5036 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Malamas et al.
(d, J ) 2.1 Hz, 1H), 7.15 (t, J ) 8.4 Hz, 1H), 7.8-7.83 (m, 2H),
(CH2Cl2/isopropyl alcohol 0.3%) gave 7-(2-bromo-1-fluoroethyl)-
2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol as a white
solid (0.25 g, mp 185-186 °C). The product was taken in
acetonitrile (2 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (150
mg) was added. The reaction mixture was stirred for 24 h,
poured into cold (0 °C) HCl (1 N, 10 mL), and extracted with
EtOAc. The organic extracts were dried over MgSO4. Evapora-
tion and purification by flash chromatography (20% EtOAc/
hexanes) gave a white solid (160 mg): mp 213-214 °C): MS
9.9 (br s, 1H), 10.9 (br s, 1H). Anal. (C13H7BrFNO3) C, H, N
2-(3-F lu or o-4-h yd r oxyp h en yl)-7-vin yl-1,3-ben zoxa zol-
5-ol (30a ; R1 ) 3′F ; R2 ) Vin yl). Dichlorobis(tri-o-tolylphos-
phine)palladium (II) (0.87 g, 1.1 mmol) was added to a mixture
of 7-bromo-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol (7.16
g, 22.1 mmol), tributyl(vinyl)tin (10.5 g, 33.25 mmol), and
ethylene glycol diethyl ether (65 mL). The reaction mixture
was stirred at 115 °C for 48 h, cooled to room temperature,
and treated with activated carbon. The mixture was filtered
through MgSO4 and concentrated. Purification by flash chro-
matography, on acidic silica gel (hexanes/EtOAc/CH2Cl2 1:1:
1), gave a white solid (4.35 g, 72% yield): mp 250-252 °C;
MS m/e 272 (M + H)+; 1H NMR (DMSO-d6) δ 5.6 (d, J ) 11.7
Hz, 1H), 6.2 (d, J ) 17.2 Hz, 1H), 6.9-6.9 (m, 2H, vinyl), 6.96
(d, J ) 2.29 Hz, 1H), 7.13 (t, J ) 8.5 Hz, 1H), 7.8-7.9 (m, 2H),
9.5(br s, 1H), 10.8 (br s, 1H). Anal. (C15H10FNO3) C, H, N.
1
m/e 290 (M + H)+; H NMR (DMSO-d6, 400 MHz) δ 5.32 (dd,
J ) 19.4, 3.88 Hz, 1H), 5.69 (dd, J ) 53, 3.88 Hz, 1H), 7.12
(m, 2H), 7.91 (m, 2H), 9.78 (s 1H), 10.84 (s, 1H). Anal. (C15H9-
BrF2NO3‚0.3H2O) C, H, N.
7-Eth yn yl-2-(4-h ydr oxyph en yl)-1,3-ben zoxazol-5-ol (32a;
R3 ) Eth yn yl). Tetrakis(triphenylphosphine)palladium (52
mg, 0.045 mmol) was added to a mixture of 7-bromo-5-
methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole (0.3 g, 0.9 mmol),
copper(I) iodide (17.1 mg, 0.09 mmol), ethynyl(trimethyl)silane
(0.2 g mg, 2 mmol), and triethylamine (12 mL). The mixture
was stirred at 110 °C for 4 h, poured into aqueous ammonium
chloride, and extracted with EtOAc/THF (1:1). The organic
extracts were dried over MgSO4. Evaporation and purification
by flash chromatography (hexanes/EtOAc 6:1) gave an off-
white solid (0.27 g, 85% yield). The product was dissolved in
CH2Cl2 (2 mL) and cooled to -78 °C, and boron tribromide
(0.6 mL) was added dropwise. The mixture was allowed to
warm to room temperature. After stirring for 18 h at room
temperature, the mixture was slowly poured into cold (0 °C)
ethyl ether (10 mL). Methyl alcohol (3 mL) was then slowly
added to the mixture. The new mixture was washed with water
(three times) and dried over MgSO4. Evaporation and purifica-
tion by flash chromatography (hexanes/EtOAc 3:1) gave a
yellow solid (86 mg, 38% yield): mp 229-231 °C; MS m/e 252
(M + H)+; 1H NMR (DMSO-d6) δ 4.57 (s, 1H), 6.84 (d, J )
2.29 Hz, 1H), 6.94 (d, J ) 8.55 Hz, 2H), 7.09 (d, J ) 2.29 Hz,
1H), 7.99 (d, J ) 8.7 Hz, 2H), 9.69 (s, 1H), 10.3 (s, 1H). Anal.
(C15H9NO3) C, H, N.
5-Meth oxy-2-(4-m eth oxyp h en yl)-7-p h en yl-1,3-ben zox-
a zole (30b, R2 ) P h , R1 ) H, Dim eth oxy In ter m ed ia te).
7-Bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole (200
mg, 0.60 mmol) and tetrakis(triphenylphosphine)palladium (63
mg, 0.03 mmol) were dissolved in toluene (5 mL) and stirred
for 10 min at room temperature under a nitrogen atmosphere.
Benzene boronic acid (110 mg, 0.90 mmol) was added followed
by aqueous sodium carbonate (2 M, 1.5 mL) and ethanol (2
mL). The mixture was refluxed for 12 h, diluted with water,
and extracted with EtOAc. The organic extracts were dried
over MgSO4. Evaporation and purification by flash chroma-
tography (20-40% EtOAc/petroleum ether) gave a light-pink
1
solid: mp 92 °C; MS m/e 332 (M + H)+; H NMR (DMSO-d6,
400 MHz) δ 3.86 (s, 3H), 3.88 (s, 3H), 7.15 (d, J ) 9.0 Hz, 2H),
7.2 (d, J ) 2.44 Hz, 1H), 7.3 (d, J ) 2.44 Hz, 1H), 7.46 (t, J )
7.32 Hz, 1H), 7.57 (t, J ) 7.63 Hz, 2H), 7.98 (d, J ) 8.39 Hz,
2H), 8.12 (d, J ) 9.0 Hz, 2H). Anal. (C21H17NO3) C, H, N.
2-(4-H yd r oxyp h en yl)-7-m et h oxy-1,3-b en zoxa zol-5-ol
(30c; R2 ) OMe). A mixture of 7-bromo-2-(4-hydroxyphenyl)-
1,3-benzoxazol-5-ol (100 mg, 0.33 mmol) and copper(I) bromide
(56 mg, 0.39 mmol) in anhydrous N,N-dimethylformamide (1.5
mL) was stirred with freshly prepared sodium methoxide (15
wt % in methanol, 1 mL) and heated to 120 °C for 4 h. The
mixture was cooled and diluted with HCl (1 N, 5 mL). Isolation
of the crude product with ethyl acetate followed by flash
chromatography (40-50% EtOAc/petroleum ether) gave the
title compound as an off-white solid (50 mg, 60% yield): mp
225-228 °C; MS m/e 258 (M + H)+; 1H NMR (DMSO-d6) δ
3.92 (s, 3H), 6.43 (s, 1H), 6.60 (s, 1H), 6.92 (d, J ) 8.5 Hz,
2H), 7.95 (d, J ) 8.4 Hz, 2H), 9.44 (br s, 1H), 10.2 (br s, 1H).
Anal. (C14H11NO4‚0.75H2O) C, H, N.
5-Meth oxy-2-(4-m eth oxyph en yl)-1,3-ben zoxazole-7-car -
bon itr ile (32b; R3 ) CN, Dim eth oxy In ter m ed ia te). A
solution of 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-ben-
zoxazole (200 mg, 0.60 mmol) in anhydrous N,N-dimethylfor-
mamide (1.5 mL) was stirred and heated to reflux under dry
nitrogen with copper(I) cyanide (80 mg, 0.90 mmol) for 4 h.
The mixture was cooled and poured into an excess of aqueous
ethylenediaminetetraacetic acid. Isolation of the crude product
gave the nitrile (164 mg, 98% yield) as tan needles from (30%
EtOAc/petroleum ether): mp 180-183 °C; MS m/e 281 (M +
+
H)
;
1H NMR (DMSO-d6, 400 MHz) δ 3.86 (s, 3H), 3.87 (s,
2-(3-Flu or o-4-h ydr oxyph en yl)-7-(1-flu or ovin yl)-1,3-ben -
zoxa zol-5-ol (31). Step a . Acetic anhydride (0.46 mL, 4.8
mmol) was added to a cold (10 °C) solution of 2-(3-fluoro-4-
hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol (0.5 g, 1.84 mmol),
N,N-dimethylpyridin-4-amine (0.54 g, 4.43 mmol), and 1,4-
dioxane (10 mL). The reaction mixture was allowed to warm
to room temperature and stirred for 48 h. Water (50 mL) was
added to the reaction mixture, and the mixture was extracted
with EtOAc and dried over MgSO4. Evaporation and crystal-
lization from EtOAc/hexane gave 4-[5-(acetyloxy)-1,3-benzox-
azol-2-yl]- 7-vinyl-2-fluorophenyl acetate as an off-white solid
(0.56 g, 86% yield): MS m/e 355 (M)+; 1H NMR (DMSO-d6,
400 MHz) δ 2.3 (s, 3H), 2.38 (s, 3H), 5.69 (d, J ) 11.45 Hz,
1H), 6.38 (d, J ) 17.86 Hz, 1H), 6.99 (m, 1H), 7.34 (d, J )
1.98 Hz, 1H), 7.54 (d, J ) 2.14 Hz, 1H), 7.57 (t, J ) 8.24 Hz,
1H), 8.13 (dd, J ) 8.4, 0.91 Hz, 1H), 8.19 (dd, J ) 10.68, 1.22
Hz, 1H). Anal. (C19H14FNO5) C, H, N.
Step b. Hydrogen fluoride pyridine (1.14 mL) was added
dropwise to a cold (0 °C) solution of 2-[4-(acetyloxy)-3-fluo-
rophenyl]-7-vinyl-1,3-benzoxazol-5-yl acetate (0.25 g, 0.7 mmol)
in sulfolane (3 mL). The reaction mixture was stirred for 5
min, and then 1,3-dibromo-5,5-dimethylimidazolidine-2,4-di-
one (120 mg) was added in one portion. The mixture was
stirred at room temperature for 24 h, diluted with HCl (1 N),
and extracted with EtOAc. The organic layer was dried over
MgSO4. Evaporation and purification by flash chromatography
3H), 7.17 (d, J ) 8.85 Hz, 2H), 7.51 (d, J ) 2.44 Hz, 1H), 7.71
(d, J ) 2.44 Hz, 1H), 8.13 (d, J ) 8.85 Hz, 2H). Anal.
(C16H12N2O3‚0.2H2O) C, H, N.
2-(4-Hydr oxyp h en yl)-7-p r opyl-1,3-ben zoxa zol-5-ol (32c;
R3 ) P r op yl). Tetrakis(triphenylphosphine)palladium (70 mg,
0.06 mmol) was added to a mixture of 7-bromo-5-methoxy-2-
(4-methoxyphenyl)-1,3-benzoxazole (0.4 g, 1.2 mmol), bromo-
(propyl)zinc (0.5 M in THF, 3.6 mL, 1.8 mmol), and THF (4
mL). The mixture was stirred at room temperature for 48 h,
poured into HCl (1 N), and extracted with EtOAc. The organic
extracts were dried over MgSO4. Evaporation and purification
by flash chromatography (hexanes/EtOAc 6:1) gave an off-
white solid (0.14 g). The product was dissolved in CH2Cl2 (2
mL) and cooled to -78 °C, and boron tribromide (0.35 mL)
was added dropwise. The mixture was allowed to warm to
room temperature. After stirring for 18 h at room temperature,
the mixture was slowly poured into cold (0 °C) ethyl ether (10
mL). Methyl alcohol (3 mL) was then slowly added to the
mixture. The new mixture was washed with water (three
times) and dried over MgSO4. Evaporation and purification
by flash chromatography (hexanes/EtOAc 4:1) gave a white
solid (90 mg, 27% yield): mp 110-112 °C; MS m/e 270 (M +
1
H)+; H NMR (DMSO-d6) δ 0.93 (t, J ) 7.52 Hz, 3H), 1.73 (q,
J ) 7.32 Hz, 2H), 2.78 (t, J ) 7.32 Hz, 2H), 6.6 (d, J ) 2.14
Hz, 1H), 6.83 (d, J ) 2.29 Hz, 1H), 6.94 (d, J ) 8.7 Hz, 2H),