Synthesis of benzo[b]thiophene carboxamides connected to 4-arylpiperazines through a benzylic spacer: Potential ligands with 5-HT1A binding affinity

Article abstract of DOI:10.1080/00397910701557499

New benzothiophene arylpiperazine derivatives 8 (a-f) were synthesized as potential serotoninergic agents with 5-HT1A receptor affinity. Preparation of the derivatives was performed by treating N-[2-(chloromethyl)phenyl]-4,7- dimethoxybenzo[b]thiophene-2-

Full text of DOI:10.1080/00397910701557499

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Synthesis of Benzo[b]thiophene
Carboxamides Connected to
4‐Arylpiperazines through a Benzylic Spacer:
Potential Ligands with 5‐HT1A Binding Affinity
Hernán Pessoa‐Mahana a , R. Acevedo a , Ramiro Araya‐Maturana a , Claudio
Saitz a & C. David Pessoa‐Mahana b
a Faculty of Chemical and Pharmaceutical Sciences, Department of Organic
and Physical Chemistry , University of Chile , Santiago, Chile
b Faculty of Chemical, Department of Pharmacy , Pontificia Universidad
Católica de Chile , Santiago, Chile
Published online: 05 Oct 2007.
To cite this article: Hernán Pessoa‐Mahana , R. Acevedo , Ramiro Araya‐Maturana , Claudio Saitz & C.
David Pessoa‐Mahana (2007) Synthesis of Benzo[b]thiophene Carboxamides Connected to 4‐Arylpiperazines
through a Benzylic Spacer: Potential Ligands with 5‐HT1A Binding Affinity, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:20, 3559-3567, DOI:
10.1080/00397910701557499
To link to this article: http://dx.doi.org/10.1080/00397910701557499
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Synthetic Communicationsw, 37: 3559–3567, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701557499
Synthesis of Benzo[b]thiophene
Carboxamides Connected
to 4-Arylpiperazines through a Benzylic
Spacer: Potential Ligands with 5-HT1A
Binding Affinity
´
Hernan Pessoa-Mahana, R. Acevedo,
Ramiro Araya-Maturana, and Claudio Saitz
Faculty of Chemical and Pharmaceutical Sciences, Department of
Organic and Physical Chemistry, University of Chile, Santiago, Chile
C. David Pessoa-Mahana
Faculty of Chemical, Department of Pharmacy, Pontificia Universidad
´
Catolica de Chile, Santiago, Chile
Abstract: New benzothiophene arylpiperazine derivatives 8 (a–f) were synthesized as
potential serotoninergic agents with 5-HT1A receptor affinity. Preparation of the deriva-
tives was performed by treating N-[2-(chloromethyl)phenyl]-4,7-dimethoxyben-
zo[b]thiophene-2-carboxamide (7) with a series of substituted 4-arylpiperazines.
Keywords: arylpiperazines, benzothiophene, depression, 5-HT1A
INTRODUCTION
The long-chain arylpiperazine derivatives provide one of the most universal
templates used for designing CNS-active agents, representing the main pharma-
cophoric fragment recognized for serotonergic, dopaminergic, and adrenergic
Received in the USA March 28, 2007
´
Address correspondence to Hernan Pessoa-Mahana, Faculty of Chemical and
Pharmaceutical Sciences, Department of Organic and Physical Chemistry, University
of Chile, P.O. Box 233, Santiago 1, Chile. E-mail: hpessoa@ciq.uchile.cl
3559

3560
H. Pessoa-Mahana et al.
Figure 1. Buspirone(I), Ipsapirone(II), and Benzo[b]thiophene carboxamide deriva-
tives (III)
receptors.[1–3] Compounds of this class have been extensively studied,
especially as 5-HT1A receptor ligands, because of their potential antianxiety
and antidepressant properties.[4,5] Among these, some long-chain arylpipera-
zines with a terminal imide fragment, such as buspirone (I) or ipsapirone (II)
(Fig. 1) are effective as antianxiety and antidepressant drugs.[6,7]
Although a number of synthetic approaches to long-chain arylpiperazines
with interesting 5-HT1A bioactivity have been reported,[8–13] the preparation
of arylpiperazinyl benzothiophene derivatives (III) with a benzylic spacer
inserted between the basic nitrogen atom of the arylpiperazine moiety and
the benzo[b]thiophene carboxamide nucleus, as far as we know, has not yet
been investigated.
In this article, the synthesis of a series of 4,7-dimethoxy-N-f2-[(4-aryl-1-
piperazinyl) methyl]phenylgbenzo[b]thiophene-2-carboxamides of general
structure (III) closely related to bioactive long-chain arylpiperazines is
reported (Fig. 1).
RESULTS AND DISCUSSION
The new compounds 8(a–f) were synthesized from the aroyl benzothiophene
(5) according to the sequence displayed in Scheme 1. The preparation of
(5)[14] was carried out in three steps from the previously described 2-nitroben-
zaldehyde (1),[15–17] which was converted to ester (3) by treatment with
methyl thioglycolate in basic medium. The mechanism of the cyclization of
the 2-nitrobenzaldehyde derivative is unknown. However, a reasonable
mechanism probably involves thiol anion displacement of the activated
nitro group followed by base-catalyzed aldol-condensation to afford (3). Sub-
sequent basic hydrolysis of (3) to acid (4) followed by treatment with thionyl
chloride under reflux conditions afforded compound (5) (Scheme 2).

Synthesis of Benzo[b]Thiophene Carboxamides
3561
Scheme 1. Reagents and conditions: a) 2-aminobenzyl alcohol/dry pyridine/anhy-
drous THF/N2 atmosphere; b) mesyl chloride/anhydrous N(Et)3/dry CH2Cl2;
c) substituted 4-arylpiperazines/anhydrous K2CO3/CH3CN, reflux.
The aroylchloride (5) was purified and reacted with 2-aminobenzyl
alcohol under inert conditions to give the corresponding amide (6) in 89%
yield. When (6) was treated with mesyl chloride in the presence of triethyl-
amine, the chlorobenzyl carboxamide (7) in 86%, was obtained instead of
the expected mesylate derivative. This product may arise from a nucleophilic
attack by chloride on previously formed mesylate under the reaction con-
ditions. In the final step, compound (7) was treated with substituted 4-arylpi-
perazines under reflux in acetonitrile to provide the expected benzothiophene
arylpiperazine carboxamides 8 (a–f) in good yield (65–96%) (Table 1).
Scheme 2. Reagents and conditions: a) methyl thioglycolate/K2CO3/DMF, 65–
708C, 4 h. b) KOH–CH3OH, 3 h, rt, H3Oþ; c) SOCl2, reflux, 3 h.

3562
H. Pessoa-Mahana et al.
Table 1. Products, melting points, and yields
Compound
R
Mp8C
Yield%
8a
8b
8c
8d
8e
8f
R ¼ H; X ¼ CH
206–207
188–189
180–181
186–187
244–245
170–171
96
74
65
95
78
78
R ¼ 4-F; X ¼ CH
R ¼ 2-F; X ¼ CH
R ¼ H; X, ¼ NH
R ¼ 4-NO2; X ¼ CH
R ¼ 2-OMe; X ¼ CH
EXPERIMENTAL
Melting points were determined on a hot-stage apparatus and are uncorrected.
The IR spectra were recorded on a FT-IR Bruker IFS 55 spectrophotometer for
1
KBr discs, and wave numbers are reported in cm21. The H NMR and 13C
NMR spectra were performed on a Bruker DRX-300 spectrometer (300 and
75 MHz) in deuteriochloroform, or DMSO-d6. Chemical shifts were recorded
in parts per million (ppm d) relative to TMS as an internal standard. J values
are given in hertz. Microanalyses were carried out on a Fisons EA 1108
analizer. Silica gel Merck 60 (70–230mesh) and DC-alufolien 60 F254 were
used for column and thin-layer chromatography (TLC) chromatography,
respectively.
N-[2-(Hydroxymethyl)phenyl]-4,7-dimethoxybenzo[b]thiophene-2-
carboxamide (6)
Aroyl chloride (5) (348 mg, 1.36 mmol) in dry THF (20 mL) was slowly
added to a stirred solution of 2-aminobenzyl alcohol (168 mg, 1.36 mmol)
and dry pyridine (0.11 mL, 108 mg, 1.36 mmol) in dry THF (50 mL) at 08C
under nitrogen atmosphere. After stirring for 10 min, the mixture was
allowed to warm to room temperature and was maintained at rt for 3 h. The
mixture was then diluted with water (100 mL), extracted with ethyl acetate
(3 ꢀ 50 mL), and dried over anhydrous Na2SO4. Concentration of the
solvent in vacuo afforded the crude amide (6) (415 mg, 89%), which was
purified by silica-gel column chromatography (AcOEt/CH2Cl2 1:2) to
afford pure benzothiophene carboxamide (6) (326 mg, 70%) as a brown
pale solid. Mp: 150–1518C; anal. calcd. for C18H17NO4S: C, 62.91; H,
4.99; N, 4.08; S, 9.32. Found: C, 61.95; H, 4.97; N, 4.18; S, 9.28%. IR
nmax
:
3350 (ArCONH), 3288 (O-H), 1635 (C55O). 1H NMR
(300 MHz,CDCl3) d: 3.86 (s, 6H, 2 ꢀ ArOMe), 4.55 (d, 2H, Ar-CH2-OH,
J ¼ 5.3 Hz), 5.50 (t, 1H, OH, J ¼ 5.3 Hz), 6.83 (d, 1H, 5-H, J ¼ 8.5 Hz),
6.92 (d, 1H, 6-H, J ¼ 8.5 Hz), 7.17–7.27 (m, 2H, 40-H & 50-H), 7.41 (d,
1H, 30-H, J ¼ 7.4 Hz), 7.56 (d, 1H, 60-H, J ¼ 7.7 Hz), 7.17–7.27 (m, 2H,

Synthesis of Benzo[b]Thiophene Carboxamides
3563
40-H & 50-H), 7.41 (d, 1H, 30-H, J ¼7.4 Hz), 7.56(d, 1H, 60-H, J ¼ 7.7 Hz),
8.20 (s, 1H, 3-H), 10.27(s, 1H, NH-CO). 13C NMR (75 MHz, CDCl3): 56.6,
56.8, 61.3, 106.5, 107.9, 123.1, 125.4, 126.3, 128.0, 128.3, 131.23, 131.7,
135.9, 136.4, 139.7, 148.7, 150.5, 160.8.
N-[2-(Chloromethyl)phenyl]-4,7-dimethoxybenzo[b]thiophene-2-
carboxamide (7)
To a solution of alcohol (6) (300 mg, 0.88 mmol) in dry CH2Cl2 (40 mL) at
08C, mesyl chloride (0.17 mL, 2.2 mmol) and dry Et3N (221 mg, 2.2 mmol)
were added. The mixture was stirred for 3 h at room temperature, diluted
with a saturated solution of NaHCO3 (20 mL), extracted with CH2Cl2
(3 ꢀ 50 mL), and dried over MgSO4. The organic layers were concentrated
to afford 316 mg of a crude residue in cuantitative yield, which was purified
by silica gel column chromatography (CH2Cl2) to afford pure benzothiophene
chlorobenzyl carboxamide (7) (272 mg, 86%) as a viscous orange-brown oil.
Anal. calcd. for C18H16NO3SCl: C, 59.75; H, 4.46; N, 3.87; S, 8.86. Found: C,
55.89; H, 4.48; N, 3.77; S, 8.82%; IR nmax: 3417 (ArCONH), 1637 (NHCO),
1575 (N-H). 1H NMR (DMSO-d6): d 3.93 (s, 6H, 2 ꢀ Ar-OMe), 4.88 (s, 2H,
Ar-CH2-Cl), 6.91 (d, 1H, 5-H, J ¼ 8.5 Hz), 6.99 (d, 1H, 6-H, J ¼ 8.5 Hz),
7.32 (t, 1H, 40-H, J ¼ 6.3 Hz), 7.42–7.49 (m, 2H, 50-H and 60-H), 7.55
(d, 1H, 30-H, J ¼ 7.5 Hz), 8.45(s, 1H, 3-H), 10.30 (s, 1H, NH-CO). 13C
NMR (75 MHz, CDCl3): d 44.6, 55.8, 56.1, 104.8, 106.6, 122.9, 124.3,
125.3, 127.8, 130.0, 130.2, 131.4, 132.0, 136.4, 137.7, 148.5, 150.3, 160.4.
General Procedure for Preparation of 4,7-Dimethoxy-N-f2-[(4-aryl-
1-piperazinyl) methyl] phenylgbenzo[b]thiophene-2-carboxamides 8
(a–f)
4,7-Dimethoxy-N-f2-[(4-phenyl-1-piperazinyl)-methyl]phenylg
benzo[b]thiophene-2-carboxamide (8a)
To a solution of chlorobenzyl benzo[b]thiophene (7) (105 mg, 0.29 mmol) in
CH3CN (20 mL), 1-phenyl piperazine (48 mg, 0.29 mmol) and anhydrous
K2CO3 (40 mg, 0.29 mmol) were added. The mixture was stirred under reflux
for 4 h and then diluted with water (50 mL). The solution was extracted with
ethyl acetate (40 mL ꢀ 3), and the organic layers were dried over anhydrous
Na2SO4. Removal of the solvent afforded benzo[b]thiophene-2-carboxamide
(8a) (136 mg, 96%) as a white powder, which was purified by silica-gel
column chromatography (CH2Cl2) (116 mg, 82%). Mp: 206–2078C
(CH2Cl2/CH3CN 1:2). Anal. calcd. for C28H29N3O3S: C, 68.97; H, 5.99; N,
8.62; S, 6.58. Found: C, 68.48; H, 5.90; N, 8.60; S, 6.38%. IR nmax: 3450
(ArCONH), 3032 (C-H, Ar), 1666 (NHC55O), 1595 (N-H). 1H NMR

3564
H. Pessoa-Mahana et al.
(300 MHz,CDCl3) d: 2.75 (bs, 4H, Piper. 200-H and 600-H), 3.41 (bs, 4H, Piper.
300-H and 500-H), 3.58 (s, 3H, Ar-OMe,C-7), 3.74 (s, 2H, Ar-CH2-), 3.92 (s, 3H,
Ar-OMe, C-4), 6.59 (d, 1H, 5-H, J ¼ 8.5 Hz), 6.71 (d, 1H, 6-H, J ¼ 8.5 Hz),
6.88 (t, 1H, 4000-H, J ¼ 7.3 Hz), 6.97 (d, 2H, 2000-H and 6000-H, J ¼ 8.0 Hz),
7.10 (t, 1H, 50-H, J ¼ 7.4 Hz), 7.18 (d, 1H, 30-H, J ¼ 6.5 Hz), 7.27 (td, 2H,
3000-H, 5000-H, Jo ¼ 6.8 Hz, Jm ¼ 2.4 Hz), 7.36 (t, 1H, 40-H, J ¼ 7.6 Hz), 8.10
(s, 1H, 3-H), 8.40 (d, 1H, 60-H, J ¼ 8.1 Hz), 11.5 (s, 1H, NH-CO). 13C NMR
(75 MHz, CDCl3): d 48.9 (2C), 53.0 (2C), 55.2, 56.0, 62.6, 104.4, 106.2,
116.3 (2C), 120.0, 120.9, 121.8, 123.6, 125.0, 128.8, 129.2 (2C), 130.1,
131.4, 132.0, 138.5, 139.8, 148.5, 150.1, 151.2, 160.4.
N-f2-[(4-(4-Fluorophenyl)-1-piperazinyl)methyl]phenylg-4,7-
dimethoxibenzo[b]thiophene-2-carboxamide (8b)
This is analogous to (8a), prepared from (7) (91 mg, 0.25 mmol), 4-(4-fluor-
ophenyl)piperazine (45 mg, 0.25 mmol), anhydrous K2CO3 (35 mg,
0.25 mmol), and CH3CN (20 mL). Crude yield (94 mg, 74%); column chro-
matographed (CH2Cl2) (79 mg, 62.4%). Mp: 188–1898C. Anal. calcd. for
C28H28FN3O3S: C, 66.51; H, 5.58; N, 8.31; S, 6.34. Found: C, 65.50; H,
5.73; N, 8.51; S, 6.20%. IR nmax: 3442 (ArCONH), 3032 (C-H, Ar), 1662
(NHC ¼ O), 1596 (N-H). 1H-NMR (300 MHz, CDCl3) d: 2.75 (bs, 4H,
Piper. 200-H and 600-H), 3.33 (bs, 4H, Piper. 300-H and 500-H), 3.59 (s, 3H, Ar-
OMe, C-7), 3.74 (s, 2H, Ar-CH2-), 3.92 (s, 3H, Ar-OMe, C-4), 6.50 (d, 1H,
5-H, J¼ 8.5 Hz), 6.72 (d, 1H, 6-H, J ¼ 8.5 Hz), 7.01–6.90 (m, 4H, 2000-H,
3000-H, 5000-H, 6000-H), 7.06 (t, 1H, 50-H, J ¼ 6.9 Hz), 7.18 (d, 1H, 30-H,
J ¼ 6.3 Hz), 7.37 (t, 1H, 40-H, J ¼ 8.0 Hz), 8.10 (s, 1H, 3-H), 8.49 (d, 1H,
60-H, J ¼ 8.1 Hz), 11.5 (s, 1H, NH-CO). 13C NMR(75 MHz, CDCl3): d 49.8
2
(2C), 52.9 (2C), 55.1, 56.0, 62.5, 104.4, 106.1, 115.6 (d, 2C, J ¼ 22 Hz),
3
118.02 (d, 2C, J ¼ 7.6 Hz), 120.8, 121.7, 123.6, 124.9, 128.8, 130.1, 131.2,
1
131.9, 138.4, 139.8, 147.8, 148.5, 149.9, 157.3 (d, J ¼ 239 Hz), 160.3.
N-f2-[(4-(2-Fluorophenyl)-1-piperazinyl) methyl] phenylg-4,7-
dimethoxibenzo[b]thiophene-2-carboxamide (8c)
This is analogous to (8a), prepared from (7) (181 mg, 0.5 mmol), 4-(2-fluoro-
phenyl)piperazine (90 mg, 0.5 mmol), anhydrous K2CO3 (69 mg, 0.5 mmol),
and CH3CN (20 mL). Crude yield (164 mg, 65%); column chromatographed
(CH2Cl2) (150 mg, 59%). Mp: 180–1818C. Anal. calcd. for C28H28FN3O3S:
C, 66.51; H, 5.58; N, 8.31; S, 6.34. Found: C, 65.81; H, 5.47; N, 8.29; S,
1
6.33%. IR nmax: 3440 (ArCONH), 1665 (NHC55O), 1592 (N-H). H MNR
(300 MHz, CDCl3): d 2.75 (m, 4H, Piper. 200-H and 600-H), 3.32 (m, 4H,
Piper. 300-H & 500-H), 3.64 (s, 3H, Ar-OMe, C-7), 3.75 (s, 2H, Ar-CH2-), 3.92
(s, 3H, Ar-OMe, C-4), 6.61 (d, 1H, 6-H, J ¼ 8.5 Hz), 6.73 (d, 1H, 5-H,
J ¼ 8.5 Hz), 6.86–7.10 (m, 5H, 40-H & 3000-H, 4000-H, 5000-H and 6000-H), 7.18
(dd, 1H, 30-H, Jo ¼ 7.3 Hz, Jm ¼ 1.3 Hz), 7.36 (td, 1H, 50-H, Jo ¼ 8.3 Hz,

Synthesis of Benzo[b]Thiophene Carboxamides
3565
Jm ¼ 1.35 Hz), 8.13 (s, 1H, 3-H), 8.42 (dd, 1H, 60-H, Jo ¼ 8.2 Hz,
Jm ¼ 0.8 Hz), 11.6 (s, 1H, NH-CO). 13C NMR (75 MHz, CDCl3): d 50.1,
50.2, 53.0, 55.3, 56.0, 62.6, 104.5, 106.2, 116.2 (d, 2J ¼ 21 Hz), 119.1
4
3
(d, J ¼ 2.9 Hz), 120.9, 121.8, 122.7 (d, J ¼ 8.0 Hz), 123.7, 124.5, 124.48
0
(d, 30 J ¼ 3.6 Hz), 125.0, 128.8, 130.1, 131.4, 132.0, 138.5, 139.8, 140.0
(d, 2J ¼ 8.6 Hz), 148.6, 150.1, 155.7 (d, 1J ¼ 246 Hz), 160.4.
4,7-Dimethoxy-N-f2-[(4-(2-pyridinyl)-1-piperazinyl) methyl]phenylg-
1-benzo[b]thio-phene-2-carboxamide (8d)
This is analogous to (8a), prepared from (7) (224 mg, 0.62 mmol), 1-(2-
pyridinyl) piperazine (101 mg, 0.62 mmol), anhydrous K2CO3 (86 mg,
0.62 mmol), and CH3CN (20 mL). Crude yield (289 mg, 95%); column chro-
matographed (CH2Cl2) (250 mg, 82.6%). Mp: 186–1878C; Anal. calcd. for
C27H28N4O3S: C, 66.37; H, 5.78; N, 11.47; S, 6.56. Found: C, 65.82; H,
5.85; N, 11.69; S, 6.51%. IR nmax: 3438 (ArCONH), 1665 (NHC55O), 1591
1
(N-H). H NMR (300 MHz, CDCl3): d 2.75 (s, 4H, 200 –H and 600-H), 3.68
(s, 3H, Ar-OMe), 3.70–3.79 (m, 6H, Ar-CH2- and Piper. 300-H 500-H), 3.92
(s, 3H, Ar-OMe), 6.58–6.72 (m, 4H, 5-H, 6-H, and 4000-H & 6000-H), 7.06
(td, 1H, 50-H, Jo ¼ 6.9 Hz; Jm ¼ 1.0 Hz), 7.18 (d, 1H, 30-H, J ¼ 6.2 Hz),
7.49 (td, 1H, 400-H, Jo ¼ 7.94; Jm ¼ 1.95 Hz), 7.37 (td, 1H, 40-H, Jo ¼ 7.95;
Jm ¼ 1.43 Hz), 8.11 (s,1H, 3-H), 8.22 (dd, 1H, Jo ¼ 4.78 Hz; Jm¼ 1.38 Hz,
60-H), 8.42 (d, 1H, 3000-H, J ¼ 7.6 Hz), 11.5 (s, 1H, NH-CO). 13C NMR
(75 MHz, CDCl3): d 44.9 (2C), 52.8 (2C), 55.3, 56.0, 62.7, 104.4, 106.2,
107.1, 113.7, 120.7, 121.7, 123.6, 124.9, 128.8, 130.1, 131.3, 132.0, 137.6,
138.5, 139.8, 148.0, 148.5, 150.1, 159.5, 160.4.
4,7-Dimethoxy-N-f2-[(4-(4-nitrophenyl)-1-piperazinyl)methyl]phenylg-
1-benzo[b]thio-phene-2-carboxamide (8e)
This is analogous to (8a), prepared from (7) (100 mg, 0.28 mmol), 1-(4-nitro-
phenyl) piperazine (58 mg, 0.24 mmol), anhydrous K2CO3 (38 mg,
0.28 mmol), and CH3CN (20 mL). Crude yield (115 mg, 78.3%); column chro-
matographed (CH2Cl2). (108 mg, 73.6%). Mp: 244–2458C. Anal. calcd. for
C28H28N4O5S: C, 63.14; H, 5.30; N, 10.52; S, 6.02. Found: C, 62.87; H,
5.59; N, 10.46; S, 5.97%. IR nmax: 3445 (ArCONH), 1667 (NHC55O), 1595
1
(NO2 asym.), 1324 (NO2 sym.). H NMR (300 MHz, DMSO-d6): d 2.76 (bs,
4H, 200 –H and 600-H), 3.73 (bs, 4H, 300-H and 500-H), 3.85 (s, 3H, Ar-OMe,
C-7), 3.93 (s, 3H, OMe, C-4), 3.74 (s, 2H, Ar-CH2-), 6.95 (d, 1H, 5-H,
J ¼ 8.4 Hz), 7.07 (d, 1H, 6-H, J ¼ 8.4 Hz), 7.24–7.40 (m, 3H, 2000-H, 6000-H
and 40-H), 7.54–7.65 (m, 2H, 30-H and 50-H), 8.32 (d,1H, 60-H, J ¼ 9.2 Hz),
8.35 (s, 1H, 3-H), 8.47 (d, 2H, 3000-H and 5000-H, J ¼ 8.1 Hz), 11.6 (s, 1H,
NHCO). 13C NMR (75 MHz, DMSO-d6): 47.0 (2C), 52.7 (2C), 56.5, 57.0,
61.6, 106.7, 108.4, 113.7 (2C), 121.3, 122.1, 122.3, 124.7, 126.5 (2C), 126.8,
129.0, 131.1, 131.5, 138.3, 138.8, 140.1, 148.8, 150.5, 155.6, 160.3.

3566
H. Pessoa-Mahana et al.
4,7-Dimethoxy-N-f2-[(4-(2-methoxyphenyl)-1-
piperazinyl)methyl]phenylg -1-benzo[b]thiophene-2-carboxamide (8f)
This is analogous to (8a), prepared from (7) (140 mg, 0.39 mmol), 1-(2-meth-
oxyphenyl) piperazine (75 mg, 0.39 mmol), anhydrous K2CO3 (54 mg,
0.39 mmol), and CH3CN (20 mL). Crude yield (156 mg, 78%); column chro-
matographed (CH2Cl2) (148 mg, 74%). Mp: 170–1718C. Anal. calcd. for
C29H31N3O4S: C, 67.29; H, 6.04; N, 8.12; S, 6.19. Found: C, 67.26; H,
6.11; N, 7.95; S, 6.02%. IR nmax: 3441 (ArCONH), 1660 (NHC55O), 1590
1
(N-H). H NMR (300 MHz, CDCl3): d 2.76 (bs, 4H, 200-H and 600-H), 3.29
(bs, 4H, 300-H and 500-H), 3.65 (s, 3H, Ar-OMe), 3.75 (s, 2H, Ar-CH2-), 3.88
(s, 3H, Ar-OMe, 7-H), 3.96 (s, 3H, Ar-OMe, 4-H), 6.62 (d, 1H, 5-H,
J ¼ 8.4 Hz), 6.73 (d, 1H, 6-H, J ¼ 8.4 Hz), 6.84–7.09 (m, 5H, 50-H and
3000H, 4000-H, 5000-H & 6000-H), 7.18 (d,1H, 30-H, J ¼ 6.9 Hz), 7.35 (t, 1H,
40-H, J ¼ 7.0 Hz), 8.16 (s, 1H, 3-H), 8.40 (d, 1H, 60-H, J ¼ 8.2 Hz), 11.6
(s, 1H, CONH). 13C NMR (75 MHz, CDCl3): 50.7 (2C), 53.6 (2C), 55.7,
55.8, 56.4, 63.1, 104.8, 106.6, 111.7, 118.8, 121.3, 121.4, 122.2, 123.9,
123.5, 125.6, 129.1 (2C), 130.4, 131.8, 138.9, 140.3, 141.6, 148.9, 150.3,
152.7, 160.8.
ACKNOWLEDGMENTS
We thank Proyectos Fondecyt 1050289 and Proyecto Cepedeq–Facultad,
´ ´
Facultad de Ciencias Quımicas y Farmaceuticas Universidad de Chile,
Santiago, Chile.
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