Y. Kim et al. / Bioorg. Med. Chem. 21 (2013) 2568–2576
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the title compound 1-17 (58 mg, 0.16 mmol, 20% yield). 1H NMR
(300 MHz, CDCl3) d 7.57–7.54 (m, 1H), 7.47–7.20 (m, 8H), 6.53–
6.50 (m, 3H), 3.45 (s, 2H), 3.10 (br t, J = 4.8 Hz, 4H), 2.49 (br t,
J = 4.8 Hz, 4H), 2.26 (s, 6H); 13C NMR (75 MHz, CDCl3) d 151.66,
142.87, 141.55, 138.60, 135.68, 130.22, 130.07, 129.62, 127.92,
127.19, 126.93, 121.58, 114.09, 59.94, 52.93, 49.48, 21.74; LC/MS
(ESI+): m/z: calcd for C24H26N2: 356.51, [M+H]+; found: 357.30.
111.31, 60.21, 55.38, 52.94, 50.84; LC/MS (ESI+): m/z: calcd for
24H25ClN2O: 392.93, [M+H]+; found: 393.20.
C
4.3.22. 1-((40-Chloro-[1,10-biphenyl]-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine (1-22)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (497 mg, 2.58 mmol),
40-chlorobiphenyl-2-carbaldehyde (280 mg, 1.29 mmol), and NaB-
H(OAc)3 (832 mg, 3.87 mmol) in methanol (20 ml) gave the title
compound 1-22 (215 mg, 0.55 mmol, 42% yield). 1H NMR
(300 MHz, CDCl3) d 7.61 (dd, J = 6.4 Hz, 2.3 Hz, 1H), 7.51–7.31 (m,
7H), 7.09–6.98 (m, 3H), 6.92 (d, J = 7.2 Hz, 1H), 3.91 (s, 3H), 3.52
(s, 2H), 3.12 (br s, 4H), 2.66 (br s, 4H); 13C NMR (75 MHz, CDCl3)
d 152.41, 141.76, 141.61, 140305, 135.78, 133.04, 121.10, 130.63,
130.15, 128.06, 127.43, 127.14, 122.87, 121.10 ,118.28, 111.43,
60.17, 55.44, 53.08, 50.89; LC/MS (ESI+): m/z: calcd for
C24H25ClN2O: 392.93, [M+H]+; found: 393.20.
4.3.18. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(3-
(trifluoromethyl)phenyl)piperazine (1-18)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(3-trifluoromethylphenyl)piperazine (437 mg,
1.64 mmol), [1,10-biphenyl]-2-carbaldehyde (150 mg, 0.82 mmol),
and NaBH(OAc)3 (529 mg, 2.46 mmol) in methanol (10 ml) gave
the title compound 1-18 (19 mg, 0.05 mmol, 6% yield). 1H NMR
(300 MHz, CDCl3) d 7.57–7.54 (m, 1H), 7.41–7.25 (m, 9H), 7.07–
7.00 (m, 3H), 3.47 (s, 2H), 3.17 (br t, J = 5.1 Hz, 4H), 2.51 (br s,
4H); 13C NMR (75 MHz, CDCl3) d 151.52, 142.85, 141.46, 135.43,
130.21, 129.97, 129.53, 129.49, 127.90, 127.19, 126.99, 126.93,
118.64, 115.60, 112.02, 59.82, 52.57, 48.77; LC/MS (ESI+): m/z:
calcd for C24H23F3N2: 396.46, [M+H]+; found: 397.30.
4.3.23. 1-(2-Methoxyphenyl)-4-((20-methyl-[1,10-biphenyl]-2-
yl)methyl)piperazine (1-23)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (196 mg, 1.02 mmol),
20-methyl-[1,10-biphenyl]-2-carbaldehyde (100 mg, 0.51 mmol),
and NaBH(OAc)3 (329 mg, 1.53 mmol) in methanol (50 ml) gave
the title compound 1-23 (186 mg, 0.50 mmol, 98% yield). 1H
NMR (300 MHz, CDCl3) d 7.58 (dd, J = 7.5 Hz, 1.2 Hz, 1H), 7.35–
7.10 (m, 7H), 6.96–6.86 (m, 3H), 6.79 (d, J = 7.5 Hz, 1H), 3.78 (s,
3H), 3.34 (d, J = 13.5 Hz, 1H), 3.22 (d, J = 13.5 Hz, 1H), 2.98 (br s,
4H), 2.47 (br s, 4H), 2.05 (s, 3H); 13C NMR (75 MHz, CDCl3) d
152.40, 142.13, 141.67, 141.05, 136.46, 136.06, 129.76, 129.68,
129.42, 127.29, 127.21, 126.68, 125.34, 122.84, 121.08, 118.29,
111.34, 59.84, 55.43, 53.48, 53.32, 50.86; LC/MS (ESI+): m/z: calcd
for C25H28N2O: 372.51, [M+H]+; found: 373.30.
4.3.19. 1-((20-Fluoro-[1,10-biphenyl]-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine (1-19)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (1.2 g, 6.20 mmol), 20-
fluorobiphenyl-2-carbaldehyde (620 mg, 3.10 mmol), and NaB-
H(OAc)3 (2.0 g, 9.30 mmol) in methanol (50 ml) gave the title com-
pound 1-19 (379 mg, 1.01 mmol, 33% yield). 1H NMR (300 MHz,
CDCl3) d 7.64 (dd, J = 6.8 Hz, 1.5 Hz, 1H), 7.44–7.11 (m, 7H), 7.03–
6.92 (m, 3H), 6.86 (d, J = 7.9 Hz, 1H), 3.85 (s, 3H), 3.48 (s, 2H),
3.00 (br s, 4H), 2.52 (br s, 4H); 13C NMR (75 MHz, CDCl3) d
160.69 (d, J = 246 Hz), 152.31, 141.59, 137.10, 136.16, 131.69 (d,
J = 3.5 Hz), 130.32, 129.63, 129.05, 128.91 (d, J = 5.6 Hz), 127.91,
126.71, 123.69 (d, J = 3.5 Hz), 122.72, 120.95, 118.18, 115.28 (d,
J = 22.4 Hz), 111.21, 59.99, 55.33, 53.08, 50.74; LC/MS (ESI+): m/z:
calcd for C24H25FN2O: 376.47, [M+H]+; found: 377.30.
4.3.24. 1-((20-Methoxy-[1,10-biphenyl]-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine (1-24)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (634 mg, 3.30 mmol),
20-methoxybiphenyl-2-carbaldehyde (350 mg, 1.65 mmol), and
NaBH(OAc)3 (1.1 g, 4.95 mmol) in methanol (25 ml) gave the title
compound 1-24 (382 mg, 0.98 mmol, 60% yield). 1H NMR
(400 MHz, CDCl3) d 7.62 (dd, J = 7.6 Hz, 1.0 Hz, 1H), 7.36–7.25 (m,
3H), 7.19–7.15 (m, 2H), 7.00–6.89 (m, 5H), 6.80 (d, J = 7.6 Hz,
1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.46 (d, J = 13.4 Hz, 1H), 3.33 (d,
J = 13.4 Hz, 1H), 2.98 (br s, 4H), 2.48 (br s, 4H); 13C NMR
4.3.20. 1-((20-Chloro-[1,10-biphenyl]-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine (1-20)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (311 mg, 1.62 mmol),
20-chlorobiphenyl-2-carbaldehyde (175 mg, 0.81 mmol), and NaB-
H(OAc)3 (523 mg, 2.43 mmol) in methanol (15 ml) gave the title
compound 1-20 (69 mg, 0.18 mmol, 22% yield). 1H NMR
(400 MHz, CDCl3) d 7.59 (dd, J = 7.6 Hz, 0.8 Hz, 1H), 7.46–7.24 (m,
6H), 7.17 (d, J = 7.6 Hz, 1H), 6.99–6.88 (m, 3H), 6.82 (d, J = 7.8 Hz,
1H), 3.81 (s, 3H), 3.44 (d, J = 13.5 Hz, 1H), 3.28 (d, J = 13.5 Hz,
1H), 2.96 (br s, 4H), 2.47 (br s, 4H); 13C NMR (100 MHz, CDCl3) d
152.29, 141.55, 140.14, 139.78, 136.72, 133.53, 131.38, 129.81,
129.45, 129.20, 128.53, 127.87, 126.64, 126.26, 122.76, 120.94,
118.19, 111.14, 59.89, 55.34, 53.17, 50.71; LC/MS (ESI+): m/z: calcd
for C24H25ClN2O: 392.93, [M+H]+; found: 393.30.
(100 MHz, CDCl3)
d 156.60, 152.34, 141.65, 138.95, 137.21,
131.30, 130.44, 130.28, 129.03, 128.38, 127.37, 126.53, 122.79,
121.03, 120.41, 118.25, 111.20, 110.51, 59.83, 55.40, 53.53, 53.25,
50.88; LC/MS (ESI+): m/z: calcd for C25H28N2O2: 388.51, [M+H]+;
found: 389.30.
4.3.25. 1-((30-Methoxy-[1,10-biphenyl]-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine (1-25)
4.3.21. 1-((30-Chloro-[1,10-biphenyl]-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine (1-21)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (181 mg, 0.94 mmol),
30-methoxybiphenyl-2-carbaldehyde (100 mg, 0.47 mmol), and
NaBH(OAc)3 (303 mg, 1.41 mmol) in methanol (10 ml) gave the ti-
tle compound 1-25 (176 mg, 0.45 mmol, 96% yield). 1H NMR
(300 MHz, CDCl3) d 7.55–7.53 (m, 1H), 7.34–7.26 (m, 4H), 7.03–
6.80 (m, 7H), 3.80 (s, 6H), 3.48 (s, 2H), 3.02 (br s, 4H), 2.58 (br s,
4H); 13C NMR (75 MHz, CDCl3) d 159.26, 152.38, 142.98, 142.80,
141.61, 135.70, 130.39, 130.10, 128.93, 127.24, 126.93, 122.87,
122.23, 121.07, 118.26, 115.42, 112.60, 111.29, 60.03, 55.42,
55.37, 53.18, 50.91; LC/MS (ESI+): m/z: calcd for C25H28N2O2:
388.51, [M+H]+; found: 389.30.
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (603 mg, 3.14 mmol),
30-chlorobiphenyl-2-carbaldehyde (340 mg, 1.57 mmol), and NaB-
H(OAc)3 (1.0 g, 4.71 mmol) in methanol (25 ml) gave the title com-
pound 1-21 (250 mg, 0.64 mmol, 41% yield). 1H NMR (300 MHz,
CDCl3) d 7.71 (br s, 1H), 7.56–7.52 (m, 1H), 7.43–7.30 (m, 6H),
7.06–6.92 (m, 3H), 6.90 (d, J = 7.5 Hz, 1H), 3.89 (s, 3H), 3.47 (s,
2H), 3.10 (br s, 4H), 2.65 (br s, 4H); 13C NMR (75 MHz, CDCl3) d
152.36, 143.34, 141.63, 141.59, 135.75, 133.70, 130.73, 130.06,
129.07, 127.79, 127.46, 127.17, 126.97, 122.80, 121.03, 118.25,