1880 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Arienti et al.
2-[4-(4-Carbamoylphenoxy)phenyl]-1H-benzoimidazole-
5-carboxylic Acid Amide (3f). Prepared according to method
A above (9.6%): 1H NMR (400 MHz, DMSO-d6) δ 8.26-8.24
(m 2H), 8.20 (d, J ) 1.3 Hz, 1H), 8.11 (br, s, 1H), 7.99-7.96
(m, 3H), 7.91 (dd, J ) 8.6, 1.3 Hz, 1H), 7.28 (d, J ) 8.6 Hz,
1H), 7.43 (br, s, 1H), 7.34 (br, s, 1H), 7.30-7.33 (m, 2H), 7.17-
7.19 (m, 2H). MS (ESI+): m/z 373.1 (M + H)+. Anal.
(C21H16N4O3) C, H, N.
2-[4-(4-Methoxyphenoxy)phenyl]-1H-benzoimidazole-
5-carboxylic Acid Amide. (3k). Prepared according to
method A (30%): 1H NMR (400 MHz, DMSO-d6) δ 8.35-8.33
(m, 3H), 8.26 (br s, 1H), 8.06 (d, J ) 8.5 Hz, 1H), 7.87 (d, J )
8.4 Hz, 1H), 7.32-7.27 (m, 4H), 7.22-7.19 (m, 2H), 3.95 (s,
3H); 13C NMR (100 MHz, DMSO-d6) δ 165.5, 159.1, 154.2,
149.4, 145.8, 135.4, 133.3, 127.9, 127.3, 121.4, 119.4, 118.2,
115.1, 113.2, 111.9, 111.6, 53.3; MS (ESI+) m/z 360.1 (M +
H)+; Anal. (C21H17N3O3‚TFA) C, H, N.
2-[4-Phenylphenyl]-1H-benzoimidazole-5-carboxylic
Acid Amide (4c). Prepared according to method A (34%): 1H
NMR (400 MHz, DMSO-d6) δ 8.3 (d, J ) 8.4 Hz, 2H), 8.23 (s,
1H), 8.12 (br s, 1H), 7.98 (d, J ) 8.4 Hz, 2H), 7.92 (dd, J )
8.5, 1.7 Hz, 1H), 7.82 (d, J ) 8.5 Hz, 2H), 7.74 (d, J ) 8.5 Hz,
1H), 7.53 (t, J ) 7.6 Hz, 2H), 7.44 (t, J ) 7.5 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6) δ 166.1, 150.1, 141.2, 137.1, 136.6,
134.7, 128.1, 127.4, 126.6, 126.1, 125.7, 125.1, 124.4, 121.7,
115.5, 113.2; MS (ESI+): m/z 314.1 (M + H)+; Anal. (C20H15N3O‚
TFA‚H2O) C, H, N.
2-[4-(4-Chlorophenyl)phenyl]-1H-benzoimidazole-5-
carboxylic Acid Amide (4f). Prepared according to method
A (26%): 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J ) 8.4 Hz,
2H), 8.21 (s, 1H), 8.09 (br s, 1H), 7.97 (d, J ) 9.35 Hz, 2H),
7.89-7.84 (m, 3H), 7.83 (d, J ) 8.5 Hz, 1H), 7.61-7.57 (m,
2H), 7.39 (br, s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 168.3,
158.7, 158.4, 152.3, 141.5, 139.5, 138.0, 133.4, 129.9, 129.4,
128.9, 128.0, 127.6, 127.4, 123.4; MS (ESI+): m/z 348.0 (M +
H)+; Anal. (C20H14ClN3O2‚TFA‚0.5 H2O) C, H, N.
(Method B) 2-[4-(3-Chloro-4-methylphenoxy)phenyl]-
1H-benzoimidazole-5-carboxylic Acid Amide (3b). To a
solution of 4-fluorobenzaldehyde (38 mg, 0.30 mmol, 1.0 equiv)
in DMF (1.5 mL) was added 3-chloro-4-ethylphenol (0.66 mmol,
2.2 equiv), followed by Cs2CO3 (220 mg, 0.66 mmol, 2.2 equiv).
The mixture was heated at 90°C for 24 h. The reaction mixture
was then cooled to room temperature, and MP-carbonate
scavenger resin (Argonaut, 311 mg, loading ) 2.64 mmol/g)
was added. The mixture was shaken for 24 h, and the MP-
carbonate resin was removed by filtration to provide crude
4-[(3-chloro-4-methyl)phenoxy]benzaldehyde.
The crude aldehyde above was treated with a solution of
3,4-diaminobenzamide (50 mg, 0.33 mM, 1.0 equiv) in DMF
(1.0 mL), followed by Na2S2O5 (94 mg, 0.50 mmol, 1.5 equiv).
The mixture was heated to 95 °C for 24 h. The reaction mixture
was then cooled to room temperature and concentrated under
reduced pressure. The residue was dissolved in DMF (1.5 mL)
and purified by reverse phase HPLC (C18, water/acetonitrile/
0.1% TFA) to provide the title compound as a white solid (TFA-
salt) (55 mg, 33% yield): 1H NMR (400 MHz, DMSO-d6) δ 8.07
(d, J ) 8.9 Hz, 2H), 8.03 (d, J ) 1.0 Hz, 1H), 7.93 (br s, 1H),
7.72 (dd, J ) 8.5, 1.5 Hz, 1H), 7.54 (d, J ) 8.5 Hz, 1H), 7.29
(d, J ) 8.8 Hz, 1H), 7.24 (br s, 1H), 7.10 (s, 1H), 7.08 (d, J )
8.9 Hz, 2H), 6.91 (dd, J ) 8.3, 2.6 Hz, 1 H), 2.19 (s, 3H); 13C
NMR (125 MHz, CD3OD) δ 171.4, 162.9, 162.7, 155.3, 153.4,
137.9, 136.2, 135.6, 133.9, 133.3, 132.2, 131.0, 125.7, 121.8,
120.8, 119.8, 119.6, 115.3, 114.9, 19.4; MS (ESI+): m/z 378.09
(M + H)+; Anal. (C21H16ClN3O2‚TFA) C, H, N.
2-[4-(4-Chloro-3-trifluoromethylphenoxy)phenyl]-1H-
benzoimidazole -5-carboxylic Acid Amide (3c). Prepared
according to the procedure described in Method B (60%): 1H
NMR (400 MHz, CD3OD) δ 8.15 (br s, 1H), 8.13 (d, J ) 8.8
Hz, 2H), 7.80 (d, J ) 7.6 Hz, 1H), 7.61 (br s, 1H), 7.60 (d, J )
8.8 Hz, 2H), 7.44 (d, J ) 2.8 Hz, 1H), 7.29-7.26 (dd, J ) 8.8,
2.7 Hz, 1H), 7.20 (d, J ) 8.8 Hz, 2H); 13C NMR (125 MHz,
DMSO-d6) δ 168.7, 157.6, 155.5, 133.8, 129.1, 128.6, 128.3,
126.3, 125.5, 124.6, 123.7, 121.6, 119.6, 118.8; MS (ESI+): m/z
432.0 (M + H)+; Anal. (C21H13ClF3N3O2) C, H, N.
2-[4-(2-Fluoro-5-trifluoromethylphenoxy)phenyl]-1H-
benzoimidazole -5-carboxylic Acid Amide (3d). Prepared
according to the procedure described in Method B (51%): 1H
NMR (400 MHz, DMSO-d6) δ 8.22 (d, J ) 8.9 Hz, 2H), 8.16 (s,
1H), 8.06 (br s, 1H), 7.85 (dd, J ) 8.5, 1.4 Hz, 1H), 7.77-7.71
(m, 3H), 7.67 (d, J ) 8.5 Hz, 1H), 7.37 (br s, 1H), 7.28 (d, J )
8.8 Hz, 2H); 13C NMR (125 MHz, CD3OD) δ 171.6, 162.0, 159.0,
157.0, 153.4, 144.0, 138.4, 136.1, 132.0, 131.1, 129.2, 128.9,
125.6, 123.7, 121.9, 121.7, 119.7, 119.5, 118.7, 115.5, 115.0;
HRMS (M + H)+ calcd, 416.1022; found, 416.1023; Anal.
(C21H13F4N3O2.C2HF3O2) C, H, N.
2-[4-(3,4-Dimethylphenoxy)phenyl]-1H-benzoimidazole-
5-carboxylic Acid Amide (3e). Prepared according to the
procedure described in Method B (61%): 1H NMR (400 MHz,
DMSO-d6) δ 8.08 (d, J ) 8.9 Hz, 2H), 8.04 (s, 1H), 7.91 (br s,
1H), 7.70 (dd, J ) 8.4, 1.5 Hz, 1H), 7.52 (d, J ) 8.5 Hz, 1H),
7.21 (br s, 1H), 7.12 (d, J ) 8.3 Hz, 1H), 7.03 (d, J ) 8.8 Hz,
2H), 6.86 (d, J ) 2.5 Hz, 1H), 6.77 (dd, J ) 8.1, 2.6 Hz, 1H),
2.14 (s, 6H); 13C NMR (125 MHz, DMSO-d6) δ 168.1, 159.7,
153.1, 152.3, 138.3, 132.4, 130.8, 128.7, 123.1, 122.2, 120.8,
117.6, 117.0, 19.4, 18.6; HRMS (M + H)+ calcd, 358.1556;
found, 358.1562; Anal. (C22H19N3O2) calculated C, 73.93; H,
5.36; N, 11.76; found: 67.77% C, 5.02% H, 10.13% N. HPLC
(Method A): tR ) 7.10, 94% pure.
2-[4-(2-Naphthyloxy)phenyl]-1H-benzoimidazole-5-car-
boxylic Acid Amide (3i). Prepared according to the proce-
dure described in Method B (56%): 1H NMR (400 MHz, DMSO-
d6) δ 8.38 (d, J ) 8.7 Hz, 2H), 8.32 (s, 1H), 8.22 (br s, 1H),
8.19 (d, J ) 9.1 Hz, 1H), 8.12 (d, J ) 7.7 Hz, 1H), 8.03 (m,
2H), 7.83 (d, J ) 8.6 Hz, 1H), 7.75 (s, 1H), 7.67 (m, 2H), 7.53
(dd, J ) 8.8, 2.4 Hz, 2H), 7.44 (d, J ) 8.7 Hz, 2H); 13C NMR
(125 MHz, DMSO-d6) δ 170.3, 162.6, 153.0, 152.1, 136.7, 134.7,
131.5, 131.0, 130.1, 128.2, 127.7, 127.3, 126.0, 125.2, 120.5,
119.0, 116.9, 114.5, 114.3; HRMS (M + H)+ calcd, 380.1399;
found, 380.1407; Anal. (C24H17N3O2‚TFA‚H2O) C, H, N.
2-[4-(3-Chlorophenoxy)phenyl]-1H-benzoimidazole-5-
carboxylic Acid Amide (3j). Prepared according to the
procedure described in Method B (43%): 1H NMR (400 MHz,
DMSO-d6) δ 8.24 (d, J ) 8.6 Hz, 2H), 8.19 (s, 1H), 8.09 (br s,
1H), 7.88 (d, J ) 8.5 Hz, 1H), 7.70 (d, J ) 8.4 Hz, 1H), 7.49 (t,
J ) 8.2 Hz, 1H), 7.40 (br s, 1H), 7.32 (s, 1H), 7.29 (d, J ) 8.6
Hz, 2H), 7.25 (m, 1H), 7.12 (m, 1H); 13C NMR (125 MHz,
DMSO-d6) δ 170.5, 162.0, 156.6, 152.2, 136.8, 136.0, 134.4,
131.6, 131.5, 130.4, 128.9, 125.7, 125.5, 120.9, 119.7, 119.5,
118.9, 117.4, 114.7, 114.4; HRMS (M + H)+ calcd, 364.0853;
found, 364.0851; Anal. (C20H14ClN3O2) calcd C, 66.03; H, 3.88;
N, 11.55; found: C, 56.36; H, 3.89; N, 7.70; HPLC (method
A): tR ) 7.30, 91% pure.
2-[4-(4-Methylphenoxy)phenyl]-1H-benzoimidazole-5-
carboxylic Acid Amide (3l). Prepared according to the
procedure described in Method B (70%): 1H NMR (400 MHz,
DMSO-d6) δ 8.20 (d, J ) 9.0 Hz, 2H), 8.11 (br s, 1H), 7.89 (dd,
J ) 8.5, 1.5 Hz, 1H), 7.70 (d, J ) 8.5 Hz, 1H), 7.42 (br s, 1H),
7.28 (d, J ) 8.6 Hz, 2H), 7.19 (d, J ) 8.9 Hz, 2H), 7.06 (d, J )
8.5 Hz, 2H), 2.34 (s, 3H); 13C NMR (125 MHz, CD3OD) δ 171.6,
164.6, 154.5, 153.6, 137.3, 136.7, 135.1, 133.0, 132.2, 131.7,
131.4, 129.6, 126.5, 121.8, 120.7, 119.5, 119.4, 119.0, 115.5,
115.2, 21.2; MS (ESI+): m/z 344.1 (M + H)+; Anal. (C21H17N3O2)
calcd C, 73.45; H, 4.99; N, 12.24: found C, 55.78; H, 3.84; N,
7.87. HPLC (method A): tR ) 7.27, 92% pure.
2-[4-(3,4-Dichlorophenoxy)phenyl]-1H-benzoimidazole-
5-carboxylic Acid Amide (3a). Prepared according to the
procedure described in Method B (65%): 1H NMR (400 MHz,
DMSO-d6) δ 8.05 (d, J ) 8.6 Hz, 2H), 7.99 (s, 1H), 7.88 (br s,
1H), 7.68 (d, J ) 8.5 Hz, 1H), 7.51 (t, J ) 8.9 Hz, 2H), 7.30 (d,
J ) 2.8 Hz, 1H), 7.19 (br s, 1H), 7.12 (d, J ) 8.6 Hz, 2H), 6.97
(dd, J ) 8.8, 2.8 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ 172.8,
160.0, 157.2, 154.9, 134.3, 132.6, 130.1, 129.6, 128.4, 126.4,
123.6, 122.3, 120.3, 120.2; HRMS (M + H)+ calcd, 398.0463;
found, 398.0468; Anal. (C20H13Cl2N3O2‚0.5H2O) C, H, N.
2-[4-(3,4-Dimethoxyphenoxy)phenyl]-1H-benzoimida-
zole-5-carboxylic Acid Amide (3m). Prepared according to
the procedure described in Method B (63%): 1H NMR (400
MHz, DMSO-d6) δ 8.17 (d, J ) 8.9 Hz, 2H), 8.15 (s, 1H), 8.06