Journal of Medicinal Chemistry
ARTICLE
Compounds 18ꢀ21 were prepared from 43b according to the
method described for 8.
6.8 Hz, 3 H), 7.36 (s, 1 H), 7.00 (s, 1 H), 6.29 (d, J = 9.3 Hz, 1 H), 6.08
(s, 1 H), 3.89 (s, 3 H); 13C NMR (150 MHz, CDCl3) δ 161.4, 156.4,
155.3, 143.6, 135.4, 129.7, 129.3, 129.3, 128.7, 126.3, 113.7, 113.0, 103.8;
MS m/z 239 (M + H)+. HRMS Calcd for C15H11O3 (M + H)+ 239.0702.
Found 239.0703.
Compound 18. Yield 66%; orange crystals (ethyl acetate); mp
71 °C; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 9.3 Hz, 1 H), 7.49
(d, J = 7.3 Hz, 2 H), 7.42 (t, J = 7.3 Hz, 2 H), 7.33 (t, J = 7.3 Hz, 1 H), 7.24
(s, 1 H), 6.87 (s, 1 H), 6.21 (d, J = 9.3 Hz, 1 H), 2.64 (s, 6 H); 13C NMR
(150 MHz, CDCl3) δ 161.8, 155.0, 154.8, 143.6, 140.9, 131.0, 129.9,
128.9, 128.4, 127.2, 112.5, 112.1, 104.4, 43.0; MS m/z 288 (M + Na+).
HRMS Calcd for C17H15NNaO2 (M + Na+) 288.0995. Found 288.0990.
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Compound 25 was prepared similarly. Yield 33%; yellow solid; H
NMR (400 MHz, CDCl3) δ 7.68 (d, J = 9.3 Hz, 1 H), 7.30 (s, 1 H), 7.29
(d, J = 8.3 Hz, 2 H), 6.94 (s, 1 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.26 (d, J =
9.8 Hz, 1 H), 5.87 (s, 1 H), 3.02 (s, 6 H); 13C NMR (150 MHz, CDCl3)
δ 161.5, 156.6, 154.9, 150.6, 143.7, 130.0, 128.9, 126.5, 122.2, 113.4, 113.3,
112.9, 103.4, 40.6; MS m/z 282 (M + H)+. HRMS Calcd for C17H16NO3
(M + H)+ 282.1124. Found 282.1117.
Anal. Calcd for C17H15NO2 1/4H2O: C, 75.68; H, 5.79; N, 5.19. Found:
3
C, 75.74; H, 5.63; N, 5.06.
Compound 19. Yield 35%; yellow crystals (ethyl acetate); mp
185 °C; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 2H), 7.64
(d, J = 8.8 Hz, 2 H), 7.61 (d, J = 9.3 Hz, 1 H), 7.24 (s, 1 H), 6.89 (s, 1 H),
6.24 (d, J = 9.3 Hz, 1 H), 2.64 (s, 6 H); 13C NMR (125 MHz, CDCl3)
δ 161.2, 155.4, 154.4, 145.5, 143.0, 132.6, 130.8, 128.9, 127.7, 118.8,
113.0, 112.3, 110.8, 104.8, 43.1; MS m/z 284 (MH+). HRMS Calcd
for C18H15N2O2 (MH+) 291.1128. Found 291.1131. Anal. Calcd for
C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C, 74.28; H, 4.91; N, 9.49.
Compound 20. Yield 85%; orange crystals (ethyl acetate); mp
125 °C; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 9.3 Hz, 1 H), 7.47
(dd, J = 8.8, 5.4 Hz, 2 H), 7.21 (s, 1 H), 7.11 (dd, J = 8.8, 6.3 Hz, 2 H),
6.87 (s, 1 H), 6.22 (d, J = 9.3 Hz, 1 H), 2.63 (s, 6 H); 13C NMR (150
MHz, CDCl3) δ 162.9, 161.7, 161.3, 155.0, 154.8, 143.4, 136.7, 130.8,
130.1, 130.0, 129.0, 115.9, 115.7, 112.8, 112.3, 104.7, 43.0; MS m/z 284
(M + H)+. HRMS Calcd for C17H15FNO2 (M + H)+ 284.1081. Found
284.1079. Anal. Calcd for C17H14FNO2: C, 72.07; H, 4.98; N, 4.94.
Found: C, 72.00; H, 4.98; N, 4.87.
Compound 21. Yield 29%; yellow crystals (methanol); mp 147 °C;
1H NMR (400 MHz, CDCl3) δ 7.84 (t, J = 1.4 Hz, 1 H), 7.76 (dt, J = 7.8,
1.4 Hz, 1 H), 7.62 (dt, J = 7.8, 1.4 Hz, 1 H), 7.61 (d, J = 9.2 Hz, 1 H), 7.54
(t, J = 7.8 Hz, 1 H), 7.23 (s, 1 H), 6.90 (s, 1 H), 6.25 (d, J = 9.2 Hz, 1 H),
2.63 (s, 6 H). HRMS Calcd for C18H15N2O2 (M + H)+ 291.1128. Found
291.1120. Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65.
Found: C, 74.19; H, 4.96; N, 9.48.
Compounds 26ꢀ33 and 35ꢀ38 were prepared from 43d according
to the method described for 8.
Compound 26. Yield 41%; colorless crystals (ethyl acetate/n-hexane);
mp 112 °C; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 9.3 Hz, 1 H),
7.56 (dd, J = 8.5, 2.0 Hz, 1 H), 7.67 (d, J = 2.0 Hz, 1 H), 7.58 (d, J =
7.3 Hz, 2 H), 7.47 (t, J = 7.3 Hz, 2 H), 7.41 (d, J = 8.8 Hz, 1 H), 7.40
(d, J = 7.3 Hz, 1 H), 6.47 (d, J = 9.3 Hz, 1 H); 13C NMR (150 MHz,
CDCl3) δ 160.9, 153.6, 143.7, 139.6, 138.0, 130.9, 129.2, 128.0, 127.2,
126.2, 119.2, 117.5, 117.2; MS m/z 223 (M + H)+. HRMS Calcd for
C15H11O2 (M + H)+ 223.0753. Found 223.0754.
Compound 27. Yield 67%; colorless solid (ethyl acetate/n-hexane);
1H NMR (400 MHz, CDCl3) δ 7.76 (m, 4 H), 7.70 (m, 3 H), 7.45 (d, J =
8.3 Hz, 1 H), 6.51 (d, J = 9.8 Hz, 1 H); 13C NMR (150 MHz, CDCl3)
δ 160.4, 154.4, 144.0, 143.2, 135.9, 133.0, 130.8, 127.8, 126.6, 119.5,
118.8, 117.9, 117.8, 111.7; MS m/z 248 (M + H)+. HRMS Calcd for
C16H10NO2 (M + H)+ 248.0706. Found 248.0705. Anal. Calcd for
C16H9NO2: C, 77.72; H, 3.67; N, 5.67. Found: C, 77.42; H, 3.91; N, 5.68.
Compound 28. Yield 62%; yellow solid (ethyl acetate/n-hexane);
1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 9.8 Hz, 1 H), 7.71 (dd, J =
8.3, 2.0 Hz, 1 H), 7.61 (d, J = 2.0 Hz, 1 H), 7.49 (d, J = 8.8 Hz, 2 H), 7.36
(d, J = 8.3 Hz, 1 H), 6.82 (d, J = 7.8 Hz, 2 H), 6.44 (d, J = 9.3 Hz, 1 H),
3.02 (s, 6 H); 13C NMR (150 MHz, CDCl3) δ 161.4, 152.8, 150.3, 143.9,
138.1, 130.2, 127.8, 124.9, 119.2, 117.2, 116.9, 112.9, 40.7; MS m/z 266
(M + Na+). HRMS Calcd for C17H16NO2 (M + H)+ 266.1175. Found
Compounds 22 and 24 were prepared from 43c according to the
synthetic method for 8.
266.1181. Anal. Calcd for C17H15NO2 1/6H2O: C, 76.10; H, 5.76, N,
Compound 22. Yield 70%; colorless crystals (ethyl acetate/
3
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5.22. Found: C, 76.00; H, 5.60; N, 5.22.
n-hexane); mp 133 °C; H NMR (400 MHz, CDCl3) δ 7.67 (d, J =
Compound 29. Yield 21%; colorless solid (ethyl acetate/n-hexane);
1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 9.3 Hz, 1 H), 7.70 (dd, J =
8.8, 2.4 Hz, 1 H), 7.62 (d, J = 2.4 Hz, 1 H), 7.54 (dd, J = 8.8, 4.9 Hz, 2 H),
7.41 (d, J = 8.3 Hz, 1 H), 7.16 (t, J = 8.5 Hz, 2 H), 6.48 (d, J = 9.3 Hz,
1 H); 13C NMR (125 MHz, CDCl3) δ 163.7, 161.7, 160.6, 153.4, 143.3,
136.9, 135.6, 130.6, 128.7, 125.9, 119.1, 117.3, 116.0; MS m/z241 (M + H)+.
HRMS Calcd for C15H10FO2 (M + H)+ 241.0659. Found 241.0652.
Compound 30. Yield 63%; colorless crystals (ethyl acetate); mp
170 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (t, J = 1.5 Hz, 1 H), 7.81
(dt, J = 7.8, 1.5 Hz, 1 H), 7.78 (d, J = 9.3 Hz, 1 H), 7.73 (dd, J = 8.8, 2.4 Hz,
1 H), 7.68 (dt, J = 7.8, 1.5 Hz, 1 H), 7.59 (dd, J = 7.8, 7.3 Hz, 1 H), 7.45
(d, J = 8.8 Hz, 1 H), 6.51 (d, J = 9.8 Hz, 1 H); 13C NMR (150 MHz,
CDCl3) δ 160.6, 154.0, 143.4, 140.7, 135.5, 131.5, 131.3, 130.7, 130.6,
130.0, 126.4, 119.4, 118.7, 117.9, 117.6, 113.2; MS m/z 248 (M + H)+,
270 (M + Na+). HRMS Calcd for C16H9NO2Na (M + Na+) 270.0525.
Found 270.0525. Anal. Calcd for C16H9NO2: C, 77.72; H, 3.67; N, 5.67.
Found: C, 77.54; H, 3.96; N, 5.83.
Compound 31. Yield 37%; colorless powder (ethyl acetate/n-hexane);
mp 162 °C; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 9.8 Hz, 1 H),
7.71 (dd, J = 8.8, 2.0 Hz, 1 H), 7.65(d, J = 2.0 Hz, 1 H), 7.43 (d, J =
8.8 Hz, 1 H), 7.10 (dd, J = 7.2, 2.0 Hz, 2 H), 6.84 (tt, J = 8.8, 2.2 Hz, 2 H),
6.50 (d, J = 9.3 Hz, 1 H); 13C NMR (150 MHz, CDCl3) δ 164.4, 164.3,
162.7, 162.6, 160.4, 154.1, 143.3, 142.8, 142.7, 142.7, 135.5, 135.5, 130.5,
126.3, 119.3, 117.7, 117.6, 110.2, 110.1, 110.0, 110.0, 103.3, 103.2,
103.0; MS m/z 259 (M + H)+. HRMS Calcd for C15H9F2O2 (M + H)+
9.3 Hz, 1 H), 7.48 (d, J = 6.8 Hz, 2 H), 7.43 (dd, J = 7.3, 6.8 Hz, 2 H), 7.37
(d, J = 7.3 Hz, 1 H), 6.91 (s, 1 H), 6.57 (d, J = 9.3 Hz, 1 H), 3.89 (s, 3 H);
13C NMR (150 MHz, CDCl3) δ 161.3, 160.0, 155.4, 143.6, 136.9, 129.6,
129.5, 128.5, 128.4, 127.7, 113.6, 112.5, 99.5, 56.3; MS m/z 275 (M + Na+).
HRMS Calcd for C16H12O3Na (M + Na+) 275.0678. Found 275.0683.
Anal. Calcd for C16H12O3: C, 76.18; H, 4.79. Found: C, 75.90; H, 4.98.
Compound 24. Yield 25%; yellow crystals (ethyl acetate/n-hexane);
mp 152 °C; 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 9.3 Hz, 1 H),
7.40 (d, J = 8.3 Hz, 2 H), 7.36 (s, 1 H), 6.88 (s, 1 H), 6.79 (d, J = 7.8 Hz,
2 H), 6.26 (d, J = 9.3 Hz, 1 H), 3.88 (s, 3 H), 3.00 (s, 6 H); 13C NMR
(150 MHz, CDCl3) δ 161.5, 160.1, 154.8, 150.1, 143.8, 130.3, 128.9,
128.8, 128.6, 113.3, 112.5, 112.3, 99.3, 56.2, 40.7; MS m/z 296 (M + H)+.
HRMS Calcd for C18H18NO3 (M + H)+ 296.1281. Found 296.1276.
Anal. Calcd for C18H17NO3: C, 73.2; H, 5.80; N, 4.74. Found: C, 72.96;
H, 5.93; N, 4.85.
Synthesis of 23. Boron tribromide (1 M in dichloromethane,
0.60 mL, 0.60 mmol) was added to a solution of 22 (27 mg, 0.108 mmol)
in dichloromethane (2 mL) at ꢀ78 °C under argon. The mixture was
stirred at room temperature for 1 day, then poured into water and extra-
cted with ethyl acetate. The organic layer was washed with water and
brine, dried over magnesium sulfate, and filtered. The solvent was removed
in vacuo, and the residue was purified by preparative thin-layer chro-
matography (silica gel, ethyl acetate/n-hexane = 1/4) to give 23 (2.0 mg,
1
0.0084 mmol, 8%) as a white powder. H NMR (400 MHz, CDCl3)
δ 7.66 (d, J = 9.3 Hz, 1 H), 7.53 (dd, J = 7.3 Hz, 2 H), 7.45 (dd, J = 7.8,
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dx.doi.org/10.1021/jm2005404 |J. Med. Chem. 2011, 54, 7055–7065