Silica sulfuric acid: An efficient and versatile acidic catalyst for the rapid and ecofriendly synthesis of 1,3,4-oxadiazoles at ambient temperature

Article abstract of DOI:10.1080/00397910701199151

A rapid and green synthesis of 2,5-disubstituted 1,3,4-oxadiazoles is reported. The title compounds were prepared by the reaction of different acyl hydrazides and orthoesters in the presence of silica sulfuric acid under solvent-free conditions. In this new process, reactions were run at ambient temperature and completed in a short period of time with high yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701199151

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Silica Sulfuric Acid: An Efficient and Versatile
Acidic Catalyst for the Rapid and Ecofriendly
Synthesis of 1,3,4‐Oxadiazoles at Ambient
Temperature
Minoo Dabiri a , Peyman Salehi b , Mostafa Baghbanzadeh a , Mohammad Ali
Zolfigol c & Mahboobeh Bahramnejad a
a Department of Chemistry, Faculty of Science, Shahid Beheshti University,
Evin, Tehran, Iran
b Department of Phytochemistry, Medicinal Plants and Drugs Research
Institute, Shahid Beheshti University, Evin, Tehran, Iran
c Department of Chemistry, Faculty of Science, Bu‐Ali Sina University,
Hamadan, Iran
Published online: 13 Oct 2010.
To cite this article: Minoo Dabiri , Peyman Salehi , Mostafa Baghbanzadeh , Mohammad Ali Zolfigol &
Mahboobeh Bahramnejad (2007) Silica Sulfuric Acid: An Efficient and Versatile Acidic Catalyst for the Rapid
and Ecofriendly Synthesis of 1,3,4‐Oxadiazoles at Ambient Temperature, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:7, 1201-1209, DOI:
10.1080/00397910701199151
To link to this article: http://dx.doi.org/10.1080/00397910701199151
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Synthetic Communicationsw, 37: 1201–1209, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701199151
Silica Sulfuric Acid: An Efficient and
Versatile Acidic Catalyst for the Rapid and
Ecofriendly Synthesis of 1,3,4-Oxadiazoles
at Ambient Temperature
Minoo Dabiri
Department of Chemistry, Faculty of Science, Shahid Beheshti
University, Evin, Tehran, Iran
Peyman Salehi
Department of Phytochemistry, Medicinal Plants and Drugs Research
Institute, Shahid Beheshti University, Evin, Tehran, Iran
Mostafa Baghbanzadeh
Department of Chemistry, Faculty of Science, Shahid Beheshti
University, Evin, Tehran, Iran
Mohammad Ali Zolfigol
Department of Chemistry, Faculty of Science, Bu-Ali Sina University,
Hamadan, Iran
Mahboobeh Bahramnejad
Department of Chemistry, Faculty of Science, Shahid Beheshti
University, Evin, Tehran, Iran
Abstract: A rapid and green synthesis of 2,5-disubstituted 1,3,4-oxadiazoles is
reported. The title compounds were prepared by the reaction of different acyl hydra-
zides and orthoesters in the presence of silica sulfuric acid under solvent-free
Received in the U.K. March 31, 2006
Address correspondence to Minoo Dabiri, Department of Chemistry, Faculty of
Science, Shahid Beheshti University, P. O. Box 1983963113, Evin, Tehran, Iran.
E-mail: m-dabiri@cc.sbu.ac.ir
1201

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M. Dabiri et al.
conditions. In this new process, reactions were run at ambient temperature and
completed in a short period of time with high yields.
Keywords: heterogeneous catalysis, heterocycles, 1,3,4-oxadiazoles, silica sulfuric
acid, solvent free
INTRODUCTION
Heterocycles form by far the largest of classical divisions of organic
chemistry and are of immense importance biologically, industrially, and
indeed to the functioning of any developed human society. The majority of
pharmaceuticals and biologically active agrochemicals are heterocyclic, as
are many additives and modifiers used in industry. Searching for simple
and efficient methods for generation of libraries of novel heterocyclic
compounds is in demand.[1,2]
Substituted 1,3,4-oxadiazoles are of considerable interest in medicinal
chemistry,[10–20] pesticide chemistry,[3] and polymer[4–6] and material
science.[7–9] As a consequence of these characteristics, oxadiazoles have an
impact in numerous drug discovery programs, including muscarinic
agonists,[10] benzodiazepine receptor partial agonists,[11] dopamine transpor-
ters,[12] antirhinovirals,[13] growth hormone secretagogoues,[14] fungicides,[15]
central nervous system (CNS) stimulants, and anti-inflammatory, hypoten-
sive,[16] insecticidal,[17,18] bactericidal,[19] and anticonvulsant agents.[20]
Because of these properties, the synthesis of this group of compounds has
attracted significant interest. There are several methods for their synthesis in
the literature, which can be classified in to four main routes: (i) cyclization
of diacyl hydrazides 2 in the presence of a dehydrating agent,[21–26] (ii)
oxidation of acyl hydrazones 3,[27,28] (iii) reaction of acyl hydarzides with
orthoesters in the presence of an acidic catalyst,[29–32] and (iv) solid-phase
synthesis (Figure 1).[33–37] In addition to these procedures, some other
methods could also be found in the literature.[38–40] Among them, one
simple and efficient method is the reaction of acyl hydrazides with different
orthoesters in the presence of an acid catalyst, which afforded the 2,5-disub-
stituted 1,3,4-oxadiazoles. Unfortunately, most of the procedures that have
been described for this reaction use toxic reagents or solvents, have long
reaction times, or use a domestic microwave oven, which could not be
adapted to an industrial scale and furthermore repeatability is low.
The principles of green chemistry dictate that chemical transformations
should be designed to minimize (a) required energy input, either mechanical
or thermal, and (b) the use of harmful organic solvents.
Many reactions proceed efficiently under solvent-free conditions.[41,42]
Indeed, in many cases, solid-state organic reactions occur efficiently and
more selectively than those of their solution counterparts, because

Silica Sulfuric Acid
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Figure 1. General methods for the synthesis of 1,3,4-oxadiazoles.
molecules in a crystal are arranged tightly and regularly.[43] For synthesis of
our target compounds, a solvent-free reaction was selected.
RESULTS AND DISCUSSION
Here we report a procedure for the synthesis of 2,5-disubstituted 1,3,4-oxadia-
zoles. Recently we found silica sulfuric acid is a green, reusable, and versatile
acidic catalyst for organic synthesis.[44–46] Upon simple mixing of neat
orthoesters with an acyl hydrazide in the presence of catalytic amounts of
silica sulfuric acid, an immediate conversion to 2,5-disubstituted 1,3,4-oxadia-
zole was observed (Scheme 1). The results summarized in Table 1 establish
the scope of this reaction.
The orthoesters were liquid at room temperature, thus making the process
easier. As the reactions were run neat and only 1 equivalent of each reagent was
needed, there were no problematic side products; the only side product was
ethanol, which was a solvent for washing and separating the catalyst; the
workup was straightforward and included separating the solid catalyst. In
addition, the reactants were not especially sensitive to air or water, so no pre-
cautions needed to be taken. It is noteworthy that the reactions were completed
in 10 min. To our knowledge, this is the first example of direct synthesis of
disubstituted oxadiazoles at room temperature in a very short period of time.
To emphasize the effect of the catalyst, the model reaction between
4-chlorobenzhydrazide and triethyl orthopropionate was described, and
different acidic catalysts were subjected to the reaction. All the reactions
were run in the same conditions, and similar amounts of catalysts
Scheme 1.

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M. Dabiri et al.
Table 1. Synthesis of mono- and disubstituted oxadiazoles toward the reaction of acyl
hydrazides and orthoesters in the presence of silica sulfuric acid at room temperature in
10 min
Producta
Ar
R
Yield (%)b
Mp (8C)
4a
4b
4c
4d
4e
4f
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
3-O2NC6H4
3-O2NC6H4
3-O2NC6H4
3-O2NC6H4
3-O2NC6H4
Ph
H
92
90
94
90
87
90
88
85
93
80
85
132–133[32]
109–111[8]
90–91[32]
70–72[32]
66–67[32]
162–163[27]
125–126
156–158
64–65
CH3
C2H5
(CH2)2CH3
(CH2)3CH3
Ph
4g
4h
4i
H
CH3
(CH2)2CH3
(CH2)3CH3
Ph
4j
70–71
4k
4l
150–151[27]
65–67[29]
135–136[27]
150–152
104–105
75–76
CH3
Ph
93, 90, 91, 84, 86c
4m
4n
4o
4p
4q
4r
Ph
Ph
90
91
93
89
95
87
H
C2H5
Ph
Ph
(CH2)2CH3
(CH2)3CH3
Ph
Ph
4-Pyridyl
70–72
148–150[28]
aThe products were characterized by comparison of their spectroscopic and physical
data with authentic samples synthesized by reported procedures.
bIsolated yield based on acyl hydrazide.
cThe catalyst was recycled for five runs.
(30 mol%) were used. As can be seen in Table 2, satisfactory results were
obtained only with silica sulfuric acid.
To investigate the possibility of recycling the catalyst, the reaction of
benzhydrazide and triethyl orthoacetate in the presence of 30 mol% of silica
sulfuric acid was investigated. After completion of the reaction, ethanol was
Table 2. Effect of acidic catalyst on the reaction of
4-chlorobenzhydrazide and triethyl orthopropionatea
Catalyst
Yield (%)
p-TsOH
NaHSO4
42
33
28
25
48
94
NaHSO3
H2SO4
Montmorillonite K-10
Silica sulfuric acid
aAll the reactions were run in 10 min.

Silica Sulfuric Acid
1205
added, and the mixture was filtered to separate the catalyst. The recycled
catalyst was used for further runs. No decrease in catalytic activity of silica
sulfuric acid was observed even after five runs (Table 1, 4l).
In conclusion, a very simple, efficient, and ecofriendly synthesis of 2,5-
disubstituted oxadiazoles has been devised. Several symmetrical and unsym-
metrical 1,3,4-oxadiazoles were synthesized to show the diversity of the
method. We believe this method could be addressed for the combinatorial
synthesis of oxadiazoles in drug discovery programs.
EXPERIMENTAL
Products 4 (a–f), 4 (k–m), and 4r are known compounds, and their physical
data, IR, and 1H NMR spectra were essentially identical with those of
authentic samples. Other products that are new were characterized by their spec-
troscopic data (IR, 1H and 13C NMR, and MS). Melting points were obtained in
open capillary tubes and also on the Electrothermal 9100 apparatus and are not
corrected. Mass spectra were recorded on a Shimadzu QP 1100 BX mass
spectrometer. IR spectra were recorded on KBr pellets on a Shimadzu IR-470
1
spectrophotometer. H and 13C NMR spectra were determined on a Bruker
300 DRX Avance instrument at 300 and 75 MHz, respectively.
General Procedure for the Synthesis of 1,3,4-Oxadiazoles
Acyl hydrazide (1 mmol), orthester (1.2 mmol), and silica sulfuric acid
(0.11 g, equal to 0.3 mmol Hþ) were placed in a round-bottomed flask. The
resulting mixture was stirred magnetically at ambient temprature. Upon com-
pletion of the reaction, as confirmed by thin-layer chromatography (TLC)
(eluent: n-hexane/ethyl acetate: 3/1), ethanol (2 mL) was added, and the
mixture was filtered to separate the catalyst. The ethanol was evaporated
under reduced pressure, and the products were recrystallized from ethanol
for further purity.
Selected Data for New Compounds
2-(3-Nitrophenyl)-1,3,4-oxadiazole (4g): mp 125–1268C. IR (KBr): 1611,
1
1583, 1524, 1462, 1059 cm21. H NMR (CDCl3, 300 MHz) d: 7.75–8.59
(m, 4H, Ar-H), 8.93 (s, 1H, C5-H). 13C NMR (CDCl3, 75 MHz) d: 122.07,
125.194, 126.43, 130.57, 132.68, 148.66, 174.81. MS (EI, 70 eV) (m/z, %):
191 (Mþ, 100), 150 (48), 117 (25), 90 (78).
2-Methyl-5(3-nitrophenyl)-1,3,4-oxadiazole (4h): mp 156–1588C. IR (KBr):
1
1586, 1561, 1467, 1062 cm21. H NMR (CDCl3, 300 MHz) d: 2.68 (s, 3H,

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M. Dabiri et al.
CH3), 7.71–8.84 (m, 4H, Ar-H). 13C NMR (CDCl3, 75 MHz) d: 11.17,
121.63, 125.57, 126.01, 130.42, 132.28, 148.61, 163.06, 164.54. MS (EI, 70
eV) (m/z, %): 205 (Mþ, 100), 150 (48), 104 (32), 76 (30), 15 (45).
2-Propyl-5(3-nitrophenyl)-1,3,4-oxadiazole (4i): mp 64–658C. IR (KBr):
1597, 1560, 1470, 1066 cm21 1H NMR (CDCl3, 300 MHz) d: 1.08
.
(t, J ¼ 7.4 Hz, 3H), 1.92 (sex, J ¼ 7.42 Hz, 2H), 2.95 (t, J ¼ 7.45 Hz, 2H),
7.71–8.84 (m, 4H, Ar-H). 13C NMR (CDCl3, 75 MHz) d: 13.62, 20.08,
27.31, 121.62, 125.73, 125.92, 130.38, 132.32, 148.6, 162.86, 167.73. MS
(EI, 70 eV) (m/z, %): 234 (MHþ, 50), 205 (100), 150 (40), 104 (30), 76
(30), 43 (45).
2-Butyl-5(3-nitrophenyl)-1,3,4-oxadiazole (4j): mp 70–718C. IR (KBr):
1593, 1558, 1471, 1003 cm21 1H NMR (CDCl3, 300 MHz) d: 0.99
.
(t, J ¼ 7.16 Hz, 3H), 1.45–1.9 (m, J ¼ 7.19 Hz, 4H), 2.97 (t, J ¼ 7.4 Hz,
2H), 7.7–8.84 (m, 4H, Ar-H). 13C NMR (CDCl3, 75 MHz) d: 13.58, 22.17,
25.17, 28.55, 121.63, 125.72, 125.94, 130.38, 132.34, 148.59, 162.85,
167.93. MS (EI, 70 eV) (m/z, %): 248 (MHþ, 25), 205 (100), 150 (25), 104
(30), 76 (46), 57 (35), 41 (40).
2-Phenyl-1,3,4-oxadiazole (4n): mp 150–1528C. IR (KBr): 1598, 1574, 1481,
1070, 712, 691 cm21. 1H NMR (DMSO-d6, 300 MHz) d: 7.45–7.83 (m, 5H,
Ar-H), 8.10 (s, 1H, C5-H). 13C NMR (DMSO-d6, 75 MHz) d: 127.91, 128.93,
129.05, 132.34, 160.39, 165.69. MS (EI, 70 eV) (m/z,%): 147 (MHþ, 21), 105
(100), 77 (100), 51 (35).
2-Ethyl-5-phenyl-1,3,4-oxadiazole (4o): mp 104–1058C. IR (KBr): 1573,
1533, 1483, 1057, 795, 689 cm21 1H NMR (CDCl3, 300 MHz) d: 1.12
.
(t, J ¼ 6.75 Hz, 3H), 2.31 (q, J ¼ 6.75 Hz, 2H), 7.34–7.84 (m, 5H, Ar-H).
13C NMR (CDCl3, 75 MHz) d: 9.61, 27.33, 127.75, 128.65, 131.31, 132.38,
165.38, 172.64. MS (EI, 70 eV) (m/z, %): 174 (Mþ, 45), 136 (23), 105
(100), 77 (73), 51 (23).
2-Propyl-5-phenyl-1,3,4-oxadiazole (4p): mp 75–768C. IR (KBr): 1575,
1533, 1484, 1072, 891, 689 cm21 1H NMR (CDCl3, 300 MHz) d: 0.93
.
(t, J ¼ 7.3 Hz 3H), 1.66 (sex, J ¼ 7.3 Hz, 2H), 2.28 (t, J ¼ 7.27 Hz, 2H),
7.27–7.84 (m, 5H, Ar-H). 13C NMR (CDCl3, 75 MHz) d: 13.61, 18.92,
35.89, 127.39, 128.56, 131.21, 132.28, 164.9, 171.33. MS (EI, 70 eV) (m/z,
%): 188 (Mþ, 21), 160 (20), 136 (25), 105 (100), 77 (85), 51 (60).
2-Butyl-5-phenyl-1,3,4-oxadiazole (4q): mp 70–728C. IR (KBr): 1599, 1552,
1481, 1086, 805, 689 cm21 1H NMR (DMSO-d6, 300 MHz) d: 0.89
.
(t, J ¼ 7.3 Hz, 3H), 1.33 (sex, J ¼ 7.3 Hz, 2H), 1.53 (quin, J ¼ 7.35 Hz,
2H), 2.17 (t, J ¼ 7.4 Hz, 2H), 7.46–7.87 (m, 5H, Ar-H). 13C NMR
(DMSO-d6, 75 MHz) d: 14.18, 22.16, 27.67, 33.46, 127.86, 128.88, 132.21,

Silica Sulfuric Acid
1207
132.96, 165.95, 172.12. MS (EI, 70 eV) (m/z, %): 202 (Mþ, 45), 178 (25), 138
(48), 105 (100), 77 (92), 57 (65).
ACKNOWLEDGMENT
Financial support from the Research Council of Shahid Beheshti University is
gratefully acknowledged.
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