B. X. Li et al. / Bioorg. Med. Chem. 20 (2012) 6811–6820
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General procedure B for synthesis of naphthamides through 9.
n-BuLi (2.5 M in hexanes, 0.2 mmol) was slowly added to a stirred
solution of a heteroaryl amine (0.2 mmol) in THF (1 mL) at 0 °C.
The reaction mixture was stirred at 0 °C for 30 min, when a solu-
tion of 9 (0.1 mmol) in THF (1 mL) was slowly added. The reaction
mixture was allowed to warm up to room temperature and stirred
at room temperature for 1 h. Saturated aqueous NH4Cl solution
(10 mL) was added to quench the reaction. CH2Cl2 (50 mL) was
then added to dilute the reaction mixture. The organic layer was
separated and washed with H2O (2 Â 5 mL) and brine (2 Â 5 mL).
The organic solution was dried over Na2SO4, filtered and the
solvent was removed in vacuo. The residue was triturated with
hexanes (3 mL) and the solid was collected by filtration, which
was then washed with CH2Cl2 (1 mL) to give desired amide.
J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H),
7.61 (d, J = 8.8 Hz, 2H), 7.50 (td, J = 8.0, 1.2 Hz, 1H), 7.35 (td,
J = 8.0, 1.2 Hz, 1H), 7.31 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d
165.6, 153.5, 138.4, 137.4, 135.7, 130.5, 128.7, 128.1, 126.8,
125.8, 123.8, 122.5, 122.2, 110.5, 87.7; HRESI-MS for
[C17H12INO2ÀH]À, Calcd 387.9840. Found 387.9835.
4.1.6. N-(4-Aminophenyl)-3-hydroxy-2-naphthamide (1g)
DIPEA (92 lL, 0.53 mmol) was added to a stirred solution ofacid 2
(100 mg, 0.53 mmol) in CH2Cl2 (2 mL) at room temperature. Then
BOP (234 mg, 0.53 mmol) was added. After 5 min, commercially
available tert-butyl(4-aminophenyl)carbamate (132 mg, 0.64 mmol)
and another portion of DIPEA (111 lL, 0.64 mmol) were sequentially
added to the reaction mixture. The reaction mixture was stirred at
room temperature for overnight. CH2Cl2 (100 mL) was added to di-
lute the reaction mixture, which was then washed with 1 N HCl
(2 Â 10 mL), a saturated aqueous solution of NaHCO3 (2 Â 10 mL)
and brine (20 mL). The organic solution was then dried over anhy-
drous Na2SO4 overnight, filtered and concentrated yielding a residue
that was subjected to silica gel flash chromatography, eluting with
hexanes/EtOAc (4:1) to give a light brown solid (126 mg, 63%): mp
208–210 °C. 1H NMR (400 MHz, DMSO-d6) d 11.41 (s, 1H), 10.53 (s,
1H), 9.38 (br s, 1H), 8.52 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.76 (d,
J = 8.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.46
(d, J = 8.8 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.32 (s, 1H), 1.48 (s, 9 H);
13C NMR (100 MHz, DMSO-d6) d 165.6, 159.6, 154.1, 152.8, 135.9,
132.7, 130.3, 128.8, 128.2, 126.8, 125.8, 123.8, 121.2, 118.4, 110.6,
79.0, 28.2. An aqueous solution of HCl (4 N, 2 mL, 8 mmol) was
4.1.1. N-(3-Chlorophenyl)-3-hydroxy-2-naphthamide (1b)
Amide 1b was obtained using general procedure A as a light
brown solid in 52% yield: mp 242–244 °C (Lit.18 258–261 °C). 1H
NMR (400 MHz, DMSO-d6) d 11.15 (s, 1H), 10.69 (s, 1H), 8.43 (s,
1H), 8.00 (t, J = 2.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.77 (d,
J = 8.0 Hz, 1H), 7.66 (dd, J = 8.0, 1.0 Hz, 1H), 7.51 (td, J = 6.8,
1.2 Hz), 7.41 (t, J = 8.0 Hz, 1H), 7.36 (td, J = 7.2, 1.2 Hz, 1H), 7.33
(s, 1H), 7.20 (dd, J = 8.0, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-
d6) d 165.8, 153.4, 140.1, 135.7, 133.1, 130.5, 128.7, 128.1, 126.9,
125.8, 123.8, 123.6, 122.4, 119.7, 118.7, 110.5; HRESI-MS for
[C17H12ClNO2ÀH]À, Calcd 296.0484. Found 296.0480.
4.1.2. N-(2-Chlorophenyl)-3-hydroxy-2-naphthamide (1c)
Amide 1c was obtained using general procedure A as a light
brown solid in 16% yield: mp 214–216 °C (Lit.37 225 °C). 1H NMR
(400 MHz, DMSO-d6) d 11.98 (s, 1H), 11.27 (s, 1H), 8.73 (s, 1H),
8.52 (dd, J = 8.0, 1.2 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.79 (d,
J = 8.4 Hz, 1H), 7.58 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 (t, J = 7.2 Hz,
1H), 7.42 (t, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.38 (t, J = 9.2 Hz, 1H),
7.20 (t, J = 8.0, Hz, 1H); 13C NMR (100 MHz, DMSO-d6) d 163.5,
152.7, 136.0, 135.4, 132.7, 129.4, 129.1, 128.5, 127.9, 127.2,
125.7, 125.2, 124.0, 123.3, 122.6, 120.5, 110.8; HRESI-MS for
[C17H12ClNO2ÀH]À, Calcd 296.0484. Found 296.0481.
added to
a stirred solution of Boc-protected amide (38 mg,
0.1 mmol) obtained above in THF (2 mL) at room temperature. The
resulting mixture was stirred at room temperature for overnight.
THF was removed in vacuo and H2O was azeotropically removed
with benzene. The residue was treated with Et2O (3 mL) and the pre-
cipitate was collected by filtration to give an off-white solid (25 mg,
92%): mp > 260 °C (dec). 1H NMR (400 MHz, DMSO-d6) d 11.31 (br s,
1H), 10.73 (s, 1H), 10.00 (br s, 2H), 8.49 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H),
7.86 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 6.8, 1H),
7.33–7.41 (m, 4H); 13C NMR (100 MHz, DMSO-d6) d 165.7, 153.6,
137.8, 135.7, 130.5, 128.7, 128.1, 126.8, 125.8, 123.8, 123.1, 122.0,
121.4, 110.5; HRESI-MS for [C17H14N2O2+H]+, Calcd 279.1128. Found
279.1128.
4.1.3. N-(4-Fluorophenyl)-3-hydroxy-2-naphthamide (1d)
Amide 1d was obtained using general procedure A as an off-
white solid in 69% yield: mp 256–258 °C. 1H NMR (400 MHz,
DMSO-d6/CDCl3 (1:1)) d 11.45 (s, 1H), 10.62 (s, 1H), 8.58 (s, 1H),
7.84 (d, J = 8.0 Hz, 1H), 7.73–7.77 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H),
7.46 (t, J = 7.2 Hz, 1H), 7.31 (t, J = 7.2 Hz, 1H), 7.27 (s, 1H), 7.07–
7.12 (m, 2H); 13C NMR (100 MHz, DMSO-d6/CDCl3 (1:1)) d 165.9,
4.1.7. 3-Hydroxy-N-(4-hydroxyphenyl)-2-naphthamide (1h)
DIPEA (85 lL, 0.49 mmol) was added to a stirred solution of acid
2 (92.1 mg, 0.49 mmol) in CH2Cl2 (1.6 mL) at room temperature.
Then BOP (217 mg, 0.49 mmol) was added. After 5 min, TBS-
protected 4-aminophenol38 (121.5 mg, 0.54 mmol) and another
1
158.5 (d, JCF = 240 Hz), 154.3, 135.9, 134.3, 130.3, 128.5, 127.9,
3
126.6, 125.5, 123.4, 122.4 (d, JCF = 8 Hz), 119.7, 114.9 (d,
portion of DIPEA (94 lL, 0.54 mmol) were sequentially added to
2JCF = 22 Hz), 110.6; HRESI-MS for [C17H12FNO2ÀH]À, Calcd
the reaction mixture, which was stirred at room temperature for
1 h. The resulting mixture was diluted with CH2Cl2 (70 mL) and
washed with 1 N HCl (2 Â 10 mL), a saturated aqueous solution
of NaHCO3 (2 Â 10 mL) and brine (20 mL). The organic solution
was then dried over anhydrous Na2SO4 overnight, filtered and con-
centrated yielding a brown oily liquid. The resulting residue was
subjected to silica gel flash chromatography, eluting with hex-
anes/EtOAc (10:1) to give a brown solid that was further triturated
with diethyl ether (2 mL) to yield a light brown solid (12.5 mg,
6.5%): mp 218–220 °C. 1H NMR (400 MHz, DMSO-d6) d 11.39 (s,
1H), 10.51 (s, 1H), 8.50 (s, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.76 (d,
J = 8.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.36
(t, J = 7.6 Hz, 1H), 7.32 (s, 1H), 6.88 (d, J = 8.4 Hz, 2H), 0.97 (s, 9
H), 0.20 (s, 6H); 13C NMR (100 MHz, DMSO-d6) d 165.6, 154.0,
151.5, 135.8, 132.2, 130.2, 128.7, 128.1, 126.8, 125.8, 123.7,
122.2, 121.4, 119.9, 110.55, 25.6, 18.0, À4.5. TBAF (1.0 M in THF,
280.0779. Found 280.0776.
4.1.4. N-(4-Bromophenyl)-3-hydroxy-2-naphthamide (1e)
Amide 1e was obtained using general procedure A as a light
brown solid in 29.3% yield: mp 248–250 °C (Lit.37 248–249 °C).
1H NMR (400 MHz, DMSO-d6) d 11.21 (br s, 1H), 10.67 (s, 1H),
8.45 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.75–7.77 (m, 3H), 7.57 (dd,
J = 7.6, 1.6 Hz, 2H), 7.51 (td, J = 8.0, 1.2 Hz, 1H), 7.36 (t, J = 8.0 Hz,
1H), 7.33 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d 165.7, 153.5,
138.0, 135.7, 132.0, 131.6, 130.5, 128.7, 128.1, 126.9, 125.8,
123.8, 122.3, 115.7, 110.5; HRESI-MS for [C17H12BrNO2ÀH]À, Calcd
399.9979. Found 399.9975.
4.1.5. 3-Hydroxy-N-(4-iodophenyl)-2-naphthamide (1f)
Amide 1f was obtained using general procedure A as an off-
white solid in 74% yield: mp > 190 °C (dec). 1H NMR (400 MHz,
DMSO-d6) d 11.20 (s, 1H), 10.62 (s, 1H), 8.44 (s, 1H), 7.92 (d,
70
lL) was added to a stirred solution of N-(4-tert-butyldimethyl-
silyloxyphenyl)-3-hydroxy-2-naphthamide (14.6 mg, 0.037 mmol)