SARs for Substituted 1-Phenylbenzimidazoles
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27 5463
portion afforded an oil which was chromatographed on silica
Ph), 7.64-7.62 (m, 2 H, Ph), 7.53 (dd, J ) 8.4, 8.1 Hz, 1 H,
H-6), 7.24 (d, J ) 8.4 Hz, 1 H, H-7), 7.15 (d, J ) 8.1 Hz, 1 H,
H-5), 4.08 (s, 3 H, OCH3); 13C NMR δ 150.50 (s), 141.65 (d),
135.98 (s), 135.31 (s), 133.24 (d), 133.11 (d), 130.96 (d), 127.28
(d), 124.57 (s), 110.09 (d), 107.48 (d), 59.02 (q). Anal. (C14H12N2O‚
HCl) C, H, N.
4-Hydr oxy-1-ph en ylben zim idazole Hydr och lor ide (56).
A solution of 55 (0.25 g, 1.11 mmol) in 48% HBr in glacial
AcOH (15 mL) was refluxed for 48 h and concentrated to
dryness. The residue was partitioned between 2 N NaOH and
Et2O, the aqueous portion was carefully neutralized with 2 N
HCl and extracted with EtOAc, and the extract was worked
up to give a solid. Chromatography of this on silica gel, eluting
with EtOAc/petroleum ether (1:1), gave 56 (77%). HCl salt:
mp 238-240 °C; 1H NMR (D2O) δ 9.41 (s, 1 H, H-2), 7.74-
7.67 (m, 5 H, Ph), 7.47 (dd, J ) 8.3, 8.2 Hz, 1 H, H-6), 7.22 (d,
J ) 8.3 Hz, 1 H, H-7), 7.08 (dd, J ) 8.2 Hz, 1 H, H-5); 13C
NMR δ 147.45 (s), 141.70 (d), 136.00 (s), 135.85 (s), 133.32 (d),
133.10 (d), 131.01 (d), 127.47 (d), 123.81 (s), 114.17 (d), 106.90
(d). Anal. (C13H10N2O‚HCl‚0.25H2O) C, H, N.
gel. Elution with EtOAc gave 83 (0.48 g, 33%). DiHCl salt:
1
mp (MeOH/Et2O) 204 °C (dec); H NMR (D2O) δ 9.67 (s, 1 H,
H-2), 8.15 (d, J ) 8.9 Hz, 1 H, H-4), 7.87 (d, J ) 1.9 Hz, 1 H,
H-7), 7.81-7.78 (m, 5 H, Ph), 7.76 (dd, J ) 8.9, 1.9 Hz, 1 H,
H-5); 13C NMR δ 144.78 (d), 135.49 (s), 134.76 (s), 133.72 (d),
133.40 (s), 133.30 (d), 132.74 (s), 127.74 (d), 124.87 (d), 119.77
(d), 110.91 (d). Anal. (C13H11N3‚2HCl) C, H, N.
1-P h en yl-1H-im id a zo[5,4-b]p yr id in e Dih yd r och lor id e
(93). A solution of 2-chloro-3-nitropyridine (96g) (0.50 g, 3.15
mmol), aniline (0.29 mL, 3.15 mmol), and concentrated HCl
(26 µL, 0.31 mmol) in 1:1 water/2-methoxyethanol (25 mL) was
refluxed for 18 h. On cooling, orange needles of 2-(N-phenyl-
amino)-3-nitropyridine (97g) separated (0.42 g, 57%): mp 66-
1
67 °C; H NMR (CDCl3) δ 10.11 (br, 1 H, NH), 8.53 (dd, J )
8.2, 1.9 Hz, 1 H, H-6), 8.48 (dd, J ) 4.5, 1.9 Hz, 1 H, H-4),
7.66-7.62 (m, 2 H, Ph), 7.42-7.38 (m, 2 H, Ph), 7.21-7.16
(m, 1 H, Ph), 6.83 (dd, J ) 8.2, 4.5 Hz, 1 H, H-5); 13C NMR δ
155.27 (d), 150.27 (s), 137.82 (s), 135.53 (d), 129.01 (d), 128.60
(s), 124.84 (d), 122.56 (d), 113.88 (d). Anal. (C11H9N3O2‚
0.25H2O) C, H, N. Reduction of 97g followed by reaction with
formamidine acetate, as above, gave 93 (77%). DiHCl salt: mp
(MeOH/Et2O) 205-209 °C; 1H NMR (D2O) δ 9.65 (s, 1 H, H-2),
8.67 (dd, J ) 7.0, 2.0 Hz, 1 H, H-6), 8.45 (dd, J ) 8.5, 2.0 Hz,
1 H, H-4), 7.81-7.70 (m, 6 H, H-5 and Ph); 13C NMR δ 150.60
(d), 145.81 (s), 144.67 (d), 134.72 (s), 133.37 (d), 132.86 (d),
128.68 (d), 128.08 (s), 127.92 (d), 125.47 (d). Anal. (C12H9N3‚
2HCl) C, H, N.
1-P h en ylben zim id a zole-4-ca r boxylic Acid Hyd r och lo-
r id e (58). To a refluxing solution of the free base of 54 (3.23
g, 0.015 mmol) in tert-butyl alcohol (200 mL) and water (50
mL) was added powdered KMnO4 in portions over 48 h (a total
of 9.00 g, 0.057 mmol). The hot solution was filtered through
Celite, and the filtrate was concentrated under reduced
pressure to a volume of ca. 80 mL. Water was added, and the
solution was washed with EtOAc. Workup of the extract
afforded starting material (0.86 g, 27%). The aqueous portion
was carefully neutralized with 3 N HCl to precipitate 58 (1.87
g, 52%). HCl salt: mp (MeOH/Et2O) 245-248 °C; 1H NMR
(D2O) δ 9.70 (s, 1 H, H-2), 8.21 (d, J ) 7.5 Hz, 1 H, H-5), 8.00
4-Meth yl-1-p h en ylben zim id a zole Hyd r och lor id e (54)
by th e Meth od of Sch em e 2. A mixture of 3-methyl-2-
nitroaniline (98a ) (12.00 g, 79 mmol), K2CO3 (6.00 g, 43 mmol),
and cuprous iodide (0.20 g, 1.05 mmol) in bromobenzene (40
mL) was refluxed with vigorous stirring for 16 h and the excess
of bromobenzene was removed under reduced pressure. The
residue was partitioned between EtOAc and water and filtered
through Celite, and the organic layer was worked up and
chromatographed on silica gel. Petroleum ether eluted 3-meth-
yl-2-nitrodiphenylamine (99a ) (8.21 g, 45%): mp (aqueous
EtOH) 59-61 °C; 1H NMR (CDCl3) δ 7.75 (br, 1 H, NH), 7.34
(dd, J ) 9.4, 7.4 Hz, 1 H, H-5), 7.24-6.98 (m, 6 H, Ph and
H-4), 6.72 (dd, J ) 7.4, 2.0 Hz, 1 H, H-6), 2.47 (s, 3 H, CH3);
13C NMR δ 140.30 (s), 139.68 (s), 134.52 (s), 132.27 (d), 129.55
(d), 123.82 (d), 123.08 (s), 122.23 (d), 121.65 (d), 115.28 (d),
20.36 (q). Anal. (C13H12N2O2) C, H, N.
Reduction of 99a with H2/Pd-C, followed by reaction of the
crude phenylenediamine with formamidine acetate, as detailed
above, gave the benzimidazole (54) (98%). HCl salt: mp
(MeOH/Et2O) 206-208 °C; 1H NMR (D2O) δ 9.49 (s, 1 H, H-2),
7.77-7.73 (m, 3 H), 7.62-7.60 (m, 2 H), 7.49-7.42 (m, 3 H),
2.66 (s, 3 H, CH3); 13C NMR δ 141.89 (d), 135.73 (s), 133.27
(d), 133.15 (d), 133.00 (s), 130.24 (d), 129.83 (d), 128.52 (s),
127.02 (d), 112.79 (d), 18.49 (q). Anal. (C14H12N2‚HCl) C, H,
N.
(d, J ) 8.3 Hz, 1 H, H-7), 7.79-7.71 (m, 6 H, Ph and H-6); 13
C
NMR δ 169.73 (s), 143.83 (d), 135.30 (s), 134.83 (s), 133.64 (d),
133.16 (d), 132.21 (s), 132.06 (d), 129.63 (d), 127.57 (d), 121.05
(d), 120.66 (s). Anal. (C14H10N2O2‚HCl) C, H, N.
Meth yl 1-P h en ylben zim id a zole-4-ca r boxyla te Hyd r o-
ch lor id e (59). A mixture of the acid 58 (0.50 g, 2.10 mmol)
and SOCl2 (10 mL) in 1,2-dichloroethane (50 mL) containing
DMF (1 drop) was refluxed for 2 h. The solution was concen-
trated to dryness under reduced pressure. The resulting crude
acid chloride was dissolved in methanol (20 mL) and the
solution refluxed for 15 min. The methanol was removed under
reduced pressure and the residue partitioned between EtOAc
and saturated aqueous NaHCO3. The organic solution was
worked up to give 59 (0.48 g, 91%). HCl salt: mp (MeOH/Et2O)
187-189 °C; 1H NMR [(CD3)2SO] δ 9.72 (s, 1 H, H-2), 8.28 (d,
J ) 8.1 Hz, 1 H, H-5), 8.04 (d, J ) 8.4 Hz, 1 H, H-7), 7.79-
7.71 (m, 6 H, Ph and H-6), 4.11 (s, 3 H, COOCH3); 13C NMR δ
168.47 (s), 144.07 (d), 135.26 (s), 134.96 (s), 133.69 (d), 133.18
(d), 132.01 (d), 131.93 (s), 129.66 (d), 127.62 (d), 121.36 (d),
119.80 (s), 55.83 (q). Anal. (C15H12N2O2‚HCl‚1.5H2O) H, N. C:
found, 56.5; calcd, 57.0%.
4-Meth oxy-1-p h en ylben zim id a zole Hyd r och lor id e (55)
by th e Meth od of Sch em e 2. A suspension of 3-methoxy-2-
nitroaniline (98b) (5.00 g, 0.030 mmol), K2CO3 (2.21 g, 0.016
mmol), and cuprous iodide (50 mg, 0.26 mmol) in bromoben-
zene (10 mL) was refluxed with vigorous stirring for 18 h and
the excess of bromobenzene was removed under reduced
pressure. The residue was partitioned between EtOAc and
water and filtered through Celite, and the organic layer was
worked up and chromatographed on silica gel. EtOAc/
petroleum ether (1:19) eluted 3-methoxy-2-nitrodiphenylamine
(99b) (4.00 g, 54%): mp (aqueous MeOH) 95 °C; 1H NMR
(CDCl3) δ 7.52 (br, 1 H, NH), 7.33 (dd, J ) 8.6, 8.3 Hz, 1 H,
H-5), 7.23-7.08 (m, 5 H, Ph), 6.84 (dd, J ) 8.6, 0.8 Hz, 1 H,
H-6), 6.44 (dd, J ) 8.3, 0.8 Hz, 1 H, H-4), 3.91 (s, 3 H, OCH3);
13C NMR δ 154.33 (s), 140.32 (s), 140.06 (s), 132.70 (d), 129.51
(d), 123.96 (d), 121.82 (d), 108.86 (d), 102.57 (d), 56.53 (q). Anal.
(C13H12N2O3) C, H, N.
1-P h en ylb en zim id a zole-4-ca r b oxa m id e H yd r och lo-
r id e (60). A solution of the acid chloride [obtained from the
acid 58 as described above] (0.50 g, 2.10 mmol) in Et2O (40
mL) was treated with concentrated aqueous ammonia (10 mL).
After the mixture was vigorously stirred at room temperature
for 10 min, saturated aqueous NaHCO3 solution (20 mL) was
added, and the ether layer was removed and worked up to give
60 (0.47 g, 94%). HCl salt: mp (MeOH/Et2O) 242-244 °C; 1H
NMR (D2O) δ 9.67 (s, 1 H, H-2), 8.08 (d, J ) 7.8 Hz, 1 H, H-5),
7.98 (d, J ) 8.5 Hz, 1 H, H-7), 7.78-7.72 (m, 6 H, Ph and H-5);
13C NMR δ 171.60 (s), 143.83 (d), 135.40 (s), 135.14 (s), 133.60
(d), 133.13 (d), 131.78 (s), 129.65 (d), 128.91 (d), 127.65 (d),
122.78 (s), 120.03 (d). Anal. (C14H13N3O‚HCl) C, H, N.
4-Am in o-1-p h en ylben zim id a zole Hyd r och lor id e (62).
A solution of sodium azide (1.00 g, 0.015 mmol) in water (3
mL) was added to a solution of the acid chloride (obtained from
the acid 58) (0.50 g, 2.10 mmol) in Me2CO (20 mL) at 5 °C.
After the mixture was stirred at this temperature for 10 min,
water was added and the mixture was extracted with CH2Cl2.
The extract was worked up to give crude acyl azide, which was
used directly. A solution of the acyl azide in glacial acetic acid
Reduction of 99b with H2/Pd-C followed by reaction of the
crude phenylenediamine with formamidine acetate, as detailed
above, gave the benzimidazole (55) (74%). HCl salt: mp 191-
193 °C; 1H NMR (D2O) δ 9.35 (s, 1 H, H-2), 7.71-7.70 (m, 3 H,