6352 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 17
Lee et al.
purified by flash column chromatography on silica gel (hexane/
CH2Cl2, 2:1) to afford the desired product 63b (0.17 g, 89%) as a
white solid. MS (ESI) m/z 374 [M þ H]þ. 1H NMR (400 MHz,
DMSO-d6) δ 8.42 (d, J = 3.2 Hz, 1H), 7.96-7.92 (m, 3H), 7.71
(t, J = 7.4 Hz, 1H), 7.09 (s, 2H), 3.80 (s, 6H), 3.79 (s, 3H).
(3-Fluoro-50-hydroxybiphenyl-4-yl)(3,4,5-trimethoxyphenyl)-
methanone (63c). This compound was made using the synthetic
procedure described for 63a. Thus 55 (80 mg, 0.22 mmol),
3-hydroxyphenylboronic acid (45 mg, 0.33 mmol), Pd(dppf)Cl2
(9 mg, 0.01 mmol), and sodium carbonate (46 mg, 0.43 mmol)
were used. Purification of the residue by flash column chroma-
tography on silica gel (hexane/EtOAc, 3:1-2:1) afforded the
desired product 63c (60 mg, 71%) as a white solid. MS (ESI) m/z
383 [M þ H]þ. 1H NMR (400 MHz, CDCl3) δ 7.58 (t, J = 7.5
Hz, 1H), 7.46 (dd, J = 8.0, 1.6 Hz, 1H), 7.34 (m, 2H), 7.20 (d,
J = 6.8 Hz, 1H), 7.14 (s, 2H), 7.11 (s, 1H), 6.90 (m, 1H), 5.31
(brs, 1H), 3.95 (s, 3H), 3.87 (s, 6H).
synthetic procedure described for 19. Thus 63b (50 mg, 0.13
mmol) and sodium 1,2,4-triazole (37 mg, 0.4 mmol) were used.
Purification of the residue by flash column chromatography on
silica gel (hexane/EtOAc, 1:1-1:2) afforded the desired product
20 (29 mg, 53%) as a white solid. MS (ESI) m/z 423 [M þ H]þ.
1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.33 (d, J = 1.7
Hz, 1H), 8.21 (dd, J = 8.0, 1.7 Hz, 1H), 8.06 (d, J = 3.2 Hz, 1H),
7.99 (s, 1H), 7.97 (d, J = 3.2 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H),
6.89 (s, 2H), 3.74 (s, 6H), 3.72 (s, 3H). 13C NMR (100 MHz,
DMSO-d6) δ 192.68, 165.26, 153.05, 152.80, 144.98, 144.81,
142.69, 136.32, 135.85, 134.73, 131.62, 131.42, 126.74, 122.81,
121.92, 106.94, 60.64, 56.48. HRMS (EI) calcd for C21H18N4-
O4S [M]þ 422.1048, found 422.1043. HPLC (method 1) 100%
(tR = 6.02 min).
(50-Hydroxy-3-(1H-1,2,4-triazol-1-yl)biphenyl-4-yl)(3,4,5-tri-
methoxyphenyl)methanone (21). This compound was made using
the synthetic procedure described for 19. Thus 63c (57 mg, 0.15
mmol) and sodium 1,2,4-triazole (41 mg, 0.45 mmol) were used.
Purification of the residue by flash column chromatography on
silica gel (hexane/EtOAc, 1:1-1:2) afforded the desired product
21 (5 mg, 8%) as a white solid. MS (ESI) m/z 432 [M þ H]þ. 1H
NMR (400 MHz, CDCl3) δ 8.3 (s, 1H), 7.94 (s, 1H), 7.80 (m,
1H), 7.76 (dd, J = 8.0, 1.7 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.36
(t, J = 7.8 Hz, 1H), 7.23 (m, 1H), 7.14 (m, 1H), 6.99 (s, 2H), 6.92
(m, 1H), 3.90 (s, 3H), 3.81 (s, 6H). 13C NMR (100 MHz, DMSO-
d6) 193.07, 158.47, 158.32, 153.00, 152.65, 144.82, 143.93,
142.41, 139.75, 135.68, 132.41, 131.91, 131.00, 130.65, 127.06,
122.51, 118.39, 118.36, 116.15, 116.05, 114.36, 114.27, 106.77,
60.62, 56.40. HRMS (EI) calcd for C24H21N3O5 [M]þ 431.1481,
found 431.1478. HPLC (method 1) 98.5% (tR = 5.87 min).
(4-(2-Isopropylthiazol-4-yl)-2-(1H-1,2,4-triazol-1-yl)phenyl)-
(3,4,5trimethoxy-phenyl)methanone (25). This compound was
made using the synthetic procedure described for 19. Thus 63d
(63 mg, 0.15 mmol) and sodium 1,2,4-triazole (21 mg, 0.23
mmol) were used. Purification of the residue by flash column
chromatography on silica gel (hexane/EtOAc, 5:1) afforded the
desired product 25 (9 mg, 13%) as a white solid. MS (ESI) m/z
465 [M þ H]þ. 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.19
(d, J = 1.6 Hz, 1H), 8.08 (dd, J = 8.04, 1.6 Hz, 1H), 7.92 (s, 1H),
7.64 (d, J = 9.4 Hz, 1H), 7.56 (s, 1H), 6.97 (s, 2H), 3.89 (s, 3H),
3.80 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 193.47, 178.84,
152.93, 152.55, 152.20, 143.19, 138.19, 135.63, 133.03, 131.18,
130.43, 126.27, 122.55, 114.27, 107.18, 60.91, 56.25, 33.49, 23.14.
HRMS (EI) calcd for C24H24N4O4S [M]þ 464.1518, found
464.1513. HPLC (method 1) 97.2% (tR = 11.74 min).
(4-(Thiazol-4-yl)-2-(1H-1,2,4-triazol-1-yl)phenyl)(3,4,5-trimeth-
oxyphenyl)methanone (26). This compound was made using
the synthetic procedure described for 19. Thus 63e (0.1 g,
0.27 mmol) and sodium 1,2,4-triazole (75 mg, 0.82 mmol) were
used. Purification of the residue by flash column chromatogra-
phy on silica gel (hexane/EtOAc, 1:1-1:3) afforded the desired
product 26 (40 mg, 35%) as a white solid. MS (ESI) m/z 423
[M þ H]þ. 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J = 1.9 Hz,
1H), 8.35 (s, 1H), 8.22 (d, J = 1.5 Hz, 1H), 8.11 (dd, J = 8.0, 1.6
Hz, 1H), 7.91 (s, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.0
Hz, 1H), 6.97 (s, 2H), 3.88 (s, 3H), 3.80 (s, 6H). 13C NMR
(100 MHz, DMSO-d6) δ 193.41, 153.80, 153.70, 152.92, 152.60,
143.65, 143.07, 137.54, 135.68, 133.30, 131.07, 130.60, 126.39,
122.57, 115.41, 107.04, 60.97, 56.23. HRMS (EI) calcd for
C21H18N4O4S [M]þ 422.1048, found 422.1045. HPLC (method
1) 95.4% (tR = 5.79 min).
(4-(Thiazol-5-yl)-2-(1H-1,2,4-triazol-1-yl)phenyl)(3,4,5-trimeth-
oxyphenyl)methanone (27). This compound was made using the
synthetic procedure described for 19. Thus 63f (60 g, 0.16 mmol)
and sodium 1,2,4-triazole (44 mg, 0.48 mmol) were used.
Purification of the residue by flash column chromatography
on silica gel (hexane/EtOAc, 3:1-1:2) afforded the desired
product 27 (20 mg, 30%) as a white solid. MS (ESI) m/z 423
[M þ H]þ. 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J = 0.4 Hz,
1H), 8.29 (s, 1H), 8.26 (d, J = 0.5 Hz, 1H), 7.95 (s, 1H), 7.84
(2-Fluoro-4-(2-isopropylthiazol-4-yl)phenyl)(3,4,5-trimethoxy-
phenyl)methanone (63d). This compound was made using the
synthetic procedure described for 63b. Thus 62d (83 mg, 0.2
˚
mmol), 4 A molecular sieves (0.1 g), and pyridinium dichromate
(0.11 g, 0.3 mmol) were used. Purification of the residue by flash
column chromatography on silica gel (hexane/EtOAc, 3:1)
afforded the desired product 63d (70 mg, 84%) as a white solid.
MS (ESI) m/z 416 [M þ H]þ. 1H NMR (400 MHz, CDCl3) δ 7.76
(m, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.48 (s, 1H), 7.11 (s. 2H), 3.93
(s, 3H), 3.85 (s, 6H).
(2-Fluoro-4-(thiazol-4-yl)phenyl)(3,4,5-trimethoxyphenyl)metha-
none (63e). This compound was made using the synthetic
procedure described for 63b. Thus 62e (0.37 g, 0.98 mmol),
˚
4 A molecular sieves (0.4 g), and pyridinium dichromate (0.56 g,
1.48 mmol) were used. Purification of the residue by flash col-
umn chromatography on silica gel (hexane/EtOAc, 3:1-1:1)
afforded the desired product 63e (0.18 g, 48%) as a white solid.
MS (ESI) m/z 374 [M þ H]þ. 1H NMR (400 MHz, CDCl3) δ 8.92
(d, J = 1.9 Hz, 1H), 7.82 (dd, J = 7.9, 1.6 Hz, 1H), 7.79 (dd, J =
10.9, 1.4 Hz, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.61 (t, J = 7.2 Hz,
1H), 7.13 (d, J = 1.1 Hz, 2H), 3.95 (s, 3H), 3.86 (s, 6H).
(2-Fluoro-4-(thiazol-5-yl)phenyl)(3,4,5-trimethoxyphenyl)metha-
none (63f). This compound was made using the synthetic
procedure described for 63b. Thus 62f (0.87 g, 2.31 mmol), 4
˚
A molecular sieves (0.9 g), and pyridinium dichromate (1.13 g,
3.0 mmol) were used. Purification of the residue by flash col-
umn chromatography on silica gel (hexane/EtOAc, 3:1-1:1)
afforded the desired product 63f (0.48 g, 56%) as a white solid.
MS (ESI) m/z 374 [M þ H]þ. 1H NMR (400 MHz, CDCl3) δ 8.84
(d, J = 0.5 Hz, 1H), 8.19 (d, J = 0.6 Hz, 1H), 7.59 (dd, J = 7.9,
7.2 Hz, 1H), 7.48 (dd, J = 8.0, 1.7 Hz, 1H), 7.39 (dd, J = 10.4,
1.6 Hz, 1H), 7.11 (d, J = 1.1 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 6H).
(4-(Furan-2-yl)-2-(1H-1,2,4-triazol-1-yl)phenyl)(3,4,5-trimeth-
oxyphenyl)methanone (19). A solution of 63a (0.48 g, 1.35 mmol)
and sodium 1,2,4-triazole (0.37 g, 4.04 mmol) in DMF (8 mL)
was heated at 120 °C for 4 h. After being cooled to rt, the
suspension was diluted with EtOAc (50 mL), washed with satd
NH4Cl solution (20 mL) and then brine (15 mL), dried over
MgSO4, filtered, and concentrated in vacuo. Purification of the
residue by flash column chromatography on silica gel (hexane/
EtOAc, 3:1-1:1) afforded the desired product 19 (0.21 g, 38%)
1
as a white solid. MS (ESI) m/z 406 [M þ H]þ. H NMR (400
MHz, CDCl3) δ; 8.29 (s, 1H), 7.92 (s, 1H), 7.90 (d, J = 1.6 Hz,
1H), 7.83 (dd, J = 8.0, 1.6 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.56
(dd, J = 1.7, 0.5 Hz, 1H), 6.95 (s, 2H), 6.87 (dd, J = 3.4, 0.5 Hz,
1H), 6.55 (dd, J = 3.4, 1.8 Hz, 1H), 3.88 (s, 3H), 3.80 (s, 6H). 13C
NMR (100 MHz, CDCl3) δ 196.26, 152.92, 152.53, 151.50,
143.75, 143.67, 143.22, 135.75, 134.13, 132.22, 131.10, 130.60,
123.59, 119.73, 112.26, 108.07, 107.18, 60.90, 56.24. HRMS (EI)
calcd for C22H19N3O5 [M]þ 405.1324, found 405.1321. HPLC
(method 1) 97.8% (tR = 8.19 min).
(4-(Thiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)phenyl)(3,4,5-trimeth-
oxyphenyl)methanone (20). This compound was made using the