N. Pradidphol et al. / European Journal of Medicinal Chemistry 49 (2012) 253e270
265
(400 MHz, CDCl3):
d
¼ 8.46 (s, 1H, ArH), 8.08e8.03 (m, 1H, ArH),
(ddd, J ¼ 8.3, 7.6, 1.0 Hz, 1H, ArH), 6.94e6.91 (m, 1H, ArH), 6.79 (s,
1H, ArH), 4.01 (s, 3H, OCH3), 3.18 (d, J ¼ 6.3 Hz, 2H, CH2eNH), 2.52
(s, 2H, CH2eAr), 0.96 (s, 6H, 2ꢃ CH3); 13C NMR (100 MHz, CDCl3):
8.01 (dd, J ¼ 2.3, 1.1 Hz, 1H, ArH), 7.99 (dd, J ¼ 2.8, 1.1 Hz, 1H, ArH),
7.93 (dd, J ¼ 6.0, 2.8 Hz, 1H, ArH), 7.88 (d, J ¼ 8.6 Hz, 1H, ArH), 7.83
(dd, J ¼ 6.3, 2.9 Hz, 1H, ArH), 7.68e7.62 (m, 2H, ArH), 7.52e7.45 (m,
2H, ArH), 4.13 (s, 3H, OCH3), 3.09 (d, J ¼ 6.4 Hz, 2H, CH2eNH), 2.60
(s, 2H, CH2eAr), 0.99 (s, 6H, 2ꢃ CH3); 13C NMR (100 MHz, CDCl3):
d
¼ 185.76 (C]O), 184.62 (C]O), 165.43 (C]O), 157.54 (C), 148.71
(C), 138.10 (CH), 133.77 (CH), 133.60 (CH), 132.55 (CH), 132.38 (CH),
132.09 (C), 132.03 (C), 126.81 (CH), 125.98 (CH), 121.71 (C), 121.13
(CH), 111.19 (CH), 55.91 (OCH3), 48.24 (CH2N), 38.22 (CH2), 36.87
~
d
¼ 186.93 (C]O), 181.14 (C]O), 167.28 (C]O), 159.81 (C), 134.70
(C), 134.00 (CH), 133.60 (CH), 132.79 (C), 132.21 (C), 131.74 (C),
131.55 (C), 131.49 (C), 129.08 (CH), 128.36 (CH), 127.69 (CH), 127.59
(CH), 127.43 (CH), 126.62 (CH), 126.55 (CH), 126.24 (CH), 123.72
(CH), 61.22 (OCH3), 47.55 (CH2N), 38.22 (CH2), 32.02 (C), 26.47 (2ꢃ
~
(C), 25.83 (2ꢃ CH3); IR (KBr): ¼ 3383 (NH), 3072 (CH), 2962 (CH3),
n
2871, 2841 (CH2), 1667, 1657, 1651 (C]O), 1598, 1538, 1484, 1470,
1328, 1302, 1274, 1240 (C]C), 1106 (CeO), 1022 (CeN); HRMS
(ESIþ): m/z [M þ Na]þ calcd for C23H23NO4: 400.1525, found:
400.1525.
CH3); IR (KBr):
n
¼ 3378 (NH), 3058 (CH), 2961, 2925 (CH3), 2870
(CH2), 1711, 1660, 1646 (C]O), 1597, 1536, 1466, 1366, 1299, 1271
(C]C), 1216 (CeN), 1129 (CeO); HRMS (ESIþ): m/z [M þ Na]þ calcd
for C27H25NO4: 450.1676, found: 450.1672.
4.1.24. N-(3-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-2,2-
dimethylpropyl)-1-methoxy-2-naphthamide (30)
To a stirred solution of naphthoquinone alcohol 20 (50 mg,
0.121 mmol) in acetone (4 mL), K2CO3 (22 mg) was added. The
reaction mixture was stirred for at room temperature until the
color of the reaction was changed from yellow to dark red. Then
Me2SO4 (0.015 mL) was added dropwise to the dark red solution
and continuously stirred for 8 h at room temperature. The reaction
mixture was cooled to 0 ꢁC, acidified with 10% HCl to pH 1, extracted
with dichloromethane (3 ꢃ 15 mL). The combined organic phases
were washed with water and brine, dried over anhydrous sodium
sulfate, filtered and the filtrate was concentrated in vacuo. The
residue was purified by flash column chromatography eluting with
15% v/v ethyl acetateehexane to afford product 30 as a yellow oil
4.1.22. 1-Methoxy-N-(3-(3-methoxy-1,4-dioxo-1,4-
dihydronaphthalen-2-yl)-2,2-dimethylpropyl)-2-naphthamide (28)
To a stirred solution of naphthoquinone alcohol 24 (20 mg,
0.045 mmol) in acetone (2.5 mL) was added K2CO3 (8.1 mg,
0.059 mmol). The reaction mixture was stirred for 1 h at room
temperature until the color of the reaction was changed from
yellow to dark red. Then Me2SO4 (0.007 mL, 0.059 mmol) was
added dropwise to the dark red solution and continuously stirred
for 6 h at room temperature. The reaction mixture was cooled to
0
ꢁC, acidified with 10% HCl to pH 1, extracted with dichloro-
methane (3 ꢃ 15 mL). The combined organic phases were washed
with water and brine, dried over anhydrous sodium sulfate, filtered
and the filtrate was concentrated in vacuo. The residue was purified
by flash column chromatography eluting with 18% v/v ethyl
acetateehexane to afford product 28 as a yellow oil (17.6 mg, 86%).
(49.7 mg, 96%). 1H NMR (400 MHz, CDCl3):
d
¼ 8.48 (t, J ¼ 6.3 Hz,1H,
NHeCH2), 8.16e8.13 (m, 1H, ArH), 8.06 (d, J ¼ 8.7 Hz, 1H, ArH),
8.04e8.01 (m, 1H, ArH), 8.00e7.97 (m, 1H, ArH), 7.82e7.79 (m, 1H,
ArH), 7.65e7.61 (m, 3H, ArH), 7.51 (dd, J ¼ 6.3, 3.3 Hz, 2H, ArH), 6.82
(s, 1H, ArH), 4.07 (s, 3H, OCH3), 3.30 (d, J ¼ 6.4 Hz, 2H, CH2eNH),
2.58 (s, 2H, CH2eAr), 1.01 (s, 6H, 2ꢃ CH3); 13C NMR (100 MHz,
1H NMR (400 MHz, CDCl3):
d
¼ 8.58 (t, J ¼ 6.2 Hz,1H, NHeCH2), 8.15
(dd, J ¼ 6.2, 3.6 Hz, 1H, ArH), 8.06 (d, J ¼ 8.7 Hz, 1H, ArH), 8.02e7.99
(m, 1H, ArH), 7.99e7.96 (m, 1H, ArH), 7.81 (dd, J ¼ 6.0, 3.4 Hz, 1H,
ArH), 7.64e7.60 (m, 3H, ArH), 7.51 (t, J ¼ 3.4 Hz, 1H, ArH), 7.49 (t,
J ¼ 3.4 Hz, 1H, ArH), 4.11 (s, 3H, OCH3), 4.06 (s, 3H, OCH3), 3.24 (d,
J ¼ 6.4 Hz, 2H, CH2eNH), 2.64 (s, 2H, CH2eAr), 0.99 (s, 6H, 2ꢃ CH3);
CDCl3):
d
¼ 191.42 (C]O), 188.21 (C]O), 184.65 (C]O), 155.29 (C),
148.55 (C), 138.27 (CH), 136.55 (C), 133.77 (CH), 133.65 (CH), 132.12
(C), 128.27 (C), 128.15 (CH), 127.75 (CH), 127.51 (C), 127.02 (CH),
126.88 (CH), 126.49 (C), 126.46 (CH), 126.05 (CH), 124.49 (CH),
122.98 (CH), 63.52 (OCH3), 48.74 (CH2N), 38.39 (CH2), 36.93 (C),
~
13C NMR (100 MHz, CDCl3):
d
¼ 186.06 (C]O),181.30 (C]O),165.94
(C]O), 159.28 (C), 155.18 (C), 136.45 (C), 133.85 (CH), 133.29 (CH),
133.03 (C), 132.11 (C),131.85 (C), 131.50 (C), 128.12 (CH),127.65 (CH),
127.61 (C),127.13 (CH),126.46 (CH),126.40 (CH),126.09 (CH),124.40
(CH), 122.97 (CH), 63.48 (OCH3), 61.09 (OCH3), 48.59 (OCH3), 37.82
~
25.83 (2ꢃ CH3); IR (KBr):
n
¼ 3381 (NH), 3060 (CH), 2963, 2929
(CH3), 2870, 2851 (CH2), 1663 (C]O), 1595, 1531, 1521, 1451, 1370,
1333,1300,1272 (C]C),1205 (CeN),1081 (CeO); HRMS (ESIþ): m/z
[M þ H]þ calcd for C27H25NO4: 450.1681, found: 450.1686.
(CH2), 32.31 (C), 26.28 (2ꢃ CH3); IR (KBr): ¼ 3380 (NH), 3060 (CH),
n
2961, 2928 (CH3), 2870, 2850 (CH2), 1660, 1644, 1634 (C]O), 1596,
1538, 1520, 1455, 1371, 1338, 1273 (C]C), 1216 (CeN), 1082 (CeO);
HRMS (ESIþ): m/z [M þ Na]þ calcd for C28H27NO5: 480.1781, found:
480.1779.
4.1.25. N-(3-(3-Hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-
2,2-dimethylpropyl)-2-methoxybenzamide (31)
A mixture of naphthoquinone 29 (40 mg, 0.106 mmol), tert-
butyl hydroperoxide (TBHP) (70% in H2O) (0.14 mL, 0.954 mmol) in
THF (2 mL) was stirred at room temperature for 15 min. Triton B
(40% in H2O) (0.13 mL, 0.318 mmol) was added dropwise to the
reaction mixture and continuously stirred for 10 min. The reaction
mixture was cooled to 0 ꢁC, acidified with 10% HCl to pH 1, extracted
with dichloromethane (3 ꢃ 15 mL). The combined organic phases
were washed with water and brine, dried over anhydrous sodium
sulfate, filtered and the filtrate was concentrated in vacuo. The
residue was purified by flash column chromatography eluting with
15% v/v ethyl acetateehexane to afford product 31 as a yellow solid
4.1.23. N-(3-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-2,2-
dimethylpropyl)-2-methoxybenzamide (29)
To the stirred solution of naphthoquinone alcohol 18 (50 mg,
0.138 mmol) in acetone (4 mL) K2CO3 (25 mg) was added. The
reaction mixture was stirred for at room temperature until the
color of the reaction was changed from yellow to dark red. Then
Me2SO4 (0.017 mL) was added dropwise to the dark red solution
and continuously stirred for 8 h at room temperature. The reaction
mixture was cooled to 0 ꢁC, acidified with 10% HCl to pH 1, extracted
with dichloromethane (3 ꢃ 15 mL). The combined organic phases
were washed with water and brine, dried over anhydrous sodium
sulfate, filtered and the filtrate was concentrated in vacuo. The
residue was purified by flash column chromatography eluting with
15% v/v ethyl acetateehexane to afford product 29 as a yellow oil
(36.27 mg, 87%). mp: 162 ꢁC; 1H NMR (400 MHz, CDCl3):
d
¼ 8.71 (t,
J ¼ 5.8 Hz,1H, NHeCH2), 8.19 (dd, J ¼ 7.8,1.8 Hz,1H, ArH), 8.12e8.09
(m, 1H, ArH), 8.09e8.06 (m, 1H, ArH), 7.74 (td, J ¼ 7.5, 1.5 Hz, 1H,
ArH), 7.70e7.63 (m, 2H, ArH and OH), 7.42 (ddd, J ¼ 8.2, 7.4, 1.9 Hz,
1H, ArH), 7.05 (td, J ¼ 7.8, 0.9 Hz, 1H, ArH), 6.98 (d, J ¼ 8.3 Hz, 1H,
ArH), 4.05 (s, 3H, OCH3), 3.23 (d, J ¼ 6.4 Hz, 2H, CH2eNH), 2.64 (s,
2H, CH2eAr), 1.01 (s, 6H, 2ꢃ CH3); 13C NMR (100 MHz, CDCl3):
(48.9 mg, 94%). 1H NMR (400 MHz, CDCl3):
d
¼ 8.45 (t, J ¼ 5.7 Hz,1H,
NHeCH2), 8.12 (dd, J ¼ 7.8, 1.9 Hz, 1H, ArH), 8.03e7.97 (m, 2H, ArH),
d
¼ 185.43 (C]O), 181.09 (C]O), 165.48 (C]O), 157.63 (C), 154.67
7.66e7.63 (m, 2H, ArH), 7.37 (ddd, J ¼ 8.3, 7.3, 1.9 Hz, 1H, ArH), 7.00
(C), 134.95 (CH), 133.03 (CH), 132.86 (C), 132.38 (2ꢃ CH), 129.38 (C),