996 Chem. Res. Toxicol., Vol. 13, No. 10, 2000
Kaiya et al.
was hydrogenated. Pd-C was removed by filtration, and the
residue was evaporated to dryness. Recrystallization of the
residue from MeOH gave 3.85 g (90%) of 3d as colorless
needles: mp 130-131 °C; 1H NMR (Me2SO-d6) δ 2.07 (s, 3H,
CH3), 5.36 (br s, 2H, NH2), 6.83 (dd, 1H, J ) 1.8, 7.9 Hz, 5-H),
7.02 (d, 1H, J ) 1.8 Hz, 3-H), 7.49 (d, 1H, J ) 7.9 Hz, 6-H),
9.24 (br s, 1H, NH); MS m/z 218 (M+), 176 (M+ - C2H2O). Anal.
Calcd for C9H9F3N2O: C, 49.54; H, 4.16; N, 12.84. Found: C,
49.32; H, 4.26; N, 12.59.
been left at 25 °C for 15 h, the solvent was removed by
evaporation, and the product was separated by column chro-
matography (silica gel, 6/4 n-hexane/CHCl
3). Recrystallization
of the product from n-hexane/CHCl3 gave 642 mg (20%) of 5e
1
as orange-colored needles: mp 155-156 °C; H NMR (Me2SO-
d6) δ 6.99 (d, 1H, J ) 9.1 Hz, 6-H), 7.58 (m, 3H, 3′-H, 4′-H, 5′-
H), 7.93 (br s, 2H, NH2), 8.05 (d, 2H, J ) 7.0 Hz, 2′-H, 6′-H),
8.08 (dd, 1H, J ) 2.7, 9.1 Hz, 5-H), 8.46 (d, 1H, J ) 2.7 Hz,
3-H); 13C NMR (Me2SO-d6) δ 116.6 (6-C), 118.1 (3-C), 122.7 (2′-
C, 6′-C), 127.3 (5-C), 129.2 (3′-C, 5′-C), 131.2 (4′-C), 133.3 (2-C),
136.1 (4-C), 151.5 (1-C), 151.9 (1′-C); MS m/z 242 (M+), 165 (M+
- C6H5), 137 (M+ - PhN2); HRMS m/z M+ calcd for C12H10N4O2
242.0804, found 242.0804.
(20) 2-P h en yla zo-4-(tr iflu or om eth yl)a ceta n ilid e (4d ).
Compound 3d (436 mg, 2.00 mmol) was dissolved in a mixture
of EtOH (0.8 mL) and AcOH (1.2 mL). Nitrosobenzene (236 mg,
2.20 mmol) was then added, and the solution was left at 25 °C
for 15 h. After the solvent had been removed by evaporation,
the product was purified by PLC (silica gel, CHCl3) to obtain
113 mg (18%) of 4d . Recrystallization from AcOEt gave orange-
colored needles: mp 209-210 °C; 1H NMR (Me2SO-d6) δ 2.26
(s, 3H, CH3), 7.63 (m, 3H, 3′-H, 4′-H, 5′-H), 7.90 (dd, 1H, J )
2.1, 8.8 Hz, 5-H), 7.94 (br s, 1H, 3-H), 8.11 (m, 2H, 2′-H, 6′-H),
8.55 (d, 1H, J ) 8.8 Hz, 6-H), 10.29 (br s, 1H, NH); MS m/z 307
(M+), 202 (M+ - PhN2). Anal. Calcd for C15H12F3N3O: C, 58.63;
H, 3.94; N, 13.68. Found: C, 58.42; H, 3.98; N, 13.64.
(25) 6-Nitr o-1-p h en yla m in oben zim id a zole (6e). Com-
pound 5e (121 mg, 0.50 mmol), AcOH (1 mL), 37% HCHO (0.1
mL), and concentrated HCl (0.1 mL) were mixed, and the
solution was heated at 80 °C for 15 min. After it had cooled,
water (20 mL) was added and the product was extracted with
CHCl3. The product was purified by PLC (silica gel, 19/1 CHCl3/
MeOH) to obtain 48 mg (38%) of 6e. Recrystallization from
AcOEt gave yellow needles: mp 194-195 °C; 1H NMR (Me2-
SO-d6) δ 6.56 (m, 2H, 2′-H, 6′-H), 6.91 (t, 1H, J ) 7.3 Hz, 4′-H),
7.23 (m, 2H, 3′-H, 5′-H), 7.96 (d, 1H, J ) 8.8 Hz, 4-H), 8.13 (d,
1H, J ) 2.4 Hz, 7-H), 8.17 (dd, J ) 2.4, 8.8 Hz, 5-H), 8.79 (s,
1H, 2-H), 9.73 (br s, 1H, NH); 13C NMR (Me2SO-d6) δ 106.4 (7-
C), 112.6 (2′-C, 6′-C), 117.8 (5-C), 120.7 (4-C), 121.2 (4′-C), 129.4
(3′-C, 5′-C), 132.4 (7a-C), 143.3 (6-C), 145.8 (3a-C), 146.9 (1′-C),
149.3 (2-C). Anal. Calcd for C13H10N4O2: C, 61.41; H, 3.96; N,
22.04. Found: C, 61.54; H, 3.97; N, 21.82.
(21) 2-P h en yla zo-4-(tr iflu or om eth yl)a n ilin e (5d ). Com-
pound 4d (230 mg, 0.749 mmol) was dissolved in 20 mL of
MeOH containing 10% KOH, and the mixture was heated under
reflux for 1 h. After the solvent had been removed by evapora-
tion, the product was separated by PLC (silica gel, 1/1 n-hexane/
CHCl3) to obtain 180 mg (91%) of 5d as orange-colored col-
umns: mp 73-74 °C; 1H NMR (Me2SO-d6) δ 7.04 (d, 1H, J )
8.9 Hz, 6H), 7.41 (br s, 2H, NH2), 7.49 (dd, 1H, J ) 2.1, 8.9 Hz,
5-H), 7.52 (m, 1H, 4′-H), 7.57 (m, 2H, 3′-H, 5′-H), 7.90 (d, 1H, J
) 2.1 Hz, 3-H), 7.99 (d, 2H, J ) 7.3 Hz, 2′-H, 6′-H); MS m/z 265
(M+), 160 (M+ - PhN2); HRMS m/z M+ calcd for C13H10F3N3
265.0827, found 265.0825.
(26) 5-Nitr o-1-m eth yl-3-p h en yla m in oben zim id a zoliu m
Iod id e (7e). Compound 6e (75 mg, 0.30 mmol) was dissolved
in 2 mL of MeOH. CH3I (75 µL, 1.20 mmol) was then added,
and the mixture was heated at 50 °C for 12 h. Further addition
of CH3I (75 µL) and a subsequent 12 h reaction were repeated
three times. After the solvent had been removed by evaporation,
the product was separated by PLC (silica gel, 9/1 CHCl3/MeOH)
to obtain 36 mg (31%) of 7e. Compound 7e was unstable and
decomposed gradually during purification by PLC: 1H NMR
(Me2SO-d6) δ 4.18 (s, 3H, CH3), 6.91 (d, 2H, J ) 8.4 Hz, 2′-H,
6′-H), 7.04 (t, 1H, J ) 7.3 Hz, 4′-H), 7.31 (m, 2H, 3′-H, 5′-H),
8.33 (d, 1H, J ) 2.2 Hz, 4-H), 8.39 (d, 1H, J ) 9.3 Hz, 7-H),
8.57 (dd, J ) 2.2, 9.3 Hz, 6-H), 10.30 (br s, 1H, NH), 10.41 (s,
(22) 1-(P h en yla m in o)-6-(tr iflu or om eth yl)ben zim id a zole
(6d ). Compound 5d (265 mg, 1.00 mmol), AcOH (1 mL), 37%
HCHO (0.1 mL, 1.34 mmol), and concentrated HCl (0.1 mL)
were mixed, and the solution was heated at 80 °C for 15 min.
After it had cooled, water (20 mL) was added and the product
was extracted with CHCl3. The product was then purified by
PLC (silica gel, 19/1 CHCl3/MeOH) to obtain 193 mg (70%) of
6d . Recrystallization from MeOH gave colorless columns: mp
172-174 °C; 1H NMR (Me2SO-d6) δ 6.61 (d, 2H, J ) 8.1 Hz,
2′-H, 6′-H), 6.95 (t, 1H, J ) 7.3 Hz, 4′-H), 7.26 (m, 2H, 3′-H,
5′-H), 7.62 (dd, 1H, J ) 1.2, 8.5 Hz, 5-H), 7.74 (d, 1H, J ) 1.2
Hz, 7-H), 7.98 (d, 1H, J ) 8.5 Hz, 4-H), 8.63 (s, 1H, 2-H); MS
m/z 277 (M+). Anal. Calcd for C14H10F3N3: C, 60.65; H,3.63; N,
15.16. Found: C, 60.64; H, 3.72; N, 15.14.
1H, 2-H, H-D exchange occurred with the addition of D2O); 13
C
NMR (Me2SO-d6) δ 34.4 (1-CH3), 108.9 (4-C), 113.9 (2′-C, 6′-C),
115.9 (7-C), 122.1 (6-C), 122.7 (4′-C), 129.5 (3′-C, 5′-C), 129.8
(3a-C), 134.9 (7a-C), 145.0 (1′-C), 145.8 (5-C), 149.3 (2-C).
(27) 1-Meth yl-3-(4-n itr op h en yla m in o)ben zim id a zoliu m
Iod id e (7f). A mixture of 1-acetylaminobenzimidazole (18) (8,
500 mg, 2.85 mmol), K2CO3 (100 mg), and 1-fluoro-4-nitroben-
zene (0.6 mL, 5.66 mmol) in n-propanol (25 mL) was heated
under reflux for 24 h. After the solvent had been removed by
evaporation, the product was separated by PLC (silica gel, 19/1
CHCl3/MeOH) to obtain 195 mg (27%) of 1-(4-nitrophenylamino)-
benzimidazole (9) as a yellow powder: 1H NMR (CDCl3) δ 6.62
(d, 2H, J ) 8.5 Hz, 2′-H, 6′-H), 7.24 (d, 1H, J ) 7.9 Hz, 4-H),
7.32 and 7.36 (each m, each 1H, 5-H, 6-H), 7.85 (d, 1H, J ) 7.9
Hz, 7-H), 8.05 (s, 1H, 2-H), 8.14 (d, 2H, J ) 8.5 Hz, 3′-H, 5′-H).
(23) 1-Meth yl-3-(p h en yla m in o)-5-(tr iflu or om eth yl)ben z-
im id a zoliu m Iod id e (7d ). Compound 6d (485 mg, 1.75 mmol)
was dissolved in 10 mL of MeOH. CH3I (438 µL, 7.04 mmol)
was then added, and the mixture was heated at 50 °C for 1 day.
Further addition of CH3I (438 µL) and a 1 day reaction were
repeated three times. After the solvent had been removed by
evaporation, the product was separated and purified by column
chromatography (silica gel, CHCl3 f 19/1 CHCl3/MeOH f 9/1
CHCl3/MeOH) to obtain 334 mg (46%) of 7d . Recrystallization
from EtOH gave colorless plates: mp 204-206 °C; 1H NMR
(Me2SO-d6) δ 6.87 (d, 2H, J ) 8.1 Hz, 2′-H, 6′-H), 7.03 (t, 1H, J
) 7.4 Hz, 4′-H), 7.30 (m, 2H, 3′-H, 5′-H), 7.91 (s, 1H, 4-H), 8.13
(d, 1H, J ) 8.9 Hz, 6-H), 8.41 (d, 1H, J ) 8.9 Hz, 7-H), 10.28 (br
s, 1H, NH), 10.35 (s, 1H, 2-H, H-D exchange occurred with the
addition of D2O); 13C NMR (Me2SO-d6) δ 34.2 (1-CH3), 110.3 (4-
C), 113.8 (2′-C, 6′-C), 116.2 (7-C), 122.5 (4′-C), 123.7 (6-C), 124.6
(5-C), 127.3 (5-CF3), 129.4 (3′-C, 5′-C), 130.0 (3a-C), 133.7 (7a-
C), 145.1 (1′-C), 147.7 (2-C); FAB MS m/z 292 [(M - I)+], 201
[(M - I)+ - PhN]. Anal. Calcd for C15H13F3IN3‚0.25H2O: C,
42.52; H, 3.21; N, 9.92. Found: C, 42.33; H, 3.26; N, 9.94.
1-(4-Nitrophenylamino)benzimidazole (9, 206 mg, 0.810 mmol)
was dissolved in MeOH (5 mL). A large excess of CH3I (10 mL)
was then added, and the solution was heated at 50 °C for 3 days.
After the solvent had been removed by evaporation, the product
was separated by column chromatography (silica gel, CHCl3 f
9/1 CHCl3/MeOH) to obtain 254 mg (79%) of 1-methyl-3-(4-
nitrophenylamino)benzimidazolium iodide (7f). Recrystal-
lization from MeOH gave pale yellow plates: mp 201.5-203.5
°C; 1H NMR (CDCl3) δ 6.62 (d, 2H, J ) 8.5 Hz, 2′-H, 6′-H), 7.24
(d, 1H, J ) 7.9 Hz, 4-H), 7.32 and 7.36 (each m, each 1H, 5-H,
6-H), 7.75 (br s, 1H, NH), 7.85 (d, 1H, J ) 7.9 Hz, 7-H), 8.05 (s,
1H, 2-H), 8.14 (d, 2H, J ) 8.5 Hz, 3′-H, 5′-H); 13C NMR (CDCl3)
δ 33.9 (1-CH3), 112.3 (7-C), 113.0 (2′-C, 6′-C), 114.3 (4-C), 125.7
(3′-C, 5′-C), 127.1 (6-C), 127.4 (5-C), 129.8 (3a-C), 131.2 (7a-C),
(24) 4-Nitr o-2-ph en ylazoan iln e (5e). 4-Nitro-1,2-phenylene-
diamine (1.99 g, 13.0 mmol, Aldrich) was dissolved in a mixture
of AcOH (7.8 mL) and EtOH (5.2 mL), and nitrosobenzene (1.53
g, 14.3 mmol) was then added. After the reaction mixture had