Microwave assisted synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from substituted amidoximes and benzoyl cyanides

Article abstract of DOI:10.1016/j.tetlet.2013.04.101

We report herein the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from amidoximes and substituted or unsubstituted benzoyl cyanides under microwave irradiation. Substituted or unsubstituted O-carboxyphenyl amidoxime is a key intermediate of this alternative method developed for the synthesis of these heterocycles. These reactions employ simple synthetic protocols devoid of lengthy purification procedures and proceed with good yield.

Full text of DOI:10.1016/j.tetlet.2013.04.101

Tetrahedron Letters 54 (2013) 3526–3529
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave assisted synthesis of 3,5-disubstituted 1,2,4-oxadiazoles
from substituted amidoximes and benzoyl cyanides
Shivaji Kandre a, Pundlik Rambhau Bhagat b, Rajiv Sharma a, Amol Gupte a,
⇑
a Department of Medicinal Chemistry, Piramal Enterprises Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400 063, Maharashtra, India
b VIT University, Vellore 632 014, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from amidoximes and substituted
or unsubstituted benzoyl cyanides under microwave irradiation. Substituted or unsubstituted O-carboxy-
phenyl amidoxime is a key intermediate of this alternative method developed for the synthesis of these
heterocycles. These reactions employ simple synthetic protocols devoid of lengthy purification proce-
dures and proceed with good yield.
Received 12 February 2013
Revised 22 April 2013
Accepted 25 April 2013
Available online 3 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Microwave-assisted synthesis
3,5-Disubstituted 1,2,4-oxadiazoles
Amidoximes
Benzoyl cyanides
The heterocycle, 1,2,4-oxadiazole is frequently observed in a
number of biologically relevant molecules.1a–e The importance of
a 1,2,4-oxadiazole motif in medicinal chemistry has increased
due to its application as a stable bioisostere in place of an amide,
ester, or urea functionality.2a–c Within literature, the 1,2,4-oxadiaz-
ole ring system appears as a part of several compounds that may
potentially act as serotonergic (5-HT3) antagonists,3 tyrosine
kinase inhibitors,4 monoamine oxidase inhibitors,5 aldose reduc-
tase inhibitors,6 metabotropic glutamate subtype 5 (mGlu5) recep-
tor antagonists,7 muscarinic agonists,8 and S1P1 agonists.9 The
application of 5-benzyloxy-1,2,4-oxadiazole as a precursor and
protecting group for amidines has also been documented.10 As a re-
sult of such a wide spread application of the 1,2,4-oxadiazole ring
system, there has been an immense interest in developing conve-
nient methodologies for the synthesis of this heterocycle.
the O-acyl amidoxime intermediate generally warrants the use of
elevated temperature coupled with varying reaction times.19
Another commonly used method for the synthesis of 1,2,4-oxadi-
azoles involves a 1,3-dipolar cycloaddition of nitriles to nitrile oxi-
des.20 Microwave assisted organic synthesis of 1,2,4-oxadiazoles
involving a one pot three-component reaction between organic
nitriles, hydroxylamine, and aldehydes has also been reported.21
This reaction requires conditions that involve heating under micro-
wave irradiation at 150 °C with an organic nitrile and exhibits
excellent yields of 3,5-disubstituted 1,2,4-oxadiazoles. The use of
PTSA-ZnCl2 provides a milder alternative for the synthesis of
3,5-disubstituted 1,2,4-oxadiazoles from amidoximes and organic
nitriles.22 Tetrabutylammonium fluoride (TBAF) has also been
developed as a mild catalyst for the synthesis of 1,2,4-oxadiazoles
from amidoximes.23 A one pot palladium mediated coupling of
amidoximes with aryliodides under one atmosphere carbon mon-
oxide for the synthesis of 1,2,4-oxadiazoles has also been pub-
lished.24 A simple catalyst-free synthesis of 1,2,4-oxadiazoles
from amidoximes and anhydrides in water with moderate yields
is also possible.25
With a variety of challenges involved in organic synthesis and
the advent of newer technologies, methodologies providing for
ease of synthesis from readily available chemical reagents, purifi-
cation, and convenient isolation of the products prove valuable
additions to existing scientific literature. The use of microwave
irradiation for shortening reaction time and improving yield has
increased dramatically in recent years. In this letter, we have eval-
uated the feasibility of synthesizing 1,2,4-oxadiazoles from ami-
doximes and commercially available benzoyl cyanides. Our
An approach commonly reported for 1,2,4-oxadiazole synthesis
undertakes O-acylation of an amidoxime by an activated carbox-
ylic acid derivative in the first step followed by a second step of
cyclodehydration.11 Activated carboxylic acid derivatives used for
the O-acylation step include esters,12 orthoesters,13 acid chlo-
rides,14 and anhydrides.15 The use of carbodiimides such as EDC,
16a–c
CDI,17 and DCC18a,b for in situ activation of carboxylic acids
has been previously published. Cyclization of the O-acyl amidox-
ime intermediate can be subsequently achieved following the use
of bases such as sodium hydride or sodium ethoxide at room
temperature, or in pyridine on heating. Effective cyclization of
⇑
Corresponding author. Tel.: +91 22 30818312; fax: +91 22 30818036.
E-mail address: amol.gupte@piramal.com (A. Gupte).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.101

S. Kandre et al. / Tetrahedron Letters 54 (2013) 3526–3529
3527
Table 1
Reaction of benzamidoxime (1a) with benzoyl cyanide (2a) in various conditions
OH
O
N
O
N
O
N
CN
N
NH2
O
NH2
2a
3
3a
1a
Entry
Solvent
Yield of 3a (reaction time) at varying conditions
Reflux
MW at 80 °C
MW at 95 °C
MW at 130 °C
1
2
3
4
5
Water
20% (8 h)
51% (8 h)
62% (8 h)
70% (8 h)
49% (16 h)
74% (4 h)
80% (4 h)
74% (4 h)
84% (1 h)
42% (4 h)
63% (1 h)
77% (1 h)
83% (1 h)
88% (1 h)
66% (1 h)
57% (40 min)
67% (40 min)
80% (20 min)
69% (20 min)
81% (20 min)
1,4-Dioxane
Toluene
DMF
Acetonitrile
a
Isolated yield.
results demonstrate the applicability of benzoyl cyanides for such
microwave assisted synthesis of 1,2,4-oxadiazoles. We have fur-
ther exemplified the applicability of this methodology for the syn-
at different temperatures under both conventional as well as
microwave heating conditions. The experimental yields of these
standardization efforts are listed in Table 1. The use of microwave
heating greatly reduced reaction time as well as improved product
yields over conventional heating. It was highlighted that the use of
higher temperature aids in the cyclization of the O-carboxyphenyl
amidoxime intermediate (3a) formed during this reaction. The sol-
vents studied included water, dioxane, toluene, DMF, and acetoni-
trile of which DMF was found to be more suitable for conducting
these reactions. The selection of DMF over toluene as a solvent
was driven by the observation of marginally improved product
thesis
of
methyl
3-(4-((4-(5-phenyl-1,2,4-oxadiazol-3-
yl)benzyl)amino)phenyl)propanoate (31) and compared the yield
with that from another microwave assisted methodology reported
in the literature.21 Our efforts, described herein, identify an effec-
tive alternative, demonstrate the applicability, and identify limita-
tions of this microwave mediated synthesis of 1,2,4-oxadiazoles.
Initially, this reaction was standardized by reacting ben-
zamidoxime (1a) with benzoyl cyanide (2a) in a variety of solvents
Table 2
Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles
O
R'
R'
N
O
OH
CN
DMF, 95 o
N
O
C
-H2O
R
N
N
R
NH2
O
Microwave irradiation, 1h
R'
R
NH2
3 - 29
1
2
Entry
R
R0
Compound
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Phenyl
Phenyl
Phenyl
–H
–F
–CH3
–H
–H
–H
–F
–F
–F
–CH3
–CH3
–CH3
–H
–H
–H
–F
–F
–F
3
4
5
6
7
8
9
88
92
80
88
79
86
93
89
92
77
65
73
58
75
76
61
72
70
56
64
53
87
93
65
89
92
77
2-Methoxyphenyl
3-Methoxyphenyl
4-Methoxyphenyl
2-Methoxyphenyl
3-Methoxyphenyl
4-Methoxyphenyl
2-Methoxyphenyl
3-Methoxyphenyl
4-Methoxyphenyl
2-Nitrophenyl
3-Nitrophenyl
4-Nitrophenyl
2-Nitrophenyl
3-Nitrophenyl
4-Nitrophenyl
2-Nitrophenyl
3-Nitrophenyl
4-Nitrophenyl
Cyclohexyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
–CH3
–CH3
–CH3
–H
–F
–CH3
–H
Cyclohexyl
Cyclohexyl
Adamantyl
Adamantyl
–F
–CH3
Adamantyl

3528
S. Kandre et al. / Tetrahedron Letters 54 (2013) 3526–3529
yields and the ease of product isolation observed in DMF.
Microwave heating in DMF at 95 °C for 1 h was found optimum
due to shorter reaction times and increased product purities and
yields. Although increasing the reaction temperature to 130 °C in
DMF lowered the time required for reaction completion to
20 min, it was also observed that the product yields reduced to
69% as a result of increased side-products seen at this elevated
temperature.
Following optimization of reaction conditions, the scope of this
simplistic method was studied by reacting several amidoximes and
substituted or unsubstituted benzoyl cyanides in DMF using
microwave heating at 95 °C for 1 h (Table 2).26 The reaction pro-
ceeds via a O-carbophenyl amidoxime intermediate (2) that subse-
quently dehydrates and undergoes cyclization to yield the
appropriately substituted 3,5-disubstituted 1,2,4-oxadiazoles.
After completion of the reaction, the desired product precipitates
as a solid on addition of water to DMF and is thus isolated using
simple filtration thereby avoiding the need for column chromato-
graphic purification techniques. The 3-position substituent is
obtained from the amidoxime whereas the 5-position substituent
is obtained from the corresponding benzoyl cyanide used in this
reaction. The aromatic and aliphatic amidoximes used to develop
this methodology were synthesized using a reported procedure.23
Although the benzoyl cyanides used in this study are commercially
available, they can also be readily synthesized from appropriate
acyl chlorides as reported in the literature.27a,b
In this study, the reactivities of an unsubstituted phenyl
amidoxime (Table 2, entries 1–3) were compared with ortho-,
meta-, or para-methoxy substituted phenyl amidoximes (Table 2,
entries 4–12) and ortho-, meta-, or para-nitro substituted phenyl
amidoximes (Table 2, entries 13–21). The reactivities of aliphatic
amidoximes such as cyclohexyl amidoxime (Table 2, entries
22–24) and an adamantly amidoxime (Table 2, entries 25–27) were
also evaluated. We have thus attempted to understand the effects
exerted by electron withdrawing and electron donating amidox-
ime substituents on the yields of corresponding 3,5-disubstituted
1,2,4-oxadiazoles. The corresponding benzoyl cyanides that have
been evaluated for their reactivity include either an unsubstituted
benzoyl cyanide yielding a phenyl substituent, an electron with-
drawing para-fluoro benzoyl cyanide yielding a para-fluorophenyl
substituent, and an electron donating para-methyl benzoyl cyanide
yielding a para-methylphenyl substituent at the 5-position.
The reactivity trend can be discussed from the benzoyl cyanide
perspective as well as from the amidoxime perspective. From the
benzoyl cyanide perspective, the general reactivity trend observed
is para-fluorophenyl substituent > phenyl substituent > para-
methylphenyl substituent indicating that the presence of an elec-
tron withdrawing substituent on the phenyl favors reactivity as
compared to the presence of an electron donating substituent.
However this reactivity trend appears reversed in the case of ami-
doximes, wherein the yields with methoxy phenyl substitu-
ents P phenyl substituent > nitrophenyl substituent indicate that
the presence of an electron donating substituent on phenyl ami-
doxime favors reactivity as compared to the presence of an elec-
tron withdrawing substituent. The order of reactivity of phenyl
amidoximes substituted with an electron donating methoxy group
appears to be ortho substituent P para substituent > meta substi-
tuent. A similar comparison with an electron withdrawing nitro
phenyl amidoxime identifies the order of reactivity to be me-
ta P para > ortho. The aliphatic cyclohexyl and adamantyl amidox-
imes exhibit similar reactivity as seen with aromatic phenyl
amidoxime thereby exemplifying the utility of this reaction. All
the studied examples (Table 2, entries 1–27) proceeded with mod-
erate to high yields and in each case the desired product was iso-
lated using simple filtration. This methodology thus provides an
attractive alternative to existing literature methodologies.
To demonstrate the utility of our developed methodology, we
compared the synthesis of methyl 3-(4-((4-(5-phenyl-1,2,4-oxa-
diazol-3-yl)benzyl)amino)phenyl)propanoate (31) with another
reported microwave reaction condition21 and compared the yields
obtained from each methodology (Table 3). The reported micro-
wave procedure for the synthesis of 1,2,4-oxadiazoles reports
yields in excess of 90% on reacting an aldehyde with an amidoxime
for 3 min at 150 °C. However the reaction of methyl 3-(4-((4-(N0-
hydroxycarbamimidoyl)benzyl)amino)phenyl)propanoate
(30)
with benzaldehyde under microwave conditions at 150 °C for
15 min yielded only 24% of 31 (Table 3, entry 1). The reaction time
was extended from the originally reported 3–15 min in an attempt
to ensure complete consumption of the starting material and
maximize the product yield. Although the yield obtained with
the reported methodology was much lower than that anticipated,
our alternative microwave methodology (Table 3, entry 2) that
involves reacting amidoxime 30 with benzoyl cyanide at 95 °C
for 1 h yielded 63% of compound 31. Moreover, we were able to
isolate compound 31 using simple filtration techniques as opposed
to the column chromatographic purification warranted when the
reported methodology21 was implemented.
In summary, an alternate intermolecular synthesis of 3,5-disub-
stituted 1,2,4-oxadiazoles has been achieved. This reaction pro-
ceeds via an O-carbophenyl amidoxime intermediate synthesized
in situ. Both aliphatic and aromatic amidoximes can undergo a
reaction with substituted or unsubstituted benzoyl cyanides to
yield 3,5-disubstituted 1,2,4-oxadiazoles in moderate to high
yields. In general, electron donating substituents on the aromatic
phenyl amidoxime are observed to favor the reactivity over elec-
tron withdrawing substituents. In the case of substituted para-
substituted benzoyl cyanides, electron withdrawing substituents
are favored over electron donating substituents. The synthetic
methodology described herein allows for ease of purification as
the desired product precipitates out as a solid and can thus be
isolated using simple filtration as opposed to lengthy column chro-
matographic purification techniques. This synthetic protocol thus
Table 3
Effect of varying reaction conditions on product yield
O
O
O
O
N
H
N
H
N
N
a
HO
31
30
N
O
NH2
Entry
Reaction conditions (a)
Yield of 31 (%)
1
2
Benzaldehyde/150 °C/MW/15 min
Benzoyl cyanide/DMF/95 °C/MW/1 h
24
63

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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
04.101.
References and notes
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26. General procedure for synthesis of 1,2,4-oxadiazoles: To
a solution of the
amidoxime (1.0 equiv) in DMF (1 mL) was added the appropriate benzoyl
cyanide (1.05 equiv) and the reaction mixture was stirred at 95 °C for 1 h under
microwave irradiation. Following reaction completion a solid precipitated on
addition of water. The slurry was subsequently filtered, washed with water,
and dried to yield 56–93% 3,5-disubstituted 1,2,4-oxadiazoles as solid. Spectral
data for the representative examples: 3,5-Diphenyl-1,2,4-oxadiazole (3) 1H NMR
(300 MHz, CDCl3): d 8.20–8.25 (m, 4H), 7.54–7.59 (m, 6H); 13C NMR (300 MHz,
CDCl3): d 177.1, 169.0, 132.7, 131.2, 129.1 (2C), 128.8 (2C), 128.2 (2C), 127.5
(2C), 126.9, 124.3; MS: m/z 223.0 [M+H]+; HRMS (ESI+) calcd for C14H11N2O
[M+H]+ 223.0866, found 223.0849; Melting point: 108–110 °C (lit.28 109–
110 °C); HPLC: Retention time—13.56 min, Purity—99.90%. 3-Phenyl-5-(p-
tolyl)-1,2,4-oxadiazole (5) 1H NMR (300 MHz, CDCl3): d 8.19–8.20 (m, 2H),
8.12 (d, J = 7.8 Hz, 2H), 7.52–7.54 (m, 3H), 7.38 (d, J = 8.1 Hz, 2H), 2.47 (s, 3H);
13C NMR (300 MHz, CDCl3): d 175.8, 168.9, 143.5, 131.1, 129.8 (2C), 128.8 (2C),
128.1 (2C), 127.5 (2C), 127.1, 121.6, 21.8; MS: m/z 237.1 [M+H]+; HRMS (ESI+)
calcd for C15H13N2O [M+H]+ 237.1022, found 237.1029; Melting point: 118–
119 °C (lit.29 117–118 °C); HPLC: Retention time—14.21 min, Purity—99.82%. 3-
(4-Methoxyphenyl)-5-phenyl-1,2,4-oxadiazole (8). 1H NMR (300 MHz, CDCl3): d
8.23 (d, J = 6.6 Hz, 2H), 8.14 (d, J = 8.1 Hz, 2H), 7.58–7.56 (m, 3H), 7.03 (d,
J = 8.1 Hz, 2H), 3.89 (s, 3H); 13C NMR (300 MHz, CDCl3): d 176.0, 168.2, 162.1,
132.6, 129.1 (2C), 129.1 (2C), 128.1 (2C), 124.5, 119.5, 114.2 (2C), 55.4; MS: m/z
253.0 [M+H]+; HRMS (ESI+) calcd for C15H13N2O2 [M+H]+ 253.0972, found
253.0986; Melting point: 98–100 °C (lit.28 98–99 °C); HPLC: Retention time—
8.14 min, Purity—99.65%.
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