Diastereoselective synthesis of 2-monosubstituted and 2,6-disubstituted piperidines

Article abstract of DOI:10.1055/s-2007-982547

An intramolecular Michael-type reaction, involving β′-amino- α,β-unsaturated ketone is used to prepare 2-mono- and 2,6-disusbtituted piperidines in a diastereoselective manner. This strategy allows an easy access to 2,6-trans-piperidine, starting from eit

Full text of DOI:10.1055/s-2007-982547

LETTER
1613
Diastereoselective Synthesis of 2-Monosubstituted and 2,6-Disubstituted
Piperidines
S
ynthesi
s
s of 2-Mo
a
nosubstitute
b
d and 2,6-D
e
isubstitute
d
l
Piperi
l
dine
s
e Abrunhosa-Thomas, Olivier Roy, Marielle Barra, Tatiana Besset, Pierre Chalard,* Yves Troin*
Laboratoire de Chimie des Hétérocycles et des Glucides, EA 987, Ecole Nationale Supérieure de Chimie de Clermont-Ferrand,
Université Blaise Pascal, BP 187, 63174 Aubière Cedex, France
Fax +33(4)73407008; E-mail: Yves.Troin@chimie.univ-bpclermont.fr
Received 15 March 2007
Conjugate addition of (R)-N-benzyl-N-methylbenzyl-
amide (1) to a,b-unsaturated esters 2 led to a wide range
of b-aminoesters 3 with high diastereoselectivity.5 Subse-
quent transformation of ester function to Weinreb amide6
followed by changing the nitrogen protective group to a
carbamate furnished the key intermediate 4 which could
be further alkylated with Grignard reagents to give com-
pounds 5. The 1,3-aminoketal 6 necessary for the forma-
tion of the piperidine is then obtained in a good yield and
a high enantiomeric excess after two steps: deprotection
of the carbonyl group with ethylene glycol in the presence
of p-TsOH and trimethyl orthoformate, following by hy-
drogenolysis of the benzyl carbamate. The deprotection of
the nitrogen atom was performed with ammonium for-
mate and palladium on charcoal. Our attention was next
focused on the use of unsaturated Grignard reagents in or-
der to generate new Michael acceptors which could allow,
in an intra- or intermolecular process,7 the introduction of
a new nucleophile. So, use of vinylmagnesium bromide
on Weinreb amide 4a (R1 = Ph) gave a mixture of the
desired b¢-amino-a,b-unsaturated ketone 7 (60% yield)
and the b,b¢-diaminoketone 8, byproduct obtained by a
sequential transformation–nucleophilic substitution–
Michael reaction of N,O-dimethylhydroxylamine
(Scheme 2).8
Abstract: An intramolecular Michael-type reaction, involving b¢-
amino-a,b-unsaturated ketone is used to prepare 2-mono- and 2,6-
disusbtituted piperidines in a diastereoselective manner. This
strategy allows an easy access to 2,6-trans-piperidine, starting from
either E- or Z-olefin configuration.
Key words: piperidines, intramolecular Michael reaction, diaste-
reoselectivity
Previous investigations from our laboratory1 have shown
that intramolecular Mannich-type cyclisation2 between an
aldehyde and a b-aminoketal offers an efficient route to
the diastereoselective preparation of 2,6-cis-disubstituted
piperidines, which are very useful synthons for alkaloid
synthesis.3 In order to generalize this strategy, it was
essential to work out an efficient preparation of enantio-
merically pure 1,3-aminoketals. Last year, our laboratory
has developed a successful approach to this target
(Scheme 1).4
Li
Ph
N
Ph
O
Ph
NBn O
3 steps
1
R1
OMe
R1
OMe
2
3a,b,c
2a R1 = Ph
de > 92%
CBz
Ph
CBz
CBz
Ph
2b R1 = n-Pr
2c R1 = n-Bu
NH
O
NH
O
NH
O
MgBr
THF
+
Me
Ph
N
0 °C
CBz
Me
OMe
CBz
NH
O
N
NH
O
R2CH2MgBr
OMe
2 steps
Me
R1
R1
N
4a
7
8
R2
OMe
isolated yield:
60%
10%
4a,b,c
5a,b,c
R2 = H, Me, Ph, n-Pr
Scheme 2
O
O
H2N
O
O
This unexpected reaction has already been reported by F.
Davis and coworkers9 who recommended to hydrolyze
the reaction mixture under acidic conditions at low
temperature, in order to increase the ratio of the Michael
acceptor adduct. Unfortunately, even under these condi-
tions, formation of a low amount of byproduct 8 was still
observed. However, a,b-unsaturated ketone 7 was a good
synthon for the diastereoselective preparation of 2-mono-
substituted piperidine, involving an intramolecular
Michael reaction. Subsequent treatment of 7 with
BF3·OEt2 in anhydrous dichloromethane gave the corre-
R1
R2
N
R1
R2
6
H
ee > 90%
Scheme 1
SYNLETT 2007, No. 10, pp 1613–1615
Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-982547; Art ID: G07707ST
© Georg Thieme Verlag Stuttgart · New York
1
8
.0
6
.2
0
07

1614
I. Abrunhosa-Thomas et al.
LETTER
sponding 4-piperidinone 9, albeit in poor yield. This This result showed that no racemization occurred during
intramolecular Michael reaction can also be achieved by the entire sequence, and this prompted us to test the addi-
using ethylene glycol in the presence of trimethylortho- tion of crotylmagnesium bromide on amide 4a in order to
formate as a water scavenger, to give, in a one-pot proce- prepare 2,6-disubstituted piperidines. The same protocol
dure, excellent conversion into the piperidine 10, in which (vide supra) was used to carry out a separable mixture of
the carbonyl function is protected as a ketal (Scheme 3).
diastereoisomers (E)-15 and (Z)-15 in 62% and 20%, re-
spectively (Scheme 5). Subsequent reactions could be
conducted either separately on each isomer or on the mix-
ture of the two diastereoisomers. Treatment of (E)-15 with
ethylene glycol and trimethylorthoformate gave quantita-
tively a mixture of trans- and cis-N-protected 2,6-disub-
stituted piperidines 16a and 16b in a 9:1 ratio. The same
ratio was obtained when (Z)-15 was used. To prevent any
deprotection, more stable compounds were required. This
mixture of two diastereoisomers 16a and 16b were con-
verted into the corresponding N-deprotected thioketals
17a and 17b by action of ethanedithiol in the presence of
BF3·OEt2. Careful separation of each isomer by silica gel
chromatography led to 17a and 17b in, respectively, 60%
and 10% yield. The relative configuration of methyl and
phenyl group in the two diastereoisomers have been as-
signed by NMR particularly with the signals correspond-
ing to H-5 and H-3 (axial and equatorial) on the piperidine
ring, showing typical coupling constants for a 2,6-trans-
or a 2,6-cis-conformation.
O
Ph
N
Ph
N
H2
Cl
BF3·OEt2
CH2Cl2
CBz
9
12
25
[α]D –0.8
30%
CBz
Ph
(c 1.2 in MeOH)
NH
O
25
lit.13 [α]D –3.1
8
W2 Raney Ni
EtOH
96%
p-TsOH
(CH2OH)2
CH(OMe)3
56%
S
O
O
HS(CH2)2SH
BF3·OEt2
S
73%
Ph
N
Ph
N
H
CBz
11
10
Scheme 3
CBz
CBz
Ph
CBz
NH
O
Finally, the treatment of piperidine 10 with an excess of
ethanedithiol in dichloromethane in the presence of
BF3·OEt2 allowed the deprotection of the nitrogen group10
and gave the corresponding dithiolane derivative 11 in
73% yield. Thioketal 11 was converted into 2-phenyl-
piperidine hydrochloride 12 after hydrogenolysis realized
in the presence of freshly prepared W2 Raney nickel11 in
refluxing ethanol, followed by a treatment with hydro-
chloric acid in diethyl ether.12 Comparison of the specific
rotation of 12 with those reported in the literature13
showed that partial racemization occurs during the de-
sulfurization step, probably due to a retro-Mannich-type
reaction. In order to circumvent this problem, we decided
to protect the nitrogen atom with a tert-butoxycarbonyl
group to decrease its nucleophilicity (Scheme 4). Thus,
treatment of piperidine 11 with di-tert-butyl dicarbonate
in dichloromethane and cleavage of the thioketal group
(W2 Raney nickel) led to the N-protected piperidine 14 in
76% yield. The specific rotation of this protected
piperidine 14 was in agrement with those reported in the
literature.14
NH
O
NH
O
MgBr
THF
Me
+
Ph
N
Ph
OMe
0 °C
82%
(Z)-15
(E)-15
4a
3:1
p-TsOH
CBz
Ph
O
O
O
O
(CH2OH)2
CH(OMe)3
NH
O
+
quant.
Ph
N
Me
Ph
N
Me
CBz
CBz
(Z)-15 or (E)-15
or (Z)-15 + (E)-15
16a
16b
9:1
S
S
S
S
HS(CH2)2SH
BF3·OEt2
16a + 16b
+
70%
Ph
N
Me
Ph
N
Me
9:1
H
H
17b
17a
9:1
25
25
[α]D –2.0
[α]D +9.1
(c 2.30 in CHCl3)
(c 1.20 in CHCl3)
25
lit.15[α]D –1.9
(Boc)2O
DMAP
S
S
S
S
W2 Raney Ni
EtOH
Scheme 5
CH2Cl2
quant.
76%
N
Ph
Ph
N
H
N
Ph
Effectively, on the 2,6-cis-diastereoisomer 17b, the phen-
yl and the methyl group were both in equatorial position
and subsequently the signal of axial H-5 was a doublet of
Boc
Boc
13
11
14
[α]D25 +80.8
(c 0.95 in CHCl3)
lit.14 +83.7
doublet with two coupling constants of 13Hz (JH5a–H5e
)
and 11 Hz (JH5a–H6a). In the case of 17a, axial H-5 also ap-
peared as a doublet of doublet with two coupling constant
Scheme 4
Synlett 2007, No. 10, 1613–1615 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Monosubstituted and 2,6-Disubstituted Piperidines
1615
of 14 Hz (JH5a–H5e) and 5 Hz (JH5a–H6e). This small value of complex structures starting from b¢-amino-a,b-unsaturat-
the coupling constant between axial H-5 and H-6 clearly ed ketone using intermolecular hetero-Michael addition.
proved the equatorial position of H-6 and consequently This approach is currently in progress and will be pro-
the axial position of the methyl group. The specific rota- posed in due course.
tion and spectral data of 17b were consistent with those
reported.15
Acknowledgment
We thank the Ministère de la Jeunesse, de l’Education Nationale et
de la Recherche for financial support.
N
H
Me
Ph
W2 Raney Ni
EtOH
18a
References
S
S
[α]D25 –2.8
60%
(1) Ciblat, S.; Calinaud, P.; Canet, J.-L.; Troin, Y. J. Chem. Soc.,
Perkin Trans. 1 2000, 353.
(2) (a) Rougnon Glasson, S.; Tratrat, C.; Canet, J.-L.; Chalard,
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(3) For successful application of our methodology in
indolizidine alkaloid enantioselective synthesis, see: Davis,
F. A.; Yang, B. Org. Lett. 2003, 5, 5011.
(c 1.04 in CHCl3)
lit.15 [α]D25 –21.0
N
H
Me
Ph
17a
70%
(Boc)2O
DMAP
1. W2 Raney Ni
EtOH
2. TFA
CH2Cl2
CH2Cl2
S
S
(4) Bariau, A.; Canet, J.-L.; Chalard, P.; Troin, Y. Tetrahedron:
Asymmetry 2005, 16, 3650.
(5) Davies, S. G.; Brackenridge, I.; Fenwick, D. R.; Ichihara, O.;
Polywka, M. E. C. Tetrahedron 1999, 55, 533; and
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(6) (a) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15.
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68%
N
H
Me
Ph
N
Me
Ph
Boc
19
18b
25
25
[α]D –31.3
(c 1.07 in CHCl3)
[α]D –37.2
(c 1.02 in CHCl3)
lit.16 [α]D
–33.4
25
(7) (a) Bartoli, G.; Bartolacci, M.; Giulani, A.; Marcantoni, E.;
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Scheme 6
Treatment of 17a with W2 Raney nickel in ethanol led to
the 2,6-cis-disubstituted piperidine 18a with extensive
racemization (Scheme 6). This epimerization process
seemed to confirm the retro-Mannich-type reaction ob-
served in the synthesis of 2-monosubstituted piperidine.
Additional control experiments are currently in progress
to prove this assertion. On the other hand, treatment of
piperidine 17a with di-tert-butyl dicarbonate in dichlo-
romethane in the presence of DMAP led to compound 19
in 70% yield. To provide the desired trans-disubstituted
piperidine 18b, the thioketal was next cleaved by W2
Raney nickel followed by deprotection of the nitrogen
atom using trifluoroacetic acid with a good yield. Spectral
data and specific rotation of 18b were in all agreement
with those reported in the literature.16
(8) Gomtsyan, A. Org. Lett. 2000, 2, 11.
(9) Davis, F. A.; Nolt, M. B.; Wu, Y.; Prasad, K. R.; Li, D.;
Yang, B.; Bowen, K.; Lee, S. H.; Eardley, J. H. J. Org.
Chem. 2005, 70, 2184.
(10) Bose, D. S.; Thurston, D. E. Tetrahedron Lett. 1990, 31,
6903.
(11) Augustine, R. L. In Catalytic Hydrogenation; M. Dekker,
Inc.: New York, 1965, 23.
(12) Ciblat, S.; Besse, P.; Papastergiou, V.; Veschambre, H.;
Canet, J.-L.; Troin, Y. Tetrahedron: Asymmetry 2000, 11,
2221.
(13) Burke, A. J.; Davies, S. G.; Garner, A. C.; McCarthy, T. D.;
Roberts, P. M.; Smith, A. D.; Rodriguez-Sola, H.; Vickers,
R. Org. Biomol. Chem. 2004, 2, 1387; and references cited
therein.
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Ohmiya, S.; Takahashi, H. Tetrahedron 1998, 54, 13955.
In summary, a new protocol for diastereoselective forma-
tion of 2-substituted and 2,6-disubstituted piperidines is
reported. Work is currently in progress to determine the
mechanism of cyclization process in order to explain the
diastereoselective formation of trans adduct starting from
either E- or Z-olefins. Our attention is also turned, on the
extension of this strategy, to the preparation of more
Synlett 2007, No. 10, 1613–1615 © Thieme Stuttgart · New York

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