Synthesis of 4-substituted 4-arylpiperidines

Article abstract of DOI:10.1016/S0040-4039(00)01610-5

Several novel 4-substituted 4-arylpiperidines were synthesized. The chemistry leading to 4-(4-chlorophenyl)-4-fluoropiperidine (6), 4-azido-4-(4-chlorophenyl)piperidine (7) and 4-(4-chlorophenyl)-4-methylpiperidine (8) is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01610-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8853–8856
Synthesis of 4-substituted 4-arylpiperidines
Geraldine C. B. Harriman,* Jianxing Shao and Jay R. Luly
Millennium Pharmaceuticals Inc., 75 Sidney Street, Cambridge, MA 02139, USA
Received 15 September 2000; accepted 19 September 2000
Abstract
Several novel 4-substituted 4-arylpiperidines were synthesized. The chemistry leading to 4-(4-
chlorophenyl)-4-fluoropiperidine (6), 4-azido-4-(4-chlorophenyl)piperidine (7) and 4-(4-chlorophenyl)-4-
methylpiperidine (8) is described. © 2000 Elsevier Science Ltd. All rights reserved.
4-Arylpiperidines are important functionalities found in several biologically active molecules.
Examples of such molecules include the analgesic Trefentanil (1),1 the antidiarrheal Loperamide
(2),2,3 the growth hormone secretagogue MK0677 (3)4 and the smooth muscle relaxant Anile-
ridine (4)5 (Fig. 1).
O
O
OH
N
N
N
N
N
N
N
Cl
O
F
Loperamide (2)
Trefentanil (1)
NH2
NH
O
O
N
N
H2N
O
O
O
N
S
O O
MK0677 (3)
Anileridine (4)
Figure 1.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01610-5

8854
In our small molecule drug discovery efforts we targeted the synthesis of several 4-substituted
4-arylpiperidines. One of the most common 4-arylpiperidines found in biologically active
molecules is 4-(4-chlorophenyl)-4-hydroxypiperidine (5). This motif is also one of the most
widely found pharmacophores utilized in G-protein coupled receptor (GPCR) antagonists. We
decided to introduce substituents at the C-4 position with both hydrogen bonding capabilities as
well as hydrophobic substituents. We herein report on the synthesis of the following 4-substi-
tuted 4-arylpiperidines: 4-(4-chlorophenyl)-4-fluoropiperidine (6), 4-azido-4-(4-chlorophenyl)-
piperidine (7) and 4-(4-chlorophenyl)-4-methylpiperidine (8) (Fig. 2). This is the first reported
synthesis of a 4-fluoro- and 4-azido-4-arylpiperidine.
HO
F
NH
NH
Cl
Cl
5
6
N3
H3C
NH
NH
Cl
Cl
7
8
Figure 2.
The synthesis of 4-(4-chlorophenyl)-4-fluoropiperidine (6) began utilizing commercially avail-
able 4-(4-chlorophenyl)-4-hydroxypiperidine (5, Scheme 1). Protection of the piperidine nitrogen
as its N-benzylamine proved necessary for ease of purification. Benzylation of 5 was accom-
plished utilizing benzyl bromide (1.1 equiv.) and K2CO3 (2 equiv.) in DMF6 at rt overnight
producing 9 in 89% yield. Conversion of the benzylic hydroxyl group to the benzylic fluoride,
10, was effected in the presence of diethylaminosulfur trifluoride (DAST, 1.2 equiv.) at −78°C in
methylene chloride.7–9 This reagent was selected as the hydroxyl group at C4 is both benzylic
and tertiary. This allows for Lewis acid mediated carbocation chemistry to be more successful.
Unfortunately, the Lewis acid also promotes formation of an olefin through the carbocation
intermediate. This reaction resulted in a quantitative conversion of 9 to an inseparable 1:1
F
HO
HO
Bn
DAST
CH2Cl2
-78ºC
BnBr
Bn
+
N
Bn
N
NH
N
K2CO3
DMF
Cl
Cl
Cl
Cl
5
10
11
9
O
Cl
1.
Bn
F
F
HO
HO
Cl
O
H
H
N
OsO4
NMMNO
N
+
Bn
N
2. MeOH
Cl
Cl
Cl
Cl
6
separable mixture 12
10
Scheme 1.

8855
mixture of fluoropiperidine 10 and 4-(4-chlorphenyl)tetrahydropyridine 11. Several unsuccessful
attempts were made to influence the ratio of desired to undesired product formation including
changes in temperature, stoichiometry of reagents and solvents utilized. In order to separate out
the desired product, the mixture of 10 and 11 was subjected to catalytic osmium tetroxide
oxidation (0.05 equiv. OsO4, 1.1 equiv. N-methylmorpholine N-oxide, rt, overnight).10 This
resulted in the dihydroxylation of the undesired 11 to 12 allowing the clean separation of the
desired fluoropiperidine 10 from the byproduct. Deprotection of 10 was accomplished using
1-chloroethylchloroformate (1.1 equiv. in CH2Cl2, rt, 1 h).11 Excess 1-chloroethylchloroformate
and CH2Cl2 was removed under reduced pressure. The resulting carbamate was then converted
to the final desired product by refluxing the crude residue in methanol for 1 h. This two-step
process resulted in the quantitatively conversion of 10 to the hydrochloride salt 6.
The synthesis of 4-azido-4-(4-chlorophenyl)piperidine (7) also began with piperidine 5
(Scheme 2). Reaction of 5 in the presence of NaN3 (1.2 equiv.) and BF3·OEt2 (1.1 equiv.) in
anhydrous dioxane at 0°C12,13 led to the formation of the azidopiperidine 7 and olefin 13 in a
one to three ratio. This mixture proved to be separable and resulted in the isolation of 7 in 25%
yield.
HO
N3
NaN3
NH
+
NH
NH
BF3•OEt
Cl
Cl
Cl
5
7
13
Scheme 2.
The synthesis of 4-(4-chlorophenyl)-4-methylpiperidine (8) began with the addition of com-
mercially available 1-benzyl-4-oxopiperidine (14) to a cold (−78°C) stirred solution of 1.0 M
methyllithium in diethyl ether (1.2 equiv.)14 (Scheme 3). Tertiary alcohol 15 was isolated in 51%
yield after flash column chromatography.
O
H3C
HO
AlCl3
CH3Li
N
H3C
N
N
Cl
Cl
16
15
14
H3C
O
Cl
1.
Cl
H
H
O
N
Cl
2. MeOH
Cl
8
Scheme 3.

8856
The order of addition proved to be critical here, as addition of the alkyl lithium reagent to a
solution of 14 resulted in the formation of adduct 17 in 55% yield (Fig. 3). No desired product
was detected. This product is presumably generated from benzylic deprotonation followed by
1,2-addition to the ketone. Friedel–Crafts arylation15 of the tertiary alcohol in the presence of
chlorobenzene (neat) and aluminum trichloride (1.1 equiv.) resulted in the formation of 16 (88%
yield). Debenzylation utilizing the chloroformate methodology mentioned above16 smoothly
produced the desired piperidine hydrochloride salt 8 quantitatively.
O
N
OH
N
17
Figure 3.
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16. All compounds were characterized via NMR (Bruker AC 250) and LC/MS (Micromass Platform LCZ with
electrospray ionization and diode array LC detection at 200–400 nm). 4-(4-Chlorophenyl)-4-fluoropiperidine·HCl
1
(6): H NMR (DMSO-d6): l 2.09 (bt, 2H, J=13 Hz), 2.36 (dt, 1H, J=7.5, 13 Hz), 2.36 (dt, 1H, J=7.5, 13 Hz),
2.49 (dt, 1H, J=7.5, 13 Hz), 3.11 (bt, 2H, J=13 Hz), 3.32 (m, 2H), 7.41 (d, 2H, J=7.5 Hz), 7.51 (d, 2H, J=7.5
1
Hz); MS: [M+] 214. 4-Azido-4-(4-chlorophenyl)piperidine (7): H NMR (DMSO-d6): l 1.71 (m, 2H), 2.04 (m,
2H), 3.00 (m, 4H), 3.33 (bs, 1H, NH), 7.42 (bs, 4H); MS: [M+1−N2] 212. 4-(4-Chlorophenyl)-4-methylpiper-
idine·HCl (8): 1H NMR (CDCl3): l 1.31 (s, 3H), 1.88–2.00 (m, 2H), 2.30–2.41 (m, 2H), 2.97–3.09 (m, 2H),
3.22–3.34 (m, 4H), 7.32–7.43 (m, 4H); MS: [M+] 210.
.