Brief Articles
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 9 1895
8.16 (dd, J ) 8.56, 1.57 Hz, 1H), 8.06 (br, 1H),7.41 (m, 1H),
7.29-7.25 (m, 2H), 7.20-7.13 (m, 3H), 6.85 (d, J ) 8.68 Hz, 1
H), 6.23 (m, 1H), 3.32 (m, 2H), 2.89 (d, J ) 11.6 Hz, 2H), 2.53
(d, J ) 6.99 Hz, 2H), 2.53 (m, 2H), 2.35 (m, 2H), 1.86 (m, 2H),
1.76-1.71 (m, 2H), 1.67-1.62 (m, 4H), 1.53-1.50 (m, 1H),
1.36-1.25 (m, 2H); APCI MS m/z 368 (M+ + 1, 100%); IR 3381,
2924,1618, 1572, 1512, 1418, 1354, 1264, 742, 699 cm-1. Anal.
(C22H29N3O2) C, H, N.
[5-(4-Be n zylp ip e r id in -1-yl)p e n t yl](2-n it r op h e n yl)-
a m in e (9c). A procedure identical to that described for the
preparation of 9a using 1-(5-chloropentyl)-2-nitroaniline (8c)
gave 9c as an orange oil (1.40 g, 89%): 1H NMR (CDCl3) δ
8.16 (dd, J ) 8.68, 1.45 Hz, 1H), 8.04 (br, 1H), 7.42 (m, 1H),
7.29-7.25 (m, 2H), 7.20-7.13 (m, 3H), 6.83 (d, J ) 8.68 Hz,
1H), 6.63 (m, 1H), 3.29 (dd, J ) 12.3, 6.99 Hz, 2H), 2.89 (d, J
) 11.3 Hz, 2H), 2.53 (d, J ) 6.99 Hz, 2H), 2.33-2.30 (m, 2H),
1.88-1.83 (m, 2H), 1.78-1.71 (m, 2H), 1.65-1.41 (m, 5H),
1.36-1.24 (m, 2H); APCI MS m/z 381 (M+, 100%); IR 3381,
2928, 1618, 1572, 1512, 1264, 1153, 742, 699 cm-1. Anal.
(C23H31N3O2) C, H, N.
{3-[4-(4-F lu or ob en zyl)p ip er id in -1-yl]p r op yl}(2-n it r o-
p h en yl)a m in e (9d ). A procedure identical to that described
for the preparation of 9a using 1-(3-chloropropyl)-2-nitroaniline
(8a ) and 4-(fluorobenzyl)piperidine19 gave 9d as an orange oil
(1.79 g, 88%): 1H NMR (CDCl3) δ 8.24 (br s, 1H), 8.16 (dd, J
) 8.56, 1.57 Hz, 1H), 2.42 (m, 2H), 7.11-7.07 (m, 2H), 6.99-
6.93 (m, 2H), 6.87 (d, J ) 8.72 Hz, 1H), 6.62 (m, 2H), 3.49-
3.34 (m, 2H), 2.91 (d, J ) 11.56 Hz, 2H), 2.52 (d, J ) 6.99 Hz,
2H), 2.44 (t, J ) 6.87 Hz, 2H), 1.92-1.85 (m, 4H), 1.61 (d, J )
13.7 Hz, 2H), 1.53-1.44 (m, 1H), 1.38-1.29 (m, 2H); APCI MS
m/z 371 (M+, 100%); IR 2922, 1618, 1571, 1509, 1418, 1350,
1155, 1038, 742 cm-1. Anal. (C21H26FN3O2) C, H, N.
1-[3-(4-Ben zylp ip er id in -1-yl)p r op yl]-1,3-d ih yd r oben z-
im id a zol-2-on e (11a ). To a solution of [3-(4-benzylpiperidin-
1-yl)propyl](2-nitrophenyl)amine (9a ) (0.91 g, 2.57 mmol) in
THF/MeOH (20 mL/20 mL) was added Raney nickel that had
been washed with water until the washings were pH ∼ 7. The
yellow solution was purged with H2 and stirred at room
temperature under 1 atm for 1 h. The colorless solution was
filtered and the catalyst washed generously with THF. The
filtrate was evaporated to give an 10a as an oil: 1H NMR
(CDCl3) δ 7.26-7.10 (m, 5H), 6.78-6.74 (m, 1H), 6.67-6.57
(m, 3H), 3.26 (br s, 1H), 3.12 (t, J ) 6.35 Hz, 2H), 2.93 (d, J )
11.5 Hz, 2H), 2.51 (d, J ) 6.84 Hz, 2H), 2.43 (t, J ) 6.59 Hz,
2H), 1.85-1.79 (m, 4H), 1.61 (d, J ) 13.4 Hz, 2H), 1.57-1.47
(m, 1H), 1.35-1.25 (m, 2H).
Exp er im en ta l Section
Gen er a l. Reagents and solvents were purchased from
commercial sources and used as received. All starting materi-
als were commercially available unless otherwise indicated.
Melting points were taken on a Mel-Temp apparatus and are
uncorrected. Tetrahydrofuran (THF) was distilled from blue
sodium benzophenone ketyl solution. Yields are of purified
product and are not optimized. 1H NMR spectra were recorded
on Varian Unity 400 spectrometers. Mass spectra were ob-
tained on Finnigan 4500 or VG Analytical 7070E/HF mass
spectrometers. IR spectra were recorded as KBr disks on a
Nicolet MX-1 FT spectrophotometer. Elemental analyses were
performed by Robertson Laboratories. TLC was performed on
0.25-mm silica gel F254 (E. Merck) glass plates. Medium-
pressure liquid chromatography (MPLC) was performed on
self-packed Michel-Miller 40-mm i.d. × 350-mm (∼200 g silica
gel) or 51-mm i.d. × 450-mm (∼400 g silica gel) glass columns
using 32-63-µm, 60 A pore silica gel.
1-(3-Ch lor op r op yl)-2-n itr oa n ilin e (8a ). A mixture of
2-nitroaniline (2.00 g, 14.5 mmol) and 1-bromo-3-chloropropane
(7.2 mL, 72.4 mmol) in THF (50 mL) was treated with NaH
(0.64 g, 60% w/w, 15.9 mmol) added in small portions. The
deep orange colored suspension was refluxed for 4 h and
1-bromo-3-chloropropane (3 mL, 30.3 mmol) added again. The
reaction was refluxed for 3 h and then quenched with
saturated aqueous NH4Cl. The mixture was extracted with
EtOAc (2 × 30 mL). The extracts were dried over MgSO4,
filtered, and evaporated to give an orange oil. The oil was
purified by MPLC loading in benzene and eluting with 10%
EtOAc/hexanes to give an orange oil (1.87 g, 50%): 1H NMR
(CDCl3) δ 8.19 (d, J ) 8.68 Hz, 1H), 8.09 (br s, 1H), 7.46 (tr,
J ) 7.72 Hz, 1H), 6.90 (d, J ) 8.44 Hz, 1H), 6.68 (dd, J )
8.32, 7.35 Hz, 1H), 3.54 (q, J ) 6.35 Hz, 2H), 2.19 (quin, J )
6.21 Hz, 2H); APCI MS m/z 215 (100%), 217 (30%); IR 3376,
1618, 1573, 1510, 742 cm-1. Anal. (C9H11ClN2O2) C, H, N, Cl.
1-(4-Ch lor obu tyl)-2-n itr oa n ilin e (8b). A procedure iden-
tical to that described for the preparation of 1a using 1-bromo-
4-chlorobutane gave 8b as an orange oil that solidified upon
1
standing (1.45 g, 44%): mp ) 40-41 °C; H NMR (CDCl3) δ
8.13 (dd, J ) 8.67, 1.59 Hz, 1H), 8.02 (br s, 1H), 7.41 (m, 1H),
6.81 (d, J ) 8.06 Hz, 1H), 6.62 (m, 1H), 3.57 (q, J ) 6.10 Hz,
2H), 3.32 (q, J ) 6.19 Hz, 2H), 1.94-1.84 (m, 4H); APCI MS
m/z 229 (100%), 231 (76%); IR 3379, 1619, 1571, 1513, 1266,
1151, 741 cm-1. Anal. (C10H13ClN2O2) C, H, N; Cl: calcd, 15.50;
found, 14.83.
1-(5-Ch lor op en tyl)-2-n itr oa n ilin e (8c). A procedure iden-
tical to that described for the preparation of 8a using 1-bromo-
4-chloropentane gave 8b as an orange oil (6.80 g, 77%): 1H
NMR (CDCl3) δ 8.13 (dd, J ) 8.55, 1.71 Hz, 1H), 8.02 (br s,
1H), 7.40 (m, 1H), 6.80 (d, J ) 8.79 Hz, 1H), 6.61 (m, 1H),
3.53 (t, J ) 6.59 Hz, 2H), 3.29 (q, J ) 6.43 Hz, 2H), 1.85-1.77
(m, 2H), 1.73 (q, J ) 7.32 Hz, 2H), 1.61-1.54 (m, 2H); APCI
MS m/z 242 (100%), 244 (32%); IR 3379, 1618, 1572, 1511,
1418, 1353, 1037, 742 cm-1. Anal. (C11H15ClN2O2) C, H, N.
[3-(4-Be n zylp ip e r id in -1-yl)p r op yl](2-n it r op h e n yl)-
a m in e (9a ). A mixture of 1-(3-chloropropyl)-2-nitroaniline (8a )
(0.60 g, 2.84 mmol), 4-benzylpiperidine (0.624 mL, 3.55 mmol),
NaI (0.43 g, 2.87 mmol), and K2CO3 (0.74 g, 5.68 mmol) in
acetonitrile (20 mL) was heated to reflux for 18 h. The solids
were filtered and washed with EtOAc. The filtrate was
evaporated, and the orange oil chromatographed on MPLC
eluting with EtOAc to give 9a as an orange oil (0.93 g, 93%):
1H NMR (CDCl3) δ 8.20 (br s, 1H), 8.13 (dd, J ) 8.67, 1.59 Hz,
1H), 7.38 (m, 1H), 7.26 (m, 2H), 7.17-7.10 (m, 3H), 6.84 (dd,
J ) 8.67, 0.85 Hz, 1H), 6.59 (m, 1H), 3.33 (q, J ) 6.27 Hz,
2H), 2.86 (d, J ) 11.23 Hz, 2H), 2.51 (d, J ) 7.08 Hz, 2H),
2.39 (t, J ) 6.84 Hz, 2 Hz), 1.88-1.81 (m, 4H), 1.60 (d, J )
14.2 Hz, 2H), 1.55 (m, 1H) 1.36-1.22 (m, 2H); APCI MS m/z
354 (M+ + 1, 100%); IR 2922, 1618, 1571, 1512, 1418, 1350,
1155, 1037, 742, 699 cm-1. Anal. (C21H27N3O2) C, H, N.
[4-(4-B e n zy lp ip e r id in -1-y l)b u t y l](2-n it r o p h e n y l)-
a m in e (9b). A procedure identical to that described for the
preparation of 9a using 1-(4-chlorobutyl)-2-nitroaniline (8b)
gave 9b as an orange oil (0.53 g, 83%): 1H NMR (CDCl3) δ
The oil from 10a was used immediately after isolation and
combined with 1,1′-carbonyldiimidazole (0.87 g, 5.36 mmol) in
THF (25 mL). The reaction was stirred at room temperature
for 18 h, after which the solvent was evaporated to give an
oil. The oil was taken up in EtOAc (75 mL), washed with water
(5 × 25 mL), dried over Na2SO4, filtered, and evaporated. The
crude material was chromatographed on MPLC loading with
EtOAc and eluting with 10% MeOH/EtOAc to give an oil (0.57
g). This oil was stirred in EtOAc (5 mL) with oxalic acid‚2H2O
in EtOH (0.21 g/5 mL) for 15 min. The solvent was evaporated,
and the oil recrystallized from acetonitrile to give a solid (0.35
g). A second crop of crystals (0.27 g) was also isolated: 1H NMR
(CDCl3) δ 10.86 (s, 1H), 7.23 (m, 2H), 7.15-7.09 (m, 4H), 6.98-
6.93 (m, 3H), 3.78 (m, 2H), 3.27 (d, J ) 11.5 Hz, 2H), 2.93 (br,
2H), 2.69 (br, 2H), 2.47-2.44 (m, 2H), 1.98-1.92 (m, 2H),
1.65-1.62 (m, 3H), 1.35-1.30 (m, 2H); APCI MS m/z 351 (M+
+ 2, 100%); IR 1710, 1689, 1486, 1404, 1200, 751, 703 cm-1
Anal. (C22H27N3O‚C2H2O4) C, H, N.
.
1-[4-(4-Ben zylp ip er id in -1-yl)b u t yl]-1,3-d ih yd r ob en z-
im id a zol-2-on e (11b). A procedure identical to that described
for the preparation of 11a using [4-(4-benzylpiperidin-1-yl)-
butyl](2-nitrophenyl)amine (9b) gave 10b as an oil (0.48 g,
100%). The oil from 10b was then converted to the benzimid-
azalone 11b using the procedure previously described for
preparation of 11a . Crystallization of the free base from
acetonitrile yielded 11b (0.22 g, 43%): mp ) 118-119 °C; 1H
NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 7.22-6.92 (m, 9H), 3.82
(t, J ) 7.32 Hz, 2H), 2.81 (d, J ) 10.99 Hz, 2H), 2.44 (d, J )