Novel method for the synthesis of 1,2,4-oxadiazoles using alumina supported ammonium fluoride under solvent-free condition

Article abstract of DOI:10.1002/jhet.5570420434

Alumina supported ammonium fluoride was found as an efficient reagent for the synthesis of 1,2,4-oxadiazoles of amidoximes under solvent free conditions using microwave irradiation. This method is a one-pot, easy, rapid, and high-yielding reaction for the

Full text of DOI:10.1002/jhet.5570420434

May-Jun 2005
Novel Method for the Synthesis of 1,2,4-Oxadiazoles using Alumina
Supported Ammonium Fluoride under Solvent-free Condition
Babak Kaboudin* and Fariba Saadati
699
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-1159, Iran
Fax: (+98) 241 4249023
E-mail: kaboudin@iasbs.ac.ir
Received August 23, 2004
Alumina supported ammonium fluoride was found as an efficient reagent for the synthesis of 1,2,4-oxadi-
azoles of amidoximes under solvent free conditions using microwave irradiation. This method is a one-pot,
easy, rapid, and high-yielding reaction for the synthesis of 1,2,4-oxadiazole derivatives from amidoximes
and acyl chlorides. Reaction of amidoximes with acylchlorides in the presence of alumina without ammo-
nium fluoride gave only the corresponding O-acylamidoximes as major product.
J. Heterocyclic Chem., 42, 699 (2005).
Oxadiazoles have been used as bioisosteres for amides
and esters. The oxadiazole moiety is an important structure
unit in drugs and chemical materials [1-7]. Among the
oxadiazoles, 1,2,4-oxadiazole derivatives are gaining in
interest in medicinal chemistry [8]. Several methods have
been reported in the literature for the synthesis of 1,2,4-
oxadiazoles [9-15]. In general, synthesis of 1,2,4-oxadia-
zoles involves first the O-acylation step of an amidoxime
by an activated carboxylic acid derivatives, followed by
cyclodehydration [16]. It has been found that cyclization
could be effected by treating an O-acylamidoxime with
NaH or NaOEt [17a-c] at room temperature, pyridine with
heating, [17d,e] tetrabutylammonium fluoride as catalyst
ods used for the synthesis of 1,2,4-oxadiazoles use
microwave irradiation. As a part of our efforts to explore
the novel utilities of solid supported reactions for the syn-
thesis of heterocyclic compounds [25,26] we describe here
a new method for one-pot synthesis 1,2,4-oxadiazoles
from amidoximes and acyl chlorides under solvent free
condition using microwave irradiation. It is found that alu-
mina supported ammonium flouride under solvent-free
conditions was capable of producing high yields of 1,2,4-
oxadiazoles by reaction from amidoximes with acyl chlo-
ride under mild reaction conditions in 71-90% yields under
microwave irradiation (Scheme 1, Table 1).
[18] and use of solid support techniques [19] for the prepa-
ration of 1,2,4-oxadiazoles. The application of microwave
energy to accelerate organic reactions is of increasing
interest and offers several advantages over conventional
techniques [20]. In recent years, microwave irradiation has
been reported for the synthesis of 1,2,4-oxadiazoles and
1
,3,4-oxadiazoles in the presence of solvent or solvent-free
As shown Table 1, benzamidoxime (1a) in the presence
of a mixture of benzoyl chloride (2a) afforded 3,5-
diphenyl-1,2,4-oxadiazole (3a) in 90% yield. The other
derivatives of amidoximes (1b-1e) also react with benzoyl
chloride in the presence of alumina supported ammonium
fluoride under microwave irradiation, to give the desired
compounds (3b-3e) in moderate to high yields. The reac-
tion also proceeds with moderate yield with p-methoxy
and p-nitrobenzoyl chloride as acylating agents affords the
conditions [21-24]. However, using microwave irradiation
in the presence of alumina under solvent-free conditions,
gave a low yield of 1,2,4-oxadiazoles [21]. Moreover,
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 environ-
mentally friendly ('green chemistry'). These observations
led us to investigate the possibility of improving the meth-
Table 1
Reaction of amidoximes with acyl chlorides in the presence of alumina supported ammonium fluoride under microwave irradiation.
Product
3
R-
1
R'
2
Yield [a]
(%)
Product
3
R-
1
R'
2
Yield [a]
(%)
a [17b]
b [27a]
c
d
e
C H -
C H -
90
86
87
75
85
f [17b]
C H -
2, 4-Cl C H -
p-CH OC H -
78
71
80
86
82
6
5
6
5
6
5
3
6 4
p-ClC H CH -
C H -
g
h
i
p-CH OC H -
6
4
2
6
5
2
6
3
3 6 4
p-ClC H -
C H -
p-ClC H CH -
p-O NC H -
2 6 4
6
4
6
5
6
4
2
2, 4-Cl C H -
C6H11
C H -
p-ClC H -
p-O NC H -
2
-
6
3
6
5
6
4
2 6 4
C H -
j
C6H11
-
p-O NC H -
2 6 4
6
5
[a] Isolated Yield.

7
00
B. Kaboudin and F. Saadati
Vol. 42
hydroxylamine hydrochloride in 5 mL of water, followed by the
further addition of 1.68 g (0.02 mol) of sodium bicarbonate in 5
mL of water. The reaction mixture was stirred overnight at rt. The
mixture was then concentrated to small volume under vacuum,
diluted with cold water, and placed in refrigerator overnight. The
precipitate that formed was recovered and recrystallized from
ethanol to give p-chlorobenzamidoxime 3.2 g (94%) [27a]; mp
desired products (3f-3j) in good yields. Alumina without
supported ammonium fluoride is not as effective and gives
O-acylamidoximes as major product. Ammonium chloride
(
NH Cl) and bromide (NH Br) was not as effective as
4 4
ammonium fluoride and failed to give the required prod-
uct. The reaction gave low yields of 1,2,4-oxadiazoles
with using of alumina supported potassium fluoride.
Since the procedure described herein proceeds at sol-
1
132-134 °C, H-NMR, δ (CDCl , TMS): 4.98 (s, 2H, -NH ),
H
3
2
+
+
7.38-7.64 (m, 4H), 8.89 (s, 1H, -OH); 172 (M +2, 30), 170 (M ,
00), 153 (75), 111 (40), 75 (65) 50 (50), 30 (35).
1
vent-free conditions, NH F is likely functioning as a
4
strong base. Fluoride ion promotes the cyclization by act-
ing as a strongly basic reagent (Scheme 2) [28].
Preparation of 1, 2, 4-oxadiazoles.
General Procedure.
This solvent-free method has operationally simple procedure.
The reagent (5 mmol) was prepared by the combination of
ammonium fluoride (5 mmol, finely ground) and alumina
(
Al O , acidic, 2 g) in a mortar and pestle by grinding them
2 3
together until a fine, homogeneous, powder was obtained (5-10
min). A 5 mmol of the amidoxime (finely ground) was added to
this mixture. The acyl chloride (7 mmol) was then added and the
mixture was shaken for 5 min and irradiated by microwave for 3
min using 600 W (A kitchen-type microwave was used in all
experiments). The reaction mixture was ground in a mortar and
pestle until a fine, homogeneous, powder is obtained. The homo-
geneous mixture was chromatographed on silica gel
In summary, simple work-up, low consumption of sol-
vent, fast reaction rates, mild reaction condition, good to
high yields, and selectivity of the reaction make this
method an attractive and a useful contribution to present
methodologies.
(Hexane:EtOAc=95:5) to give pure product in 71-90 % yield. All
products gave satisfactory spectral data in accord with the
assigned structures and literature reports [17b,26b]. For new
compounds spectral data are reported as follows:
EXPERIMENTAL
3
-(4-Chlorophenylmethyl)-5-phenyl-1,2,4-oxadiazole (3b).
This oxadiazole was prepared using the general procedure and
General.
1
has mp 76-78 °C (ethanol); H-NMR, δ (CDCl , TMS): 4.10
H
3
All chemicals were commercial products and distilled or
recrystallized before use. All melting points were obtained by a
Buchi 510 and are uncorrected. A commercially available pulse
microwave at 2450 MHz (900 W) was used in all experiments.
IR spectra were determined using a FT-IR Brucker-Vector 22.
NMR spectra were taken with a DMX-500 Bruker Avance instru-
ment with the chemical shifts being reported as δ ppm and cou-
plings expressed in Hertz. Silica gel column chromatography was
carried out with Silica gel 100 (Merck No. 10184). Merck Silica-
gel 60 F254 plates (No. 5744) were used for the preparative TLC.
(
s, 2H), 7.28-7.35 (m, 4H), 7.46-7.55 (m, 3H), 8.09 (d, 2H, J=8
13
Hz); C-NMR, δc (CDCl , TMS): 31.73, 124.02, 128.02,
1
1
3
28.97, 129.05, 129.23, 130.33, 131.10, 132.70, 132.97, 133.94,
69.63, 175.81.
Anal. Calcd for C H ClN O: C, 66.55; H, 4.10; N, 10.35.
1
5
11
2
Found: C, 66.38; H, 4.36; N, 9.89.
3
-(2, 4-Dichlorophenyl)-5-phenyl-1,2,4-oxadiazole (3d).
This oxadiazole was prepared in the general way and has mp
140-142 °C (ethanol); 1H-NMR, δ (CDCl , TMS): 7.41 (dd,
H
3
2
H, J=8.4 Hz and J=1.7 Hz), 7.52-7.68 (m, 4H), 8.02 (d, 1H,
Preparation of Amidoximes (1).
1
3
J=8.4 Hz), 8.21(d, 2H, J=7.2 Hz): C-NMR, δ (CDCl , TMS):
1
1
c
3
General Procedure.
23.85, 124.76, 127.26, 128.14, 129.09, 130.78, 132.48, 132.90,
34.28, 137.18, 166.97, 175.28.
To a solution of 0.01 mol of nitrile in 200 mL of ethanol was
added a solution of 0.695 g (0.01 mol) of hydroxylamine
hydrochloride in 10 mL of water, followed by the further addition
of 0.420 g (0.005 mol) of sodium carbonate in 10 mL of water.
The reaction mixture was stirred overnight at rt. The mixture was
then concentrated to small volume under vacuum, diluted with
cold water, and placed in refrigerator overnight. The precipitate
that formed was recovered and recrystallized from ethanol. All
amidoximes were known and characterized by comparison of
their physical data with those prepared in accordance with litera-
ture procedures [17,27a-c].
Anal. Calcd for C H Cl N O: C, 57.73; H, 2.74; N, 9.62.
14
8
2 2
Found: C, 57.48; H, 2.86; N, 9.30.
3
-Cyclohexyl-5-phenyl-1,2,4-oxadiazole (3e).
This oxadiazole was prepared in the general way and has mp
1
1
59-161 °C (ethanol); H-NMR, δ (CDCl , TMS): 1.20 (tt, 1H,
H
3
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, 7 Hz), 7.88 (d, 1H,
1
3
8
1
Hz); C-NMR, δ (CDCl , TMS): 25.56, 25.73, 29.16, 45.26,
c 3
Preparation of p-Chlorobenzamidoxime (1c).
27.94, 128.28, 132.40, 136.07, 203.31.
Anal. Calcd for C14H16N O: C, 73.65; H, 7.06; N, 12.27.
To a solution of 2.75 g (0.02 mol) of p-chlorobenzonitrile in 50
2
mL of ethanol was added a solution of 1.39 g (0.02 mol) of
Found: C, 73.39; H, 6.85; N, 12.10.

May-Jun 2005
Novel Method for the Synthesis of 1,2,4-Oxadiazoles
701
3
(
-(2, 4-Dichlorophenyl)-5-(p-methoxyphenyl)-1,2,4-oxadiazole
3g).
This oxadiazole was prepared in the general way and has mp
Wyman, J. Med. Chem., 34, 2726 (1991).
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and J. P. Springer, J. Med. Chem., 32, 2282(1989).
1
1
7
7
39-141 °C (ethanol); H-NMR, δ (CDCl , TMS): 3.91 (s, 3H),
.04 (d, 2H, J=8.9 Hz), 7.40 (dd, 1H, J=8.4 Hz and J=2.0 Hz),
.57 (d, 1H, J=1.9 Hz), 8.00 (d, 1H, J=8.4 Hz), 8.21(d, 2H, J=8.8
H 3
[
4] F. I. Carroll, J. L. Gray, P. Abrahm, M. A. Kuzemko, A. H.
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5] G. D. Diana, D. L. Volkots, T. J. Nitz, T. R. Bailey, M. A.
[
1
3
Hz); C-NMR, δc (CDCl , TMS): 55.45, 114.50, 116.37,
1
1
Long, N. Vescio, S. Aldous, D. C. Pevear, and F. J. Dutko, J. Med. Chem.,
37, 2421 (1994).
[6] M. Ankersen, B. Peschke, B. S. Hansen, and T. K. Hansen,
Bioorg. Med. Chem. Lett., 7, 1293 (1997).
3
24.95, 127.21, 130.06, 130.72, 132.46, 134.25, 137.04, 163.28,
66.81, 175.15.
Anal. Calcd for C H Cl N O : C, 56.07; H, 3.11; N, 8.723.
1
5
10
2 2 2
[7] C. Chen, C. H. Senanayake, T. J. Bill, R. D. Larsen, T. R.
Found: C, 55.83; H, 3.18; N, 8.38.
Verhoeven, and P. J. Reider, J. Org. Chem., 59, 3738 (1994).
[8] R. J. Mathvink, A. M. Barritta, M. R. Candelore, M. A.
Cascieri, L. Deng, L. Tota, C. D. Strader, M. J. Wyvratt, M. H. Fisher, and
A. E. Weber, Bioorg. Med. Chem. Lett., 9, 1869 (1999).
3
-(4-Chlorophenylmethyl)-5-(4-nitrophenyl)-1, 2, 4-oxadiazole
(3h).
This oxadiazole was prepared in the general way and has mp
[
9] J. L. LaMattina and C. J. Mularski, J. Org. Chem., 49, 4800
(1984).
[10] G. B. Liang and X. Qian, Bioorg. Med. Chem. Lett., 9, 2101
(1999).
1
1
32-134 °C (ethanol); H-NMR, δ (CDCl , TMS): 4.13 (s, 2H),
H 3
7
.20-7.35(m, 4H), 8.27 (d, 2H, J=4.6 Hz), 8.34 (d, 2H, J=4.6 Hz);
1
3
C-NMR, δ (CDCl , TMS): 31.58, 124.21, 125.43, 128.54,
c
3
[11] G. B. Liang and D. D. Feng, Tetrahedron Lett., 37, 6627
1
29.18, 129.25, 130.41, 133.46, 150.12, 170.17, 173.75.
Anal. Calcd for C H ClN O : C, 57.06; H, 3.19; N, 13.31.
(
(
(
1996).
1
5
10
3 3
[12] A. G. Tyrkov, Khimiya i Khimicheskaya Tekhnologiya, 43, 73
Found: C, 57.40; H, 3.25; N, 13.20.
2000).
3
-(4-Chlorophenyl)-5-(4-nitrophenyl)-1,2,4-oxadiazole (3i).
[13] J. R. Young and R. J. DeVita, Tetrahedron Lett., 39, 3931
1998).
This oxadiazole was prepared in the general way and has mp
[14] R. Neidlein and L. Sheng, Syn. Commun., 25, 2379 (1995).
1
1
63-165 °C (ethanol); H-NMR, δ (CDCl , TMS): 7.54 (d, 2H,
H
3
[15] R. Neidlein and L. Sheng, J. Heterocyclic Chem., 33, 1943
1
3
J=5.8 Hz), 8.14 (d, 1H, J=5.8 Hz), 8.30-8.45 (m, 4H); C-NMR,
δ (CDCl , TMS): 124.31, 128.78, 129.14, 129.25, 129.36,
(1996).
c
3
[16] L. B. Clapp, Adv. Heterocycl. Chem., 20, 65 (1976).
1
29.47, 137.74, 150.20, 168.54, 173.75.
[17a] D. Korbonits and K. Horvath, Heterocycles, 37, 2051 (1994);
Anal. Calcd for C H ClN O : C, 55.73; H, 2.67; N, 13.93.
Found: C, 55.42; H, 2.87; N, 13.63.
[b] S. Chiou and H. J. Shine, J. Heterocyclic Chem., 26, 125 (1989); [c] L.
A. Kayukova, K. D. Praliev, I. S. Zhumadildaeva, and S. G. Klepikova,
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Wilson, J. Chem. Soc., Perkin Trans. II, 1792 (1980); [e] K. E. Andersen,
B. F. Lundt, A. S. Joergensen, and C. Braestrup, Eur. J. Med. Chem., 31,
1
4
8
3 3
3
-Cyclohexyl-5-(4-nitrophenyl)-1,2,4-oxadiazole (3j).
This oxadiazole was prepared in the general way and has mp
4
17 (1996).
18] A. R. Gangloff, J. Litvak, J. E. J. Shelton, D. Sperandio, V. R.
Wang, and K. D. Rice, Tetrahedron Lett., 42, 1441 (2001).
19] N. Hebert, A. L. Hannah, and S. C. Sutton, Tetrahedron Lett.,
40, 8547 (1999).
[20] S. Caddick, Tetrahedron, 51, 10403 (1995).
1
1
(
1
1
01-103°C (ethanol); H-NMR, δ (CDCl , TMS): 1.26-1.50
H
3
[
m, 3H), 1.65 (dq, 2H, J=13 Hz and J=3 Hz), 1.71-1.78 (m, 1H),
.89 (td, 2H, J=13 Hz and J=3 Hz), 1.97-2.11 (m, 2H), 2.91 (tt,
H, J=13 Hz and J=3 Hz), 8.32 (d, 2H, J=8.9Hz), 8.39 (d, 2H,
[
1
3
J=8.9 Hz); C-NMR, δ (CDCl , TMS): 25.56, 25.73, 29.16,
c
3
+
4
3
5.26, 127.94, 128.28, 132.40, 136.07, 203.31; MS m/z: 228 (M ,
[21] V. Santagada, F. Frecentese, E. Perissutti, D. Cirillo, S.
Terracciano and G. Caloendo, Bioorg. Med. Chem. Lett., 14, 4491 (2004).
0), 125 (80), 123 (75), 109 (70), 105 (100), 83 (65).
[
22] M. D. Evans, J. Ring, A. Schoen, A. Bell, P. Edwards, D.
Berthelot, R. Nicewonger, and C. M. Baldino, Tetrahedron Lett., 44, 9337
2003).
[23] S. Rostamizadeh and S. A. G. Housaini, Tetrahedron Lett., 45,
753 (2004).
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Garrigues, Synth. Commun., 25, 1451 (1995).
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127 (2001).
26a] B. Kaboudin and K. Navaee, Heterocycles, 55, 1443 (2001);
Anal. Calcd for C H N O . C, 61.53; H, 5.49; N, 15.38.
1
4 15 3 3
Found: C, 61.28; H, 5.65; N, 15.10.
(
Acknowledgement.
8
The authors thank the Institute for Advanced Studies in Basic
Sciences (IASBS) for supporting this work.
[
[
1
REFERENCES AND NOTES
[
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[