Synthesis, characterization, and antimicrobial activities of clubbed [1,2,4]-oxadiazoles with fluorobenzimidazoles

Article abstract of DOI:10.1002/jhet.177

(Chemical Equation Presented) In this study, a novel series of substituted 4,6-difluoro-2-{2-[3-(substituted-phenyl)-[1,2,4]-oxadiazol-5-yl]-ethyl} -1H-benzo[d]imidazole derivatives were synthesized by condensation of 2,4-difluoro-6-nitrophenyl amine with 3-(substitutedphenyl-[1,2,4]-oxadiazol- 5yl) propionic acid by using 2,4,6-trichlorobenzoyl chloride in the presence of triethyl amine base. The compounds were evaluated for their preliminary in vitro antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and Salmonella typhosa. The antibacterial data of the tested compounds indicated that most of the synthesized compounds showed moderate activity with reference standard Gentamycin.

Full text of DOI:10.1002/jhet.177

980
Synthesis, Characterization, and Antimicrobial Activities of
Clubbed [1,2,4]-Oxadiazoles with Fluorobenzimidazoles
Vol 46
Ganesh R. Jadhav, Mohammad U. Shaikh, Rajesh P. Kale,
Anand R. Ghawalkar, and Charansingh H. Gill*
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad, Maharashtra, 431 004, India
*E-mail: chgill50@yahoo.com
Received July 18, 2008
DOI 10.1002/jhet.177
Published online 4 September 2009 in Wiley InterScience (www.interscience.wiley.com).
In this study, a novel series of substituted 4,6-difluoro-2-{2-[3-(substituted-phenyl)-[1,2,4]-oxadiazol-
5-yl]-ethyl}-1H-benzo[d]imidazole derivatives were synthesized by condensation of 2,4-difluoro-6-
nitrophenyl amine with 3-(substitutedphenyl-[1,2,4]-oxadiazol-5yl) propionic acid by using 2,4,6-tri-
chlorobenzoyl chloride in the presence of triethyl amine base. The compounds were evaluated for
their preliminary in vitro antibacterial activity against Pseudomonas aeruginosa, Escherichia coli,
Staphylococcus aureus, and Salmonella typhosa. The antibacterial data of the tested compounds indi-
cated that most of the synthesized compounds showed moderate activity with reference standard
Gentamycin.
J. Heterocyclic Chem., 46, 980 (2009).
INTRODUCTION
spectrum of pharmacological activity, due to its hydro-
lytic and metabolic stability of the oxadiazole ring along
with improved pharmacokinetics and in vivo perform-
ance [7]. The biological activities of the compounds
containing [1,2,4]-oxadiazoles have been well docu-
mented in the literature [8–11]. The oxadiazole moiety
is an important structure unit in drugs and chemical
materials [12]. Among these oxadiazoles, [1,2,4]-oxadia-
zoles are gaining interest in the medicinal chemistry
[13] and shows numerous biological activities including
muscarinic agonists [14], dopamine transporters [15],
benzodiazepine receptor partial agonists [16], nematoci-
dal, fungicidal, and microbicides [17], immunosuppres-
sants [18], Fab I inhibitors as antibacterial agents [19],
antiplatelet and antithrombotic agents [20], etc. Also,
oxadiazoles plays an important role as bioisosteres for
amides and esters [21]. Several methods have been
reported for the synthesis of [1,2,4]-oxadiazoles in the
literature [22–30].
After nitrogen, fluorine occupies the position of sec-
ond favorite heteroelement in life science-oriented
research. Over 10% of newly registered pharmaceutical
drugs and some 40% of newly registered agrochemicals
contain one or more fluorine atoms [1]. Fluorine con-
taining benzimidazoles, which show promising biologi-
cal activities, are well documented in the literature.
Some of these are like Astemizole (antiallergic, anti-his-
taminic), Lansoprazole (antiulcerative), Flubendazole
(Anthelmintic), and Droperidol (antipsychotic) [2]. So
by this idea in view, synthesis of fluorobenzimidazole is
the interesting area of research. Interest in benzimida-
zole containing structure stems not only because of
exhibiting broad spectrum of pharmacological activity
[3] but also displaying significant activities against sev-
eral viruses such as casein kinase 2 [4], factor Xa [5],
hepatitis C virus [6].
In continuation, heterocyclic species like [1,2,4]-oxa-
diazole and fluorobenzimidazole derivatives represent a
novel emerging major chemical entity as antimicrobial
agent. As we know that [1,2,4]-oxadiazoles are an im-
portant class of heterocyclic compounds with broad
In continuation of our research work [31] and after
extensive search, it was observed that enough efforts
have not been made till date, to combine these two moi-
eties as a single molecule scaffold. So, we wish to dis-
close the derivatives of difluorobenzimidazoles clubbed
C
V
2009 HeteroCorporation

September 2009
Synthesis, Characterization, and Antimicrobial Activities of Clubbed
[1,2,4]-Oxadiazoles with Fluorobenzimidazoles
981
Scheme 1
with different substituted [1,2,4]-oxadiazoles and studied
their antibacterial activity against different organisms.
aqueous NH3 in tetrahydrofuran at room temperature,
gave substituted benzonitrile 6a-6k. The compounds
were characterized by IR showing cyano functional
group at 2210–2245 cmꢁ1. Then followed by amidox-
ime formation by using hydroxylamine hydrochloride
and sodium bicarbonate in methanol at reflux tempera-
ture for 8–10 h gives substituted N-hydroxy benzami-
dine 7a-7k (Scheme 2).
In the next reaction, condensation of 7a-7k with
monomethyl succinate was carried out by using coupling
reagent dicyclohexylcarbodiimide (DCC) and N-hydroxy
benzotriazole, and dimethylaminopyridine (DMAP) as a
base in dichloromethane at room temperature to obtain
8a-8k.
RESULTS AND DISCUSSION
Synthesis of 2,4-difluoro-6-nitrophenyl amine
[32]. In neat reaction condition, acetic anhydride was
added slowly in 2,4-difluorophenyl amine 1 at 0ꢀC, a
solid material precipitates. The reaction mixture was
quenched in ice water and stirred continuously for 30
min. An off violet colored solid compound separated
out, which was filtered and suck dried to obtain 2, 4
difluoro acetanilide 2 as a free solid (Scheme 1).
In the second stage, 2,4-difluoro acetanilide 2 was dis-
solved in nitric acid and conc. sulfuric acid was added
slowly at 5–10ꢀC. The reaction mixture was stirred con-
tinuously for 3 h at room temperature. Reaction progress
was monitored by TLC system (EA: Hexane 2:8). After
completion of reaction, the reaction mixture was quenched
in ice water, a pale yellow color solid separated, which
was filtered through Bu¨chner funnel and suck dried to
obtain 2,4-difluoro-6-nitro acetanilide 3 as a free solid.
In the final stage, to a reaction mixture of 3 in 2N
HCl, a catalytic amount of sulfuric acid was added
slowly. Reaction mixture was heated to reflux for 3–4 h.
After completion of reaction, the reaction mixture was
cooled slowly at 0–5ꢀC, a yellow color needle type crys-
tal separated, which was filtered and suck dried to
obtain as 2,4-difluoro-6-nitro aniline 4.
In the penultimate step, dehydration followed by cy-
clization of 8a-8k was carried out in toluene at reflux
temperature in the presence of molecular sieves as a
dehydrating agent. It gives 3-(substituted phenyl-[1,2,4]-
oxadiazol-5-yl)-propionic acid ethyl ester 9a-9k as a
free solid. In the final step, hydrolysis of 9a-9k by lith-
ium hydroxide in THF: EtOH: H2O (7:2:1) at room tem-
perature gives 3-(substituted phenyl-[1,2,4] oxadiazol-5-
yl)-propionic acid 10a-10k.
Synthesis of 4,6-difluoro-2-[2-(5-substituted-phenyl-
[1,2,4]-oxadiazol-3-yl)-ethyl]-1H-benzo[d]imidazole. Con-
densation of 2, 4 difluoro 6-nitro phenyl amine 4 and 3-
(substituted phenyl-[1,2,4]oxadiazol-5yl)-propionic acid
10a-10k in 2,4,6 trichlorobenzoyl chloride [33] as a
coupling reagent, in the presence of triethylamine and
DMAP in THF: DMF (7:3) solvent at room temperature
11a-11k. After workup, catalytic reduction of 11a-11k
by using 10% Pd/C in tetrahydrofuran was carried out
Synthesis of 3-(substitutedphenyl-[1,2,4]-oxadiazol-
5-yl)-propionic acid. By using different substituted aro-
matic aldehydes 5a-5k in the presence of iodine and
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

982
G. R. Jadhav, M. U. Shaikh, R. P. Kale, A. R. Ghawalkar, and C. H. Gill
Vol 46
Scheme 3
mentor Vario instrument. EIMS spectra recorded on micro-
mass-quatro –II. The purity of the compounds was checked on
Merck precoated silica gel 60 F-254.
to obtain 12a-12k. Then 12a-12k undergoes cyclization
reaction in 2N HCl at 100ꢀC to furnish with 4, 6
difluoro-2-{2-[3-(substituted-phenyl)-[1,2,4]-oxadiazol-5-
yl]-ethyl}-1H-benzo[d] imidazole derivatives 13a-13k.
The details of the reaction condition were explained in
experimental section (Scheme 3).
General experimental procedure for the preparation of
2,4-difluoro-6-nitro phenyl amine (4). In the first stage, under
neat reaction condition, acetic anhydride (7.9 g, 77.5 mmol)
was added slowly in 2,4-difluoro phenyl amine 1 (10 g, 77.5
mmol) at 0ꢀC, a solid compound precipitates out after 30–45
min. After completion of reaction, the reaction mixture was
quenched in ice water with continues stirring for 30 min. The
solid was filtered through Bu¨chner funnel and suck dried to
obtain 2,4-difluoro acetanilide 2 as a off violet color solid
(12.0 g, 92% yield). m/z: 172 (Mþ).
ANTIMICROBIAL ACTIVITY
The in vitro antibacterial screening of 13a-13k was
assessed against two gram positive and two gram nega-
tive bacteria viz. Staphylococcus aureus (ATCC 25923),
Pseudomonas aeruginosa (ATCC 27853), E. coli
(ATCC 25922), and Salmonella typhosa (ATCC 14028).
From the antibacterial screening, it was observed that all
the compounds exhibited activity against different
organisms employed. In this, we studied different elec-
tron withdrawing or electron donating moieties. Some of
the compounds showed better activity against gram posi-
tive organisms compared to gram negative organisms.
Looking at the structure-activity relationship, marked in-
hibition in bacteria was observed in the number of com-
pounds 13a, 13f, 13g, and 13i have shown moderate ac-
tivity and others 13b, 13c, 13d, 13e, 13h, 13j, and 13k
showed least activity.
In the second stage, to a solution of 2,4-difluoro acetanilide
2 (12 g) in nitric acid (25 mL), Conc. sulfuric acid (25 mL)
was added slowly at 5–10ꢀC. The reaction mixture was stirred
continuously for 3 h at room temperature. The progress of the
reaction was monitored on TLC system (Ethyl acetate: Hex-
ane, 2:8). After completion of reaction, the reaction mass was
quenched slowly in ice water and a pale yellow color solid
was observed, which was filtered through Bu¨chner funnel and
suck dried to obtain 2,4-difluoro-6-nitro acetanilide 3 as a free
solid (12.0 g, 80% yield). The compound was characterized by
1
mass and NMR. H NMR (CDCl3) d (ppm): 2.23 (3H, ACH3,
s), 7.26 (1H, ArH, m), 7.62 (1H, ArH, m), 8.01 (1H, ANH, s).
m/z: 215 (Mꢁ).
In the final stage, to a suspension of 2, 4 difluoro 6-nitro ac-
etanilide 3 (12 g, 69.0 mmol) in 2N HCl (25 mL), a catalytic
amount of sulfuric acid (1.2 mL) was added slowly and the
reaction mixture was heated to reflux for 3–4 h. After comple-
tion of reaction, the reaction mixture was cooled gradually at
10ꢀC, a yellow color needle type crystal separated out. The
solid compound was filtered and suck dried to obtain 2,4-
difluoro-6-nitro aniline 4 as a free solid (7.0 g, 72.9% yield).
EXPERIMENTAL
The melting points were estimated by Veggo programmable
(microprocessor based) melting point apparatus and are uncor-
1
rected. H NMR spectra were recorded on a Varian 400 MHz
spectrometer MHz instrument using CDCl3 as solvent using
TMS as internal standard; the chemical shifts (d) are reported
in ppm Signal multiplicities are represented by s (singlet), d
(doublet), t (triplet), ds (double singlet), dd (double doublet),
m (multiplet), and br s (broad singlet). IR spectra were
recorded on (KBr disc) using a FTIR bruker Vector 22 Spec-
trophotometer. Elemental analyses were determined on Ele-
1
The compound was characterized by mass and NMR. H NMR
(CDCl3) d (ppm): 6.05 (2H, ANH2, s), 7.12 (1H, ArH, m),
7.73 (1H, ArH, s). m/z: 173 (Mꢁ).
General experimental procedure for the preparation of
3-{3-substituted-phenyl-[1,2,4]-oxadiazole-5-yl)-propionic acid
(10a). To a solution of 4-nitrobenzaldehyde 5a (6.0 g, 39.73
mmol) in tetrahydrofuran (30 mL), aqueous NH3 (120 mL)
was added and then followed by iodine (10.59 g, 41.69 mmol).
The reaction mixture was stirred further for 2 h. After
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
Synthesis, Characterization, and Antimicrobial Activities of Clubbed
[1,2,4]-Oxadiazoles with Fluorobenzimidazoles
983
completion of reaction, color of the reaction mixture changed
from brownish to colorless. The reaction mixture was extracted
with ethyl acetate (50 mL ꢂ 2) twice, and the organic layer
was dried over sodium sulfate and evaporated under vaccum
till dryness. The crude compound was triturated with diethyl
ether to obtain a free solid of 4-nitro benzonitrile 6a (5.1 g,
84% yield). The compound was characterized by IR showing
cyano functional group at around 2238 cmꢁ1 in this example.
To a solution of 6a (5.0 g, 33.78 mmol) in methanol (50
mL), hydroxylamine hydrochloride (2.56 g, 37.16 mmol), so-
dium bicarbonate (4.35 g, 50.67 mmol) were added and the
reaction mixture was heated to reflux for 8–10 h. Progress of
reaction was monitored on TLC. After completion of reaction,
methanol was distilled completely under vaccum. A pale yel-
low solid compound precipitates after charging water (100
mL), which was filtered through funnel and suck dried to
obtain N-hydroxy-4-nitrobenzamidine (4.9 g, 80% yield) 7a as
a free solid.
In the second stage, monomethyl succinate (5.14 g, 38.94
mmol) was dissolved in THF: DMF (7:3 ratio) (25 mL) at 25–
30ꢀC. Then DCC (11.15 g, 54.14mmol) a coupling reagent, N-
hydroxybenzo triazole (1.09 g, 8.12 mmol) was added at 25–
30ꢀC and stirred continuously for 30 min. Mixed anhydride
formation, charged 4- nitrobenzamidine, 7a (4.8 g, 27.07
mmol), and DMAP (0.99 g, 8.12 mmol) with continuous stir-
ring for 60 min. Progress of the reaction was monitored on
TLC (ethyl acetate: hexane 3:7). After completion of reaction,
the reaction mixture was filtered through Bu¨chner funnel with
bed wash of ethyl acetate (25 mL) twice. Water wash given to
the organic layer (100 mL ꢂ 2) twice separated the organic
solution, which was dried over sodium sulphate and distilled
out as organic layer under vaccum. The crude compound was
triturated with diethyl ether to obtain 8a (6.2 g, 74% yield) as
a free off white solid.
mmol) was dissolved in THF: DMF (7:3) 25 mL volume. Then
2,4,6-trichlorobenzoyl chloride (1.47 g, 6.03 mmol) followed by
triethyl amine (0.696 g, 6.89 mmol) was added for the mixed
anhydride formation. The reaction mass was stirred for 60 min
at 25–30ꢀC. DMAP (0.701 g, 5.74mmol) and 4 (1.0 g, 5.74
mmol) were added and stirred continuously for 2 h. Progress of
the reaction was monitored on TLC system (ethyl acetate: hex-
ane 3:7). After completion of reaction, the reaction mixture was
filtered through Bu¨chner funnel and bed wash of ethyl acetate.
Water wash given to the organic solution, dried over sodium
sulphate and concentrated under vacuum completely. Finally,
the crude compound was triturated with diethyl ether to obtain
as a off white color solid 11a (1.6 g, 66% yield).
Similarly, by using the respective 3-{3-substituted-phenyl-
[1,2,4]-oxadiazol-5-yl)-propionic acid 10b-10k, we have syn-
thesized 11b-11k for the next stage.
In the second stage. 11a (1.5 g, 3.58 mmol) was dissolved
in THF (50 mL), and 10% Pd/C was added (0.3 g, 20% w/w)
at room temperature under nitrogen. Reaction mass was stirred
for 2 h at 25–30ꢀC. Progress of the reaction was monitored on
TLC system (ethyl acetate: hexane 3:7). After completion of
the reaction the mixture was filtered through celite with bed
wash of tetrahydrofuran (25 mL). The filtrate was concentrated
under vacuum to obtain 12a-12k. Without isolation of 12a-
12k, next cyclization reaction in 2N HCl (15 mL) at reflux
temperature for 4–5 h was proceeded. After completion of
reaction, aqueous NaHCO3 solution (50 mL) was added to the
reaction mixture slowly at 5–10ꢀC. A solid product was sepa-
rated out, which was filtered through Bu¨chner funnel and suck
dried to obtain 4-6-difluoro-2-{2-[3-(4-nitrophenyl)-[1,2,4]-
oxadizol-5-yl]-ethyl}-4-6-difluoro-1H-benzo[d]imidazole 13a
as pale yellow colored solid.
Similarly, by using respective substituted [1,2,4]-oxadiazoles
10a-10k, we synthesized the respective 13b-13k by using
aforementioned procedure. 1H NMR, ms, IR, and elemental
analysis characterized all the synthesized compounds. The
details of the intermediates were given in Table 2.
In the penultimate stage, 8a compound (6.2 g, 20.06 mmol)
was dissolved in toluene (60 mL) and molecular sieves were
added as dehydrating agent. The reaction mass was stirred at
reflux temperature for 2–3 h. After completion of reaction, the
reaction mixture was filtered through Bu¨chner funnel with bed
wash of toluene (10 mL). The filtrate was concentrated under
vaccum and recrystallized with diethyl ether to obtain 3-(3-4-
nitrophenyl-[1,2,4]-oxadiazol-5-yl)-propionic acid ethyl ester
9a (4.5 g, 77% yield) as a pure compound.
Synthesis of 4,6-difluoro-2-{2-[3-(4-nitrophenyl)-[1,2,4]-oxadi-
zol-5-yl]-ethyl}-4,6-difluoro-1H-benzo[d]-imidazole (13a). The
compound was obtained using 3-(3-(4-nitrophenyl)-[1,2,4]-oxa-
diazol-5-yl) propanoic acid as a pale yellow solid (diethyl
ether); IR (KBr): 3242, 2768, 2547, 2362, 1719, 1578, 1516,
1438, 1340, 1219, 914, 869, 719 cmꢁ1 1H NMR (400 MHz,
;
In the final stage, 3-(3-4 nitrophenyl-[1,2,4] oxadiazol-5-yl)-
propionic acid ethyl ester 9a (4.5 g, 15.46 mmol) was dis-
solved in THF: EtOH: H2O (7:2:1) with 25 mL volume.
LiOH.H2O was added (0.630 g, 18.55 mmol) at room tempera-
ture and the reaction mixture was stirred for 2 h at 25–30ꢀC.
After completion of reaction, the mixture was acidified by 2N
HCl, a solid material separated, which was filtered through
Bu¨chner funnel and suck dried to obtain 3-(3-4-nitrophenyl-
[1,2,4]-oxadiazol-5-yl) propionic acid 10a (2.9 g) as a pale
yellow solid.
DMSO d6): d 2.87 (2H, t), 3.19 (2H, t), 7.12 (1H, m), 7.29
(1H, d), 8.22 (2H, d), 8.39 (2H, d), 12.4 (1H, s ANH).
Synthesis of 2-(2-(3-(3-bromophenyl)-[1,2,4]-oxadizol-5-
yl)-4,6-difluoro-1H-benzo[d]imidazole (13b). The compound
was obtained using 3-[3-(3-bromo-phenyl)-[1,2,4]-oxadiazol-5-
yl) propionic acid as a pale yellow solid (diethyl ether); IR
(KBr): 3433, 2714, 2608, 2361, 1701, 1566, 1535, 1443, 1358,
1
846, 744, cmꢁ1; H NMR (400 MHz, DMSO d6): d 2.84 (2H,
t), 3.19 (2H, t), 7.18(1H, m), 7.52 (2H, m), 7.78–7.81 (1H, m),
7.98 (1H, m), 8.08 (1H, m), 12.14 (1H, s, ANH).
All the intermediates 10b-10k were synthesized by the
aforementioned procedure using different substituted aldehydes
5b-5k, respectively, and were characterized by 1H NMR and
ms. The details of the intermediates were given in Table 1.
General procedure for the preparation of 4,6-difluoro-2-
[2-(5-substituted-phenyl-[1,2,4]-oxadiazol-3-yl)-ethyl]-1H-
benzimidazole: (13a-13k). In the reaction, 3-(3-4-nitro-
phenyl-[1,2,4] oxadiazol-5-yl)-propionic acid 10a (1.5 g, 5.74
Synthesis of 4,6-difluoro-2-[2-(3-phenyl-[1,2,4]-oxadizol-5-
yl)-ethyl]-1H-benzo[d]imidazole (13c). The compound was
obtained using 3-(3-phenyl-[1,2,4]-oxadiazol-5-yl) propionic
acid as a off white solid (diethyl ether); IR (KBr): 3133, 2933
2714, 2608, 2361, 1701, 1632, 1590, 1443, 1358, 1231, 912,
846, 718 cmꢁ1 ;1H NMR (400 MHz, DMSO d6): d 2.8 (2H, t),
3.15 (2H, t), 7.08(1H, m), 7.12 (1H, d), 7.55 (3H, m), 7.95
(2H, m), 12.21 (1H, s, ANH).
Journal of Heterocyclic Chemistry
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G. R. Jadhav, M. U. Shaikh, R. P. Kale, A. R. Ghawalkar, and C. H. Gill
Vol 46
Table 1
Characterization of intermediates 10a–10k.
No.
Intermediates
ms (m/z)
1H NMR (d ppm)
10a
264.0
2.9 (2H, t), 3.3 (2H, t), 8.2 (2H,d), 8.4 (2H,d), 12.0 (1H,s)
10b
10c
298.1
219.2
2.85 (2H,t), 3.25 (2H,t), 7.4 (1H,t), 7.8 (1H,d), 8.0 (1H,d) 8.1(1H,s),
12.16 (ACOOH, 1H,s)
2.75 (2H,t), 3.05 (2H,m), 7.4 (2H,t), 7.8 (2H,m), 8.0(1H,dd),12.2
(ACOOH,1H,s)
10d
10e
253.2
269.3
2.9(2H,t), 3.2 (2H,t), 7.4–7.8 (2H, m), 8.0 (2H, m).12.22 (ACOOH,1H,s)
2.8 (2H,t), 3.2 (2H,t), 7.45–7.55 (2H,m), 8.0–8.3 (2H,m) 8.8 (1H,d)
12.22 (ACOOH, 1H, s)
10f
209.0
220.1
2.8 (2H, t), 3.3 (2H, t), 6.7(1H, d), 7.2(1H, d), 8.0 (1H, s), 12.2(1H, s)
10g
2.8 (2H, t), 3.2 (2H, t), 7.6(1H, m) 7.7(1H, m), 8.0 (1H, m), 8.8 (1H, s),
12.2(1H, s).
10h
279.2
2.8 (2H,t),3.2 (2H,t),3.9 (3H,s), 6.7 (1H,t), 7.1 (2H,d), 12.18 (ACOOH,1H,s).
10i
10j
249.1
237.0
2.8 (2H,t), 3.2(2H,t), 3.85(3H,s), 7.1(2H,d),7.9(2H, d), 12.4 (1H, s)
2.9 (2H, t), 3.2 (2H, t), 7.4 (1H, t ), 7.6 (1H,t), 7.7 (1H, d), 7.8 (1H, d),
12.2(1H, s)
10k
249.2
2.78 (2H, t), 3.25 (2H, t), 7.15 (2H, d), 8.01 (2H, d), 12.29 (1H, s)
MHz, DMSO d6): d 2.8–3.08 (4H, s), 7.04 (1H, m), 7.21
(1H, d), 7.62 (2H, m), 7.74 (1H, m), 7.92 (1H, m), 12.1
(1H, s, ANH).
Synthesis of 4,6-difluoro-2-[2-(3-pyridin-3-yl-[1,2,4]-oxa-
dizol-5-yl)-ethyl]-1H-benzo[d]imidazole (13e). The com-
pound was obtained using 3-(3-pyridin-3-yl)-[1,2,4]-oxadiazol-
Synthesis of 2-{2-[3-(3-chlorophenyl)-[1,2,4]-oxadizol-5-yl]-
ethyl}-4,6-difluoro-1H-benzo[d]-imidazole (13d). The compound
was obtained using 3-[3-(3-chloro-phenyl)-[1,2,4]-oxadiazol-
5-yl) propionic acid as a brownish solid (diethyl ether); IR
(KBr): 3233, 2878, 2731, 2624, 2548, 2362, 1696, 1591,
1432, 1337, 1239, 1168, 898,752 cmꢁ1 ;1H NMR (400
Journal of Heterocyclic Chemistry
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Synthesis, Characterization, and Antimicrobial Activities of Clubbed
[1,2,4]-Oxadiazoles with Fluorobenzimidazoles
985
Table 2
Characterization of the compounds 13a–13k.
Analysis (%)
Calcd./Found
H
Compound
R
Time (h)
4
Mp (ꢀC)
120–122
Yield %
75
Molecular Formula
C17H11F2N5O3
C
N
13a
4-NO2
54.99
55.09
50.39
50.47
62.58
62.71
56.60
56.74
58.72
58.72
56.97
56.89
67.02
67.11
59.07
59.12
60.67
60.62
56.60
56.59
60.67
60.80
2.99
3.01
2.74
2.79
3.71
3.67
3.07
3.15
3.39
3.46
3.19
3.30
3.75
3.78
4.17
4.23
3.96
3.97
3.07
3.16
3.96
4.06
18.86
18.88
13.83
13.85
17.17
17.26
15.53
15.74
21.40
21.52
17.71
17.70
14.89
14.99
14.50
14.53
15.72
15.71
15.53
15.52
15.72
15.91
13b
13c
13d
13e
13f
13g
13h
13i
3-Br
H
4
5
5
4
6
5
5
5
4
4
129–131
112–114
71
74
69
69
72
73
75
70
68
76
C17H11BrF2N4O
C17H12F2N4O
3-Cl
118–120
C17H11ClF2N4O
3-Pyridyl
3-furan
Naphthalene
3,5-Di-OMe
4-OMe
3-F
162–164 (dec)
134–136
C
16H11F2N5O
15H10F2N4O2
C
123–125
C
21H14F2N4O
19H16F2N4O3
18H14F2N4O2
129–131
C
C
136–138
13j
13k
141–143
C17H11ClF2N4O
3-OMe
156–158
C18H14F2N4O2
1
5-yl) propionic acid as a off white solid (diethyl ether); IR
(KBr): 3331, 2922, 2731, 2624, 2362, 1695, 1570, 1440, 1358,
1127, 853, 743 cmꢁ1; H NMR (400 MHz, DMSO d6): d 2.77
(2H, t), 3.12 (2H, t) 7.27 (1H, d), 7.57 (2H, m), 7.69 (2H, m),
12.11(1H, s ANH).
1
1244, 910, 844, 738 cmꢁ1; H NMR (400 MHz, DMSO d6): d
2.75 (2H, t), 3.18 (2H, t) 7.18 (1H, d), 7.31 (1H, m), 7.89 (2H,
Synthesis of 4,6-difluoro-2-[2-(3-napthalen-2-yl-[1,2,4]-
oxadizol-5-yl)-ethyl]-1H-benzo[d]imidazole (13g). The com-
pound was obtained using 3-(3-naphthalen-2-yl-[1,2,4]-oxadia-
zol-5-yl)-propionic acid as a buff colored solid (diethyl ether);
IR (KBr): 3274, 3054, 2932, 2720, 2362, 1739, 1708,
1584,1499, 1428, 1306, 1157, 898, 749 cmꢁ1
MHz, DMSO d6): d 2.96 (2H, t), 3.21 (2H, t), 7.22 (1H, d),
m), 8.51 (2H, m), 12.14 (1H, s ANH).
Synthesis of 4,6-difluoro-2-[2-(3-furan-3-yl-[1,2,4]-oxadi-
zol-5-yl)-ethyl]-1H-benzo[d] imidazole (13f). The compound
was obtained using 3-(3-(furan-2-yl)-[1,2,4]-oxadiazol-5-yl)
propanoic acid as a off white solid (diethyl ether); IR (KBr):
3327, 2928, 2714, 2604, 2361, 1628, 1580, 1437, 1312, 1275,
;
1H NMR (400
Table 3
Antibacterial activity of compounds 13a–13k.
Organisms
Compound
R
Sa
Pa
Ec
St
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
Gentamycin
4-NO2
3-Br
H
3-Cl
27
23
21
21
20
25
27
19
29
20
22
34
25
18
23
25
22
23
26
20
26
22
23
35
20
16
18
18
23
21
24
15
22
19
21
30
19
14
19
14
23
24
20
13
19
18
20
29
3-Pyridyl
3-Furan
Naphthalene
3,5 Di-OMe
4-OMe
3-F
3-OMe
–
Sa: Staphylococcus aureus, Ec: Escherichia coli, Pa: Pseudomonas aeruginosa, St: Salmonella typhosa.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

986
G. R. Jadhav, M. U. Shaikh, R. P. Kale, A. R. Ghawalkar, and C. H. Gill
Vol 46
7.52– 7.74 (4H, m), 8.05 (1H, d), 8.2 (2H, m), 8.8 (1H, d),
12.36 (1H, s ANH).
ranging from 50 and 100 lM using a micropipette. The
plates were left over for 24 h at 24–28ꢀC. The antibiotic
Gentamycin was used as a standard for comparative
study.
Synthesis of 4,6-difluoro-2-{2-[3-(3,5-dimethoxy phenyl)-
[1,2,4]-oxadizol-5-yl]-ethyl}-1H-benzo[d] imidazole (13h). The
compound was obtained using 3-(3-(3,5-dimethoxyphenyl)-
[1,2,4]-oxadiazol-5-yl) propanoic acid as a buff colored solid
(diethyl ether); IR (KBr): 3101, 2714, 2612, 2361, 1701, 1559,
;
1535, 1443, 1358, 900, 740 cmꢁ1 1H NMR (400 MHz,
DMSO d6): d 2.75–3.1(4H, s), 3.99 (6H, s), 7.11 (2H, m), 7.22
(2H, m), 7.46 (1H, m), 12.14 (1H, s ANH).
The percentage of inhibition was calculated by the
formula% Inhibition ¼ Diameter of the inhibition zone
ꢂ 100.
Acknowledgment. The authors are thankful to The Head,
Department of Chemistry, Dr. Babasaheb Ambedkar Mar-
athwada University, Aurangabad- 431004 (MS), India for
providing laboratory facility and Wockhardt Research
Centre, Aurangabad, Maharashtra, India for their valuable
support.
Synthesis of 4,6-difluoro-2-{2-[3-(4-methoxy phenyl)–
[1,2,4]-oxadizol-5-yl]-ethyl}-1H-benzo[d]-imidazole (13i). The
compound was obtained using 3-(3-(4-methoxyphenyl)-[1,2,4]-
oxadiazol-5-yl) propanoic acid as a brownish colored solid
(diethyl ether); IR (KBr): 2940, 2608, 2362, 1710, 1596, 1482,
1362, 1255, 1029, 843, 749 cmꢁ1 1H NMR (400 MHz,
;
DMSO d6): d 2.75–3.1(4H, s), 4.02 (3H, s), 7.11 (1H, d), 7.24
(3H, m), 7.46 (2H, m), 12.04 (1H, s ANH).
REFERENCES AND NOTES
Synthesis of 4,6-difluoro-2-{2-[3-(3-fluorophenyl)-[1,2,4]-
oxadizol-5-yl]-ethyl}-1H-benzo[d]imidazole (13j). The com-
pound was obtained using 3-(3-(3-fluorophenyl)-[1,2,4]-oxadia-
zol-5-yl) propanoic acid as a brownish solid (diethyl ether); IR
(KBr): 3233, 2878, 2731, 2624, 2548, 2362, 1696, 1591, 1432,
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PHARMACOLOGICAL ACTIVITY
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Method: Well diffusion method [34], Medium: The
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Solvent: Chloroform: Concentrations: 50 and 100 lM.
Condition: 24 h at 24–28ꢀC, Standard: The antibiotic
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The nutrient agar medium, 20 mL was poured into
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