May-Jun 2007
Synthesis of Substituted 1,2,4-Oxadiazoles from Substituted Acid Chlorides
647
rated under vacuum and ice cold water was added to the crude
reaction mass. The solid that precipitated was collected by
filtration and dried under vacuum and recrystallized from
ethanol to obtain pure N-[4-(N-Hydroxycarbaimidoylmethyl)-
phenyl]-acetamide 4 as a white solid (9.0 g, 85 %).
CH3), 3.2 (s, 2H, CH2-Ph), 3.7 (s, 2H, CH2-Ph), 6.5 (s, 2H, NH2),
7.2-7.3 (d, 2H, Ar-H), 7.3-7.4 (m, 5H, Ar-H), 7.4-7.5 (d, 2H, Ar-
H), 9.9 (s, 1H, NH). ms: m/z 326 [M+]. Anal. Calcd. For
C18H19N3O3: C, 66.45; H, 5.89; N, 12.91. Found: C, 66.83; H,
6.34; N, 13.35.
General procedure for the preparation of O-[alkyl or aryl
substituted carbonyl]-4-acetamidophenyl methylamidoxime
5(a-i). To a stirred solution of N-[4-(N-hydroxycarbaimidoyl-
methyl)-phenyl]-acetamide 4 (1.0 g, 0.005 mol) in 1,4-dioxan
(10.0 ml) was added anhydrous K2CO3 (0.9 g, 0.0065 mol, 1.3
eq.). After 15 min, acid chloride (0.0055 mol, 1.1 eq.) was added
to the above reaction mixture and stirred at r.t. After completion
of the reaction, the solvent was removed under vacuum and
water was added to the crude reaction mass. The solid that
precipitated was collected by filtration, dried then either
recrystallized or purified by column chromatography to give
compounds 5(a-i). The yield, Rf value, mp and other details of
each compound are given below.
O-Phenylpropionyl-(4-acetamidophenyl)-methyl-amid-
oxime (5f). This compound was prepared using the general
procedure in 78 % yield as pale yellow solid, mp 163-64 ºC; Rf =
0.41 (CHCl3:MeOH; 9:1); IR (KBr): 3527, 3417, 3071, 2935,
1728, 1668, 1607 cm-1; 1H NMR (200 MHz, DMSO d6): ꢀ 2.1 (s,
3H, O=C-CH3), 2.6-2.7 (t, 2H, CH2), 2.8-2.9 (t, 2H, CH2), 3.3
(s, 2H, CH2Ph), 6.4 (s, 2H, NH2), 7.2-7.3 (d, 2H, Ar-H), 7.3-7.5
( m, 5H, Ar-H), 7.5-7.6 (d, 2H, Ar-H), 9.9 (s, 1H, NH). ms:
m/z 340 [M+]. Anal. Calcd. For C19H21N3O3: C, 67.24; H, 6.24;
N, 12.38. Found: C, 67.60; H, 6.55; N, 12.80.
O-3-Phenyl-acryloyl-(4-acetamidophenyl)-methyl-amid-
oxime (5g). This compound was prepared using the general
procedure in 83 % yield as white solid, mp 180-81 ºC; Rf = 0.36
(CHCl3:MeOH; 9:1). IR (KBr): 3547, 3433, 3095, 2967, 1742,
O-Acetyl-(4-acetamidophenyl)-methylamidoxime (5a). This
compound was prepared using general procedure in 80 % yield,
as white solid, mp 138-139 ºC; Rf = 0.27 (CHCl3:MeOH ; 9:1);
1
1673, 1617cm-1; H NMR (200 MHz, DMSO d6): ꢀ 2.0 (s, 3H,
O=C-CH3), 3.3 (s, 2H, CH2-Ph), 6.5 (s, 2H, NH2), 6.7 (d, 1H,
CH), 7.2-7.3 (d, 2H, Ar-H), 7.3-7.5 (m, 5H, Ar-H) 7.5 (d, 2H,
Ar-H), 7.8 (d, 1H, CH), 9.9 (s, 1H, NH). ms: m/z 338 [M+].
Anal. Calcd. For C19H2N3O3: C, 67.64; H, 5.68; N, 12.45. Found:
C, 67.99; H, 6.05; N, 12.89.
1
IR (KBr): 3538, 3442, 3125, 2967, 1741, 1670, 1615 cm-1; H
NMR (200 MHz, CDCl3): ꢀ 2.2 (s, 3H, CH3), 3.5 (s, 2H, CH2-
Ph), 4.7 (s, 2H, NH2), 7.2-7.3 (d, 2H, Ar-H), 7.4 (s, 1H, NH),
7.5-7.6 (d, 2H, Ar-H). ms: m/z 250 [M+].
Anal. Calcd for C12H15N3O3: C, 57.82; H, 6.07; N, 16.86.
Found: C, 58.18; H, 6.37; N, 17.34.
O-3-Furan-2-yl-acryloyl-(4-acetamidophenyl)-methyl-amid-
oxime (5h). This compound was prepared using general
procedure in 79 % yield as white solid, mp 190-91 ºC. Rf = 0.38
(CHCl3:MeOH; 9:1). IR (KBr): 3519, 3428, 3067, 2973, 1729,
O-Propionyl-(4-acetamidophenyl)-methylamidoxime (5b).
This compound was prepared using general procedure in 78 %
yield, as off-white solid, mp 150-51ºC; Rf = 0.25 (CHCl3:
MeOH; 9:1); IR (KBr): 3546, 3437, 3065, 2926, 1748, 1665,
1
1679, 1627 cm-1; H NMR (200 MHz, DMSO d6): ꢀ 2.2 (s, 3H,
O=C-CH3), 3.6 (s, 2H, CH2-Ph), 4.9 (s, 2H, NH2), 6.4 (d, 1H,
CH), 6.6 (m, 1H, CH), 6.8 (d, 1H, CH), 7.2-7.3 (d, 2H, Ar-H),
7.3-7.4 (d, 2H, Ar-H), 7.4-7.5 (s, 1H, CH), 7.6 (d, 1H, CH), 9.9
(s, 1H, NH). ms: m/z 328 [M+]. Anal. Calcd. For C17H17N3O4:
C, 62.38; H, 5.23; N, 12.84. Found: C, 62.75; H, 5.60; N, 13.30.
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1600 cm-1; H NMR (200 MHz, DMSO d6): ꢀ 1.0-1.1 (t, 3H,
CH3), 2.0 (s, 3H, O=C-CH3), 2.3-2.4 (q, 2H, CH2), 3.3 (s, 2H,
CH2Ph), 6.4 (s, 2H, NH2), 7.2-7.3 (d, 2H, Ar-H), 7.4-7.6 (d, 2H,
Ar-H), 9.9 (s, 1H, NH). ms: m/z 264.30 [M+]. Anal. Calcd. For
C13H17N3O3: C, 59.30; H, 6.51; N, 15.96. Found: C, 59.65; H,
6.87; N, 16.50.
O-Benzoyl-(4-acetamidophenyl)-methylamidoxme (5c).
This compound was prepared using general procedure in 86 %
yield, as buff colored solid, mp 180-81ºC; Rf = 0.35
O-Pivaloyl-(4-acetamidophenyl)-methylamidoxime
(5i).
This compound was prepared using general procedure in 81 %
yield as white solid, mp 146-47 ºC. Rf = 0.43 (CHCl3:MeOH;
9:1). IR (KBr): 3522, 3413, 3079, 2981, 1737, 1681, 1621 cm-1;
t
1H NMR (200 MHz, CDCl3): ꢀ 1.3 (s, 9H, butyl), 2.2 (s, 3H,
(CHCl3:MeOH; 9:1); IR (KBr): 3520, 3330, 3180, 2960, 1735,
O=C-CH3), 3.5 (s, 2H, CH2-Ph), 4.8 (s, 2H, NH2), 7.2-7.3 (d,
2H, Ar-H), 7.4-7.6 (d, 2H, Ar-H), 7.7 (s, 1H, NH). ms: m/z 292
[M+]. Anal. Calcd. For C15H21N3O3: C, 61.84; H, 7.27; N,
14.42. Found: C, 62.20; H, 7.63; N, 14.87.
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1675, 1607 cm-1; H NMR (200 MHz, DMSO d6): ꢀ 2.0 (s, 3H,
O=C-CH3), 3.4 (s, 2H, CH2-Ph), 6.6 (s, 2H, NH2), 7.2-7.3 (d,
2H, Ar-H), 7.4-7.6 (d, 2H, Ar-H), 7.6-7.7 (m, 3H, Ar-H), 8.0-8.2
(d, 2H, Ar-H), 9.9 (s, 1H, NH). ms: m/z 312 [M+]. Anal. Calcd.
For C17H17N3O3: C, 65.58; H, 5.50; N, 13.50. Found: C, 65.96;
H, 5.87; N, 13.96.
O-Pyridyl-(4-acetamidophenyl)-methylamidoxime (5d).
This compound was prepared using general procedure in 83 %
yield, as white solid, mp 198-99 ºC; Rf = 0.24 (CHCl3:MeOH;
9:1); IR (KBr): 3475, 3320, 3115, 2990, 1725, 1677, 1600 cm-1;
1H NMR (200 MHz, DMSO d6): ꢀ 2.0 (s, 3H, O=C-CH3), 3.4 (s,
2H, CH2-Ph), 6.7 (s, 2H, NH2), 7.2-7.3 (d, 2H, Ar-H), 7.4-7.5 (d,
2H, Ar-H), 7.5-7.6 (m, 1H, Py-H), 8.4 (dd, 1H, Py-H), 8.8 (dd,
1H, Py-H), 9.2 (s, 1H, Py-H), 9.9 (s, 1H, NH). ms: m/z 313
[M+]. Anal. Calcd. For C16H16N4O3: C, 61.53; H, 5.16; N, 17.94.
Found: C, 61.90; H, 5.52; N, 18.48.
General procedure for the preparation of N-[4-(5-
substituted-1,2,4-oxadiazol-3-ylmethyl)-phenyl]-acetamide 6
(a-i). To a solution of 5 (a-i) (0.001 mol) in toluene (10.0 ml)
and N,N-dimethylformamide (2.0 ml) was added freshly dried
mol. sieves 4Å and refluxed for 6-15 h. After completion of
reaction, the reaction mixture was cooled to r.t. and filtered. The
filtrate was evaporated under vacuum to obtain crude cyclized
product that was then purified either by recrystallization or by
column chromatography using CHCl3:MeOH (9:1) to afford
pure solid compounds 6 (a-i). The yield, Rf value, mp and other
details of each product are given below.
N-[4-(5-Methyl-1,2,4-oxadiazol-3-ylmethyl)-phenyl]-aceta-
mide (6a). This compound was prepared using the general
procedure in 76 % yield as white powder, mp 148-149 ºC; Rf =
0.37 (CHCl3:MeOH; 9:1); IR (KBr): 3315, 3085, 2975, 1690,
1607 cm-1; 1H NMR (200 MHz, CDCl3): ꢀ 2.2 (s, 3H, CH3), 4.0
(s, 2H, CH2-Ph), 7.2 (s, 1H, NH), 7.2-7.3 (d, 2H, Ar-H), 7.4-7.5
(s, 2H, Ar-H). ms: m/z 232 [M+]. Anal. Calcd for C12H13N3O2:
O-Phenylacetyl-(4-acetamidophenyl)-methylamidoxime
(5e). This compound was prepared using general procedure in
80 % yield as pale yellow solid; mp 161-162 °C ; Rf = 0.28
(CHCl3:MeOH ; 9:1); IR (KBr) : 3446, 3342, 3058, 2967, 1715,
1658, 1595; 1H NMR (200 MHz, DMSO d6): ꢀ 2.0 (s, 3H, O=C-