Electrosynthesis and screening of novel 1,3,4-oxadiazoles as potent and selective antifungal agents

Article abstract of DOI:10.1039/c3ra21904f

The electrochemical oxidation of aldehyde-N-aroylhydrazone has been studied in the presence of NaClO₄ as supporting electrolyte in MeOH solution using cyclic voltammetry and controlled potential electrolysis. The results indicate that intramolecular cyclization of aldehyde-N-aroylhydrazone has been successfully performed at a platinum electrode in an undivided cell with good yields of the corresponding 1,3,4-oxadiazoles at ambient conditions. The reaction products were characterized by spectroscopic methods and a mechanism was deduced from voltammetry studies. The antifungal activity of the synthesized compounds was evaluated on Fusarium oxysporum, Alternaria solani, Candida albicans and Aspergillus niger. The results revealed that all the synthesized compounds have significant antifungal activity against the tested fungi. Among the synthesized derivatives 7b, 7d, 7g, 7h, 7i, 7j and 7r were found to be the most effective antifungal compounds. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra21904f

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Electrosynthesis and screening of novel 1,3,4-
oxadiazoles as potent and selective antifungal agents
Cite this: RSC Advances, 2013, 3, 4237
Sushma Singh,a Laxmi Kant Sharma,a Apoorv Saraswat,a Ibadur R. Siddiqui,a Harbans
K. Kehrib and Rana K. Pal Singh*a
The electrochemical oxidation of aldehyde-N-aroylhydrazone has been studied in the presence of NaClO4
as supporting electrolyte in MeOH solution using cyclic voltammetry and controlled potential electrolysis.
The results indicate that intramolecular cyclization of aldehyde-N-aroylhydrazone has been successfully
performed at a platinum electrode in an undivided cell with good yields of the corresponding 1,3,4-
oxadiazoles at ambient conditions. The reaction products were characterized by spectroscopic methods
and a mechanism was deduced from voltammetry studies. The antifungal activity of the synthesized
compounds was evaluated on Fusarium oxysporum, Alternaria solani, Candida albicans and Aspergillus
niger. The results revealed that all the synthesized compounds have significant antifungal activity against
the tested fungi. Among the synthesized derivatives 7b, 7d, 7g, 7h, 7i, 7j and 7r were found to be the
most effective antifungal compounds.
Received 22nd August 2012,
Accepted 10th January 2013
DOI: 10.1039/c3ra21904f
www.rsc.org/advances
It is not surprising that a number of synthetic methods for
the preparation of 1,3,4-oxadiazoles have been developed over
Introduction
the years15 and among these, the most common employ
cyclodehydration of semicarbazides or cyclodesulfurization of
thiosemicarbazides as two main strategies. The cyclodehydra-
N-Containing heterocycles, especially five-membered rings, are
of great interest as they are found in natural products and
used frequently in biologically active compounds.1 Amongst
these heterocycles, the 1,3,4-oxadiazole scaffold is established
as a member of the privileged structural class particularly from
a medicinal point of view. Due to their metabolic profile,
improved pharmacokinetics and in vivo performance they are
recognized as biologically important pharmacophores.2–5
Their biological activities encompass analgesic, anti-inflam-
matory, anticonvulsive, diuretic, antineoplastic, antimitotic,
antiemetic and muscle relaxant properties.6 Some display
insecticidal7 and herbicidal8 properties as well. Besides, 2,5-
diaryl-1,3,4-oxadiazoles exhibit platelet aggregation inhibi-
tion,9 while derivatives of 2-hydroxyphenyl-1,3,4-oxadiazole
possess hypnotic and sedative properties.10 The wide spectrum
of biological importance has led to the emergence of a number
of marketed medicines bearing a 1,3,4-oxadiazole core (Fig. 1).
Instances of medicinally important compounds containing a
1,3,4-oxadiazole core are MK-0633p-toluenesulfonate,4 nesapi-
dil,8,5 ABT-751-oxadiazole,11 and furamizole12,13 (Fig. 1).
Apart from their latent potential in medicinal chemistry
they also find applications in the field of material science and
have received much attention particularly in the field of
organic electronics because of their good electron-transporting
and hole-blocking abilities.14
tion processes are mediated typically by POCl3,16–19 SOCl2,20
21–23
conc. H2SO4
or tosyl chloride.24 Alternatively, phospho-
nium salts25–28 and Burgess-type reagents29,30 are also found
to be equally effective in promoting dehydrative cyclization. In
the case of thiosemicarbazides as oxadiazole precursors,
thiophilic reagents such as salts of mercury31,32 and lead3
have been used extensively to accomplish the desired
desulfurative cyclization. Alternatively, activation of sulfur
aElectrochemical Laboratory of Green Synthesis, Department of Chemistry, University
of Allahabad, Allahabad-211 002, India
bSadasivan Mycopathology Laboratory, Department of Botany, University of
Fig. 1 Pharmaceuticals containing the 1,3,4-oxadiazole motif.
RSC Adv., 2013, 3, 4237–4245 | 4237
Allahabad, Allahabad-211 002, India
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using iodine in the presence of strong base (NaOH)33–35 or
tosyl chloride in combination with triethylamine36 or toxic
pyridine,2 have been performed under refluxing conditions.
Coupling reagents such as EDC37,38 and DCC39–41 as well as
alkylating agents such as methyl iodide42,43 and ethyl
bromoacetate44 have been exploited to afford various oxadia-
zoles. The 1,3,4-oxadiazoles have also been accomplished
through a multicomponent reaction involving a Ugi-4CR/aza-
Wittig sequence.45
Although numerous procedures are enumerated in litera-
ture for the synthesis of oxadiazoles, most of them suffer a
major setback from the standpoint of environmental concerns
as they involve direct or indirect use of strong alkaline or
acidic conditions, highly toxic and corrosive reagents and
emission of odoriferous thiol as a by-product which are
undesirable in pharmaceuticals. Besides expensive reagents
and catalysts, elevated temperatures and longer reaction times
and hygroscopic/moisture sensitive reagents are also some of
the associated drawbacks. In addition, a number of methods
seem to have limited substrate scope, resulting in the
stoichiometric formation of intractable by-products which
impedes their generality. Keeping in view the properties of
1,3,4-oxadiazoles, a more sustainable synthesis is of prime
importance.
In recent years, electrochemical methods provide a better
environment for subsequent reactions involving the electro-
chemically generated reactive species.46 Electrochemical reac-
tions offer a clean route to the formation of anion and cation
radical species from neutral organic molecules. Electrons can
be added or removed from the substrates under mild
conditions without using oxidizing or reducing reagents which
might complicate the reaction sequence.47 A major advantage
of electrochemical methods is the reduced formation of side
products.
Scheme 1 Synthetic protocol of 2,5-disubstituted-1,3,4-oxadiazoles 7.
oxadiazoles via their condensation reaction with aroylhydra-
zones and successive intramolecular cyclization of the result-
ing aldehyde-N-aroylhydrazone intermediates (Scheme 1).
Here, aroylhydrazones 1a–z, were reacted with arylalde-
hydes 2a–z to give rise to aldehyde-N-aroylhydrazones 3a–z,
which precipitated by mixing the aroylhydrazones 1a–z and
corresponding ArCHO 2a–z in hot ethanol.53 Successively,
NaClO4 mediated intramolecular electrooxidative cyclization
of 3a–z to provide was investigated on the basis of solvent/
supporting electrolyte screening carried out for 3a (Table 1).
In general, the efficiency of electrooxidation process can be
enhanced by increasing the concentration of the intermediate
and using a suitable solvent and supporting electrolyte. After
screening several solvents/supporting electrolyte, we found
that dry CH3OH/NaClO4 promoted the intramolecular cycliza-
tion of aldehyde-N-aroylhydrazone to the corresponding 1,3,4-
oxadiazole in excellent yield with short reaction time (Table 1,
entry 10). It was found that DMF/LiClO4, MeCN/NaClO4,
MeCN/LiClO4, AcOH/NaClO4, AcOH/LiClO4, MeOH/LiClO4
gave compound 7a in moderate yield (40–60%) (Table 1,
entries 2, 4, 5, 7, 8 and 11) while DMF/Bu4BrN, MeCN/Bu4BrN,
AcOH/Bu4BrN, MeOH/Bu4BrN provided compound 7a in lower
yields (Table 1, entries 3, 6, 9 and 12).
Substrate 3a was chosen as a model substrate, in order to
test the effectiveness of the process. We found that placing 3a
in the presence of NaClO4 as a supporting electrolyte in pure
Inspired by the above facts and in continuation of an
ongoing research program in the field of synthesis and
determination of the antifungal activity of medicinally
important compounds,48 the synthesis and antifungal evalua-
tion of oxadiazole derivatives are reported herein.
Table 1 Optimization of reaction conditions for the construction of 2,5-
disubstituted-1,3,4-oxadiazolesa
7
Results and discussion
In the course of our studies towards the synthesis of 1,3,4-
oxadiazoles, we have reported the highly effective electro-
chemical technique for the oxidative conversion of semicarba-
zones and arylthiosemicarbazones to several useful
heterocyclic compounds.49–52 Among the variety of available
methods for the synthesis of 1,3,4-oxadiazoles, we focused on
the electrooxidative cyclization of aldehyde-N-aroylhydrazones.
Herein aiming at the optimization of the synthesis of
biologically active chemical entities, our interest is, in
establishing a convenient, practical and general methodology
for preparing a variety of 2,5-disubstituted-1,3,4-oxadiazoles.
The commercial availability of a wide range of aldehydes
prompted us to investigate the synthesis of 2,5-diaryl-1,3,4-
Entry
Solvent
Electrolyte
tb/min
Yieldc (%)
1
2
3
4
5
6
7
8
DMF
DMF
DMF
NaClO4
LiClO4
Bu4BrN
NaClO4
LiClO4
Bu4BrN
NaClO4
LiClO4
Bu4BrN
NaClO4
LiClO4
Bu4BrN
395
300
350
285
200
325
270
210
330
195
245
375
30
41
35
43
57
38
46
56
37
79
50
32
MeCN
MeCN
MeCN
AcOH
AcOH
AcOH
MeOH
MeOH
MeOH
9
10
11
12
a
b
c
Reactions were monitored by TLC. Reaction time at r.t. Isolated
yield.
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MeOH at room temperature resulted in the formation of
corresponding 2,5-diaryl-1,3,4-oxadiazole 7a with complete
consumption of the starting material in a few hours. No
significant by-products were detected by 1H and 13C NMR
spectroscopy.
Having these preliminary observations in hand, we synthe-
sized a series of aldehyde-N-aroylhydrazones 3a–z in order to
test the scope of their oxidative cyclization. These substrates
are easily accessible in high yields and purity from the
corresponding aroylhydrazides and aldehydes. We then sub-
jected this series of aldehyde-N-aroylhydrazones 3a–z to the
optimized reaction conditions.
All the reactions went to completion within 3–4 h. 1H NMR
analysis of the reaction mixture clearly indicated the formation
of corresponding 2,5-diaryl-1,3,4-oxadiazoles 7a–z as the major
product with high yields and excellent purity.
Fig. 2 Cyclic voltammogram of a 0.1 M solution of aldehyde-N-aroylhydrazones
3a in 0.1 M (NaClO4–MeOH) at Pt-electrode. Scan rate: 0.01 V s21, counter
electrode; Pt-mesh, reference electrode; saturated calomel electrode (SCE), t =
25 ¡ 1 uC.
gave low yield of 1,3,4-oxadiazole, as in this reaction the
acetate ion formed from ionization, reacts with the radical
cation of species which simultaneously suppresses the
intramolecular cyclization of aldehyde-N-aroylhydrazones,
while in our reaction we have used sodium perchlorate as
supporting electrolyte which is inert and gives good yield of
product without formation of any by-product at the platinum
electrode.
In the process of our study regarding variation of the nature
of aldehyde moiety participating in the formation of oxadia-
zoles 7 we have observed that the nature of R1/R2 groups on
aldehyde-N-aroylhydrazone 3 slightly affected the reaction
rates and yields. Electron-donating groups (Table 2, entries
5, 9, 22, 16, 10, 23, 20, 1, 4, 6, 14, 18, 7, 11, 3 and 17)
substituted compounds showed slightly higher reactivity with
higher yields than electron withdrawing groups (Table 2,
entries 26, 21, 2, 25, 8, 13, 15, 12, 19 and 24).
The compounds were screened for their fungicidal activity
in comparison to the control antifungal drugs Griseofulvin
and Dithane M-45. Results of the antifungal screening data
revealed that most of the synthesized compounds showed
significant inhibition of mycelia growth of all the tested fungi
at 1000 ppm but their activity decreased considerably at lower
concentration 100 and 10 ppm (Table 3). Of the screened
compounds, 7b, 7d, 7g, 7h, 7i, 7j and 7r exhibited highest
The structures of isolated products 7a–z were deduced by
1
means of IR, H NMR, 13C NMR spectroscopy, mass spectro-
metry and elemental analysis. The obtained spectral data were
in accordance with the proposed structures.
The IR spectrum of 7a showed the characteristic absorption
bands for 1640 (CLN), 1472 (aromatic C–C), 3030 (aromatic C–
H), 3015 (aliphatic C–H). In addition, detection of two new
absorption bands at 1090 cm21 (C–O–C) and 1245 cm21 (–N–
NLC) indicating the presence of a cyclic –C–O–C linkage and
formation of –N–NLC respectively, evidenced the formation of
a 1,3,4-oxadiazole ring. The 1H NMR spectrum of 7a consisted
of a singlet for the methyl group (d 2.40 ppm) and aromatic
protons were observed between d 7.32 and 8.01 ppm (see
Experimental section). The 13C NMR spectrum of 7a showed
two distinct resonance at d = 21.1 ppm for the methyl group
and d = 163.9 ppm arising from the oxadiazole ring carbon
atom as well as four signals for aryl substituents consistent
with the proposed structure. Results of elemental analyses
were found in good agreement with the calculated values.
Cyclic voltammetry of substrate 3a were recorded using
MeOH as solvent and NaClO4 as supporting electrolyte at
ambient temperature. The experiments were carried out using
a three-electrode compartment cell. Both working and counter
electrodes were platinum plates. The potential of the working
electrode was measured vs. saturated calomel electrode (SCE)
as reference electrode at scan rate of 0.01 V s21
.
As shown by the results of the voltammetric experiments
(Fig. 2), the methanolic solution of 3a containing NaClO4 was
oxidized at the platinum electrode at a potential at 0.90 V and
exhibited no reduction peak potential (even when swept to 2.0
V vs. SCE). The results suggest that the electrooxidation
involves a transformation of 3a to 7a within a two-electron
oxidation process.
In the proposed mechanism (Scheme 2), aldehyde-
N-aroylhydrazones 3, undergo a two-electron oxidation fol-
lowed by deprotonation and intramolecular cyclization and
results in the formation of oxadiazoles 7 in 50–95% yields.
Chiba and Okimoto54 reported the electrolysis of
N-acylhydrazone in methanol as organic solvent and sodium
acetate as a supporting electrolyte at carbon electrode that
Scheme 2 Proposed mechanism for the synthesis of 2,5-disubstituted-1,3,4-
oxadiazoles 7.
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Table 2 Electroorganic synthesis of 2,5-disubstituted-1,3,4-oxadiazoles 7a–z via intramolecular cyclization of aldehyde-N-aroylhydrazones 3a–z
Anode
potentialc/V
Yieldd
(%)
Entry
1
Conversiona
R1
R2
tb/min
(vs. SCE)
Current/A
0.61
Producte 7
3a A 7a
p-MeC6H4
p-MeC6H4
195
2.0
2.2
2.1
79
57
67
2
3
3b A 7b
3c A 7c
p-ClC6H4
Ph
Ph
215
195
0.59
0.62
Ph
4
5
6
7
3d A 7d
3e A 7e
3f A 7f
3g A 7g
p-MeOC6H4
2-Furyl
Ph
180
180
195
205
1.8
1.6
1.8
1.9
0.58
0.57
0.53
0.60
78
95
76
70
2-Furyl
Ph
p-MeC6H4
p-HOC6H4
Ph
8
9
3h A 7h
3i A 7i
p-ClC6H4
p-ClC6H4
215
185
2.1
1.6
0.55
0.49
55
94
2-Furyl
p-MeOC6H4
10
11
3j A 7j
p-MeOC6H4
o-HOC6H4
p-MeOC6H4
o-HOC6H4
195
210
1.7
1.9
0.63
0.68
84
70
3k A 7k
12
3l A 7l
m-NO2C6H4
m-NO2C6H4
225
2.1
0.56
50
13
14
15
3m A 7m
3n A 7n
3o A 7o
p-FC6H4
2-Furyl
p-FC6H4
3—Pyridyl
Ph
220
195
225
2.2
1.8
2.2
0.59
0.78
0.54
53
74
52
m-NO2C6H4
16
3p A 7p
m,p-(MeO)2C6H3
m,p-(MeO)2C6H3
195
1.9
0.64
87
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Table 2 (Continued)
Anode
potentialc/V
(vs. SCE)
Yieldd
(%)
Entry
17
Conversiona
R1
R2
tb/min
Current/A
0.67
Producte 7
3q A 7q
2-Naphthyl
Ph
185
2.1
65
18
19
3r A 7r
3s A 7s
p-HOC6H4
p-HOC6H4
230
235
1.9
2.2
0.52
0.58
72
49
Ph
3-Pyridyl
20
21
3t A 7t
p-NH2C6H4
m-BrC6H4
p-NH2C6H4
m-BrC6H4
190
215
1.8
2.1
0.48
0.54
81
60
3u A 7u
22
23
3v A 7v
2-Furyl
Ph
190
200
1.7
1.8
0.62
0.57
90
84
3w A 7w
o-MeOC6H4
o-MeOC6H4
24
25
3x A 7x
3y A 7y
c-C6H11
Ph
Ph
235
220
2.2
2.1
0.69
0.71
47
57
o-ClC6H4
26
3z A 7z
2-Naphthyl
p-BrC6H4
210
1.9
0.65
61
a
b
c
d
e
Prepared according to Scheme 1. Reaction time at r.t. Applied potential of the substrates. Yield of the isolated product. Products were
characterized by spectral (IR, 1H NMR, 13C NMR and EIMS) and elemental data.
antifungal activity against all fungal strains, while compounds
7k, 7l, 7m, 7o, 7p, 7w, 7y and 7z showed moderate (70–89%)
Experimental
Cyclic voltammetry measurements were performed using a
Versastat 3-200 (USA) with a traditional three-electrode system.
All experiments were carried out in a conventional electro-
chemical cell, the electrode system contained platinum plates
antifungal activity. Among all synthesized derivatives, com-
pound 7x was found to be least active compound against the
fungal strains. From these results, it could be generalized that
p-chloro, p-hydroxy and p-methoxy substituted oxadiazole
(flattened sheets of dimension 1.0 cm x 1.0 cm) as working as
derivatives 7b, 7d, 7g, 7h, 7i, 7j and 7r showed higher
well as counter electrode and saturated calomel electrode
antifungal activity than the other analogues. It was also
(SCE) as reference electrode.
observed that the derivatives having chloro, hydroxy and
methoxy substituents at ortho or meta positions were not as
potent as the derivatives having the same substituent at para
Melting points were obtained using a capillary melting
point apparatus (Mel-Temp1) and are uncorrected. IR spectra
were registered with a Shimadzu 8201 PC spectrometer in KBr
position. Thus, from the obtained results it was found that
pellets. 1H and 13C NMR spectra were recorded with a DRX 400
nature and position of the substituent had marked effects on
(400 MHz) spectrometer in CDCl3. Chemical shifts values are
antifungal activity.
relative to Me4Si. Mass spectra were obtained directly with a
Shimadzu GCMS-QP5050A (EI) spectrometer. Elemental ana-
lyses were performed with a Carlo Erba CHNS-OEA 1108
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solution of substrate 3a (10 mmol) in dry MeOH (80 mL)
containing NaClO4 (5 mmol) as a supporting electrolyte in an
undivided cell equipped with a magnetic stirrer at ambient
temperature indicated in Table 2. The reference electrode was
kept in close proximity to the working electrode to minimize
the ohmic drop. The progress of electrolysis was followed by
recording periodically the decreases in current with time.
When the reaction was completed as monitored by TLC, the
cell was disconnected from the circuit and the solvent was
evaporated in vacuum. The residue was shaken with dry
diethyl ether and water (1 : 1) and the supporting electrolyte
was filtered off. The ethereal layer was evaporated in turn, the
obtained residue was purified using EtOH and recrystallized
from a small amount of EtOH. The structures of the products
Table 3 Antifungal screening results of compounds 7a–z
Average inhibition after 96 h (%)
F. oxisporium A. solani
C. albicans A. niger
ppm
1000 100 10 1000 100 10 1000 100 10 1000 100 10
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
7t
7u
7v
5w
7x
65 42 20 64 43 19 66 42 18 65 42 19
99 77 56 99 76 55 99 76 55 98 77 54
62 40 18 63 41 19 63 40 17 61 41 18
92 74 54 92 73 53 93 75 54 91 74 53
51 26 11 52 25 12 50 27 10 52 26 10
64 41 18 63 40 17 64 42 17 65 41 16
96 74 53 96 73 52 97 74 53 96 73 51
100 78 57 100 79 56 100 77 56 99 78 55
91 71 50 92 72 51 91 70 50 90 71 49
94 73 53 94 74 54 95 72 52 93 73 52
73 51 23 72 50 22 71 51 22 71 50 21
74 52 24 75 51 25 73 53 24 74 52 23
78 56 27 77 55 26 79 56 27 77 54 26
50 23 10 50 24 11 51 22 09 49 21 10
71 49 21 72 48 22 72 48 20 70 47 20
80 60 41 82 61 41 81 59 40 80 59 40
59 28 12 59 27 11 60 28 12 58 27 10
97 75 54 98 76 53 96 75 53 96 74 52
59 33 15 58 34 16 59 32 15 57 33 14
67 46 19 66 45 19 67 47 19 65 46 18
69 48 21 70 47 20 69 48 21 68 46 20
58 32 13 58 33 12 57 33 12 56 32 13
71 50 22 70 51 23 72 50 22 69 49 21
42 21 09 42 22 08 41 21 10 41 20 07
76 54 25 75 55 25 76 53 23 74 54 22
85 63 43 85 64 42 86 65 41 84 63 42
100 84 65 100 86 67 100 85 68 100 84 64
1
7a–z were confirmed by comparison of their mp, IR, H NMR,
13C NMR, mass spectroscopy and elemental data with
literature values.57–66
2,5-Bis(4-methylphenyl)-1,3,4-oxadiazole (7a)
Mp 175–177 uC (lit.57 175 uC). IR (KBr): nmax/cm21 1070, 1619,
1468, 3030, 3015, 980, 895, 745. dH (400 MHz, CDCl3) 2.40 (s,
6H), 7.32 (d, 4H, J = 8.3 Hz), 8.01 (d, 4H, J = 8.3 Hz). dC (100
MHz, CDCl3) 21.1, 121.2, 126.7, 129.6, 142.0, 164.4. EIMS m/z
(%): 250 [M+]. Anal. Calc. for C16H14N2O: C, 76.78; H, 5.64; N,
11.19. Found: C, 76.90; H, 5.49; N, 11.30%.
7y
7z
2-(4-Chlorophenyl)-5-phenyl-1,3,4-oxadiazole (7b)
Grisefulvin
Mp 217–219 uC (lit.58 216–218 uC). IR (KBr): nmax/cm21 1065,
1605, 1462, 3052, 689, 960, 865, 750. dH (400 MHz, CDCl3)
8.17–8.12 (m, 2H), 8.10 (d, 2H, J = 8.8 Hz), 7.61–7.50 (m, 5H).
dC (100 MHz, CDCl3) 164.73, 163.77, 137.99, 131.86, 129.48,
129.10, 128.17, 126.95, 123.74, 122.41. EIMS m/z (%): 256 [M+],
258 [M+ + 2]. Anal. Calc. for C14H9ClN2O: C, 65.53; H, 3.56; N,
10.91. Found: C, 65.62; H, 3.49; N, 10.83%.
Dithane M-45 100 83 66 100 85 66 100 86 67 100 83 63
elemental analyser. The purity of synthesized compounds was
checked by TLC aluminium sheets-silica gel 60 F254 (0.2 mm).
Chemicals used in reaction were reagent-grade, from Merck
and Fluka. These chemicals were used without further
purification. The water used was double distilled.
2,5-Bis(phenyl)-1,3,4-oxadiazole (7c)
Mp 139–140 uC (lit.57 138–139 uC). IR (KBr): nmax/cm21 1066,
1614, 1465, 3045. dH (400 MHz, CDCl3) 7.52–8.16 (m, 10H). dC
(100 MHz, CDCl3) 123.9, 126.9, 129.0, 131.7, 164.6. EIMS m/z
(%): 222 [M+]. Anal. Calc. for C14H10N2O: C, 75.66; H, 4.54; N,
12.60. Found: C, 75.81; H, 4.41; N, 12.46%.
Details of antifungal assays
The fungicidal activity of compounds 7a–z were evaluated
against fungal strains Fusarium oxysporum, Alternaria solani,
Candida albicans and Aspergillus niger by the usual agar growth
technique55 at 1000, 100 and 10 ppm concentration.
Griseofulvin and Dithane M-45 as standard commercial
fungicide was also tested under similar conditions for
comparison. The numbers of replicate assays for each were
three, and six replicate controls were used and no remarkable
morphological changes were observed in the developing fungi.
The test fungi were inoculated in the centre of the Petri-dishes
and incubated at 28 ¡ 1 uC for 96 h. After this time the percent
inhibition of the mycelia growth compared with that in control
dishes was recorded and the results thus obtained are
summarized in Table 3.
2-(4-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazole (7d)
Mp 145–147 uC (lit.58 145–148 uC). IR (KBr): nmax/cm21 1076,
1640, 1472, 3060, 2815, 980, 810, 765. dH (400 MHz, CDCl3)
8.17–8.11 (m, 2H), 8.09 (d, 2H, J = 9.0 Hz), 7.59–7.51 (m, 3H),
7.05 (d, 2H, J = 9.0 Hz), 3.90 (s, 3H). dC (100 MHz, CDCl3)
164.53, 164.12, 162.33, 131.53, 129.02, 128.69, 126.81, 124.05,
116.41, 114.50, 55.46. EIMS m/z (%) 252 [M+]. Anal. Calc. for
C
15H12N2O3: C, 71.47; H, 4.78; N, 11.10. Found: C, 71.36; H,
4.88; N, 11.21%.
2,5-Bis(furan-2-yl)-1,3,4-oxadiazole (7e)
Typical electrolysis procedure
Mp 142–143 uC (lit.59 143–144 uC). IR (KBr): nmax/cm21 1075,
1617. dH (400 MHz, CDCl3) 6.60 (dd, 2H, J = 1.6 Hz, J = 3.6 Hz),
7.22 (dd, 2H, J = 0.8 Hz, J = 3.6 Hz), 7.65 (dd, 2H, J = 0.8 Hz, J =
1.6 Hz). dC (100 MHz, CDCl3) 104.9, 111.5, 141.9, 153.9, 158.2.
EIMS m/z (%) 202 [M+]. Anal. Calc. for C10H6N2O3: C, 59.41; H,
2.99; N, 13.86. Found: C, 59.30; H, 2.77; N, 13.99%.
Preparative-scale56 electrolysis was performed at room tem-
perature in a 250 mL three-electrode cell assembly with
platinum plates as working as well as counter electrode and
saturated calomel electrode (SCE) as reference electrode.
Controlled potential electrolysis (CPE) was carried to a
4242 | RSC Adv., 2013, 3, 4237–4245
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(%) 312 [M+]. Anal. Calc. for C14H8N4O5: C, 53.85; H, 2.58; N,
17.94. Found: C, 53.70; H, 2.71; N, 17.76%.
2-(4-Methylphenyl)-5-phenyl-1,3,4-oxadiazole (7f)
Mp 218–220 uC (lit.58 219 uC). IR (KBr): nmax/cm21 1075, 1617,
1475, 3035, 3010, 985, 890, 755. dH (400 MHz, CDCl3) 8.21–8.09
(m, 2H), 8.04 (d, 2H, J = 8.1 Hz), 7.61–7.49 (m, 3H), 7.35 (d, 2H,
J = 8.1 Hz), 2.46 (s, 3H). dC (100 MHz, CDCl3) 164.73, 164.33,
142.26, 131.60, 129.76, 129.03, 126.88, 124.04, 121.16, 21.66.
EIMS (m/z) 236 [M+]. Anal. Calc. for C15H12N2O: C, 76.25; H,
5.12; N, 11.86. Found: C, 76.39; H, 5.01; N, 11.71%.
2,5-Bis(4-fluorophenyl)-1,3,4-oxadiazole (7m)
Mp 200–201 uC (lit.63 200 uC). IR (KBr): nmax/cm21 1058, 1622,
1465, 3048, 830, 984, 832, 765. dH (400 MHz, CDCl3) 6.99–7.15
(m, 4H), 7.96–8.16 (m, 4H). dC (100 MHz, CDCl3) 116.0, 128.5,
132.1, 162.1, 167.8, 172.6. EIMS m/z (%) 258 [M+]. Anal. Calc.
for C14H8N2OF2: C, 65.12; H, 3.12; N, 10.85. Found: C, 65.35; H,
3.29; N, 10.71%.
2-(4-Hydroxyphenyl)-5-phenyl-1,3,4-oxadiazole (7g)
Mp 165–167 uC (lit.60 165–166 uC). IR (KBr): nmax/cm21 1046,
1606, 1465, 3052, 3594, 967, 885, 760. dH (400 MHz, CDCl3)
7.12–8.18 (m, 9H), 10.18 (s, 1H). dC (100 MHz, CDCl3) 165.12,
164.06, 155.84, 136.53, 129.91, 129.02, 128.53, 128.42, 127.01,
123.74, 121.62, 116.23. EIMS m/z (%) 238 [M+]. Anal. Calc. for
C14H10N2O2: C, 70.58; H, 4.23; N, 11.76. Found: C, 70.73; H,
4.09; N, 11.59%.
3-(5-Furan-2-yl-1,3,4-oxadiazol-2-yl)pyridine (7n)
Mp 132–134 uC (lit.59 134–135 uC). IR (KBr): nmax/cm21 1065,
1605, 1462, 3052. dH (400 MHz, CDCl3) 6.66 (dd, 1H, J = 2.0 Hz,
J = 3.6 Hz), 7.29 (d, 1H, J = 3.6 Hz), 7.50 (dd, 1H, J = 4.8 Hz, J =
8.0 Hz), 7.71 (m, 1H, J = 0.8 Hz), 8.41–8.44 (m, 1H), 8.80 (dd,
1H, J = 1.6 Hz, J = 4.8 Hz), 9.35 (d, 1H, J = 2.0 Hz). dC (100 MHz,
CDCl3) 104.9, 111.5, 123.7, 133.3, 134.1, 141.9, 148.0, 149.3,
153.9, 154.9, 163.9. EIMS m/z (%) 213 [M+]. Anal. Calc. for
C11H7N3O2: C, 61.97; H, 3.31; N, 19.71. Found: C, 61.73; H,
3.20; N, 19.59%.
2,5-Bis(4-chlorophenyl)-1,3,4-oxadiazole (7h)
Mp 239–241 uC (lit.57 241–242 uC). IR (KBr): nmax/cm21 1065,
1605, 1462, 3052, 689, 960, 865, 750. dH (400 MHz, CDCl3) 7.45
(d, 4H, J = 8.8 Hz), 8.00 (d, 4H, J = 8.8 Hz). dC (100 MHz, CDCl3)
122.0, 128.1, 129.4, 138.0, 167.8. EIMS m/z (%) 290 [M+], 292
[M+ + 2]. Anal. Calc. for C14H8N2OCl2: C, 57.76; H, 2.77; N, 9.62.
Found: C, 57.60; H, 2.94; N, 9.46%.
2-(3-Nitrophenyl)-5-phenyl-1,3,4-oxadiazole (7o)
Mp 189–190 uC (lit.58 188–189 uC). IR (KBr): nmax/cm21 1080,
1622, 1456, 3059, 1550, 915, 870, 775. dH (400 MHz, CDCl3)
8.52 (m, 3H), 8.98 (s, 1H), 7.61–7.83 (m, 5H). dC (100 MHz,
CDCl3) 165.72, 164.18, 148.95, 137.15, 134.85, 131.69, 131.28,
129.01, 128.60, 123.73, 123.08, 120.77. EIMS m/z (%) 267 [M+].
Anal. Calc. for C14H9N3O3: C, 62.92; H, 3.39; N, 15.72. Found:
C, 62.76; H, 3.26; N, 15.89%.
2-(Furan-2-yl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole (7i)
Mp 129–131 uC (lit.59 129–130 uC). IR (KBr): nmax/cm21 1076,
1640, 1472, 3060, 2815, 2965, 980, 810, 765. dH (400 MHz,
CDCl3) 3.85 (s, 3H), 6.58 (dd, 1H, J = 1.6 Hz, J = 3.2 Hz), 6.98
(dd, 2H, J = 2.0 Hz, J = 3.2 Hz), 7.17 (dd, 1H, J = 0.8 Hz, J = 4.0
Hz), 7.63 (dd, 1H, J = 0.4 Hz, J = 1.6 Hz), 8.02 (dd, 2H, J = 2.0
Hz, J = 6.8 Hz). dC (100 MHz, CDCl3) 56.0, 104.9, 111.5, 114.5,
127.9, 128.7, 141.9, 153.9, 157.4, 161.9, 164.8. EIMS m/z (%)
242 [M+]. Anal. Calc. for C13H10N2O3: C, 64.46; H, 4.16; N,
11.41. Found: C, 64.29; H, 4.34; N, 11.56%.
2,5-Bis(3,4-dimethoxyphenyl)-1,3,4-oxadiazole (7p)
Mp 178–180 uC (lit.57 179–181 uC). IR (KBr): nmax/cm21 1050,
1621, 1459, 3045, 2810, 978, 866, 751. dH (400 MHz, CDCl3)
3.95 (s, 6H), 3.98 (s, 6H), 6.96 (d, 2H, J = 9.0 Hz), 7.63–7.68 (m,
4H). dC (100 MHz, CDCl3) 56.0, 56.2, 109.5, 111.1, 116.6, 120.3,
149.4, 151.9, 164.2. EIMS m/z (%) 342 [M+]. Anal. Calc. for
C18H18N2O5: C, 63.15; H, 5.30; N, 8.18. Found: C, 63.32; H,
5.49; N, 8.07%.
2,5-Bis(4-methoxyphenyl)-1,3,4-oxadiazole (7j)
Mp 161–163 uC (lit.57 162 uC). IR (KBr): nmax/cm21 1076, 1640,
1472, 3060, 2815, 980, 810, 765. dH (400 MHz, CDCl3) 3.88 (s,
6H), 7.01–7.03 (d, 4H, J = 9.0 Hz), 8.04–8.06 (d, 4H, J = 9.0 Hz).
dC (100 MHz, CDCl3) 55.5, 114.5, 116.5, 128.6, 162.2, 164.1.
EIMS m/z (%) 282 [M+]. Anal. Calc. for C16H14N2O3: C, 68.07; H,
5.00; N, 9.92; Found: C, 68.20; H, 4.84; N, 9.71%.
2-(2-Naphthalenyl)-5-phenyl-1,3,4-oxadiazole (7q)
Mp 133–134 uC (lit.64 132 uC). IR (KBr): nmax/cm21 1080, 1624,
1456, 3062, 916, 875, 775. dH (400 MHz, CDCl3) 8.65 (br. s, 1H),
8.26–8.18 (m, 3H), 8.03–7.97 (m, 2H), 7.95–7.89 (m, 1H), 7.65–
7.54 (m, 5H). dC (100 MHz, CDCl3) 164.80, 164.68, 134.72,
132.86, 131.76, 129.10, 129.07, 128.84, 127.98, 127.32, 127.12,
127.00, 123.95, 123.25, 121.17. EIMS m/z (%) 272 [M+]. Anal.
Calc. for C18H12N2O: C, 79.39; H, 4.44; N, 10.29. Found: C,
79.21; H, 4.57; N, 10.12%.
2,5-Bis(2-hydroxyphenyl)-1,3,4-oxadiazole (7k)
Mp 119–121 uC (lit.61 121 uC). IR (KBr): nmax/cm21 1035, 1609,
1449, 3018, 983, 891, 753. dH (400 MHz, CDCl3) 10.91 (s, 2H),
6.97–7.94 (m, 8H). dC (100 MHz, CDCl3) 116.1, 121.5, 123.6,
128.3, 129.8, 155.7, 167.2, 172.6. EIMS m/z (%) 254 [M+]. Anal.
Calc. for C14H10N2O3: C, 66.14; H, 3.96; N, 11.02. Found: C,
66.34; H, 3.80; N, 11.19%.
2,5-Bis(4-hydroxyphenyl)-1,3,4-oxadiazole (7r)
Mp 349–350 uC (lit.57 350 uC). IR (KBr): nmax/cm21 1046, 1606,
1465, 3052, 3594, 967, 885, 785. dH (400 MHz, CDCl3) 6.95–7.91
(m, 4H), 10.27 (s, 2H). dC (100 MHz, CDCl3) 114.2, 116.1, 128.4,
160.6, 163.5. EIMS m/z (%) 254 [M+]. Anal. Calc. for
2,5-Bis(3-nitrophenyl)-1,3,4-oxadiazole (7l)
Mp 137–139 uC (lit.62 136–138 uC). IR (KBr): nmax/cm21 1080,
1622, 1456, 3059, 1550, 915, 870, 775. dH (400 MHz, CDCl3)
8.02–8.06 (m, 2H), 7.58–8.61 (m, 8H). dC (100 MHz, CDCl3)
122.0, 123.5, 129.8, 133.0, 137.3, 148.7, 163.6, 172.7. EIMS m/z
C
14H10N2O3: C, 66.14; H, 3.96; N, 11.02. Found: C, 66.37; H,
3.79; N, 11.21%.
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z (%) 256 [M+], 258 [M+ + 2]. Anal. Calc. for C14H9ClN2O: C,
2-Phenyl-5-(3-pyridinyl)-1,3,4-oxadizole (7s)
65.51; H, 3.53; N, 10.91. Found: C, 65.70; H, 3.68; N, 10.83%.
Mp 137–139 uC (lit.59 136–137 uC). IR (KBr): nmax/cm21 1070,
1619, 1468, 3030. dH (400 MHz, CDCl3) 7.51–7.59 (m, 4H),
8.14–8.17 (m, 2H), 8.45–8.48 (m, 1H), 8.81 (d, 1H, J = 4.0 Hz),
9.37 (s, 1H). dC (100 MHz, CDCl3) 123.7, 126.9, 128.4, 128.9,
133.3, 134.1, 136.4, 148.0, 149.3, 154.9, 163.9. EIMS m/z (%)
223 [M+]. Anal. Calc. for C13H9N3O: C, 69.86; H, 4.06; N, 18.71.
Found: C, 69.71; H, 4.24; N, 18.54%.
2-(4-Bromophenyl)-5-(naphthalen-1-yl)-1,3,4-oxadiazole (7z)
Mp 145–147 uC (lit.66 146.2–147.3 uC). IR (KBr): nmax/cm21
1597, 1577, 1543, 1403, 1071, 769. dH (400 MHz, CDCl3) 9.28 (d,
1H, J = 8.2 Hz), 8.29–8.26 (1H, dd, J = 7.3, J = 1.0 Hz), 8.09–8.06
(3H, m), 7.96 (1H, d, J = 8.2 Hz), 7.74–7.70 (3H, m), 7.64–7.60
(2H, m). dC (100 MHz, CDCl3) 164.6, 163.3, 133.8, 132.6, 132.4,
130.0, 128.6, 128.3, 128.1, 126.7, 126.4, 126.1, 124.7, 122.7,
120.2. EIMS m/z (%) 350 [M+]. Anal. Calc. for C18H11BrN2O: C,
61.56; H, 3.16; N, 7.98. Found: C, 61.41; H, 3.29; N, 8.11%.
2,5-Bis(4-aminophenyl)-1,3,4-oxadiazole (7t)
Mp 254–255 uC (lit.65 253–254 uC). IR (KBr): nmax/cm21 1062,
1618, 1468, 3058, 3416, 985, 890, 755. dH (400 MHz, CDCl3)
6.61–6.66 (m, 4H), 7.85–7.87 (m, 4H), 7.16 (s, 4H). dC (100
MHz, CDCl3) 115.5, 126.4, 127.7, 146.6, 164.3, 171.5. EIMS m/z
(%) 252 [M+]. Anal. Calc. for C14H12N4O: C, 66.65; H, 4.79; N,
22.21. Found: C, 66.79; H, 4.54; N, 22.09%.
Conclusion
In conclusion, we have developed a mild and efficient one-pot
methodology to synthesize a variety of 2,5-aryl-, and 2,5-
heteroaryl-1,3,4-oxadiazoles and their in vitro antifungal
activities were studied against different strain of fungi. The
investigation on the structure–activity relationship showed
that the para-substitution in the phenyl group of the
oxadiazoles was found to enhance their potency, especially
in compounds 7b, 7d, 7g, 7h, 7i, 7j and 7r. Apart from being
simple, milder and environmentally sustainable, this method
gives easy access to the preparation of the chemically and
pharmaceutically important heterocyclic scaffold and is
compatible with a wide range of functional groups and thus
has potential industrial application.
2,5-Bis(3-bromophenyl)-1,3,4-oxadiazole (7u)
Mp 198–200 uC (lit.61 200–201 uC). IR (KBr): nmax/cm21 1056,
1621, 1461, 3032, 736, 985, 890, 755. dH (400 MHz, CDCl3)
7.35–7.75 (m, 6H), 7.54 (br s, 2H). dC (100 MHz, CDCl3) 123.5,
126.0, 130.2, 131.1, 131.7, 138.6, 162.5, 172.8. EIMS m/z (%)
380 [M+]. Anal. Calc. for C14H8N2OBr2: C, 44.25; H, 2.12; N,
7.37. Found: C, 44.38; H, 2.01; N, 7.20%.
2-(Furan-2-yl)-5-phenyl-1,3,4-oxadiazole (7v)
Mp 102–104 uC (lit.59 102–103 uC). IR (KBr): nmax/cm21 1066,
1614, 1465, 3045. dH (400 MHz, CDCl3) 6.61 (dd, 1H, J = 2.0 Hz,
J = 3.6 Hz), 7.22 (dd, 1H, J = 0.8 Hz, J = 3.6 Hz), 7.52 (m, 3H),
7.65 (dd, 1H, J = 0.8 Hz, J = 2.0 Hz), 8.09–8.11 (m, 2H). dC (100
MHz, CDCl3) 104.9, 111.5, 126.9, 128.4, 128.9, 136.4, 141.9,
153.9, 158.6, 164.7. EIMS m/z (%) 212 [M+]. Anal. Calc. for
C12H8N2O2: C, 67.92; H, 3.88; N, 13.14. Found: C, 67.72; H,
3.69; N, 3.64%.
Acknowledgements
The authors are grateful to Head, Department of Chemistry,
University of Allahabad for providing necessary facilities, SAIF,
Punjab University, Chandigarh, for providing microanalysis
and spectra and also CST-UP for financial support for
accomplishment of the work.
2,5-Bis(2-methoxyphenyl)-1,3,4-oxadiazole (7w)
Mp 99–100 uC (lit.61 98–99 uC). IR (KBr): nmax/cm21 1056, 1617,
1465, 3049, 2815, 965, 892, 750. dH (400 MHz, CDCl3) 3.95 (s,
6H), 7.03–7.07 (d, 4H, J = 8.0 Hz), 7.97–7.99 (d, 4H, J = 8.0 Hz).
dC (100 MHz, CDCl3) 56.2, 114.5, 121.2, 122.0, 128.0, 129.4,
160.4 167.4, 172.7. EIMS m/z (%) 282 [M+]. Anal. Calc. for
C16H14N2O3: C, 68.07; H, 5.00; N, 9.92. Found: C, 68.24; H,
4.81; N, 9.77%.
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RSC Adv., 2013, 3, 4237–4245 | 4245