KF/Al2O3/PEG-400: An efficient catalytic system for the fiesselmann-type synthesis of thiophene derivatives

Article abstract of DOI:10.1055/s-0033-1338299

A simple and mild protocol has been developed for the synthesis of novel steroidal and nonsteroidal thiophene derivatives from β-halo-α, β-unsaturated aldehydes using KF/Al₂O₃/PEG-400 as an efficient catalytic system. The β-halo-α,β-

Full text of DOI:10.1055/s-0033-1338299

PAPER
▌1341
pKapFer /Al2O3/PEG-400: An Efficient Catalytic System for the Fiesselmann-Type
Synthesis of Thiophene Derivatives
Fiesselmann-Type Synthesis of Thiophene Derivatives
Pranjal Bezboruah, Pranjal Gogoi,* Junali Gogoi, Romesh C. Boruah*
Medicinal Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, India
Fax +91(376)2370011; E-mail: gogoipranj@yahoo.co.uk; E-mail: rc_boruah@yahoo.co.in
Received: 01.02.2013; Accepted after revision: 11.03.2013
Fiesselmann thiophene synthesis has been well studied in
Abstract: A simple and mild protocol has been developed for the
the case of ethyl thioglyconate and β-halo-α,β-unsaturated
synthesis of novel steroidal and nonsteroidal thiophene derivatives
aldehydes.12 The formation of the thiophene is known to
take place via a domino process involving Michael addi-
from β-halo-α,β-unsaturated aldehydes using KF/Al2O3/PEG-400
as an efficient catalytic system. The β-halo-α,β-unsaturated alde-
hydes are synthesized from the corresponding ketones using tion, followed by an internal Knoevenagel reaction in the
presence of bases such as sodium in ethanol,13 sodium hy-
Vilsmeier formylation reaction and converted into β-halo-α,β-un-
saturated nitriles. The synthetic protocol is subsequently applied to
the synthesis of 3-aminothiophene derivatives using β-halo-α,β-un-
clo[5.4.0]undec-7-ene (DBU).16 However, most of these
saturated nitriles.
dride,14 pyridine/triethylamine,14,15 and 1,8-diazabicy-
processes have the disadvantage of having stringent reac-
Key words: Fiesselmann synthesis, KF/Al2O3/PEG-400, thio-
phene, unsaturated aldehyde, unsaturated nitrile
tion conditions, such as strongly basic conditions, low re-
action temperatures,14 longer reaction times,14 or use of
toxic pyridine as reaction medium.15
Furthermore, the majority of these synthetic protocols are
Thiophene and its derivatives constitute the core struc-
based on annulations of the thiophene moiety to nonste-
tures of many natural products1 and pharmaceutically
roidal building blocks without adequate emphasis on ste-
active agents,2 and they have become a subject of consid-
roidal systems. On the other hand, the studies on steroidal
erable interest in material chemistry.3 Materials contain-
heterocycles emerge as an important area of research and
ing thiophene core units have been reported to exhibit
enormous efforts have been made in the synthesis of novel
significant lateral dipole moments that help to contribute
heterosteroids because of their inherent biological activi-
to physical parameters such as increased dielectric anisot-
ty.17 To the best of our knowledge, there is only one ex-
ropy and dielectric biaxiality.4 They find commercial ap-
ample available in the literature for the incorporation of a
plications in organic light-emitting diodes, organic field-
thiophene moiety in the steroidal core. For example,
effect transistors, and organic photovoltaic cells.5 In me-
Kumar et al.14 reported the synthesis of A-ring fused ste-
dicinal chemistry, thiophene derivatives are known to ex-
roidal thiophene from a 3-chloro-2-aldehyde and ethyl
hibit biological activity as BACE1 inhibitors,6 anti-
thioglyconate in the presence of pyridine/triethylamine to
inflammatory agents,7 anti-HIV PR inhibitors,8 and anti-
give a mixture of cyclized thiophene product with appre-
breast cancer agent.9 Moreover, thiophene-2-carboxylic
ciable uncyclized intermediate. However, a very strong
acid derivatives are reported as one of the most potent G
base such as sodium hydride in refluxing toluene was em-
protein-coupled receptor 35 (GPR35) agonists.10 Addi-
ployed subsequently to afford the cyclized product from
uncyclized intermediate.
tionally, 3-aminothiophene-2-carboxylic acid and its de-
rivatives are pharmaceutically important precursors, such
Nonetheless, solid-supported recyclable catalysts have
emerging advantages, such as enhanced reactivity, selec-
tivity, mild conditions, avoidance of cumbersome aque-
ous workup conditions, and a decrease in solvent waste.18
The catalyst KF/Al2O3 is an interesting solid-supported
base and well-known green catalytic system, which tends
to replace organic as well as inorganic bases in a variety
of reactions.19 On the other hand, polyethylene glycol
(PEG-400) is a nontoxic, nonvolatile, and recyclable sol-
vent used in organic synthesis.20 In continuation of our re-
search interests on β-halo-α,β-unsaturated aldehydes,21
herein we report KF/Al2O3/PEG-400 as an efficient recy-
clable catalytic system for the Fiesselmann-type synthesis
of steroidal and nonsteroidal thiophenes and their amino
derivatives. This synthetic protocol is a domino process
that involves the reaction of easily accessible A- and D-
ring annulated β-halo-α,β-unsaturated aldehydes with eth-
yl thioglyconate at room temperature. For the synthesis of
as in the synthesis of articaine (Figure 1), which is used
for local dental anesthetic purposes.11
NH
O
NH
OMe
S
O
Figure 1 Local dental anesthetic articanine
SYNTHESIS 2013, 45, 1341–1348
Advanced online publication: 28.03.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338299; Art ID: SS-2013-Z0096-OP
© Georg Thieme Verlag Stuttgart · New York

1342
P. Bezboruah et al.
PAPER
3-aminothiophene derivatives, β-halo-α,β-unsaturated ni- In the absence of a catalyst, the reaction of 1a with 2a did
triles were used as starting substrates, these were derived not proceed (entry 1) and the use of solid-phase KF/Al2O3
from β-halo-α,β-unsaturated aldehydes in a one-pot reac- (40%) afforded a poor yield of the product (entry 2). On
tion.22 The present synthetic protocol utilizes inexpensive the other hand, the KF/Al2O3 catalyzed reaction in aceto-
and readily available KF/Al2O3 as a heterogeneous cata- nitrile and methanol led to good yields of 3a in shorter re-
lyst in the green solvent PEG-400 for the one-step synthe- action times (entries 3 and 4). However, our attempt to
sis of thiophene and its derivatives in high yields (Scheme utilize the recovered KF/Al2O3 afforded uncyclized
1).
Michael adduct 4a as the major product even under the
conditions of enhanced loading capacity of the catalytic
system (entries 6 and 8). When we used PEG-400 as the
reaction media, the thiophene synthesis was efficiently ac-
complished within a short period of time at room temper-
ature (entries 10 and 11). The recovered catalyst could be
used consecutively for another three times to afford prod-
uct 3a in high yield (entries 12–14). Interestingly, the use
of potassium hydroxide (4 molar equiv) in place of the
catalytic system, afforded 3a in 48% yield along with the
mixture of undesired products.
FG
X
S
KF/Al2O3/PEG-400
r.t., stirring
CO2Et
HS
CO2Et
+
2
R
1a–q
3a–q
FG = CHO
FG = CN
R = H
R = NH2
X = Cl or Br
68–97%
Scheme 1 Synthesis of steroidal and nonsteroidal thiophene deriva-
tives
Initially, we chose 1-chloro-3,4-dihydronaphthalene-2-
carbaldehyde (1a) as the starting material to perform the
optimization studies for the products 3a and 4a employing
different catalytic conditions (Table 1).
A series of steroidal and nonsteroidal thiophene deriva-
tives were synthesized under the optimized reaction con-
ditions (Table 2). For the synthesis of D-ring fused
thiophene, a mixture of 3β-acetoxy-17-bromo-16-formyl-
Table 1 Optimization of the Synthesis of Thiophene 3aa
CO2Et
CO2Et
Cl
S
S
CHO
CHO
catalyst
+
+
HS
CO2Et
1a
2
3a
4a
Entry
Catalyst
System
Yieldb (%)
Loading (g)
No. of recycle
3a
4a
c
c
1
2d,e
3
–
–
–
0
0
0
0
1
0
1
0
0
0
1
2
–
–
c
KF/Al2O3
0.2
0.2
0.2
0.5
0.5
0.5
0.5
0.5
0.2
0.5
0.5
0.5
40
57
51
68
10
67
trace
60
71
97
80
77
–
c
KF/Al2O3/MeCN
KF/Al2O3/MeOH
KF/Al2O3/MeCN
KF/Al2O3/MeCN
KF/Al2O3/MeOH
KF/Al2O3/MeOH
KF/Al2O3/THF
KF/Al2O3/PEG-400
KF/Al2O3/PEG-400
KF/Al2O3/PEG-400
KF/Al2O3/PEG-400
–
4
trace
c
5
–
6
61
c
7
–
8
65
15
9
c
10
11
12
13
–
c
–
c
–
c
–
a Reaction conditions: 1a (1.0 mmol), ethyl thioglyconate (1.0 mmol), KF/Al2O3 (40%), solvent (3 mL), r.t., 45 min.
b Isolated yield.
c Not detected.
d Neat.
e Overnight, r.t.
Synthesis 2013, 45, 1341–1348
© Georg Thieme Verlag Stuttgart · New York

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Fiesselmann-Type Synthesis of Thiophene Derivatives
1343
androsta-5,16-diene (1j, 1 mmol) and ethyl thioglyconate yl thioglyconate (2) afforded corresponding thiophenes
(2, 1 mmol) was stirred in the presence of KF/Al2O3 (40%, 3l,m,o, respectively in high yields (entries 11, 12, and 14).
0.5 g) and PEG-400 (3 mL) at room temperature to afford The synthesis of A- and D-ring fused steroidal bisthio-
ethyl 3β-acetoxyandrosta-5,16-dieno[17,16-b]thiophene- phene 3p was accomplished from androst-4-ene-3,17-di-
5′-carboxylate (3j) in 88% yield (entry 9). The product 3j one by initial reduction to androstane-3,17-dione
was characterized by physical and high-resolution spec- followed by Vilsmeier formylation reaction to 3,17-dibro-
tral data. When the same reaction was carried out with a mo-2,16-diformylandrosta-2,16-diene (1p). The reaction
chloro-formyl steroid, for example, 3β-acetoxy-17-chlo- of 1p with two equivalents of ethyl thioglyconate afforded
ro-16-formylandrosta-5,16-diene (1k), we obtained the the desired diethyl androsta-2,16-dieno[3,2-b:17,16-
desired product 3j in 85% yield. However, the chloro-for- b′]bisthiophene-5′,5′′-dicarboxylate (3p) in 75% yield
myl substrate required more reaction time in comparison (entry 15). Similarly, the nonsteroidal β-bromo-α,β-unsat-
to the bromo-formyl substrate (entries 9 and 10). The urated aldehyde analogue, for example, 2-bromocyclo-
starting materials 1j,k were conveniently prepared from hex-1-enecarbaldehyde (1b) reacted with 2 under the
3β-acetoxyandrost-5-en-17-one using the Vilsmeier reac- catalytic conditions to afford ethyl 4,5,6,7-tetrahydroben-
tion.21 Similarly, steroidal A- and D-ring annulated β- zo[b]thiophene-2-carboxylate (3b) in 88% yield. In order
halo-α,β-unsaturated aldehydes 1l,m,o were accom- to broaden the scope of our reaction, we used eight-mem-
plished, respectively, from the Vilsmeier reaction of com- bered and acyclic β-chloro-α,β-unsaturated aldehydes 1d
mercially available estrone and cholesterol. The reaction and 1f to synthesize corresponding thiophene derivatives
of each β-halo-α,β-unsaturated aldehydes 1l,m,o with eth- 3d and 3f in high yields (entries 3 and 5).
Table 2 KF/Al2O3/PEG-400-Catalyzed Synthesis of Steroidal and Nonsteroidal Thiophene Derivatives 3a
FG
S
KF/Al2O3/PEG-400
r.t., stirring
CO2Et
HS
CO2Et
+
X
2
R
3b–q
1b–q
X = Cl or Br
Entry Substrate
Product
Time Yieldb
(min) (%)
CO2Et
R
Br
S
1
2
FG = CHO 1b
FG = CN 1c
R = H 3b
R = NH2 3c 45
30
88
85
FG
Cl
CO2Et
S
FG
3
4
FG = CHO 1d
FG = CN 1e
R = H 3d
R = NH2 3e 90
70
70
68
R
S
Cl
CO2Et
5
6
FG = CHO 1f
FG = CN 1g
R = H 3f
R = NH2 3g 80
60
85
88
FG
R
CO2Et
Br
S
FG
7
8
FG = CHO 1h
FG = CN 1i
R = H 3h
R = NH2 3i
30
50
95
92
R
MeO
MeO
AcO
CO2Et
X
S
CHO
9
10
X = Br 1j
X = Cl 1k
40
90
88
85
3j
H
H
AcO
© Georg Thieme Verlag Stuttgart · New York
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P. Bezboruah et al.
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Table 2 KF/Al2O3/PEG-400-Catalyzed Synthesis of Steroidal and Nonsteroidal Thiophene Derivatives 3a (continued)
FG
X
S
KF/Al2O3/PEG-400
r.t., stirring
CO2Et
HS
CO2Et
+
2
R
1b–q
3b–q
X = Cl or Br
Entry Substrate
Product
Time Yieldb
(min) (%)
CO2Et
Cl
S
CHO
11
1l
3l
70
90
H
H
AcO
AcO
H
H
R
12
13
FG = CHO 1m
R = H 3m
R = NH2 3n 70
50
89
85
FG
FG = CN 1n
H
EtO2C
H
S
Br
H
H
H
H
O
14
1o
3o
70
70
H
EtO2C
H
S
Cl
O
O
CO2Et
Br
S
O
CHO
15
16
1p
1q
3p
3q
90
60
75
80
H
H
EtO2C
H
S
Br
H
H
CO2Et
Cl
S
CHO
O
O
O
O
a Reaction conditions: 1 (1 mmol), 2 (1 mmol), KF/Al2O3 (0.5 g of 40%), PEG-400 (3 mL), r.t.
b Isolated yield.
Ethyl
4-oxo-4H-thieno[3,2-c]chromene-2-carboxylate F– and [Al–OH]. It may be presumed that PEG 400, ad-
(3q) was synthesized from 4-chloro-2-oxo-2H-chromene- sorbed on surface of alumina, may chelate with K+ to form
3-carbaldehyde (1q) in 80% yield. 3-Aminothiophene a chelate cation, with subsequent release of F– as the bal-
derivatives 3c,e,g,i,n were synthesized from β-halo-α,β- ance ion.25 The three basic species generated through a co-
unsaturated nitriles 1c,e,g,i,n that were derived from their operative action of potassium fluoride on the surface of
corresponding β-halo-α,β-unsaturated aldehydes 1b,d,f,h,m, alumina and PEG 400 would take part in Michael addition
respectively (Table 2).
of thioglyconate to β-halo-α,β-unsaturated aldehyde to af-
ford intermediate 4a. The intermediate 4a subsequently
undergoes Knoevenagel condensation under the basic
conditions to form the desired product 3a. To establish the
mechanism, the intermediate 4a was isolated and indepen-
dently treated with KF/Al2O3/PEG-400, to give the final
product 3a in excellent yield.
The mechanism of the basicity of KF/Al2O3 is not clear.
Weinstock et al.23 reported that KF/Al2O3 derives its ba-
sicity from the formation of potassium hydroxide in the
initial preparation of the solid supported material by reac-
tion of potassium fluoride with alumina. However, Ando
et al.24 reported that there are three basic species for the
basicity of KF/Al2O3; (a) the presence of active fluoride, In conclusion, we have developed a simple and mild pro-
(b) [Al–O–] ions that generate OH–, and (c) cooperation of tocol for the synthesis of novel steroidal and nonsteroidal
Synthesis 2013, 45, 1341–1348
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fiesselmann-Type Synthesis of Thiophene Derivatives
IR (CHCl3): 1733, 1706, 1463, 1282, 1263, 1070 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.45 (s, 1 H), 4.32 (q, J = 7.1 Hz,
2 H), 2.76 (t, J = 5.7 Hz, 2 H), 2.61 (t, J = 5.6 Hz, 2 H), 1.82 (m, 4
H), 1.33 (t, J = 7.1 Hz, 3 H).
1345
thiophene derivatives from the reaction of β-halo-α,β-un-
saturated aldehydes using KF/Al2O3/PEG-400 as an effi-
cient catalytic system. In addition, the synthetic strategy is
also highly compatible for the generation of 3-aminothio-
phene derivatives from β-halo-α,β-unsaturated nitriles. 13C NMR (90 MHz, CDCl3): δ = 162.6, 143.9, 136.2, 134.0, 129.4,
60.7, 25.4, 25.3, 23.2, 22.6, 14.1.
MS (ESI): m/z = 210 [M+].
This synthetic protocol is advantageous because of merits
such as high conversions, simplicity of operation, and cost
efficiency, and it can be used for the synthesis of thio-
phene fused steroidal derivatives. Our protocol will facil-
itate the generation of libraries of compounds of potential
biological significance in medicinal chemistry and drug
discovery.
Anal. Calcd for C11H14O2S (210.29): C, 62.83; H, 6.71. Found: C,
62.85; H, 6.74.
Ethyl 3-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carbox-
ylate (3c)
Off-white solid; yield: 191 mg (85%); mp 58–61 °C; Rf = 0.4
(hexanes–EtOAc, 7:3).
IR (CHCl3): 3459, 3359, 2932, 2869, 1666, 1606, 1495, 1445, 1289,
1125, 768 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.34 (br s, 2 H), 4.26 (q, J = 7.1
Hz, 2 H), 2.68 (m, 2 H), 2.31 (m, 2 H), 1.83 (m, 4 H), 1.33 (t, J = 7.1
Hz, 3 H).
13C NMR (90 MHz, CDCl3): δ = 164.9, 152.3, 143.1, 128.8, 97.4,
59.7, 25.6, 22.9, 22.4, 21.7, 14.6.
Melting points were recorded in open capillary (Pyrex) tubes with a
Buchi-540 micro melting point apparatus and are uncorrected. IR
spectra were recorded on a Perkin-Elmer 1640 FT-IR spectropho-
tometer as a thin film using CHCl3 or as a KBr pellet. All NMR
spectra were recorded on Bruker Advance DPX 300 MHz spec-
trometer downfield from TMS (δ = 0.0) using the residual solvent
signal at δ = 7.26 (1H) or δ = 77 (13C) as internal standard. Hydro-
genation reactions were done in a Parr Hydrogenation apparatus
(model: Baldor). ESI-MS (LC) were recorded on a Bruker Daltonic
Data analysis 2-0 spectrometer. EI-MS (GC) were recorded on a
Trace DSQ GC-MS instrument (Thermo Electron, Austria) through
a direct insertion probe (DIP). Elemental analysis was done using
Perkin-Elmer series II CSNS/O Model 2400 machine calibrated
against standard acetanilide. Yields refer to chromatographically
purified compounds, unless otherwise stated.
MS (LCMS): m/z = 227.3 [M+ + 2].
Anal. Calcd for C11H15NO2S (225.31): C, 58.64; H, 6.71; N, 6.22.
Found: C, 58.61; H, 6.74; N, 6.25.
Ethyl 4-Methyl-5-phenylthiophene-2-carboxylate (3d)
Light yellow gum; yield: 172 mg (70%); Rf = 0.45 (hexanes–
EtOAc, 10:1).
IR (CHCl3): 2980, 1706, 1450, 1280, 1244, 1189, 1072, 761, 696
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.61 (s, 1 H), 7.51–7.29 (m, 5 H),
4.35 (q, J = 7.1 Hz, 2 H), 2.30 (s, 3 H), 1.37 (t, J = 7.1 Hz, 3 H).
13C NMR (90 MHz, CDCl3): δ = 162.0, 145.0, 136.6, 133.7, 133.5,
130.6, 128.7, 128.4, 127.9, 60.8, 14.7, 14.1.
Preparation of KF/Al2O3 (40%)
In a 100-mL round-bottom flask, KF (4 g) was dissolved in H2O (25
mL) and neutral alumina (6 g, 100–200 mesh) was added. The mix-
ture was vigorously stirred for 10 min and then H2O was removed
under reduced pressure. The resultant solid KF/Al2O3 was dried at
100 °C for 5 h in an oven and kept in a desiccator.
MS (ESI): m/z = 246 [M+].
Thiophenes 3; General Procedure
A mixture of β-halo-α,β-unsaturated aldehyde (1 mmol, 1 equiv),
ethyl thioglyconate (1 mmol, 1 equiv), and KF/Al2O3 (0.5 g) were
taken in PEG-400 (3 mL) and stirred at r.t. When the reaction was
complete ( (TLC monitoring), the product was extracted with
EtOAc–hexanes (10:90, 3 × 10 mL) and the residue,
KF/Al2O3/PEG-400, was separated and dried under vacuum for re-
use. The upper organic phase was dried and concentrated under re-
duced pressure. The product was purified by column
chromatography.
Anal. Calcd for C14H14O2S (246.32): C, 68.26; H, 5.73. Found: C,
68.21; H, 5.75.
Ethyl 3-Amino-4-methyl-5-phenylthiophene-2-carboxylate (3e)
Colorless gum; yield: 178 mg (68%); Rf = 0.25 (hexanes–EtOAc,
7:3).
IR (CHCl3): 3466, 3362, 2983, 2926, 1736, 1669, 1606, 1444, 1300,
1154, 1026, 758, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.41 (m, 5 H), 5.47 (br s, 2 H),
4.06 (q, J = 7.1 Hz, 2 H), 2.21 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (90 MHz, CDCl3): δ = 168.3, 155.1, 135.2, 129.7, 128.9
(3C), 128.7 (3C), 118.9, 61.6, 18.5, 13.9.
The same experimental procedure was followed for the synthesis of
2-aminothiophene derivatives from β-halo-α,β-unsaturated nitriles.
Ethyl 4,5-Dihydronaphtho[1,2-b]thiophene-2-carboxylate (3a)
White solid; yield: 251 mg (97%); mp 78–81 °C; Rf = 0.6 (hexanes–
EtOAc, 10:1).
MS (ESI): m/z = 259.4 [M+ – 2].
IR (CHCl3): 2934, 1702, 1433, 1272, 1073, 759 cm–1.
Anal. Calcd for C14H15NO2S (261.34): C, 64.34; H, 5.79; N, 5.36.
Found: C, 64.33; H, 5.76; N, 5.38.
1H NMR (300 MHz, CDCl3): δ = 7.51 (s, 1 H), 7.34 (m, 2 H), 7.15
(m, 2 H), 4.27 (q, J = 7.1 Hz, 2 H), 2.87 (m, 2 H), 2.74 (m, 2 H),
1.30 (t, J = 7.1 Hz, 3 H).
13C NMR (90 MHz, CDCl3): δ = 162.5, 143.1, 137.7, 135.4, 133.6,
130.7, 130.5, 128.3 (2 C), 127.2, 123.6, 61.1, 29.7, 23.8, 14.4.
Ethyl 4,5,6,7,8,9-Hexahydrocycloocta[b]thiophene-2-carboxyl-
ate (3f)
Colorless gum; yield: 191 mg (85%); Rf = 0.4 (hexanes–EtOAc,
10:1).
MS (ESI): m/z = 258.1 [M+].
IR (CHCl3): 2927, 2852, 1706, 1556, 1465, 1278, 1248, 1177, 1076,
753 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.39 (s, 1 H), 4.23 (q, J = 7.1 Hz,
2 H), 2.8–2.71 (m, 2 H), 2. 6–2.52 (m, 2 H), 1.56 (m, 8 H), 1.28 (t,
J = 7.1 Hz, 3 H).
13C NMR (90 MHz, CDCl3): δ = 162.4, 147.1, 139.8, 135.1, 128.9,
60.7, 32.0, 30.9, 27.0, 26.9, 25.6, 25.4, 14.3.
Anal. Calcd for C15H14O2S (258.34): C, 69.74; H, 5.46. Found: C,
69.70; H, 5.48.
Ethyl 4,5,6,7-Tetrahydrobenzo[b]thiophene-2-carboxylate (3b)
Light yellow gum; yield: 185 mg (88%); Rf = 0.5 (hexanes–EtOAc,
10:1).
© Georg Thieme Verlag Stuttgart · New York
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1346
P. Bezboruah et al.
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MS (ESI): m/z = 237.9 [M+].
13C NMR (90 MHz, CDCl3): δ = 170.5, 162.7, 162.0, 144.1, 140.0,
133.6, 129.2, 122.0, 73.7, 60.9, 60.7, 50.1, 45.4, 38.1, 36.8 (2C),
35.3, 31.3, 30.8, 28.9, 27.7, 21.4, 20.6, 19.2, 19.1, 14.4.
Anal. Calcd for C13H18O2S (238.35): C, 65.51; H, 7.61. Found: C,
65.55; H, 7.63.
MS (ESI): m/z = 442.2 [M+].
Ethyl 3-Amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophene-2-
carboxylate (3g)
White solid; yield: 210 mg (88%); mp 73–75 °C; Rf = 0.3 (hexanes–
EtOAc, 7:3).
Anal. Calcd for C26H34O4S (442.61): C, 70.55; H, 7.74. Found: C,
70.58; H, 7.71.
Ethyl 3-Acetoxyestra-1,3,5(10),16-tetraeno[17,16-b]thiophene-
5′-carboxylate (3l)
White solid; yield: 382 mg (90%); mp 165–168 °C; Rf = 0.45
(hexanes–EtOAc, 10:1).
IR (CHCl3): 3462, 3359, 2925, 2851, 1666, 1601, 1486, 1304, 1230,
1077, 770 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.39 (br s, 2 H), 4.28 (q, J = 7.0
Hz, 2 H), 2.75 (t, J = 5.8 Hz, 2 H), 2.51 (t, J = 5.9 Hz, 2 H), 1.66 (m,
8 H), 1.33 (t, J = 7.1 Hz, 3 H).
IR (CHCl3): 2933, 2855, 1762, 1702, 1494, 1407, 1204, 1171, 1072,
1014, 753 cm–1.
13C NMR (90 MHz, CDCl3): δ = 164.9, 152.4, 146.1, 128.4, 98.1,
59.8, 32.0, 28.5, 28.1, 26.0, 25.4, 23.6, 14.6.
MS (ESI): m/z = 254.6 [M+ + 1].
1H NMR (300 MHz, CDCl3): δ = 7.58 (s, 1 H), 7.28 (d, J = 8.5 Hz,
1 H), 6.78–6.9 (m, 2 H), 4.33 (q, J = 7.1 Hz, 2 H), 2.8–3 (m, 2 H),
2.74 (dd, J1 = 6.3 Hz, J2 = 14.0 Hz, 1 H), 2.29 (s, 3 H), 1.61 (s, 3 H),
1.43–2.52 (m, 7 H), 1.35 (t, J = 7.1 Hz, 3 H), 1.02 (s, 3 H).
13C NMR (90 MHz, CDCl3): δ = 169.9, 162.7, 162, 148.5, 144.0,
138.0, 137.6, 133.6, 129.3, 126.1, 121.6, 118.7, 60.8, 60.2, 45.8,
44.2, 37.2, 35.4, 29.3, 28.7, 27.3, 26.1, 21.1, 19.3, 14.4.
Anal. Calcd for C13H19NO2S (253.36): C, 61.63; H, 7.56; N, 5.53.
Found: C, 61.65; H, 7.53; N, 5.55.
Ethyl 7-Methoxy-4,5-dihydronaphtho[1,2-b]thiophene-2-car-
boxylate (3h)
Brown solid; yield: 274 mg (95%); mp 72–75 °C; Rf = 0.4
(hexanes–EtOAc, 10:1).
MS (LCMS): m/z = 424.9 [M+ + 1].
Anal. Calcd for C25H28O4S (424.55): C, 70.73; H, 6.65. Found: C,
70.70; H, 6.68.
IR (CHCl3): 2980, 2937, 1702, 1607, 1576, 1451, 1422, 1286, 1248,
1260, 1073, 1035, 752 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.57 (s, 1 H), 7.39–7.31 (m, 1 H),
6.74–6.80 (m, 2 H), 4.35 (q, J = 7.1 Hz, 2 H), 3.82 (s, 3 H), 2.75–
2.98 (m, 4 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (90 MHz, CDCl3): 162.6, 159.7, 143.3, 137.4, 136.0,
133.7, 129.1, 124.9, 123.9, 114.1, 112.2, 60.9, 55.3, 29.4, 23.7,
14.4.
Ethyl Cholest-2-eno[3,2-b]thiophene-5′-carboxylate (3m)
White solid; yield: 444 mg (89%); mp 118–120 °C; Rf = 0.5
(hexanes–EtOAc, 10:1).
IR (CHCl3): 2932, 2868, 1709, 1467, 1280, 1249, 1181, 1067, 753
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.43 (s, 1 H), 4.31 (q, J = 7.1 Hz,
2 H), 1.34 (t, J = 7.1 Hz, 3 H), 0.92 (d, J = 6.5 Hz, 3 H), 0.87 (d,
J = 6.6 Hz, 6 H), 0.74 (s, 3 H), 0.67 (s, 3 H), 2.75–0.96 (m, 29 H).
MS (ESI): m/z = 288 [M+].
13C NMR (90 MHz, CDCl3): δ = 162.6, 142.5, 135.8, 134.5, 129.9,
60.7, 56.3, 56.2, 53.6, 42.4, 42.3, 39.9, 39.7, 39.5, 36.1, 35.7, 35.5
(2 C), 31.6, 28.8, 28.2, 28.0 (2 C), 24.2, 23.8, 22.8, 22.6, 21.0, 18.7,
14.3, 11.9, 11.5.
Anal. Calcd for C16H16O3S (288.36): C, 66.64; H, 5.59. Found: C,
66.61; H, 5.61.
Ethyl 3-Amino-7-methoxy-4,5-dihydronaphtho[1,2-b]thio-
phene-2-carboxylate (3i)
Light yellow solid; yield: 279 mg (92%); mp 127–129 °C; Rf = 0.4
(hexanes–EtOAc, 7:3).
MS (ESI): m/z = 498.3 [M+].
Anal. Calcd for C32H50O2S (498.80): C, 77.05; H, 10.10. Found: C,
77.01; H, 10.12.
IR (CHCl3): 3467, 3359, 2978, 2935, 1733, 1663, 1606, 1578, 1479,
1300, 1251, 1163, 1069, 767 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.34 (d, J = 9.1 Hz, 1 H), 6.72–6.8
(m, 2 H), 5.42 (br s, 2 H), 4.32 (q, J = 7.1 Hz, 2 H), 3.82 (s, 3 H),
2.96 (t, J = 7.7 Hz, 2 H), 2.57 (t, J = 7.7 Hz, 2 H), 1.36 (t, J = 7.1
Hz, 3 H).
13C NMR (90 MHz, CDCl3): δ = 164.9, 159.9, 151.9, 141.4, 137.4,
125.0, 124.93, 123.7, 114.0, 112.0, 98.7, 59.9, 55.3, 28.7, 20.7,
14.6.
Ethyl 4′-Aminocholest-2-eno[3,2-b]thiophene-5′-carboxylate
(3n)
Light yellow solid; yield: 437 mg (85%); mp 83–85 °C; Rf = 0.45
(hexanes–EtOAc, 7:3).
IR (CHCl3): 3459, 2935, 2859, 1666, 1606, 1492, 1370, 1297, 1195,
1095, 1070, 768 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.34 (br s, 2 H), 4.25 (q, J = 7.1
Hz, 2 H), 2.56 (dd, J1 = 4.6 Hz, J2 = 17.6 Hz, 1 H), 2.33 (m, 3 H),
1.59 (s, 3 H), 1.32 (t, J = 7.1 Hz, 3 H), 0.96–2.08 (m, 22 H), 0.93 (d,
J = 6.5 Hz, 3 H), 0.87 (d, J = 6.5 Hz, 6 H), 0.76 (s, 3 H), 0.68 (s, 3
H).
13C NMR (90 MHz, CDCl3): δ = 164.9, 152.6, 141.6, 125.6, 97.9,
59.6, 56.3, 56.2, 53.6, 42.4, 42.2, 39.8, 39.5, 36.9, 36.1, 35.7, 35.5,
35.0, 31.5, 30.0, 28.6, 28.2, 27.9, 24.2, 23.6, 22.8, 22.5, 21.1, 18.6,
14.5, 11.9, 11.6.
MS (ESI): m/z = 304.9 [M+ + 2].
Anal. Calcd for C16H17NO3S (303.38): C, 63.34; H, 5.65; N, 4.62.
Found: C, 63.35; H, 5.68; N, 4.60.
Ethyl 3β-Acetoxyandrosta-5,16-dieno[17,16-b]thiophene-5′-
carboxylate (3j)
Off white solid; yield: 389 mg (88%); mp 138–141 °C; Rf = 0.4
(hexanes–EtOAc, 10:1).
MS (EI): m/z = 513.3 [M+].
IR (CHCl3): 2941, 2854, 1733, 1702, 1407, 1244, 1155, 1031, 773
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.55 (s, 1 H), 5.42 (d, J = 4.8 Hz,
1 H), 4.63 (m, 1 H), 4.34 (q, J = 7.1 Hz, 2 H), 2.64 (dd, J1 = 6.2 Hz,
J2 = 14.2 Hz, 1 H), 2.26–2.45 (m, 3 H), 2.04 (s, 3 H), 1.34 (t, J = 6.9
Hz, 3 H), 1.09 (s, 3 H), 1.02 (s, 3 H), 1.53–2.0 (m, 13 H).
Anal. Calcd for C32H51NO2S (513.82): C, 74.80; H, 10.00; N, 2.73.
Found: C, 74.82; H, 10.04; N, 2.70.
Ethyl 6-Oxocholesta-2,4-dieno[3,2-b]thiophene-5′-carboxylate
(3o)
Yellow solid; yield: 357 mg (70%); mp 144–147 °C; Rf = 0.3
(hexanes–EtOAc, 4:1).
Synthesis 2013, 45, 1341–1348
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fiesselmann-Type Synthesis of Thiophene Derivatives
1347
IR (CHCl3): 2931, 2868, 1709, 1673, 1573, 1530, 1466, 1265, 1237,
1077, 772 cm–1.
Acknowledgement
We acknowledge CSIR, New Delhi for their financial support. One
of us (P.B.) thanks UGC, New Delhi for a Junior Research Fellow-
ship. We are grateful to the Director, CSIR-NEIST, Jorhat for his
keen interests.
1H NMR (300 MHz, CDCl3): δ = 7.57 (s, 1 H), 7.33 (s, 1 H), 4.35
(q, J = 7.1 Hz, 2 H), 2.99 (d, J = 16.2 Hz, 1 H), 2.6–2.72 (m, 1 H),
1.75–2.18 (m, 3 H), 1.36 (t, J = 7.1 Hz, 3 H), 1.04–1.71 (m, 16 H),
1.25 (s, 3 H), 1.0 (s, 3 H), 0.94 (d, J = 6.4 Hz, 3 H), 0.88 (d, J = 6.5
Hz, 6 H), 0.72 (s, 3 H).
13C NMR (90 MHz, CDCl3): δ = 199.2, 162.1, 141.6, 138.6, 138.5,
134.4, 133.4, 124.4, 61.4, 56.5, 56.0, 49.6, 45.5, 42.4, 39.5, 39.3,
38.6, 37.8, 36.1, 35.7, 32.9, 29.7, 28.1, 24.1, 23.8, 22.9, 22.6, 21.3,
18.7, 18.4, 14.4, 11.9.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
MS (LCMS): m/z = 511.6 [M+ + 1].
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Diethyl Androsta-2,16-dieno[3,2-b:17,16-b′]bisthiophene-5′,5′′-
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White solid; yield: 385 mg (75%); mp 144–147 °C; Rf = 0.5
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IR (CHCl3): 2918, 1336, 1705, 1466, 1406, 1282, 1245, 1174, 1071,
1026, 753 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.55 (s, 1 H), 7.44 (s, 1 H), 4.3 (m,
4 H), 2.57–2.77 (m, 3 H), 1.51–2.54 (m, 15 H), 1.34 (t, J = 6.4 Hz,
6 H), 1.01 (s, 3 H), 0.80 (s, 3 H).
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135.6, 134.4, 133.5, 130.1, 129.3, 61.6, 60.8, 53.6, 45.4, 42.4, 41.4,
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67.90; H, 7.05.
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Ethyl 4-Oxo-4H-thieno[3,2-c]chromene-2-carboxylate (3q)
Light brown powder; yield: 219 mg (80%); mp 147–149 °C;
Rf = 0.3 (hexanes–EtOAc, 7:3).
IR (KBr): 3388, 1744, 1715, 1539, 1260, 1122, 741, 605 cm–1.
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132.3, 131.8, 125.3, 125.0, 123.8, 117.7, 116.4, 62.1, 14.3.
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Ethyl 2-[(2-Formyl-3,4-dihydronaphthalen-1-yl)thio]acetate
(4a)
Yellow oil; yield: 180 mg (65%, Table 1, entry 8); Rf = 0.75
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IR (CHCl3): 2982, 1733, 1663, 1551, 1256, 1176, 1029, 769 cm–1.
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131.9, 130.7, 128.3, 127.1, 126.9, 61.6, 36.1, 27.1, 22.2, 14.1.
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65.17; H, 5.81.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1341–1348

1348
P. Bezboruah et al.
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Synthesis 2013, 45, 1341–1348
© Georg Thieme Verlag Stuttgart · New York