Organic reactions in water: An efficient method for the synthesis of 1,2,4-oxadiazoles in water

Article abstract of DOI:10.1016/j.tetlet.2011.09.081

A simple and efficient process has been developed for the synthesis of 1,2,4-oxadiazoles in good yields through the reaction of amidoximes with anhydrides under catalyst-free conditions in water.

Full text of DOI:10.1016/j.tetlet.2011.09.081

Tetrahedron Letters 52 (2011) 6424–6426
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Organic reactions in water: an efficient method for the synthesis
of 1,2,4-oxadiazoles in water
⇑
Babak Kaboudin , Leila Malekzadeh
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45137-66731, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2011
Revised 3 September 2011
Accepted 16 September 2011
Available online 22 September 2011
A simple and efficient process has been developed for the synthesis of 1,2,4-oxadiazoles in good yields
through the reaction of amidoximes with anhydrides under catalyst-free conditions in water.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Oxadiazoles
Water
Amidoximes
Anhydrides
Catalyst-free
Heterocyclic compounds are valuable natural and synthetic
materials that have been used as intermediates and solvents in
pharmaceutical, chemical, textile, dye-stuff, petroleum, and pho-
tography industries. The remarkable ability of the heterocyclic nu-
clei to serve both as biomimetics and active pharmacophores has
largely contributed to their value as traditional key elements of
numerous drugs.1 The oxadiazole nucleus is a well studied phar-
macophoric scaffold that has emerged as a core structural unit of
various muscarinic agonists,2 benzodiazepine receptor partial ago-
nists,3 dopamine transporters,4 antirhinovirals,5 a growth hormone
secretagogue,6 and 5-HT agonists.7 Among oxadiazoles, 1,2,4-oxa-
diazole derivatives have gained importance in medicinal chemis-
try. 1,2,4-Oxadiazoles have shown affinities for serotonin,
norepinephrine transporters,4 and have also been used as a urea
bioisostere in b3 adrenergic receptor agonists.8 The 1,2,4-oxadiaz-
ole motif is found in several drugs including the potent S1P1 ago-
nist I and the metabotropic glutamate subtype 5 (mGlu5) receptor
antagonist II (Fig. 1).9 Recently, the anticancer activities of a library
of 1,2,4-oxadiazoles were studied by Kumar et al.10 Several meth-
ods have been reported for the synthesis of 1,2,4-oxadiazoles.11–17
In general, the two most common routes are: (i) 1,3-dipolar cyclo-
addition of nitriles to nitrile oxides; (ii) cyclization of amidoxime
derivatives.18 In the second method, 1,2,4-oxadiazoles are pre-
pared in two steps by O-acylation of an amidoxime, which can
be easily prepared by the reaction of nitriles with hydroxylamine,
with an activated carboxylic acid derivative, typically an active acyl
chloride, followed by cyclodehydration (Scheme 1). Cyclization can
be achieved by treating the O-acylamidoxime with bases such as
NaH or NaOEt at room temperature, or pyridine on heating.19
Cyclization of the O-acyl amidoxime formed from the reaction of
an amidoxime with an acyl chloride is generally the most difficult
and time-consuming step and often requires sealed tube condi-
tions and long reaction times. Recently, the use of tetrabutylam-
monium fluoride as a catalyst and solid support was reported for
the cyclization of O-acylamidoximes into 1,2,4-oxadiazoles.20 In
an attempt to improve on these procedures, microwave-assisted
methods for this cyclization have recently been reported.21
The development of simple and general routes for widely used
organic compounds from the readily available reagents is one of
the major challenges in organic synthesis. Organic reactions in
aqueous media have attracted much recent attention.22 Water is
an abundant, cheap, and environmentally friendly solvent. Indeed
water exhibits unique reactivity and selectivity, which is different
N
HOOC
N
N
N
N
O
N
O
CN
II
I
⇑
Corresponding author. Tel.: +98 241 4153220; fax: +98 241 4214949.
E-mail address: kaboudin@iasbs.ac.ir (B. Kaboudin).
Figure 1. Biologically active 1,2,4-oxadiazoles.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.081

B. Kaboudin, L. Malekzadeh / Tetrahedron Letters 52 (2011) 6424–6426
6425
Table 2
OH
R
N
Reaction of amidoximes with anhydrides in water under catalyst-free conditions
NH2OH
reflux, EtOH
1) R'COX
2) NaH or NaOEt
N
R
C N
N
Entry
R
R0
Product
Yield %a
R
NH2
R'
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
C6H5–
C6H5–
C6H5–
C6H5–
C6H5–
C6H5–
C6H5–
C6H5–
p-CH3C6H4–
p-CH3C6H4–
p-CH3C6H4–
n-C5H11
n-C5H11
n-C5H11
n-C5H11
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
93
60
81
52
85
69
86
81
72
76
53
40
35
48
p-ClC6H4–
p-BrC6H4–
2,4-Cl2C6H3–
m-ClC6H4–
p-MeOC6H4CH2
Cyclohexyl
C6H5–
2,4-Cl2C6H3–
p-BrC6H4–
C6H5–
Scheme 1. Preparation of 1,2,4-oxadiazoles.
from that of conventional organic solvents. Thus, the development
of novel reactivity and selectivity is one of the challenges of aque-
ous chemistry. As part of our efforts to explore the utility of novel
methods for the synthesis of heterocyclic compounds,23 we report
here a new method for the synthesis of 1,2,4-oxadiazoles via reac-
tion of amidoximes with anhydrides under mild, catalyst-free con-
ditions in water.
Initially, we carried out the reaction of benzamidoxime (1a)
with benzoic anhydride (2a), as a model reaction, in various sol-
vents under catalyst-free conditions. The progress of the reaction
was monitored by TLC and the experimental data for the screening
conditions are listed in Table 1.
Among the solvents studied (EtOH, EtOAc, dichloromethane,
chloroform, toluene, and water), water was found to be the most
suitable (Table 1). Treatment of 1a with 2a failed to give the corre-
sponding 1,2,4-oxadiazole adduct 3a in water after 24 h at ambient
temperature (entry 11). When the reaction was carried out at re-
flux, compound 3a was obtained in 93% isolated yield after 12 h
(entry 12). Benzoyl chloride (PhCOCl) was not as effective as ben-
zoic anhydride and gave a very low yield of the product. These re-
sults prompted us to extend this process to other amidoximes and
anhydrides. Interestingly, amidoximes reacted smoothly with
anhydrides under catalyst-free conditions in water to produce
the corresponding 1,2,4-oxadiazoles in good yields (Table 2 and
Scheme 2). As shown in Table 2, various substituted benzamidox-
imes 1a–1e in the presence of benzoic anhydride (2a) afforded
1,2,4-oxadiazoles 3a–3e in 52–93% isolated yields. Treatment of
benzoic anhydride with aliphatic amidoximes 1f,g gave the desired
compounds 3f,g in good yields (entries 6 and 7). The reaction of
p-methylbenzoic anhydride with amidoximes in water under
catalyst-free conditions gave the desired compounds 3h–3j in
moderate to good yields (entries 8–10). The reaction of hexanoic
anhydride, an aliphatic anhydride, with various amidoximes gave
the corresponding adducts 3k–3n in lower 35–53% yields, which
is possibly due to the electronic effect (entries 11–14). Thus, the
cyclization reaction reported herein tolerates a wide variety of
–
–
–
–
2,4-Cl2C6H3–
m-ClC6H4–
p-BrC6H4–
a
Yield refers to isolated yield following column chromatography.
OH
R
N
N
H2O
reflux, 12 h
(R'CO)2O
+
N
R
NH2
R'
O
1
2
3
Scheme 2. Reaction of amidoximes with anhydrides in water.
amidoximes and anhydrides for the synthesis of 1,2,4-
oxadiazoles.24
In summary, we have developed a simple and practical method
for the synthesis of 1,2,4-oxadiazoles via the reaction of readily
available amidoximes with anhydrides in water under catalyst-free
conditions. The simple work-up, mild reaction conditions, moder-
ate to good yields, and clean reactions are the advantages of this
method.
Acknowledgment
The authors gratefully acknowledge support from the Institute
for Advanced Studies in Basic Sciences (IASBS) (Research Council
Grant No. G20109IASBS120).
Supplementary data
Supplementary data (experimental procedures and spectro-
scopic characterization for compounds 3b–3n) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.09.081.
Table 1
Reaction of benamidoxime (1a) with benzoic anhydride (2a) in various solvents
OH
Ph
N
N
(PhCO)2O
+
References and notes
N
Ph
NH2
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24. The amidoxime (10 mmol, amidoxime was obtained according to the method
of our previously published article)23d and anhydride (11 mmol) were added to
H2O (20 mL) and the solution was stirred for 12 h at reflux. After cooling, the
reaction mixture was washed with Et2O (3 ꢀ 50 mL). Organic layers were dried
over MgSO4 and evaporated. The residue was subjected to column
chromatography on silica gel with EtOAc/n-hexane (1:9) and evaporation of
the solvent under reduced pressure gave pure products in 35–93% yields. All
products gave satisfactory spectral data in accord with the assigned structures.
Spectral data for the representative examples: 3,5-diphenyl-1,2,4-oxadiazole
(3a): mp: 108–109 °C [Lit.18b 109–110 °C]; 1H NMR, dH (CDCl3, 400 MHz):
7.52–7.67 (m, 6H), 8.20–8.28 (m, 4H); 13C NMR, dc (CDCl3, 100 MHz): 124.34,
127.00, 127.56, 128.20, 128.88, 129.13, 131.22, 132.76, 169.00, 175.74. 3-(2,4-
Dichlorophenyl)-5-phenyl-1,2,4-oxadiazole (3d): mp: 138–140 °C[Lit.23d 140–
142 °C]; 1H NMR, dH (CDCl3, 400 MHz): 7.44 (dd, 1H, J = 8.4 and J = 2.0 Hz),
7.57–7.66 (m, 4H), 8.04–8.24 (m, 3H); 13C NMR, dc (CDCl3, 100 MHz): 123.95,
124.86, 127.38, 128.26, 129.20, 130.89, 132.60, 133.02, 134.55, 137.29, 167.08,
175.39.