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CHAPTER-2
SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL
STUDIES OF SOME NEW 1,3,4-OXADIAZOLE DERIVATIVES
57
2.1. Introduction
1,3,4-Oxadiazole is a thermally stable and neutral Heteroaromatic molecule1
having a wide variety of uses, particularly as biologically active compounds in medicine,
agriculture, dye stuffs, UV absorbing and fluorescent materials, heat resistant polymers
and scintillators.
Oxadiazoles and their analogues can be considered as simple five membered
heterocycles possessing one oxygen and two nitrogen atoms. The oxadiazole exists in
different isomeric forms such as 1,3,4- (a), 1,2,5-(b), 1,2,4-(c), and 1,2,3-(d) oxadiazole,
out of which thermally stable 1,3,4-oxadiazole is the only isomer not containing a
nitrogen-oxygen bond.
N
O
N
N
O
N
N
O
N
O
N
N
a b c d
Fig. 2.1: Different isomeric forms of 1,3,4-Oxadiazole
1,3,4-Oxadiazole is a thermally stable neutral aromatic molecule and its estimated
resonance energy is 167.4 kJ/mol. particularly, aryl group at position 2 increases the
thermal stability of 1,3,4-oxadiazole. The ring is stable to heat, a property which has been
exploited in the production of heat-resistant poly-1,3,4-oxadiazoles. UV spectra of
substituted 1,3,4-oxadiazoles are similar to those of substituted benzenes, particularly in
the case of 2-phenyl-1,3,4-oxadiazoles (λmax in ethanol = 247.5 nm, log ε 4.26). Studies
on 1,3,4-oxadiazoles and its cation indicates a maximum positive charge on the second
position. Alkyl and aryl-1,3,4-oxadiazoles are neutral compounds and 2-amino-1,3,4-
oxadiazoles are weakly basic.
58
1,3,4-oxadiazoles have a relatively low electron density at carbon (position 2 and
5) and relatively high electron density at nitrogen (position 3 and 4). Consequently the
major reactions performed by nucleophilic attack at carbon, followed by ring cleavage
and electrophilic attack at nitrogen atom. The attack of a nucleophile at carbon 2 leads
either to nucleophilic displacement (path A) or ring cleavage (path B) as shown below.
(Fig. 2.2) The latter being the most common result. For instance, the most frequently
encountered result of the reaction of a 1,3,4-oxadiazole with a nucleophile is the ring
opening reaction which leads to hydrazine derivatives, as shown below.
R
NH
O
N
Nu
X
N
O
N
XR
Nu-N
O
N
R
X
Nu
N
O
N
R Nu
N
O
N
XR_
Nu
A
B
Fig. 2.2: Reactions of 1,3,4-Oxadiazoles with nucleophile
The relatively low electron density at carbon, coupled with the possibility of
protonation at nitrogen, make electrophilic substitution at carbon difficult. No examples
of nitration of sulfonation of the oxadiazole ring have been reported and attempted
bromination reactions were unsuccessful.
1,3,4-oxadiazole is associated with potent pharmacological activity due to the
presence of toxophoric –N=C-O- linkage.2 Considerable evidence have been accumulated
to demonstrate the efficacy of 1,3,4-oxadiazole including antimicrobial, 3 anti-
inflammatory, 4, 5
Antihypertensive, 6 Anticonvulsant,
7 Anticancer,
8 Anti-tubercular,
9
Anthelmintic, 10
1,3,4-oxadaizoles show herbicidal activity, particularly against broad
59
leafed weeds and grasses in crops such as rice and corn.11
Therefore many methods for
the synthesis of substituted 1,3,4-oxdaiazole have been explored. A large no. of drugs
used clinically have oxadiazole ring as a structural building block.
2.1.1 Synthetic Approaches and Pharmacological Activity of 1,3,4-Oxadiazoles:
Literature survey reveals that the derivatives of the 1,3,4-oxadiazoles played a
vital role in the medicinal chemistry. The derivative of 1,3,4-oxadiazole with suitable
substitution at 2, 5-position are becoming an important member in the heterocyclic family
not only because of their wide range usages as photosensitive & electrical materials but
also because of their broad spectrum in biological activities. Taking into account the
importance of these compounds to both heterocyclic and medicinal chemistry, we have
decided to present the main synthesis approaches used for obtaining the heterocyclic
nucleus, as well as the broad spectrum of pharmacological activities.
Katritzky and co-workers (2002)12
have prepared 5-aryl-2-amino-1,3,4-oxadiazole
derivatives (139) by the reaction between bis (benzotriazol-1-yl) methanimine (137) and
arylhydrazides in excellent yield (Scheme-2.1).
N N
N
N
HN
NN
R1 NHNH2
O
THF
N
O
N
NH2R1
HN
N
N
2
3h
+
137 138 139
Scheme-2.1: Synthesis of 2-amino-5-aryl-1,3,4-oxadiazoles
A series of new derivatives of 5-(1-/2-naphthyloxymethyl)-1,3,4-oxadiazol-2(3H)-
thione (R=SH), 5-(1-/2-naphthyloxymethyl)-1,3,4-oxadiazole-2-amino (R=NH2), and 5-
60
(1-/2-naphthyloxymethyl)-1,3,4-oxadiazol-2(3H)-ones (R=OH) (140) (Fig. 2.3) were
synthesized by Sahin et al, (2002)13
and evaluated for their antimicrobial activity.
O
O
NN
R
140
Fig. 2.3: 2-Naphthyloxymethyl substituted 1,3,4-Oxadiazoles
It has been found that 5‐ (4‐Aroyl)‐aryloxy methyl‐2‐thio‐1,3,4‐oxadiazole (141)
were synthesized by Sudha et al, (2003)14
by the Intramolecular cyclization of
thiosemicarbazide generated by the action of hydrazides on carbon disulphide in the
presence of potassium hydroxide (Fig. 2.4). Among synthesized compound ‘c’,‘d’ shows
promising anticonvulsant activity.
O
O
O
NH
N
S
R1
R2
Where a: R1,R2=H,
b: R1, R2=CH3, H,
c: R 1, R2=H, Cl
d: R1, R2 =CH3, Cl
Fig. 2.4: 5‐ (4‐Aroyl) ‐aryloxy methyl‐2‐thio‐1,3,4‐oxadiazoles
Ouyang et al, (2006)15
synthesized and evaluated various 1,3,4-oxadiazole
derivatives (142) as to their ability to inhibit tubulin polymerization and block the mitotic
division of tumor cells (Fig. 2.5).
141
61
N NH
O
NN
NH O
O
N
Fig. 2.5: Dihydro-benzo [1, 4] dioxin-6-ylamino substituted 1,3,4-Oxadiazoles
Rivera and co-workers (2006)16
reported that 1,3-dibromo-5, 5-dimethylhydantoin
is an effective oxidizing agent for cyclization reactions of acylthiosemicarbazide (143).
Compound 5-aryl-2-amino-1,3,4-oxadiazoles (144) was obtained in excellent yield
(Scheme-2.2).
NH
O
NH
S
NH2 O
NN
NH2
R
R
5N NaOH, KI
H2O, i-prOH
1,3-dibromo-5,5-dimethylhydantoin
Where R=Ph, 4-ClC6H4, 4-MeOC6H4
Scheme-2.2: Synthesis of 2-amino-5-substituted-1,3,4-oxadiazoles using 1, 3-dibromo-5,
5-dimethylhydantoin
Another method for one pot synthesis of 2, 5-disubstituted-1,3,4-oxadiazoles
(146) from benzohydrazide (145) and carboxylic acid (Scheme-2.3) was reported by
Rajapakse (2006)17
using the coupling agent, 1’-carbonyldiimidazole (CDI) and
triphenylphosphyne as dehydrating agent.
142
144 143
62
NH
O
NH2
R OH
O
+
N
O
N
R
CDI, Ph3P, CBr4
MDC
Scheme-2.3: One pot synthesis of 1,3,4-oxadiazoles from carboxylic acids and acyl
hydrazides
Where R= NNHBoc
Ph
It has been reported, in general 5-aryl (alkyl)-2-amino-1,3,4-oxadiazoles can be
prepared by dehydration of derivatives of semicarbazides or thiosemicarbazide using
POCl3 as dehydrating agent. Dolman and co-workers (2006)18
reported a new method of
synthesis for 5-aryl (alkyl)-2-amino-1,3,4-oxadiazoles (148) from acylsemicarbazides
(X=O) and acylthiosemicarbazides 149 (X=S) mediated by tosyl chloride (Scheme-2.4).
R1 NH
O
NH
X
N
R2
N
O
N
N
R2
H
R1TsCl (1.2 eq), Py (2.1 eq)
THF, 70 oC
Where R1, R2=alkyl, aryl
X=O, S
N
S
N
N
R2
H
R1
Scheme-2.4: 5-Aryl (alkyl)-2-amino-1,3,4-oxadiazoles acylsemicarbazides
acylthiosemicarbazides
The Huisgein reaction also proceeds well with acid anhydrides in place of acid
chlorides, which was demonstrated by Efimova and co-workers (2008)19
, by synthesizing
1,3,4-oxadiazole compounds (151, 152) by acylation of a series of 5-aryl (hetaryl)
145 146
147
148
149
63
tetrazoles with acetic and benzoic anhydrides under microwave irradiation conditions
(Scheme-2.5).
NN
N
HN
R
N
O
N
R
N
O
N
BzR
Ac2O
Bz2O
70-80%
70-90%
150
151
152
Scheme-2.5: Microwave-activated acylation of 5-substituted tetrazoles
Pore and co-workers (2008)20
developed an efficient method for one-pot synthesis
of unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles (155) using trichloroisocyanuric
acid (TCCA) at ambient temperatures (Scheme-2.6). The main advantages of this method
are the mild nature of the synthesis, and the short reaction time.
R2
O
OHR1
O
NH
NH2+
N N
N OO
O
Cl
ClCl
TCCA
EtOH, RT, 20 min
N
O
N
R2R1
153 154155
Scheme-2.6: Trichloroisocyanuric acid-mediated one-pot synthesis of unsymmetrical 2,
5-disubstituted 1,3,4-oxadiazoles
R1= Ph, 4-ClC6H4, 4-OCH3C6H4, 4-CH3C6H4
R2=Ph, 4-OCH3C6H4, 4-ClC6H4, 4-CH3C6H4
Bhardwaj et al, (2009)21
have synthesized indole containing 1,3,4‐oxadiazoles
(156) and valuated for antimicrobial activity (Scheme-2.7). The activity reveals R1
64
(against B.subtilis and P. aeruginosa), R2 (against S.aureus, E.coli and B. subtilis) and R5
(against S.aureus) found effective against tested bacterial strains.
NH
N N
OR1
NH
N N
O
R2
Cl
NH
N N
O
R3OH
NH
N N
O
R4 NH
N N
O
R5 Cl
NH N N
O R
156
157
158
159
160
161
Scheme-2.7: Indole containing 1,3,4-Oxadiazole derivatives
Fuloria et al, (2009)22
have synthesized a series of new 1‐ (2‐aryl‐
5‐phenethyl‐1,3,4‐oxadiazol‐3(2H)‐yl) ethanones derivatives (162) (Fig. 2.6). These
products were evaluated for antibacterial and anti‐fungal activity against freshly cultured
strains of S. aureus (SA) and P. aeruginosa (PA) using sterile nutrient agar media and for
antifungal activity against freshly cultured strains of C. albicans (CA) and A. flavus (AF)
using sterile sabouraud’s agar medium by the disk diffusion method at a concentration of
2 mg per mL using DMF as solvent.
N
O
N
O
R1
R2162
Where
a: R1=H, R2=N(CH3)2
b: R1=H, R2=Cl
c: R1=OH, R2=OH
d: R1=OH, R2=H
e:R1=H, R2=OH
Fig. 2.6: Some New Oxadiazoles derived from Phenylpropionohydrazides
65
A new series of different 3-substituted- indole containing 1,3,4-Oxadiazoles (163)
were prepared and studied its SAR by screening invitro for their anti cancer activity by
Kumar and his co-workers (2009).23
The SAR study reveals that substitution at the C‐2
position of the 1,3,4‐oxadiazole ring plays an important role (Fig. 2.7). Also,
N‐methylation of indole ring nitrogen dramatically improved the cytotoxic activity.
NH
O
N
N
R
163
Where R=C6H5
R=CH2C6H5
R= 4-Pyridyl R= 4-CH3OC6H4
R= 4-ClC6H5
R= 3,4-di-CH3OC6H3
R= CH3
R=CF3
R=2,3,4-tri-CH3OC6H2
Fig. 2.7: Novel indolyl containing 1,3,4‐oxadiazoles
Li and Dickson (2009)24
stabilized a suitable one-pot practice for the synthesis of
1,3,4-oxadiazoles (166) from carboxylic acids and hydrazide using HATU as coupling
agent and Burgess reagent as dehydrating agent (Scheme-2.8).
R OH
O
NH
O
NH2
N
O
N
R
HATU, DIEA
Burgess Reagent THF, RT, 3h
+
166164165
Scheme-2.8: One-pot preparation of 1,3,4-oxadiazoles using Burgess reagent.
Where R=MeO
OMe NH2
NCSBr
N
H3C
Cl
66
Dobrota and co-workers (2009)25
reported the synthesis of 2, 5-disubstituted-
1,3,4-oxadiazoles (168) was easily prepared by oxidative cyclization of N-acylhydrazones
(Scheme-2.9) through use of an excess of Dess-Martin periodinane under mild
conditions.
R1 NH
O
R2
N
O
N
R2R1
O
I
AcO OAc
OAc
O
DMF, RT, 92%167 168
Where R1= Ph, 4-ClC6H4, 4-NO2C6H4,2-furyl, 4-pyridyl, 3-chloro-benzo[b]thien-2-yl
R2= ph, 4-MeOC6H4, 4-BrC6H4, 2-furyl, 2-thienyl, 4-pyridyl, 3-MeO-4-BnOC6H3
Scheme- 2.9: Preparation of unsymmetrical 2, 5-disubstituted 1,3,4-oxadiazoles
promoted by Dess-Martin reagent
Patel et al, (2010)26
synthesized 5-Aryl-2-amino-1,3,4-oxadiazole and Kerimov et
al, (2012)29
synthesized 2-amino-1,3,4-oxadiazoles carrying a benzimidazole moiety
(Scheme-2.10) in 33%–60% yield from the reaction between 2-(2-(4-substituted-phenyl)-
1H-benzo[d]imidazol-1-yl) acetohydrazide (170, 172) and cyanogen bromide.
NH
O
NH2
O
NN
NH2
RRCNBr/MeOH
R=2-Cl, 4-Cl
169 170
Scheme-2.10: Synthesis of 5-Aryl-2-amino-1,3,4-oxadiazole using zinc bromide
67
N
N
HN
O
NH2
R
N
NO
NN
NH2
R
CNBr/EtOH
60-70 oC
171 172
R=H, Cl, OMe, OCH2Ph
33-60%
Scheme-2.11: 3-(1,3,4-oxadiazol-2-il) quinazolin-4(3H)-one derivatives
Maccioni and co-workers (2011)27
synthesized a set of 3-acetyl-2, 5-diaryl-2, 3-
dihydro-1,3,4-Oxadiazoles (173) and tested them as inhibitors of human monoamine
oxidase (MAO) A and B isoform. Some of the tested compounds (Fig. 2.8) exhibit
interesting biological properties with an IC50 for the B isoform ranging from micromolar
to nanomolar values.
O
NN
R
Cl
O
173
Where R = NO2, IC50 = 121.62 ± 9.63 nM
Cl, IC50 = 115.31 ± 8.39 nM
Br, IC50 = 220.61 ± 12.6 nM
Fig. 2.8: 3-Acetyl-2, 5-diaryl-2, 3-dihydro-1,3,4-oxadiazoles
Sangshetti and co-workers (2011)28
investigated the antifungal activity of a
number of disubstituted oxadiazoles (174), each of which contained a triazole unit at
position 5 of the oxadiazole ring (Fig. 2.9). The compounds containing the methyl
sulfone (R1=SO2CH3) group attached to the nitrogen of the piperidine ring, and Cl or Br
(R2) groups exhibited excellent pharmacological profiles (equal to miconazole) against
some of the fungi.
68
N
N
N
N
R1
O
NN
R2
174 Where R1=-SO2CH3
R2=Cl, Br
Fig. 2.9: Synthesis of some Novel 2, 5-disubstituted 1,3,4-oxadiazoles
El-Sayed and co-workers (2012)30
prepared 5-substituted-2-amino-1,3,4-
oxadiazoles by cyclising acylthiosemicarbazides using iodine as the oxidizing agent
(Scheme-2.12). It was observed that synthesis of 5-((naphthalen-2-yloxy)methyl)-N
phenyl-1,3,4-oxadiazol-2- amine (176) was afford 62% yield, by heating compound in
ethanol in the presence of sodium hydroxide and Iodine in potassium iodide.
ONH
O
NHHN
OEtOH, NaOH
I2/KI
Reflux, 2h, 62%
OO
NN
NH
175 176
Scheme-2.12: Synthesis of 5-substituted-2-amino-1,3,4-oxadiazoles
Ahsan and co-workers, (2012)31
synthesized series of pyrazolo-one containg
1,3,4-Oxadiazole derivatives (Fig. 2.10). Among, compound (177) was found to be the
most promising compound active against Mycobacterium tuberculosis minimum
inhibitory concentrations, 0.78 and 3.12 μg/mL respectively.
N
O
N
NH
F
HNN
N
O
177
Fig.. 2.10:1, 5-Dimethyl-2-phenyl-4-([5-(arylamino)-1,3,4-oxadiazol-2-yl] methylamino)-
1, 2-dihydro-3H-pyrazol-3-one
69
Bondock et al, (2012)
32 synthesized some 1,3,4-Oxadiazole based heterocycles
(Scheme-2.13) and studied its antitumor activities. The results revealed that some of the
compounds like (179) and (180) displayed promising in-vitro antitumor activity in the 4-
cell lines assay.
N
O
N
NH
O
OO
179
N
O
N
NH
O
NH
N
PhHN
H2N
180
NH
O
NH
S
NH
O
CN
178
Scheme-2.13:1,3,4-Oxadiazole based heterocycles.
Review of literature indicated that 1,3,4-oxadiazole derivatives possess significant
biological activities. Prompted by the therapeutic importance, it was contemplated to
synthesize some 4-fluoro-3-methoxy phenyl substituted 1,3,4-oxadiazole derivatives.
Antimicrobial activity of such heterocyclic compounds was also discussed. Many azole
classes of compounds especially imidazole derivatives are reported to possess excellent
antimicrobial properties. Azoles are the most widely studied and currently used class of
antifungal agents. However, the emergence of azole resistant strains has spurred the
search for new antimicrobial compounds. With the aim of obtaining new antimicrobial
compounds with enhanced biological activity, we synthesized a series of new 1,3,4-
oxadizole derivatives containing 2-fluoro-4-methoxy phenyl derivatives. Newly
synthesized compounds were screened for their antimicrobial activity. The results of such
studies were presented in this chapter.
70
2.2. Results and discussions:
2.2.1 Discussion on the experimental leading to the synthesis of 1,3,4-oxadiazole
derivatives bearing 2-fluoro-4-methoxy phenyl derivatives:
1,3,4- Oxadiazole are of considerable pharmaceutical and material interest, which
is documented by a steadily increasing number of publications and patents.33
Consequently, a number of synthetic approaches to the 1,3,4-oxadiazole systems have
been developed and most of these involve the use of acetohydrazide or its derivatives, as
a source of two nitrogen atoms, and a variety of cyclizing agents. Typically, the reaction
is promoted by heat and anhydrous reagents including thionyl chloride, 34
imino
triphenylphosphorane, 35
triflicanhydride, 36
and phosphorous oxychloride.37
Alternative
synthetic methods comprise reaction of acetohydrazides with keteneylidene
triphenylphosphorane38
or base catalyzed cyclization reaction of trichloroacetic acid
hydrozones.39
O
NH
HN
O
P
O
Cl ClCl
O
N
HN
OP
O
Cl Cl
Cl ON NH
PO
Cl
Cl
O
NN
H
O
NN
HO
H
OP
O
Cl
ClH
Cl
Cl
O
F
RR
R
R
F
O
F
O
F
O
F
O
R
F
O
OH
OF
O
NH
O
NH2
O OH
POCl3
R
F
O
O
O
H+
MeOH181 182 183
188(a-m)
184 185 186
187
71
Scheme-2.14: Synthetic route for the substituted 1,3,4-oxadiazoles
In the present study, 2-fluoro-4-methoxybenzoic acid (181) was converted into
ethyl 2-fluoro-4-methoxybenzoate (182), by the esterification reaction using known
procedure. Further this ester was converted into 2-fluoro-4-methoxybenzohydrazide
(183), by reacting with hydrazine hydrate in ethanol medium. Title compounds 2-(2-
fluoro-4-methoxyphenyl)-5-substituted-1,3,4-oxadiazoles 188 (a-m) were synthesized by
refluxing equimolar mixture of 2-fluoro-4-methoxybenzohydrazide (183), with different
aromatic carboxylic acid in phosphorous oxychloride (10 vol) for 3 h (Scheme–2.14).
The resulting compounds were confirmed by NMR, Mass, IR spectral studies and also by
C, H, N analyses. The synthesized compounds from corresponding amines are mentioned
in Table-2.1.
Table 2.1: List of compounds synthesized from the scheme-2.1
Sl.No Acid Product
M.p (oC)
Yield
(%)
1
O OH
Br
N
O
NF
O
Br
188a
290-291 78
2
OHO
F
F
F
O
N N
F
FF
O
F
188b
235-236 90
72
3
O OH
F
F
F
O
N N
FF
F
O
F
188c
222-224 81
4
OHO
N
O
N N CN
O
F
188d
222-223 85
5
O OH
O
N N
O
F
188e
222-223 92
6 N
OHO
Cl
O
N N
NCl
O
F
188f
224-225 90
7
OHO
N+
O
O-F
F
O
N NO2N
FF
O
F
188g
200-201 89
8
OHO
F
O
N N
F
O
F
188h
210-212 90
73
9
O OH
Cl
Br
O
N NBr
Cl
F
O
188i
215-216 90
10
N
O
HO
O
N N
NO
F
188j
255-256
86
11
ON
O
HO
O
N N
ONO
F
188k
215-216
80
12
O OH
N+
O O-
F
O
N N
N+
O
O-
F
O
F
188l
235-237
99
13
O OH
F F
O
N N F
F
O
F
188m
265-267 87
The completion of the reaction was checked by thin layer chromatography (TLC)
on silica gel coated aluminium sheets (silica gel 60 F254) obtained from Merck. Melting
point was determined on a Buchi Melting point B-545 apparatus. The IR spectra (in KBr,
νmax cm-1
pellets) were recorded on a Nicolet 6700 FT-IR spectrometry. 1H NMR spectra
were recorded on Bruker (300 and 400MHz) spectrometer instruments, in CDCl3, DMSO
solvent. All the δ values presented in parts per million (ppm) scale. Mass spectra were
recorded on LCMS Agilent 1100 series using 0.1% aqueous TFA in acetonitrile system
(Column: Atlantis dC18, 75x4.6mm-5µm). Elemental analysis was performed on thermo
74
Finningan Flash EA 1112 CHN analyzer. Commercial grade solvents and reagents were
used without further purification. Chromatography was performed on silica gel (60-120
mesh) for compound purification.
Formation of 2-(2-fluoro-4-methoxy phenyl)-5-substituted 1,3,4-Oxadiazoles
were confirmed by recording their IR, 1H NMR and mass spectra. IR spectrum of
oxadiazole (188c) showed absorption at 3070 cm-1
which is due to the aromatic
stretching. An absorption band at 1545 cm-1
is due to C=N group, band at 1070 cm-1
1 is
due to stretching of oxadiazole ring and absorption band appeared at 1050 cm-1
is due to
C-F group. The 1H-NMR spectrum of (188c) showed triplet in the region of δ 8.39-8.33
(J = 7.8 Hz) and triplet in the region of 8.15-8.11 (J = 8.6 Hz) is due to 2-(trifluoro
methyl) phenyl ring proton. The doublet of doublet observed in the region of δ 7.16-7.12
(with J1 = 12.4, J2 =2.4 Hz) and doublet in the region δ 7.04-7.02 (J = 11.28 Hz) is
indicates the presence of 2-fluoro-4-methoxy phenyl ring protons. The singlet peak at δ
3.88 is due to the methoxy group of 2-fluoro phenyl ring protons. The mass spectrum of
(188c) showed molecular ion peak m/z 339. This is agreement with the molecular
formula C16H10F4N2O2. Similarly the spectral values for all the compounds and C, H, N
analysis are given in experimental part. In 13
C NMR, the peak at δ 56.22 indicates the
presence of methoxy group in the moiety.
The 1H NMR of compound (188f) shows singlet peak at δ 9.09 is indicates N-CH
proton of pyridine ring. Similarly the doublet of doublet and triplet in the region of δ
8.50-8.48 (J1 = 8.64, J2 =1.92 Hz) and δ 8.13-8.08 (J = 8.8 Hz) correspong to pyridne ring
protons. Mass spectrum shows m/z = 306.0 which compiles for the molecular weight of
the compound. Similarly the presence of peak in the region of δ 56.22 in 13
C NMR
confirmed the presence of methoxy group in phenyl ring. In the 1H NMR spectrum of
compound (188j) the singlet peak observed at the region of δ 9.50 and at δ 9.10 shows
75
presence of quinoline ring protons. Similarly the doublet peak in the region of δ 7.17-7.13
(J = 12.9 Hz), δ 7.06-7.04 (J = 8.8 Hz) shows the presence of 2-fluoro substituted phenyl
ring protons. A singlet peak at δ 3.89 is indicates presence of methoxy group.
2.3 Synthesis
2.3.1 General procedure
2.3.1.1 Preparation of Ethyl 2-fluoro-4-methoxybenzoate (182)
To a mixture of 2-Fluoro-4-methoxybenzoic acid (181) (10 g, 0.0587 mol) in
ethanol (100 mL) was added conc. Sulphuric acid (1 mL) and refluxed for 5 h. The
reaction mixture was concentrated and the solid separated was filtered, washed with water
and recrystallized with ethanol to give (182) as white crystals. (10g, 85 %), mp. 250-252
0C.
2.3.1.2 Preparation of 2-Fluoro-4-methoxybenzohydrazide (183)
A mixture of Ethyl 2-fluoro-4-methoxybenzoate (182) (10 g, 0.051 mol) and
hydrazine hydrate (5.0 mL, 0.12 mol) in ethanol (100 mL) was heated under reflux for 8
h. The reaction mixture was concentrated and left to cool. The solid product obtained was
filtered, washed with water and recrystallized with ethanol to give (183) as white crystals.
(7 g, 89 %) mp. 275-276 0C.
2.3.1.3. General procedure for preparation of 2-(2-fluoro-4 methoxy phenyl)-5-
substituted 1,3,4-oxadiazole 188 (a-m)
A mixture of Acid hydrazide (183) with different aromatic carboxylic acid was
refluxed with phosphorous oxychloride (10 Vol) for 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 188 (a-m) as white crystalline solid.
76
2.4. Characterization
2.4.1. Experimental data
2.4.1.1 2-(3-Bromo-2-methylphenyl)-5-(2-fluoro-4-methoxyphenyl)-1,3,4-oxadiazole
(188a)
Yield 78 %, white solid. (1.5g). IR (KBr, νmax cm-1
) 3097(Ar-H), C=N (1594), C=C
(1560), C-O (1057, stretch of oxadiazole ring), C-F (1093); mass m/z (M +) 363:
1H NMR
(300MHz-DMSO-d6- ppm) 8.07-8.02 (m, 1H), 7.98-7.95 (d, 1H, J = 7.8 Hz), 7.89-7.87
(d, 1H, J = 7.14 Hz), 7.16-7.15 (d, 1H, J = 2.4 Hz), 7.11-7.01 (d, 1H, J = 2.4 Hz), 7.04-
7.00 (m, 1H), 3.8 (s, 3H, -CH3), 2.73 (s, 3H, -OCH3). Anal. Calcd. For C16H12BrFN2O2:
C 52.91 (52.91), H 3.3 (3.29), N 7.71 (7.8).
2.4.1.2 2-(2-Fluoro-4-methoxyphenyl)-5-(2, 3, 4-trifluorophenyl)-1,3,4-oxadiazole (188b)
Yield 90 %, off white solid. (1.6 g); IR (KBr, νmax cm-1
) 3070 (Ar-H), C=N (1585), C=C
(1580), C-O (1040, stretch of oxadiazole ring), C-F (1090); mass m/z (M +) 325:
1H NMR
(400MHz-DMSO-d6- ppm) 8.09-8.04 (t, 1H, J = 8.5), 7.93-7.91 (d, 1H, J = 5.85 Hz),
7.18-7.15 (m, 1H), 6.89-6.88 (d, 1H, J = 3.2 Hz), 6.86-6.77 (m, 1H), 3.9 (s, 3H, -CH3)
Anal. Calcd. For C15H8F4N2O2: C 55.57 (55.58), H 2.49 (2.42), N 8.64 (8.44).
2.4.1.3 2-(2-Fluoro-4-methoxyphenyl)-5-[2-(trifluoromethyl) phenyl]-1,3,4-oxadiazole
(188c)
Yield 81 %, Pale yellow solid. (1.5 g); IR (KBr, νmax cm-1
) 3070 (Ar-H), C=N (1545),
C=C (1560), C-O (1070, stretch of oxadiazole ring), C-F (1050); mass m/z (M +) 339:
1H
NMR (400MHz-DMSO-d6- ppm) 8.39-8.37 (d, 1H, J = 7.8 Hz), 8.33 (s, 1H), 8.15-8.11(t,
1H, J = 8.6 Hz), 8.04-8.02 (d, 1H, J = 7.8 Hz), 7.90-7.886 (t, 1H, J = 8.6 Hz), 7.16-7.12
(dd, 1H, J = 12.1 Hz), 7.04-7.02 (dd, 1H, J = 8.8 Hz), 3.88 (s, 3H). 13
C-NMR (DMSO-d6)
163.8, 163.7, 162.4, 161.9, 161.18, 161.11, 159.42, 130.88, 130.74, 130.71, 130.58,
130.28, 129.9, 128.45, 128.42, 124.43, 122.95, 122.91, 111.81, 111.79, 103.7, 103.64,
77
102.84, 102.6, 56.22. Anal. Calcd. For C16H10F4N2O2: C 56.83 (56.81), H 2.97 (2.98), N
8.27 (8.28).
2.4.1.4 3-[5-(2-Fluoro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl] benzonitrile (188d)
Yield 85 %, pale brown solid. (1.5g); IR (KBr, νmax cm-1
) 3030(Ar C-H), C=N (1615),
C=C (1540), C-O (1060, stretch of oxadiazole ring), C-F (1070); mass m/z (M +) 296:
1H
NMR (400MHz-DMSO-d6- ppm) 8.44-8.39 (m, 2H), 8.11-8.06 (t, 1H, J = 8.3 Hz), 7.87-
7.83 (t, 1H, J = 7.08 Hz), 7.76-7.66 (m, 1H), 6.9-6.79 (m, 2H), 3.91 (s, 3H). 13
C-NMR
(DMSO-d6) 163.97, 162.72, 159.33, 138.72, 136.76, 133.33, 130.95, 127.60, 126.49,
123.39, 112.25, 103.34, 103.02, 56.65, 20.68, 17.19. Anal. Calcd. For C16H10FN3O2: C
65.08 (65.09), H 3.41 (3.48), N 14.23 (14.44).
2.4.1.5 2-(2, 3-Dimethylphenyl)-5-(2-fluoro-4-methoxyphenyl)-1,3,4-oxadiazole (188e)
Yield 92 %, white solid. (1.5g); IR (KBr, KBr, νmax cm-1
) 3098 (Ar C-H), C=N (1621),
C=C (1540), C-O (1060, stretch of oxadiazole ring), C-F (1070); mass m/z (M +) 299:
1H
NMR (400MHz-DMSO-d6- ppm) 8.10-8.04 (t, 1H, J = 11.36 Hz), 7.82 -7.80 (d, 1H J =
10.12 Hz), 7.35-7.33 (d, 2H, J = 7.29 Hz), 7.27-7.24 (d, 1H, J = 6.42 Hz), 6.88-6.76 (m, 2
H), 3.89 (s, 3H, OMe), 2.65 (s, 3H, -CH3), 2.65 (s, 3H, -CH3) Anal. Calcd. For
C17H15FN2O2: C 68.45 (68.55), H 5.07 (5.09), N 9.39(9.5)
2.4.1.6 2-Chloro-5- [5-(2-fluoro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl] pyridine (188f)
Yield 90 %, white solid. (1.5 g); IR (KBr, νmax cm-1
) 3062 (Ar C-H), C=N
(1626), C=C (1591), C-O (1024, stretch of oxadiazole ring), C-F (1040), C-Cl (821);
mass m/z (M +) 306:
1H NMR (400MHz-DMSO-d6- ppm) 9.09 (s, 1H), 8.50-8.48 (d, 1H,
J = 8.64 Hz), 8.13-8.08 (t, 1H, J = 8.8 Hz) 7.80-7.78 (d, 1H, J = 8.72 Hz), 7.16-7.13 (d,
1H, J = 13.2Hz), 7.05-7.03 (d, 1H, J = 9.16 Hz), 3.88 (s, 3H, -OCH3). 13
C NMR
(400MHz-DMSO-d6- ppm) 163.8, 163.7, 161.9, 161.1, 161.0, 159.4, 152.9, 147.7, 137.5,
78
130.69, 125.1, 119.4, 118.8, 103.6, 102.8, 102.6, 56.22. Anal. Calcd. For C14H9ClFN3O2:
C 55.01(55.9), H 2.97 (3.01), N 13.75 (13).
2.4.1.7 2-(2, 3-Difluoro-6-nitrophenyl)-5-(2-fluoro-4-methoxyphenyl)-1,3,4-oxadiazole
(188g)
Yield 89 %, white solid. (1.7g); IR (KBr, νmax cm-1
) 3098 (Ar C-H), C=N (1621),
C=C (1535), C-O (1014, stretch of oxadiazole ring), C-F (1070); mass m/z (M +) 352:
1H
NMR (400 MHz-DMSO-d6- ppm) 8.63-8.59 (dd, 1H, J1 = 10.0 Hz, J2 = 7.2 Hz), 8.38-
8.33 (dd, 1H, J1 = 10 Hz, J2 = 7.60 Hz), 8.03-7.99 (t, 1H, J = 10.08 Hz) 7.18-7.14 (dd, 1H
J1 = 12.8 Hz, J2 = 2.4 Hz), 7.06-7.04 (d, 1H, J = 8.8 Hz), 3.88 (s, 3H, -OCH3). 13
C NMR
(400MHz-DMSO-d6- ppm):164.12, 164.01, 161.97, 161.75, 161.69, 159.42, 158.67,
130.57, 130.54, 120.68, 120.47, 116.17, 115.94, 112.00, 111.97, 103.14, 103.02, 102.93,
102.69, 56.25. Anal. Calcd. For C15H8F3N3O4: C 51.29 (51.3), H 2.30 (2.4), N 11.96
(11.3).
2.4.1.8 2-(4-Fluorophenyl)-5-(2-fluoro-4-methoxyphenyl)-1,3,4 oxadiazole (188h)
Yield 90 %, white solid. (1.4 g); IR KBr, νmax cm-1
) 3062 (Ar C-H), C=N (1626),
C=C (1591), C-O (1030, stretch of oxadiazole ring), C-F (1060); mass m/z (M +) 289:
1H
NMR (400MHz-DMSO-d6- ppm) 8.16-8.07 (m, 3H), 7.50-7.44 (m, 2H), 7.16-7.15 (d,
1H, J = 2.4 Hz), 7.04-7.03 (d, 1H, J = 2.4Hz), 3.88 (s, 3H, -OCH3). Anal. Calcd. For
C15H10F2N2O2: C 62.50 (61.3), H 3.50 (3.48), N 13.18 (13.2).
2.4.1.9 2-(2-Bromo-5-chlorophenyl)-5-(2-fluoro-4-methoxyphenyl)-1,3,4-oxadiazole
(188i)
Yield 90 %, off white solid. (1.9 g); IR (KBr, νmax cm-1
) 3020(Ar C-H), C=N
(1625), C=C (1540), C-O (1040, stretch of oxadiazole ring), C-F (1065); mass m/z (M +)
382: 1
H NMR (400MHz-DMSO-d6- ppm) 8.09 (s, 1H), 8.08-8.066 (d, 1H, J = 8.23 Hz),
7.94-7.91(d, 1H, J = 8.78 Hz) 7.67-7.66 (dd, 1H, J1 = 12.52, J2= 6.5 Hz), 7.16-7.12 (m,
79
1H), 7.02-7.01 (m, 1H), 3.88 (s, 3H, -CH3) Anal. Calcd. For C15H9BrClFN2O5: C 46.97
(47), H 2.36 (2.5), N 7.30 (7.2).
2.4.1.10 3-[5-(2-Fluoro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl] quinoline (188j)
Yield 86 %, Pale yellow solid. (1.5g); mp; IR (KBr, νmax cm-1
) 3015 (Ar C-H),
C=N (1622), C=C (1588), C-O (1482, stretch of oxadiazole ring), C-F (1135); mass m/z
(M +) 322:
1H NMR (400MHz-DMSO-d6- ppm) 9.50 (s, 1H), 9.10 (s, 1H), 8.24-8.23 (d,
1H, J = 7.6 Hz), 8.15-8.11 (m, 2H), 7.93-7.89 (t, 1H, J = 6.9 Hz), 7.76 -7.74 (t, 1H, J =
8.04 Hz), 7.17-7.13 (d, 1H, J = 12.9 Hz), 7.06-7.04 ( t, 1H, J = 8.8 Hz), 3.89 (s, 3H, -
CH3). 13
C NMR (400MHz-DMSO-d6- ppm). 163.82, 163.7, 162.1, 161.9, 161.08, 161.02,
159.42, 148.3, 147.2, 134.6, 131.7, 130.6, 130.63, 129.18, 128.9, 127.98, 126.75, 111.8,
103.80, 103.68, 102.8, 102.63, 56.22. Anal. Calcd. For C18H12FN3O2: C 67.29(67.5), H
3.76 (3.6), N 13.08 (13.2).
2.4.1.11 2-(2-Fluoro-4-methoxyphenyl)-5-(5-methylisoxazol-3-yl)-1,3,4-oxadiazole
(188k)
Yield 80 %, off white solid. (1.2g); IR (KBr, νmax cm-1
) cm –1
3090(Ar C-H), C=N
(1655), C=C (1550), C-O (1090, stretch of oxadiazole ring), C-F (1050), C=O (1643);
mass m/z (M +) 275:
1H NMR (400MHz-DMSO-d6- ppm) 9.18 (s, 1H), 8.04-7.99 (t, 1H, J
= 11.52 Hz), 7.15-7.11 (d, 1H, J = 17.36 Hz) 7.03-7.011 (d, 1H, J = 11.52 Hz), 3.87 (s,
3H, OMe), 2.80 (s, 3H, isoxazole ring –CH3) Anal. Calcd. For C13H10FN3O3: C
55.18(54), H 3.09 (3.01), N 16.09(16).
2.4.1.12 2-(2-Fluoro-4-methoxyphenyl)-5-(3-fluoro-4-nitrophenyl)-1,3,4-oxadiazole
(188l)
Yield 99 %, white solid. (1.8g); IR (KBr, νmax cm-1
) cm –1
3070(Ar C-H), C=N
(1697), C=C (1570), C-O (1054, stretch of oxadiazole ring), C-F (1084); mass m/z (M +)
334: 1
H NMR (400MHz-DMSO-d6- ppm) 8.41-8.37 (t, 1H, J = 8.00 Hz), 8.28-8.25 (d,
80
1H, J = 11.2 Hz), 8.16-8.11 (m, 2H) 7.17-7.14 (d, 1H, J = 12.4 Hz), 7.06-7.04 (d, 1H, J
= 8.8Hz) 3.8 (s, 3H). 13
C NMR (400MHz-DMSO-d6- ppm). 164.04, 163.93, 162.08,
161.77, 161.71, 161.36, 159.53, 156.20, 153.59, 138.46, 138.38, 130.82, 130.79, 129.97,
129.88, 127.76, 123.21, 123.17, 116.61, 116.38, 111.84, 103.51, 103.39, 102.88, 102.64,
56.25. Anal. Calcd. For C15H9F2N3O4: C 54.06 (54), H 2.72 (2.8), N 11.4 (11.3).
2.4.1.13 2-(3, 5-Difluorophenyl)-5-(2-fluoro-4-methoxyphenyl)-1,3,4-oxadiazole (188m).
Yield 87 %, off white solid. (1.4 g); IR (KBr, νmax cm-1
) cm –1
3015, 2949 (Ar C-H), C=N
(1622), C=C (1588), C-O (1482, stretch of oxadiazole ring), C-F (1083); mass m/z (M +)
307: 1
H NMR (400MHz-DMSO-d6- ppm) 8.10-8.04 (t, 1H, J = 11.24 Hz), 7.69-7.66 (m,
1H), 7.04-6.98 (m, 1H), 6.89-6.78 (m, 2H), 3.88 (s, 3H). Anal. Calcd. For C15H9F3N2O2:
C 57.06 (57), H 2.75 (2.8), N 9.55(9.4).
2.4.2. Spectral data
Fig. 2.11:
1H NMR spectrum of 2-(2-fluoro-4-methoxyphenyl)-5-[2-(trifluoromethyl)
phenyl]-1,3,4-oxadiazole (188c)
O
N N
F
FF
O
F
188c
81
Fig. 2.12: 13
C NMR spectrum of 2-(2-fluoro-4-methoxyphenyl)-5-[2-(trifluoromethyl)
phenyl]-1,3,4-oxadiazole (188c)
O
N N
F
FF
O
F
188c
82
Fig. 2.13:LCMS spectrum of 2-(2-fluoro-4-methoxyphenyl)-5-[2-(trifluoromethyl)
phenyl]-1,3,4-oxadiazole (188c)
O
N N
F
FF
O
F
188c Ms:338
83
Fig. 2.14:1
H NMR spectrum of 2-chloro-5- [5-(2-fluoro-4-methoxyphenyl)-1,3,4-
oxadiazol-2-yl] pyridine (188f)
Fig. 2.15: 13
C NMR spectrum of 2-chloro-5- [5-(2-fluoro-4-methoxyphenyl)-1,3,4-
oxadiazol-2-yl] pyridine (188f)
N
O
N N
O
F
Cl
188f
N
O
N N
O
F
Cl
188f
84
Fig. 2.16:
1H NMR spectrum of 3-[5-(2-fluoro-4-methoxyphenyl)-1,3,4-
oxadiazol-2-yl] quinoline (188j)
Fig. 2.17:13
C NMR spectrum of 3-[5-(2-fluoro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]
quinoline (188j)
N
O
N N
O
F
188j
N
O
N N
O
F
188j
85
Fig. 2.18: LC-MS spectrum of 3-[5-(2-fluoro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]
quinoline (188j)
N
O
N N
O
F
188jMass:321
86
2.5 Biological activity
2.5.1 Antimicrobial studies, result and discussion:
All the newly synthesized Oxadiazoles were screened for their antibacterial and
antifungal activity. For antibacterial studies microorganism employed were
staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginas.
For antifungal Candida albicans was used as organism. Both microbial studies were
assessed by MIC by serial dilution method.40
For this compound whose MIC has to be
determined is dissolved in serially diluted DMF. Then standard drop of culture prepared
for the assay is added to each of the dilutions and incubated for 16-18h at 37 0C. MIC is
the highest dilution of the compound, which shows clear fluid with no development of
turbidity.
Table-2.2: Antibacterial and antifungal data for the newly synthesized 1,3,4 oxadiazoles
188 (a-m)
Antibacterial activity data in MIC (mg/mL
Antifung
al activity
data in
MIC
(mg/mL)
Compound
No.
S. aureus
B. subtilis
E.coli
P.aerugin
osa
C.albicans
188a 6 6 3 3 6
188b 6 6 3 3 6
188c 6 6 6 6 6
188d 6 6 6 6 6
188e 6 6 6 12.5 6
188f 12.5 6 6 12.5 6
188g 6 6 12.5 6 6
188h 6 6 12.5 6 6
188i 6 6 6 6 3
87
188j 6 6 6 6 6
188 k 12.5 12.5 6 6 3
188l 6 6 6 6 6
188m 6 6 6 6 6
Furacin
(Std)
12.5 12.5 6 12.5 Flucanazol
(std)
DMF
(Control)
- - - -
-
2.6 Conclusions
All the newly synthesized compounds were screened for their antibacterial and
antifungal activity. Among the screened samples, compounds (188a) and (188b) showed
excellent antibacterial activity against E. coli and P. aeruginosa even at low
concentration of 3 μg/mL. Compound (188a) has 3-bromo-2-methyl phenyl group and
(188b) has 2, 3, 4-trifluoro phenyl group as substituent.
Remaining compounds have showed significant antibacterial activity. Antifungal
screening was carried out on C. albicans. Among the tested compounds, (188i) and
(188k) showed highest inhibition at 3 μg/mL concentration (188i) has 2-bromo-5-
chlorophenyl group and (188k) has 5-methylisoxazole groups respectively.
88
N
O
NF
O
Br
O
N N
F
FF
O
F
188a 188b
O
N NF
O
Cl
Br
188i
O
N N
ONO
F
188k
Fig. 2.19: Most potent compounds among the newly synthesized compounds
It can be concluded that, introduction of fluorine on oxadiazole ring has enhanced
the pharmacological effect and hence they are ideally suited for further modifications to
obtain more efficient antimicrobial compounds.
89
2.7 References
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12 Katritzky, A. R., Vedensky, V., Cai, X., Rogovoy, B., Steel, P. J. “Synthesis of
5-(2-arylazenyl)-1,2,4-triazoles and 2-amino-5-aryl-1,3,4-oxadiazoles”
ARKIVOC, 2002, 6, 82–90.
13 Sahin, G., Palaska, E., Ekizoglu, M., Ozalp, M. “Synthesis and antimicrobial
activity of some 1,3,4-oxadiazole derivatives. Il Farmaco 2002, 57, 539–542.
14 Sudha, B. S, Shashikanth, S, Khanum, S. A, Sriharsha, S. N. “Synthesis and
Pharmacological Screening of 5‐ (4‐Aroyl)‐aryloxy
methyl‐2‐thio‐1,3,4‐oxadiazole” Ind. J. Pharm. Sci. 2003; 65 (5), 465‐ 470.
15 Ouyang, X., Piatnitski, E.L., Pattaropong, V., Chen, X., He, H.Y., Kiselyov,
A.S., Velankar, A., Kawakami, J., Labelle, M., Smith, L., Lohman, J., Lee, S. P.,
Malikzay, A., Fleming, J., Gerlak, J., Wang, Y., Rosler, R. L., Zhou, K.,
Mitelaman, S., Camara, M., Surguladze, D., Doody, J. F., Tuma, M. C.
“Oxadiazole derivatives as a novel class of antimitotic agents: Synthesis,
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16 Rivera, N. R., Balsells, J., Hansen, K. B. “Synthesis of 2-amino-5-substituted-
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