S. Dettmann et al. / Bioorg. Med. Chem. 18 (2010) 4905–4916
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were combined, stirred for 2 h at 0 °C and further 4 h at room
temperature. The reaction mixture was poured into water (20 mL),
extracted with CH2Cl2 (3 ꢂ 50 mL), dried over Na2SO4, filtered and
then the solvent was evaporated. The product was purified by col-
umn chromatography on silica gel with CH2Cl2/MeOH 98:2.
d = 1.26–1.39 (m, 2H, CH2), 1.40–1.59 (m, 4H, CH2), 2.34–2.42
(m, 4H, CH2), 2.54–2.63 (m, 2H, @N–CH2–), 3.86–4.07 (m, 2H,
–O–CH2–), 5.46 (s, 2H, phenyl-CH2–), 6.85 (d, 3J = 8.6 Hz, 2H,
ArH), 6.89 (d, 3J = 8.7 Hz, 2H, ArH), 6.92 (d, 3J = 8.6 Hz, 2H, ArH),
7.09–7.25 (m, 2H, ArH), 7.34–7.47 (m, 1H, ArH), 7.55 (d, 3J =
8.5 Hz, 2H, ArH), 7.62–7.70 (m, 1H, ArH), 9.95 (s, 1H, OH). MS (EI,
330 °C): m/z (%) = 427 [M]+Å (8.4), 329 (0.2), 316 (0.8), 210 (4.7),
5.2.3.1. 2-(4-Methoxyphenyl)-1-[4-(2-piperidin-1-ylethoxy)ben-
zyl]-1H-benzimidazole (6a). From 4a (128 mg, 0.57 mmol).
Yield: 160 mg (63%), yellow oil. 1H NMR (DMSO-d6): d = 1.30–
1.38 (m, 2H, CH2), 1.38–1.55 (m, 4H, CH2), 2.35–2.41 (m, 4H,
CH2), 2.54–2.61 (m, 2H, CH2), 3.82 (s, 3H, OCH3), 3.97 (t,
3J = 5.9 Hz, 2H, –O–CH2–), 5.47 (s, 2H, phenyl-CH2–), 6.84 (d,
3J = 8.6 Hz, 2H, ArH), 6.92 (d, 3J = 8.6 Hz, 2H, ArH), 7.08 (d,
3J = 8.7 Hz, 2H, ArH), 7.17–7.25 (m, 2H, ArH), 7.38–7.48 (m, 1H,
ArH), 7.62–7.72 (m, 3H, ArH). MS (EI, 135 °C): m/z (%) = 441 [M]+Å
(8.5), 411 (1.0), 343 (0.4), 329 (0.3), 251 (0.2), 217 (1.1), 113
113 (0.5), 98 (100.0). IR (KBr):
m = 3426 (m), 3056 (m), 2933 (s),
1611 (s), 840 (w), 746 (m). Anal. Calcd for C27H29N3O2: C, 75.85;
H, 6.84; N, 9.83. Found: C, 75.87; H, 6.85; N, 9.84.
5.2.4.2. 5-Hydroxy-2-phenyl-1-[4-(2-piperidin-1-ylethoxy)ben-
zyl]-1H-benzimidazole (7b). From 6b (150 mg, 0.34 mmol).
Yield: 16 mg (11%), colorless oil. 1H NMR (DMSO-d6): d = 1.27–
1.41 (m, 2H, CH2), 1.41–1.55 (m, 4H, CH2), 2.34–2.42 (m, 4H,
CH2), 2.58–2.65 (m, 2H, @N–CH2–), 3.85–4.05 (m, 2H, –O–CH2–),
5.40 (s, 2H, phenyl-CH2–), 6.72 (dd, 3J = 8.6 Hz, 4J = 2.0 Hz, 1H,
ArH), 6.82 (d, 3J = 8.5 Hz, 2H, ArH), 6.90 (d, 3J = 8.5 Hz, 2H, ArH),
7.01 (d, 4J = 1.8 Hz, 1H, ArH), 7.24 (d, 3J = 8.7 Hz, 1H, ArH), 7.45–
7.57 (m, 3H, ArH), 7.65–7.75 (m, 2H, ArH), 9.09 (s, 1H, OH). MS
(EI, 270 °C): m/z (%) = 427 [M]+Å (5.8), 329 (3.1), 210 (1.7), 113
(4.2), 98 (100.0). IR (film):
m = 3005 (w), 2934 (m), 2854 (w),
1674 (w), 1612 (m), 1580 (w), 1512 (m), 1251 (s), 837 (m), 750 (s).
5.2.3.2. 5-(6)-Methoxy-2-phenyl-1-[4-(2-piperidin-1-ylethoxy)-
benzyl]-1H-benzimidazole (6b). From 4b (239 mg, 1.07 mmol).
Yield: 150 mg (32%), yellow oil. Ratio of the isomeres 0.8:1. 1H
NMR (DMSO-d6): d = 1.27–1.40 (m, 3.6H, CH2), 1.40–1.52 (m,
7.2H, CH2), 2.34–2.42 (m, 7.2H, CH2), 2.58 (t, 3J = 5.9 Hz, 3.6H,
@N–CH2–), 3.75 (s, 3H, OCH3), 3.80 (s, 2.4H, OCH3), 3.97 (t,
3J = 6.0 Hz, 3.6H, –O–CH2–), 5.46 (s, 1.6H, phenyl-CH2–), 5.48 (s,
2H, phenyl-CH2–), 6.79–6.85 (d, 3J = 8.7 Hz, 3.6H, ArH), 6.85–6.95
(m, 5.4H, ArH), 7.04 (d, 4J = 2.3 Hz, 1H, ArH), 7.23 (d, 4J = 2.3 Hz,
0.8H, ArH), 7.35 (d, 3J = 8.9 Hz, 0.8H, ArH), 7.41–7.56 (m, 5.4H,
ArH), 7.60 (d, 3J = 8.8 Hz, 1H, ArH), 7.64–7.76 (m, 3.6H, ArH). MS
(EI, 320 °C): m/z (%) = 442 [M]+Å (4.7), 343 (0.3), 330 (0.2), 113
(0.6), 98 (100.0). IR (film):
m = 3435 (s), 2927 (m), 1616 (w), 1512
(w), 802 (w), 775 (w), 699 (w). Anal. Calcd for C27H29N3O2: C,
75.85; H, 6.84; N, 9.83. Found: C, 75.79; H, 6.85; N, 9.84.
5.2.4.3. 6-Hydroxy-2-phenyl-1-[4-(2-piperidin-1-ylethoxy)ben-
zyl]-1H-benzimidazole (7c). From 6b (150 mg, 0.34 mmol).
Yield: 25 mg (17%), colorless solid (mp 94.5 °C). 1H NMR (DMSO-
d6): d = 1.28–1.41 (m, 2H, CH2), 1.41–1.52 (m, 4H, CH2), 2.34–
2.43 (m, 4H, CH2), 2.60 (t, 3J = 5.9 Hz, 2H, @N–CH2–), 3.97 (t,
3J = 5.9 Hz, 2H, –O–CH2–), 5.36 (s, 2H, phenyl-CH2–), 6.68 (d,
4J = 2.0 Hz, 1H, ArH), 6.73 (dd, 3J = 8.7 Hz, 4J = 2.2 Hz, 1H, ArH),
6.86 (d, 3J = 8.7 Hz, 2H, ArH), 6.93 (d, 3J = 8.7 Hz, 2H, ArH), 7.44–
7.48 (m, 4H, ArH), 7.62–7.73 (m, 2H, ArH), 9.28 (s, 1H, OH). MS
(EI, 270 °C): m/z (%) = 427 [M]+Å (5.8), 329 (3.1), 210 (1.7), 113
(0.4), 98 (100.0). IR (film):
m = 3431 (s), 3033 (w), 2924 (m), 2853
(w), 1616 (m), 1512 (w), 1243 (w), 818 (w), 743 (w), 697 (w).
5.2.3.3. 5-(6)-Methoxy-2-(4-methoxyphenyl)-1-[4-(2-piperidin-
1-ylethoxy)benzyl]-1H-benzimidazole (6c). From 4c (250 mg,
0.98 mmol). Yield: 94 mg (20%), colorless oil. Ratio of the isomeres
0.8:1. 1H NMR (DMSO-d6): d = 1.30–1.40 (m, 3.6H, CH2), 1.40–1.53
(m, 7.2H, CH2), 2.35–2.43 (m, 7.2H, CH2), 2.54–2.64 (m, 3.6H,
@N–CH2–), 3.74 (s, 2.4H, OCH3), 3.79 (s, 3H, OCH3), 3.81 (s, 2.4H,
OCH3), 3.82 (s, 3H, OCH3), 3.91–4.11 (m, 3.6H, –O–CH2–), 5.44
(s, 2H, phenyl-CH2–), 5.45 (s, 1.6H, phenyl-CH2–), 6.78–6.89
(m, 5.4H, ArH), 6.91 (d, 3J = 8.6 Hz, 3.6H, ArH), 7.00 (d, 4J = 2.4 Hz,
0.8H, ArH), 7.07 (d, 3J = 8.7 Hz, 3.6H, ArH), 7.20 (d, 4J = 2.4 Hz, 1H,
ArH), 7.31 (d, 3J = 8.8 Hz, 1H, ArH), 7.55 (d, 3J = 8.8 Hz, 0.8H, ArH),
7.63 (d, 3J = 8.8 Hz, 1.6H, ArH), 7.67 (d, 3J = 8.8 Hz, 2H, ArH). MS
(EI, 135 °C): m/z (%) = 472 [M]+Å (33.0), 254 (7.2), 113 (5.4), 98
(0.6), 98 (100.0). IR (KBr):
m = 3400 (m), 3065 (m), 3031 (m),
2935 (s), 1620 (m), 1512 (s), 1246 (s), 824 (m), 754 (m), 700 (m).
Anal. Calcd for C27H29N3O2: C, 75.85; H, 6.84; N, 9.83. Found: C,
75.95; H, 6.75; N, 9.81.
5.2.4.4. 5-Hydroxy-2-(4-hydroxyphenyl)-1-[4-(2-piperidin-1-
ylethoxy)benzyl]-1H-benzimidazole (7d). From 6c (263 mg,
0.56 mmol). Yield: 112 mg (45%), colorless oil. 1H NMR (DMSO-
d6): d = 1.31–1.41 (m, 2H, CH2), 1.41–1.52 (m, 4H, CH2), 2.34–
2.42 (m, 4H, CH2), 2.61 (t, 3J = 5.7 Hz, 2H, @N–CH2–), 3.98 (t,
3J = 5.9 Hz, 2H, –O–CH2–), 5.38 (s, 2H, phenyl-CH2–), 6.63 (dd,
3J = 8.6 Hz, 4J = 2.1 Hz, 1H, ArH), 6.84 (d, 3J = 8.7 Hz, 2H, ArH), 6.87
(d, 3J = 8.6 Hz, 2H, ArH), 6.91 (d, 3J = 8.7 Hz, 2H, ArH), 6.96 (d,
4J = 2.0 Hz, 1H, ArH), 7.15 (d, 3J = 8.7 Hz, 1H, ArH), 7.52 (d,
3J = 8.5 Hz, 2H, ArH), 9.05 (s, 1H, OH), 9.92 (s, 1H, OH). MS (EI,
300 °C): m/z (%) = 443 [M]+Å (2.3), 332 (2.3), 226 (59.4), 113 (5.5),
(100.0). IR (film):
m = 3005 (w), 2934 (m), 2854 (w), 1674 (w),
1612 (m), 1580 (w), 1512 (m), 1251 (s), 837 (m), 750 (s).
5.2.4. General procedure for the ether cleavage with AlCl3 and
ethanethiole
98 (100.0). IR (film):
m = 3365 (m), 3117 (s), 2954 (s), 2872 (m),
A solution of 1H-benzimidazole (1 mmol) in 15 mL of dry
CH2Cl2 was cooled to 0 °C. Then AlCl3 (2 mmol) and ethanethiole
(3 mmol) were added under N2 atmosphere. The reaction mixture
was stirred for 30 min under cooling and further 30 min at room
temperature. The excess of AlCl3 was hydrolyzed by addition of
10 mL water. After neutralization using 5% NaHCO3 the phenolic
product was extracted with CH2Cl2 (3 ꢂ 50 mL), the organic layers
were combined, dried over Na2SO4 and filtered. The solvent was re-
moved under reduced pressure.
1609 (s), 1512 (s), 1476 (m), 1461 (m), 1246 (s), 843 (m), 820
(m). Anal. Calcd for C27H29N3O3: C, 73.11; H, 6.59; N, 9.47. Found:
C, 73.14; H, 6.61; N, 9.50.
5.2.4.5. 6-Hydroxy-2-(4-hydroxyphenyl)-1-[4-(2-piperidin-1-yl-
ethoxy)benzyl]-1H-benzimidazole (7e). From 6c (263 mg,
0.56 mmol). Yield: 124 mg (50%), colorless oil. 1H NMR (DMSO-
d6): d = 1.30–1.41 (m, 2H, CH2), 1.41–1.51 (m, 4H, CH2), 2.34–
2.44 (m, 4H, CH2), 2.57–2.65 (m, 2H, @N–CH2–), 3.99 (t,
3J = 5.8 Hz, 2H, –O–CH2–), 5.32 (s, 2H, phenyl-CH2–), 6.63 (d,
4J = 1.9 Hz, 1H, ArH), 6.68 (dd, 3J = 8.5 Hz, 4J = 2.1 Hz, 1H, ArH),
6.86 (d, 3J = 8.6 Hz, 2H, ArH), 6.87 (d, 3J = 8.9 Hz, 2H, ArH), 6.93
(d, 3J = 8.6 Hz, 2H, ArH), 7.42 (d, 3J = 8.6 Hz, 1H, ArH), 7.48 (d,
3J = 8.5 Hz, 2H, ArH), 9.21 (s, 1H, OH), 9.89 (s, 1H, OH). MS (EI,
5.2.4.1. 2-(4-Hydroxyphenyl)-1-[4-(2-piperidin-1-ylethoxy)ben-
zyl]-1H-benzimidazole (7a). From 6a (106 mg, 0.24 mmol). Col-
umn chromatography on silica gel with CH2Cl2/MeOH 9:1. Yield:
77 mg (75%), colorless solid (mp 102 °C). 1H NMR (DMSO-d6):