Synthesis of a novel series of 4-arylpiperazinyl derivatives linked to a 2-(Pyridin-3-yl)-1H-benzimidazole as new delavirdine analogues

Article abstract of DOI:10.1590/S0103-50532010000100011

The synthesis of a series of substituted arylpiperazines linked to a 2-(pyridin-3-yl)-1H-benzo[d] imidazole scaffold through an alkylic linker is reported. The novel 1-(2-(4-arylpiperazin-1-yl) alkyl)-2-(pyridin-3-yl)-1H- benzimidazole derivatives are structurally related to the anti-HIV-1 drug Delavirdine and belong to the bis(heteroaryl)piperazines family (BHAPs), a well known HIV-1 reverse transcriptase inhibitors group.

Full text of DOI:10.1590/S0103-50532010000100011

J. Braz. Chem. Soc., Vol. 21, No. 1, 63-70, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Synthesis of a Novel Series of 4-Arylpiperazinyl Derivatives Linked to a
2-(Pyridin-3-yl)-1H-benzimidazole as New Delavirdine Analogues
David Pessoa-Mahana,*,a Andrés Núñez,a Christian Espinosa,a Jaime Mella-Raipána
and Hernán Pessoa-Mahanab
aDepartamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile,
Casilla 306, Santiago 22, Chile
bDepartamento de Química Orgánica y Físico-Química, Facultad de Ciencias Químicas y
Farmacéuticas, Universidad de Chile, Casilla 233, Santiago 1, Chile
A síntese de uma série de arilpiperazinas ligadas à estrutura 2-(piridina-3-il)-1H-benzo[d]
imidazol, através de um linker alquílico é relatada. Os novos derivados 1-(2-(4-arilpiperazina-1-
il)alquil)-2-(piridina-3-il)-1H-benzimidazol são estruturalmente relacionados à droga anti-HIV-1
Delavirdina e pertencem à família bis(heteroaril)piperazinas (BHAPs), um conhecido grupo de
inibidores da transcriptase reversa HIV-1.
The synthesis of a series of substituted arylpiperazines linked to a 2-(pyridin-3-yl)-1H-benzo[d]
imidazole scaffold through an alkylic linker is reported. The novel 1-(2-(4-arylpiperazin-1-yl)
alkyl)-2-(pyridin-3-yl)-1H-benzimidazole derivatives are structurally related to the anti-HIV-1
drug Delavirdine and belong to the bis(heteroaryl)piperazines family (BHAPs), a well known
HIV-1 reverse transcriptase inhibitors group.
Keywords: arylpiperazinyl derivatives, benzo[d]imidazole, delavirdine analogues, alkylation
Introduction
The efforts along this line led to the discovery of the
bis-(heteroaryl)piperazine (BHAP) class of HIV-1 reverse
transcriptase inhibitors.4,5 Delavirdine, a BHAP derivative
and first-generation NNRTI is displayed in Figure 1.6
AvarietyofpapersreportingthesynthesisofDelavirdine
analogues have been published up to the date.7,8 However,
structural modifications have been mainly focused on the
4-heteroaryl piperazyne moiety, being the substitution
of the indol ring by other heterocycles less explored.9 To
Non nucleoside HIV-1 reverse transcriptase inhibitors
(NNRTIs) such as nevirapine, have been approved for the
treatmentofacquiredimmunedeficiencysyndrome(AIDS).1
A major limitation of such treatment is the emergence
of resistant virus with specific mutations in the reverse
transcriptase (RT) gene.Therefore, the development of new
active compounds has been the focus in many laboratories.2,3
O
N
HN S CH3
O
NH
R
N
O
N
N
N
N
N
N
N
(CH2)n
Bridge
H
Arylpiperazine
moiety
Arylpiperazine
moiety
Bridge
Heterocycle
Heterocycle
DELAVIRDINE
TARGET COMPOUNDS
Figure 1. Common structural pattern shared by Delavirdine and the target compounds.
*e-mail: cpessoa@uc.cl

64
Synthesis of a Novel Series of 4-Arylpiperazinyl Derivatives Linked
J. Braz. Chem. Soc.
the best of our knowledge, there is not any report about
the synthesis of BHAPs containing benzimidazole as the
heterocyclic framework. The main reason we adopted to use
benzimidazole framework, is the well known bioisosteric
equivalence of this ring, respect to 1(H)-Indole. Besides,
preliminary docking studies carried out by our research
group supported this bioisosteric change.
In this paper, we describe the synthesis of a new BHAP
series combining two scaffolds, the 2-(pyridin-3-yl)-1H-
benzo[d]imidazole and substituted 4-arylpiperazines linked
by methilenic spacers. The structural similitude between
Delavirdine and the target compounds is displayed in
Figure 1.
The intermediate arylpiperazinyl building blocks
3(a-k) were synthesized as follows. Treatment of
the appropriate substituted arylpiperazine 1 with
1-bromoethanol (1-bromopropanol) in acetone at room
temperature, gave the corresponding alcohols 2(a-k)
in 40-54% yield along with the ethers 6 and 7 as minority
side products (Scheme 2). The alcohols were easily purified
by column chromatography, showing the characteristics
hydroxyl spectral signals (IR:3590-3644 cm-1;
1
1H-NMR, broad singlet dOH 2.86-3.87). The H-NMR
spectra displayed also the piperazine and the methylene
protons at high field (dCH2 1.70-3.87), supporting the
presence of these functions.
Reaction of the alcohols 2a-k with mesyl chloride
and triethylamine in dichlorometane at 0 °C provided the
respective mesylated alcohols 3a-k in moderate to good
yields (Scheme 2). The mesylation was mainly deduced
by their IR spectra (absence of the hydroxyl signal and
presence of the two characteristic SO2 signals at 1348 and
1173 cm-1) and their 1H-NMR spectra which displayed the
singlet for the methyl group protons at d: 2.78-3.08 ppm.
Interestingly, the chloroethyl arylpiperazines 3b’ and 3e’
were obtained instead of the expected mesylated products.
Results and Discussion
The Delavirdine analogues 5(a-k) were prepared
according to the retrosynthetic strategy displayed in
scheme 1. We developed a general and useful synthesis
of substituted 4-arylpiperazinyl ethyl (propyl) alcohol
scaffolds 3(a-k), which were utilized for coupling reactions
with 2-(pyridin-3-yl)-1H-benzo[d]imidazole 4 leading to
the desires substituted target compounds.
N
N
R
(CH2)n
H
N
N
OMes
N
+
N
(CH2)n
N
N
N
N
R
4
5
3
Scheme 1. Retrosynthetic strategy for the synthesis of 5(a-k).
X
R
X
N
N
side products (traces)
O
O
N
OH
N
N
N
a
OH
X
X
N
N
X
N
+
+
X
X
R
X
NH
X
X
R
X
N
(CH2)n
R
R
7
6
1
2a-k
f: R=H; n=3, X=N
g: R=H; n=3; X=C
h: R=2-F; n=3; X=C
i: R=4-Cl; n=3; X=C
j: R=4-NO2; n=3, X=C
k: R=3-OMe; n=3, X=C
a: R=H; n=2; X=C
b: R=2-F; n=2; X=C
c: R=4-Cl; n=2; X=C
d: R=4-NO2; n=2, X=C
e: R=3-OMe; n=2, X=C
b
OH
OMes
N (CH2)
X
N
X
N
(CH2)
n
X
n
R
R
3a-k
2a-k
Scheme 2. Synthesis of Phenylpiperazinyl alkyl methanesulphonates intermediates and side products detected as traces. Reagents and conditions. a.
1,2-Bromoethanol or 1,3-bromopropanol, acetone, triethylamine, continuous stirring, RT, 24 h; b. Methanesulfonyl chlorhide, dichloromethane, triethylamine,
0-5 ºC, continuous stirring, RT, 4 h.

Vol. 21, No. 1, 2010
Pessoa-Mahana et al.
65
Cl
O
S
N
N
O
N
CH3
N
R
R
O
3
N
Cl
N
R
3b': R= 2-F
3e': R= 3-OMe
Scheme 3. A reasonable mechanistic proposal for the formation of chloroethyl arylpipera-zines 3e and 3b.
Table 1. Novel arylpiperazinil-benzimidazole derivatives obtained.Yields
are expressed for pure products
A plausible mechanistic pathway (Scheme 3) probably
involves the formation of an aziridinium intermediate
generated by intramolecular attack of the basic piperazinic
nitrogen followed by an SN2 attack of the chloride anion.
Benzimidazole 4 was efficiently obtained by
condensation of o-phenylenediamine 8 with 3-pyridine-
carboxaldehyde in ethanol at room temperature.According
to the literature,8 the generation of benzimidazole 4 may
be assumed to proceed through a three-step sequence:
a) nucleophilic attack of the amino group onto the
carbonylic carbon to give the imine intermediate 9,
b) intramolecular cyclization of 9 to the benzimidazolydine
intermediate 10, and c) aerobic oxidation to provide the
benzimidazole ring 4 (Scheme 4).
N
X
R
Linker
N
N
N
N
X
Chemical Data for Compounds 5a-k
Entry
5a
5b
5c
5d
5e
5f
Linker
-(CH2)2-
-(CH2)2-
-(CH2)2-
-(CH2)2-
-(CH2)2-
-(CH2)2-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
R
H
X
C
C
C
C
C
N
C
C
C
C
C
Formula Yield / %
C24H25N5
C24H24FN5
C24H22ClN5
C24H24N6O2
C25H27N5O
C22H23N7
45
21
35
46
20
38
48
28
38
24
33
2-F
4-Cl
4-NO2
3-OMe
H
Alkylation of the obtained benzimidazole moiety
was readily accomplished using NaOH as the base in
acetonitrile. As is shown is scheme 4, coupling of the
benzimidazole anion with substituted alkyl arylpiperazines
in the presence of triethylamine in acetonitrile at room
temperature for 12 h, provided target compounds 5(a-k)
5g
5h
5i
H
C25H27N5
2-F
C25H26FN5
C25H26ClN5
C25H26N6O2
C26H29N5O
4-Cl
4-NO2
3-OMe
5j
5k
1
(Table 1) in low to moderate yields. H-NMR analysis
of 5a displayed the four characteristic high field signals
corresponding to the methylene protons of piperazine ring
(d:3.10 and 2.50 ppm) and the linker chain (d:4.40 and
2.84 ppm), along with four aromatic doublets at low field
(d: 9.10, 8.78, 8.22 and 7.92 ppm ) typical of the pyridine
ring attached to the 1H-benzimidazole system.
H
NH2
N
a
H
N
N
H
NH2
o-Phenilenediamine
N
NH2
N
10
9
8
N
N
R
(CH2)n
H
N
b
N
N
N
N
N
4
5
Scheme 4. Coupling of the benzimidazole moiety with substituted alkyl arylpiperazines. Reagents and conditions: a) 3-pyridincarboxaldehyde, ethanol,
room temp., 48 h; b) 2-(4-phenylpiperazin-1-yl)alkl methanesulfonates or 1-(2-chloroethyl)-4-phenylpiperazines, acetonitrile, continuous stirring, RT, 12 h.

66
Synthesis of a Novel Series of 4-Arylpiperazinyl Derivatives Linked
J. Braz. Chem. Soc.
In summary, a convenient method for the synthesis
62.7, 57.8, 2×52.8, 2×46.6. Anal. Calc. for C10H16N4O: C,
57.67; H, 7.74; N, 26.90. Found: C, 57.55; H, 7.75; N,
26.82%.
of 1-(2-(4-Arylpiperazin-1-yl)alkyl)-2-(pyridin-3-
yl)-1H-benzimidazole derivatives has been provided.
Further studies on the application will be reported in
due course.
3-[4-(4-Nitrophenyl)piperazin-1-yl]propan-1-ol (2j)
Yellow oil (54%), IR νmax/cm-1: 3630 (OH), 1527 (NO2);
1H-NMR (CDCl3) d 8.11 (d, 2H, J 11 Hz, H-3,5), 6.80
(d, 2H, J 9.4Hz, H-2,6), 3.87-3.84 (m, 3H, CH2-1, OH),
3.53-3.44 (m, 4H, 2 × CH2-pip.), 2.60 (m, 6H, 2×CH2-pip.,
CH2-3), 1.70 (m, 2H, CH2-2); 13C-NMR (CDCl3) d 154.7,
138.5, 2×125.9, 2×112.7, 58.3, 2×52.7, 52.4, 2×46.9, 28.7.
Anal. Calc. for C13H19N3O3: C, 58.85; H, 7.22; N, 15.84;
Found: C, 58.52; H, 7.34; N, 16.01%.
Experimental
All organic solvents used for the synthesis were of
analytical grade. IR spectra were recorded on a Brucker
1
Vector 22 spectrophotometer using KBr discs. H and
13C NMR spectra were obtained on Brucker APC-200
spectrometer using tetramethylsilane as internal reference.
Column chromatography was performed on Merck
silica gel 60 (70-230 mesh). Thin layer chromatography
separations were performed on Merck Kiesselgel 60
(70-230 mesh). Elemental analyses were carried out on a
FISONS EA 1108 CHNS-O analyzer.
Synthesis of 2-(4-Arylpiperazinyl) alkyl methanesulphonate
derivatives 3(a-k). General procedure
Alcohols 2a-k (2.4 mmol) were added to a solution of
methanesulfonyl chloride (2.5 mmol) in dichloromethane
(15 mL) and triethylamine (2.5 mmol) at 0 ºC. The
mixture was maintained with stirring for 4 h and then
concentrated in vacuo. Purification of the crude by column
chromatography CH2Cl2 / AcOEt (1:2) as the eluent,
afforded the title compounds (3a-k) as yellow oils in
moderated yields (35-50%).
Synthesis of arylpiperazinyl alcohols 2(a-k). General
procedure
A mixture of the commercial 4-arylpiperazines
(6 mmol) and bromoethanol (bromopropanol) (6 mmol)
and triethylamine (6 mmol) was stirred for 24 h in
acetone (30 mL) at room temperature. The precipitate
was filtered off and the filtrate was extracted with ethyl
acetate (3 × 50 mL), subsequently dried over anhydrous
MgSO4 and evaporated under vacuum conditions. Column
chromatography of the residue over silica gel (eluent
EtOAc) afforded the corresponding alcohols. Spectral
data for 2-(4-Arylpiperazin-1-yl) alcohols derivatives
2a-2c, 2e, 2g-2i and 2k were consistent with the assigned
structures.10
2-(4-Phenylpiperazin-1-yl)ethyl methanesulphonate (3a)
(48%), IR νmax/cm-1: 1347(SO2), 1172 (SO2); 1H-NMR
(CDCl3) d 7.30 (t, 2H, J 8.0 Hz, H-3, 5), 6.94 (m, 3H,
H-2,4,6), 3.83 (t, 2H, J 7.0 Hz, CH2-1), 3.44-3.20 (m, 4H,
2×CH2 pip.), 2.98 (s, 3H, CH3), 2.89 (t, 2H, J 7.2 Hz, CH2-
2), 2.70 (t, 4H, J 5.1Hz, 2×CH2 pip.); 13C-NMR (CDCl3) d
151.2, 2×129.3, 119.9, 2×116.1, 65.3, 59.8, 2×53.2, 2×49.4,
37.1. Anal. Calc. for C13H20N2O3S: C, 54.91; H, 7.09; N,
9.85. Found: C, 55.02; H, 7.11; N, 10.02%.
2-[4-(4-Nitrophenyl)piperazin-1-yl]ethanol (2d)
Yellow oil (40%), IR νmax/cm-1: 3590 (OH), 1529
(NO2),1292 (NO2). H-NMR (CDCl3) d 7.99 (d, 2H, J
1-(2-Chloroethyl)-4-(2-fluorophenyl)piperazine (3b’)
(35%), IR νmax/cm-1: 1007 (C-F), 728 (C-Cl); 1H-NMR
(CDCl3) d 7.18-6.85 (m, 3H, H-3,4,5), 6.68-6.57 (m, 1H,
H-6), 3.73 (t, 2H, J 13.5 Hz, CH2-1), 3.25 (t, 4H, J 9.5 Hz,
2×CH2 pip.), 2.89 (m, 6H, 2×CH2 pip.,CH2-2); 13C-NMR
(CDCl3) d 158.16 (d, 2C, JC-F 337 Hz), 151,78 , 124.6,
123.1, 122.9, 119.1, 116.4, 115.9, 59.5, 2×53.2, 2×49.7,
39.9. Anal. Calc. for C12H16ClFN2: C, 59.38; H, 6.64; N,
11.54. Found: C, 59.49; H, 6.67; N, 11.38%.
1
8.1 Hz, H-3,5), 6.78 (d, 2H, J 8.9Hz, H-2,6), 3.63 (t, 2H,
J 9.8Hz, CH2-1), 3.57-2.89 (m, 5H, 2×CH2 pip., OH),
2.59-2.55 (m, 6H, 2×CH2 pip.,CH2-2). 13C-NMR (CDCl3)
d 154.7, 137.8, 2×25.8, 2 ×112.5, 59.6, 58.2, 2×52.5, 2 ×
46.8. Anal. Calc. for C12H17N3O3: C, 57.36; H, 6.82; N,
16.72. Found: C, 57.70; H, 7.01; N, 16.66%.
2-(4-(Pyrazin-2-yl)piperazin-1-yl)ethanol (2f)
Yellow oil (44%), IR νmax/cm-1: 3644 (OH), 1348 (C-N);
1H-NMR (CDCl3) d 8.39 (s, 1H, H-2), 7.97 (m, 1H, H-6),
7.49 (d, 1H, J 6.24Hz, H-5), 3.56-3.51 (m, 6H, 2×CH2
pip., CH2-1), 2.86 (1H, b.s., OH), 2.60-2.55 (m, 6H, 2×CH2
pip., CH2-2); 13C-NMR (CDCl3) d 157.7, 130.9, 110, 65.1,
2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl methane-
sulphonate (3c)
(38%), IR νmax/cm-1: 1349 (SO2), 1173 (SO2), 933 (C-
1
Cl); H-NMR (CDCl3) d 7.30 (d, 2H, J 8.4 Hz, H-3,5),
6.91 (d, 2H, J 8.4 Hz, H-2,6), 4.18 (m, 2H, CH2-1),

Vol. 21, No. 1, 2010
Pessoa-Mahana et al.
67
3.52-3.37 (m, 4H, 2×CH2 pip.), 3.32-2.80 (m, 9H, 2×CH2
pip.,CH2-2, CH3); 13C-NMR (CDCl3) d 149.3, 130.9,
2×129.4, 2×118.6, 66.2, 2×52.6, 2×49.7, 38.7, 29.7. Anal.
Calc. for C13H19ClN2O3S: C, 48.97; H, 6.01; N, 8.79. Found:
C, 49.05; H, 6.14; N, 8.72%.
3-[4-(2-Fluorophenyl)piperazin-1-yl]propyl methane-
sulphonate (3h)
(50%), IR νmax/cm-1: 1348 (SO2), 1170 (SO2), 1010
(C-F); 1H-NMR (CDCl3) d 7.28-6.87 (m, 4H, H-3,4,5,6),
3.82 (t, 2H, J 10.2 Hz, CH2-1), 3.47 (m, 4H, 2×CH2-pip.),
3.36-2.92 (m, 9H, 2×CH2-pip., CH2-3, CH3), 2.12-1.90
(m, 2H, CH2-2); 13C-NMR (CDCl3) d 158.10 (d, 2C, JC-F
318 Hz), 153.10, 137.5, 124.4, 118.9, 116.2, 115.9, 68.4,
62.4, 59.4, 53.9, 2×53.2, 2×45.5, 39.7, 26.7. Anal. Calc.
for C14H21FN2O3S: C, 53.15; H, 6.69; N, 8.85. Found: C,
52.73; H, 6.66; N, 8.24%.
2-[4-(4-Nitrophenyl)piperazin-1-yl]ethyl methane-
sulphonate (3d)
(35%), IR νmax/cm-1: 1348 (SO2), 1173 (SO2), 1529,1292
(NO2).; 1H-NMR (CDCl3) d 8.20 (d, 2H, J 7.9Hz, H-3,5),
6.90 (d, 2H, J 7.2 Hz, H-2,6), 3.81 (t, 2H, J 11.5Hz, CH2-1),
3.52-3.39 (m, 4H, 2×CH2 pip), 3.29-2.78 (m, 9H, 2xCH2
pip.,CH2-2, CH3); 13C-NMR (CDCl3) d 153.8, 137.5,
2×125.8, 2×113.7, 63.4, 55.2, 2×52.6, 2×50.1, 37.9. Anal.
Calc. for C13H19N3O5S: C, 47.41; H, 5.81; N, 12.76. Found:
C, 47.12; H, 5.61; N, 12.59%.
3-[4-(4-Chlorophenyl)piperazin-1-yl]propyl methane-
sulphonate (3i)
(50%), IR νmax/cm-1: 1350 (SO2), 1178 (SO2), 938 (C-Cl);
1H-NMR (CDCl3) d 7.41 (d, 2H, J 12.3 Hz, H-3,5), 6.94 (d,
2H, J 8.8 Hz, H-2,6), 3.71 (t, 2H, J 5.8 Hz,CH2-1), 3.50 (m,
4H, 2×CH2-pip), 3.36-2.92(m, 6H, 2×CH2-pip., CH2-3), 2.87
(s, 3H, CH3), 2.25-2.00 (m, 2H, CH2-2); 13C-NMR (CDCl3) d
147.9, 2×129.4, 126.9, 2×118.5, 66.9, 2×52.1, 2×46.8, 41.6,
39.6, 26.5.Anal. Calc. for C14H21ClN2O3S: C, 50.52; H, 6.36;
N, 8.42. Found C14H21ClN2O3S: C, 49.97; H, 6.72; N, 8.14%.
1-(2-Chloroethyl)-4-(3-methoxyphenyl)piperazine (3e’)
(37%), IR νmax/cm-1: 2835 (CO-CH3), 728 (C-Cl);
1H-NMR (CDCl3) d 7.22 (dd, 1H, J1 8.3 Hz, J2 2.6 Hz,
H-5), 6.61-6.22 (m, 3H, H-4,5,6), 3.82-3.71 (m, 5H,
CH2-2, OCH3), 3.60 (t, 2H, J 11.9 Hz, CH2-1), 3.38-3.20
(m, 4H, 2×CH2-pip.), 2.67 (t, 4H, J 10 Hz, 2×CH2-pip.);
13C-NMR (CDCl3) d 160.6, 152.5, 129.8, 108.9, 104.6,
102.6, 97.34, 59.7, 55.2, 2×53.1, 2×49.3, 37.9. Anal. Calc.
for C14H19ClN2O: C, 61.29; H, 7.52; N, 11.00. Found: C,
60.94; H, 7.65; N, 11.32%.
3-[4-(4-Nitrophenyl)piperazin-1-yl]propyl methane-
sulphonate (3j)
(46%), IR νmax/cm-1: 1351 (SO2), 1173 (SO2); 1H-NMR
(CDCl3) d 8.11 (d, 2H, J 6.5 Hz, H-3,5), 6.80 (d, 2H, J 9.5
Hz, H-2,6), 4.28 (t, 2H, J 6.2 Hz, H-1), 3.65-3.43 (m, 4H,
2×CH2-pip), 3.32-2.92 (m, 6H, 2×CH2-pip., CH2-2), 2.88
(s, 3H, CH3), 2.26 (t, 2H, J 6.6 Hz, H-2); 13C-NMR (CDCl3)
d 150.8, 137.9, 2×125.9, 2×112.7, 68.12, 2×52.6, 2×46.9,
37.5, 29.7.Anal. Calc. for C14H21N3O5S: C, 48.97; H, 6.16;
N, 12.24. Found: C, 49.14; H, 6.28; N, 12.09%.
2-(4-Pyrazin-2-yl-piperazin-1-yl)ethyl methanesulphonate
(3f)
(37%), IR νmax/cm-1: 1347 (SO2), 1171 (SO2); 1H-NMR
(CDCl3) d 13C NMR (CDCl3) d 8.35 (s, 1H, H-6), 8.08 (d,
1H, J 8 Hz, H-4), 6.44 (d, 1H, J 8.5 Hz, H-3), 4.26 (t, 2H,
J 11.0 Hz, CH2-1), 3.80 (m, 4H, 2 × CH2 pip), 3.03-2.86
(m, 5H, CH2-2, CH3), 2.63-2.48 (m, 4H, 2 × 2 × CH2 pip).
13C RMN (CDCL3) d 162.3, 159.1, 156.5, 103.6, 53.6,
2×52.0, 2×49.8, 46.7, 42.1. Anal. Calc. for C11H18N4O3S:
C, 46.14; H, 6.34; N, 19.57. Found: C, 45.94; H, 6.45;
N, 19.82%.
3-[4-(3-Methoxyphenyl)piperazin-1-yl]propyl methane-
sulphonate (3k)
(37%), IR νmax/cm-1: 1349 (SO2), 1170 (SO2), 2835 (C-
1
H); H-NMR (CDCl3) d 7.22 (dd, 1H, J1 8.2 Hz, J2 2.86
Hz, H-5), 6.61-6.21 (m, 3H, H-4,5,6), 4.30 (t, 2H, J 6.3 Hz,
H-1), 3.82 (d, 3H, J 9.6 Hz, H-2), 3.75 (s, 3H, OCH3), 3.25
(t, 4H, J 9.8 Hz, 2×CH2-pip.), 2.9-2.5 (m, 6H, CH2-pip,
CH2-3), 2.18 (t, 2H, J 6.7 Hz, H-2); 13C-NMR(CDCl3) d
160.4, 148.2, 129.8, 108.9, 104.6, 102.6, 68.3, 55.2, 53.9,
2×53.1, 2×48.9, 37.3, 26.4.Anal. Calc. for C15H24N2O4S: C,
54.86; H, 7.37; N, 8.53. Found: C, 54.49; H, 7.65; N, 8.24%.
3-[4-(3-Methoxyphenyl)piperazin-1-yl]propyl methane-
sulphonate (3g)
(35%), IR νmax/cm-1: 1347 (SO2), 1173 (SO2); 1H-NMR
(CDCl3) d 7.30 (t, 2H, J 8.4Hz, H-3,5), 6.96 (m, 3H,
H-2,4,6), 4.31 (m, 2H, CH2-1), 3.2 (t, 4H, J 5 Hz, 2×CH2-
pip.), 2.90 (s, 3H, CH3), 2.63-2.43 (m, 6H, 2×CH2-pip.,
CH2-3), 2.10-1.90 (m, 2H, CH2-2); 13C-NMR (CDCl3) d
160.6, 151.1, 129.5, 119.7, 116, 68.5, 55.0, 53.9, 2×53.1,
2×48.9, 37.8, 26.9. Anal. Calc. for C14H22N2O3S: C,
56.35; H, 7.43; N, 9.39; O. Found: C, 56.47; H, 7.76;
N, 9.12%.
Synthesis of 1-[2-(4-Arylpiperazin-1-il)alkyl]-2-(pyridin-3-
yl)-1H-benzimidazoles 5a-k. General procedures
A solution of 2-(pyridin-3-yl)-1H-benzimidazole 4
(0.15 g, 0.75 mmol) in acetonitrile was stirred with NaOH

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Synthesis of a Novel Series of 4-Arylpiperazinyl Derivatives Linked
J. Braz. Chem. Soc.
for 2 hours. The benzimidazole anion afforded was added
to a solution of the corresponding arylpiperazinyl alkyl
methanesulphonate derivatives 3 (0.70 mmol) in acetonitrile
(12 mL). The mixture was stirred at room temperature for
12 hours and concentrated in vacuo. Purification of the
crude by column chromatography with dichloromethane
as the eluent afforded the target compounds 5a-k as yellow
oils.
1-{2-[4-(4-Nitrophenyl)piperazin-1-yl]ethyl}-2-pyridin-3-
yl-1H-benzimidazole (5d)
(46%), IR νmax/cm-1: 1529 (NO2), 1292 (NO2), 1324
(C-N); 1H-NMR(CDCl3) d 9.10 (d, 1H, J 1.5 Hz, H-2 pyr.),
8.78 (d, 1H, J 4.8 Hz, H-4 pyr.), 8.23 (m, 1H, H-6 pyr.), 8.12
(d, 1H, J 6.5 Hz, H-3,5), 7.91 (d, 1H J 7.1 Hz, H-5-pyr.),
7.69-7.36 (m, 5H, Ar), 6.89 (d, 2H, J 9.5 Hz, H-2,6), 4.40
(t, 2H, J 12.6 Hz, CH2-1), 3.15 (t, 4H, J 10.2 Hz, 2×CH2-
pip.), 2.85 (t, 2H, J 12.6 Hz, CH2-2), 2.50 (t, 4H, J 10.1
Hz, 2×CH2 pip.). 13C-NMR (CDCl3) d 154.6, 150.7, 149.9,
147.5, 137.2, 134.2, 130.8, 2×125.9, 124.7, 123.6, 123.4,
122.9, 120.4, 2×112.8, 110.1, 58.4, 57,3 2×53.1, 2×47.9,
39.8. Anal. Calc. for C24H24N6O2: C, 67.27; H, 5.65; N,
19.61. Found: C, 66.93; H, 5.42; N, 19.42%.
1-[2-(4-Phenylpiperazin-1-yl)ethyl]-2-pyridin-3-yl-1H-
benzimidazole (5a)
(45%), IR νmax/cm-1: 2885 (C-H), 1338 (C-N). 1H-NMR
(CDCl3) d 9.10 (d, 1H, J 2.1 Hz, H-2 pyr.), 8.78 (d, 1H, J
4.9 Hz, H-4 pyr.), 8.22 (d, 1H, J 7.9 Hz, H-6 pyr.), 7.92 (d,
1H, J 8.5 Hz, H-5-pyr.), 7.53-7.14 (m, 6H, Ar), 6.85 (m,
3H, H-2,4,6), 4.40 (t, 2H, J 6.5 Hz, CH2-1), 3.10 (t, 4H, J
4.9 Hz, 2×CH2-pip.), 2.84 (t, 2H, J 6.5 Hz, CH2-2), 2.50
(t, 4H, J 5.1 Hz, 2×CH2 pip.). 13C-NMR (CDCL3) d 151.3,
150.7, 149.9, 143.3, 137.2, 135.6, 2×129.1, 2×123.6, 123.4,
2×120.3, 119.9, 2×116.1, 110.2, 57.2, 2×53.6, 2×48.9,
42.9.Anal. Calc. for C24H25N5: C, 75.17; H, 6.57; N, 18.26.
Found: C, 75.36; H, 6.42; N, 18.22%.
1-{2-[4-(3-Methoxyphenyl)piperazin-1-yl]ethyl}-2-
pyridin-3-yl-1H-benzimidazole (5e)
(20%), IR νmax/cm-1: 2883 (C-H), 1313 (C-N); 1H-NMR
(CDCl3) d 9.10 (d, 1H, J 2.1 Hz, H-2 pyr.), 8.78 (d, 1H, J
4.9 Hz, H-4 pyr.), 8.22 (d, 1H, J 7.9 Hz, H-6 pyr.), 7.92 (d,
1H J 7.1Hz, H-5-pyr.), 7.62-7.12 (m, 5H, Ar), 6.61-6.21
(m, 3H, H-4,5,6), 4.40 (t, 2H, J 6.6 Hz, CH2-1), 3.86 (s, 3H,
OCH3), 3.15 (t, 4H, J 5.0 Hz, 2×CH2-pip.), 2.84 (t, 2H, J 13
Hz, CH2-2), 2.58 (t, 4H, J 5.1 Hz, 2×CH2 pip.). 13C-NMR
(CDCl3) d 160.6, 152.4, 150.7, 149.9, 147.2, 143.2, 137.2,
135.6, 129.8, 127.3, 123.6, 123.4, 122.9, 120.3, 110.2,
108.9, 104.5, 102.6, 57.2, 55.2, 2×53.6, 2×48.9, 42.9.Anal.
Calc. for C25H27N5O: C, 72.61; H, 6.58; N, 16.94. Found:
C, 72.76; H, 6.23; N, 16.82%.
1-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}-2-pyridin-
3-yl-1H-benzimidazole (5b)
(21%), IR νmax/cm-1: 1321 (C-N), 1007 (C-F); 1H-NMR
(CDCl3) d 9.10 (d, 1H, J 1.4Hz, H-2 pyr.), 8.78 (d, 1H, J
4.8 Hz, H-4 pyr.), 8.24 (d, 1H, J 7.9 Hz, H-6 pyr.), 7.92 (d,
1H, J 7.8 Hz, H-5-pyr.), 7.62-7.21 (m, 6H, Ar), 7.12-6.85
(m, 2H, H-4,6), 4.40 (t, 2H, J 6.5 Hz, CH2-1), 2.97 (t, 4H,
J 4.9 Hz, 2×CH2-pip.), 2.84 (t, 2H, J 6.5 Hz, CH2-2), 2.50
(m, 4H, J 4.9 Hz, 2×CH2 pip.). 13C-NMR (CDCl3) d 158.10
(d, 2C, JC-F 318 Hz), 153.10, 151.1, 150.7, 149.9, 143.2,
137.2, 135.6, 124.5, 124.4, 123.6, 123.4, 122.9, 122.7,
122.5, 120.2, 118.9, 116.3, 115.9, 110.2, 57.2, 2×53.7,
2×50.3. Anal. Calc. for C24H24FN5: C, 71.80; H, 6.03; N,
17.44. Found: C, 72.14; H, 6.14; N, 17.62%.
1-(2-(4-(Pyrazin-2-yl)piperazin-1-yl)ethyl)-2-(pyridin-3-
yl)-1H-benzo[d]imidazole (5f)
(38%), IR νmax/cm-1: 2856 (C-H), 1311 (C-N); 1H-NMR
(CDCl3) d 9.10 (d, 1H, J 2.1 Hz, H-2 pyr.), 8.78 (d, 1H, J
4.8 Hz, H-4 pyr.), 8.36-8.21 (m, 2H, H-2 pyr., H-6 pyr.),
7.91 (d, 1H, J 9.0 Hz, H-5-pyr.), 7.76-7.31 (m, 5H, Ar),
6.50 (t, 1H, J 4.1 Hz, H-6), 4.42 (t, 2H, J 6.6 Hz, CH2-1),
3.17 (t, 4H, J 4.9 Hz, 2×CH2-pip.), 2.83 (t, 2H, J 6.4 Hz,
CH2-2), 2.49 (t, 4H, J 5 Hz, 2×CH2 pip.). 13C-NMR (CDCl3)
d 162.3, 157.7, 156.2, 150.7, 149.9, 147.5, 143.3, 137.1,
135.6, 129.8, 127.5, 123.4, 122.9, 120.3, 110.7, 110.0,
57.3, 2×53.4, 2×48.4, 42.8. Anal. Calc. for C22H23N7:
C, 68.55; H, 6.01; N, 25.44. Found: C, 68.36; H, 6.26;
N, 25.23%.
1-{2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl}-2-pyridin-
3-yl-1H-benzimidazole (5c)
(35%), IR νmax/cm-1: 1317 (C-N), 933 (C-Cl); 1H-NMR
(CDCl3) d: 9.11 (d, 1H, J 2.1Hz, H-2 pyr.), 8.78 (d, 1H, J
4.9 Hz, H-4-pyr.), 8.25 (d, 1H, J 7.9 Hz, H-6 pyr.), 7.91 (d,
1H J 7.1 Hz, H-5-pyr.), 7.54-7.16 (m, 6HAr) 7.11-6.87 (m,
2H, H-2,6) 4.41 (t, 2H, J 6.4 Hz, CH2-1), 3.10 (t, 4H, J 5
Hz, 2×CH2-pip.), 2.88 (t, 2H, J 12 Hz, CH2-2), 2.56 (t, 4H,
J 9.8 Hz, 2×CH2-pip.). 13C-NMR (CDCl3) d 151.7, 150.8,
147.2, 137.2, 134.4, 132.5, 2×128.9, 124,4 123.6, 123.5,
123.4, 122.9, 120.3, 2×117.3, 110.2, 58.2, 57.1, 2×53.5,
2×48.9, 42.9.Anal. Calc. for C24H22ClN5:C, 68.97; H, 5.79;
N, 16.76. Found: C, 69.02; H, 5.62; N, 17.00%.
1-[3-(4-Phenylpiperazin-1-yl)propyl]-2-pyridin-3-yl-1H-
benzimidazole (5g)
(48%), IR νmax/cm-1: 2875 (C-H), 1306 (C-N); 1H-NMR
(CDCl3) d 9.10 (d, 1H, J 2.2 Hz, H-2 pyr.), 8.78 (d, 1H,
J 4.9 Hz, H-4 pyr.), 8.22 (d, 1H, J 8 Hz, H-6 pyr.), 7.89
(d, 1H, J 9.2 Hz, H-5-pyr.), 7.53-7.20 (m, 6H, Ar), 6.95

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(m, 3H, H-2,4,6), 4.40 (t, 2H, J 7.8 Hz, CH2-1), 3.16 (t,
4H, J 9.8 Hz, 2×CH2-pip.), 2.50 (t, 4H, J 9.9 Hz, 2×CH2
pip.), 2.37 (t, 2H, J 6.6 Hz, CH2-3), 1.91 (m, 2H, CH2-2).
13C-NMR (CDCl3) d 151.1, 150.7, 150.4, 149.7, 147.6,
143.1, 136.9, 135.7, 134.4, 2×129.4, 127.6, 123.6, 123.1,
122.9, 120.1, 119.8, 2×116.1, 54.6, 2×53.1, 2×49,7, 29.8.
Anal. Calc. for C25H27N5: C, 75.54; H, 6.85; N, 17.62.
Found: C, 75.31; H, 6.90; N, 17.79%.
124.7, 123.6, 123.4, 122.9, 120.4, 2×112.8, 110.1, 58.4,
57,3 2×53.1, 2×47.9, 22.8. Anal. Calc. for C25H26N6O2:
C, 67.86; H, 5.92; N, 18.99. Found: C, 68.14; H, 5.69; N,
19.23% .
1-{3-[4-(3-Methoxyphenyl)piperazin-1-yl]propyl}-2-
pyridin-3-yl-1H-benzimidazole (5k)
(33%), IR νmax/cm-1: 2835 (C-H), 1315 (C-N); 1H-NMR
(CDCl3) d 9.10 (d, 1H, J 2.19 Hz, H-2 pyr.), 8.78 (d, 1H, J
4.9 Hz, H-4 pyr.), 8.21 (d, 1H, J 7.9 Hz, H-6 pyr.), 7.91 (d,
1H, J 5.5 Hz, H-5-pyr.), 7.63-7.13 (m, 5H, Ar), 6.61-6.24
(m, 3H, H-4,5,6), 4.40 (t, 2H, J 7.3 Hz, H CH2-1), 3.86 (s,
3H, OCH3), 3.17 (t, 4H, J 5.0 Hz, 2×CH2-pip.), 2.50 (t, 4H,
J 5 Hz, 2×CH2 pip.), 2.36 (t, 2H, J 6.5 Hz, CH2-3), 2.0 (b.s.,
2H, J 13.8 Hz, CH2-2). 13C-NMR (CDCl3) d 160.8, 152.3,
150.7, 150.0, 147.2, 143.3, 137.1, 136.6, 135.6, 129.8,
127.3, 123.6, 123.3, 122.9, 120.3, 110.4, 109.0, 104.6,
102.6, 57.3, 55.2, 2×53.6, 2×48.9, 22.9. Anal. Calc. for
C26H29N5O: C, 73.04; H, 6.84; N, 16.38. Found: C, 72.89;
H, 6.98; N, 16.78%.
1-{3-[4-(2-Fluorophenyl)piperazin-1-yl]propyl}-2-pyridin-
3-yl-1H-benzimidazole (5h)
(28%), IR νmax/cm-1: 1225 (C-N), 1007 (C-F);
1H-NMR(CDCl3) d 9.10 (d, 1H, J 3Hz, H-2 pyr.), 8.80 (d,
1H, J 6.6 Hz, H-4 pyr.), 8.23 (d, 1H, J 7.9 Hz, H-6 pyr.),
7.91 (d, 1H, J 5.3 Hz, H-5-pyr.), 7.61-7.21 (m, 6H, Ar),
7.12-6.86 (m, 2H,Ar), 4.41 (t, 2H, J 7.1 Hz, H CH2-1), 3.20
(t, 4H, J 4.5 Hz, CH2-2×CH2-pip.), 2.50 (t, 4H, J 4.9 Hz,
2×CH2 pip.), 2.36 (t, 2H, J 6.7 Hz, CH2-3), 1.97 (t, 2H, J
13.8 Hz, CH2-2). 13C-NMR (CDCl3) d 158.10 (d, 2C, JC-F
318 Hz), 153.10, 150.7, 147.4, 143.1, 139.1, 136.9, 135.7,
134.4, 127.1, 124.5, 123.9, 123.3, 122.9, 120.1, 118.9,
116.3, 116.9, 115.9, 110.4, 54.7, 2×53.2, 2×50,4, 50.4,
29.9.Anal. Calc. for C25H26FN5: C, 72.27; H, 6.31; N, 16.85.
Found: C, 71.99; H, 6.67; N, 16.49%.
Acknowledgments
This work was supported by VRAID (grant No.
01/2008).
1-{3-[4-(4-Chlorophenyl)piperazin-1-yl]propyl}-2-pyridin-
3-yl-1H-benzimidazole (5i)
Supplementary Information
(38%), IR νmax/cm-1: 1227 (C-N), 933 (C-Cl); 1H-NMR
(CDCl3) d 9.10 (d, 1H, J 2.5 Hz, H-2 pyr.), 8.78 (d, 1H,
J 4.8 Hz, H-4 pyr.), 8.22 (d,1H, J 8.0 Hz, H-6 pyr.), 7.90
(d, 1H J 7.4 Hz, H-5-pyr.), 7.52-7.14 (m, 6H, Ar), 7.11-
6.87 (m, 2H, H-2,6), 4.41 (m, 2H, H CH2-1), 3.15 (m, 4H,
CH2-2×CH2-pip.), 2.48 (m, 4H, 2×CH2 pip.), 2.32 (m, 2H,
CH2-3), 2.0 (m, 2H, CH2-2). 13C-NMR (CDCl3) d 151.6,
150.8, 147.3, 137.1, 134.5, 132.7, 2×129.0, 127.5, 124,2
123.6, 123.5, 123.3, 122.9, 120.3, 2x118.3, 110.2, 58.4,
57.1, 2×53.7, 2×49.1, 29.7. Anal. Calc. for: C25H26ClN5:
C, 69.51; H, 6.07; N, 16.21. Found: C, 69.27; H, 6.14;
N,15.99%.
Supplementary data are available free of charge at http://
jbcs.sbq.org.br, as PDF file.
References
1. Basavapathruni, A.; Anderson, K. S.; Curr. Pharm. Des. 2006,
12, 1857.
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2000, 25, 47.
1-{3-[4-(4-Nitrophenyl)piperazin-1-yl]propyl}-2-pyridin-
3-yl-1H-benzimidazole (5j)
(24%), IR νmax/cm-1: 1530 (NO2), 1296 (NO2). 1H-NMR
(CDCl3) d 9.10 (d, 1H, J 1.5 Hz, d, H-2 pyr.), 8.78 (d, 1H,
J 4.9 Hz, H-4 pyr.), 8.22 (m, 1H, H-6 pyr.), 8.13 (d, 1H, J
6.7 Hz, H-3,5), 7.90 (d, 1H, J 6.9 Hz, H-5-pyr.), 7.68-7.36
(m, 5H, Ar), 6.89 (d, 2H, J 9.4 Hz, H-2,6), 4.40 (t, 2H, J
7.1 Hz, CH2-1), 3.23 (t, 4H, J 5.0 Hz, 2×CH2-pip.), 2.48 (t,
4H, J 5.2 Hz, 2×CH2 pip.), 2.35 (t, 2H, J 6.3 Hz, CH2-3),
2.10 (bs, 2H, J 6.8 Hz, CH2-2). 13C-NMR (CDCl3) d 154.6,
150.7, 149.9, 147.5, 137.2, 136.7, 134.2, 130.8, 2×125.9,
6. Esnouf, R. M.; Ren, J.; Hopkins, A. L.; Ross, C. K.; Jones, E.
Y.; Stammers, D. K.; Stuart, D. I.; Proc. Natl. Acad. Sci. U. S.
A. 1997, 94, 3984.
7. Genin, M. J.; Poel, T. J.; Yagi, Y.; Biles, C.; Althaus, I.;
Keiser, B. J.; Kopta, L. A.; Friis, J. M.; Reusser, F.; Adams, W.
J.; Olmsted, R.A.;Voorman, R. L.; Thomas, R. C.; Romero, D.
L.; J. Med. Chem. 1996, 39, 5267.

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Synthesis of a Novel Series of 4-Arylpiperazinyl Derivatives Linked
J. Braz. Chem. Soc.
8. Pinna, G.; Loriga, G.; Murineddu, G.; Grella, G.; Mura, M.;
Vargiu, L.; Murgioni, C.; La Colla, P.; Chem. Pharm. Bull. 2001,
40, 1406.
20000127; (Comp. 2c) Pollard, C. B.; Wicker, T. H., Jr.; J. Am.
Chem. Soc. 1954, 76, 1853; (Comp. 2h) Kanno, T.; Gaino, M.;
Yamamura, M.; Ishida, R.; Shintomi, K.; Eur. Pat. Appl. 89
1981, CODEN: EPXXDW EP 34284 A2 19810826; (Comps.
2g, 2i, 2k) Felfoldi, K.; Molnar, A.; Apjok, J.; Czombos, J.;
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Received: February 5, 2009
Web Release Date: October 16, 2009

J. Braz. Chem. Soc., Vol. 21, No. 1, S1-S9, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Synthesis of a Novel Series of 4-Arylpiperazinyl Derivatives Linked to a
2-(Pyridin-3-yl)-1H-benzimidazole as New Delavirdine Analogues
David Pessoa-Mahana,*,a Andrés Núñez,a Christian Espinosa,a Jaime Mella-Raipána
and Hernán Pessoa-Mahanab
aDepartamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile,
Casilla 306, Santiago 22, Chile
bDepartamento de Química Orgánica y Físico-Química, Facultad de Ciencias Químicas y
Farmacéuticas, Universidad de Chile, Casilla 233, Santiago 1, Chile
Figure S1. 1H NMR spectrum of compound 5a (CDCl3, 200 MHz).
*e-mail: cpessoa@uc.cl

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Synthesis of a Novel Series of 4-Arylpiperazinyl Derivatives Linked
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Figure S2. 1H NMR spectrum of compound 5b (CDCl3, 200 MHz).
Figure S3. 1H NMR spectrum of compound 5c (CDCl3, 200 MHz).

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Figure S4. 1H NMR spectrum of compound 5d (CDCl3, 200 MHz).
Figure S5. 1H NMR spectrum of compound 5e (CDCl3, 200 MHz).

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Synthesis of a Novel Series of 4-Arylpiperazinyl Derivatives Linked
J. Braz. Chem. Soc.
Figure S6. 1H NMR spectrum of compound 5f (CDCl3, 200 MHz).
Figure S7. 1H NMR spectrum of compound 5g (CDCl3, 200 MHz).

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Figure S8. 1H NMR spectrum of compound 5h (CDCl3, 200 MHz).
Figure S9. 1H NMR spectrum of compound 5j (CDCl3, 200 MHz).

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Synthesis of a Novel Series of 4-Arylpiperazinyl Derivatives Linked
J. Braz. Chem. Soc.
Figure S10. 1H NMR spectrum of compound 5k (CDCl3, 200 MHz).
Figure S11. 13C NMR spectrum of compound 5a (CDCl3, 50 MHz).

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Figure S12. 13C NMR spectrum of compound 5e (CDCl3, 50 MHz).
Figure S13. 13C NMR spectrum of compound 5f (CDCl3, 50 MHz).

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Synthesis of a Novel Series of 4-Arylpiperazinyl Derivatives Linked
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Figure S14. 13C NMR spectrum of compound 5g (CDCl3, 50 MHz).
Figure S15. 13C NMR spectrum of compound 5h (CDCl3, 50 MHz).

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Figure S16. 13C NMR spectrum of compound 5j (CDCl3, 50 MHz).