Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18 5631
acetonitrile as solvent B (λdet = 280 nm) with Luna C18 Synergi
column (50 mm ꢀ 4.66 mm, 5 μm) for LC, with the ESI-MS
operating in positive mode unless mentioned otherwise. The 1H
NMR spectra were recorded in DMSO-d6 using a Bruker
DMSO-d6) δ 12.63 (s, 1H), 10.39 (s, 1H), 8.34 (d, J = 2.2 Hz,
1H), 8.30 (d, J = 8.8 Hz, 2H), 8.12 (dd, J = 2.2, 8.9 Hz, 1H),
7.81 (d, J = 8.9 Hz, 2H, and s, 1H), 7.31 (dd, J = 8.5, 5.8 Hz,
2H), 7.12 (t, J = 8.8 Hz, 2H), 2.94 (t, J = 7.4 Hz, 2H), 2.69 (t,
J = 7.8 Hz, 2H). MS (ESI, positive): calcd for [C22H17F1N4O4],
420.40; found, 421.09 [M þ H]þ.
1
DPX300 NMR spectrometer operating at 300 MHz. The H
NMR chemical shifts are reported in ppm (δ) relative to the
residual protonated solvent peak. The purity of final com-
pounds was assessed based on analytical HPLC, and the results
were greater than 95% unless specified otherwise.
(E)-3-(4-Fluoro-phenyl)-N-[4-(1-hydroxy-6-nitro-1H-benzoimi-
dazol-2-yl)-phenyl]-acrylamide (14). 1H NMR (300 MHz,
DMSO-d6) δ 12.61 (s, 1H), 10.54 (s, 1H), 8.37 (d, J = 2.0 Hz,
1H), 8.35 (d, J = 8.7 Hz, 2H), 8.14 (dd, J = 2.2, 8.9 Hz, 1H), 7.94
(d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.9 Hz, 1H), 7.73 (dd, J = 5.7,
8.6 Hz, 2H), 7.66 (d, J = 15.7 Hz, 1H), 7.31 (t, J = 8.8 Hz, 2H),
6.83 (d, J = 15.7 Hz, 1H). MS (ESI, positive): calcd for
[C22H15F1N4O4], 418.39; found, 419.08 [M þ H]þ.
Method A: General Synthesis of 4-Aminobenzyl-(2,4-dinitro-
phenyl)-amine Derivatives (3). To a solution of 4-aminobenzyl
amine derivatives (25.5 mL, 225 mmol) and powdered NaHCO3
(94.5 g, 1125 mmol) in anhydrous DMF (300 mL) was added
2,4-dinitrofluoro benzene (18.8 mL, 150 mmol) dropwise at
room temperature. After 2 h, the solution was slowly diluted
with water (1000 mL) to precipitate the product, which was
collected on a fritted funnel rinsing with water until the eluent
was colorless. The solid was further dried under high vacuum to
afford the product 3 as a bright-orange solid (43 g, 99% yield).
This crude material was used for the next step without further
(E)-3-(4-Fluoro-phenyl)-N-[4-(1-hydroxy-6-nitro-1H-benzoimi-
dazol-2-yl)-benzyl]-acrylamide(15). 1HNMR (300 MHz, DMSO-
d6) δ 12.65 (s, 1H), 8.75 (t, J = 5.9 Hz, 1H), 8.39 (d, J = 2.4 Hz,
1H), 8.30 (d, J = 8.4 Hz, 2H), 8.14 (dd, J = 2.4, 9 Hz, 1H), 7.86
(d, J = 9 Hz, 1H), 7.66 (dd, J = 5.7, 8.4 Hz, 2H), 7.53 (d, J =
8.4 Hz, 2H), 7.51 (d, J = 16.2 Hz, 1H), 7.27 (t, J = 9 Hz, 2H), 6.68
(d, J = 15.9 Hz, 1H), 4.52 (d, J = 6 Hz, 2H). MS (ESI, positive):
calcd for [C23H17F1N4O4], 432.41; found, 433.23 [M þ H]þ.
(E)-N-[4-(1-Hydroxy-6-nitro-1H-benzoimidazol-2-yl)-phenyl]-
3-phenyl-acrylamide (16). 1H NMR (300 MHz, DMSO-d6) δ
12.65 (s, 1H), 10.51 (s, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.30 (d, J =
8.8 Hz, 2H), 8.09 (dd, J = 2.3, 8.9 Hz, 1H), 7.90 (d, J = 8.8 Hz,
2H), 7.78 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.61 (d,
J = 15.2 Hz, 1H), 7.47-7.37 (m, 3H), 6.85 (d, J = 15.8 Hz, 1H).
MS (ESI, positive): calcd for [C22H16N4O4], 400.40; found,
401.11 [M þ H]þ.
1
purification. H NMR (300 MHz, DMSO-d6) δ 9.18 (t, J =
5.7 Hz, 1H), 8.86 (d, J = 3.0 Hz, 1H), 8.22 (dd, J = 2.7, 9.6 Hz,
1H), 7.13 (d, J = 9.6 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.53 (d,
J = 8.4 Hz, 2H), 5.05 (s, 2H), 4.54 (d, J = 6.0 Hz, 2H). MS (ESI,
positive): calcd for [C13H12N4O4], 288.26; found, 330.10 [M þ H
þ CH3CN]þ.
General Synthesis of 6-Nitro-2-(4-aminophenyl)-1-hydroxy-
benzimidazole Derivatives (4). To a solution of N-(4-amino-
benzyl)-2,4-dinitroaniline derivative 3 (21.6 g, 74.9 mmol) in
anhydrous DMF (75 mL) was slowly added NaOMe (30% w/w
in MeOH) (67.5 g, 375 mmol) at room temperature under argon
atmosphere. After the addition, the solution was warmed to
60 °C for 2 h. After cooling to ambient temperature, the solution
was transferred to an Erlenmeyer flask or tall beaker, diluted
with water (700 mL), and then acidified with saturated citric
acid. The resulting precipitate was collected on a sintered funnel
rinsing with water. The crude product was purified by recrys-
tallization in hot EtOH to afford 4 as a brown solid (18.1 g, 90%
yield). 1H NMR (300 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.22 (d,
J = 2.4 Hz, 1H), 8.08-8.04 (m, 3H), 7.67 (d, J = 8.7 Hz, 1H),
6.68 (d, J = 8.7 Hz, 2H), 5.91 (br s, 2H). MS (ESI, positive):
calcd for [C13H10N4O3], 270.25; found, 271.05 [M þ H]þ.
General Synthesis of N-Acyl-6-nitro-2-(4-aminophenyl)-1-hydro-
xybenzimidazole Derivatives (6). To a solution of 6-nitro-2-(4-
aminophenyl)-1-hydroxybenzimidazole derivative 4 (1.0 mmol)
in anhydrous pyridine (2.0 mL) was added an acid chloride
(2.5 mmol) at room temperature. After stirring for 2-3 h, the
solution was diluted with 3N NaOH (6.0 mL) and stirred for
another hour. The deep-amber solution was transferred to an
Erlenmeyer flask or beaker through dilution with water (100 mL)
and then acidified with saturated citric acid. The resulting pre-
cipitate was collected on a sintered funnel rinsing with water. The
crude product 6 was further purified either by preparative HPLC
or by recrystallization in hot EtOH.
(E)-3-(2,4-Difluoro-phenyl)-N-[4-(1-hydroxy-6-nitro-1H-ben-
zoimidazol-2-yl)-phenyl]-acrylamide (17). 1H NMR (300 MHz,
DMSO-d6) δ 12.62 (br s, 1H), 10.62 (s, 1H), 8.34 (d, J = 2.2 Hz,
1H), 8.33 (d, J = 8.7 Hz, 2H), 8.11 (dd, J = 2.4, 9 Hz, 1H), 7.93
(d, J = 9 Hz, 2H), 7.81 (d, J = 9 Hz, 1H), 7.78 (t, J = 8.7 Hz,
1H), 7.63 (d, J = 15.9 Hz, 1H), 7.39 (dt, J = 2.7, 9.6 Hz, 1H),
7.21 (dt, J = 2.1, 8.4 Hz, 1H), 6.94 (d, J = 15.9 Hz, 1H). MS
(ESI, positive): calcd for [C22H14F2N4O4], 436.38; found,
437.08 [M þ H]þ.
(E)-3-(3,4-Difluoro-phenyl)-N-[4-(1-hydroxy-6-nitro-1H-ben-
zoimidazol-2-yl)-phenyl]-acrylamide (18). 1H NMR (300 MHz,
DMSO-d6) δ 12.64 (br, 1H), 10.62 (s, 1H), 8.37 (d, J = 2.4 Hz,
1H), 8.35 (d, J = 8.7 Hz, 2H), 8.14 (dd, J = 2.4, 9 Hz, 1H), 7.94
(d, J = 9.0 Hz, 2H), 7.84 (d, J = 9.0 Hz, 1H), 7.77 (m, 1H), 7.63
(d, J = 15.9 Hz, 1H), 7.57-7.53 (m, 2H), 6.87 (d, J = 15.6 Hz,
1H). MS (ESI, positive): calcd for [C22H14F2N4O4], 436.38;
found, 437.15 [M þ H]þ.
(E)-N-[4-(1-Hydroxy-6-nitro-1H-benzoimidazol-2-yl)-phenyl]-
3-p-tolyl-acrylamide (20). 1H NMR (300 MHz, DMSO-d6) δ
12.63 (s, 1H), 10.52 (s, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.35 (d, J =
9 Hz, 2H), 8.13 (dd, J = 2.1, 8.7 Hz, 1H), 7.94 (d, J = 9 Hz, 2H),
7.83 (d, J = 9 Hz, 1H), 7.61 (d, J = 15.9 Hz, 1H), 7.55 (d, J =
8.1 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 6.83 (d, J = 15.6 Hz, 1H),
2.35 (s, 3H). MS (ESI, positive): calcd for [C23H18N4O4], 414.42;
found, 415.15 [M þ H]þ.
4-Fluoro-N-[4-(1-hydroxy-6-nitro-1H-benzoimidazol-2-yl)-benzyl]-
benzamide (11). 1H NMR (300 MHz, DMSO-d6) δ 12.64 (s, 1H),
9.19 (t, J = 5.7 Hz, 1H), 8.39 (d, J = 2.1 Hz, 1H), 8.29 (d, J =
8.4 Hz, 2H), 8.14 (dd, J = 2.4, 9 Hz, 1H), 8.01 (dd, J = 5.7, 8.7 Hz,
2H), 7.85 (d, J = 9 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.34 (t, J =
9 Hz, 2H), 4.59 (d, J = 6 Hz, 2H). MS (ESI, positive): calcd for
[C21H15F1N4O4], 406.38; found, 407.18 [M þ H]þ.
(E)-N-[4-(1-Hydroxy-6-nitro-1H-benzoimidazol-2-yl)-phenyl]-
3-(2-methoxy-phenyl)-acrylamide (21). 1H NMR (300 MHz,
DMSO-d6) δ 12.58 (s, 1H), 10.46 (s, 1H), 8.30 (d, J = 2.0 Hz,
1H), 8.29 (d, J = 8.6 Hz, 2H), 8.08 (dd, J = 2.2, 8.9 Hz, 1H), 7.89
(d, J = 8.8 Hz, 2H), 7.81 (d, J = 14.4 Hz, 1H), 7.77 (d, J =
8.8 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 8.3 Hz, 1H),
7.07 (d, J = 8.3 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.88 (d, J =
15.8 Hz, 1H), 3.86 (s, 3H). MS (ESI, positive): calcd for
[C23H18N4O5], 430.42; found, 431.14 [M þ H]þ.
2-(4-Fluoro-phenyl)-N-[4-(1-hydroxy-6-nitro-1H-benzoimida-
zol-2-yl)-phenyl]-acetamide (12). 1H NMR (300 MHz, DMSO-
d6) δ 12.56 (s, 1H), 10.41 (s, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.20
(d, J = 8.8 Hz, 2H), 8.01 (dd, J = 2.3, 8.9 Hz, 1H), 7.71 (d, J =
8.8 Hz, 2H), 7.70 (d, J = 8.9 Hz, 1H), 7.28 (dd, J = 5.7, 8.6 Hz,
2H), 7.06 (t, J = 8.9 Hz, 2H), 3.60 (s, 2H). MS (ESI, positive):
calcd for [C21H15F1N4O4], 406.38; found, 407.17 [M þ H]þ.
3-(4-Fluoro-phenyl)-N-[4-(1-hydroxy-6-nitro-1H-benzoimida-
zol-2-yl)-phenyl]-propionamide (13). 1H NMR (300 MHz,
(E)-N-[4-(1-Hydroxy-6-nitro-1H-benzoimidazol-2-yl)-phenyl]-
3-(4-methoxy-phenyl)-acrylamide (22). 1H NMR (300 MHz,
DMSO-d6) δ 12.57 (s, 1H), 10.40 (s, 1H), 8.31 (d, J = 2.3 Hz,
1H), 8.28 (d, J = 9.0 Hz, 2H), 8.08 (dd, J = 2.3, 8.9 Hz, 1H), 7.88
(d, J = 8.9 Hz, 2H), 7.77 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 9.0 Hz,
2H), 7.55 (d, J = 14.6 Hz, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.68 (d,