Preparation of 3-aminoalkylbenzo[b]thiophenes

Article abstract of DOI:10.1002/jhet.5570390611

We report an efficient entry into substituted 3-(ω-aminoalkyl)-benzo[b]thiophenes that allows rapid generation of structural diversity. Alkylation of α,ω-dihaloketones with thiophenols followed by acid-catalysed cyclisation led to an efficient synthesis o

Full text of DOI:10.1002/jhet.5570390611

Nov-Dec 2002
Preparation of 3-Aminoalkylbenzo[b]thiophenes
1177
Frank Burkamp* and Stephen R. Fletcher
Department of Chemistry, Merck Sharp and Dohme Research Laboratories,
Neuroscience Research Centre, Terlings Park,
Eastwick Road, Harlow, Essex CM20 2QR, U.K.
Received December 18, 2001
We report an efficient entry into substituted 3-(w-aminoalkyl)-benzo[b]thiophenes that allows rapid gen-
eration of structural diversity. Alkylation of a,w -dihaloketones with thiophenols followed by acid-catalysed
cyclisation led to an efficient synthesis of 3-(w-aminoalkyl)benzo[b]thiophenes. 2-Carboethoxy derivatives
were prepared using a directed ortho-metallation approach. These derivatives were readily converted into
the corresponding amines.
J. Heterocyclic Chem., 39, 1177(2002).
In the course of investigating compounds as potential
anti-depressants we wanted access to a diverse set of sub-
stituted benzo[b]thiophenes. In particular, we required
benzo[b]thiophenes functionalised at the 3-position with a
variety of amino groups linked via an n-propyl (1) or n-
butyl chain (2).
After surveying known methodologies [1] we envisaged
an extension of the reported preparation of 3-methyl-
benzo[b]thiophene from thiophenol and chloroacetone [2].
Thus, S-alkylation of thiophenol was followed by
intramolecular condensation under strongly acidic condi-
tions at elevated temperature. We were intrigued by the
possibility that a,w-dihaloketones might be used in place
of chloroacetone to afford the required 3-(w -haloalkyl)-
benzo[b]thiophenes directly (Scheme 1) [3]. Our sequence
was consequently dependent both on a selective nucle-
ophilic mono-displacement of the a,w -dihaloketone (4)
with a substituted thiophenol (5) and on the stability of the
w-chloroalkyl derivatives (6) and (3) towards the cyclisa-
tion conditions. The approach was attractive, since it
would take advantage of commercially available substi-
tuted thiophenols and non-commercial thiophenols could
be effectively accessed via the corresponding phenols
(Newman-Kwart rearrangement) [4]. It was also antici-
pated that the required a -haloketones (4) would be acces-
sible by Clibbens-Nierenstein [5] reaction of the appropri-
ate acid chloride.
We set out to prepare late stage intermediates which
could be modified to enable introduction of the amino and
benzo[b]thiophene substituents independently. To provide
such flexibility we initially targeted 3-(w-chloroalkyl)-
benzo[b]thiophenes (3) substituted on the aromatic core
with a variety of groups including those suitable for subse-
quent modification via palladium cross-coupling reactions
either directly, such as halogen substituents, or following
modification, such as alkoxy substituents.
1,5-Dichloro-2-pentanone (4a) was prepared from 4-
chlorobutanoyl chloride by treatment with diazomethane
according to the literature [6]. Alternatively, the use of
commercial (trimethylsilyl)diazomethane circumvented
the use of diazomethane as a potential hazard and led to
similar results. The yields and purities of the crude product
1
obtained were >95 % as judged by H-nmr spectroscopy
on a laboratory scale of up to 0.4 mol, and the product
could be reacted in the next step without further purifica-

1178
F. Burkamp and S. R. Fletcher
Vol. 39
tion. As a possible alternative, the a -bromination of
5-chloro-2-pentanone according to Dumas [7] was also
investigated but led to inseparable mixtures of the 1- and
3-bromoisomers which decomposed on storage at -18°
within a few days. 1,5-Dichloro-2-pentanone, however,
proved stable on storage at 3° for several weeks.
With the required (4a) in hand, we were delighted to find
that a range of substituted thiophenols reacted selectively
at the a -position by stirring with the appropriate thiophe-
nol in N,N-dimethylformamide at room temperature for 2
hours, using potassium carbonate as base. The w-chloro
substituent proved inert under the reaction conditions
employed. After aqueous work-up, the crude a -arylthio
As depicted in Scheme 2, 2-bromo-5-fluorophenol (7)
was converted into the corresponding thiophenol (8) [8]
following the precedent of Newman and Kwart [4]. In
accordance with similar reports in the literature [9], we
found that heating the intermediate thiocarbamate neat
under a blanket of nitrogen for 3 hours at 230° resulted in a
clean rearrangement. The resulting S-thiocarbamoyl deriv-
ative could be saponified using 1 N sodium hydroxide in
ethanol at reflux to furnish the desired thiophenol in 60 %
yield after distillation. Alkylation of (8) using 1,6-
dichlorohexan-2-one (4b) [10] proceeded via displacement
of the chlorine adjacent to the carbonyl group to give (9).
Cyclisation afforded the 7-bromo-4-fluorobenzo[b]thio-
ketones (6) were dissolved in chlorobenzene and heated at
150° in the presence of polyphosphoric acid for 2 - 36
hours, depending on the electronic nature of the substituent
on the aromatic ring, to yield the required substituted 3-w-
(chloroalkyl)benzo[b]thiophenes (3) in moderate to good
overall yields.
phene (10) within 36 hours in 59 % yield after column
chromatography.
In exploring the influence of chain length on cyclisation,
it was found that the desired products could be obtained for
n > 2. Using 1,3-dichloroacetone (n = 1) and 1,4-dichloro-
In the cyclisation step, methoxy substituted thiophenols
readily cyclised within 2 hours whereas the halo-deriva-
tives required prolonged heating (in general 24 to 36
hours). a -Sulfenylated ketones (6) having electron with-
drawing groups on the aromatic ring such as nitro or
trifluoromethyl were found to be inert under the reaction
conditions (Table 1). m-Substituted thiophenols furnished
mixtures of 3,4- and 3,6-disubstituted benzo[b]thiophenes
in ratios of 1:1 (3-bromothiophenol) up to 1:3 (3-methoxy-
and 3-fluorothiophenol). These were separable by column
chromatography.
In order to prepare 3,4-disubstituted benzo[b]thiophenes
(3) regioselectively, the following blocking group strategy
was devised. It was envisaged that 2,5-disubstituted thiophe-
nols would cyclise in a regiospecific manner. Subsequent
removal of the substituent at the 7-position of the resultant
benzo[b]thiophene would afford the requisite 3,4-disubstitu-
tion pattern. Bromine was selected as the blocking group,
because of its robust nature and the possibility of reductive
removal. Furthermore, the bromine also offers further struc-
tural modification of the 3,4,7-trisubstituted benzo[b]thio-
phene core via transition metal mediated couplings [11].
Table 1
Results of Cyclisation Studies
Compound
R
R
n
X
Reaction Yield [a]
1
2
Time
(%)
(hours)
3a
3b
3c
3d
3e
3f
3g:3h
3i:3k
3l:3m
3n:3o
10
7-Br
7-OMe
5-Br
5-OMe
5-Br
H
H
H
H
H
H
H
H
H
3
3
3
3
1
2
3
3
3
3
4
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
60
3
96
51
60
3
85
55
60
60
20
3
20
60
60
60
60
_ [b]
_ [b]
23 : 24
19 : 61
13 : 46
_ [c]
59
5-Br
4-Br:6-Br
4-OMe:6-OMe
4-F:6-F
4-CF :6-CF
H
7-Br
H
3
3
4-F
4-F:6-F
4-F
11:12
13
CO Me
3:14
8
2
7-Br
CO Me
2
[a] Isolated yield; [b] Complex mixture obtained; [c] No product could
be detected.

Nov-Dec 2002
Preparation of 3-Aminoalkylbenzo[b]thiophenes
1179
2-butanone (n = 2), in an effort to prepare (3e) and (3f)
respectively, resulted in complex mixtures which were not
purified any further. In addition, substituting the w- chloro-
functionality for a methyl ester resulted in poor isolated
yields of the corresponding benzo[b]thiophenes (11, 12
and 13), presumably due to the harsh reaction conditions.
A selection of benzo[b]thiophenes synthesised following
this approach is shown in Table 1.
The substituted 3-(chloroalkyl)benzo[b]thiophenes (3a-
n) provide various opportunities for 2-dimensional struc-
tural modification. In our search for antidepressant com-
pounds we chose first to react the chloro functionality with
substituted piperazines to yield (14). Palladium mediated
couplings [11] of the aromatic halogen were then carried
out, leading to the desired targets (15) (Scheme 3).
An alternative strategy designed to enable derivatisation
of the piperazine at the final stage is outlined in Scheme 4.
Thus, chlorobutyl derivative (10) was reacted with 1-(2,3-
dihydro-1,4-benzodioxine-5-yl)piperazine to give (18) in
analogy to Scheme 3. Due to our specific interest in 4-flu-
oro-substituted benzo[b]thiophene cores, the 7-bromo sub-
stituent was removed via lithium aluminium hydride
reduction to give (19) rather than being utilised in trans-
ition metal mediated couplings. To further vary the 1,4-
benzodioxin motif on the piperazine, (10) was initially
reacted with N-Boc piperazine followed by reduction of

1180
F. Burkamp and S. R. Fletcher
Vol. 39
Table 2
the bromine and removal of the Boc-group to give the
4-fluorobenzothiophene derivative (17). This compound
readily underwent palladium mediated amination accord-
ing to Buchwald et al. [11b] as exemplified by the forma-
tion of (20, 21 and 22). Table 2 shows selected results of
our efforts following both strategies.
3-(Aminoalkyl)benzo[b]thiophenes Prepared
An alternative sequence was established to access
benzo[b]thiophene-2-carboxylates (26). Bridges et al.
reported a directed ortho-metallation-acylation approach
using fluorine as the directing group followed by displace-
ment of the activated fluorine [12]. In an extension of this
approach (Scheme 5), 3-fluoro-benzotrifluoride (23) was
metallated with lithium diisopropylamide in tetrahydrofu-
rane at –78° and equilibrated for 1 hour at the same tem-
perature. Trans-metallation to the corresponding zinc
derivative followed by palladium mediated acylation with
3-chloropropionyl chloride and substitution with methyl
thioglycolate in the presence of 1,8-diazabicyclo[5.4.0]-
undec-7-ene yielded the 6-trifluoromethylbenzo[b]thio-
phene-2-carboxylate (25) as the only detectable regioiso-
Compound
Starting
Material
R
n
NR R
Yield [a]
(%)
4
5
14a
14b
14c
14d
14e
14f
14g
14i
14k
14l
15a
15b
15c
15d
15e
17
3I
3d
3k
3b
3g
3e
3h
3l
4-OMe
5-OMe
6-OMe
7-OMe
4-Br
5-Br
6-Br
4-F
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
I
I
I
I
I
I
I
II
III
IV
I
62
81
53
71
65
78
47
55
90
57
89
71
80
80
85
81
86
67
27
39
74
1
mer ( H-nmr spectroscopy) in 40% overall yield.
Treatment with 1-(2-methoxyphenyl)piperazine afforded
the required target derivative (26).
Interestingly, reaction of (25) with phenethylamine fol-
lowed by trimethylaluminium-mediated cyclisation and
reduction of the resulting lactam with lithium aluminium
hydride afforded the tricyclic thiophene (27) in 40 % yield
(Scheme 6).
In conclusion, we have demonstrated two efficient
approaches from commercially available starting materials
to prepare substituted 3-(chloroalkyl)-benzo[b]thiophenes.
These sequences allow a minimum number of purification
steps involving column chromatography. It has also been
demonstrated that the advanced intermediate (10) provides
a specific entry into 4-fluorobenzo[b]thiophenes and may
be further modified orthogonally, resulting in a quick gen-
eration of structural diversity.
3b
3l
7-OMe
4-F
4-Ph
4-(4-Morpholinyl)
6-Ph
6-(4-Morpholinyl)
7-(4-Anisyl)
4-F
4-F, 7-Br
4-F
14e
14e
14g
14g
14h
10
10
18
17
17
I
I
I
I
V
VI
VI
I
VII
VIII
18
19
20
21
4-F
4-F
4-F
22
17
[a] Isolated yield.

Nov-Dec 2002
Preparation of 3-Aminoalkylbenzo[b]thiophenes
1181
EXPERIMENTAL
2-Bromo-5-fluorothiophenol (8).
This compound was obtained in 51% yield, 35 g colourless liq-
1
All reactions involving air- and/or water-sensitive reagents were
carried out under an atmosphere of nitrogen. Unless otherwise
noted, starting materials were obtained from commercial sources
and used without further purification. Solvents for reactions and
chromatography were also of commercial origin. Solutions in
organic solvents were dried over anhydrous sodium sulfate.
Melting points were determined on a Kofler hot-stage apparatus
and are uncorrected. The 1H nmr spectra were recorded on a Varian
Unity Plus-300 (300 MHz) spectrometer using deuteriochloroform
or deuteriodimethyl sulfoxide as solvent and tetramethylsilane as
internal standard. Mass spectra were obtained using a VG-quattro
spectrometer. Gas-chromatography coupled mass spectroscopy
was carried out using an HP5890 gas chromatograph with an
HP5971 EI mass spectrometer connected to chemstation software
(v 3.0). The column used was an RTX1 (15m by 0.25 mm inner
diameter) with a flow rate of 1 mL/minute and a temperature gradi-
ent as follows: 0 to 1 minute: 50°, heat up to 340° at 15°/minute,
hold at 340° for 1 minute. Column chromatography was performed
using silica gel 60, 70-230 mesh ASTM (Merck).
uid; bp: 82 - 92° / 10 torr (lit. [9]: bp: 112 - 116° / 35 torr).
H
nmr (deuteriochloroform): d 6.73 (td, J (F,H) = 6.8 Hz, J = 6.8
Hz, J = 2.2 Hz, 1H, CH), 7.08 (dd, J (F,H) = 6.8 Hz, J = 2.2 Hz,
1H, CH), 7.46 (dd, J (F,H) = 4.2 Hz, J = 6.8 Hz, 1H, CH).
General Procedure for the Preparation of 3-(w-Chloroalkyl)-
benzo[b]thiophenes (3).
At room temperature anhydrous potassium carbonate (1.1
equivalents) was added in one portion to a 1 molar solution of the
corresponding thiophenol in dry N,N-dimethyl formamide fol-
lowed by the dropwise addition of the corresponding a -chloro
ketone (4a, 4b or 4c; 1.1 equivalents). The mixture was stirred at
room temperature under nitrogen for one hour and poured onto
ice-water and the product was extraced into diethyl ether. The
organic extract was washed with water and brine, then dried over
anhydrous sodium sulfate and finally filtered and concentrated to
yield the crude a -sulfenylated ketones, which were used without
further purification.
A 1 molar solution of the a -sulfenylated ketone (6) in
chlorobenzene was heated up to 150° while stirring under nitro-
gen. Polyphosphoric acid (1mL / 5 mmoles substrate) was heated
in a round bottomed flask to yield a mobile clear liquid and then
added to the chlorobenzene solution. Stirring was continued for
the time indicated in Table 1 and the upper phase of the resulting
dark two-phase system was decanted off the polyphosphoric acid.
After adding the same amount of chlorobenzene, the mixture was
heated for another 30 minutes at 150° while stirring to extract the
remaining product. The decanted chlorobenzene phases were
combined and concentrated under reduced pressure using a rotary
evaporator and the dark residue was dissolved in diethyl ether
and adsorbed onto silica gel. Purification by column chromatog-
raphy yielded the title compounds as viscous oils.
2-(2-Aminoethyl)pyridine [13], spiro(1H-indene-1,4'-piperi-
dine) [14] and 1-(2,3-dihydro[1,4]benzodioxin-5-yl)piperazine
[15] were prepared according to the literature.
General Procedure for the Preparation of a -Chloroketones (4a)
[6], (4b) [10] and (4c)[16].
According to the literature preparation, the corresponding acid
chlorides were converted with diazomethane into the correspond-
ing a -diazomethyl ketones followed by treatment with hydrogen
chloride in diethyl ether (Clibbens-Nieren-stein reaction) [5].
1,5-Dichloropentan-2-one (4a) [6].
This compound was obtained in 97% yield,15 g colourless liq-
1
uid; bp: 60 - 66° / 0.01 torr (lit.[6]: 82%; 43 - 45° / 0.001 torr); H
nmr (deuteriochloroform): d 2,10 (m, 2H, CH2), 2.81 (t, J = 5.4
Hz, 2H, CH2), 3.60 (t, J = 4.8 Hz, 2H, CH2), 4.12 (s, 2H, CH2).
7-Bromo-3-(3-chloropropyl)benzo[b]thiophene (3a).
The product was purified by column chromatography (iso-
1,6-Dichlorohexan-2-one (4b) [10].
hexane/ethyl acetate = 20:1) to yield 0.91 g (96 %) of a yellow
1
oil; H nmr (deuteriochloroform): d 2,19 (m, 2H, CH2), 3.00 (t,
This compound was obtained in quantitative yield, 34.9 g
colourless liquid; bp: 74 - 80° / 0.01 torr (lit.[10]: 120 - 125° / 14
J = 5.7 Hz, 2H, CH2), 3.57 (t, J = 4.8 Hz, 2H, CH2), 7.21 (s, 1H,
CH), 7.27 (t, J = 6.0 Hz, 1H, CH), 7.50 (d, J = 6.0 Hz, 1H, CH),
7.71 (d, J = 6.0 Hz, 1H, CH).
Anal. Calcd. for C11H10BrClS•0.1 C6H14 (289.62): C, 46.72;
H, 3.85. Found: C, 46.59; H, 3.50.
1
torr); H nmr (deuteriochloroform): d 1.81 (m, 4H, CH2), 2.65
(m, 2H, CH2), 3.55 (m, 2H, CH2), 4.08 (s, 2H, CH2).
Methyl 5-Chloro-4-oxopentanoate (4c) [16].
This compound was obtained in quantitative yield, 31.8 g
colourless liquid (lit.[16]: 74 %); H nmr (deuteriochloroform):
3-(3-Chloropropyl)-7-methoxybenzo[b]thiophene (3b).
1
d 2.66 (m, 4H, CH2), 2.90 (m, 2H, CH2), 3.69 (s, 3H, CH3), 4.16
(s, 2H, CH2); Lit.: d 2.67 (t, J = 7 Hz, 2H, CH2), 2.90 (t, J = 7 Hz,
2H, CH2), 3.68 (s, 3H, CH3), 4.18 (s, 2H, CH2).
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 20:1) to yield 3.56 g (51 %) of a yellow
1
oil; H nmr (deuteriochloroform): d 2,19 (m, 2H, CH2), 3.17 (m,

1182
F. Burkamp and S. R. Fletcher
Vol. 39
2H, CH2), 3.39 (m, 2H, CH2), 3.86 (s, 3H, CH3), 6.78 (d, J = 6.3
Hz, 1H, CH), 7.12 (s, 1H, CH), 7.33 (dd, J = 6.0 Hz, J = 5.7 Hz,
1H, CH), 7.39 (d, J = 5.7 Hz, 1H, CH).
Anal. Calcd. for C12H13ClOS (240.75): C, 59.87; H, 5.44.
Found: C, 60.01; H, 5.38.
Anal. Calcd. for C12H13ClOS (240.75): C, 59.87; H, 5.44.
Found: C, 59.66; H, 5.41.
3-(3-Chloropropyl)-4-fluorobenzo[b]thiophene (3l).
The product was purified by column chromatography (iso-
1
hexane) to yield 1.61 g (13 %) of a yellow oil; H nmr (deuteri-
5-Bromo-3-(3-chloropropyl)benzo[b]thiophene (3c).
ochloroform): d 2,19 (m, 2H, CH2), 3.13 (t, J = 5.7 Hz, 2H, CH2),
3.58 (t, J = 4.9 Hz, 2H, CH2), 6.99 (dd, J(F,H) = 9.1 Hz, J = 8.9
Hz, 1H, CH), 7.08 (s, 1H, CH), 7.24 (m, 1H, CH), 7.24 (m, 1H,
CH), 7.59 (d, J = 6.1 Hz, 1H, CH).
Anal. Calcd. for C11H10ClFS (228.71): C, 57.77; H, 4.41.
Found: C, 57.43; H, 4.51.
The product was purified by column chromatography (iso-
1
hexane) to yield 1.31 g (85 %) of a yellow oil; H nmr (deuteri-
ochloroform): d 2,20 (m, 2H, CH2), 3.21 (m, 2H, CH2), 3.38 (m,
2H, CH2), 7.12 (t, J = 5.7 Hz, 1H, CH), 7.21 (s, 1H, CH), 7.57 (d,
J = 5.7 Hz, 1H, CH), 7.80 (d, J = 5.7 Hz, 1H, CH).
Anal. Calcd. for C11H10BrClS (289.62): C, 45.62; H, 3.48.
Found: C, 45.85; H, 3.67.
3-(3-Chloropropyl)-6-fluorobenzo[b]thiophene (3m).
The product was purified by column chromatography (iso-
hexane) to yield 5.67 g (46 %) of a yellow oil; H nmr (deuteri-
3-(3-Chloropropyl)-5-methoxybenzo[b]thiophene (3d).
1
ochloroform): d 2,20 (m, 2H, CH2), 2.99 (t, J = 5.8 Hz, 2H, CH2),
3.57 (t, J = 4.9 Hz, 2H, CH2), 7.10 (s, 1H, CH), 7.13 (ddd, J (F,H)
= 6.8 Hz, J = 6.8 Hz, J = 1.8 Hz, 1H, CH), 7.51 (dd, J (F,H) = 6.8
Hz, J = 1.8 Hz, 1H, CH), 7.67 (dd, J (F,H) = 3.9 Hz, J = 6.8 Hz,
1H, CH).
The product was purified by column chromatography (iso-
hexane/ ethyl acetate = 20:1) to yield 1.11 g (55 %) of a yellow
1
oil; H nmr (deuteriochloroform): d 1.81 (m, 2H, CH2), 3.13 (m,
2H, CH2), 3.37 (m, 2H, CH2), 3.91 (s, 3H, CH3), 6.95 (dd, J = 6.5
Hz, J = 1.7 Hz, 1H, CH), 7.11 (s, 1H, CH), 7.22 (d, J = 1.7 Hz,
1H, CH), 7.69 (d, J = 6.5 Hz, 1H, CH).
Anal. Calcd. for C12H13ClOS (240.75): C, 59.87; H, 5.44.
Found: C, 60.05; H, 5.70.
Anal. Calcd. for C11H10ClFS (228.71): C, 57.77; H, 4.41.
Found: C, 57.44; H, 4.35.
7-Bromo-3-(4-chlorobutyl)-4-fluorobenzo[b]thiophene (10).
4-Bromo-3-(3-chloropropyl)benzo[b]thiophene (3g).
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 20:1) to yield 9.44 g (59 %) of a yellow
solid; mp 65°; H nmr (deuteriochloroform): d 1.85 (m, 2H, CH,
The product was purified by column chromatography (iso-
hexane/ ethyl acetate = 20:1) to yield 1.85 g (23 %) of a yellow oil;
H nmr (deuteriochloroform): d 2,20 (m, 2H, CH2), 3.23 (m, 2H,
CH2), 3.48 (m, 2H, CH2), 7.13 (t, J = 6.0 Hz, 1H, CH), 7.22 (s, 1H,
CH), 7.57 (d, J = 6.0 Hz, 1H, CH), 7.79 (d, J = 6.0 Hz, 1H, CH).
Anal. Calcd. for C11H10BrClS•0.33C4H8O2 (289.62): C,
46.44; H, 4.00. Found: C, 46.68; H, 3.56.
1
1
CH2), 1.96 (m, 2H, CH, CH2), 3.11 (m, 2H, CH, CH2), 3.57 (m,
2H, CH, CH2), 6.93 (dd, J (F,H) = 8.5 Hz, J = 6.5 Hz, 1H, CH),
7.11 (s, 1H, CH), 7.40 (dd, J (F,H) = 3.0 Hz, J = 6.5 Hz, 1H, CH).
Anal. Calcd. for C12H11BrClFS (321.64): C, 44.81; H, 3.45.
Found: C, 44.95; H, 3.39.
Methyl 3-(4-Fluorobenzo[b]thiophene-3-yl)propionate (11).
The product was purified by column chromatography (iso-
6-Bromo-3-(3-chloropropyl)benzo[b]thiophene (3h).
The product was purified by column chromatography (iso-
1
1
hexane) to yield 0.12 g (3 %) of a yellow oil; H nmr (deuteri-
hexane) to yield 1.93 g (24 %) of a yellow oil; H nmr (deuteri-
ochloroform): d 2,75 (t, J = 5.7 Hz, 2H, CH2), 3.31 (t, J = 5.7 Hz,
2H, CH2), 3.68 (s, 3H, CH3), 6.99 (dd, J(F,H) = 8.9 Hz, J = 6.2
Hz, 1H, CH), 7.08 (s, 1H, CH), 7.25 (m, 1H, CH), 7.59 (d, J =
6.2 Hz, 1H, CH).
Anal. Calcd. for C12H11FSO2 (238.28): C, 60.49; H, 4.65.
Found: C, 60.42; H, 4.66.
ochloroform): d 2,14 (m, 2H, CH2), 2.96 (m, 2H, CH2), 3.59 (m,
2H, CH2), 7.09 (s, 1H, CH), 7.48 (dd, J = 6.7 Hz, J = 1.4 Hz, 1H,
CH), 7.62 (d, J = 6.7 Hz, 1H, CH), 7.98 (d, J = 1.4 Hz, 1H, CH).
Anal. Calcd. for C11H10BrClS•0.1C6H14 (289.62): C, 46.72;
H, 3.85. Found: C, 46.61; H, 3.50.
3-(3-Chloropropyl)-4-methoxybenzo[b]thiophene (3i).
Methyl 3-(6-Fluorobenzo[b]thiophene-3-yl)propionate (12).
The product was purified by column chromatography (iso-
The product was purified by column chromatography (gradient:
iso-hexane to iso-hexane/ethyl acetate = 20 :1) to yield 0.45 g (19
1
1
%) of a yellow oil; H nmr (deuteriochloroform): d 2.15 (m, 2H,
hexane) to yield 0.62 g (14 %) of a yellow oil; H nmr (deuteri-
CH2), 3.17 (t, J = 5.5 Hz, 2H, CH2), 3.57 (t, J = 5.0 Hz, 2H, CH2),
ochloroform): d 2,73 (t, J = 5.7 Hz, 2H, CH2), 3.14 (t, J = 5.7 Hz,
2H, CH2), 3.69 (s, 3H, CH3), 7.06 (s, 1H, CH), 7.12 (ddd, J (F,H)
= 6.8 Hz, J = 6.8 Hz, J = 1.9 Hz, 1H, CH), 7.51 (dd, J (F,H) = 6.8
Hz, J = 1.8 Hz, 1H, CH), 7.65 (dd, J (F,H) = 3.9 Hz, J = 6.8 Hz,
1H, CH).
3.92 (s, 3H, CH ), 6.73 (d, J = 6.0 Hz, 1H, CH), 6.96 (s, 1H, CH),
3
7.23 (t, J = 6.0 Hz, 1H, CH), 7.41 (d, J = 6.0 Hz, 1H, CH).
Anal. Calcd. for C12H13ClOS (240.75): C, 59.87; H, 5.44.
Found: C, 60.19; H, 5.51.
Anal. Calcd. for C12H11FSO2 (238.28): C, 60.49; H, 4.65.
Found: C, 60.09; H, 4.34.
3-(3-Chloropropyl)-6-methoxybenzo[b]thiophene (3k).
The product was purified by column chromatography (gradi-
Methyl 3-(7-Bromo-4-fluorobenzo[b]thiophene-3-yl)propionate
(13).
ent: iso-hexane to iso-hexane/ethyl acetate = 20 :1) to yield 1.46
1
g (61 %) of a yellow oil; H nmr (deuteriochloroform): d 2.18
(m, 2H, CH2), 2.97 (t, J = 5.5 Hz, 2H, CH2), 3.58 (t, J = 4.9 Hz,
2H, CH2), 3.87 (s, 3H, CH3), 6.94 (s, 1H, CH), 7.0 (dd, J = 6.8
Hz, J = 1.8 Hz, 1H, CH), 7.32 (d, J = 1.8 Hz, 1H, CH), 7.61 (d, J =
6.8 Hz, 1H, CH).
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 20:1) to yield 2.32 g (8 %) of a red oil; H
nmr (deuteriochloroform): d 2,73 (t, J = 5.7 Hz, 2H, CH2), 3.27
(t, J = 5.7 Hz, 2H, CH2), 3.68 (s, 3H, CH3), 6.92 (dd, J (F,H) = 8.5
1

Nov-Dec 2002
Preparation of 3-Aminoalkylbenzo[b]thiophenes
1183
Hz, J = 6.5 Hz, 1H, CH), 7.16 (s, 1H, CH), 7.38 (dd, J (F,H) = 3.2
Hz, J = 6.5 Hz, 1H, CH).
1-[3-(4-Methoxybenzo[b]thiophene-3-yl)propyl]-4-(2-methoxy-
phenyl)-piperazine (14a).
Anal. Calcd. for C12H10BrFSO2 (317.18): C, 45.44; H, 3.18.
Found: C, 45.58; H, 3.35.
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 0.46 g (62 %) of a yellow oil;
H nmr (deuteriochloroform): d 1.95 (m, 2H, CH, CH2), 2.50 (m,
1
Methyl 3-(3-Chloropropyl)-6-trifluoromethylbenzo[b]thiophene-
2-carboxylate (25).
2H, CH2), 2.67 (broad s, 4H, CH2), 3.02 - 3.10 (broad s + m, 6H,
CH2), 3.84 (s, 3H, CH3), 3.90 (s, 3H, CH3), 6.71 (d, J = 6.0 Hz, 1H,
CH), 6.82 - 7.00 (m, 5H, CH), 7.21 (t, J = 6.0 Hz, 1H, CH), 7.39 (d,
J = 6.0 Hz, 1H, CH); gc-ms: 14.4 minutes; m/z 396. The oil was dis-
solved in ethanol (4 mL) and oxalic acid (0.13 g; 1.2 equivalents)
was added and the mixture heated up to reflux for 30 minutes. After
cooling down to room temperature the obtained solid was collected
by filtration, washed with ethanol (2 mL) and dried in vacuo to yield
0.41 g (72 %) of a colourless solid; mp 164 - 166°.
3-Fluorobenzotrifluoride (2.52 mL; 20 mmoles) was dis-
solved in 50 mL dry tetrahydrofurane under nitrogen using a
250 mL 3-necked flask equipped with a stirring bar. The solu-
tion was cooled to -78° and t-butyl lithium (12 mL of a 1.7 M
solution in diethyl ether) was added dropwise over 10 minutes
to yield a yellow solution. Stirring was continued for 1 hour
followed by the dropwise addition of zinc chloride (40 mL of a
1.0 M solution in diethyl ether) and the resulting solution was
warmed up to room temperature and stirred for 1 hour.
Tetrakis(triphenylphosphine)palladium(0) (1.16 g; 0.05 mol
%) was added followed by addition of 20 mL of a 1.0 M solu-
tion of 4-chlorobutanoyl chloride in tetrahydrofuran and the
resulting yellow mixture was heated under reflux for 12 hours.
The dark hot reaction mixture was poured into water/ethyl
acetate (1:1; 100 mL) and the phases separated. After another
extraction, the organic phases were combined, washed with
water and brine and dried over sodium sulfate. Filtration and
concentration under vacuum yielded crude 3-chloropropyl 2-
fluoro-4-(trifluoromethyl)phenyl ketone as a brown oil which
was dissolved in 20 mL dry toluene and cooled to 0° under
nitrogen. After subsequent addition of methyl thioglycolate
(1.82 mL; 20 mmoles) and 1,8-diazabicyclo[5.4.0]undec-7-ene
(6.0 mL; 40 mmoles), the mixture was stirred at 0° for addi-
tional 3 hours, slowly warmed up to room temperature
overnight and poured into water /ethyl acetate (1:1; 100 mL).
The phases were separated and after another extraction the
organic phases were combined, washed with 6 N hydrochloric
acid, water and brine and dried over sodium sulfate. Filtration,
concentration under vacuum and chromatographic purification
yielded 1.81 g (58 %) of the target molecule as a colourless oil;
Anal. Calcd. for C23H28N2O2S•C2O4H2•C2H5OH: C, 60.88;
H, 6.81; N, 5.26. Found: C, 60.58; H, 6.88; N, 4.95.
1-[3-(5-Methoxybenzo[b]thiophene-3-yl)propyl]-4-(2-
methoxyphenyl)-piperazine (14b).
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 1.48 g (81 %) of a yellow
1
syrup; H nmr (deuteriochloroform): d 2.01 (m, 2H, CH, CH2),
2.53 (m, 2H, CH2), 2.67 (broad s, 4H, CH2), 2.85 (m, 2H, CH2),
3.11 (broad s, 4H, CH2), 3.85 (s, 3H, CH3), 3.89 (s, 3H, CH3),
6.84 - 7.01 (m, 5H, CH), 7.11 (s, 1H, CH), 7.19 (d, J = 1.9 Hz,
1H, CH), 7.70 (d, J = 6.7 Hz, 1H, CH); gc-ms: 14.5 minutes; m/z
396; The syrup was dissolved in ethanol (20 mL) and oxalic acid
(0.4 g; 1.2 equivalents) was added and the mixture heated up to
reflux for 30 minutes. After cooling down to room temperature
the obtained solid was collected by filtration, washed with
ethanol (10 mL) and dried in vacuo to yield 1.47 g (81 %) of a
colourless solid; mp 143 - 145°.
Anal. Calcd. for C23H28N2O2S•C2O4H2•C2H5OH: C, 60.88;
H, 6.81; N, 5.26. Found: C, 60.72; H, 6.76; N, 5.37.
1-[3-(6-Methoxybenzo[b]thiophene-3-yl)propyl]-4-(2-methoxy-
phenyl)-piperazine (14c).
The product was purified by column chromatography (iso-
1
H nmr (deuteriochloroform): d 2,17 (m, 2H, CH2), 3.48 (t, J =
hexane/ethyl acetate = 3:1) to yield 1.11 g (53 %) of a yellow
5.8 Hz, 2H, CH2), 3.63 (t, J = 4.8 Hz, 2H, CH2), 3.96 (s, 3H,
CH3), 7.66 (br. d, J = 6.5 Hz, 1H, CH), 8.02 (d, J = 6.5 Hz, 1H,
CH), 8.14 (br. s, 1H, CH).
1
solid which was recrystallised from diethyl ether; H nmr (deu-
teriochloroform): d 1.99 (m, 2H, CH, CH2), 2.50 (m, 2H, CH2),
2.66 (broad s, 4H, CH2), 2.84 (m, 2H, CH2), 3.11 (broad s, 4H,
CH2), 3.84 (s, 3H, CH3), 3.86 (s, 3H, CH3), 6.82 - 7.02 (m, 6H,
CH), 7.31 (d, J = 1.8 Hz, 1H, CH), 7.63 (d, J = 6.8 Hz, 1H, CH);
gc-ms: 14.5 minutes; m/z 396; mp 96 - 97°.
.
Anal. Calcd. for C14H13ClF3SO2 0.5 H2O (336.76): C, 50.07;
H, 4.20. Found: C, 50.29; H, 4.12.
General Procedure for the Preparation of 3-(w-Aminoalkyl)-
benzo[b]thiophenes (14, 16 and 26) via Nucleophilic Substitution
of 3-(w-Chloroalkyl)benzo[b]thiophenes (3).
Anal. Calcd. for C23H28N2O2S: C, 69.66; H, 7.12; N, 7.06.
Found: C, 69.37; H, 7.20; N, 6.83.
1-[3-(7-Methoxybenzo[b]thiophene-3-yl)propyl]-4-(2-methoxy-
phenyl)-piperazine (14d).
At room temperature anhydrous potassium carbonate (3 equiv-
alents) was mixed with the corresponding 3-(w-chloroalkyl)-
benzo[b]thiophene (3) and the corresponding amine or amine salt
(1.1 equivalents) respectively using a round bottomed flask. After
flushing with nitrogen, sodium iodide (1.1 equivalents) was added
in one portion followed by dry acetonitrile to result in a 1.0 M
solution of the 3-(w-chloroalkyl)benzo[b]thiophene (3). The
resulting mixture was heated at 80° while stirring for 18 hours,
poured into ice-water and the product was extraced into ethyl
acetate. The organic extract was washed with water and brine,
dried over anhydrous sodium sulfate and finally filtered and con-
centrated to yield the crude target compounds, which were
adsorbed onto silicagel and purified by column chromatography.
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 0.49 g (71 %) of a yellow
1
syrup; H nmr (deuteriochloroform): d 1.99 (m, 2H, CH, CH2),
2.50 (m, 2H, CH2), 2.66 (broad s, 4H, CH2), 2.87 (m, 2H, CH2),
3.10 (broad s, 4H, CH2), 3.78 (s, 3H, CH3), 3.98 (s, 3H, CH3),
6.77 (d, J = 6.1 Hz, 1H, CH), 6.83 - 7.01 (m, 4H, CH), 7.09 (s,
1H, CH), 7.32 (t, J = 6.1 Hz, 1H, CH), 7.38 (d, J = 6.1 Hz, 1H,
CH); gc-ms: 14.6 minutes; m/z 396; The syrup was dissolved in
ethanol (4 mL) and oxalic acid (0.13 g; 1.2 equivalents) was
added and the mixture heated up to reflux for 30 minutes. After
cooling down to room temperature the obtained solid was

1184
F. Burkamp and S. R. Fletcher
Vol. 39
collected by filtration, washed with ethanol (2 mL) and dried in
vacuo to yield 0.45 g (75 %) of a colourless solid; mp 110 - 113°.
Anal. Calcd. for C23H28N2O2S•C2O4H2•C2H5OH: C, 60.88;
H, 6.81; N, 5.26. Found: C, 60.88; H, 6.45; N, 5.27.
syrup was dissolved in isopropanol (4 mL) and 1 M hydrogen chlo-
ride in diethyl ether (0.9 mL; 2 equivalents) was added and the mix-
ture heated up to reflux for 30 minutes. After cooling down to room
temperature the obtained solid was collected by filtration, washed
with isopropanol (2 mL), diethyl ether (2 mL) and dried in vacuoto
yield 0.13 g (78 %) of a colourless solid; mp 170 - 174°.
1-[3-(4-Bromobenzo[b]thiophene-3-yl)propyl]-4-(2-methoxy-
phenyl)piperazine (14e).
Anal. Calcd. for C18H19FN2OS•HCl: C, 58.93; H, 5.49; N,
7.64. Found: C, 58.82; H, 5.29; N, 7.74.
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 1.85 g (65 %) of a yellow
syrup; H nmr (deuteriochloroform): d 2.00 (m, 2H, CH, CH2),
1'-[3-(7-Methoxybenzo[b]thiophene-3-yl)propyl]spiro(indene-
1,4' (1H) piperidine) (14k).
1
2.54 (m, 2H, CH2), 2.68 (broad s, 4H, CH2), 3.11 (broad s, 4H,
CH2), 3.19 (m, 2H, CH2), 3.85 (s, 3H, CH3), 6.84 - 7.01 (m, 4H,
CH), 7.11 (t, J = 6.0 Hz, 1H, CH), 7.19 (s, 1H, CH), 7.55 (d, J =
6.0 Hz, 1H, CH), 7.77 (d, J = 6.0 Hz, 1H, CH); gc-ms: 14.7 min-
utes; m/z 444/446. The syrup was dissolved in ethanol (20 mL)
and oxalic acid (0.45 g; 1.2 equivalents) was added and the mix-
ture heated up to reflux for 30 minutes. After cooling down to
room temperature the obtained solid was filtered, washed with
ethanol (10 mL) and dried in vacuo to yield 1.51 g (68 %) of a
colourless solid; mp 153 - 155°.
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 0.46 g (90 %) of a white solid
1
which was recrystallised from diethyl ether; H nmr (deuteri-
ochloroform): d 1.34 (broad d, J = 10 Hz, 2H, CH), 2.01 (m, 2H,
CH2), 2.19 (ddd, J = 10 Hz, J = 9.2 Hz, J = 2.5 Hz, 2H, CH), 2.31
(td, J = 9.2 Hz, J = 1.5 Hz, 2H, CH), 2.54 (m, 2H, CH2), 2.89 (m,
2H, CH2), 2.99 (broad d, J = 9.2 Hz, CH), 3.96 (s, 3H, CH3), 6.71
(d, J = 4.4 Hz, 1H, CH), 6.76 (d, J = 5.9 Hz, 1H, CH), 6.81 (d, J =
4.4 Hz, 1H, CH), 7.10 (s, 1H, CH), 7.21 (m, 2H, CH), 7.29 (d, J =
5.3 Hz, 1H, CH), 7.32 (dd, J = 6.2 Hz, J = 5.9 Hz, 1H, CH), 7.35
(d, J = 5.3 Hz, 1H, CH), 7.40 (d, J = 6.2 Hz, 1H, CH); ms: m/z
390; mp 93 - 94°.
Anal. Calcd. for C22H25N2OS•C2O4H2•C2H5OH: C, 53.70; H,
5.72; N, 4.82. Found: C, 53.38; H, 5.76; N, 4.62.
1-[3-(5-Bromobenzo[b]thiophene-3-yl)propyl]-4-(2-methoxy-
phenyl)piperazine (14f).
Anal. Calcd. for C25H27NOS: C, 77.08; H, 6.99; N, 3.60.
Found: C, 77.04; H, 7.03; N, 3.83.
The product was purified by column chromatography (iso-
1-[3-(4-Fluorobenzo[b]thiophen-3-yl)propyl]-4-(pyridin-2-
yl)piperazine (14l).
hexane/ethyl acetate = 3:1) to yield 1.58 g (78 %) of a yellow
1
solid which was recrystallised from ethyl acetate; H nmr (deu-
teriochloroform): d 1.95 (m, 2H, CH, CH2), 2.48 (t, J = 5.4 Hz,
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 0.11 g (57 %) of a colourless
syrup which was dissolved in isopropanol (4 mL) and 1 M hydro-
gen chloride in diethyl ether (0.62 mL; 2 equivalents) was added
and the mixture heated up to reflux for 30 minutes. After cooling
down to room temperature the obtained solid was collected by
filtration, washed with isopropanol (2 mL), diethyl ether (2 mL)
and dried in vacuo to yield 0.105 g (85 %) of a colourless solid;
2H, CH2), 2.66 (broad s, 4H, CH ), 2.86 (t, J = 5.4 Hz, 2H, CH2),
2
3.12 (broad s, 4H, CH2), 3.86 (s, 3H, CH3), 6.84 - 7.02 (m, 4H,
CH), 7.13 (s, 1H, CH), 7.41 (dd, J = 6.5 Hz, J = 1.4 Hz, 1H, CH),
7.68 (d, J = 6.5 Hz, 1H, CH), 7.93 (d, J = 1.4 Hz, 1H, CH); gc-ms:
14.7 minutes; m/z 444/446; mp 97 - 99°.
Anal. Calcd. For C22H25N2OS•0.5 C4H8O2: C, 58.89; H, 5.97;
N, 5.72. Found: C, 58.71; H, 5.63; N, 5.99.
1
H nmr (deuteriodimethyl sulfoxide): d 2.18 (m, 2H, CH2), 2.98
1-[3-(6-Bromobenzo[b]thiophene-3-yl)propyl]-4-(2-methoxy-
phenyl)piperazine (14g).
- 3.65 (broad m, 10H, CH2), 4.37 (m, 2H, CH2), 4.33 (t, J = 4,0
Hz, 2H, CH2), 6.78 (dd, J = 5.3 Hz, J = 4.0 Hz, 1H, CH), 6.99 (d,
J = 6.6 Hz, 1H, CH), 7.19 (dd, J (F,H) = 9.2 Hz, J = 6.1 Hz, 1H,
CH), 7.37 (m, 1H, CH), 7.58 (s, 1H, CH), 7.65 (dd, J = 6.6 Hz, J =
5.3 Hz, 1H, CH), 7.82 (d, J = 6.1 Hz, 1H, CH), 8.16 (d, J = 4.0
Hz, 1H, CH); ms: m/z 356 (M+); mp 197 - 198°.
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 1.32 g (47%) of a white solid
1
which was recrystallised from ethyl acetate; H nmr (deuteri-
ochloroform): d 1.95 (m, 2H, CH, CH2), 2.49 (m, 2H, CH2), 2.65
(broad s, 4H, CH2), 2.85 (m, 2H, CH2), 3.10 (broad s, 4H, CH2),
3.85 (s, 3H, CH3), 6.83 - 7.01 (m, 4H, CH), 7.07 (s, 1H, CH),
7.45 (dd, J = 6.7 Hz, J = 1.4 Hz, 1H, CH), 7.60 (d, J = 6.7 Hz, 1H,
CH), 7.96 (d, J = 1.4 Hz, 1H, CH); gc-ms: 14.8 minutes; m/z
444/446; mp 116 - 118°.
.
.
Anal. Calcd. for C20H22FN3S HCl 0.5 H2O: C, 59.91; H,
6.03; N, 10.48. Found: C, 59.94; H, 5.85; N, 10.21.
1-[4-(7-Bromo-4-fluorobenzo[b]thiophen-3-yl)butyl]-4-(2,3-
dihydro-benzo[1,4]dioxin-5-yl)piperazine (18).
Anal. Calcd. fr C22H25N2OS: C, 59.32; H, 5.66; N, 6.29.
Found: C, 59.30; H, 5.57; N, 6.34.
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 1.35 g (86 %) of a colourless
1
syrup; H nmr (deuteriochloroform): d 1.63 (m, 2H, CH2), 1.75
[3-(4-Fluorobenzo[b]thiophene-3-yl)propyl]-[2-(pyridin-2yl-
oxy)ethyl]amine (14i).
(m, 2H, CH2), 2.44 (m, 2H, CH2), 2.63 (broad s, 4H, CH2), 2.97
(m, 2H, CH2), 3.08 (broad s, 4H, CH2), 4.24 (m, 2H, CH2), 4.31
(m, 2H, CH2), 6.53 (d, J = 6.2 Hz, 1H, CH), 6.58 (d, J = 6.2 Hz,
1H, CH), 6.77 (t, J = 6.3 Hz, 1H, CH), 6.91 (dd, J (F,H) = 8.5 Hz,
J = 6.5 Hz, 1H, CH), 7.09 (s, 1H, CH), 7.37 (dd, J (F,H) = 3.0 Hz,
J = 6.5 Hz, 1H, CH); ms: m/z 505/507 (M+ + 1).
The syrup was dissolved in isopropanol (20 mL) and 1 M
hydrogen chloride in diethyl ether (5.35 mL; 2 equivalents) was
added and the mixture heated up to reflux for 30 minutes. After
cooling down to room temperature the obtained solid was
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 0.15 g (55 %) of a colourless
1
syrup; H nmr (deuteriochloroform): d 1.58 (broad s, 1H, NH), 1.86
(m, 2H, CH2), 2.69 (t, J = 5.5 Hz, 2H, CH2), 2.93 (m, 4H, CH2),
4.33 (t, J = 4,0 Hz, 2H, CH2), 6.65 (d, J = 6.5 Hz, 1H, CH), 6.76 (t,
J = 4.5 Hz, 1H, CH), 6.89 (dd, J (F,H) = 9.1 Hz, J = 6.0 Hz, 1H, CH),
6.93 (s, 1H, CH), 7.14 (m, 1H, CH), 7.46 (m, 2H, CH), 8.05 (d, J =
3.8 Hz, 1H, CH); ms: m/z 331 (M+) and 236 (M+ - C5H5NO). The

Nov-Dec 2002
Preparation of 3-Aminoalkylbenzo[b]thiophenes
1185
collected by filtration, washed with isopropanol (4 mL), diethyl
ether (4 mL) and dried in vacuo to yield 1.16 g (80 %) of a
colourless solid; mp 238 - 240°.
Anal. Calcd. for C24H26BrFN2O2S•HCl•0.5 H2O: C, 52.32; H,
5.12; N, 5.08. Found: C, 52.13; H, 4.92; N, 5.10.
ylate as an oil which was dissolved in 2 mL dichloroethane under
nitrogen and 0.5 mL (0.5 mmoles) trimethylaluminium (1 M in
toluene) was added and the mixture was stirred at 60° for 2 hours.
The solution was poured into a water/dichloromethane mixture (5
mL/50 mL) and the mixture adjusted to pH = 2 on addition of 1 N
hydrochloric acid. The phases were separated and, after an extrac-
tion with dichloromethane, the organic phases were combined,
washed with water and brine, dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to result in a yel-
low syrup. This was dissolved in 3 mL of dry tetrahydrofuran, and
0.5 mL of a 1 M solution of lithium aluminium hydride (0.5
mmoles) was added dropwise under nitrogen while stirring at room
temperature. After stirring for 15 hours the reaction was carefully
quenched by adding 20 % aqueous potassium hydroxide solution
dropwise. The resulting mixture was extracted 3 times with
dichloromethane and the organic phases were combined, washed
with brine and dried over anhydrous potassium carbonate.
Filtration and concentration under reduced pressure yielded the
crude target compound which was adsorbed onto silica and puri-
fied by column chromatography (ethyl acetate/iso-hexane = 3:1) to
1-[4-(4-Fluorobenzo[b]thiophen-3-yl)butyl]-4-(2,3-dihydro-
benzo[1,4]dioxin-5-yl)piperazine (19).
1-[4-(7-Bromo-4-fluorobenzo[b]thiophen-3-yl)butyl]-4-(2,3-
dihydrobenzo[1,4]-dioxin-5-yl)piperazine (18) 0.28 g (0.55
mmoles) was dissolved in dry tetrahydrofuran (20 mL) and 1.4
mL of a 1 M solution of lithium aluminium hydride was added
dropwise under nitrogen while stirring at room temperature. The
resulting mixture was heated under reflux for 12 hours, cooled to
room temperature and carefully quenched by adding 20 % aque-
ous potassium hydroxide solution dropwise. The resulting mixture
was extracted 3 times with dichloromethane, the organic phases
were combined, washed with brine and dried over anhydrous
sodium sulfate. Filtration and concentration under reduced pres-
sure yielded the crude target compound which was adsorbed onto
silica gel and purified by column chromatography (hexane/ethyl
1
yield 70 mg (40 %) of a colourless syrup; H nmr (deuteriochloro-
1
form): d 1.80 (m, 2H, CH, CH2), 2.73 (m, 2H, CH ), 2.81 (m, 2H,
acetate = 3: 1) to yield 0.16 g (67 %) of a colourless syrup; H nmr
2
CH2), 3.00 (m, 2H, CH2), 3.30 (m, 2H, CH2); 4.14 (s, 2H, CH2),
7.16 (m, 3H, CH), 7.24 (m, 2H, CH), 7.56 (d, J = 6.5 Hz, 1H, CH),
7.69 (d, J = 6.5 Hz, 1H, CH), 8.04 (broad s, 1H, CH); ms: m/z 376
(M++1). The syrup was dissolved in ethanol (4 mL) and 1 M
hydrogen chloride in diethyl ether (0.37 mL; 2 equivalents) was
added and the mixture heated up to reflux for 30 minutes. After
cooling down to room temperature the obtained solid was collected
by filtration, washed with ethanol (1 mL), diethyl ether (1 mL) and
dried in vacuo to yield 50 mg (65 %) of a colourless solid; mp >
230° (decomposition).
(deuteriochloroform): d 1.64 (m, 2H, CH2), 1.76 (m, 2H, CH2),
2.45 (m, 2H, CH2), 2.64 (broad s, 4H, CH2), 2.99 (m, 2H, CH2),
3.09 (broad s, 4H, CH2), 4.23 (m, 2H, CH2), 4.31 (m, 2H, CH2),
6.53 (d, J = 6.2 Hz, 1H, CH), 6.58 (d, J = 6.2 Hz, 1H, CH), 6.76 (t,
J = 6.2 Hz, 1H, CH), 6.98 (dd, J (F,H) = 9.0 Hz, J = 6.1 Hz, 1H,
CH), 7.01 (s, 1H, CH), 7.24 (m, 1H, CH), 7.58 (d, J = 6.2 Hz, 1H,
CH); ms: m/z 427 (M+ + 1). The syrup was dissolved in iso-
propanol (4 mL) and 1M hydrogen chloride in diethyl ether (0.38
mL; 2 equivalents) was added and the mixture heated up to reflux
for 30 minutes. After cooling down to room temperature the
obtained solid was collected by filtration, washed with iso-
propanol (2 mL), diethyl ether (2 mL) and driedin vacuo to yield
0.15 g (85 %) of a colourless solid; mp 220 - 221°.
Anal. Calcd. for C21H20F3NS•HCl: C, 61.23; H, 5.14; N, 3.40.
Found: C, 61.15; H, 5.02; N, 3.35.
1-[4-(4-Fluorobenzo[b]thiophen-3-yl)butyl]piperazine (17).
Anal. Calcd. for C24H27FN2O2S•HCl•0.6H2O: C, 60.68; H,
6.22; N, 5.90. Found: C, 60.32; H, 5.98; N, 6.04.
Following the general procedure for the preparation of 3-(w-
aminoalkyl)-benzo[b]thiophenes via nucleophilic substitution of 3-
(w-chloroalkyl)benzo[b]-thiophenes, 3.16 g (9.83 mmoles) of 7-
bromo-4-fluoro-3-(4-chlorobutyl)-benzo[b]thiophene (10) was
reacted with 2.05 g of N-(t-butoxy-carbonyl)-piperazine to yield,
after aqueous work-up, the required t-butyl 4-[4-(7-bromo-4-fluo-
robenzo[b]thiophen-3-yl)piperazine-1-carboxylate as an oil which
was dissolved in 100 mL dichloromethane/trifluoroacetic acid (4:1)
and stirred at room temperature for 1 hour. The solution was poured
into 250 mL of 10 % aqueous sodium hydroxide and the phases sep-
arated. After a further extraction with dichloromethane, the organic
phases were combined, washed with water and brine, dried over
anhydrous potassium carbonate, filtered and concentrated under
reduced pressure to result in 1-[4-(7-bromo-4-fluorobenzo[b]thio-
phen-3-yl)butyl]piperazine (17) as a yellow oil. This was dissolved
in 50 mL of dry tetrahydrofuran, and 20 mL of a 1 M solution of
lithium aluminium hydride was added dropwise under nitrogen
while stirring at room temperature. The resulting mixture was
heated under reflux for 12 hours, cooled to room temperature and
carefully quenched by adding 20 % aqueous potassium hydroxide
solution dropwise. The resulting mixture was extracted 3 times with
dichloromethane and the organic phases were combined, washed
with brine and dried over anhydrous potassium carbonate. Filtration
and concentration under reduced pressure yielded the crude target
compound which was adsorbed onto silica and purified by column
Methyl 3-(3-[4-(2-Methoxyphenyl)piperazin-1-yl]propyl)-6-(tri-
fluoromethyl)-benzo[b]thiophene-2-carboxylate (26).
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 1.37 g (58 %) of a white solid
1
which was recrystallised from ethyl acetate/n-hexane (1:1);
H
nmr (deuteriochloroform): d 1.91 (m, 2H, CH, CH2), 2.51 (m,
2H, CH2), 2.63 (broad s, 4H, CH2), 3.09 (broad s, 4H, CH2), 3.38
(m, 2H, CH2), 3.86 (s, 3H, CH3); 3.95 (s, 3H, CH3), 6.85 - 7.02
(m, 4H, CH), 7.62 (dd, J = 6.7 Hz, J = 1.1 Hz, 1H, CH), 8.05 (d,
J = 6.7 Hz, 1H, CH); 8.12 (d, J = 1.1 Hz, 1H, CH); ms: m/z 493
(M++1); mp 109 - 110°.
Anal. Calcd. for C25H27F3N2O3S: C, 60.96; H, 5.52; N, 5.69.
Found: C, 61.26; H, 5.42; N, 5.59.
3-(2-Phenylethyl)-9-trifluoromethyl-3,4,5,6-tetrahydro-2H-
azepino[2,3-b]benzo[d]thiophene (27).
Following the general procedure for the preparation of 3-(w-
aminoalkyl)-benzo[b]thiophenesvia nucleophilic substitution of 3-
(w-chloroalkyl)-benzo[b]thiophenes, methyl 3-(3-chloropropyl)-6-
(trifluoromethyl)benzo[b]thio-phene-2-carboxylate (25) 0.16 g
(0.48 mmoles) was reacted with 60 mg (0.5 mmoles) 2-phenethy-
lamine to yield, after aqueous work-up, the methyl 3-(3-phenethy-
laminopropyl)-6-(trifluoromethyl)benzo[b]thiophene-2-carbox-

1186
F. Burkamp and S. R. Fletcher
Vol. 39
.
.
chromatography (dichloromethane/methanol/ammonia =
100:10:1) to yield 2.28 g (81 %) of a colourless syrup which slowly
crystallises; H nmr (deuteriochloroform): d 1.59 (m, 2H, CH2),
1.72 (m, 2H, CH2), 1.86 (broad s, 1H, NH), 2.36 (m, 6H, CH2), 2.88
(t, J = 4.0 Hz, 4H, CH2), 2.97 (m, 2H, CH2), 6.98 (dd, J (F,H) = 9.2
Hz, J = 6.1 Hz, 1H, CH), 7.01 (s, 1H, CH), 7.24 (m, 1H, CH), 7.56
(d, J = 6.1 Hz, 1H, CH); ms: m/z 293 (M+ + 1); mp 47 - 50°.
Anal. Calcd. for C16H21FN2S: C, 65.72; H, 7.24; N, 9.58.
Found: C, 65.98; H, 7.55; N, 9.38.
Anal. Calcd. for C28H30N2OS HCl 0.5 H2O: C, 68.90; H,
6.61; N, 5.74. Found: C, 68.56; H, 6.27; N, 5.73.
1
1-(2-Methoxyphenyl)-4-(3-[7-(4-methoxyphenyl)benzo[b]thio-
phen-3-yl]propyl)-piperazine (15e).
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 0.20 g (85 %) of a white
solid; H nmr (deuteriodimethyl sulfoxide): d 2.10 (m, 2H, CH2)
1
3.10 (m, 2H, CH2), 3.10 - 3.38 (broad m, 6H, CH2), 3.79 (s, 3H,
CH3), 3.80 - 4.20 (broad m, 7H, CH2, CH3), 6.89 - 7.01 (m, 4H,
CH), 7.11 (d, J = 6.8 Hz, 1H, CH), 7.39 (d, J = 5.4 Hz, 1H, CH),
7.53 (m, 2H, CH), 7.64 (d, J = 6.8 Hz, 2H, CH), 7.82 (d, J = 6.1
Hz, 1H, CH); ms: m/z = 473 (M+ +1). The solid was dissolved in
isopropanol (4 mL) and oxalic acid (50 mg; 1.2 equivalents) was
added and the mixture heated up to reflux for 30 minutes. After
cooling down to room temperature the obtained solid was col-
lected by filtration, washed with isopropanol (1 mL), diethyl
ether (1 mL) and dried in vacuo to yield 170 mg (73 %) of a
colourless solid; mp 119 - 120°.
General Procedure for the Preparation of 4-, 6- and 7-Arylbenzo-
[b]thiophenes (15a, 15c and 15e) via Suzuki-reaction [11a] of
Substitution of 4-, 6- and 7-Bromobenzo[b]thiophenes (14e, 14g
and 14h).
At room temperature, tetrakis(triphenylphosphine)palla-
dium(0) (5 mol%) was mixed with the corresponding bro-
mobenzo[b]thiophene (14) using a two-necked flask under nitro-
gen and the corresponding boronic acid (1.5 equivalents) was
added. After the addition of toluene (5 mL/mmol) and 2 M aque-
ous sodium carbonate solution (2 equivalents), the resulting mix-
ture was heated at 100° while stirring for 18 hours and poured
onto ice-water. The product was extracted into ethyl acetate and
the organic extract was washed with water and brine. After dry-
ing over anhydrous sodium sulfate and filtering, the extract was
concentrated to yield the crude target compounds, which were
adsorbed onto silica gel and purified by column chromatography.
Anal. Calcd. for C29H32N2O2S•C2O4H2•0.5 H2O: C, 65.13; H,
6.17; N, 4.90. Found: C, 65.12; H, 6.13; N, 4.84.
General Procedure for the Preparation of Substituted Benzo[b]thio-
phenes (15b, 15d, 20, 21 and 22) via Palladium Mediated
Amination-reaction [11b] of Benzo[b]thiophenes (14e, 14g and 17).
At room temperature, palladium (II) acetate (5 mol%), (R)-(+)-
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (5 mol%) and
cesium carbonate (1.5 equivalents) were mixed with the corre-
sponding bromoarene (14) using a two-necked flask under nitro-
gen, and toluene (5 mL/mmol) was added. After the addition of
the corresponding amine (1.2 equivalents), the resulting mixture
was heated at 100° while stirring for 18 hours and poured onto
ice-water. The product was extraced into ethyl acetate and the
organic extract was washed with water and brine, dried over
anhydrous sodium sulfate, filtered and concentrated to yield the
crude target compounds which were adsorbed onto silica gel and
purified by column chromatography.
1-(2-Methoxyphenyl)-4-[3-(4-phenylbenzo[b]thiophen-3-yl)-
propyl]piperazine (15a).
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 0.16 g (89 %) of a yellow
1
syrup; H nmr (deuteriochloroform): d 1.97 (m, 2H, CH2), 2.00
(m, 2H, CH2), 2.25 (m, 2H, CH2), 2.48 (broad s, 4H, CH2), 3.03
(broad s, 4H, CH2), 3.83 (s, 3H, CH3), 6.82 - 7.00 (m, 4H, CH),
7.10 (s, 1H, CH), 7.15 (d, J = 5.5 Hz, 1H, CH), 7.33 (dd, J = 6.0
Hz, J = 5.5 Hz, 1H, CH), 7.43 (m, 5H, CH), 7.84 (d, J = 6.0 Hz,
1H, CH); ms: m/z 443 (M+ +1). The syrup was dissolved in
ethanol (4 mL) and 1 M hydrogen chloride in diethyl ether (0.72
mL; 2 equivalents) was added and the mixture heated up to reflux
for 30 minutes. After cooling down to room temperature the
obtained solid was collected by filtration, washed with ethanol
(1 mL), diethyl ether (1 mL) and dried in vacuo to yield 100 mg
(57 %) of a colourless solid; mp 154 - 155°.
4-[3-(3-[4-(2-Methoxyphenyl)piperazin-1-yl]propyl)benzo[b]-
thiophen-4-yl]-morpholine (15b).
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 0.18 g (71%) of a colourless
syrup; H nmr (deuteriochloroform): d 1.97 (m, 2H, CH2), 2.54
1
(m, 2H, CH2), 2.67 (broad s, 4H, CH2), 3.01 (broad m, 4H, CH2),
3.10 (broad s, 4H, CH2), 3.18 (m, 2H, CH2), 3.85 (s, 3H, CH3),
3.94 (m, 4H, CH2), 6.84 - 7.01 (m, 4H, CH), 7.07 (s, 1H, CH),
7.14 (d, J = 5.9 Hz, 1H, CH), 7.27 (dd, J = 6.1 Hz, J = 5.9 Hz, 1H,
CH), 7.61 (d, J = 6.1 Hz, 1H, CH); ms: m/z 452 (M+ +1). The
syrup was dissolved in ethanol (4 mL) and 1 M hydrogen chloride
in diethyl ether (0.8 mL; 2 equivalents) was added and the mixture
heated up to reflux for 30 minutes. After cooling down to room
temperature the obtained solid was collected by filtration, washed
with ethanol (1 mL), diethyl ether (1 mL) and dried in vacuo to
yield 170 mg (89 %) of a colourless solid; mp 235 - 236°.
Anal. Calcd. for C28H30N2OS•HCl•0.5 H2O: C, 68.90; H,
6.61; N, 5.74. Found: C, 68.94; H, 6.24; N, 5.98.
1-(2-Methoxyphenyl)-4-[3-(6-phenylbenzo[b]thiophen-3-yl)-
propyl]piperazine (15c).
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 0.13 g (80 %) of a yellow syrup;
1
H nmr (deuteriochloroform): d 2.00 (m, 2H, CH2) 2.52 (m, 2H,
CH2), 2.67 (broad s, 4H, CH2), 2.90 (m, 2H, CH2), 3.11 (broad s,
4H, CH2), 3.83 (s, 3H, CH3), 6.82 - 6.98 (m, 4H, CH), 7.11 (s, 1H,
CH), 7.43 (m, 3H, CH), 7.59 - 7.65 (m, 3H, CH), 7.81 (d, J = 6.4
Hz, 1H, CH), 8.04 (d, J = 1.0 Hz, 1H, CH); ms: m/z 443 (M+ +1).
The syrup was dissolved in isopropanol (4 mL) and 1 M hydrogen
chloride in diethyl ether (0.58 mL; 2 equivalents) was added and
the mixture heated up to reflux for 30 minutes. After cooling down
to room temperature the obtained solid was collected by filtration,
washed with ethanol (1 mL), diethyl ether (1 mL) and dried in
vacuo to yield 97 mg (69 %) of a colourless solid; mp 232 - 234°.
Anal. Calcd. for C26H33N3O2S•HCl•0.5 H2O: C, 62.82; H,
7.10; N, 8.45. Found: C, 62.89; H, 7.10; N, 8.40.
4-[3-(3-[4-(2-Methoxyphenyl)piperazin-1-yl]propyl)benzo-
[b]thiophen-6-yl]-morpholine (15d).
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 0.13 g (80%) of a white solid

Nov-Dec 2002
Preparation of 3-Aminoalkylbenzo[b]thiophenes
1187
1
which was recrystallised from iso-hexane/ethyl acetate (1: );
H
6.1 Hz, 1H, CH), 7.02 (s, 1H, CH), 7.13 (m, 1H, CH), 7.22 (m,
1H, CH), 7.33 (dd, J = 6.3 Hz, J = 3.2 Hz, 1H, CH), 7.41 (m, 2H,
CH), 7.57 (d, J = 6.2 Hz, 1H, CH), 8.07 (d, J = 6.3 Hz, 1H, CH),
8.87 (m, 1H, CH); ms: m/z 420 (M++1). The syrup was dissolved
in ethanol (4 mL) and 1 M hydrogen chloride in diethyl ether
(1.34 mL; 2 equivalents) was added and the mixture heated up to
reflux for 30 minutes. After cooling down to room temperature
the obtained solid was collected by filtration, washed with
ethanol (2 mL), diethyl ether (2 mL) and dried in vacuo to yield
235 mg (77 %) of a colourless solid; mp 232 - 235°.
nmr (deuteriochloroform): d 1.91 (m, 2H, CH2) 2.43 (m, 2H,
CH2), 2.59 (broad s, 4H, CH2), 2.76 (m, 2H, CH2), 3.03 (broad s,
4H, CH2), 3.11 (m, 4H, CH2), 3.78 (s, 3H, CH3), 3.81 (m, 4H,
CH2), 6.77 - 6.94 (m, 5H, CH), 6.97 (dd, J = 6.8 Hz, J = 1.7 Hz,
1H, CH), 7.23 (d, J = 1.7 Hz, 1H, CH), 7.57 (d, J = 6.8 Hz, 1H,
CH); ms: m/z 452 (M+ +1); mp 134 - 135°.
Anal. Calcd. for C26H33N3O2S: C, 69.15; H, 7.36; N, 9.30.
Found: C, 69.08; H, 7.21; N, 9.31.
1-[4-(4-Fluorobenzo[b]thiophene-3-yl)butyl]-4-(2-methoxy-
phenyl)piperazine (20).
Anal. Calcd. for C25H26FN3S•2 HCl•H2O: C, 58.82; H, 5.92;
N, 8.23. Found: C, 58.69; H, 5.97; N, 7.90.
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 0.11 g (27%) of a yellow
syrup; H nmr (deuteriochloroform): d 1.64 (m, 2H, CH2), 1.79
REFERENCES AND NOTES
1
(m, 2H, CH, CH2), 2.47 (m, 2H, CH2), 2.67 (broad s, 4H, CH2),
2.99 (m, 2H, CH2), 3.10 (broad s, 4H, CH2), 3.85 (s, 3H, CH3),
6.84 - 6.99 (m, 5H, CH), 7.23 (m, 2H, CH), 7.57 (d, J = 6.2 Hz,
1H, CH); ms: m/z 399 (M++1). The syrup was dissolved in
ethanol (4 mL) and 1 M hydrogen chloride in diethyl ether (0.56
mL; 2 equivalents) was added and the mixture heated up to reflux
for 30 minutes. After cooling down to room temperature the
obtained solid was collected by filtration, washed with ethanol (1
mL), diethyl ether (1 mL) and dried in vacuo to yield 90 mg (75
%) of a colourless solid; mp 203 - 204°.
[1] Review: T. Y. Zhang, J. O'Toole and P. C. Scott, Sulfur
Rep., 22, 1 (1999); For the synthesis of 3-alkyl substituted
benzo[b]thiophenes see: [a] S. Cabiddu, D. Cancellu, C. Floris, G.
Gelli and S. Melis, Synthesis, 888 (1988); [b] R. Patra, R. Gosh, S. B.
Maiti and A. Chatterjee, Tetrahedron Lett., 30, 4279 (1989).
[2a] M. R. Cuberes, M. Moreno-Mañas and F. Sánchez-
Ferrando, Magnetic Resonance in Chemistry, 23, 814 (1985); [b] P.
A. Plé and L. J. Marnett, J. Heterocyclic Chem., 25, 1271 (1988).
[3] For a similar approach in indole chemistry see: P. R.
Brodfuehrer, B.-C. Chen, T. R. Sattelberg, Sr., P. R. Smith, J. P.
Reddy, Derron, R. Stark, S. L. Quinlan and J. G. Reid, J. Org. Chem.,
62, 9192 (1997).
Anal. Calcd. for C23H27FN2OS2•HCl•0.5H2O: C, 62.22; H,
6.58; N, 6.31. Found: C, 62.54; H, 6.48; N, 6.13.
[4a] M. S. Newman and H. K. Karnes, J. Org. Chem., 31, 3980
(1966); [b] H. Kwart and E. R. Evans, J. Org. Chem., 31, 410 (1966).
[5] D. A. Clibbens and M. Nierenstein, J. Chem. Soc., 107,
1491 (1915).
[6] J. Barluenga, J. R. Fernandez and M. Yus, Synthesis, 977
(1985).
1-(Benzo[b]thiophen-7-yl)-4-[4-(4-fluorobenzo[b]thiophene-3-
yl)butyl]-piperazine (21).
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 0.19 g (39%) of a yellow
1
syrup; H nmr (deuteriochloroform): d 1.58 (m, 2H, CH2), 1.71
(m, 2H, CH, CH2), 2.39 (m, 2H, CH2), 2.59 (broad s, 4H, CH2),
2.92 (m, 2H, CH2), 3.17 (broad s, 4H, CH2), 6.83 (d, J = 5.9 Hz,
1H, CH), 6.90 (dd, J = 9.0 Hz, J = 6.1 Hz, 1H, CH), 6.92 (s, 1H,
CH), 7.14 (m, 1H, CH), 7.20 - 7.24 (m, 2H, CH), 7.29 (d, J = 4.2
Hz, 1H, CH), 7.41 (d, J = 6.0 Hz, 1H, CH), 7.48 (d, J = 6.2 Hz,
1H, CH); ms: m/z 425 (M+ +1). The syrup was dissolved in
ethanol (4 mL) and 1 M hydrogen chloride in diethyl ether (0.9
mL; 2 equivalents) was added and the mixture heated up to reflux
for 30 minutes. After cooling down to room temperature the
obtained solid was collected by filtration, washed with ethanol (1
mL), diethyl ether (1 mL) and dried in vacuo to yield 190 mg (92
%) of a colourless solid; mp 237 - 239°.
[7] D. J. Dumas, J. Org. Chem., 53, 4650 (1988).
[8] J. L. M. Buus, L. Bjaverskov and N. Lassen, German
Patent 2426149 (1974); Chem. Abstr., 55389-14-5.
[9] For a similar preparation see: S. Krishnamurthy and D.
Aimino, J. Org. Chem., 54, 4458 (1989).
[10] I. Yanagisawa, Y. Hirata and Y. Ishii, J. Med. Chem., 27,
849 (1984).
[11a] Review: A. Suzuki, J. Organomet. Chem., 576, 147
(1999); [b] J. P. Wolfe and S. L. Buchwald, J. Org. Chem. 65, 1144
(2000).
[12] A. J. Bridges, A. Lee, E. C. Maduakor and C. E. Schwartz,
Tetrahedron Lett., 33, 7499 (1992).
[13] G. Terrago, I. Zidane, C. Marzin and A. Tep, Tetrahedron,
44, 91 (1988).
[14] B. E. Evans, J. L. Leighton, K. E. Rittle, K. F. Gilbert, G.
F. Lundell, N. P. Gould, D. W. Hobbs, R. M. DiPardo, D. F. Veber, D.
J. Pettibone, B. V. Clineschmidt, P. S. Anderson and R. M.
Freidinger, J. Med. Chem., 35, 3919 (1992).
[15] J.-L. Peglion, H. Canton, K. Bervoets, V. Audinot, M.
Brocco, A. Gobert, S. Le Marouille-Girardon and M. J. Millan, J.
Med. Chem., 38, 4044 (1995).
Anal. Calcd. for C24H25FN2S2•HCl: C, 62.52; H, 5.68; N,
6.08. Found: C, 62.44; H, 5.71; N, 5.98.
8-[4-(4-[4-Fluorobenzo[b]thiophene-3-yl]butyl)piperazin-1-yl]-
quinoline (22).
The product was purified by column chromatography (iso-
hexane/ethyl acetate = 3:1) to yield 0.28 g (74 %) of a yellow
1
syrup; H nmr (deuteriochloroform): d 1.68 (m, 2H, CH2), 1.79
(m, 2H, CH, CH2), 2.52 (m, 2H, CH2), 2.80 (m, 4H, CH2), 3.01
(m, 2H, CH2), 3.45 (broad s, 4H, CH2), 6.98 (dd, J = 9.0 Hz, J =
[16] F.-P. Montforts, U. M. Schwartz, P. Maib and G. Mai,
Liebigs Ann. Chem., 1037 (1990).