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solid (982 mg, 68%): m.p.: 158–1598C (EtOH); 1H NMR (400 MHz,
CDCl3): d=1.34–1.52 (m, 2H), 2.06 (d, J=10.0 Hz, 2H), 2.12 (s, 3H),
2.10–2.24 (m, 5H), 2.46–2.58 (m, 2H), 2.63–2.75 (m, 2H), 2.85 (d,
J=10.8 Hz, 2H), 3.69 (s, 2H, exchangeable with D), 3.77 (s, 3H),
4.21–4.35 (m, 1H), 5.73 (d, J=8.0 Hz, 1H, exchangeable with D),
6.58 (s, 1H), 6.75–6.84 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 7.37 ppm (s,
1H, exchangeable with D); 13C NMR (100 MHz, CDCl3): d=18.9,
19.8, 31.8, 33.0, 52.1, 52.3, 55.4, 60.7, 114.0, 118.1, 118.4, 127.7,
128.9, 129.7, 132.3, 138.7, 140.9, 158.1, 180.1 ppm; HRMS (ESI): m/z
[M+H]+ calcd for C23H33N4OS: 413.2370, found 413.2370.
for compound 10 afforded a crude residue that, after column chro-
matography (silica gel, EtOAc/MeOH, 6:1, v/v), yielded 17 as a color-
less solid (139 mg, 41%): Rf =0.20 (EtOAc/MeOH, 6:1, v/v); melting
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range: 60–1608C; H NMR (400 MHz, CDCl3): d=1.42–1.59 (m, 2H),
2.12 (d, J=10.8 Hz, 2H), 2.22–2.38 (m, 8H), 2.53–2.63 (m, 2H),
2.70–2.80 (m, 2H), 2.87 (d, J=9.6 Hz, 2H), 3.78 (s, 3H), 3.86 (br s,
1H), 3.88–4.03 (m, 1H), 5.03 (s, 2H), 6.79–6.87 (m, 3H), 6.97–7.05
(m, 2H), 7.06–7.15 (m, 4H), 7.30 ppm (s, 1H); 13C NMR (100 MHz,
CDCl3): d=20.3, 20.4, 32.5, 32.7, 45.2, 49.6, 52.3, 55.4, 60.7, 108.1,
114.0, 116.2, 116.3 (d, J2C,F =21.5 Hz), 117.5, 128.3 (d, J3C,F =8.1 Hz),
128.4, 129.7, 129.9, 131.5 (d, J4C,F =2.7 Hz), 132.0, 133.0, 140.6,
152.9, 158.2, 162.6 ppm (d, J1C,F =245.6 Hz); 19F NMR (376 MHz,
CDCl3): d=À114.7 ppm (septet); HRMS (ESI): m/z [M+H]+ calcd for
C30H36FN4O: 487.2868, found 487.2869.
1-(2-Amino-4,5-dichlorophenyl)-3-(1-(2-(4-methoxyphenyl)ethyl)-
piperidin-4-yl)thiourea (14): A solution of compound 11 (1106 mg,
4 mmol) in EtOH (2 mL) was added to a warm solution of 4,5-di-
chloro-1,2-diaminobenzene (708 mg, 4 mmol) in EtOH (8 mL), and
the mixture was stirred at RT for 19 h. The solid that precipitated
was filtered, washed with cold EtOH (5 mL), and recrystallized to
afford 14 as a tan solid (871 mg, 48%): m.p.: 171–1728C (EtOAc/
MeOH, 1:1, v/v); 1H NMR (400 MHz, [D6]DMSO): d=1.37–1.58 (m,
2H), 1.87 (d, J=10.8 Hz, 2H), 1.94–2.15 (m, 2H), 2.45 (t, J=7.6 Hz,
2H), 2.64 (t, J=7.6 Hz, 2H), 2.85 (d, J=9.6 Hz, 2H), 3.71 (s, 3H),
4.10 (br s, 1H), 5.22 (s, 2H, exchangeable with D), 6.82 (d, J=
8.0 Hz, 2H), 6.91 (s, 1H), 7.12 (d, J=8.0 Hz, 2H), 7.31 (s, 1H), 7.64
(br s, 1H, exchangeable with D), 8.67 ppm (s, 1H, exchangeable
with D); 13C NMR (100 MHz, [D6]DMSO): d=31.1, 32.1, 51.4, 52.0,
55.0, 60.0, 113.6, 115.8, 116.0, 124.1, 128.2, 129.0, 129.5, 132.4,
144.2, 157.4, 180.2 ppm; HRMS (ESI): m/z [M+H]+ calcd for
C21H27Cl2N4OS: 453.1277, found 453.1287.
(5,6-Dichloro-1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)-(1-(2-(4-
methoxyphenyl)ethyl)piperidin-4-yl)amine (18): Benzimidazole
16 (336 mg, 0.8 mmol) was alkylated with 4-fluorobenzyl chloride
(174 mg, 1.2 mmol) in DMF (5 mL) in the presence of anhydrous
K2CO3 (221 mg, 1.6 mmol) and a few crystals of KI at 80–858C for
18 h. Subsequent processing of the reaction mixture as reported
for compound 10 afforded a crude residue that was subjected to
column chromatography (silica gel, EtOAc/MeOH, 9:1, v/v). Treat-
ment of the isolated material with charcoal yielded 18 as a colorless
solid (270 mg, 64%): Rf =0.26 (EtOAc/MeOH, 9:1, v/v); m.p.: 173–
1
1748C; H NMR (400 MHz, CDCl3): d=1.35–1.49 (m, 2H), 2.08 (d, J=
11.6 Hz, 2H), 2.22 (t, J=10.8 Hz, 2H), 2.48–2.58 (m, 2H), 2.66–2.75
(m, 2H), 2.80 (d, J=9.6 Hz, 2H), 3.78 (s, 3H), 3.84–3.97 (m, 2H),
4.98 (s, 2H), 6.82 (d, J=8.4 Hz, 2H), 7.01–7.15 (m, 7H), 7.53 ppm (s,
1H); 13C NMR (100 MHz, CDCl3): d=32.7, 33.0, 45.5, 50.0, 52.1, 55.4,
60.8, 108.5, 114.0, 116.6 (d, J2C,F =21.8 Hz), 117.8, 123.1, 125.2, 128.3
(d, J3C,F =8.2 Hz), 129.7, 130.3 (d, J4C,F =3.2 Hz), 132.4, 134.2, 142.3,
154.6, 158.1, 162.8 ppm (d, J1C,F =246.5 Hz); 19F NMR (376 MHz,
CDCl3): d=À113.7 ppm (septet); HRMS (ESI): m/z [M
H]+ calcd for C28H30Cl2FN4O: 527.1775, found 527.1768.
(5,6-Dimethyl-1H-benzimidazol-2-yl)-(1-(2-(4-methoxyphenyl)-
ethyl)piperidin-4-yl)amine (15): The procedure reported for com-
pound 5 was used, starting from thiourea 13 (825 mg, 2 mmol) to
yield a crude residue that was subjected to column chromatogra-
phy (silica gel, EtOAc/MeOH, 3:1, v/v). The light green solid that
was isolated was dissolved in EtOAc (4 mL), treated with charcoal,
filtered, and slowly diluted with hexanes (40 mL) to give 15 as
a colorless solid (553 mg, 73%): Rf =0.14 (EtOAc/MeOH, 3:1, v/v);
(1-Benzyl-1H-benzimidazol-2-yl)-(1-(2-(4-methoxyphenyl)ethyl)-
piperidin-4-yl)amine (19): A mixture of compound 5 (280 mg,
0.8 mmol), benzyl bromide (205 mg, 1.2 mmol), anhydrous K2CO3
(222 mg, 1.6 mmol), and a few crystals of KI in dry DMF (4 mL) was
stirred at 85–1008C for 20 h. The cooled mixture was diluted with
water (50 mL) and extracted with EtOAc (2ꢂ50 mL), then the com-
bined organic phases were washed with water (50 mL) and brine
(20 mL) and dried over anhydrous Na2SO4. After the solvent was re-
moved under reduced pressure, the residue was purified by chro-
matography (silica gel, EtOAc/MeOH, 9:1, v/v) to give an oil that
was dissolved in EtOAc (1 mL) and gradually diluted with hexanes
(50 mL). The solid was filtered and washed with hexanes to afford
19 as a colorless solid (151 mg, 43%): Rf =0.45 (EtOAc/MeOH, 9:1,
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m.p.: 218–2198C; H NMR (400 MHz, CDCl3): d=1.43–1.58 (m, 2H),
2.03–2.18 (m, 4H), 2.28 (s, 6H), 2.47–2.56 (m, 2H), 2.64–2.74 (m,
2H), 2.86 (d, J=11.6 Hz, 2H), 3.69–3.77 (m, 1H), 3.78 (s, 3H), 4.89
(br s, 1H), 6.78–6.85 (m, 2H), 7.03–7.11 ppm (m, 4H); 13C NMR
(100 MHz, CDCl3): d=20.2, 32.9, 33.0, 50.2, 52.3, 55.4, 60.8, 113.2,
114.0, 129.0, 129.7, 132.5, 154.1, 158.1 ppm; HRMS (ESI): m/z
[M+H]+ calcd for C23H31N4O: 379.2492, found 379.2492.
(5,6-Dichloro-1H-benzimidazol-2-yl)-(1-(2-(4-methoxyphenyl)-
ethyl)piperidin-4-yl)amine (16): The procedure reported for com-
pound 5 was used, starting from thiourea 14 (680 mg, 1.5 mmol)
to yield a crude residue that was subjected to column chromatog-
raphy (silica gel, EtOAc/MeOH, 4:1, v/v) to give 16 as an off-white
solid (515 mg, 82%): Rf 0.30 (EtOAc/MeOH, 4:1, v/v); m.p.: 223–
2258C; 1H NMR (400 MHz, CD3OD): d=1.55–1.73 (m, 2H), 2.07 (d,
J=11.2 Hz, 2H), 2.26 (t, J=11.2 Hz, 2H), 2.53–2.65 (m, 2H), 2.70–
2.82 (m, 2H), 3.03 (d, J=11.6 Hz, 2H), 3.59–3.71 (m, 1H), 3.75 (s,
3H), 6.83 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 7.25 ppm (s,
2H); 13C NMR (100 MHz, CD3OD): d=32.9, 33.3, 50.8, 53.4, 55.6,
61.8, 114.9, 130.6, 133.1, 157.6, 159.6 ppm; HRMS (ESI): m/z [M+H]+
calcd for C21H25Cl2N4O: 419.1400, found 419.1410.
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v/v); m.p.: 139–1408C; H NMR (400 MHz, CDCl3): d=1.42–1.58 (m,
2H), 2.11 (d, J=11.2 Hz, 2H), 2.29 (t, J=10.4 Hz, 2H), 2.51–2.62 (m,
2H), 2.69–2.94 (m, 4H), 3.78 (s, 3H), 3.88–4.08 (2H), 6.83 (d, J=
8.4 Hz, 2H), 7.01–7.20 (m, 7H), 7.27–7.38 (m, 3H), 7.52 ppm (d, J=
7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=32.3, 32.7, 45.9, 49.5,
52.1, 55.4, 60.7, 107.3, 114.0, 116.6, 119.8, 121.5, 126.7, 128.4, 129.4,
129.7, 132.0, 134.8, 135.5, 142.4, 153.5, 158.1 ppm; HRMS (ESI): m/z
[M+H]+ calcd for C28H33N4O 441.2649, found 441.2645.
(1-(4-Methoxyphenethyl)piperidin-4-yl)-(1-(4-(trifluoromethyl)-
benzyl)-1H-benzimidazol-2-yl)amine (20): Compound 5 (525 mg,
1.5 mmol), 4-(trifluoromethyl)benzyl bromide (538 mg, 2.25 mmol),
anhydrous K2CO3 (417 mg, 3 mmol), and a few crystals of KI in dry
DMF (5 mL) were combined following a synthetic procedure similar
to that described for compound 19 to give a crude material that
was purified by chromatography (silica gel, EtOAc/MeOH, 9:1, v/v).
(1-(4-Fluorobenzyl)-5,6-dimethyl-1H-benzimidazol-2-yl)-(1-(2-(4-
methoxyphenyl)ethyl)piperidin-4-yl)amine (17): Benzimidazole
15 (265 mg, 0.7 mmol) was alkylated with 4-fluorobenzyl chloride
(152 mg, 1.05 mmol) in DMF (4 mL) in the presence of anhydrous
K2CO3 (193 mg, 1.4 mmol) and a few crystals of KI at 80–858C for
18 h. Subsequent processing of the reaction mixture as reported
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