2378 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13
Palmer et al.
1
hydrobromide (97 mg, 0.47 mmol) was added, and the mixture
was warmed at 45 °C for 30 min. A further portion of sodium
hydride (28.5 mg) followed by the bromoethylamine hydrobro-
mide (97 mg) was added, and stirring was continued at this
temperature for 1 h. Water was added, followed by brine, and
the mixture was extracted into EtOAc. The organic solution
was extracted into 2 N HCl, the extract was basified with 2 N
NaOH and extracted into ether, and the ether solution worked
up to give an oil which was chromatographed on alumina.
EtOAc eluted foreruns while MeOH/EtOAc (1:9) gave 15 (68.5
mg, 58%). DiHCl salt: mp (MeOH/Et2O) 252-254 °C; 1H NMR
(D2O) δ 9.43 (s, 1 H, H-2), 7.78-7.72 (m, 6 H, Ph and H-7),
7.51 (d, J ) 2.3 Hz, 1 H, H-4), 7.38 (dd, J ) 9.2, 2.3 Hz, 1 H,
H-6), 4.46 (t, J ) 4.9 Hz, 2 H, CH2NH3), 3.56 (t, J ) 4.9 Hz, 2
H, OCH2); 13C NMR δ 160.02 (s), 142.22 (d), 135.96 (s), 134.61
(s), 133.40 (d), 133.16 (d), 129.29 (s), 127.54 (d), 120.04 (d),
117.02 (d), 100.97 (d), 67.55 (t), 41.64 (t). Anal. (C15H15N3O‚
2HCl‚0.5H2O) C, H, N.
dec above 84 °C (hygroscopic solid); H NMR (D2O) δ 9.42 (s,
1 H, H-2), 7.81-7.74 (m, 5 H, Ph), 7.72 (d, J ) 9.2 Hz, 1 H,
H-7), 7.47 (d, J ) 2.2 Hz, 1 H, H-4), 7.34 (dd, J ) 9.2, 2.2 Hz,
1 H, H-6), 4.33 (t, J ) 5.6 Hz, 2 H, CH2N+), 4.23 (br d, J )
12.9 Hz, 2 H, morpholino CH2N+), 3.92 (br t, J ) 12.9 Hz, 2
H, morpholino CH2N+), 3.70 (br d, J ) 12.6 Hz, 2 H,
morpholino CH2O), 3.52 (t, J ) 5.6 Hz, 2 H, CH2O), 3.36-
3.28 (m, 2 H, morpholino CH2O), 2.42-2.36 (m, 2 H, CH2CH2-
CH2); 13C NMR δ 160.39 (s), 142.00 (d), 135.93 (s), 134.61 (s),
133.35 (d), 133.14 (d), 128.94 (s), 127.43 (d), 120.08 (d), 116.89
(d), 100.79 (d), 68.65 (t), 66.58 (t), 57.58 (t), 54.62 (t), 25.86
(t). Anal. (C20H23N3O2‚2HCl‚3.5H2O) C, H, N.
5-[4-(4-Mor ph olin o)bu toxy]-1]ph en ylben zim idazole Di-
h yd r och lor id e (21). The remaining half of the crude mesylate
solution obtained from 12 during preparation of 18 (see earlier)
was concentrated to dryness and the residue dissolved in
morpholine (10 mL) and refluxed for 30 min. After removal of
excess morpholine under reduced pressure, the residue was
partitioned between brine and EtOAc and the organic portion
was worked up and chromatographed on alumina. EtOAc
eluted 21 (0.27 g, 49%): mp (dihydrochloride salt from MeOH/
Et2O) 100-103 °C (hygroscopic powder); 1H NMR (D2O) δ 9.40
(s, 1 H, H-2), 7.75-7.72 (m, 5 H, Ph), 7.70 (d, J ) 9.2 Hz, 1 H,
H-7), 7.45 (d, J ) 2.3 Hz, 1 H, H-4), 7.32 (dd, J ) 9.2, 2.3 Hz,
1 H, H-6), 4.24 (t, J ) 5.9 Hz, 2 H, CH2O), 4.17 (dd, J ) 13.2,
3.4 Hz, 2 H, CH2O), 3.90-3.82 (m, 2 H, CH2O), 3.61-3.59 (m,
2 H, CH2N+), 3.32 (t, J ) 6.9 Hz, 2 H, CH2N+), 3.28-3.21 (m,
2 H, CH2N+); 13C NMR δ 160.69 (s), 141.91 (d), 135.95 (s),
134.54 (s), 133.37 (d), 133.14 (d), 128.88 (s), 127.50 (d), 120.17
(d), 116.89 (d), 100.80 (d), 71.02 (t), 66.54 (t), 59.64 (t), 54.39
(t), 28.13 (t), 22.89 (t). CIMS [M + H]+ C21H26N3O2 requires
352.2025. Found 352.2013.
1-(4-Am in op h en yl)-5-m eth oxyben zim id a zole Dih yd r o-
ch lor id e (22). A mixture of 4-methoxy-2-nitroaniline (1.00 g,
5.95 mmol), K2CO3 (0.34 g, 2.46 mmol), CuI (50 mg), and
4-nitrobromobenzene (3.00 g, 0.015 mmol) was heated with
stirring to 150 °C for 48 h. The cooled mixture was partitioned
between EtOAc and brine, and the organic portion was worked
up and chromatographed on silica gel. EtOAc/petroleum ether
(1:1) eluted 4-methoxy-2-nitro-N-(4-methoxyphenyl)aniline (1.12
g), contaminated with some starting material, which was used
directly. The mixture was dissolved in EtOAc/MeOH (1:1) (50
mL) and hydrogenated over 5% Pd-C (0.20 g) for 3 h. The
solution was filtered through Celite to remove catalyst and
evaporated under reduced pressure. The residue was dissolved
in 4 N HCl (30 mL) containing formic acid (1 mL) the solution
was heated under reflux for 90 min and then concentrated to
dryness, the residue was partitioned between EtOAc and
ammonia, and the organic layer was worked up and chromato-
graphed on silica gel. EtOAc/petroleum ether (1:1) eluted
foreruns while EtOAc gave 22 (0.26 g, 17%). DiHCl salt: mp
(MeOH/Et2O) 237-239 °C; 1H NMR (D2O) δ 9.44 (s, 1 H, H-2),
7.86 (d, J ) 8.7 Hz, 2 H, H-3′,5′), 7.70 (d, J ) 9.2 Hz, 1 H, 7),
7.69 (d, J ) 8.7 Hz, 2 H, H-2′,6′), 7.46 (d, J ) 2.3 Hz, 1 H,
H-4), 7.33 (dd, J ) 9.2, 2.3 Hz, 1 H, H-6), 3.98 (s, 3 H, OCH3);
13C NMR δ 161.69 (s), 142.02 (d), 137.08 (s), 135.28 (s), 134.53
(s), 129.41 (d), 128.71 (s), 126.89 (d), 120.08 (d), 116.64 (d),
99.97 (d), 58.90 (q). Anal. (C14H13N3O‚2HCl‚0.5H2O) C, H, N.
The following ethers were obtained from 5 and the ap-
propriate haloamines in a similar manner:
5-[2-(N,N-Dim eth yla m in o)eth oxy]-1-p h en ylben zim id -
a zole Dih yd r och lor id e (16) (47%) (diHCl salt): mp (MeOH/
1
Et2O) 205-207 °C (hygroscopic foam); H NMR (D2O) δ 9.45
(s, 1 H, H-2), 7.77-7.72 (m, 6 H, Ph and H-7), 7.53 (d, J ) 2.3
Hz, 1 H, H-4), 7.39 (dd, J ) 9.2, 2.3 Hz, 1 H, H-6), 4.55 (t, J )
5.0 Hz, 2 H, CH2N+Me2), 3.73 (t, J ) 5.0 Hz, 2 H, OCH2), 3.06
(s, 6 H, N+Me2); 13C NMR δ 159.71 (s), 142.27 (d), 135.91 (s),
134.42 (s), 133.43 (d), 133.15 (d), 129.39 (s), 127.57 (d), 119.97
(d), 117.08 (d), 100.98 (d), 65.16 (t), 58.91 (t), 45.63 (q). Anal.
(C17H19N3O‚2HCl) C, H, N.
5-[3-(N,N-Dim et h yla m in o)p r op oxy]-1-p h en ylb en zim -
idazole Dih ydr och lor ide (17) (52%) (diHCl salt): mp (MeOH/
Et2O) dec above 76 °C (hygroscopic); 1H NMR (D2O) δ 9.41 (s,
1 H, H-2), 7.75-7.71 (m, 6 H, Ph and H-7), 7.46 (d, J ) 2.3
Hz, 1 H, H-4), 7.33 (dd, J ) 9.2, 2.3 Hz, 1 H, H-6), 4.30 (t, J )
5.7 Hz, 2 H, CH2 N+Me2), 3.44 (t, J ) 7.7 Hz, 2 H, CH2O),
2.98 (s, 6 H, N+Me2), 2.36-2.29 (m, 2 H, CH2CH2CH2); 13C
NMR δ 160.49 (s), 142.01 (d), 135.94 (s), 134.43 (s), 133.42 (d),
133.14 (d), 129.08 (s), 127.58 (d), 120.15 (d), 116.97 (d), 100.76
(d), 68.73 (t), 58.21 (t), 45.63 (q), 26.69 (t). Anal. (C18H21N3O‚
2HCl‚3.5H2O) C, H, N.
5-[4-(N,N-Dim eth yla m in o)bu toxy]-1-p h en ylben zim id -
a zole Dih yd r och lor id e (18). Methanesulfonyl chloride (0.27
mL, 3.31 mmol) was added dropwise at 20 °C to a stirred
solution of the butanol 12 (0.85 g, 3.01 mmol) and Et3N (0.50
mL, 3.61 mmol) in CH2Cl2 (50 mL). After 5 min the resulting
solution was evaporated to dryness under reduced pressure
to give the crude mesylate. Half of this was dissolved in MeOH
(20 mL) containing dimethylamine (5 mL of a 40% aqueous
solution), and the mixture was warmed in a pressure vessel
at 80 °C for 15 h. After concentration to dryness the residue
was partitioned between EtOAc and water, and the organic
portion was chromatographed on alumina. EtOAc eluted
foreruns while MeOH/EtOAc (1:9) gave 18 (0.32 g, 65%): mp
(dihydrochloride salt from MeOH/Et2O) 88 °C (hygroscopic
1
foam). H NMR (D2O) δ 9.31 (s, 1 H, H-2), 7.75-7.70 (m, 5 H,
Ph), 7.70 (d, J ) 9.2 Hz, 1 H, H-7), 7.43 (d, J ) 2.3 Hz, 1 H,
H-4), 7.30 (dd, J ) 9.2, 2.3 Hz, 1 H, H-6), 4.23 (t, J ) 5.7 Hz,
2 H, CH2O), 3.25 (t, J ) 7.0 Hz, 2 H, CH2N+), 2.91 (s, 6 H,
+NMe2), 2.00-1.91 (m, 4 H, CH2). EIMS [M+] C19H23N3O
requires 309.1841. Found 309.1810.
5-Mer capto-1-ph en ylben zim idazole Hydr och lor ide (23).
A solution of 5 (0.88 g, 4.10 mmol) in 1:1 THF/DMF (15 mL)
was added dropwise under nitrogen to a stirred suspension of
NaH (0.24 g of a 50% dispersion in oil, 5.00 mmol) in THF (10
mL). After 10 min a solution of dimethylthiocarbamoyl chloride
(0.57 g, 4.6 mmol) in THF (5 mL) was added, and the solution
was warmed at 60 °C for 1 h. The cooled solution was
partitioned between ether and 2 N KOH, and the organic
portion was worked up and chromatographed on silica. Elution
with EtOAc/petroleum ether (7:3) gave the O-benzimidazolyl
dimethylthiocarbamate (26) (0.76 g, 65%): mp (EtOAc/
petroleum ether) 173-174.5 °C; 1H NMR [(CD3)2SO] δ 8.61
(s, 1 H, H-2), 7.72-7.62 (m, 4 H, Ph), 7.60 (d, J ) 8.7 Hz, 1 H,
H-7), 7.54-7.49 (m, 1 H, Ph), 7.45 (d, J ) 2.2 Hz, 1 H, H-4),
7.04 (dd, J ) 8.7, 2.2 Hz, 1 H, H-6), 3.39, 3.36 (2s, each 3 H,
NMe2); 13C NMR δ 187.03 (s), 149.51 (s), 144.27 (d), 143.78
5-[2-(4-Mor ph olin o)eth oxy]-1-p h en ylben zim id a zole Di-
h yd r och lor id e (19) (57%) (diHCl salt): mp (MeOH/Et2O)
232-234 °C (hygroscopic foam); 1H NMR (D2O) δ 9.44 (s, 1 H,
H-2), 7.78-7.72 (m, 6 H, Ph and H-7), 7.53 (d, J ) 2.3 Hz, 1
H, H-4), 7.39 (dd, J ) 9.2, 2.3 Hz, 1 H, H-6), 4.60 (t, J ) 4.8
Hz, 2 H, CH2N+), 4.19-3.95 (2 × br, 4 H, morpholino CH2N+),
3.79 (t, J ) 4.8 Hz, 2 H, CH2O); 13C NMR δ 159.61 (s), 142.34
(d), 135.95 (s), 134.60 (s), 133.40 (d), 133.16 (d), 129.42 (s),
127.55 (d), 119.93 (d), 117.07 (d), 101.05 (d), 66.38 (t), 64.70
(t), 58.57 (t), 54.73 (t). Anal. (C19H21N3O2‚2HCl‚0.5H2O) C, H,
N.
5-[3-(4-Mor p h olin o)p r op oxy]-1]p h en ylb en zim id a zole
Dih yd r och lor id e (20) (52%) (diHCl salt): mp (MeOH/Et2O)