Propylene oxide assisted one-pot, tandem synthesis of substituted-1,3,4- oxadiazole-2(3H)-ones in water

Article abstract of DOI:10.1016/j.tet.2012.07.004

It has been developed for the synthesis of substituted-1,3,4-oxadiazole- 2(3H)-one derivatives via a novel one-pot, tandem procedure assisted by propylene oxide. The 5-substitued-1,3,4-oxadiazole-2(3H)-ones and 3,5-disubstitued-1,3,4-oxadiazole-2(3H)-ones were, respectively, obtained from three-component reaction of acylhydrazines, carbon disulfide, and propylene oxide, and four-component reaction of acylhydarazines, carbon disulfide, propylene oxide, and organic halides. The reactions were carried out using water as solvent in the presence of potassium phosphate to afford the expected products in good to excellent yields.

Full text of DOI:10.1016/j.tet.2012.07.004

Tetrahedron 68 (2012) 7978e7983
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Propylene oxide assisted one-pot, tandem synthesis of substituted-1,3,
4-oxadiazole-2(3H)-ones in water
*
*
Xu Yan, Shuo Zhou, Yuanqiang Wang, Zemei Ge , Tieming Cheng, Runtao Li
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
It has been developed for the synthesis of substituted-1,3,4-oxadiazole-2(3H)-one derivatives via a novel
one-pot, tandem procedure assisted by propylene oxide. The 5-substitued-1,3,4-oxadiazole-2(3H)-ones
and 3,5-disubstitued-1,3,4-oxadiazole-2(3H)-ones were, respectively, obtained from three-component
reaction of acylhydrazines, carbon disulfide, and propylene oxide, and four-component reaction of
acylhydarazines, carbon disulfide, propylene oxide, and organic halides. The reactions were carried out
using water as solvent in the presence of potassium phosphate to afford the expected products in good to
excellent yields.
Received 12 March 2012
Received in revised form 22 June 2012
Accepted 3 July 2012
Available online 7 July 2012
Keywords:
Substituted-1,3,4-oxadiazole-2(3H)-ones
One-pot
Ó 2012 Elsevier Ltd. All rights reserved.
Tandem procedure
Propylene oxide
Environmentally friendly
1. Introduction
1,3,4-Oxadiazole-2(3H)-one core is a privileged scaffold in me-
dicinal chemistry. A wide variety of substituted-1,3,4-oxadiazole-
2(3H)-ones have been found to exhibit a broad spectrum of bi-
ological activity. Recently successful examples include anti-HCV
and anti-tumor agents (1),1 antibacterial agents (2),2 openers of
large-conductance Ca2þ-activated potassium (Maxi-K) channels
(3),3 GABAA receptor agonists (4),4 selective monoamine oxidase B
inhibitors (5),5 and fungicides (6)6 (Scheme 1). In addition,
substituted-1,3,4-oxadiazole-2-ones, as functional tools, are widely
applied in the chemical synthesis.7
The representative procedures for the synthesis of substituted-
1,3,4-oxadiazole-2(3H)-ones are listed in Scheme 2. 5-Substituted-
1,3,4-oxadiazole-2(3H)-ones can be readily prepared from the re-
action of acylhydrazine with phosgene5a,b,7,8 or its substitutions,
such as triphosgene or N,N0-carbonyldiimidazole.1,2a,d,4 However,
phosgene and its substitutions are hazardous to use and display
poor long-term stability with the formation of side products in
some solvents, such as water and alcoholic media. Golfier and co-
workers tried to replace the phosgene with benzo-trichloride and
thionyl chloride,9 but the toxic and expensive reagents were still
not avoided. Recently, it was reported that 5-substitued-1,3,4-
oxadiazole-2(3H)-ones could be obtained from oxidation of 1,3,4-
oxadiazole-5-thioethers, which was prepared from the reaction of
Scheme 1. Structures of pharmacologically important substitued-1,3,4-oxadiazole-
2(3H)-ones.
acylhydrazine with carbon disulfide and methyl iodine in base
conditions.2b,6,7b Though this method could avoid the use of
phosgene or its substitutions, it involved the three-step reactions
and the use of oxidation reagent. For the preparation of 3,5-
disubstituted-1,3,4-oxadiazole-2(3H)-ones, usually there are two
strategies, one is carried out from the substitution of 5-substituted-
1,3,4-oxadiazole-2-(3H)-ones with alkyl halide; the other way is
from the cyclization of N-substituted-acylhydrazines with phos-
gene or selenium-activated carbon monoxide.3a,9b,10 More recently,
M. Bancerz and M. K. Georges reported a new procedure for the
synthesis of 3-methyl-5-aryl-1,3,4-oxadiazole-2(3H)-ones from the
* Corresponding authors. E-mail address: lirt@mail.bjmu.edu.cn (R. Li).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.004

X. Yan et al. / Tetrahedron 68 (2012) 7978e7983
7979
excellent yield, and the desire product 1,3,4-oxadiazole-5-thioether
9 was not detected (Scheme 4).
R2X, CS2
O
N
N
R2
R1
R1
NHNH2
S
K3PO4
H2O
O
8
7
Scheme 3. Synthesis of 1,3,4-oxadiazole-5-thioether.
N
N
S
OH
O
O
9
a) K3PO4, CS2
Scheme 2. Reported methods for synthesis of substituted-1,3,4-oxadiazole-2(3H)-
ones.
NHNH2
O
b)
NH
N
O
O
7a
hydrolysis of cycloaddition products of tetrazinone ring.11 Ravindra
and co-workers converted 1,2,3-oxadiazoles to subtituted-1,3,4-
oxadiazole-2(3H)-ones under the catalysis of bromine and acetic
anhydride.12 However, there are several disadvantages to these
methods, such as the use of the toxic reagents, the expensive cat-
alysts and/or the harmful organic solvents; the unsatisfactory
yields (40e70%); and multistep procedures. Therefore, it remains
a challenge to develop more environmentally friendly and efficient
procedure for the synthesis of substituted-1,3,4-oxadiazole-2(3H)-
ones.
10a
Scheme 4. Reaction of benzonyl hydrazine 7a, carbon disulfide, and propylene oxide.
It is apparent that this novel one-step, multi-component pro-
cedure for the synthesis of 5-substituted-1,3,4-oxadiazole-2(3H)-
ones is more environmentally friendly and convenient than the
known methods. Thus, the scope and the limitation of this pro-
cedure were examined. As showed in Table 1, all the selected
acylhydrazines 7, such as alkyl, aryl, and heteroaromatic acylhy-
drazines, could smoothly react with carbon disulfide and propylene
oxide to afford the corresponding 5-substituted-1,3,4-oxadiazole-
2(3H)-ones 10 in good to excellent yields within 4 h (Table 1, entries
1e12). The electronic features of the substituent groups on the
aromatic acylhydrazines did not obviously influence the reaction.
Meanwhile, due to the mild reaction conditions, the reaction has
good tolerance to sensitive functional groups in substrates, such as
amino, hydroxyl and methoxy groups (Table 1, entries 3, 4, and12).
After obtaining the satisfactory results for the synthesis of
5-substituted-1,3,4-oxadiaozle-2(3H)-ones, we then turned our
attention to the preparation of 3,5-disubstituted-1,3,4-oxadiaozle-
2(3H)-ones 11. We noticed that 3,5-disubstituted-1,3,4-oxadiaozle-
2(3H)-ones 11 could be prepared from the substitution of
5-substituted-1,3,4-oxadiaozle-2(3H)-ones 10 with organic halides
2. Results and discussion
In previous work, we developed a simple one-pot procedure for
the preparation of 1,3,4-oxadiazole-5-thioethers 8 by the reaction
of acylhydrazines 7 with carbon disulfide and organic halides in the
presence of potassium phosphate in water (Scheme 3).13 As a con-
tinuous effort to extent the application scope of this method, we
intend to use epoxy compounds instead of organic halides. To our
surprise, when the reaction of benzonyl hydrazine 7a, carbon
disulfide, and propylene oxide was carried out in the presence of
potassium phosphate at refluxing temperature in water,
5-benzonyl-1,3,4-oxadiazole-2(3H)-one 10a was obtained in
Table 1
One-pot, multi-component synthesis of substituted-1,3,4-oxadiazole-2(3H)-ones in water
O
R1
NHNH2
R2
N
1) K3PO4, H2O
7
N
K3PO4, H2O
NH
r.t
N
O
O
+
R1
R2-X
O
R1
2) TBAI,
r.t
O
O
r.t
CS2
11
10
Entry
R1
R2X
Product
10a
Time (h)
Yielda (%)
1
2
3
92
91
10b
3.5
Br
3
4
10c
10d
3.5
4
91
H3CO
H2N
83
(continued on next page)

7980
X. Yan et al. / Tetrahedron 68 (2012) 7978e7983
Table 1 (continued )
Entry
R1
R2X
Product
Time (h)
4
Yielda (%)
88
5
6
10e
N
10f
4
90
N
7
8
10g
10h
2.5
4
79
83
N
N
9
10i
4
92
10
11
10j
3
3
89
94
O
10k
F3C
12
10l
4
87
OH
Cl
13
14
15
11a
11b
11c
3.5
3.5
3.5
92
89
90
O
Cl
O
16
17
18
19
11d
11e
11f
11g
3.5
3.5
3.5
3.5
82
87
84
91
Br
N
Br
O
S
O
Cl
Cl
20
21
11h
3
5
4
86
90
Br
OH
F3C
Cl
a
Isolated yield.
under basic condition, which is similar to the one of the forming
5-substituted-1,3,4-oxadiaozle-2(3H)-ones 10. Therefore, we try to
combine these two procedures into a one-pot tandem method for
the synthesis of 3,5-disubstituted-1,3,4-oxadiazole-2(3H)-ones 11.
The result showed that acylhydrazine reacted with carbon
disulfide, and then treated with propylene oxide and benzyl chloride
in one-pot did produce the desired product 3-benzyl-5-phenyl-
1,3,4-oxadiazole-2(3H)-one 11a in 92% yield, when the reaction was
performed in the presence of potassium phosphate in water.
The scope of this simple process was explored by using a variety
of structurally diverse organic halides. In all cases studied, no
matter whether the active organic halides, which contained ester,
nitrile, alkene, or the inactive organic halides, such as methyl iodide
were used, the reactions proceeded smoothly to afford the desired
3,5-disubstituted-1,3,4-oxadiazole-2(3H)-ones 11 in good to ex-
cellent yields (Table 1, entries 13e20).
To further illustrate the synthetic usage of the present method,
we successfully synthesized compound 3, an important neuro-
protective agent, in 90% yield under our conditions. Compared with
reported method, our method is more efficient and environmen-
tally friendly.3a
The possible pathway for the formation of 1,3,4-oxadiaozle-
2(3H)-ones is proposed in Scheme 5. Acylhydrazine 7 reacted with
carbon disulfide to form the intermediate 12, which lost 1 mol of
potassium hydrosulfide to afford the closed-ring intermediate 13.
Then, the nucleophilic ring-opening reaction of 13 with propylene

X. Yan et al. / Tetrahedron 68 (2012) 7978e7983
7981
oxide was taken place affording the key intermediate
b
-hydrox-
spectra were determined in CDCl3 or DMSO on a Bruke 400 MHz
spectrometer and chemical shifts were reported in parts per million
ysulfide 14. Subsequently, the intramolecular nucleophilic addition
of 14 led to the spiro intermediate 15. Afterward, the ring-opening
reaction of 15 and loss of 2-methylthiirane afforded the desired
product 10. It is obvious that the propylene oxide plays an important
role in this process.
from internal TMS (
chemical shift
d
). Data for 1H NMR are recorded as follows:
(d
,
ppm), multiplicity (integration, s¼singlet,
d¼doublet, t¼triplet, qn¼quintet, m¼multiplet or unresolved,
coupling constant(s) in hertz). Column chromatography was per-
formed with 200e300 mesh silica gel using flash column tech-
niques. All of the reagents were used directly as obtained
commercially unless otherwise noted.
N
O
O
N
H
N
CS2, K3PO4
H2O, r.t
K3PO4
-HSK
SH
SK
NH2
R
N
H
R
N
H
O
R
S
N
7
12
13
4.2. General procedure for the synthesis of 5-substituted-
1,3,4-oxadiazole-2(3H)-ones (10)
H
N
HO
O
HS
N
O
N
N
N
K3PO4
S
O
A mixture of the corresponding acylhydrazine (3 mmol), po-
tassium phosphate (1.02 g, 3 mmol), and carbon disulfide (0.23 g,
3 mmol) in water (15 mL) was stirred at rt for 10 min. After
refluxing for an additional 2e3 h, propylene oxide (0.18 g, 3 mmol)
was added. Stirring was continued at rt until the intermediate
convert completely (monitored by TLC, about 0.5e1 h), the mixture
was extracted with EtOAc (3ꢀ10 mL). The combined organic layer
was washed with water and dried over Na2SO4. The solvent was
evaporated under reduced pressure, and the residue was purified
by recrystallization or silica gel column to afford the corresponding
product 10ael.
O
O
S
R
R
O
R
14
15
NH
N
S
O
+
O
R
10
Scheme 5. Possible mechanism of the formation of 1,3,4-oxadiazole-2-(3H)-ones.
To confirm this possible mechanism, we prepared the important
intermediate14(R¼Ph)bythereactionoftheintermediate13(R¼Ph)
with propylene oxide in CH2Cl2 in the presence of triethylamine. It
was found that the 14 could convert to the product 10a under our
reaction conditions. To prove theexistence ofby-product thiirane, we
replaced propylene oxide with styrene oxide, reaction proceeded
smoothly to afford product 10a and by-product 2-phenylthiirane 16
(Scheme 6). In addition, the reactions recently developed by Wang
and co-workers also support this possible mechanism.14
4.2.1. 5-Phenyl-oxadiazole-2(3H)-one (10a).7b Colorless crystal.
Mp: 138e139 ꢁC (lit.139e140 ꢁC). 1H NMR (300 MHz, CDCl3):
(s, 1H), 7.85e7.89 (dd, 2H), 7.46e7.54 (m, 3H).
d 9.27
4.2.2. 5-(4-Bromophenyl)-1,3,4-oxadiazol-2(3H)-one (10b).7b Color-
less crystal. Mp: 241e242 ꢁC (lit. 244e245 ꢁC). 1H NMR (300 MHz,
CDCl3):
d 9.12 (s, 1H), 7.98e8.02 (m, 2H), 7.67e7.71 (m, 2H).
HO
K3PO4, H2O
N
NH
TEA, CH2Cl2
O
N
N
N
N
4.2.3. 5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2(3H)-one (10c).15 Color-
less crystal. Mp: 183e184 ꢁC (lit. 186e187 ꢁC). 1H NMR (300 MHz,
C6H5
O
O
SH
C6H5
C6H5
S
O
O
10a
13
14
CDCl3):
(s, 3H).
d 9.07 (s, 1H), 7.78e7.94 (m, 2H), 6.91e7.02 (m, 2H), 3.88
O
N
NH
4.2.4. 5-(4-Aminophenyl)-1,3,4-oxadiazol-2(3H)-one (10d).16 White
solid. Mp: 168e169 ꢁC (lit.163e165 ꢁC). 1H NMR (400 MHz, DMSO):
CS2, K3PO4, H2O
S
Ph
NH2
C6H5
O
+
N
O
H
O
Ph
16
10a
d
6.64e6.62 (d, 2H, J¼8.4 Hz), 6.64e6.62 (d, 2H, J¼8.4 Hz).
Scheme 6. The testing experiment of possible mechanism of the formation of 1,3,4-
oxadiazole-2-(3H)-ones.
4.2.5. 5-(Pyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one
(10e).2e White
solid. Mp: 195e196 ꢁC (lit. 198e200 ꢁC). 1H NMR (400 MHz, DMSO)
12.80 (s, 1H), 9.06e8.84 (s, 1H), 8.71 (s, 1H), 8.16 (s, 1H), 7.55
3. Conclusion
d
(s, 1H).
In summary, we have developed a one-pot tandem synthesis of
5-substituted-1,3,4-oxadiazole-2-(3H)-ones from three-component
reaction of acylhydrazine, carbon disulfide, and propylene oxide,
and 3,5-disubstituted-1,3,4-oxadiazole-2-(3H)-ones from four-
component reaction of acylhydrazine, carbon disulfide, propylene
oxide, and organic halides. Avarietyof substituted-1,3,4-oxadiazole-
2-(3H)-one derivatives were obtained in good to excellent yields.
Additionally, this new procedure associated by propylene oxide was
carried out in water at mild reaction condition. The environmentally
friendly reaction conditions and a broad substrate scope will make
this method widely applicable in the synthesis of diverse
substituted-1,3,4-oxadiazole-2-(3H)-one derivatives.
4.2.6. 5-(Pyridin-4-yl)-1,3,4-oxadiazol-2(3H)-one
(10f).7c White
solid. Mp: decomposed 273 ꢁC (lit. decomposed 279 ꢁC). 1H NMR
(400 MHz, DMSO)
d 8.79e8.67 (m, 2H), 7.75e7.62 (m, 2H).
4.2.7. 5-Methyl-1,3,4-oxadiazol-2(3H)-one (10g).17 White solid.
Mp: 116e117 ꢁC (lit. 110e111 ꢁC). 1H NMR (400 MHz, CDCl3)
d 9.62
(s, 1H), 2.27 (s, 3H).
4.2.8. 5-Benzyl-1,3,4-oxadiazol-2(3H)-one (10h).7c Colorless crys-
tal. Mp: 43e45 ꢁC (lit. 47e50 ꢁC). 1H NMR (400 MHz, CDCl3)
d 10.14
(s, 1H), 7.31 (m, 5H), 3.86 (s, 2H).
4. Experimental section
4.1. General
4.2.9. 5-(Pyrazin-2-yl)-1,3,4-oxadiazol-2(3H)-one
solid. Mp: 204e205 ꢁC (lit. 208e210 ꢁC). 1H NMR (400 MHz, DMSO)
12.96 (s, 1H), 9.12 (d, J¼1.2 Hz, 1H), 8.81 (dd, J¼6.4, 2.0 Hz, 2H).
(10i).2e White
d
All melting points were measured on a melting point apparatus
with a microscope and a hot stage and were uncorrected. 1H NMR
4.2.10. 5-(Furan-2-yl)-1,3,4-oxadiazol-2(3H)-one (10j).7c Colorless
crystal. Mp: 106e108 ꢁC (lit. 111e114 ꢁC). 1H NMR (400 MHz, CDCl3)

7982
X. Yan et al. / Tetrahedron 68 (2012) 7978e7983
d
9.71 (s, 1H), 7.61 (d, J¼1.0 Hz, 1H), 7.02 (d, J¼3.5 Hz, 1H), 6.57 (dd,
(s, 2H), 3.87 (s, 2H). 13C NMR (100 MHz, CDCl3)
d 154.96, 153.96,
134.99, 132.98, 128.94, 128.89, 128.88, 128.37, 128.29, 127.77, 49.48,
32.98. Anal. Calcd for C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found:
C, 71.88; H, 5.51; N, 10.28.
J¼3.5, 1.8 Hz, 1H).
4.2.11. 5-(4-(Trifluoromethyl)phenyl)-1,3,4-oxadiazol-2(3H)-one
(10k).3a White solid. Mp: 144e145 ꢁC (lit. 144e145 ꢁC). 1H NMR
(400 MHz, DMSO)
J¼8.4 Hz, 2H).
d
12.81 (s, 1H), 8.00 (d, J¼8.2 Hz, 2H), 7.91 (d,
4.3.9. 3-(4-Chloro-2-hydroxybenzyl)-5-(4-(trifluoromethyl)phenyl)-
1,3,4-oxadiazol-2(3H)-one (3).3a White solid. Mp: 218e219 ꢁC (lit.
217e218 ꢁC). 1H NMR (400 MHz, DMSO)
d
7.94 (dd, J¼34.1, 8.3 Hz,
4.2.12. 5-(2-Hydroxyphenyl)-1,3,4-oxadiazol-2(3H)-one
White solid. Mp: 197e199 ꢁC (lit. 197e199 ꢁC). 1H NMR (300 MHz,
CDCl3) 12.49 (s, 1H), 10.01 (s, 1H), 7.57e7.54 (m, 1H), 7.40e7.36 (m,
(4l).15
4H), 7.30 (d, J¼2.6 Hz, 1H), 7.21 (dd, J¼8.6, 2.7 Hz, 1H), 6.86 (d,
J¼8.6 Hz, 1H), 4.90 (s, 2H).
d
1H), 7.02e6.91 (m, 2H).
4.4. Synthesis of 5-phenyl-1,3,4-oxadiazole-2-thiol (13)
4.3. General procedure for the synthesis of 3,5-disubstituted-1,3,4-
oxadiazole-2(3H)-ones (11) A mixture of the corresponding acyl-
hydrazine (3 mmol), potassium phosphate (1.02 g, 3 mmol), and
carbon disulfide (0.23 g, 3 mmol) in water (15 mL) was stirred at rt
for 10 min. After refluxing for an additional 2e3 h, propylene oxide
(0.18 g, 3 mmol) was added. Stirring was continued at rt until the
intermediate convert completely (monitored by TLC, about 0.5e1 h),
and then organic halide (3 mmol) and TBAI (0.3 mmol) were added.
After refluxing for 0.5 h, the mixture was extracted with EtOAc
(3ꢀ10 mL). The combined organic layer was washed with water and
dried over Na2SO4. The solvent was evaporated under reduced
pressure, and the residue was purified by recrystallization or silica
gel column to afford the corresponding product 11aeh.
A
mixture of benzohydrazine (0.41 g, 3 mmol), potassium
phosphate (1.02 g, 3 mmol), and carbon disulfide (0.23 g, 3 mmol)
in water (15 mL) was stirred at rt for 10 min. After refluxing for an
additional 2 h, 1 N HCl was added to pH¼7, the solid formed was
filtered and dried in vacuum to afford 5-phenyl-1,3,4-oxadiazole-2-
thiol 13 (0.51 g, 96%) as a white solid. Mp: 197e199 ꢁC (lit.22
199e201 ꢁC). 1H NMR (400 MHz, CDCl3)
J¼7.2 Hz, 2H), 7.42e7.65 (m, 3H).
d 10.52 (br s, 1H), 7.93 (d,
4.5. Synthesis of 1-(5-phenyl-1,3,4-oxadiazol-2-ylthio)
propan-2-ol (14)
A mixture of 5-phenyl-1,3,4-oxadiazole-2-thiol (3 mmol), TEA
(0.30 g, 3 mmol), and propylene oxide (0.18 g, 3 mmol) in DCM was
stirred at rt for 6 h. The mixture was washed with water and brine,
dried over Na2SO4, concentrated, and purified by silica gel column
to afford the corresponding product 14 in 95% yield. White solid.
4.3.1. 3-Benzyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (11a).18 White
solid. Mp: 118e119 ꢁC (lit. 118e120 ꢁC). 1H NMR (400 MHz, CDCl3)
d
7.83 (d, J¼7.7 Hz, 2H), 7.60e7.29 (m, 7H), 4.96 (s, 2H).
Mp: 68e69 ꢁC. 1H NMR (400 MHz, CDCl3)
d 8.06e7.93 (m, 2H),
4.3.2. 3-Methyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (11b).19 White
solid. Mp: 106e107 ꢁC (lit. 105e106 ꢁC). 1H NMR (400 MHz, CDCl3)
7.63e7.41 (m, 3H), 4.40e4.20 (m, 1H), 3.51 (dd, J¼13.9, 4.0 Hz, 1H),
3.31 (dd, J¼13.9, 7.2 Hz, 2H), 1.39 (d, J¼6.3 Hz, 3H). 13C NMR
d
7.92e7.73 (m, 2H), 7.55e7.38 (m, 3H), 3.49 (s, 3H).
(100 MHz, CDCl3)
d 165.90, 164.79, 131.74, 129.05, 126.67, 123.46,
4.3.3. Ethyl 2-(2-oxo-5-phenyl-1,3,4-oxadiazol-3-yl)acetate (11c).20
White solid. Mp: 82e84 ꢁC (lit. 91 ꢁC). 1H NMR (400 MHz, CDCl3)
66.66, 40.97, 22.27. Anal. Calcd for C11H12N2O2S: C, 55.91; H, 5.12; N,
11.86. Found: C, 55.88; H, 5.51; N, 11.94.
d
7.84 (d, J¼7.6 Hz, 2H), 7.49 (td, J¼14.4, 7.1 Hz, 3H), 4.59 (d,
J¼6.9 Hz, 2H), 3.82 (d, J¼6.9 Hz, 3H).
4.6. Synthesis of 5-phenyl-oxadiazole-2(3H)-one (10a) with
styrene oxide as OeS exchanging reagent
4.3.4. 3-(2-Oxo-5-phenyl-1,3,4-oxadiazol-3-yl)propanenitrile
(11d).5b White solid. Mp: 118e119 ꢁC (lit. 121 ꢁC). 1H NMR
A
mixture of benzohydrazine (0.41 g, 3 mmol), potassium
(400 MHz, CDCl3)
4.13 (t, J¼6.9 Hz, 2H), 2.91 (t, J¼6.9 Hz, 2H).
d
7.87e7.81 (m, 2H), 7.52 (dq, J¼14.5, 7.2 Hz, 3H),
phosphate (1.02 g, 3 mmol), and carbon disulfide (0.23 g, 3 mmol)
in water (15 mL) was stirred at rt for 10 min. After refluxing for an
additional 2 h, styrene oxide (0.36 g, 3 mmol) was added. Stirring
was continued at 70 ꢁC for 1 h, the mixture was extracted with
EtOAc (3ꢀ10 mL). The combined organic layer was washed with
water and dried over Na2SO4. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel column
to afford the desired product 10a (0.46 g, 94%), and by-product 2-
phenylthiirane 16, which is consistent with literature.23 1H NMR
4.3.5. 3-Allyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one
(11e).21 White
solid. Mp: 58e59 ꢁC (lit. 58e59 ꢁC). 1H NMR (400 MHz, CDCl3)
d
7.94e7.73 (m, 1H), 7.56e7.37 (m, 2H), 5.95 (ddt, J¼16.2, 10.3,
5.9 Hz, 1H), 5.34 (dd, J¼23.0, 5.6 Hz, 1H), 4.40 (d, J¼5.9 Hz, 1H).
4.3.6. 3-Butyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (11f) White solid.
Mp: 42e43 ꢁC. 1H NMR (400 MHz, CDCl3)
d 7.85e7.78 (m, 1H),
(400 MHz, CDCl3)
(dd, J¼6.6, 1.37 Hz, 1H), 2.64 (dd, J¼5.7, 1.37 Hz, 1H).
d
7.27e7.33 (m, 5H), 3.88 (t, J¼6.1 Hz, 1H), 2.86
7.50e7.41 (m, 1H), 3.81e3.73 (m, 1H), 1.85e1.70 (m, 1H), 1.45e1.32
(m, 1H), 0.96 (t, J¼7.4 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 153.57,
153.05, 131.36, 128.89, 125.54, 124.00, 45.69, 30.18, 19.59, 13.49.
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
65.93; H, 6.33; N, 12.59.
Acknowledgements
The authors thank the National Natural Science Foundation of
China (No. 21172011) and the State Key New Drug Development
Program (contract grant No. 2009ZX09103-131) for financial
support.
4.3.7. 5-Phenyl-3-tosyl-1,3,4-oxadiazol-2(3H)-one (11g) White solid.
Mp: 144e146 ꢁC. 1H NMR (400 MHz, DMSO)
7.84e7.75 (m, 2H), 7.72e7.48 (m, 6H), 2.42 (s, 3H). Anal. Calcd for
C15H12N2O4S: C, 56.95; H, 3.82; N, 8.86. Found: C, 56.89; H, 4.21; N,
9.39.
d
7.94 (d, J¼8.4 Hz, 2H),
Supplementary data
4.3.8. 3,5-Dibenzyl-1,3,4-oxadiazol-2(3H)-one (11h) White solid.
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.07.004.
Mp: 47e49 ꢁC. 1H NMR (400 MHz, CDCl3)
d 7.46e7.21 (m, 10H), 4.86

X. Yan et al. / Tetrahedron 68 (2012) 7978e7983
7983
E.; Chernitsa, B.; Yakovlev, V. Russ. J. Org. Chem. 2006, 42, 1089e1090; (c) Levins,
C.; Wan, Z. Org. Lett. 2008, 10, 1755e1758.
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