Microwave-mediated synthesis and antibacterial activity of some novel 2-(substituted biphenyl) benzimidazoles via Suzuki-Miyaura cross coupling reaction and their N-substituted derivatives

Article abstract of DOI:10.1002/jhet.610

A series of some novel 2-(substituted biphenyl) benzimidazoles and their N-substituted derivatives were synthesized via microwave-mediated Suzuki-Miyaura coupling of 2-(4-iodophenyl)-1H-benzimidazole or 2-(4-iodophenyl)-6-amino-1H- benzimidazole and arylb

Full text of DOI:10.1002/jhet.610

March 2011
Microwave-Mediated Synthesis and Antibacterial Activity of
Some Novel 2-(Substituted Biphenyl) Benzimidazoles via
Suzuki-Miyaura Cross Coupling Reaction and Their
N-Substituted Derivatives
419
Changdev Namdev Raut,a Shailendra Mitharam Bharambe,b Yogesh Ashok
Pawar,b and Pramod Pandurang Mahulikarb*
aGlenmark Research Center, T.T.C. Industrial Area, M.I.D.C., Mahape,
Navi Mumbai-400 709, India
bSchool of Chemical Sciences, North Maharashtra University, Jalgaon-425 001, India
*E-mail: mahulikarpp@rediffmail.com
Received March 28, 2010
DOI 10.1002/jhet.610
Published online 21 January 2011 in Wiley Online Library (wileyonlinelibrary.com).
A series of some novel 2-(substituted biphenyl) benzimidazoles and their N-substituted derivatives
were synthesized via microwave-mediated Suzuki-Miyaura coupling of 2-(4-iodophenyl)-1H-benzimida-
zole or 2-(4-iodophenyl)-6-amino-1H-benzimidazole and arylboronic acids. The method reported herein
offers advantageous shorter reaction times, higher yields and is applicable to a large set of substrates.
All the synthesized compounds were screened for their antibacterial activity against Staphylococcus
aureus and Salmonella typhimurium bacterial species.
J. Heterocyclic Chem., 48, 419 (2011).
decreasing the yields and increases pollution level and
time wastage [16–18]. Therefore organic chemists are
engaged in efforts to find new reagents with increased
selectivity.
INTRODUCTION
Various substituted benzimidazoles are important
compounds because of their varied biological activities
[1–10]. These classes of compounds, which act as angio-
tensin II AT1 receptor blockers and used in the treat-
ment of hypertension, are Sartans [11] that possess
biphenyl moiety as an integral part. Losartan potassium
is commercially known as Covance, Lorzaar and Losa-
prex; Telmisartan as Kinzalmono, Micardis and Pritor;
Candesartan cilexetil as Amias, Atacand and Blopress;
Olmesartan medoxomil as Benevas, Benicar and Olme-
tec and Irbesartan as Aprovel, Avapro and Karvea. Bifo-
nazol having biphenyl as an integral part exhibits anti-
fungal and antimycotic activity [12]. Fluoro substituted
biphenyls like Diflunisal and Flurbiprofen sodium ex-
hibit anti-inflammatory activity and Diflunisal [13] is
commercially known as Dolobid and Flurbiprofen so-
dium as Ocufen [14].
Green chemistry is destined to be a global goal in the
near future. In the course of studies on green chemistry
one of our goals has been to design microwave-medi-
ated synthetic methods in aqueous medium and make
them more ecofriendly and consistent with higher atom
economy. Microwave (MW) irradiation is widely used
to promote chemical reactions and a number of reviews
have advocated the use of MW technology in organic
synthesis [19,20]. Microwave activation as a nonconven-
tional energy source is becoming a very popular and
useful technique in organic chemistry. The combination
of solvent-free reaction conditions and microwave irradi-
ation leads to significantly reduced reaction times,
enhanced conversions and sometimes higher selectivity
with several advantages for the ecofriendly approach,
termed green chemistry [21].
The Suzuki-Miyaura cross coupling reaction has
emerged as one of the most powerful platform for car-
bon–carbon bond formation because of its mild reaction
conditions and its compatibility with a broad range of
functional groups [15]. Suzuki-Miyaura cross coupling
reactions on the multifunctional molecules requires pro-
tection and deprotection, which unnecessarily increases
the number of steps in organic synthesis, thereby
Looking the importance of microwave irradiation in
organic synthesis, we nicely demonstrated the use of
microwave conditions for Suzuki-Miyaura cross cou-
pling of unprotected halogen-substituted benzimidazoles.
The synthesized compounds were tested for their
antibacterial action against two different bacterial spe-
cies namely, Staphylococcus aureus and Salmonella
C
V
2011 HeteroCorporation

420
C. N. Raut, S. M. Bharambe, Y. A. Pawar, and P. P. Mahulikar
Vol 48
Scheme 1
typhimurium in comparison with Cephalexin as a refer-
ence standard.
quent deprotection to obtain a series of novel 2-(substi-
tuted biphenyl)-1H-benzimidazoles (5, a-c), or 2-(substi-
tuted biphenyl)-6-amino-1H-benzimidazoles (50, a-e).
The Suzuki-Miyaura coupling product 5b was then
alkylated or acylated at the benzimidazole -NH with dif-
ferent electrophilic reagents leading to functionalized
derivatives (6, a-f) (Scheme 1). The structure of synthe-
RESULT AND DISCUSSION
All the reactions were carried out under both micro-
wave irradiation and conventional methods.
1
sized compounds was confirmed by IR, H-NMR, Mass,
and 13C-NMR.
The condensation o-phenylenediamine (OPDA) (1) or
4-nitrobenzene 1,2-diamine (10) with 4-iodobenzoic acid
(2) in presence of polyphosphoric acid (PPA) was car-
ried out in microwave oven at 100 W for 5–10 minutes
at 150ꢀC to obtain the 2-(4-iodophenyl)-1H-benzimida-
zole (3) or 2-(4-iodophenyl)-6-nitro-1H-benzimidazole
(30). The reduction of (30) using SnCl2.6H2O in ethyl ac-
etate and tetrahydrofuran yielded 2-(4-iodophenyl)-6-
amino-1H-benzimidazole (4).
Suzuki-Miyaura coupling of compounds 3, 4 ideally,
the approach should allow access to the free NH and
NH2 benzimidazoles utilizing readily available compo-
nents and catalysts directly without the need for subse-
EXPERIMENTAL
Melting points were recorded on a MRVIS series, Lab India
Instrument and are uncorrected. The monitoring of reaction
and checking of purity of the product were done using pre-
coated silica gel plates and visualization using iodine chamber/
UV lamp. IR spectra were recorded on a Perkin-Elmer Spec-
trum One FTIR spectrometer. 1H (300 MHz) and 13C (75
MHz) NMR spectra were recorded on a (Varian Mercury Vx)
SWBB 300 MHz spectrometer. Chemical shifts (d) are
reported in ppm from internal TMS standard. The solvents for
NMR spectra were CD3OD. Mass spectra were recorded from
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Microwave-Mediated Synthesis and Antibacterial Activity of Some Novel
2-(Substituted Biphenyl) Benzimidazoles
421
an HP 1100 LC/MSD mass spectral instrument (positive and
negative APCI ion source, 50–200 V, nitrogen). Elemental
analysis was carried out on a Perkin-Elmer Series-II CHNS/O
Analyzer 2400. All microwave reactions were carried out in
Biotage (InitiatorTM Eight) microwave synthesizer. Arylbor-
onic acid, o-phenylenediamine, 4-nitrobenzene-1,2-diamine,
and 4-iodobenzoic acid were obtained from S. D. Fine Chem,
Mumbai, India. Palladium catalyst was obtained from Aldrich,
India.
Synthesis of compounds 3 and 30 via microwave irradia-
tion method. A mixture of o-phenylenediamine (1) (1.29 g,
12 mmole) or 4-nitrobenzene-1,2-diamine (10) (1.83 g, 12
mmole), 4-iodobenzoic acid (2) (2.47 g, 10 mmole) and poly-
phosphoric acid (PPA) (20 g) were stirred and irradiated in
microwave oven at 100 W for 10 min at 150ꢀC in sealed ves-
sel (monitored by TLC, Hexane: Ethyl acetate, 7:3). The reac-
tion mixture was then cooled to room temperature and neutral-
ized with aqueous ammonia solution. The product was
extracted with ethyl acetate (10 mL ꢁ 2). The combined or-
ganic layer was washed with 5N HCl (10 mL) and sodium bi-
carbonate solution (5%, 10 mL), water (10 mL) and then or-
ganic layer was dried over anhydrous sodium sulphate. The
solvent was evaporated under reduced pressure to obtain crude
product, which was recrystallized from ethyl acetate to afford
an off-white solid 2-(4-iodophenyl)-1H-benzimidazole (3) or
2-(4-iodophenyl)-6-nitro-1H-benzimidazole (30).
General procedure for the synthesis of compounds 3 and
30. A mixture of o-phenylenediamine (1) (1.29 g, 12 mmole)
or 4-nitrobenzene-1, 2-diamine (10) (1.83 g, 12 mmole), 4-
iodobenzoic acid (2) (2.47g, 10 mmole), and PPA (20 g) was
stirred at 150ꢀC for 6 h (monitored by TLC, Hexane: Ethyl ac-
etate, 7:3). The reaction mixture was then cooled to room tem-
perature and neutralized with aqueous ammonia solution. The
product was extracted with ethyl acetate (10 mL ꢁ 2). The
combined organic layer was washed with 5N HCl (10 mL) and
sodium bicarbonate solution (5%, 10 mL), water (10 mL) and
then organic layer was dried over anhydrous sodium sulphate.
The solvent was evaporated under reduced pressure to obtain
crude product, which was recrystallized from ethyl acetate to
afford an off-white solid 2-(4-iodophenyl)-1H-benzimidazole
(3) or 2-(4-iodophenyl)-6-nitro-1H-benzimidazole (30).
Synthesis of 2-(4-iodophenyl)-6-amino-1H-benzimidazole
(4). A solution of compound 30 (3.65 g, 10 mmole) dissolved
in tetrahydrofuran (15 ml) and water (15 mL). Stannous chlo-
ride hexahydrate (10 g, 36 mmole) was added in the reaction
mass room temperature. After complete addition, the mixture
was stirred at room temperature for 30 min. Thereafter, the so-
lution was allowed to the 40–45ꢀC and stirring continued for
2 h (monitored by TLC, Hexane: Ethyl acetate 1:1). The mix-
ture was again cooled to room temperature and then ethyl ace-
tate (50 mL), and aqueous ammonia solution (20 mL) was
added at same temperature. The ethyl acetate layer was sepa-
rated, dried over anhydrous sodium sulphate and the solvent
was evaporated under reduced pressure to obtain the crude
product, which was recrystallized from ethyl acetate to afford a
white solid of 2-(4-iodophenyl)-6-amino-1H-benzimidazole (4).
Synthesis of compound 4 by alternative method. A solu-
tion of compound 30 (3.65 g, 10 mmole) dissolved in methanol
(20 mL). Palladium carbon (5%, 0.5 g) was added under nitro-
gen atmosphere. The reaction was hydrogenated in an auto-
clave at 60 psig pressure for 3 h (monitored by TLC, Hexane:
Ethyl acetate 1:1). After completion of reaction the mixture
was filtered and solvent was evaporated under reduced pres-
sure to obtain the crude product, which was recrystallized
from ethyl acetate to afford a white solid 4.
Synthesis of compounds (5, a-c) and (50, a-e) via micro-
wave irradiation method. To the solution of compound 3
(3.19 g, 10 mmole) or 4 (3.35 g, 10 mmole) in ethanol (20
mL), arylboronic acids (12 mmole), aqueous sodium carbonate
solution 10% (20 mmole) and bis(triphenylphosphine)palladiu-
m(II)dichloride (0.87 g, 0.125 mmole) were irradiated in
microwave oven at 100 W for 5–15 min at 80ꢀC in sealed ves-
sel (monitored by TLC, Hexane: Ethyl acetate, 7:3). After
completion of reaction, the mixture was cooled to room tem-
perature and filtered through celite. The filtrate was extracted
with ethyl acetate (25 mL ꢁ 2), and the organic layer was
washed with water (25 mL ꢁ 2) and dried over anhydrous so-
dium sulphate. Evaporation of the solvent yielded crude prod-
ucts which were subjected to column chromatography (silica
gel) using hexane and ethyl acetate mixture (9:1) to isolate the
pure products (5, a-c) or (50, a-e), respectively.
Synthesis of compounds (5, a-c) and (50, a-e) by conven-
tional heating method. To the solution of compound 3 (3.19
g, 10 mmole) or 4 (3.35 g, 10 mmole) in ethanol (50 mL),
arylboronic acids (12 mmole), 10% aqueous sodium carbonate
solution (20 mmole) and bis(triphenylphosphine)palladium(II)-
dichloride (0.87 g, 0.125 mmole) were added and the mass
was refluxed for 8–10 h (monitored by TLC, Hexane: Ethyl
acetate, 7:3). After completion of reaction, the mixture was
cooled to room temperature and filtered through celite. The fil-
trate was extracted with ethyl acetate (50 mL ꢁ 2), and the or-
ganic layer was washed with water (25 mL ꢁ 2) and dried
over anhydrous sodium sulphate. Evaporation of the solvent
yielded crude products which were subjected to column chro-
matography (silica gel) using hexane and ethyl acetate mixture
(9:1) to isolate the pure products (5, a-c) or (50, a-e).
Synthesis of compounds 6a and 6b via microwave irradi-
ation method. To a solution of compound 5b (3.38 g, 10
mmole) in pyridine (10 mL), ethyl chloroformate (1.62 g, 15
mmole)or methane sulfonyl chloride (1.7 g, 15 mmole) were
irradiated in microwave oven at 100 W for 5–10 min at 45–
50ꢀC in sealed vessel (monitored by TLC, Hexane: Ethyl ace-
tate, 1:1). After completion of reaction the mixture was cooled
to room temperature, then a solution of 2N HCl was added to
neutralize the reaction mixture. The solid was then extracted
with ethyl acetate (50 mL), which was washed with aqueous
sodium bicarbonate (5%, 25 mL), water (50 mL ꢁ 2), and
dried over anhydrous sodium sulphate. Solvent was evaporated
under reduced pressure to give the crude product, which was
recrystallized from ethyl acetate to afford compound 6a or 6b.
Synthesis of compounds 6a and 6b by conventional
method. To a solution of compound 5b (3.38 g, 10 mmole) in
pyridine (25 mL), ethyl chloroformate (1.62 g, 15 mmole) or
methane sulfonyl chloride (1.7 g, 15 mmole) was added slowly
at 0oC. After complete addition, the reaction mixture was
allowed to attain room temperature and stirred for 6–8 h at
same temperature (monitored by TLC, Hexane Ethyl acetate,
1:1). A solution of 2N HCl was then added to neutralize the
reaction mixture. The solid was then extracted with ethyl ace-
tate (50 mL), which was washed with aqueous sodium bicar-
bonate (5 %, 25 mL), water (50 mL ꢁ 2), and dried over an-
hydrous sodium sulphate. Solvent was evaporated under
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

422
C. N. Raut, S. M. Bharambe, Y. A. Pawar, and P. P. Mahulikar
Vol 48
Table 1
Physical and yield comparison data of synthesized compounds
Microwave irradiation
Conventional heating
Time (h) Yield (%)
75
Sr. No.
Compd. No.
Molecular formula
M.P. (ꢀC)
289–290
Time (min)
Yield (%)
1
2
3
30
C13H9IN2
C13H8IN3O2
C20H16N2O
C20H13 F3N2
C41H33N3
10
10
10
10
15
10
15
10
10
15
10
15
10
15
10
10
85
87
90
91
87
92
90
90
91
85
90
90
92
90
89
93
6
6
8
10
9
80
82
85
82
78
75
87
78
78
75
85
90
87
83
87
3
4
5a
5b
5c
50a
50b
50c
50d
50e
6a
6b
6c
6d
6e
6f
215–216
203–205
150–152
250–254
220–221
280–281
285–286
230–231
80–81
5
6
7
C19H15N3
8
10
9
C19H14ClN3
C20H17N3O
C20H14N3F3
C41H34N4
C23H17N2O2F3
C21H15N2O2SF3
C27H19N2F3
C27H18N2F4
C27H17N2F5
C27H18ClN2F3
8
9
9
10
11
12
13
14
15
16
10
6
240–245
185–186
85–86
10
8
10
8
105–108
78–80
9
reduced pressure to give the crude product, which was recrys-
tallized from ethyl acetate to afford compound 6a or 6b.
eus (Gram positive) and Salmonella typhimurium (Gram
negative) bacteria strains in comparison with Cephalexin
as reference standard and the results are summarized in
Tables 2 and 3. Most of the compounds tested were
found to have good antibacterial activity against Staphy-
lococcus aureus NCIM 5021 and Salmonella typhimu-
rium NCIM 2501 when compared to standard.
Synthesis of compounds (6, c-f) via microwave irradia-
tion method. To a solution of compound 5b (3.38 g, 10
mmole) in acetonitrile (20 mL), aqueous sodium hydroxide so-
lution (10%, 20 mmole) was added and the mixture was stirred
for 15 min. Various benzyl bromides (15 mmole) were added
and irradiated in microwave oven at 100 W for 5–10 min at
50–55ꢀC in sealed vessel (monitored by TLC, Hexane: Ethyl
acetate, 1:1). After the completion of the reaction, acetonitrile
from the reaction mixture was evaporated under reduced pres-
sure and water (50 mL) was added to residue to separate solid.
The solid was then extracted with ethyl acetate (20 mL), the
extract was washed with water (25 mL ꢁ 2), and dried over
anhydrous sodium sulphate. Solvent was evaporated under
reduced pressure to afford the crude products, which were
recrystallized from ethanol to yield pure compounds (6, c-f).
Synthesis of compounds (6, c-f) by conventional
method. To a solution of compound 5b (3.38 g, 10 mmole) in
acetonitrile (50 mL), aqueous sodium hydroxide solution (5%,
25 mL) was added and the mixture was stirred for 15 min. Vari-
ous benzyl bromides (15 mmole) were then added slowly with
stirring to the reaction mixture at 0–10oC. After complete addi-
tion, the reaction mixture was allowed to attain room tempera-
ture and stirred for 8–10 h (monitored by TLC, Hexane: Ethyl
acetate, 7:3). After the completion of the reaction, acetonitrile
from the reaction mixture was evaporated under reduced pres-
sure and water (50 mL) was added to residue to separate solid.
The solid was then extracted with ethyl acetate (50 mL), the
extract was washed with water (50 mL ꢁ 2), and dried over an-
hydrous sodium sulphate. Solvent was evaporated under reduced
pressure to afford the crude products, which were recrystallized
from ethanol to yield pure compounds (6, c- f). (Table 1)
CONCLUSION
We report a simple, rapid, efficient, economic, and
environment-friendly method for the synthesis of some
novel 2-(substituted biphenyl-2-yl)-1H-benzimidazoles
and their N-substituted derivatives using microwave-
mediated Suzuki-Miyaura coupling reaction. The advant-
age of the microwave irradiation shorter reaction times
with an excellent yield compared to conventional
method and also tested their antibacterial activity. The
compounds 5a, 5b, 50b, 50c, 50c, 50d, 6c, 6d, and 6e
showed completely inhibited the growth of both test
bacterial species, namely, S. aureus and S. typhi, how-
ever, 6c, 6d, and 6e showed better antibacterial activity
against S. typhi.
2-(4-Iodophenyl-1H-benzimidazole (3). IR (KBr):
3300, 2970, 1458, 1410, 1326, 1074, 834, 816 cmꢂ1
;
1H-NMR (DMSO-d6) d 7.22–7.26 (m, 2H, ArAH),
7.62–7.63 (m, 2H, ArAH), 7.78 (d, J ¼ 8.4 Hz, 2H,
ArAH), 8.17 (d, J ¼ 8.4 Hz, 2H, ArAH), 13.08 (bs, 1H,
ANH); Anal. Calcd. for C13H9IN2: C, 48.77; H, 2.83; N,
8.75; Found: C, 48.64; H, 3.10; N, 8.57.
2-(2-Methoxybiphenyl-4-yl)-1H-benzimidazole (5a). IR
(KBr): 3421, 2962, 1740, 1621, 1596, 1427, 1261, 1161,
BIOLOGICAL ACTIVITY
All the compounds prepared herein were screened for
their antibacterial activities against Staphylococcus aur-
1099, 799, 741 cmꢂ1 1H-NMR (CD3OD): d 3.82 (s,
;
3H, OCH3), 7.01–7.10 (m, 2H, ArAH), 7.24–7.27 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Microwave-Mediated Synthesis and Antibacterial Activity of Some Novel
2-(Substituted Biphenyl) Benzimidazoles
423
Table 2
Antibacterial activity of synthesized compounds against staphylococcus aureus.
Concentrations (lg/mL)
Comp. No.
1
10
100
200
500
Approx. MIC (lg/mL)
5a
5b
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þ
þ
þ
ꢂꢂ
ꢂꢂ
þ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
200
200
500
500
200
100
100
500
200
500
200
100
100
200
10
5c
þþ
þþ
P
50a
þ
500b
ꢂꢂ
ꢂꢂ
ꢂꢂ
þ
50c
ꢂꢂ
ꢂꢂ
þþ
þ
50d
50e
6a
þþ
þþ
þþ
þþ
þ
ꢂꢂ
þ
6b
6c
6d
þþ
þ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
P
6e
P
6f
Cephalexin
þþ
ꢂꢂ
ꢂꢂ
ꢂꢂ, Total inhibition, no growth of organism; P, poor growth compared to controls; þ, medium growth compared to controls; þþ, confluent
growth, no inhibition.
2H, ArAH), 7.32–7.59 (m, 3H, ArAH), 7.60–7.68 (m,
3H, ArAH), 8.08–8.11 (m, 2H, ArAH); ms: m/z 301.28
(Mþþ1); Anal. Calcd. for C20H16N2O: C, 79.98; H,
5.37; N, 9.33; Found: C, 80.12; H, 5.15; N, 9.48.
71.00; H, 3.87; F, 16.85; N, 8.28; Found: C, 71.14; H,
4.02; N, 8.06.
2-(1-Methyl-2-tritylisoindolin-4-yl)phenyl-1H-benzim-
idazole (5c). IR (KBr): 2924, 2854, 1747, 1594, 1463,
1377, 1314, 1276, 1156, 1032, 901, 848, 825, 768, 749,
2-(4-Ttrifluoromethylbiphenyl-4-yl)-1H-benzimidazole
(5b). IR (KBr): 2924, 1618, 1449, 1428, 1333, 1262,
1
708, 638.cm-1; H-NMR (CD3OD): d 1.44 (d, J ¼ 6.6
1
1159, 1079, 799 cm-1; H-NMR (CD3OD): d 7.21–7.24
Hz, 3H, ACH), 4.08–4.13, 4.53–4.54 (2H, ACH2),
4.38–4.43 (m, 1H, ACH), 6.85 (d, J ¼ 7.8 Hz, 2H,
ArAH), 6.94 (s, 1H, ArAH), 7.02 (d, J ¼ 6.9Hz, 2H,
ArAH), 7.06–7.16 (m, 4H, ArAH), 7.25 (d, J ¼ 3Hz,
(m, 2H, ArAH), 7.49–7.64 (m, 4H, ArAH), 7.78–7.92
(m, 4H, ArAH), 8.14–8.16; (m, 2H, ArAH); ms: m/z
339.30 (Mþþ1); Anal. Calcd. for C20H13 F3N2: C,
Table 3
Antibacterial activity of synthesized compounds against Salmonella typhimurium.
Concentrations (lg/mL)
Comp. No.
1
10
100
200
500
Approx. MIC (lg/mL)
5a
5b
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þ
þ
P
ꢂꢂ
ꢂꢂ
500
200
500
500
500
200
200
500
500
500
500
200
200
500
200
ꢂꢂ
þþ
þþ
P
5c
þþ
þþ
þ
p
50a
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
50b
50c
þ
ꢂꢂ
ꢂꢂ
þ
50d
þ
50e
6a
þþ
þþ
þþ
þþ
P
P
6f
6b
6c
6d
þ
þ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
þ
6e
Cephalexin
P
P
ꢂꢂ, Total inhibition, no growth of organism; P, poor growth compared to controls; þ, medium growth compared to controls; þþ, confluent
growth, no inhibition.
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DOI 10.1002/jhet

424
C. N. Raut, S. M. Bharambe, Y. A. Pawar, and P. P. Mahulikar
Vol 48
2H, ArAH), 7.44–7.55 (m, 8H, ArAH), 7.58–7.70 (m,
2H, ArAH), 7.81 (s, 2H, ArAH), 7.97 (s, 1H, ArAH),
8.07 (d, 8.4Hz, 2H, ArAH); ms: m/z Fragments 326.33
2-(1R)-2,3-dihydro-1-methyl-1H-5-isoindol, 243.25- tri-
phenylmethyl; Anal. Calcd. for C41H33N3: C, 86.74; H,
5.86; N, 7.40; Found: C, 86.64; H, 5.98; N, 7.52.
4.35–4.45 (2H, ACH2), 4.50–4.56 (m, 1H, ACH), 4.99
(s, 1H, ANH), 6.51(d, J ¼ 8.7Hz, 1H, ArAH), 6.57(d, J
¼ 7.8Hz, 1H, ArAH), 6.71 (m, 1H, ArAH), 6.91 (d, J
¼ 7.8Hz, 2H, ArAH), 7.07–7.20 (m, 2H, ArAH), 7.29
(d, J ¼ 8.7Hz, 2H, ArAH), 7.43–7.47 (m, 6H, ArAH),
7.50–7.56 (m, 6H, ArAH), 7.62–7.79 (m, 2H, ArAH),
8.04 (d, J ¼ 8.1Hz, 2H, ArAH); ms: m/z 583.25
(Mþþ1); Anal. Calcd. for C41H34N4: C, 84.50; H, 5.88;
N, 9.61; Found: C, 84.61; H, 5.76; N, 9.74.
2-(Biphenyl-4-yl)-6-amino-1H-benzimidazole (50a). IR
(KBr): 3421, 3320, 3205, 1635, 1476, 1476, 1419, 1363,
1
1123, 813, 770, 728 cmꢂ1; H-NMR (CD3OD): d 6.76
(d, J ¼ 8.1 Hz, 1 H, ArAH), 6.93 (s, 1H, ArAH), 7.35–
7.47 (m, 4H, ArAH), 7.66 (d, J ¼ 7.8Hz, 2H, ArAH),
7.75 (d, J ¼ 7.8 Hz, 2H, ArAH), 8.08 (d, J ¼ 8.1Hz,
2H, ArAH); Anal. Calcd. for C19H15N3: C, 79.98; H,
5.30; N, 14.73; Found: C, 79.86; H, 5.38; N, 14.62.
2-(4-Chlorobiphenyl-4-yl)-6-amino-1H-benzimidazole
(50b). IR (KBr): 3396, 1902, 1635, 1475, 1436, 1403,
2-(4-Ttrifluoromethylbiphenyl-4-yl)-1-(ethylcarboxy-
late)-1H-benzimidazole (6a). IR (KBr): 2936, 1739,
1476,1 452, 1398, 1377,1338, 1283, 1214, 1065, 1007,
854 cmꢂ1 1H-NMR (CD3OD): d 1.15–1.26 (m, 3H,
;
ACH3), 4.35–4.42 (m, 2H, CH2), 7.39–7.47 (m, 2H,
ArAH), 7.64–7.69 (m, 3H, ArAH), 7.71–7.74 (m, 4H,
ArAH), 7.96–8.08 (m, 2H, ArAH), 8.1 (d, J ¼ 2.1Hz,
1H, ArAH); ms: m/z 411.04 (Mþþ1); Anal. Calcd. for
C23H17N2O2F3: C, 67.31; H, 4.18; F, 13.89; N, 6.83;
Found: C, 67.22; H, 4.11; F, 13.97; N, 6.72.
1261, 1180, 1091 cmꢂ1 1H-NMR (CD3OD): d 6.61–
;
6.68 (m, 1H, ArAH), 7.30–7.35 (m, 3H, ArAH), 7.45–
7.65 (m, 5H, ArAH), 7.98 (d, J ¼ 9 Hz, 2H, ArAH);
13C-NMR (CD3OD): d 114.80, 117.65, 127.89, 127.89,
128.37, 128.37, 129.36, 129.36, 129.40, 129.40, 129.45,
129.89, 129.95, 130.03, 134.90, 139.72, 141.10, 145.18,
151.46, 157.46 (aromatic carbons); ms: m/z 320.37
(Mþþ1); Anal. Calcd. for C19H14ClN3: C, 71.36; H,
4.41; N, 13.14; Found: C, 71.28; H, 4.54; N, 13.31.
2-(2-Methoxybiphenyl-4-yl)-6-amino-1H-benzimidazole
(50c). IR (KBr): 3391, 2036, 1612, 1509, 1471, 1392,
2-(4-Trifluoromethylbiphenyl-4-yl)-1-(methylsulfonyl)-
1H-benzimidazloe (6b). IR (KBr): 3420, 2627, 1633,
1518, 1458, 1436, 1334, 1264, 1239, 1149, 1037, 796,
;
751 cmꢂ1 1H-NMR (CD3OD): d 2.7 (s, 3H, ACH3),
7.63–7.66 (m, 2H, ArAH), 7.71–7.76 (m, 2H, ArAH),
7.84–7.87 (m, 2H, ArAH), 7.88–8.09 (m, 4H, ArAH),
8.26 (d, J ¼ 8.4 Hz, 2 H, ArAH); ms: m/z Fragment
339.2 (fragment of without methane sulfonyl group);
Anal. Calcd. for C21H15N2O2SF3: C, 60.57; H, 3.63; N,
6.73; Found: C, 60.66; H, 3.72; N, 6.64.
1259, 1239, 1181, 1124, 1057, 1025, 835, 762 cmꢂ1
;
1H-NMR (CD3OD): d 3.83 (s, 3H, OCH3), 7.06–7.16
(m, 2H, ArAH), 7.4 (d, J ¼ 7.8Hz, 2H, ArAH), 7.58 (d,
J ¼ 8.7Hz, 1H, ArAH), 7.85–7.98 (m, 4H, ArAH), 8.18
(d, J ¼ 8.4 Hz, 2H, ArAH); 13C-NMR (CD3OD): d
56.10 (OCH3), 109.56, 112.8, 116.69, 121.67, 122.21,
122.47, 128.83, 128.83, 129.57, 131.40, 131.57, 131.57,
132.17, 132.68, 133.60, 133.63, 145.51, 146.45, 157.98
(aromatic carbons); ms: m/z 316.22 (Mþþ1); Anal.
Calcd. for C20H17N3O: C, 76.17; H, 5.43; N, 13.32;
Found: 76.32; H, 5.30; N, 13.44.
2-(4-Trifluoromethylbiphenyl-4-yl)-1-benzyl-1H-benz-
imidazole (6c). IR (KBr): 2958, 1600, 1509, 1470,
1452, 1389, 1271, 1222, 1190, 1168, 1006, 836 cmꢂ1
;
1H-NMR (CD3OD): d 5.68 (s, 2H, CH2), 7.04–7.09 (m,
2H, ArAH), 7.18–7.22 (m, 2H, ArAH), 7.72–7.80 (m,
7H, ArAH), 7.93–8.03 (m, 6H, ArAH); ms: m/z 429.25
(Mþþ1); Anal. Calcd. for C27H19N2F3: C, 75.69; H,
4.47; N, 6.54; Found: C, 75.71; H, 4.36; N, 6.65.
2-(4-Trifluoromethylbiphenyl-4-yl)-1-(4-fluorobenzyl)-
1H-benzimidazole (6d). IR (KBr): 2922, 2853, 1747,
1610, 1494, 1460, 1406, 1377, 1337, 1264, 1162, 1122,
2-(4-Trifluoromethylbiphenyl-4-yl)-6-amino-1H-benz-
imidazole (50d). IR (KBr): 3399, 2712, 1634, 1571, 1473,
1
1
1367, 1337, 1261, 1122, 807, 826, 699 cmꢂ1; H-NMR
1097, 1075, 1035, 978, 900, 851, 805, 764 cmꢂ1; H-
(CD3OD): d 7.51 (d, J ¼ 8.1Hz, 1H, ArAH), 7.62–7.67 (m,
2H, ArAH), 7.79 (s, 1H, ArAH), 7.88–8.01 (m, 5H,
ArAH), 8.2 (d, J ¼ 8.1Hz, 2H, ArAH); 13C-NMR
(CD3OD): d 109.70, 116.81, 122.60, 122.68, 123.25,
124.87, 126.55, 129.79, 129.79, 131.40, 130.05, 130.05,
131.27, 132.11, 132.79, 133.75, 133.80, 145.56, 146.39,
157.42 (aromatic carbons); ms: m/z 354.34 (Mþþ1); Anal.
Calcd. for C20H14N3F3: C, 67.98; H, 3.99; 13; N, 11.89;
Found: C, 68.04; H, 4.18; 13; N, 11.74.
NMR (CD3OD): d 5.69 (s, 2H, CH2), 7.05 (d, J ¼ 6.9 Hz,
2H, ArAH), 7.16–7.21(m, 3H, ArAH), 7.27–7.39 (m, 3H,
ArAH), 7.62–7.67 (m, 3H, ArAH), 7.73–7.79 (m, 3H,
ArAH), 7.94 (d, J ¼ 8.7 Hz, 2H, ArAH); ms: m/z 447.28
(Mþþ1); Anal. Calcd. for C27H18N2F4: C, 72.64; H, 4.06;
N, 6.27; Found: C, 72.76; H, 4.18; N, 6.20.
2-(4-Trifluoromethylbiphenyl-4-yl)-1-(3,5-difluoroben-
zyl)-1H-benzimidazole (6e). IR (KBr): 2924, 2854, 1731,
1611, 1520, 1458, 1438, 1332, 1161, 1126, 804, 751
cmꢂ1; 1H-NMR (CD3OD): d 5.58 (s, 2H, ACH2), 6.83 (d,
J ¼ 8.1Hz, 1H, ArAH), 6.96–7.01 (m, 1H, ArAH), 7.14–
7.23 (m, 1H, ArAH), 7.29–7.37 (m, 2H, ArAH), 7.41–
7.44 (m, 1H, ArAH), 7.64–7.69 (m, 2H, ArAH), 7.75–
2-(1-Methyl-2-tritylisoindolin-4-yl)phenyl-6-amino-1H-
benzimidazole (50e). IR (KBr): 2925, 2854, 2727,. 1747,
1
1594, 1463, 1377, 1156, 1023, 722, 540 cmꢂ1; H-NMR
(CD3OD): d 1.39 (d, J ¼ 6.8 Hz, 3H, ACH), 3.99–4.05,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Microwave-Mediated Synthesis and Antibacterial Activity of Some Novel
2-(Substituted Biphenyl) Benzimidazoles
425
[9] Goker, H.; Kus, C.; Boykin, D. W.; Yildiz, S.; Altanlar, N.
Bioorg Med Chem 2007, 17, 2233.
7.86 (m, 5H, ArAH), 7.96 (s, 2H, ArAH); ms: m/z 465.35
(Mþþ1); Anal. Calcd. for C27H17N2F5: C, 69.83; H, 3.69;
N, 6.03; Found: C, 69.72; H, 3.58; N, 6.13.
[10] Ozden, S.; Atabey, D.; Yildiz, S.; Goker, H. Bioorg Med
Chem 2005, 13, 1587.
2-(4-Trifluoromethylbiphenyl-4-yl)-1-(4-chlorobenzyl)-
1H-benzimidzloe (6f). IR (KBr): 2926, 1898, 1611,
[11] (a) Carini, D. J.; Duncia, J. V.; Chiu, A. T.; Gregory, G.
B.; Johnson, A. L.; Price W. A.; Wells, G. J.; Wong, P. C.; Calabrese,
J. C.; Timmermans, P. B. J Med Chem 1990, 33, 1312; (b) Carini, D.
J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.; Pierce,
M. E.; Santella, J. B., III; Price, W. A.; Wells, G. J.; Wexler, R. R.; Wong,
P. C.; Yoo, S. E.; Timmermans, P. B. J Med Chem 1991, 34, 2525.
[12] (a) Plempel, M.; Regel, E.; Buchel, K. H. Arz Forsch.
1983, 33, 517; (b) Patzschke, K.; Riter, W.; Siefert, H. M.; Wegner, L.
A. Arz Forsch. 1983, 33, 745.
1406, 1334, 1263, 1164, 1097, 1014, 801 cmꢂ1 1H-
;
NMR (CD3OD): d 5.63, (s, 2H, ACH2), 7.04 (d, J ¼
7.8 Hz, 1H, ArAH), 7.16 (d, J ¼ 7.8 Hz, 1H, ArAH),
7.30–7.39 (m, 7H, ArAH), 7.68–7.85 (m, 5H, ArAH),
7.96–8.0 (m, 2H, ArAH); ms: m/z 463.12 (Mþþ1);
Anal. Calcd. for C27H18ClN2F3: C, 70.06; H, 3.92; N,
6.05 Found: C, 70.14; H, 3.81; N, 5.82.
[13] Hannah, J.; Ruyle, W. V.; Jones, H.; Matzuk, A, R.; Kelly,
K. W.; Witzel, B. E.; Holtz, W. J.; Houser, R, A.; Shen, T, Y.; Sarett,
L, H. J Med Chem 1978, 21, 1093.
Acknowledgment. The authors thank Glenmark Pharma-
ceuticals Limited for grant permission to carry out the
present research work.
[14] Sunshine, A. Am J Med 1986, 80, Suppl 1, 153.
[15] For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem Rev
1995, 95, 2457; (b) Chemler, S. R.; Trauner, D.; Danishefsky, S. J.
Angew Chem, Int Ed 2001, 40, 4544; (c) Suzuki, A.; Brown, H. C.
Organic Syntheses Via Boranes; Aldrich Chemical Co., Inc.: Milwau-
kee, 2002; Vol. 3; (d) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron
2002, 58, 9633; (e) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004,
2419.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet