Efficient methods for the synthesis of thieno[3,2-b]thiophene and thieno[3,2-b]furan derivatives

Article abstract of DOI:10.1055/s-0029-1217019

A novel approach to the synthesis of thieno[3,2b]thiophenes and thieno[3,2-b]furans bearing various substituents from readily accessible starting materials has been developed. The methodology is based on C- and O-alkylation of ethyl 4-hydroxy-2methylthiop

Full text of DOI:10.1055/s-0029-1217019

PAPER
3803
Efficient Methods for the Synthesis of Thieno[3,2-b]thiophene and
Thieno[3,2-b]furan Derivatives
Synthesis of
T
hien
a
o[3,2-
b
]thio
l
phene
e
s
and Thien
r
o[3,2-
b
]
i
furans i Z. Shirinian,* Alexey A. Shimkin, Stepan N. Tipikin, Mikhail M. Krayushkin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow, Russian Federation
Fax +7(499)1355328; E-mail: shir@ioc.ac.ru
Received 18 June 2009; revised 14 July 2009
CO2Et
Abstract: A novel approach to the synthesis of thieno[3,2-
S
b]thiophenes and thieno[3,2-b]furans bearing various substituents
R
base
O
from readily accessible starting materials has been developed. The
methodology is based on C- and O-alkylation of ethyl 4-hydroxy-2-
methylthiophene-3-carboxylate with a-halo ketones, followed by
cyclization.
X
A
B
S
CO2R'
R
SOCl2
R
Key words: alkylation, cyclization, heterocycles, thienothio-
phenes, thienofurans
CO2H
CO2R'
X
X
X = O, S
HS
A great interest has been concentrated on thieno[3,2-
b]thiophene and thieno[3,2-b]furan derivatives, because
of both their biological activity1,2 and their potential elec-
trooptical properties for use as molecular devices.3–5
These compounds could be used as aryl residues for di-
hetarylethenes that possess good photochromic proper-
ties;6,7 however, research in this area has been impeded by
the lack of efficient synthetic routes to thieno[3,2-
b]thiophene and thieno[3,2-b]furan derivatives. There are
only a few basic methods for the construction of these het-
erocyclic systems.8–10 The most general is intramolecular
cyclization of aldehydes A11,12 which can be synthesized
from 3-bromothiophene (3-bromofuran) derivatives
(Scheme 1). The main limitation of this method is that the
starting 3-bromo-substituted thiophenes or furans are not
easily accessible. Other ways for the preparation of these
heterocyclic compounds are based on the cyclization of
acrylic acid derivatives B13–15 or C.16–18 In the first case,
the reaction of arylacrylic acids (compounds of type B)
with thionyl chloride leads to formation of the substituted
thienothiophene system. For compounds of type C, iodine
or bromine can be used as the cyclizing agent. While these
methods are perfectly suitable, the use of halogenous
compounds for the preparation of thienothiophene and
thienofuran systems often results in the formation of halo-
genated derivatives of the target heterocycles as side prod-
ucts.
[O]
R
X
C
Scheme 1
a-halo ketones, and heterocyclization of the alkylated
products 2 and 3.
The alkylation of hydroxythiophenes, unlike phenols, is
known19 to give mixtures of O- and C-alkylated products.
The direction of the reaction depends on the structure of
the starting hydroxythiophene, the nature of the alkylating
agent, and the base employed.20–22 Recently, we have
found that the alkylation of hydroxythiophene 1 with a-
halo ketones is strongly dependent on the polarity of the
solvent.23 The C-alkylated products 2a–d were obtained
in high yields when the reaction was carried out in ben-
zene in the presence of metallic sodium. The same reac-
tion of hydroxythiophene 1 with a-halo ketones carried
out in N,N-dimethylformamide or acetonitrile with potas-
sium carbonate as a base exclusively gave O-alkylated
compounds 3. The synthesized alkylated products 2 and 3
are useful synthones for the preparation of thiophene-con-
densed heterocycles, and we have now studied in detail
the cyclization process of both alkylated compound types.
The cyclization of compounds 2 to thieno[3,2-b]thio-
phene derivatives 4 was investigated in different solvents
(1,4-dioxane, toluene, benzene, THF, monoglyme, di-
glyme, and p-xylene) using phosphorus pentasulfide or
Lawesson’s reagent as the cyclizing agent. The best re-
sults were achieved by heating ketones 2a–d with Lawes-
son’s reagent in p-xylene at 110–120 °C.
In this work, we present the synthesis of thieno[3,2-
b]thiophene and thieno[3,2-b]furan derivatives starting
from the easily accessible 3-hydroxythiophene
1
(Scheme 2). This approach includes two stages: regiose-
lective C- or O-alkylation of the 3-hydroxythiophene with
In order to synthesize the thieno[3,2-b]furan derivatives 5,
we have studied the heterocyclization of compounds 2 un-
der different conditions. The heating of ketones 2a–d in
polyphosphoric acid or in the melt, as well as using tolu-
ene or xylene as a solvent, gave low yields of thieno[3,2-
SYNTHESIS 2009, No. 22, pp 3803–3806
Advanced online publication: 23.09.2009
DOI: 10.1055/s-0029-1217019; Art ID: Z13009SS
x
x.
x
x
.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

3804
V. Z. Shirinian et al.
PAPER
EtO2C
S
R
Lawesson's
reagent
EtO2C
OH
p-xylene
S
O
Na
4a–d
R
benzene
S
EtO2C
O
R
TsOH
O
2a–d
EtO2C
OH
benzene
X
R
S
5a–d
S
O
1
EtO2C
EtO2C
O
O
K2CO3
DMF
R
Tf2O
benzene
S
S
R
3a–d
6a–d
R = Me (a); Ph (b); 4-ClC6H4 (c); 4-BrC6H4 (d); X = Cl, Br
Scheme 2
corrected. The completion of the reactions was detected using TLC
[Silufol UV-254, elution with petroleum ether (60–80 °C)–EtOAc].
Column chromatography was performed using Merck silica gel
(0.063–0.200 mm). Hydroxythiophene derivatives 2a–d and 3a,d
were prepared by the procedures reported previously.23
b]furans 5. It was found that p-toluenesulfonic acid is an
efficient catalyst for this reaction; thieno[3,2-b]furans 5a–
d were synthesized in good yields by the heterocyclization
of compounds 2a–d in boiling benzene in the presence of
catalytic amounts of p-toluenesulfonic acid.
Alkylated Thiophenes 3; General Procedure
For the cyclization of compounds 3 to thieno[3,2-b]furan
derivatives 6, we have tested various acids and anhydrides
(sulfuric acid, polyphosphoric acid, and acetic, trifluoro-
acetic and trifluoromethanesulfonic anhydride) as cycliz-
ing agents and anhydrous ethanol or benzene as solvent.
The reaction of thiophenes 3a–d with a catalytic amount
of sulfuric acid in ethanol at 5–10 °C leads to an insepara-
ble complex mixture. Considerably better results were ob-
tained when the reaction was carried out in benzene in the
presence of a catalytic amount of trifluoromethanesulfon-
ic anhydride, and the thieno[3,2-b]furans 6a–d were pre-
pared in high yields.
To a stirred mixture of ethyl 4-hydroxy-2-methylthiophene-3-car-
boxylate (1; 1.86 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) in
DMF (10 mL), a soln of a 2-bromoacetophenone (10.5 mmol) in
DMF (3 mL) was added dropwise at 5–10 °C. The reaction mixture
was stirred at 20–25 °C until the starting hydroxythiophene 1 com-
pletely disappeared; the progress of the reaction was monitored by
TLC (petroleum ether–EtOAc, 6:1). The mixture was poured onto
ice, the product was extracted with EtOAc (3 × 50 mL), and the ex-
tract was washed with brine (30 mL) and dried (anhyd MgSO4). The
solvent was removed, and the residue was purified by column chro-
matography (petroleum ether–EtOAc, 6:1).
Ethyl 2-Methyl-4-(2-oxo-2-phenylethoxy)thiophene-3-carboxy-
late (3b)
Yield: 1.21 g (40%); yellowish powder; mp 56–57 °C.
The structures of the synthesized compounds were proved
1
by H NMR spectroscopy and mass spectrometry, and
1H NMR (250 MHz, CDCl3): d = 1.35 (t, J = 7.3 Hz, 3 H, CH2CH3),
2.61 (s, 3 H, CH3), 4.32 (q, J = 7.3 Hz, 2 H, CH2CH3), 5.21 (s, 2 H,
OCH2CO), 6.06 (s, 1 H, Hthioph), 7.42–7.63 (m, 3 H, Harom), 8.02 (d,
J = 7.3 Hz, 2 H, Harom).
13C NMR (75 MHz, CDCl3): d = 14.21, 16.86, 60.33, 73.63
(OCH2CO), 96.48 (CHthioph), 120.57, 128.45 (CHarom), 128.67
(CHarom), 133.79 (CHarom), 134.58, 148.06, 155.04, 162.94, 194.65
(OCH2CO).
confirmed by elemental analysis. The signals of the
1
thiophene and furan aromatic protons in the H NMR
spectra of the compounds containing aryl substituents,
4b,c,d–6b,c,d, are shifted downfield by 0.5–0.65 ppm rel-
ative to the methyl derivatives 4a–6a. The significant dif-
1
ference in the H NMR chemical shifts of the furan
aromatic protons (about 1 ppm) between the 2- and 3-sub-
stituted thieno[3,2-b]furans 5 and 6 is also noteworthy.
MS (EI, 70 eV): m/z (%) = 304 (34) [M+], 105 (100).
In summary, we have developed efficient methods for the
synthesis of thieno[3,2-b]thiophenes and thieno[3,2-
b]furans starting from the readily accessible ethyl 4-hy-
droxy-2-methylthiophene-3-carboxylate. Previously un-
known thienothiophene and thienofuran derivatives
bearing various substituents were synthesized, com-
pounds that are otherwise hard to obtain.
Anal. Calcd for C16H16O4S: C, 63.14; H, 5.30; S, 10.54. Found: C,
63.23; H, 5.40; S, 10.46.
Ethyl 4-[2-(4-Chlorophenyl)-2-oxoethoxy]-2-methylthiophene-
3-carboxylate (3c)
Yield: 2.16 g (64%); yellowish powder; mp 81–82 °C.
1H NMR (250 MHz, CDCl3): d = 1.36 (t, J = 7.3 Hz, 3 H, CH2CH3),
2.62 (s, 3 H, CH3), 4.33 (q, J = 7.3 Hz, 2 H, CH2CH3), 5.14 (s, 2 H,
OCH2CO), 6.09 (s, 1 H, Hthioph), 7.45 (d, J = 7.3 Hz, 2 H, Harom),
8.08 (d, J = 7.3 Hz, 2 H, Harom).
1H and 13C NMR spectra were recorded in CDCl3 on Bruker WM-
250 and AM-300 spectrometers. Mass spectra (MS) were recorded
on a Kratos instrument at 70 eV using electron impact (EI). Melting
points were measured on a Boetius hot-stage apparatus and are un-
MS (EI, 70 eV): m/z (%) = 338/340 (20/10) [M+], 139/141 (100/53).
Synthesis 2009, No. 22, 3803–3806 © Thieme Stuttgart · New York

PAPER
Synthesis of Thieno[3,2-b]thiophenes and Thieno[3,2-b]furans
3805
Anal. Calcd for C16H15ClO4S: C, 56.72; H, 4.46; S, 9.46. Found: C,
56.62; H, 4.53; S, 9.30.
cooled, the solvent was evaporated, and the residue was purified by
column chromatography (petroleum ether–EtOAc, 5:1).
Thieno[3,2-b]thiophenes 4; General Procedure
Ethyl 2,5-Dimethylthieno[3,2-b]furan-6-carboxylate (5a)
Yield: 0.55 g (30%); mp 66–68 °C.
1H NMR (250 MHz, CDCl3): d = 1.45 (t, J = 7.2 Hz, 3 H, CH2CH3),
2.46 (s, 3 H, CH3), 2.78 (s, 3 H, CH3), 4.41 (q, J = 7.3 Hz, 2 H,
CH2CH3), 6.27 (s, 1 H, Hfuran).
To a hot soln (70–80 °C) of a hydroxythiophene 2 (8.2 mmol) in p-
xylene (20 mL), Lawesson’s reagent (6.63 g, 16.4 mmol) was added
in several portions with stirring. The reaction mixture was heated at
110–120 °C until the starting compound completely disappeared;
the progress of the reaction was monitored by TLC (petroleum
ether–EtOAc, 5:1). The reaction mixture was cooled, the solvent
was removed under reduced pressure, and the crude product was pu-
rified by column chromatography (petroleum ether–EtOAc, 5:1).
MS (EI, 70 eV): m/z (%) = 224 (69) [M+], 195 (100) [M+ – Et].
Anal. Calcd for C11H12O3S: C, 58.91; H, 5.39. Found: C, 58.51; H,
5.29.
Ethyl 2,5-Dimethylthieno[3,2-b]thiophene-3-carboxylate (4a)
Yield: 1.06 g (56%); mp 85–87 °C.
Ethyl 5-Methyl-2-phenylthieno[3,2-b]furan-6-carboxylate (5b)
Yield: 1.36 g (58%); mp 83–85 °C.
1H NMR (250 MHz, CDCl3): d = 1.44 (t, J = 7.2 Hz, 3 H, CH2CH3),
2.55 (s, 3 H, CH3), 2.82 (s, 3 H, CH3), 4.39 (q, J = 7.2 Hz, 2 H,
CH2CH3), 6.81 (s, 1 H, Hthioph).
1H NMR (300 MHz, CDCl3): d = 1.49 (t, J = 7.4 Hz, 3 H, CH2CH3),
2.83 (s, 3 H, CH3), 4.45 (q, J = 7.4 Hz, 2 H, CH2CH3), 6.92 (s, 1 H,
Hfuran), 7.29 (t, J = 7.4 Hz, 1 H, Harom), 7.42 (t, J = 7.4 Hz, 2 H,
Harom), 7.76 (d, J = 7.4 Hz, 2 H, Harom).
MS (EI, 70 eV): m/z (%) = 240 (83) [M+], 211 (100) [M+ – Et].
13C NMR (75 MHz, CDCl3): d = 14.49, 17.16, 60.59, 100.48
(CHfuran), 114.25, 120.83, 123.96 (CHarom), 127.83 (CHarom), 128.83
(CHarom), 130.92, 149.91, 155.12, 156.89, 162.24 (CO2Et).
Anal. Calcd for C11H12O2S2: C, 54.97; H, 5.03; S, 26.68. Found: C,
54.78; H, 5.08; S, 26.40.
MS (EI, 70 eV): m/z (%) = 286 (59) [M+], 257 (100) [M+ – Et].
Ethyl 2-Methyl-5-phenylthieno[3,2-b]thiophene-3-carboxylate
(4b)
Yield: 1.33 g (54%); mp 69–71 °C.
1H NMR (250 MHz, CDCl3): d = 1.49 (t, J = 7.2 Hz, 3 H, CH2CH3),
2.86 (s, 3 H, CH3), 4.44 (q, J = 7.2 Hz, 2 H, CH2CH3), 7.27–7.45 (m,
4 H, 3 × Harom and Hthioph), 7.65 (d, J = 7.1 Hz, 2 H, Harom).
Anal. Calcd for C16H14O3S: C, 67.11; H, 4.93; S, 11.20. Found: C,
67.31; H, 5.01; S, 10.96.
Ethyl 2-(4-Chlorophenyl)-5-methylthieno[3,2-b]furan-6-car-
boxylate (5c)
Yield: 1.62 g (62%); mp 77–79 °C.
MS (EI, 70 eV): m/z (%) = 302 (97) [M+], 273 (100) [M+ – Et].
1H NMR (300 MHz, CDCl3): d = 1.48 (t, J = 7.2 Hz, 3 H, CH2CH3),
2.82 (s, 3 H, CH3), 4.44 (q, J = 7.2 Hz, 2 H, CH2CH3), 6.90 (s, 1 H,
Hfuran), 7.37 (d, J = 8.5 Hz, 2 H, Harom), 7.67 (d, J = 8.5 Hz, 2 H,
Harom).
Anal. Calcd for C16H14O2S2: C, 63.55; H, 4.67; S, 21.21. Found: C,
63.59; H, 4.76; S, 20.86.
Ethyl 5-(4-Chlorophenyl)-2-methylthieno[3,2-b]thiophene-3-
carboxylate (4c)
Yield: 0.91 g (33%); mp 86–88 °C.
MS (EI, 70 eV): m/z (%) = 320/322 (52/19) [M+], 291/293 (100/33)
[M+ – Et].
1H NMR (250 MHz, CDCl3): d = 1.48 (t, J = 7.3 Hz, 3 H, CH2CH3),
2.87 (s, 3 H, CH3), 4.44 (q, J = 7.3 Hz, 2 H, CH2CH3), 7.35–7.45 (m,
3 H, 2 × Harom and Hthioph), 7.57 (d, J = 7.4 Hz, 2 H, Harom).
Anal. Calcd for C16H13ClO3S: C, 59.91; H, 4.08; S, 10.00. Found:
C, 60.06; H, 4.15; S, 9.69.
MS (EI, 70 eV): m/z (%) = 336/338 (97/52) [M+], 307/309 (100/40)
Ethyl 2-(4-Bromophenyl)-5-methylthieno[3,2-b]furan-6-car-
boxylate (5d)
Yield: 1.61 g (54%); mp 79–81 °C.
1H NMR (250 MHz, CDCl3): d = 1.48 (t, J = 7.2 Hz, 3 H, CH2CH3),
2.81 (s, 3 H, CH3), 4.44 (q, J = 7.2 Hz, 2 H, CH2CH3), 6.90 (s, 1 H,
Hfuran), 7.47–7.65 (m, 4 H, Harom).
[M+ – Et].
Anal. Calcd for C16H13ClO2S2: C, 57.05; H, 3.89; S, 19.04. Found:
C, 57.09; H, 4.01; S, 18.86.
Ethyl 5-(4-Bromophenyl)-2-methylthieno[3,2-b]thiophene-3-
carboxylate (4d)
Yield: 1.72 g (55%); mp 112–114 °C.
1H NMR (250 MHz, CDCl3): d = 1.47 (t, J = 7.3 Hz, 3 H, CH2CH3),
2.85 (s, 3 H, CH3), 4.44 (q, J = 7.3 Hz, 2 H, CH2CH3), 7.33 (s, 1 H,
Hthioph), 7.42–7.55 (m, 4 H, Harom).
13C NMR (75 MHz, CDCl3): d = 14.51, 16.80, 60.93, 114.92,
115.02 (CHthioph), 121.56, 127.16 (CHarom), 132.07 (CHarom),
133.69, 134.41, 139.21, 144.62, 151.94, 162.93.
MS (EI, 70 eV): m/z (%) = 364/366 (100/98) [M+].
Anal. Calcd for C16H13BrO3S: C, 52.62; H, 3.59; S, 8.78. Found: C,
52.21; H, 3.66; S, 8.54.
3-Substituted Thieno[3,2-b]furans 6; General Procedure
To a stirred soln of an alkylated thiophene 3 (8.2 mmol) in benzene
(20 mL), trifluoromethanesulfonic anhydride (5 drops) was added at
r.t. After 5–10 min, the reaction mixture was poured into H2O (100
mL) and extracted with EtOAc (3 × 50 mL). The extract was
washed with dilute NaHCO3 soln (50 mL) and brine (50 mL), and
dried (anhyd MgSO4). The solvent was removed, and the residue
was purified by column chromatography (petroleum ether–EtOAc,
5:1).
MS (EI, 70 eV): m/z (%) = 380/382 (100/97) [M+].
Anal. Calcd for C16H13BrO2S2: C, 50.40; H, 3.44; S, 16.82. Found:
C, 50.45; H, 3.49; S, 16.52.
2-Substituted Thieno[3,2-b]furans 5; General Procedure
To a soln of a hydroxythiophene 2 (8.2 mmol) in benzene (15 mL),
p-toluenesulfonic acid (0.16 g, 0.82 mmol) was added, and the re-
action mixture was refluxed until the starting compound completely
disappeared. The progress of the reaction was monitored by TLC
(petroleum ether–EtOAc, 5:1). After the reaction mixture was
Ethyl 3,5-Dimethylthieno[3,2-b]furan-6-carboxylate (6a)
Yield: 1.56 g (85%); viscous oil.
1H NMR (250 MHz, CDCl3): d = 1.42 (t, J = 7.2 Hz, 3 H, CH2CH3),
2.17 (s, 3 H, CH3), 2.80 (s, 3 H, CH3), 4.41 (q, J = 7.3 Hz, 2 H,
CH2CH3), 7.34 (s, 1 H, Hfuran).
Synthesis 2009, No. 22, 3803–3806 © Thieme Stuttgart · New York

3806
V. Z. Shirinian et al.
PAPER
MS (EI, 70 eV): m/z (%) = 224 (58) [M+], 195 (100) [M+ – Et].
Homnick, C. F.; Holahan, M. A.; Libby, L. A.; Sitko, G. R.;
Straniert, M. T.; Vassalo, L. M. J. Med. Chem. 1999, 42,
2409.
Anal. Calcd for C11H12O3S: C, 58.91; H, 5.39. Found: C, 58.65; H,
5.31.
(3) Blenkle, M.; Boldt, P.; Bräuchle, C.; Grahn, W.; Ledoux, I.;
Nerenz, H.; Stadler, S.; Wichern, J.; Zyss, J. J. Chem. Soc.,
Perkin Trans. 2 1996, 1377.
(4) Rutherford, D. R.; Stille, J. K.; Elliott, C. M.; Reichert, V. R.
Macromolecules 1992, 25, 2294.
Ethyl 5-Methyl-3-phenylthieno[3,2-b]furan-6-carboxylate (6b)
Yield: 2.20 g (94%); mp 84–86 °C.
1H NMR (250 MHz, CDCl3): d = 1.45 (t, J = 7.2 Hz, 3 H, CH2CH3),
2.85 (s, 3 H, CH3), 4.44 (q, J = 7.2 Hz, 2 H, CH2CH3), 7.32 (t,
J = 7.2 Hz, 1 H, Harom), 7.44 (t, J = 7.2 Hz, 2 H, Harom), 7.56 (d,
J = 7.2 Hz, 2 H, Harom), 7.89 (s, 1 H, Hfuran).
(5) Pihera, P.; Dvořáková, H.; Svoboda, J. Collect. Czech.
Chem. Commun. 1999, 64, 389.
(6) Strokach, Yu. P.; Valova, T. M.; Golotyuk, Z. O.;
Barachevsky, V. A.; Kuznetsova, O. Yu.; Yarovenko, V. N.;
Semenov, S. L.; Zavarzin, I. V.; Shirinian, V. Z.;
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Shirinian, V.; Krayushkin, M. Macromol. Chem. Phys.
2006, 207, 770.
MS (EI, 70 eV): m/z (%) = 286 (77) [M+], 257 (100) [M+ – Et].
Anal. Calcd for C16H14O3S: C, 67.11; H, 4.93. Found: C, 66.78; H,
5.01.
Ethyl 3-(4-Chlorophenyl)-5-methylthieno[3,2-b]furan-6-car-
boxylate (6c)
Yield: 2.36 g (90%); mp 130–132 °C.
1H NMR (250 MHz, CDCl3): d = 1.44 (t, J = 7.2 Hz, 3 H, CH2CH3),
2.84 (s, 3 H, CH3), 4.44 (q, J = 7.2 Hz, 2 H, CH2CH3), 7.36–7.53 (m,
4 H, Harom), 7.86 (s, 1 H, Hfuran).
(8) Litvinov, V. P. Russ. Chem. Rev. (Engl. Transl.) 2005, 74,
217.
(9) Gewald, K.; Bellmann, P. J. Prakt. Chem. 1983, 325, 457.
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J. Chem. Soc., Perkin Trans. 1 1994, 2735.
(11) Fuller, L. S.; Iddon, F.; Smith, K. A. J. Chem. Soc., Perkin
Trans. 1 1997, 3465.
MS (EI, 70 eV): m/z (%) = 320/322 (81/38) [M+], 291/293 (100/40)
[M+ – Et].
(12) Prim, D.; Kirsch, G. J. Chem. Soc., Perkin Trans. 1 1994,
Anal. Calcd for C16H13ClO3S: C, 59.91; H, 4.08; S, 10.00. Found:
C, 60.16; H, 4.15; S, 9.44.
2603.
(13) Král’ovčová, E.; Krutošíková, A.; Kováč, J. Collect. Czech.
Chem. Commun. 1986, 51, 1685.
(14) Pavlicic, D.; Koruznjak, J. D.; Banic-Tomisic, Z.;
Karminski-Zamola, G. Molecules 2002, 7, 871.
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Heterocycles 1991, 32, 2323.
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(17) Capozzi, G.; Sio, F. D.; Menichetti, S.; Nativi, C. P.; Pacini,
Ethyl 3-(4-Bromophenyl)-5-methylthieno[3,2-b]furan-6-car-
boxylate (6d)
Yield: 2.42 g (81%); mp 171–173 °C.
1H NMR (250 MHz, CDCl3): d = 1.44 (t, J = 7.2 Hz, 3 H, CH2CH3),
2.84 (s, 3 H, CH3), 4.44 (q, J = 7.2 Hz, 2 H, CH2CH3), 7.40 (d,
J = 8.5 Hz, 2 H, Harom), 7.55 (d, J = 8.5 Hz, 2 H, Harom), 7.87 (s, 1 H,
Hfuran).
13C NMR (75 MHz, CDCl3): d = 14.40, 17.21, 60.68, 114.50,
117.27, 121.24, 121.62, 127.17, 127.18 (CHarom), 129.86, 132.16
(CHarom), 140.98 (CHfuran), 150.73, 161.99.
L. Synthesis 1994, 521.
(18) Kukolja, S.; Draheim, S. E.; Graves, B. J.; Hunden, D. C.;
Pfeil, J. L.; Cooper, R. D.; Ott, J. L.; Counter, F. T. J. Med.
Chem. 1985, 28, 1896.
(19) Gronowitz, S.; Hornfeldt, A.-B. In The Chemistry of
Heterocyclic Compounds: Thiophene and Its Derivatives,
Part 2, Vol. 44; Gronowitz, S., Ed.; Wiley & Sons: New
York, 1986, Chap. 1, 73.
(20) Skramstad, J.; Lunde, A.; Hope, H.; Bjørnstad, V.; Frøyen,
P. J. Chem. Soc., Perkin Trans. 2 2000, 1453.
(21) Hurter, G. A.; McNab, H. J. Chem. Soc., Chem. Commun.
1990, 375.
(22) Zhang, Y.; Hornfeldt, A.-B.; Gronowitz, S. J. Heterocycl.
Chem. 1993, 30, 1293.
MS (EI, 70 eV): m/z (%) = 364/366 (31/37) [M+], 335/337 (97/100)
[M+ – Et].
Anal. Calcd for C16H13BrO3S: C, 52.61; H, 3.59; S, 8.78. Found: C,
52.93; H, 3.65; S, 8.56.
References
(1) Prugh, J. D.; Hartman, G. D.; Mallorga, P. J.; McKeever,
B. M.; Michelson, S. R.; Murcko, M. A.; Schwam, H.;
Smith, R. L.; Sondey, J. M.; Springer, J. P.; Sugure, M. F.
J. Med. Chem. 1991, 34, 1805.
(2) Egberston, M. S.; Cook, J. J.; Bednar, B.; Prugh, J. D.;
Bednar, R. A.; Gaul, S. L.; Gould, R. J.; Hartman, G. D.;
(23) Krayushkin, M. M.; Shirinian, V. Z.; Nikalin, D. M.;
Shimkin, A. A. Russ. Chem. Bull. 2004, 53, 631.
Synthesis 2009, No. 22, 3803–3806 © Thieme Stuttgart · New York