3976 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 12
Mewshaw et al.
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solid: mp 163-165 °C; H NMR (CDCl3) δ 3.88 (3H, s), 3.96
Hz, J ) 1.41 Hz), 8.09 (1H, s), 8.21 (1H, d, J ) 8.97 Hz), 10.18
(1H, bs), 11.25 (1H, bs); MS (ESI) m/z 312 (M - H)-. Anal.
(C17H9ClFNO2‚0.1H2O) C, H, N.
(3H, s), 7.01-7.06 (2H, m), 7.39 (1H, d, J ) 2.40 Hz), 7.59
(1H, d, J ) 2.50 Hz), 7.65-7.70 (2H, m), 7.81 (1H, dd, J )
8.59 Hz, J ) 1.64 Hz), 7.85 (1H, d J ) 8.51 Hz), 8.26 (1H, s).
Anal. (C19H15NO2) C, H, N.
7-(3-Fluoro-4-methoxyphenyl)-3-methoxy-1-naphthoni-
trile (152). Treatment of 150 (0.71 g, 2.14 mmol) with 3-fluoro-
4-methoxyphenylboronic acid7,8 according to method A afforded
0.48 g (73%) a white solid: mp 204-207 °C; 1H NMR (CDCl3)
δ 3.97 (6H, s), 7.06-7.12 (1H, m), 7.40 (1H, d, J ) 2.44 Hz),
7.45-7.50 (2H, m), 7.60 (1H, d, J ) 2.55 Hz), 7.77 (1H, dd, J
) 8.58 Hz, J ) 1.80 Hz), 7.76 (1H, d, J ) 9.57 Hz), 8.24-8.25
(1H, m). Anal. (C19H14FNO2) C, H, N.
4-Bromo-7-(3-fluoro-4-methoxyphenyl)-3-methoxy-1-
naphthonitrile (153). A solution of 152 (0.98 g, 3.19 mmol)
and bromine (0.56 g, 3.5 mmol) in acetic acid (10 mL) was
heated to 100 °C overnight in a pressure flask. The flask was
cooled to room temperature and the reaction was poured into
300 mL of water. The resulting dark yellow solid was collected
by filtration and triturated with THF to yield 0.83 g (69%) of
the product as a yellow solid: mp 192-194 °C; 1H NMR
(CDCl3) δ 3.97 (3H, s), 4.07 (3H, s), 7.07-7.12 (1H, m), 7.46-
7.50 (2H, m), 7.64 (1H, s), 7.87 (1H, dd, J ) 8.92 Hz, J ) 1.81
Hz), 8.26 (1H, d, J ) 1.43 Hz), 8.35 (1H, d, J ) 8.92 Hz); MS
(EI) m/z 385 (M•)+. Anal. (C19H13BrFNO2) C, H, N.
6-(3-Fluoro-4-methoxyphenyl)-2-methoxynaphthalene-
1,4-dicarbonitrile (154). A mixture of 153 (0.48 g, 1.24
mmol), Zn(CN)2 (0.10 g, 0.87 mmol), tris(dibenzylideneacetone-
)dipalladium(0) (0.11 g, 0.12 mmol), zinc dust (0.039 g, 0.62
mmol), and dppf (0.069 g, 0.12 mmol) in DMF (15 mL) was
stirred for 3 h at 120 °C. The reaction was cooled to room
temperature and poured into 200 mL of 1 N NaOH. The
resulting dark gray solid was collected by filtration. The crude
product was filtered through a silica pad (50%THF/hexanes)
and the filtrate was concentrated. The product was further
purified by trituration to yield 0.33 g (80%) of a yellow solid:
mp >220 °C; 1H NMR (CDCl3) δ 3.98 (3H, s), 4.14 (3H, s),
7.09-7.13 (1H, m), 7.46-7.49 (2H, m), 7.69 (1H, s), 7.98 (1H,
dd, J ) 8.73 Hz, J ) 1.36 Hz), 8.24 (1H, d, J ) 8.79 Hz), 8.30
(1H, s); MS (EI) m/z 332 (M•)+. Anal. (C20H13FN2O2) calcd, C:
72.28 N: 8.43; found, C: 70.26 N: 6.66.
3-Hydroxy-7-(4-hydroxyphenyl)-1-naphthonitrile (61).
Compound 151 (0.42 g, 1.45 mmol) was reacted with pyri-
dinium HCl according to method D to yield 0.30 g (80%) of a
1
light yellow solid: mp >250 °C; H NMR (DMSO-d6) δ 6.90-
6.94 (2H, m), 7.53 (1H, d, J ) 2.27 Hz), 7.60-7.64 (2H, m),
7.68 (1H, d, J ) 2.39 Hz), 7.85 (1H, dd, J ) 8.67 Hz, J ) 1.72
Hz), 7.95 (1H, d, J ) 8.68 Hz), 8.02 (1H, d, J ) 0.68 Hz), 9.69
(1H, s), 10.43 (1H, s); MS (ESI) m/z 260 (M - H)-. Anal.
(C17H11NO2) C, H, N.
7-(3-Fluoro-4-hydroxyphenyl)-3-hydroxy-1-naphthoni-
trile (62). Compound 152 (0.34 g, 1.11 mmol) was treated with
pyridine HCl according to method D to afford 0.27 g (88%) of
a light yellow solid: mp >250 °C; 1H NMR (DMSO-d6) δ 7.07-
7.13 (1H, m), 7.45 (1H, dd, J ) 8.38 Hz, J ) 1.64 Hz), 7.54
(1H, d, J ) 2.26 Hz), 7.61 (1H, dd, J ) 12.70 Hz, J ) 2.20 Hz),
7.69 (1H, d, J ) 2.39 Hz), 7.87 (1H, dd, J ) 8.68 Hz, J ) 1.73
Hz), 7.96 (1H, d, J ) 8.70 Hz), 8.04 (1H, d, J ) 0.63 Hz), 10.26
(2H, bs); MS (ESI) m/z 278 (M - H)-. Anal. (C17H10FNO2‚
0.3H2O) C, H, N.
6-(3-Fluoro-4-hydroxyphenyl)-2-hydroxynaphthalene-
1,4-dicarbonitrile (64). Treatment of 154 (0.10 g, 0.31 mmol)
with pyridinium HCl according to method D yielded 0.070 g
(74%) of a yellow solid: 1H NMR (DMSO-d6) δ 7.10-7.14 (1H,
m), 7.47-7.49 (1H, m), 7.65 (1H, dd, J ) 12.60 Hz, J ) 2.21
Hz), 7.81 (1H, s), 8.03 (1H, dd, J ) 7.74 Hz, J ) 1.76 Hz),
8.13-8.15 (2H, m), 10.19 (1H, s), 12.41 (1H, s); MS (ESI) m/z
303 (M - H)-. Anal. (C18H9FN2O2) C, H, N: calcd, C: 71.05
N: 9.21; found, C: 66.20 N: 8.00.
4-Bromo-7-(3-fluoro-4-hydroxyphenyl)-3-hydroxy-1-
naphthonitrile (63). A solution of 62 (0.82 g, 2.94 mmol) and
NBS (0.55 g, 3.1 mmol) in THF (30 mL) was stirred overnight
at room temperature, according to the procedure used to
prepare 16, to yield 0.82 g (78%) of a white solid: mp >250
1
°C; H NMR (DMSO-d6) δ 7.110-7.14 (1H, m), 7.48 (1H, d, J
) 7.94 Hz), 7.64 (1H, d, J ) 12.30 Hz), 7.79 (1H, s), 8.04-8.09
(2H, m), 8.21 (1H, d J ) 8.84 Hz), 10.17 (1H, s), 11.32 (1H, s);
MS (ESI) m/z 356 (M - H)-. Anal. (C17H9BrFNO2‚0.1H2O) C,
H, N.
3-[[tert-Butyl(dimethyl)silyl]oxy]-7-(4-[[tert-butyl(di-
methyl)silyl]oxy]-3-fluorophenyl)-1-naphthonitrile (155).
The title compound was prepared by reacting 62 (2.28 g, 8.17
mmol) with TBDMSCl (4.9 g, 32.7 mmol) according to the
procedure used to prepared compound 101 to yield 2.44 g
7-(3-Fluoro-4-hydroxyphenyl)-3-hydroxy-4-methyl-1-
naphthonitrile (65). A solution of 63 (0.22 g, 0.61 mmol),
tetramethyltin (0.16 g, 0.9 mmol), and dichlorobis(tri-o-
tolylphosphine)palladium(II) (0.048 g, 0.006 mmol) in DMF (3
mL) was stirred overnight at 80 °C. The reaction was cooled
to room temperature, poured into 50 mL of 1 N NH4Cl, and
extracted with ethyl acetate (2 × 75 mL). The combined
organic layers were washed with water, dried over sodium
sulfate, filtered, concentrated, and the product was purified
on silica (30% ethyl acetate/hexanes) to yield 0.10 g (56%) of
1
(59%) of a white solid: mp 112-114 °C; H NMR (CDCl3) δ
0.24 (3H, s), 0.25 (3H, s), 0.28 (6H, s), 1.03 (9H, s), 1.04 (9H,
s), 7.00-7.05 (1H, m), 7.35-7.39 (1H, m), 7.41-7.46 (2H, m),
7.51 (1H,d, J ) 2.38 Hz), 7.75 (1H, dd, J ) 8.61 Hz, J ) 1.66
Hz), 7.81 (1H, d, J ) 8.61 Hz), 8.25 (1H, s); MS (EI) m/z 507.2
(M•)+. Anal. (C29H38FNO2Si2) C, H, N: calcd, 68.59; found,
68.00.
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a white solid: mp >250 °C; H NMR (acetone-d6) δ 2.63 (3H,
3-[[tert-Butyl(dimethyl)silyl]oxy]-7-(4-[[tert-butyl(di-
methyl)silyl]oxy]-3-fluorophenyl)-1-naphthaldehyde (156).
The title compound was prepared by reacting 155 (2.27 g, 4.47
mmol) with DIBAL (4.9 mL of 1 N solution, 4.9 mmol)
according to the procedure used to prepare compound 143 to
s), 7.15-7.19 (1H, m), 7.50-7.53 (1H, m), 7.60 (1H, dd, J )
12.43 Hz, J ) 2.18 Hz), 7.72 (1H, s), 7.94 (1H, dd, J ) 8.84
Hz, J ) 1.92 Hz), 8.17 (1H, dd, J ) 8.97 Hz, J ) 0.51 Hz),
8.21 (1H, d, J ) 1.54 Hz), 8.95 (2H, bs); MS (ESI) m/z 292 (M
- H)-. Anal. (C18H12FNO2‚0.1H2O) C, H, N.
1
yield 1.13 g (49%) of a yellow solid: mp 67-68 °C; H NMR
(CDCl3) δ 0.24 (3H, s), 0.25 (3H, s), 0.30 (6H, s), 1.04 (9H, s),
1.05 (9H, s), 6.99-7.04 (1H, m), 7.38-7.41 (1H, m), 7.43-7.48
(2H, m), 7.58 (1H, d, J ) 2.52 Hz), 7.74 (1H, dd, J ) 8.59 Hz,
J ) 1.78 Hz), 7.81 (1H, d, J ) 8.60 Hz), 9.32 (1H, d, J ) 1.20
Hz), 10.36 (1H, s). Anal. (C29H39FO3Si2) C, H: calcd, 68.19;
found, C: 67.65.
7-(3-Fluoro-4-hydroxyphenyl)-3-hydroxy-1-naphthal-
dehyde (70). The title compound was prepared by reacting
156 (0.21 g, 0.41 mmol) with TBAF in THF according to
method G to yield 0.080 g (68%) of a yellow solid: mp >250
°C; 1H NMR (DMSO-d6) δ 7.07-7.11 (1H, m), 7.43-7.46 (1H,
m), 7.50 (1H, d, J ) 2.46 Hz), 7.58 (1H, dd, J ) 12.81 Hz, J )
2.20 Hz), 7.74 (1H, d, J ) 2.58 Hz), 7.82 (1H, dd, J ) 8.61 Hz,
J ) 1.88 Hz), 7.91 (1H, d, J ) 8.67 Hz), 9.17-9.18 (1H, m),
10.03 (1H, s), 10.24 (1H, s), 10.45 (1H, s); MS (ESI) m/z 281
(M - H)-. Anal. (C17H11FO3‚0.5H2O) C, H.
4-Chloro-3-hydroxy-7-(4-hydroxyphenyl)-1-naphthoni-
trile (66). Treatment of 61 (0.24 g, 0.92 mmol) with NCS (0.15
g, 1.10 mmol) in THF (10 mL) at room temperature according
to method E yielded 0.15 g (56%) of a yellow solid: mp >250
°C; 1H NMR (DMSO-d6) δ 6.94 (2H, d, J ) 8.59 Hz), 7.77 (2H,
d, J ) 8.61 Hz), 7.83 (1H, s), 8.04 (1H, dd, J ) 8.89 Hz, J )
1.70 Hz), 8.08 (1H, d, J ) 1.16 Hz), 8.22 (1H, d, J ) 8.87 Hz),
9.75 (1H, bs), 11.24 (1H, bs); MS (ESI) m/z 294 (M - H)-. Anal.
(C17H10ClNO2‚0.3H2O) C, H, N.
4-Chloro-7-(3-fluoro-4-hydroxyphenyl)-3-hydroxy-1-
naphthonitrile (67). Reacting 62 (0.13 g, 0.47 mmol) with
NCS (0.079 g, 0.6 mmol) in THF (10 mL) at room temperature
according to method E produced 0.063 g (43%) of a white
solid: mp >250 °C; 1H NMR (DMSO-d6) δ 7.10-7.12 (1H, m),
7.48 (1H, dd, J ) 8.39 hz, J ) 1.60 Hz), 7.64 (1H, dd, J )
12.62 Hz, J ) 1.98 Hz), 7.83 (1H, s), 8.05 (1H, dd, J ) 8.97