Metal-Free Synthesis of 1,3,4-Oxadiazoles from N′-(Arylmethyl)hydrazides or 1-(Arylmethyl)-2-(arylmethylene)hydrazines

Article abstract of DOI:10.1055/s-0034-1379974

An efficient and versatile metal-free synthesis of 1,3,4-oxadiazoles from N′-(arylmethyl)hydrazides or 1-(arylmethyl)-2-(arylmethylene)hydrazines through oxidative dehydrogenation is reported. A range of 2,5-disubstituted 1,3,4-oxadiazoles were prepared by treating N′-(arylmethyl)hydrazides with (diacetoxyiodo)benzene in acetonitrile or by treating 1-(arylmethyl)-2-(arylmethylene)hydrazines with [bis(trifluoroacetoxy)iodo]benzene in methyl tert-butyl ether. Aldehyde N-acylhydrazones and aldazines were initially generated in situ as intermediates.

Full text of DOI:10.1055/s-0034-1379974

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1032–1040
paper
1032
Z. Shang et al.
Paper
Synthesis
Metal-Free Synthesis of 1,3,4-Oxadiazoles from N′-(Arylmeth-
yl)hydrazides or 1-(Arylmethyl)-2-(arylmethylene)hydrazines
Zhenhua Shang*a,b
Qianqian Chua
Sheng Tan*c
H
H
I(III)
R2
N
R2
N
R1
N
R1
N
H
N
N
O
O
R2
R1
O
a College of Chemical and Pharmaceutical Engineering, Hebei University of
Science and Technology, Hebei Research Center of Pharmaceutical and Chemical
Engineering, Shijiazhuang 050018, P. R. of China
metal-free, oxidative dehydrogenation
N
R2
N
R2
I(III)
R1
N
R1
N
shangzhenhua@hebust.edu.cn
H
b State Key Laboratory Breeding Base, Hebei Province Key Laboratory of Molecular
Chemistry for Drugs, Shijiazhuang 050018, P. R. of China
c Shijiazhuang Chemical Engineering Institute, Shijiazhuang 050000, P. R. of China
tanshen1973@126.com
MeO
N
Received 03.09.2014
Accepted after revision: 11.12.2014
Published online: 02.02.2015
N
N
OMe
N
H
N
O
O2S
DOI: 10.1055/s-0034-1379974; Art ID: ss-2014-h0594-op
N
N
O
Abstract An efficient and versatile metal-free synthesis of 1,3,4-oxadi-
azoles from N′-(arylmethyl)hydrazides or 1-(arylmethyl)-2-(arylmeth-
ylene)hydrazines through oxidative dehydrogenation is reported. A
range of 2,5-disubstituted 1,3,4-oxadiazoles were prepared by treating
N′-(arylmethyl)hydrazides with (diacetoxyiodo)benzene in acetonitrile
or by treating 1-(arylmethyl)-2-(arylmethylene)hydrazines with [bis(tri-
fluoroacetoxy)iodo]benzene in methyl tert-butyl ether. Aldehyde N-
acylhydrazones and aldazines were initially generated in situ as inter-
mediates.
N
N
O
N
HO
zibotentan
anticancer agent
nesapidil
antihypertensive agent
O
N
N
O2N
O
O
NH2
Key words oxadiazoles, cyclizations, oxidations, hydrazines, hydra-
zides
F
O
furamizole
antibiotic
Me
OH
N
N
N
H
H
2,5-Disubstituted oxadiazoles are found in a wide vari-
ety of biologically active molecules of interest to the drug-
discovery community. Oxadiazole-containing compounds
have a broad spectrum of biological activities, including an-
tibacterial,1 antifungal,2 antiinflammatory,3 antiviral,4 anti-
cancer,5 antihypertensive,6 anticonvulsant, and antidiabet-
ic7 properties. Others display insecticidal8 or herbicidal9
properties. Furthermore, 2,5-dialkyl-1,3,4-oxadiazoles can
inhibit platelet aggregation10 and have attracted interest
from medicinal chemists for their use as bioisosteres for
carboxylic acids, esters, or carboxamides.11 Examples of
medicinally important compounds that contain a 1,3,4-oxa-
diazole moiety include raltegravir,4 zibotentan,5 nesapidil,6
and furamizole12 (Figure 1). Moreover, substituted oxadi-
azoles are useful in applied materials sciences, especially in
electron-transport devices and organic light-emitting di-
odes, as a consequence of their improved optoelectronic
properties.13
N
N
O
N
O
O
raltegravir
anti-HIV agent
Figure 1 Examples of medicinal compounds containing 1,3,4-oxadi-
azole moieties
The development of methods for synthesizing function-
alized oxadiazoles is therefore of great importance to syn-
thetic organic chemists. Various synthetic methods have
been developed for the synthesis of 2,5-disubstituted 1,3,4-
oxadiazoles. Commonly used routes for the synthesis of
1,3,4-oxadiazoles employ cyclodehydration reactions of
semicarbazides or cyclodesulfurization reactions of
thiosemicarbazides as major strategies (Scheme 1; method
A). These cyclization processes are typically effected by us-
ing thionyl chloride,14 phosphoryl chloride,15 or other re-
agents.16 An alternative route to 1,3,4-oxadiazoles involves
the oxidative cyclization of aldehyde N-acylhydrazones.
This reaction proceeds with transition metals such as lead,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1032–1040

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Z. Shang et al.
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Synthesis
O
previous work
R1
NHNH2
R2CH(OEt)3
or
R2NC
(method D)
O(S)
H
Pb4+, I(III)
N
N
SOCl2, POCl3
N
R2
R1
N
H
N
R2
R1
N
R1
R2
dehydration
(method A)
O
(method C)
O
Mn+, I(III, V)
(method B)
oxidative
dehydrogenation
H
N
R2
R1
N
this work
Ar
O
H
N
R
H
dehydrogenation
dehydrogenation
N
N
R
H
Ar
N
O
O
N
N
2
4
5
Ar
R
O
N
R
N
R
Ar
N
H
1
Ar
N
3
Scheme 1 Methods for the synthesis of 2,5-disubstituted 1,3,5-oxadiazoles
manganese, iron, cerium, or copper in their highest oxida-
tion states;17 with chloramine T, trichloroisocyanuric acid,
(diacetoxyiodo)benzene, the Dess–Martin reagent, or other
oxidants;18 or by electrochemical methods19 (Scheme 1,
method B). The use of aldazines as oxidative cyclization
precursors has been reported by LaMontagne and co-work-
ers20a and by us20b (Scheme 1, method C). Recently, synthe-
ses of 1,3,4-oxadiazoles by condensation of hydrazides with
triethyl orthoesters or isocyanides have been reported
(Scheme 1, method D).21
As part of our continuing studies on oxidative reac-
tions,22 we speculated that hydrazides 2 or hydrazones 3
might be dehydrogenated to form the corresponding alde-
hyde N-acylhydrazone or aldazine, which might be subse-
quently oxidized to form a 1,3,4-oxadiazole.
Table 1 Optimization of the Oxidative Cyclization of Hydrazide 2aa
N
N
H
N
N
H
O
O
2a
1a
Entry
Catalyst
Base (mmol)
Time (h)
Yield (%)
1
2
3
4
5
6
CuCl2
CuCl2
CuCl2
K2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (2)
15
15
15
15
15
15
48
48
50
41
34
38
Cu(OAc)2
CuSO4
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.5)
CuCl2
Reports in the literature suggest that copper(II)/base
combinations can convert secondary amines into imines by
oxidative dehydrogenation.23 On this basis, we began our
studies by treating N′-benzylbenzohydrazide (2a) with cop-
per(II) chloride and potassium carbonate in N,N-dimethyl-
formamide at 110 °C under air. Gratifyingly, 2,5-diphenyl-
1,3,4-oxadiazole (1a) was obtained in 38.3% yield after 15
hours. Encouraged by this result, we tested other copper
salts and various bases (Table 1). We found that both cop-
per(II) and copper(I) compounds can effect this transforma-
tion. Copper(II) chloride was selected as the best catalyst
and cesium carbonate was selected as the best base for pro-
moting the reaction.
a Reaction conditions: 2a (1 mmol), Cu catalyst (0.2 mmol), DMF (5 mL),
110 °C, stirring.
Although the results clearly show that N′-benzylbenzo-
hydrazide (2a) can be dehydrogenated and oxidized to give
the 1,3,4-oxadiazole (3a) under the given conditions, the
best yield was only 50% and the reaction time was very
long. There therefore remained an urgent need to develop
improved reaction conditions.
Somogyi reported that oxidative dehydrogenations of
benzothiazolines to give benzothiazoles can be effected by
using iron(III) chloride, potassium permanganate, hydrogen
peroxide, sodium periodate, or cerium(IV) ammonium ni-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1032–1040

1034
Z. Shang et al.
Paper
Synthesis
trate (CAN).24 In recent years, many attempts have been
made at tandem preparations of imines from amines.25 On
the basis of these reports in the literature, we tested several
oxidants for dehydrogenating hydrazide 2a (Table 2, entries
1–6), and we found that CAN effected the transformation to
give the product in yields of about 30% (entries 1, 2),
whereas only a 10% yield was obtained when potassium
permanganate was used (entry 3). Benzaldehyde was the
sole product obtained with iron or manganese reagents
(entries 4–6).
tert-butyl hydroperoxide (TBHP; 220 mol%) can be used to
effect a dehydrogenation.27 Inspired by the report, we tried
using tetrabutylammonium iodide as the catalyst with
TBHP or UHP as oxidants (entries 9 and 10); only TBHP oxi-
dized the substrate to give the desired product in a yield of
8.2%. On the basis of this finding, we tested other hyperva-
lent iodane compounds (entries 11 and 12), and we found
that (diacetoxyiodo)benzene was a better oxidant than
[bis(trifluoroacetoxy)iodo]benzene, giving oxadiazole 1a in
more than 70% yield.
Overall, with various metal inorganic salts, the yield of
the target product was relatively low, the best reaching only
32% (Table 2, entry 2). However, the use of iodanes resulted
in a marked improvement in the yield of the target com-
pound 1a, reaching as much as 75% when (diacetoxyio-
do)benzene was used as the oxidant (entry 12). Having
identified the optimal oxidant, we then screened various
solvents (entries 12–16), and we identified acetonitrile as
the best solvent.
Next, we examined the reactions of a wide range of sub-
strates, the results for which are presented in Table 3. The
method was found to be compatible with many substrates.
N-Acylhydrazones with aryl (entries 1–9 and 17–19), alkyl
Table 2 Oxidation of Hydrazide 2a to Oxadiazole 1a with Various Oxi-
dantsa
N
N
H
N
N
H
O
O
2a
1a
Time (h) Yield (%)
Entry Oxidant
Oxidant/2a ratio Solvent
1
2
CAN
CAN
2.2:1
MeCN
MeCN
acetone
CH2Cl2
acetone
AcOH
2
2
30
32
10
0
3.1:1
3
KMnO4
2.2:1
2
b
4
MnO2
2.2:1
3
Table 3 Oxidative Cyclization of Hydrazides 2 to Oxadiazoles 1a
5
FeCl3
FeCl3
2.2:1
4
0
6
2.2:1
4
0
N
N
H
PhI(OAc)2
N
R
7
MCPBA + PhI
UHPc + PhI
3:0.2:1
3:0.2:1
2.2:0.1:1
2.4:0.15:1
2.2:1
AcOH
1
59
trace
8
Ar
N
H
Ar
R
O
1
MeCN, 40 °C
O
8
AcOH
27
8
2
9
TBHPd + Bu4NI
UHPc + Bu4NI
PhI(O2CCF3)2
PhI(OAc)2
CHCl3
EtOAc
MeCN
10
11
20
2
nre
71
Entry Ar
R
Product Time (min) Yield (%)
1
2
Ph
Ph
1a
1b
1c
1d
1e
1f
120
110
120
110
110
125
120
145
128
120
120
110
105
120
110
110
156
120
120
75
12
13
14
15
16
2.2:1
2.2:1
2.2:1
2.2:1
2.2:1
MeCN
CH2Cl2
MeOH
THF
2
2
2
2
2
75
50
18
49
60
4-MeOC6H4
2-ClC6H4
Ph
58
3
Ph
41
4
2-BnO-3-MeOC6H3
3-O2NC6H4
Ph
Ph
68
CHCl3
5
Ph
trace
71
a Reaction conditions: 2a (1.0 mmol), solvent (20 mL), 40 °C, stirring.
b Commercial.
6
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
Me
c UHP = CO(NH2)2·H2O2.
d TBHP = t-BuOOH.
e nr = no reaction.
7
4-MeOC6H4
3-O2NC6H4
2-ClC6H4
1g
1h
1i
48
8
38
9
46
Recently, a catalytic strategy has been developed for
performing many representative types of oxidative bond-
forming reactions through mediation by iodobenzene,
which, in the presence of a suitable terminal oxidant such
as m-chloroperbenzoic acid or Oxone (potassium peroxy-
sulfate), generates an active hypervalent iodine(III) or io-
dine(V) species in situ.26 We therefore selected iodoben-
zene as a potential catalyst, and we found that the yield of
oxadiazole 1a was higher when m-chloroperbenzoic acid
was used as the oxidant than when urea–hydrogen perox-
ide [UHP; CO(NH2)2·H2O2] was used (Table 2, entries 7 and
8). Uanik and Chen and their co-workers reported that a
combination of tetrabutylammonium iodide (20 mol%) and
10
11
12
13
14
15
16
17
18
19
Ph
1j
48
4-MeOC6H4
2-BnO-3-MeOC6H3
3-O2NC6H4
Ph
Me
1k
1l
40
Me
45
Me
1m
1n
1o
1p
1q
1r
trace
68
OMe
OMe
OMe
2-furyl
2-furyl
2-furyl
4-MeOC6H4
3-O2NC6H4
Ph
60
72
43
4-MeOC6H4
3-O2NC6H4
71
1s
trace
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1032–1040

1035
Z. Shang et al.
Paper
Synthesis
(entries 10–13), or alkoxy substituents (entries 14–16)
were all suitable substrates. Whereas substrates with elec-
tron-donating substituents on the aryl group gave 1,3,4-
oxadiazoles, those with electron-withdrawing substituents
did not do so. Specifically, when R = OMe or 3-pyridyl and
Ar = 3-O2NC6H4, the corresponding oxadiazole was obtained
in good yield (entries 8 and 16). However, when R = Me or
Ph, and Ar = 3-O2NC6H4, only traces of the desired product
were obtained (entries 5, 13, and 19). Note also that when
the R = Me, the yield of the oxadiazole was lower than when
R = Ph, 3-pyridyl, or OMe.
Inspired by this successful oxidative dehydrogenation
and by our previous studies,20b in which aldazines were
smoothly oxidized with an organic iodine(III) reagent at
room temperature to form 1,3,4-oxadiazoles in good yields,
we reasoned that 1-(arylmethyl)-2-(arylmethylene)hydra-
zines (3) might be dehydrogenated to form the correspond-
ing aldazines, which, in turn, might be subsequently trans-
formed into 1,3,4-oxadiazoles. In our first attempt, we used
potassium persulfate as the oxidant and obtained no cy-
clization product (Table 4, entry 1). When we used Oxone,
we obtained the desired product, but in very low yield (8%;
entry 2). In oxidant screening tests with a variety of hyper-
valent iodine compounds, the solvent had a marked effect.
When dimethyl sulfoxide was used as the solvent, the reac-
tion was very slow and no cyclization product was detect-
ed; however, when acetonitrile was used, the reaction pro-
ceeded smoothly and the cyclization product could be de-
tected by TLC; however, yields were generally low. After a
series of screening experiments, we increased the yield to
48% (entry 15). The use of methyl tert-butyl ether as solvent
and [bis(trifluoroacetoxy)iodo]benzene as oxidant at 40 °C
gave good results in most solvents examined (entries 11–
16).
Having optimized the choice of oxidant, solvent, and
temperature for the synthesis, we extended this protocol to
the synthesis of various 1,3,4-oxadiazoles from the corre-
sponding 1-(arylmethyl)-2-(arylmethylene)hydrazines 3.
The results are summarized in Table 5.
Table 5 Oxidation of Various 1-(Arylmethyl)-2-(Arylmethylene)hydra-
zines 3a
N
N
PhI(OCOCF3)2
MTBE, 40 °C
N
R
Ar
N
H
Ar
R
O
1
3
Entry
Ar
R
Product Time
(min)
Yield
(%)
Table 4 Optimization of Oxidation of Hydrazone 3aa
1
2
Ph
Ph
Ph
1a
1b
1b
1d
1e
1e
1q
1r
1s
1t
–
240
210
240
225
360
360
240
240
480
60
48
63
48
58
40
52
43
44
44
4-MeOC6H4
Ph
N
N
3
4-MeOC6H4
Ph
N
4
2-BnO-3-MeOC6H3
3-O2NC6H4
Ph
N
H
O
5
Ph
3a
1a
Temp (°C) Time (h) Yield (%)
6
3-O2NC6H4
Ph
7
2-furyl
Entry Oxidant (equiv)
Solvent
8
4-MeOC6H4
3-O2NC6H4
Ph
2-furyl
1
2
3
4
5
K2S2O8 (2.2)
DMSO
MeNO2
DMSO
50
50
12
3
0
8
9
2-furyl
Oxone (3.1)/KBr
DDQ (1.2)/Ph3P (1)
10
11
12
3-Me2NC6H4
3-O2NC6H4
4-MeOC6H4
trace
100
30
24
12
12
0
3-O2NC6H4
4-MeOC6H4
240
225
nrb
52
PhIO (3.2)/Bu4NI (0.2) MeCN
PhIO (3.2)/Bu4NI (0.2) DMSO
14
1u
30 to
0b
a Reaction conditions: 2a (1.0 mmol), PhI(O2CCF3)2 (3.2 mmol), MTBE (20
100
30
30
30
mL), 40 °C, stirring.
IBXc (3.2)/Bu4NI (0.2) DMSO
Koser’s reagentd (3.2) DMSO
12
12
0
0
b nr = no reaction
6
7
8
9
The method was found to be compatible with a wide
range of substrates and gave yields of up to 63%. Substrates
in which the benzene rings were substituted by electron-
donating groups such as methoxy (Table 5, entries 2, 4, 8,
and 12) or with electron-withdrawing groups such as nitro
(entries 5 and 9) all gave 1,3,4-oxadiazoles successfully. In
general, when the Ar group was substituted with a nitro
group (entries 5 and 9) or dimethylamino group (entry 7),
the yields were lower than those from hydrazones contain-
ing a methoxy group, possibly as a result of resonance sta-
bilization by the methoxy group. The R group can be a phe-
nyl group (entries 2, 4, 5, and 12) or a heteroaryl group
Koser’s reagent (3.2)
PhI(OAC)2 (3.2)
MeCN
MeCN
0.5
25
12
40
1
10
11
12
13
14
15
16
PhI(CO2CF3)2 (3.2)
DMSO
MeCN
CH2Cl2
MeOH
DCE
MTBE
MeO(CH2)2OH
100
40
40
40
40
40
40
12
1
1
6
1
4
3
0
37
21
trace
35
48
39
a Reaction conditions: 3a (1.0 mol); solvent (20 mL), stirring.
b 0 = no target product.
c 1-hydroxy-1λ5,2-benziodoxol-1,3-dione.
d PhI(OH)OTs.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1032–1040

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Z. Shang et al.
Paper
Synthesis
(entries 7–9). 2-(4-Methoxyphenyl)-5-phenyl-1,3,4-oxadi-
azole (1b) could be prepared from either 1-benzyl-2-(4-
methoxybenzylidene)hydrazine (entry 2) or 1-ben-
zylidene-2-(4-methoxybenzyl)hydrazine (entry 3), because
of the symmetry of the 1,3,4-oxadiazole ring. 2-(3-Nitro-
phenyl)-5-phenyl-1,3,4-oxadiazole (1e) could be similarly
prepared from 1-benzyl-2-(3-nitrobenzylidene)hydrazine
(entry 5) or 1-benzylidene-2-(4-nitrobenzyl)hydrazine (en-
try 6). The yields were always higher when the R group
contained an electron-donating substituent (entries 2, 4,
and 12). Yields were generally lower with a heterocyclic
moiety as the R group, and the electronic properties of the
N-substituents play a role in the cyclization process (entries
7–9). When 4-[(benzylhydrazono)methyl]-N,N-dimeth-
ylaniline (3t) was oxidized, the major product was benzal-
dehyde (entry 10). No reaction occurred when 1-(3-nitro-
benzyl)-2-(3-nitrobenzylidene)hydrazine was used as the
substrate (entry 11), probably as a result of the poor solu-
bility of the substrate.
On the basis of the two oxidative dehydrogenative cy-
clizations described above, we propose the plausible mech-
anism shown in Scheme 2. First, the nitrogen atom of the
C–N group is attacked by ArI(X)2, and the sp3 carbon atom
adjacent to the nitrogen atom is activated, losing its hydro-
gen atom to form a carbon–nitrogen double bond. During
the reaction screening, we observed an interesting phe-
nomenon in that substrate 3 was oxidized into the corre-
sponding 1,3,4-oxadiazole in different ways depending on
the solvent. It was converted into the target molecule via
the corresponding aldazine (path a) in methyl tert-butyl
ether, but in acetonitrile the substrate was initially oxidized
to form the hydrazide 2 (path b). The mechanism of the ox-
idation of intermediates 4 and 5 by organoiodine(III) re-
agents to give 1,3,4-oxadiazoles has been previously report-
ed.18,20
When we monitored the reaction by TLC, a new inter-
mediate appeared and subsequently disappeared slowly as
the 1,3,4-oxadazole formed. We surmised that this inter-
mediate was the N-aldehyde acylhydrazone 4 or the al-
dazine 5, in accord with the proposed mechanism. We at-
tempted to confirm this hypothesis by using N′-benzylben-
zohydrazide (2a)22a and 1-benzyl-2-benzylidenehydrazine
(3a).20b During these reactions, obvious new spots were ob-
served on the TLC when it was subjected to ultraviolet irra-
diation (354 nm), and the corresponding new intermediates
were isolated and identified by NMR spectroscopy as N'-
(phenylmethylene)benzohydrazide (4a) and the diben-
zylidenehydrazine (5a). These findings confirmed our pro-
posed mechanism (see Supporting Information).
In conclusion, we have developed a general, mild, and
selective method for synthesizing 2,5-disubstituted 1,3,4-
oxadiazoles from N′-arylmethylhydrazides or 1-(arylmeth-
yl)-2-(arylmethylene)hydrazines. The reaction proceeds
through oxidative dehydrogenation and subsequent oxida-
tive cyclization in situ, and it tolerates a range of functional
groups. It therefore provides a straightforward and practi-
cal method for preparing a range of 1,3,4-oxadiazoles.
R1
H
H
N
H
ArI(X)2
– HX
N
R2
R2
R2
R1
N
N
R1
N
H
H
N
I
– HX
– ArI
O
O
O
X
Ar
4
2
N
N
R2
R1
H
ref. 18
OH
N
R2
R1
N
H
N
N
X
R2
R1
– ArI
– HX
path a: in MTBE
path b: in MeCN
O
1
Ar
X
I
N
H
R1
N
H
X
R2
ref. 20b
path b
R1
N
R2
ArI(X)2
N
R2
R2
R1
N
N
H
N
I
R1
N
H
– HX
– ArI
– HX
X
Ar
5
path a
3
Scheme 2 A plausible mechanism for the oxidative cyclization reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1032–1040

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Z. Shang et al.
Paper
Synthesis
Starting materials for the synthesis were obtained from commercial
sources and were used as received. All solvents were dried. Melting
points were determined on an X-4 micro hot stage and are uncorrect-
ed. IR spectra were recorded on a Bio-Rad FTS 3000 spectrophotome-
ter. 1H and 13C NMR spectra were recorded on Bruker AV 500 MHz
spectrometer with CDCl3 as the solvent and TMS as the internal stan-
dard. Mass spectra were recorded on a VG-Analytical AutoSpec Q in-
strument or an Agilent 6224 Accurate Mass TOF LC/MS spectrometer.
13C NMR (125 MHz, CDCl3): δ = 56.26, 70.94, 110.02, 113.51, 116.89,
120.27, 124.05, 126.69, 127.29, 128.13, 128.71, 129.06, 131.58,
136.36, 149.98, 151.22, 164.26, 164.55.
HRMS-ESI: m/z [M + Na]+ calcd for C22H18N2NaO3: 381.1215; found:
381.1209.
3-(5-Phenyl-1,3,4-oxadiazol-2-yl)pyridine (1f)
White solid; yield: 158 mg (71%); mp 133–134 °C (Lit.22a 131–132 °C).
IR (KBr): 1600, 1573, 1553, 1482, 1267 cm–1
.
1,3,4-Oxadiazoles 1 from N′-(arylmethyl)hydrazides 2; General
1H NMR (500 MHz, CDCl3): δ = 7.49–7.60 (m, 4 H), 8.15–8.17 (m, 2 H),
8.43–8.46 (m, 1 H), 8.81 (d, J = 4.5 Hz, 1 H), 9.37 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 120.50, 123.52, 123.86, 127.07,
129.20, 132.09, 134.17, 147.88, 152.43, 162.51, 165.10.
HRMS-ESI: m/z [M + Na]+ calcd for C13H9N3NaO: 246.0644; found:
Procedure
PhI(OAc)2 (0.7g, 2.2mmol) was added to a stirred solution of the
appropriate hydrazide 2 (1.0 mmol) in MeCN (20 mL) at 40 °C, and the
mixture was heated at 40 °C until the reaction was complete (TLC).
The solvent was then evaporated in vacuo, and the residue was
purified by column chromatography (silica gel; hexane–EtOAc, 1:10).
246.0639.
3-[5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]pyridine (1g)
White solid; yield: 122 mg (48%); mp 173 °C (Lit.22a 173–174 °C).
IR (KBr): 2960, 2927, 2874, 2851, 1729, 1618, 1503, 1438, 1314, 1276,
2,5-Diphenyl-1,3,4-oxadiazole (1a)
White solid; yield: 167 mg (75%); mp 138 °C (Lit.28 139–140 °C).
IR (KBr): 1616, 1503, 1264 cm–1
.
1266 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.54–8.17 (m, 10 H).
13C NMR (125 MHz, CDCl3): δ = 122.94, 125.90, 128.08, 130.70,
1H NMR (500 MHz, CDCl3): δ = 3.91 (s, 3 H), 7.04–7.07 (dd, J1 = 2 Hz,
J2 = 6 Hz, 2 H), 7.47–7.51 (m, 1 H), 8.08–8.11 (d, J1 = 2 Hz, J2 = 6 Hz, 2
H), 8.43 (dt, J1 = 8 Hz, J2 = 2 Hz, 1 H), 8.79 (d, J = 4 Hz, 1 H), 9.35 (s, 1
H).
163.58.
HRMS-ESI: m/z [M + Na]+ calcd for C14H10N2NaO: 245.0691; found:
245.0690.
13C NMR (125 MHz, CDCl3): δ = 55.50, 114.62, 115.96, 120.63, 123.81,
128.85, 130.89, 134.03, 147.74, 152.20, 162.63, 165.04.
HRMS-ESI: m/z [M + Na]+ calcd for C14H11NaN3O2: 276.0749; found:
276.0746.
2-(4-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazole (1b)
White solid; yield: 146 mg (58%); mp 150 °C (Lit.17f 151–152 °C).
IR (KBr): 2960, 1616, 1503, 1428, 1312, 1264 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.89 (s, 3 H), 7.03 (dd, J1 = 2 Hz, J2 = 6
Hz, 2 H), 7.52–7.55 (m, 3 H), 8.08 (dd, J1 = 2 Hz, J2 = 6 Hz, 2 H), 8.11–
8.14 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 54.42, 113.46, 115.36, 123.02, 125.76,
127.63, 127.99, 130.48, 161.30, 163.07, 163.48.
3-[5-(3-Nitrophenyl)-1,3,4-oxadiazol-2-yl]pyridine (1h)
White solid; yield: 102 mg (38%); mp 192 °C [Lit.29 135–137 °C
(EtOH)].
IR (KBr): 1596, 1524, 1354, 1288 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.53–7.56 (dd, J1 = 5 Hz, J2 = 8 Hz, 1 H),
7.78–7.82 (t, J = 3 Hz, 1 H), 8.44–8.49 (m, 2 H), 8.52–8.54 (d, J = 7.5 Hz,
1 H), 8.84–8.86 (d, J = 3.5 Hz, 1 H), 8.98 (s, 1 H), 9.41 (s, 1 H).
HRMS-ESI: m/z [M + Na]+ calcd for C15H12NaN2O2: 275.0797; found:
275.0791.
13C NMR (125 MHz, CDCl3): δ = 120.01, 121.91, 123.97, 125.22,
126.46, 130.59, 132.56, 134.39, 148.02, 148.76, 152.85, 163.22,
163.29.
2-(2-Chlorophenyl)-5-phenyl-1,3,4-oxadiazole (1c)
White solid; yield: 105 mg (41%); mp 97 °C (Lit.16a,b 96–97 °C).
IR (KBr): 1595, 1551, 1489, 1273, 779 cm–1
.
HRMS-ESI: m/z [M + Na]+ calcd for C13H8N4NaO3: 291.0494; found:
1H NMR (500 MHz, CDCl3): δ = 7.26–7.59 (m, 6 H), 8.10–8.12 (m, 1 H),
291.0497.
8.15–8.16 (m, 2 H).
3-[5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl]pyridine (1i)
13C NMR (125 MHz, CDCl3): δ = 123.28, 123.82, 127.08, 127.12,
129.12, 131.27, 131.29, 131.88, 132.40, 133.13, 163.07, 165.13.
White solid; yield: 118 mg (46%); mp 108–110 °C.
IR (KBr): 1599, 1541, 1262, 802 cm–1
.
HRMS-ESI: m/z [M + Na]+ calcd for C14H9ClN2NaO: 279.0301; found:
1H NMR (500 MHz, CDCl3): δ = 7.19–7.52 (m, 4 H), 8.04–8.06 (m, 1 H),
8.38 (d, J = 9 Hz, 1 H), 8.74 (s, 1 H), 9.31 (s, 1 H).
279.0300.
2-[4-(Benzyloxy)-3-methoxyphenyl]-5-phenyl-1,3,4-oxadiazole
(1d)
White solid; yield: 244 mg (68%); mp 178 °C (Lit.22a 174–175 °C).
13C NMR (125 MHz, CDCl3): δ = 120.37, 122.82, 123.91, 127.24,
131.33, 131.40, 132.75, 133.20, 134.26, 148.05, 152.59, 163.04,
163.57.
MS-ESI: m/z = 258.7 [M + H]+.
HRMS-ESI: m/z [M + Na]+ calcd for C13H8ClN3NaO: 280.0254; found:
IR (KBr): 2956, 2923, 2870, 2853, 1607, 1511, 1452, 1443, 1378, 1337,
1280, 1225 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.01 (s, 3 H), 5.25 (s, 2 H), 6.99–8.14
280.0247.
(m, 13 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1032–1040

1038
Z. Shang et al.
Paper
Synthesis
2-Methyl-5-phenyl-1,3,4-oxadiazole (1j)
HRMS-ESI: m/z [M + Na]+ calcd for C10H10N2NaO3: 229.0589; found:
White solid; yield: 77 mg (48%); mp 78 °C (Lit.22a 67–69 °C).
229.0582.
IR (KBr): 2927, 2854, 1580, 1449, 1351, 1247 cm–1
1H NMR (500 MHz, CDCl3): δ = 2.62 (s, 3 H), 7.5–7.53 (m, 3 H), 8.03
(dd, J1 = 1.5 Hz, J2 = 3 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 10.09, 123.00, 125.72, 127.99, 130.52,
162.60, 163.89.
.
2-Methoxy-5-(3-nitrophenyl)-1,3,4-oxadiazole (1p)
White solid; yield: 159 mg (72%); mp 147 °C.
IR (KBr): 2960, 2863, 1610, 1524, 1424, 1381, 1353, 1277 cm–1
1H NMR (500 MHz, CDCl3): δ = 4.29 (s, 3 H), 7.71 (t, J = 3 Hz, 1 H), 8.30
(d, J = 3 Hz, 1 H), 8.36 (dd, J1 = 1.5 Hz, J2 = 8.5 Hz, 1 H), 8.76 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 59.79, 120.99, 125.65, 130.30, 131.51,
.
HRMS-ESI: m/z [M + H]+ calcd for C9H9N2O: 161.0709; found:
161.0720.
131.55, 148.63, 158.84, 166.67.
2-(4-Methoxyphenyl)-5-methyl-1,3,4-oxadiazole (1k)
White solid; yield: 76 mg (40%); mp 91 °C (Lit.22a 91–92 °C).
IR (KBr): 2927, 2854, 1580, 1449, 1351, 1247 cm–1
MS-ESI: m/z = 222.2 [M + H]+.
HRMS-ESI: m/z [M + Na]+ calcd for C9H7N3NaO4: 244.0335; found:
244.0331.
1H NMR (500 MHz, CDCl3): δ = 2.60 (s, 3 H), 3.88 (s, 3 H), 6.99–7.97
(m, 4 H).
13C NMR (125 MHz, CDCl3): δ = 11.24, 55.59, 114.59, 116.73, 128.62,
162.32, 163.23, 164.97.
2-(2-Furyl)-5-phenyl-1,3,4-oxadiazole (1q)
White solid; yield: 91 mg (43%); mp 95–102 °C (Lit.22a 102–103 °C).
IR (KBr): 2965, 1635, 1521, 1263 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.13 (d, J = 7.5 Hz, 2 H), 7.24–7.68 (m, 5
HRMS-ESI: m/z [M + Na]+ calcd for C10H10N2NaO2: 213.0640; found:
H), 6.62–6.64 (m, 1 H).
213.0642.
13C NMR (125 MHz, CDCl3): δ = 112.36, 114.30, 123.63, 127.16,
2-[4-(Benzyloxy)-3-methoxyphenyl]-5-methyl-1,3,4-oxadiazole
(1l)
129.24, 132.01, 139.60, 145.91, 157.60, 164.11.
HRMS-ESI: m/z [M + Na]+ calcd for C12H8N2NaO2: 235.0484; found:
White solid; yield: 133 mg (45%); mp 119–120 °C.
235.0482.
IR (KBr): 2975, 2940, 2879, 2847, 1607, 1581, 1507, 1457, 1445, 1386,
1362, 1267, 1237 cm–1
.
2-(2-Furyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole (1r)
White solid; yield: 172 mg (71%); mp 129–137 °C (Lit.15 129–130 °C).
1H NMR (500 MHz, CDCl3): δ = 2.59 (s, 3 H), 3.97 (s, 3 H), 5.22 (s, 2 H),
6.96 (d, J = 8 Hz, 1 H), 7.32 (t, J = 2.5 Hz, 1 H), 7.38 (t, J = 2.5 Hz, 2 H),
7.44 (d, J = 2.5 Hz, 2 H), 7.51 (dd, J1 = 2 Hz, J2 = 8.5 Hz, 1 H), 7.58 (d, J =
2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 11.11, 56.22, 70.97, 109.86, 113.53,
117.04, 119.99, 127.29, 128.13, 128.71, 136.41, 149.96, 151.03,
163.22, 164.84.
IR (KBr): 2964, 1617, 1503, 1453, 1311, 1262 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.88 (3 H), 6.61–6.63 (m, 1 H), 7.03 (d,
J = 9 Hz, 2 H), 7.20–7.27 (m, 1 H), 7.66 (d, J = 1 Hz, 1 H), 8.06 (d, J = 9
Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 54.46, 111.12, 112.71, 113.49, 115.00,
127.75, 138.63, 144.52, 156.03, 161.45, 162.92.
MS-ESI: m/z = 297.3 [M + H]+.
HRMS-ESI: m/z [M + Na]+ calcd for C17H16N2NaO3: 319.1059; found:
HRMS-ESI: m/z [M + Na]+ calcd for C13H10N2NaO3: 265.0589; found:
265.0589.
319.1053.
1,3,4-Oxadiazoles 1 from 1-(Arylmethyl)-2-(arylmethylene)hydra-
zines 3; General Procedure
2-Methoxy-5-phenyl-1,3,4-oxadiazole (1n)
White solid; yield: 120 mg (68%); mp 49–50 °C (Lit.22a 45–48 °C).
IR (KBr): 2943, 1780, 1612, 1554, 1454, 1392, 1284 cm–1
1H NMR (500 MHz, CDCl3): δ = 4.24 (s, 3 H), 7.45–7.95 (m, 5 H).
13C NMR (125 MHz, CDCl3): δ = 59.38, 124.02, 126.04, 128.92, 131.22,
160.75, 166.34.
PhI(O2CCF3)2 (0.7 g, 3.2 mmol) was added to a stirred solution of the
appropriate hydrazine 3 (1.0 mmol) in MTBE (20 mL) at 40 °C, and the
mixture was heated at 40 °C. When the reaction was complete (TLC),
the solvent was evaporated in vacuo, and the residue was purified by
column chromatography (silica gel; hexane–EtOAc, 1:10).
.
HRMS-ESI: m/z [M + Na]+ calcd for C9H8N2NaO2: 199.0484; found:
199.0478.
2-(3-Nitrophenyl)-5-phenyl-1,3,4-oxadiazole (1e)
White solid; yield: 139 mg (52%); mp 152–153 °C (Lit.17b 153 °C).
IR (KBr): 1695, 1606, 1523, 1355, 1293 cm–1
.
2-Methoxy-5-(4-methoxyphenyl)-1,3,4-oxadiazole (1o)
1H NMR (500 MHz, CDCl3): δ = 7.55–7.62 (m, 3 H), 7.77 (t, J = 3 Hz, 1
H), 8.18 (dd, J1 = 1.5 Hz, J2 = 8 Hz, 2 H), 8.40–8.43 (m, 1 H), 8.50–8.53
(m, 1 H), 8.95 (t, J = 2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 121.81, 123.44, 125.69, 126.20,
127.22, 129.33, 130.56, 132.34, 132.56, 148.77, 162.77, 165.41.
White solid; yield: 124 mg (60%); mp 117–119 °C.
IR (KBr): 2960, 2841, 1780, 1614, 1505, 1450, 1311, 1257 cm–1
1H NMR (500 MHz, CDCl3): δ = 3.47 (s, 1 H), 3.84 (s, 3 H), 4.22 (s, 2 H),
6.95–6.98 (m, 2 H), 7.74–7.88 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 32.74, 55.54, 114.53, 116.38, 127.44,
153.30, 153.91, 162.28.
MS-ESI: m/z = 207.2 [M + H]+.
.
HRMS-ESI: m/z [M + Na]+ calcd for C14H9N3NaO3: 290.0542; found:
290.0536.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1032–1040

1039
Z. Shang et al.
Paper
Synthesis
2-(2-Furyl)-5-(3-nitrophenyl)-1,3,4-oxadiazole (1s)
White solid; yield: 113 mg (44%); mp 180–183 °C (Lit.22d 176–177 °C).
IR (KBr): 2964, 1638, 1524, 1354, 1262 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.41–8.96 (m, 3 H), 7.26–7.78 (m, 3 H),
6.66–6.68 (m, 1 H).
(5) (a) James, N. D.; Growcott, J. W. Drugs Future 2009, 34, 624.
(b) Valente, S.; Trisciuoglio, D.; De Luca, T.; Nebbioso, A.;
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.
13C NMR (125 MHz, CDCl3): δ = 112.46, 115.04, 121.86, 125.28,
126.25, 130.50, 132.54, 138.99, 146.28, 148.74, 158.10, 162.07.
(8) Zheng, X.; Li, Z.; Wang, Y.; Chen, W.; Huang, Q.; Liu, C.; Song, G.
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(9) Plant, A.; Boehmer, J. E.; Black, J.; Sparks, T. D. WO 2006024820,
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HRMS-ESI: m/z [M + Na]+ calcd for C12H7N3NaO4: 280.0335 found:
280.0337.
2,5-Bis(4-methoxyphenyl)-1,3,4-oxadiazole (1u)
White solid; yield: 147 mg (52%); mp 159–161 °C (Lit.15c 161.5 °C).
IR (KBr): 2940, 2835, 1611, 1587, 1436, 1257 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.89 (s, 6 H), 7.02 (d, J = 9 Hz, 4 H), 8.05
(d, J = 9 Hz, 4 H).
13C NMR (125 MHz, CDCl3): δ = 55.47, 114.47, 116.65, 128.58, 162.21,
(12) Ogata, M.; Atobe, H.; Kushida, H.; Yamamoto, K. J. Antibiot. 1971,
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164.10.
HRMS-ESI: m/z [M + Na]+ calcd for C16H14N2NaO3: 283.1077; found:
283.1082.
Acknowledgment
The project was supported by the Hebei Provincial Natural Science
Foundation of the China-Shijiazhuang Pharmaceutical Group (CSPC)
Foundation (H2012208045), the Hebei Hundred Innovative Talents
Support Program (II) (BR2-212), the 973 Program (No.
2012CB723501), and the Program for Innovative Research Team of
Hebei University of Science and Technology.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379974.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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