I2-mediated oxidative C-O bond formation for the synthesis of 1,3,4-oxadiazoles from aldehydes and hydrazides

Article abstract of DOI:10.1021/jo401751h

A practical and transition-metal-free oxidative cyclization of acylhydrazones into 1,3,4-oxadiazoles has been developed by employing stoichiometric molecular iodine in the presence of potassium carbonate. The conditions of this cyclization reaction also work well with crude acylhydrazone substrates obtained from the condensation of aldehydes and hydrazides. A series of symmetrical and asymmetrical 2,5-disubstituted (aryl, alkyl, and/or vinyl) 1,3,4-oxadiazoles can be conveniently generated in an efficient and scalable fashion.

Full text of DOI:10.1021/jo401751h

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Article
I2-Mediated Oxidative C-O Bond Formation for the Synthesis
of 1,3,4-Oxadiazoles from Aldehydes and Hydrazides
Wenquan Yu, Gang Huang, Yueteng Zhang, Hongxu Liu,
Lihong Dong, Xuejun Yu, Yujiang Li, and Junbiao Chang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401751h • Publication Date (Web): 23 Sep 2013
Downloaded from http://pubs.acs.org on September 24, 2013
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I2-Mediated Oxidative C−O Bond Formation for the Synthesis of
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1,3,4-Oxadiazoles from Aldehydes and Hydrazides
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Wenquan Yu,*,† Gang Huang,† Yueteng Zhang,† Hongxu Liu,† Lihong Dong,‡ Xuejun Yu,‡ Yujiang
Li,‡ Junbiao Chang*,†,‡
†College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan
Province 450001, China
‡High and New Technology Research Center of Henan Academy of Sciences, Zhengzhou, Henan
Province 450002, China
changjunbiao@zzu.edu.cn; wenquan_yu@zzu.edu.cn
Abstract: A practical and transition metal-free oxidative cyclization of acylhydrazones into
1,3,4-oxadiazoles has been developed by employing stoichiometric molecular iodine in the
presence of potassium carbonate. The conditions of this cyclization reaction also work well with
crude acylhydrazone substrates obtained from the condensation of aldehydes and hydrazides. A
series of symmetrical and asymmetrical 2,5-disubstituted (aryl, alkyl and/or vinyl)
1,3,4-oxadiazoles can be conveniently generated in an efficient and scalable fashion.
Introduction
The intramolecular carbon−oxygen (C−O) bond formation via the oxidation of carbon−hydrogen
(C−H) and oxygen−hydrogen (O−H) bonds has become a very useful tool for the construction of
oxygen-containing heterocycles, which resulted in the discovery of numerous novel synthetic
methods.1-10 Compared with the coupling cyclization (Scheme 1), this oxidative cyclization
strategy does not require prefunctionalization of the reaction center, which makes the substrates
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more accessible and allows more efficient synthesis of structurally diverse products. Many recent
developments published in literature, however, require the use of hypervalent iodine,1,2 transition
metal-catalyzed aerobic oxidative cyclization,3 FeCl3,4 etc. In this work, we report a simple,
molecular iodine-mediated and transition metal-free approach that oxidatively forms the C−O
bond in an intramolecular setting.
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Scheme 1. Coupling and Oxidative Cyclization for the Construction of Oxygen-containing
Heterocycles
1,3,4-Oxadiazoles are important five-membered aromatic heterocycles that have been widely used
in many compounds with broad pharmaceutical and biological activities,11-17 including
antibacterial, anti-inflammatory, anticonvulsant, anticancer, anti-diabetic, analgesic, antiviral and
antifungal properties. A number of methods have been developed for the synthesis of
1,3,4-oxadiazoles.3,18-22 Generally, these methodologies can be divided into two classes (Scheme
2): a) dehydrative cyclization of 1,2-diacylhydrazines using reagents such as SOCl2, PPA, POCl3,
H2SO4; b) oxidative cyclization of acylhydrazones utilizing oxidants (e.g. hypervalent iodines,
chloramine T, CAN, FeCl3, PbO2, Br2, KMnO4, HgO/I2) or via Cu(II) catalyzed aerobic oxidation.
Yet, there are still limitations associated with these methods, such as, harsh reaction conditions,
hazardous materials, limited substrate scope and/or scalability. Therefore, more general and
eco-friendly procedures for the synthesis of 1,3,4-oxadiazoles from easily available starting
materials are still highly desirable. This promoted us to explore for a simpler and more efficient
methodology.
Scheme 2. Two Classical Strategies for the Construction of 1,3,4-Oxadiazole Framework
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Results and Discussion
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Molecular iodine plays an important role in organic synthesis, owing to its commercial availability,
low cost, and low toxicity.23-24 Recently, it has been successfully employed to synthesize indole
derivatives25-27 and oxazoles.28-30 Inspired by these advances, we sought to investigate the
application of this reagent in oxadiazole synthesis.31 Our investigation started with the cyclization
of benzoyl hydrazone 4b to the corresponding 1,3,4-oxadiazole 1b (Table 1). The substrate 4b
was readily prepared via the condensation of 4-methylbenzaldehyde (2b, 1 equiv) and
benzohydrazide (3b, 1 equiv) in ethanol at refluxing temperature in 90% yield. The oxidative
cyclization of 4b was acheived by ultilizing molecualr iodine in the presence of cesium carbonate.
Our initial screening of reaction conditions indicated that DMSO was the most effective media for
this conversion, with 100 ºC being the optimal temperature. It needs at least 1.2 equiv of iodine,
3.0 equiv of the base to complete the transformation with the yield of 84% (entry 1). Further
optimization demonstrated that the usage of potassium carbonate as base gave the best result (96%
yield, entry 2). With organic base, like triethylamine (entry 3) or DBU (entry 4), the yields of
product 1b were significantly lower.
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Table 1. Screening of Reaction Conditions for the Synthesis of 1,3,4-Oxadiazole 1b from Benzoyl
Hydrazone 4ba
entry
base
Cs2CO3
K2CO3
NEt3
time
0.5 h
1.0 h
6.0 h
1.5 h
yieldb
84%
96%
trace
58%
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2
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4
DBU
a
b
Optimal reaction conditions: I2 (1.2 mmol), K2CO3 (3.0 mmol), DMSO, 100 ºC. Isolated yields after silica gel column
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chromatography.
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With these results in hand, we sought to probe the feasibility of using crude benzoyl hydrazone 4b
for this transformation. After the first-step condensation was complete (monitored by TLC), the
solvent was evaporated under reduced pressure to give the crude intermediate 4b, which was then
re-dissolved in DMSO, followed by the treatment of molecular iodine and potassium carbonate.
To our delight, the desired oxadiazole 1b was generated in equally good yield (95%) at 100 ºC,
when 1.2 equiv of iodine and 3 equiv of potassium carbonate were used (Scheme 3).
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Scheme 3. Direct Synthesis of 1,3,4-Oxadiazole 1b from benzaldehyde 2b and hydrazide 3ba
a
Optimal reaction conditions: 1) condensation of 2 (1 mmol) and 3 (1 mmol) in
EtOH at refluxing temperature; 2) I2 (1.2 mmol), K2CO3 (3 mmol), DMSO, 100 ºC.
Then, a variety of aryl aldehydes (2a−2m, entries 1-13, Table 2) were subjected to these optimal
reaction conditions to examine the scope and generality of this method. These aldehydes were first
condensed with benzohydrazide, followed by the iodine-mediated oxidative cyclization to afford a
series of symmetric (1a) and asymmetric (1b−1m) oxadiazoles. As shown in Table 2, this
methodology is compatible with a variety of electron-donating groups (EDGs, 2b−2c, 2j) and
electron-withdrawing groups (EWGs, 2d−2i) on the arylaldehydes. Methyl- and nitro- substituting
groups (2b, 2g−2h) are among the best, giving excellent yields of products. Taking
3-nitrobenzaldehyde (2h) as an example, the reaction was successfully carried out in gram scale.
Multiple substituted arylaldehydes produced the oxadiazole products (1i−1j) in as good yields as
the mono-substituted ones did (entry 9 vs entries 5-6; entry 10 vs entry 2). α-Naphthylaldehyde
(2k, entry 11) and pyridine-2-aldehyde (2l, entry 12) were also converted to the desired
oxadiazoles in good yield. 2-Furyl oxadiazole (1m) was obtained from 2-furaldehyde (2m) in
moderate yield with some unidentified byproducts during both the first-step condensation and the
following cyclization (entry 13).
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Table 2. Scope of Aldehydes 2a
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entry
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aldehyde (2)
product (1)
Yieldb
76%
entry
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aldehyde (2)
product (1)
Yieldb
97%
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1a
1j
2j
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4
95%
83%
93%
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91%
83%
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1c
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2l
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2n
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1n
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1d
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88%
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72%
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80%
94%
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75%
91%
2o
2p
1o
1p
2g
1g
98%
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17
97%
71%
(91% c)
2q
1q
2h
2i
1h
1i
9
89%
18d
2r
1r
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Optimal reaction conditions: 1) condensation of 2 (1 mmol) and 3 (1 mmol) in EtOH at refluxing temperature; 2) I2 (1.2 mmol),
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K2CO3 (3 mmol), DMSO, 100 ºC. Isolated yields after silica gel column chromatography. The reaction was conducted on
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gram-scale. d This oxadiazole was obtained from the purified acyl hydrazone.
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In light of these encouraging results, we initiated further studies with aliphatic aldehydes (entries
14-17, Table 2). The desired oxadiazoles (1n−1q) were successfully obtained under the optimal
reaction conditions. Interestingly, we noticed that the yields of products were somehow related to
the degree of the α-carbons of aldehydes in this order: 4º carbon (2q) > 3º carbon (2p) > 2º carbon
(2n−2o). In addition, reaction of cinnamaldehyde (2r) with benzohydrazide formed 5-vinyl
substituted oxadiazole 1r in 71% yield.
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To further explore the reaction scope, we replaced benzohydrazide with other hydrazides (Table 3).
4-Methyl benzohydrazide (3s) reacted with 4-methylbenzaldehyde and 3-nitrobenzaldehyde under
the optimal reaction conditions to give symmetric (1s) and asymmetric (1t) oxadiazoles,
respectively. Isonicotinohydrazide (3u) was converted to the desired product 1u in good yield with
the corresponding aldehyde. Aliphatic hydrazides (R2 group in hydrazides 3 is alkyl) also work
well (3v-3x). Oxadiazoles 1v−1w were successfully achieved in moderate to good yields. The
relatively low yield of 1w might be due to the side reaction of the acetyl group in acyl hydrazone
4w (e.g. haloform reaction). Reaction of dihydrazide 3x and 4-methylbenzaldehyde afforded the
symmetric dioxadiazole 1x.
Table 3. Scope of Hydrazides 3a
entry
1
Hydrazide (3)
product (1)
yieldb
87%
1s
1t
3s
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79%
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1u
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1v
5c,d
3w
1w
6
81%
3x
1x
a
Optimal reaction conditions: 1) condensation of 2 (1 mmol) and 3 (1 mmol) in EtOH at refluxing temperature; 2) I2 (1.2
mmol), K2CO3 (3 mmol), DMSO, 100 ºC. b Isolated yields after silica gel column chromatography. c Oxadiazoles were obtained
from purified acyl hydrazones. d 2 mmol of I2 was used in this reaction.
A plausible reaction mechanism for the formation of 1,3,4-oxadiazoles 1 is proposed (Schems
4).25 Taking the formation of 1b as an example, the base-promoted oxidative iodination of benzoyl
hydrazone 4b generates an iodide intermediate A. Consequently, the intemediate B is formed via a
SN2'-type cyclization of A, with a new C−O bond formed. Finally, the subsequent deprotonation
by base affords the oxadiazole structure 1b.
Scheme 4. Proposed Mechanism for the Formation of 1,3,4-Oxadiazole 1b
Conclusions
In summary, we have developed a simple and convenient oxidative C−O bond formation reaction
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for the synthesis of 1,3,4-oxadiazoles. This reaction can be applied to the crude acylhydrazones,
obtained via the condensation of aldehydes and hydrazides, to give a series of symmetrical and
asymmetrical 2,5-disubstituted 1,3,4-oxadiazoles. It works with a range of aldehydes (aryl, alkyl
and vinyl substituted) and hydrazides (both aryl and alkyl substituted), showing good
functional-group tolerance. This versatility allows the efficient synthesis of structurally diverse
1,3,4-oxadiazoles under mild reaction conditions. In this transition metal-free methodology, the
oxidative cyclization was accomplished by employing stoichiometric molecular iodine in the
presence of potassium carbonate, which makes it friendlier to the environment. In addition, the
reaction can be safely conducted on gram scale.
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Experimental Section
1
General Information. H NMR spectra were recorded on a 400 MHz or 300 MHz (13C NMR
spectra were recorded on a 100 MHz) spectrometer. Chemical shift values are given in ppm and
referred as the internal standard to TMS (tetramethylsilane). The peak patterns are indicated as
follows: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet and dd, doublet of doublets.
The coupling constants (J) are reported in Hertz (Hz). Melting points were determined on a
micromelting point apparatus without corrections. Flash column chromatography was performed
over silica gel 200-300 mesh, and the eluent was a mixture of ethyl acetate (EA) and petroleum
ether (PE). High-resolution mass spectra (HRMS-ESI) were obtained on a Q-TOF Mass
Spectrometer. Infrared (IR) spectra were obtained on a FTIR spectrometer.
General Procedure for the Synthesis of 2,5-Disubstituted-1,3,4-oxadiazoles 1. A solution of
aldehydes 2 (1.0 mmol) and acyl hydrazine 3 (1.0 mmol) in EtOH (10 mL) was refluxed until the
condensation was complete (monitored by TLC, 3-11 h), and then the solvent was evaporated
under reduced pressure, and the resulting residue was re-dissolved in DMSO (5 mL), followed by
addition of potassium carbonate (3 mmol), iodine (1.2 mmol) in sequence. The reaction mixture
was stirred at 100 oC until the conversion was complete (monitored by TLC, 1−4 h). After cooled
to room temperature, it was treated with 5% Na2S2O3 (20 mL), extracted with EA (10 mL x 3).
The combined organic layer was washed with brine (10 mL x 1), dried over anhydrous sodium
sulfate and concentrated. The given residue was purified through silica gel column
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chromatography using a mixture of ethyl acetate (EA) and petroleum ether (PE) as eluent to afford
the desired oxadiazoles 1.
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2,5-Diphenyl-1,3,4-oxadiazole (1a). The product was obtained according to the general procedure,
as white solid (168 mg, 0.76mmol, 76%). mp 138-139 ºC (ref. 138-139 ºC);32 RF = 0.35 (EA/PE
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15:85); H NMR (400 MHz, CDCl3): δ 8.15-8.13 (m, 4H), 7.54-7.53 (m, 6H); 13C NMR (100
MHz, CDCl3): δ 164.5, 131.7, 129.0, 126.9, 123.9; IR (KBr): 3057, 3007, 2992, 1604, 1546, 1484,
1445, 1267, 1069, 784, 711, 686; HRMS (m/z) (M+Na) calcd for C14H10N2ONa: 245.0685, found
245.0677.
2-phenyl-5-(p-tolyl)-1,3,4-oxadiazole (1b). The product was obtained according to the general
procedure, as white solid (225 mg, 0.95 mmol, 95%). mp 126-127 ºC (ref. 125 ºC);33 RF = 0.25
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(EA/PE 15:85); H NMR (400 MHz, CDCl3): δ 8.15-8.13 (m, 2H), 8.04 (d, J = 8.0 Hz, 2H),
7.55-7.53 (m, 3H), 7.34 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.7,
164.3, 142.2, 131.6, 129.7, 129.0, 126.8, 124.0, 121.1, 21.6; IR (KBr): 3058, 3025, 2915, 1782,
1550, 1496, 1445, 1174, 1076, 822, 782, 687; HRMS (m/z) (M+Na) calcd for C15H12N2ONa:
259.0842, found 259.0831.
2-(4-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazole (1c). The product was obtained according to
the general procedure, as white solid (210mg, 0.83 mmol, 83%). mp 150-151 ºC (ref. 150-151
ºC);34 RF = 0.30 (EA/PE 15:85); H NMR (400 MHz, CDCl3): δ 8.14-8.11 (m, 2H), 8.09-8.06 (m,
1
2H), 7.55-7.51 (m, 3H), 7.04-7.02 (m, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.5,
164.1, 162.3, 131.5, 129.0, 128.6, 126.8, 124.0, 116.4, 114.5, 55.4; IR (KBr): 3011, 2955, 2843,
1616, 1503, 1313, 1263, 1179, 1078, 831, 738, 684; HRMS (m/z) (M+Na) calcd for
C15H12N2O2Na: 275.0791, found 275.0791.
2-(2-Fluorophenyl)-5-phenyl-1,3,4-oxadiazole (1d). The product was obtained according to the
general procedure, as white solid (223 mg, 0.93 mmol, 93%). mp 120-122 ºC; RF = 0.30 (EA/PE
1
20:80); H NMR (300 MHz, CDCl3): δ 8.19-8.14 (m, 3H), 7.59-7.53 (m, 4H), 7.37-7.25 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 164.9 (d, JC-F = 1.4 Hz), 161.4 (d, JC-F = 4.8 Hz), 160.0 (d, JC-F
=
257 Hz), 133.5 (d, JC-F = 8.4 Hz), 131.8, 129.8 (d, JC-F = 1.5 Hz), 129.1, 127.0, 124.6 (d, JC-F = 3.7
Hz), 123.7, 117.0 (d, JC-F = 20.8 Hz), 112.4 (d, JC-F = 11.7 Hz); HRMS (m/z) (M+Na) calcd for
C14H9FN2ONa: 263.0591, found 263.0591.
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2-(2-Chlorophenyl)-5-phenyl-1,3,4-oxadiazole (1e). The product was obtained according to the
general procedure, as white solid (227mg, 0.88 mmol, 88%). mp 95-98 ºC (ref. 96-98 ºC);35 RF =
0.30 (EA/PE 15:85); 1H NMR (400 MHz, CDCl3): δ 8.17-8.15 (m, 2H), 8.12 (dd, J = 7.6, 1.6 Hz,
1H), 7.59-7.42 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 165.1, 163.0, 133.0, 132.4, 131.9, 131.3,
131.2, 129.1, 127.1, 127.0, 123.7, 123.2; IR (KBr): 3067, 2922, 1594, 1550, 1489, 1454, 1433,
1087, 779, 729, 687; HRMS (m/z) (M+Na) calcd for C14H9ClN2ONa: 279.0296, found 279.0290.
2-(4-Chlorophenyl)-5-phenyl-1,3,4-oxadiazole (1f). The product was obtained according to the
general procedure, as white solid (204 mg, 0.80 mmol, 80%). mp 165-167 ºC (ref. 166 ºC);36 RF =
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0.35 (EA/PE 10:90); H NMR (400 MHz, CDCl3): δ 8.16-8.12 (m, 2H), 8.10-8.07 (m, 2H),
7.58-7.51 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 164.7, 163.7, 138.0, 131.8, 129.4, 129.1, 128.1,
126.9, 123.7, 122.4; IR (KBr): 3086, 3061, 2918, 1605, 1550, 1478, 1406, 1089, 1011, 839, 730,
688; HRMS (m/z) (M+Na) calcd for C14H9ClN2ONa: 279.0296, found 279.0283.
2-(4-Nitrophenyl)-5-phenyl-1,3,4-oxadiazole (1g). The product was obtained according to the
general procedure, as light yellow solid (252 mg, 0.94 mmol, 94%). mp 222-223 ºC; RF = 0.25
(EA/PE 15:85); 1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 8.8 Hz, 2H), 8.35 (d, J = 8.8 Hz, 2H),
8.18-8.16 (m, 2H), 7.61-7.55 (m, 3H). 13C NMR (100 MHz, DMSO-d6): δ 165.3, 163.2, 149.6,
132.8, 129.9, 129.4, 128.5, 127.4, 125.0, 123.5; IR (KBr): 3220, 3074, 2844, 1607, 1553, 1515,
1339, 1078, 859, 718, 690; HRMS (m/z) (M+Na) calcd for C14H9N3O3Na: 290.0536, found
290.0533.
2-(3-Nitrophenyl)-5-phenyl-1,3,4-oxadiazole (1h). The product was obtained according to the
general procedure, as light yellow solid (1 mmol scale: 261 mg, 0.98 mmol, 98%; 7 mmol scale:
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1.71 g, 6.40 mmol, 91%). mp 150-151 ºC (ref. 150-151 ºC);37 RF = 0.25 (EA/PE 15:85); H NMR
(400 MHz, CDCl3): δ 8.94 (t, J = 2.0 Hz, 1H), 8.52-8.50 (m, 1H), 8.43-8.41 (m, 1H), 8.18-8.16 (m,
2H), 7.77 (t, J = 8.0 Hz, 1H), 7.61-7.54 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 165.3, 162.6,
148.6, 132.4, 132.2, 130.4, 129.2, 127.1, 126.1, 125.5, 123.3, 121.7; IR (KBr): 3083, 2924, 2862,
1608, 1526, 1443, 1349, 1269, 1091, 779, 713, 690; HRMS (m/z) (M+Na) calcd for C14H9N3O3Na:
290.0536, found 290.0522.
2-(2,4-Dichlorophenyl)-5-phenyl-1,3,4-oxadiazole (1i). The product was obtained according to
the general procedure, as white solid (259 mg, 0.89 mmol, 89%). mp 121-122 ºC; RF = 0.25
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(EA/PE 15:85); H NMR (400 MHz, CDCl3): δ 8.16-8.13 (m, 2H), 8.08 (d, J = 8.4 Hz, 1H), 7.60
(d, J = 2.0 Hz, 1H), 7.58-7.53 (m, 3H), 7.43 (dd, J = 8.4, 2.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 165.1, 162.3, 138.1, 133.8, 132.0, 131.8, 131.2, 129.1, 127.6, 127.0, 123.5, 121.7; IR
(KBr): 3085, 2924, 2849, 1593, 1551, 1457, 1400, 1107, 839, 734, 690; HRMS (m/z) (M+H)
calcd for C14H9Cl2N2O: 291.0086, found 291.0086.
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2-Mesityl-5-phenyl-1,3,4-oxadiazole (1j). The product was obtained according to the general
procedure, as yellow solid (256 mg, 0.97 mmol, 97%). mp 92-94 ºC (ref. 91-92 ºC);38 RF = 0.35
(EA/PE 10:90); 1H NMR (400 MHz, CDCl3): δ 8.12-8.10 (m, 2H), 7.55-7.51 (m, 3H), 7.00 (s, 2H),
2.35 (s, 3H), 2.33 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 164.8, 163.9, 141.0, 138.7, 131.6,
129.1, 128.9, 126.8, 124.0, 121.1, 21.3, 20.5; IR (KBr): 3072, 2956, 2918, 2857, 1894, 1609, 1551,
1480, 1448, 1048, 866, 704, 689; HRMS (m/z) (M+Na) calcd for C17H16N2ONa: 287.1155, found
287.1155.
2-(Naphthalen-2-yl)-5-phenyl-1,3,4-oxadiazole (1k). The product was obtained according to the
general procedure, as yellow solid (247 mg, 0.91 mmol, 91%). mp 120-122 ºC (ref. 120 ºC);39 RF =
1
0.35 (EA/PE 10:90); H NMR (400 MHz, CDCl3): δ 9.30 (d, J = 8.8 Hz, 1H), 8.28 (dd, J = 7.2,
1.2 Hz, 1H), 8.22-8.18 (m, 2H), 8.04 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.72-7.68 (m,
1H), 7.62- 7.54 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 164.5, 164.1, 133.8, 132.6, 131.7, 130.1,
129.1, 128.7, 128.3, 128.1, 127.0, 126.7, 126.2, 124.8, 123.9, 120.5; IR (KBr): 3089, 3053, 1549,
1527, 1443, 1249, 1070, 805, 772, 690; HRMS (m/z) (M+Na) calcd for C18H12N2ONa: 295.0842,
found 295.0842.
2-Phenyl-5-(pyridine-2-yl)-1,3,4-oxadiazole (1l). The product was obtained according to the
general procedure, as yellow solid (184 mg, 0.83 mmol, 83%). mp 123-125 ºC (ref. 124-125 ºC);40
RF = 0.25 (EA/PE 50:50); 1H NMR (400 MHz, CDCl3): δ 8.82 (d, J = 4.8 Hz, 1H), 8.32 (d, J = 8.0
Hz, 1H), 8.23-8.21 (m, 2H), 7.91 (dt, J = 8.0, 1.6 Hz, 1H), 7.59-7.51 (m, 3H), 7.48 (dd, J = 7.6,
4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 165.5, 163.8, 150.3, 143.6, 137.2, 132.0, 129.0,
127.2, 125.7, 123.6, 123.2; IR (KBr): 3090, 3051, 1586, 1548, 1486, 1457, 1276, 1069, 970, 794,
714, 688; HRMS (m/z) (M+Na) calcd for C13H9N3ONa: 246.0638, found 246.0638.
2-(Furan-2-yl)-5-phenyl-1,3,4-oxadiazole (1m). The product was obtained according to the
general procedure, as white solid (117 mg, 0.55 mmol, 55%). mp 101-102 ºC (ref. 102-103 ºC);41
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RF = 0.30 (EA/PE 30:70); H NMR (400 MHz, CDCl3): δ 8.12-8.10 (m, 2H), 7.67 (m, 1H),
7.55-7.50 (m, 3H), 7.23 (d, J = 3.2 Hz, 1H), 6.62 (dd, J = 3.6, 1.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 163.9, 157.4, 145.7, 139.4, 131.8, 129.0, 127.0, 123.5, 114.1, 112.2; IR (KBr): 3141,
3109, 2923, 1633, 1519, 1490, 1450, 1173, 1082, 898, 776, 688; HRMS (m/z) (M+Na) calcd for
C12H8N2O2Na: 235.0478, found 235.0475.
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2-Phenyl-5-propyl-1,3,4-oxadiazole (1n). The product was obtained according to the general
procedure, as pale yellow oil (136 mg, 0.72 mmol, 72%). RF = 0.20 (EA/PE 25:75); 1H NMR (400
MHz, CDCl3): δ 8.05-8.02 (m, 2H), 7.52-7.47 (m, 3H), 2.91 (t, J = 7.2 Hz, 2H), 1.93-1.84 (m, 2H),
1.06 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 166.8, 164.6, 131.4, 128.9, 126.7, 124.0,
27.2, 20.1, 13.6; IR (KBr): 3063, 2967, 2875, 1964, 1898, 1609, 1571, 1450, 1252, 1068, 1005,
776, 691; HRMS (m/z) (M+Na) calcd for C11H12N2ONa: 211.0842, found 211.0849.
2-Pentyl-5-phenyl-1,3,4-oxadiazole (1o). The product was obtained according to the general
procedure, as pale yellow oil (163 mg, 0.75 mmol, 75%). RF = 0.25 (EA/PE 10:90); 1H NMR (400
MHz, CDCl3): δ 8.05-8.02 (m, 2H), 7.54-7.46 (m, 3H), 2.92 (t, J = 7.6 Hz, 2H), 1.89-1.81 (m, 2H),
1.44-1.35 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 166.9, 164.6, 131.4,
128.9, 126.6, 124.0, 31.1, 26.2, 25.3, 22.1, 13.8; IR (KBr): 3063, 2931, 2871, 1728, 1609, 1572,
1450, 1245, 1087, 960, 776, 691; HRMS (m/z) (M+Na) calcd for C13H16N2ONa: 239.1155, found
239.1153.
2-Isopropyl-5-phenyl-1,3,4-oxadiazole (1p). The product was obtained according to the general
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procedure, as yellow oil (172 mg, 0.91 mmol, 91%). RF = 0.25 (EA/PE 15:85); H NMR (400
MHz, CDCl3): δ 8.06-8.03 (m, 2H), 7.53-7.47 (m, 3H), 3.33-3.23 (m, 1H), 1.46 (d, J = 6.8 Hz,
6H). 13C NMR (100 MHz, CDCl3): δ 170.7, 164.5, 131.4, 128.9, 126.6, 124.0, 26.4, 20.0; IR
(KBr): 3063, 2976, 2877, 1610, 1568, 1483, 1450, 1366, 1154, 1068, 961, 778, 691; HRMS (m/z)
(M+Na) calcd for C11H12N2ONa: 211.0842, found 211.0833.
2-(Tert-butyl)-5-phenyl-1,3,4-oxadiazole (1q). The product was obtained according to the
general procedure, as colorless oil (195 mg, 0.97 mmol, 97%). RF = 0.25 (EA/PE 20:80); 1H NMR
(400 MHz, CDCl3): δ 8.06-8.03 (m, 2H), 7.52-7.48 (m, 3H), 1.49 (s, 9H); 13C NMR (100 MHz,
CDCl3): δ 173.0, 164.5, 131.4, 128.9, 126.7, 124.1, 32.4, 28.2; IR (KBr): 3062, 2974, 2873, 1609,
1561, 1449, 1355, 1158, 1084, 779, 705, 692; HRMS (m/z) (M+Na) calcd for C12H14N2ONa:
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225.0998, found 225.0998.
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(E)-2-Phenyl-5-styryl-1,3,4-oxadiazole (1r). The product was obtained according to the general
procedure using purified acyl hydrazone 4r, as white solid (177 mg, 0.71 mmol, 71%). mp 123 ºC;
RF = 0.29 (EA/PE 10:90); 1H NMR (400 MHz, CDCl3): δ 8.14-8.11 (m, 2H), 7.64 (d, J = 16.4 Hz,
1H), 7.60-7.57 (m, 2H), 7.56-7.50 (m, 3H), 7.45-7.39 (m, 3H), 7.10 (d, J = 16.4 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 164.2, 164.0, 138.9, 134.7, 131.7, 130.0, 129.05, 129.00, 127.5, 126.9,
123.8, 110.0; IR (KBr): 3062, 2621, 2850, 1644, 1547, 1523, 1446, 1014, 971, 760, 694; HRMS
(m/z) (M+H) calcd for C16H13N2O: 249.1022, found 249.1027.
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2,5-Di-p-tolyl-1,3,4-oxadiazole (1s). The product was obtained according to the general
procedure, as white solid (218 mg, 0.87 mmol, 87%). mp 175-177 ºC; RF = 0.30 (EA/PE 15:85);
1H NMR (300 MHz, CDCl3): δ 8.02-8.00 (m, 4H), 7.33-7.30 (m, 4H); 2.43 (s, 6H); 13C NMR (100
MHz, CDCl3): 164.4, 142.1, 129.7, 126.8, 121.2, 21.6; IR (KBr): 3064, 1616, 1589, 1546, 1492,
1468, 1063, 780, 738, 689; HRMS (m/z) (M+Na) calcd for C16H14N2ONa: 273.0998, found
273.0998.
2-(3-Nitrophenyl)-5-(p-tolyl)-1,3,4-oxadiazole (1t). The product was obtained according to the
general procedure, as white solid (256 mg, 0.91 mmol, 91%). mp 177-178 ºC; RF = 0.25 (EA/PE
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25:75); H NMR (300 MHz, CDCl3): δ 8.94-8.93 (m, 1H), 8.52-8.49 (m, 1H), 8.43-8.39 (m, 1H),
8.06-8.04 (m, 2H), 7.76 (t, J = 8.4 Hz, 1H), 7.38-7.35 (m, 2H), 2.46 (s, 3H); 13C NMR (100 MHz,
CDCl3): 165.4, 162.4, 148.6, 142.9, 132.4, 130.3, 129.9, 127.0, 125.9, 125.6, 121.6, 120.5, 21.7;
IR (KBr): 3094, 2922, 2860, 1612, 1528, 1495, 1347, 1087, 823, 729, 705; HRMS (m/z) (M+Na)
calcd for C15H11N3O3Na: 304.0693, found 304.0685.
2-(Pyridin-4-yl)-5-(p-tolyl)-1,3,4-oxadiazole (1u). The product was obtained according to the
general procedure, as white solid (187 mg, 0.79 mmol, 79%). mp 143-144 ºC; RF = 0.25 (EA/PE
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50:50); H NMR (400 MHz, CDCl3): δ 8.84 (d, J = 5.6 Hz, 2H), 8.04 (d, J = 8.0 Hz, 2H),
7.99-7.98 (m, 2H), 7.35 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 165.5,
162.4, 150.8, 142.9, 131.0, 129.9, 127.0, 120.5, 120.2, 21.6; IR (KBr): 3043, 2919, 1610, 1538,
1495, 1481, 1412, 1059, 828, 728, 700; HRMS (m/z) (M+Na) calcd for C14H11N3ONa: 260.0794,
found 260.0794.
2-pentyl-5-(p-tolyl)-1,3,4-oxadiazole (1v). The product was obtained according to the general
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procedure using purified acyl hydrazone 4v, as pale yellow oil (184 mg, 0.80 mmol, 80%). RF =
0.20 (EA/PE 20:80); 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz,
2H), 2.91 (t, J = 7.6 Hz, 2H), 2.42 (s, 3H), 1.88-1.81 (m, 2H), 1.44-1.35 (m, 4H), 0.92 (t, J = 6.8
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 166.7, 164.7, 141.9, 129.6, 126.6, 121.3, 31.1, 26.3, 25.4,
22.2, 21.5, 13.8; IR (KBr): 3030, 2969, 2870, 1915, 1618, 1571, 1500, 1458, 1181, 1083, 1009,
824, 792; HRMS (m/z) (M+Na) calcd for C14H18N2ONa: 253.1311, found 253.1311.
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2-Methyl-5-(p-tolyl)-1,3,4-oxadiazole (1w). The product was obtained according to the general
procedure using purified acyl hydrazone 4w, as yellow solid (92 mg, 0.53 mmol, 53%). mp
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99-101 ºC; RF = 0.30 (EA/PE 30:70); H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.4 Hz, 2H),
7.29 (d, J = 8.0 Hz, 2H), 2.60 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.0, 163.3,
142.0, 129.7, 126.6, 121.2, 21.6, 11.0; IR (KBr): 3046, 2919, 2849, 1593, 1498, 1248, 1089, 829,
734, 700; HRMS (m/z) (M+Na) calcd for C10H10N2ONa: 197.0685, found 197.0685.
1,4-Bis(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)butane (1x). The product was obtained according to the
general procedure, as yellow solid (303 mg, 0.81 mmol, 81%). mp 150-154 ºC; RF = 0.20 (EA/PE
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20:80); H NMR (300 MHz, CDCl3): δ 7.95 (d, J = 8.4 Hz, 4H), 7.28 (d, J = 8.1 Hz, 4H),
3.03-2.98 (m, 4H), 2.42 (s, 6H), 2.05-2.01 (m, 4H); 13C NMR (100 MHz, CDCl3): 165.9, 164.9,
142.0, 129.6, 126.7, 121.1, 25.7. 25.0. 21.5; IR (KBr): 3031, 2921, 2850, 1613, 1571, 1499, 1177,
1085, 823, 724; HRMS (m/z) (M+Na) calcd for C22H22N4O2Na: 397.1635, found 397.1623.
Acknowledgements
We acknowledge the National Natural Science Foudation of China (No. 21172202) and the China
Postdoctoral Science Foundation (No. 2013M530341) for financial support.
1
Supporting Information. Copies of H and 13C NMR spectra of all the oxadiazoles 1. This
material is available free of charge via the Internet at http://pubs.acs.org.
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(31) Synthesis of 2-(4,5-dihydronaphtho[1,2-c]-pyrazolyl)-5-phenyl-1,3,4-oxadiazoles and
2-naphtho[2,1-b]furan-2-yl-5-aryl-1,3,4-oxadiazoles were acheived by using I2/HgO in
moderate yields, see: (a) Flidallah, H. M.; Sharshira, E. M.; Basaif, S. A.; A-Ba-Oum, A.
E.-K. Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 67. (b) Ravindra, K. C.; Vagdevi,
H. M.; Vaidya, V. P.; Padmashali, B. Indian J. Chem. 2006, 45B, 2506.; Synthesis of
2-quinolyl-5-(pyridin-4-yl)-1,3,4-oxadiazoles were acheived by using catalytic amount of I2
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