Magnesia-supported hydroxylamine hydrochloride in the presence of sodium carbonate as an efficient reagent for the synthesis of 1,2,4-oxadiazoles from nitriles

Article abstract of DOI:10.1016/j.tetlet.2007.02.105

An efficient one-pot method has been developed for the synthesis of 1,2,4-oxadiazoles through a one-pot reaction of nitriles with hydroxylamine hydrochloride in the presence of magnesia-supported sodium carbonate followed by reaction with acyl halides under solvent-free conditions using microwave irradiation. This method is easy, rapid and good yielding.

Full text of DOI:10.1016/j.tetlet.2007.02.105

Tetrahedron Letters 48 (2007) 2829–2832
Magnesia-supported hydroxylamine hydrochloride in the
presence of sodium carbonate as an efficient reagent for
the synthesis of 1,2,4-oxadiazoles from nitriles
*
Babak Kaboudin and Fariba Saadati
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-1159, Iran
Received 18 January 2007; revised 9 February 2007; accepted 22 February 2007
Available online 25 February 2007
Abstract—An efficient one-pot method has been developed for the synthesis of 1,2,4-oxadiazoles through a one-pot reaction of nitr-
iles with hydroxylamine hydrochloride in the presence of magnesia-supported sodium carbonate followed by reaction with acyl
halides under solvent-free conditions using microwave irradiation. This method is easy, rapid and good yielding.
Ó 2007 Elsevier Ltd. All rights reserved.
Many heterocyclic compounds are pharmaceutically
important natural and synthetic materials. The remark-
able ability of heterocyclic nuclei to serve both as
biomimetics and active pharmacophores has largely
contributed to their unique value as traditional key ele-
can be effected by treating an O-acylamidoxime with
bases such as NaH or NaOEt at room temperature, or
1
7
pyridine with heating. Recently, the use of tetrabutyl-
ammonium fluoride as catalyst and solid support has
been reported for the cyclization of O-acylamidoximes
1
18,19
ments of numerous drugs. The oxadiazole nucleus is a
to 1,2,4-oxadiazoles.
well studied pharmacophoric scaffold that has emerged
2
as a core structural unit of various muscarinic agonists,
The development of simple and general synthetic routes
for widely used organic compounds from readily avail-
able reagents is one of the major challenges in organic
synthesis. In recent years, the use of reagents and cata-
lysts immobilised on solid supports has received consid-
3
benzodiazepine receptor partial agonists, dopamine
transporters, antirhinovirals, a growth hormone secre-
tagogue, and 5-HT agonists. Among oxadiazoles,
,2,4-oxadiazole derivatives have gained importance in
medicinal chemistry. In the literature, 1,2,4-oxadiazoles
have shown affinities for serotonin and norepinephrine
transporters. The 1,2,4-oxadiazole ring system has also
been used as a urea bioisostere in b adrenergic receptor
agonists. Several methods have been reported in the lit-
4
5
6
7
1
2
0
erable attention. Such reagents not only simplify
purification processes but also help prevent release of
reaction residues into the environment. Reagents sup-
ported on organic polymers and within and/or on the
surface of inorganic matrices have all been reported.
The application of microwave energy to accelerate or-
ganic reactions is of increasing interest and offers several
4
3
8
9
–15
erature for the synthesis of 1,2,4-oxadiazoles.
In gen-
eral 1,2,4-oxadiazoles are prepared in two steps by O-
acylation of an amidoxime with an activated carboxylic
acid derivative, typically an active acyl chloride, fol-
2
1
advantages over conventional techniques. Syntheses
that normally require lengthy periods, can be achieved
conveniently and very rapidly in a microwave oven. In
1
6
lowed by cyclodehydration (Scheme 1). Cyclization
OH
N
R
O
R'
N
NH OH
reflux-EtOH
R'COX
N
2
heat
or catalyst
N
R
C N
O
R
NH2
R
NH2
R'
O
Scheme 1.
*
0
Corresponding author. Tel.: +98 241 4242239; fax: +98 241 4249023; e-mail: kaboudin@iasbs.ac.ir
040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.105

2830
B. Kaboudin, F. Saadati / Tetrahedron Letters 48 (2007) 2829–2832
recent years, microwave irradiation has been reported
for the synthesis of 1,2,4-oxadiazoles in the presence of
R
MgO-NH OH.HCl
2
N
Na CO , MW
2
3
2
2
R
C
N
solvent or under solvent-free conditions. However,
often when carrying out a reaction in a microwave oven
the use of a solvent can sometimes be avoided, which
is important in order to make the synthesis more envi-
ronmentally friendly (‘green chemistry’). Moreover, all
of the above methods are not one-pot methods and
require amidoximes as starting materials. These obser-
vations led us to investigate the possibility of improving
the methods used for the synthesis of 1,2,4-oxadiazoles
under microwave irradiation. As part of our efforts to
explore the utility of solid-supported reagents for the
synthesis of heterocyclic compounds under microwave
N
R'COCl
MW
O
R'
1
2
Scheme 3.
this reaction was carried out in the presence of sodium
carbonate for 2 min, it afforded the corresponding benz-
amidoxime in 78% yield. Reaction of the benz-
amidoxime, without separation, with benzoyl chloride
under solvent-free conditions using microwave irradia-
tion, gave 3,5-diphenyl-1,2,4-oxadiazole (2a) in 50%
yield (over two steps, based on benzonitrile). Reaction
of the benzamidoxime with benzoyl chloride in the pres-
ence of alumina-supported sodium carbonate gave only
the corresponding O-acylamidoxime as the major prod-
2
3
irradiation, we report a new method for the synthesis
of 1,2,4-oxadiazoles from nitriles through a one-pot
reaction of nitriles with hydroxylamine hydrochloride
in the presence of magnesia-supported sodium carbon-
ate followed by reaction with acyl halides under sol-
vent-free conditions (Scheme 2, Table 1).
uct (Scheme 2). Sodium bicarbonate (NaHCO ) was not
as effective as sodium carbonate and gave very low
yields of the required product.
3
Initially, we carried out the reaction of benzonitrile 1a in
a mixture of magnesia-supported hydroxylamine hydro-
chloride under microwave irradiation to afford the cor-
responding benzamide in 80% yield after 2 min. When
These results prompted us to extend this process to
other nitriles. Interestingly, nitriles reacted smoothly
with hydroxylamine hydrochloride in the presence of
magnesia-supported sodium carbonate followed by
reaction with acyl halides under solvent-free conditions
using microwave irradiation to produce the correspond-
ing 1,2,4-oxadiazoles in good yields (Table 1 and
Scheme 3). As shown in Table 1, benzonitrile (1a) in
the presence of p-methoxybenzoyl chloride afforded 3-
phenyl-5-(p-methoxyphenyl)-1,2,4-oxadiazole (2b) in
O
MgO-NH OH.HCl
2
Ph
C
N
Ph
C
NH2
MW
MgO-NH OH.HCl
2
Na CO , MW
2
3
4
2% yield. Other benzonitriles also reacted with hydrox-
Al O
2
3
N
OH
N
O
Ph
Na CO3
ylamine hydrochloride in the presence of magnesia-sup-
ported sodium carbonate under microwave irradiation
followed by reaction with acyl halides to give the desired
2
Ph
Ph
Ph
PhCOCl
MW
O
NH2
NH2
Ph
2
4
compounds in good yields.
MgO-NH OH.HCl
2
Na CO , MW
N
2
3
C
N
In summary, the rapid reaction rates, mild reaction con-
ditions, moderate to good yields and the relatively clean
reactions make this method an attractive and useful con-
tribution to present methodologies for the synthesis of
PhCOCl
MW
N
O
Ph
1
a
2
a
Scheme 2.
1
,2,4-oxadiazoles.
Table 1. Reaction of nitriles with hydroxylamine hydrochloride in the
presence of magnesia-supported sodium carbonate followed by reac-
tion with acyl halides under solvent-free conditions using microwave
irradiation
Acknowledgement
The Institute for Advanced Studies in Basic Sciences
(IASBS) is thanked for supporting this work.
0
a
Entry R 1
R
Reaction
Yield
time (min) (%) 2
References and notes
a
b
c
d
e
f
C
C
C
p-ClC
p-ClC
p-ClC
p-ClC
2,4-Cl
2,4-Cl
2,4-Cl
6
6
6
H
H
H
5
5
5
–
–
–
C
p-CH
p-O NC
6 5
C H –
p-O
6 5
C H –
p-CH
6 5
C H –
p-O
p-CH
C
C
6
H
5
–
3
3
3
4
4
2
2
2
2
2
2
5
50
42
43
40
46
53
42
46
41
40
70
44
3
OC
6
H
4
–
1
2
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–
–
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a
Yield (over two steps, based on nitrile) refers to total isolated yield by
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mortar and pestle by grinding them together until a fine,
homogeneous, powder was obtained (5–10 min). Nitrile
(5 mmol, finely ground for solid nitriles) was added to this
mixture. The reaction mixture was irradiated with micro-
waves for 3 min at 180 W. The acyl chloride (7 mmol) was
then added and the mixture was shaken for 5 min and
irradiated for 2–5 min at 600 W (a kitchen-type Samsung
microwave oven, model number CE290DN, was used in
all experiments). The reaction mixture was ground in a
mortar and pestle until a fine, homogeneous, powder was
obtained. The mixture was chromatographed on silica gel
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accord with the assigned structures and literature
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For new compounds, spectral data are
reported as follows:
(
3-(4-Chlorophenylmethyl)-5-phenyl-1,2,4-oxadiazole (2d):
Mp 76–78 °C (ethanol). IR (KBr): 3020, 2910, 1655,
1
2
146–1148; (g) Kaboudin, B.; Norouzi, H. Synthesis 2004,
035–2039; (h) Shimizu, K.-I.; Hayashi, E.; Hatamachi,
ꢀ
1 1
H 3
1635 cm ; H NMR, d (CDCl , TMS-500 MHz): 4.10
T.; Kodama, T.; Kitayama, Y. Tetrahedron Lett. 2004, 45,
135–5138; (i) Dongare, M. K.; Bhagwat, V. V.; Ramana,
C. V.; Gurjar, M. K. Tetrahedron Lett. 2004, 45, 4759–
(s, 2H), 7.28–7.35 (m, 4H), 7.46–7.55 (m, 3H), 8.09 (d, 2H,
J = 8 Hz); C NMR, d (CDCl , TMS-125 MHz): 31.73,
C 3
13
5
124.02, 128.02, 128.97, 129.05, 129.23, 130.33, 131.10,
132.70, 132.97, 133.94, 169.63, 175.81. Anal. Calcd for
C H ClN O: C, 66.55; H, 4.10; N, 10.35. Found: C,
4
762; (j) Kaboudin, B.; Saadati, F. Synthesis 2004, 1249–
1
252; (k) Song, Y.-M.; Choi, J. S.; Yang, J. W.; Han, H.
1
5
11
2
Tetrahedron Lett. 2004, 45, 3301–3304; (l) Kaboudin, B.;
Norouzi, H. Tetrahedron Lett. 2004, 45, 1283–1285; (m)
Kaboudin, B.; Rahmani, A. Org. Prep. Proced. Int. 2004,
66.38; H, 4.36; N, 9.89.
3-(4-Chlorophenylmethyl)-5-(4-nitrophenyl)-1,2,4-oxadi-
azole (2e): Mp 132–134 °C (ethanol). IR (KBr): 3015, 2920,
ꢀ
1 1
36, 82–86; (n) Kaboudin, B.; Rahmani, A. Synthesis 2003,
2705–2708; (o) Danks, T. N.; Desai, B. Green Chem. 2002,
4, 179–180.
H 3
1632, 1625 cm ; H NMR, d (CDCl , TMS-500 MHz):
4.13 (s, 2H), 7.20–7.35 (m, 4H), 8.27 (d, 2H, J = 4.6 Hz),
8.34 (d, 2H, J = 4.6 Hz); C NMR, d
1
3
C 3
(CDCl , TMS-
2
1. (a) Caddick, S. Tetrahedron 1995, 51, 10403–10432; (b)
Zlotorzynsky, A. Crit. Rev. Anal. Chem. 1995, 25, 43–76;
125 MHz): 31.58, 124.21, 125.43, 128.54, 129.18, 129.25,
130.41, 133.46, 150.12, 170.17, 173.75. Anal. Calcd for
(
c) Varma, R. S. Green Chem. 1999, 43–55; (d) Lidstrom,
C
15
H10ClN
3 3
O : C, 57.06; H, 3.19; N, 13.31. Found: C,
P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
57.40; H, 3.25; N, 13.20.

2832
B. Kaboudin, F. Saadati / Tetrahedron Letters 48 (2007) 2829–2832
3
1
5
7
-(2,4-Dichlorophenyl)-5-phenyl-1,2,4-oxadiazole (2h): Mp
132.46, 134.25, 137.04, 163.28, 166.81, 175.15. Anal. Calcd
for C15 : C, 56.07; H, 3.11; N, 8.72. Found: C,
55.83; H, 3.18; N, 8.38.
1
40–142 °C (ethanol). H NMR, d
H
(CDCl
3
, TMS-
2 2 2
H10Cl N O
00 MHz): 7.41 (dd, 1H, J = 8.4 Hz and J = 1.7 Hz),
.52–7.68 (m, 4H), 8.02 (d, 1H, J = 8.4 Hz), 8.21 (d, 2H,
3-Cyclohexyl-5-phenyl-1,2,4-oxadiazole (2l): Mp 159–
161 °C (ethanol). IR (KBr): 3072, 2931, 1663,
13
J = 7.2 Hz): C NMR, d
C
(CDCl
23.85, 124.76, 127.26, 128.14, 129.09, 130.78, 132.48,
32.90, 134.28, 137.18, 166.97, 175.28; Anal. Calcd for
Cl O: C, 57.73; H, 2.74; N, 9.62. Found: C,
3
, TMS-125 MHz):
ꢀ
1 1
1
1
C
H 3
1643 cm ; H NMR, d (CDCl , TMS-500 MHz): 1.20
(tt, 1H, J = 13 Hz and J = 3 Hz), 1.21 (tq, 2H, J = 13 Hz
and J = 3 Hz), 1.43 (dq, 2H, J = 13 Hz and J = 3 Hz),
1.65–1.67 (m, 1H), 1.76 (td, 2H, J = 13 Hz and J = 3 Hz),
1.81–1.84 (m, 2H), 3.20 (tt, 1H, J = 13 Hz and J = 3 Hz)
7.37 (t, 2H, J = 7 Hz), 7.45 (t, 1H, J = 7 Hz), 7.88 (d, 2H,
14
H
8
2 2
N
5
3
7.48; H, 2.86; N, 9.30.
-(2,4-Dichlorophenyl)-5-(p-methoxyphenyl)-1,2,4-oxadia-
(CDCl
1
zole (2j): Mp 139–141 °C (ethanol). H NMR, d
H
3
,
1
3
TMS-500 MHz): 3.91 (s, 3H), 7.04 (d, 2H, J = 8.9 Hz),
.40 (dd, 1H, J = 8.4 Hz and J = 2.0 Hz), 7.57 (d, 1H,
J = 1.9 Hz), 8.00 (d, 1H, J = 8.4 Hz), 8.21 (d, 2H,
C 3
J = 8 Hz); C NMR, d (CDCl , TMS-125 MHz): 25.56,
7
25.73, 29.16, 45.26, 127.94, 128.28, 132.40, 136.07, 203.31;
+
EI–MS m/z: 228 (M , 30), 125 (80), 123 (75), 109 (70), 105
13
J = 8.8 Hz); C NMR, d
C
(CDCl
3
, TMS-125 MHz):
(100), 83 (65). Anal. Calcd for C14
16 2
H N O: C, 73.65; H,
55.45, 114.50, 116.37, 124.95, 127.21, 130.06, 130.72,
7.06; N, 12.27. Found: C, 73.39; H, 6.85; N, 12.10.