New methodology toward chiral, non-racemic 2,5-cis-substituted piperidines via Suzuki cross-coupling

Article abstract of DOI:10.1021/ol061415d

1,2,3,4-Tetrahydropyridines were halogenated upon treatment with iodine to obtain the desired cross-coupling precursors. Diastereoselective hydrogenation of Suzuki cross-coupling adducts allowed the facile asymmetric synthesis of 2,5-cis-substituted piper

Full text of DOI:10.1021/ol061415d

ORGANIC
LETTERS
2006
Vol. 8, No. 18
3955-3957
New Methodology Toward Chiral,
Non-Racemic 2,5-cis-Substituted
Piperidines via Suzuki Cross-Coupling
Alexandre Larive´e and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received June 9, 2006
ABSTRACT
1,2,3,4-Tetrahydropyridines were halogenated upon treatment with iodine to obtain the desired cross-coupling precursors. Diastereoselective
hydrogenation of Suzuki cross-coupling adducts allowed the facile asymmetric synthesis of 2,5-cis-substituted piperidines in five steps from
readily available pyridine.
Piperidine units are found in many natural products and are
key pharmacophores in several biologically active com-
pounds. Their stereoselective synthesis remains a great
challenge.1,2 During our studies on the enantioselective
synthesis of piperidines with different substitution patterns
from readily available pyridine derivatives,3 we have been
interested in the preparation of the 2,5-cis-substituted adducts.
intermediate in the synthesis of a serotonin receptor agonist
patented by Pfizer.4h
We have previously reported that the addition of organo-
metallic reagents to 3-substituted N-pyridinium imidate salts
bearing an electron-donating group (EDG) resulted in the
(3) (a) Sales, M.; Charette, A. B. Org. Lett. 2005, 7, 5773-5776. (b)
Charette, A. B.; Mathieu, S.; Martel, J. Org. Lett. 2005, 7, 5401-5404. (c)
Lemire, A.; Charette, A. B. Org. Lett. 2005, 7, 2747-2750. (d) Lemire,
A.; Beaudoin, D.; Grenon, M.; Charette, A. B. J. Org. Chem. 2005, 70,
2368-2371. (e) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005,
127, 8966-8967. (f) Lemire, A.; Grenon, M.; Pourashraf, M.; Charette, A.
B. Org. Lett. 2004, 6, 3517-3520. (g) Legault, C. Y.; Charette, A. B. J.
Am. Chem. Soc. 2003, 125, 6360-6361. (h) Charette, A. B.; Grenon, M.;
Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123, 11829-
11830.
(4) For examples of non-natural 2,5-substituted piperidines of interest,
see: (a) Houlihan, W. J. U.S. Patent 3,334,104. (b) Houlihan, W. J. German
Patent, DE 1 964 441 (in German); U.S. Patent 3,709,677. (c) Tilles, H.
French Patent FR 2 095 399 (in French). (d) Balsamo, A.; Barili, P. L.;
Gagliardi, M.; Lapucci, A.; Macchia, B.; Macchia, F.; Bergamaschi, M.
Chim. Ind. 1976, 58, 222-222. (e) Balsamo, A.; Barili, P. L.; Gagliardi,
M.; Lapucci, A.; Macchia, B.; Macchia, F.; Bergamaschi, M. Eur. J. Med.
Chem. 1982, 17, 285-289. (f) Desai, M. C.; Stramiello, L. M. S.
Tetrahedron Lett. 1993, 34, 7685-7688. (g) Macchia, B.; Macchia, M.;
Martinelli, A.; Martinotti, E.; Orlandini, E.; Romagnoli, F.; Scatizzi, R.
Eur. J. Med. Chem. 1997, 32, 231-240. (h) Bright, G. M. World Patent
WO 9952907.
An increasing number of non-natural 2,5-substituted
piperidines has sparked the interest of the scientific com-
munity in the recent years due to their abilities to interact
with adrenergic receptors (1), their anti-inflammatory proper-
ties (3), and their herbicidal activities (3, 4; Figure 1).4,5 For
example, octahydropyrido-1,2-pyrazine 6 is an advanced
(1) For recent reviews on the stereoselective synthesis of piperidines,
see: (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701-1729. (b) Felpin,
F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693-3712. (c) Weintraub,
P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59,
2953-2989.
(2) For recent examples, see: (a) Ijzendoorn, D. R.; Botman, P. N. M.;
Blaauw, R. H. Org. Lett. 2006, 8, 239-242. (b) Zhang, Y.; Liebeskind, L.
S. J. Am. Chem. Soc. 2006, 128, 465-472. (c) Comins, D. L.; Sahn, J. J.
Org. Lett. 2005, 7, 5227-5228. (d) Davis, F. A.; Yang, B. J. Am. Chem.
Soc. 2005, 127, 8398-8407. (e) Ichikawa, E.; Suzuki, M.; Yabu, K.; Albert,
M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 11808-11809.
(f) Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi, T. J. Am. Chem. Soc.
2004, 126, 6240-6241. (g) Ge´nisson, Y. Marazano, C.; Das, B. C. J. Org.
Chem. 1993, 58, 2052-2057.
(5) For examples of recent synthesis of 2,5-substituted piperidines, see:
(a) Gnecco, D.; Marazano, C.; Das, B. C. Chem. Commun. 1991, 625-
626. (b) Varea, T.; Dufour, M.; Micouin, L.; Riche, C.; Chiaroni, A.;
Quirion, J.-C.; Husson, H.-P. Tetrahedron Lett. 1995, 36, 1035-1038. (c)
Kuethe, J. T.; Brooks, C. A.; Comins, D. L. Org. Lett. 2003, 5, 321-323.
10.1021/ol061415d CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/11/2006

Scheme 3. Retrosynthetic Approach to 2,5-Substituted
Piperidines
Figure 1. 2,5-Substituted piperidines of importance.
when the 1,2,3,4-tetrahydropyridines 7 are added over 6 h
to a mixture of iodine and cesium carbonate (Table 1).
highly regioselective formation of 2,3-substituted 1,2-dihy-
dropyridines (Scheme 1).3f
Table 1. Preparation of Vinyl Iodidesa
Scheme 1. Organometallic Reagent Addition to 3-Substituted
Pyridinium Salts
entry
Ar
R1
R2
yield (%)
product
We also reported that, N-imidate 1,2,3,4-tetrahydropyri-
dines can be synthesized in good yields and high diastereo-
selectivities in two steps from chiral pyridinium salts
(Scheme 2).3c We envisioned that their iodination, followed
1
2
3
4
Ph
Ph
Ph
Me
Ph
Me
Me
Me
Me
Bn
Me
80
84
66
73
8a
8b
8c
8d
2-(CH2OTBS)Ph
a 3 equiv of iodine and cesium carbonate were used.
Scheme 2. Preparation of 1,2,3,4-Tetrahydropyridines from
With the vinyl iodide adducts in hand, we turned our
attention to the Suzuki cross-coupling reaction. A screening
of palladium catalysts showed that the commercially avail-
able bis(tri-tert-butylphosphine) palladium complex8 cata-
lyzes the coupling of 1,2,3,4-tetrahydro-5-iodopyridines 8
and aryl boroxins 9 to generate in high yields 2,5-substituted
1,2,3,4-tetrahydropyridines (Table 2).
Chiral Pyridinium Salts
(6) (a) Katayama, S.; Ae, N.; Nagata, R. J. Org. Chem. 2001, 66, 3474-
3483. (b) Petersen, L.; Pedersen, E. B.; Nielsen, C. Synthesis 2001, 559-
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Tetrahedron Lett. 2001, 42, 315-317. (e) Nam, G.; Yoon, C. M.; Kim, E.;
Rhee, C. K.; Kim, J. H.; Shin, J. H.; Kim, S. H. Bioorg. Med. Chem. Lett.
2001, 11, 611-614. (f) Comins, D. L.; Fulp, A. B. Org. Lett. 1999, 1,
1941-1943. (g) Tani, M.; Ikegami, H.; Tashiro, M.; Hiura, T.; Tsukioka,
H.; Kaneko, C.; Notoya, T.; Shimizu, M.; Uchida, M.; Aida, Y.; Yokoyama,
Y.; Murakami, Y. Heterocycles 1992, 34, 2349-2362.
(7) (a) Lavilla, R.; Coll, O.; Kumar, R.; Bosch, J. J. Org. Chem. 1998,
63, 2728-2730. (b) Lavilla, R.; Kumar, R.; Coll, O.; Masdeu, C.; Bosch,
J. Chem. Commun. 1998, 2715-2716. (c) Norton Matos, M.; Afonso, C.
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by their cross-coupling and their diastereoselective reduction,
would afford the 2,5-cis-disubstituted piperidines (Scheme
3).
Halogenation of vinylogous amides and indoles at the 3
position are well-documented and normally straightforward
reactions.5c,6
However, iodination of simple enamines is difficult
because of the higher pKa of the proton to be removed. Under
the reaction conditions, the generated iminium intermediate
can react with a nucleophilic base, the solvent, or dimerize.7
Fortunately, formation of the vinyl iodide 8 proceeds cleanly
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Org. Lett., Vol. 8, No. 18, 2006

tetrahydropyridines 10f and 10d to standard hydrogenation
conditions afforded the corresponding piperidines in a good
ratio of diastereomers favoring the cis isomer (Scheme 4).
Table 2. Suzuki Cross-Coupling with
1,2,3,4-Tetrahydro-5-iodopyridines
Scheme 4. Stereocontrolled Hydrogenation of 5-Substituted
1,2,3,4-Tetrahydropyridines
entry
substrate
R3
yield (%)
product
1
2
3
4
5
6
7
8a
9b
10
11
8a
8a
8a
8b
8b
8b
8b
8b
8b
8c
8d
4-(MeO)Ph (9a)
4-(Cl)Ph (9b)
3,4-(BnO)2Ph (9c)
4-(MeO)Ph (9a)
4-(Cl)Ph (9b)
Ph (9d)
2-(Me)Ph (9e)
4-(NC)Ph (9f)
n-Bu (9g)
92
85
83
85
70
91
80
84
65
97
74
10a
10b
10c
10d
10e
10f
10g
10h
10i
In conclusion, we have developed a new methodology for
the stereoselective synthesis of 2,5-cis-disubstituted piperi-
dines. For example, 11a was synthesized in 5 steps from
pyridine in 57% overall isolated yield demonstrating that the
halogenation of 1,2,3,4-tetrahydropyridines forms a versatile
vinyl iodide intermediate. Previous studies showed that
reduction of amidine in high yields is straighforward.3 The
application of this methodology to the synthesis of biologi-
cally active compounds is under examination and will be
reported in due course.
3,4-(BnO)2Ph (9c)
3,4-(BnO)2Ph (9c)
10j
10k
a CsF was used instead of t-BuOK in this case. b Pd2(dba)3 and
P(t-Bu)2Me were used instead of the Pd(t-Bu3P) complex in this case.
Electron-rich boroxins were efficient coupling partners for
these Suzuki cross-couplings when t-BuOK was used as a
base. However, an improved yield was obtained if the base
was switched to CsF for cross-coupling with boroxins bearing
electron withdrawing substituents (entry 8). Pd2(dba)3 and
P(t-Bu)2Me forms an active complex for the cross-coupling
of alkyl boroxin, as opposed to Pd(P(t-Bu)3)2 which mostly
led to dehalogenation products 7 (entry 9).
Acknowledgment. This work was supported by the
Natural Science and Engineering Research Council of
Canada (NSERC), Merck Frosst Canada & Co., Boehringer
Ingelheim (Canada), Ltd., and the Universite´ de Montre´al.
Conformational analysis of N-imidate tetrahydropyridines
10 indicates that the R1 substituent rests in a pseudo-axial
conformation due to A1,3 allylic strain interactions with the
amidine group. We, therefore, expected this substituent to
shield one face of the cyclic alkene. Gratifyingly, subjecting
Supporting Information Available: Experimental pro-
cedures and data for each reaction. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL061415D
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