3902 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21
Wei et al.
brine and dried over MgSO4. Removal of solvents gave a crude
product, which was purified by flash chromatography eluting
with MeOH-CH2Cl2 (2:98) to provide 10d (3.15 g, 28%): 1H
NMR (CDCl3) δ 1.08 (brs, 3H), 1.23 (brs, 3H), 1.43 (s, 9H), 1.61
(m, 2H), 1.80 (m, 2H), 2.89 (m, 2H), 3.20 (brs, 2H), 3.40 (m,
1H), 3.53 (brs, 2H), 4.11 (brs, 2H), 7.44 (d, J ) 8.0 Hz, 2H),
7.94 (d, J ) 8.0 Hz, 2H).
N,N-Dieth yl-4-(3-flu or oph en ylpiper idin -4-yliden em eth -
yl)ben za m id e (6e). Method as described for 6a , but starting
with 7e (242 mg, 0.5 mmol) led to 6e (159 mg, 87%): 1H NMR
(CDCl3) δ 1.08 (br, 3 H, CH3CH2N-), 1.19 (br, 3 H, CH3CH2-
N-), 2.09 (s, 1 H, NH), 2.25 (m, 4 H, piperidine CH-), 2.84 (br,
4 H, piperidine CH-), 3.23 (br, 2 H, CH3CH2N-), 3.47 (br, 2 H,
CH3CH2N-), 6.74 (m, 1 H, ArH), 6.86 (m, 2 H, ArH), 7.06 (d,
J ) 8.0 Hz, 2 H, ArH), 7.18 (m, 1 H, ArH), 7.24 (d, J ) 8.0 Hz,
4-(r-Hyd r oxy-r-(4-N-ter t-bu toxyca r bon ylp ip er id in yl)-
r-(1-n a p h th yl)m eth yl)-N,N-d ieth ylben za m id e (7d ). To a
solution of 1-bromonaphthalene (0.52 g, 2.5 mmol) in dry THF
(10 mL) was added n-butyllithium (1.1 mL, 2.5 M, 2.75 mmol)
at -78 °C. After 30 min, 10d (776 mg, 2.0 mmol) in THF (2
mL) was dropwise added. The reaction mixture was warmed
to room temperature, quenched with aqueous NH4Cl solution,
and extracted with ethyl acetate (2 × 50 mL). The combined
organic layers were washed with brine and dried over MgSO4.
Removal of solvents gave a crude product, which was puri-
fied by flash chromatography eluting with MeOH-CH2Cl2 (0.5:
99.5 f 5:95) to provide 7d (760 mg, 74%): mp 121-124 °C
(CH2Cl2); IR (KBr) 3402, 1685, 1626 cm-1; 1H NMR (CDCl3) δ
1.03 (brs, 3H), 1.16 (brs, 3H), 1.18-1.35 (m, 3H), 1.95 (m, 1H),
2.60 (m, 2H), 2.75 (brs, 2H), 3.15 (brs, 2H), 3.42 (brs, 2H), 4.10
2 H, ArH). HCl salt: mp g 70 °C dec; IR (NaCl) 1605 cm-1
Anal. (C23H27FN2O‚2.2HCl) C, H, N.
.
N,N-Dieth yl-4-(3-m eth oxyp h en ylp ip er id in -4-ylid en e-
m eth yl)ben za m id e (6f). Method as described for 6a , but
starting with 7f (199 mg, 0.4 mmol) led to 6f18 (148 mg, 98%).
Anal. (C24H30N2O2‚1.8HCl) C, H, N.
N,N-Dieth yl-4-(2,6-dim eth ylph en ylpiper idin -4-yliden e-
m eth yl)ben za m id e (6 g). Method as described for 6a , but
starting with 7g (495 mg, 1.0 mmol) led to 6g (301 mg, 80%):
1H NMR (CDCl3) δ 1.10 (brs, 3H), 1.21 (brs, 3H), 2.08 (m, 4H),
2.21 (s, 6H), 2.84 (m, 2H), 3.00 (m, 2H), 3.20 (brs, 1H), 3.25
(brs, 2H), 3.46 (brs, 2H), 6.94 (m, 1H), 7.00 (m, 2H), 7.04 (d,
J ) 8.0 Hz, 2H), 7.16 (d, J ) 8.0 Hz, 2H). HCl salt: dec g 115
°C (CH2Cl2); IR (KBr) 1590 cm-1. Anal. (C25H32N2O‚2.2HCl)
C, H, N.
(brs, 2H), 7.10-7.50 (m, 7H), 7.75 (m, 3H), 8.27 (brs, 1H); 13
C
4-(4-Met h oxyca r b on ylb en zylid en e)p ip er id in e-1-ca r -
boxylic Acid ter t-Bu tyl Ester (15). A mixture of 13 (11.2 g,
49 mmol) and trimethyl phosphite (25 mL) was refluxed under
N2 for 5 h. Excess trimethyl phosphite was removed by
codistillation with toluene to give 14 in quantitative yield: 1H
NMR (CDCl3) δ 3.20 (d, 2H, J ) 22 Hz), 3.68 (d, 3H, 10.8 Hz),
3.78 (d, 3H, 11.2 Hz), 3.91 (s, 3H), 7.38 (m, 2H), 8.00 (d, 2H,
J ) 8 Hz).
To a solution of the above product (14) in dry THF (200 mL)
was added dropwise lithium diisopropylamide (32.7 mL 1.5
M in hexanes, 49 mmol) at -78 °C. The reaction mixture was
then allowed to warm to room temperature prior to addition
of N-tert-butoxycarbonyl-4-piperidone (9.76 g, 49 mmol in 100
mL dry THF). After 12 h, the reaction mixture was quenched
with water (300 mL) and extracted with ethyl acetate (3 ×
300 mL). The combined organic phases were dried over MgSO4
and evaporated to give a crude product, which was purified
by flash chromatography (0-33% ethyl acetate in hexanes) to
provide 15 as a white solid (5.64 g, 35%): IR (NaC1) 1718,
1688, 1606 cm-1; 1H NMR (CDCl3) δ 1.44 (s, 1H), 2.31 (t, J )
5.5 Hz, 2H), 2.42 (t, J ) 5.5 Hz, 2H), 3.37 (t, J ) 5.5 Hz, 2H),
3.48 (t, J ) 5.5 Hz, 2H), 3.87 (s, 3H), 6.33 (s, 1H), 7.20 (d J )
6.7 Hz, 2H), 7.94 (d, J ) 6.7 Hz, 2H); 13C NMR (CDCl3) δ 28.3,
29.2, 36.19, 51.9, 123.7, 127.8, 128.7, 129.4, 140.5, 142.1, 154.6,
166.8. Anal. (C19H25NO4) C, H, N.
4-Br om o-4-[br om o(4-m eth oxyca r bon ylp h en yl)m eth yl]-
p ip er id in e-1-ca r boxylic Acid ter t-Bu tyl Ester (16). To a
mixture of 15 (5.2 g, 16 mmol) and K2CO3 (1.0 g) in dry
dichloromethane (200 mL) was added a solution of bromine
(2.9 g, 18 mmol) in 30 mL CH2Cl2 at 0 °C. after 1.5 h at room
temperature, the solution after filtration of K2CO3 was con-
centrated. The residue was then dissolved in ethyl acetate (200
mL), washed with water (200 mL), 0.5 M HC1 (200 mL) and
brine (200 mL), and dried over MgSO4. Removal of solvents
provided a crude product, which was recrystallized from
methanol to give 16 as a white solid (6.07 g, 78%): IR (NaC1)
1725, 1669 cm-1; 1H NMR (CDCl3) δ 1.28 (s, 9H), 1.75 (m, 2H),
1.90 (m, 2H), 2.1 (m, 4H), 3.08 (br, 4H), 3.90 (s, 3H), 4.08 (br,
4H), 5.14 (s, 1H), 7.57 (d, J ) 8.4 Hz, 2H) 7.98 (d, J ) 8.4 Hz,
2H); 13C NMR (CDCl3) δ 28.3, 36.6, 38.3, 40.3, 52.1, 63.2, 72.9,
129.0, 130.3, 130.4, 141.9, 154.4, 166.3. Anal. (C19H25Br2NO4)
C, H, N.
4-[Br om o(4-ca r b oxyp h en yl)m et h ylen e]p ip er id in e-1-
ca r boxylic Acid ter t-Bu tyl Ester (17). A solution of 16 (5.4
g 11 mmol) in methanol (300 mL) and 2.0 M NaOH (100 mL)
was heated at 40 °C for 3 h. The solid was collected by filtration
and dried overnight under vacuum. The dry salt was dissolved
in 40% acetonitrile/water and was adjusted to pH 2 using
concentrated HCl. The desired product (17; 3.8 g, 87%) was
isolated as a white powder by filtration: 1H NMR (CDCl3) δ
1.45 (s, 9H), 2.22 (dd, J ) 5.5 Hz, 6.1 Hz, 2H), 2.64 (dd, J )
NMR (CDCl3) δ 12.8, 14.1, 27.1, 27.2, 28.4, 39.2, 43.3, 45.4,
79.3, 80.4, 124.1, 124.9, 125.2, 125.3, 126.0, 127.3, 128.8, 129.2,
131.4, 135.0, 135.2, 139.4, 146.5, 154.6, 171.0. Anal. (C32H40N2O4‚
0.5H2O) C, H, N.
N,N-Dieth yl-4-[(N-ter t-bu toxyca r bon ylp ip er id in -4-yl)-
3-flu or op h en ylh yd r oxym et h yl]ben za m id e (7e). Method
as for 7d using 3-bromofluorobenzene provided 7e (262 mg,
27%): 1H NMR (CDCl3) δ 1.03 (br, 3 H, CH3CH2N-), 1.15 (br,
3 H, CH3CH2N-), 1.19-1.29 (m, 4 H, piperidine CH-), 1.35 (s,
9 H, CH3C), 2.39 (m, 1 H, piperidine CH-), 2.59 (br, 2 H,
piperidine CH-), 3.17 (br, 2 H, CH3CH2N-), 3.28 (s, 1 H, OH),
3.45 (br, 2 H, CH3CH2N-), 4.02 (br, 2 H, piperidine CH-), 6.80
(m, 1 H, ArH), 7.15 (m, 3 H, ArH), 7.18 (d, J ) 8.0 Hz, 2 H,
ArH), 7.39 (d, J ) 8.0 Hz, 2 H, ArH).
N,N-Dieth yl-4-[(N-ter t-bu toxyca r bon ylp ip er id in -4-yl)-
3-m eth oxyp h en ylh yd r oxym eth yl]ben za m id e (7f). Method
as for 7d using 3-bromoanisole provided 7f (228 mg, 23%): mp
95-103 °C (CH2Cl2); IR (NaCl) 3422, 1684, 1614 cm-1; 1H NMR
(CDCl3) δ 1.07 (br, 3 H, CH3CH2N-), 1.19 (br, 3 H, CH3CH2N-
), 1.31 (m, 4 H, piperidine CH-), 1.41 (s, 9 H, CH3C), 2.46 (m,
1 H, piperidine CH-), 2.64 (br, 2 H, piperidine CH-), 3.22 (br,
2 H, CH3CH2N-), 3.49 (br, 2 H, CH3CH2N-), 3.65 (s, 1 H, OH),
3.72 (s, 3 H, OCH3), 4.06 (br, 2 H, piperidine CH-), 6.69 (m, 1
H, ArH), 7.01 (d, J ) 7.6 Hz, 1 H, ArH), 7.08 (s, 1 H, ArH),
7.17 (d, J ) 8.0 Hz, 1 H, ArH), 7.21 (d, J ) 8.0 Hz, 2 H, ArH),
7.48 (d, J ) 8.0 Hz, 2 H, ArH). Anal. (C29H40N2O5‚0.6H2O) C,
H, N.
4-(r-Hyd r oxy-r-(4-N-ter t-bu toxyca r bon ylp ip er id in yl)-
2,6-d im eth ylben zyl)-N,N-d ieth ylben za m id e (7g). Method
as described for 7d , but using 2-bromo-m-xylene led to 7g (752
mg, 76%): mp 92-96 °C (CH2Cl2); IR (KBr) 3451, 1690, 1631
1
cm-1; H NMR (CDCl3) δ 1.10 (brs, 3H), 1.21 (brs, 3H), 1.32
(m, 2H), 1.43 (s, 9H), 1.69 (m, 1H), 1.77 (m, 1H), 2.32 (s, 6H),
2.47 (s, 1H), 2.75 (m, 3H), 3.25 (brs, 2H), 3.51 (brs, 2H), 4.13
(brs, 2H), 6.91 (m, 2H), 7.00 (m, 1H), 7.26 (d, J ) 8.4 Hz, 2H),
7.39 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3) δ 12.6, 14.0, 25.0,
27.7, 28.2, 39.1, 42.9, 43.1, 44.4, 53.3, 79.1, 83.0, 125.8, 126.3,
127.2, 131.2, 135.3, 136.7, 142.9, 147.8, 154.5, 170.7. Anal.
(C30H42N2O4‚0.5H2O) C, H, N.
N,N-Dieth yl-4-(1-n a p h th ylp ip er id in -4-ylid en em eth yl)-
ben za m id e (6d ). Method as described for 6a , but starting
with 7d (517 mg, 1.0 mmol) led to 6d (283 mg, 71%): mp 80-
1
85 °C (CH2Cl2); IR (KBr) 1628 cm-1; H NMR (CDCl3) δ 1.06
(brs, 3H), 1.16 (brs, 3H), 2.00 (m, 2H), 2.53 (m, 2H), 2.64 (brs,
NH), 2.77 (m, 2H), 2.97 (m, 2H), 3.20 (brs, 2H), 3.47 (brs, 2H),
7.26 (m, 5H), 7.43 (m, 3H), 7.74 (m, 2H), 8.0 (m, 1H); 13C NMR
(CDCl3) δ 12.8, 14.1, 32.6, 33.5, 39.1, 43.2, 47.9, 48.2, 125.5,
125.7, 125.8, 126.1, 127.1, 127.2, 129.1, 131.9, 132.5, 133.8,
135.1, 138.3, 139.8, 142.6, 171.1. Anal. (C27H30N2O‚0.4HCl) C,
H, N.