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D. M. Cottrell et al. / Bioorg. Med. Chem. 12 (2004) 2815–2824
The analytical sample was obtained by sublimation of
the recrystallized solid at 60–70 ꢁC (0.75–1 Torr). 1H
NMR (400 MHz, CDCl3): d 8.09 (m, 2H), 7.18 (m, 2H),
4.40 (s, 2H); 13C NMR (150 MHz, CDCl3): d 173.0,
168.3, 164.9 (d, JCF ¼ 252:5 Hz), 129.8 (d, JCF ¼ 8:8 Hz),
122.1 (d, JCF ¼ 2:3 Hz), 116.3 (d, JCF ¼ 22:1 Hz), 109.4,
27.4. Anal. (C10H6FN3OS) C, H, N.
50 mL of dry DMF was added ammonium thiocyanate
(2.6 g, 0.03 mol). The reaction mixture was heated and
stirred at 75–95 ꢁC for 1 h, then cooled. Ice/water
(50 mL) was added with stirring to the reaction mixture
to precipitate the product, then the yellow solid was
filtered, washed with water, and dissolved in ethyl
acetate (500 mL). The organic layer was washed with
water (3 · 100 mL), brine (2 · 100 mL), and dried
(Na2SO4). Solvent was removed in vacuo to give the
crude product as an orange-yellow solid. Gradient elu-
tion of the product from a silica gel column using
chloroform/hexane (1:4 to 1:1) afforded 1.87 g of prod-
uct. Recrystallization from chloroform-hexane gave
1.44 g (50%) of the title compound as a light yellow
solid, mp 106–108 ꢁC. Sublimation of the solid at 90–
95 ꢁC (0.50 Torr) gave the analytical sample as a white
3.5.6.
3-(3-Chlorophenyl)-5-(thiocyanatomethyl)-1,2,4-
oxadiazole 4f. To a solution of 3f (4.0 g, 0.017 mol) in
40 mL of dry DMF was added ammonium thiocyanate
(3.88 g, 0.051 mol). This solution was heated and stirred
at 60–90 ꢁC for 30 min. To the cooled solution was
added ice/water (80 mL), followed by stirring for 15 min to
give a light yellow precipitate. The solid was filtered and
washed with water (2 · 100 mL). This solid was dissolved
in ethyl acetate (200 mL), then the organic layer was
washed with water (3 · 100 mL), brine (3 · 100 mL),
dried over Na2SO4, and the solvent removed in vacuo to
give a yellow solid. Chromatography on silica gel
employing ethyl acetate/hexane (1:4) as the eluent gave
2.5 g of the product as a pale yellow solid. The product
was recrystallized from chloroform to afford 2.35 g
(54%) of the title compound as an off-white crystalline
solid, mp 113.5–115 ꢁC. The analytical sample was
obtained by sublimation of the solid at 90 ꢁC (1 Torr) to
give the compound as a white crystalline solid. 1H NMR
(600 MHz, CDCl3): d 8.09 (m, 1H), 7.98 (d, J ¼ 7:6 Hz,
1H), 7.52 (m, 1H), 7.45 (dd, J1 ¼ J2 ¼ 7:8 Hz, 1H), 4.41
(s, 2H); 13C NMR (150 MHz, CDCl3): d 173.3, 168.1,
135.1, 131.8, 130.4, 127.7, 127.6, 125.7, 109.3, 27.4.
Anal. (C10H6ClN3OS) C, H, N.
1
crystalline solid, mp 108–109 ꢁC. H NMR (400 MHz,
CDCl3):
d
8.20 (d, J ¼ 2:0 Hz, 1H), 7.94 (dd,
J1 ¼ 8:4 Hz, J2 ¼ 2:0 Hz, 1H), 7.59 (d, J ¼ 8:4 Hz, 1H),
4.40 (s, 2H). 13C NMR (150 MHz, CDCl3): d 173.4,
167.5, 136.2, 133.6, 131.2, 129.4, 126.6, 125.8, 109.2,
27.3. Anal. (C10H5Cl2N3OS) C, H, N.
3.6. Preparation of 3-aryl-5-alkyl-1,2,4-oxadiazoles 5a–f
These compounds were prepared from benzamidoximes
2a–c and acetyl or isobutyryl chloride in pyridine
according to the general procedure of Chiou and
Shine.15 Representative procedure for the preparation of
3-(4-methoxyphenyl)-5-methyl-1,2,4-oxadiazole 5c. To a
three-necked flask equipped with an addition funnel and
a condenser was added 2c (3.04 g, 0.018 mol) and pyr-
idine (4 mL). Acetyl chloride (2.75 g, 0.035 mol) was then
added dropwise to this suspension over a period of
15 min, then the reaction mixture was heated to reflux
for 45 min. Upon cooling, the mixture solidified. Water
(30 mL) was added, at which point the product precip-
itated. The precipitate was filtered, washed with water,
then chromatographed on silica gel using a methylene
chloride/hexane (1:4 to 2:3) step gradient as eluent to
give 2.90 g (85%) of the desired product as a white
crystalline solid, mp 61–63 ꢁC, lit. 58–59 ꢁC.24 1H NMR
(250 MHz, CDCl3): d 8.00 (d, J ¼ 8:9 Hz, 2H), 6.98 (d,
J ¼ 8:9 Hz, 2H), 3.87 (s, 3H), 2.64 (s, 3H).
3.5.7. 3-(2-Chlorophenyl)-5-(thiocyanatomethyl)-1,2,4-
oxadiazole 4g. To a solution of 3g (4.0 g, 0.017 mol) in
30 mL of dry DMF was added ammonium thiocyanate
(3.88 g, 0.051 mol). The reaction mixture was heated and
stirred at 60–90 ꢁC for 30 min. Ice/water (80 mL) was
added to the cooled reaction mixture followed by stir-
ring for 20 min until precipitation of the product was
complete. The yellow solid that was formed was filtered,
washed with water (3 · 50 mL), and dissolved in ethyl
acetate (300 mL). This organic layer was washed with
water (1 · 50 mL), brine (3 · 50 mL), dried over Na2SO4,
then solvent was evaporated to give the product as a
yellow solid. Chromatography on silica gel using ethyl
acetate/hexane (1.5:8.5) as eluent gave 3.72 g of product,
which was recrystallized from chloroform/hexane to give
3.01 g (70%) of the title compound as a light yellow
crystalline solid, mp 86–90 ꢁC. The analytical sample
was obtained by sublimation of the light yellow recrys-
tallized compound at 60–80 ꢁC (0.6–0.7 Torr) to give the
title compound as a white crystalline compound, mp
3.6.1. 3-Phenyl-5-methyl-1,2,4-oxadiazole 5a. Melting
point 40–41 ꢁC, lit. 39–41 ꢁC.15 1H NMR (250 MHz,
CDCl3): d 8.06 (m, 2H), 7.48 (m, 3H), 2.66 (s, 3H).
3.6.2. 3-(4-Chlorophenyl)-5-methyl-1,2,4-oxadiazole 5b.
Melting point 103–105 ꢁC, lit. 90–92 ꢁC.25 1H NMR
(250 MHz, CDCl3): d 8.01 (d, J ¼ 8:4 Hz, 2H), 7.46 (d,
J ¼ 8:4 Hz, 2H), 2.66 (s, 3H).
1
unchanged. H NMR (400 MHz, CDCl3): d 7.96 (dd,
J1 ¼ 7:6 Hz, J2 ¼ 1:8 Hz, 1H), 7.56 (dd, J1 ¼ 7:9 Hz,
J2 ¼ 1:3 Hz, 1H), 7.49–7.39 (m, 2H), 4.44 (s, 2H). 13C
NMR (150 MHz, CDCl3): d 172.5, 167.9, 133.5, 132.2,
131.8, 131.1, 127.0, 125.2, 109.4, 27.3. Anal.
(C10H6ClN3OS) C, H, N.
3.6.3. 3-Phenyl-5-isopropyl-1,2,4-oxadiazole 5d. Color-
less oil,26 1H NMR (250 MHz, CDCl3): d 8.09 (m, 2H),
7.48 (m, 3H), 3.30 (sep, J ¼ 7:0 Hz, 1H), 1.47 (d,
J ¼ 7:0 Hz, 6H).
3.5.8. 3-(3,4-Dichlorophenyl)-5-(thiocyanatomethyl)-1,2,4-
oxadiazole 4h. To a solution of 3h (3.17 g, 0.01 mol) in