244 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Malamas et al.
general structure 12a ,b (Scheme 1) were synthesized from
alcohols 7a ,b by the representative procedure illustrated for
analog 22 (Table 1). Alcohols 7a ,b were obtained from
commercially available benzamide 5a or thiobenzamide 5b
according to literature methods.19
The oxadiazole hydroxyurea 40 (Table 1) was prepared
according to the procedure described for compound 22, using
3-(2′-hydroxyethyl)-5-phenyl-1,2,4-oxadiazole (21), which was
prepared as follows.
3-(2′-Hydr oxyeth yl)-5-ph en yl-1,2,4-oxadiazole (21). Ben-
zoyl chloride (24.3 g, 173 mmol) in dioxane (50 mL) was added
dropwise into a suspension of 2′-hydroxyethylamidoxime29 (36
g, 346 mmol) and potassium carbonate (23.9 g, 173 mmol) in
dioxane (400 mL). The mixture was stirred for 4 h, poured
into water, and extracted with EtOAc. The organic extracts
were dried over MgSO4. Evaporation gave an off-white solid
(40.0 g), which was taken in AcOH (275 mL) and refluxed for
2 h. The mixture was poured into water and extracted with
EtOAc. The organic extracts were dried over MgSO4. Evapo-
ration and purification by flash chromatography, on silica gel
(hexane/EtOAc, 3/2), gave a white solid (18.3 g, 28% yield):
mp 58-59 °C; 1H NMR (DMSO-d6, 400 MHz) δ 2.9 (t, J ) 6.64
Hz, 2H, CH2), 3.81 (m, 2H, CH2), 4.82 (t, J ) 5.6 Hz, 1H, OH),
7.6-7.68 (m, 3H, Ar-H), 8.1 (m, 2H, Ar-H); IR (KBr, cm-1) 3200
(OH); MS m/ e 190 (M+). Anal. (C10H20N2O2) C, H, N.
1-Hydr oxy-1-[4-[2-(5-ph en yl-1,2,4-oxadiazol-3-yl)eth oxy]-
ben zyl]u r ea (40): mp 135-136 °C; 1H NMR (DMSO-d6, 400
MHz) δ 3.25 (t, J ) 6.22 Hz, 2H, CH2), 4.39 (t, J ) 6.22 Hz,
2H, CH2), 4.41 (s, 2H, CH2), 6.28 (s, 2H, NH2), 6.88 (d, J ) 8.7
Hz, 2H, Ar-H), 7.18 (d, J ) 8.7 Hz, 2H, Ar-H), 7.6-7.7 (m,
4-[2-(5-Met h yl-2-p h en yloxa zol-4-yl)et h oxy]b en za ld e-
h yd e (9a , R1,R3 ) H, R2 ) CH3, X ) O, P a r a -Su bstitu ted ).
Diethyl azodicarboxylate (3.87 mL, 24.63 mmol) was added
dropwise into a cold (0 °C) solution of 4-(2′-hydroxyethyl)-5-
methyl-2-phenyloxazole19 (5.0 g, 24.63 mmol), triphenylphos-
phine (6.45 g, 24.63 mmol), and 4-hydroxybenzaldehyde (3.0
g, 24.63 mmol) in anhydrous THF (100 mL). The reaction
temperature was allowed to come to room temperature, and
the mixture was stirred for 48 h, poured into H2O, and
extracted with EtOAc. The organic extracts were dried over
MgSO4. Evaporation and purification by flash chromatogra-
phy on silica gel (hexane/EtOAc, 4/1) gave a yellow solid (5.9
g, 78% yield): mp 77-78 °C; 1H NMR (DMSO-d6, 400 MHz) δ
2.35 (s, 3H, CH3), 2.96 (t, J ) 6.64 Hz, 2H, CH2), 4.33 (t, J )
6.64 Hz, 2H, CH2), 7.1 (d, J ) 8.7 Hz, 2H, Ar-H), 7.46 (m, 3H,
Ar-H), 7.84 (d, J ) 8.7 Hz, 2H, Ar-H), 7.89 (m, 2H, Ar-H), 9.85
(s, 1H, CHO); IR (KBr, cm-1) 1690 (CO); MS m/ e 308 (M +
H)+. Anal. (C19H12NO3) C, H, N.
4-[2-(5-Met h yl-2-p h en yloxa zol-4-yl)et h oxy]b en za ld e-
h yd e Oxim e (10a , R1,R3 ) H, R2 ) CH3, X ) O, P a r a -
Su bstitu ted ). Hydroxylamine hydrochloride (3.67 g, 52.76
mmol) and sodium acetate (5.77 g, 70.36 mmol) in H2O (50
mL) were added into a solution of 4-[2-(5-methyl-2-phenylox-
azol-4-yl)ethoxy]benzaldehyde (5.4 g, 17.59 mmol) in EtOH
(300 mL). The mixture was stirred at room temperature for
24 h, poured into H2O, and extracted with EtOAc. The organic
extracts were dried over MgSO4. Evaporation and crystal-
lization from acetone/ethyl ether (after cooling to 0 °C) gave a
white solid (5.1 g, 90% yield): mp 153-155 °C; 1H NMR
(DMSO-d6, 400 MHz) δ 2.35 (s, 3H, CH3), 2.93 (t, J ) 6.64 Hz,
2H, CH2), 4.23 (t, J ) 6.64 Hz, 2H, CH2), 6.95 (d, J ) 8.7 Hz,
2H, Ar-H), 7.49 (m, 5H, Ar-H), 7.89 (m, 2H, Ar-H), 8.04 (s,
1H, CH), 10.94 (s, 1H, OH); IR (KBr, cm-1) 3200 (OH); MS
m/ e 322 (M+). Anal. (C19H18N2O3) C, H, N.
3H, Ar-H), 8.01 (m, 2H, Ar-H), 9.25 (s, 1H, OH); IR (KBr, cm-1
)
3450 (NH), 3200 (OH), 1620 (CO); MS m/ e 355 (M + H)+. Anal.
(C18H18N4O4) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of Azole Meth -
oxyp h en yl N-Hyd r oxyu r ea s (Ta ble 2). Compounds of the
general structure 19a -c (Scheme 2) were synthesized from
chlorides 17a ,b and phenol 8. Chlorides 17a ,b were obtained
from commercially available benzaldehyde 13 or benzamide
16a /thioamide 16b according to literature methods.21,22 After
coupling of 8 with 17a ,b in the presence of potassium carbon-
ate, a similar experimental process as described for compounds
of Table 1 was followed.
4-[(5-Met h yl-2-p h en yloxa zol-4-yl)m et h oxy]b en za ld e-
h yd e (18a , R1,R3 ) H, R2 ) CH3, X ) O, P a r a -Su bstitu ted ).
A mixture of 4-(chloromethyl)-5-methyl-2-phenyloxazole30 (5.5
g, 26.5 mmol), 4-hydroxybenzaldehyde (3.23 g, 26.5 mmol),
potassium carbonate (3.66 g, 26.5 mL), and DMF (80 mL) was
stirred at 80 °C for 8 h. The mixture was poured into H2O
and extracted with EtOAc. The organic extracts were dried
over MgSO4. Evaporation and purification by flash chroma-
tography on silica gel (hexane/EtOAc, 4/1) gave a yellow solid
N-[4-[2-(5-Meth yl-2-p h en yloxa zol-4-yl)eth oxy]ben zyl]-
h yd r oxyla m in e (11a , R1,R3 ) H, R2 ) CH3, X ) O, P a r a -
Su bstitu ted ). Sodium cyanoborohydride (3.87 g, 62.11 mmol)
was added into a solution of 4-[2-(5-methyl-2-phenyloxazol-4-
yl)ethoxy]benzaldehyde oxime (4.0 g, 19.42 mmol) and methyl
orange (indicator, 10 mg) in MeOH (300 mL) in THF (50 mL).
After 5 min, a solution of HCl (4 N) in dioxane was added
dropwise in order to maintain the pH solution in the range of
3-4. When a steady red color was obtained, the mixture was
poured into H2O, basified with NaOH (1 N), and extracted with
EtOAc. The organic extracts were dried over MgSO4. Evapo-
ration and purification by flash chromatography, on silica gel
(EtOAc/MeOH, 10/1), gave a white solid (3.4 g, 85% yield): mp
95-96 °C; 1H NMR (DMSO-d6, 400 MHz) δ 2.35 (s, 3H, CH3),
2.91 (t, J ) 6.64 Hz, 2H, CH2), 3.77 (s, 2H, CH2), 4.18 (t, J )
6.64 Hz, 2H, CH2), 5.9 (br s, 1H, NH), 6.87 (d, J ) 8.7 Hz, 2H,
Ar-H), 7.23 (m, 3H, Ar-H), 7.48 (m, 3H, OH, Ar-H), 7.91 (m,
2H, Ar-H); IR (KBr, cm-1) 3400 (NH), 3200 (OH); MS m/ e 325
(M + H)+. Anal. (C19H20N2O3) C, H, N.
1-Hydroxy-1-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-
ben zyl]u r ea (22 or 12a , R1,R3 ) H, R2 ) CH3, X ) O, P a r a -
su bstitu ted ). Trimethylsilyl isocyanate (1.4 mL, 10.0 mmol)
was added into a solution of N-[4-[2-(5-methyl-2-phenyloxazol-
4-yl)ethoxy]benzyl]hydroxylamine (2.5 g, 7.71 mmol) in diox-
ane (30 mL). After being stirred for 2 h, the mixture was
poured into H2O, acidified with HCl (2 N), and extracted with
EtOAc. The organic extracts were dried over MgSO4. Evapo-
ration and crystallization from acetone/ethyl ether (after
cooling to 0 °C) gave a white solid (1.96 g, 69% yield): mp 128-
129 °C; 1H NMR (DMSO-d6, 400 MHz) δ 2.35 (s, 3H, CH3),
2.91 (t, J ) 6.64 Hz, 2H, CH2), 4.18 (t, J ) 6.64 Hz, 2H, CH2),
4.4 (s, 2H, CH2), 6.28 (s, 2H, NH2), 6.87 (d, J ) 8.7 Hz, 2H,
Ar-H), 7.18 (d, J ) 8.7 Hz, 2H, Ar-H), 7.51 (m, 3H, Ar-H), 7.91
(m, 2H, Ar-H), 9.24 (s, 1H, OH); IR (KBr, cm-1) 3450 (NH),
3200 (OH), 1670 (CO); MS m/ e 368 (M + H)+. Anal.
(C20H21N3O4) C, H, N.
1
(6.8 g, 86% yield): mp 103-105° C; H NMR (DMSO-d6, 400
MHz) δ 2.46 (s, 3H, CH3), 5.14 (s, 2H, CH2), 7.24 (d, J ) 8.7
Hz, 2H, Ar-H), 7.9 (d, J ) 8.7 Hz, 2H, Ar-H), 7.94 (m, 2H,
Ar-H), 9.88 (s, 1H, CHO); IR (KBr, cm-1) 1690 (CO); MS m/ e
294 (M + H)+. Anal. (C18H15NO3) C, H, N.
Ack n ow led gm en t. We gratefully acknowledge Mrs.
L. Bayless, Mrs. S. Woeppel, Mrs. L. J enkins, Mrs. E.
Rubin, and Mrs. D. Howell for their expert assistance
in the in vivo studies; Mrs. C. Palka for the chemical
preparation of several compounds; Dr. K. Ghosh for his
assistance in the statistical analysis of the data; and
Mr. B. Hofmann and his staff for the analytical data.
Refer en ces
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