A. Naya et al. / Bioorg. Med. Chem. 11 (2003) 875–884
881
was added benzylamine (50 mL, 0.46 mmol), and the
mixture was stirred for 11 h. The mixture was diluted
with EtOAc, washed with saturated NaHCO3 solution
and brine, dried (MgSO4), and concentrated in vacuo.
The residue was purified by preparative TLC (5%
MeOH in CHCl3) to give 2j (22 mg, 36%) as a colorless
1H), 8.58 (dd, J=0.9, 5.0 Hz, 1H); HRMS calcd for
C36H43N4O3 (M+H)+: 579.3335, found 579.3320.
N9-[1-(1-Cyclononenylmethyl)piperidin-4-yl]-N2-(3-pyridyl-
methyl)xanthen-2,9-dicarboxamide (2o). This compound
was prepared from 3-picolylamine (20%): 1H NMR
(CDCl3) d 1.19–2.22 (m, 20H), 2.58–2.74 (m, 2H), 2.77
(s, 2H), 3.55–3.74 (m, 1H), 4.58 (dd, J=5.8, 14.7Hz,
1H), 4.63 (dd, J=5.8, 14.7Hz, 1H), 4.82 (s, 1H), 5.38 (t,
J=8.4 Hz, 1H), 5.60–5.85 (m, 1H), 7.05–7.41 (m, 7H),
7.70 (ddd, J=1.6, 2.2, 7.9 Hz, 1H), 7.76 (dd, J=2.1, 8.5
Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 8.50 (dd, J=1.6, 4.8
Hz, 1H), 8.59 (d, J=2.2 Hz, 1H); HRMS calcd for
C36H43N4O3 (M+H)+: 579.3335, found 579.3329.
1
solid: H NMR (CDCl3) d 1.10–2.20 (m, 20H), 2.50–
2.56 (m, 2H), 2.73 (s, 2H), 3.55–3.74 (m, 1H), 4.61 (dd,
J=5.6, 14.4 Hz, 1H), 4.67(dd, J=5.6, 14.4 Hz, 1H),
4.83 (s, 1H), 5.16 (d, J=7.8 Hz, 1H), 5.36 (t, J=8.5 Hz,
1H), 6.48 (t, J=5.6 Hz, 1H), 7.10–7.21 (m, 3H), 7.24–
7.41 (m, 7H), 7.81 (dd, J=2.1, 8.6 Hz, 1H), 7.86 (d,
J=2.1 Hz, 1H); HRMS calcd for C37H44N3O3
(M+H)+: 578.3383, found 578.3370.
The following compounds (2k–p) were prepared in a
similar manner to the procedure described for 2j by
using 8 and an appropriate amine.
N9-[1-(1-Cyclononenylmethyl)piperidin-4-yl]-N2-(4-pyridyl-
methyl)xanthen-2,9-dicarboxamide (2p). This compound
was prepared from 4-picolylamine (25%): 1H NMR
(CDCl3) d 1.20–2.75 (m, 22H), 2.78 (s, 2H), 3.56–3.74
(m, 1H), 4.57(dd, J=6.1, 16.0 Hz, 1H), 4.63 (dd,
J=6.1, 16.0 Hz, 1H), 4.83 (s, 1H), 5.38 (t, J=8.4 Hz,
1H), 5.58–5.71 (m, 1H), 7.09–7.42 (m, 6H), 7.24 (d,
J=5.9 Hz, 2H), 7.79 (dd, J=2.0, 8.5 Hz, 1H), 7.92 (d,
J=2.0 Hz, 1H), 8.53 (d, J=5.9 Hz, 2H); HRMS calcd
for C36H43N4O3 (M+H)+: 579.3335, found 579.3334.
N9-[1-(1-Cyclononenylmethyl)piperidin-4-yl]-N2-(2-meth-
oxybenzyl)xanthen-2,9-dicarboxamide (2k). This com-
pound was prepared from 2-methoxybenzylamine (13%):
1H NMR (CDCl3) d 1.18–2.25 (m, 20H), 2.52–2.72 (m,
2H), 2.75 (s, 2H), 3.58–3.75 (m, 1H), 3.90 (s, 3H), 4.61
(dd, J=5.7, 14.5 Hz, 1H), 4.66 (dd, J=5.7, 14.5 Hz, 1H),
4.84 (s, 1H), 5.31 (d, J=7.3 Hz, 1H), 5.37 (t, J=8.4 Hz,
1H), 6.75 (t, J=5.7 Hz, 1H), 6.85–7.00 (m, 2H), 7.09–
7.19 (m, 3H), 7.21–7.39 (m, 4H), 7.76 (dd, J=1.8, 8.6 Hz,
1H), 7.83 (d, J=1.8 Hz, 1H); HRMS calcd for
C38H46N3O4 (M+H)+: 608.3488, found 608.3479.
N-[1-(1-Cyclononenylmethyl)piperidin-4-yl]-2-allyloxy-
carbonylaminoxanthen-9-carboxamide (2h). To a stirred
suspension of 8 (40 mg, 0.082 mmol) in 1,4-dioxane
(2.0 mL) were added diphenylphosphoryl azide (26.5 mL,
0.123 mmol), allyl alcohol (20.0 mL, 0.294 mmol) and
Et3N (17.0 mL, 0.122 mmol) at room temperature. After
being refluxed for 17h, the reaction mixture was cooled
and diluted with brine, extracted with CHCl3, dried
(MgSO4), and concentrated in vacuo. The residue was
purified by preparative TLC (9% MeOH in CHCl3) to
N9-[1-(1-Cyclononenylmethyl)piperidin-4-yl]-N2-(3-meth-
oxybenzyl)xanthen-2,9-dicarboxamide (2l). This com-
pound was prepared from 3-methoxybenzylamine
1
(27%): H NMR (CDCl3) d 1.11–2.19 (m, 20H), 2.45–
2.69 (m, 2H), 2.73 (s, 2H), 3.55–3.75 (m, 1H), 3.81 (s,
3H), 4.59 (dd, J=5.6, 14.0 Hz, 1H), 4.62 (dd, J=5.6,
14.0 Hz, 1H), 4.83 (s, 1H), 5.13 (d, J=7.3 Hz, 1H), 5.36
(t, J=8.8 Hz, 1H), 6.40 (t, J=5.6 Hz, 1H), 6.84 (d,
J=8.2 Hz, 1H), 6.91 (s, 1H), 6.95 (d, J=7.4 Hz, 1H),
7.10–7.38 (m, 6H), 7.81 (dd, J=2.1, 8.4 Hz, 1H), 7.86
(d, J=2.1 Hz, 1H); HRMS calcd for C38H46N3O4
(M+H)+: 608.3488, found 608.3475.
1
give 2h (29 mg, 65%) as a colorless solid: H NMR
(CDCl3) d 1.15–2.22 (m, 20H), 2.50–2.68 (m, 2H), 2.75
(s, 2H), 3.68–3.78 (m, 1H), 4.67 (d, J=5.7Hz, 2H), 4.79
(s, 1H), 5.12–5.43 (m, 4H), 5.86–6.04 ( m, 1H), 6.70 (s,
1H), 7.02.18 (m, 3H), 7.21–7.48 (m, 4H); HRMS calcd
for C33H42N3O4 (M+H)+: 544.3175, found 544.3165.
N-[1-(1-Cyclononenylmethyl)piperidin-4-yl]-2-amino-
xanthen-9-carboxamide (2i). To a stirred solution of 2h
(20 mg, 0.037mmol) in CH 2Cl2 (2.0 mL) was added
PdCl2(Ph3P)2 (2.9 mg, 0.004 mmol), AcOH (5.0 mL,
0.087mmol) and n-Bu3SnH (11.0 mL, 0.041 mmol) at
room temperature. After being stirred for 1 h, the reac-
tion mixture was diluted with brine, extracted with
CHCl3, dried (MgSO4), and concentrated in vacuo. The
residue was purified by preparative TLC (9% MeOH in
N9-[1-(1-Cyclononenylmethyl)piperidin-4-yl]-N2-(4-meth-
oxybenzyl)xanthen-2,9-dicarboxamide (2m). This com-
pound was prepared from 4-methoxybenzylamine (8%):
1H NMR (CDCl3) d 1.18–2.22 (m, 20H), 2.52–2.71 (m,
2H), 2.76 (s, 2H), 3.57–3.75 (m, 1H), 3.80 (s, 3H), 4.54
(dd, J=5.5, 14.5 Hz, 1H), 4.59 (dd, J=5.5, 14.5 Hz,
1H), 4.82 (s, 1H), 5.28 (d, J=9.2 Hz, 1H), 5.37(t,
J=8.6 Hz, 1H), 6.42–6.53 (m, 1H), 6.88 (d, J=8.6 Hz,
2H), 7.05–7.38 (m, 7H), 7.79 (dd, J=2.1, 8.5 Hz, 1H),
7.85 (d, J=2.1 Hz, 1H); HRMS calcd for C38H46N3O4
(M+H)+: 608.3488, found 608.3479.
1
CHCl3) to give 2i (7.0 mg, 41%) as a yellow solid: H
NMR (CDCl3) d 1.08–2.22 (m, 20H), 2.48–2.65 (m, 2H),
2.73 (s, 2H), 3.40.75 (m, 3H), 4.74 (s, 1H), 5.14 (d, J=7.5
Hz, 1H), 5.36 (t, J=8.4 Hz, 1H), 6.66 (dd, J=2.6, 8.6 Hz,
1H), 6.69 (d, J=2.9 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H),
7.00–7.15 (m, 2H), 7.21–7.40 (m, 2H); HRMS calcd for
C29H38N3O2 (M+H)+: 460.2964, found 460.2964.
N9-[1-(1-Cyclononenylmethyl)piperidin-4-yl]-N2-(2-pyridyl-
methyl)xanthen-2,9-dicarboxamide (2n). This compound
was prepared from 2-picolylamine (32%): 1H NMR
(CDCl3) d 1.16–2.21 (m, 20H), 2.50–2.69 (m, 2H), 2.75 (s,
2H), 3.58–3.75 (m, 1H), 4.68–4.82 (m, 2H), 4.88 (s, 1H),
5.23 (d, J=8.4 Hz, 1H), 5.37(t, J=8.4 Hz, 1H), 7.09–7.75
(m, 9H), 7.87 (dd, J=2.0, 8.6 Hz, 1H), 7.95 (d, J=2.0 Hz,
General method: N2-(2-aminoethyl)-N9-[1-(1-cyclononenyl-
methyl)piperidin-4-yl]xanthen-2,9-dicarboxamide (2t). To
a stirred solution of 8 (30 mg, 0.061 mmol) and t-butyl