Y. Li et al. / Bioorg. Med. Chem. 19 (2011) 4529–4535
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4.1.1. Synthesis of 2-p-tolyl-1H-benzo[d]imidazol-5-amine (4a)
The reaction was performed under nitrogen atmosphere. 4-ni-
tro-o-phenylenediamine 1 (4 g, 26.14 mmol) and p-tolualdehyde
2a (3.77 g, 31.37 mmol) in 50 ml of DMF was added into a dried
round-bottom flask. The mixture was stirred at room tempera-
ture for 5 min before sodium metabisulfite (12.4 g, 65.36 mmol)
was added. The reaction mixture was then heated to 120 °C
and kept at this temperature for 15 h. Once the starting materi-
als were consumed (followed by TLC), the reaction was cooled
down to room temperature, poured into water (200 mL), ex-
tracted with ethyl acetate (3 Â 80 mL), and dried over anhydrous
Na2SO4. The organic extracts were concentrated in vacuo and the
crude product compound 3a was obtained. Compound 3a, Tin(II)
chloride anhydrous (13.47 g, 71 mmol) and ethanol (100 mL)
were added into a dried round-bottom flask and the mixture
was refluxed for 4 h and then cooled to room temperature. Sat-
urated NaOH solution was added to the reaction mixture until
white precipitation produced. The slurry was filtered and the fil-
trate was extracted with ethyl acetate (3 Â 80 mL). After the or-
ganic phase was dried over anhydrous Na2SO4, the crude product
was purified by column chromatography (ethyl acetate/ammo-
nium hydroxide, 100:1) to yield a brown solid. Yield: 55%; 1H
NMR (400 MHz, CDCl3) d 7.90 (d, J = 7.2 Hz, 2H), 7.47 (s, 1H),
7.28 (s, 2H), 6.86 (s, 1H), 6.69 (d, J = 7.6, 1H), 5.32 (s, 2H), 2.41
(s, 3H); 13C NMR (100 MHz, CDCl3) d 142.59, 139.65, 129.45,
127.12, 125.86, 112.55, 21.12; HR-MS(ESI): calcd for C14H14N3
[M+H]+ 224.1188; found: 224.1186.
4.1.3.2.
2-(4-Methylpiperazin-1-yl)-N-(2-p-tolyl-1H-benzo[d]-
imidazol-5-yl)acetamide (6a2). Yield: 33%; mp 234–237 °C; 1H
NMR (400 MHz, CDCl3) d 9.34 (s, 1H), 8.35 (s, 1H), 7.99 (d,
J = 7.6 Hz, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H),
6.99 (s, 1H), 3.18 (s, 2H), 2.80–2.60 (m, 4H), 2.60–2.40 (m, 4H),
2.40 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) d 168.40,
152.60, 139.94, 132.25, 129.31, 127.13, 126.46, 115.01, 61.66,
54.97, 53.14, 45.65, 29.44, 21.17; HR-MS(ESI): calcd for
C
21H26N5O [M+H]+ 364.2137; found: 364.2129.
4.1.3.3. 2-Morpholino-N-(2-p-tolyl-1H-benzo[d]imidazol-5-yl)-
acetamide (6a3). Yield: 61%; mp 273–277 °C; 1H NMR (400 MHz,
CDCl3) d 9.25 (s, 1H), 8.30 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.61 (d,
J = 8.4 Hz, 1H), 7.26 (d, J = 6.4 Hz, 2H), 7.05 (d, J = 7.6 Hz, 1H),
3.80 (t, J = 4.6 Hz, 4H), 3.19 (s, 2H), 2.65 (t, J = 4.6 Hz, 4H), 2.40 (s,
3H); 13C NMR (100 MHz, CDCl3) d 140.26, 132.53, 129.45, 126.31,
66.83, 62.28, 53.63, 21.19; HR-MS(ESI): calcd for C20H23N4O2
[M+H]+ 351.1821; found: 351.1819.
4.1.3.4. 2-(Piperidin-1-yl)-N-(2-p-tolyl-1H-benzo[d]imidazol-5-
yl)acetamide (6a4). Yield: 27%; mp 245–249 °C; 1H NMR
(400 MHz, CDCl3) d 9.57 (s, 1H), 8.33 (s, 1H), 7.99 (d, J = 8.0 Hz,
2H), 7.62 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 4.8 Hz, 2H), 7.03 (d,
J = 8.4 Hz, 1H), 3.17 (s, 2H), 2.61 (m, 4H), 2.40 (s, 3H), 1.68–1.66
(m, 4H), 1.51 (s, 2H); 13C NMR (100 MHz, CDCl3) d 168.62,
152.28, 139.99, 132.58, 129.34, 126.93, 126.42, 115.14, 62.39,
54.70, 29.45, 25.90, 23.29, 21.18; HR-MS(ESI): calcd for
C
21H25N4O [M+H]+ 349.2028; found: 349.2023.
4.1.2. Synthesis of 2-chloro-N-(2-p-tolyl-1H-benzo[d]imidazol-
5-yl)acetamide (5a)
4.1.3.5. 2-(Pyrrolidin-1-yl)-N-(2-p-tolyl-1H-benzo[d]imidazol-5-
yl)acetamide (6a5). Yield: 22%; mp 229–233 °C; 1H NMR
(400 MHz, CDCl3) d 9.36 (s, 1H), 8.34 (s, 1H), 7.98 (d, J = 8.4 Hz,
2H), 7.62 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 5.6 Hz, 2H), 7.04 (s, 1H),
3.37 (s, 2H), 2.75 (m, 4H), 2.40 (s, 3H), 1.88 (m, 4H); 13C NMR
Compound 4a (200 mg) was refluxed in chloracetyl chloride
(5 mL) for 4 h and the reaction was ended by adding 20 mL of
water. Saturated NaOH solution was added until the pH was 8–9.
The mixture was extracted with ethyl acetate (3 Â 30 mL) and
dried over anhydrous Na2SO4. The crude product was purified by
column chromatography (ethyl acetate/ammonium hydroxide,
100:1) to yield a brown solid. Yield: 84%; mp 180–184 °C; 1H
NMR (400 MHz, DMSO-d6) d 10.79 (s, 1H), 8.30 (s, 1H), 8.15 (d,
J = 8.4 Hz, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.55 (dd, J = 8.8, 1.6 Hz,
1H), 7.51 (d, J = 8.4 Hz, 2H), 4.34 (s, 2H), 2.44 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) d 165.29, 149.07, 144.03, 136.92, 132.40,
130.41, 128.50, 128.06, 120.71, 118.55, 114.50, 103.67, 43.79,
(100 MHz, CDCl3)
d
168.87, 152.20, 139.98, 132.67, 129.38,
127.00, 126.32, 115.20, 59.49, 58.20, 54.43, 23.87, 21.17, 18.19;
HR-MS(ESI): calcd for
335.1867.
C
20H23N4O [M+H]+ 335.1872; found:
4.1.4. Synthesis of 3-chloro-N-(2-p-tolyl-1H-benzo[d]imidazol-
5-yl)propanamide (5b)
Compound 5b was synthesized in the same way as compound
5a. Yield: 79%; mp 248–252 °C; 1H NMR (400 MHz, DMSO-d6) d
8.38 (d, J = 1.2 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.8 Hz,
1H), 7.59 (dd, J = 8.8, 1.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 3.93 (t,
J = 6.2 Hz, 2H), 2.91 (t, J = 6.2 Hz, 2H), 2.45 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) d 168.63, 148.80, 143.97, 137.43, 132.38,
130.39, 128.05, 120.69, 118.41, 114.35, 103.31, 40.95, 21.44;
21.45; HR-MS(ESI): calcd for
found: 300.0903.
C
16H15ClN3O [M+H]+ 300.0904;
4.1.3. General procedure for preparation of compounds 6a1–
6a5
Compound 5a (100 mg, 0.334 mmol) was dissolved in anhy-
drous THF (8 mL). Then, corresponding secondary amines
(5.015 mmol) and KI (50 mg, 0.334 mmol) were added and the
mixture was refluxed under nitrogen atmosphere for 3 h. Once
the starting materials were consumed (followed by TLC), the sol-
vent was removed by in vacuo and the crude solid was washed
with water. The crude product was purified by column chromatog-
raphy (ethyl acetate/methanol/ammonium hydroxide, 100:10:1).
HR-MS(ESI): calcd for
314.1051.
C
17H17ClN3O [M+H]+ 314.1060; found:
4.1.5. General procedure for preparation of compounds 6b1,
6b2, 6b3
Compounds were synthesized in the same way as compounds
6a1–6a5.
4.1.3.1. 2-(4-Ethylpiperazin-1-yl)-N-(2-p-tolyl-1H-benzo[d]imi-
dazol-5-yl)acetamide (6a1). Yield: 56%; mp 233–237 °C; 1H NMR
(400 MHz, CDCl3) d 9.35 (s, 1H), 8.36 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H),
7.62 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 7.6 Hz,
1H), 3.19 (s, 2H), 2.82–2.45 (m, 10H), 2.39 (s, 3H), 1.13 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 168.35, 152.49,
139.98, 132.34, 129.33, 127.08, 126.42, 115.01, 61.68, 53.04,
4.1.5.1. 3-(4-Ethylpiperazin-1-yl)-N-(2-p-tolyl-1H-benzo[d]imi-
dazol-5-yl)propanamide (6b1). Yield: 39%; mp 193–195 °C; 1H
NMR (400 MHz, CDCl3) d 11.20 (s, 1H), 8.34 (s, 1H), 7.99 (d,
J = 7.6 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H),
6.98 (s, 1H), 2.81–2.43 (m, 14H), 2.38 (s, 3H), 1.12 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 170.83, 152.56, 140.04, 133.76,
129.54, 127.41, 126.66, 53.63, 52.85, 52.21, 52.10, 32.43, 21.44,
11.89; HR-MS(ESI): calcd for C23H30N5O [M+H]+ 392.2450; found:
392.2444.
52.52, 51.97, 21.18, 11.51; HR-MS(ESI): calcd for
C22H28N5O
[M+H]+ 378.2294; found: 378.2292.