X. Wang et al. / Bioorg. Med. Chem. 14 (2006) 4879–4887
4885
6
. Synthesis of CAPE derivatives
6.2.3. 3-(3-Fluoro-4,5-dihydroxyphenyl)-acrylic acid
phenethyl ester (3b). Demethylation of 3-fluoro-4-hy-
droxy-5-methoxy-benzaldehyde (2a, 200 mg, 1.18 mmol)
6
6
.1. General procedure for demethylation
with BBr (3 ml, 3 mmol) afforded crude 3-fluoro-4,5-
3
.1.1. 2-Fluoro-4,5-dihydroxybenzaldehyde (2e). Com-
dihydroxy-benzaldehyde (2b), which was used in the
subsequent Wittig reaction with 4 to give 307 mg
(86% yield) of 3b as an off-white solid after column
chromatography and recrystallization from EtOAc/
pound
(
2d,
2-fluoro-4,5-dimethoxybenzaldehyde
500 mg, 2.715 mmol), was dissolved in 12 ml CH Cl
2
2
and cooled to ꢀ70 ꢁC in a dry ice/acetone bath under
1
argon. A 1 M solution of BBr in CH Cl (8.15 ml,
3
CH Cl : mp 135 ꢁC; H NMR (CD OD) d 2.98 (t,
2
2
2
2
3
8
.15 mmol) was added slowly with vigorous stirring.
J = 7.0 Hz, 2H), 4.36 (t, J = 7.0 Hz, 2H), 6.25 (d,
J = 15.9 Hz, 1H), 6.83 (t, J = 1.5 Hz, 1H), 6.85 (d,
J = 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 7.24 (m,
The reaction mixture was stirred overnight without fur-
ther cooling. After 24 h, MeOH (10 ml) was added to
the reaction mixture to quench excess BBr and the sol-
1
3
5H), 7.45 (d, J = 15.9 Hz, 1H); C NMR (CD OD) d
3
3
vent was evaporated. This process was repeated two
additional times and the crude product 2e was used in
the next step without further purification.
36.18, 66.22, 108.36 (d, JC–F = 19.8 Hz), 111.84,
116.75, 126.62 (d, JC–F = 8.9 Hz), 127.55, 129.51,
129.97, 137.36, 139.41, 145.92, 148.84 (d, JC–F =
.9 Hz), 153.43 (d, J = 238.1 Hz), 168.76; CI-MS
5
m/z 303 (MH , 100). HRCI-MS: calcd for
C–F
+
6
6
.2. General procedure for Wittig reaction
C H FO ; 303.1033. Found 303.1030; Anal. Calcd
1
7
15
4
.2.1. 3-(2-Fluoro-4,5-dihydroxyphenyl)-acrylic acid phen-
for C H FO + 1/4H O: C, 66.55; H, 5.09. Found:
17 15 4 2
ethyl ester (3e). The crude 2-fluoro-4,5-dihydroxybenzal-
dehyde (2e) was dissolved in 7.5 ml of 1,4-dioxane. The
phosphonium chloride 4 (1.7 g, 3.7 mmol), 7.5 ml CHCl3,
C, 66.76; H, 4.84.
6.2.4. 3-(3-Fluoro-4-hydroxyphenyl)-acrylic acid pheneth-
yl ester (3c). Demethylation of 3-fluoro-4-methoxy-
benzaldehyde (1, 200 mg, 1.30 mmol) with BBr3
(3.3 ml, 3.3 mmol) afforded crude 3-fluoro-4-hydroxy-
benzaldehyde (2c), which was used in the subsequent
Wittig reaction with 4 to give 290.6 mg (78% yield) of
compound 3c as an off-white solid after column chroma-
and KHCO (815 mg, 8.15 mmol) were added. The reac-
3
tion mixture was heated under reflux in a 110 ꢁC oil bath
with vigorous stirring under argon for 18 h. The resulting
mixture was filtered, washed with CH Cl , and concen-
2
2
trated on a rotary evaporator. Column chromatography
EtOAc/CH Cl (2:3, v/v)) afforded 456 mg (55% yield)
(
2
2
of 3e as a white solid: mp 157 ꢁC; TLC (Silica gel,
tography and recrystallization from EtOAc/hexane: mp
1
EtOAc/CH Cl (2:3, v/v)), R 0.45; H NMR (CD OD)
1
80 ꢁC; H NMR (CDCl ) d 3.01 (t, J = 7.1 Hz, 2H),
2
2
f
3
3
d 2.97 (t, J = 7.0 Hz, 2H), 4.35 (t, J = 7.0 Hz, 2H), 6.26
d, J = 16.0 Hz, 1H), 6.54 (d, J = 11.7 Hz, 1H), 6.97 (d,
J = 7.2 Hz, 1H), 7.23 (m, 5H), 7.66 (d, J = 16.0 Hz, 1H);
4.42 (t, J = 7.1 Hz, 2H), 6.27 (d, J = 16.0 Hz, 1H), 6.98
(s, 1H), 7.00 (s, 1H), 7.01 (s, 1H), 7.26 (m, 5H), 7.55
(
1
3
(d, J = 15.9 Hz, 1H); C NMR (CDCl ) d 35.22,
3
1
3
C NMR (CD OD) d 36.14, 66.22, 103.96 (d, J
=
=
(40.48), 65.10, 114.72 (d, JC–F = 18.5 Hz), 116.83,
117.71, 125.57 (d, JC–F = 3.1 Hz), 126.60, 127.67 (d,
JC–F = 6.3 Hz), 128.54, 128.94, 137.87, 143.66, 145.79
(d, JC–F = 14.7 Hz), 151.16 (d, JC–F = 238.9 Hz),
3
C–F
2
3
1
6.4 Hz), 113.82 (d, JC–F = 12.9 Hz), 114.02 (d, JC–F
.9 Hz), 116.98 (d, JC–F = 5.4 Hz), 127.52, 129.48,
29.95, 138.87 (d, JC–F = 3.5 Hz), 139.35, 143.39, 150.79
+
(
d, JC–F = 11.9 Hz), 157.21 (d, JC–F = 245.1 Hz), 168.90;
CI-MS m/z 303 (MH , 100). HRCI-MS: calcd for
167.04; CI-MS m/z 287 (MH , 100). HRCI-MS: calcd
for C H FO ; 287.1083. Found 287.1089; Anal. Calcd
+
1
7
15
3
C H FO ; 303.1033. Found 303.1023; Anal. Calcd for
15
for C H FO + 1/4H O: C, 70.21; H, 5.37; F, 6.53.
17 15 3 2
1
7
4
C H FO : C, 67.54; H, 5.00; F, 6.28. Found: C, 67.53;
1
Found: C, 70.02; H, 5.27; F, 6.50.
7
15
4
H, 4.97; F, 6.18.
6.2.5. 3-(2-Fluoro-4,5-dimethoxyphenyl)-acrylic acid
6
.2.2. 3-(3-Fluoro-4-hydroxy-5-methoxyphenyl)-acrylic
phenethyl ester (3d). This compound was a co-product
from the above reaction leading to compound 3f. It
was isolated as 69 mg (6% yield) of an off-white solid
after repeated column chromatography and recrystalli-
acid phenethyl ester (3a). The 3-fluoro-4-hydroxy-5-
methoxy-benzaldehyde (2a, 200 mg, 1.18 mmol) was
used directly in the Wittig reaction to afford 214 mg
(57% yield) of compound 3a as an off-white solid after
column chromatography and recrystallization from
EtOAc/hexane: mp 94 ꢁC; H NMR (CDCl ) d 3.02 (t,
J = 7.0 Hz, 2H), 3.94 (s, 3H), 4.42 (t, J = 7.0 Hz, 2H),
6
1
zation from CH Cl /hexane: mp 86 ꢁC; H NMR
2
2
(CDCl ) d (ppm): 3.02 (t, J = 7.1 Hz, 2H), 3.88 (s,
3
1
3H), 3.89 (s, 3H), 4.43 (t, J = 7.1 Hz, 2H), 6.36 (d,
J = 16.1 Hz, 1H), 6.64 (d, J = 11.6 Hz, 1H), 6.94 (d,
J = 6.8 Hz, 1H), 7.26 (m, 5H), 7.78 (d, J = 16.1 Hz,
3
.28 (d, J = 16.1 Hz, 1H), 6.83 (d, J = 1.6 Hz, 1H),
.95 (dd, J = 10.8, 1.8 Hz, 1H), 7.28 (m, 5H), 7.53 (d,
1
3
6
1H); C NMR (CDCl ) d (ppm): 35.24, 56.28, 56.40,
3
1
3
J = 16.1 Hz, 1H); C NMR (CDCl ) d 35.23, 56.54,
64.99, 100.15 (d, JC–F = 28.0 Hz), 109.42 (d, JC–F
4.5 Hz), 113.46 (d, JC–F = 12.7 Hz), 117.64 (d, JC–F
6.0 Hz), 126.57, 128.53, 128.94, 137.17 (d, JC–F
=
=
=
3
65.03, 106.03, 109.54 (d, JC–F = 19.2 Hz), 117.07,
126.11 (d, JC–F = 7.8 Hz), 126.60, 128.55, 128.92,
135.38 (d, JC–F = 13.9 Hz), 137.88, 143.86, 148.30 (d,
3.0 Hz), 137.92, 145.65 (d, JC–F = 2.5 Hz), 152.01 (d,
JC–F = 10.2 Hz), 156.51 (d, J = 248.8 Hz), 166.95;
CI-MS m/z 331 (MH , 100). HRCI-MS: calcd for
JC–F = 6.2 Hz), 150.55 (d, J
CI-MS m/z 317 (MH , 100). HRCI-MS: calcd for
= 242.6 Hz), 166.77;
C–F
C–F
+
+
C H FO ; 317.1189. Found 317.1184; Anal. Calcd
4
C H FO ; 331.1346. Found 331.1354; Anal. Calcd
19 19 4
1
8
17
for C H FO : C, 68.35; H, 5.42; F, 6.01. Found: C,
1
for C H FO + 1/4H O: C, 68.15; H, 5.87. Found: C,
19 19 4 2
8
17
4
6
8.24; H, 5.36; F, 5.98.
68.47; H, 5.70.