A novel, one-pot synthesis of 2,5-disubstituted-1,3,4-oxadiazoles using 1,4-bis(Triphenylphosphonium)-2-butene peroxodisulfate

Article abstract of DOI:10.1080/10426500902840887

An efficient and convenient synthesis of 1,3,4-oxadiazoles from aromatic aldehydes, acyl hydrazide, and 1,4- bis(triphenylphosphonium)-2-butene peroxodisulfate is reported. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426500902840887

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A Novel, One-Pot Synthesis of 2,5-
Disubstituted-1,3,4-Oxadiazoles Using
1,4-Bis(Triphenylphosphonium)-2-Butene
Peroxodisulfate
Rashid Badri a & Maryam Gorjizadeh a
a Department of Chemistry , Shahid Chamran University , Ahvaz, Iran
Published online: 24 Feb 2010.
To cite this article: Rashid Badri & Maryam Gorjizadeh (2010) A Novel, One-Pot Synthesis
of 2,5-Disubstituted-1,3,4-Oxadiazoles Using 1,4-Bis(Triphenylphosphonium)-2-Butene
Peroxodisulfate, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:3, 544-549, DOI:
10.1080/10426500902840887
To link to this article: http://dx.doi.org/10.1080/10426500902840887
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Phosphorus, Sulfur, and Silicon, 185:544–549, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902840887
A NOVEL, ONE-POT SYNTHESIS OF
2,5-DISUBSTITUTED-1,3,4-OXADIAZOLES USING
1,4-BIS(TRIPHENYLPHOSPHONIUM)-2-BUTENE
PEROXODISULFATE
Rashid Badri and Maryam Gorjizadeh
Department of Chemistry, Shahid Chamran University, Ahvaz, Iran
An efficient and convenient synthesis of 1,3,4-oxadiazoles from aromatic aldehydes, acyl
hydrazide, and 1,4- bis(triphenylphosphonium)-2-butene peroxodisulfate is reported.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Acyl hydrazide; aromatic aldehyde; 1,4-bis(triphenylphosphonium)-2-butene per-
oxodisulfate; oxadiazole
INTRODUCTION
1,3,4-Oxadiazole derivatives have been reported to possess significant pharmacolog-
ical1 and biological activities including antimicrobial,2 antifungal,3 and anti-inflammatory.4
2,5-Disubstituted-1,3,4-oxadiazoles were disclosed as a broad-spectrum insecticide acari-
cide having potential agricultural use.5 The common synthetic route to 1,3,4-oxadiazole
involves the cyclization of diacylhydrazines and thiosemicarbazides. Typically, this re-
action is carried out by using thionyl chloride,6 phosphorous oxychloride,7 phosphorous
pentoxide,8 triphenylphosphine,9 or tosyl chloride/pyridine.10 In these methods, the reaction
conditions tend to be harsh, and long reaction times are generally needed. An alternative
route to 1,3,4-oxadiazoles by oxidative cyclization from the corresponding acylhydrazones
proceeds with lead tetraacetate,11 lead(IV) oxide,12 potassium permanganate,13 or electro-
chemical methods.14 These protocols are routinely multistep in nature. Few reliable, simple
examples have been reported for the one-pot synthesis of 1,3,4-oxadiazoles.15
Peroxodisulfate ion is an excellent and versatile oxidant, used mostly for the oxidation
of compounds in aqueous solution.16 In spite of the great convenience of using K2S2O8,
Na2S2O8, or (NH4)2S2O8 and relatively high oxidation potential, oxidation by peroxodisul-
fate generally does not proceed at a convenient rate. This can be largely attributed to the
Received 19 November 2008; accepted 23 February 2009.
We thank Shahid Chamran University for financial support of this work.
Address correspondence to Rashid Badri, Department of Chemistry, Shahid Chamran University, Ahvaz,
Iran. E-mail: rashidbadri@scu.ac.ir
544

SYNTHESIS OF 2,5-DISUBSTITUTED-1,3,4-OXADIAZOLES
545
rate-limiting homolysis given in Equation (1), which has an activation energy of approxi-
mately 30 kcal/mol.
.
S2O28− −→ 2SO4
(1)
¯
Thus certain limitations may be observed with these reagents. The decomposition of the
peroxodisulfate ion requires strong mineral acids and heavy metal ions17 as catalysts, and
also protic and polar solvents are needed, so, recently the modification of K2S2O8, Na2S2O8,
or (NH4)2S2O8 has attracted a great deal of attention.
In this article we report our efficient, one-pot, solution-phase preparation of 2,5-
disubstituted-1,3,4-oxadiazoles directly from the acyl hydrazide and aromatic aldehydes
using 1,4-bis(triphenylphosphonium)-2-butene peroxodisulfate as an oxidant under non-
aqueous and aprotic conditions (Scheme 1).
O
H NHN
2
Ph
R
[BTPBP]
+
R-CHO
O
reflux, CHCl3
N
N
Ph
+PPh3
+
S2O28-
PPh3
[BTPBP]
Scheme 1 Synthesis of 1,3,4-oxadiazoles from aromatic aldehyde, acyl hydrazide, and 1,4-
bis(triphenylphosphonium)-2-butene peroxodisulfate as an oxidant.
This reagent can be readily prepared by adding an aqueous solution of potassium per-
oxodisulfate to a solution of 1,4-bis(triphenylphosphonium)-2-butene dichloride in water.
This white solid is very stable and can be stored for months without losing its activity. It
is soluble in acetonitrile, methanol, dichloromethane, chloroform, and ethyl acetate and is
slightly soluble in CCl4 and diethyl ether (Scheme 2).
+
+
CHCl3
2 PPh3
+
PPh3
Cl
PPh3
2Cl-
1
Cl
reflux
K2S2O8
, r.t.
+
+
PPh3
S2O82-
2
PPh3
H2O
Scheme 2 Preparation of 1,4-bis(triphenylphosphonium)-2-butene peroxodisulfate.
1
Compounds 1 and 2 were confirmed by elemental analysis, IR, H NMR, and 13C
NMR.

546
R. BADRI AND M. GORJIZADEH
RESULTS AND DISCUSSION
Stirring a mixture of compound 2, acyl hydrazide, and an aromatic aldehyde in chlo-
roform at reflux gave, after workup and isolation, the desired 1,3,4-oxadiazole compound
in high yield. The results obtained are summarized in Table I.
As indicated in Table I, a variety of aromatic aldehydes bearing electron-releasing or
electron-withdrawing substituents reacted smoothly and gave corresponding oxadiazoles
in moderate to good yields.
The possible mechanism of the oxidation of the initially formed cyclic intermediate
I in the presence of proxodisulfate involves an initial one electron transfer from I to the
sulfate anion radical to give radical cation II. This radical cation loses a proton to form
the intermediate III, which transfers an electron to the sulfate anion radical to form the
cation and subsequently results in the aromatized product by homolysis. Before the use
of oxidant 2, we conducted the same reactions with all aldehydes of Table I under the
same reaction conditions in the presence of K2S2O8 as the oxidant, and found out that a
mixture of possible desired and unidentified products was formed. The yields of isolated
oxadiazoles were especially low, and the reaction times were higher than in the case of
oxidant 2. Also, the saturated form of compound 2 was prepared either via hydrogenation
of compound 1 followed by Cl−→S2O82− exchange or the reaction of 1,4-dichlorobutane
with triphenylphosphine followed by anion exchange. Utilizing this saturated oxidant for
the synthesis of oxadiazoles faces with long reaction times and lower yields than unsaturated
oxidant 2 (see Scheme S1, available online in the Supplemental Materials).
The influence of the various solvents such as H2Cl2, CCl4, CHCl3, and CH3CN on
the yield of the reaction was investigated using benzaldehyde as the substrate. The obtained
results showed that chloroform is the best choice for the oxidation reaction. This can be
attributed to the enhanced solubilizing power of the solvent for the oxidant. In conclusion,
the present work offers several advantages including a simple oxidation method, employing
readily available reagents, high conversions, and high isolated yields, which make it a useful
and attractive process for the synthesis of 1,3,4-oxadiazoles.
Table I Yield and physical characteristic of 1,3,4-oxadiazoles using 1,4-bis(triphenylphosphonium)-2-butene
peroxodisulfatea
Entry
R
Yieldb(%)
Mp (◦C)
Ref.
18
18
18
18
18
18
19
20
19
19
21
22
1
2
3
4
5
6
7
8
Ph
60
73
81
60
72
75
83
69
72
80
68
70
200–204
216–218
219
145–148
244–246
188–189
218
102
194
228
99
4-Cl–C6H4
4-Me–C6H4
4-MeO–C6H4
4-O2N–C6H4
3-O2N–C6H4
4-I–C6H4
2,4-Cl2–C6H3
3-Cl–C6H4
4-Br–C6H4
2-Furyl
9
10
11
12
3-Pyridyl
105–107
aProducts were identified by comparison of their physical and spectral data with those of authentic samples.
bIsolated yields based on the aldehyde.

SYNTHESIS OF 2,5-DISUBSTITUTED-1,3,4-OXADIAZOLES
547
EXPERIMENTAL
All products were characterized by comparison of their physical data, IR, 1H NMR,
and 13 C NMR spectra with authentic samples. The IR spectra were recorded on a Bomem
1
FT-IR Spectrometer. H NMR and 13C NMR spectra were taken on a 400 MHz Brucker
Spectrometer. 1,4-Bis(triphenylphosphonium)-2-butene peroxodisulfate was prepared and
other chemicals were purchased from the Merck Chemical Company, Darmstadt, Germany.
The purity determination of the products and reaction monitoring were accomplished by
TLC on polygram SILG/UV 254 plates.
Preparation of 1,4-Bis(triphenylphosphonium)-2-butene Dichloride (1)
To a solution of 1,4-dichlorobutene (0.63 g, 5 mmol) in CHCl3 (10 mL) in a 50
mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser, triph-
enylphosphine (2.62 g, 10 mmol) was added. The reaction mixture was refluxed for 2.5 h.
The solution was cooled to room temperature, and then diethyl ether was added dropwise
until an oily product was separated. The ether was removed by decantation, and acetone
(40 mL) was added. The acetone solution, stirred for 40 min, afforded a white precipitate,
which was filtered and then dried by anhydrous CaCl2. Yield (80%), mp 278–279◦C. IR
(KBr): υ = 3053, 2755, 1613, 1575, 1478, 1437,754, 693, 556 (cm−1). 13C NMR, (CDCl3):
δ = 20.7, 120.8, 132.15, 134.2, 137.01, 140.17. 1H NMR, (CDCl3): δ = 5.7 (dd, 4H), 6.3
(m, 2H), 7.79–8 (m, 30H). Anal. Calcd: C, 73.994; H, 5.544; P, 9.542; Cl, 10.920. found:
C, 73.899; H, 5.552; P, 9.523; Cl, 10.897%.
Preparation of 1,4-Bis(triphenylphosphonium)-2-butene
Peroxodisulfate (2)
In a 25 mL round-bottomed flask with a magnetic stirrer, a solution of K2S2O8 (0.54
g, 2 mmol) in H2O (5 mL) was prepared. Compound 1 (1.298 g, 2 mmol) was added to this
solution, and the reaction mixture was stirred at ambient temperature for 3 h. The resulting
white precipitate was filtered, washed with distilled water (10 mL), and dried in vacuo;
yield (78%), mp 205–208◦C. IR (KBr): υ = 3053, 2750, 1623, 1585, 1472, 1437, 750, 724,
689, 556 (cm−1). 13C NMR, (CDCl3): δ = 19.04, 119.45, 130.05, 133.98, 136.91, 138.8. 1H
NMR, (CDCl3): δ = 4.7 (dd, 4H), 5.8 (m, 2H), 7.68–8 (m, 30H). Anal. Calcd: C, 62.350;
H, 4.672; P, 8.039; S, 8.324. found: C, 62.345; H, 4.670; P, 8.036; S, 8.314%.
General Procedure for Preparation
of 2,5-Disubstituted-1,3,4-oxadiazoles
To a solution of acyl hydrazide (1 mmol) and aromatic aldehyde (1 mmol) in chloro-
form (15 mL) in a 50 mL round-bottomed flask equipped with a condenser and a magnetic
stirrer, 1,4-bis(triphenylphosphonium)-2-butene peroxodisulfate (1 mmol) was added in
small portions. The reaction mixture was refluxed for 12 h. The progress of the reaction
was monitored by TLC. Upon completion of the reaction, it was cooled to room temperature
and filtered. Water (15 mL) was added and extracted with chloroform (3 × 15 mL). The
combined organic layers solution was dried over MgSO4. The solvent was concentrated in
vacuo; the resulting product was directly charged on a small silica gel column and eluted
with a mixture of diethyl ether and n-hexane (1:4) to afford the pure product.

548
R. BADRI AND M. GORJIZADEH
2,5-Diphenyl-1,3,4-oxadiazole (entry 1). mp: 200–204◦C. 1H NMR (400 MHz,
CDCl3): δ = 7.53–7.76 (m, 6H), 8.14–8.18 (d, 4H). 13C NMR (100 MHz, CDCl3): δ =
123.73, 128.58, 129.01, 131.69, 164.17.
2-(4-Chlorophenyl)-5-phenyl-1,3,4-oxadiazole (entry 2). mp: 216–218◦C.
1H NMR (400 MHz, CDCl3): δ = 7.53–7.66 (m, 3H), 7.83–7.86 (d, 2H), 8.23–8.41 (d,
2H), 8.14–8.18 (d, 2H). 13C NMR (100 MHz, CDCl3): δ = 123.67, 125.98, 128.58, 128.63,
129.07, 130.18, 131.67, 135.81, 164.05.
2-(4-Metylphenyl)-5-phenyl-1,3,4-oxadiazole (entry 3). mp: 219◦C. 1H
NMR (400 MHz, CDCl3): δ = 2.53 (s, 3H), 7.23 (d, 2H), 7.53–7.71 (m, 3H), 7.94–7.97 (d,
2H), 8.14–8.18 (d, 2H). 13C NMR (100 MHz, CDCl3): δ = 23.1, 126.57, 123.78, 128.58,
128.93, 129.01, 129.97, 131.69, 142.21, 164.15.
2-(4-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazole (entry 4). mp: 145–148◦C.
1H NMR (400 MHz, CDCl3): δ = 3.63 (s, 3H), 7.12 (d, 2H), 7.53–7.71 (m, 3H), 7.86 (d,
2H), 8.14–8.15 (d, 2H). 13C NMR (100 MHz, CDCl3): δ = 53.5, 118.37, 118.98, 122.54,
123.73, 125.58, 129.07, 131.61, 164.11, 165.85.
2-(4-Nitrophenyl)-5-phenyl-1,3,4-oxadiazole (entry 5). mp: 244–246◦C. 1H
NMR (400 MHz, CDCl3): δ = 7.55–7.61 (m, 3H), 8.13–8.16 (d, 2H), 8.33–8.44 (d, 2H),
8.58 (d, 2H). 13C NMR (100 MHz, CDCl3): δ = 122.77, 122.98, 123.73, 125.60, 129.01,
131.68, 138.60, 149.85, 164.15.
2-(3-Nitrophenyl)-5-phenyl-1,3,4-oxadiazole (entry 6). mp: 188–189◦C. 1H
NMR (400 MHz, CDCl3): δ = 7.55–7.61 (m, 3H), 8.03–8.06 (dd, 1H), 8.14–8.17 (d, 2H),
8.98 (s, 1H). 13C NMR (100 MHz, CDCl3): δ = 120.77, 123.08, 123.73, 128.60, 129.01,
131.28, 131.69, 134.85, 137.15, 1489.5, 164.18, 165.72.
2-(4-Iodophenyl)-5-phenyl-1,3,4-oxadiazole (entry 7). mp: 218◦C. 1H NMR
(400 MHz, CDCl3): δ = 7.53–7.66 (m, 3H), 7.86 (d, 2H), 7.98–8.01 (d, 2H), 8.14–8.18
(d, 2H). 13C NMR (100 MHz, CDCl3): δ = 93.67, 122.18, 123.78, 128.65, 129.07, 131.68,
131.97, 138.83, 164.01.
2-(2,4-Dichlorophenyl)-5-phenyl-1,3,4-oxadiazole (entry 8). mp: 102◦C. 1H
NMR (400 MHz, CDCl3): δ = 7.53–7.66 (m, 4H), 7.72 (s, 1H), 8.07 (d, 1H), 8.14–8.17 (d,
2H). 13C NMR (100 MHz, CDCl3): δ = 122.97, 123.74, 123.23, 128.55, 129.03, 131.69,
133.67, 134.19, 135.89, 138.02, 164.05, 166.12.
2-(3-Chlorophenyl)-5-phenyl-1,3,4-oxadiazole (entry 9). mp: 194◦C. 1H
NMR (400 MHz, CDCl3): δ = 7.53–7.66 (m, 4H), 7.77–7.87 (dd, 1H), 7.97 (s, 1H),
8.14–8.17 (d, 2H), 8.71 (d, 1H). 13C NMR (100 MHz, CDCl3): δ = 120.67, 121.98, 123.73,
124.33, 128.54, 129.01, 130.67, 131.69, 133.89, 136.02, 164.05, 165.1.
1
2-(4-Bromophenyl)-5-phenyl-1,3,4-oxadiazole (entry 10). mp: 228◦C. H
NMR (400 MHz, CDCl3): δ = 7.53–7.57 (m, 3H), 7.66 (d, 2H), 7.79(d, 2H), 8.14–8.18 (d,
2H). 13C NMR (100 MHz, CDCl3): δ = 123.17, 123.48, 123.78, 128.55, 129.05, 131.58,
131.69, 164.01.
1
2-(2-Furyl)-5-phenyl-1,3,4-oxadiazole (entry 11). mp: 99◦C. H NMR (400
MHz, CDCl3): δ = 6.58 (dd, 1H), 7.37 (d, 1H), 7.55–7.71 (m, 4H), 8.14–8.17 (d, 2H). 13
C
NMR (100 MHz, CDCl3): δ = 102.48, 113.79, 123.73, 128.58, 129.03, 131.69, 141.89,
146.30, 152.85, 164.17.
2-(3-Pyridyle)-5-phenyl-1,3,4-oxadiazole (entry 12). mp: 105–107◦C. 1H
NMR (400 MHz, CDCl3): δ = 7.55–7.71 (m, 3H), 7.82–7.87 (m, 2H), 8.14–8.17 (d, 2H),
8.78 (d, 1H), 9.27 (s, 1H). 13C NMR (100 MHz, CDCl3): δ = 121.77, 122.98, 123.73,
128.60, 129.03, 130.51, 131.69, 146.85, 157.05, 164.18.

SYNTHESIS OF 2,5-DISUBSTITUTED-1,3,4-OXADIAZOLES
549
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