214 Yoo et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 208–215
2-[4-[N-[NЈ-(4-Methylbenzenesulfonyl)]aminoethyl]-4-piper-
idinyl]piperazinyl]pyridine (15 c)
General Procedure for the Preparation of 1-Substituted-1Ј-
(2-pyridyl)-4,4Ј-bipiperidine (20 a–d, 21 a–c, and 22 a–c)
Yield 94.6 %; mp 138–140 °C; IR (KBr) 3284, 2924, 2844,
To a solution of bipiperidinylpyridine 19 (0.50 mmol) and the ap-
propriate halide 3 (1.00 mmol) in methylethylketone (or THF,
CH3CN) (5 mL) was were added K2CO3 (1.75 mmol) and a cat-
alytic amount of KI (for 21 c, 22 b), and the mixture was stirred
at room temperature (or refluxed) for 4–15 h.When the reaction
was completed, the solvent was removed in vacuum and the
residue was extracted with CH2Cl2 and washed with water.The
organic extracts were dried over anhydrous Na2SO4, and the
solvent was removed.The residue was purified by silica gel col-
umn chromatography to yield the title compound as a solid.
1
1594, 1476, 1436 cm–1; H NMR (CDCl3) δ 8.12 (d, 1H, J =
3.7 Hz), 7.70 (m, 2 H), 7.43 (t, 1 H, J = 7.1 Hz), 7.24 (m, 2 H),
6.60 (m, 2 H), 3.73 (m, 4 H), 3.06 (m, 4 H), 2.97 (m, 2 H), 2.84
(m, 4 H), 2.64 (m, 2 H), 2.36 (s, 3 H), 2.27 (m, 1 H), 2.01 (m,
2 H), 1.87 (m, 2 H); 13C NMR (CDCl3) d 159.9, 148.4, 143.7,
137.8, 137.5, 130.0, 127.5, 113.7, 107.4, 62.1, 55.8, 52.9,
49.4, 46.0, 39.9, 28.6, 21.9. Anal. Calcd for C23H33N5O2S: C,
62.27; H, 7.50; N, 15.79. Found: C, 62.41; H, 7.40; N, 15.37.
2-[4-[N-[NЈ-(4-Methylbenzenesulfonyl)]aminoethyl]-4-piper-
idinyl]piperazinyl]-pyrimidine (16 c)
1-(4-Methylbenzenesulfonyl)-1’-(2-pyridyl)-4,4Ј-bipiperidine
(20 c)
Yield 91.7 %; mp 165–166 °C; IR (KBr) 3252, 2952, 2822,
1738, 1584, 1548, 1476, 1446, 1416 cm–1; 1H NMR (CDCl3) δ
8.25 (d, 2 H, J = 4.7 Hz), 7.70 (m, 2 H), 7.24 (m, 2 H), 6.47 (t,
1 H, J = 4.7 Hz), 4.02 (m, 4 H), 3.04 (m, 4 H), 2.90 (m, 2 H), 2.73
(m, 4 H), 2.36 (m, 2 H), 2.35 (s, 3 H), 2.21 (m, 1 H), 1.96 (m,
2 H), 1.77 (m, 2 H); 13C NMR (CDCl3) δ 162.0, 158.1, 143.7,
137.0, 130.0, 127.5, 110.2, 62.2, 55.8, 52.9, 49.5, 44.4, 39.9,
28.6, 21.9. Anal. Calcd for C22H32N6O2S: C, 59.43; H, 7.25; N,
18.90. Found: C, 59.42; H, 7.38; N, 18.84.
Yield 87.9 %; mp 226–228 °C; IR (KBr) 3432, 2948, 2846,
1592, 1472, 1436 cm–1; 1H NMR (CDCl3) δ 8.18 (m, 1 H), 7.56
(m, 2 H), 7.29 (m, 2 H), 6.66–6.56 (m, 2 H), 4.30 (m, 2 H), 3.84
(m, 2 H), 2.75 (t, 2 H, J = 12.1 Hz), 2.45 (s, 3 H), 2.17 (td, 2 H, J =
11.9, 2.3 Hz), 1.78 (m, 4 H), 1.44–1.24 (m, 6 H); 13C NMR
(CDCl3) δ 146.4, 143.7, 138.7, 133.1, 129.8, 128.0, 112.8,
108.1, 98.3, 46.9, 46.3, 40.8, 40.4, 29.1, 28.9, 21.8.Anal.Calcd
for C22H29N3O2S: C, 66.13; H, 7.32; N, 10.52. Found: C, 66.14;
H, 7.43; N, 10.65.
General Procedure for the Preparation of 2-[4-[N-[(8-azaspiro-
[4,5]decane-7,9-dionyl)-8-ethyl]-4-piperidinyl]-1-piperazi-
nyl]pyridine (or pyrimidine) (15 e and 16 e)
1-(N,N-Diethylcarbamoylmethylene)-1Ј-(2-pyridyl)-4,4Ј-bipiperi-
dine (21 c)
3,3-Tetramethylene glutaric anhydride (0.55 mmol) was com-
bined with aminoethyl compound 17 a, b (0.50 mmol) in xylene
(10 mL), and the mixture was heated to reflux with Dean Stark
trap until the theoretical amount of water was removed.The re-
action mixture was then cooled and diluted with EtOAc.The re-
sulting solution was washed with brine, dried over MgSO4, and
evaporated to dryness. The residue was purified by silica gel
column chromatography to yield the title compound as a solid.
Yield >99.0 %; mp 157–160 °C; IR (KBr) 3468, 2940, 2822,
1632, 1478, 1438, 1380 cm–1; 1H NMR (CDCl3) δ 8.10 (d, 1H, J
= 3.4 Hz), 7.38 (t, 1 H, J = 6.0 Hz), 6.60–6.50 (m, 2 H), 4.23 (m,
2 H), 4.08 (m, 1 H), 3.39–3.26 (m, 6 H), 3.09 (m, 1 H), 2.95 (m,
2 H), 2.66 (t, 2 H, J = 12.2 Hz), 1.71 (m, 4 H), 1.38 (m, 2 H),
1.24–1.03 (m, 10 H); 13C NMR (CDCl3) δ 168.8, 159.8, 148.1,
137.6, 112.8, 107.4, 61.3, 54.4, 46.1, 41.9, 41.3, 40.6, 40.2,
29.4, 29.3, 14.5, 13.1. Anal. Calcd for C21H34N4O: C, 70.35; H,
9.56; N, 15.63. Found: C, 70.34; H, 79.65; N, 14.85.
2-[4-[N-[(8-Azaspiro[4,5]decane-7,9-dionyl)-8-ethyl]-4-piper-
idinyl]-1-piperazinyl]-pyrimidine (16 e)
1-(4-Benzenesulfonylethylene)-1Ј-(2-pyridyl)-4,4Ј-bipiperidine
(22 c)
Yield 54.5 %; mp 129–130 °C; IR (KBr) 3045, 2932, 2858,
2808, 1726, 1676, 1584, 1546, 1488, 1448 cm–1 1H NMR
;
Yield 66.0 %;mp 121–122 °C;IR (KBr) 3433, 2940, 2839, 1594,
(CDCl3) δ 8.29 (d, 2 H, J = 4.7 Hz), 6.47 (t, 1 H, J = 4.7 Hz), 3.91
(t, 2 H, J = 6.7 Hz), 3.82 (m, 4 H), 3.01 (m, 2 H), 2.60 (m, 8 H),
2.44 (t, 2 H, J = 6.7 Hz), 2.32 (m, 1 H), 1.99 (t, 2 H, J = 11.3 Hz),
1.81–1.69 (m, 6 H), 1.54–1.52 (m, 6 H); 13C NMR (CDCl3) δ
172.5, 162.4, 158.1, 110.1, 62.5, 55.7, 53.7, 49.4, 45.2, 44.4,
39.9, 37.8, 37.1, 28.6, 24.5. Anal. Calcd for C24H36N6O2: C,
65.43; H, 8.24; N, 19.07. Found: C, 65.73; H, 8.22; N, 19.02.
1
1478, 1438 cm–1; H NMR (CDCl3) δ 8.19 (m, 1 H), 8.16 (m,
2 H), 7.66 (m, 1 H), 7.59 (m, 2 H), 7.46 (m, 1 H), 6.67–6.56 (m,
2 H), 4.31 (m, 2 H), 3.36 (t, 2 H, J = 7.0 Hz), 2.75 (m, 6 H), 2.66
(t, 2 H, J = 12.2 Hz), 2.00 (m, 2 H), 1.75 (m, 2 H), 1.66 (m, 2 H),
1.30–1.06 (m, 6 H); 13C NMR (CDCl3) δ 160.0, 148.4, 140.2,
137.7, 134.0, 129.5, 128.4, 113.0, 107.5, 54.2, 54.1, 51.9,
46.2, 41.5, 40.9, 29.5, 29.4. Anal. Calcd for C23H31N3O2S: C,
66.79; H, 7.56; N, 10.16. Found: C, 66.56; H, 7.76; N, 10.25.
2-[(4,4’-Bipiperidin)-1-yl]pyridine (19)
A mixture of 2-fluoropyridine 18 (0.39 g, 4.00 mmol), 4,4Ј-bip-
iperidine dihydrochloride (0.48 g, 2.00 mmol), and NaHCO3
(0.76 g, 9.0 mmol) in EtOH (5 mL) was stirred under reflux for
15 h.After cooling, the solvent was removed in vacuum and the
residue was extracted with EtOAc and washed with water.The
organic extracts were dried over anhydrous Na2SO4, and the
solvent was removed. The residue was purified by silica gel
1-Phthalimidoethyl-1Ј-(2-pyridyl)-4,4Ј-bipiperidine (23 a)
To a stirred solution of bipiperidinylpyridine 19 (0.50 mmol) and
N-bromoethylphthalimide (1.00 mmol) in CH3CN (10 mL) was
were added K2CO3 (1.75 mmol) and NaI (0.10 mmol), and the
mixture was heated at reflux for 15 h.The solvent was removed
and the residue was treated with CH2Cl2 and water.The aque-
ous layer was separated and extracts were washed with water,
dried over anhydrous Na2SO4, and evaporated to dryness to
yield a residue. The residue was purified by silica gel column
column chromatography using as eluent
a mixture of
CH2Cl2:MeOH:NH4OH (5:4:1) to yield 19 as a white solid (0.30
g, 60.0 %): mp 148–150 °C; IR (KBr) 3430, 2948, 2843, 1574,
1
1516, 1485, 1436 cm–1; H NMR (CDCl3) δ 8.15 (d, 1H, J =
chromatography using as eluent a mixture of CH2Cl2:
3.7 Hz), 7.43 (m, 1 H), 6.65–6.53 (m, 2 H), 4.30 (m, 2 H), 3.08
(m, 2 H), 2.74 (t, 2 H, J = 10.8 Hz), 2.55 (t, 2 H, J = 10.8 Hz), 2.05
(m, 1 H), 1.78 (d, 2 H, J = 7.4 Hz), 1.68 (d, 2 H, J = 7.4 Hz),
1.27–1.18 (m, 5 H); 13C NMR (CDCl3) δ 148.6, 138.4, 113.3,
108.0, 95.5, 46.5, 46.1, 41.9, 29.7, 29.3.
MeOH:NH4OH (5:4:1) to yield 23 a as a yellow solid (0.20 g,
95.6 %): mp 196–197 °C; IR (KBr) 2948, 2816, 1770, 1708,
1594, 1480, 1436, 1400 cm–1; 1H NMR (CDCl3) δ 8.17 (d, 1 H, J
= 3.3 Hz), 7.86 (m, 2 H), 7.73 (m, 2 H), 7.44 (m, 1 H), 6.67–6.55
(m, 2 H), 4.30 (m, 2 H), 3.84 (t, 2 H, J = 6.9 Hz), 3.04 (m,