Y. Nagaoka et al. / European Journal of Medicinal Chemistry 41 (2006) 697–708
705
gave the pure compound 18 as a brownish oil (0.38 g, 0.78
5.3.26. 4-{[(3,4-Difluorobenzyl)amino]methyl}-N-(2-
nitrophenyl)benzamide (19d)
mmol, 59% yield): IR (KBr): ν (cm–1) 2928, 2855, 2822,
1
1649, 1502, 1452, 1315, 1099, 937, 835; H NMR (CD3OD):
3,4-Difluorobenzaldehyde (1.27 ml, 11.6 mmol), Et3N (1.62
ml, 11.6 mmol), 15 (3.6 g, 11.6 mmol), 1% methanolic AcOH
(3.17 ml, 55.8 mmol) and NaBH3CN (0.73 g, 11.6 mmol) were
reacted in MeOH (317 ml) in the usual way, giving the pure
compound 19d a yellowish solid (1.49 g, 3.75 mmol, 32.0%
yield): m.p. 65.6–67.8 °C; IR (KBr): ν (cm–1) 3346, 3261,
δ 0.03 (6H, s, Si(CH3)2), 0.87 (9H, s, SitBu), 2.62 (2H, t,
J = 5.6 Hz, NCH2CH2OSi), 3.71(2H, t, J = 4.4 Hz, NCH2CH2
OSi), 3.73 (2H, s, CH2PhenyleneCO), 3.74 (2H, s, pyridine-C
H2), 6.74–8.51 (12H, m, arom. H12); FAB-MS m/z: 491 (M +
H)+; HR-FAB-MS m/z: (M + H)+ calcd for C28H39N4O2Si,
491.2842; found, 491.2827.
1
2835, 1923, 1678, 1607, 1433, 1344, 1271, 899; H NMR
(CDCl3): δ 3.77 (2H, s, 3,4-difluorophenyl-CH2), 3.89 (2H, s,
PhenyleneCH2,), 7.06–7.26 (5H, m, arom. H4), 7.52 (2H, d,
J = 8.0 Hz, arom. H2), 7.74 (1H, t, J = 7.2 Hz, arom. H1),
7.97 (2H, dd, J = 2.0, 8.4 Hz, arom. H2), 8.29 (1H, dd,
J = 1.6, 8.4 Hz, arom. H1); EI-MS m/z: 397 (M)+; HR-EI-MS
m/z: (M)+ calcd for C21H17F2N3O3, 397.1238; found,
397.1259.
5.3.23. 4-[(Benzylamino)methyl]-N-(2-nitrophenyl)benzamide
(19a)
Benzaldehyde (1.8 ml, 17.9 mmol), Et3N (2.5 ml,
17.9 mmol), 15 (5.5 g, 17.9 mmol), 1% methanolic AcOH
(4.4 ml, 77 mmol) and NaBH3CN (1.13 g, 17.9 mmol) were
reacted in MeOH (440 ml) in the usual way, giving the pure
compound 19a as a yellowish solid (3.34 g, 9.25 mmol, 51.6%
yield): m.p. 91.0–92.8 °C; IR (KBr): ν (cm–1) 3377, 3328,
2939, 2332, 1682, 1607, 1583, 1435, 1273; 1H NMR
(CDCl3): δ 3.81 (2H, s, PhCH2NH), 3.90 (2H, s, C
H2PhenyleneCO), 7.19 –7.35 (6H, m, arom. H6), 7.53 (2H, d,
J = 8.4 Hz, arom. H2), 7.73 (1H, t, J = 7.2 Hz, arom. H1), 7.96
(2H, d, J = 8.0 Hz, arom. H2), 8.28 (1H, dd, J = 1.6, 8.4 Hz,
arom. H1), 9.00 (1H, dd, J = 1.2, 8.6 Hz, arom. H1), 11.3 (1H,
s, CONH); EI-MS m/z: 361 (M)+; HR-EI-MS m/z: (M)+ calcd
for C21H19N3O3, 361.1426; found, 361.1450.
5.3.27. 4-{[(4-Methoxybenzyl)amino]methyl}-N-(2-
nitrophenyl)benzamide (19e)
4-Methoxybenzaldehyde (0.4 ml, 3.25 mmol), Et3N (0.45
ml, 3.25 mmol), 15 (1.0 g, 3.25 mmol), 1% methanolic AcOH
(1.0 ml, 17.6 mmol) and NaBH3CN (0.20 g, 3.25 mmol) were
reacted in MeOH (100 ml) in the usual way, giving the pure
compound 19e a greenish solid (0.25 g, 0.64 mmol, 20.0%
yield): m.p. 58.0–60.3 °C; IR (KBr): ν (cm–1) 3369, 2822,
1682, 1607, 1551, 1508, 1437, 1339, 986, 935; 1H NMR
(CDCl3): δ 3.71 (2H, s, 4-methoxyphenyl-CH2), 3.78 (3H, s,
OMe), 3.88 (2H, s, PhenyleneCH2,), 6.86 (2H, d, J = 6.4 Hz,
arom. H2), 7.17 (1H, t, J = 7.2 Hz, arom. H1), 7.25 (2H, d,
J = 8.4 Hz, arom. H2), 7.49 (2H, d, J = 8.0 Hz, arom. H2),
7.66 (1H, t, J = 6.0 Hz, arom. H1), 7.93 (2H, d, J = 8.4 Hz,
arom. H2), 8.23 (1H, dd, J = 1.6, 8.6 Hz, arom. H1), 8.97
(1H, dd, J = 1.2, 8.4 Hz, arom. H1), 11.30 (1H, s, CONH);
EI-MS m/z: 391 (M)+; HR-EI-MS m/z: (M)+ calcd for
C22H21N3O4, 391.1532; found, 391.1534.
5.3.24. 4-({[(1-Methyl-1H-indole-3-yl)methyl]amino}methyl)-
N-(2-nitrophenyl)benzamide (19b)
1-Methylindole-3-carboxaldehyde (1.56 g, 9.8 mmol), Et3N
(1.5 ml, 9.8 mmol), 15 (3.0 g, 9.8 mmol), 1% methanolic
AcOH (3.3 ml, 58 mmol) and NaBH3CN (0.61 g, 9.8 mmol)
were reacted in MeOH (330 ml) in the usual way, giving the
pure compound 19b as a yellowish solid (1.65 g, 4.0 mmol,
40.6% yield): m.p. 178.5–181.3 °C; IR (KBr): ν (cm–1) 2878,
2773, 2704, 1674, 1585, 1506, 1339, 1251, 1150, 972, 739; 1H
NMR (DMSO-d6): δ 3.83 (3H, s, NMe), 4.27 (2H, s, 1-methyl-
1H-indol-CH2), 4.34 (2H, s, CH2Phenylene), 7.12–8.03 (13H,
m, arom. H13), 9.52 (1H, brs, CH2NH), 10.88 (1H, s, CONH);
FAB-MS m/z: 415 (M + H)+; HR-FAB-MS m/z: (M + H)+
calcd for C24H23N4O3, 415.1770; found, 415.1786.
5.3.28. 4-{[Benzyl(2-hydroxyethyl)amino]methyl}-N-(2-
nitrophenyl)benzamide (20a)
19a (3.2 g, 8.9 mmol) was reacted with 2-bromoethanol
(12.5 ml, 176 mmol) in the presence of K2CO3 (4.9 g,
35.5 mmol) in MeCN (85 ml) in the usual way, to give the
pure compound 20a as a yellowish oil (1.47 g, 3.63 mmol,
41.0% yield): IR (KBr): ν (cm–1) 3362, 2806, 1688, 1607,
5.3.25. 4-{[(1,3-Benzodioxol-5-ylmethyl)amino]methyl}-N-(2-
nitrophenyl)benzamide (19c)
1
1502, 1454, 1433, 1275, 1146, 980, 862; H NMR (CD3OD):
1,3-Benzodioxol-5-carboxaldehyde (0.5 g, 3.3 mmol), Et3N
(0.5 ml, 3.3 mmol), 15 (1.0 g, 3.3 mmol), 1 % methanolic
AcOH (0.88 ml, 15.5 mmol) and NaBH3CN (0.20 g, 3.2 mmol)
were reacted in MeOH (88 ml) in the usual way, giving the
pure compound 19c as a yellowish solid (0.33 g, 0.8 mmol,
24.8% yield): m.p. 74.6–76.8 °C; IR (KBr): ν (cm–1); 3371,
2885, 2800, 2340, 1684, 1604, 1450, 1377, 1192, 988, 899;
1H NMR (CD3OD): δ 3.68 (2H, s, 1,3-benzodioxol-CH2),
3.82 (2H, s, PhenyleneCH2), 5.92 (2H, s, OCH2), 6.75–6.81
(2H, m, arom. H2), 6.88 (1H, d, J = 1.2 Hz, arom. H1), 7.36–
8.43 (8H, m, arom. H8); FAB-MS m/z: 406 (M + H)+; HR-
FAB-MS m/z: (M + H)+ calcd for C22H20N3O5, 406.1403;
found, 406.1388.
δ 2.54 (2H, t, J = 6.4 Hz, NCH2CH2OH), 3.52 (2H, s, PhC
H2NH), 3.55 (2H, s, CH2PhenyleneCO), 3.58 (2H, t,
J = 6.4 Hz, NCH2CH2OH), 7.08–7.75 (9H, m, arom. H9),
7.76 (2H, t, J = 8.8 Hz, arom. H2), 8.00 (1H, dd, J = 1.6,
8.4 Hz, arom. H1), 8.49 (1H, dd, J = 1.2, 8.4 Hz, arom. H1);
FAB-MS m/z: 406 (M + H)+; HR-FAB-MS m/z: (M + H)+
calcd for C23H24N3O4, 406.1767; found, 407.1765.
5.3.29. 4-({(2-Hydroxyethyl)[(1-methyl-1H-indol-3-yl)methyl]
amino}methyl)-N-(2-nitrophenyl)benzamide (20b)
19b (0.7 g, 1.7 mmol) was reacted with 2-bromoethanol
(2.4 ml, 33.8 mmol) in the presence of K2CO3 (0.93 g,
6.7 mmol) in MeCN (17 ml) in the usual way to give the pure