Efficient oxidative cyclisation of acid hydrazides to 2,5-disubstituted 1,3,4-oxadiazoles catalysed by Bu4NI with t-BuOOH as oxidant

Article abstract of DOI:10.3184/174751913X13736408126236

Acid hydrazides or araldehyde N-acylhydrazones can be converted in good yields to, respectively, symmetrical or unsymmetrical, 2,5-disubstituted 1,3,4-oxadiazoles at 60 °C by a Bu4NI-catalysed procedure which requires the presence of a base and 2.5 equiv. of t-butyl hydroperoxide.

Full text of DOI:10.3184/174751913X13736408126236

506 RESEARCH PAPER
AUGUST, 506–510
JOURNAL OF CHEMICAL RESEARCH 2013
Efficient oxidative cyclisation of acid hydrazides to 2,5-disubstituted
1,3,4-oxadiazoles catalysed by Bu4NI with t-BuOOH as oxidant
Peng Gao and Yunyang Wei*
School of Chemical Engineering, Nanjing University of Science andTechnology, Nanjing 210094, P. R. China
Acid hydrazides or araldehyde N-acylhydrazones can be converted in good yields to, respectively, symmetrical or
unsymmetrical, 2,5-disubstituted 1,3,4-oxadiazoles at 60 °C by a Bu4NI-catalysed procedure which requires the pres-
ence of a base and 2.5 equiv. of t-butyl hydroperoxide.
Keywords: hydrazides, N-acylhydrazones, oxadiazoles, oxidation, metal-free reactions
The 2,5-disubstituted, 1,3,4-oxadiazole ring system as a basic
structure unit occurs in many biologically active natural and
synthetic compounds as well as in optoelectronic functional
materials.1–5 For example, raltegravir, a clinically used antiret-
roviral drug for the treatment of HIV infection, possesses the
2,5-disubstituted, 1,3,4-oxadiazole ring system.6 As a conse-
quence, extensive efforts have been directed toward the
development of methods for the synthesis of 2,5-disubstituted
1,3,4-oxadiazoles, including cyclodehydration of 1,2-diacyl-
hydrazines in a dehydrating media or in the presence of an
acidic catalyst, such as POCl3,7 TsCl,8 or silica sulfuric acid;9
oxidative cyclisation of N-acylhydrazones with various oxidis-
ing agents such as Cu(OTf)2,10 NCS11 or Dess–Martin reagent;12
and one-pot synthesis of 2,5-disubstituted 1,3,4-oxadiazoles
from acid hydrazines and carboxylic acid derivatives or alde-
hydes promoted by ceric ammonium nitrate,13 permanganate
under microwave conditions,14 or trichloroisocyanuric acid.15
Acid hydrazides can be oxidised to aldehydes or carboxylic
acid derivatives with various oxidants, such as tetravalent lead
reagents,16 hypervalent iodine compounds,17 permanganate,18
a copper(II) catalyst,19 ceric ammonium nitrate20 or N-bromo-
succinimide.21 In some cases, N, N′-diacylhydrazines can be
obtained with oxidising reagents such as oxone,22 halogens,23
or aryl sulfonyl peroxides.24,25 To our knowledge, only a few
papers mentioned the transformation of acid hydrazides to
2,5-disubstituted, 1,3,4-oxadiazoles as byproducts, albeit in
very low yields.16
In recent years, catalytic oxidative organic transformations
under metal free conditions, especially using I2 or iodides as
catalysts, have drawn considerable attention.26–28 Systems
like Bu4NI\t-butyl hydroperoxide (TBHP) and I2\TBHP have
been widely used for the formation of C–O,29–31 C–N32–34 bonds
and heterocycles.35–36 Inspired by these developments and in
continuation of our efforts on metal free oxidative reactions,37–39
we now report an efficient procedure for the synthesis of 2,5-
disubstituted 1,3,4-oxadiazoles from acid hydrazides or N-
acylhydrazones catalysed by Bu4NI with TBHP as an oxidant.
A screen of suitable conditions for the one pot transforma-
tion of acid hydrazides to symmetrical 2,5-disubstituted, 1,3,4-
oxadiazoles was carried out with benzohydrazide 1a as the
test substrate and the results are shown in Table 1. Reaction
of 1a with a hexane solution of TBHP (2.5 equiv.) in MeOH
at 60 °C in the presence of 10 mol% of Bu4NI and 15 mol% of
K2CO3 or 1,4-diazabicyclo-[2,2,2]-octane (DABCO) gave the
known 2,5-diphenyl 1,3,4-oxadiazole 3a in 47 and 22% yield,
respectively (Table 1, entries 1 and 2). When mixed bases,
Table 1 Optimisation of reaction conditionsa for the conversion of benzohydrazide 1a to 2,5-diphenyl-1,3,4-oxadiazole 3a
Entry
I Source
Base
Oxidant
Solvent
Yield/%b
1
2
Bu4I
Bu4I
Bu4I
Bu4I
Bu4I
Bu4I
Bu4I
Bu4I
Bu4I
Bu4I
Bu4I
Bu4I
NaI
I2
K2CO3
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
H2O2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH3CN
DMSO
ClCH2CH2Cl
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
47
25
DABCO
3
K2CO3/DABCO (1:1)
K2CO3/DABCO (1:2)
K2CO3/DABCO (2:1)
Na2CO3/DABCO (2:1)
Cs2CO3/DABCO (2:1)
K2CO3/DBU (2:1)
K2CO3/Et3N (2:1)
K2CO3/DABCO (2:1)
K2CO3/DABCO (2:1)
K2CO3/DABCO (2:1)
K2CO3/DABCO (2:1)
K2CO3/DABCO (2:1)
K2CO3/DABCO (2:1)
K2CO3/DABCO (2:1)
K2CO3/DABCO (2:1)
–
67
4
75
5
87
6
80
7
83
8
65
9
Trace
45
10
11
12
13
14
15
16
17
18
19
38
Trace
Trace
39
Bu4I
Bu4I
–
Bu4I
Bu4I
73c
Trace
Trace
Trace
Trace
TBHP
TBHP
–
K2CO3/DABCO (2:1)
a Reaction conditions: 1a (1 mmol), I Source (0.1 mmol), base (0.15 mmol), oxidant (2.5 mmol), in solvent (3 mL) at 60 °C.
b Isolated yield.
c 70% TBHP in water was used.
* Correspondent. E-mail: ywei@mail.njust.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2013 507
such as K2CO3/1,4-diazabicyclo-[2,2,2]-octane (DABCO) or
K2CO3/1,8-diazabi-cyclo[5.4.0]-undec-7-ene (DBU), were
used instead of K2CO3 alone, higher yields of product were
obtained in most cases (Table 1, entries 3–8). However, when
10 mol% K2CO3 and 5 mol% triethylamine were employed in
the reaction, no desired product was formed (Table 1, entry 9).
It was found that 10 mol% K2CO3 and 5 mol% of DABCO was
the best combination. Optimisation of the solvent revealed that
MeOH was superior to CH3CN, DMSO and ClCH2CH2Cl
(Table 1, entries 10–12). The use of Bu4NI as catalyst provided
the best result for this transformation (Table 1, entry 5). When
other iodides were used as catalyst, the desired product 2a was
generated in low yield (Table 1, entries 13 and 14). The oxi-
dant also showed a key role in this transformation and lower
yields of products were isolated when 70% TBHP in water
or H2O2 was used as the oxidant instead of TBHP solution in
hexane (Table 1, entries 15 and16). Blank tests showed that the
desired product was not formed in the absence of catalyst, base
or oxidant (Table 1, entries 17–19). The optimised procedure
was chosen as follows: reaction in MeOH at 60 °C for 4h in
the presence of 10 mol% K2CO3, 5 mol% DABCO, 10 mol%
BuN4I and 2.5 equiv. of TBHP (entry 5).
Under the optimised conditions, the scope of the reaction
was tested for the synthesis of other symmetric 2,5-disubsti-
tuted 1,3,4-oxadiazoles (Table 2). We were delighted to observe
tat numerous useful functional groups were well tolerated,
including alkyl, methoxy, halo and nitro substituents. When
alkyl substituents, such as Me- or Me3C-, were on the benzene
ring, moderate to good yield of products were isolated
(Table 2, entries 1–5). 4-Methoxylbenzohydrazide was so
easily oxidised to t-butyl p-methoxyperoxybenzoate and only
45% of 2,5-bis(4-methoxyphenyl)- 1,3,4-oxadiazole 3f was
obtained (Table 2, entry 6). When an electron-withdrawing
group (Cl, Br, I or NO2) was on the benzene ring, good yields
of product were obtained (Table 2, entries 7–11). With
substrate 1l a heteroaromatic hydrazide the desired 2,5-disub-
stituted 1,3,4-oxadiazole was also obtained in 55% yield
(entry 12).
In an effort to synthesise unsymmetrical 2,5-disubstituted
1,3,4-oxadiazoles via the same procedure, crossed condensa-
tion of different acid hydrazides was then tested. However,
treatment of a 1:1 mixture of acid hydrazide 1a and 1g
with Bu4NI/TBHP system under the optimised conditions
gave a mixture of crossed condensation product 3p and self
condensation products 3a and 3g in 1:2.1:1.8 ratios.
To make the method more practical, we explored Bu4NI/TBHP
catalytic system for the synthesis of various 2,5-disubstituted
1,3,4-oxadiazoles from N-acylhydrazones. N-benzoylhydra-
zones derived from aromatic arylaldehydes bearing electron-
donating or electron-withdrawing groups on the benzene ring
could be smoothly converted into the corresponding products
in yields ranging from 75 to 94% (Table 3, entries 2–7). Sub-
strates derived from heterocyclic aldehydes, such as furfural
and 2-thiophenecarboxaldehyde, also gave the corresponding
products in moderate yields (Table 3, entries 8 and 9).
Acylhydrazones derived from different acid hydrazides
were tested, too. The corresponding products were obtained in
moderate to good yields (Table 3, entries 10–15). Especially,
substrates derived from heterocyclic acid hydrazides, such as
isonicotinyl hydrazide and 2-furoic hydrazide, showed good
reactivity under this system (Table 3, entries 12, 13). Acylhy-
drazones derived from alkyl acid hydrazides, such as acetohy-
drazide and phenylacetic hydrazide, also reacted under the
optimised conditions, giving 81% and 83% yields, respectively
(Table 3, entries 14 and 15).
All but three of the 25 2,5-disubstituted 1,3,4-oxadiazoles
that were synthesised were characterised by comparison of
melting point and 1H NMR with literature data. The three new
compounds, 3o, 3u and 3v were additionally characterised by
13C NMR and Elemental Analysis.
To gain insights into the reaction pathway, several control
experiments were carried out (Scheme 1). We first investigated
the one-pot oxidation of acid hydrazides to symmetrical
2,5-disubstituted 1,3,4-oxadiazoles. When the reaction was
performed for 25 min the generation of N-benzylidenebenzo-
hydrazide 2a could be identified as the expected intermediate.
Table 2 Yieldsa of symmetrical 2,5-disubstituted 1,3,4-oxadia-
zoles 3a–l from acid hydrazides 1a–l using the Bu4NI/TBHP
system (Method Ab)
Table 3 Yieldsa of 2,5-disubstituted 1,3,4-oxadiazoles 3 from
araldehyde N-acylhydrazone 2 using the Bu4NI/TBHP system
(Method Bb)
Entry
Ar
Yield/%
Entry
R1
Ar
Yield [%]
1
2
Ph
3a, 87
3b, 85
3c, 79
3d, 83
3e, 68
3f, 45c
3g, 80
3h, 75
3i, 81
3j, 86
3k 84
3l, 55
1
2
Ph
Ph
4-MeC6H4
4-MeOC6H4
3-PhOC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
2-Thienyl
2-Furyl
2-BrC6H4
3-PhOC6H4
Ph
3a,94
3m,93
3n,94
3o,92
3p, 91
3q, 89
3r, 83
3s, 88
3t, 75
3u 87
3v, 89
3w, 80
3t, 84
3x, 81
3y, 83
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-Me3CC6H4
4-MeOC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
3-IC6H4
Ph
3
3
Ph
Ph
4
4
5
5
Ph
6
6
Ph
7
7
Ph
8
8
Ph
9
9
Ph
10
11
12
10
11
12
13
14
15
4-MeOC6H4
2-MeC6H4
4-Pyridinyl
2-Furyl
Me
3-NO2C6H4
2-Furyl
Ph
a Isolated yield.
Ph
Ph
b Reaction conditions: TBHP (2.5 mmol) in hexane was added
dropwise over 2 h to a mixture of acid hydrazide (1 mmol),
K2CO3 (0.1 mmol), DABCO (0.05 mmol) and Bu4NI (0.1 mmol) in
MeOH (3 mL) at 60 °C; the reaction was continued for another
2 h.
Bn
a Isolated yield.
b Reaction conditions: N-acylhydrazone (0.5 mmol), K2CO3
(0.1 mmol), Bu4NI (0.1 mmol), TBHP in water (1.25 mmol) in
EtOAc (3 mL) at 60 °C for 1 h.
c Reaction was carried out at room temperature.

508 JOURNAL OF CHEMICAL RESEARCH 2013
On the other hand, 1,2-dibenzoylhydrazine showed little reac-
tivity under Method B (see Experimental), which confirmed
that N-benzylidenebenzohydrazide is the main intermediate in
this transformation (Scheme 1, f). Addition of 2,2,6,6-tetra-
methyl-1-piperidinyloxy(TEMPO), a radical-trapping reagent
led to no formation of the desired product and as anticipated,
the TEMPO adduct was obtained in 65% yield under the
optimised conditions (Scheme 1, a). Similarly, if 1.2 equiv. of
iodine were used instead of Bu4NI/TBHP, no target product
was obtained, too (Scheme 1, b). These observations implied
that the direct oxidative cyclisation of acid hydrazides to
symmetrical 2,5-disubstituted 1,3,4-oxadiazoles may involve a
radical pathway. For the synthesis of 3a from N-acylhydrazone
2a, it was found that the radical-trapping reagent (TEMPO)
had no effects on the yield of the desired product and if
1.2 equiv. of iodine were used instead of Bu4NI/TBHP, excel-
lent yields of the desired product could be obtained (Scheme 1,
c, d). These results suggested that transformation of N-acylhy-
drazones to 2,5-disubstituted 1,3,4-oxadiazoles probably
followed an iodine-catalysed mechanism. When N-benzyli-
denebenzohydrazide 2a was reacted in the absence of base,
no product was formed (Scheme 1, e). This result showed
that base plays an important role in the oxidative cyclisation
procedure.
On the basis of the results described above and previous
reports,16,34,40 a plausible mechanism is proposed in Scheme 2.
For the one-pot transformation of hydrazide 1 to symmetrical
2,5-disubstituted 1,3,4-oxadiazoles 3, aldehydes 4 may be
formed first from hydrazide 1 following a radical pathway
involving t-BuO. Condensation of the newly formed aldehyde
4 with hydrazide 1 gave N-acylhydrazone 2 in situ. The cata-
lyst Bu4NI was oxidised to I2 by TBHP. Nucleophilic attack of
the imine nitrogen of N-acylhydrazone 2 on molecular iodine
led to cyclisation, as shown. The byproduct hydrogen iodide
was then neutralised with a base and oxidised to iodine by
TBHP to complete the catalytic cycle.
In conclusion, an efficient and simple procedure for the
synthesis of symmetrical as well as unsymmetrical 2,5-disub-
stituted 1,3,4-oxadiazoles from acid hydrazides or N-acylhy-
drazones was developed. The reactions were carried out under
mild conditions without the need of a transition-metal catalyst
using easily available starting materials. Good functional
group tolerance, mild reaction conditions and excellent yields
of products make the procedure a good alternative for the
synthesis of 2,5-disubstituted 1,3,4-oxadiazoles.
Experimental
All solvents and reagents were obtained from commercially sources
and used without further purification. NMR spectra were obtained on
a Bruker Avance 500 spectrometer (1H NMR at 500 MHz, 13C NMR at
125 MHz) in CDCl3 or DMSO-d6 using TMS as internal standard.
Elemental analysis was performed at the elemental analysis of ISIC at
EPFL. ESI-MS were recorded on a Thermal Finnigan TSQ Quantum
ultra AM spectrometer using a TRB-5MS (30 m×0.25 mm×0.25 mm)
column. Melting points were determined on a Yamato melting point
apparatus Model MP-21. Silica gel (200–300 mesh) was used for
column chromatographic separations and purifications. Petroleum
ether (PE) refers to the fraction boiling at 60–90 °C. Most of the
2,5-disubstituted 1,3,4-oxadiazoles obtained are known compounds
with physical and spectral properties in agreement with those reported
in the literature closely.
Typical procedure
Preparation of acid hydrazides:41 A mixture of carboxylic acid ester
(10 mmol) and hydrazine hydrate (40.0 mmol, 80% in H2O) in ethanol
(20 mL) was refluxed overnight. After cooling to room temperature,
the solution was concentrated in vacuo and the crude product was
washed with hexane (2 × 10 mL) to give the corresponding acid
hydrazide. Acid hydrazides 1b–m all are known compounds and
determined by comparison of melting points with literatures reported.
1a, 1q, 1r were obtained from commercially sources and used without
further purification.
Synthesis of N-acylhydrazones;general procedure11
N-acylhydrazones were prepared by the condensation of one equiva-
lent of corresponding hydrazides and aldehydes in ethanolic medium
Scheme 1 Investigations into the reaction mechanism.

JOURNAL OF CHEMICAL RESEARCH 2013 509
Scheme 2 Plausible mechanism of synthesis of 2,5-disubstituted 1,3,4-oxadiazoles.
under reflux condition for 10 h. The precipitates formed were
filtered and washed with diethyl ether to afford the corresponding
N-acylhydrazones. Most of the N-acylhydrazones obtained are known
compounds with properties in close agreement with those reported in
the literature. 2u and 2v are new compounds and 1H NMR, 13C NMR
and HR-MS spectra data and elemental analyses are given.
Method B: Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from
araldehyde N-acylhydrazones using a Bu4NI/TBHP system: A 10 mL
round-bottomed flask was charged with N-acylhydrazone (0.5 mmol),
K2CO3 (0.1 mmol, 14 mg), Bu4NI (0.1 mmol, 37 mg), TBHP 70% in
water (1.25 mmol) and ethyl acetate (3 mL). The mixture was stirred
at 60 °C for 1h. After completion of the reaction, ethyl acetate (10 mL)
was added and the mixture was washed with saturated Na2S2O3 solu-
tion (5 mL), then with water (2×5 mL). The organic layer was dried by
anhydrous Na2SO4 and concentrated in vacuo. The crude products
were purified on silica gel columns by using petroleum ether/ethyl
acetate (10:1). All the products were characterised bymelting
point and 1H NMR; new compounds 3o, 3u and 3v were additionally
characterised by 13C NMR and elemental analysis. Spectral data of the
products are given below.
N-(2-Bromobenzylidene)-4-methoxybenzohydrazide (2u): White
1
solid, m.p. 164–165 °C (EtOH); H NMR (DMSO-d6): δ 11.99 (br,
1H, NH), 8.80 (s, 1H, CH), 7.92–8.00 (m, 3H, PhH), 7.67–7.68 (m,
1H, PhH), 7.35–7.45 (m, 2H, PhH), 7.04–7.06 (m, 2H, PhH), 3.83 (s,
3H, PhH); 13C NMR: δ 163.05, 162.64, 145.79, 133.70, 133.63,
132.07, 130.12, 128.58, 127.68, 125.63, 123.95, 114.23, 55.93; HR-
MS (m/z) (M+1) calcd for C15H13BrN2O2: 333.0168, found 333.0171.
N-(3-phenoxybenzylidene)-2-methylbenzohydrazide (2v): Light
yellow solid, m.p. 156–158 °C (EtOH); 1H NMR (DMSO-d6): δ 11.74
(br, 1H, NH), 8.26 (s, 1H, CH), 7.35–7.48 (m, 6H, PhH), 7.25–7.32
(m, 2H, PhH), 7.15–7.19 (m, 2H, PhH), 7.05–7.10 (m, 2H, PhH),
6.96–6.97 (m, 1H, PhH); 13C NMR: δ 165.702, 157.78, 147.08,
136.76, 136.36, 135.66, 130.69, 130.44, 127.91, 126.12, 124.35,
123.28, 120.83, 119.66, 119.49, 115.97; HR-MS (m/z) (M+1) calcd
for C21H18N2O2: 331.1371, found 331.1372.
2,5-Diphenyl-1,3,4-oxadiazole (3a): White solid, m.p. 138–139 °C
1
(lit.11 136–138 °C); H NMR (CDCl3): δ 7.53–7.58 (m, 6H, PhH),
8.17 (m, 4H, PhH).
2,5-Di-(p-tolyl)-1,3,4-oxadiazole (3b): White solid, m.p. 172–
1
174 °C (lit.12 178 °C); H NMR (CDCl3): δ 8.03 (d, J = 8.0 Hz, 4H,
PhH), 7.33 (d, J = 8.0 Hz, 4H, PhH), 2.44 (s, 6H, CH3).
2,5-Di-(m-tolyl)-1,3,4-oxadiazole (3c): White solid, m.p. 77–79 °C
1
(lit.10 76–78 °C); H NMR (CDCl3): δ 7.98 (s, 2H, PhH), 7.95 (d,
Preparation of anhydrous t-butyl hydroperoxide in hexane42
J = 7.7 Hz, 2H, PhH), 7.43 (t, J = 7.7 Hz, 2H, PhH), 7.37 (d, J =
7.7 Hz, 2H, PhH), 2.47 (s, 6H, CH3).
t-Butyl hydroperoxide in hexane was prepared according to the litera-
ture procedure with some modification. To a clean separatory funnel
was added 10 mL of 70% TBHP in water, and hexane (12.5 mL) was
added. The mixture was shaken several times and it should be noted
that the gas produced in the process needed to be released quickly.
Then, the aqueous layer was separated and the organic layer was dried
with 4Å molecular sieves (5g) and stored in a brown glass bottle. The
concentration of t-butyl hydroperoxide in hexane was determined by
iodimetric analysis and the concentration found to be 5.03 M.
Method A: Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from
acid hydrazides using a Bu4NI/TBHP system: A 10 mL round-bottomed
flask was charged with acid hydrazide (1 mmol), K2CO3 (0.1 mmol,
14 mg), DABCO (0.05 mmol, 6 mg), Bu4NI (0.1 mmol, 37 mg)
and MeOH (3 mL). The mixture was stirred at 60 °C and TBHP
(2.5 mmol) was added dropwise over 2h; then the stirring was contin-
ued for another 2h. After the completion of the reaction, ethyl acetate
(10 mL) was added and the mixture was washed with saturated
Na2S2O3 solution (5 mL), then with water (2×5 mL). The organic layer
was dried by anhydrous Na2SO4 and concentrated in vacuo. The crude
products were purified on silica gel columns by using petroleum
ether/ethyl acetate (10:1).
2,5-Di-(o-tolyl)-1,3,4-oxadiazole (3d): White solid, m.p. 127–
1
128 °C (lit.11 123–125 °C); H NMR (500 MHz, CDCl3): δ 8.05 (m,
2H, PhH), 7.45 (m, 2H, PhH), 7.37 (m, 4H, PhH), 2.80 (s, 6H, CH3).
2,5-Bis-(4-t-butyl-phenyl)-1,3,4-oxadiazole (3e): White solid, m.p.
139–140 °C (lit.7 145 °C); 1H NMR (CDCl3): δ 8.05 (d, J = 8.5, 4H,
PhH), 7.54 (d, J = 8.5 Hz, 4H, PhH), 1.35 (s, 12H, CH3).
2,5-Bis-(4-methoxyphenyl)-1,3,4-oxadiazole (3f): White solid,
m.p. 158–160 °C (lit.11 158–160 °C); 1H NMR (CDCl3): δ 8.06 (d, J =
8.8 Hz, 4H, PhH), 7.03 (d, J = 8.8 Hz, 4H, PhH), 3.90 (s, 6H, CH3).
2,5-Bis-(4-chlorophenyl)-1,3,4-oxadiazole (3g): White solid, m.p.
1
248–250 °C (lit.11 250–251 °C);. H NMR (CDCl3): δ 8.08 (d, J =
8.5 Hz, 4H, PhH), 7.53 (d, J = 8.5 Hz, 4H, PhH).
2,5-Bis-(2-chlorophenyl)-1,3,4-oxadiazole (3h): White solid, 97–
98 °C (lit.10 94–96 °C); 1H NMR (CDCl3): δ 8.08 (d, J = 8.5 Hz, 4H,
PhH), 7.53 (d, J = 8.5 Hz, 4H, PhH).
2,5-Bis-(4-bromophenyl)-1,3,4-oxadiazole (3i): White solid, m.p.
1
219–221 °C (lit.43 219–220 °C); H NMR (CDCl3): δ 8.00 (d, J =
8.5 Hz, 4H, PhH), 7.68 (d, J = 8.5 Hz, 4H, PhH).
2,5-Bis-(3-iodophenyl)-1,3,4-oxadiazole (3j): White solid, m.p.
1
233–235 °C (lit.44 230–233 °C); H NMR (CDCl3). δ 8.47 (s, 2H,

510 JOURNAL OF CHEMICAL RESEARCH 2013
PhH), 8.12 (d, J = 7.7 Hz, 2H, PhH), 7.90 (d, J = 7.7 Hz, 2H, PhH),
7.28 (t, J = 7.7 Hz, 2H, PhH).
PhH), 7.47–7.52 (m, 3H, PhH), 7.34–7.38 (m, 4H, PhH), 7.29–7.31
(m, 1H, PhH), 4.29 (s, 2H, CH2).
2,5-Bis-(3-nitrophenyl)-1,3,4-oxadiazole (3k): Light yellow solid,
m.p. 226–228 °C (lit.45 225–227 °C); H NMR (CDCl3): δ 9.01 (s,
2H, PhH), 8.57 (m, 2H, PhH), 8.48 (m, 2H, PhH), 7.82 (t, J = 8.0 Hz,
2H, PhH).
1
Received 5 June 2013; accepted 11 June 2013
Paper 1301933 doi: 10.3184/174751913X13736408126236
Published online: 9 August 2013
2,5-Di-(furan-2-yl)-1,3,4-oxadiazole (3l): Yellow solid, m.p. 134–
1
136 °C (lit.10 136–138 °C); H NMR (CDCl3): δ 7.68 (m, 2H, ArH),
7.25 (m, 2H, ArH), 6.63 (m, 2H, ArH).
References
2-p-Tolyl-5-phenyl-1,3,4-oxadiazole (3m): White solid, m.p. 124–
1
2
3
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1
125 °C (lit.11 121–122 °C); H NMR (CDCl3): δ 8.14–8.16 (m, 2H,
PhH), 8.03–8.05 (m, 2H, PhH), 7.54–7.56 (m, 3H, PhH), 7.33–7.35
(m, 2H, PhH), 2.46 (s, 3H, CH3).
2-(4-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazole (3n): White solid,
m.p. 148–149 °C (lit.11 149–150 °C); 1H NMR (CDCl3): δ 8.13–8.15
(m, 2H, PhH), 8.08–8.10 (m, 2H, PhH), 7.53–7.55 (m, 3H, PhH),
7.04–7.05 (m, 2H, PhH), 3.90 (s, 3H, CH3).
4
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V. Summa, A. Petrocchi, F. Bonelli, et al., J. Med. Chem., 2008, 51, 5843.
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2-(3-Phenoxyphenyl)-5-phenyl-1,3,4-oxadiazole (3o): White solid,
m.p. 129–130 °C; 1H NMR (CDCl3): δ 8.13–8.14 (m, 2H, PhH), 7.88–
7.90 (m, 1H, PhH), 7.79 (s, 1H, PhH), 7.49–7.57 (m, 4H, PhH), 7.37–
7.41(m, 2H, PhH), 7.10–7.20 (m, 2H, PhH), 7.08–7.09(m, 2H, PhH);
13C NMR: δ 164.72, 164.13, 158.04, 156.48, 131.87, 130.63, 130.05,
129.13, 127.02, 125.47, 124.04, 123.78, 121.93, 121.65, 119.27,
116.95; Anal. Calcd for C20H14N2O2: C, 76.42; H, 4.49; N, 8.91.
Found: C, 76.34; H, 4.40; N, 8.85%.
2-(4-Chlorophenyl)-5-phenyl-1,3,4-oxadiazole (3p): White solid,
m.p. 161–162 °C (lit.11 161–162 °C); 1H NMR (CDCl3): δ 8.14–
8.16(m, 2H, PhH), 8.09–8.11 (m, 2H, PhH), 7.52–7.57 (m, 5H, PhH).
2-(4-Bromophenyl)-5-phenyl-1,3,4-oxadiazole (3q): White solid,
m.p. 169–170 °C (lit.11 169–170 °C); 1H NMR (CDCl3): δ 8.13–8.15
(m, 2H, PhH), 8.01–8.03 (m, 2H, PhH, 7.68–7.70 (m, 2H, PhH),
7.55–7.57 (m, 3H, PhH).
2-(4-Nitrophenyl)-5-phenyl-1,3,4-oxadiazole (3r): Yellow solid,
m.p. 200–201 °C (lit.10 196–198 °C); 1H NMR (CDCl3): δ 8.41–8.43
(m, 2H, PhH), 834–8.35 (m, 2H, PhH), 8.15–8.18 (m, 2H, PhH),
7.56–7.62 (m, 3H, PhH).
2-(Thiophen-2-yl)-5-phenyl-1,3,4-oxadiazole (3s): White solid,
m.p. 112–113 °C (lit.11 114–115 °C); 1H NMR (CDCl3): δ 8.12–8.14
(m, 2H, PhH), 7.85–7.86 (m, 1H, PhH), 7.54–8.59 (m, 4H, ArH),
7.20–7.22 (m, 1H, ArH).
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2-(Furan-2-yl)-5-phenyl-1,3,4-oxadiazole (3t): White solid, m.p.
100–102 °C (lit.11 98–100 °C); 1H NMR (CDCl3): δ 8.13–8.15 (m, 2H,
PhH), 7.68–7.69 (m, 1H, PhH), 7.52–8.57 (m, 3H, ArH), 7.25–7.26
(m, 1H, ArH), 6.64–6.65 (m, 1H, ArH).
2-(2-Bromophenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole (3u):
White solid, m.p. 139–141 °C; 1H NMR (CDCl3): δ 8.09–8.10 (m, 2H,
PhH), 8.04–8.05 (m, 2H, PhH), 7.45–7.49 (m, 1H, PhH), 7.38–7.41
(m, 1H, PhH), 7.03–7.05 (m, 2H, PhH), 3.90 (s, 3H, CH3); 13C NMR:
δ 165.10, 163.08, 162.55, 134.60, 132.41, 131.65, 128.92, 127.65,
125.40, 121.46, 116.18, 114.59, 55.52; Anal. Calcd for C15H11BrN2O2:
C, 54.40; H, 3.35%; N, 8.46. Found: C, 54.35; H, 3.40; N, 8.35%.
2-(3-Phenoxyphenyl)-5-o-tolyl-1,3,4-oxadiazole (3v): White solid,
m.p. 98–100 °C; 1H NMR (CDCl3): δ 8.01–8.03 (m, 1H, PhH), 7.86–
7.88 (m, 1H, PhH), 7.77–7.78 (m, 1H, PhH), 7.49(t, J = 8.0 Hz, 1H,
PhH), 7.33–7.45(m, 5H, PhH), 7.16–7.19(m, 2H, PhH), 7.07–7.09 (m,
2H, PhH), 2.75(s, 3H, CH3); 13C NMR: δ 165.01, 163.70, 158.10,
156.40, 138.51, 131.86, 130.64, 130.06, 129.02, 126.24, 125.53,
124.08, 122.89, 121.79, 121.57, 119.36, 116.83, 22.19; Anal. Calcd
for C21H16N2O2: C, 76.81; H, 4.91; N, 8.53. Found C 76.70; H, 5.00;
N, 8.47%.
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3325.
4-(5-Phenyl-1,3,4-oxadiazol-2-yl)-pyridine (3w): White solid, m.p.
1
154–156 °C (lit.14 m.p. 153 °C); H NMR (CDCl3): δ 8.86 (d, J =
5.9 Hz, 2H, ArH), 8.15–8.18 (m, 2H, ArH), 8.03–8.04 (m, 2H, PhH),
7.57–7.60 (m, 2H, PhH).
2-Methyl-5-phenyl-1,3,4-oxadiazole (3x): White solid, m.p. 114–
116 °C (lit.9 116 °C); 1H NMR (CDCl3): δ 8.02 (d, J = 8 Hz, 2H, PhH),
7.46–7.53 (m, 3H, PhH), 2.61 (s, 3H, CH3).
45 A. Blackhall, D.L. Brydon, A.J.G. Brydon and D.M. Smith, J. Chem. Soc.,
Perkin Trans.2, 1980, 0, 773.
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2-Benzyl-5-phenyl-1,3,4-oxadiazole (3y): White solid, m.p. 100–
102 °C (lit.46 102.3–102.8 °C); 1H NMR (CDCl3): δ 8.00–8.02 (m, 2H,

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