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J. Obniska et al. / Bioorg. Med. Chem. 20 (2012) 4872–4880
(300 MHz, CDCl3) d: 2.77 (d, 1H, Hb imide, J = 5.90 Hz), 2.82–2.85
(m, 4H, piperazine), 3.19 (t, 4H, piperazine, J = 5.13 Hz), 3.29 (dd,
1H, Ha imide, J = 9.74 Hz, J = 18.46 Hz), 4.43 (q, 1H, Hc imide
J = 5.90 Hz), 4.63 (s, 2H, CH2), 6.83–6.93 (m, 3H, ArH), 7.16–7.35
(m, 5H, ArH), 7.59–7.62 (m, 1H, ArH); 13C NMR (75 MHz, CDCl3)
d: 36.57, 46.81, 50.97, 51.20, 60.48, 120.44, 123.75, 123.98,
127.58, 128.25, 128.79, 129.67, 129.93, 130.64, 133.64, 136.78,
149.17, 176.68, 178.11. ESI-MS: 428.30 (C21H22O2N3Br [M+H]+).
Anal. calcd for C21H22O2N3Br (428.33): C: 58.93, H: 5.18, N: 9.82;
found C: 58.82, H: 5.22, N: 9.75.
(75 MHz, CDCl3) d: 36.54, 46.79, 50.95, 51.19, 60.46, 120.42,
123.76, 123.98, 127.60, 128.24, 128.79, 129.64, 129.93, 130.61,
133.64, 136.77, 149.16, 176.67, 178.09. ESI-MS: 462.13
(C21H21O2N3ClBr [M+H]+). Anal. calcd for C21H21O2N3ClBr
(462.72): C: 54.48, H: 4.57, N: 9.08; found C: 54.70, H: 4.55, N:
9.09.
4.1.2.13.
1-[{4-(4-Chlorophenyl)-piperazin-1-yl}-methyl]-3-(2-
White solid. Yield:
bromophenyl)-pyrrolidine-2,5-dione (17).
62%; mp 126–128 °C; TLC: Rf = 0.32 (S1), Rf = 0.61 (S2); 1H NMR
(300 MHz, CDCl3) d: 2.77–2.89 (m, 5H, 4H piperazine, 1H, Hb
imide), 3.15 (t, 4H, piperazine J = 4.87 Hz), 3.29 (dd, 1H, Ha imide,
J = 10.0 Hz, J = 18.46 Hz), 4.42 (q, 1H, Hc imide, J = 5.90 Hz), 4.62
(s, 2H, CH2), 6.79–6.91 (m, 2H, ArH), 7.15–7.35 (m, 5H, ArH),
7.59–7.62(m, 1H, ArH); 13C NMR (75 MHz, CDCl3) d: 36.53, 46.78,
50.93, 51.18, 60.45, 120.41, 123.75, 123.96, 127.57, 128.20,
128.77, 129.61, 129.90, 130.61, 133.64, 136.75, 149.12, 176.65,
178.09. ESI-MS: 462.12 (C21H21O2N3ClBr [M+H]+). Anal. calcd for
4.1.2.9.
1-[{4-(2-Fluorophenyl)-piperazin-1-yl}-methyl]-3-(2-
White solid.
bromophenyl)-pyrrolidine-2,5-dione (13).
Yield: 87%; mp 147–149 °C; TLC: Rf = 0.84 (S1), Rf = 0.78 (S2); 1H
NMR (300 MHz, CDCl3) d: 2.77 (d, 1H, Hb imide, J = 6.15 Hz),
2.82–2.87 (m, 4H, piperazine), 3.09 (t, 4H, piperazine,
J = 4.87 Hz), 3.30 (dd, 1H, Ha imide, J = 10.0 Hz, J = 18.72 Hz), 4.45
(q, 1H, Hc imide, J = 5.90 Hz), 4.63 (s, 2H, CH2), 6.90–7.09 (m, 5H,
ArH), 7.17–7.24 (m, 1H, ArH), 7.31–7.36 (m, 1H, ArH), 7.59–7.63
(m, 1H, ArH); 13C NMR (75 MHz, CDCl3) d: 36.53, 41.89, 50.20,
50.54, 60.30, 115.31, 115.61, 116.04, 116.28, 117.83, 117.91,
124.54, 124.72, 124.76, 129.96, 130.02, 130.31, 130.39, 147.90,
155.58, 158.78, 159.08, 162.35, 176.68; 178.19; 19F NMR
(282 MHz, CDCl3) d: À122.86 (s, 1F). ESI-MS: 446.22
(C21H21O2N3FBr [M+H]+). Anal. calcd for C21H21O2N3FBr (446.32):
C: 56.55, H: 4.75, N: 9.42; found C: 56.78, H: 4.84, N: 9.23.
C21H21O2N3ClBr (462.72): C: 54.48, H: 4.57, N: 9.08; found C:
54.79, H: 4.52, N: 9.05.
4.1.2.14. 1-[{4-(3-Trifluoromethylphenyl)-piperazin-1-yl}-methyl]-
3-(2-bromophenyl)-pyrrolidine-2,5-dione (18).
White solid.
Yield: 63%; mp 108–110 °C; TLC: Rf = 0.45 (S1), Rf = 0.69 (S2); 1H
NMR (300 MHz, CDCl3) d: 2.78–2.89 (m, 5H, 4H piperazine, 1H,
Hb imide), 3.12–3.58 (m, 5H, 4H piperazine, 1H imide), 4.12 (q,
1H, Hc imide, J = 6.15 Hz), 4.63 (s, 2H, CH2), 7.03–7.19 (m, 3H,
ArH), 7.22–7.37 (m, 4H, ArH), 7.59–7.62 (m, 1H, ArH); 13C NMR
(75 MHz, CDCl3) d: 36.55, 46.79, 50.96, 51.21, 60.48, 120.44,
123.76, 123.98, 127.60, 128.24, 128.79, 129.65, 129.93, 130.64,
133.66, 136.76, 149.16, 176.66, 178.11; 19F NMR (282 MHz, CDCl3)
d: À62.82 (s, 3F). ESI-MS: 496.18 (C22H21O2N3F3Br [M+H]+). Anal.
calcd for C22H21O2N3F3Br (496.33): C: 53.28, H: 4.27, N: 8.47; found
C: 53.58, H: 4.24, N: 8.23.
4.1.2.10. 1-[{4-(4-Fluorophenyl)-piperazin-1-yl}-methyl]-3-(2-
bromophenyl)-pyrrolidine-2,5-dione (14).
White solid.
Yield: 65%; mp 96–98 °C; TLC: Rf = 0.83 (S1), Rf = 0.87 (S2); 1H
NMR (300 MHz, CDCl3) d: 2.78 (d, 1H, Hb imide, J = 5.90 Hz), 2.83
(t, 4H, piperazine, J = 5.0 Hz), 3.11 (t, 4H piperazine, J = 4.87 Hz),
3.29 (dd, 1H, Ha imide, J = 9.74 Hz, J = 18.46 Hz), 4.43 (q, 1H, Hc
imide, J = 5.90 Hz), 4.63 (s, 2H, CH2), 6.84–6.99 (m, 4H, ArH),
7.17–7.23 (m, 2H, ArH), 7.30–7.36 (m, 1H, ArH), 7.60–7.62 (m,
1H, ArH); 13C NMR (75 MHz, CDCl3) d: 36.52, 46.78, 50.91, 51.19,
60.45, 120.40, 123.75, 123.95, 127.56, 128.22, 128.76, 129.68,
129.93, 130.64, 133.68, 136.75, 149.17, 176.68, 178.10; 19F NMR
(282 MHz, CDCl3) d: -124.29 (s, 1F). ESI-MS: 446.23
(C21H21O2N3FBr [M+H]+). Anal. calcd for C21H21O2N3FBr (446.32):
C: 56.55, H: 4.75, N: 9.42; found C: 56.28, H: 4.59, N: 9.63.
4.1.2.15.
1-[(4-Benzylpiperazin-1-yl)-methyl]-3-(2-fluoro-
White solid. Yield:
phenyl)-pyrrolidine-2,5-dione (19).
85%; mp 57–59; TLC: Rf = 0.83 (S1), Rf = 0.87 (S2); 1H NMR
(300 MHz, CDCl3) d: 2.45 (br s, 4H, piperazine), 2.68 (t, 4H, pipera-
zine, J = 4.49 Hz), 2.76 (dd, 1H, Hb imide, J = 1.02 Hz, J = 5.64 Hz),
2.82 (dd, 1H, Ha imide, J = 1.02 Hz, J = 5.77 Hz), 3.49 (d, 2H, CH2,
J = 5.90 Hz), 4.12 (q, 1H, Hc imide, J = 9.74 Hz), 4.56 (s, 2H, CH2),
7.07–7.36 (m, 9H, ArH); 13C NMR (75 MHz, CDCl3) d: 36.19,
41.66, 50.58, 52.93, 60.34, 62.90, 115.96, 116.24, 124.63, 124.70,
124.75, 124.81, 127.05, 128.20, 129.14, 129.89, 129.99, 130.24,
130.29, 137.96, 159.11, 162.38, 176.67, 178.13; 19F NMR
(282 MHz, CDCl3) d: À116.18 (s, 1F). ESI-MS: 382.26 (C22H24FN3O2
[M+H]+). Anal. calcd for C22H24O2N3F (381.45): C: 69.36, H: 6.35, N:
11.03; found C: 69.58, H: 6.24, N: 11.23.
4.1.2.11. 1-[{4-(2-Chlorophenyl)-piperazin-1-yl}-methyl]-3-(2-
bromophenyl)-pyrrolidine-2,5-dione (15).
White solid.
Yield: 55%; mp 113–115 °C; TLC: Rf = 0.67 (S1), Rf = 0.75 (S2); 1H
NMR (300 MHz, CDCl3) d: 2.80–2.92 (m, 5H, 4H piperazine, 1H,
Hb imide), 3.05 (t, 4H, piperazine J = 4.49 Hz), 3.31 (dd, 1H, Ha
imide, J = 10.0 Hz, J = 18.46 Hz), 4.44 (q, 1H, Hc, imide,
J = 5.90 Hz), 4.64 (s, 2H, CH2), 6.94–7.05 (m, 2H, ArH), 7.17–7.27
(m, 3H, ArH), 7.31–7.36 (m, 2H, ArH), 7.60–7.64 (m, 1H, ArH);
13C NMR (75 MHz, CDCl3) d: 36.56, 46.80, 50.96, 51.21, 60.47,
120.43, 123.76, 123.97, 127.59, 128.23, 128.78, 129.65, 129.92,
130.63, 133.65, 136.76, 149.15, 176.66, 178.10. ESI-MS: 462.11
(C21H21O2N3ClBr [M+H]+). Anal. calcd for C21H21O2N3ClBr
(462.72): C: 54.48, H: 4.57, N: 9.08; found C: 54.18, H: 4.44, N:
8.93.
4.1.2.16.
1-[{4-(Pyrimid-2-yl)-piperazin-1-yl}-methyl]-3-(2-
(20). White solid.
fluorophenyl)-pyrrolidine-2,5-dione
Yield: 72%; mp 123–126 °C; TLC: Rf = 0.83 (S1), Rf = 0.93 (S2); 1H
NMR (300 MHz, CDCl3) d: 2.70 (t, 4H, piperazine, J = 5.0 Hz), 2.79
(dd, 5H, 1H, Hb imide, J = 0.77 Hz, J = 5.26 Hz), 3.16 (dd, 1H, Ha
imide, J = 1.02 Hz, J = 5.77 Hz), 2.81 (t, 4H piperazine, J = 5.13 Hz),
4.08 (q, 1H, Hc imide, J = 5.64 Hz), 4.61 (s, 2H, CH2), 6.46–6.49 (m,
1H, pyrimidine), 7.02–7.34 (m, 4H, ArH), 8.29 (d, 2H, pyrimidine,
J = 4.62 Hz); 13C NMR (75 MHz, CDCl3) d: 36.45, 36.47, 41.81,
41.83, 43.67, 50.46, 60.49, 109.93, 115.97, 116.25, 124.58, 124.69,
124.74, 124.76, 129.91, 130.02, 130.32, 130.37, 157.68, 159.06,
161.70, 162.33, 176.58, 178.06; 19F NMR (282 MHz, CDCl3) d:
À116.19 (s, 1F). ESI-MS: 370.26 (C19H20O2N5F [M+H]+). Anal. calcd
for C19H20O2N5F (369.40): C: 61.85, H: 5.56, N: 18.98; found C:
61.58, H: 5.24, N: 19.13.
4.1.2.12. 1-[{4-(3-Chlorophenyl)-piperazin-1-yl}-methyl]-3-(2-
bromophenyl)-pyrrolidine-2,5-dione (16).
White solid.
Yield: 70%; mp 122–124 °C; TLC: Rf = 0.46 (S1), Rf = 0.67 (S2); 1H
NMR (300 MHz, CDCl3) d: 2.79–2.86 (m, 5H, 4H piperazine, 1H,
Hb imide), 3.19 (t, 4H, piperazine J = 4.91 Hz), 3.29 (dd, 1H, Ha
imide, J = 10.0 Hz, J = 18.46 Hz), 4.42 (q, 1H, Hc imide, J = 5.90 Hz),
4.61 (s, 2H, CH2), 6.74–6.86 (m, 3H, ArH), 7.13–7.24 (m, 3H, ArH),
7.29–7.35 (m, 1H, ArH), 7.59–7.62 (m, 1H, ArH); 13C NMR