Phenylimidazole-DeriVed Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 16 4973
Hz), 7.34 (s, 1H), 7.11 (t, 1H, J ) 7.20 Hz), 6.93 (d, 1H, J ) 8.13
Hz), 6.84 (t, 1H, J ) 7.47). 13C NMR (CDCl3 + CD3OD) δd 156.3,
139.3, 119.3; δu 135.2, 128.9, 126.7, 120.6, 117.5, 115.4. IR (KBr)
3207, 2602, 1583 1488 cm-1. NP-HPLC tR ) 8.41 (40:60,
2-propanol/n-hexane, 1 mL/min). MS m/z 160.
4-(4-Fluorophenyl)-1H-imidazole (9). Synthesized from 2-bromo-
(4-fluorophenyl)ethanone48
and formamide according to the general
procedure to afford 9 as off-white solid in 51% yield. Mp )
125-126 °C. TLC Rf ) 0.24 (10% MeOH/CHCl3). 1H NMR
(CDCl3) δ 10.67 (s, 1H), 7.70-7.74 (m, 3H), 7.26 (s, 1H),
7.08-7.00 (m, 2H). 13C NMR (CDCl3) δd 162.2 (J1C-F ) 244.33
4-(2-Fluorophenyl)-1H-imidazole (2). Synthesized from 2-bromo-
(2-fluorophenyl)ethanone48 and formamide according to the general
procedure to afford 2 as an off-white solid in 52% yield. Mp )
107-108 °C. TLC Rf ) 0.25 (10% MeOH/CHCl3). 1H NMR
(CDCl3) δ 11.2 (br s, 1H), 8.00-7.95 (m, 1H), 7.73 (s, 1H), 7.53
(d, 1H, J ) 3.09 Hz), 7.24-7.07 (m, 3H). 13C NMR (CDCl3) δd
Hz), 138.6, 129.6; δu 135.9, 126.8 (J3C-F ) 7.94 Hz), 115.84 (J2
C-F
) 21.48 Hz), 114.9. IR (KBr) 3099, 3053, 2858, 1658, 1606, 1562,
1465 cm-1 NP-HPLC tR ) 6.91 (30:70, 2-propanol/n-hexanes, 1
.
mL/min). MS m/z 162.
4-(2,6-Dimethoxyphenyl)-1H-imidazole (10). Synthesized from
2-bromo-1-(2,6-dimethoxyphenyl)ethanone54 and formamide ac-
cording to the general procedure to afford 10 as yellow oil in 65%
159.3 (J1
) 246.32 Hz), 132.8, 121.1 (J2
) 12.77 Hz); δu
C-F
135.6, 128.0 (J3
) 8.31 Hz), 127.51(J3 C-)F 3.83 Hz), 124.5
C-F
C-F
(J4
) 3.15 Hz), 119.0 (J3
) 11.49 Hz), 115.98 (J2
)
C-F
1
C-F
C-F
yield. TLC Rf ) 0.43 (20% MeOH/CHCl3). H NMR (CDCl3) δ
21.97 Hz). IR (KBr) 3080, 3005, 2839, 1678 cm-1. NP-HPLC tR
) 5.29 (30:70, 2-propanol/n-hexane, 1 mL/min) mixture of two
isomers. GC m/z 162.
10.80 (br s, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.13 (t, 1H, J ) 8.43
Hz), 6.61 (s, 1H), 6.58 (s, 1H), 3.82 (s, 6H). 13C NMR (CDCl3) δd
156.6, 124.2, 107.8; δu 133.8, 129.3, 127.5, 124.4, 104.2, 103.8,
55.6 (2C). IR (film) 3417, 3118, 1589, 1483 cm-1. NP-HPLC tR )
9.81 (30:70, 2-propanol/n-hexane, 1 mL/min). MS m/z 204.
2-(1H-Imidazol-4-yl)benzene-1,3-diol (11). The dimethoxy com-
pound 10 (100 mg, 0.489 mmol) was heated to reflux (145-150
°C) in HBr (5 mL, 48% aqueous solution) for 10 h. After the
mixture was cooled, excess of HBr was distilled off and the residue
was diluted with MeOH (15 mL), treated with solid NaHCO3, and
filtered. The filtrate was taken in EtOAc (50 mL), washed with
water, dried (Na2SO4), and concentrated in vacuo to afford a light-
brown solid, which was purified by chromatography to afford 11
as an off-white solid in 78% yield. Mp ) 205-206 °C. TLC Rf )
0.61 (20% MeOH/CHCl3). 1H NMR (CD3OD) δ 7.73 (d, 1H, J )
4-(Thiophen-2-yl)-1H-imidazole (3). Synthesized from 2-bromo-
1-(thiophen-2-yl)ethanone49 and formamide according to the general
procedure to afford 3 as brown crystalline solid in 60% yield. Mp
1
) 126-127 °C. TLC Rf ) 0.62 (20% MeOH/CHCl3). H NMR
(CDCl3) δ 7.60 (s, 1H), 7.23-7.20 (m, 2H), 7.15 (d, 1H, J ) 4.98
Hz), 6.98 (dd, 1H, J ) 3.75, 1.05 Hz). 13C NMR (CDCl3) δd 136.7,
134.4; δu 135.6, 127.8, 123.6, 122.5, 114.2. IR (KBr) 3115, 3080,
2872, 1658 cm-1. NP-HPLC tR ) 5.85 (30:70, 2-propanol/n-hexane,
1 mL/min). MS m/z 150.
3-(1H-Imidazol-4-yl)phenol (4). Synthesized from 3-(2-bro-
moacetyl)phenol46 and formamide according to the general proce-
dure to afford 4 as brown solid in 53% yield. Mp ) 209-210 °C.
TLC Rf ) 0.45 (20% MeOH/CHCl3). 1H NMR (CDCl3 + CD3OD)
δ 7.69 (s, 1H), 7.33 (s, 1H), 7.22-7.17 (m, 3H), 6.75-6.68 (m,
1H). 13C NMR (CDCl3 + CD3OD) δd 158.7, 139.2, 135.4; δu 136.8,
130.8, 117.4, 117.0, 115.0, 112.8. IR (KBr) 3294, 2802, 1619, 1582,
2.19 Hz), 6.89 (t, 1H, J ) 8.13 Hz), 6.40 (s, 1H), 6.37 (s, 1H). 13
C
NMR (CD3OD) δd 157.6, 137.6, 107.2; δu 132.9, 128.3, 117.2,
108.0. IR (KBr) 3416, 3261, 1614, 1596 cm-1 NP-HPLC tR
)
.
11.60 (60:40, 2-propanol/n-hexane 0.5 mL/min).
1492, 1471 cm-1 NP-HPLC tR ) 10.81 (40:60, 2-propanol/n-
.
3-(1H-Imidazol-4-yl)benzaldehyde (12). The nitrile was reduced
with Raney Ni following a literature procedure.19 Chromatographic
purification gave 12 as white solid in 71% yield. Mp ) 137-138
°C. TLC Rf ) 0.57 (20% MeOH/CHCl3). 1H NMR (CDCl3 +
CD3OD) δ 10.03 (s, 1H), 8.22 (t, 1H, J ) 1.50 Hz), 8.01 (dt, 1H,
J ) 1.59, 4.89 Hz), 7.77 (dt, 1H, J ) 1.23, 5.04 Hz), 7.57 (t, 1H,
J ) 7.68 Hz), 7.45 (s, 1H). NP-HPLC tR ) 6.48 (40:60, 2-propanol/
n-hexane, 0.5 mL/min).
General Procedure for the Suzuki Coupling. A mixture of
4-bromoimidazole (0.680 mmol), substituted thiomethylphenylbo-
ronic acid (0.748 mmol), Pd(OAc)2 (0.0340 mmol), PPh3 (0.102
mmol), and K2CO3 in n-propanol (7 mL) and water (2 mL) was
heated to reflux for 24 h. After cooling, the reaction mixture was
diluted with water (10 mL) and extracted with EtOAc (3 × 50
mL). The combined organic extract was dried (Na2SO4) and
concentrated in vacuo to afford a yellowish oil. Chromatographic
purification afforded the desired products as a white solid.
4-(2-(Methylthio)phenyl)-1H-imidazole (13). Synthesized from
4-bromoimidazole and 2-thiomethylphenylboronic acid according
to the general procedure to afford 13 as a white crystalline solid in
31% yield. Mp ) 123-125 °C. TLC Rf ) 0.52 (20%MeOH/
CHCl3). 1H NMR (CDCl3) δ 8.94 (br s, 1H), 7.70 (d, 1H, J ) 0.96
Hz), 7.66-7.63 (dd, 1H, J ) 1.62, 5.67 Hz), 7.46 (d, 1H, J ) 1.02
Hz), 7.32-7.17 (m, 3H), 2.42 (s, 3H). 13C NMR (CDCl3) δd 135.6,
135.0, 131.6; δu 135.1, 129.4, 127.9, 127.5, 125.8, 121.1, 16.7. IR
(KBr) 3060, 2872, 1586, 1463 cm-1. NP-HPLC tR ) 9.26 (20:80,
2-propanol/n-hexane, 1 mL/min). MS m/z 190.
hexane, 1 mL/min). MS m/z 160.
4-(3-Fluorophenyl)-1H-imidazole (5). Synthesized from 2-bromo-
(3-fluorophenyl)ethanone48 and formamide according to the general
procedure to afford 5 as off-white solid in 52% yield. Mp ) 94-95
°C. TLC Rf ) 0.27 (10% MeOH/CHCl3). 1H NMR (CDCl3) δ 10.06
(br s, 1H), 7.68 (d, 1H, J ) 0.72 Hz), 7.51 (d, 1H, J ) 11.76 Hz),
7.46-7.23 (m, 3H), 6.97-6.87 (m, 1H). 13C NMR (CDCl3) δd
163.48 (J1
) 243.34 Hz), 138.9, 135.7 (J3
) 8.28 Hz); δu
C-F
C-F
135.9, 130.5 (J3
) 8.52 Hz), 120.7 (J4
) 2.74 Hz), 115.1,
C-F
C-F
113.9 (J2
) 21.19 Hz), 112.05 (J2
) 22.57 Hz). IR (KBr)
C-F
C-F
3057, 3000, 2861, 1607, 1561, 1511 cm-1 NP-HPLC tR ) 6.41
.
(30:70, 2-propanol/n-hexane, 1 mL/min). MS m/z 162.
3-(1H-Imidazol-4-yl)benzonitrile (6). Synthesized from 3-(2-
bromoacetyl)benzonitrile50 and formamide according to the general
procedure to afford 6 as white solid in 43% yield. Mp ) 191-192
°C. TLC Rf ) 0.63 (20% MeOH/CHCl3). 1H NMR (CDCl3) δ
7.98-7.94 (m, 2H), 7.66 (d, 1H, J ) 1.05 Hz), 7.52-7.44 (m,
2H), 7.36 (d, 1H, J ) 1.08 Hz). NP-HPLC tR ) 8.39 min 30:70
(2-propanol/n-hexane, 1 mL/min). MS m/z 169.
3-(1H-Imidazol-4-yl)pyridine (7). Synthesized from 2-bromo-1-
(pyridine-3-yl)ethanone hydrobromide51 and formamide according
to the literature procedure52 to afford 7 as yellow oil in 67% yield.
TLC Rf ) 0.37 (20% MeOH/CHCl3). 1H NMR (CDCl3) δ 9.01 (d,
1H, J ) 1.68 Hz), 8.48 (dd, 1H, J ) 1.59, 3.24 Hz), 8.09 (dt, 1H,
J ) 1.83, 4.11 Hz), 7.78 (d, 1H, J ) 0.96 Hz), 7.45 (d, 1H, J )
0.96 Hz), 7.36-7.32 (m, 1H). NP-HPLC tR ) 30.19 (30:70,
2-propanol/n-hexane, 1 mL/min). MS m/z 145.
4-(3-(Methylthio)phenyl)-1H-imidazole (14). Synthesized from
4-bromoimidazole and 3-thiomethylphenylboronic acid according
to the general procedure to afford 14 as a white crystalline solid in
57% yield. Mp ) 126-127 °C. TLC Rf ) 0.50 (20% MeOH/
CHCl3). 1H NMR (CDCl3) δ 9.43 (br s, 1H), 7.70 (s, 1H), 7.65 (t,
1H, J ) 1.65 Hz), 7.48-7.45 (dt, J ) 1.32, 5.1 Hz), 7.35 (s, 1H),
7.27 (t, 1H, J ) 7.74 Hz), 7.15-7.12 (m, 1H). 13C NMR (CDCl3)
δd 139.3, 138.8, 133.9; δu 135.9, 129.4, 125.3, 123.2, 122.0, 115.7,
15.9. IR (KBr) 3109, 3052, 2810, 2620 cm-1. NP-HPLC tR ) 9.58
(20:80, 2-propanol/n-hexane, 1 mL/min). MS m/z 190.
4-(1H-Imidazol-4-yl)phenol (8). Synthesized from 4-(2-bro-
moacetyl)phenol46 and formamide following the general procedure
to afford 8 as brown solid in 52% yield. Mp ) 221-222 °C; lit
225-226 °C.53 TLC Rf ) 0.28 (20% MeOH/CHCl3). 1H NMR
(CDCl3 + CD3OD) δ 7.66 (d, 1H, J ) 1.08 Hz), 7.53 (t, 1H, J )
2.79 Hz), 7.50 (t, 1H, J ) 2.76 Hz), 7.23 (d, 1H, J ) 1.08 Hz),
6.83 (t, 1H, J ) 2.76 Hz), 6.80 (t, 1H, J ) 2.76 Hz). 13C NMR
(CDCl3 + CD3OD) δd 157.9, 139.3, 125.9; δu 136.6, 127.4, 116.7,
116.1. IR (KBr) 3196, 2589, 1610, 1515 cm-1 NP-HPLC tR
)
.
11.53 (40:60, 2-propanol/n-hexane, 1 mL/min). MS m/z 160.