A Practical Synthesis of 4-(Substituted-benzyl)piperidines and (±)-3-(Substituted-benzyl)pyrrolidines via a Wittig Reaction

Full text of DOI:10.1021/jo9824697

J . Org. Chem. 1999, 64, 3763-3766
3763
Sch em e 1
A P r a ctica l Syn th esis of
4-(Su bstitu ted -ben zyl)p ip er id in es a n d
(()-3-(Su bstitu ted -ben zyl)p yr r olid in es via a
Wittig Rea ction
Zhang-Lin Zhou*,† and J ohn F. W. Keana*,‡
CoCensys Inc., 201 Technology Drive, Irvine, California
92618, and Department of Chemistry, University of Oregon,
Eugene, Oregon 97403
Received December 18, 1998
Sch em e 2a
In tr od u ction
4-Benzylpiperidines and their derivatives possess a
range of physiological and pharmacological activities. For
example, the antihypertensive agent ifenprodil (1) ex-
hibits subtype selective NMDA antagonist activity, as
well as high affinity for several other central nervous
system (CNS) receptors, such as R1 adrenergic, 5HT1A
,
5HT2, and σ receptors.1 Eliprodil (2) is a relative of
ifenprodil that has been used for the treatment of stroke
in clinical trials.2 It was recently found that 4-benzyl-1-
[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine (3) and
related compounds exhibit highly potent acetylcholinest-
erase inhibitor activity.3 Novel phenylacetamides such
as N-[3-(4-benzylpiperidin-1-yl)propyl]-2,2-diphenylaceta-
mide (4) have been shown to act as sodium channel
blockers (Scheme 1).4
Our research program required a variety of 4-(substi-
tuted-benzyl)piperidines in gram quantities. Wick and co-
workers5 reported a four-step procedure for the prepa-
ration of 4-benzylpiperidines: (i) preparation of isonicotinic
acid chloride; (ii) Friedel-Craft acylation of a substituted
benzene to a ketone; (iii) Wolff-Kishner reduction of the
ketone to the corresponding benzyl pyridines; and (iv)
hydrogenation of the pyridines to the benzyl piperidines.
The Friedel-Crafts reaction sometimes gave a mixture
of ortho and para acylation products. Meta-substituted
acylation products cannot be prepared by this route. In
our hands, the yield of the Wolff-Kishner reduction step
was highly variable, particularly in the case of 2-fluoro
substitution on the phenyl ring. For example, Wolff-
Kishner reduction of 2-fluoro-4-methylphenyl- and 2-fluo-
rophenyl 4-pyridyl ketones proceeded in 0-50% yield.
Herein, we report a practical approach to 4-(substituted-
benzyl)piperidines in multigram amounts via a Wittig
olefination reaction (Scheme 2).
a
Key: (i) Ph3P/ether/rt; (ii) NaH/DMSO/80 °C, then 1-benzyl-
4-piperidone; (iii) PtO2/MeOH/H2, then HCl/MeOH; (iv) 10% Pd/
C, 95% EtOH/H2.
phine in ether at room temperature afforded the corre-
sponding (3-fluorobenzyltriphenyl)phosphonium bromide
(6b) in 85% yield. Treatment of 6b with sodium meth-
ylsulfinyl carbanion6 in dimethyl sulfoxide at 80 °C gave
the corresponding ylide, which reacted with 1-benzyl-4-
piperidone to form 4-(3-fluorobenzylidene)-1-benzylpip-
eridine (7b) in 73% yield. Reduction of 7b with H2 in the
presence of PtO2 and 1 M HCl gave 1-benzyl-4-(3-
fluorobenzyl)piperidine hydrochloride (8b) in 82% yield.
Further debenzylation of 8b by hydrogenation in the
presence of 10% Pd/C gave 4-(3-fluorobenzyl)piperidine
hydrochloride (9b) in quantitative yield.
Two observations are noteworthy. Initial attempts to
accomplish the Wittig olefination through the usual BuLi/
ether gave alkene 7b in only 13% yield, probably due to
the poor solubility of the phosphonium salt in ether. In
contrast, the methylsulfinyl carbanion-dimethyl sulfox-
ide system has been satisfactory for this Wittig reaction
in every case investigated. Second, attempts to reduce
the double bond and remove the benzyl group in one step
resulted in partial reduction of the double bond and
partial debenzylation. Stepwise reduction of the double
bond and removal of the N-benzyl group consistently gave
good yields.
The synthesis of 4-(3-fluorobenzyl)piperidine hydro-
chloride (9b) is illustrative. Reaction of commercially
available 3-fluorobenzyl bromide (5b) with triphenylphos-
† CoCensys Inc.
‡ University of Oregon.
Ten different substituted benzyl piperidines were
prepared using this methodology (Table 1). Both mono-
and disubstituted benzyl bromides including 2,6-difluo-
robenzyl bromide (5e) underwent the four-step procedure
to afford the corresponding 4-(substituted-benzyl)piperi-
dine hydrochloride in 58-80% overall yield.
(1) Ohshima, E.; Takami, H.; Harakawa, H.; Sato, H.; Obase, H.;
Miki, I.; Ishii, A.; Ishii, H.; Sasaki, Y.; Ohmori, K.; Karasawa, A.; Kubo,
K. J . Med. Chem. 1993, 36, 417.
(2) Shanklin, J . R., J r.; J ohnson, C. P., III; Proakis A. G.; Barrett,
R. J . J . Med. Chem. 1991, 34, 3011.
(3) (a) Sugimoto, H.; Iimura, Y.; Yamanishi, Y.; Yamatsu, K. J . Med.
Chem. 1995, 38, 4821. (b) Cardozo, M. G.; Kawai, T.; Iimura, Y.;
Sugimoto, H.; Yamanishi, Y.; Hopfinger, A. J . J . Med. Chem. 1992,
35, 590.
(4) Roufos, I.; Hays, S.; Schwarz, R. D. J . Med. Chem. 1996, 39, 1514.
(5) Wick, A.; Frost, J .; Gaudilliere, B.; Bertin, J .; Dupont, R.;
Rousseau, J . US Patent 4,690,931, 1987.
The same methodology can also be successfully em-
ployed for the synthesis of the corresponding (()-3-
(6) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1962, 84, 866.
10.1021/jo9824697 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/22/1999

3764 J . Org. Chem., Vol. 64, No. 10, 1999
Notes
Ta ble 1. Syn th esis of 4-(Su bstitu ted -ben zyl)p ip er id in es
via a Wittig Rea ction a
conditions provided an E/Z mixture of 3-(2-fluoroben-
zylidene)-1-benzylpyrrolidine (10) in 63% yield. Reduction
of the double bond and debenzylation provided the
desired (()-3-(2-fluorobenzyl)pyrrolidine hydrochloride
(12) in 93% yield as a clear oil. Reaction of 12 with 2-(4-
benzyloxyphenoxy)ethyl bromide (13) provided the cor-
responding N-alkylation product (()-14 in 50% yield.
Debenzylation of 14 gave (()-3-(2-fluorobenzyl)-1-[2-(4-
hydroxyphenoxy)ethyl]pyrrolidine hydrochloride (15) in
80% yield. Both compounds 14 and 15 gave satisfactory
1H NMR and elemental analysis.
In summary, we describe herein a practical approach
to 4-(substituted-benzyl)piperidines and (()-3-(substituted-
benzyl)pyrrolidines starting from a substituted benzyl
bromide via phosphonium salt formation, Wittig olefina-
tion, reduction, and N-debenzylation with the advantage
of mild reaction conditions, simple workup procedures,
and satisfactory yields.
Exp er im en ta l Section
Melting points were determined in open capillary tubes on a
Mel-Temp apparatus and are uncorrected. The 1H NMR spectra
were recorded at 300 MHz. Chemical shifts are reported in ppm
(δ), and J coupling constants are reported in Hz. Elemental
analyses were performed by Desert Analytics, Tucson, AZ. Mass
spectra (MS) were obtained with a VG 12-250 or VG ZAB-2FHF
mass spectrometer. Reagent grade solvents were used without
further purification unless otherwise specified. Reversed-phase
HPLC analyses were monitored at 254 nM on a 4.6 × 250 mM
Microsorb-MV C18 column, using as solvents 0.1% trifluoroacetic
acid in water (A) and 0.1% trifluoroacetic acid in acetonitrile
(B). The linear gradient was 20% B in A to 95% B in A with a
flow rate of 1 mL/min.
Typ ica l P r oced u r e: (3-F lu or oben zyl)tr ip h en ylp h osp h o-
n iu m Br om id e (6b). To a solution of triphenylphosphine (31.48
g, 0.12 mol) in 200 mL of ether was added 3-fluorobenzyl bromide
(5b) (22.68 g, 0.12 mol). The resulting solution was allowed to
stir at room temperature overnight. The white solid was collected
by filtration and dried to give 46.0 g (85%) of 6b as a white
a
All intermediates gave satisfactory 1H NMR spectra. b Isolated
1
solid: mp 290-292 °C; H NMR (CDCl3, 300 MHz) δ 5.52 (d, J
yields based on starting benzyl bromide.
) 14.7 Hz, 2 H), 6.73 (d, J ) 9.6 Hz, 1 H), 6.89 (m, 2 H), 7.08
(m, 2 H), 7.62-7.76 (m, 15 H). Anal. Calcd for C25H21BrFP: C,
66.53; H, 4.69. Found: C, 66.30; H, 4.51.
Sch em e 3a
1-Ben zyl-4-(3-flu or oben zylid en e)p ip er id in e (7b). To a
250-mL three-necked round-bottom flask was added 1.2 g (60%
in mineral oil, 0.03 mol) of NaH and 20 mL of dry DMSO. The
mixture was heated at 80 °C for 1 h. The resulting solution was
cooled in an ice-water bath. To this solution was added a
suspension of (3-fluorobenzyl)triphenylphosphonium bromide
(6b) (16.98 g, 0.03 mol) in 120 mL of warm DMSO. The resulting
mixture was stirred at room temperature for 10 min. Then
1-benzyl-4-piperidone (5.67 g, 0.03 mol) was added dropwise
under N2. The resulting mixture was allowed to stir overnight
and then was heated to 80 °C for another 8 h. The mixture was
poured over ice and extracted with ether. The combined extract
was dried over sodium sulfate. The solvent was evaporated in
vacuo to give an oil, which was purified by flash chromatography,
giving 6.12 g (73%) of 7b as pale yellow oil: 1H NMR (CDCl3,
300 MHz) δ 2.41 (m, 2 H), 2.47 (m, 2 H), 2.56 (m, 4 H), 3.56 (s,
2 H), 6.26 (s, 1 H), 6.91 (m, 3 H), 7.28 (m, 6 H); EIMS (m/e) 281
(M+, 100), 204 (20), 190 (20), 146 (30), 91 (90). 42 (48); HRMS
calcd for C19H20FN 281.1586, found 281.1583 (HPLC 100%).
1-Ben zyl-4-(3-flu or ob en zyl)p ip er id in e H yd r och lor id e
(8b). To a solution of 1-benzyl-4-(3-fluorobenzylidene)piperidine
(7b) (2.9 g, 10 mmol) in 100 mL of methanol was added 150 mg
of PtO2. The resulting mixture was hydrogenated at 30 psi for
4 h. The catalyst was removed through a short column of Celite
(10 g) and was washed with methanol. To the filtrate was added
20 mL of 1 M HCl in methanol. The resulting mixture was
a
Key: (i) NaH/DMSO/80 °C, then 1-benzyl-3-pyrrolidinone; (ii)
PtO2, MeOH/H2, then 1 M HCl/MeOH; (iii) 10% Pd/C, 95% EtOH/
H2; (iv) p-BrCH2CH2OC6H4OBn (13)/K2CO3/CH3CN/reflux; (v) then
1 M HCl/MeOH, 66%; (v) 20% Pd(OH)2/MeOH, 95%.
(substituted-benzyl)pyrrolidines (Scheme 3), which are
otherwise difficult to make.7 As an example, Wittig
reaction of (2-fluorobenzyl)triphenylphosphonium bro-
mide (6a ) with 1-benzyl-3-pyrrolidinone under similar
(7) Horwell, D. C.; Howson, W.; Naylor, D.; Willems, H. M. G. Bioorg.
Med. Chem. Lett. 1995, 5, 1445.

Notes
J . Org. Chem., Vol. 64, No. 10, 1999 3765
stirred for 10 min. Evaporation of the solvent gave a residue to
which ether (50 mL) was added. The resulting mixture was
allowed to stir overnight. The white solid was collected by
filtration and dried in vacuo, giving 4.0 g (96%) of 8b: mp 153-
2 H), 9.30 (brs, 1 H), 9.61 (brs, 1 H). Anal. Calcd for C15H26ClN‚
0.3H2O: C, 70.33; H, 9.81; N, 5.13. Found: C, 70.20; H, 9.62; N,
5.03.
(E/Z)-1-Ben zyl-3-(2-flu or oben zylid en e)p yr r olid in e Hy-
d r och lor id e (10). To a 250-mL three-necked round-bottom flask
was added 0.64 g (60% in mineral oil) of sodium hydride and 15
mL of dry DMSO under N2. The mixture was heated at 80 °C
for 1 h. The resulting solution was cooled in an ice-water bath.
To this solution was added a suspension of (2-fluorobenzyl)-
triphenylphosphonium bromide (6a ) (8.2 g, 0.018 mol) in 80 mL
of warm DMSO. The resulting solution was stirred at 0 °C for
10 min and at room temperature for 15 min. Then 1-benzyl-3-
pyrrolidinone (2.63 g, 15 mol) was added dropwise under N2.
The resulting mixture was allowed to stir at 80 °C overnight.
Then the mixture was poured into ice and extracted with ether.
The combined extracts were dried over sodium sulfate. The
solvent was evaporated in vacuo to give a residue, which was
purified by flash chromatography (eluent 5% EtOAc in hexanes),
giving 2.5 g (63%) of the product as a pale yellow oil, 200 mg of
which was dissolved into 10 mL of methanol and 2 mL of 1 M
HCl in methanol was added. Evaporation of methanol gave a
residue to which was added 30 mL of ether. A white solid was
collected by filtration and dried to give 230 mg (100%) of the
title compound: mp 187-189 °C; 1H NMR (CDCl3, 300 MHz) δ
2.90-3.17 (m, 3 H), 3.68 (m, 2 H), 4.15-4.43 (m, 3 H), 6.65 (s,
1 H), 7.14 (m, 3 H), 7.28 (m,1 H), 7.15 (m, 3 H), 7.62 (m, 2H),
13.30 (brs, 1 H).
(()-1-Ben zyl-3-(2-flu or oben zyl)p yr r olid in e Hyd r och lo-
r id e (11). To a solution of 1-benzyl-3-(2-fluorobenzylidene)-
pyrrolidine (10) (1.34 g, 5.0 mmol) in 50 mL of methanol was
added 100 mg of PtO2. The resulting mixture was hydrogenated
at 40 psi for 8 h. The catalyst was removed through a short
column of Celite and was washed with methanol. The filtrate
was evaporated in vacuo and dissolved into 20 mL of methanol,
to which was added 24 mL of 1 M HCl in methanol. The resulting
solution was stirred for 10 min. Evaporation of methanol gave
a residue, to which ether (60 mL) was added, and the mixture
was stirred overnight. Evaporation of solvent gave 11 as a
colorless oil: 1H NMR (CDCl3, 300 MHz) δ 1.62 (m, 3 H), 2.73
(m, 2 H), 2.93 (m, 2 H), 3.49 (m, 2 H), 3.65 (m, 2 H), 7.13 (m, 3
H), 7.26 (m, 2 H), 7.36 (m, 2 H), 7.62 (m, 2 H), 12.80 (brs, 1 H).
(()-3-(2-F lu or oben zyl)p yr r olid in e Hyd r och lor id e (12).
A mixture of 1-benzyl-3-(2-fluorobenzyl)pyrrolidine hydrochloride
(11) (1.53 g, 5.0 mmol) and 0.66 g of 10% Pd/C in 50 mL of 95%
ethanol was hydrogenated at 50 psi for 12 h. The catalyst was
removed through a short column of Celite (10 g) and was washed
with methanol. The filtrate was evaporated in vacuo to give a
residue, to which ether (50 mL) was added, and the resulting
mixture was stirred overnight. Evaporation of the solvent gave
12 as a clear oil: 1H NMR (CDCl3, 300 MHz) δ 1.77 (m, 2 H),
2.11 (m, 1 H), 2.660-2.96 (m, 4 H), 3.39 (m, 2 H), 6.99-7.20 (m,
4 H), 9.80 (s, 2 H).
1
155 °C; H NMR (CDCl3, 300 MHz) δ 1.65 (m, 1 H), 1.78 (m, 2
H), 2.11 (s, 2 H), 2.60 (s, 4 H), 3.45 (s, 2 H), 4.13 (s, 2 H), 6.86
(m, 3 H), 7.26 (m, 1 H), 7.43 (s, 3 H), 7.59 (s, 2 H), 12.40 (brs, 1
H). Anal. Calcd for C19H23ClFN: C, 71.35; H, 7.25; N, 4.38.
Found: C, 71.33; H, 7.19; N, 4.60.
4-(3-F lu or oben zyl)p ip er id in e Hyd r och lor id e (9b). To a
solution of 1-benzyl-4-(3-fluorobenzyl)piperidine hydrochloride
(8b) (4.0 g, 13 mmol) in 100 mL of 95% ethanol was added 1.0
g of 10% Pd/C. The resulting mixture was hydrogenated at 50
psi for 4 h. The catalyst was removed through a short column
of Celite (10 g) and was washed with ethanol. The filtrate was
evaporated in vacuo to give a residue to which ether (50 mL)
was added. The resulting mixture was allowed to stir overnight.
The white solid was collected by filtration and dried in vacuo,
giving 2.8 g (98%) of 9b: mp 173-175 °C; 1H NMR (CDCl3, 300
MHz) δ 1.61-1.81 (m, 5 H), 2.59 (m, 2 H), 2.79 (m, 2 H), 3.48
(m, 2 H), 6.88 (m, 3 H), 7.25 (m, 1 H), 9.36 (s, 1 H), 9.63 (s, 1 H);
EIMS m/e 194 (M+ + 1, 15), 193 (M+, 100), 192 (M+ - 1, 60),
109 (50), 84 (80), 69 (60), 56 (95). Anal. Calcd for C12H17ClFN:
C, 62.74; H, 7.46; N, 6.10. Found: C, 62.63; H, 7.25; N, 6.01.
4-(2-F lu or oben zyl)p ip er id in e h yd r och lor id e (9a ): mp
1
178-180 °C; H NMR (CDCl3, 300 MHz) δ 1.78 (m, 5 H), 2.64
(d, J ) 4.3 Hz, 2 H), 3.45 (d, J ) 9.0 Hz, 2 H), 7.00-7.09 (m, 3
H), 7.19 (m, 1 H), 9.38 (s, 1 H), 9.62 (s, 1 H). Anal. Calcd for
C12H17ClFN: C, 62.74; H, 7.46; N, 6.10. Found: C, 62.46; H,
7.36; N, 5.95.
4-(4-F lu or oben zyl)p ip er id in e h yd r och lor id e (9c): mp
1
158-160 °C (lit.5 mp 158-160 °C); H NMR (CDCl3, 300 MHz)
δ 1.79 (m, 2 H), 1.96 (m, 2 H), 2.54 (d, J ) 5.4 Hz, 2 H), 2.37 (m,
2 H), 3.42 (d, J ) 14.7 Hz, 2 H), 6.98 (m, 2 H), 7.05 (m, 2 H),
9.50 (brs, 2 H).
4-(3,4-Diflu or oben zyl)p ip er id in e h yd r och lor id e (9d ): mp
1
174-175 °C; H NMR (CDCl3, 300 MHz) δ 1.70-1.83 (m, 5 H),
2.56 (m, 2 H), 2.80 (m, 2 H), 3.46 (d, J ) 8.1 Hz, 2 H), 6.83 (m,
1 H), 6.89 (m, 1 H), 7.05 (m, 1 H), 9.38 (s, 1 H), 9.60 (s, 1 H).
Anal. Calcd for C12H16ClF2N: C, 58.18; H, 6.51; N, 5.65. Found:
C, 57.89; H, 6.43; N, 5.59.
4-(2,6-Diflu or oben zyl)p ip er id in e h yd r och lor id e (9e): mp
1
216-218 °C; H NMR (CDCl3, 300 MHz) δ 1.83 (m, 5 H), 2.68
(s, 2 H), 2.81 (m, 2 H), 3.46 (d, J ) 11.1 Hz, 2 H), 6.86 (m, 2 H),
7.18 (m, 1 H), 9.40 (s, 1 H), 9.62 (s, 1 H). Anal. Calcd for C12H16
-
ClF2N‚0.2H2O: C, 57.35; H, 6.58; N, 5.57. Found: C, 57.50; H,
6.62; N, 5.36.
4-(4-Tr iflu or om et h ylb en zyl)p ip er id in e h yd r och lor id e
1
(9f): mp 208-210 °C; H NMR (CDCl3, 300 MHz) δ 1.76-1.85
(m, 5 H), 2.66 (s, 2 H), 2.79 (m, 2 H), 3.45 (d, J ) 11.7 Hz, 2 H),
7.23 (d, J ) 7.8 Hz, 2 H), 7.54 (d, J ) 7.8 Hz, 2 H), 9.41 (s, 1 H),
9.66 (s, 1 H). Anal. Calcd for C13H17ClF3N‚0.1H2O: C, 55.46; H,
6.16; N, 4.98. Found: C, 55.46; H, 6.00; N, 5.07.
(()-1-[2-(4-Ben zoxyp h en oxy)et h yl]-3-(2-flu or ob en zyl)-
p yr r olid in e Hyd r och lor id e (14). A mixture of 2-(4-benzoxy-
phenoxy)ethyl bromide (13) (0.46 g, 1.50 mmol), 3-(2-fluorobenz-
yl)pyrrolidine hydrochloride (12) (0.323 g, 1.50 mmol), and
potassium carbonate (0.518 g, 3.8 mmol) in 30 mL of acetonitrile
was allowed to reflux for 12 h. The inorganic salt was removed
through a short column of silica gel and washed with ethyl
acetate. The combined filtrate was evaporated in vacuo to give
a crude mixture, which was purified by flash chromatography
(20% methanol in ethyl acetate) to give an oil, to which was
added 3 mL of 1 M HCl in methanol. Evaporation of methanol
gave a residue, to which ether (30 mL) was added, and then the
mixture was allowed to stir overnight. An off-white solid was
collected by filtration and dried in vacuo to give 0.25 g (38%) of
the title compound: mp 116-118 °C; 1H NMR (CDCl3, 300 MHz)
δ 1.82-2.30 (m, 3 H), 2.82 (m, 1 H), 2.94 (m, 3 H), 3.42 (m, 2 H),
3.86 (m, 2 H), 4.44 (m, 2 H), 5.02 (s, 2 H), 6.82-6.88 (m, 4 H),
7.06 (m, 2 H), 7.26 (m, 2 H), 7.41 (m, 5 H), 12.87 (brs, 1 H).
Anal. Calcd for C26H29ClFNO2‚0.5H2O: C, 69.24; H, 6.70; N, 3.11.
Found: C, 69.15; H, 6.45; N, 3.11.
4-(4-Meth ylben zyl)p ip er id in e h yd r och lor id e (9g): mp
209-211 °C; H NMR (CDCl3, 300 MHz) δ 1.70 (m, 3 H), 1.82
(m, 2 H), 2.32 (s, 3 H), 2.55 (m, 2 H), 2.78 (m, 2 H), 3.44 (d, J )
8.7 Hz, 2 H), 6.99 (d, J ) 7.8 Hz, 2 H), 7.05 (d, J ) 7.8 Hz, 2 H),
9.30 (s, 1 H), 9.60 (s, 1 H). Anal. Calcd for C13H20ClN: C, 69.16;
H, 8.93; N, 6.20. Found: C, 69.02; H, 9.12; N, 6.10.
1
4-(4-Eth ylben zyl)piper idin e h ydr och lor ide (9h ): mp 175-
1
177 °C; H NMR (CDCl3, 300 MHz) δ 1.22 (t, J ) 7.8 Hz, 3 H),
1.71 (m, 2 H), 1.83 (m, 3 H), 2.55-2.65 (m, 4 H), 2.78 (m, 2 H),
3.44 (d, J ) 8.7 Hz, 2 H), 7.02 (d, J ) 7.8 Hz, 2 H), 7.11 (d, J )
7.8 Hz, 2 H), 9.30 (s, 1 H), 9.60 (s, 1 H). Anal. Calcd for C14H22
-
ClN: C, 70.13; H, 9.25; N, 5.84. Found: C, 69.78; H, 9.48; N,
5.71.
4-(4-Isop r op ylben zyl)p ip er id in e h yd r och lor id e (9i): mp
1
183-185 °C; H NMR (CDCl3, 300 MHz) δ 1.22 (d, J ) 7.2 Hz,
6 H), 1.71 (m, 2 H), 1.83 (m, 3 H), 2.55 (m, 2 H), 2.78-2.88 (m,
3 H), 3.43 (d, J ) 11.7 Hz, 2 H), 7.03 (d, J ) 7.8 Hz, 2 H), 7.14
(d, J ) 7.8 Hz, 2 H), 9.30 (s, 1 H), 9.60 (s, 1 H). Anal. Calcd for
C15H24ClN‚0.2H2O: C, 69.98; H, 9.55; N, 5.44. Found: C, 70.06;
H, 9.30; N, 5.29.
(()-1-[2-(4-H yd r oxyp h en oxy)et h yl]-3-(2-flu or ob en zyl)-
p yr r olid in e Hyd r och lor id e (15). To a solution of 1-[2-(4-
benzoxyphenyl)ethoxy]-3-(2-fluorobenzyl)pyrrolidine hydrochlo-
ride (14) (0.2 g, 0.45 mmol) in 30 mL of methanol was added
0.050 g of 20% Pd(OH)2. The resulting mixture was hydroge-
4-(4-ter t-Bu tylben zyl)p ip er id in e h yd r och lor id e (9j): mp
208-210 °C; 1H NMR (CDCl3, 300 MHz) δ 1.30 (s, 9 H), 1.68
(m, 3 H), 1.84 (m, 2 H), 2.55 (m, 2 H), 2.80 (m, 2 H), 3.44 (d, J
) 12.3 Hz, 2 H), 7.04 (d, J ) 8.1 Hz, 2 H), 7.29 (d, J ) 8.1 Hz,

3766 J . Org. Chem., Vol. 64, No. 10, 1999
Notes
nated at 30 psi of hydrogen for 4 h. The catalyst was removed
H), 7.09 (m, 2 H). Anal. Calcd for C19H23ClFNO2‚0.7H2O: C,
62.61; H, 6.75; N, 3.84. Found: C, 62.60; H, 6.51; N, 4.19. (HPLC
100%).
through
a short column of Celite (5 g) and washed with
methanol. Evaporation of methanol gave a residue, to which
ether (100 mL) was added, and the mixture was allowed to stir
at room temperature overnight. The off-white solid was collected
by filtration and dried in vacuo, giving 0.125 g (79%) of the title
product: mp 75-77 °C; 1H NMR (300 MHz, CD3OD) δ 1.70 (m,
2 H), 2.00(m, 2 H), 2.67 (m, 3 H), 3.42 (m, 4 H), 4.03 (m, 2 H),
6.52 (d, J ) 9.0 Hz, 2 H), 6.64 (d, J ) 9.0 Hz, 2 H), 6.94 (m, 2
Ack n ow led gm en t. Financial support from CoCen-
sys, Inc., is gratefully acknowledged.
J O9824697