Synthesis of 2-(N-benzylpyrrolyl)-benzimidazoles using polyphosphoric acid prompted cyclocondensation

Article abstract of DOI:10.1002/jhet.480

Synthesis of a series of 2-substituted benzimidazoles was carried out for screening anti-inflammatory activities. 2-(N-benzylpyrrolyl)-benzimidazoles 9a-k were synthesized from N-benzyl-2-pyrrole carboxylic acids 8a-d and 4-substituted-1,2-phenylenediamin

Full text of DOI:10.1002/jhet.480

November 2010
Synthesis of 2-(N-Benzylpyrrolyl)-benzimidazoles Using
Polyphosphoric Acid Prompted Cyclocondensation
1367
Bereket Mochona,a* Laine Le,a Madhavi Gangapuram,b Nelly Mateeva,a
Tiffany Ardley,b and Kinfe K. Reddab
aDepartment of Chemistry, College of Arts and Sciences, Florida A&M University,
Tallahassee, Florida 32307
bCollege of Pharmacy and Pharmaceutical Sciences, Florida A&M University,
Tallahassee, Florida 32307
*E-mail: bereket.mochona@famu.edu
Received January 20, 2010
DOI 10.1002/jhet.480
Published online 25 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
Synthesis of a series of 2-substituted benzimidazoles was carried out for screening anti-inflammatory
activities. 2-(N-benzylpyrrolyl)-benzimidazoles 9a–k were synthesized from N-benzyl-2-pyrrole carbox-
ylic acids 8a–d and 4-substituted-1,2-phenylenediamines by cyclocondensation utilizing polyphosphoric
acid (PPA) as condensing agent. The N-benzyl-2-pyrrole carboxylic acids were prepared by standard
method of N-benzylation of 2-pyrrole carboxylate using NaH/DMF and appropriately substituted benzyl
halides followed by alkaline hydrolysis.
J. Heterocyclic Chem., 47, 1367 (2010).
INTRODUCTION
received much attention as potential NSAIDs [15–25].
Literature survey also revealed that when one bioactive
heterocyclic system was coupled with another, a mole-
cule with enhanced biological activity was produced
[26–28]. Based on these considerations, in the course of
research devoted to the development of new classes of
anti-inflammatory agents [29–31], we have speculated
that incorporating pyrrole ring into the 2-position of
benzimidazole moiety result in compounds with single
Benzimidazole derivatives are known to possess
varied biological activities. Substituted benzimidazole
derivatives have been reported to possess anticancer,
antiulcer, antiviral, antifungal, antimicrobial, and anti-
inflammatory activities [1–6]. Prostaglandins and leuko-
triens from oxidative metabolism of arachidonic acid
play established roles in the pathophysiology of inflam-
matory disorders [7,8]. Pharmacological interference
with cyclooxygenase (COX) and 5-lipooxygenase (5-
LOX), enzymes involved in production of prostaglandins
and leukotriens is a hallmark feature of virtually all
marked nonsteroidal anti-inflammatory drugs (NSAIDs).
This property is believed to play an important role in
their therapeutic effects and certain mechanism-based
side effects including gastrointestinal bleeding, nephro-
toxicity, and cardiovascular problems in the case of
highly selective cyclooxygenase-2 inhibitors [9–14].
There have been remarkable efforts in developing new
classes of compounds to minimize the side effects of the
existing NSAIDs. Recent investigations on triazole, im-
idazole, pyrrole, benzimidazole, and indole derivatives
Figure 1 have shown that these classes of heterocycles
Figure 1. Structures of some pyrrole, benzimidazole, and indole deriv-
atives with anti-inflammatory activity.
C
V
2010 HeteroCorporation

1368
B. Mochona, L. Le, M. Gangapuram, N. Mateeva, T. Ardley, and K. K. Redda
Vol 47
EXPERIMENTAL
molecular scaffold that could enhance biological activ-
ities. Herein, we report the synthesis of this new class
of compounds. The screening of anti-inflammatory
activities of these compounds is underway.
Melting points (mp) were determined on Gallenkamp melt-
ing point apparatus and are uncorrected. Reagents and solvents
were purchased from Sigma-Aldrich Chemical Company
(Milwaukee, WI) and used as received. The structures of the
products described were confirmed by IR, 1H NMR, and ele-
mental analysis data. The IR spectra were run with KBr pellets
on Perkin-Elmer 1430 FT spectrometer and are reported in
RESULTS AND DISCUSSION
cmꢀ1. H NMR spectra were recorded on Varian Gemini HX-
1
300 MHz spectrometer. All 1H chemical shifts (in ppm) are
reported relative to tetramethylsilane as internal standard for
solutions in DMSO-d6 and CDCl3 as the solvent unless other-
wise specified. Elemental microanalysis was performed in Gal-
braith Laboratories (Knoxville, Tennessee). Analysis indicated
by the symbols of the elements was within 60.4% of the theo-
retical values. Analytical thin layer chromatography was per-
formed on 250 lm-layer flexible plates. Spots were visualized
under Ultraviolet illumination. Reaction products were puri-
fied, when necessary, by column chromatography on silica gel
60 (200–425 mesh), with the solvent system indicated. Sol-
vents were evaporated in vacuo. Anhydrous sodium sulphate
was used as drying agent.
Preparation of N-benzyl-2-pyrrole carboxylates (7a–d);
general procedure A. To a cooled solution of methyl-2-pyrrol
carboxylate 6 (1 equiv, 10 mmol), in 12 mL of DMF, NaH
(1.5 equiv, 15 mmol) was added in small portions. The reac-
tion mixture was stirred at 0ꢁC for 20 min, the appropriately
substituted benzyl halide (1 equiv, 10 mmol) in 0.6 mL DMF
was added dropwise. The mixture was warmed to room tem-
perature and stirred for 2 h. Excess hydride was decomposed
with a small amount of methyl alcohol. After evaporation to
dryness under reduced pressure, the crude residue was washed
with water and extracted with ethyl acetate. The combined or-
ganic layers were dried over Na2SO4, and the solvent was
evaporated in vacuo. The resulting solid was purified by col-
umn chromatography (ethyl acetate: hexane) to afford N-(4-
substitutedbenzyl)-2-pyrrole carboxylates (7a–d).
The synthetic routes for the title compounds are out-
lined in Scheme 1. Pyrrolylbenzimidazoles, 9a–k were
synthesized starting from the commercially available 2-
pyrrole carboxylic acid in four steps. Esterification of an
acid by refluxing in thionylchloride/methanol mixture
afforded the corresponding ester 6. N-benzylation of 6
by treating with NaH/DMF followed by appropriately
substituted benzyl halides afforded the corresponding N-
benzyl-2-pyrrole carboxylates 7a–d. Alkaline hydrolysis
of 7 using 30% aqueous potassium hydroxide gave the
carboxylic acids 8a–d, as key intermediates for the prep-
aration of the targeted benzimidazoles. Cyclocondensa-
tion of 8 with 4-substituted-1,2-phenylenediamine car-
ried out utilizing polyphosphoric acid (PPA) as condens-
ing agent afforded the titled compounds in fair to good
yield. The chemical structures of all new compounds
1
were established by infrared (IR), H NMR spectra as
well as elemental analysis. The IR-spectral characteris-
tics (all spectra taken in KBr) are quite similar and
could be summarized as: m (NAH): 3150–3185 cmꢀ1; m
(CAH) 2900 cmꢀ1; m (AC¼¼NA): 1620–1760 cmꢀ1
.
1
Detailed H NMR spectra of the targeted and intermedi-
ate compounds is given in the experimental section. The
elemental analysis indicated by the symbols of the ele-
ments was within 60.4% of theoretical values. Relevant
physical data of the targeted compounds were collected
and summarized in Table 1.
Methyl-N-benzylpyrrole-2-carboxylate (7a). Isolated as
white crystalline solid, yield 1.86 g (86.5%); 1H NMR (300
Scheme 1. Reagents and conditions: (i) NaH, DMF, PhCH2Br, 0–65ꢁC, 2–4 h, (ii) 30% KOH/MeOH, reflux, 1–2 h. (iii) O-phenylene diamine,
PPA/xylene, 160ꢁC, 4–6 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis of 2-(N-Benzylpyrrolyl)-benzimidazoles Using Polyphosphoric Acid
Prompted Cyclocondensation
1369
Table 1
Physical and analytical data of N-benzyl-2-pyrrolylbenzimidazoles.
Analysis (%) (Calc./Found)
Entry
X
H
Y
H
Yield (%)
77.4
mp (ꢁC)
121–123
M. Formula
C18H15N3
C
H
N
9a
79.10
79.14
79.41
79.07
67.91
67.87
70.24
70.07
79.41
79.15
68.66
68.35
70.24
70.19
61.28
61.15
67.91
67.77
68.66
68.35
61.28
61.15
5.53
5.52
5.96
5.92
4.43
4.52
4.58
4.52
5.96
5.98
4.85
4.98
4.58
4.52
3.71
3.88
4.43
4.41
4.85
4.98
3.71
3.88
15.37
15.36
14.62
14.36
17.60
17.44
13.65
13.36
14.62
14.76
16.86
16.76
13.65
13.44
15.88
15.74
17.60
17.63
16.86
16.76
15.88
15.74
9b
9c
9d
H
H
H
CH3
NO2
Cl
80.1
67
133–134
151–153
167–168
176–177
204–205
233–235
239–241
202–205
246–248
222–224
C19H17N3
C18H14N4O2
C18H14ClN3
C19H17N3
79
9e
9f
CH3
CH3
Cl
H
74
NO2
H
74.7
78.8
61.9
61.6
63.8
63.6
C19H16N4O2
C18H14ClN3
C18H13ClN4O2
C18H14N4O2
C19H16N4O2
C18H13ClN4O2
9g
9h
9i
Cl
NO2
H
NO2
NO2
NO2
9j
CH3
Cl
9k
0
0
MHz, CDCl3): d 7.78 (d, J ¼ 7.6 Hz, 2H, C3 ,C5 Ar-H), 7.37
Preparation of N-benzyl-2-pyrrole carboxylic acids
(8a–d): general procedure B. A suspension of the N-benzyl-
pyrrole-2-carboxylates 7a–d (1 equiv, 10 mmol) was dissolved
in MeOH/H2O (3:1) and 30% KOH (4 equiv). The mixture
was heated under reflux for 1–2 h. After cooling to room tem-
perature, the reaction mixture was acidified using 2N HCl. The
resulting precipitate was filtered and washed with water and
petroleum ether to give the desired acids 8a–d.
0
0
0
(d, 1H, J ¼ 1.5 Hz, pyrrole-C5 H), 7.15–7.22 (m, 3H, C2 , C4 ,
0
0
C6 -Ar-H), 6.4 (d, 1H, J ¼ 1.5 Hz, pyrrole-C3 H), 6.23 (m, 1H,
0
pyrrole-C4 H), 4.98 (s, 2H, benzyl-CH2), 3.77 (s, 3H,
ACOOCH3).
Methyl-N-(4-methylbenzyl)-pyrrole-2-carboxylate (7b). Isolated
as light yellow oily liquid. Crystallized from absolute ethanol
1
as white crystalline solid, yield 1.68 g (73.3%); H NMR (300
0
0
0
0
MHz, CDCl3): d 7.0–7.4 (m, 4H, C2 ,C3 C5 ,C6 Ar-H), 7.37 (d,
N-benzyl-2-pyrrol carboxylic acid (8a). Isolated as white
solid, yield 1.92 g (95.5%); 1H NMR (300 MHz, CDCl3): d
0
1H, J ¼ 1.5 Hz, pyrrole-C5 H), 6.4 (d, 1H, J ¼ 1.5 Hz, pyr-
0
role-C3 H), 6.23 (m, 1H, pyrrole-C4 H), 5.08 (s, 2H, benzyl-
0
0
0
13.66 (br, s, 1H, ACOOH), 7.7 (d, J ¼ 7.6 Hz, 2H, C3 ,C5
CH2), 3.72 (s, 3H, ACOOCH3), 2.32 (s, 3H, Ar-CH3).
Methyl-N-(4-chlorobenzyl)-pyrrole-2-carboxylate (7c). Isolated
as white solid, yield 1.52 g (60.8%); 1H NMR (300 MHz,
0
Ar-H), 7.37 (d, 1H, J ¼ 1.5 Hz, pyrrole-C5 H), 7.25–7.32 (m,
0
0
0
0
3H, C2 , C4 , C6 -Ar-H), 6.4 (d, 1H, J ¼ 1.5 Hz, pyrrole-C3 H),
0
6.23 (m, 1H, pyrrole-C4 H), 4.98 (s, 2H, benzyl-CH2).
0
0
CDCl3): d 7.08 (d, J ¼ 8.1 Hz, 2H, C2 ,C6 Ar-H), 7.26 (d, 1H, J
N-(4-methylbenzyl)-2-pyrrole carboxylic acid (8b). Isolated
as white solid, yield 2.07 g (96.2%); 1H NMR (300 MHz,
DMSO-d6): d 13.78 (br, s, 1H, ACOOH), 7.06–7,4 (m, 4H,
0
0
0
¼ 1.5 Hz, pyrrole-C5 H), 7.20 (d, 2H, J ¼ 8.4 Hz, C3 , C5 -Ar-H),
0
6.4 (d, 1H, J ¼ 1.5 Hz, pyrrole-C3 H), 6.23 (m, 1H, pyrrole-
0
C4 H), 5.28 (s, 2H, benzyl-CH2), 3.67 (s, 3H, ACOOCH3).
Methyl-N-(4-nitrobenzyl)-pyrrole-2-carboxylate (7d). Isolated
0
0
0
0
0
C2 ,C3 C5 , C6 Ar-H), 7.37 (d, 1H, J ¼ 1.5 Hz, pyrrole-C5 H),
as white solid, yield 1.68 g (64.6%); 1H NMR (300 MHz,
0
6.38 (d, 1H, J ¼ 1.5 Hz, pyrrole-C3 H), 6.20 (m, 1H, pyrrole-
0
C4 H), 5.58 (s, 2H, benzyl-CH2), 2.32 (s, 3H, Ar-CH3).
0
0
CDCl3): d 7.98 (d, J ¼ 8.1 Hz, 2H, C3 ,C5 Ar-H), 7.37 (d, 1H, J
0
0
0
N-(4-chlorobenzyl)-2-pyrrole carboxylic acid (8c). Isolated
as white solid, yield 2.18 g (93%); 1H NMR (300 MHz,
DMSO-d6): d 13.80 (br, s, 1H, ACOOH), 7.11 (d, J ¼ 8.1 Hz,
¼ 1.5 Hz, pyrrole-C5 H), 7.20 (d, 2H, J ¼ 8.4 Hz, C2 , C6 -Ar-
0
H), 6.4 (d, 1H, J ¼ 1.5 Hz, pyrrole-C3 H), 6.23 (m, 1H, pyrrole-
0
C4 H), 5.58 (s, 2H, benzyl-CH2), 3.77 (s, 3H, ACOOCH3).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1370
B. Mochona, L. Le, M. Gangapuram, N. Mateeva, T. Ardley, and K. K. Redda
Vol 47
0
0
0
0
0
2H, C3 ,C5 Ar-H), 7.27 (d, 1H, J ¼ 1.5 Hz, pyrrole-C5 H),
MHz, DMSO-d6): d 7.64 (d, J 7.6 Hz, 2H, C2 ,C6 Ar-H), 7.61
0
0
7.20 (d, 2H, J ¼ 8.4 Hz, C2 , C6 -Ar-H), 6.4 (d, 1H, J ¼ 1.5
(d, 1H, J ¼ 8.7 Hz, Bzi-C7H), 7.37 (d, 1H, J ¼ 1.5 Hz, pyr-
0
0
0
Hz, pyrrole-C3 H), 6.21 (m, 1H, pyrrole-C4 H), 5.52 (s, 2H,
0
role-C5 H), 6.23 (m, 1H, pyrrole-C4 H), 7.33 (s, 1H, Bzi-C4H),
benzyl-CH2).
7.23 (d, 1H, J ¼ 8.7 Hz, Bzi-C6H), 7.22 (d, 2H, J ¼ 8.4 Hz,
0
0
0
N-(4-nitrobenzyl)-2-pyrrole carboxylic acid (8d). Isolated as
white solid, yield 2.22 g (90.2%); 1H NMR (300 MHz,
DMSO-d6): d 13.78 (br, s, 1H, ACOOH), 7.96 (d, J ¼ 8.1 Hz,
C3 , C5 -Ar-H), 6.4 (d, 1H, J ¼ 1.5 Hz, pyrrole-C3 H), 5.48 (s,
2H, benzyl-CH2), 5.04 (br, s, 1H, NH), 2.42 (s, 3H, Ar-CH3).
N-(4-chlorobenzyl)-2-pyrrolylbenzimidazole (9g). Isolated
as white solid, yield 1.21 g (78.8%). 1H NMR (300 MHz,
0
0
0
2H, C3 ,C5 Ar-H), 7.37 (d, 1H, J ¼ 1.5 Hz, pyrrole-C5 H),
0
0
7.20 (d, 2H, J ¼ 8.4 Hz, C2 , C6 -Ar-H), 6.4 (d, 1H, J ¼ 1.5
0
0
DMSO-d6): d 7.60 (d, J 7.6 Hz, 2H, C2 ,C6 Ar-H), 7.58 (d,
2H, J ¼ 8.7 Hz, Bzi-C4,C7AH), 7.37 (d, 1H, J ¼ 1.5 Hz, pyr-
0
0
Hz, pyrrole-C3 H), 6.23 (m, 1H, pyrrole-C4 H), 5.58 (s, 2H,
benzyl-CH2).
0
role-C5 H), 7.33 (d, 2H, J ¼ 8.7 Hz, Bzi-C5,C6AH), 7.22 (d,
Preparation of N-benzylpyrrole-2-benzimidazoles (9a–k);
general procedure C. To a suspension of PPA (5.2 g) in xy-
lene (15 mL) at 80ꢁC, 4-substituted-1,2-phenylenediamine (1
equiv, 0.2 mmol) and the corresponding acid (8a–d) (1 equiv,
0.2 mmol) were added. The temperature was raised to 145ꢁC
and stirred for 4 h. The reaction mixture was cooled and
diluted with hot water with stirring. The hot reaction mixture
was filtered through a Buchner funnel and solid was isolated.
The solid was taken in water (60 mL) and neutralized with
NaHCO3. The solid was filtered and washed with hot water (2
ꢂ 40 mL) and recrystallized from THF.
0
0
2H, J ¼ 8.4 Hz, C3 , C5 -Ar-H), 6.4 (d, 1H, J ¼ 1.5 Hz, pyr-
0
0
role-C3 H), 6.23 (m, 1H, pyrrole-C4 H), 5.52 (s, 2H, benzyl-
CH2), 5.0 (br, s, 1H, NH).
N-(4-chlorobenzyl)-2-pyrrolyl-5-nitrobenzimidazole (9h). Iso-
lated as white solid, yield 1.09 g (61.9%); 1H NMR (300
0
0
MHz, DMSO-d6): d 7.61 (d, 2H, J 7.6 Hz, C2 ,C6 Ar-H), 7.62
(d, 1H, J ¼ 8.7 Hz, Bzi-C7H), 7.37 (d, 1H, J ¼ 1.5 Hz, pyr-
0
role-C5 H), 7.31 (d, 1H, J ¼ 8.7 Hz, Bzi-C4H), 7.23 (d, 1H,
0
J ¼ 8.7 Hz, Bzi-C6H), 6.4 (d, 1H, J ¼ 1.5 Hz, pyrrole-C3 H),
0
0
0
6.23 (m, 1H, pyrrole-C4 H), 7.22 (d, 2H, J ¼ 8.4 Hz, C3 , C5 -
Ar-H), 5.49 (s, 2H, benzyl-CH2), 5.06 (br, s, 1H, NH).
N-(4-nitrobenzyl)-2-pyrrolylbenzimidazole (9i). Isolated as
white solid, yield 0.98 g (61.6%); 1H NMR (300 MHz,
2-(N-benzyl-2-pyrrolyl)-benzimidazole (9a). Isolated as
white solid, yield 2.06 g (75.4%); 1H NMR (300 MHz,
DMSO-d6): d 7.59 (d, 2H, J ¼ 8.7 Hz, Bzi-C4,C7AH), 7.37
0
0
DMSO-d6): d 8.02 (d, 2H, J ¼ 8.4 Hz, C3 , C5 -Ar-H), 7.59 (d,
0
0
2H, J ¼ 8.7 Hz, Bzi-C4,C7AH), 7.54 (d, J 7.6 Hz, 2H, C2 ,C6
0
(d, 1H, J ¼ 1.5 Hz, pyrrole-C5 H), 7.33 (d, 2H, J ¼ 8.7 Hz,
0
Ar-H), 7.37 (d, 1H, J ¼ 1.5 Hz, pyrrole-C5 H), 7.33 (d, 2H, J
Bzi-C5,C6AH), 7.02–7.16 (m, 5H, Ar-H), 6.4 (d, 1H, J ¼ 1.5
0
¼ 8.7 Hz, Bzi-C5,C6AH), 6.4 (d, 1H, J ¼ 1.5 Hz, pyrrole-
0
Hz, pyrrole-C3 H), 6.23 (m, 1H, pyrrole-C4 H), 5.28 (s, 2H,
benzyl-CH2), 5.02 (br, s, 1H, NH).
0
C3 H), 6.23 (m, 1H, pyrrole-C4 H), 5.35 (s, 2H, benzyl-CH2),
0
5.20 (br, s, 1H, NH).
N-(4-nitrobenzyl)-2-pyrrolyl-5-methylbenzimidazole (9j). Iso-
lated as white solid, yield 1.06 g (63.85%); 1H NMR (300
2-(N-benzyl-2-pyrrolyl)-5-methylbenzimidazole (9b). Isolated
as white solid, yield 1.15 g (80.14%); 1H NMR (300 MHz,
DMSO-d6): d 7.52 (d, 1H, J ¼ 8.7 Hz, Bzi-C7H), 7.34 (d, 1H,
0
MHz, DMSO-d6): d 8.02 (d, 2H, J ¼ 8.4 Hz, C3 , 7.59 (d, 1H,
0
J ¼ 1.5 Hz, pyrrole-C5 H), 7.13 (s, 1H, Bzi-C4H), 7.05 (d, 1H,
0
J ¼ 8.7 Hz, Bzi-C7H), C5 -Ar-H), 7.54 (d, J 7.6 Hz, 2H,
J ¼ 8.7 Hz, Bzi-C6H), 6.98–7.02 (m, 5H, Ar-H), 6.4 (d, 1H, J
0
0
0
C2 ,C6 Ar-H), 7.37 (d, 1H, J ¼ 1.5 Hz, pyrrole-C5 H), 6.4 (d,
0
0
¼ 1.5 Hz, pyrrole-C3 H), 6.23 (m, 1H, pyrrole-C4 H), 5.56 (s,
0
0
1H, J ¼ 1.5 Hz, pyrrole-C3 H), 6.23 (m, 1H, pyrrole-C4 H),
7.33 (d, 1H, J ¼ 8.7 Hz, Bzi-C4H), 7.23 (d, 1H, J ¼ 6 Hz,
C6H). 5.44 (s, 2H, benzyl-CH2), 5.20 (br, s, 1H, NH), 2.51 (s,
3H, Ar-CH3).
2H, benzyl-CH2), 5.11 (br, s, 1H, NH), 2.30 (s, 3H, Bzi-CH3).
2-(N-benzyl-2-pyrrolyl)-5-nitrobenzimidazole (9c). Isolated
1
as pale yellow solid, yield 1.06 g (67%); H NMR (300 MHz,
DMSO-d6): d 7.59 (d, 1H, J ¼ 8.7 Hz, Bzi-C7H), 7.37 (d, 1H,
N-(4-nitrobenzyl)-2-pyrrolyl-5-chlorobenzimidazole (9k). Iso-
lated as white solid, yield 1.12 g (63.6%); 1H NMR (300
0
J ¼ 1.5 Hz, pyrrole-C5 H), 7.32 (s, 1H, Bzi-C4H), 7.23 (d, 1H,
J ¼ 8.7 Hz, Bzi-C6H), 6.98–7.11 (m, 5H, Ar-H), 6.4 (d, 1H, J
0
0
MHz, DMSO-d6): d 8.02 (d, 2H, J ¼ 8.4 Hz, C3 ,C5 -Ar-H),
0
0
¼ 1.5 Hz, pyrrole-C3 H), 6.23 (m, 1H, pyrrole-C4 H), 5.39 (s,
7.59 (d,1H, J ¼ 8.7 Hz, Bzi-C7H), 7.54 (d, J 7.6 Hz, 2H,
2H, benzyl-CH2), 5.06 (br, s, 1H, NH).
N-benzyl-2-pyrrole-5-chlorobenzimidazole (9d). Isolated as
0
0
0
C2 ,C6 Ar-H), 7.37 (d, 1H, J ¼ 1.5 Hz, pyrrole-C5 H), 6.4 (d,
0
0
1H, J ¼ 1.5 Hz, pyrrole-C3 H), 6.23 (m, 1H, pyrrole-C4 H),
7.33 (d, 1H, J ¼ 8.7 Hz, Bzi-C4H), 7.23 (d, 2H, J ¼ 6 Hz,
C6H). 5.51 (s, 2H, benzyl-CH2), 5.18 (br, s, 1H, NH).
1
yellow solid, yield 1.21 g (79%); H NMR (300 MHz, DMSO-
d6): d 7.59 (d, 1H, J ¼ 8.7 Hz, Bzi-C7H), 7.37 (d, 1H, J ¼ 1.5
0
Hz, pyrrole-C5 H), 7.33 (s, 1H, Bzi-C4H), 7.23 (d, 1H, J ¼
8.7Hz, Bzi-C6H), 7.02–7.16 (m, 5H, Ar-H), 6.4 (d, 1H, J ¼
Acknowledgments. The authors thank the National Institute of
Health, the National Institute of General Medical Sciences,
MBRS Program (GM 08111), and Research Center at Minority
Institutions Grant (RCMI) RR 03020.
0
0
1.5 Hz, pyrrole-C3 H), 6.23 (m, 1H, pyrrole-C4 H), 5.44 (s, 2H,
benzyl-CH2), 5.11 (br, s, 1H, NH).
2-[N-(4-methylbenzyl)-2-pyrrolyl]-benzimidazole (9e). Isolated
as white solid, yield 1.07 g (74%); 1H NMR (300 MHz,
0
0
REFERENCES AND NOTES
DMSO-d6): d 7.61 (d, J 7.6 Hz, 2H, C2 ,C6 Ar-H), 7.59 (d,
2H, J ¼ 8.7 Hz, Bzi-C4,C7AH), 7.37 (d, 1H, J ¼ 1.5 Hz, pyr-
[1] Jarak, I.; Kralij, M.; Piantanida, I.; Suman, L.; Zinic, M.;
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Chem 2005, 13, 1587.
0
role-C5 H), 7.33 (d, 2H, J ¼ 8.7 Hz, Bzi-C5,C6AH), 7.22 (d,
0
0
2H, J ¼ 8.4 Hz, C3 , C5 -Ar-H), 6.4 (d, 1H, J ¼ 1.5 Hz, pyr-
0
0
role-C3 H), 6.23 (m, 1H, pyrrole-C4 H), 5.43 (s, 2H, benzyl-
CH2), 5.0 (br, s, 1H, NH), 2.32 (s, 3H, Ar-CH3).
N-(4-methylbenzyl)-2-pyrrolyl-5-nitrobenzimidazole (9f).
Isolated as white solid, yield 1.24 g (74.7%); 1H NMR (300
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis of 2-(N-Benzylpyrrolyl)-benzimidazoles Using Polyphosphoric Acid
Prompted Cyclocondensation
1371
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DOI 10.1002/jhet