Y. Chen et al. / European Journal of Medicinal Chemistry 74 (2014) 427e439
435
6.1.2.1. 7-(3-Bromopropoxy)-2,3-dihydrocyclopenta[c]chromen-
J ¼ 6.0 Hz), 3.22 (t, 2H, J ¼ 4.0 Hz), 4.05 (t, 2H, J ¼ 6.0 Hz), 6.83e6.87
(m, 3H), 6.93 (d, 2H, J ¼ 8.0 Hz), 7.25e7.26 (m, 2H), 7.32 (d, 1H,
J ¼ 4.0 Hz). MS (ESI) m/z 419.2 ([M þ H]þ).
4(1H)-one (6a). Yield: 62.1%; mp: 103e105 ꢃC. 1H NMR (CDCl3)
d
2.16e2.34 (m, 4H), 2.88 (t, 2H, J ¼ 6.4 Hz), 3.03 (t, 2H, J ¼ 6.4 Hz),
3.60e3.63 (m, 1H), 3.75e3.78 (m, 1H), 4.16 (t, 2H, J ¼ 6.4 Hz), 6.84e
6.88 (m, 2H), 7.33e7.36 (m, 1H). MS (ESI) m/z 323.2 ([M þ H]þ).
6.1.3.2. 7-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butoxy)-2,3-
dihydrocyclo-penta[c]chromen-4(1H)-one (8). Yield: 65.9%; mp:
6.1.2.2. 7-(4-Bromobutoxy)-2,3-dihydrocyclopenta[c]chromen-
115e116 ꢃC. 1H NMR (CDCl3)
d 1.70e1.90 (m, 4H), 2.15e2.21 (m, 2H),
4(1H)-one (6b). Yield: 72.6%; mp: 81e83 ꢃC. 1H NMR (CDCl3)
2.49 (t, 2H, J ¼ 6.0 Hz), 2.65 (s, br, 3H), 2.87 (t, 2H, J ¼ 4.0 Hz), 3.01e
3.07 (m, 6H), 4.05 (t, 2H, J ¼ 4.0 Hz), 6.82e6.84 (m, 2H), 6.94e6.97
(m, 1H), 7.13e7.14 (m, 2H), 7.30e7.32 (m, 1H). MS (ESI) m/z 487.1
([M þ H]þ).
d
1.99e2.22 (m, 6H), 2.87 (t, 2H, J ¼ 6.6 Hz), 3.04 (t, 2H, J ¼ 8 Hz),
3.50 (t, 2H, J ¼ 6.4 Hz), 4.04 (t, 2H, J ¼ 6 Hz), 6.83e6.84 (m, 2H),
7.31e7.33 (m, 1H). MS (ESI) m/z 337.2 ([M þ H]þ).
6.1.2.3. 7-(4-Bromobutoxy)-9-methyl-2,3-dihydrocyclopenta[c]chro-
6.1.3.3. 7-(4-(4-(4-Fluorophenyl)piperazin-1-yl)butoxy)-2,3-
men-4(1H)-one (6c). Yield: 72.1%; mp: 91e93 ꢃC. 1H NMR (CDCl3)
dihydrocyclopent-a[c]chromen-4(1H)-one (9). Yield: 54.3%; mp:
d
1.71e1.88 (m, 4H), 1.99e2.16 (m, 4H), 2.34 (s, 3H), 2.75 (t, 2H,
104e106 ꢃC. 1H NMR (CDCl3)
d 1.71e1.89 (m, 4H), 2.15e2.19 (m, 2H),
J ¼ 6.4 Hz), 3.53 (t, 2H, J ¼ 6.6 Hz), 4.09 (t, 2H, J ¼ 6.4 Hz), 6.79e6.81
2.47 (t, 2H, J ¼ 6.0 Hz), 2.62 (t, 4H, J ¼ 4.0 Hz), 2.88 (t, 2H, J ¼ 4.0 Hz),
3.03 (t, 2H, J ¼ 4.0 Hz), 3.12 (t, 2H, J ¼ 4.0 Hz), 4.05 (t, 2H, J ¼ 6.0 Hz),
6.82e6.97 (m, 6H), 7.32 (d, 1H, J ¼ 4.0 Hz) MS (ESI) m/z 437.2
([M þ H]þ).
(m, 1H), 7.35e7.37 (m, 1H). MS (ESI) m/z 351.0 ([M þ H]þ).
6.1.2.4. 7-(4-Bromobutoxy)-8-chloro-2,3-dihydrocyclopenta[c]chro-
men-4(1H)-one (6d). Yield: 63.3%; mp: 104e105 ꢃC. 1H NMR
(CDCl3)
d
2.01e2.27 (m, 6H), 2.93 (t, 2H, J ¼ 8 Hz), 3.07 (t, 2H,
6.1.3.4. 7-(4-(4-(2,3-Dimethylphenyl)piperazin-1-yl)butoxy)-2,3-
J ¼ 8 Hz), 3.56 (t, 2H, J ¼ 6.4 Hz), 4.20 (t, 2H, J ¼ 6.4 Hz) 6.88e6.90
dihydrocyclo-penta[c]chromen-4(1H)-one (10). Yield: 56.2%; mp:
(m, 1H), 7.30e7.32 (m, 1H). MS (ESI) m/z 371.0 ([M þ H]þ).
108e110 ꢃC. 1H NMR (CDCl3)
d 1.75e1.93 (m, 4H), 2.17e2.19 (m, 2H),
2.24 (s, 3H), 2.28 (s, 3H), 2.53e2.56 (m, 3H), 2.69 (s, br, 3H), 2.89e
2.97 (m, 6H), 3.04e3.08 (m, 2H), 4.07 (t, 2H, J ¼ 6.0 Hz), 6.85e6.87
(m, 2H), 6.91e6.95 (m, 2H), 7.07e7.11 (m, 1H), 7.34e7.36 (m, 1H).
MS (ESI) m/z 447.2 ([M þ H]þ).
6.1.2.5. 7-(4-Bromobutoxy)-6-chloro-2,3-dihydrocyclopenta[c]chro-
men-4(1H)-one (6e). Yield: 58.3%; mp: 94e96 ꢃC. 1H NMR (CDCl3)
d
2.01e2.23 (m, 6H), 2.92 (t, 2H, J ¼ 6.4 Hz), 3.05 (t, 2H, J ¼ 6.4 Hz),
3.56 (t, 2H, J ¼ 6.4 Hz), 4.20 (t, 2H, J ¼ 6 Hz), 6.88 (s, 1H), 7.43 (s, 1H).
MS (ESI) m/z 371.0 ([M þ H]þ).
6.1.3.5. 7-(4-(4-(3-(Trifluoromethyl)phenyl)piperazin-1-yl)butoxy)-
2,3-dihydro-cyclopenta[c]chromen-4(1H)-one (11). Yield: 66.1%;
6.1.2.6. 7-(4-Bromobutoxy)-6-methyl-2,3-dihydrocyclopenta[c]chro-
mp: 101e103 ꢃC. 1H NMR (CDCl3)
d 1.76e1.92 (m, 4H), 2.17e2.25 (m,
men-4(1H)-one (6f). Yield: 69.2%; mp: 104e106 ꢃC. 1H NMR (CDCl3)
2H), 2.51 (t, 2H, J ¼ 6.0 Hz), 2.68e2.70 (m, 4H), 2.91 (t, 2H,
J ¼ 6.0 Hz), 3.05 (t, 2H, J ¼ 6.0 Hz), 3.28e3.31 (m, 4H), 4.07 (t, 2H,
J ¼ 6.0 Hz), 6.84e6.87 (m, 2H), 7.07e7.12 (m, 3H),7.34e7.36 (m, 2H)
MS (ESI) m/z 477.3 ([M þ H]þ).
d
2.00e2.25 (m, 6H), 2.34 (s, 3H), 2.91 (t, 2H, J ¼ 6.4 Hz), 3.05 (t, 2H,
J ¼ 6 Hz), 3.53 (t, 2H, J ¼ 6.4 Hz), 4.10 (t, 2H, J ¼ 6.4 Hz), 6.81e6.83
(m, 1H), 7.24e7.26 (m, 1H). MS (ESI) m/z 351.0 ([M þ H]þ).
6.1.2.7. 3-(4-Bromobutoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chro-
6.1.3.6. 7-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)butoxy)-2,3-
men-6-one (6g). Yield: 52.0%; mp: 79e81 ꢃC. 1H NMR (CDCl3)
dihydrocyclo-penta[c]chromen-4(1H)-one (12). Yield: 69.3%; mp:
d
1.77e2.12 (m, 8H), 2.56 (t, 2H, J ¼ 6.4 Hz), 2.74 (t, 2H, J ¼ 6 Hz),
88e90 ꢃC. 1H NMR (CDCl3)
d 1.69e1.89 (m, 4H), 2.09e2.17 (m, 2H),
3.50 (t, 2H, J ¼ 6.4 Hz), 4.04 (t, 2H, J ¼ 6 Hz), 6.77e6.84 (m, 2H),
2.48 (t, 2H, J ¼ 6.0 Hz), 2.66 (br, 4H), 2.82e2.84 (m, 2H), 2.93e3.13
(m, 6H), 3.83 (s, 3H), 4.01 (t, 2H, J ¼ 6.0 Hz), 6.76e6.91 (m, 6H),
7.23e7.254 (m, 1H). MS (ESI) m/z 449.3 ([M þ H]þ).
7.44e7.46 (m, 1H). MS (ESI) m/z 351.1 ([M þ H]þ).
6.1.2.8. 7-((5-Bromopentyl)oxy)-2,3-dihydrocyclopenta[c]chromen-
4(1H)-one (6h). Yield: 62.8%; mp: 85e87 ꢃC. 1H NMR (CDCl3)
6.1.3.7. 7-(4-(4-(3-Methoxyphenyl)piperazin-1-yl)butoxy)-2,3-
d
1.62e1.67 (m, 2H), 1.83e1.97 (m, 4H), 2.16e2.20 (m, 2H), 2.86 (t,
dihydrocyclo-penta[c]chromen-4(1H)-one (13). Yield: 70.1%; mp:
2H, J ¼ 6 Hz), 3.02 (t, 2H, J ¼ 6 Hz) 3.45 (t, 2H, J ¼ 6.4 Hz), 4.03 (t, 2H,
J ¼ 6 Hz) 6.80e6.84 (m, 2H), 7.30e7.32 (m, 1H). MS (ESI) m/z 351.2
([M þ H]þ).
86e88 ꢃC. 1H NMR (CDCl3) 1H NMR (CDCl3)
d d 1.72e1.89 (m, 4H),
2.16e2.21 (m, 2H), 2.48 (t, 2H, J ¼ 6.0 Hz), 2.61e2.63 (m, 4H), 2.89e
2.91 (m, 2H), 3.05 (t, 2H, J ¼ 6.0 Hz), 3.09e3.12 (m, 4H), 3.78 (s, 3H),
4.06 (t, 2H, J ¼ 6.0 Hz), 6.45 (d, 1H, J ¼ 4.0 Hz), 6.49 (d, 1H,
J ¼ 4.0 Hz), 6.56e6.59 (m, 1H), 6.81e6.85 (m, 1H), 6.88 (d, 1H,
J ¼ 4.0 Hz), 7.19 (t,1H, J ¼ 4.0 Hz), 7.51 (d, 1H, J ¼ 4.0 Hz). MS (ESI) m/
z 449.3.
6.1.3. General procedure for the preparation of compounds 7e31
To a suspension of compounds 6 (0.32 mmol) and K2CO3
(1.22 mmol) in acetonitrile (5.0 mL), arylpiperazine (piperidine)
(0.32 mmol) and a catalytic amount of KI were added and the
resulting mixture was refluxed for 7e9 h. After filtering, the
resulting filtrate was evaporated to dryness under reduced pres-
sure. The residue was suspended in water (10.0 mL) and extracted
with dichloromethane (3 ꢁ 25 mL). The combined organic layers
were evaporated under reduced pressure, and the crude product
was purified by means of chromatography (10% MeOH/CHCl3) to
yield compounds 7e30.
6.1.3.8. 7-(4-(4-(4-Methoxyphenyl)piperazin-1-yl)butoxy)-2,3-
dihydrocyclo-penta[c]chromen-4(1H)-one (14). Yield: 64.2%; mp:
91e93 ꢃC. 1H NMR (CDCl3)
d 1.71e1.87 (m, 4H), 2.15e2.21 (m, 2H),
2.47 (t, 2H, J ¼ 6.0 Hz), 2.62e2.64 (m, 4H), 2.88e2.90 (m, 2H), 3.04
(t, 2H, J ¼ 6.0 Hz), 3.09e3.11 (m, 4H), 3.77 (s, 3H), 4.05 (t, 2H,
J ¼ 6.0 Hz), 6.82e6.92 (m, 6H), 7.32 (d, 1H, J ¼ 4.0 Hz). MS (ESI) m/z
449.3.
6.1.3.1. 7-(4-(4-Phenylpiperazin-1-yl)butoxy)-2,3-dihydrocyclopenta
6.1.3.9. 7-(4-(4-(Pyridin-2-yl)piperazin-1-yl)butoxy)-2,3-
[c]chromen-4(1H)-one (7). Yield: 64.2%; mp: 86e88 ꢃC. 1H NMR
dihydrocyclopent-a[c]chromen-4(1H)-one (15). Yield: 71.3%; mp:
(CDCl3)
d
1.74e1.90 (m, 4H), 2.17e2.22 (m, 2H), 2.50 (t, 2H,
79e81 ꢃC. 1H NMR (CDCl3)
d
1.65e1.79 (m, 4H), 2.05e2.08 (m, 2H),
J ¼ 6.0 Hz), 2.64e2.66 (m, 4H), 2.88 (t, 2H, J ¼ 6.0 Hz), 3.03 (t, 2H,
2.37 (t, 2H, J ¼ 6.4 Hz), 2.47e2.49 (m, 4H), 2.75 (t, 2H, J ¼ 6.0 Hz),