Efficient three-component synthesis of tetrahydrothieno[3,2-f]quinolines

Article abstract of DOI:10.1016/j.tet.2011.04.053

An efficient one-pot method for the synthesis of tetrahydrothieno[3,2-f] quinolines is described, using the imino Diels-Alder reaction between ethyl-5-aminobenzothiophene-2-carboxylate, aromatic aldehydes and cyclic enol ethers. Furthermore, hydroxyalkyl-

Full text of DOI:10.1016/j.tet.2011.04.053

Tetrahedron 67 (2011) 4179e4184
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Tetrahedron
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Efficient three-component synthesis of tetrahydrothieno[3,2-f]quinolines
*
Wim Van Snick, Anastasia Parchina, 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 8 March 2011
Received in revised form 8 April 2011
Accepted 15 April 2011
Available online 21 April 2011
An efficient one-pot method for the synthesis of tetrahydrothieno[3,2-f]quinolines is described, using the
imino DielseAlder reaction between ethyl-5-aminobenzothiophene-2-carboxylate, aromatic aldehydes
and cyclic enol ethers. Furthermore, hydroxyalkyl-substituted tetrahydrothieno[3,2-f]quinolines were
synthesized in good yields, by performing the same imino DielseAlder reaction in absence of aldehydes.
The intramolecular aza-DielseAlder reaction of 5-aminobenzothiophene with o-(allyloxy)benzaldehyde
was also performed resulting in the fully oxidized thienoquinoline derivative.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
prepared by the condensation of 2-chloro-4-nitrobenzaldehyde
with ethyl-2-mercaptoacetate, followed by reduction of the nitro
A limited number of methods exists for the synthesis of tetrahy-
drothieno[3,2-f]quinolines. The thermally induced cyclization re-
actionof thienyl-substituted dienamines isone of the most applicable
methods found in literature.1 However, the use of high temperatures
(up to 200 ꢀC) in this procedure is an important drawback and limits
the number of possible substituents. The tetrahydroquinoline moiety
is a widely used scaffold in the synthesis of pharmaceutically relevant
compounds,2 showing a wide range of biological activities, such as
antitumoral,3 antioxidant,4 antimalarial,5 antagonist activity on the
FSH receptor6 and NMDA antagonist activities.7 A variety of
approaches have been developed for the synthesis of this tetrahy-
droquinoline skeleton.2 The [4þ2] cycloaddition between N-aryli-
mines and electron-rich alkenes is probably the most powerful
synthetic tool for the construction of N-containing heterocyclic
compounds, such as tetrahydroquinolines. This imino DielseAlder
reaction (or Povarov reaction)8,9 has been reported to be catalyzed by
various Lewis acid catalysts, such as BiCl3, BF3$Et2O, InCl3, TFA and
p-TsOH.10ꢁ19 Fluorinated alcohols were also reported to promote this
imino DielseAlder reaction.20 Moreover, this imino DielseAlder
method allows the generation of tetrahydroquinoline derivatives
with several degrees of structural diversity.
group.
In this manuscript, we wish to report the synthesis of tetracyclic
tetrahydrothieno[3,2-f]quinolines in moderate to high yields via
the three-component imino DielseAlder reaction of 5-amino-
benzothiophene 1, aromatic aldehyde and cyclic enol ethers
(Scheme 1). In addition, we also performed this imino DielseAlder
reaction in the absence of aldehyde. This resulted in the formation
of alkoxy-substituted tetrahydrothienoquinolines (R¼alkoxy). We
also wish to report the cyclocondensation of the benzothiophene
scaffold 1 with 2-(allyloxy)benzaldehyde, resulting in the fully
unsaturated thienoquinoline derivative.
R
O
H2N
HN
CO2Et
CO2Et
S
S
1
Scheme 1. Synthesis of tetrahydrothieno[3,2-f]quinolines.
Our point of interest goes to the synthesis of 4,5-annulated
benzothiophenes with N-containing heterocycles, thus providing
easy strategies towards the synthesis of (new) benzothiophene
fused structures. Therefore, we use the 5-aminobenzothiophene
scaffold as a starting material. In our preceding work we described
the synthesis of this compound, being ethyl-5-aminobenzothio-
phene-2-carboxylate (1).21 This compound was conveniently
2. Results and discussion
The imino DielseAlder reaction performed herein is a LUMO-
diene-controlled DielseAlder reaction between an electron-deficient
2-azadiene (formed in situ from 1 with an aromatic aldehyde) and
electron-rich dienophiles, such as cyclic enol ethers.10,11 This aza-
DielseAlder reaction was first optimized using benzaldehyde and
3,4-dihydro-2H-pyran (DHP). So, different catalysts and solvents
(acetonitrile and CH2Cl2) were used, as is depicted in Table 1, entries
* Corresponding author. Fax: þ32 (16) 327990; e-mail address: wim.dehaen@
chem.kuleuven.be (W. Dehaen).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.053

4180
W. Van Snick et al. / Tetrahedron 67 (2011) 4179e4184
Table 1
H
4a and H5, as shown in Fig.1. The structures of 2a, both cis and trans,
Varying reaction conditions for reaction of 1 with benzaldehyde and dihydropyran
or dihydrofuran
were also confirmed by COSY, HMQC, HMBC and NOE experiments.
The large coupling constant (11.9 Hz) in the trans isomer in-
dicates that H4a and H5 are in a trans configuration, and thus having
the phenyl group cis towards both protons H4a and H11c, and trans
towards the pyran ring. The cis isomer shows a coupling constant of
5.5 Hz, which depicts the cis configuration between both protons
H4a and H5. In this case, the phenyl group is in a cis configuration
with the pyran ring.
n (0,1)
PhCHO
cat.
Na2SO4
DHP or DHF
Ph
O
H2N
HN
CO2Et
CO2Et
solvent
S
S
Next, we explored this imino DielseAlder reaction of 1 and DHP
with different aromatic aldehydes using the optimized reaction
condition (BiCl3 in acetonitrile). The results of these reactions are
listed in Table 2. From these results we can conclude that reactions
with electron-poor aldehydes run faster and mostly at lower
temperatures and they result in higher yields. Electron-
withdrawing substituents in ortho or para-position lower the
LUMO of the 2-azadiene. This lowers the energy gap between
HOMOdienophile and LUMOazadiene and makes it easier to reach the
transition state.10 The reaction with indole-3-carboxaldehyde did
not result in any product. We want to point out that the use of
aldehydes with electron-withdrawing substituents leads to almost
equal ratios of both isomers (cis/trans). Conversely, aldehydes with
electron-donating substituents give rise to more of the trans iso-
mer (2h,i, Table 2). There is no specific explanation for this dif-
ference in ratios.
2a (n = 1)
3 (n = 0)
1
Entry Catalysta Dienophile Solvent Temperature Time 2a/3,
trans/cisc
(h)
yieldb (%)
1
2
3
4
5
6
7
8
BiCl3
BiCl3
DHP
DHP
CH3CN 60 ꢀC
CH2Cl2 Reflux
CH3CN 25 ꢀC
CH2Cl2 Reflux
CH3CN 60 ꢀC
CH3CN 60 ꢀC
CH3CN 25 ꢀC
CH3CN 25 ꢀC
CH2Cl2 25 ꢀC
CH3CN 25 ꢀC
CH2Cl2 Reflux
1
2a, 90
2a, 71
2a, 72
2a, 40
2a, 43
2a, 58
2a, 54
3, 84
65/35
60/40
55/45
70/30
94/6
70/30
60/40
60/40
60/40
52/48
50/50
3.5
1.5
5
2
2
2
0.5
1.5
BF3$OEt2 DHP
BF3$OEt2 DHP
AlCl3
DHP
p-TsOH DHP
TFA
BiCl3
BiCl3
DHP
DHF
DHF
9
10
11
3, 54
BF3$OEt2 DHF
BF3$OEt2 DHF
25 min 3, 69
3, 73
1
a
Catalyst (10 mol %) is used.
b
c
Yields refer to isolated products.
Product ratio is based on 1H NMR analysis.
Table 2
1e7. Thereafter we performed the same imino DielseAlder reaction
of 5-aminobenzothiophene 1 with benzaldehyde in the presence of
2,3-dihydrofuran (DHF), using either BiCl3 or BF3$Et2O in acetoni-
trile or CH2Cl2 (Table 1, entries 8e11). This resulted for both enol
ethers (DHP and DHF) in the same optimized reaction condition,
being BiCl3 in acetonitrile with yields of 90% and 84% (for 2a and 3,
respectively). It is worth noting that reactions with the more
strained DHF run faster and at lower temperatures than those with
DHP.
Generally, the aza-DielseAlder reaction using asymmetrical an-
ilines can result in mixtures of tetrahydroquinoline isomers, because
of the possible reaction at both ortho-positions.22 In this paper, we
want to point out that 5-aminobenzothiophene 1 solely reacts in the
4-position, resulting in the formation of angular thienoquinoline, as
only product (Scheme 1 and Table 1). So, no linear products, as result
of reaction at the ortho-position 6, were observed.
Results of BiCl3-catalyzed imino DielseAlder reaction of 1 with DHP using different
aldehydes
Substituent-CHO
Temp (ꢀC) Time (h) Yielda (%) trans/cisb
2b 4-Nitrophenyl
2c 4-(Trifluoromethyl)phenyl 25
25
1
57
70
80
70
77
59
51
66
d
51/49
52/48
59/41
65/35
63/37
60/40
91/9
1
2d 2-Chlorophenyl
2e 4-Fluorophenyl
2f 4-Cyanophenyl
2g 2-Furanyl
2h 4-Methoxyphenyl
2i 4-Acetamidophenyl
2j 3-Indolyl
25
60
60
25
60
60
60
1.5
1
0.3
0.5
3
2
48
86/14
d
a
Yields refer to isolated products.
b
Product ratio is based on 1H NMR analysis.
In addition, we performed the imino DielseAlder reaction of 1
with 2-(allyloxy)benzaldehyde (Scheme 2A).9,23,24 In analogy to the
previous results, one should expect to observe the formation of the
tetrahydrothienoquinoline. Nevertheless, we obtained the fully
aromatized thienoquinoline derivative 4. The side product, formed
in this reaction, was the reduced form of the imine-intermediate.
So, it seems likely that the imine behaves as an oxidant of the
final product. The highest possible yield for 4 is the one we ob-
served (34%), because twice the amount of imine is needed in this
oxidation side-reaction. The formation of chromenoquinolines
through DielseAlder cycloaddition has also been reported in liter-
ature.23,24 We tried to block this side-reaction by the addition of
DMSO or DDQ as oxidizing agents, but this was to no avail. We
briefly studied the possibility to convert the synthesized tetrahy-
drothienoquinoline into the fully aromatic thienoquinoline
(Scheme 2B). Using acidic conditions (2 M HCl in acetonitrile),19,25
2a was air-oxidized into 5 with a non-optimized yield of 40%.
As a last part, we performed the imino DielseAlder procedure
without the addition of aldehyde.15ꢁ18,26,27 So, the alkoxy-
substituted tetrahydrothienoquinolines 6 and 7 were prepared as
shown in Table 3. The use of 2 equiv of enol ether, DHP or DHF, and
molecular iodine as catalyst resulted in good yields. In these re-
actions, both cis and trans configurations were formed, with the
trans isomer in excess (about 80%).
This aza-DielseAlder reaction always results in the formation of
two pairs of diastereomers (wavy bond in Table 1), in which the
phenyl-substituent is situated cis or trans towards protons H4a, H11c
or the pyran ring (Fig. 1). Herein, both protons always take a cis
configuration, since the enol ether approaches the azadiene endo or
exo. Moreover, the presence of small coupling constants for protons
H4a and H11c (1.8e2.8 Hz) proves this cis ring junction between the
pyran and the quinoline rings. The relative ratio between both iso-
mers was derived from 1H NMR spectral data, and assigned by
comparison of literature NMR data.10,12,14 The stereochemistry was
determined on the basis of the coupling constants between protons
3
3
11.9 Hz
5.5 Hz
4
4
2
1
2
1
4a H
4a H
H
O
Ph
O
5
Ph
H
HN
H11c
H11c
5
HN
11
11
6
6
CO2Et
CO2Et
10
10
7
7
S
9
S
9
8
8
2a (trans)
2a (cis)
Fig. 1. Coupling constants between H-4a and H-5.

W. Van Snick et al. / Tetrahedron 67 (2011) 4179e4184
4181
good yields with electron-withdrawing and electron-donating ar-
omatic aldehydes. Aromatic thienoquinolines were obtained by
oxidation of the tetrahydroquinoline in acidic medium, and via the
intramolecular aza-DielseAlder reaction with allyloxybenzal-
dehyde. Performing the imino DielseAlder reaction using electron-
rich olefins, without the addition of aldehyde, results in the
formation of alkoxy-substituted tetrahydrothienoquinolines.
O
O
A
BiCl3
Na2SO4
CHO
N
H2N
MeCN
reflux
CO2Et
CO2Et
S
S
1
4 (34%)
3. Experimental section
3.1. General
B
HO
Ph
Melting points (not corrected) were determined using a Reich-
ert Thermovar apparatus. IR spectra were recorded using a Bruker
ALPHA-P spectrometer. 1H and 13C NMR spectroscopy was per-
formed on commercial instruments (Bruker Avance 300 MHz and
Ph
O
2 M HCl
MeCN, RT
HN
N
CO2Et
CO2Et
Bruker AMX 400 MHz) and chemical shifts (d) are reported in parts
per million (ppm) referenced to tetramethylsilane (TMS) (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 resolu-
tion of 10,000). For column chromatography 70e230 mesh silica 60
(E.M. Merck) was used as the stationary phase. Chemicals received
from commercial sources were used without further purification.
The synthetic procedure for the preparation of ethyl 5-aminobenzo
[b]thiophene-2-carboxylate (1) is described in our previous work.21
S
S
2a
5 (40%)
Scheme 2. (A) Intramolecular aza-DielseAlder reaction; (B) aromatization of
tetrahydrothienoquinoline.
Table 3
Imino DielseAlder reaction of 1 with cyclic enol ether
n
n
HO
O
cat.
H2N
HN
DHP
3.2. Typical procedure for the preparation of pyrano[3,2-c]
thieno[3,2-f]quinolines (2)
or DHF
CO2Et
CO2Et
S
S
solvent
1
6 (n = 0)
7 (n = 1)
The aldehyde (1.10 mmol) was added to a mixture of ethyl 5-
aminobenzo[b]thiophene-2-carboxylate (1) (221 mg; 1.00 mmol),
Na2SO4 (284 mg; 2.00 mmol) and BiCl3 (31.5 mg; 10 mol %) in
CH3CN (4 mL). After 15 min stirring at room temperature, DHP
Catalysta
Dienophileb
Solvent
Time (h)
6, 7, Yieldc (%)
trans/cisd
BiCl3
I2
DHF
DHF
DHF
DHP
CH3CN
CH3CN
CH2Cl2
CH3CN
3
2
0.5
3
6, 65
6, 71
6, 76
7, 71
74/26
81/19
86/14
82/18
(120 mL; 1.30 mmol) was added. This mixture was stirred for the
I2
I2
appropriate time and at the temperature, as indicated in Tables 1
and 2. After complete conversion, as indicated by TLC, the solvent
was removed under reduced pressure, diluted with CH2Cl2 and
filtered. The organic layer was washed with water and brine and
dried over MgSO4. The mixture was filtered, evaporated to dryness,
and the residue was purified by column chromatography (silica,
eluent: CH2Cl2) to afford a mixture of both isomers. For some of the
products, the isomers were separated by column chromatography,
using a mixture of petroleum ether and ethyl acetate as eluent. In
case, the isomers were not separated. The 1H NMR data of both
isomers were assigned by comparison with previously synthesized
compounds and based on the relative ratio between both isomers.
e
a
Catalyst (10 mol %) used.
b
c
Dienophile (2.2 equiv) was used.
Yields refer to isolated products.
Product ratio is based on 1H NMR analysis of crude mixture.
I2 (20 mol %) used.
d
e
The relative ratio between both isomers was derived from 1H
NMR spectral data, and assigned by comparison with literature
NMR data.15,16,26,27 In compound 6, the small coupling constant
(5.6e8.0 Hz) for proton H10c shows that the furan and quinoline
rings are cis fused, as both protons H3a and H10c have a cis config-
uration. However, a coupling constant for protons H4 and H3a could
not be derived from the 1H NMR spectrum, making it difficult to
determine the configuration of the isomers. In accordance with
literature data,15,16,26,27 we thus appointed the cis and trans con-
figurations by comparison of the coupling constants for proton H10c
in both isomers. The trans isomer of compound 6 has a coupling
constant JH10c¼5.6 Hz (4.83 ppm), while the corresponding cis
isomer of 6 has a coupling constant JH10c¼8.0 Hz (5.47 ppm). In
addition, compound 7 shows the same analogy with literature,
having a coupling constant JH11c¼5.5 Hz (5.35 ppm) for the cis
isomer and JH11c¼2.3 Hz (4.76 ppm) for the trans isomer.
3.2.1. Ethyl 5-phenyl-3,4,4a,5,6,11c-hexahydro-2H-pyrano[3,2-c]thieno
[3,2-f]quinoline-10-carboxylate (2a). Both isomers were separated by
column chromatography (silica, eluent: petroleum ether/EtOAc (90/
10)) to afford pure products.
trans-2a. Obtained as a yellow solid; mp 158e161 ꢀC; IR: 3359,
3323, 2922, 1712, 1233 cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 1.41 (t,
J¼7.0 Hz, 3H, CH3), 1.64e1.97 (m, 4H, H3 and H4), 2.13 (dd, J¼11.0,
1.8 Hz, 1H, H4a), 3.84 (dt, J¼11.9, 1.8 Hz, 1H, H2), 4.14 (m, 2H, H2 and
H6), 4.39 (q, J¼7.0 Hz, 2H, CO2CH2), 4.76 (d, J¼11.9 Hz,1H, H5), 4.82 (d,
J¼2.8 Hz, 1H, H11c), 6.71 (d, J¼8.6 Hz, 1H, H7), 7.33e7.48 (m, 5H, Ph),
7.53 (d, J¼8.6 Hz, 1H, H8), 8.07 (s, 1H, H11); 13C NMR (100 MHz,
In conclusion, we have reported an efficient procedure for the
synthesis of tetrahydrothieno[3,2-f]quinolines, using the imino
DielseAlder approach. Different catalysts and solvents were ex-
amined and the best results were obtained with BiCl3 in acetoni-
trile. Both isomers (cis/trans) were assigned by analysis of 1H NMR
spectra. Tetrahydrothienoquinolines were obtained in moderate to
CDCl3): d 14.5, 22.0, 24.1, 38.8, 54.9, 61.5, 69.1, 72.2,114.6,117.5,123.5,
127.8,128.1,128.2,128.9,132.8,134.4,139.7,141.9,142.5,163.3; HRMS
(EI): m/z calcd for C23H23O3NS (Mþ): 393.1399; found 393.1385.
cis-2a. Obtained as a yellow solid; mp 162e165 ꢀC; IR: 3387,
2932, 2846, 1698, 1235 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
1.40 (t,
J¼7.3 Hz, 3H, CH3), 1.50e1.75 (m, 4H, H3 and H4), 2.25 (m, 1H, H4a),

4182
W. Van Snick et al. / Tetrahedron 67 (2011) 4179e4184
3.15 (dt, J¼11.0, 1.8 Hz, 1H, H2), 3.62 (dd, J¼10.0, 1.8 Hz, 2H, H2), 3.94
(br s, 1H, H6), 4.37 (q, J¼7.1 Hz, 2H, CO2CH2), 4.66 (d, J¼1.8 Hz, 1H,
H11c), 5.62 (d, J¼5.5 Hz, 1H, H5), 6.79 (d, J¼8.8 Hz, 1H, H7), 7.29e7.49
(m, 5H, Ph), 7.56 (d, J¼8.6 Hz, 1H, H8), 8.56 (s, 1H, H11); 13C NMR
H2 and H6), 4.40 (q, J¼7.1 Hz, 2H, CO2CH2), 4.84 (d, J¼3.0 Hz, 1H,
H11c), 5.32 (d, J¼10.5 Hz, 1H, H5), 6.72 (d, J¼9.1 Hz, 1H, H7),
7.21e7.65 (m, 5H, Ph and H8), 8.09 (s, 1H, H11); cis-2d:
d 1.40 (t,
J¼7.3 Hz, 3H, CH3), 1.76e2.04 (m, 4H, H3 and H4), 2.48 (m, 1H, H4a),
3.15 (t, J¼11.0 Hz, 1H, H2), 3.61 (m, 1H, H2), 3.80 (s, 1H, H6), 4.40 (q,
J¼7.3 Hz, 2H, CO2CH2), 5.05 (d, J¼2.1 Hz, 1H, H11c), 5.65 (d, J¼5.6 Hz,
1H, H5), 6.81 (d, J¼8.2 Hz, 1H, H7), 7.21e7.65 (m, 5H, Ph and H8),
(100 MHz, CDCl3): d 14.5, 18.5, 25.0, 39.1, 59.8, 61.3, 61.5, 73.2, 114.6,
117.6,122.6, 127.0,127.8,128.6, 130.7,134.2,134.3,138.6,141.0,143.4,
163.4; HRMS (EI): m/z calcd for C23H23O3NS (Mþ): 393.1399; found
393.1385.
8.58 (s, 1H, H11); 13C NMR (75 MHz, CDCl3):
d 14.4, 18.6, 22.6, 24.1,
24.9, 35.0, 56.2, 61.1, 61.4, 61.5, 71.9, 72.7, 114.3, 117.4, 122.5, 123.4,
126.6, 127.3, 127.8, 128.4, 129.0, 129.4, 129.9, 130.6, 132.7, 132.9,
134.0, 134.3, 134.4, 135.1, 137.8, 138.5, 139.5, 142.2, 143.3, 163.2,
163.3, 189.9; HRMS (EI): m/z calcd for C23H22O3NSCl (Mþ):
427.1009; found 427.1011.
3.2.2. Ethyl 5-(4-nitrophenyl)-3,4,4a,5,6,11c-hexahydro-2H-pyrano[3,
2-c]thieno[3,2-f]quinoline-10-carboxylate (2b). Both isomers were
separated by column chromatography (silica, eluent: petroleum
ether/EtOAc (80/20)) to afford pure product.
trans-2b. Obtained as a yellow solid; mp 224e231 ꢀC; IR: 3367,
2929, 1711, 1232 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
1.42 (t,
3.2.5. Ethyl 5-(4-fluorophenyl)-3,4,4a,5,6,11c-hexahydro-2H-pyrano
[3,2-c]thieno[3,2-f]quinoline-10-carboxylate (2e). Both isomers
were separated by column chromatography (silica, eluent: petro-
leum ether/EtOAc (80/20)) to afford pure products.
J¼7.1 Hz, 3H, CH3), 1.80 (m, 4H, H3 and H4), 2.15 (d, J¼11.0 Hz, 1H,
H4a), 3.86 (t, J¼11.0 Hz, 1H, H2), 4.16 (m, 2H, H2 and H6), 4.40 (q,
J¼7.1 Hz, 2H, CO2CH2), 4.84 (d, J¼2.8 Hz,1H, H11c), 4.90 (d, J¼11.1 Hz,
1H, H5), 6.77 (d, J¼8.8 Hz, 1H, H7), 7.57 (d, J¼8.6 Hz, 1H, H8), 7.64 (d,
J¼8.6 Hz, 2H, Ph), 8.07 (s, 1H, H11), 8.25 (d, J¼8.6 Hz, 1H, Ph); 13C
trans-2e. Obtained as a yellow solid; mp 206e210 ꢀC; IR: 3379,
2924, 2854, 1682, 1255 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 1.40 (t,
NMR (100 MHz, CDCl3):
d
14.5, 22.0, 24.1, 39.1, 54.7, 61.7, 69.1, 71.9,
J¼7.2 Hz, 3H, CH3), 1.73 (m, 4H, H3 and H4), 2.08 (d, J¼11.3 Hz, 1H,
H4a), 3.85 (dt, J¼11.5 Hz, 2.1 Hz, 1H, H2), 4.14 (m, 2H, H2 and H6),
4.39 (q, J¼7.2 Hz, 2H, CO2CH2), 4.75 (d, J¼11.3 Hz, 1H, H5), 4.81 (d,
J¼2.6 Hz, 1H, H11c), 6.72 (d, J¼8.2 Hz, 1H, H7), 7.07 (m, 2H, Ph), 7.40
(m, 2H, Ph), 7.52 (d, J¼8.2 Hz, 1H, H8), 8.05 (s, 1H, H11); 13C NMR
114.8, 117.5, 123.8, 124.1, 127.6, 129.0, 133.4, 134.8, 139.6, 141.9, 147.9,
149.5, 163.2; HRMS (EI): m/z calcd for C23H22O5N2S (Mþ): 438.1249;
found 438.1254.
cis-2b. Obtained as a yellow solid; mp 228e236 ꢀC; IR: 3364,
2922, 1682, 1234 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
1.42 (t,
(75 MHz, CDCl3): d 14.4, 21.8, 23.9, 29.7, 38.8, 54.1, 61.5, 69.0, 72.0,
J¼7.1 Hz, 3H, CH3), 1.50e1.82 (2 m, 4H, H3 and H4), 2.30 (m, 1H, H4a),
3.18 (t, J¼11.0 Hz, 1H, H2), 3.64 (m, 1H, H2), 3.98 (s, 1H, H6), 4.40 (q,
J¼7.3 Hz, 2H, CO2CH2), 4.79 (d, J¼1.8 Hz, 1H, H11c), 5.64 (d, J¼5.5 Hz,
1H, H5), 6.85 (d, J¼8.6 Hz, 1H, H7), 7.61 (d, J¼8.6 Hz, 1H, H8), 7.64 (d,
J¼8.8 Hz, 2H, Ph), 8.26 (d, J¼8.8 Hz, 2H, Ph), 8.56 (s, 1H, H11); 13C
114.5, 115.5, 115.7, 117.4, 123.5, 127.6, 129.4, 129.5, 132.8, 134.4, 137.4,
137.5, 139.6, 142.3, 160.8, 163.1, 164.1; HRMS (EI): m/z calcd for
C23H22O3NSF (Mþ): 411.1304; found 411.1313.
cis-2e. Obtained as a yellow solid; mp 183e186 ꢀC; IR: 3339,
2936, 2856, 1697, 1221 cmꢁ1 1H NMR (300 MHz, CDCl3):
; d 1.40 (t,
NMR (100 MHz, CDCl3):
d
14.5, 18.7, 24.8, 29.9, 39.0, 59.5, 61.4, 72.9,
J¼7.2 Hz, 3H, CH3), 1.62 (m, 4H, H3 and H4), 2.21 (m, 1H, H4a), 3.15 (t,
J¼11.3 Hz, 1H, H2), 3.61 (d, J¼10.5 Hz, 1H, H2), 3.91 (s, 1H, H6), 4.39
(q, J¼7.2 Hz, 2H, CO2CH2), 4.65 (s, 1H, H11c), 5.60 (d, J¼5.6 Hz, 1H,
H5), 6.80 (d, J¼8.6 Hz,1H, H7), 7.07 (m, 2H, Ph), 7.40 (m, 2H, Ph), 7.57
(d, J¼8.6 Hz, 1H, H8), 8.55 (s, 1H, H11); 13C NMR (75 MHz, CDCl3):
114.8,117.7,123.0,123.8, 127.9,130.5,134.6,134.9,138.6,142.6,147.6,
148.7, 163.3; HRMS (EI): m/z calcd for C23H22O5N2S (Mþ): 438.1249;
found 438.1254.
3.2.3. Ethyl 5-(4-(trifluoromethyl)phenyl)-3,4,4a,5,6,11c-hexahydro-
d 14.5, 18.5, 24.9, 39.1, 59.2, 61.3, 61.5, 73.1, 114.6, 115.2, 115.5, 117.7,
2H-pyrano[3,2-c]thieno[3,2-f]quinoline-10-carboxylate
(2c). The
122.7, 128.5, 128.6, 130.7, 134.2, 134.4, 136.6, 136.7, 138.6, 143.3,
160.6, 163.4, 163.9; HRMS (EI): m/z calcd for C23H22O3NSF (Mþ):
411.1304; found 411.1313.
isomers were not separated. The 1H NMR data of both isomers were
assigned by comparison with previously synthesized compounds
and based on the relative ratio between both isomers. Obtained as
a yellow solid; mp 155e166 ꢀC; IR: 3358, 3329, 2937, 1715, 1686,
3.2.6. Ethyl 5-(4-cyanophenyl)-3,4,4a,5,6,11c-hexahydro-2H-pyrano
[3,2-c]thieno[3,2-f]quinoline-10-carboxylate (2f). The isomers were
not separated. The 1H NMR data of both isomers were assigned by
comparison with previously synthesized compounds and based on
the relative ratio between both isomers. Obtained as a yellowꢁs1olid;
1232 cmꢁ1; 1H NMR (300 MHz, CDCl3): trans-2c:
d
1.38 (t, J¼7.3 Hz,
3H, CH3), 1.40e1.90 (m, 4H, H3 and H4), 2.15 (d, J¼11.0 Hz, 1H, H4a),
3.84 (t, J¼11.0 Hz, 1H, H2), 4.14 (m, 2H, H2 and H6), 4.40 (q, J¼7.1 Hz,
2H, CO2CH2), 4.82 (m, 2H, H5 and H11c), 6.73 (d, J¼8.7 Hz, 1H, H7),
7.57 (m, 5H, Ph and H8), 8.06 (s, 1H, H11); cis-2c:
d
1.38 (t, J¼7.3 Hz,
mp 222e240 ꢀC; IR: 3356, 2945, 2860, 2225, 1709, 1235 cm
;
1H
3H, CH3), 1.40e1.90 (m, 4H, H3 and H4), 2.24 (m, 1H, H4a), 3.15 (t,
J¼11.0 Hz, 1H, H2), 3.62 (m, 1H, H2), 3.96 (s, 1H, H6), 4.40 (q,
J¼7.3 Hz, 2H, CO2CH2), 4.68 (s, 1H, H11c), 5.61 (d, J¼5.5 Hz, 1H, H5),
6.81 (d, J¼8.6 Hz, 1H, H7), 7.57 (m, 5H, Ph and H8), 8.56 (s, 1H, H11);
NMR (300 MHz, CDCl3): trans-2f:
d
1.41 (t, J¼7.3 Hz, 3H, CH3), 1.73
(m, 4H, H3 and H4), 2.10 (d, J¼10.7 Hz, 1H, H4a), 3.85 (t, J¼10.9 Hz,
1H, H2), 4.16 (m, 2H, H2 and H6), 4.40 (q, J¼7.3 Hz, 2H, CO2CH2), 4.80
(m, 2H, H5 and H11c), 6.75 (d, J¼8.2 Hz,1H, H7), 7.52e7.78 (m, 5H, Ph
13C NMR (75 MHz, CDCl3):
d
14.5, 18.4, 22.0, 24.0, 24.9, 31.0, 39.0,
and H8), 8.05 (s,1H, H11); cis-2f:
d
1.41 (t, J¼7.3 Hz, 3H, CH3),1.73 (m,
54.7, 49.4, 61.3, 61.5, 61.6, 69.1, 72.0, 73.0, 114.6, 117.5, 117.7, 122.8,
123.6, 125.4, 125.5, 125.7, 125.8, 126.0, 127.3, 127.7, 128.5, 130.1,
130.2, 130.6, 130.7, 133.1, 134.3, 134.6, 138.5, 139.6, 142.2, 143.0,
145.2, 146.0, 163.2, 163.4; HRMS (EI): m/z calcd for C24H22O3NSF3
(Mþ): 461.1272; found 461.1257.
4H, H3 and H4), 2.25 (m, 1H, H4a), 3.17 (dt, J¼11.3, 1.5 Hz, 1H, H2),
3.62 (dd, J¼11.1,1.9 Hz,1H, H2), 3.98 (s,1H, H6), 4.40 (q, J¼7.3 Hz, 2H,
CO2CH2), 4.67 (s, 1H, H11c), 5.59 (d, J¼5.5 Hz, 1H, H5), 6.82 (d,
J¼8.2 Hz, 1H, H7), 7.52e7.78 (m, 5H, Ph and H8), 8.53 (s, 1H, H11); 13
C
NMR (75 MHz, CDCl3):
d 14.5, 18.5, 22.0, 24.0, 24.7, 28.8, 38.9, 54.8,
59.5, 61.3, 61.5, 61.6, 69.0, 71.9, 72.9, 111.5, 112.0, 114.6, 114.7, 117.5,
117.7, 118.7, 118.8, 122.8, 123.7, 127.6, 127.8, 128.8, 130.5, 132.3, 132.6,
133.2, 134.4, 134.6, 134.7, 138.5, 139.6, 142.0, 142.7, 146.6, 147.5,
163.1, 163.3; HRMS (EI): m/z calcd for C24H22O3N2S (Mþ): 418.1351;
found 418.1350.
3.2.4. Ethyl 5-(2-chlorophenyl)-3,4,4a,5,6,11c-hexahydro-2H-pyrano
[3,2-c]thieno[3,2-f]quinoline-10-carboxylate (2d). The isomers were
not separated. The 1H NMR data of both isomers were assigned by
comparison with previously synthesized compounds and based on
the relative ratio between both isomers. Obtained as a yellow solid;
mp 65e76 ꢀC; IR: 3360, 2936, 2854, 1697, 1231 cmꢁ1
(300 MHz, CDCl3): trans-2d:
(m, 4H, H3 and H4), 2.23 (m, 1H, H4a), 3.80 (m, 1H, H2), 4.09 (m, 2H,
;
1H NMR
3.2.7. Ethyl 5-(furan-2-yl)-3,4,4a,5,6,11c-hexahydro-2H-pyrano[3,2-
c]thieno[3,2-f]quinoline-10-carboxylate (2g). The isomers were not
separated. The 1H NMR data of both isomers were assigned by
d
1.40 (t, J¼7.3 Hz, 3H, CH3), 1.76e2.04

W. Van Snick et al. / Tetrahedron 67 (2011) 4179e4184
4183
comparison with previously synthesized compounds and based on
the relative ratio between both isomers. Mp 62e73 ꢀC; IR: 3367,
2936, 2855, 1699, 1231 cmꢁ1; 1H NMR (300 MHz, CDCl3): trans-2g:
trans-3. Obtained as a yellow solid; mp 164e170 ꢀC; IR: 3362,
2923, 2852, 1693, 1233 cmꢁ1; 1H NMR (400 MHz, CDCl3):
1.41 (t,
d
J¼7.0 Hz, 3H, CH3), 1.76 (m, 1H, H3), 2.07 (m, 1H, H3), 2.54 (m, 1H,
H3a), 3.83 (d, J¼11.1 Hz, 1H, H4), 3.91 (m, 1H, H2), 4.07 (m, 1H, H2),
4.26 (br s, 1H, H5), 4.39 (q, J¼7.0 Hz, 2H, CO2CH2), 4.91 (d, J¼5.0 Hz,
1H, H10c), 6.80 (d, J¼8.6 Hz, 1H, H6), 7.33e7.48 (m, 5H, Ph), 7.57 (d,
J¼8.6 Hz, 1H, H7), 8.21 (s, 1H, H10); 13C NMR (100 MHz, CDCl3):
d
1.39 (t, J¼7.3 Hz, 3H, CH3), 1.52e1.87 (m, 4H, H3 and H4), 2.24 (d,
J¼11.0 Hz, 1H, H4a), 3.78 (t, J¼11.0 Hz, 1H, H2), 4.04e4.17 (m, 2H, H2
and H6), 4.39 (q, J¼7.3 Hz, 2H, CO2CH2), 4.78 (d, J¼2.8 Hz, 2H, H11c),
4.83 (d, J¼11.1 Hz, 2H, H5), 6.34 (m, 2H, furan), 6.74 (d, J¼9.2 Hz, 1H,
H7), 7.39 (m, 1H, furan), 7.51 (d, J¼9.2 Hz, 1H, H8), 8.03 (s, 1H, H11);
d
14.5, 28.8, 43.3, 58.3, 61.6, 65.6, 74.5, 108.8, 114.5, 117.4, 123.2,
cis-2g:
d
1.39 (t, J¼7.3 Hz, 3H, CH3), 1.52e1.87 (m, 4H, H3 and H4),
125.3, 128.5, 128.9, 133.4, 134.8, 140.4, 141.4, 143.1,163.2; HRMS (EI):
m/z calcd for C22H21O3NS (Mþ): 379.1242; found 379.1242.
cis-3. Obtained as a yellow solid; mp 140e143 ꢀC; IR: 3333,
2.39 (m, 1H, H4a), 3.12 (t, J¼10.0 Hz, 1H, H2), 3.58 (d, J¼11.0 Hz, 1H,
H2), 4.05 (br s, 1H, H6), 4.39 (q, J¼7.3 Hz, 2H, CO2CH2), 4.56 (d,
J¼2.1 Hz, 1H, H11c), 5.45 (d, J¼5.5 Hz, 1H, H5), 6.34 (m, 2H, furan),
6.74 (d, J¼9.2 Hz, 1H, H7), 7.39 (m, 1H, furan), 7.51 (d, J¼9.2 Hz, 1H,
2922, 1713 cmꢁ1
;
1H NMR (400 MHz, CDCl3): 1.41 (t, J¼7.3 Hz, 3H,
CH3), 1.58 (m, 1H, H3), 2.27 (m, 1H, H3), 2.91 (m, J¼10.6 Hz, 2.5 Hz,
1H, H3a), 3.78 (m, 2H, H2), 3.92 (s, 1H, H5), 4.40 (q, J¼7.3 Hz, 2H,
CO2CH2), 4.70 (d, J¼2.5 Hz, 1H, H10c), 5.65 (d, J¼8.1 Hz, 1H, H4), 6.79
(d, J¼8.8 Hz, 1H, H6), 7.29e7.54 (m, 5H, Ph), 7.56 (d, J¼8.6 Hz, 1H,
H8), 8.51 (s, 1H, H11); 13C NMR (75 MHz, CDCl3):
d 14.5, 18.5, 22.0,
24.0, 24.7, 28.8, 38.9, 54.8, 59.5, 61.3, 61.5, 61.6, 69.0, 71.9, 72.9,111.5,
112.0, 114.6, 114.7, 117.5, 117.7, 118.7, 118.8, 122.8, 123.7, 127.6, 127.8,
128.8, 130.5, 132.3, 132.6, 133.2, 134.4, 134.6, 134.7, 138.5, 139.6,
142.0, 142.7, 146.6, 147.5, 163.1, 163.3; HRMS (EI): m/z calcd for
C21H21O4NS (Mþ): 383.1191; found 383.1168.
H7), 8.26 (s, 1H, H10); 13C NMR (100 MHz, CDCl3):
d 14.5, 25.0, 46.4,
58.0, 61.5, 67.3, 74.7, 117.1, 117.7, 122.8, 126.7, 127.9, 128.9, 129.3,
134.3, 134.6, 139.6, 142.0, 142.6, 163.3; HRMS (EI): m/z calcd for
C22H21O3NS (Mþ): 379.1242; found 379.1242.
3.2.8. Ethyl 5-(4-methoxyphenyl)-3,4,4a,5,6,11c-hexahydro-2H-pyr-
ano[3,2-c]thieno[3,2-f]quinoline-10-carboxylate (2h). Only 9% of cis
isomer was formed, making it difficult to characterize. Obtained as
a yellow solid; mp 169e182 ꢀC; IR: 3366, 2950, 2833, 1688,
3.4. Ethyl 12H-chromeno[4,3-b]thieno[3,2-f]quinoline-2-
carboxylate (4)
1233 cmꢁ1; trans-2h: 1H NMR (300 MHz, CDCl3):
d
1.40 (t, J¼7.3 Hz,
2-(Allyloxy)benzaldehyde (178 mg; 1.10 mmol) was added to
a solution of ethyl 5-aminobenzo[b]thiophene-2-carboxylate (1)
(221 mg; 1.00 mmol), Na2SO4 (284 mg; 2.00 mmol) and BiCl3
(31.5 mg; 10 mol %) in CH3CN (4 mL). This mixture was refluxed for
48 h. After cooling, the reaction mixture was diluted with CH2Cl2
and washed with water. The combined organic layers were washed
with brine and dried over MgSO4. The mixture was filtered, evap-
orated to dryness, and the residue was purified by column chro-
matography on silica gel using CH2Cl2/petroleum ether (50/50) as
eluent to afford ethyl 12H-chromeno[4,3-b]thieno[3,2-f]quinoline-
2-carboxylate (124 mg, 34%). Mp 170e172 ꢀC; 1H NMR (400 MHz,
3H, CH3), 1.79 (m, 4H, H3 and H4), 2.08 (d, J¼11.8 Hz, 1H, H4a), 3.82
(m, 4H, OCH3, H2), 4.13 (m, 2H, H2 and H6), 4.40 (q, J¼7.3 Hz, 2H,
CO2CH2), 4.70 (d, J¼11.0 Hz,1H, H5), 4.81 (d, J¼2.5 Hz,1H, H11c), 6.69
(d, J¼8.6 Hz, 1H, H7), 6.92 (d, J¼8.7 Hz, 2H, Ph), 7.34 (d, J¼8.6 Hz, 2H,
Ph), 7.51 (d, J¼8.7 Hz, 1H, H8), 8.06 (s, 1H, H11); 13C NMR (75 MHz,
CDCl3): d 14.5, 22.0, 24.1, 28.8, 54.2, 55.4, 61.5, 69.1, 72.3,114.2,114.6,
117.5, 123.5, 127.8, 139.1, 132.7, 133.8, 134.4, 139.7, 142.6, 159.5,
163.2; HRMS (EI): m/z calcd for C24H25O4NS (Mþ): 423.1504; found
423.1487.
3.2.9. Ethyl 5-(4-acetamidophenyl)-3,4,4a,5,6,11c-hexahydro-2H-pyr-
CDCl3):
d
1.45 (t, J¼7.1 Hz, 3H, CH3), 4.44 (q, J¼7.3 Hz, 2H, CO2CH2),
ano[3,2-c]thieno[3,2-f]quinoline-10-carboxylate (2i). Only
a
small
5.42 (s, 1H, CH2), 7.04 (d, J¼8.0 Hz, 1H), 7.17 (t, J¼7.6 Hz, 1H), 7.38 (t,
J¼7.6 Hz, 1H), 8.03 (d, J¼9.1 Hz, 1H), 8.11 (d, J¼9.0 Hz, 1H), 8.29 (s,
1H), 8.47 (d, J¼7.8 Hz, 1H), 8.58 (s, 1H); 13C NMR (100 MHz, CDCl3):
amount of cis isomer was formed, making it difficult to fully char-
acterize. Obtained as a yellow solid; mp 153e166 ꢀC; IR: 3369, 3250,
2926, 2847, 1712, 1230 cmꢁ1; trans-2i: 1H NMR (300 MHz, CDCl3):
d
14.5, 61.9, 68.4, 117.4, 122.7, 123.1, 124.1, 124.2, 125.4, 125.8, 126.7,
d
1.42 (t, J¼7.2 Hz, 3H, CH3), 1.65 (m, 4H, H3 and H4), 2.10 (m, 1H,
127.7, 129.3, 132.0, 134.6, 134.8, 140.8, 147.0, 148.4, 157.2, 162.6;
HRMS (EI): m/z calcd for C21H15O3NS (Mþ): 361.0773; found
361.0782.
H4a), 2.20 (1, 3H, COCH3), 3.84 (t, J¼11.9 Hz, 1H, H2), 4.13 (m, 2H, H2
and H6), 4.39 (q, J¼7.3 Hz, 2H, CO2CH2), 4.75 (d, J¼11.0 Hz, 1H, H5),
4.82 (d, J¼2.6 Hz, 1H, H11c), 6.73 (d, J¼8.2 Hz, 1H, H7), 7.31e7.59 (m,
5H, H8, Ph), 8.06 (s, 1H, H11); 13C NMR (75 MHz, CDCl3):
d
14.5, 21.9,
3.5. Ethyl 8-(3-hydroxypropyl)-7-phenylthieno[3,2-f]
24.0, 24.6, 38.8, 54.3, 61.6, 69.1, 72.2, 114.5, 117.5, 120.3, 123.5, 127.7,
128.5, 132.7, 134.3, 137.6, 137.8, 139.7, 142.5, 163.3, 168.7; HRMS (EI):
m/z calcd for C25H26O4N2S (Mþ): 450.1613; found 450.1604.
quinoline-2-carboxylate (5)
2 N HCl (1.5 mL) was added to a solution of ethyl 5-phenyl-
3,4,4a,5,6,11c-hexahydro-2H-pyrano[3,2-c]thieno[3,2-f]quinoline-
10-carboxylate (2a) (197 mg; 0.50 mmol) in CH3CN (2 mL). This
mixture was refluxed for 2.5 h. After cooling, the reaction mixture
was neutralized with Na2CO3 solution and extracted Et2O. The
organic layer was washed with water and brine 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 ethyl 8-(3-hydrox-
ypropyl)-7-phenylthieno[3,2-f]quinoline-2-carboxylate (78 mg,
3.3. Ethyl 4-phenyl-2,3,3a,4,5,10c-hexahydrofuro[3,2-c]thieno
[3,2-f]quinoline-9-carboxylate (3)
Benzaldehyde (0.11 mL; 1.10 mmol) was added to a mixture of
ethyl 5-aminobenzo[b]thiophene-2-carboxylate (1) (221 mg;
1.00 mmol), Na2SO4 (284 mg; 2.00 mmol) and BiCl3 (31.5 mg;
10 mol %) in CH3CN (4 mL). After 15 min stirring at room temper-
ature, DHF (0.10 mL; 1.30 mmol) was added. This mixture was
stirred for 30 min at room temperature. After complete conversion,
as indicated by TLC, the solvent was diluted with Et2O and filtered.
The organic layer was extracted with water and brine and dried
over MgSO4. The mixture was filtered, evaporated to dryness, and
the residue was purified by column chromatography (silica, eluent:
CH2Cl2) to afford a mixture of both isomers. The isomers were
separated by column chromatography using petroleum ether/
EtOAc (95/5) as eluent to afford pure products.
40%). Mp 141e144 ꢀC; IR: 3324, 3341, 2924, 2853, 1699, 1251 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
1.46 (t, J¼7.2 Hz, 3H, CH3), 1.81 (m, 2H,
CH2), 2.95 (t, J¼7.5 Hz, 2H, CH2), 3.54 (m, J¼6.2 Hz, 2H, CH2), 4.45
(q, J¼7.1 Hz, 2H, CO2CH2), 7.42e7.57 (m, 5H, Ph), 7.98 (d, J¼9.0 Hz,
1H), 8.09 (d, J¼9.0 Hz, 1H, Ph), 8.50 (s, 1H), 8.64 (s, 1H); 13C NMR
(75 MHz, CDCl3):
d 14.5, 29.4, 29.8, 33.6, 61.9, 123.7, 124.3, 127.9,
128.4, 128.6, 128.9, 129.1, 131.9, 134.3, 134.4, 134.5, 140.6, 141.1,
145.0, 159.8, 162.7; HRMS (EI): m/z calcd for C23H21O3NS (Mþ):
391.1242; found 391.1245.

4184
W. Van Snick et al. / Tetrahedron 67 (2011) 4179e4184
3.6. Ethyl 4-(3-hydroxypropyl)-2,3,3a,4,5,10c-hexahydrofuro
[3,2-c]thieno[3,2-f]quinoline-9-carboxylate (6)
H2), 4.02 (m, 1H, H6), 4.40 (q, J¼7.3 Hz, 2H, CO2CH2), 4.76 (d,
J¼2.3 Hz, 1H, H11c), 6.72 (d, J¼8.6 Hz, 1H, H7), 7.50 (d, J¼8.9 Hz, 1H,
H8), 8.05 (s, 1H, H11); 13C NMR (75 MHz, CDCl3):
d 14.5, 21.0, 22.2,
DHF (0.17 mL; 2.20 mmol) and I2 (25.4 mg; 10 mol %) were
added to a solution of ethyl 5-aminobenzo[b]-thiophene-2-car-
boxylate (1) (221 mg; 1.00 mmol) in CH2Cl2 (4.5 mL). This mixture
was stirred for 30 min at room temperature. After complete con-
version, as indicated by TLC, a saturated solution of Na2S2O3
(20 mL) was added, and the mixture was extracted with EtOAc. The
combined organic layers were washed with water and brine 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 (50/50) as eluent to afford a mixture of both
isomers. The cis isomer was obtained as pure product by re-
crystallization from EtOAc. NMR-values of the trans isomer were
determined based on the ratio of both isomers (trans/cis, 86/14).
trans-6. Mp 122e144 ꢀC; IR: 3369, 3280, 2915, 2852, 1695,
24.0, 32.3, 32.9, 36.5, 48.6, 61.5, 62.7, 68.5, 72.3, 114.5, 117.7, 123.3,
127.9, 132.5, 134.2, 139.6, 142.6, 163.3; HRMS (EI): m/z calcd for
C21H27O4NS (Mþ): 389.1661; found 389.1661.
Acknowledgements
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.
References and notes
1254 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
1.40 (t, J¼7.3 Hz, 3H, CH3),
1. Reinhard, R.; Glaser, M.; Neumann, R.; Maas, G. J. Org. Chem. 1997, 62, 7744.
2. Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031.
3. Dorey, G.; Lockhart, B.; Lestage, P.; Casara, P. Bioorg. Med. Chem. Lett. 2000, 10,
935.
4. Wallace, O. B.; Lauwers, K. S.; Dodge, S. A. Bioorg. Med. Chem. Lett. 2003, 13,
1907.
5. (a) Bendale, P.; Olepu, S.; Suryadevara, P. K.; Bulbule, V. J.; Rivas, K.; Nallan, L.;
Smart, B.; Yokoyama, K.; Ankala, S.; Pendyala, P. R.; Floyd, D.; Lombardo, L. J.;
Williams, D. K.; Buckner, F. S.; Chakrabarti, D.; Verlinde, C. L. M. J.; Van Voorhis,
W. C.; Gelb, M. H. J. Med. Chem. 2007, 50, 4585; (b) Bulbule, V. J.; Rivas, K.;
Verlinde, C. L. M. J.; Van Voorhis, W. C.; Gelb, M. H. J. Med. Chem. 2008, 51, 384.
6. (a) van Straten, N. C. R.; van Berkel, T. H. J.; Demont, D. R.; Karstens, W.-J. F.;
Merkx, R.; oosterom, J.; Schulz, J.; van Someren, R. G.; Timmers, C. M.; van
Zandvoort, P. M. J. Med. Chem. 2005, 48, 1697; (b) Manivannan, E.; Prasanna, S.
Bioorg. Med. Chem. Lett. 2005, 15, 4496.
1.57e1.94 (m, 6H, CH2CH2, H3), 2.20 (m, 1H, H3a), 2.83 (dt, J¼8.2,
2.3 Hz, 1H, H4), 3.70 (t, J¼5.5 Hz, 2H, CH2OH), 3.84 (m, 2H, H2, H5),
3.99 (m, 1H, H2), 4.39 (q, J¼7.3 Hz, 2H, CO2CH2), 4.83 (d, J¼5.6 Hz,
1H, H10c), 6.79 (d, J¼8.8 Hz,1H, H6), 7.53 (d, J¼8.8 Hz,1H, H7), 8.17 (s,
1H, H10); 13C NMR (100 MHz, CDCl3):
d 14.5, 28.8, 29.2, 29.8, 41.2,
52.4, 61.5, 62.8, 65.9, 74.2, 117.6, 123.0, 128.7, 133.2, 134.5, 140.2,
142.5, 163.3; MS (CI): m/z¼362 (MHþ).
cis-6. Mp 169 ꢀC; IR: 3479, 3329, 2931, 1685, 1259 cmꢁ1; 1H NMR
(400 MHz, CDCl3): 1.40 (t, J¼7.3 Hz, 3H, CH3), 1.69 (m, 5H, CH2CH2,
H3), 1.92 (m, 1H, H3), 2.08 (m, 1H, H3a), 2.74 (m, 1H, H4), 3.45 (br s,
1H, H5), 3.74 (t, J¼5.5 Hz, 2H, CH2OH), 3.80 (m, 2H, H2), 4.40 (q,
J¼7.3 Hz, 2H, CO2CH2), 5.47 (d, J¼8.0 Hz, 1H, H10c), 6.71 (d, J¼8.6 Hz,
1H, H6), 7.50 (d, J¼8.6 Hz, 1H, H7), 8.22 (s, 1H, H10); 13C NMR
7. Leeson, P. D.; Carling, R. W.; Moore, K. W.; Mosely, A. M.; Smith, J. D.; Stevenson,
G.; Chan, T.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, J. A.; Marshall, G. R.;
Hoogsteen, K. J. Med. Chem. 1992, 35, 1954.
8. Povarov, L. S. Russian Chem. Rev. 1967, 36, 656.
9. Kouznetsov, V. V. Tetrahedron 2009, 65, 2721.
(100 MHz, CDCl3): d 14.5, 24.3, 29.2, 30.8, 43.1, 52.9, 61.5, 62.8, 67.0,
10. Buonora, P.; Olsen, J.-O.; Oh, T. Tetrahedron 2001, 57, 6099.
11. Reddy, B. V. S.; Srinivas, R.; Yadav, J. S.; Ramalingam, T. Synth. Commun. 2001, 31,
1075.
74.5, 117.0, 117.5, 122.6, 129.3, 133.9, 134.4, 139.6, 142.5, 163.3; HRMS
(EI): m/z calcd for C19H23O4NS (Mþ): 361.1348; found 361.1358.
ꢀ
12. Kouznetsov, V. V.; Bohorquez, A. R. R.; Stahenko, E. E. Tetrahedron Lett. 2007, 48,
8855.
3.7. Ethyl 5-(4-hydroxybutyl)-3,4,4a,5,6,11c-hexahydro-2H-
pyrano[3,2-c]thieno[3,2-f]quinoline-10-carboxylate (7)
13. Mahesh, M.; Reddy, C. V.; Reddy, K. S.; Raju, P. V. K.; Reddy, V. V. N. Synth.
Commun. 2004, 34, 4089.
14. Srinivasa, A.; Mahadevan, K. M.; Hosamani, K. M.; Hulikal, V. Monatsh. Chem.
2008, 139, 141.
15. Lin, X.-F.; Cui, S.-L.; Wang, Y.-G. Tetrahedron Lett. 2006, 47, 4509.
16. Yadav, J. S.; Reddy, B. V. S.; Rao, R. S.; Kumar, S. K.; Kunwar, A. C. Tetrahedron
2002, 58, 7891.
DHP (0.20 mL; 2.20 mmol) and I2 (50.8 mg; 20 mol %) were
added to a solution of ethyl 5-aminobenzo[b]-thiophene-2-car-
boxylate (1) (221 mg; 1.00 mmol) in CH3CN (5 mL). This mixture
was stirred for 3 h at room temperature. After complete conversion,
as indicated by TLC, a saturated solution of Na2S2O3 (20 mL) was
added, and the mixture was extracted with EtOAc. The combined
organic layers were washed with water and brine 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 (50/50) as eluent to afford a mixture of both isomers
(trans/cis, 82/18). The isomers were separated by column chro-
matography, using petroleum ether/EtOAc (90/10) as eluent, to af-
ford pure trans isomer. The cis isomer easily oxidized and was thus
not possible to further characterize. trans-7. Obtained as a yellow
solid; mp 53e57 ꢀC; IR: 3369, 2933, 2856,1697,1235 cmꢁ1; 1H NMR
17. Zhang, J.; Li, C.-J. J. Org. Chem. 2002, 67, 3969.
18. Chen, L.; Li, C.-J. Green Chem. 2003, 5, 627.
ꢀ
ꢀ
19. Crousse, B.; Begue, J.-P.; Bonnet-Delpon, D. J. Org. Chem. 2000, 65, 5009.
ꢀ
20. (a) Legros, J.; Crousse, B.; Ourevitch, M.; Bonnet-Delpon, D. Synlett 2006, 1899;
ꢀ
ꢀ
(b) Spanedda, M. V.; Hoang, V. D.; Crousse, B.; Bonnet-Delpon, D.; Begue, J.-P.
Tetrahedron Lett. 2004, 44, 219; (c) De, K.; Legros, J.; Crousse, B.; Chan-
drasekaran, S.; Bonnet-Delpon, D. Org. Biomol. Chem. 2011, 9, 347.
21. (a) Van Snick, W.; Nulens, W.; Jambon, S.; Dehaen, W. Synthesis 2009, 767; (b)
Van Snick, W.; Dehaen, W. Tetrahedron 2009, 65, 8497.
22. Yang, F.; Zheng, L.; Xiang, J.; Dang, Q.; Bai, X. J. Comb. Chem. 2010, 12, 476.
23. Yadav, J. S.; Reddy, B. V. S.; Kondaji, G.; Sowjanya, S.; Nagaiah, K. J. Mol. Catal.
2006, 258, 361.
24. Tomashevskaya, M. M.; Tomashenko, O. A.; Tomashevskii, A. A.; Sokolov, V. V.;
Potekhin, A. A. Russian J. Org. Chem. 2007, 43, 77.
~
ꢀ
25. Sridharan, V.; Avendano, C.; Menendez, J. C. Tetrahedron 2007, 63, 673.
26. Kamal, A.; Prasad, B. R.; Ramana, A. V.; Babu, A. H.; Reddey, K. S. Tetrahedron
Lett. 2004, 45, 3507.
(300 MHz, CDCl3):
d
1.40 (t, J¼7.3 Hz, 3H, CH3), 1.40e1.92 (m, 11H),
2.06 (m, 1H), 3.69 (m, 3H, CH2OH, H2), 3.84 (dt, J¼8.9, 2.3 Hz, 1H,
27. Kamal, A.; Prasad, B. R.; Khan, M. N. J. Mol. Catal. 2007, 274, 133.