 9.1 Hz, 1 H), 7.98 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.4, 61.7, 78.4, 116.5, 123.1,
131.7, 133.6, 134.5, 142.7, 144.9, 162.7.
HRMS (EI): m/z [M]+ calcd for C11H10INO2S: 346.9477; found:
346.9479.
13C NMR (75 MHz, CDCl3): d = 14.5, 32.0, 61.7, 66.2, 75.7, 101.6,
5-Amino-4-ethynylbenzo[b]thiophenes 4a–d and 5-Acetamido-
4-ethynylbenzo[b]thiophenes 5a–i; General Procedure for the
Sonogashira Reaction
104.2, 116.7, 123.6, 129.2, 132.0, 134.9, 140.6, 146.6, 162.9.
HRMS (EI): m/z [M]+ calcd for C16H17NO3S: 303.0929; found:
A suspension of Pd(PPh3)4 (1 mol%) and CuI (2 mol%) in THF–i-
Pr2NH (1:1, 10 mL) was purged with N2. 4-Iodobenzo[b]thiophene
3 or 7 (1 mmol) and acetylene (1.5 mmol) were added, and the mix-
ture was stirred overnight at 45 °C. After cooling, EtOAc (20 mL)
and sat. NH4Cl soln (20 mL) were added. The mixture was extracted
with EtOAc (3 × 20 mL) and the combined organic layers were
washed with brine (20 mL) and dried (MgSO4). The mixture was fil-
tered, evaporated to dryness, and the residue was purified by col-
umn chromatography (silica gel, CH2Cl2–EtOAc) to afford 4 or 5.
303.0932.
Ethyl 5-Acetamido-4-(phenylethynyl)benzo[b]thiophene-2-car-
boxylate (5a)
Yield: 94%; mp 157 °C.
IR: 3400, 3350, 2900, 2200, 1720, 1670 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (t, J = 7.3 Hz, 3 H, CH3),
2.29 (s, 3 H, CH3CO), 4.42 (q, J = 7.3 Hz, 2 H, CO2CH2), 7.45 (m,
3 H, Ph), 7.61 (m, 2 H, Ph), 7.79 (d, J = 9.1 Hz, 1 H), 8.03 (s, 1 H,
NH), 8.23 (s, 1 H), 8.57 (d, J = 8.2 Hz, 1 H).
Ethyl 5-Amino-4-(phenylethynyl)benzo[b]thiophene-2-carbox-
ylate (4a)
Yield: 97%.
IR: 3450, 3360, 2990, 2190, 1710 cm–1.
13C NMR (75 MHz, CDCl3): d = 14.5, 25.1, 61.9, 82.2, 101.2,
122.2, 123.6, 128.9, 129.5, 129.6, 131.8, 135.6, 137.2, 137.4, 139.5,
162.7, 168.4.
HRMS (EI): m/z [M]+ calcd for C21H17NO3S: 363.0929; found:
363.0922.
Synthesis 2009, No. 5, 767–774 © Thieme Stuttgart · New York

PAPER
A Facile Synthetic Route towards Substituted Thieno[3,2-e]indoles
771
Ethyl 5-Acetamido-4-[(trimethylsilyl)ethynyl]benzo[b]thio-
phene-2-carboxylate (5b)
Yield: 86%; mp 152 °C.
IR: 3380, 2960, 2140, 1700 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.37 [s, 9 H, Si(CH3)3], 1.43 (t,
J = 7.3 Hz, 3 H, CH3), 2.26 (s, 3 H, CH3CO), 4.42 (q, J = 7.3 Hz, 2
H, CO2CH2), 7.78 (d, J = 9.1 Hz, 1 H), 8.05 (s, 1 H, NH), 8.15 (s, 1
H), 8.57 (d, J = 9.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 0.0, 14.3, 24.9, 61.8, 97.8, 107.2,
107.5, 119.1, 123.7, 129.5, 135.4, 136.8, 138.1, 139.2, 162.6, 168.2.
1H NMR (300 MHz, CDCl3): d = 1.42 (t, J = 7.3 Hz, 3 H, CH3),
1.84–1.59 (m, 6 H, THP), 2.27 (s, 3 H, CH3CO), 3.62 (m, 1 H,
THP), 3.96 (m, 1 H, THP), 4.42 (q, J = 7.3 Hz, 2 H, CO2CH2), 4.69
(s, 2 H, C≡CCH2), 4.98 (m, 1 H, THP), 7.78 (d, J = 9.1 Hz, 1 H),
8.12 (s, 1 H, NH), 8.16 (s, 1 H), 8.57 (d, J = 9.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.5, 19.2, 25.0, 25.5, 30.6, 55.6,
61.9, 62.4, 79.2, 97.6, 98.1, 107.0, 119.7, 123.7, 129.6, 135.6,
137.0, 138.2, 139.7, 162.7, 168.7.
HRMS (EI): m/z [M]+ calcd for C21H23NO5S: 401.1297; found:
401.1308.
HRMS (EI): m/z [M]+ calcd for C18H21NO3SSi: 359.1011; found:
359.1016.
Ethyl 5-Acetamido-4-[3-methyl-3-(tetrahydro-2H-pyran-2-
yloxy)but-1-ynyl]benzo[b]thiophene-2-carboxylate (5g)
Yield: 95%; mp 96 °C.
IR: 3300, 2940, 1710, 1690 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.42 (t, J = 7.3 Hz, 3 H, CH3),
1.67 (m, 12 H, C(CH3)2, THP), 2.27 (s, 3 H, CH3CO), 3.56 (m, 1 H,
THP), 4.05 (m, 1 H, THP), 4.42 (q, J = 7.3 Hz, 2 H, CO2CH2), 5.29
(m, 1 H, THP), 7.75 (d, J = 9.1 Hz, 1 H), 8.10 (s, 1 H), 8.55 (d,
J = 9.1 Hz, 1 H), 8.69 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.4, 19.5, 24.4, 25.6, 29.3, 31.1,
32.0, 61.9, 62.2, 70.6, 95.2, 103.8, 107.4, 120.3, 123.2, 129.6,
135.2, 136.9, 138.4, 139.3, 162.7, 169.3.
Ethyl 5-Acetamido-4-(3-hydroxyprop-1-ynyl)benzo[b]thio-
phene-2-carboxylate (5c)
Yield: 44%; mp 190–191 °C.
IR: 3280, 2920, 1700, 1665 cm–1.
1H NMR (300 MHz, CD3OD–CDCl3): d = 1.43 (t, J = 7.3 Hz, 3 H,
CH3), 1.60 (br s, 1 H, OH), 2.27 (s, 3 H, CH3CO), 4.42 (q, J = 7.3
Hz, 2 H, CO2CH2), 4.62 (s, 2 H, CH2O), 7.81 (d, J = 9.1 Hz, 1 H),
8.09 (s, 1 H), 8.18 (d, J = 9.1 Hz, 1 H).
13C NMR (75 MHz, CD3OD–CDCl3): d = 13.1, 22.5, 49.8, 61.2,
71.3, 98.2, 109.9, 122.2, 128.2, 131.2, 134.4, 136.3, 137.4, 139.3,
162.2, 170.0.
HRMS (EI): m/z [M]+ calcd for C23H27NO5S: 429.1610; found:
429.1616.
HRMS (EI): m/z [M]+ calcd for C16H15NO4S: 317.0722; found:
317.0706.
Ethyl 5-Acetamido-4-[4-(tetrahydro-2H-pyran-2-yloxy)but-1-
ynyl]benzo[b]thiophene-2-carboxylate (5h)
Yield: 73%; mp 130 °C.
IR: 3280, 2940, 2230, 1710, 1660 cm–1.
Ethyl 5-Acetamido-4-(3-hydroxy-3-methylbut-1-ynyl)ben-
zo[b]thiophene-2-carboxylate (5d)
Yield: 86%; mp 122–123 °C.
1H NMR (300 MHz, CDCl3): d = 1.42 (t, J = 7.3 Hz, 3 H, CH3),
1.9–1.5 (m, 6 H, THP), 2.26 (s, 3 H, CH3CO), 2.93 (t, J = 7.3 Hz, 2
H, C≡CCH2), 3.55 (m, 1 H, THP), 3.79 (m, 1 H, CH2O), 3.93 (m, 1
H, CH2O), 4.02 (m, 1 H, THP), 4.41 (q, J = 7.3 Hz, 2 H, CO2CH2),
4.73 (m, 1 H, THP), 7.73 (d, J = 9.1 Hz, 1 H), 8.09 (s, 1 H, NH),
8.15 (s, 1 H), 8.52 (d, J = 9.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.5, 19.7, 21.6, 25.0, 25.5, 30.8,
61.8, 62.8, 65.8, 74.9, 99.2, 100.0, 108.2, 119.6, 122.9, 129.8,
135.2, 137.0, 137.6, 139.7, 162.7, 168.6.
IR: 3240, 2920, 1710, 1670 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (t, J = 7.3 Hz, 3 H, CH3),
1.75 [s, 6 H, C(CH3)2], 2.26 (s, 3 H, CH3CO), 2.67 (br s, 1 H, OH),
4.42 (q, J = 7.3 Hz, 2 H, CO2CH2), 7.73 (d, J = 9.1 Hz, 1 H), 7.97
(s, 1 H, NH), 8.07 (s, 1 H), 8.46 (d, J = 9.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.4, 24.8, 31.7, 62.0, 65.9, 75.4,
106.3, 107.7, 120.0, 123.3, 129.4, 135.3, 137.2, 137.3, 139.2, 162.7,
168.8.
HRMS (EI): m/z [M]+ calcd for C18H19NO4S: 345.1035; found:
345.1039.
HRMS (EI): m/z [M]+ calcd for C22H25NO5S: 415.1453; found:
415.1454.
Ethyl 5-Acetamido-4-(4-hydroxybut-1-ynyl)benzo[b]thio-
phene-2-carboxylate (5e)
Yield: 90%; mp 131 °C.
IR: 3490, 3390, 3340, 2900, 2230, 1700, 1680 cm–1.
Ethyl 5-Acetamido-4-(hex-1-ynyl)benzo[b]thiophene-2-carbox-
ylate (5i)
Yield: 82%; mp 116–118 °C.
IR: 3380, 2960, 2230, 1710, 1650 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.42 (t, J = 7.3 Hz, 3 H, CH3),
1.92 (s, 1 H, OH), 2.26 (s, 3 H, CH3CO), 2.89 (t, J = 6.4 Hz, 2 H,
C≡CCH2), 3.96 (m, 2 H, CH2OH), 4.42 (q, J = 7.3 Hz, 2 H,
CO2CH2), 7.75 (d, J = 9.1 Hz, 1 H), 8.15 (s, 1 H), 8.21 (s, 1 H, NH),
8.55 (d, J = 9.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.5, 24.2, 25.0, 61.1, 61.9, 99.5,
108.0, 119.7, 123.0, 129.7, 135.0, 135.3, 137.9, 139.5, 162.8, 168.8.
1H NMR (300 MHz, CDCl3): d = 1.02 (t, J = 7.3 Hz, 3 H, CH3),
1.42 (t, J = 7.3 Hz, 3 H, CH3), 1.59 (m, 2 H, CH2), 1.73 (m, 2 H,
CH2), 2.26 (s, 3 H, CH3CO), 2.64 (t, J = 7.3 Hz, 2 H, C≡CCH2), 4.41
(q, J = 7.3 Hz, 2 H, CO2CH2), 7.72 (d, J = 9.1 Hz, 1 H), 7.99 (s, 1
H, NH), 8.14 (s, 1 H), 8.55 (d, J = 9.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.6, 14.3, 19.6, 22.2, 24.9, 30.8,
61.7, 73.9, 102.9, 108.4, 119.4, 122.5, 129.8, 134.9, 136.9, 137.1,
139.6, 162.6, 168.2.
HRMS (EI): m/z [M]+ calcd for C17H17NO4S: 331.0878; found:
331.0879.
HRMS (EI): m/z [M]+ calcd for C19H21NO3S: 343.1242; found:
343.1242.
Ethyl 5-Acetamido-4-[3-(tetrahydro-2H-pyran-2-yloxy)prop-1-
ynyl]benzo[b]thiophene-2-carboxylate (5f)
Yield: 81%; mp 130 °C.
IR: 3300, 2930, 2220, 1710, 1670 cm–1.
Ethyl 5-Acetamido-4-(phenylethynyl)benzo[b]thiophene-2-car-
boxylate (5a); Typical Procedure by Acetylation of 4a
To a stirred soln of 4a (404 mg, 1.24 mmol) and Et3N (0.19 mL,
1.37 mmol) in CH2Cl2 (10 mL) at 0 °C was added AcCl (106 mg,
1.37 mmol). The mixture was allowed to warm to r.t., stirred for 2.5
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772
W. Van Snick et al.
PAPER
h and then poured into H2O (15 mL). The product was extracted, the
combined organic layers were washed with sat. NaHCO3 (10 mL)
and brine (10 mL) and dried (MgSO4). The mixture was filtered and
evaporated to afford 5a; yield: 443 mg (98%).
Ethyl 5-Acetamido-4-iodobenzo[b]thiophene-2-carboxylate (7)
To a stirred soln of 6 (11.4 g, 43.4 mmol) and NaHCO3 (7.28 g, 86.7
mmol) in CH2Cl2 (320 mL) was added dropwise a soln of ICl
(7.74g, 47.7 mmol) in CH2Cl2 (70 mL). The mixture was stirred at
r.t. for 18 h. The resulting soln was washed with sat. Na2S2O3 (200
mL) and extracted with CH2Cl2 (3 × 200 mL). The combined organ-
ic layers were washed with sat. NaHCO3 (200 mL) and brine (200
mL) and dried (MgSO4). The mixture was filtered and evaporated
to dryness to afford 7 as a brownish solid; yield: 15.4 g (91%); mp
188 °C. The product was used without further purification.
Ethyl 5-Acetamido-4-[(trimethylsilyl)ethynyl]benzo[b]thio-
phene-2-carboxylate (5b)
Following the typical procedure for 5a using 4b (140 mg, 0.441
mmol). The crude product was purified by column chromatography
(silica gel, CH2Cl2–EtOAc, 95:5) to afford 5b; yield: 149 mg (94%).
IR: 3270, 2980, 1700, 1660 cm–1.
Ethyl 5-Acetamido-4-(3-acetoxyprop-1-ynyl)benzo[b]thio-
phene-2-carboxylate (5cc); Acetylation of 4c
1H NMR (400 MHz, CDCl3): d = 1.43 (t, J = 7.3 Hz, 3 H, CH3),
2.30 (s, 3 H, CH3CO), 4.43 (q, J = 7.3 Hz, 2 H, CO2CH2), 7.51 (s, 1
H, NH), 7.78 (d, J = 8.2 Hz, 1 H), 8.08 (s, 1 H), 8.24 (d, J = 8.2 Hz,
1 H).
13C NMR (100 MHz, CDCl3): d = 14.4, 24.8, 62.0, 122.0, 122.3,
123.2, 134.5, 135.3, 136.7, 137.4, 142.3, 162.4, 168.6.
To a stirred soln of 4c (50.0 mg, 182 mmol) and pyridine (32.3 mL,
399 mmol) in CH2Cl2 (4 mL) at 0 °C was added Ac2O (37.7 mL, 399
mmol). The mixture was allowed to warm to r.t., stirred overnight
and then poured into H2O (10 mL). The product was extracted, the
combined organic layers were washed with sat. NaHCO3 (10 mL)
and brine (10 mL) and dried (MgSO4). The mixture was filtered and
evaporated to dryness. The residue was purified by column chroma-
tography (silica gel, CH2Cl2–EtOAc, 95:5) to afford 5cc; yield: 56.0
mg (85%); mp 126 °C.
HRMS (EI): m/z [M]+ calcd for C13H12INO3S: 388.9583; found:
388.9568.
Ethyl 5-(N-Acetylacetamido)-4-iodobenzo[b]thiophene-2-car-
boxylate (8)
IR: 3290, 2990, 2230, 1740, 1700, 1670 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (t, J = 7.3 Hz, 3 H, CH3),
2.18 (s, 3 H, CH3CON), 2.33 (s, 3 H, CH3CO2), 4.42 (q, J = 7.3 Hz,
2 H, CO2CH2), 5.01 (s, 2 H, C≡CCH2), 7.79 (d, J = 9.1 Hz, 1 H),
8.14 (s, 2 H, NH, Ar), 8.60 (d, J = 9.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.5, 21.0, 24.9, 53.2, 61.9, 80.0,
95.2, 106.1, 119.6, 124.2, 129.4, 135.8, 136.9, 139.1, 139.6, 162.6,
169.2, 170.9.
Following the typical procedure for 5a using 2 (2.08 g, 6.0 mmol).
The crude product was purified by column chromatography (silica
gel, CH2Cl2) to afford ethyl 5-acetamido-4-iodobenzo[b]thiophene-
2-carboxylate (7) (1.66 g, 71%) and the doubly acetylated product
ethyl 5-(N-acetylacetamido)-4-iodobenzo[b]thiophene-2-carboxy-
late (8) (677 mg, 26%); mp 168–169 °C.
IR: 2990, 1710, 1690 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.44 (t, J = 7.3 Hz, 3 H, CH3),
2.32 (s, 6 H, Ac2N), 4.44 (q, J = 7.3 Hz, 2 H, CO2CH2), 7.27 (d,
J = 9.1 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 1 H), 8.15 (s, 1 H).
HRMS (EI): m/z [M]+ calcd for C18H17NO5S: 359.0827; found:
359.0835.
13C NMR (75 MHz, CDCl3): d = 14.6, 27.3, 62.4, 99.2, 124.5,
127.6, 134.9, 136.6, 140.3, 141.2, 144.0, 162.3, 172.6.
Ethyl 5-Acetamido-4-(3-hydroxyprop-1-ynyl)benzo[b]thio-
phene-2-carboxylate (5c); Acetylation of 4c Using NaHSO4–
Silica Gel
To a stirred soln of 4c (50.0 mg, 182 mmol) and NaHSO4–silica gel
(18 mg) in CH2Cl2 (4 mL) at 0 °C was added Ac2O (20.5 mL, 218
mmol). The mixture was allowed to warm to r.t. and stirred for 30
min. The mixture was filtered and the filtrate evaporated to dryness.
The residue was purified by column chromatography (silica gel,
EtOAc–petroleum ether, 90:10) to afford 5c; yield: 49.3 mg (69%).
Ethyl (E)-5-[N-(3-Ethoxy-3-oxoprop-1-enyl)acetamido]-4-iodo-
benzo[b]thiophene-2-carboxylate (9)
A mixture of 7 (389 mg, 1 mmol), Pd(PPh3)4 (57.8 mg, 0.05 mmol),
and ZnBr2 (270 mg, 1.20 mmol) in THF (4 mL) was purged with N2.
Et3N (670 mL, 4.80 mmol) and ethyl propynoate (486 mL, 4.8 mmol)
were added. The mixture was stirred at 45 °C for 18 h. After evap-
oration of the solvent, EtOAc (50 mL) and H2O (50 mL) were add-
ed. The mixture was extracted (2 × 50 mL), the combined organic
layers were washed with sat. NaHCO3 (50 mL) and brine (50 mL)
and dried (MgSO4). The mixture was filtered and evaporated to dry-
ness and the residue was purified by column chromatography (silica
gel, CH2Cl2–EtOAc, 80:20 to afford 9; yield: 219 mg (45%); mp
170–171 °C.
Ethyl 5-Acetamidobenzo[b]thiophene-2-carboxylate (6)
To a soln of ethyl 5-aminobenzo[b]thiophene-2-carboxylate (2,
10.6 g, 48.5 mmol) and Et3N (8.1 mL, 93.7 mmol) in CH2Cl2 (400
mL) at 0 °C was added AcCl (4.2 mL, 58.2 mmol). The mixture was
allowed to warm to r.t., stirred for 2.5 h and then poured into H2O
(400 mL). The product was extracted; the combined organic layers
were washed with brine (400 mL), and dried (MgSO4). The mixture
was filtered and evaporated to afford 6 as an off-white solid; yield:
11.4 g (89%); mp 172–174 °C. The product was used without fur-
ther purification.
IR: 3000, 2920, 1700, 1690, 1630 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.3 Hz, 3 H, CH3),
1.46 (t, J = 7.3 Hz, 3 H, CH3), 1.93 (s, 3 H, AcN), 4.15 (q, J = 7.3
Hz, 2 H, CO2CH2), 4.46 (q, J = 7.3 Hz, 2 H, CO2CH2), 7.27 (m, 2
H), 7.96 (d, J = 8.2 Hz, 1 H). 8.18 (s, 1 H), 8.69 (d, J = 14.6 Hz, 1
H).
13C NMR (75 MHz, CDCl3): d = 14.4, 23.6, 60.4, 62.4, 98.1, 102.7,
125.0, 126.9, 134.7, 137.0, 138.7, 140.4, 141.4, 144.2, 162.0, 167.2,
169.0.
IR: 3290, 2980, 1715, 1650 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.41 (t, J = 7.3 Hz, 3 H, CH3),
2.22 (s, 3 H, CH3CO), 4.40 (q, J = 7.3 Hz, 2 H, CO2CH2), 7.34 (s, 1
H, NH), 7.43 (d, J = 8.2 Hz, 1 H), 7.77 (d, J = 8.2 Hz, 1 H), 8.00 (s,
1 H), 8.21 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.5, 24.8, 61.8, 116.1, 120.4,
123.2, 130.4, 135.3, 135.4, 138.1, 139.5, 162.6, 168.5.
Ethyl 4-Iodo-5-(methylsulfonamido)benzo[b]thiophene-2-car-
boxylate (10)
To a soln of 2 (5.0 g, 14.4 mmol) and Et3N (6.0 mL, 43.2 mmol) in
CH2Cl2 (150 mL) at 0 °C was added dropwise a soln of MsCl (2.9
mL, 37.5 mmol) in CH2Cl2 (20 mL). The mixture was stirred at 0 °C
HRMS (EI): m/z [M]+ calcd for C13H13NO3S: 263.0616; found:
263.0613.
Synthesis 2009, No. 5, 767–774 © Thieme Stuttgart · New York

PAPER
A Facile Synthetic Route towards Substituted Thieno[3,2-e]indoles
773
for 30 min and then poured into H2O (200 mL). The product was ex-
tracted and the organic layer was washed with brine (200 mL) and
dried (MgSO4). The mixture was filtered and evaporated to dryness
to afford ethyl 4-iodo-5-[N-(methylsulfonyl)methylsulfonami-
do]benzo[b]thiophene-2-carboxylate (7.0 g). Without purification,
this product (7.0 g, 13.9 mmol) was refluxed together with K2CO3
(2.6 g, 18.7 mmol) in MeCN (100 mL). The mixture was stirred
overnight, then poured into H2O (200 mL), and extracted with
EtOAc (5 × 150 mL). The combined organic layers were washed
with brine (200 mL) and dried (MgSO4). The mixture was filtered
and evaporated to dryness to afford 10 as a brownish solid; yield:
4.5 g (76%); mp 192 °C. The product was used without further pu-
rification.
Ethyl 7-(2-Hydroxyethyl)-6H-thieno[3,2-e]indole-2-carboxy-
late (11e)
Yield: 53%; mp 69–70 °C.
IR: 3410, 3250, 2900, 1670 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (t, J = 7.3 Hz, 3 H, CH3),
1.84 (s, 1 H, OH), 3.09 (m, 2 H, C=CCH2), 4.03 (m, 2 H, CH2O),
4.42 (q, 2 H, CO2CH2), 6.62 (s, 1 H), 7.44 (d, J = 9.1 Hz, 1 H), 7.54
(d, J = 9.1 Hz, 1 H), 8.30 (s, 1 H), 8.89 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.5, 31.2, 61.5, 62.5, 99.6, 112.4,
115.3, 124.0, 128.6, 131.5, 132.4, 133.0, 136.1, 137.3, 163.5.
HRMS (EI): m/z [M]+ calcd for C15H15NO3S: 289.0773; found:
289.0777.
IR: 3250, 2930, 1700, 1370, 1330, 1300, 1280, 1160 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (t, J = 7.3 Hz, 3 H, CH3),
3.02 (s, 3 H, CH3SO2), 4.43 (q, J = 7.3 Hz, 2 H, CO2CH2), 6.75 (s,
1 H, NH), 7.75 (d, J = 8.2 Hz, 1 H), 7.81 (d, J = 8.2 Hz, 1 H), 8.08
(s, 1 H).
Ethyl 7-[(Tetrahydro-2H-pyran-2-yloxy)methyl]-6H-
thieno[3,2-e]indole-2-carboxylate (11f)
Yield: 91%; mp 145 °C.
IR: 3280, 2920, 1690 cm–1.
13C NMR (75 MHz, CDCl3): d = 14.4, 40.5, 62.2, 90.2, 122.5,
1
1H NMR (400 MHz, CDCl3): d = 1.43 (t, J = 5.3 Hz, 3 H, CH3),
124.0, 134.4, 135.9, 136.2, 138.7, 142.8, 162.2.
1.61 (m, 6 H, THP), 3.60 (m, 1 H, THP), 3.97 (m, 1 H, THP), 4.42
(q, J = 5.3 Hz, 2 H, CO2CH2), 4.72 (m, 1 H, THP), 4.87 (dd, J = 9.8,
26.4 Hz, 2 H, OCH2), 6.76 (s, 1 H), 7.48 (d, J = 7.1 Hz, 1 H), 7.57
(d, J = 6.4 Hz, 1 H), 8.33 (s, 1 H), 8.90 (s, 1 H, NH).
HRMS (EI): m/z [M]+ calcd for C12H12INO4S2: 424.9252; found:
424.9243.
13C NMR (100 MHz, CDCl3): d = 14.5, 20.0, 25.4, 30.8, 61.5, 63.1,
63.3, 99.1, 100.7, 112.7, 116.2, 123.8, 128.6, 132.0, 132.8, 133.4,
135.3, 136.2, 163.4.
HRMS (EI): m/z [M]+ calcd for C19H21NO4S: 359.1191; found:
359.1190.
7-Substituted Thienoindoles 11; General Procedure for TBAF-
Mediated Indolization
5-Acetamido-4-ethynylbenzo[b]thiophene 5 (0.25 mmol) was dis-
solved in THF (5 mL). 1 M TBAF in THF (3 equiv) was added, and
the resulting mixture was heated at reflux for 18 h. After completion
of the reaction, THF was evaporated and H2O (10 mL) and EtOAc
(10 mL) were added. The mixture was extracted using EtOAc
(3 × 10 mL) and the combined organic layers were washed with
brine. The mixture was filtered and evaporated and the residue was
purified by column chromatography (silica gel, CH2Cl2–EtOAc) to
afford 11.
Ethyl 7-[1-Methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]-6H-
thieno[3,2-e]indole-2-carboxylate (11g)
Yield: 57%.
IR: 3340, 2920, 1680 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (t, J = 7.3 Hz, 3 H, CH3),
1.69 [m, 12 H, C(CH3)2, THP], 3.40 (m, 1 H, THP), 3.97 (m, 1 H,
THP), 4.42 (q, J = 7.3 Hz, 2 H, CO2CH2), 4.55 (m, 1 H, THP), 6.71
(s, 1 H), 7.48 (d, J = 9.1 Hz, 1 H), 7.57 (d, J = 9.1 Hz, 1 H), 8.35 (s,
1 H), 9.01 (s, 1 H, NH).
HRMS (EI): m/z [M]+ calcd for C21H25NO4S: 387.1504; found:
387.1497.
Ethyl 7-Phenyl-6H-thieno[3,2-e]indole-2-carboxylate (11a)
Yield: 89%; mp 199–201 °C.
IR: 3350, 2900, 1670 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.45 (t, J = 7.3 Hz, 3 H, CH3),
4.43 (q, J = 7.3 Hz, 2 H, CO2CH2), 7.15 (s, 1 H), 7.35 (t, J = 7.3 Hz,
1 H, Ph), 7.47 (t, J = 7.3 Hz, 2 H, Ph), 7.53 (d, J = 9.1 Hz, 1 H), 7.60
(d, J = 9.1 Hz, 1 H), 7.71 (d, J = 7.3 Hz, 2 H, Ph), 8.40 (s, 1 H), 8.72
(s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.6, 61.5, 99.1, 112.5, 116.5,
125.0, 125.3, 128.0, 128.6, 129.3, 131.9, 132.1, 132.9, 133.9, 136.6,
137.8, 163.4.
No further characterization was possible due to the instability of this
product.
Ethyl 7-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-6H-
thieno[3,2-e]indole-2-carboxylate (11h)
Yield: 47%.
IR: 3330, 2920, 2850, 1700 cm–1.
HRMS (EI): m/z [M]+ calcd for C19H15NO2S: 321.0823; found:
321.0824.
1H NMR (300 MHz, CDCl3): d = 1.43 (t, J = 7.3 Hz, 3 H, CH3),
1.70 (m, 6 H, THP), 3.13 (m, 2 H, C=CCH2), 3.52 (m, 1 H, THP),
3.81 (m, 2 H, THP, OCH2), 4.11 (m, 1 H, OCH2), 4.42 (q, J = 7.3
Hz, 2 H, CO2CH2), 4.66 (m, 1 H, THP), 6.59 (s, 1 H), 7.45 (d,
J = 9.1 Hz, 1 H), 7.53 (d, J = 9.1 Hz, 1 H), 8.33 (s, 1 H), 9.00 (s, 1
H, NH).
13C NMR (75 MHz, CDCl3): d = 14.5, 20.1, 25.4, 28.8, 31.0, 61.4,
63.1, 67.4, 99.3, 99.7, 112.4, 115.1, 124.0, 128.7, 131.5, 132.3,
132.9, 136.0, 137.8, 163.5.
Ethyl 6H-Thieno[3,2-e]indole-2-carboxylate (11b)
Yield: 94%; mp 151 °C.
IR: 3290, 2920, 1690 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.44 (t, J = 7.3 Hz, 3 H, CH3),
4.42 (q, J = 7.3 Hz, 2 H, CO2CH2), 6.88 (s, 1 H), 7.31 (s, 1 H), 7.52
(d, J = 9.1 Hz, 1 H), 7.61 (d, J = 9.1 Hz, 1 H), 8.38 (s, 1 H), 8.55 (s,
1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.5, 61.5, 101.8, 112.8, 116.2,
123.5, 124.0, 128.6, 132.1, 132.8, 132.9, 136.3, 163.4.
HRMS (EI): m/z [M]+ calcd for C20H23NO4S: 373.1348; found:
373.1343.
HRMS (EI): m/z [M]+ calcd for C13H11NO2S: 245.0510; found:
245.0511.
Ethyl 7-Butyl-6H-thieno[3,2-e]indole-2-carboxylate (11i)
Yield: 88%; mp 138 °C.
IR: 3360, 3330, 2960, 2930, 1670 cm–1.
Synthesis 2009, No. 5, 767–774 © Thieme Stuttgart · New York

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W. Van Snick et al.
PAPER
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1H NMR (600 MHz, CDCl3): d = 0.97 (t, J = 3.6 Hz, 3 H, CH3),
1.43 (t, J = 3.6 Hz, 3 H, CH3), 1.44 (m, J = 3.6 Hz, 2 H, CH2), 1.75
(m, J = 3.6 Hz, 2 H, CH2), 2.83 (t, J = 3.6 Hz, 2 H, CH2), 4.41 (q,
J = 3.6 Hz, 2 H, CO2CH2), 6.58 (s, 1 H), 7.43 (d, J = 4.4 Hz, 1 H),
7.52 (d, J = 4.4 Hz, 1 H), 8.19 (s, 1 H, NH), 8.32 (s, 1 H).
13C NMR (150 MHz, CDCl3): d = 14.0, 14.6, 22.5, 28.2, 31.6, 61.4,
99.0, 112.2, 115.0, 124.5, 128.7, 131.5, 132.4, 132.6, 136.1, 140.1,
163.5.
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HRMS (EI): m/z [M]+ calcd for C17H19NO2S: 301.1136; found:
301.1128.
Ethyl 7-Vinyl-6H-thieno[3,2-e]indole-2-carboxylate (11j)
Yield: 40%; mp 138 °C.
IR: 3360, 3330, 2920, 1690 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (t, J = 7.3 Hz, 3 H, CH3),
4.42 (q, J = 7.3 Hz, 2 H, CO2CH2), 5.32 (d, J = 11.0 Hz, 1 H,
CH2=C), 5.63 (d, J = 17.4 Hz, 1 H, CH2=C), 6.79 (dd, J = 17.4 Hz,
11.0 Hz, 1 H, CH=C), 6.83 (s, 1 H), 7.46 (d, J = 9.1 Hz, 1 H), 7.59
(d, J = 9.1 Hz, 1 H), 8.33 (s, 1 H), 8.48 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.3, 61.6, 102.0, 112.3, 112.8,
117.0, 124.5, 127.5, 128.5, 132.0, 133.0, 133.6, 136.1, 136.4, 163.3.
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Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1
1999, 529. (b) Hiroya, K.; Jouka, R.; Kameda, M.;
Yasuhara, A.; Sakamoto, T. Tetrahedron 2001, 57, 9697.
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S. P. J. Med. Chem. 2006, 49, 800.
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HRMS (EI): m/z [M]+ calcd for C15H13NO2S: 271.0667; found:
271.0675.
Acknowledgment
The authors are grateful to the F.W.O. and the Katholieke Universi-
teit Leuven for financial support. W.V.S. thanks the IWT [Institute
for the Promotion of Innovation through Science and Technology in
Flanders (IWT-Vlaanderen) for a doctoral fellowship.
(14) Zhang, H.-C.; Ye, H.; Moretto, A. F.; Brumfield, K. K.;
Maryanoff, B. E. Org. Lett. 2000, 2, 89.
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Gao, Z.-G.; Jacobson, K. A. J. Med. Chem. 2007, 50, 1810.
References
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Synthesis 2009, No. 5, 767–774 © Thieme Stuttgart · New York