Synthesis of new 5-substitutedbenzo[b]thiophene derivatives

Article abstract of DOI:10.1002/jhet.5570380502

Previous works of our group have dealt with the synthesis of 1-(aryl)-3-[4-(aryl)piperazin-1-yl]propane derivatives in the search for new and efficient antidepressants with a dual mode of action: serotonin reuptake inhibition and 5-HT_1A receptor afinity [1-4]. From these studies we concluded that the 3-[4-(aryl)piperazin-1-yl]-l-(benzo[b]thiophen-3-yl)propane derivatives led to the best results. The continuation of this research project required the preparation of some new 3-acyl-5-substituted benzo[b]thiophenes with a wide variety of substituents at the 5 position, ranging from nitro to hydroxyl derivatives. To obtain these derivatives we acylated the corresponding 5-substituted benzo[b]thiophenes when it was possible.

Full text of DOI:10.1002/jhet.5570380502

Sep-Oct 2001
Synthesis of New 5-Substitutedbenzo[b]thiophene Derivatives
1025
S. Pérez-Silanes, J. Martínez-Esparza,
A. M. Oficialdegui, H. Villanueva, L. Orús and A. Monge*
Unidad de Investigación y Desarrollo de Nuevos Medicamentos, CIFA, Universidad de Navarra, Pamplona, Spain
Received January 24, 2001
Previous works of our group have dealt with the synthesis of 1-(aryl)-3-[4-(aryl)piperazin-1-yl]propane
derivatives in the search for new and efficient antidepressants with a dual mode of action: serotonin reuptake
inhibition and 5-HT receptor afinity [1-4]. From these studies we concluded that the 3-[4-(aryl)piperazin-
1A
1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives led to the best results. The continuation of this research
project required the preparation of some new 3-acyl-5-substituted benzo[b]thiophenes with a wide variety of
substituents at the 5 position, ranging from nitro to hydroxyl derivatives. To obtain these derivatives we
acylated the corresponding 5-substituted benzo[b]thiophenes when it was possible.
J. Heterocyclic Chem., 38, 1025 (2001).
It has been described that Friedel-Crafts acylation of
described in the literature [10], yielded 5-hydroxybenzo-
[b]thiophene only in moderate yields (32%). In a second
attempt, 5-aminobenzo[b]thiophene sulfate 6, obtained by
reduction of the nitro compound with hydrazine mono-
hydrate and Raney nickel [10], was converted to the hydroxy
derivative via a Bücherer reaction. This method was aban-
doned due to its poor yield (5%). We then tried to convert the
amine sulfate to the 5-hydroxy derivative by forming the
diazonium salt of the amine, followed by the generation and
oxidation of the benzo[b]thiophenyl radical (Scheme 2) [11].
This reaction is fundamentally different from the previous
thermal method via benzo[b]thiophenyl cation described in
the literature [8]. The product was obtained by this method
with a moderate yield (40%) . Finally, 5-hydroxybenzo-
[b]thiophene was more easily obtained when starting from
4-methoxybenzenethiol according to Scheme 2. Cyclization
of (arylthio)acetaldehyde dialkyl acetals has been exten-
sively used to synthesize a wide variety of benzo[b]thio-
phenes, but very poor yields were obtained for 5-methoxy-
benzo[b]thiophene in neat polyphosphoric acid (PPA) at
180 °C [12]. Although better yields are obtained in a hetero-
geneous system of PPA and chlorobenzene, no cyclization
5-substituted benzo[b]thiophene derivatives gives
different isomers depending on the susbstituent; benzo[b]-
thiophene derivatives with weakly activating or
deactivating substituents such as chloro or acetoxy, mainly
give the 3-acylated product [5]. Acetylation of 5-methyl-
benzo[b]thiophene gives a mixture of the 2- and 3-ketone
derivatives in which the 3-isomer predominates [6]. A very
similar mixture of isomers is obtained when the starting
material is benzo[b]thiophene itself [7]. Finally, although
we also needed 3-acylbenzo[b]thiophenes with activating
substituents at the 5-position, they could not be obtained
directly from the acetylation of their corresponding
benzo[b]thiophenes: the acylation of benzo[b]thiophenes
containing 5-hydroxy, 5-methoxy or 5-amino groups at the
5 position occurs mainly on the benzene ring [5]. For this
reason, these types of derivatives had to be obtained from
benzo[b]thiophenes already acylated at the 3 position.
In this paper we describe the synthesis of 3-acyl-5-
substitutedbenzo[b]thiophenes by Friedel-Crafts acylation
of 5-substitutedbenzo[b]thiophenes. The starting
compounds for the acylating reactions were synthesized
according to described methods, which in most cases, were
modified in order to optimize the yields and to facilitate
the isolation of the product.
5-Nitrobenzo[b]thiophene was synthesized according to
the literature [8,9], with slight modifications. In the first
step, 5-nitro-2-chlorobenzaldehyde was treated with
sodium sulfide nonahydrate and ethyl bromoacetate in
basic medium, yielding ethyl 5-nitrobenzo[b]thiophene-2-
carboxylate 1 (Scheme 1). Alkaline hydrolysis of this
compound gave the corresponding acid 2, which was
decarboxylated in copper-quinoline to 5-nitrobenzo[b]-
thiophene 3 following described methods [8].
5-Acetoxybenzo[b]thiophene 4 was readily available by
reaction of 5-hydroxybenzo[b]thiophene 5 with acetic
anhydride [9]. Four different methods were tried in order to
obtain 5-hydroxybenzo[b]thiophene (Scheme 2). Decar-
boxylation of 5-hydroxybenzo[b]thiophene-2-carboxylic
acid with copper-quinoline, following the synthetic pathway

1026
Vol. 38
S. Pérez-Silanes, J. Martínez-Esparza,
A. M. Oficialdegui, H. Villanueva, L. Orús and A. Monge
was observed for p-methoxyphenylacetaldehyde dimethyl
acetal, and the starting material was quickly degraded [13].
We describe here conditions that support the synthesis of
5-methoxybenzo[b]thiophene 8 by cyclization of
p-methoxyphenylacetaldehyde diethyl acetal 7 instead of
dimethyl acetal. The change of methyl acetal by ethyl acetal
could be important in this reaction. A better product yield is
sometimes obtained using diethyl acetals as the starting
material instead of the corresponding dimethyl acetals [14].
The acetal was synthesized by reaction of p-methoxy-
benzenethiol with bromoactaldehyde diethyl acetal and
1,8-diazabycicle[5.4.0]undec-7-ene (DBU), according to an
adaptation of a synthesis of sulfides described in the
literature [15]. Reaction of 5-methoxybenzo[b]thiophene 8
with boron tribromide afforded 5 in 50% yield
5-Halobenzo[b]thiophene derivatives were better
prepared by reaction of their corresponding (arylthio)-
acetaldehyde diethyl acetals with PPA in chlorobenzene as
shown in Scheme 3. 5-Fluorobenzo[b]thiophene 9 was
obtained according to literature [16]. 5-Chlorobenzo[b]-
thiophene 10 was prepared in a similar way [2], and was
also prepared by two alternative routes (Scheme 3); in the
first one, 5-chlorobenzo[b]thiophene-2-carboxylic acid 11
was decarboxylated with copper-quinoline, but the yield
was not satisfactory (19%). 5-chlorobenzo[b]thiophene-2-
carboxilic acid was prepared from ethyl 5-nitrobenzo[b]-
thiophene-2-carboxylate according to a previously
described method [17]. In the second one, the sulfate of
5-aminobenzo[b]thiophene 6 was diazotizated according
to a classic Sandmeyer reaction, but the yield of the

1027
Sep-Oct 2001
Synthesis of New 5-Substitutedbenzo[b]thiophene Derivatives
Table I
Yields and Reaction Conditions for the Acetylation and/or Acylation of Benzo[b]thiophene and 5-Substituted Benzo[b]thiophene
Compound
R
Acylating agent
Reaction
Time (hours)
Catalyst/solvent
R'
Yield
(%)
Ref.
12
13
14
15
16
17
18
19
20
21
22
23
NO
NO
CH
CH
H
Ac O
24
48
8
48
48
48
6
48
56
48
39
24
FeCl /AcOH
CH
3
50
35
60
37
40
27
35
43
58
43
39
60
-
-
[5]
-
-
-
[9]
-
[2]
[2]
-
2
2
3
3
2
3
Cl(CH ) COCl
AlCl /CHCl
CH CH Cl
2 2
3
3
2
2
Ac O
BF ·EtO /C H
CH
2
3
2
6
6
3
Cl(CH ) COCl
AlCl /CHCl
CH CH Cl
2 2
3
3
3
3
3
3
3
3
3
3
2
2
Cl(CH ) COCl
AlCl /CHCl
CH CH Cl
2 2
3
2
2
H
Cl(CH ) COCl
AlCl /CHCl
CH CH CH Cl
2 3
3
2
2
2
CH COO
AcCl
AlCl /CHCl
CH
3
3
3
CH COO
Cl(CH ) COCl
AlCl /CHCl
CH CH Cl
3
2 2
3
2
2
F
F
F
AcCl
AlCl /CHCl
CH
3
3
Cl(CH ) COCl
AlCl /CHCl
CH CH Cl
2 2
3
2 2
Cl(CH ) COCl
AlCl /CHCl
CH CH CH Cl
2 3
3
2
2
2
Cl
AcCl
AlCl /CHCl
CH
[2,17]
3
3
reaction was also slightly higher than that obtained for the
decarboxylation, which was low (23%). In conclusion, the
cyclization of the acetal seems to be the best synthetic
method, presenting a significant higher yield (73%).
Finally, destruction of the catalyst in the reaction
mixture was carried out in most cases by slow addition of
dilute sulfuric acid. The rate of the addition seems to be
critical for the yield of the reaction, probably because rapid
addition causes destruction of the benzo[b]thiophene ring.
Reaction conditions for acetylation and acylation of
benzo[b]thiophene and 5-substituted benzo[b]thiophene
are summarized in Table I.
In general, better yields were obtained in acetylation
than in acylation reactions. On the other hand, no
significant differences were found between yields of the
different benzo[b]thiophenes with 3-chloropropionyl
chloride, being the yields moderate in each case. However,
acylation with 4-chlorobutanoyl chloride afforded lower
yields (compounds 17 and 22), even though the method
followed was similar to that used to synthesize the
propanone derivatives (compounds 16 and 21).
3-Acetyl-5-nitrobenzo[b]thiophene 12 was obtained by
acetylation of 3 with acetic anhydride in refluxing acetic
acid in the presence of a catalytic amount of anhydrous
iron(III)chloride. Under these conditions, a small amount
of the 2-isomer also formed and could be identified in the
1
mixture by H-nmr. We could not detect formation of the
2-isomer in the other acylation reactions of benzo[b]thio-
phene derivatives with electron-withdrawing substituents
such as acetoxy, chloro or fluoro, under the conditions that
were used. The method previously described for the
acetylation of 5-chlorobenzo[b]thiophene [18] was slightly
modified in a previous work in our laboratory in order to
obtain both the 5-chloro and the 5-fluoro-3-acetyl deriva-
tives (compounds 20 and 23, Table I) [2]. Acylation of all
benzo[b]thiophene derivatives with 3-chloropropionyl
chloride (compounds 13, 15, 16, 19 and 21) and with
4-chlorobutanoyl chloride (compounds 17 and 22) were
carried out using chloroform as solvent and aluminum
trichloride as catalyst.
In conclusion, we have synthesized new 3-acyl-5-
substitutedbenzo[b]thiophene derivatives using Friedel-
Crafts acylation of benzo[b]thiophene derivatives. A
number of different methods were evaluated in order to
discover the best synthetic route to each of the 5-substi-
tuted benzo[b]thiophene derivatives.
Acylation of both benzo[b]thiophene and 5-methyl-
benzo[b]thiophene gives a mixture of the 2- and 3-isomers,
in which the 3-isomer predominates (about 80%). The
desired 3-isomer could be separated by flash chromato-
graphy or by recrystallization of the mixture from
dichloromethane/light petroleum (compounds 14, 15, 16
and 17). The 2-isomers were not isolated because this was
not of interest in our investigation; nevertheless, as in the
case of the acetylation reaction, their presence in the crude
EXPERIMENTAL
Melting points were determined using a Mettler FP82+FP80
apparatus and are uncorrected. Elemental analyses were obtained
from vacuum-dried samples (over phosphorus pentoxide at 4 mm
Hg, 24 hours, at ca. 80-100 °C). Infrared spectra were recorded
on a Perkin-Elmer 1600 series FTIR apparatus, using potassium
bromide tablets for solid products and sodium chloride plates for
1
-1
1
reaction product was easily detected by H-nmr.
liquid products; the frequencies are expressed in cm . The H

1028
Vol. 38
S. Pérez-Silanes, J. Martínez-Esparza,
A. M. Oficialdegui, H. Villanueva, L. Orús and A. Monge
NMR spectra were obtained on a Brucker AC-200E (200 MHz)
instrument, with tetramethylsilane as the internal reference, at a
5-Methoxybenzo[b]thiophene (8).
All the equipment necessary for this reaction must be dried in
an oven. Chlorobenzene was dried with calcium hydride and
distilled before use.
concentration of ca. 0.1 g/mL and with dimethyl sulfoxide-d
6
(DMSO-d ) or chloroform (CDCl ) as the solvent; the chemical
6
3
shifts are reported in parts per million (PPM) of tetramethylsilane
in δ units, and the J values are given in hertz (Hz). The mass
spectra were recorded on a Hewlett-Packard 5988-A instrument
at 70 eV.
Thin-layer chromatography (TLC) was carried out on silica gel
(DSF-5, Cammaga 0.3 mm thickness) with the indicated
solvents, and the plates were scanned under ultraviolet light at
254 and 366 nm. Column chromatography was carried out with
Merck silica gel 60 (70-230 mesh ASTM).
A mixture of polyphosphoric acid (PPA) (3.64 mL) and
chlorobenzene was refluxed with vigorous stirring under an
atmosphere of dry nitrogen. 4-Methoxyphenylthioacetaldehyde
diethyl acetal (7) was added drop by drop to this mixture. The
reaction mixture was refluxed for 24 hours and then allowed to
cool. Chlorobenzene was decanted and water (50 mL) was added
to the PPA and stirred for 3 hours. The organic layers were
collected, washed with water and dried with anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure and
the product purified by flash chromatography using light
petroleum as eluent. The product was obtained as a liquid that
Elemental analyses were performed on a Carlo -Erba 1106
instrumental apparatus and the experimentally determined values
are within ± 0.4% of the theoretical values.
1
was pure enough for the next reaction, yield 55%. H-nmr
(deuteriochloroform): δ 3.87 (s, 3H, OCH ); 6.99 (dd, 1H, H ,
3
6
Ethyl 5-Nitrobenzo[b]thiophene-2-carboxylate (1).
J
= 2.3, J = 8.8); 7.23-7.27 (m, 2H, H +H ); 7.43 (d, 1H, H );
46
67 3 4 2
A solution of 2-chloro-5-nitrobenzaldehyde (15.0 g, 0.081 mol)
in ethanol (50 mL) was added to a solution of sodium sulfide non-
ahydrate (19.41 g, 0.081 mol) in ethanol (1.0 L) at 40 °C. The reac-
tion mixture was refluxed for two hours, and then ethyl
bromoacetate (9.0 mL, 0.081 mol) was added drop by drop. The
reaction temperature was kept at 50 °C, triethyl amine (11 mL) was
added and the reaction mixture was allowed to stand overnight at
room temperature. The precipitate which formed during this time
was filtered and recrystallized from light-petroleum/ethyl acetate,
7.72 (d, 1H, H ).
7
5-Hydroxybenzo[b]thiophene (5).
a) With Copper(II)nitrate and Copper(I)oxide.
5-Aminobenzo[b]thiophene sulfate (6) (0.50 g, 0.002 mol) was
added to a 30 mL of 40% solution of sodium hydrogen sulfite in
water. The reaction was refluxed for 48 hours and then cooled.
Sodium hydroxide was added until basic pH was obtained, and
the reaction mixture was refluxed again for one hour. After
cooling the reaction, the reaction was extracted with diethyl ether
(15 mL) to remove unreacted amine. The reaction was acidified
by adding slowly concentrated hydrochloric acid and then
extracted with diethyl ether (2x15 mL). The collected organic
layers were dried over anhydrous sodium sulfate and the solvent
evaporated under reduced pressure. Further purification was not
needed, yield 5%.
1
15.24 g (75%), mp 165 °C; H-nmr (deuteriochloroform): δ 1,36
(t, 3H, CH CH O); 4,38 (c, 2H, CH CH O); 8,28 (s, 2H, H +H );
3
2
3
2
6
7
8,36 (s, 1H, H ); 8,92 (s, 1H, H ).
3
4
Anal. Calcd. for C H NO S: C, 52.59; H, 3.59; N, 5.58.
11
9
4
Found: C, 52.41; H, 3.68; N, 5.41.
5-Nitrobenzo[b]thiophene-2-carboxylic Acid (2).
A solution of ethyl 5-nitrobenzo[b]thiophene-2-carboxylate
(1) (10 g, 0.040 mol) in ethanol (250 mL) and water (60 mL) was
treated with 85% potassium hydroxide (3.8 g, 0.068 mol) and the
reaction mixture refluxed for two hours. The reaction was cooled
and the salt of the acid filtered and washed with isopropanol. The
salt was dissolved in water, and concentrated hydrochloric acid
was added drop by drop until pH became acidic. The solid was
b) By Bücherer Reaction.
5-Aminobenzo[b]thiophene sulfate (6) (1.8 g, 0.0012 mol) was
dissolved in sulfuric acid (35%). The temperature was cooled to
15 °C and ice (12.5 g) was added to bring the temperature to
0-5 °C. A solution of sodium nitrite (1.06 g, 0.016 mol) in water
(12 mL) was then added slowly under the surface at such a rate
that the temperature did not exceed 5 °C. The reaction was stirred
for 5 minutes, and then urea (200 mg) was added to destroy the
remaining nitrite. Copper nitrate (150 g) in water (200 mL) and
copper(I)oxide (1.6 g) was added successively, and the reaction
mixture was shaken vigorously for 10 minutes. The product was
extracted with diethyl ether (3x50 mL) and the collected organic
layers washed with water and dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure and
the product purified by flash chromatography (toluene). (40%).
M.p.: 104 °C;
filtered, washed with water and recrystallized from water/ethanol
1
7.56 g (85%), mp 238 °C; H-nmr (dimethylsulfoxide-d ): δ 8,30
6
(s, 2H, H +H ); 8,32 (s, 1H, H ); 8,96 (s, 1H, H )
6
7
3
4
Anal. Calcd. for C H NO S: C, 48.43; H, 2.23; N, 6.28.
9
5
4
Found: C, 48.21; H, 2.36; N, 6.54.
4-Methoxythiophenoxylacetaldehyde Diethyl Acetal (7).
1,8 Diazabicyclo[5.4.0]undec-7-ene (DBU) (5.4 mL,
0.036 mol) was added dropwise to a stirred solution of
4-methoxybenzenethiol (5.00g, 0.036 mol) and bromoacetalde-
hyde diethyl acetal (7.04 g, 5.03 mL, 0.036 mol) in toluene
(80 mL) in an ice bath. The reaction mixture was allowed to stand
for 24 hours at room temperature and then filtered. The filtrate
was washed with water, dried with anhydrous sodium sulfate and
evaporated to dryness under reduced pressure. The product was
purified by column chromatography (light petroleum to light
c) By Removal of Methoxy from 5-methoxybenzo[b]thiophene.
A solution of (8) (2.80 g, 0.017 mol) in dichloromethane
(48 mL, previously dried over calcium chloride and freshly
distilled) was placed in a dried 100 mL three-necked found-
bottomed flask fitted with two rubber septums and a calcium
1
petroleum/toluene 1:1), obtaining a liquid. Yield: 65%. H-nmr
(deuteriochloroform): δ 1.16 (t, 6H, CH CH ); 3.04 (d, 2H,
chloride drying tube. The reaction was purged with N and
2
3
2
SCH ); 3.48-3.73 (m, 4H, O(CH ) ); 3.84 (s, 3H, OCH ); 3.58
cooled at 0 °C in an ice-bath for half an hour. A solution of 1 M
2
2 2
3
(t, 1H, SCH CH); 6.74 (d, 2H, H +H ); 7.29 (d, 2H, H +H ).
boron tribromide in dichloromethane (22.0 mL, 0.017 mol) was
2
2
6
3
5

1029
Sep-Oct 2001
Synthesis of New 5-Substitutedbenzo[b]thiophene Derivatives
added drop by drop. The reaction was stirred for 3 hours at room
temperature and monitored by TLC (toluene). When the reaction
finished, water (20 mL) was slowly added. The organic layer was
washed with water, dried with anhydrous sodium sulfate, and
evaporated under reduced pressure. The product was purified by
flash chromatography (toluene). Yield: 50%. mp 102-104 °C;
phase was dried with anhydrous sodium sulfate and the solvent
evaporated under reduced pressure. The product was purified by
chromatography using toluene as eluent (50%). mp 147 °C;
1
H-nmr (deuteriochloroform): δ 2,67 (s, 3H, CH ); 7,95
3
(d, 1H, H ); 8,26 (d, 1H, H ); 8,42 (s, 1H, H ); 9,62 (s, 1H, H )
7
6
2
4
Anal. Calcd. for C H NO S: C, 54.30; H, 3.18; N, 6.33.
10
7
3
1
Found: C, 53.99; H, 3.43; N, 5.96.
H-nmr (deuteriochloroform): δ 4.83 (s, 1H, OH); 6.91 (dd, 1H,
H ); 7.23 (d, 1H, H ); 7.24 (d, 1H, H ); 7.44 (d, 1H, H ); 7.71
6
2
4
3
3-Cloro-1-(5-nitrobenzo[b]thiophen-3-yl)-1-propanona (13).
(d, 1H, H ).
7
To a solution of aluminium trichloride (0.65 g) in dry chloro-
form (20 mL) at room temperature a solution of 5-nitro-
benzo[b]thiophene (3) (1.00 g, 5.59 x 10-3 mol) and 3-chloro-
propionyl chloride (0.65 mL, 6.64 x 10-3 mol) in chloroform
(40 mL) was added drop by drop. After 24 hours of reaction at
room temperature, the same quantities of aluminium trichloride
and 3-chloropropionyl chloride were added. The reaction was
allowed to react for another 48 hours, and after that cooled with
an ice-salt bath. Then, 1.5 N hydrochloric acid (100 mL) was
added drop by drop with efficient stirring. The organic layer was
decanted and washed with diluted sodium hydrogen carbonate
and water. The organic phase was dried with anhydrous sodium
sulfate and the solvent evaporated under reduced pressure. The
product was purified by chromatography using light
Anal. Calcd. for C H OS: C, 55.67; H, 3.09. Found: C, 55.28;
H, 3.11.
8
6
5-Chlorobenzo[b]thiophene (10).
a) By Decarboxylation of 5-Chlorobenzo[b]thiophene-2-
carboxylic Acid.
To a solution of 5-chlorobenzo[b]thiophene-2-carboxylic acid
[17] (1.00 g, 0.005 mol) in quinoline (50 mL) copper (0.40 g )
was added. The reaction mixture was heated with magnetic
stirring at 180-190 °C for half an hour and allowed to cool. It was
then extracted with diethyl ether (3 x 50 mL) and the collected
organic layers washed thoroughly with 6 N hydrochloric acid
until the aqueous layer became nearly colorless. The organic
phase was dried with anhydrous sodium sulfate and the solvent
evaporated under reduced pressure. No further purification was
needed (18%).
1
petroleum/toluene (1:3) as eluent (30%). mp 128 °C; H-nmr
(deuteriochloroform): δ 3,51 (t, 2H, CH CO); 3,98 (t, 2H,
2
CH Cl); 7,99 (d, 1H, H ), 8.29 (dd, 1H, H ); 8,49 (s, 1H, H );
2
7
6
2
9,64 (d, 1H, H ).
Anal. Calcd. for C H ClNO S: C, 48.98; H, 2.97; N, 5.19.
Found: C, 48.63; H, 2.81; N, 5.35.
4
b) By diazotization of 5-Aminobenzo[b]thiophene.
11
8
3
-3
5-Aminobenzo[b]thiophene sulfate (6) (0.50 g, 3.30 x 10
mol) was dissolved in sulfuric acid (0.6 mL) and water (1.0 mL).
The solution was cooled at 15 °C. Ice (1.60 g) was added and the
solution cooled at 0-5 °C. A solution of sodium nitrite (0.14 g) in
water (1.50 mL) at 0 °C was added slowly keeping the reaction
temperature below 5 °C. After finishing the addition, a solution
of copper(II)chloride (0.27 g) in water (2.7 mL) was added and
the reaction stirred at room temperature for half an hour. The
reaction was then refluxed for one hour. After cooling, it was
poured over water and extracted with diethyl ether. The organic
phase was washed with water and dried with anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure and
the product purified by chromatography using light petroleum as
eluent (23%).
3-Chloro-1-(5-methylbenzo[b]thiophen-3-yl)-1-propanone (15).
To a solution of aluminum trichloride (1.35 g) in dry chloro-
form (20 mL) cooled at 0 °C, a solution of 5-methylbenzo[b]thio-
phene (1.50 g, 0.010 mol) and 3-chloropropionyl chloride
(0.9 mL, 0.010 mol) in dry chloroform (20 mL) was slowly
added. The reaction mixture was allowed to react for 48 hours,
and cooled. After cooling the reaction with an acetone-carbon
dioxide bath, a solution of 96% sulfuric acid (0.8 mL) and water
(12 mL) was slowly added. The organic layer was decanted and
the aqueous layer extracted with dichlomethane. The collected
organic phases were washed with water and dried with anhydrous
sodium sulfate. The solvent was evaporated under reduced
pressure and the product purified by chromatography (light
Cyclization of the Acetal with PPA.
petroleum to light petroleum/toluene 9:1). Yield: 37%. mp
1
A better yield of 10 was obtained by reaction of 4-chloro-
phenylthiooxyacetaldehyde diethyl acetal with a refluxing
mixture of PPA and chlorobenzene as it has been described [2].
100-102 °C; H-nmr (deuteriochloroform): δ 2.45 (s, 3H, CH );
3
3.41 (t, 2H, COCH ); 3.90 (t, 2H, CH Cl); 7.21 (d, 1H, H ,
2
2
6
J = 8.2); 7.68 (d, 1H, H ); 8.22 (s, 1H, H ); 8.53 (s, 1H, H ).
7
2
4
1
mp liquid. Yield: 80% [12] and 73% [2]; H-nmr (deuterio-
Anal. Calcd. for C H ClOS: C, 62.27; H, 4.39. Found: C,
12 11
chloroform): δ 7,26-7,32 (m, 2H, H +H ); 7,50 (d, 1H, H ,
62.11; H, 4.65.
2
6
3
J = 5,4); 7,76-7,80 (m, 2H, H +H ).
4
7
1-(3-Benzo[b]thiophenyl)-3-chloro-1-propanone (16).
To a solution of aluminum trichloride (20.50 g, 0.14 mol) in
Anal. Calcd. for C H ClS: C, 56.97; H, 2.97. Found: C, 56.64;
8
5
H, 3.06.
dry chloroform (75 mL) cooled at 0 °C and in N atmosphere, a
2
3-Acetyl-5-nitrobenzo[b]thiophene (12).
solution of benzo[b]thiophene (18.78 g, 0.14 mol) and 3-chloro-
propionyl chloride (15.9 mL, 0.14 mol) in dry chloroform
(75 mL) was added as such rate that the addition was completed
after 2 hours. The reaction mixture was allowed to react for
24 hours, and then refluxed for one hour. The reaction was cooled
with an acetone-carbon dioxide bath and a solution of 96%
sulphuric acid (9.5 mL) and water (150 mL) was slowly added.
The organic layer was decanted, washed with water and dried
with anhydrous sodium sulfate. The solvent was evaporated
A solution of 5-nitrobenzo[b]thiophene (3) (1.00 g, 5.59 x
10 mol), acetic anhydride (5.0 mL) and iron trichloride (0.50 g)
-3
was refluxed for 24 hours. The same quantity of iron trichloride
and acetic anhydride were then added and the reaction was
refluxed for another 24 hours. The reaction was diluted with
water (250 mL), filtered to remove inorganic salts, and extracted
with ethyl acetate (2 x 40 mL). The organic layer was washed
with diluted sodium hydrogen carbonate and water. The organic

1030
Vol. 38
S. Pérez-Silanes, J. Martínez-Esparza,
A. M. Oficialdegui, H. Villanueva, L. Orús and A. Monge
under reduced pressure and the product purified by flash chroma-
tography (light petroleum to light petroleum/ethyl acetate 95:5).
Yield: 40%. mp 55-57 °C H-nmr (deuteriochloroform): δ 3,43
solvent was evaporated under reduced pressure and the product
purified by recrystallisation from light petroleum (39%). H-nmr
1
1
(deuteriochloroform): δ 2.23 (q, 2H, COCH CH ); 3.16 (t, 2H,
2
2
(t, 2H, CH CO); 3,87 (t, 2H, CH Cl); 7,32-7,48 (m, 2H, H +H ),
COCH ); 3.67 (t, 2H, CH Cl); 7.10-7.20 (m, 1H, H ); 7.74
2
2
5
6
2
2
6
7,80 (d, 1H, H , J= 7,6); 8,24 (s, 1H, H ); 8,47 (d, 1H, H ).
(dd, 1H, H , J = 9.0, J = 4.8); 8.37 (s, 1H, H ); 8.43 (dd, 1H,
4
2
7
7
67
F7
2
Anal. Calcd. for C H ClOS: C, 58.80; H, 4.01. Found: C,
H , J = 10.4, J = 2.6).
11
9
4
F4
46
59.01; H, 3.93.
Anal. Calcd. for C H ClFOS: C, 56.14; H, 3.90. Found: C,
12 10
56.49; H, 4.19.
1-(3-Benzo[b]thiophenyl)-4-chloro-1-butanone (17).
Acknowledgments
To a solution of aluminium trichloride (10.00 g, 0.075 mol) in
dry chloroform (40 mL) cooled at 0 °C and in N atmosphere, a
The authors are grateful to VITA-INVEST S.A. for financial
support.
2
solution of benzo[b]thiophene (10.00 g, 0.075 mol) and
4-chlorobutanoyl chloride (10.5 mL, 0.075 mol) in dry chloro-
form (40 mL) was slowly added. The reaction mixture was
allowed to react for 24 hours, and then refluxed for one hour. The
reaction was cooled with an acetone-carbon dioxide bath and a
solution of 96% sulphuric acid (4.75 mL) and water (80 mL) was
slowly added. The organic layer was decanted, washed with
water and dried with anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure and the product purified by
recrystallisation from light petroleum (27%). The product was
REFERENCES AND NOTES
[*] Address correspondence to this author at Centro de
Investigación en Farmacobiología Aplicada (CIFA). Universidad de
Navarra, C/ Irunlarrea s/n, 31080, Pamplona. (Spain). e-mail:
amonge@unav.es Phone: 3448 425600 ext. 6343. Fax 3448425652.
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[4] A. Monge Vega, J. Del Rio Zambrana, B. Lasheras Aldaz, J.
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Acin. (Vita-Invest, S.A., Spain). Int. Appl. WO 9902516 A1 21 Jan 1999,
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[5] B. Iddon and R. M. Scrowston. Adv. Heterocyclic Chem., 11,
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[6] Y. Matsuki and T. Kanda. Chem. Abstr., 62: 16172f (1965).
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1
characterized as an oil. H-nmr (deuteriochloroform): δ 2.22
(q, 2H, CH CH Cl); 3.13 (t, 2H, COCH ); 3.66 (t, 2H, CH Cl);
2
2
2
2
7.34-7.51 (m, 2H, H +H ); 7.83 (d, 1H, H , J = 8.0); 8.25 (s, 1H,
5
6
7
H ); 8.74 (d, 1H, H ).
2
4
1-(5-Acetoxybenzo[b]thiophen-3-yl)-3-chloro-1-propanone (19).
To a solution of aluminium trichloride (1.20 g) in chloroform
(35 mL) cooled at 0 °C a solution of 5-actoxybenzo[b]thiophene
-3
(4) (1.70 g, 8.85 x 10 mol)and 3-chloropropionyl chloride
-3
(1.12 g, 8.85 x 10 mol) in chloroform (60 mL) was added drop
by drop. The reaction was stirred at room temperature for
24 hours. Monitoring the reaction with TLC (toluene) showed
unreacted benzo[b]thiophene, so the reaction mixture was
refluxed for one hour and then allowed to cool. After cooling the
reaction with an ice-salt bath, a solution of 96% sulphuric acid
(0.5 mL) and water (7.5 mL) was slowly added drop by drop. The
organic layer was decanted, and the aqueous layer extracted with
dichloromethane. The collected organic phases were washed with
diluted sodium hydrogen carbonate and water. The organic phase
was dried with anhydrous sodium sulfate and the solvent evapo-
rated under reduced pressure. The product was purified by chro-
1
matography using toluene as eluent (38%). mp 84 °C; H-nmr
[10] M. Martin-Smith and M. Gates. J. Am. Chem. Soc., 20, 5351
(1956).
(deuteriochloroform): δ 2.35 (s, 3H, CH ); 3.47 (t, 2H, CH CO);
3
2
[11] T. Cohen, A. G. Dietz and J. R. Miser. J. Org. Chem., 42,
2053(1977).
[12] A. V. Sunthankar and B. D. Tilak. Proc. Indina. Acad. Sci.,
33A. 35 (1951).
[13] P. A. Plé, and L. J. Marnett. J. Heterocyclic Chem., 25,
1271(1988).
3.96 (t, 2H, CH Cl); 7.18 (dd, 1H, J = 8.6 and J = 1.8); 7.84
2
67
46
(d, 1H, H ); 8.35 (s, 1H, H ); 8.48 (d, 1H, H )
6
2
4
Anal. Calcd. for C H ClO S: C, 55.22; H, 3.89. Found: C,
13 11
3
55.49; H, 3.81.
4-Chloro-1-(5-fluorobenzo[b]thiophen-3-yl)-1-butanone (22).
[14] J. E. Banfield, W. Davies, B. C. Ennies, S. Middleton and Q.
N. Porter. J. Chem. Soc., 2603 (1956)
[15] O. Noboru, M. Hideyoshi, S. Tadashi and K. A Aritsune.
Synthesis, 952 (1980).
[16] B. Février, G. Dupas, Bourguignon and G. Queginer. J.
Heterocyclic Chem., 30, 1085 (1993).
[17] N. B. Chapman, K. Clarke and S. D. Saraf. J. Chem. Soc. (C).,
731 (1967).
To a solution of aluminium trichloride (2.05 g, 0.015 mol) in dry
chloroform (7.5 mL) cooled at 0 °C and in N atmosphere, a solu-
2
tion of 5-fluorobenzo[b]thiophene (2.30 g, 0.015 mol) and
4-chlorobutanoyl chloride (1.7 mL, 0.015 mol) in dry chloroform
(7.5 mL) was slowly added. The reaction mixture was allowed to
react for 24 hours. The reaction was cooled with an acetone-carbon
dioxide bath and a solution of 96% sulphuric acid (1 mL) and
water (15 mL) was slowly added. The organic layer was decanted,
washed with water and dried with anhydrous sodium sulfate. The
[18] M. S. Shanta and R. M. Scrowston. J. Chem. Soc. (C)., 2084
(1967).