Article
The following compounds were prepared according to previ-
ously described procedures: 6-(3-hydroxyphenyl)-2-naphthol
A,47 6-(3-hydroxyphenyl)-1-phenyl-2-naphthol B,48 1-bromo-6-
(3-hydroxyphenyl)-2-naphthol 1a,48 1-bromo-2-methoxy-
6-(3-methoxyphenyl)naphthalene 1b,48 5-oxo-5,6,7,8-tetra-
hydronaphthalen-2-yl trifluoromethanesulfonate 16e,60
6-(3-methoxyphenyl)-3,4-dihydronaphthalen-1(2H)-one 17d,61 6-(4-
hydroxyphenyl)-2-naphthol 20b.52
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2 543
acetate 3:2 to 0:1) in 59% yield (59 mg); C21H15NO2; MW 313.
1H NMR (CD3OD): δ 9.03-9.02 (m, 1H), 8.95 (d, J = 5.7 Hz,
1H), 8.81-8.79 (m, 1H), 8.30 (dd, J = 5.7 Hz, J = 7.9 Hz, 1H),
8.12 (d, J = 1.9 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.75 (dd, J =
1.9 Hz, J = 8.8 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.35 (d, J =
9.1 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.23-7.21 (m, 1H),
7.18-7.17 (m, 1H), 6.83 (ddd, J = 0.9 Hz, J = 2.5 Hz, J = 7.9 Hz,
1H). 13C NMR (CD3OD): δ 159.1, 154.1, 151.0, 144.8, 143.2,
140.8, 133.3, 133.1, 131.0, 130.3, 128.4, 128.2, 127.2, 124.1,
119.3, 119.1, 115.4, 114.8. IR: 3091, 1581, 1493, 1276, 1209,
1180 cm-1. MS (ESI): 314 (M þ H)þ.
General Procedure for Ether Cleavage. Method A. To a solu-
tion of methoxy derivative (1 equivalent (equiv)) in dichloro-
methane cooled at -78 ꢀC boron tribromide (1 M solution in
dichloromethane, 3-5 equiv per methoxy function) was slowly
added under N2. The reaction mixture was stirred at -78 ꢀC for
1 h and at room temperature overnight. The reaction was quenched
by the addition of 2% Na2CO3 and extracted with dichloro-
methane. The combined organic layers were washed with brine
and dried over magnesium sulfate and concentrated to dryness.
General Procedures for Suzuki Coupling. Method B. A mix-
ture of arylbromide (1 equiv), boronic acid (1 equiv), 10% aqueous
solution of sodium carbonate (2 equiv), and tetrakis(tri-
phenylphosphine) palladium(0) (0.05 equiv) in toluene/ethanol
mixture (oxygen free) was stirred at 80 ꢀC under nitrogen for
several hours. The reaction mixture was cooled to room tem-
perature, quenched by the addition of 2% HCl, and extracted
with ethyl acetate. The organic layer was washed with brine,
dried over magnesium sulfate, and concentrated to dryness.
Method C. A mixture of arylbromide (1 equiv), boronic acid
(1.3 equiv), cesium carbonate (2 equiv), and tetrakis(triphenyl-
phosphine) palladium(0) (0.05 equiv) was suspended in a DME/
EtOH/water (1:1:1) solution. The reaction mixture was exposed
to microwave irradiation (25 min, 150 W, 150 ꢀC, 15 bar). After
reaching room temperature, 1N NH4Cl was added and the
aqueous layer was extracted with ethyl acetate. The organic
layer was washed with brine, dried over sodium sulfate, filtered,
and concentrated to dryness.
Method D. A mixture of arylbromide (1 equiv), boronic acid
(1.2 equiv), potassium carbonate (2 equiv), palladium acetate
(0.1 equiv), and triphenylphosphine (0.2 equiv) was dissolved in
a 1,4-dioxane/EtOH (2:1) solution. The reaction mixture was
exposed to microwave irradiation (15 min, 150 W, 150 ꢀC, 15 bar).
After reaching room temperature, the solution was filtered off
and water and dichloromethane were added to the filtrate. The
aqueous layer was extracted with dichloromethane, and the
combined organic layers were washed with brine, dried over sodium
sulfate, filtered, and concentrated to dryness.
1-(3-Furyl)-6-(3-hydroxyphenyl)-2-naphthol (1). The title
compound was prepared by reaction of 1-bromo-6-(3-hydro-
xyphenyl)-2-naphthol 1a (80 mg, 0.25 mmol, 1 equiv) with
furan-3-boronic acid (28 mg, 0.25 mmol, 1 equiv) in toluene/
ethanol 5:1 at 80 ꢀC for 2 h according to Method B. The
analytically pure compound was obtained after purification
by column chromatography under pressure (dichloromethane/
methanol 98:2) in 46% yield (35 mg); C20H14O3; MW 302. 1H
NMR (CD3OD þ 3 drops CDCl3): δ 7.98 (d, J = 1.9 Hz, 1H),
7.86 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.71-7.70
(m, 1H), 7.68-7.67 (m, 1H), 7.64 (dd, J = 2.2 Hz, J = 8.8 Hz,
1H), 7.31-7.28 (m, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.20-7.19
(m, 1H), 7.18-7.17 (m, 1H), 6.81 (ddd, J = 0.9 Hz, J = 2.5
Hz, J = 7.9 Hz, 1H), 6.65 (dd, J = 0.9 Hz, J = 1.9 Hz, 1H).
13C NMR (CD3OD þ 3 drops CDCl3): δ 161.3, 156.1, 146.6,
146.3, 145.8, 139.4, 137.2, 133.5, 133.0, 132.8, 129.4, 128.7,
122.5, 122.1, 121.9, 117.7, 117.5, 116.9, 116.1. IR: 3340,
1601, 1493 cm-1. MS (ESI): 301 (M - H)-.
6-(3-Hydroxyphenyl)-1-(4-methoxypyridin-3-yl)-2-naphthol (3).
The title compound was prepared by reaction of 1-bromo-6-(3-
hydroxyphenyl)-2-naphthol 1a (100 mg, 0.32 mmol, 1 equiv) with
4-methoxypyridin-3-boronic acid (49 mg, 0.32 mmol, 1 equiv) in
toluene/ethanol 5:1 at 80 ꢀC for 3 h according to Method B. The
analytically pure compound was obtained after purification by
column chromatography under pressure(hexane/ethyl acetate 8:2)
in 84% yield (92 mg); C22H17NO3; MW 343. 1H NMR (CD3OD):
δ 8.15 (d, J = 2.5 Hz, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.84 (d, J =
8.8 Hz, 1H), 7.72 (dd, J = 2.5 Hz, J = 8.5 Hz, 1H), 7.61 (dd, J =
1.9 Hz, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.29-7.26
(m, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.20-7.19 (m, 1H), 7.18-7.17
(m, 1H), 6.98 (dd, J = 0.6 Hz, J = 8.5 Hz, 1H), 6.81 (ddd, J = 0.9
Hz, J = 2.5 Hz, J = 8.2 Hz, 1H), 4.02 (s, 3H). 13C NMR
(CD3OD): δ 164.8, 158.9, 153.6, 149.5, 143.7, 143.5, 136.8,
134.7, 130.9, 130.3, 126.9, 126.8, 125.5, 119.4, 118.9, 115.1,
114.8, 111.2, 54.2. IR: 3357, 2917, 2849, 1586, 1493 cm-1. MS
(ESI): 344 (M þ H)þ.
6-(3-Hydroxyphenyl)-1-(pyridin-4-yl)-2-naphthol (4). The title
compound was prepared by reaction of 1-bromo-6-(3-hydro-
xyphenyl)-2-naphthol 1a (100 mg, 0.32 mmol, 1 equiv) with
pyridine-4-boronic acid (39 mg, 0.32 mmol, 1 equiv) in toluene/
ethanol 5:1 at 100 ꢀC for 1 h according to Method B. The
analytically pure compound was obtained after purification by
column chromatography under pressure (hexane/ethyl acetate
8:2) in 44% yield (44 mg); C21H15NO2; MW 313. 1H NMR
(CD3OD): δ 8.95 (d, J = 6.9 Hz, 2H), 8.26 (d, J = 2.6 Hz, 2H),
8.13 (d, J = 1.9 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.77 (dd, J =
1.9 Hz, J = 8.8 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.34 (d, J =
8.8 Hz, 1H), 7.34-7.31 (m, 1H), 7.24-7.22 (m, 1H), 7.18-7.17
(m, 1H), 6.84 (ddd, J = 0.9 Hz, J = 2.2 Hz, J = 7.9 Hz, 1H). 13
C
NMR (CD3OD): δ 159.0, 153.0, 149.9, 148.1, 143.5, 137.1,
133.8, 133.1, 133.0, 131.6, 130.9, 130.0, 129.9, 128.4, 127.2,
126.8, 125.2, 119.4, 119.3, 115.2, 114.8. IR: 3080, 1631, 1596,
1580, 1359, 1276, 1201, 1179 cm-1. MS (ESI): 314 (M þ H)þ.
1,6-Bis(3-hydroxyphenyl)-2-naphthol (9). The title compound
was prepared by reaction of 1,6-dibromo-2-naphthol 9a (200 mg,
0.66 mmol, 1 equiv) with 3-hydroxyphenylboronic acid (366 mg,
2.64 mmol, 4 equiv) in toluene for 15 h according to Method B.
The analytically pure compound was obtained after purification
by column chromatography (gradient dichloromethane/metha-
nol 99:1 to 90:10) in 20% yield (43 mg); C22H16O3; MW 328. 1H
NMR (CDCl3 þ 3 drops CD3OD): δ 7.92 (d, J = 1.6 Hz, 1H),
7.76 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 1.9 Hz, J = 8.8 Hz, 1H),
7.48 (d, J = 8.8 Hz, 1H), 7.39-7.36 (m, 1H), 7.26-7.23 (m, 1H),
7.20 (d, J = 8.8 Hz, 1H), 7.16-7.14 (m, 1H), 7.11-7.10 (m, 1H),
6.92 (ddd, J = 0.9 Hz, J = 2.5 Hz, J = 8.2 Hz, 1H), 6.89-6.87
(m, 1H), 6.85-6.84 (m, 1H), 6.78 (ddd, J = 0.9 Hz, J = 2.5 Hz,
J = 7.9 Hz, 1H). 13C NMR (CDCl3 þ 3 drops CD3OD): 190.7,
157.5, 156.9, 150.3, 142.6, 135.9, 135.8, 132.5, 130.5, 129.8,
129.5, 125.7, 125.2, 122.4, 121.0, 118.9, 117.9, 117.8, 115.3,
114.0. IR: 3355, 1702, 1581, 1494, 1447, 1203, 1154 cm-1. MS
(ESI): 327 (M - H)-.
6-(3-Hydroxyphenyl)-1-(pyridin-3-yl)-2-naphthol (2). The title
compound was prepared by reaction of 1-bromo-6-(3-hydro-
xyphenyl)-2-naphthol 1a (100 mg, 0.32 mmol, 1 equiv) with
pyridine-3-boronic acid (39 mg, 0.32 mmol, 1 equiv) in toluene/
ethanol 2:1 at 80 ꢀC for 1 h according to Method B. The
analytically pure compound was obtained after purification by
column chromatography under pressure (gradient hexane/ethyl
1-(3-Aminophenyl)-6-(3-hydroxyphenyl)-2-naphthol (11). The
title compound was prepared by reaction of 3-[2-methoxy-6-(3-
methoxyphenyl)-1-naphthyl]aniline 11a (1.0 g, 2.82 mmol, 1
equiv) with boron tribromide (14.1 mL, 14.1 mmol, 5 equiv)
according to Method A. The title compound was obtained pure
in a quantitative yield (922 mg); C22H17NO2; MW 327. 1H NMR