Thieno[3,2-b]benzofuran - Synthesis and reactions

Article abstract of DOI:10.1135/cccc19971468

Thieno[3,2-b]benzofuran was synthesized starling from benzo[b]furan-3(2h)-one or benzo[b]furan-2-carbaldehyde. Electrophilic substitution reactions such as bromination, formylation, acelylation or nitration, take place in position 2. An election donating group in position 2 directs further electrophilic substitution into positions 3 and 6, whereas compounds with an electron acceptor in position 2 are substituted exclusively in position 6. Metallalation with butyllithium took place in position 2. the ¹H and 13 C NMR signals of the title compound were fully assigned.

Full text of DOI:10.1135/cccc19971468

1468
Vachal, Pihera, Svoboda:
THIENO[3,2-b]BENZOFURAN – SYNTHESIS AND REACTIONS
1
2
3
Petr VACHAL , Pavel PIHERA and Jiri SVOBODA
Department of Organic Chemistry, Prague Institute of Chemical Technology, 166 28 Prague 6,
Czech Republic; e-mail: 1 petr.vachal@vscht.cz, 2 pavel.pihera@vscht.cz, 3 jiri.svoboda@vscht.cz
Received April 15, 1997
Accepted June 12, 1997
Thieno[3,2-b]benzofuran was synthesized starting from benzo[b]furan-3(2H)-one or benzo[b]furan-2-
carbaldehyde. Electrophilic substitution reactions such as bromination, formylation, acetylation or ni-
tration, take place in position 2. An electron donating group in position 2 directs further electrophilic
substitution into positions 3 and 6, whereas compounds with an electron acceptor in position 2 are sub-
stituted exclusively in position 6. Metallation with butyllithium took place in position 2. The 1H and
13C NMR signals of the title compound were fully assigned.
Key words: Fused heterocycles; Thieno[3,2-b]benzofuran; Benzothieno[3,2-b]furan; Electrophilic
substitution; Metallation.
In our previous communications we discussed the synthesis1 and reactivity2 of a novel
heterocyclic system, [1]benzothieno[3,2-b]furan (1). We observed its lower stability in
acidic media, indicating an imperfect aromaticity and a weak enol ether character. Al-
though the isomeric thieno[3,2-b]benzofuran (2) was prepared3, its synthesis has not
been described in detail and no data on its reactivity are known. Neither compound 2
nor intermediates of its synthesis have been fully characterized by physicochemical
methods. In this communication we describe novel synthetic approaches to compound 2
and discuss its reactivity in selected substitution reactions as compared with compound 1.
O
S
S
O
1
2
In our search for an effective synthesis of heterocycle 2 we first tried the reaction
sequence starting from benzo[b]furan-3(2H)-one (Scheme 1). This compound was con-
verted into 3-chlorobenzo[b]furan-2-carbaldehyde (3) by the Vilsmeier–Haack formyla-
tion with N,N-dimethylformamide and phosphorus oxychloride. In contrast to the
published data3, the nucleophilic substitution of chlorine atom with sulfanylacetic
(thioglycolic) acid in an alkaline medium gave the desired [(2-formylbenzo[b]furan-3-
yl)sulfanyl]acetic acid (4) only in a low yield (43%). Most probably, the starting
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

Thieno[3,2-b]benzofuran
1469
chloroaldehyde 3 is not very stable and under the reaction conditions undergoes poly-
merization reactions. No improvement was observed with N,N-dimethylformamide as a solvent.
On treatment with sodium acetate in acetic acid4, acid 4 cyclized to thieno[3,2-b]benzofuran-
2-carboxylic acid (5) which spontaneously decarboxylated to give the desired com-
pound 2 in 49% yield. Acid 5 was isolated from the reaction mixture as a minor product
(4%). The yield of the whole reaction sequence was thus not very satisfactory and therefore
we looked for a more advantageous procedure leading to compound 2.
S
S
COCl
CH CHCOOH
O
O
O
Cl
X
X = H
X = Cl
2,
9
10
13,
R = H
X = H
R = H
S
X
SCH COOR
2
COOR
X = Cl
CHO
CHO
O
O
O
X
R = X = H
5,
X = Cl
X = H
R = H
3,
8,
4,
6,
R = CH ; X = H
3
7,
R = CH
3
R = H; X = Cl
11,
12,
R = CH ; X = Cl
3
X = H
S
S
SH
C
NH
C
H
C
H
COOH
O
O
O
14
15
SCHEME 1
We modified the above procedure in that the substitution of the chlorine atom in
aldehyde 3 was performed with methyl sulfanylacetate in alkaline medium instead of
sulfanylacetic acid. The obtained methyl [(2-formylbenzo[b]furan-3-yl)sulfanyl]acetate (6)
was easily isolable, however, the yield was again low (31%). Ester 6 was easily cyclized
under catalysis with sodium methoxide to give methyl thieno[3,2-b]benzofuran-2-car-
boxylate (7). We have found that with an excess of methyl sulfanylacetate in alkaline
medium the replacement of the chlorine atom in aldehyde 3 is followed by spontaneous
cyclization of the arising formyl ester 6 to ester 7. In this case, the thiolate anion is
basic enough to start the condensation reaction of 6 to 7. Analogous condensations
leading to formation of the thiophene ring are known to proceed also smoothly5,6. Ester 7
was practically quantitatively hydrolyzed to the acid 5 which on standard decarboxyla-
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

1470
Vachal, Pihera, Svoboda:
tion by treatment with copper in quinoline at 160 °C afforded compound 2 in high
yield.
Since acid 5 was readily decarboxylated, it is obvious that this compound is an im-
portant intermediate in the synthesis of compound 2. In order to find a facile synthesis
of acid 5, we tried to utilize known derivatives7 of compound 2. Condensation of
benzo[b]furan-2-carbaldehyde 8 with malonic acid8 smoothly afforded (2-benzo-
[b]furan-3-yl)acrylic acid (9) which underwent Higa’s cyclization9 by treatment with
thionyl chloride. Although the reaction conditions were optimized10, the yield did not
exceed 31%. The obtained 3-chlorothieno[3,2-b]benzofuran-2-carbonyl chloride (10)
was hydrolyzed and methanolyzed to give 3-chlorothieno[3,2-b]benzofuran-2-carbo-
xylic acid (11) and its methyl ester 12, respectively. Decarboxylation of acid 11 by
heating with copper in quinoline afforded the known7 3-chlorothieno[3,2-b]benzofuran (13).
We failed to remove the chlorine atom by reduction with zinc in acetic acid, with
magnesium in propan-2-ol, by hydrogenation on palladium or by palladium-catalyzed
hydrogenation transfer. Reduction with Ni(0) in the system Zn/NiCl2/NaI/Ph3P (ref.11)
afforded compound 2 only with low conversion (25%). Therefore, we tried to reduce
the chlorine atom in ester 12. In this case the reduction with Ni(0) proceeded well and
ester 7 was obtained in high yield (90%).
Finally, we tried a method consisting in cyclization of substituted 2-sulfanylacrylic
acids by the action of halogens12–14. Condensation of aldehyde 8 with rhodanine in the
presence of sodium acetate in acetic acid afforded smoothly 5-[(benzo[b]furan-2-
yl)methylene]-2-thioxothiazolidin-4-one (14). Base-catalyzed hydrolysis of the rho-
danine skeleton in compound 14 proceeded readily and the resulting
3-(benzo[b]furan-2-yl)-2-sulfanylacrylic acid (15) was obtained in a good yield. Upon
treatment with bromine, acid 15 was cyclized via intermediate sulfenyl bromide13 to
give acid 5 in 76% yield. Using this reaction sequence, compound 2 could be obtained
on the preparative scale.
As we have shown previously2, the heterocyclic system in compound 1 is substituted
with a range of electrophilic reagents selectively in position 2. We compared now the
reactivity of the heterocyclic systems in compounds 1 and 2, using a series of electro-
philic substitution reactions which, except acetylation3, have not been hitherto de-
scribed (Scheme 2).
Compound 2 was smoothly monobrominated with dioxane dibromide in dichloro-
methane, giving 2-bromothieno[3,2-b]benzofuran (16) in good yield. On the other
hand, dibromination of compound 2 with excess of dioxane dibromide or bromination
of compound 16 with bromine proceeded very slowly. In both cases we obtained iden-
tical product, 2,6-dibromothieno[3,2-b]benzofuran (17).
Vilsmeier–Haack formylation of compound 2 afforded thieno[3,2-b]benzofuran-2-
carbaldehyde (18). Similarly to the analogous reaction of benzo[b]thiophene15, the for-
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

Thieno[3,2-b]benzofuran
1471
mylation was very slow and a satisfactory conversion of the compound 2 was achieved
only at a higher temperature (50 °C).
Acetylation of compound 2 with acetyl chloride in the presence of aluminium
chloride led only to polymeric products, whereas treatment with acetic anhydride af-
forded the desired 2-acetylthieno[3,2-b]benzofuran (19) in the yield of 54%. With
weaker Lewis acids such as zinc chloride or tin tetrachloride, no reaction was observed.
Whereas nitration of compound 1 was not very successful2 and, moreover, the ob-
tained 2-nitro derivative was unstable, compound 2 was successfully converted into
2-nitrothieno[3,2-b]benzofuran (20) by treatment with acetyl nitrate. In strongly acidic
medium, the reaction was also accompanied by significant decomposition of the start-
ing compound 2.
Some heterocyclic compounds easily undergo metallation reactions16 upon action of
strong bases. Thiophene as well as benzo[b]thiophene are attacked by organometallic
S
S
S
S
S
S
Br
Br
b
Br
O
O
16
17
a
a
CHO
COCH
3
d
c
2
O
O
f
e
18
19
NO
CH
3
2
O
O
20
21
7
a
b
S
S
COOCH
CH
3
3
Br
Y
O
O
X
25
X = Br; Y = H
X = H; Y = Br
X = Y = Br
22,
23,
24,
a) dioxane dibromide; b) Br ; c) POCl , DMF; d) Ac O, AlCl ; e) HNO , Ac O;
2
3
2
3
3
2
f) i, BuLi, ii, CH I
3
SCHEME 2
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Vachal, Pihera, Svoboda:
reagents in position 2. Therefore we studied an analogous reaction with the heterocycle 2.
Upon treatment with butyllithium at low temperature (–70 to –30 °C), the arising li-
thium derivative was trapped by reaction with methyl iodide. We have found that the
reaction is regioselective and gives 2-methylthieno[3,2-b]benzofuran (21) in high yield.
It has been shown3 that in the acetylation of methyl derivative 21 the substituent
enters both position 3 and 6. The same result was obtained in bromination of compound 21
with dioxane dibromide. From the reaction mixture we isolated by thin-layer chromato-
graphy a mixture of 3-bromo-2-methylthieno[3,2-b]benzofuran (22) and 6-bromo-2-
methylthieno[3,2-b]benzofuran (23) (1.3 : 1) and pure 3,6-dibromo-2-methylthieno-
[3,2-b]benzofuran (24).
On the other hand, ester 7 was brominated exclusively in position 6 under formation
of methyl 6-bromothieno[3,2-b]benzofuran-2-carboxylate (25) as the sole product.
We may thus summarize that under conditions of electrophilic substitution the he-
terocyclic system in compound 2 is more stable than in compound 1. In analogy to
other isosteric heterocyclic systems, electrophilic substitution occurs in position 2. If
this position is already occupied by an electron donor substituent, the electrophilic rea-
gent attacks position 3 or 6. On the other hand, if an electron acceptor substituent (Br,
COOCH3) is in position 2, the electrophile enters regioselectively position 6.
The structure of compounds 3–15 was confirmed by elemental analyses and infrared
1
1
and H NMR spectra. For compound 2, both the H and 13C NMR signals were com-
pletely assigned (Table I). First we assigned the signals of atoms in positions 2 and 3.
TABLE I
1H and 13C NMR (δ, ppm; J in Hz) data of 2a
Position
δ(H)
J(H,H)
J(2,3) = 5.2
δ(C)b
1J(C,H)
nJ(C,H)
2
7.35 d
7.14 d
–
128.2 Dd
112.1 Dd
160.0 Sdd
159.9 Sddd
113.1 Ddd
125.0 Dd
123.7 Dd
119.7 Ddd
124.5 Sm
120.0 Sm
192
176
–
5
2
3
3a
4a
5
–
14; 2
–
–
–
10; 9; 3
7.55 dd
J(5,6) = 7.2; J(5,7) = 1.8
161
161
160
158
–
6; 2
6
7.30 ddd J(6,7) = 7.7; J(6,8) = 2.2
7.27 ddd J(7,8) = 6.7
7.66 dd
8
7
7
8
6; 2
8a
8b
–
–
–
–
not determined
not determined
–
a
b
Abbreviations used: s singlet, d doublet, m multiplet. Capital letters denote direct coupling, small
letters denote long-range coupling.
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Thieno[3,2-b]benzofuran
1473
The thiophene protons H-2 and H-3 differ significantly from the benzene protons of the
system in their multiplicity and lower vicinal coupling constant. They were distin-
guished by the heteronuclear correlation method. Analogously to benzo[b]thiophene17,
proton that directly interacts with carbon, whose signal is shifted downfield due to the
attached sulfur atom, is bonded in position 2. The quaternary carbon atom with largest
chemical shift (i.e. bonded to oxygen) interacting with H-2 and H-3 can be assigned as
C-3a. The second quaternary carbon interacting with these protons is then C-8b.
Protons H-5 and H-8, which differ in chemical shifts and multiplicities from H-6 and
H-7, were distinguished on the basis of the 3J(C,H) interaction with C-8b, possible only
for H-8. Correlation experiments then assigned signals to the remaining protons and
carbon atoms. Signals of the quaternary carbon atoms C-4a and C-8a differ signifi-
3
cantly and were assigned on the basis of the J(C,H) interactions with H-8 and H-5,
respectively. The chemical shifts of protons and carbon atoms in the benzene part of the
molecule exhibit thus similar behaviour as described for benzo[b]furan18. The values of
the coupling constants J(H-2,H-3), J(C-2,H-3) and J(C-3,H-2) resemble those reported
for benzo[b]thiophene17,19; the chemical shifts of C-2 and H-2 are similar whereas
those for C-3 and H-3 are significantly smaller. The coupling constant J(H-2,H-3) is
also the same as the corresponding constant for thieno[3,2-b]furan20.
The structure of derivatives 16–25 was confirmed by elemental analyses and IR and
1H NMR spectra. Proton signals were assigned using the NMR spectra of the parent
heterocycle 2, benzo[b]furan and analogies2 found for the substitution derivatives of
compound 1.
EXPERIMENTAL
Melting points were determined on a Boetius block and are uncorrected. Proton NMR spectra of
compounds 3–25 were taken on a Varian Gemini-300 (300 MHz) instrument. Compound 2 was stu-
1
died on a Bruker 400 (400 MHz for H, 100 MHz for 13C) instrument at 25 °C. Deuteriochloroform
was used as solvent, except for compounds 11, 14 and 15 which were measured in hexadeuteriodi-
methyl sulfoxide. Chemical shifts are given in the δ-scale (ppm), coupling constants in Hz. The sol-
vent signal served as internal standard (δ(C) 77.0). Signal multiplicities in the 13C NMR spectra were
determined in APT experiments. The proton-coupled spectra were measured by the “gated decoupl-
ing” method (decoupler off during the acquisition). 2D NMR experiments – COSY, HETCOR,
INEPT and COLOC – were carried out using pulse sequences and programs provided by the manu-
facturer. Infrared spectra (ν, cm–1) were recorded on a Nicolet FTIR 740 spectrometer in chloroform
or in KBr (compounds 5, 14, 15). Benzo[b]furan-3(2H)-one was prepared according to the lite-
rature21, benzo[b]furan-2-carbaldehyde (8) according to ref.22, 3-(benzo[b]furan-2-yl)acrylic acid (9)
was obtained as described in ref.8. Preparative thin-layer chromatography was performed on Merck
plates (20 × 20 cm), column chromatography on Kieselgel 60 (Merck).
Thieno[3,2-b]benzofuran (2)
A. A mixture of acid 4 (5.0 g, 21.2 mmol), freshly fused sodium acetate (20 g, 238 mmol) and
glacial acetic acid (50 ml) was refluxed with stirring for 13 h and poured into an excess of cold 5%
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

1474
Vachal, Pihera, Svoboda:
aqueous sodium hydroxide. The alkaline solution was washed with ether (3 × 100 ml), the combined
ethereal solutions were washed with water (2 × 50 ml), saturated solution of sodium chloride (50 ml)
and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was puri-
fied by column chromatography on silica gel in hexane. Yield 1.8 g (49%) of compound 2, m.p.
61.5–62 °C (reported3 m.p. 63 °C). For C10H6OS (174.2) calculated: 68.94% C, 3.47% H, 18.40% S;
found: 68.80% C, 3.53% H, 18.41% S. IR spectrum: 3 014, 1 482, 1 449, 1 371, 1 195, 1 111, 1 086,
1 034, 838. The aqueous portion was acidified with hydrochloric acid (1 : 1) to pH 2 and washed
with chloroform (2 × 30 ml), the organic phase was washed with water (2 × 30 ml), brine (30 ml)
and dried over anhydrous magnesium sulfate. Evaporation of the solvent afforded 0.2 g (4%) of
thieno[3,2-b]benzofuran-2-carboxylic acid (5), m.p. 249–250 °C (reported23 m.p. 250–253 °C).
B. A mixture of acid 5 (2.4 g, 11.0 mmol), copper powder (1.3 g, 20.5 mmol) and distilled qui-
noline (25 ml) was heated at 165 °C for 15 min under nitrogen. After cooling, the mixture was
poured into ice-cold dilute hydrochloric acid (1 : 1, 200 ml) and extracted with hexane (3 × 50 ml).
The organic solution was washed with water (2 × 25 ml), saturated solution of sodium hydrogencar-
bonate (25 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvent and crystal-
lization of the residue from pentane afforded 1.88 g (98%) of compound 2, m.p. 61 °C.
3-Chlorobenzo[b]furan-2-carbaldehyde (3)
Phosphorus oxychloride (167.5 g, 1.09 mmol) was added dropwise during 4 h to a stirred and exter-
nally ice-cooled suspension of benzo[b]furan-3(2H)-one (32.0 g, 0.239 mol) in dry N,N-dimethyl-
formamide (100 ml). The cooling bath was removed and the mixture was stirred at room temperatute
for 1.5 h and at 40 °C for 5 h. After addition of another portion of phosphorus oxychloride (33.5 g,
0.218 mol), the mixture was heated at 50 °C for 0.5 h, poured on ice (1 kg), the solid was collected,
washed thoroughly with ice-cold water and dried. Yield 37.5 g (87%) of product 3, m.p. 73–76 °C
(reported24 m.p. 78 °C).
[(2-Formylbenzo[b]furan-3-yl)sulfanyl]acetic Acid (4)
A stirred mixture of aldehyde 3 (20.0 g, 111 mmol), sulfanylacetic acid (15.4 g, 167 mmol), sodium
carbonate (17.7 g, 167 mmol), methanol (300 ml) and water (20 ml) was refluxed for 14 h. After
cooling, methanol was evaporated and the residue diluted with water (300 ml) and washed with chlo-
roform (2 × 30 ml). The aqueous layer was acidified with hydrochloric acid (1 : 1) to pH 2 and the
solid was collected and washed with water.
Crystallization from chloroform–hexane afforded acid 4 (11.15 g, 43%), m.p. 134.5–136 °C (re-
1
ported3 m.p. 127 °C). IR spectrum: 1 716, 1 679 (CO). H NMR spectrum: 3.73 s, 2 H (CH2); 7.42 t,
1 H, J = 7.4; 7.58 t, 1 H; 7.63 d, 1 H, J = 7.8 (H-4); 7.85 d, 1 H (H-7); 10.19 s, 1 H (CHO).
Thieno[3,2-b]benzofuran-2-carboxylic Acid (5)
A. Ester 7 (2.8 g, 12.1 mmol) was added to a solution of sodium hydroxide (1.45 g, 36.2 mmol)
in 1 : 1 aqueous methanol (120 ml) and the stirred mixture was boiled for 30 min. Most of the methanol
was evaporated on an evaporator and the residue was diluted with water and adjusted to pH 3 with
dilute hydrochloric acid (1 : 1). The solid was collected, washed on the filter with water and air-
dried. Yield 1.53 g (96%) of acid 5, m.p. 249 °C (reported23 m.p. 250–253 °C). IR spectrum (KBr):
1
1 675 (COOH). H NMR spectrum: 7.38 t, 1 H, J = 7.6 (H-7); 7.47 t, J = 7.5 (H-6); 7.63 d, 1 H, J =
8.2 (H-5); 7.79 d, 1 H, J = 8.2 (H-8); 7.94 s, 1 H (H-3).
B. A solution of bromine (2.2 ml of 1 M solution) in acetic acid was added at 60 °C to a stirred
solution of acid 15 (0.3 g, 1.36 mmol) in glacial acetic acid (14 ml). After reflux for 15 min, the
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

Thieno[3,2-b]benzofuran
1475
mixture was diluted with water (15 ml) and refluxed for another 15 min. The mixture was cooled and
the solid was filtered, washed with water and dried. Yield 0.27 g (91%) of acid 5, m.p. 248–250 °C.
Methyl [(2-Formylbenzo[b]furan-3-yl)sulfanyl]acetate (6)
A mixture of methyl sulfanylacetate (0.588 g, 5.54 mmol), sodium hydrogencarbonate (0.44 g, 5.23 mmol)
and N,N-dimethylformamide (10 ml) was stirred under nitrogen for 45 min. A solution of aldehyde 3
(1.0 g, 5.54 mmol) in N,N-dimethylformamide (5 ml) was added dropwise during 5 min, the mixture
was stirred at 60 °C for 4 h, poured into ice-cold water (200 ml) and extracted with dichloromethane
(3 × 20 ml). The organic phase was washed with water (20 ml), dried over anhydrous magnesium sulfate
and the solvent was evaporated. Column chromatography of the residue on silica gel in hexane–ethyl
acetate recovered the starting aldehyde 3 (0.06 g, 6%) and afforded 0.36 g (31%) of compound 6,
m.p. 61.5–62 °C. For C12H10O4S (250.3) calculated: 57.59% C, 4.03% H, 12.81% S; found: 57.44% C,
1
3.89% H, 12.67% S. IR spectrum: 1 739 (COOCH3), 1 679 (CHO). H NMR spectrum: 3.65 s, 3 H
(OCH3); 3.69 s, 2 H (CH2); 7.43 t, 1 H, J = 8.0; 7.57 t, 1 H; 7.63 d, 1 H, J = 8.4 (H-4); 7.85 d, 1 H
(H-7); 10.20 s, 1 H (CHO).
Methyl Thieno[3,2-b]benzofuran-2-carboxylate (7)
A. Methyl sulfanylacetate (17.9 g, 166 mmol) was added dropwise at room temperature under ni-
trogen to a stirred solution of sodium methoxide prepared by dissolving sodium (3.15 g, 137 mmol)
in dry methanol (200 ml). After stirring for 5 min, aldehyde 3 (13.0 g, 72 mmol) was added in one
portion and the mixture was refluxed for 17 h. After cooling, the solvent was evaporated, the residue
dissolved in dichloromethane (200 ml) and the solution washed with 2% aqueous sodium hydroxide
(2 × 100 ml), water (2 × 50 ml), brine (50 ml) and dried over anhydrous magnesium sulfate. Evaporation
of the solvent and crystallization from methanol afforded 9.20 g (55%) of ester 7, m.p. 119–120 °C.
For C12H8O3S (232.2) calculated: 62.06% C, 3.47% H, 13.80% S; found: 61.78% C, 3.46% H,
1
13.64% S. IR spectrum: 1 710 (COOCH3). H NMR spectrum: 3.95 s, 3 H (OCH3); 7.36 dt, 1 H, J1 =
7.6, J2 = 1.5 (H-5); 7.43 dt, 1 H (H-6); 7.60 d, 1 H, J = 8.1 (H-5); 7.76 d, 1 H, J = 8.2 (H-8); 7.85 s,
1 H (H-3). 13C NMR spectrum: 53.1, 113.4, 117.4, 120.8, 123.6, 124.2, 126.4, 127.1, 134.7, 158.0,
160.5, 163.7.
B. A solution of ester 6 (0.19 g, 0.76 mmol) in methanol (5 ml) was added dropwise at room
temperature under nitrogen to a stirred solution of sodium methoxide prepared by dissolving sodium
(0.052 g, 2.3 mmol) in methanol (20 ml). The mixture was refluxed for 10 min, cooled and the sol-
vent was evaporated. The residue was dissolved in dichloromethane (30 ml) and the solution was
washed with water (2 × 5 ml), brine (5 ml) and dried over anhydrous magnesium sulfate. Evapora-
tion of the solvent and crystallization from methanol afforded 0.15 g (85%) of ester 7.
C. A mixture of triphenylphosphine (0.685 g, 2.61 mmol), zinc powder (1.37 g, 29.9 mmol),
nickel(II) chloride hexahydrate (0.131 g, 0.55 mmol), sodium iodide (0.455 g, 3.03 mmol) and
aqueous N,N-dimethylformamide (10 ml, DMF : H2O = 25 : 1) was stirred under nitrogen for 1 h.
Ester 12 (1.0 g, 3.75 mmol) was added dropwise and the mixture was heated at 70 °C for 48 h. After
cooling, the solid was collected by filtration, washed with chloroform (50 ml) and the filtrate was
evaporated. The residue was dissolved in chloroform (50 ml), washed with water (20 ml), brine (20 ml)
and dried over anhydrous magnesium sulfate. Purification by column chromatography on silica gel in
hexane–toluene (1 : 1) afforded 0.78 g (90%) of compound 7.
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

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Vachal, Pihera, Svoboda:
3-Chlorothieno[3,2-b]benzofuran-2-carbonyl Chloride (10)
A mixture of acid 9 (ref.8) (52.4 g, 0.278 mmol), pyridinium chloride (8.0 g, 0.07 mol) and thionyl
chloride (265 g, 2.23 mol) was stirred and heated at 130 °C in an oil bath for 25 h. After cooling,
the formed suspension was diluted with chloroform (350 ml) and the solvent was evaporated to dry-
ness. Crystallization from benzene–hexane gave 23.6 g (31%) of compound 10, m.p. 182–184 °C
(reported7 m.p. 183 °C).
3-Chlorothieno[3,2-b]benzofuran-2-carboxylic Acid (11)
The title acid was prepared according to the literature7 in 92% yield, m.p. 310–312 °C (reported7 m.p.
1
312 °C). H NMR spectrum (hexadeuteriodimethyl sulfoxide): 7.47 t, 1 H, J = 7.7 (H-7); 7.51 t, 1 H,
J = 7.7 (H-6); 7.83 d, 1 H, J = 8.2 (H-5); 8.19 d, 1 H, J = 7.6 (H-8).
Methyl 3-Chlorothieno[3,2-b]benzofuran-2-carboxylate (12)
A mixture of chloride 10 (3.5 g, 12.9 mmol) and dry methanol (100 ml) was refluxed for 2 h, cooled
and the deposited crystals were collected on filter and washed with methanol. Yield 3.27 g (95%) of
ester 12, m.p. 143–144 °C. For C12H7ClO3S (266.7) calculated: 54.04% C, 2.65% H, 13.29% Cl,
12.02% S; found: 53.88% C, 2.55% H, 13.11% Cl, 11.86% S. IR spectrum: 1 717 (COOCH3). 1H NMR
spectrum: 3.98 s, 3 H (OCH3); 7.38 dt, 1 H, J1 = 7.8, J2 = 1.1 (H-7); 7.48 dt, 1 H (H-6); 7.68 d, 1 H,
J = 7.7 (H-5); 7.76 dd, 1 H, J1 = 8.2, J2 = 1.1 (H-8).
3-Chlorothieno[3,2-b]benzofuran (13)
A mixture of acid 11 (0.5 g, 1.98 mmol), copper powder (0.3 g, 4.7 mmol) and quinoline (20 ml)
was heated at 130–150 °C for 1 h. The mixture was cooled and poured into ice-cold dilute hydro-
chloric acid (1 : 1, 200 ml). The product was taken up in ether (3 × 50 ml), the extract was washed
with water (2 × 25 ml) and saturated solution of sodium hydrogen carbonate and dried over anhy-
drous magnesium sulfate. Evaporation of the solvent afforded 0.42 g (100%) of compound 13, m.p.
68–68.5 °C (reported7 m.p. 67 °C). IR spectrum: 3 116, 1 447, 1 300, 1 176, 1 084, 991, 823, 808.
1H NMR spectrum: 7.20 s, 1 H (H-2); 7.33 dt, 1 H, J1 = 7.5, J2 = 1.1 (H-7); 7.38 dt, 1 H, J1 = 7.5,
J2 = 1.6 (H-6); 7.62 dd, 1 H, J1 = 7.6, J2 = 1.1 (H-5); 7.68 dd, 1 H, J1 = 7.5, J2 = 1.6 (H-8).
5-[(Benzo[b]furan-2-yl)methylene]-2-thioxothiazolidin-4-one (14)
A mixture of aldehyde 8 (2.0 g, 13.7 mmol), rhodanine (1.83 g, 13.7 mmol), freshly fused sodium
acetate (3.30 g, 40.2 mmol) and glacial acetic acid (30 ml) was refluxed for 45 min. After cooling,
the suspension was poured into water (75 ml), the solid was filtered and washed with water. Crystal-
lization from toluene afforded 3.30 g (90%) of compound 14, m.p. 255–257 °C (subl.). For
C12H7NO2S2 (261.3) calculated: 55.16% C, 2.70% H, 5.36% N, 24.54% S; found: 54.99% C,
1
2.84% H, 5.22% N, 24.66% S. IR spectrum (KBr): 1 694 (CO). H NMR spectrum (hexadeuteriodi-
methyl sulfoxide): 7.34 t, 1 H, J = 7.1 (H-7); 7.48 t, 1 H, J = 7.7 (H-6); 7.59 s, 1 H; 7.65 s, 1 H;
7.72 d, 1 H, J = 7.7 (H-5); 7.78 d, 1 H, J = 7.7 (H-8).
3-(Benzo[b]furan-2-yl)-2-sulfanylacrylic Acid (15)
A stirred mixture of compound 14 (0.5 g, 1.91 mmol), sodium hydroxide (2.4 g, 60 mmol) and water
(15 ml) was refluxed under nitrogen for 1.5 h, the clear solution was cooled and poured into dilute
hydrochloric acid (1 : 1, 75 ml) and the solid was collected and washed with water. Yield 1.95 g
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Thieno[3,2-b]benzofuran
1477
(89%) of acid 15, m.p. 175–177 °C. For C11H8O3S (220.2) calculated: 59.99% C, 3.66% H, 14.56% S;
found: 59.69% C, 3.74% H, 14.11% S. IR spectrum (KBr): 2 564 (SH), 1 668 (COOH). 1H NMR
spectrum (hexadeuteriomedimethyl sulfoxide): 7.31 s, 1 H (H-3); 7.41 m, 2 H, J = 7.7 (H-5 and
H-6); 7.61 d, 1 H, J = 7.7 (H-5); 7.46 s, 1 H (–CH=); 7.77 d, 1 H (H-8).
2-Bromothieno[3,2-b]benzofuran (16)
A solution of dioxane dibromide (158 mg, 0.637 mmol) in dichloromethane (2 ml) was added drop-
wise during 20 min to a stirred solution of compound 2 (100 mg, 0.574 mmol) in a mixture of di-
chloromethane (2 ml) and dioxane (2 ml) under external cooling with ice. After 5 min the mixture
was neutralized with solid sodium hydrogencarbonate (0.5 g, 6.0 mmol), diluted with dichloromethane (10 ml),
washed with water (10 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvent
and crystallization from methanol afforded 115 mg (79%) of bromo derivative 16, m.p. 68.5–70.5 °C.
For C10H5BrOS (253.1) calculated: 47.45% C, 1.99% H, 31.57% Br, 12.67% S; found: 47.61% C,
2.01% H, 31.29% Br, 12.70% S. IR spectrum: 3 014, 1 523, 1 481, 1 448, 1 197, 1 109, 1060, 989.
1H NMR spectrum: 7.03 s, 1 H (H-3); 7.30 t, 1 H, J = 6.6 (H-7); 7.34 t, 1 H, J = 6.1 (H-6); 7.55 d,
1 H, J = 7.7 (H-5); 7.62 d, 1 H, J = 7.1 (H-8).
2,6-Dibromothieno[3,2-b]benzofuran (17)
A. A solution of dioxane dibromide (311 mg, 1.25 mmol) in dichloromethane (2 ml) was added
during 5 min to a stirred ice-cool solution of compound 2 (100 mg, 0.574 mmol) in a mixture of
dichloromethane (2 ml) and dioxane (2 ml). The mixture was stirred at room temperature for 3 h and
then refluxed for 2 h. The subsequent work-up procedure was the same as described for compound
16. Column chromatography on silica gel in hexane afforded 20 mg (11%) of compound 17, m.p.
171–172 °C, and 80 mg (16%) of bromo derivative 16. For C10H4Br2OS (332.0) calculated: 36.18% C,
1.21% H; found: 36.02% C, 1.45% H. IR spectrum: 3 017, 1 470, 1 451, 1 411, 1 379, 1 262, 1 062,
1 048. 1H NMR spectrum: 7.26 s, 1 H (H-3); 7.43 dd, 1 H, J1 = 8.2, J2 = 1.1 (H-7); 7.48 d, 1 H
(H-5); 7.72 d, 1 H, J = 1.1 (H-8).
B. A solution of bromine in dichloromethane (0.7 ml of 2 M solution) was added to a solution of
bromo derivative 16 (27 mg, 0.107 mmol) in dichloromethane (2 ml) and the mixture was stirred at
room temperature for 120 h. An analogous work-up as described for compound 16 gave 35 mg (99%)
of dibromo derivative 17, m.p. 172–172.5 °C.
Thieno[3,2-b]benzofuran-2-carbaldehyde (18)
Phosphorus oxychloride (1.6 g, 10.4 mmol) was added dropwise during 15 min under nitrogen to
N,N-dimethylformamide (5 ml) under external cooling with ice. After stirring for 20 min, compound 2
(200 mg, 1.15 mmol) was added in one portion. The mixture was heated at 50 °C for 2 h and then decom-
posed with saturated solution of sodium hydrogencarbonate and extracted with hexane (3 × 20 ml).
The organic extract was washed with water, dried over anhydrous magnesium sulfate and the solvent
was evaporated. The residue was chromatographed on a column of silica gel in hexane and then in
hexane–ethyl acetate (2 : 1). After the recovered starting compound 2 (50 mg, 25%), the chromato-
graphy afforded 110 mg (63%, corrected for recovered 2) of aldehyde 18, m.p. 122–123.5 °C (hexane).
For C11H6O2S (202.2) calculated: 65.33% C, 2.99% H, 15.85% S; found: 65.02% C, 3.32% H,
1
15.45% S. IR spectrum: 1 686 (CHO). H NMR spectrum: 7.38 t, 1 H, J = 7.1 (H-7); 7.47 t, 1 H, J =
7.2 (H-6); 7.62 d, 1 H, J = 7.7 (H-5); 7.79 s, 1 H (H-3); 7.81 d, 1 H, J = 7.7 (H-8); 9.96 s, 1 H
(CHO).
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Vachal, Pihera, Svoboda:
2-Acetylthieno[3,2-b]benzofuran (19)
Acetic anhydride (0.585 g, 5.74 mmol) was added dropwise to a stirred suspension of aluminium
chloride (765 mg, 5.74 mmol) in dichloromethane (10 ml) under external cooling with ice. After 15 min,
compound 2 (100 mg, 0.574 mmol) was added. The mixture was stirred at room temperature for 10 min
and then decomposed by pouring into 5% aqueous potassium carbonate solution (100 ml). The pro-
duct was extracted with chloroform (3 × 20 ml) and the organic extract was washed with water (20 ml),
brine (20 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvent and crystal-
lization from methanol afforded 67 mg (54%) of compound 19, m.p. 201–201.5 °C (reported3 m.p.
200 °C). For C12H8O2S (216.3) calculated: 66.65% C, 3.73% H, 14.83% S; found: 66.36% C, 3.91% H,
14.61% S. IR spectrum: 1 660 (CO). 1H NMR spectrum: 2.63 s, 3 H (CH3); 7.36 t, 1 H, J = 7.7
(H-7); 7.44 t, 1 H, J = 7.7 (H-6); 7.60 d, 1 H, J = 8.2 (H-5); 7.74 s, 1 H, (H-3); 7.78 d, 1 H, J = 7.7
(H-8).
2-Nitrothieno[3,2-b]benzofuran (20)
Fuming nitric acid (52 mg, 0.833 mmol) was added dropwise to acetic anhydride (1 ml) under stir-
ring and cooling to 0 °C. After 15 min, a solution of compound 2 (100 mg, 0.574 mmol) in acetic
acid (1 ml) was added. The mixture was stirred at 0 °C for 4 h, poured into ice-cold water (50 ml)
and extracted with chloroform (50 ml). The organic extract was washed with water (20 ml), saturated
solution of sodium hydrogencarbonate (10 ml) and dried over anhydrous magnesium sulfate. Eva-
poration of the solvent and crystallization from hexane gave 26 mg (21%) of nitro derivative 20, m.p.
161–163.5 °C (sealed tube). For C10H5NO3S (219.2) calculated: 54.79% C, 2.30% H; found: 54.64% C,
2.48% H. IR spectrum: 3 026, 1 447, 1 379, 1 321, 1 298. 1H NMR spectrum: 7.41 t, 1 H, J = 7.7
(H-7); 7.52 t, 1 H, J = 7.6 (H-6); 7.64 d, 1 H, J = 8.2 (H-5); 7.80 d, 1 H, J = 8.2 (H-8); 8.07 s, 1 H
(H-3).
2-Methylthieno[3,2-b]benzofuran (21)
A solution of butyllithium in hexane (1.0 ml of 2 M solution, 2 mmol) was added dropwise under
nitrogen at –70 °C to a stirred solution of compound 2 (150 mg, 0.861 mmol) in tetrahydrofuran (15 ml).
The reaction mixture was stirred at –30 °C for 2 h, methyl iodide (0.8 g, 5.62 mmol) was then added
in a single portion and stirring was continued at room temperature for 2 h. The solution was eva-
porated and the residue purified by column chromatography on silica gel in hexane. Yield 140 mg
(86%) of compound 21, m.p. 56–57 °C (reported3 m.p. 57.5 °C). For C11H8OS (188.2) calculated:
70.18% C, 4.28% H, 17.03% S; found: 70.01% C, 4.21% H, 16.79% S. IR spectrum: 3 012, 1 497,
1 447, 1 405, 1 191, 1 049, 935. 1H NMR spectrum: 2.63 s, 3 H (CH3); 6.90 s, 1 H (H-3); 7.31 m,
1 H (H-7); 7.33 m, 1 H (H-6); 7.59 m, 1 H (H-5); 7.65 m, 1 H (H-8).
Bromination of 2-Methylthieno[3,2-b]benzofuran (21)
A solution of dioxane dibromide (134 mg, 0.55 mmol) in dichloromethane (4 ml) was added drop-
wise during 5 min at 0 °C to a solution of methyl derivative 21 (95 mg, 0.521 mmol) in a mixture
of dichloromethane (2 ml) and dioxane (2 ml) and the mixture was stirred at 0 °C for 1 h. The reac-
tion mixture was worked up as described for compound 16 and the crude product was subjected to
preparative thin-layer chromatography in hexane to give 43 mg (32%) of a mixture of 3-bromo-2-
methylthieno[3,2-b]benzofuran (22) and 6-bromo-2-methylthieno[3,2-b]benzofuran (23) (1.3 : 1), and
5 mg (4%) of 3,6-dibromo-2-methylthieno[3,2-b]benzofuran (24). The elemental analysis of the mix-
ture of monobromo derivatives 22 and 23 was in accord with the calculated values. For C11H7BrOS
1
(267.1) calculated: 49.46% C, 2.64% H, 29.91% Br; found: 49.41% C, 2.76% H, 29.58% Br. H NMR
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

Thieno[3,2-b]benzofuran
1479
1
spectrum of 22: 2.54 s, 3 H (CH3); 7.31 m, 2 H (H-6 and H-7); 7.60 m, 2 H (H-5 and H-8). H NMR
spectrum of 23: 2.61 s, 3 H (CH3); 6.86 s, 1 H (H-3); 7.38 dd, 1 H, J1 = 8.8, J2 = 1.6 (H-7); 7.44 d,
1
1 H, J = 8.2 (H-5); 7.68 d, 1 H, J = 1.6 (H-8). H NMR spectrum of 24: 2.54 s, 3 H (CH3); 7.43 dd,
1 H, J1 = 8.2, J2 = 1.7 (H-7); 7.47 d, 1 H (H-5); 7.75 d, 1 H, J = 1.7 (H-8).
Methyl 6-Bromothieno[3,2-b]benzofuran-2-carboxylate (25)
A solution of bromine (1.8 g, 11.3 mmol) in chloroform (20 ml) was added dropwise at room tem-
perature during 5 min to a stirred solution of ester 7 (2.0 g, 8.61 mmol) in chloroform (10 ml) and
the mixture was stirred for 50 h. The reaction was quenched by addition of sodium hydrogensulfite
(2 g, 10.5 mmol) and the mixture was stirred until it decolorized. The solution was washed with
water (10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent was eva-
porated and the residue was crystallized from methanol to give 1.36 g (51%) of compound 25, m.p.
147–148 °C. For C12H7BrO3S (311.2) calculated: 46.32% C, 2.27% H, 25.68% Br, 13.30% S; found:
1
46.08% C, 2.34% H, 25.42% Br, 13.27% S. IR spectrum: 1 709 (COOCH3). H NMR spectrum: 3.94 s,
3 H (OCH3); 7.47 dd, 1 H, J1 = 8.2, J2 = 1.1 (H-7); 7.59 dd, 1 H (H-8); 7.75 d, 1 H (H-5); 7.81 s, 1 H
(H-3). 13C NMR spectrum: 53.2, 116.9, 117.4, 120.2, 121.6, 122.7, 125.8, 127.6, 135.4, 158.3, 160.5,
163.4.
The authors’ thanks are due to Dr Hana Dvorakova for the NMR experiments in the structure deter-
mination of compound 2. For elemental analyses and spectral measurements the authors are indebted to
the corresponding departments of Central Laboratories of the Prague Institute of Chemical Technology.
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