FeCl3-catalyzed highly diastereoselective synthesis of substituted piperidines and tetrahydropyrans

Article abstract of DOI:10.1021/ol100422d

The eco-friendly and highly diastereoselective synthesis of substituted cis-2,6-piperidines and cis-2,6-tetrahydropyrans is described. The key step of this method is the iron-catalyzed thermodynamic equilibration of 2-alkenyl 6-substituted piperidines and 2-alkenyl 6-substituted tetrahydropyrans allowing the isolation of enriched mixtures of the most stable cis-isomers.

Full text of DOI:10.1021/ol100422d

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1808-1811
FeCl3-Catalyzed Highly
Diastereoselective Synthesis of
Substituted Piperidines and
Tetrahydropyrans
Amandine Gue´rinot, Anna Serra-Muns, Christian Gnamm, Charle´lie Bensoussan,
Se´bastien Reymond,* and Janine Cossy*
ESPCI ParisTech, Laboratoire de Chimie Organique, UMR CNRS 7084,
10, Rue Vauquelin, 75231 Paris Cedex 05, France
sebastien.reymond@espci.fr; janine.cossy@espci.fr
Received February 19, 2010
ABSTRACT
The eco-friendly and highly diastereoselective synthesis of substituted cis-2,6-piperidines and cis-2,6-tetrahydropyrans is described. The key
step of this method is the iron-catalyzed thermodynamic equilibration of 2-alkenyl 6-substituted piperidines and 2-alkenyl 6-substituted
tetrahydropyrans allowing the isolation of enriched mixtures of the most stable cis-isomers.
Nitrogen- and oxygen-containing heterocyclic frameworks
are ubiquitous subunits in biologically active products.1-3
Although convenient methods for the construction of sub-
stituted piperidines2 and tetrahydropyrans2b,3 exist, the
development of highly stereoselective and eco-friendly
reactions to access these heterocycles remains a great
challenge.
The metal-catalyzed activation of allylic, propargylic, or
benzylic alcohols is of outstanding importance in organic
synthesis.4–6 Indeed, this process is particularly interesting
from both an atom-economy and eco-friendly point of view
as water is the only byproduct formed when a reaction is
performed in the presence of a nucleophile such as NuH.
Among the different metal salt catalysts used, the low-toxic
and inexpensive FeCl3 is known to activate allylic, propar-
gylic, and benzylic alcohols or acetate derivatives toward
the addition of various nucleophiles such as arenes,7 indoles,8
or active methylene compounds.9 It is worth mentioning
that only a few examples involving nitrogen7b,10 and
oxygen5q,7b,11 nucleophiles have been reported.12
Among the existing methods to form piperidines and
tetrahydropyrans B, the metal-catalyzed cyclization of
ꢀ-amino and ꢀ-hydroxy allylic alcohol derivatives A using
mercury,13 palladium,14 iridium,15 or gold complexes16
is an attractive strategy. Herein, we report that FeCl3 is
able to catalyze the cyclization of allylic substrate A to
produce substituted piperidines (X ) NPG) and tetrahy-
dropyrans (X ) O) B with high diastereoselectivities
(Scheme 1).
(1) Bates, R.; Sa-Ei, K. Tetrahedron 2002, 58, 5957
.
(2) (a) Mitchinson, A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1 2000,
2862. (b) Baliah, V.; Jeyaraman, R.; Chandrasekaran, L. Chem. ReV. 1983,
83, 379. (c) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun.
1998, 633. (d) Laschat, S.; Dickner, T. Synthesis 2000, 1781. (e) Weintraub,
P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59,
2953. (f) Buffat, M. G. P. Tetrahedron 2004, 60, 1701
.
(3) (a) Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045. (b)
Boivin, T. L. B. Tetrahedron 1987, 43, 3309. (c) Larrosa, I.; Romea, P.;
(4) Acid Catalysis in Modern Organic Synthesis; Yamamoto, H.,
Ishihara, K., Eds.; Wiley-VCH: Weinheim, 2008; Vols. 1 and 2.
Urpi, F. Tetrahedron 2008, 64, 2683
.
10.1021/ol100422d  2010 American Chemical Society
Published on Web 03/25/2010

Scheme 1
.
FeCl3-Catalyzed Cyclization of ꢀ-Amino and
Table 1. FeCl3-Catalyzed Synthesis of 2-Alkenylpiperidines
ꢀ-Hydroxy Allylic Alcohol Derivatives (PG ) Protective Group)
entry
PG
R1
R2
1
2
yielda (%)
1
2
3
4
5
6
7
Boc
CBz
Ts
Ts
Ts
Ph
Ph
Ph
Me
H
Ac
Ac
Ac
Ac
Ac
H
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2c
2e
72
65
99
96
61
95
16b
The reactivity of N-protected ꢀ-amino allylic alcohol
derivatives 1a-g (R2 ) H) was examined first (Table 1).
When the N-protected ꢀ-amino allylic acetates 1a-c were
treated with FeCl3·6H2O (5 mol %) in CH2Cl2 at rt, a smooth
and fast reaction took place and the corresponding mono-
substituted piperidines 2a-c were isolated in good to
excellent yields (65-99%).17 The best result was obtained
when the N-tosyl protecting group was used (99% yield)
(Table 1, entry 3).18 The influence of the allylic substituent
R1 on the outcome of the cyclization was then investigated.
Replacing the phenyl substituent with a methyl group such
as in 1d virtually did not affect the reactivity of the substrate
Ts
Ts
Ph
H
H
1g
a Isolated yields. b FeCl3·6H2O (40 mol %), CH2Cl2, rt, 18 h.
as piperidine 2d was obtained in 96% yield (Table 1, entry
4). The strong activating influence of the allylic substituent
became obvious when the latter was completely removed.
Indeed, the yield in piperidine 2e obtained from the cylization
of primary allylic acetate 1e dropped to 61% (Table 1, entry
5). The reactivity of ꢀ-amino allylic alcohols and acetates
was found to be similar; when 1f (R1 ) Ph) was treated
with 5 mol % of FeCl3·6H2O, 2c was isolated in good yield
(95%) (Table 1, entry 6), whereas under the same conditions,
1g was poorly reactive even with 40 mol % of FeCl3·6H2O
(16% yield) (Table 1, entry 7).
(5) For recent examples, see: (a) Georgy, M.; Boucard, V.; Campagne,
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W.; Chan, P. W. H. Org. Biomol. Chem. 2008, 2426. (d) Lu, J.; Muth, E.;
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Rueping, M.; Nachtsheim, B. J.; Kuenkel, A. Org. Lett. 2007, 9, 825. (h)
Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org. Chem. 2006, 71,
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Ueba, M.; Baba, A. Angew. Chem., Int. Ed. 2004, 43, 1414. (l) Yue, Y.;
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G. V. M.; Kumar, K. R.; Sreenivas, P.; Krishna, P. R.; Chorgade, M. S.
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The reaction was generalized concerning N-protected
ꢀ-amino allylic acetates 3a-g in order to access
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T. Tetrahedron Lett. 2002, 43, 8959. (b) Jana, U.; Biswas, S.; Maiti, S.
Eur. J. Org. Chem. 2008, 5798. (c) Yadav, J. S.; Reddy, R. V. S.; Charry,
D. N.; Madavi, C.; Kunwar, A. C. Tetrahedron Lett. 2009, 50, 81. (d) Liu,
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2004, 104, 6217. (f) Nishimoto, Y.; Onishi, Y.; Yasuda, M.; Baba, A.
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3077, and references cited therein. (b) Muzart, J. Tetrahedron 2005, 61,
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A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 11770. (d) Yamashita, Y.;
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Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.; Uemura, S. J. Am.
Chem. Soc. 2002, 124, 11846. (h) Zaitsev, A. B.; Gruber, S.; Pregosin,
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Org. Lett., Vol. 12, No. 8, 2010
1809

2,6-disubstituted piperidines (X ) NPG, R2 * H)19 (Scheme
1), and the results are summarized in Table 2.
cis-isomer. This epimerization can be explained by the
formation of a zwitterion intermediate C (Scheme 2). In
addition, when the optically active acetate (R)-1c was treated
with FeCl3·6H2O, the corresponding piperidine 2c was
obtained as a racemate, thus supporting the hypothesis of a
carbocation intermediate.
Table 2. FeCl3-Catalyzed Synthesis of cis-2,6-Piperidines
Scheme 2
.
FeCl3-Mediated Epimerization of N-Protected
2-Alkenylpiperidines
entry
PG
R
3
4
yieldb (%)
drc
1
2
3
4
5
6
7
8
Ts
Ts
Ts
Ts
Boc
CBz
Ns
Ns
i-Pr
n-C5H13
Me
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
99
70
80
>99/1
97/3
92/8
90/10
>99/1
>99/1
>99/1e
50/50f
Ph
80
i-Pr
i-Pr
i-Pr
i-Pr
66d
66
3g
3g
4g
4g
90e
90f
a Mixture of diastereoisomers. b Isolated yields. c Determined by 1H
NMR. d rt, 6 h. e FeCl3·6H2O (10 mol %), rt, 10 h. f rt, 2 h. Ns )
o-nitrobenzenesulfonyl.
In order to demonstrate the broad scope of this reaction,
the FeCl3-catalyzed heterocyclization process was applied
to ꢀ-hydroxy allylic alcohols and acetates A (X ) O)
(Scheme 1) to form 2,6-disubstituted tetrahydropyrans of type
B.21 Treatment of 5a with FeCl3·6H2O produced the expected
tetrahydropyran 6a in good yield (Table 3, entry 1). In order
to study the diastereoselectivty of the reaction, various
derivatives 5b-h were screened. When substrate 5b bearing
a phenyl group at the allylic position was treated with
FeCl3·6H2O, the corresponding tetrahydropyran 6b was
isolated with an excellent diastereomeric ratio of 97/3 in favor
of the cis-isomer (Table 3, entry 2).22 The reaction is general
as different aryl groups such as phenyl and mesityl (Mes)
can be present at the allylic position, and various alkyl groups
(n-C5H11, i-Pr, Me) or an electron-withdrawing group
(CO2Me) are tolerated as R1 substituent (Table 3, entries
2-6). In all cases, cis-2,6-tetrahydropyrans were obtained
in good yields (up to 82%) and with excellent diastereo-
selectivities (90/10 to 98/2). The change from a phenyl group
to a mesityl group at the allylic position shortened the
reaction time, while similar yields and diastereoselectivities
were obtained (Table 3, entries 3 and 4). Furthermore, the
chiral alcohol (1RS,7R)-5e furnished the optically active
tetrahydropyran (R,R)-6e with excellent diastereoselectivity
and enantiomeric excess (ee >98%, Table 3, entry 5).23
Nonbenzylic secondary and tertiary allylic alcohols such as
5g and 5h are also excellent substrates for synthesizing
cis-2,6-tetrahydropyrans as 6g and 6h were isolated in good
yields and with diastereoselectivities up to 97/3 (Table 3,
entries 7 and 8). It is worth mentioning that the formation
of tetrahydropyran 6h required an additional 5 mol % of
catalyst and 24 h of reaction; after 5.5 h, a poor 52/48 dr
As N-tosyl derivatives previously exhibited the best
reactivity, they were first examined (Table 2, entries 1-4).
The R substituent has a low influence on the cyclization
process as compounds 3a-d were transformed to the
corresponding cis-2,6-piperidines 4a-d in good yields (up
to 80%) and high diastereoselectivities in favor of the cis-
diastereoisomers (cis/trans from 90/10 to 99/1).20 In order
to investigate the influence of the N-protecting group (PG
) Boc, Cbz, Ns) on the diastereoselectivity of the cyclization,
various substrates bearing an isopropyl substituent (R ) i-Pr)
were treated with FeCl3·6H2O (Table 2, entries 5-7). In all
cases, the diastereoselectivity was excellent as the
N-protected cis-2,6-disubstituted piperidines 4e-g were
isolated as a single diastereoisomer (Table 2, entries 5-7).20
However, in the presence of a nosyl group (3g), longer
reaction times and higher catalyst loadings (10 mol %) were
required to reach high diastereoselectivity (dr >99/1) (Table
2, entry 7). Indeed, when 3g was treated with 5 mol % of
FeCl3·6H2O, after 2 h at rt, piperidine 4g was isolated as a
1/1 diastereomeric mixture (Table 2, entry 8). Intrigued by
this last result, a 1/1 mixture of cis-4g and trans-4g was
treated with FeCl3·6H2O (10 mol %), and interestingly,
piperidine cis-4g was isolated as the sole diastereoisomer
after 10 h at rt (dr >99/1). This observation indicates that
epimerization of the piperidine occurs in the presence of
FeCl3·6H2O, leading to the thermodynamically most stable
(18) When the N-benzyl-protected substrate 1 (R1 ) Ph, R2 ) Ac) was
treated with 25 mol % of FeCl3·6H2O at rt in CH2Cl2, no conversion was
observed.
(19) Due to synthetic purposes, N-protected ꢀ-amino allylic acetates were
used in this study rather than the corresponding N-protected ꢀ-amino allylic
alcohols. See the Supporting Information for details.
(20) The cis-relationship for piperidine 4a was unambiguously estab-
lished by X-ray structure analysis. See the Supporting Information for details.
The cis-relationship for piperidines 4b-g was assigned by comparison with
piperidine 4a.
(21) Similar allylic substrates have been previously used for related
cyclizations using Pd, Ir, or Au catalysts; see refs 3c, 15b, and 16.
(22) The cis-relationship was confirmed by NOE experiments for
tetrahydropyrans 6b, 6d, 6g, and 6i.
(23) (1RS,7R)-5e was prepared from the commercially available (R)-
propylene oxide (ee >98%).
1810
Org. Lett., Vol. 12, No. 8, 2010

Table 3. FeCl3-Catalyzed Synthesis of cis-2,6-Tetrahydropyrans
entry
R1
R2, R3, R4
5
6
yieldb (%) (time, h)
drc
1
2
3
4
5
6
7
8
H
Ph, H, H
Ph, H, H
Mes, H, H
Mes, H, H
Mes, H, H
Ph, H, Ac
Me, Me, H
Me, H, H
5a
5b
5c
5d
6a
81 (0.5)
83 (2)
89 (1)
82 (1)
51 (1)
n-C5H13
n-C5H13
i-Pr
6bd
6c
97/3
95/5
95/5
98/2
90/10e
91/9
97/3f
6dd
Me
(1RS,7R)-5e
5f
5g
5h
(R,R)-6e
6f
CO2Et
n-C5H13
n-C5H13
quant (48)e
87 (0.25)
82 (24)f
6gd
6h
a Mixture of diastereoisomers. b Isolated yields. c Determined by 1H NMR or by GC/MS analysis. d 2,6-Cis-relationship confirmed by NOE studies.
e FeCl3·6H2O (15 mol %), rt. f An additional 5 mol % of FeCl3·6H2O was added after 5.5 h when the dr was 52/48.
was observed. The latter result serves to illustrate the
remarkable capacity of FeCl3 to equilibrate 2-alkenyl-6-
alkyltetrahydropyrans.
ingly, spiroketal 6i was formed from the corresponding
hydroxyketone 5i in good yield and with excellent diaste-
reoselectivity (Scheme 3).24,22
In contrast to the Au-catalyzed formation of 2,6-tetrahy-
dropyrans which proceeds through an SN2′ pathway,16a
FeCl3·6H2O is able to catalyze the cyclization of 1,5-
monoallylic diols. Indeed, when 5c′ was treated with
FeCl3·6H2O, tetrahydropyran 6c was obtained with the same
diastereoselectivity as the one obtained from 5c (Scheme 3
and Table 3, entry 3). Additionally, the (E)-configuration of
the double bond of the allylic alcohol in 5d or the (Z)-
configuration in 5d′ has no influence on the cis/trans ratio
of the obtained tetrahydropyran, probably due to the forma-
tion of a carbocation intermediate (Scheme 3).12d,e Interest-
In summary, we have developed an eco-friendly and highly
diastereoselective synthesis of cis-2,6-disubstituted piper-
idines and cis-2,6-disubstituted tetrahydropyrans, which are
valuable building blocks for the synthesis of biologically
active targets. The mild catalytic conditions developed
allowed the use of substrates bearing alkyl or ester groups.
The thermodynamic epimerization of the produced 2-alkenyl
6-substituted piperidines and 2-alkenyl 6-substituted tetrahy-
dropyrans induced by FeCl3 is the key to account for the
high diastereoselectivities observed in favor of the most
stable cis-isomers.
Acknowledgment. The CNRS (grant to A.G.), the Com-
missionat per a Universitats I Recerca del Departament
d’Innovacio´ Universitats I Empresa de la Generalitat de
Catalunya (grant to A.S.-M.), and the Studienstiftung des
deutschen Volkes (grant to C.G.) are gratefully acknowl-
edged. We thank Dr. F. Rominger (University of Heidelberg)
for the X-ray analysis of 4a.
Scheme 3
Supporting Information Available: General procedure
for the heterocyclization reactions, substrate preparation, and
1H and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL100422D
(24) In this case, the equilibration conditions led to the formation of
the most stable spiroketal resulting from double anomeric stabilization.
Org. Lett., Vol. 12, No. 8, 2010
1811