A rapid and general access to 3-arylpiperidines

Article abstract of DOI:10.1016/S0040-4039(01)01045-0

A short and efficient synthetic sequence to produce a wide variety of 3-arylpiperidines from three simple building blocks is described. The key step is a palladium-catalyzed arylation of cyclopentene.

Full text of DOI:10.1016/S0040-4039(01)01045-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5381–5383
A rapid and general access to 3-arylpiperidines
Isabel K. Bu¨chner and Peter Metz*
Institut fu¨r Organische Chemie, Technische Universita¨t Dresden, Mommsenstraße 13, D-01062 Dresden, Germany
Received 17 May 2001; accepted 15 June 2001
Abstract—A short and efficient synthetic sequence to produce a wide variety of 3-arylpiperidines from three simple building blocks
is described. The key step is a palladium-catalyzed arylation of cyclopentene. © 2001 Elsevier Science Ltd. All rights reserved.
Drugs that are able to control dopamine synthesis and/or
release by action upon the autoreceptor could be benefi-
cial for the treatment of various central nervous system
related diseases.1 Especially, agents acting selectively or
at least preferentially on the presynaptic or postsynaptic
site might provide a means for more specific manipula-
tion of dopamine related neural processes as compared
to the effects caused by classical dopamine antagonists
or agonists. A prototype for a compound showing a
selectivity of this kind is (−)-3-(3-hydroxyphenyl)-N-
propylpiperidine [(S)-(−)-3-PPP, preclamol], a presynap-
tic agonist (autoreceptor agonist) with only partial effect
on the postsynaptic site (Fig. 1). Potent dopaminergic
substances, such as 3-PPP and related compounds, could
be effective antipsychotic agents with therapeutic effect
in the treatment of schizophrenia, Parkinson’s disease,
depression or drug addiction.
Using iodobenzene (2a) as a model substrate, some
modifications of the reaction conditions were tested to
study their effect on the isomerization of 3 to 4 during
the palladium-catalyzed arylation (Table 2). The pres-
ence or absence of molecular sieves or triphenylphos-
phine had no profound influence on the isomeric ratio
when the reaction was run at room temperature (entries
1–3). However, upon changing the solvent from DMF to
acetonitrile at room temperature, the percentage of 3a in
the product mixture slightly decreased (entries 6 and 7),
and at 80°C in DMF small amounts of 1-phenylcyclopen-
tene were detected in addition to 3a and 4a (entries 4 and
5).
H
OH
N
We have recently developed a novel access to 3-arylpipe-
ridines 12 by which a wide range of these compounds is
available from three simple building blocks in only four
straightforward steps (Fig. 2). All starting materials are
commercially available and inexpensive.
Figure 1. (−)-3-(3-Hydroxyphenyl)-N-propylpiperidine.
The key step in our preparation of 1 is a high yielding
Heck reaction of meta substituted aryl halides 2 with
cyclopentene to give the 3-arylcyclopentenes 3 (Scheme
1, Table 1).3,4 Only small amounts of the unwanted
regioisomers 4 were formed at room temperature (entries
a–c and e). For entries d and f–i, increasing the temper-
ature to 80°C was necessary in order to improve the
yields, which resulted in slightly higher proportions of
isomers 4 for the latter cases.
Ar
N
R
Ar-X
1
R-NH2
Keywords: physiologically active compounds; piperidines; Heck reac-
tions; ozonolysis.
Figure 2. Assembly of 3-arylpiperidines from three simple
building blocks.
* Corresponding author. Tel.: +49-351-463-7006; fax: +49-351-463-
3162; e-mail: metz@coch01.chm.tu-dresden.de
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01045-0

5382
I. K. Bu¨chner, P. Metz / Tetrahedron Letters 42 (2001) 5381–5383
Pd(OAc)2, KOAc, Bu4NCl
R
molecular sieves 4 Å, DMF
+
+
R
R
X
2
3
4
Scheme 1.
Table 1. Heck reaction of meta substituted aryl halides 2 with cyclopentenea
Entry
R
X
T (°C)
t (days)
Ratio 3:4b
Yield 3+4 (%)c
a
b
c
d
H
OMe
CN
Me
F
OH
CH2OH
NO2
NH2
I
I
Br
I
I
I
I
I
I
rt
rt
rt
80
rt
80
80
80
80
1
1
2
1
1.5
1
1
1
2
94:6
94:6
92:8
93:7
98
96
95
95
90
89
83
82
70
e
92:8
fd
gd
hd
id
87:13
87:13
86:14
87:13
a ArX (1 mmol), cyclopentene (5 mmol), Pd(OAc)2 (2.5 mol%), Bu4NCl (1 mmol), KOAc (3 mmol), DMF (5 mL), molecular sieves 4 A (0.1
,
g/mmol ArX), exclusion of light, argon atmosphere.
b Isomeric ratio determined by GC and 1H NMR.
c Isolated yield.
d Ph3P (2.5 mol%) added.
Table 2. Heck reaction of iodobenzene (2a) with cyclopentenea
Ratio 3a:4ab
,
Entry
Solvent
T (°C)
Molecular sieves 4 A (mg)
Ph3P (mmol)
1
2
3
4
5
6
7
DMF
DMF
DMF
DMF
DMF
MeCN
MeCN
rt
rt
rt
80
80
rt
100
100
–
100
–
2.5
–
2.5
–
2.5
2.5
–
94:6
94:6
93:7
85:4:11c
88:5:7c
87:13
87:13
100
100
rt
a 2a (1 mmol), cyclopentene (5 mmol), Pd(OAc)2 (2.5 mol%), Bu4NCl (1 mmol), KOAc (3 mmol), solvent (5 mL), exclusion of light, argon
atmosphere.
b Isomeric ratio determined by GC.
c Ratio 3a:4a:1-phenylcyclopentene.
The 3-arylcyclopentenes 3a–e were ozonized followed
by reductive work-up with a suitable hydride reagent to
give the diols 5a–e (Scheme 2, Table 3). After activation
of both hydroxyl groups of 5 by mesylation under
standard conditions, ring closure5 to piperidines 1a–e
was smoothly achieved by treatment of the mesylates
6a–e with an excess of propylamine at room tempera-
ture for 4 days.
In conclusion, the synthetic sequence described here
constitutes a simple and efficient route to produce a
wide variety of 3-arylpiperidines 1. Electron-withdraw-
a) O3
R
b) reduction
Pr-NH2, r.t.
R
N
R
R'O
OR'
3
5: R' = H
MsCl, Et3N
1
CH2Cl2, −20°C to r.t.
6: R' = Ms
Scheme 2.

I. K. Bu¨chner, P. Metz / Tetrahedron Letters 42 (2001) 5381–5383
5383
Table 3. Conversion of 3-arylcyclopentenes 3 to 3-
arylpiperidines 1
2–11; (b) Pirtosek, Z.; Merello, M.; Carlsson, A.; Stern, G.
Adv. Neurol. 1996, 69, 535–540; (c) Clark, D.; Hjort, S.;
Carlsson, A. J. Neural Transm. 1985, 62, 171–207; (d)
Clark, D.; Hjort, S.; Carlsson, A. J. Neural Transm. 1985,
62, 1–52.
Entry
R
Yield 5 (%)a
Yield 6 (%)a
Yield 1 (%)a
a
b
c
d
e
H
90b
100
97
95
95
100
85
62
63
70
90
2. For recent synthetic work in this area, see: (a) Cervetto,
L.; Demontis, G. C.; Giannaccini, G.; Longoni, B.; Mac-
chia, B.; Macchia, M.; Martinelli, A.; Orlandini, E. J.
Med. Chem. 1998, 41, 4933–4938; (b) Wong, Y.-S.; Mara-
zano, C.; Gnecco, D.; Genisson, Y.; Chiaroni, A.; Das, B.
C. J. Org. Chem. 1997, 62, 729–733; (c) Sonesson, C.; Lin,
C.-H.; Hansson, L. O.; Waters, N.; Svensson, K.;
Carlsson, A.; Smith, M. W.; Wikstro¨m, H. J. Med. Chem.
1994, 37, 2735–2753; (d) Grayson, N. A.; Bowen, W. D.;
Rice, K. C. Heterocycles 1992, 34, 2281–2292; (e) Nilsson,
K.; Hallberg, A. J. Org. Chem. 1992, 57, 4015–4017; (f)
Law, H.; Leclerc, G. A.; Neumeyer, J. L. Tetrahedron:
Asymmetry 1991, 2, 989–992.
3. (a) Larock, R. C.; Gong, W. H.; Baker, B. E. Tetrahedron
Lett. 1989, 30, 2603–2606; (b) Larock, R. C.; Baker, B. E.
Tetrahedron Lett. 1988, 29, 905–908.
4. For current reviews, see: (a) Beletskaya, I. P.; Cheprakov,
A. V. Chem. Rev. 2000, 100, 3009–3066; (b) de Meijere, A.;
Bra¨se, S. J. Organomet. Chem. 1999, 576, 88–110.
5. (a) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem.
Commun. 1998, 633–640; (b) Veith, H. J.; Collas, M.;
Zimmer, R. Liebigs Ann. Recueil 1997, 391–394.
OMe 83c
CN
Me
F
50d
81c
68c
a Isolated yield.
b (a) O3, CH2Cl2, −78°C; (b) LiAlH4, ether, rt.
c (a) O3, MeOH, −78°C; (b) NaBH4, MeOH, rt.
d (a) O3, MeOH, −78°C; (b) NaBH4, MeOH, reflux.
ing as well as electron-donating substituents in the meta
position of the aryl moiety are both tolerated. Using an
enantioselective version of the Heck reaction,6,7 the
absolute configuration of 1 would be controlled as well.
Studies toward the asymmetric synthesis of 1 along
these lines will be reported in due course.
Acknowledgements
Financial support of this work by the BMBF, SMWK,
Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie is gratefully acknowledged.
6. Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Syn-
thesis 1997, 1338–1345.
7. For current reviews, see: (a) Shibasaki, M.; Vogl, E. M. In
Comprehensive Asymmetric Catalysis I–III; Jacobsen, E.
N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin,
1999; Vol. 1, 457–487; (b) Shibasaki, M.; Vogl, E. M. J.
Organomet. Chem. 1999, 576, 1–15; (c) Loiseleur, O.;
Hayashi, M.; Keenan, M.; Schmees, N.; Pfaltz, A. J.
Organomet. Chem. 1999, 576, 16–22.
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