4-Phenoxypiperidines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2235
119.1, 116.1, 103.7, 73.0, 62.3, 60.1, 31.1, 30.9; MS m/z 261.1
(M + H+); Anal. (C16H20N2O2) H, N; C: calcd. 69.20; found,
68.76.
4.26 (m, 1H), 3.49 (s, 2H), 2.82-2.70 (m, 4H), 2.50 (q, J ) 7.1
Hz, 4H), 2.37 (m, 2H), 2.04-1.96 (m, 2H), 1.85-1.76 (m, 2H),
1.60 (m, 9H), 1.07-1.00 (m, 12H); 13C NMR (100 MHz) δ 156.3,
130.0, 128.6, 115.7, 73.1, 56.7, 54.4, 46.4, 45.8, 31.2, 18.4, 11.6;
MS m/z 305.1 (M + H+); Anal. (C19H32N2O) C, H, N.
Butyl-[4-(1-isopropyl-piperidin-4-yloxy)-benzyl]-meth-
yl-amine (13c). Prepared according to Method B (73%). 1H
NMR (400 MHz) δ 7.19 (d, J ) 8.6 Hz, 2H), 6.85 (d, J ) 8.6
Hz, 2H), 4.27 (m, 1H), 3.40 (s, 2H), 2.82-2.71 (m, 3H), 2.39
(m, 2H), 2.34 (m, 2H), 2.16 (s, 3H), 2.00 (m, 2H), 1.85-1.76
(m, 2H), 1.52-1.45 (m, 2H), 1.38-1.27 (m, 2H) 1.06 (d, J )
6.6 Hz, 6H), 0.90 (t, J ) 7.3 Hz, 3H). 13C NMR (100 MHz) δ
156.4, 131.3, 130.1, 115.8, 73.2, 61.6, 57.1, 54.4, 45.7, 42.1, 31.2,
29.5, 20.6, 18.4, 14.0; MS m/z 319.2 (M + H+); Anal. (C20H34N2O)
C, H, N.
4-(1-sec-Butyl-piperidin-4-yloxy)-benzonitrile (11g). Pre-
pared according to Method A (34%). 1H NMR (400 MHz) δ 7.56
(d, J ) 9.1 Hz, 2H), 6.93 (d, J ) 9.1 Hz, 2H), 4.36 (br, 1H),
2.77 (br, 2H), 2.50 (br, 2H), 2.37 (br, 1H), 2.02 (br, 2H), 1.81
(br, 2H), 1.58 (br, 1H), 1.30 (m, 1H), 1.0 (br, d, J ) 6.1 Hz,
3H), 0.91 (t, J ) 7.3 Hz, 3H); 13C NMR (125 MHz) δ 161.0,
133.9, 119.2, 116.1, 103.5, 73.4, 60.8, 44.8, 31.1, 26.3, 13.8, 11.4;
MS m/z 259.1 (M + H+); Anal. (C16H22N2O) C, H, N.
4-(1-Isobutyl-piperidin-4-yloxy)-benzonitrile (11h). Pre-
pared according to Method A (72%). 1H NMR (400 MHz) δ 7.56
(d, J ) 9.1 Hz, 2H), 6.93 (d, J ) 9.1 Hz, 2H), 4.37 (br, 1H),
2.69 (br, 2H), 2.22 (br, 2H), 2.09 (br, 2H), 1.98 (br, 2H), 187-
1.73 (m, 3H), 0.90 (d, br, J ) 7.3 Hz, 6H); 13C NMR (125 MHz)
δ 161.0, 133.9, 119.2, 116.1, 103.4, 73.5, 66.7, 50.8, 30.6, 25.7,
20.8; MS m/z 259.1 (M + H+); Anal. (C16H22N2O) C, H, N.
4-(1-Cyclopentyl-piperidin-4-yloxy)-benzonitrile (11i).
1-Isopropyl-4-(4-pyrrolidin-1-ylmethyl-phenoxy)-pi-
1
peridine (13d). Prepared according to Method B (70%). H
NMR (400 MHz) δ 7.21 (d, J ) 8.8 Hz, 2H), 6.84 (d, J ) 8.8
Hz, 2H), 4.26 (m, 1H), 3.53 (s, 2H), 2.82-2.71 (m, 3H), 2.48
(m, 4H), 2.37 (m, 2H), 2.03-1.96 (m, 2H), 1.85-1.74 (m, 6H),
1.05 (d, J ) 6.6 Hz, 6H); 13C NMR (100 MHz) δ 156.4, 131.6,
130.0, 115.8, 73.2, 60.0, 54.0, 45.8, 31.2, 23.3, 18.4; MS m/z
303.1 (M + H+); Anal. (C19H30N2O) H, N; C: calcd. 75.45; found
75.03.
1
Prepared according to Method A (84%). H NMR (400 MHz,
CDCl3) δ 7.57 (d, J ) 8.8 Hz, 2H), 6.94 (d, J ) 8.9 Hz, 2H),
4.40 (br, 1H), 2.91-2.23 (br, m, 5H), 2.13-1.35 (m, 12H); 13C
NMR (125 MHz, CDCl3) δ 160.9, 133.9, 119.2, 116.1, 103.6,
73.1, 67.3, 49.3, 30.6, 30.5, 24.1; MS m/z 271.1 (M + H+); Anal.
(C17H22N2O) C, H, N.
1-[4-(1-Isopropyl-piperidin-4-yloxy)-benzyl]-piperi-
1
dine (13e). Prepared according to Method B (84%). H NMR
4-(1-Cyclohexyl-piperidin-4-yloxy)-benzonitrile (11j).
Prepared according to Method A (79%). 1H NMR (400 MHz) δ
7.56 (d, J ) 8.8 Hz, 2H), 6.93 (d, J ) 8.8 Hz, 2H), 4.37 (m,
1H), 2.84 (m, 2H), 2.47 (m, 2H), 2.32 (br, 1H), 2.01 (br, 2H),
1.89-1.77 (m, 6H), 1.63 (m, 1H), 1.30-1.17 (m, 4H), 1.10 (m,
1H); 13C NMR (125 MHz) δ 161.0, 133.9, 119.2, 116.1, 103.4,
73.6, 63.6, 45.9, 31.1, 28.8, 26.2, 25.9; MS m/z 285.1 (M + H+);
Anal. (C18H24N2O) C, H, N.
(400 MHz) δ 7.19 (d, J ) 8.5 Hz, 2H), 6.84 (d, J ) 8.6 Hz, 2H),
4.29-4.25 (m, 1H), 3.40 (s, 2H), 2.82-2.71 (m, 3H), 2.41-2.35
(m, 6H), 2.40-2.26 (m, 6H), 2.03-1.99 (m, 2H), 1.85-1.77 (m,
2H), 1.59-1.53 (m, 4H), 1.43-1.38 (m, 2H), 1.06 (d, J ) 6.6
Hz, 6H); 13C NMR (100 MHz) δ 156.4, 130.5, 130.4, 115.6, 73.0,
63.2, 54.3, 45.7, 31.2, 25.9, 24.3, 18.4; MS m/z 317.1 (M + H+);
Maleate salt Anal. (C24H36N2O5) H, N; C: calcd. 66.64; found
65.99.
4-(1-Benzyl-piperidin-4-yloxy)-benzonitrile (11k). Pre-
pared according to Method A (38%). 1H NMR (400 MHz) δ 7.56
(d, J ) 8.8 Hz, 2H), 7.33 (m, 3H), 7.27 (m, 2H), 6.93 (d, J )
8.8 Hz, 2H), 4.40 (br, 1H), 3.54 (br, 2H), 2.73 (br, 2H), 2.32
(br, 2H), 1.99 (br, 2H), 1.84 (br, 2H), 1.56 (br, 1H); 13C NMR
(100 MHz) δ 160.9, 138.2, 133.9, 129.0, 128.2, 127.0, 119.2,
116.1, 103.6, 73.2, 62.9, 50.3, 30.6; MS m/z 293.0 (M + H+);
Anal. (C18H20N2O) H, N; C: calcd. 78.05; found 77.54.
4-(1-Isopropyl-piperidin-4-yloxy)-benzaldehyde (12).
To a solution of 4-(1-isopropyl-piperidin-4-yloxy)-benzonitrile
11e (48.6 g, 199 mmol) in CH2Cl2 (500 mL) cooled to 0 °C was
added DIBAL-H (250 mL, 1.0 M CH2Cl2, 1.25 equiv) via
syringe. The reaction was stirred at 0 °C for 30 min then
quenched with ethyl acetate (30 mL). Aqueous Rochelle’s salt
(1.5 L) was added slowly. Caution! Gas Evolution! The result-
ing suspension was stirred for 12 h (reaches clarity). The layers
were separated and the aqueous was extracted with CH2Cl2
(4 × 400 mL). The solvent was removed to reveal a thick syrup
that was treated with HCl (300 mL, pH 1) and stirred for 2 h.
Water (1.4 L) was added and the pH adjusted with 50% NaOH
(pH ∼ 12). The produce was extracted with CH2Cl2 (5 × 300
mL) and washed with water and brine. The solvent was
removed to reveal 46.6 g (95%) of a thick oil that solidified on
standing to a light brown solid. 1H NMR (400 MHz) δ 9.86 (s,
1H), 7.81 (d, J ) 8.6 Hz, 2H), 6.99 (d, J ) 8.6 Hz, 2H), 4.43
(m, 1H), 2.82-2.72 (m, 3H), 2.42 (m, 4H), 2.08-2.00 (m, 2H),
1.89-1.80 (m, 2H), 1.06 (d, J ) 6.6 Hz, 6H); 13C NMR (100
MHz) δ 190.7, 162.8, 131.9, 129.6, 115.7, 73.2, 54.4, 45.5, 31.0,
18.4; MS m/z 248.3 (M + H+).
1-[4-(1-Isopropyl-piperidin-4-yloxy)-benzyl]-azepane
1
(13f). Prepared according to Method B (73%). H NMR (400
MHz) δ 7.22 (d, J ) 8.6 Hz, 2H), 6.84 (d, J ) 8.6 Hz, 2H), 4.26
(m, 1H), 3.56 (s, 2H), 2.85-2.71 (m, 3H), 2.60 (m, 4H), 2.38
(m, 2H), 2.04-1.96 (m, 2H), 1.85-1.76 (m, 2H), 1.60 (m, 9H),
1.06 (d, J ) 6.6 Hz, 6H); 13C NMR (100 MHz) δ 156.3, 132.0,
129.9, 115.7, 73.1, 62.0, 55.4, 54.4, 45.8, 31.2, 28.0, 27.0, 18.4;
MS m/z 331.2 (M + H+); Anal. (C21H34N2O) C, H, N.
4-[4-(1-Isopropyl-piperidin-4-yloxy)-benzyl]-morpho-
1
line (13g). Prepared according to Method B (96%). H NMR
(400 MHz) δ 7.20 (d, J ) 8.6 Hz, 2H), 6.82 (d, J ) 8.6 Hz, 2H),
4.27 (m, 1H), 3.69 (m, 4H), 3.42 (s, 2H), 2.82-2.70 (m, 3H),
2.41 (m, 4H), 2.36 (m, 2H), 2.04-1.96 (m, 2H), 1.84-1.75 (m,
2H), 1.05 (d, J ) 6.6 Hz, 6H); 13C NMR (100 MHz) δ 156.6,
130.3, 129.7, 115.8, 73.0, 66.9, 62.8, 54.4, 53.5, 45.7, 31.2, 18.4;
MS m/z 319.3 (M + H+). Maleate salt: Anal. (C23H34N2O6) C,
H, N.
1-[4-(1-Isopropyl-piperidin-4-yloxy)-benzyl]-piperidin-
1
4-ol (13h). Prepared according to Method B (74%). H NMR
(400 MHz) δ 7.17 (d, J ) 8.6 Hz, 2H), 6.82 (d, J ) 8.6 Hz, 2H),
4.25 (m, 1H), 3.64 (m, 1H), 3.42 (s, 1H), 3.40 (s, 2H), 2.80-
2.69 (m, 5H), 2.36 (m, 2H), 2.08 (m, 2H), 2.02-1.94 (m, 2H),
1.87-1.74 (m, 2H), 1.55 (m, 2H), 1.04 (d, J ) 6.6 Hz, 6H); 13
C
NMR (100 MHz) δ 156.5, 130.2, 130.3, 115.6, 72.9, 67.8, 62.2,
54.3, 50.2, 45.6, 34.4, 31.0, 18.3; MS m/z 333.1 (M + H+); Anal.
(C20H32N2O2) C, H, N.
{1-[4-(1-Isopropyl-piperidin-4-yloxy)-benzyl]-piperidin-
4-yl}-methanol (13i). Prepared according to Method B (75%).
1H NMR (400 MHz) δ 7.17 (d, J ) 8.6 Hz, 2H), 6.82 (d, J ) 8.6
Hz, 2H), 4.25 (m, 1H), 3.24 (d, J ) 6.6 Hz, 2H), 3.39 (s, 2H),
2.87 (m, 2H), 2.80-2.69 (m, 3H), 2.37 (m, 2H), 2.02-1.94 (m,
2H), 1.90 (m, 2H), 1.83-1.74 (m, 2H), 1.69 (m, 2H) 1.45 (m,
1H), 1.23 (m, 2H), 1.04 (d, J ) 6.6 Hz, 6H); 13C NMR (100
MHz) δ 156.4, 130.3, 130.4, 115.6, 72.8, 67.5, 62.7, 54.3, 53.2,
45.6, 38.5, 31.0, 28.7, 18.3; MS m/z 347.3 (M + H+); Anal.
(C21H34N2O2) H, N; calcd. 72.79; found 71.27.
{1-[4-(1-Isopropyl-piperidin-4-yloxy)-benzyl]-piperidin-
4-}-methylbenzene (13j). Prepared according to Method B
(51%). 1H NMR (400 MHz) δ 7.29-7.23 (m, 3H), 7.19-7.10
(m, 4H), 6.83 (m, 2H), 4.26 (m, 1H), 3.39 (s, 2H), 2.87-2.70
[4-(1-Isopropyl-piperidin-4-yloxy)-benzyl]-dimethyl-
amine (13a). Prepared according to Method B (86%). 1H NMR
(400 MHz) δ 7.18 (d, J ) 8.6 Hz, 2H), 6.85 (d, J ) 8.6 Hz, 2H),
4.27 (m, 1H), 3.34 (s, 2H), 3.37 (s, 3H), 2.81-2.70 (m, 3H), 2.38
(m, 2H), 2.21 (s, 6H), 2.05-1.96 (m, 2H), 1.85-1.75 (m, 2H),
1.05 (d, J ) 6.6 Hz, 6H); 13C NMR (100 MHz) δ 156.5, 130.9,
130.2, 115.8, 73.0, 63.7, 54.4, 45.7, 45.2, 31.2, 18.4; MS m/z
277.1 (M + H+); Anal. (C17H28N2O) H, N; C: calcd. 73.87; found
73.38.
Diethyl-[4-(1-isopropyl-piperidin-4-yloxy)-benzyl]-
amine (13b). Prepared according to Method B (37%). 1H NMR
(400 MHz) δ 7.21 (d, J ) 8.6 Hz, 2H), 6.84 (d, J ) 8.6 Hz, 2H),