Synthesis of 2-benzothienyl carbonyl 4-arylpiperazines as novel delavirdine analogs

Article abstract of DOI:10.1080/00397910701215759

A novel series of 2-benzothienyl carbonyl arylpiperazines (6a-f) was synthesized as potential HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs). Preparation of the derivatives was performed by reacting benzo[b]thiophene carbonyl chloride (5) wit

Full text of DOI:10.1080/00397910701215759

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Synthesis of 2‐Benzothienyl Carbonyl
4‐Arylpiperazines as Novel Delavirdine
Analogs
Hernán Pessoa‐Mahana a , R. Rodrigo Acevedo a , B. Claudio Saitz a , Ramiro
Araya‐Maturana a & C. D. Pessoa‐Mahana b
a Department of Organic Physical Chemistry, Faculty of Chemical and
Pharmaceutical Sciences, University of Chile, Santiago1, Chile
b Department of Pharmacy, Faculty of Chemistry, Pontifical Catholic
University of Chile, Santiago, Chile
Published online: 13 Apr 2007.
To cite this article: Hernán Pessoa‐Mahana , R. Rodrigo Acevedo , B. Claudio Saitz , Ramiro Araya‐Maturana
& C. D. Pessoa‐Mahana (2007): Synthesis of 2‐Benzothienyl Carbonyl 4‐Arylpiperazines as Novel Delavirdine
Analogs, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 37:8, 1227-1235
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Synthetic Communicationsw, 37: 1227–1235, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701215759
Synthesis of 2-Benzothienyl Carbonyl
4-Arylpiperazines as Novel Delavirdine
Analogs
´
Hernan Pessoa-Mahana, R. Rodrigo Acevedo,
B. Claudio Saitz, and Ramiro Araya-Maturana
Department of Organic Physical Chemistry, Faculty of Chemical and
Pharmaceutical Sciences, University of Chile, Santiago, Chile
C. D. Pessoa-Mahana
Department of Pharmacy, Faculty of Chemistry, Pontifical Catholic
University of Chile, Santiago, Chile
Abstract: A novel series of 2-benzothienyl carbonyl arylpiperazines (6a–f) was syn-
thesized as potential HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs).
Preparation of the derivatives was performed by reacting benzo[b]thiophene
carbonyl chloride (5) with a series of substituted 4-arylpiperazines.
Keywords: arylpiperazines, benzothiophene, delavirdine, HIV-1 reverse transcriptase
inhibitors
INTRODUCTION
Heteroaryl amides bearing an arylpiperazine moiety are interesting frameworks
utilized in antipsychotic drugs and HIV nonnucleoside reverse transcriptase
inhibitors (NNRTIs), such as delavirdine (Fig. 1).[1–6] As a retrovirus, HIV is dis-
tinguished by the presence of a viral reverse transcriptase (RT), an enzyme
responsible for the synthesis of DNA from the viral RNA genome. This
Received in the USA October 2, 2006
´
Address correspondence to Hernan Pessoa-Mahana, Department of Organic
Physical Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University
of Chile, Casilla 233, Santiago1, Chile. E-mail: hpessoa@ciq.uchile.cl
1227

1228
H. Pessoa-Mahana et al.
Figure 1.
enzyme is one of the most important antiviral targets in the chemotherapy of
acquired immunodeficiency syndrome (AIDS). Reverse transcriptase inhibitors
of HIV-1 have successfully been used in combination with HIV-1 protease inhibi-
tors as a treatment regimen termed highly active antiretroviral therapy
(HAART),[7,8] in which efavirenz, nevirapine, and delavirdine are the NNRTIs
agents currently used.
A major drawback with AIDS drugs is the rapid development of resistance;[9]
thus, continued efforts need to be focused on the synthesis of new compounds
with enhanced activity or metabolic stability. In 2001, Pinna and coworkers[10]
reported the synthesis and pharmacological evaluation of a series of arylpyrrol
piperazines as delavirdine analogs in acutely infected MT4 cells.
Although a number of synthetic approaches to molecules with potential
NNRTI activity have been reported,[11–13] the preparation of arylpiperazinil
benzo[b]thiophene derivatives as potential anti-HIV-1 agents has not yet
been investigated to the best of our knowledge.
The present study describes the synthesis of a series of 1-[(4,7-
dimethoxy-1-benzothien-2-yl)carbonyl]-4-arylpiperazines 6(a–f) structurally
related to the NNRTI delavirdine.
RESULTS AND DISCUSSION
The synthesis of 2-benzothienyl arylpiperazines 6(a–f) is outlined in
Scheme 1. Treatment of the starting 2,5-dimethoxy benzaldehyde (1)
with nitric acid in glacial acetic acid gave the corresponding nitro
compound, (2),[14] which reacted with methyl thioglycolate in basic medium
at 65–708C to provide the benzo[b]thiophene ester (3)[15] in 74% crude yield.

2-Benzothienyl Carbonyl 4-Arylpiperazines
1229
Scheme 1. Reagents and conditions: a) HNO3/HOAc; b) methyl thioglycolate/
K2CO3/DMF, 65–708C, 4 h, c) KOH-CH3OH, 3 h, rt, H3Oþ; d) SOCl2, reflux 3 h;
e) substituted 4-arylpiperazines, dry pyridine/anhydrous THF/N2 atmosphere.
The ester (3) was subsequently hydrolyzed at room temperature in a
methanolic potassium hydroxide solution to afford the heteroaromatic car-
boxylic acid derivative (4) in 82% yield. The aroylchloride (5) was obtained
by reaction of acid (4) with thionyl chloride under reflux conditions to
provide a yellow solid, which was purified and subsequently treated under
an inert atmosphere with different 4-arylpiperazines to afford the expected
benzothiophene carboxamides in good yield (Table 1).
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

1230
H. Pessoa-Mahana et al.
Table 1. Products, mp, and yields
Compound
R
mp(8C)
Yield (%)
6-a
6-b
6-c
6-d
6-e
6-f
H; X,Y55CH
4-F; X,Y55CH
2-F; X,Y55CH
4-NO2; X,Y55CH
H; X55N, Y55CH
H; X,Y55N
151–152
119–120
143–144
192–193
155–156
150–151
83
87
65
81
87
89
KBr disc, and wave numbers are reported in cm21. The 1H NMR and 13C NMR
measurements were performed on a Bruker DRX-300 spectrometer (300 and
75 MHz) in deuteriochloroform, or DMSO-d6. Chemical shifts were recorded
in 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 60
(Merck, 70–230 mesh) and DC-alufolien 60 F254 were normally used for
column chromatography and thin-layer chromatography (TLC) respectively.
4,7-Dimethoxy-2-methoxycarbonyl-benzo[b]thiophene (3)
To a solution of nitrobenzaldehyde 2 (774 mg, 3.7 mmol) in DMF (10 mL),
anhydrous K2CO3 (507 mg, 3.7 mmol) and methylthioglycolate (0.34 mL,
3.7 mmol) were added. The suspension was stirred at 708C for 4 h, then poured
onto crushed ice, and vigorously stirred for 15 min. The resultant precipitate
was filtered off and washed with water (3 ꢀ 25 mL) to afford crude benzothio-
phene ester 3 (682 mg, 74%) as a pale yellow solid, which was purified by
column chromatography (CH2Cl2) to afford pure benzothiophene ester 3
(623 mg, 67.4%), mp 124–1258C. Anal. calcd. for C12H12O4 S: C, 57.13; H,
4.80; S, 12.69. Found: C, 56.78; H, 4.90; S, 12.52%. IR vmax: 3010 (C-H, Ar),
1702 (C55O), 1260 (C-O). 1H NMR (300 MHz, CDCl3) d: 3.91 (s, 3H, OCH3),
3.93 (s, 3H, Ar-OCH3), 3.94 (s, 3H, Ar-OCH3), 6.66 (d, 1H, 5-H, J ¼ 8.5 Hz),
6.76 (d, 1H, 6-H, J ¼ 8.5 Hz), 8.2 (s, 1H, 3-H). 13C NMR (75 MHz, CDCl3):
52.4, 55.8, 56.0, 104.6, 106.8, 128.0, 131.1, 132.4, 132.9, 148.4, 150.5, 163.2.
4,7-Dimethoxy-benzo[b]thiophene-2-carboxylic Acid (4)
A solution of the methyl ester 3 (800 mg, 3.17 mmol) in potassium hydroxide
0.5 N:ethanol (1:1 v/v) (60 mL) was stirred at room temperature for 3 h. The
mixture was then concentrated in vacuo and acidified with HCl (c) at 08C. The
resulting precipitate was filtered off, washed with a small amount of cold
water, and dried to provide a yellow pale solid 5 (620 mg, 82%), which was
used without further purification, Mp 129–1308C. Anal. calcd. for C11H10O4S:

2-Benzothienyl Carbonyl 4-Arylpiperazines
1231
C, 55.45; H, 4.23; S, 13.46. Found: C, 55.45; H, 4.50; S, 13.21%. IR vmax
:
(cm21): 3650–2800 (O-H), 1670 (C55O), 1529 (C55C Ar). 1H NMR
(300 MHz, CDCl3) d: 3.91 (s, 3H, OCH3), 3.94 (s, 3H, Ar-OCH3), 6.86
(d, 1H, 5-H, J ¼ 8.5 Hz), 6.95 (d, 1H, 6-H, J ¼ 8.5 Hz), 8.24 (s, 1H, 3-H),
12.7 (s, 1H, COOH). 13CNMR (75 MHz, CDCl3): 56.2, 56.4, 105.9, 107.3,
122.6, 130.7, 131.4, 135.4, 148.3, 150.0, 171.6.
4,7-Dimethoxy-benzo[b]thiophene-2-carbonyl Chloride (5)
A solution of carboxylic acid 4 (910 mg, 3.8 mmol) in thionyl chloride
(50 mL) was heated under reflux for 4 h. Once the reaction proceeded, the
excess of the thionyl chloride was removed under reduced pressure, and the
crude residue immediately chromatographed on a silica-gel column
(CH2Cl2) to give compound 5 as a bright yellow solid (820 mg, 84% yield),
mp 84–858C; Anal. calcd. for C11H9ClO3S: C, 51.47; H, 3.53; S, 12.49.
Found: C, 50.54; H, 3.64; S, 12.45%. IR vmax: 1730 (ArCOCl), 1600 (C55C
Ar). 1HNMR (300 MHz, CDCl3) d: 3.93 (s, 3H, OCH3), 3.95 (s, 3H,
OCH3), 6.68 (d, 1H, 5-H, J ¼ 8.5 Hz), 6.84 (d, 1H, 6-H, J ¼ 8.5 Hz), 8.38
(s, 1H, 3-H). 13C NMR (75 MHz, CDCl3): 55.8, 56.1, 104.9, 108.6, 130.6,
133.5, 134.8, 135.5, 148.0, 151.1, 161.1.
General Procedure for Preparation of the [(4,7-Dimethoxy-1-
benzothien-2-yl) carbonyl]-4-arylpiperazines (6a–f): Compound
(6a) as a Model
[(4,7-Dimethoxy-1-benzothien-2-yl)carbonyl]-4-phenylpiperazine (6a)
Aroyl chloride 5 (277 mg, 1.08 mmol) in dry THF (20 mL) was slowly added
to a stirred solution at 08C of 1-phenylpiperazine (175 mg, 1.08 mmol) and dry
pyridine (85 mg, 1.08 mmol) in dry THF (50 mL) under a nitrogen atmosphere.
The mixture was maintained with stirring for 3 h at room temperature and then
diluted with water (100 mL). The solution was extracted with ethyl acetate
(3 ꢀ 50 mL), and the organic layers were dried over MgSO4. Concentration
of the solvent in vacuo afforded a residue, which was purified by silica-gel
column chromatography (CH2Cl2) to give benzothiophene carboxamide 6a
(345 mg, 83.4%) as a yellow pale solid, mp 156–1578C (EtOH). Anal.
calcd. for C21H22N2O3S: C, 65.95; H, 5.80; N, 7.32; S, 8.38. Found: C,
65.83; H, 5.91; N, 7.19; S, 8.15%; IR v : 3032 (C-H Ar), 2931 (C-H
1max
Aliph.), 1620 (NHCO), 1484 (C55C Ar). H NMR (CDCl3): d 3.25 [t, 4H,
CON-(CH2)2, J ¼ 5.0 Hz], 3.91–3.95 [m, 10H, (CH2)2-N-Ph and C-4 Ar
OMe, C-7 Ar OMe], 6.68 (d, 1H, 5-H, J ¼ 8.4 Hz), 6.74 (d, 1H, 6-H,
J ¼ 8.4 Hz), 6.90 (d, 1H, 40-H, J ¼ 7.4 Hz), 6.95 (d, 2H, 20-H and 60-H,

1232
H. Pessoa-Mahana et al.
J ¼ 8.4 Hz), 7.29 (t, 2H, 30-H and 50-H J ¼ 7.8 Hz), 7.66 (s,1H, 3-H). 13C
NMR (75 MHz, CDCl3): d 46.1 (2C), 49.8 (2C), 55.8, 56.0, 104.8, 105.8,
116.8 (2C), 120.7, 122.8, 129.3 (2C), 130.9 (2C), 135.7, 148.5, 150, 151, 163.9.
[(4,7-Dimethoxy-1-benzothien-2-yl) carbonyl]-4-(4-
fluorophenyl)piperazine (6b)
White pale crystals (column chromatographed, CH2Cl2) (325 mg, 87.3%).
Prepared from 5 (238 mg, 0.93 mmol) and 4-(4-fluorophenyl)piperazine
(167 mg, 0.93 mmol), mp 119–1208C (ethanol/petroleum benzin 5:1).
Anal. calcd. for C21H21FN2O3S: C, 62.98; H, 5.29; F, 4.74; N, 7.00; S 7.99.
Found: C, 62.25; H, 5.20; N, 6.90; S, 7.60%. IR nmax: 3030 (C-H Ar), 2935
1
(C-H Aliph), 1626 (C55O), 1510 and 1485 (C55C Ar). H NMR (CDCl3): d
3.15 [t, 4H, CON-(CH2)2, J ¼ 5.0 Hz,], 3.91 (s, 3H, C-7 OMe), 3.93–3.95
[m, 7H, (CH2)2-N-Ar and C-4 OMe], 6.68 (d, 1 H, 5-H, J ¼ 8.4 Hz), 6.74
(d, 1H, 6-H, J ¼ 8.4 Hz), 6.87–6.92 (m, 2H, 20-H and 60-H), 6.96–7.02
(m, 2H, 30-H and 50-H), 7.66 (s, 1H, 3-H). 13C NMR (75 MHz, CDCl3): d
2
45.2 (2C), 50.8 (2C), 55.8, 56.1, 104.8, 105.8, 115.7 (d, 2C, J ¼ 22.1 Hz),
118.7 (d, 2C, 3J ¼ 7.7 Hz), 122.8, 135.6, 130.9 (2C), 147.6.0
1
(d, 4J ¼ 2.3 Hz), 149.0, 150.0, 157.7 (d, J ¼ 240 Hz), 163.9 (NCO).
[(4,7-Dimethoxy-1-benzothien-2-yl) carbonyl]-4-(2-
fluorophenyl)piperazine (6c)
White pale crystals (column chromatographed, CH2Cl2) (176 mg, 65%).
Prepared from 5 (200 mg, 0.78 mmol) and 4-(2-fluorophenyl)piperazine
(141 mg, 0.78 mmol), mp 156–1578C (ethanol). Anal. calcd. for
C21H21FN2O3S: C, 62.98; H, 5.29; F, 4.74; N, 7.00; S, 7.99. Found: C, 62.63;
H, 5.35; N, 6.97; S, 7.63%. IR vmax: 3030 (C-H Ar), 2935, (C-H Aliph.), 1626
1
(C55O), 1510 and 1485 (C55C Ar). H NMR (CDCl3): d 3.14 [t, 4H, CON-
(CH2)2, J ¼ 5.0 Hz], 3.91 (s, 3H, C-7 OMe), 3.95 [m, 7H, (CH2)2-N-Ar and
C-4 OMe], 6.68 (d, 1H, 5-H, J ¼ 8.4 Hz), 6.73 (d, 1H, 6-H, J ¼ 8.4 Hz),
6.92–7.05 (m, 2H, 20-H and 60-H), 7.03–7.08 (m, 2H, 30-H and 50-H), 7.66
(s, 1H, 3-H). 13C NMR (75 MHz, CDCl3): d 45.6 (2C), 49.8 (2C), 54.7, 55.0,
0
2
103.8, 104.8, 115.3 (d, J ¼ 21 Hz), 118.3 (d, 2 J ¼2.6 Hz), 121.7, 122.2
(d, 3J ¼ 8.0 Hz), 123.6 (d, 4J ¼ 3.6 Hz), 129.8, 129.9, 134.7, 138.5 (d,
0
2 J ¼ 3.6 Hz), 147.5, 148.9, 154.8 (d, 1J ¼ 246 Hz), 162.9.
[(4,7-Dimethoxy-1-benzothien-2-yl) carbonyl]-4-(4-
nitrophenyl)piperazine (6d)
Yellow crystals (column chromatographed, CH2Cl2) (233 mg, 81%). Prepared
from 5 (186 mg, 0.73 mmol) and 4-(4-nitrophenyl)piperazine (152 mg,
0.73 mmol), mp 192–1938C (ethanol). Anal. calcd. for C21H21N3O5S: C,
58.95; H, 4.91; N, 9.83; S, 7.50. Found: C, 58.66; H, 5.00; N, 9.68; S,

2-Benzothienyl Carbonyl 4-Arylpiperazines
1233
7.46%. IR vmax: 1625 (C55O), 1598 (NO2 asym.), 1485 (C55C Ar), 1335 (NO2
sym.). 1H NMR (300 MHz, CDCl3): d 3.53 [t, 4H, CON-(CH2)2, J ¼ 5.1 Hz],
3.92 (s, 3H, C-7 OMe), 3.96 (s, 3H, C-4 OMe), 3.98 [t, 4H, (CH2)2-N-Ar,
J ¼ 5.1 Hz], 6.69 (d, 1H, 5-H, J ¼ 8.5 Hz), 6.76 (d, 1H, 6-H, J ¼ 8.5 Hz),
6.83 (d, 2H, 20-H and 60-H, J ¼ 9.4 Hz), 7.69 (s, 1H, 3-H), 8.15 (d, 2H, 30-
H and 50-H, J ¼ 9.4 Hz). 13CNMR (75 MHz, CDCl3): d 44.6 (2C), 47.6
(2C), 56.3, 56.6, 105.4, 106.6, 113.5 (2C), 123.8, 126.5 (2C), 131.4, 131.5,
135.8, 139.7, 149.0, 150.5, 154.9, 164.6.
[(4,7-Dimethoxy-1-benzothien-2-il) carbonil]-4-(2-
pyridinil)piperazine (6e)
White crystals (column chromatographed, CH2Cl2) (264 mg, 87%). Prepared
from 5 (225 mg, 0.88 mmol) and 4-(2-pyridinyl)piperazine (337 mg,
0.88 mmol), mp 156–1578C. (ethanol). Anal. calcd. for C20H21N3O3S: C,
62.64; H, 5.52; N, 10.96; S, 8.36. Found: C, 62.39; H, 5.25; N, 10.99; S,
1
8.52%. IR vmax: 1619 (C55O), 1600 (C55N), 1483 (C55C Ar). H NMR
(300 MHz, CDCl3): d 3.63 [m, 4H, CON-(CH2)2], 3.83–3.95 [m, 10H,
(CH2)2-N-Ar, C-4 OMe and C-7 OMe], 6.65–6.67 (m, 4 H, 5-H, 6-H and
40-H, 60-H), 7.51 (td, 1H, 50-H, Jo ¼ 8.3 Hz, Jm ¼ 2.3 Hz), 7.67 (s, 1H,
3-H), 8.21 (d,1H, 30-H, J ¼ 3.9 Hz). 13C NMR (75 MHz, CDCl3): d 43.5
(2C), 46.1 (2C), 56.5, 56.8, 105.5, 106.5, 108.1, 114.8, 123.6, 131.5, 131.6,
136.5, 138.5, 148.8, 149.2, 150.7, 159.8, 164.8.
2-f4-[(4,7-dimethoxy-1-benzothien-2-yl) carbonyl]piperazin-1-ylg
pyrimidine (6f)
White crystals (column chromatographed, CH2Cl2) (205 mg, 89%). Prepared
from 5 (154 mg, 0.60 mmol) and 2-(piperazin-1-yl) pyrimidine (98.5 mg,
0.60 mmol), mp 150–1518C. (ethanol). Anal. calcd. for C19H20N4O3S: C,
59.36; H, 5.24; N, 14.57; S, 8.34. Found: C, 58.65; H, 5.25; N, 14.21; S,
1
8.17%. IR vmax: 1627 (C55O), 1589 (C55N), 1546 (C55C Ar). H NMR
(300 MHz, CDCl3): d 3.81–3.98 [m, 14H, CON-(CH2)2, (CH2)2-N-Ar, C-4
OMe and C-7 OMe], 6.57 (m,1H, 40-H), 6.69 (d, 1H, 5-H, J ¼ 8.4 Hz), 6.74
(d, 1H, 6-H, J ¼ 8.4 Hz), 7.67 (s, 1H, 3-H), 8.34 (d, 2H, 30-H and 50-H,
J ¼ 4.7 Hz). 13C NMR (75 MHz, CDCl3): d 42.8 (2C), 48.7 (2C), 55.7,
56.0, 104.7, 105.7, 110.6, 122.8, 130.8 (2C), 135.7, 148.4, 149.9, 156.8
(2C), 161.5, 164.1.
ACKNOWLEDGMENTS
We thank Proyectos Fondecyt 1050289–1050950 and Proyecto Cepedeq–
´ ´
Facultad, Facultad de Ciencias Quımicas y Farmaceuticas, Universidad de
Chile.

1234
H. Pessoa-Mahana et al.
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