A facile procedure for the one-pot synthesis of unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles

Article abstract of DOI:10.1016/j.tetlet.2006.07.127

Unsymmetrically 2,5-disubstituted 1,3,4-oxadiazoles were efficiently synthesized from the cyclization-oxidation reaction of acyl hydrazones. Also, the synthesis of the title compounds was achieved by the condensation of acyl hydrazides and aromatic aldehydes in the presence of ceric ammonium nitrate in dichloromethane.

Full text of DOI:10.1016/j.tetlet.2006.07.127

Tetrahedron Letters 47 (2006) 6983–6986
A facile procedure for the one-pot synthesis of unsymmetrical
2,5-disubstituted 1,3,4-oxadiazoles
b,
a
Minoo Dabiri,a,* Peyman Salehi, Mostafa Baghbanzadeh and
*
Mahboobeh Bahramnejada
aDepartment of Chemistry, Faculty of Science, Shahid Beheshti University, Tehran 1983963113, Iran
bDepartment of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, Tehran,
PO Box 19835-389, Iran
Received 7 June 2006; revised 17 July 2006; accepted 25 July 2006
Abstract—Unsymmetrically 2,5-disubstituted 1,3,4-oxadiazoles were efficiently synthesized from the cyclization–oxidation reaction
of acyl hydrazones. Also, the synthesis of the title compounds was achieved by the condensation of acyl hydrazides and aromatic
aldehydes in the presence of ceric ammonium nitrate in dichloromethane.
ꢀ 2006 Published by Elsevier Ltd.
Heterocycles form by far the largest of classical divisions
of organic chemistry and are of immense importance
biologically and industrially. The majority of pharma-
ceuticals and biologically active agrochemicals are het-
erocyclic while countless additives and modifiers used
in industrial applications ranging from cosmetics, repro-
graphy, information storage and plastics are hetero-
cyclic in nature. One striking structural feature inherent
to heterocycles, which continue to be exploited to great
advantage by the drug industry, lies in their ability to
manifest substituents around a core scaffold in defined
three-dimensional representations.
of diacylhydrazines prepared from the reaction of acyl
chlorides and hydrazine. Several cyclodehydrating
agents such as BF3–OEt2,6 1,1,1,3,3,3-hexamethydisil-
azane,5 triflic anhydride,7 phosphorus pentoxide,8 poly-
phosphoric acid,1a thionyl chloride,9 phosphorus
oxychloride10 and sulfuric acid11 have been used. Due
to the high reactivity of acyl chlorides their reaction with
unprotected hydrazine results in the formation of diacyl
hydrazides. Using 2-acylpyridazin-3-one as a mild acyl-
ating agent is a good method for the synthesis of unsym-
metrical derivatives, reported by Park et al.12
One-pot syntheses of 1,3,4-oxadiazoles from hydrazine
with carboxylic acids have also been reported.13 An-
other synthetic route for the preparation of these
compounds is via acylation of tetrazoles.14 1,3,4-
Oxadiazoles have also been prepared by oxidation of
acyl hydrazones with different oxidizing agents.15–17
Reaction of acyl hydrazides with orthoesters in the pres-
ence of an acidic catalyst,18 and solid phase syntheses of
oxadiazoles19 are other approaches for the synthesis of
this group of compounds.
1,3,4-Oxadiazoles are a class of heterocycles which have
attracted significant interest in medicinal and pesticide
chemistry,1,2 and polymer and material science.3,4
Among the 1,3,4-oxadiazoles, 2,5-unsymmetrical disub-
stituted derivatives have attracted considerable attention
because of their biological5 and electrochemical
properties.3
Several synthetic methods have been reported for the
preparation of symmetrical disubstituted 1,3,4-oxadi-
azoles. One of the popular methods involve cyclization
Ceric ammonium nitrate (CAN), was introduced by
Smith et al. in 1936.20 CAN has received considerable
attention as an inexpensive and easily available catalyst
for various organic reactions such as oxidation, oxida-
tive addition, nitration, photo-oxidation, deprotection,
graft polymerization, etc.21
Keywords: Heterocycles; 1,3,4-Oxadiazole; Ceric ammonium nitrate;
Cyclization–oxidation.
*
Corresponding authors. Tel.: +98 21 22431661; fax: +98 21
22431663; e-mail: m-dabiri@sbu.ac.ir
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.07.127

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M. Dabiri et al. / Tetrahedron Letters 47 (2006) 6983–6986
As a part of our ongoing investigation on developing
versatile and efficient methods for the synthesis of
important heterocyclic compounds,22 we report here a
new procedure for the synthesis of unsymmetrically
2,5-disubstituted 1,3,4-oxadiazoles.
O
O
R1
R2
CAN (1 mmol)
R2-CHO
R1
+
N
N
reflux, CH2Cl2 (dry)
11 h
NHNH2
4
1
2
First, the synthesis of 1,3,4-oxadiazoles was investigated
through a two-step pathway (Scheme 1). Thus, the reac-
tion of acyl hydrazides with aromatic aldehydes in the
presence of catalytic amounts of CAN resulted in
formation of the corresponding acyl hydrazones 3. As
shown, acyl hydrazones 3 bearing a variety of other
functional groups were prepared in good to excellent
yields in a short period of time (Table 1).
Scheme 2.
Table 2. The products were isolated by simple aqueous
work-up followed by filtration.
Aliphatic aldehydes were also investigated in this reac-
tion but unfortunately, a mixture of compounds was
produced and the desired oxadiazoles were obtained in
low yields (Table 2, entries 19 and 20).
Subsequently, compounds 3 underwent cyclization–
oxidation using CAN under solvent-free conditions
(Scheme 1, Table 1). This step occurred in 20 min under
mild conditions at room temperature. Sensitive func-
tional groups such as methoxy, nitro, hydroxyl and pyr-
idyl remained unaffected during the reaction.
In conclusion, this investigation constitutes a novel and
efficient route for the construction of unsymmetrical
disubstituted 1,3,4-oxadiazoles. To the best of our
knowledge this is the first report on the one-pot synthe-
sis of this valuable heterocyclic core from cheap and
easily available aldehydes.
The ability of CAN to promote both steps led us to
investigate the one-pot synthesis of unsymmetrical 2,5-
disubstituted 1,3,4-oxadiazoles starting from the same
substrates.
1. General procedure for the synthesis of acyl hydrazones
A mixture of acyl hydrazide (1 mmol), aromatic alde-
hyde (1 mmol) and ceric ammonium nitrate (0.25 mmol)
in ethanol (5 mL) was heated under reflux with stirring
for 30 min. Water (5 mL) was added and the precipi-
tated product was filtered and recrystallized from
DMF and water.
When acyl hydrazides 1 and aromatic aldehydes 2 were
stirred in dry dichloromethane under reflux in the pres-
ence of CAN, the corresponding 2,5-disubstitued 1,3,4-
oxadiazoles 4 were obtained in moderate to good yields
after 11 h (Scheme 2). The results are summarized in
O
O
R1
R2
O
CAN (1 mmol)
solvent-free, rt,
20 min
CAN (0.25 mmol)
R2-CHO
R1
R1
+
reflux, EtOH, 30 min
NHNH2
NH-N=CH-R2
N
N
4
1
3
2
Scheme 1.
Table 1. Synthesis of acyl hydrazones 3 and 1,3,4-oxadiazoles 4
Entry
R1
R2
Product 3
Product 4
Yielda,b (%)
Mp (ꢁC)
Yielda (%)
Mp (ꢁC)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
4-Cl–C6H4
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
Ph
87
90
85
82
90
95
92
83
89
87
77
81
79
80
203–20524
240–24225
18826
71
76
80
72
84
64
73
67
69
73
78
75
63
72
133–13527
200–20327
144–14628
158–15928
143–14529
145–14627
163–16428
15023
4-O2N–C6H4
3-O2N–C6H4
4-Cl–C6H4
4-Me–C6H4
4-MeO–C6H4
Ph
218–22025
21725
14525
23024
Ph
15923
9
4-O2N–C6H4
3-O2N–C6H4
4-Cl–C6H4
4-Me–C6H4
4-MeO–C6H4
2-HO–C6H4
190–19223
26723
19823
10
11
12
13
14
12523
21023
170–17223
129–13025
18823
190–19223
15823
260–26223
225–22623
a The products were characterized by comparison of their spectroscopic and physical data with those reported in the literature.
b Isolated yield based on the aldehyde.

M. Dabiri et al. / Tetrahedron Letters 47 (2006) 6983–6986
6985
Table 2. One-pot synthesis of 2,5-disubstituted 1,3,4-oxadiazoles 4
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Entry R1
R2
Yielda (%) Mp (ꢁC)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
48
51
45
60
67
139–14016b
202–20416b
143–14616b
160–16216b
145–14616b
149–15116b
98–10030
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4-O2N–C6H4
3-O2N–C6H4
4-Cl–C6H4
4-Me–C6H4
4-MeO–C6H4 45
2-Furyl
42
52
55
3-Pyridyl
2,4-Cl2–C6H3
108–10932
98–10033
9
10
11
12
13
14
15
16
17
18
19
20
4-Cl–C6H4 4-MeO–C6H4 59
4-Cl–C6H4 Ph
152–15333
158–16016b
15323
65
48
45
47
56
62
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
Ph
Ph
4-O2N–C6H4
3-O2N–C6H4
4-Cl–C6H4
4-Me–C6H4
4-MeO–C6H4 49
2-HO–C6H4
Et
198–19923
118–12123
168–17023
130–13223
180–18323
230–23124
104–10533
76–7831
43
25
30
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3. General procedure for the one-pot synthesis of
2,5-disubstituted 1,3,4-oxadiazoles
To a solution of acyl hydrazides (1 mmol) and aromatic
aldehyde (1 mmol) in dry dichloromethane (5 mL) was
added ceric ammonium nitrate (1 mmol). The reaction
mixture was stirred for 11 h at reflux. Water (5 mL)
was added and the mixture was extracted with chloro-
form (3 · 5 mL). The organic layer was separated and
dried over MgSO4. The solvent was evaporated and
the crude product was recrystallized from dichloro-
methane to give the desired product (Table 2).
Acknowledgements
The authors would like to acknowledge financial
support from the Research Council of Shahid Beheshti
University.
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33. 2-(2,4-Dichlorophenyl)-5-phenyl-1,3,4-oxadiazole (entry 9,
Table 2): mp: 98–100 ꢁC. IR (KBr) m/cmÀ1: 1588, 1450,
1101, 836, 701. 1H NMR (CDCl3, 300 MHz) d (ppm):
7.43–7.46 (m, 1H, Ar–H), 7.54–7.62 (m, 4H, Ar–H), 8.08–
8.17 (m, 3H, Ar–H). 13C NMR (CDCl3, 75 MHz) d (ppm):
121.73, 123.58, 127.01, 127.69, 129.17, 131.24, 131.91,
132.05, 133.81, 138.13, 162.36, 165.21. MS (EI, 70 eV)
( m/z, %): 290 (M+, 25), 152 (23), 121 (20), 105 (100), 77 (52).
2-(4-Chlorophenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole
(entry 10, Table 2): mp: 152–153 ꢁC. IR (KBr) m/cmÀ1
1612, 1497, 1259, 1090, 830, 740. 1H NMR (CDCl3,
300 MHz) (ppm): 3.90 (s, 3H, OCH3), 7.03 (d,
:
d
J = 7.74 Hz, 2H, Ar–H), 7.51 (d, J = 7.50 Hz, 2H, Ar–
H), 8.05–8.08 (m, 4H, Ar–H). 13C NMR (CDCl3, 75 MHz)
d (ppm): 55.49, 114.55, 116.18, 122.54, 128.07, 128.74,
129.43, 137.77, 162.46, 163.32, 164.68. MS (EI, 70 eV)
(m/z, %): 286 (M+, 60), 195 (20), 152 (23), 135 (100), 111
(25), 77 (20).
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2-Ethyl-5-phenyl-1,3,4-oxadiazole (entry 19, Table 2):
white solid, mp: 104–105 ꢁC. IR (KBr): m/cmÀ1: 1573,
1
1533, 1483, 1057, 795, 689. H NMR (CDCl3, 300 MHz):
d
(ppm): 1.12 (t, J = 6.75 Hz, 3H, CH3), 2.31 (q,
J = 6.75 Hz, 2H, CH2), 7.34–7.51 (m, 3H, Ar–H), 7.83
(d, J = 7.80 Hz, 2H, Ar–H). 13C NMR (CDCl3, 75 MHz)
d (ppm): 9.61, 27.33, 127.57, 128.65, 131.31, 132.38,
165.38, 172.64. MS (EI, 70 eV) (m/z, %): 174 (M+, 45),
136 (23), 105 (100), 77 (73), 51 (23).