Synthesis, characterization and biological activity of some new 1,3,4-oxadiazole bearing 2-flouro-4-methoxy phenyl moiety

Article abstract of DOI:10.1016/j.ejmech.2009.11.046

In the present study a series of new 1,3,4-oxadiazole derivatives containing 2-fluoro-4-methoxy moiety were synthesized. These newly synthesized compounds were characterized by NMR, mass spectral, IR spectral study and also by C, H, N analyses. All the newly synthesized compounds were screened for their antibacterial and antifungal studies. Antimicrobial studies revealed that compounds 4a and 4b showed significant antibacterial activity against Escherichia coli and Pseudomonas aeruginosa Compound 4i showed significant antifungal activity against C. albicans.

Full text of DOI:10.1016/j.ejmech.2009.11.046

European Journal of Medicinal Chemistry 45 (2010) 1206–1210
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis, characterization and biological activity of some new 1,3,4-oxadiazole
bearing 2-flouro-4-methoxy phenyl moiety
,
B. Chandrakantha a, Prakash Shetty b, Vijesh Nambiyar c, Nishitha Isloor d, Arun M. Isloor c
*
a Syngene International Ltd, Biocon Park, Plot Nos. 2 and 3, Bommasandra 4th Phase, Jigani Link Road, Bangalore 560 100, India
b Department of Printing and Media Engineering, Manipal Institute of Technology, Manipal University, 576 104, India
c Department of Chemistry, National Institute of Technology, Surathkal, Mangalore 575 025, India
d Chemical Engineering Department, Biotechnology Division, National Institute of Technology, Surathkal, Mangalore 575 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present study a series of new 1,3,4-oxadiazole derivatives containing 2-fluoro-4-methoxy moiety
were synthesized. These newly synthesized compounds were characterized by NMR, mass spectral, IR
spectral study and also by C, H, N analyses. All the newly synthesized compounds were screened for their
antibacterial and antifungal studies. Antimicrobial studies revealed that compounds 4a and 4b showed
significant antibacterial activity against Escherichia coli and Pseudomonas aeruginosa Compound 4i
showed significant antifungal activity against C. albicans.
Received 13 July 2009
Received in revised form
13 November 2009
Accepted 20 November 2009
Available online 4 December 2009
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
1,3,4-Oxadiazole
Antibacterial study
Antifungal study
1. Introduction
Further fluorine containing molecules showed wide spectrum
antimicrobial and biological properties. Keeping in view of these
1,3,4-Oxadiazole is a versatile lead molecule for designing
potential bioactive agents. The 1,3,4-oxadiazole derivatives have
been found to exhibit diverse biological activities such as antimi-
crobial [1], anti-HIV [1], antitubercular [2], antimalarial [3], anal-
gesic [4], anti-inflammatory [5], anticonvulsant [6], hypoglycemic
[7] and other biological properties such as genotoxic studies [8] and
lipid peroxidation inhibitor [9].
Used extensively in the symptomatic treatment of rheumatic
fever, arthritis [10] (rheumatoid, osteo and Jaundice arthritis),
myocardial infarctions and management of primary dysmenorrheal
[11]. The major side effects in the use of aryl alkanoic acids is their
gastric irritation, which is partly due to the corrosive nature of
carboxylic acid group present in them. In order to reduce or mask
the side effects of carboxylic moiety we planned to synthesize
different 2,5-disubstituted-1,3,4-oxadiazoles (4a–m) via the
condensation of 4-hydroxybenzohydrazide with various aromatic
acids in presence of phosphorus oxychloride respectively in the
hope of getting potent biodynamic agents and evaluate their anti-
microbial activity.
and in continuation of our research on biologically active mole-
cules, we hereby report the synthesis of some novel 1,3,4-oxadia-
zoles containing 2-fluoro-4-methoxy phenyl containing moieties.
2. Chemistry
2-Fluoro-4-methoxybenzoic acid was converted into ethyl 2-fluo-
ro-4-methoxybenzoate 2, by the esterification reaction using known
procedure [12]. Further this ester was converted into 2-fluoro-
4-methoxybenzohydrazide 3, by reacting with hydrazine hydrate in
ethanol medium. Title compounds 2-(2-fluoro-4-methoxyphenyl)-
5-substituted-1,3,4-oxadiazoles were synthesized by refluxing
equimolar mixture of 2-fluoro-4-methoxybenzohydrazide 3,
with different aromatic carboxylic acid (a–m) in phosphorous
oxychloride (10 vol) for 3 h (Scheme 1).
3. Antimicrobial studies
All the newly synthesized oxadiazoles were screened for their
antibacterial and antifungal activity. For antibacterial studies micro-
organisms employed were Staphylococcus aureus, Bacillus subtilis,
Escherichia coli and Pseudomonas aeruginosa. For antifungal, Candida
albicans was used as organism. Both microbial studies were assessed
by Minimum Inhibitory Concentration (MIC) by serial dilution
* Corresponding author. Fax: þ91 824 2474033.
E-mail address: isloor@yahoo.com (A.M. Isloor).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.11.046

B. Chandrakantha et al. / European Journal of Medicinal Chemistry 45 (2010) 1206–1210
O
1207
F
F
O
F
O
NH2
O
CH
3
NH
OH
H+,Ethanol
NH2 -NH2
O
O
O
CH
3
CH3
CH3
1
3
2
N
F
N
R
O
POCl3
R-COOH
+
O
110 0C
4
CH
3
Scheme 1. Scheme for synthesis of the new oxadiazoles.
method [13]. Forthis, the compound whose MIC hasto bedetermined
is dissolved in serially diluted DMF. Then a standard drop of the
culture prepared for the assay is added to each of the dilutions, and
incubated for 16–18 h at 37 ꢀC. MIC is the highest dilution of the
compound,whichshowsclearfluidwithnodevelopmentof turbidity.
6. Experimental
Melting points were determined by open capillary method and
were uncorrected. Elemental analysis was performed on Thermo
FinninganFLASHEA1112CHNanalyzer. TheIRspectra(InKBrpellets)
were recorded on a Shimadzu FT-IR 157 spectrophotometer. 1H NMR
spectra were recorded on a Perkin–Elmer EM 300 MHz spectrometer
using TMS as internal standard. Mass spectra were recorded on LC–
MS-Aglilent 1100 series with MSD (Ion trap) using 0.1% aqueous TFA
in acetonitrile system on C18-BDS column for 10 min duration.
Ionization mode is EI for all the compounds. Purity of the compounds
was checked by TLC silica coated plates obtained from Merck.
4. Results and discussion
Formation of 2-(2-fluoro-4-methoxyphenyl)-5-substituted-
1,3,4-oxadiazoles was confirmed by recording their IR, 1H NMR and
mass spectra. IR spectrum of oxadiazole 4a showed absorption at
3097 cmꢁ1 which is due to the aromatic stretching. An absorption
band at 1594 cmꢁ1 is due to the C]N group, band at 1057 cmꢁ1 is
due to stretching of oxadiazole ring and the absorption band
appeared at 1093 cmꢁ1 is due to C–F group.
6.1. Preparation of ethyl 2-fluoro-4-methoxybenzoate (2)
To
a
mixture of 2-fluoro-4-methoxybenzoic acid (10 g,
The 1H NMR spectrum of 4a showed multiplet in the region of
8.07–7.00. , 8.07 is due to aromatic proton, , 8.04–8.01 appeared as
doublet of twoprotons, , 8.0–7.9 as doubletof one protonand triplet
, 7.39 is due to the single proton. Similarly a singlet
, 2.73 is due to the three protons of the methoxy group.
d,
0.0587 mol) in Ethanol (100 ml) was added conc. Sulphuric acid
(1 ml)andrefluxedfor5 h. Thereactionmixturewasconcentratedthe
solid separated was filtered, washed with water and recrystallised
with ethanol to give 2 as white crystals. (10 g, 85%) Mp. 158–160 ꢀC.
d
d
d
appeared at
appeared at
d
d
The mass spectrum of 4a showed molecular ion peak at m/z 364,
which is in agreement with the molecular formula C16H12BrFN2O2.
Similarly the spectral values for all the compounds and C, H, N
analyses are given in the experimental part.
6.2. Preparation of 2-fluoro-4-methoxybenzohydrazide (3)
A
mixture of ethyl 2-fluoro-4-methoxybenzoate (10 g,
0.0602 mol) and hydrazine hydrate (5.0 ml, 0.1009 mol) in ethanol
(100 ml) was heated under reflux for 8 h. The reaction mixture was
Table 1
5. Conclusions
Antibacterial and antifungal data for the newly synthesized oxadiazoles.
Compound No. Antibacterial activity data in MIC (
m
g/ml) Antifungal activity
data in MIC ( g/ml)
A series of novel 2-(2-fluoro-4-methoxyphenyl)-5-substituted-
1,3,4-oxadiazoles were synthesized and characterized by 1H NMR,
Mass spectrometry and IR studies. All the newly synthesized
compounds were screened for their antibacterial and antifungal
activity. Among the screened samples, compounds 4a and 4b
showed excellent antibacterial activity against E. coli and P. aeru-
m
S. aureus B. subtilis E. coli P. aeruginosa C. albicans
4a
6
6
3
3
6
6
6
6
6
6
6
6
3
6
3
6
6
4b
6
6
3
3
4c
6
6
6
6
4d
6
6
6
6
ginosa even at low concentration of 3 mg/ml. Compound 4a has
4e
4f
4g
4h
6
12.5
6
6
6
6
6
6
6
6
6
12.5
12.5
6
12.5
12.5
6
6
6
3-bromo-2-methyl phenyl group and 4b has 2,3,4-trifluoro phenyl
group as substituents. Remaining compounds have showed
significant antibacterial activity. Antifungal screening was carried
out on C. albicans. Among the tested compounds, 4i and 4k showed
4i
6
4j
6
6
6
6
highest inhibition at 3 mg/ml concentration. 4i has 2-bromo-
4k
4l
12.5
6
12.5
6
6
6
6
6
5-chloro phenyl group and 4k has 5-methylisoxazole groups
respectively (Table 1). All the newly synthesized compounds have
2-fluoro-4-methoxy phenyl substituents, which is accounted for
their significant antimicrobial activity.
4m
6
6
6
6
Furacin (Std)
DMF (Control)
12.5
–
12.5
–
6
–
12.5
–
Flucanazol (Std) 6
–

1208
B. Chandrakantha et al. / European Journal of Medicinal Chemistry 45 (2010) 1206–1210
concentrated and left to cool. The solid product obtained was
filtered, washed with water and recrystallised with ethanol to give
3 as white crystals. (7 g, 74%) Mp. 158–160 ꢀC.
afford title compound 4c as white solid. (1.5 g, 81%); mp
222–228 ꢀC; IR (KBr) cmꢁ1 3070 (Ar-H), C]N (1545), C]C (1560),
C–O (1070, stretch of oxadiazole ring), C–F (1050); mass m/z (Mþ)
339: 1H NMR (400 MHz-DMSO-d6-ppm).
d 8.34–8.39 (m, 2H, Ar-H),
6.3. General procedure for preparation of 2-(2-fluoro-4-
methoxyphenyl)-5-substituted 1,3,4-oxadiazole (4)
8.07–8.11 (m, 1H, Ar-H), 7.81–7.83 (m, 1H, Ar-H), 7.67–7.71 (m, 1H,
Ar-H), 6.79–6.89 (dd, 2H, Ar-H, J ¼ 8.8 Hz), 3.9 (s, 3H, –OCH3). Anal.
Found (calc.) for C16H10F4N2O2 (%): C, 57.01 (56.91); H, 2.18 (3.00);
N, 8.43 (8.3).
An equimolar mixture of Acid hydrazide 3 with different
aromatic carboxylic acid (a–e) was refluxed with phosphorous
oxychloride (10 vol) for 2–3 h. Reaction mixture was concentrated
through rotovap, the residue was quenched with ice water and the
solid separated was filtered off, washed with water and further
purified by recrystallization with ethanol to afford 5-substituted
1,3,4-oxadiazole bearing 2-fluoro-4-methoxy phenyl moiety as
white crystalline solid.
6.7. Preparation of 3-[5-(2-fluoro-4-methoxyphenyl)-1,3,4-
oxadiazol-2-yl] benzonitrile (4d)
To a mixture of 2-fluoro-4-methoxybenzohydrazide 1 (1 g,
0.0054 mol) and 3-cyanobenzoic acid (0.8053 g, 0.0054 mol) was
added phosphorous oxychloride (10 ml). The reaction mixture was
refluxed at 100 ꢀC for 2 h. The reaction mixture was cooled to
room temperature, the excess of POCl3 was concentrated through
high vacuum, the residue was quenched with ice and the solid
separated was filtered and dried through pump to afford title
compound 4d as white solid. (1.5 g, 81%); mp 222–228 ꢀC; IR (KBr)
cmꢁ1 3030 (Ar C-H), C]N (1615), C]C (1540), C–O (1060, stretch
of oxadiazole ring), C–F (1070); mass m/z (Mþ) 296: 1H NMR
6.4. Preparation of 2-(3-bromo-2-methylphenyl)-5-(2-fluoro-4-
methoxyphenyl)-1,3,4-oxadiazole (4a)
To a mixture of 2-fluoro-4-methoxybenzohydrazide 1 (1 g,
0.0054 mol) and 3-bromo 2-methyl benzoic acid (1.16 g,
0.0054 mol) was added phosphorous oxychloride (10 ml). The
reaction mixture was refluxed at 100 ꢀC for 2 h. The reaction
mixture was cooled to room temperature, the excess of POCl3 was
concentrated through high vacuum, the residue was quenched with
ice and the solid separated was filtered and dried through pump to
afford title compound 4a as white solid. (1.5 g, 78%); mp
290–295 ꢀC; IR (KBr) cmꢁ1 3097 (Ar-H), C]N (1594), C]C (1560),
C–O (1057, stretch of oxadiazole ring), C–F (1093); mass m/z (Mþ)
(400 MHz-DMSO-d6-ppm).
d 8.39–8.41 (m, 2H, Ar-H), 8.11–8.17
(m, 2H, Ar-H), 7.82–7.86 (m, 1H, Ar-H), 7.14–7.18 (dd, 1H, Ar-H,
J ¼ 2.4 Hz), 7.03–7.06 (dd, 1H, Ar-H, J ¼ 2.4 Hz), 3.89 (s, 3H, –OCH3).
Anal. Found (calc.) for C16H10FN3O2 (%): C, 65.29 (65.09); H, 3.51
(3.39); N, 14.23 (14.44).
364: 1H NMR (300 MHz-DMSO-d6-ppm)
d 8.02–8.07 (m, 1H, Ar-H),
6.8. Preparation of 2-(2,3-dimethylphenyl)-5-(2-fluoro-4-
methoxyphenyl)-1,3,4-oxadiazole (4e)
7.95–7.98 (d, 1H, Ar-H, J ¼ 7.8 Hz), 7.87–7.89 (d, 1H, Ar-H,
J ¼ 7.14 Hz), 7.34–7.39 (m, 1H, Ar-H), 7.10–7.16 (dd, 1H, Ar-H,
J ¼ 2.4 Hz), 7.00–7.04 (dd,1H, Ar-H, J ¼ 2.31 Hz), 3.87 (s, 3H, –OCH3),
2.73 (s, 3H, –CH3). Anal. found (calc.) for C16H12BrFN2O2 (%): C,
53.01 (52.91); H, 3.45 (3.29); N, 7.96 (7.8).
To a mixture of 2-fluoro-4-methoxybenzohydrazide 1 (1 g,
0.0054 mol) and 2,3-dimethyl benzoic acid (0.8109 g, 0.0054 mol)
was added phosphorous oxychloride (10 ml). The reaction mixture
was refluxed at 100 ꢀC for 2 h. The reaction mixture was cooled to
room temperature, the excess of POCl3 was concentrated through
high vacuum, the residue was quenched with ice and the solid
separated was filtered and dried through pump to afford title
compound 4e as white solid. (1.5 g, 92%); mp 222–228 ꢀC; IR (KBr)
cmꢁ1 3020 (Ar C-H), C]N (1615), C]C (1540), C–O (1060, stretch of
oxadiazole ring), C–F (1070); mass m/z (Mþ) 299: 1H NMR
6.5. Preparation of 2-(2-fluoro-4-methoxyphenyl)-5-(2,3,4-
trifluorophenyl)-1,3,4-oxadiazole (4b)
To a mixture of 2-fluoro-4-methoxybenzohydrazide 1 (1 g,
0.0054 mol) and 2,3,4-trifluorobenzoic acid (0.95 g, 0.0054 mol)
was added phosphorous oxychloride (10 ml). The reaction
mixture was refluxed at 100 ꢀC for 2 h. The reaction mixture was
cooled to room temperature, the excess of POCl3 was concen-
trated through high vacuum, the residue was quenched with ice
and the solid separated was filtered and dried through pump to
afford title compound 4b as white solid. (1.6 g, 90%); mp
235–238 ꢀC; IR (KBr) cmꢁ1 3070 (Ar-H), C]N (1585), C]C
(1580), C–O (1040, stretch of oxadiazole ring), C–F (1090); mass
(300 MHz-DMSO-d6-ppm).
d
8.04–8.10 (t, 1H, Ar-H, J ¼ 8.52 Hz),
7.80–7.82 (d, 1H, Ar-H, J ¼ 7.59 Hz), 7.24–7.35 (m, 2H, Ar-H) 6.76–
6.88 (m, 2H, Ar-H), 3.89 (s, 3H, –OCH3), 2.65 (s, 3H, –CH3), 2.40 (s,
3H, –CH3). Anal. Found (calc.) for C17H15FN2O2 (%): C, 68.65 (68.55);
H, 5.38 (5.09); N, 9.64 (9.50).
6.9. Preparation of 2-chloro-5-[5-(2-fluoro-4-methoxyphenyl)-
1,3,4-oxadiazol-2-yl] pyridine (4f)
m/z (Mþ) 325: 1H NMR (300 MHz-DMSO-d6-ppm)
d
8.04–8.09 (t,
1H, Ar-H, J ¼ 8.5 Hz), 7.91–7.93 (m, 1H, Ar-H), 7.15–7.19 (m, 1H,
Ar-H), 6.77–6.89 (m, 2H, Ar-H), 3.9 (s, 3H, –OCH3). Anal. Found
(calc.) for C15H8F4N2O2 (%): C, 55.65 (55.56); H, 2.60 (2.47); N,
8.78 (8.64).
To a mixture of 2-fluoro-4-methoxybenzohydrazide 1 (1 g,
0.0054 mol) and 6-chloronicotinic acid (0.84 g, 0.0054 mol) was
added phosphorous oxychloride (10 ml). The reaction mixture was
refluxed at 100 ꢀC for 2 h. The reaction mixture was cooled to room
temperature, the excess of POCl3 was concentrated through high
vacuum, the residue was quenched with ice and the solid separated
was filtered and dried through pump to afford title comꢁp1ound 4f as
white solid. (1.5 g, 90%); mp 224–235 ꢀC; IR (KBr) cm 3030 (Ar
C-H), C]N (1625), C]C (1560), C–O (1080, stretch of oxadiazole
ring), C–F (1040), C–Cl (833); mass m/z (Mþ) 306: 1H NMR
6.6. Preparation of 2-(2-fluoro-4-methoxyphenyl)-5-[2-
(trifluoromethyl) phenyl]-1,3,4-oxadiazole (4c)
To a mixture of 2-fluoro-4-methoxybenzohydrazide 1 (1 g,
0.0054 mol) and 2-trifluoromethyl benzoic acid (1.026 g,
0.0054 mol) was added phosphorous oxychloride (10 ml). The
reaction mixture was refluxed at 100 ꢀC for 2 h. The reaction
mixture was cooled to room temperature, the excess of POCl3 was
concentrated through high vacuum, the residue was quenched with
ice and the solid separated was filtered and dried through pump to
(300 MHz-DMSO-d6-ppm)
d
9.08–9.09 (d, 1H, Ar-H, J ¼ 2.4 Hz),
8.47–8.50 (dd, 1H, Ar-H, J ¼ 1.98 Hz), 8.07–8.13 (t, 1H, Ar-H,
J ¼ 8.61 Hz), 7.78–7.80 (d, 1H, Ar-H, J ¼ 8.4 Hz), 7.12–7.17 (dd, 1H, Ar-
H, J ¼ 11.2 Hz), 7.01–7.05 (dd, 1H, Ar-H, J ¼ 8.73 Hz), 3.88 (s, 3H,

B. Chandrakantha et al. / European Journal of Medicinal Chemistry 45 (2010) 1206–1210
1209
–OCH3). Anal. Found (calc.) for C14H9ClFN3O2 (%): C, 55.61 (55.9); H,
3.17 (3.01); N, 13.35 (13.0).
was added phosphorous oxychloride (10 ml). The reaction mixture
was refluxed at 100 ꢀC for 2 h. The reaction mixture was cooled to
room temperature, the excess of POCl3 was concentrated through
high vacuum, the residue was quenched with ice and the solid
separated was filtered and dried through pump to afford title
compound 4j as white solid. (1.5 g, 86%); mp 255–259 ꢀC; IR (KBr)
cmꢁ1 3020 (Ar C-H), C]N (1625), C]C (1520), C–O (1020, stretch of
oxadiazole ring), C–F (1050); mass m/z (Mþ) 322: 1H NMR (300 MHz-
6.10. Preparation of 2-(2,3-difluoro-6-nitrophenyl)-5-(2-fluoro-4-
methoxyphenyl)-1,3,4-oxadiazole (4g)
To a mixture of 2-fluoro-4-methoxybenzohydrazide 1 (1 g,
0.0054 mol) and 5,6-difluoro-2-nitrobenzoic acid (1.1 g, 0.0054 mol)
was added phosphorous oxychloride (10 ml). The reaction mixture
was refluxed at 100 ꢀC for 2 h. The reaction mixture was cooled to
room temperature, the excess of POCl3 was concentrated through
high vacuum, the residue was quenched with ice and the solid
separated was filtered and dried through pump to afford title
compound 4g as white solid. (1.7 g, 89%); mp 200–203 ꢀC; IR (KBr)
cmꢁ1 3040 (Ar C-H), C]N (1645), C]C (1540), C–O (1070, stretch of
oxadiazole ring), C–F (1070); mass m/z (Mþ) 352: 1H NMR (400 MHz-
DMSO-d6-ppm) d 9.65 (s, 1H, Ar-H), 8.89 (s, 1H, Ar-H), 8.10–8.22 (m,
2H, Ar-H) 7.98–8.01 (m,1H, Ar-H), 7.67–7.85 (m, 2H, Ar-H), 6.80–6.91
(m, 2H, Ar-H), 3.88 (s, 3H, –OCH3). Anal. found (calc.) for C18H12FN3O2
(%): C, 67.29 (67.5); H, 3.76 (3.6); N, 13.08 (13.2).
6.14. Preparation of 2-(2-fluoro-4-methoxyphenyl)-5-(5-
methylisoxazol-3-yl)-1,3,4-oxadiazole (4k)
DMSO d6-ppm).
d
8.59–8.63 (dd, 1H, Ar-H, J ¼ 7.2 Hz), 8.33–8.38 (dd,
To a mixture of 2-fluoro-4-methoxy benzohydrazide 1 (1 g,
0.0054 mol) and 5-methylisoxazole-3-carboxylic acid (0.68 g,
0.0054 mol) was added phosphorous oxychloride (10 ml). The
reaction mixture was refluxed at 100 ꢀC for 2 h. The reaction
mixture was cooled to room temperature, the excess of POCl3 was
concentrated through high vacuum, the residue was quenched with
ice and the solid separated was filtered and dried through pump to
afford title compound 4k as white solid. (1.2 g, 80%); mp
215–218 ꢀC; IR (KBr) cmꢁ1 3090 (Ar C-H), C]N (1655), C]C (1550),
C–O (1090, stretch of oxadiazole ring), C–F (1050), C]O (1643);
1H, Ar-H, J ¼ 7.2 Hz), 7.99–8.04 (t, 1H, Ar-H, J ¼ 7.6 Hz), 7.14–7.18 (d,
1H, Ar-H, J ¼ 15 Hz), 7.039–7.07 (dd, 1H, Ar-H, J ¼ 2.4 Hz), 3.88 (s, 3H,
–OCH3).Anal. Found(calc.)forC15H8F3N3O4 (%):C,51.44(51.3);H, 2.56
(2.4); N, 11.46 (11.3).
6.11. Preparation of 2-(4-fluorophenyl)-5-(2-fluoro-4-
methoxyphenyl)-1,3,4-oxadiazole (4h)
To a mixture of 2-fluoro-4-methoxybenzohydrazide 1 (1 g,
0.0054 mol) and 4-fluoro benzoic acid (0.76 g, 0.0054 mol) was
added phosphorous oxychloride (10 ml). The reaction mixture was
refluxed at 100 ꢀC for 2 h. The reaction mixture was cooled to room
temperature, the excess of POCl3 was concentrated through high
vacuum, the residue was quenched with ice and the solid separated
was filtered and dried through pump to afford title compound 4h as
white solid. (1.4 g, 90%); mp 210–212 ꢀC; IR (KBr) cmꢁ1 3030 (Ar C-
H), C]N (1635), C]C (1530), C–O (1030, stretch of oxadiazole ring),
C–F (1060); mass m/z (Mþ) 289: 1H NMR (300 MHz-DMSO d6-
mass m/z (Mþ) 275: 1H NMR (300 MHz-DMSO-d6-ppm)
d 9.18
(s, 1H, Ar-H), 7.99–8.05 (t, 1H, Ar-H, J ¼ 8.64 Hz), 7.11–7.15 (m, 2H,
Ar-H), 3.8 (s, 3H, –OCH3), 2.80 (s, 3H, –CH3). Anal. found (calc.) for
C13H10FN3O3 (%): C, 56.65 (56.73); H, 3.86 (3.66); N, 15.5 (15.3).
6.15. Preparation of 2-(2-fluoro-4-methoxyphenyl)-5-(3-fluoro-4-
nitrophenyl)-1,3,4-oxadiazole (4l)
To a mixture of 2-fluoro-4-methoxy benzohydrazide 1 (1 g,
0.0054 mol) and 3-fluoro-4-nitrobenzoic acid (0.99 g, 0.0054 mol)
was added phosphorous oxychloride (10 ml). The reaction mixture
was refluxed at 100 ꢀC for 2 h. The reaction mixture was cooled to
room temperature, the excess of POCl3 was concentrated through
high vacuum, the residue was quenched with ice and the solid
separated was filtered and dried through pump to afford title
compound 4l as white solid. (1.8 g, 99.45%); mp 235–235 ꢀC; IR
(KBr) cmꢁ1 3070 (Ar C-H), C]N (1697), C]C (1570), C–O (1054,
stretch of oxadiazole ring), C–F (1084); mass m/z (Mþ) 334: 1H NMR
ppm).
d 8.07–8.16 (m, 3H, Ar-H), 7.44–7.50 (m, 2H, Ar-H), 7.11–7.16
(dd, 1H, Ar-H, J ¼ 2.4 Hz), 7.0–7.04 (dd, 1H, Ar-H, J ¼ 2.4 Hz), 3.87 (s,
3H, –OCH3). Anal. Found (calc.) for C15H10F2N2O2 (%): C, 61.65 (61.3);
H, 3.66 (3.48); N, 9.72 (9.8).
6.12. Preparation of 2-(2-bromo-5-chlorophenyl)-5-(2-fluoro-4-
methoxyphenyl)-1,3,4-oxadiazole (4i)
To a mixture of 2-fluoro-4-methoxybenzohydrazide 1 (1 g,
0.0054 mol) and 2-bromo-5-chloro benzoic acid (1.27 g,
0.0054 mol) was added phosphorous oxychloride (10 ml). The
reaction mixture was refluxed at 100 ꢀC for 2 h. The reaction
mixture was cooled to room temperature, the excess of POCl3 was
concentrated through high vacuum, the residue was quenched
with ice and the solid separated was filtered and dried through
pump to afford title compꢁo1und 4i as white solid. (1.9 g, 90%); mp
(400 MHz-DMSO-d6-ppm)
d
8.37–8.41 (t, 1H, Ar-H, J ¼ 8 Hz),
8.25–8.28 (d, 1H, Ar-H, J ¼ 11.2 Hz), 8.11–8.16 (m, 2H, Ar-H),
7.14–7.17 (dd, 1H, Ar-H, J ¼ 12.4 Hz), 7.04–7.06 (dd, 1H, Ar-H,
J ¼ 8.8 Hz), 3.8 (s, 3H, –OCH3). Anal. found (calc.) for C15H9F2N3O4
(%): C, 54.23 (54.0); H, 3.12 (3.0); N, 12.81 (12.7).
6.16. Preparation of 2-(3,5-difluorophenyl)-5-(2-fluoro-4-
methoxyphenyl)-1,3,4-oxadiazole (4m)
215–218 ꢀC; IR (KBr) cm
3020 (Ar C-H), C]N (1625), C]C
(1540), C–O (1040, stretch of oxadiazole ring), C–F (1065); mass m/
z (Mþ) 382: 1H NMR (400 MHz-DMSO-d6-ppm)
d
8.03–8.08 (m,
To a mixture of 2-fluoro-4-methoxy benzohydrazide 1 (1 g,
0.0054 mol) and 3,5 diflurobenzoic acid (0.85 g, 0.0054 mol) was
added phosphorous oxychloride (10 ml). The reaction mixture was
refluxed at 100 ꢀC for 2 h. The reaction mixture was cooled to room
temperature, the excess of POCl3 was concentrated through high
vacuum, the residue was quenched with ice and the solid separated
was filtered and dried through pump to afford title compound 4m as
white solid. (1.4 g, 87%); mp 265–269 ꢀC; IR (KBr) cmꢁ1 3070 (Ar C-
H), C]N (1675), C]C (1576), C–O (1054, stretch of oxadiazole ring),
C–F (1083); mass m/z (Mþ) 307: 1H NMR (300 MHz-DMSO-d6-ppm)
1H, Ar-H), 8.00–8.03 (d, 1H, Ar-H, J ¼ 7.8 Hz), 7.82–7.84 (d, 1H, Ar-
H, J ¼ 7.0 Hz), 7.38–7.43 (m, 1H, Ar-H), 7.12–7.18 (dd, 1H, Ar-H,
J ¼ 2.4 Hz), 7.00–7.04 (dd, 1H, Ar-H, J ¼ 2.31 Hz), 3.88 (s, 3H,
–OCH3). Anal. Found (calc.) for C15H9BrClFN2O2 (%): C, 46.97 (47.0);
H, 2.36 (2.5); N, 7.30 (7.2).
6.13. Preparation of 3-[5-(2-fluoro-4-methoxyphenyl)-1,3,4-
oxadiazol-2-yl] quinoline (4j)
To a mixture of 2-fluoro-4-methoxy benzohydrazide 1 (1 g,
0.0054 mol) and quinoline-3-carboxylic acid (0.94 g, 0.0054 mol)
d
8.10–8.16 (t, 1H, Ar-H, J ¼ 8.64 Hz), 7.78–7.81 (m, 2H, Ar-H), 7.57–
7.64 (m, 1H, Ar-H) 7.12–7.17 (dd, 1H, Ar-H, J ¼ 2.4 Hz), 7.01–7.05 (dd,

1210
B. Chandrakantha et al. / European Journal of Medicinal Chemistry 45 (2010) 1206–1210
[3] P.R. Kagthara, N.S. Shah, R.K. Doshi, H.H. Parekh, Indian J. Chem. 38B (1999)
572–576.
[4] M. Akhter, A. Husain, B. Azad, M. Ajmal, Eur. J. Med. Chem. 44 (2009)
2372–2378.
1H, Ar-H, J ¼ 2.52 Hz) 3.88 (s, 3H, –OCH3). Anal. found (calc.) for
C15H9F3N2O2 (%): C, 58.43 (58.8); H, 3.16 (2.96); N, 9.34 (9.2).
[5] P.C. Unangast, G.P. Shrum, D.T. Conner, C.D. Dyer, D.J. Schrier, J. Med. Chem. 35
(1992) 3691–3698.
Acknowledgements
[6] M.S.Y. Khan, R.M. Khan, S. Drabu, Indian J. Heterocycl. Chem. 11 (2001)
119–122.
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[8] A.O. Maslat, M. Abussaud, H. Tashtoush, M. Al-Talib, Pharmacology 54 (2002)
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[9] A.A. Farghaly, A.A. Bekhit, J.Y. Park, Arch. Pharm. (Weinheim) 333 (2000)
53–57.
AMI is thankful to Director, NITK Surathkal, India for providing
research facilities and also to Board of Research in Nuclear Sciences,
Department of Atomic Energy, Government of India for YOUNG
SCIENTIST award. C.B is thankful to Dr. John Kallikat and Premsai
Rai. N of Syngene International Ltd. Bangalore, India, for their
encouragement.
[10] Song Cao, Xu Hong Qian, Gonghua Song, Bing Chai, Zhisheng Jiang, J. Agric.
Food Chem. 15 (2003) 152–155.
[11] S.N. Pandeya, A Text Book of Medicinal Chemistry. S.G. Publisher, Varanasi,
2001, 353p.
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