3942 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18
Apodaca et al.
sodium triacetoxyborohydride (296 mg, 1.40 mmol, 1.3 equiv).
After 16 h, the resulting mixture was treated with 10%
aqueous potassium hydroxide (4 mL). The organic phase was
extracted with DCM (2 × 3 mL), and the combined organic
phases were dried (MgSO4) and evaporated. Chromatography
of the residue (0-6% 2 M methanolic ammonia-DCM) gave
the title compound as a pale-yellow oil (193 mg, 64%): 1H NMR
(CDCl3) δ 7.20 (d, J ) 8.3 Hz, 2H), 6.84 (d, J ) 8.4 Hz, 2H),
4.09 (t, J ) 6.1 Hz, 2H), 3.40 (s, 2H), 2.76 (t, J ) 6.1 Hz, 2H),
2.55-2.45 (br m, 4H), 2.40-2.29 (m, 4H), 1.64-1.52 (m, 8H),
1.48-1.37 (m, 4H); 13C NMR (CDCl3) δ 157.8, 130.5, 130.3,
114.1, 65.9, 63.2, 57.9, 55.0, 54.3, 25.9, 25.8, 24.4, 24.2; MS
m/z 303.2 (M + H)+. Anal. (C19H30N2O) C, H, N.
Meth od B: Rep r esen ta tive P r oced u r e for th e P r ep a -
r a tion of 4-[3-(4-P ip er id in -1-ylm eth ylp h en oxy)p r op yl]-
m or p h olin e (7f). A suspension of chloropropane 10 (268 mg,
1.00 mmol, 1.0 equiv), morpholine (0.11 mL, 1.3 mmol, 1.3
equiv), sodium carbonate (159 mg, 1.50 mmol, 1.5 equiv), and
potassium iodide (8.3 mg, 5.0 × 10-1 mmol, 0.050 equiv) in
1-butanol (4 mL) was heated in a 105 °C bath for 16 h. Water
was added (4 mL), and the aqueous phase was extracted with
DCM (3 × 4 mL). The combined organic extracts were dried
(MgSO4) and evaporated. Chromatography of the residue (0-
6% 2 M methanolic ammonia-DCM) gave the title compound
as a colorless oil (138 mg, 43%): 1H NMR (CDCl3) δ 7.20 (d, J
) 8.4 Hz, 2H), 6.84 (d, J ) 8.4 Hz, 2H), 4.01 (t, J ) 6.3 Hz,
2H), 3.74-3.69 (m, 4H), 3.40 (s, 2H), 2.51 (t, J ) 7.3 Hz, 2H),
2.48-2.43 (m, 4H), 2.40-2.30 (br s, 4H), 2.00-1.91 (m, 2H),
1.59-1.51 (m, 4H), 1.45-1.37 (m, 2H); 13C NMR (CDCl3) δ
157.9, 130.3, 114.0, 66.9, 66.0, 63.2, 55.5, 54.2, 53.7, 26.4, 25.9,
24.3; MS m/z 319.3 (M + H)+. Anal. (C19H30N2O2) C, H, N.
Meth od C: Rep r esen ta tive P r oced u r e for th e P r ep a -
r a tion of 4-[4-(3-P ip er id in -1-ylp r op oxy)ben zyl]m or p h o-
lin e (7i). A solution of aldehyde 11 (207 mg, 0.837 mmol, 1.0
equiv), morpholine (74 µL, 0.85 mmol, 1.0 equiv), and acetic
acid (55 µL, 0.87 mmol, 1.0 equiv) in DCE (3 mL) was treated
with sodium triacetoxyborohydride (258 mg, 1.22 mmol, 1.4
equiv). After 16 h, the resulting mixture was treated with 10%
aqueous potassium hydroxide (5 mL). The organic phase was
extracted with DCM (3 × 10 mL), and the combined organic
phases were evaporated. Chromatography of the residue (0-
8% 2 M methanolic ammonia-DCM) gave the title compound
as an oil (172 mg, 64%): 1H NMR (CDCl3) δ 7.21 (d, J ) 8.8
Hz, 2H), 6.84 (d, J ) 8.8 Hz, 2H), 3.99 (t, J ) 6.4 Hz, 2H),
3.69 (t, J ) 4.7 Hz, 4H), 3.42 (s, 2H), 2.48 (t, J ) 7.1 Hz, 2H),
2.45-2.36 (br m, 8H), 1.97 (m, 2H), 1.63-1.56 (m, 4H), 1.44
(m, 2H); 13C NMR (CDCl3) δ 158.2, 130.3, 129.6, 114.2, 67.0,
66.5, 62.8, 56.0, 54.6, 53.5, 26.8, 25.9, 24.4; MS m/z 319.3 (M
+ H)+. Anal. (C19H30N2O2) C, H, N.
1-[4-(3-P ip er id in -1-ylp r op oxy)ben zyl]p ip er id in e (7b).
7b was prepared according to method A (41%): 1H NMR
(CDCl3) δ 7.20 (d, J ) 8.4 Hz, 2H), 6.84 (d, J ) 8.6 Hz, 2H),
3.99 (t, J ) 6.4 Hz, 2H), 3.40 (s, 2H), 2.50-2.30 (m, 10H), 2.01-
1.97 (m, 2H), 1.62-1.52 (m, 8H), 1.45-1.38 (m, 4H); 13C NMR
(CDCl3) δ 158.0, 130.3, 114.0, 66.4, 63.2, 56.0, 54.6, 54.3, 26.9,
26.0, 25.9, 24.5, 24.4; MS m/z 317.3 (M + H)+. Anal. (C20H32N2O)
C, H, N.
2.29 (br s, 4H), 1.96-1.87 (m, 2H), 1.60-1.52 (m, 4H), 1.45-
1.37 (m, 2H), 1.03 (t, J ) 7.1 Hz, 6H); 13C NMR (CDCl3) δ
158.0, 130.3, 114.0, 66.3, 63.2, 54.3, 49.4, 46.9, 27.0, 25.9, 24.4,
11.7; MS m/z 305.2 (M + H)+. Anal. (C19H32N2O) C, H, N.
Dim eth yl[3-(4-p ip er id in -1-ylm eth ylp h en oxy)p r op yl]-
a m in e (7e). 7e was prepared according to method A (43%):
1H NMR (CDCl3) δ 7.20 (d, J ) 8.2 Hz, 2H), 6.84 (d, J ) 8.3
Hz, 2H), 3.99 (t, J ) 6.5 Hz, 2H), 3.40 (s, 2H), 2.44 (t, J ) 7.3
Hz, 2H), 2.40-2.30 (br s, 4H), 2.25 (s, 6H), 1.99-1.90 (m, 2H),
1.60-1.52 (m, 4H), 1.46-1.37 (m, 2H); 13C NMR (CDCl3) δ
158.0, 130.4, 130.3, 114.0, 66.1, 63.2, 56.4, 54.3, 45.5, 27.6, 25.9,
24.4; MS m/z 277.3 (M + H)+. Anal. (C17H28N2O) C, H, N.
1-Meth yl-4-[3-(4-p ip er id in -1-ylm eth ylp h en oxy)p r op yl]-
p ip er a zin e (7g). 7g was prepared according to method B
(39%): 1H NMR (CDCl3) δ 7.20 (d, J ) 8.6 Hz, 2H), 6.83 (d, J
) 8.6 Hz, 2H), 3.99 (t, J ) 6.3 Hz, 2H), 3.40 (s, 2H), 2.60-
2.31 (m, 14H), 2.28 (s, 3H), 2.00-1.91 (m, 2H), 1.59-1.52 (m,
4H), 1.45-1.36 (m, 2H); 13C NMR (CDCl3) δ 157.9, 130.3, 114.0,
66.1, 63.2, 55.1, 55.1, 54.2, 53.1, 46.0, 26.8, 25.9, 24.3; MS m/z
332.3 (M + H)+. Anal. (C20H33N3O) C, H, N.
Dim eth yl[4-(3-piper idin -1-ylpr opoxy)ben zyl]am in e (7h ).
7h was prepared according to method C using 2.5 equiv of
dimethylamine hydrochloride (75%): 1H NMR (CDCl3) δ 7.19
(d, J ) 8.8 Hz, 2H), 6.84 (d, J ) 8.8 Hz, 2H), 3.99 (t, J ) 6.5
Hz, 2H), 3.34 (s, 2H), 2.47 (t, J ) 7.5 Hz, 2H), 2.42-2.36 (br,
4H), 2.21 (s, 6H), 1.99-1.94 (m, 2H), 1.61-1.56 (m, 4H), 1.47-
1.40 (br, 2H); 13C NMR (CDCl3) δ 158.1, 130.8, 130.1, 114.2,
66.5, 63.7, 56.0, 54.6, 45.2, 26.9, 26.0, 24.4; MS m/z 277.3 (M
+ H)+. Anal. (C17H28N2O) C, H, N.
Cycloh exyl[4-(3-p ip er id in -1-ylp r op oxy)ben zyl]a m in e
(7j). 7j was prepared according to method C (53%): 1H NMR
(CDCl3) δ 7.21 (d, J ) 8.5 Hz, 2H), 6.85 (d, J ) 8.5 Hz, 2H),
3.99 (t, J ) 6.5 Hz, 2H), 3.73 (s, 2H), 2.50-2.35 (m, 7H), 2.00-
1.94 (m, 2H), 1.90 (m, 2H), 1.72 (m, 2H), 1.63-1.56 (m, 5H),
1.47-1.41 (br, 2H) 1.29-1.06 (m, 6H); 13C NMR (CDCl3) δ
157.9, 129.2, 114.4, 66.5, 56.1, 56.0, 54.6, 50.4, 33.5, 26.8, 26.2,
25.9, 25.0, 24.4; MS m/z 331.3 (M + H)+. Anal. (C21H34N2O) C,
H, N.
P h en yl[4-(3-p ip er id in -1-ylp r op oxy)ben zyl]a m in e (7k ).
7k was prepared according to method C (79%): 1H NMR
(CDCl3) δ 7.27 (d, J ) 8.8 Hz, 2H), 7.17 (t, J ) 7.4 Hz, 2H),
6.87 (d, J ) 8.8 Hz, 2H), 6.71 (t, J ) 7.4 Hz, 1H), 6.64 (d, J )
7.7 Hz, 2H), 4.24 (br, 2H), 4.00 (t, J ) 6.4 Hz, 2H), 3.93 (br,
1H), 2.48 (t, J ) 7.1 Hz, 2H), 2.45-2.36 (br, 4H), 2.01-1.95
(m, 2H), 1.63-1.58 (m, 4H), 1.48-1.42 (m, 2H); 13C NMR
(CDCl3) δ 158.3, 148.2, 131.2, 129.2, 128.7, 117.4, 114.6, 112.8,
66.5, 55.9, 54.6, 47.8, 26.8, 25.9, 24.3; MS m/z 325.3 (M + H)+.
Anal. (C21H28N2O) C, H, N.
1-[4-(3-P ip er id in -1-ylp r op oxy)ben zyl]-4-ben zylp ip er i-
d in e (7l). 7l was prepared according to method C (86%): 1H
NMR (CDCl3) δ 7.26 (m, 2H), 7.18 (m, 3H), 7.12 (m, 2H), 6.83
(d, J ) 8.5 Hz, 2H), 3.98 (t, J ) 6.6 Hz, 2H), 3.40 (s, 2H), 2.84
(m, 2H), 2.52 (d, J ) 6.9 Hz, 2H), 2.47 (t, J ) 7.4 Hz, 2H),
2.44-2.35 (br, 4H), 1.99-1.93 (m, 2H), 1.86 (t, J ) 11.8 Hz,
2H), 1.62-1.56 (m, 6H), 1.54-1.47 (m, 1H), 1.46-1.41 (m, 2H),
1.34-1.25 (m, 2H); 13C NMR (CDCl3) δ 158.0, 140.7, 130.3,
130.2, 129.0, 128.0, 125.6, 114.0, 66.4, 62.8, 56.0, 54.6, 53.6,
43.2, 37.9, 32.1, 26.8, 25.9, 24.4; MS m/z 407.3 (M + H)+. Anal.
(C27H38N2O) C, H, N.
1-Meth yl-4-[4-(3-p ip er id in -1-ylp r op oxy)ben zyl]p ip er a -
zin e (7m ). 7m was prepared according to method C (86%):
1H NMR (CDCl3) δ 7.20 (d, J ) 8.5 Hz, 2H), 6.83 (d, J ) 8.8
Hz, 2H), 3.98 (t, J ) 6.3 Hz, 2H), 3.43 (s, 2H), 2.46 (t, J ) 7.4
Hz, 2H), 2.45-2.34 (br, 12H), 2.27 (s, 3H), 1.99-1.93 (m, 2H),
1.61-1.56 (m, 4H), 1.47-1.41 (m, 2H); 13C NMR (CDCl3) δ
158.1, 130.3, 130.0, 114.1, 66.5, 62.4, 56.0, 55.1, 54.6, 52.9, 46.0,
26.8, 25.9, 24.4; MS m/z 332.3 (M + H)+. Anal. (C20H33N3O) C,
H, N.
Die t h yl[2-(4-p ip e r id in -1-ylm e t h ylp h e n oxy)e t h yl]-
a m in e (7c). 7c was prepared according to method A (21%):
1H NMR (CDCl3) δ 7.20 (d, J ) 8.4 Hz, 2H), 6.84 (d, J ) 8.6
Hz, 2H), 4.03 (t, J ) 6.5 Hz, 2H), 3.40 (s, 2H), 2.87 (t, J ) 6.5
Hz, 2H), 2.63 (q, J ) 7.1 Hz, 4H), 2.40-2.29 (br s, 4H), 1.60-
1.52 (m, 4H), 1.46-1.37 (m, 2H), 1.07 (t, J ) 7.1 Hz, 6H); 13
C
NMR (CDCl3) δ 157.9, 130.5, 130.4, 114.1, 66.5, 63.3, 54.3, 51.8,
47.8, 26.0, 24.4, 11.9; MS m/z 291.3 (M + H)+. Anal. (C18H30N2O)
C, H, N.
Die t h yl[3-(4-p ip e r id in -1-ylm e t h ylp h e n oxy)p r op yl]-
a m in e (7d ). 7d was prepared according to method B from
chloropropane 10 (268 mg, 1.00 mmol, 1.0 equiv), diethylamine
(0.41 mL, 4.0 mmol, 4.0 equiv), sodium carbonate (159 mg,
1.50 mmol, 1.5 equiv), and potassium iodide (17 mg, 1.0 × 10-1
mmol, 0.10 equiv) to give the title compound (38%): 1H NMR
(CDCl3) δ 7.20 (d, J ) 8.2 Hz, 2H), 6.84 (d, J ) 8.2 Hz, 2H),
3.98 (d, J ) 6.3 Hz, 2H), 3.40 (s, 2H), 2.63-2.51 (m, 6H), 2.40-
1-[4-(3-P ip er id in -1-ylp r op oxy)ben zyl]p ip er id in e-4-ca r -
boxylic Acid Am id e (7n ). 7n was prepared according to
method C (40%): 1H NMR (CDCl3) δ 7.19 (d, J ) 8.5 Hz, 2H),
6.84 (d, J ) 8.8 Hz, 2H), 5.48-5.34 (br, 2H), 3.99 (t, J ) 6.3
Hz, 2H), 3.42 (s, 2H), 2.91 (m, 2H), 2.47 (t, J ) 7.4 Hz, 2H),
2.43-2.34 (br, 4H), 2.17-2.10 (m, 1H), 2.00-1.93 (m, 4H),