Mendeleev Commun., 2010, 20, 50–51
of the reaction mixture indicated the formation of the corre-
at d 22.87 and 46.25 ppm, and the signals of four carbon atoms
of the aryl substituent were seen at appropriate chemical shifts
and coupling constants along with two characteristic signals at
d 167.56 and 170.70 ppm arising from two carbon atoms of the
1,2,4-oxadiazole ring.†
Mechanistically, it is reasonable to assume that in situ prepared
amidoxime 5 initially attacks carbodiimide 6 to give isourea inter-
mediate 8. This intermediate is probably cyclized to 4,5-dihydro-
1,2,4-oxadiazole intermediate 9. Isolated 1,2,4-oxadiazole 7 is
finally formed by removal of an amine molecule from 9 under
the reaction conditions (Scheme 2).
sponding 3-aryl-1,2,4-oxadiazol-5-amine in nearly 45–50% yield.
Almost half of in situ prepared amidoxime 5 was recovered
unreacted at the end of the reaction and half of the added carbo-
diimide reacted with the water present in the used hydroxyl-
amine hydrate and converted to the corresponding N,N'-dialkyl-
urea. The best results were obtained when the reactions were
carried out in the presence of molecular sieves (Scheme 1).
The reactions were carried out by heating a mixture of the
nitrile and hydroxylamine under solvent-free conditions. After
nearly complete conversion to amidoxime 5, as indicated by
TLC monitoring, molecular sieves were added to the reaction
mixture and stirred for 20 min at room temperature. Then, the
carbodiimide was added to the reaction mixture, which was
NR
RN=C=NR
NOH
NH2
NO
6
1
heated for a further 3 h. H NMR analysis of the reaction mix-
Ar
Ar
NHR
tures clearly indicated the formation of 1,2,4-oxadiazoles 7 in
excellent yields. Any product other than 7 could not be detected
by NMR spectroscopy.†
NH2
5
8
The isolated 3-aryl-1,2,4-oxadiazol-5-amines 7a–l were char-
Ar
Ar
1
acterized on the basis of IR, H and 13C NMR spectroscopy,
NH
N
NHR
NHR
mass spectrometry and elemental analysis. The mass spectrum
of 7f displayed the molecular ion (M+) peak at m/z 221, which
was consistent with the product structure. The IR spectrum of
7f showed an absorption band at 3230 cm–1 indicating the
N
N
NHR
– RNH2
O
O
9
7
Scheme 2
1
presence of amine functionality. The H NMR spectrum of 7f
exhibited characteristic signals with appropriate chemical shifts
and coupling constants for seven H atoms of the isopropyl
group (d 1.26 and 3.98 ppm, J 6.5 Hz) and four H atoms of the
In conclusion, we have developed an efficient one-pot reac-
tion for the preparation of 3-aryl-1,2,4-oxadiazol-5-amines of
potential synthetic and pharmacological interest.
3
aryl substituent (d 7.11 and 7.98 ppm, JFH 8.7 Hz, 4JFH 5.4 Hz
and 3JHH 8.7 Hz). A fairly sharp doublet (d 5.84 ppm, J 6.9 Hz)
was observed for the NH group due to coupling with the
adjacent C–H of the isopropyl group. In the 1H decoupled
13C NMR spectrum of 7f, the isopropyl carbon atoms resonated
This study was supported by the Research Council of the
University of Tehran (research project no. 6102036/1/03).
References
1
Solvent-free Organic Synthesis, 1st edn., ed. K. Tanaka, Wiley-VCH,
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†
The procedure for the preparation of N-cyclohexyl-3-(4-methylphenyl)-
1,2,4-oxadiazol-5-amine 7c is described as an example. A mixture of
4-methylbenzonitrile (0.23 g, 2 mmol) and hydroxylamine 50% (0.13 g,
2 mmol) was stirred at 150 °C for 40 min. After nearly complete con-
version to the corresponding amidoxime as was indicated by TLC
monitoring, 3 Å molecular sieves (1.1 g) were added to the reaction
mixture and stirred for 20 min at room temperature. Then dicyclohexyl
carbodiimide (0.41 g, 2 mmol) was added to the reaction mixture, which
was additionally stirred for 3 h at 150 °C. After cooling to room tem-
perature, the residue was purified by column chromatography using
n-hexane–EtOAc (4:1) as an eluent. The solvent was removed and the
product was obtained as colourless crystals, mp 112 °C, yield 0.47 g, 91%.
IR (KBr, nmax/cm–1): 3250 (NH), 1649, 1612, 1578, 1499, 1463, 1450,
2
3
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4
5
6
1
1416, 1389, 1300, 1182, 1005, 1010, 827, 766. H NMR (500.1 MHz,
CDCl3) d: 1.15–2.09 [m, 10H, CH(CH2)5], 2.39 (s, 3H, Me), 3.64–3.68
[m, 1H, CH(CH2)5], 5.59 (d, 1H, NH, J 7.5 Hz), 7.24 (d, 2H, 2CH,
J 8.0 Hz), 7.88 (d, 2H, 2CH, J 8.0 Hz). 13C NMR (125.8 MHz, CDCl3)
d: 21.49 (Me), 24.62, 25.48 and 33.21 (3CH2), 52.84 (NHCH), 124.95
(C), 127.18 and 129.27 (2CH), 140.88 (C), 132.04 (C), 168.44 (NCN),
170.58 (NCO). EI-MS, m/z (%): 257 (M+, 14), 241 (7), 228 (11), 202
(21), 176 (37), 161 (23), 149 (31), 142 (26), 132 (21), 117 (23), 76 (54),
70 (38), 64 (92), 59 (100). Found (%): C, 69.9; H, 7.5; N, 16.2. Calc. for
C15H19N3O (257.34) (%): C, 70.01; H, 7.44; N, 16.33.
3-(4-Fluorophenyl)-N-isopropl-1,2,4-oxadiazol-5-amine 7f: colourless
crystals, mp 136 °C, yield 0.40 g, 91%. IR (KBr, nmax/cm–1): 3230 (NH),
1630, 1600, 1545, 1481, 1421, 1381, 1344, 1254, 1229, 1151, 847, 768.
1H NMR (500.1 MHz, CDCl3) d: 1.26 (d, 6H, CHMe2, J 6.5 Hz), 3.98
(octet, 1H, CHMe2, J 6.5 Hz), 5.84 (d, 1H, NH, J 6.9 Hz), 7.11 (dd,
7
8
9
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3
3
4
2H, 2CH, JFH 8.7 Hz, JHH 8.7 Hz), 7.98 (dd, 2H, 2CH, JFH 5.4 Hz,
3JHH 8.7 Hz). 13C NMR (125.8 MHz, CDCl3) d: 22.87 (CHMe2), 46.25
(CHMe2), 115.69 (d, CH, JFC 22.0 Hz), 123.93 (d, C, JFC 3.1 Hz),
129.35 (d, CH, JFC 8.6 Hz), 164.33 (d, C–F, JFC 250.7 Hz), 167.56
(NCN), 170.70 (NCO). EI-MS, m/z (%): 221 (M+, 83), 206 (14), 179
(48), 163 (100), 149 (12), 136 (63), 121 (40), 109 (25), 95 (29), 75 (21), 57
(19), 43 (59). Found (%): C, 59.5; H, 5.6; N, 18.7. Calc for C11H12FN3O
(221.23) (%): C, 59.72; H, 5.47; N, 18.99.
2
4
3
1
Received: 24th August 2009; Com. 09/3383
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