New one step synthesis of 3,5-disubstituted 1,2,4-oxadiazoles

Article abstract of DOI:10.1002/jhet.5570440647

(Chemical Equation Presented) Disubstituted 1,2,4-oxadiazoles have been synthesized in good yields and good purity in one pot procedure by reaction of aromatic nitriles, hydroxylamine hydrochloride and sodium carbonate in ethylene glycol under heating at

Full text of DOI:10.1002/jhet.5570440647

Nov-Dec 2007
1529
New One Step Synthesis of 3,5-Disubstituted 1,2,4-Oxadiazoles
Moha Outirite a, Mounim Lebrini a, Michel Lagrenéea,* and Fouad Bentiss b
a Unité de Catalyse et de Chimie du Solide, CNRS UMR 8181, ENSCL,
B.P. 90108, F-59652 Villeneuve d’Ascq Cedex, France
b Laboratoire de Chimie de Coordination et d'Analytique, Université Chouaib Doukkali, Faculté des Sciences,
B.P. 20, M-24000 El Jadida, Morocco
Received December 6, 2006
Ethylene glycol
O
N
Ar
C
N
+ NH2OH, HCl; Na2CO3
Reflux for 30 h
Ar
Ar
N
1
2
Disubstituted 1,2,4-oxadiazoles have been synthesized in good yields and good purity in one pot
procedure by reaction of aromatic nitriles, hydroxylamine hydrochloride and sodium carbonate in ethylene
glycol under heating at 195°C. The structures of different 1,2,4-oxadiazoles obtained were confirmed by
1H, 13C NMR and mass spectroscopy.
J. Heterocyclic Chem., 44, 1529 (2007).
3,5-disubstited 1,2,4-oxadiazoles 2a-k were obtained in
excellent yields and good state of purity. It has been
demonstrated that in the thiadiazole series, the
unsymmetrical 1,2,4-thiadiazole was more efficient than
the symmetrical one, the 1,3,4-thiadiazole, against acid
corrosion of mild steel [12], and we hope to study this
effect with some oxadiazoles compounds. The properties
of these new compounds, as corrosion inhibitors, are
under investigation (Scheme 1). The reaction between
aromatic nitriles and hydroxylamine hydrochloride leads
first to the formation of amidoximes. The latter and
nitriles in ethylene glycol were converted into the final
3,5-diaryl 1,2,4-oxadiazoles. In ethylene glycol, the 3,5-
disubstited 1,2,4-oxadiazoles 2a-k were obtained in good
yields and excellent state of purity.
INTRODUCTION
Oxadiazoles are interesting heterocycles present in a
variety of biological compounds such as coronary
vasodilators, local anesthetics, anxiolytics [1] and
diuretics [2]. These compounds can exhibit antimicotic
properties [3], can act as anti-inflammatory agents [4] and
were tested on their antibacterial activity against
Staphylococcus Aureus, Streptococcus Pneumoniae,
Escherichia Coli, Pseudomonas Aeruginosa, and
Micrococcus [5,6]. Several methods are already described
in the literature to synthesize 1,2,4-oxadiazoles [7],
among them, the condensation of amidoximes with
carboxylic acids in the presence of a coupling reagent [8]
and the cycloaddition of nitrile oxides to amidoximes in
solution and on solid support [9,10]. As a part of a
program directed to obtain 3,5-disubstituted 1,2,4-
oxadiazole molecules which can be used as corrosion
inhibitors [11], we have finalized a simple new one step
synthesis of the 3,5-disubstituted 1,2,4-oxadiazoles from
aromatic nitriles and hydroxylamine hydrochloride. The
RESULTS AND DISCUSSION
Compounds (2a-k) were prepared by condensation of
aromatic nitriles with hydroxylamine hydrochloride in a
mixture of sodium carbonate in ethylene glycol
Scheme 1
1, 2a
Ar = C6H5
1, 2g
Ar = 3,4-CH3OC6H3
Ar = 2,6-CH3OC6H3
Ar = 4-CH3C6H4
Ar = 4-ClC6H4
b
Ar = 2-pyridyl
Ar = 3-pyridyl
Ar = 4-pyridyl
Ar = 3-CH3OC6H4
Ar = 4-CH3OC6H4
h
i
j
c
d
e
f
k
Ar = 4-NO2C6H4

1530
M. Outirite, M.Lebrini, F. Bentiss and M. Lagrenée
Vol 44
(Scheme 1). The reaction between aromatic nitriles and
hydroxylamine hydrochloride leads first to the formation
of amidoximes. The latter and nitriles in ethylene glycol
were converted into the final 3,5-diaryl 1,2,4-oxadiazoles.
In ethylene glycol, the 3,5-disubstituted 1,2,4-oxadiazoles
2a-k were obtained in good yields and excellent state of
purity. The mechanism of the addition reaction of the
aromatic nitriles 1a-k with hydroxylamine hydrochloride
to the corresponding amidoximes intermediate is given in
Scheme 2. The oxime function can exist in two forms, the
classical structure and the zwitterion structure [13]. These
forms have been evidenced by X-ray diffraction studies
[14,15].
In the case of amidoximes the hydrogen atom born by the
nitrogen atom of the oxime function can migrate to the
nitrogen atom of the amino group and this latter form can
react easily with the nitrile group. The mechanism is
presented in Scheme 2. The evolution of the reaction has been
followed by measuring the release of ammonia during the
formation of 1,2,4-oxadiazoles. This reaction takes place in
good yields in ethylene glycol at 195°C for 30 hours (Table).
EXPERIMENTAL
Melting points were determined with on an IA 9000 series
1
Electrothermal apparatus and are uncorrected. H and 13C nmr
Table 1
Physical and Analytical Data of 2,5-Diaryl-1,2,4-oxadiazoles 2a-k.
Compound
No.
Ar
Yield
(%)
Mp
(°C)
Molecular
Formula
Analysis %
Calcd./Found
H
Ref
16
C
N
C14H10N2O
C12H8N4O
75.66
75.81
64.28
64.23
64.28
64.41
64.28
64.79
68.07
68.31
68.07
68.28
63.15
63.36
63.15
63.40
76.78
76.95
57.76
57.45
53.85
54.01
4.54
4.69
3.60
3.75
3.60
3.71
3.60
4.00
5.00
5.12
5.00
5.15
5.30
5.47
5.30
5.41
5.64
5.78
2.77
2.98
2.58
2.69
12.60
12.51
24.99
24.86
24.99
24.82
24.99
24.80
9.92
9.79
9.92
9.75
8.18
8.09
8.18
8.12
11.19
11.09
9.62
9.48
17.94
17.83
2a
2b
2c
2d
2e
2f
C6H5
2-pyridyl
75
57
66
80
82
91
71
62
76
88
70
110
174
170
183
96
17
18
18
—
19
—
—
20
21
—
C12H8N4O
3-pyridyl
C12H8N4O
4-pyridyl
C16H14N2O3
C16H14N2O3
C18H18N2O5
C18H18N2O5
C16H14N2O
C14H8Cl2N2O
C14H8N4O5
3-OCH3C6H4
4-OCH3C6H4
3,4-(OCH3)2C6H3
2,6-(OCH3)2C6H3
4-CH3C6H4
4-ClC6H4
127
178
2g
2h
2i
126
133-
134
2j
183
235
2k
4-NO2C6H4
spectra were recorded on a Bruker F.T. AC 300 spectrometer
(300 MHz for 1H nmr and 75 MHz for 13C nmr) using dimethyl-
d6 sulfoxide (DMSO). Matrix assisted laser desorption ionization
(MALDI) and time-of-flight mass spectrometry (TOF-MS) are
used to record the mass spectra of the oxadiazole compounds.
All starting materials were of reagent grade and used as
purchased.
Scheme 2
OH
+
H2N
Ar
C
N
+
H2N
OH
C
-
Ar
N
OH
OH
NH
General Procedure for the Synthesis of Oxadiazole 2a-k. A
solution of sodium carbonate (0.05 mol) in water (5 ml) was
added to a mixture of aromatic nitriles 1a-k (0.05 moles) and
hydroxylamine hydrochloride (0.05 moles) in ethylene glycol
(15 ml). The resulting mixture was heated under reflux (T=
195°C) for 30 hours with vigorous stirring. After cooling, the
reaction mixture was filtered in order to remove the sodium
chloride formed during the reaction and 100 ml water was added
to dilute the solvent. Upon allowing the reaction mixture to cool,
colourless crystals separated which were removed by filtration.
The resulting solid was crystallized from ethanol and dried
under vacuum. Yields, Mp and elemental analysis are given in
Table. 1H, 13C nmr, MS and elemental analysis: data are in
accordance with the proposed structures, are given below.
N
HN
C
C
Ar
NH2
Ar
-
O
OH
H
O
+
N
-
N
N
C
C
C
+
Ar
NH3
Ar
NH2
-
Ar
NH2
NH3
Ar
C
O
N
Ar
Ar
_
N
C
O
N
+
N
Ar
NH3

Nov-Dec 2007
New One Step Synthesis of 3,5-Disubstituted 1,2,4-Oxadiazoles
1531
The general formula of the parent oxadiazoles with
corresponding numbering scheme is given below:
111.65 (C6), 160.25 (C7), 170.38 (C8), 104.06 (C9), 152.23 (C10),
109.11 (C11), 130.12 (C12), 109.11 (C13), 152.23 (C14),
substituent 55.02 and 55.73. MALDI-TOFMS: m/z 343 (M +1).
3,5-Bis(4-methylphenyl)-1,2,4-oxadiazole (2i). 1H nmr (DMSO-
d6): ꢀ (ppm) 7.21-7.30 (m, 4H); 7.76 (d, J = 7.93 Hz, 2H); 7.87 (d, J
= 7.93 Hz, 2H), 2.31 (s, 3H) CH3, 2.35 (s, 3H) CH3. 13C nmr
(DMSO-d6): ꢀ (ppm) 175.55 (C1), 127.44 (C2), 131.19 (C3), 129.17
(C4), 143.53 (C5), 129.17 (C6), 131.19 (C7), 168.78 (C8), 127.02 (C9),
129.23 (C10), 128.72 (C11), 141.17 (C12), 128.72 (C13), 129.23 (C14),
substituent 20.85 and 21.07. MALDI-TOFMS: m/z 251 (M +1).
3,5-Bis(4-chlorophenyl)-1,2,4-oxadiazole (2j). 1H nmr
(DMSO-d6): ꢀ (ppm) 7.03 (d, J = 7.03 Hz, 2H); 7.11 (d, J = 7.95
Hz, 2H); 7.49 (d, J = 7.03 Hz, 2H); 7.87 (d, J = 7.33 Hz, 2H).
13C nmr (DMSO-d6): ꢀ (ppm) 170.89 (C1), 125.18 (C2), 132.11
(C3), 128.55 (C4),139.40 (C5),128.76 (C6), 132.11 (C7), 166.32
(C8), 124.31 (C9), 129.68 (C10),127.12(C11),136.15 (C12), 127.12
(C13), 129.68 (C14). MALDI-TOFMS: m/z 292 (M +1).
11
4
3
10
12
13
5
9
N
2
8
1
R
R
6
14
7
N
O
3,5-Bis(phenyl)-1,2,4-oxadiazole (2a). 1H nmr ( DMSO-d6): ꢀ
(ppm) 7.67 (m, 6H); 8.09 (d, J = 7.63 Hz, 1H); 8.13 (d, J = 7.63
Hz, 1H); 8.17 (d, J = 6.41 Hz, 1H); 8.21(d, J = 6.41 Hz, 1H). 13C
nmr (DMSO-d6): ꢀ (ppm) 175.42 (C1), 126.12 (C2), 129.56 (C3),
129.27 (C4), 133.36 (C5), 129.27 (C6), 129.56 (C7), 168.25 (C8),
123.35 (C9), 127.90 (C10), 127.09 (C11), 131.66 (C12), 127.09
(C13), 127.90 (C14). MALDI-TOFMS: m/z 223 (M +1).
3,5-Bis(2-pyridyl)-1,2,4-oxadiazole (2b). 1H nmr (DMSO-
d6): ꢀ (ppm) 7.65 (t, J = 6.10 Hz, 1H); 7.75 (t, J = 6.71 Hz, 1H);
8.13 (m, 3H); 8.36 (d, J = 7.63 Hz, 1H); 8.84 (d, J = 6.72 Hz,
2H). 13C nmr (DMSO-d6): ꢀ (ppm) 174.89 (C1), 145.46 (C2),
124.51 (C3), 138.19 (C4), 127.58 (C5), 150.58 (C6), 168.95 (C8),
142.66 (C9), 150.35 (C11), 126.28 (C12), 137.81 (C13), 123.44
(C14). MALDI-TOFMS: m/z 225 (M +1).
3,5-Bis(4-nitrophenyl)-1,2,4-oxadiazole (2k). 1H nmr
(DMSO-d6): ꢀ (ppm) 8.08 (d, J = 8.56 Hz, 2H); 8.18-8.30 (m,
6H). 13C nmr (DMSO-d6):ꢀ (ppm) 171.37 (C1), 139.89 (C2),
130.66 (C3), 123.76 (C4),150.16 (C5), 130.66 (C6), 128.86(C7),
167.25 (C8), 135.19 (C9), 128.86 (C10),123.40(C11), 149.00 (C12),
123.40 (C13), 123.76 (C14). MALDI-TOFMS: m/z 313 (M +1).
3,5-Bis(3-pyridyl)-1,2,4-oxadiazole (2c). 1H nmr (DMSO-
d6): ꢀ (ppm) 7.70 (m, 2H); 8.45 (t, J= 3.36 Hz, 1H); 8.56 (t, J=
7.93Hz, 1H); 8.82 (d, J= 3.36 Hz, 1H); 8.90 (d, J= 3.36 Hz, 1H);
9.26 (s,1H); 9.36(s,1H). 13C nmr (DMSO-d6): ꢀ (ppm) 173.75
(C1), 121.80 (C2), 148.11 (C3), 153.38 (C5), 124.08 (C6), 135.22
(C7), 166.18 (C8), 119.42 (C9), 147.40 (C10), 152.12 (C12),
123.97 (C13), 134.34 (C14). MALDI-TOFMS: m/z 225 (M +1).
REFERENCES AND NOTES
*
Corresponding author. Tel.: +33-320-337-746; fax: +33-320-
436-814; E-mail address: michel.lagrenee@ensc-lille.fr (Michel
Lagrenée).
[1] Oussaid, B.; Moeini, L.; Garriques, B.; Villemin, D.
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1
3,5-Bis(4-pyridyl)-1,2,4-oxadiazole (2d). H nmr (DMSO-d6): ꢀ
(ppm) 7.99 (d, J = 4.10 Hz, 2H); 8.07 (d, J = 4.22 Hz, 2H); 8.83 (d, J
= 4.22 Hz, 2H); 8.90 (d, J = 4.10 Hz, 2H). 13C nmr (DMSO-d6): ꢀ
(ppm) 174.55 (C1), 132.99 (C2), 121.28 (C3), 151.05 (C4), 151.05
(C6), 121.28 (C7), 167.19 (C8), 130.00 (C9), 120.97 (C10), 150.75
(C11), 150.75 (C13), 120.97 (C14). MALDI-TOFMS: m/z 225 (M +1).
3,5-Bis(3-methoxyphenyl)-1,2,4-oxadiazole (2e). 1H nmr
(DMSO-d6): ꢀ (ppm) 7.18 (d, J = 6.11 Hz, 2H); 7.29 (d, J = 8.25
Hz, 2H) 7.51-7.74 (m, 4H) 3.86 (s, 6H) OCH3. 13C nmr (DMSO-
d6): ꢀ (ppm) 175.24 (C1), 127.29 (C2), 130.84 (C3), 130.51 (C4),
117.50 (C5), 168.12 (C6), 119.39 (C7), 159.66 (C8), 124.41 (C9),
120.20 (C10), 120.20 (C11), 112.43 (C12), 159.60 (C13), 111.93 (C14),
substituent 55.31 and 55.49. MALDI-TOFMS: m/z 283 (M +1).
3,5-Bis(4-methoxyphenyl)-1,2,4-oxadiazole (2f). 1H nmr
(DMSO-d6): ꢀ (ppm) 7.10 (d, J = 8.56 Hz, 2H); 7.17 (d, J = 8.86
Hz, 2H); 8.0 (d, J = 8.86 Hz, 2H); 7.11 (d, J = 8.56 Hz, 2H) 3.83
(s, 3H) OCH3 3.86 (s,3H) OCH3. 13C nmr (DMSO-d6): ꢀ (ppm)
174.96 (C1), 118.55 (C2), 129.89 (C3), 114.98 (C4), 163.05 (C5),
114.63 (C6), 129.89 (C7), 167.79 (C8), 115.79 (C9), 128.75 (C10),
114.63 (C11), 161.71 (C12), 114.98 (C13), 128.75 (C14),
substituent 55.39 and 55.64. MALDI-TOFMS: m/z 283 (M +1).
3,5-Bis(3,4-dimethoxyphenyl)-1,2,4-oxadiazole (2g). 1H nmr
(DMSO-d6): ꢀ (ppm) 6.76 (d, J = 8.55Hz, 4H); 7.57 (s, 2H), 3.85
(s, 12H) OCH3. 13C nmr (DMSO-d6): ꢀ (ppm) 173.14 (C1),
129.94 (C2), 114.04 (C3), 157.37 (C4), 154.22 (C5), 121.02 (C6),
126.31 (C7), 166.89 (C8), 125.66 (C9), 107.72 (C10), 152.43
(C11), 153.86 (C12), 111.13 (C13), 124.28 (C14), substituent 55.46
and 56.81. MALDI-TOFMS: m/z 343 (M +1).
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3,5-Bis(2,6-dimethoxyphenyl)-1,2,4-oxadiazole (2h). 1H
nmr (DMSO-d6): ꢀ (ppm) 6.75 (d, J = 8.53Hz, 4H); 7.55 (d, J =
8.55Hz, 2H), 3.85 (s, 12H) OCH3. 13C nmr (DMSO-d6): ꢀ (ppm)
177.52 (C1), 106.71 (C2), 160.25 (C3), 111.65 (C4), 133.47 (C5),