Diastereoselective synthesis of 2,3,6-trisubstituted piperidines

Article abstract of DOI:10.1021/jo9003184

(Chemical Equation Presented) We report the diastereoselective and chromatography-free syntheses of four 2-phenyl-6-alkyl-3-aminopiperidines. Ring construction was accomplished through a nitro-Mannich reaction linking a nitroketone and phenylmethanimine,

Full text of DOI:10.1021/jo9003184

Diastereoselective Synthesis of 2,3,6-Trisubstituted Piperidines
John M. Humphrey,* Eric P. Arnold, Thomas A. Chappie, John B. Feltenberger,
Arthur Nagel, Wendy Simon, Melani Suarez-Contreras, Norma J. Tom, and
Brian T. O’Neill*
Pfizer Global Research and DeVelopment, Eastern Point Road, Groton, Connecticut 06340
john.m.humphrey@pfizer.com; brian.t.oneill@pfizer.com
ReceiVed February 12, 2009
We report the diastereoselective and chromatography-free syntheses of four 2-phenyl-6-alkyl-3-
aminopiperidines. Ring construction was accomplished through a nitro-Mannich reaction linking a
nitroketone and phenylmethanimine, followed by a ring-closure condensation. Relative stereocontrol was
achieved between C-2 and C-3 by kinetic protonation of a nitronate or by equilibration of the nitro group
under thermodynamic control. Stereocontrol at C-6 was accomplished by utilizing a variety of imine
reduction methods. The C-2/C-6-cis stereochemistry was established via triacetoxyborohydride iminium
ion reduction, whereas the trans relationship was set either by triethylsilane/TFA acyliminium ion reduction
or by Lewis acid catalyzed imine reduction with lithium aluminum hydride.
Introduction
Variably substituted piperidines are attractive scaffolds pos-
sessing well-characterized geometries dictated by predictable
ring conformations. In addition to providing high stereochemical
definition, extensive arrays of piperidine substitution patterns
are possible in both chiral and achiral formats. Pfizer chemists
exploited this rich piperidine chemistry years ago during work
on NK-1 antagonists, exemplified by the phenylpiperidine CP-
0999945 and the rigidified piperidine, quinuclidine CP-963456
(Scheme 1). These structures possess a cis-2,3-piperidine
scaffold and project a 2-aryl group equatorially and a 3-(2-
methoxy)benzylamine group axially in defining the basic NK-1
pharmacophore. The piperidine ring, apart from the amino
residue, does not appear to be an integral part of the pharma-
cophore but merely serves to present the necessary groups in
the correct orientation for efficient receptor interaction.7,8
In medicinal chemistry the elucidation of structure-activity
relationships can be greatly facilitated through the use of rigid
ligand scaffolds that project key substituents in a stereochemi-
cally defined way. In concert with the inherent binding interac-
tions of the scaffold, the orientation of substituents and the
efficiency of their interaction with individual binding pockets
is partially dependent upon the geometry imparted by the skeletal
framework. However, once the pharmacophore is understood,
new scaffolds can be created to afford ligands of similar or
enhanced affinity.1-4 Whereas increased ligand potency is often
the primary goal of such a study, secondary objectives such as
adjustment of lipohilicity, solubility, and/or blockade of meta-
bolic sites are equally important and ideally target regions of
the molecule that will augment receptor binding.
Insight into the NK-1 pharmacophore presented an op-
portunity to further explore the pharmacological characteristics
of this class of piperidine derivative. Specifically, we were
interested in improving the pharmacokinetic/pharmacodynamic
(1) Lowe, J. A., III.; Drozda, S. E.; Snider, R. M.; Longo, K. P.; Zorn, S. H.;
Morrone, J.; Jackson, E. R.; McLean, S.; Bryce, D. K. J. Med. Chem. 1992, 35,
2591–2600.
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Gohda, Y.; Tsuchiya, M.; Nagahisa, A.; Masami, N.; Lowe, J. A., III. Bioorg.
Med. Chem. Lett. 1998, 8, 281–284.
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351–354.
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D.; Alelyunas, Y.; Russell, D. J.; Potts, W.; Sherwood, S. A.; Lihong, S.; Dedinas,
R. F.; Palmer, W. E.; Russell, K. J. Med. Chem. 2004, 47, 519–529.
(5) Desai, M. C.; Thadeio, P. F.; Lefkowitz, S. L. Tetrahedron Lett. 1993,
34, 5831–5834.
(6) Lowe, J. A., III. Med. Res. ReV. 1996, 16, 527–545.
(7) O’Neill, B. T. US 5521220, 1996.
(8) Humphrey, J. M. Curr. Top. Med. Chem. 2003, 3, 1423–1435.
10.1021/jo9003184 CCC: $40.75
Published on Web 05/14/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4525–4536 4525

Humphrey et al.
SCHEME 1
SCHEME 2
We devised a selective route to the 2,3-cis targets 1 and 2
because this stereochemistry afforded greater receptor affinity
for this class of antagonist. We anticipated that the 2,6-trans
arrangement of alkyl and aromatic residues in 1 would likely
pose the greatest challenge due to conformational and steric
factors (vide infra) but expected that all four possible diaster-
eomers would be accessible from a versatile strategy through
careful choice of reaction conditions and functionality.
(PK/PD) profile by blocking sites of metabolism and by
adjustment of log P. However, any modification to the core
structure that added stereochemical complexity needed to be
balanced by the simplicity of chemical construction for this
approach to be viable. Our target choice coincided with SAR
hypothesis around the influence of position C-6 of the piperidine
ring. We therefore considered various known cyclization strate-
gies (vide infra) which would be facilitated by ring closure onto
the nitrogen atom at this site. Thus, trisubstituted piperidines
of the type 1-4 (Scheme 1) became the primary targets of the
campaign.
Previous work from our laboratories demonstrated that the
nitro group would be an effective surrogate for the C-3 amine
while affording a synthon to aid in ring construction and
adjustment of C-3 stereochemistry.25 Related chemistry prece-
dent included a nitro-Mannich reaction reported by Jain26 and
Desai5 to prepare early members of this series lacking the
6-substituent. According to this method, condensation of ethyl
4-nitrobutanoate with phenylmethanimine (obtained in situ via
condensation of benzaldehyde and ammonium acetate; Scheme
2) afforded lactam 6 in good yield. We reasoned that an
analogous sequence, substituting a ketone (i.e., 7) for the ester,
would provide an intermediate imine (8), which could then be
reduced selectively via precedented methods to give either the
common 2,6-cis or the more challenging 2,6-trans relationship
present in 2 and 1, respectively. Owing to the rich chemistry
offered by the nitro group, we anticipated stereocontrol of the
piperidine 3-position through selective epimerization and/or nitro
group reduction sequences utilizing known methods (vide
infra).25 The cis and trans isomers of 8 would thus constitute
key synthetic intermediates from which we hoped to selectively
access each of the four trisubstituted piperidines 1-4. Addition-
ally, because the variable 6-alkyl group was to be incorporated
in the first step of the synthesis, we needed a route that could
be prosecuted efficiently.
Compounds 1 and 2 possess the 2,3-cis stereochemistry
present in CP-099994 and other potent NK-1 analogues from
the piperidine class. However, SAR from other series demon-
strated that the trans-orientation can provide good activity with
the optimum choice of functionality. Ideally, we wanted a
synthetic route that would provide each diastereomer 1-4
selectively, on large scale, and with minimal chromatography.
A literature search uncovered several synthetic routes to 2,3,6-
trisubstituted piperidines, primarily from the cassine class of
alkaloids (Scheme 1).9-14 However, these compounds lacked
amino and phenyl substituents, and the synthetic routes were
not readily amenable for eventual scale-up. A recent report by
Compain et al. described the diastereoselective synthesis of 2,6-
cis-piperidine derivatives through an iterative process involving
Rh-catalyzed functionalization of C-H bonds.15 Stereocontrol
in the synthesis of 2,6-disubstituted piperidines has been studied,
but its application to more complex piperidines has not been
reported.16-21 Aside from an early Pfizer report on a lengthy,
nonselective route to the 6-methyl derivatives 1a and 2a,22 and
a more recent report from Takemoto et al.23 on the asymmetric
synthesis of the related compound 5, the literature contained
no account of a stereoselective route to each of the diastereomers
1-4.24
(16) Jourdant, A.; Jieping, Z. Heterocycles 2004, 64, 249–259.
(17) Highet, R. J. J. Org. Chem. 1964, 29, 471–474.
(18) Liu, L.-X.; Ruan, Y.-P.; Guo, Z.-Q.; Huang, P.-Q. J. Org. Chem. 2004,
69, 6001–609.
(19) Wang, Q.; Sasaki, N. A. J. Org. Chem. 2004, 69, 4767–4773.
(20) Botman, P. N. M.; Dommerholt, F. J.; deGelder, R.; Broxterman, Q. B.;
Schoemaker, H. E.; Rutjes, F. P. J.; Blaauw, R. H. Org. Lett. 2004, 6, 4941–
4944.
(21) Cassidy, M. P.; Padwa, A. Org. Lett. 2004, 6, 4029–4031.
(22) Desai, M. C.; Rosen, T. J. US 5232929, 1993.
(23) Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y. Chem.
Eur. 2006, 466–476.
(24) Portions of this work were presented by J.M.H. at the 29th Medicinal
Chemistry Symposium of the American Chemical Society in Madison, WI, in
2004, and by T.A.C. at the 228th National Meeting of the American Chemical
Society in Philadelphia, PA, in 2004.
(9) Singh, R. P.; Ghosh, S. Tetrahedron Lett. 2002, 43, 7711–7715.
(10) Toyooka, N.; Yoshida, Y.; Yotsui, Y.; Momose, T. J. Org. Chem. 1999,
64, 4914–4919.
(11) Hasseberg, H. A.; Gerlach, H. Liebigs Ann. Chim. 1989, 3, 255–261.
(12) Brown, E.; Dhal, R. Bull. Soc. Chim. Fr. 1972, 11, 4292–4303.
(13) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem.
2003, 68, 1919–1928.
(14) Makabe, H.; Kong, L. K.; Hirota, M. Org. Lett. 2003, 5, 27–29.
(15) Toumieux, S.; Compain, P.; Martin, O. R. J. Org. Chem. 2008, 73, 2155–
2162.
(25) O’Neill, B. T.; Thadeio, P. F.; Bundesmann, M. W.; Elder, A. M.;
McLean, S.; Bryce, D. K. Tetrahedron 1997, 53, 11121–11140.
(26) Bhagwatheeswaran, H.; Gaur, S. P.; Jain, P. C. Synthesis 1976, 9, 615–
616.
4526 J. Org. Chem. Vol. 74, No. 12, 2009

DiastereoselectiVe Synthesis of 2,3,6-Trisubstituted Piperidines
SCHEME 3
Results and Discussion27
improvements, including an optional one-pot 9-12 conversion,
afforded an efficient two-step procedure for the synthesis of the
crystalline 12-cis/trans (tosylate salt) from ethyl vinyl ketone
as shown in Scheme 3.
We began with the synthesis of 6-nitro-3-hexanone 9 and its
subsequent conversion into the key cyclic imine 12 (Scheme
3). Of several literature reports on the preparation of this ketone,
we chose the original method of Shechter which included
purification of the product by distillation.28-30 The main
drawback to this method was the formation of multiple-addition
side products that were thermally unstable and which could
decompose violently near the end of the distillation process.
After some experimentation, we found that most of the
byproduct could be eliminated by replacing ether with methanol
as the solvent and by conducting the reaction at a low
temperature. Under the new conditions, the desired product was
afforded on a kilogram scale in >90% yield with only small
amounts of undesired 14 detected (∼6%). Since this minor
product did not affect future reactions in this sequence, the
capricious distillation step could be eliminated.
With 12-cis/trans in hand, we considered options for separa-
tion of the isomers. Due to a significantly higher polarity of
the cis isomer, the two could be readily separated by silica gel
chromatography after conversion into the free base imines. This
provided pure material for stereochemical assignment through
both NMR spectroscopy and X-ray crystallography of 12-trans
(tosylate). However, we were still interested in other options
that would facilitate eventual scale-up. We expected that the
12-cis/trans mixture could be equilibrated to the more stable
trans isomer via base-catalyzed epimerization of the nitro group.
This was indeed the case as simple treatment of the mixture
with neat triethylamine gave a 6:1 trans/cis equilibrium ratio
from which the pure isomer 12-trans could be precipitated as
the p-toluenesulfonate salt in 73% yield (Scheme 4).
The nitro-Mannich reaction of intermediate 9 en route to the
formation of the cyclic imine 12 was the next step in the
sequence. Unfortunately, the reaction of 9 with benzaldehy-
de and ammonium acetate in methanol afforded a complex
mixture containing only small quantities (∼10%) of the desired
product. All subsequent attempts to improve this yield by
adjusting reagent stoichiometry and reaction temperature failed.
We concluded from these studies that unrestrained secondary
aldol or Mannich reactions were interfering with the desired
process and that the products of these fast side reactions could
not be funneled into the desired cyclic 12 via thermodynamic
control. With the ketone functionality of 9 a likely participant
in these side reactions, an easy remedy was anticipated via
protection of the ketone as an acetal. In practice, the dimethyl
acetal of 9 (not shown) underwent smooth reaction with 2 equiv
of benzaldehyde in the presence of ammonium acetate to provide
the acyclic benzylimine 13 in ∼60% crystallized yield as a 1:1
mixture of diastereomers (Scheme 3). Subsequent hydrolysis
of the benzylidine and cyclization to yield crystalline 12-cis/
trans (1:1 cis/trans) was easily achieved by treatment with
toluenesulfonic acid (hydrate) in ethyl acetate. Final process
Selective formation of 12-cis posed a greater challenge, which
we hoped to meet using the nitronate anion as a key intermedi-
ate. According to a recent report by Takemoto, protonation of
the related 2-phenyl-3-nitropiperidine selectively afforded the
kinetic cis product in a 95:5 ratio.23 This has been explained
by allylic strain arguments31,32 that predict a pseudoaxial
conformation of the adjacent phenyl group and a preferential
axial approach of a quenching proton from the less hindered
opposite face to produce the kinetic product. Alternative
arguments have been postulated to explain the observed
selectivity in this type of system.33-38 Our early attempts
centered around employment of a bulky proton donor,25,39 but
repeated attempts to effect this strategy with a variety of bases,
acids, and solvents afforded only moderate improvements in
the cis/trans ratio (up to 3:1 cis/trans). However, during these
experiments we made the serendipitous discovery that the
nitronate could be quenched directly onto a silica TLC plate to
(31) Johnson, F.; Malhotra, S. K. J. Am. Chem. Soc. 1965, 87, 5492–5493.
(32) Malhotra, S. K.; Johnson, F. J. Am. Chem. Soc. 1965, 87, 5493–5495.
(33) Zimmerman, H. E.; Mariano, P. S. J. Am. Chem. Soc. 1968, 90, 6091–
6096.
(34) Bordwell, F. G.; Boyle, W. J.; Yee, K.-C. J. Am. Chem. Soc. 1970, 92,
5926–5932.
(27) Throughout this manuscript, the methyl series will be designated by
the suffix “a” following each numerical descriptor. For example, “9” designates
an ethyl analogue, and “9a” designates a methyl analogue.
(28) Shechter, H.; Ley, D. E.; Zeldin, L. J. Am. Chem. Soc. 1952, 74, 3664–
3668.
(29) Lubineau, A.; Auge´, J. Tetrahedron Lett. 1992, 33, 8073–8074.
(30) Ballini, R.; Bosica, G. Tetrahedron Lett. 1996, 37, 8027–8030.
(35) Bordwell, F. G.; Yee, K.-C. J. Am. Chem. Soc. 1970, 92, 5933–5938.
(36) Zimmerman, H. E. J. Org. Chem. 1955, 20, 549–557.
(37) Zimmerman, H. E. Acc. Chem. Res. 1987, 20, 263–268.
(38) Bordwell, F. G.; Yee, K.-C. J. Am. Chem. Soc. 1970, 92, 5939–5944.
(39) Lu¨ning, U.; Baumstark, R.; Mu¨ller, M.; Wangnick, C.; Schillinger, F.
Chem. Ber. 1990, 123, 221–223.
J. Org. Chem. Vol. 74, No. 12, 2009 4527

Humphrey et al.
SCHEME 4
SCHEME 5
acid hydrate in ethyl acetate as was done previously with the
cis/trans 12 mixture. Thus, the selective and scaleable synthesis
of each of the key intermediates 12-cis and 12-trans was
achieved in approximately three easy steps from ethyl vinyl
ketone.
The 2,6-cis-aminopiperidines 2 and 4 were accessed from
12-cis and 12-trans, respectively, as follows. Assuming an
equatorial phenyl group orientation and Fu¨rst-Plattner control
(trans-diaxial addition) for the reduction of 12-cis and 12-trans,
we expected that 2,6-cis stereochemistry would be available via
simple borohydride reduction of the imine (axial approach A,
Scheme 5).43,44 This would be followed by nitro group reduction
to complete the synthesis. In practice, this strategy worked well:
imine reduction gave the expected stereochemical result and
subsequent zinc/HCl reduction afforded the piperidines 2 and
4 from the respective precursors 12-cis and 12-trans in 58%
and 96% yield, respectively, as crystalline ditosylate salts
(Scheme 5). The low yield in the former case was due to a less
efficient crystallization. Stereochemistry was initially assigned
using established predictions of piperidine conformational
provide pure cis isomer as indicated by TLC cospot with
authentic 12-cis. In subsequent experiments, the direct quench
of the nitronate into slurries of silica gel in THF afforded the
cis isomer exclusively. The difficulty in obtaining a majority
of the cis isomer under most conditions in our more function-
alized system (relative to the Takemoto example) might be
ascribed to the internal imine which adds ring strain and basic
character that could elicit equilibration prior to isolation. We
surmised that silica gel may circumvent equilibration in one of
two ways: by mitigating the basicity of the imine, or by
coordination of the nitronate to enhance C-protonation over
nitronate (NO2-) protonation.
While this method was quite suitable for processing quantities
up to 100 g, we were not satisfied that it would be amenable to
large-scale synthesis due to technical difficulties associated with
mixing voluminous slurries of silica gel. In the course of this
work, we noted that product 13 (1:1 syn/anti) readily crystallized
to afford the expected 1:1 mixture of syn and anti isomers.
However, NMR experiments demonstrated that, in the presence
of an equilibration catalyst (NH4OAc), 13-syn was favored
thermodynamically over 13-anti by a 2:1 ratio in methanolic
solution. Further experimentation revealed that stirred slurries
of 13-syn/anti in methanolic NH4OAc yielded syn-isomer
crystals, free of detectable isomeric impurities, within 3 days
(Scheme 4).40,41 This thermodynamically driven crystallization
process42 ultimately provided us with the desired 13-syn on
kilogram scale. The subsequent cyclization of 13-syn to form
12-cis was accomplished via treatment with p-toluenesulfonic
1
preferences and experimentally determined H NMR coupling
constants and was later confirmed by analogy with the X-ray
structure of 34 (Scheme 12).
The remaining two diastereomers 1 and 3, possessing the trans
arrangement of substituents at C2/C6, posed a greater challenge
in requiring the opposite facial selectivity of reduction. With
axial hydride approach heavily favored in this type of imine
system, reversal of selectivity can be realized in some cases
via a “chair flip” induced through complexation of the imine
nitrogen atom with a bulky Lewis acid such as trimethylalu-
minum (Scheme 5).44 As applied to the present system, A1,2-
strain between the nitrogen/Lewis acid complex and the
R-phenyl substituent should favor the flipped chair form which
places the phenyl in the pseudoaxial position. Axial hydride
addition, this time from the same face as the phenyl group,
would afford the “trans” ethyl product (see “axial approach B,”
Scheme 5).44-46
(43) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289–296.
(44) Matsumura, Y.; Maruoka, K.; Yamamoto, H. Tetrahedron Lett. 1982,
1929–1932.
(45) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Permagon Press: Oxford, 1983; pp 209-221.
(46) Kirby, A. J. Stereoelectronic Effects; Oxford University Press: New York,
1996; pp 54-55.
(40) Deuterium enrichment studies in methanol-d4 revealed that equilibration
occurrs by proton exchange at the nitro center rather than through reversal of
the nitro-Mannich process.
(41) The stereochemistry of the syn isomer, including the trans-geometry of
the benzylidine group, was determined by X-ray crystallography.
(42) Brands, K. M. J.; Davies, A. J. Chem. ReV. 2006, 106, 2711–2733.
4528 J. Org. Chem. Vol. 74, No. 12, 2009

DiastereoselectiVe Synthesis of 2,3,6-Trisubstituted Piperidines
SCHEME 6
SCHEME 7
camphorsulfonate salt (Scheme 8). This procedure worked
equally well with the methyl series to provide 22a.
Subsequent treatment of 22 with AlMe3 and LiAlH4 at -78
°C gave the 2,6-trans isomer 23 selectively (10:1) over the 2,6-
cis isomer. On further experimentation, we found that the trans
isomer could be obtained exclusively when the bulkier AlEt3
was used in place of AlMe3. For the methyl imine 22a,
reductions catalyzed by AlMe3 provided a 4:1 trans/cis ratio,
whereas reductions mediated by AlEt3 again provided the trans
isomer 23a exclusively. In each case, the desired 2,6-trans-
piperidine (23 and 23a) was obtained in high yield as a
crystalline p-toluenesulfonate salt.
In practice, a THF solution of 12-cis was pretreated with
trimethylaluminum at -78 °C followed by addition of LiAlH4
according to the method of Yamamoto. The nitro group was
subsequently reduced with zinc/HCl prior to characterization
of the products. Unfortunately, this method produced a disap-
pointing ∼60:40 ratio of the products 1 and 2 (Scheme 6). On
considering successful literature reports from less functionalized
systems, we attributed this poor selectivity to interference of
the nitro group with the action of the Lewis acid. In an effort
to mitigate this effect, we reversed the order of the two-stage
reduction sequence by attempting the zinc/HCl nitro-reduction
first, followed by the Yamamoto reduction protocol. Under these
conditions, we instead obtained a 1:1 stereoisomeric mixture
of the undesired rearrangement product 16 formed via inter-
mediate 15 (Scheme 6). A similar transformation was noted by
Nicolaou et al. during the total synthesis of thiostrepton.47
The AlR3/LiAlH4 reduction was even less successful on scale-
up and afforded significant recovery of starting material. NMR
studies demonstrated that prolonged stirring of the imine 12-
cis with triethylaluminum prior to hydride addition affected
deprotonation of the Lewis acid complex 17 to afford the
unreactive species 18 (Scheme 7). The propensity for imine-
enamine tautomerization was also observed upon dissolution
of the camphorsulfonate imine salt 19 in CD3OD. Rapid proton/
deuterium exchange via the presumed intermediate 20 resulted
in deuterium enrichment at C-5 to provide 21.
An alternative plan to effect the transformation of 12-cis into
1 hinged on removal of the problematic nitro group via the Nef
reaction, with the resultant ketone functionality providing a route
for introduction of the requisite 3-amino group later in the
synthesis (Scheme 8).5 However, this strategy was thwarted by
the instability of 25, which rapidly aromatized to yield the
hydroxypyridine 26. Fortunately, the Nef reaction conducted
in dry methanol provided acetal products that averted aroma-
tization. Thus, a solution of 12-cis/trans in methanol and
trimethylorthoformate was treated at -20 °C with sodium
methoxide followed by quenching into sulfuric acid. The desired
acetal 22 was isolated in 80% yield as a stable crystalline
We then set about reintroduction of the C-3 nitrogen atom
in the required 2,3-cis fashion and planned to accomplish this
via precedented hydrogenation of the oxime 24 (Scheme 8).5
Allylic strain imparted by the oxime group should favor an axial
phenyl conformation and direct the approach of hydrogen to
the opposite face (Scheme 9). This plan was immediately
complicated by the instability of the oxime precursor, ketone
27. Epimerization at C2 gave 28, and air-oxidation gave the
imine 29. Fortunately, both of these side products could be
avoided through a one-pot process involving acetal hydrolysis
in the presence of hydroxylamine. Under these conditions, the
ketone was trapped as the oxime prior to side reaction. In both
the ethyl and methyl series, treatment of the crude product with
p-TsOH provided the crystalline oximes (24 and 24a, respec-
tively) in good yield as a 1:1 mixture of oxime isomers.
Hydrogenation of the methyl-series oxime 24a with freshly
prepared Raney nickel catalyst gave a 12:1 mixture of 1a and
3a (1H NMR), from which isomer 1a was obtained cleanly in
63% yield after a single crystallization. Unfortunately, this
success with the methyl derivative did not carry over to the
ethyl series. Under a variety of conditions, oxime 24 suffered
poor facial selectivity in the hydrogenation. The origins of this
effect remain unexplained but given the unsatisfactory outcome
of several Raney nickel reduction attempts, we shifted focus to
an alternative method under concurrent development.
As stated previously, we could not achieve acceptable 2,6-
trans selectivity in reduction of 12-cis via the Yamamoto
precedent (Scheme 6). We believed this resulted from an
inefficient complexation of the Lewis acid with the imine. To
test this hypothesis, we replaced the transient Lewis acid
complex with a covalently attached urethane group to enhance
imine reactivity and control reduction selectivity. This meth-
odology has been used to accomplish trans-selective reductions
in less functionalized systems as reported independently by
(47) Nicolaou, K. C.; Safina, B. S.; Zak, M.; Lee, S. H.; Nevalainen, M.;
Bella, M.; Estrada, A. A.; Funke, C.; Zecri, F. J.; Bulat, S. J. Am. Chem. Soc.
2005, 127, 11159–11175.
J. Org. Chem. Vol. 74, No. 12, 2009 4529

Humphrey et al.
SCHEME 8
SCHEME 9
SCHEME 11
SCHEME 10
Comins and Jefford (Scheme 10).48,49 According to these
reports, the planar urethane C-N bond induced a conformational
shift that placed the phenyl substituent in an axial position and,
in addition, activated the imine toward stereocontrolled reduction.
Thus, the nitroimine 12-cis was converted into the crystalline
enecarbamate 30 by treatment with benzylchloroformate and
sodium bicarbonate in a methylene chloride/water mixture
(Scheme 11). Efficient stirring was required for this two-phase
reaction mixture to ensure a basic pH in the organic phase and
to prevent formation of significant amounts of the acid-catalyzed
hydrolysis product 31. X-ray crystallography of the correspond-
ing methyl isomer 30a confirmed retention of the cis-configu-
ration and verified a quasi-axial ring orientation of the phenyl
group. Reduction of 30 with triethylsilane and trifluoroacetic
acid provided an 80:20 trans/cis ratio of 32 and 33 from which
the desired trans isomer was obtained cleanly via crystallization
in 72% yield.
SCHEME 12
The 2,6-trans product 32 was converted into the desired
3-aminopiperidine 1 by either of two methods. According to
the first method, the benzylchloroformate group was cleaved
with HBr and the nitro group was reduced by hydrogenation
over Raney nickel to yield the final product 1 in 77% yield. In
the second method, hydrogenation of 32 over palladium at 500
psi provided 1 in a comparable yield in one pot. We were also
gratified to find that chiral resolution of 1 was efficiently
accomplished by crystallization as the dibenzoyl-L-tartarate salt
to give the (2S,3S,6S)-enantiomer in >98% ee.50 No attempt
was made at chiral resolution of isomers 2-4.
(48) Comins, D. L.; Weglarz, M. A. J. Org. Chem. 1991, 56, 2506–2512.
(49) Jefford, C. W.; Wang, J. B. Tetrahedron Lett. 1993, 34, 2911–2914.
4530 J. Org. Chem. Vol. 74, No. 12, 2009

DiastereoselectiVe Synthesis of 2,3,6-Trisubstituted Piperidines
rel-(1S,2S)- and rel-(1S,2R)-Benzylidene-(5,5-dimethoxy-2-nitro-
1-phenylheptyl)amine (13-syn/anti). To 6-nitrohexan-3-one (9) (66.4
g, 457 mmol) in methanol (90 mL) and trimethylorthoformate (90
mL) was added camphorsulfonic acid (5.70 g, 24.7 mmol). After
30 min, a solution of ammonium acetate (75.9 g, 986 mmol) in
methanol (200 mL) was added followed by benzaldehyde (110 g,
1030 mmol). The solution was stirred for 7 h and then seeded to
induce crystallization. The resultant slurry was stirred overnight,
and the crystals were collected and rinsed with 300 mL of cold
methanol to yield 100 g (53%) of an inseparable mixture of 1:1
syn- and anti-benzylidene-(5,5-dimethoxy-2-nitro-1-phenylheptyl)-
With efficient, selective routes to diastereomers 1, 2, and 4
in place, the remaining diastereomer 3 was prepared using
similar chemistry as illustrated in Scheme 12. First, the
carbamate group of the triethylsilane reduction product 32 was
cleaved by treatment with HBr in acetic acid to provide the
piperidine 34 in 85% yield as a crystalline HBr salt. Single-
crystal X-ray analysis of 34 provided definitive confirmation
of stereochemistry. Epimerization of 34 with triethylamine
afforded a 4:1 thermodynamic ratio of isomers favoring the trans
nitro epimer 35 (not shown), and subsequent zinc/HCl reduction
of the nitro group afforded the remaining target piperidine 3
after workup to give a crystalline dibenzoyl-L-tartaric acid salt.
1
amine as a white powder: mp 105-106 °C; H NMR (400 MHz,
CDCl3, δ) 8.31 (s, 1H), 8.21 (s, 1H), 7.78 (m, 1H), 7.72 (m, 1H),
7.30-7.46 (m, 8H), 5.00-5.05 (m, 2H), 4.77 (d, J ) 7.9 Hz, 1H),
4.66 (d, J ) 10.0 Hz, 1H), 3.09 (s, 3H), 3.06 (s, 3H), 3.05 (s, 3H),
2.98 (s, 3H), 2.02 (m, 1H), 1.95-1.80 (comp, 2H), 1.50-1.61
(comp, 9H), 1.41 (q, J ) 7.4 Hz, 2H), 0.75 (t, J ) 7.4 Hz, 3H),
0.66 (t, J ) 7.5 Hz, 3H); MS m/z (ion) 353 (M - OCH3).
Combustion analysis and IR data for the pure syn isomer is provided
below.
Conclusions
Each of the possible diastereomers of the racemic 2-phenyl-
3-amino-6-ethylpiperidines (1-4) were prepared selectively in
four to six steps from ethyl vinyl ketone in routes diverging
from a common tetrahydropyridine intermediate (12). The
methyl isomers, described in part, were prepared via similar
chemistry starting from methyl vinyl ketone. The 2,3-trans and
2,3-cis stereochemical arrangements were established via ther-
modynamic epimerization processes conducted on the cyclic
and acyclic intermediates 12 and 13, respectively. The 2,6-cis
and 2,6-trans arrangements were established through precedented
iminium ion reductions. Compound stereochemistry was deter-
cis/trans-6-Ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahydropyridine p-
Toluenesulfonate (12-cis/trans). To a stirred solution of 1:1 rel-
(1S,2S)- and rel-(1S,2R)-benzylidene-[(1,2-syn)-5,5-dimethoxy-2-
nitro-1-phenylheptyl] amine (13-syn/anti) (100 g, 260 mmol) in
ethyl acetate (300 mL) was added a solution of p-toluenesulfonic
acid hydrate (p-TsOH·H2O) (54.3 g, 286 mmol) and water (4.68
g, 260 mmol) in warm EtOAc (300 mL). The mixture was stirred
at rt overnight, and the resultant precipitate was collected and rinsed
with 250 mL of EtOAc followed by 250 mL of ether to yield 95 g
(90%) of the title compounds as a 1:1 cis/trans mixture: MS m/z
(ion) 233 (M + H). Analytical data for the individual pure isomers
is provided below.
1
mined via H NMR methods and confirmed by single-crystal
X-ray analysis of intermediate 34. With the exception of the
starting nitroketone 9, all products and intermediates are either
crystalline, or form crystalline salts, such that each isomer (1-4)
was prepared selectively without chromatography. An efficient
chiral salt resolution was employed for the resolution of isomer
1 using dibenzoyl-L-tartaric acid. The 2,3-cis isomers 1 and 2
are of particular interest as precursors to potent neurokinin NK-1
antagonists.
trans-6-Ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahydropyridine p-Tol-
uenesulfonate (12-trans). A 1:1 mixture of cis/trans-6-ethyl-3-nitro-
2-phenyl-2,3,4,5-tetrahydropyridine p-toluenesulfonate (12-cis/
trans) (9.97 g, 24.7 mmol) was converted into the free base as
follows: the white powder was stirred vigorously with satd NaHCO3
(50 mL) for 10 min. The mixture was extracted with CHCl3 (2 ×
50 mL), and the extracts were dried via filtration through cotton
and concentrated to give a colorless oil. The oil was dissolved in
triethylamine (15 mL) and kept at rt for 4 h. The triethylamine
was removed via rotary evaporator, and the residue was reconcen-
trated from CHCl3 (2 × 30 mL) to remove residual triethylamine.
The resultant oil comprised a 6:1 trans/cis mixture of isomers by
1H NMR analysis. The oil was then stirred with EtOAc (80 mL)
and treated with a solution of p-TsOH·H2O (4.92 g, 25.9 mmol)
in methanol (20 mL). After being stirred for 40 min, the resultant
precipitate was collected, rinsed with EtOAc, and dried to give
Experimental Section
Active Raney Nickel Catalyst. To 7.0 g of nickel-aluminum
alloy (50/50 wt. %) in 100 mL of water in a 1 L Erlenmeyer flask
was added 14.0 g (350 mmol) of sodium hydroxide. The mixture
was swirled by hand several times over 15-20 min. When foaming
subsided, the mixture was cooled to rt and the solid was collected
by filtration taking care to keep the filter cake moist. The filter
cake was rinsed with 200 mL of water, and the active catalyst was
carefully transferred to a vial and stored under 5 mL of water.
Aliquots were transferred via pipet and weighed as thick aqueous
slurries.
1
7.28 g (73%) of the pure trans isomer according to H NMR and
TLC analysis: mp 169-170 °C; IR (DRIFTS) 2980, 2689, 1683,
1553, 1454, 1436, 1374, 1228, 1209, 1164, 1123, 1029, 1007 cm-1
.
1
A sample was converted into the free base for NMR analysis: H
NMR (400 MHz, CDCl3, δ) 7.34-7.22 (comp, 3H), 7.14 (d, J )
7.0 Hz, 2H), 5.22 (d, J ) 6.2 Hz, 1H), 4.49 (ddd, J ) 8.3, 6.6, 3.7
Hz, 1H), 2.49 (m, 1H), 2.40-2.23 (comp, 4H), 2.13 (m, 1H), 1.47
(t, J ) 7.5 Hz, 3H);13C NMR (DMSO-d6, δ): 195.0, 146.1, 138.5,
134.5, 130.3, 129.8, 128.8, 128.8, 126.2, 82.9, 60.0, 31.4, 27.9,
21.5, 21.0, 10.8; MS m/z (ion) 233 (M + H); HRMS calcd for
C13H17N2O2 M + H 233.1284, obsd 233.1287. Anal. Calcd for
C13H16N2O2 ·p-TsOH: C, 59.39; H, 5.98; N, 6.93. Found: C, 59.34;
H, 6.06; N, 6.86.
cis-6-Ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahydropyridine (12-cis).
To a 1:1 cis/trans-6-ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahydropyri-
dine p-toluenesulfonate (12-cis/trans) (250 mg, 1.07 mmol) in THF
(5 mL) at -78 °C was added LiHMDS (1.07 mL of a 1 M solution
in THF). The solution was stirred for 20 min and was then quenched
directly into a well-stirred mixture of Baker silica gel (40 µM flash
chromatography grade) (2.0 g) in THF (5 mL). The silica gel was
removed via filtration, and the filtrate was concentrated under
6-Nitrohexan-3-one (9). This compound was prepared through
a modification of the literature procedure.28 To ethyl vinyl ketone
(90.1 g, 1280 mmol) in methanol (550 mL) was added nitromethane
(550 mL) at -40 °C as a steady stream of 25% methanolic NaOMe
(84 mL, 386 mmol). The resultant pale yellow slurry was allowed
to warm to rt over 5 h and was stirred overnight. The mixture was
quenched with satd NH4Cl (300 mL) followed by water (250 mL)
and brine (250 mL). The mixture was then extracted with CH2Cl2
(250 mL × 4). The extracts were treated with MgSO4 and
decolorizing carbon for 10 min, filtered, and concentrated to yield
154 g (92%) of a pale yellow liquid that was used without further
1
purification. H NMR (400 MHz, CDCl3, δ): 4.43 (t, J ) 6.6 Hz,
2H), 2.56 (t, J ) 6.6 Hz, 2H), 2.44 (t, J ) 7.5 Hz, 2H), 2.25 (m,
2H), 1.06 (t, J ) 7.5 Hz, 3H).
(50) The absolute stereochemistry of the resolved piperidine was determined
by conversion into the known NK-1 antagonist CP-728663 (D-lactate salt), for
which we subsequently obtained an X-ray crystal structure. See ref 24.
J. Org. Chem. Vol. 74, No. 12, 2009 4531

Humphrey et al.
vacuum to afford 230 mg (92%) of a red-orange oil consisting solely
of the cis isomer. See below for characterization data on this
compound.
MS m/z (ion) 233 (M - OTs); HRMS calcd for C13H17N2O2 M +
H 233.1284, obsd 233.1288.
cis-6-Methyl-3-nitro-2-phenyl-2,3,4,5-tetrahydropyridine p-Tolu-
enesulfonate (12a-cis). To benzylidene[(1,2-syn)-5,5-dimethoxy-2-
nitro-1-phenylhexyl]amine (13a-cis) (47.0 g, 127 mmol) in EtOAc
(200 mL) was added a solution of p-TsOH·H2O (26.5 g, 140 mmol)
in EtOAc (100 mL). The solution was stirred overnight, and the
resultant precipitate was collected via filtration and rinsed with
EtOAc and Et2O to provide 42.2 g (85%) of a white solid: mp
160-162 °C; IR (DRIFTS) 3046, 2968, 2696, 1695, 1557, 1228,
1217, 1165, 1122, 1030, 1006, 814, 681, 570 cm-1. Anal. Calcd
for C12H14N2O2: C, 58.45; H, 5.68; N, 7.17. Found: C, 58.40; H,
5.50; N, 7.05. A sample was converted into the free base by
partitioning between CHCl3 and satd NaHCO3: 1H NMR (400 MHz,
CDCl3, δ) 7.26-7.30 (comp, 3H), 7.08-7.10 (m, 2H), 2.27 (br d,
J ) 5.0 Hz, 1H), 4.91 (ddd, J ) 3.7, 5.4, 9.1 Hz, 1H), 2.62 (dddd,
J ) 1.2, 6.6, 6.6, 19.1 Hz, 1H), 2.37 (dddd, J ) 1.7, 7.5, 7.5, 18.7
Hz, 1H), 2.17-2.27 (m, 1H), 2.14 (s, 3H), 2.06-2.14 (m, 1H);
MS m/z (ion) 219 (M + H); 13C NMR (DMSO-d6, δ) 191.9, 146.1,
138.4, 132.5, 130.3, 129.5, 128.8, 128.5, 126.1, 81.0, 58.6, 29.6,
24.9, 21.4, 18.9; HRMS calcd for C12H15N2O2 M + H 219.1128,
obsd 219.1137.
rel-(1S,2S)-Benzylidene(5,5-dimethoxy-2-nitro-1-phenylheptyl)-
amine (13-syn). To a solution of 6-nitrohexan-3-one (9) (13.9 g,
95.7 mmol) in methanol (28 mL) and trimethylorthoformate (28
mL) was added camphorsulfonic acid (1.11 g, 4.78 mmol). After
30 min, a solution of ammonium acetate (36.9 g, 478 mmol) in
methanol (120 mL) was added followed by benzaldehyde (19.5
1
mL, 191 mmol). A precipitate appeared within 6 h, and H NMR
analysis revealed a 1:1 mixture of syn/anti-benzylidene(5,5-
dimethoxy-2-nitro-1-phenylheptyl)amine isomers. The remaining
slurry was heated to 40 °C for 7 h: 1H analysis of an aliquot revealed
that the crystals were free of detectable isomeric impurities and
that the solution consisted of a mixture of syn and anti isomers.
The slurry was then gradually cooled to rt and stirred for 48 h.
The slurry was finally cooled on ice for 1 h, and the crystals were
collected via filtration to afford 24.3 g (66%) of the title compound
as a white powder: mp 104 °C; IR (DRIFTS) 2967, 1635, 1552,
1452, 1079, 1060, 757, 707 cm-1; 1H NMR (400 MHz, CDCl3, δ)
8.2 (s, 1H), 7.72 (dd, J ) 1.7, 8.3 Hz, 2H), 7.45 (m, 1H), 7.35 (m,
8H), 5.03 (dt, J ) 1.7, 10 Hz, 1H), 4.65 (d, J ) 10 Hz, 1H), 3.04
(s, 3H), 2.98 (s, 3H), 1.85 (m, 1H) 1.5 - 1.6 (comp, 3H), 1.42 (q,
J ) 7.5 Hz, 2H), 0.65 (t, J ) 7.5 Hz, 3H); 13C NMR (DMSO-d6,
δ) 163.5, 138.9, 136.0, 132.0, 129.5, 129.4, 129.0, 128.88, 128.87,
103.0, 93.6, 76.6, 47.7, 28.2, 25.6, 25.2, 8.2; MS m/z (ion) 353 (M
- OCH3). Anal. Calcd for C22H28N2O4: C, 68.73; H, 7.34; N: 7.29.
Found: C, 68.73; H, 7.45; N, 7.25.
rel-(1S,2S)-Benzylidene(5,5-dimethoxy-2-nitro-1-phenylhexyl)-
amine (13a-syn). To a solution of 1-nitropentan-2-one (9a) (55.0 g
420 mmol) in MeOH (150 mL) and trimethyl orthoformate (180
mL) was added camphorsulfonic acid (2.45 g, 21 mmol). After 4 h,
ammonium acetate (80.8 g, 1.05 mol) was added followed by
benzaldehyde (91.2 g, 861 mmol). The mixture was stirred for 36 h
and then was diluted with water (150 mL) followed by (carefully)
satd NaHCO3 (200 mL). The mixture was extracted with chloroform
(2 × 200 mL), and the extracts were dried via filtration through
cotton and concentrated. The resultant oil was dissolved in MeOH
(400 mL) and diluted with water (40 mL). To the mixture was added
ammonium acetate (32.3 g, 420 mmol), which caused an oil to
precipitate. An additional volume of MeOH (135 mL) and water
(15 mL) was added, and the mixture was stirred vigorously for 5
days. The resultant crystalline precipitate was collected via filtration,
rinsed with a solution of 1:10 water/MeOH (150 mL), and dried
under vacuum to provide 88.5 g (57%) of the title compound as a
white powder: mp 71-72 °C; IR (DRIFTS) 2994, 1645, 1549, 1379,
1047, 696 cm-1; 1H NMR (400 MHz, CDCl3, δ) 8.21 (s, 1H), 7.72
(dd, J ) 1.6, 7.8 Hz, 2H), 7.30-7.48 (comp, 8H), 5.05 (ddd, J )
12, 12, 2.5 Hz, 1H), 4.66 (d, J ) 9.5 Hz, 1H), 3.07 (s, 3H), 3.02
(s, 3H), 1.82-2.00 (m, 1H), 1.50-1.60 (comp, 3H), 1.09 (s, 3H);
MS m/z (ion) 307 (M - OCH3).
cis-6-Ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahydropyridine p-Tolu-
enesulfonate (12-cis). To syn-benzylidene[(1,2-syn)-5,5-dimethoxy-
2-nitro-1-phenylheptyl]amine (13-syn) (1.00 g, 2.6 mmol) in EtOAc
(3 mL) was added a solution of p-TsOH·H2O (543 mg, 2.60 mmol)
in EtOAc (3 mL). The solution was stirred at rt overnight. The
resultant slurry was diluted with ether (3 mL), and the solids were
collected via filtration to yield 1.02 g (97%) of the title compound
as a white powder: mp 161-162 °C; IR (DRIFTS) 2924, 2676,
1679, 1551, 1221, 1160, 1031, 680, 564 cm-1; 1H NMR (400 MHz,
CD3OD, δ): 7.66 (d, J ) 8.3 Hz, 2H), 7.43-7.45 (comp, 3H),
7.27-7.30 (m, 2H), 7.20 (d, J ) 7.9 Hz, 2H), 5.59 (d, J ) 5.3 Hz,
1H), 5.42 (app q, J ) 5.8 Hz, 1H), 4.87 (br s, 1H), 3.32 (solvent-
exchangeable, par obsc ddd, J ) 2.1, 6.6, 21.5 Hz, 1H), 3.17
(solvent-exchangeable, dt, J ) 6.6, 21.5 Hz, 1H), 2.88 (ddq, J )
1.7, 1.7, 7.5 Hz, 2H), 2.46 (m, 2H), 2.34 (s, 3H), 1.36 (t, J ) 7.5
Hz, 3H); 13C NMR (DMSO-d6, δ) 195.5, 146.1, 138.5, 132.5, 130.2,
129.5, 128.8, 128.5, 126.1, 81.8, 58.7, 31.4, 27.9, 21.4, 18.8, 11.0;
rel-(2S,3S,6R)-6-Ethyl-2-phenylpiperidin-3-ylamine Hydrochlo-
ride (2). To a slurry of cis-6-ethyl-3-nitro-2-phenyl-2,3,4,5-tetrahy-
dropyridine p-toluenesulfonate (12-cis) (341 mg, 0.844 mmol) in
THF (4 mL) was added a 1 M THF solution of sodium cyanoboro-
hydride (1.69 mmol). The solution was stirred for 40 min and was
then quenched carefully with 6 M HCl (10 mL). To the solution
was added zinc powder (549 mg, 8.44 mmol), and the resultant
mixture was stirred overnight. The resultant colorless solution was
diluted with water (20 mL) and basified by the slow addition of a
1 M NaOH solution. The resultant cloudy mixture was stirred for
30 min and extracted three times with methylene chloride. The
combined extracts were dried via filtration through cotton and
concentrated. The resultant colorless oil was then dissolved in
EtOAc (3 mL) and methanol (1 mL). To the stirred solution was
added a solution of 12 N HCl (155 uL, 1.86 mmol) in methanol (1
mL). After being stirred for 15 min, the solution was diluted with
EtOAc (5 mL), and a precipitate formed within a few minutes. The
mixture was stirred for 2 days, and the resultant crystals were
isolated via filtration to provide 135 mg (58%) of the title
compound: mp 347 °C; IR (DRIFTS) 2942, 2048, 2009, 1613, 1571,
1548, 1528, 1460, 1432, 980, 751, 703 cm-1; 1H NMR (400 MHz,
D2O, δ) 7.35-7.45 (comp, 3H), 7.25 (d, J ) 7.4 Hz, 2H), 4.83 (d,
J ) 3.5 Hz, 1H), 3.98 (ddd, J ) 3.3, 3.3, 3.3 Hz, 1H), 3.29 (m,
1H), 2.02-2.20 (comp, 3H), 1.76 (m, 1H), 1.62 (m, 1H), 1.5 (m,
1H), 0.92 (br t, 3H); MS m/z (relative intensity, ion) 205 (100, M
+ H), 188 (M - NH2, 86). Anal. Calcd for C13H20N2 ·2HCl: C,
56.32; H, 8.00; N, 10.01. Found: C, 56.07; H, 8.10; N, 10.00.
rel-(2S,3S,6R)-6-Methyl-2-phenylpiperidin-3-ylamine Di(p-tolu-
enesulfonate) (2a). To cis-6-methyl-3-nitro-2-phenyl-2,3,4,5-tet-
rahydropyridine hydro-p-toluenesulfonate (12a-cis) (5.10 g, 12.5
mmol) in THF (60 mL) was added NaBH(OAc)3 (5.3 g, 25 mmol).
After 1 h, the mixture was cooled in an ice bath, and 6 M HCl (60
mL) was carefully added followed by zinc powder (4.5 g, 100
mmol). The ice bath was removed, and the solution was stirred
overnight. The solution was then cooled in an ice bath and diluted
with ice-cold 6 M NaOH (170 mL). After 10 min, the mixture was
extracted with CHCl3 (3 × 170 mL). The extracts were dried via
filtration through cotton and concentrated to provide 2.5 g of an
1
oil. H NMR revealed the presence of the desired cis-isomer and
ca. 4% of the 2,6-trans isomer. The material was dissolved in EtOAc
(50 mL), and p-toluenesulfonic acid hydrate (4.75 g, 25 mmol) was
added as a solution in methanol (10 mL). The mixture was stirred
for 2.5 h, and the resultant precipitate was collected via filtration
and rinsed with EtOAc to provide 6.1 g (91%) of the title compound
1
as a single isomer according to H NMR analysis: mp 241-242
1
°C. A sample was converted into the free base for analysis: H
NMR (400 MHz, CDCl3, δ) 7.20-7.38 (comp, 5H), 3.87 (d, J )
4532 J. Org. Chem. Vol. 74, No. 12, 2009

DiastereoselectiVe Synthesis of 2,3,6-Trisubstituted Piperidines
2.1 Hz, 1H), 2.90 (ddd, J ) 3.3, 3.3, 3.3 Hz, 1H), 2.79 (m, 1H),
1.70-1.85 (comp, 2H), 1.25-1.60 (comp, 2H), 1.11 (d, J ) 6.2
Hz, 3H); IR (DRIFTS) 2855, 2585, 1601, 1548, 1452, 1175, 1124,
1034, 1010, 683, 568 cm-1; MS m/z (relative intensity, ion) 191;
HRMS calcd for C12H19N2 M + H 191.1542, obsd 191.1548. Anal.
Calcd for C12H18N2 ·2p-TsOH: C, 58.4; H, 6.32; N, 5.24. Found:
C, 58.34; H, 6.41; N, 5.17.
) 7.8 Hz, 3H), 1.19-1.28 (m, 1H), 1.01 (s, 3H), 0.74 (s, 3H); MS
m/z (relative intensity, ion) 248 (98, M + H), 216 (100, M -
OCH3).
3,3-Dimethoxy-6-methyl-2-phenyl-2,3,4,5-tetrahydropyridine Cam-
phorsulfonate (22a). To trans-6-methyl-3-nitro-2-phenyl-2,3,4,5-
tetrahydropyridine (12a-trans) (30.5 g 74.8 mmol) in methanol (270
mL) at rt was added 49 mL of 25 wt %/wt NaOMe/MeOH solution.
After 15 min, the resultant colorless solution was added rapidly
dropwise over 45 min to an ice-cold solution of H2SO4 (73.3 g,
748 mmol) in MeOH (374 mL) containing trimethyl orthoformate
(39.6 g, 374 mmol). The resultant blue-gray solution was allowed
to warm to rt and was stirred overnight. The near-colorless solution
was then concentrated via rotary evaporator to ca. half it is original
volume and was poured into an ice-cold, stirred solution of Na2CO3
(67.4 g, 636 mmol) in water (700 mL). The mixture was then
extracted with CHCl3 (2 × 250 mL), dried via filtration through
cotton, and concentrated. The resultant oil was dissolved in THF
(40 mL) and cooled to ice-bath temperature. To the stirred solution
was added camphorsulfonic acid (CSA) (17.3 g, 74.8 mmol) as a
solution in THF (40 mL), followed by ether (80 mL). The mixture
was warmed to rt and stirred for 3 h. The crystals were collected
via filtration and rinsed with THF until colorless to yield 29.1 g
(84%) of a white powder: mp 182.8-183.4 °C; IR (DRIFTS) 2958,
2701, 1739, 1686, 1166, 1036 cm-1. A sample was converted into
the free base for NMR analysis by partitioning between satd
rel-(2S,3R,6R)-6-Ethyl-2-phenylpiperidin-3-ylamine Di(p-tolu-
ensulfonate) (4). To a slurry of trans-6-ethyl-3-nitro-2-phenyl-
2,3,4,5-tetrahydropyridine p-toluenesulfonate (12-trans) (6.00 g,
14.9 mmol) in THF (40 mL) was added a 1 M solution of sodium
cyanoborohydride in THF (30 mmol, 30 mL). The mixture was
stirred for 30 min, cooled in an ice bath, and carefully diluted with
6 M HCl (60 mL) added in portions over 20 min. Zinc powder
(6.7 g, 149 mmol) was then added in two portions 5 min apart.
The mixture was warmed to rt and stirred 4 h. The mixture was
cooled in an ice bath and quenched via slow addition of ice-cold 3
M NaOH (140 mL). The resultant milk-white mixture was warmed
to rt for 15 min and filtered through Celite to remove zinc salts.
The filter cake was rinsed with water, and the combined filtrates
were extracted twice with chloroform. The extracts were dried via
filtration through cotton and concentrated to give a 3.02 g (99%)
of a colorless oil. The oil was dissolved in EtOAc (50 mL) and
MeOH (3 mL). To the stirred solution was added p-TsOH·H2O as
a solution in MeOH (10 mL). After the solution was stirred
overnight, the resultant solid was collected via filtration, rinsed
sequentially with EtOAc and ether, and dried to give 7.83 g (96%)
of the title compound as a white powder: mp 311-312 °C; 1H NMR
(400 MHz, D2O, δ) 7.48 (d, J ) 8.3 Hz, 4H), 7.37 (comp, 5H),
7.16 (d, J ) 7.9 Hz, 4H), 4.16 (d, J ) 11.2 Hz, 1H), 3.72 (dt, J )
3.7, 11.6 Hz, 1H), 3.14 (m, 1 H), 2.27-2.10 (comp, 2H), 2.19 (s,
6H), 1.68 (dq, J ) 3.7, 12.9 Hz, 1H), 1.60-1.40 (comp, 3H), 0.78
(t, J ) 7.5 Hz, 3H); 13C NMR (DMSO-d6, δ) 145.4, 139.0, 132.5,
130.1, 130.0, 129.8, 129.0, 126.1, 62.4, 59.5, 49.8, 28.2, 25.7, 21.5,
10.4. Anal. Calcd for C13H20N2 ·2p-TsOH: C, 59.1; H, 6.61; N, 5.11.
Found: C, 59.02; H, 6.61; N, 5.11. A sample was converted into
the free base via neutralization with satd NaHCO3 and extraction
with chloroform: 1H NMR (400 MHz, CDCl3) δ 7.25-7.41 (comp,
5H), 3.21 (d, J ) 9.1 Hz, 1H), 2.75 (m, 1H), 2.54 (m, 1H), 2.02
(m, 1H), 1.76 (m, 1H), 1.46-1.22 (comp, 7H), 0.88 (t, J ) 7.9
Hz, 3H); IR (DRIFTS) 2971, 2731, 1617, 1545, 1174, 1036, 1011,
684 cm-1; MS m/z (relative intensity, ion) 205 (15, M + H), 188
(100, M - NH2); HRMS calc’d for C13H21N2 M + H 205.1699,
obsd 205.1703.
6-Ethyl-3,3-dimethoxy-2-phenyl-2,3,4,5-tetrahydropyridine Cam-
phorsulfonate (22). To a 1:1 mixture of trans- and cis-6-ethyl-3-
nitro-2-phenyl-2,3,4,5-tetrahydropyridine p-toluenesulfonate (12-
cis/trans) (18.8 g, 46.5 mmol) in methanol (150 mL) was added a
25 wt %/wt solution of NaOMe in methanol (30 mL). The solution
was stirred at rt for 5 min and then was added rapidly dropwise to
an ice-cold solution of H2SO4 (45.6 g, 465 mmol) in MeOH (200
mL). The mixture was warmed rt over ∼2 h and stirred overnight.
The mixture was then concentrated under vacuum until a viscous
cloudy oil resulted. The oil was poured carefully into a stirred
solution of ice-cold aqueous Na2CO3 (41.8 g, 394 mmol) in water
(400 mL). The mixture was then extracted with CH2Cl2 (3 × 200
mL), and the combined extracts were dried and concentrated. The
resultant oil was dissolved in a 1:1 solution of ether/EtOAc (100
mL) and cooled in an ice bath. To the stirred solution was added
camphorsulfonic acid (10.7 g, 46.5 mmol) as a solution in 1:1 ether/
EtOAc (100 mL). The mixture was warmed to rt and stirred
overnight. The precipitate was collected via filtration and rinsed
with THF to supply 18.0 g (81%) of the title compound as a white
powder: mp 156-157 °C; 1H NMR (300 MHz, CDCl3, δ)
7.40-7.03 (comp, 3H), 7.20-7.17 (comp, 2H), 5.55 (s, 1H), 3.4
(s, 3H), 3.20 (s, 3H), 3.11 (d, J ) 14.6 Hz, 1H), 3.06-2.96 (comp,
3H), 2.65 (d, J ) 14.6 Hz, 1H), 2.54 (ddd, J ) 4.2 Hz, 12, 15,
1H), 2.38-2.22 (comp, 2H), 2.08-2.16 (m, 1H), 1.98 (t, J ) 3.6
Hz, 1H), 1.73-1.94 (comp, 3H), 1.46 (par obsc m, 1H), 1.44 (t, J
1
NaHCO3 and CDCl3: H NMR (free base) (400 MHz, CDCl3, δ)
7.18-7.31 (comp, 3H), 7.16 (d, J ) 6.7 Hz, 2H), 5.00 (s, 1H),
3.28 (s, 3H), 3.14 (s, 3H), 2.48-2.44 (comp, 2H), 2.11 (s, 3H),
1.88 (ddd, J ) 2.5, 3.7, 6.2 Hz, 1H), 1.65 (ddd, J ) 7.8, 9.9, 13.6
Hz, 1H); 13C NMR (CDCl3, δ) 216.6, 189.4, 133.6, 128.9, 128.7,
128.6, 99.9, 97.6, 61.1, 58.5, 48.9, 48.7, 47.9, 47.3, 43.0, 42.7, 31.5,
27.2, 24.6, 24.0, 21.28, 20.1, 19.9; MS m/z (relative intensity, ion)
202 (M - OCH3); HRMS calcd for C14H20NO2 M + H 234.1488,
obsd 234.1492;. Anal. Calcd for C14H19NO2 ·CSA: C, 61.91; H,
7.58; N, 3.01. Found: C, 61.80; H, 7.74; N, 3.00.
trans-6-Ethyl-3,3-dimethoxy-2-phenylpiperidine (23). The imine
salt 6-ethyl-3,3-dimethoxy-2-phenyl-2,3,4,5-tetrahydropyridine cam-
phorsulfonate (22) (14.1 g, 29.4 mmol) was partitioned between
satd NaHCO3 (1 × 100 mL) and methylene chloride (2 × 100 mL).
The combined organic extracts were dried via filtration through
cotton and concentrated. The resultant oil was dissolved in 40 mL
of THF and cooled to -78 °C. Triethylaluminum (31 mL of a 1 M
solution in hexanes) was added, and the solution was stirred for 10
min. To the solution was then added via cannula over 10 min
LiAlH4 (35.3 mL of a 0.5 M solution in THF), with precooling
along the side of the flask. After 90 min of stirring, the mixture
was quenched carefully via dropwise addition of a 50% satd solution
of sodium potassium tartrate (Rochelle’s salt). When vigorous
bubbling stopped, the mixture was diluted with additional 50% satd
Rochelle’s salt solution (100 mL) and stirred overnight. The mixture
was then diluted with water (100 mL) and extracted once with ether
(50 mL) and once with ethyl acetate (50 mL). The combined
extracts were washed with brine, dried with MgSO4, and cooled in
an ice bath. A 1 M solution of HCl in methanol was added (32
mL), and the solution was concentrated to a thin oil under vacuum.
With stirring, the oil was diluted with ether (150 mL), which
initiated crystallization. The resultant slurry was stirred for 1 h,
and the precipitate was collected via filtration to yield 6.15 g of
the title compound as a white powder. A second crop obtained from
ethyl acetate/methanol provided another 786 mg for a total
1
combined yield of 6.94 g (83%): mp 135-136 °C; H NMR (400
MHz, free base, CDCl3, δ) 7.78 (d, J ) 7.5 Hz, 2H), 7.25-7.40
(comp, 3H), 4.15 (s, 1H), 3.23 (s, 3H), 3.19 (s, 3H), 2.43 (m, 1H),
1.91-2.10 (comp, 2H), 1.68-1.74 (m, 1H), 1.29-1.50 (comp, 3H),
0.89 (t, J ) 7.5 Hz, 3H). MS m/z (ion) 218 (M - OMe).
trans-3,3-Dimethoxy-6-methyl-2-phenylpiperidine Hydrochlo-
ride (23a). 3,3-Dimethoxy-6-methyl-2-phenyl-2,3,4,5-tetrahydro-
pyridine camphorsulfonate (22a) (10.0 g 21.5 mmol) was converted
into the free base by partitioning between satd NaHCO3 and CH2Cl2.
J. Org. Chem. Vol. 74, No. 12, 2009 4533

Humphrey et al.
The organic portion was dried via passage through a cotton plug
and concentrated to a colorless oil. The oil was dissolved in dry
THF (25 mL) and cooled to -78 °C. Triethylaluminum (23.7 mmol,
23.7 mL of a 1.0 M solution in hexanes) was added rapidly
dropwise. After the mixture was stirred for 10 min, LiAlH4 (25.8
mmol of a 1.0 M solution in THF) was added over 15 min with
precooling along the flask side. The solution was stirred for 70
min and quenched via dropwise addition of 100 mL of a 50% satd
Rochelle’s salt solution. The mixture was warmed to rt and stirred
vigorously for 2.5 h. The mixture was then diluted with 50 mL
each of water and brine and extracted sequentially with ether and
ethyl acetate. The combined extracts were washed with brine, dried
with magnesium sulfate, and filtered. The resultant colorless solution
was cooled to 0 °C with stirring, and a solution of 1 M HCl in
methanol (21.5 mL) was added. Cooling and stirring were continued
for 2 h. The resultant slurry was reduced under vacuum to
approximately half the original volume, and the precipitate was
collected via filtration to provide a first crop of 3.33 g (57%). Two
additional crops were obtained from ethyl acetate/ether to provide
another 1.81 g (31%). The mother liquor was washed with satd
NaHCO3, dried, concentrated, and chromatographed to yield another
366 mg of free-base product. This was converted into the
hydrochloride salt and crystallized as above to yield an additional
303 mg (5%) of the title compound for a total combined yield of
5.44 g (93%): mp 197.0-197.6 °C; IR (DRIFTS) 2956, 2704, 2540,
The mixture was then diluted with water, basified carefully with
satd NaHCO3, and extracted with ethyl acetate (2 × 75 mL). The
combined extracts were washed with brine. To the extract was then
added, with stirring, p-toluenesulfonic acid hydrate (7.98 g, 42
mmol) as a solution in 15 mL of methanol. The mixture was stirred
overnight, and the resultant precipitate was collected via filtration,
rinsing with 1:1 ethyl acetate/ether, to provide 12.3 g (78%) of the
title compound as a white powder: mp 186-187 °C; IR (DRIFTS)
3359, 3308, 2990, 2771, 2582, 1616, 1455, 1212, 1175, 1159, 1034,
1
1009, 703, 682, 571 cm-1; H NMR (400 MHz, D2O, δ) (∼1:1
mixture of two geometrical oxime isomers) 7.51 (d, J ) 8.3, 4H),
7.34-7.36 (comp, 6H), 7.28 (m, 4H), 7.16 (d, J ) 8.3, 4H), 5.95
(s, 1H), 5.16 (s, 1 H), 3.53 (m, 1H), 3.37 (m, 1H), 2.99 (dt, J )
16.6, 4.9, 1H), 2.52-2.57 (comp, 2H), 2.39 (m, 1H), 2.19 (s, 6H),
1.90-2.01 (comp, 2H), 1.60 (m, 2H), 1.24 (d, J ) 6.2, 3H), 1.16
(d, J ) 6.2, 3H); MS m/z (ion) 205 (M - pTsO-); HRMS calcd
for C12H17N2O M + H 205.1335, obsd 205.1342. Anal. Calcd for
C12H16N2O·pTsOH: C, 60.62; H, 6.43; N, 7.44. Found: C, 60.47;
H, 6.32; N, 7.36.
rel-(2S,3S,6S)-6-Methyl-2-phenylpiperidin-3-ylamine (1a). rel-
(2S,6S)-6-Methyl-2-phenylpiperidin-3-one oxime p-toluenesulfonate
(24a) (3.59 g, 9.56 mmol) was partitioned between satd NaHCO3
and CH2Cl2. The organic phase was removed, and the aqueous phase
was extracted with CH2Cl2. The combined organic portions were
dried through cotton and concentrated, and the residue was dissolved
in 2 mL of ethyl acetate. To freshly prepared Raney nickel catalyst
(1.8 g of a thick aqueous slurry) in a Parr bottle were added EtOH
(2.5 mL) and the oxime solution utilizing 2.5 mL of EtOH as a
rinse. The mixture was hydrogenated at 45 psi for 8 h. The catalyst
was carefully removed via filtration, and the filter cake was rinsed
with 1:1 ethyl acetate/EtOH. To the filtrate was added 25 mL of 1
M HCl in methanol, and the solution was concentrated. The residue
was dissolved in a warm solution of 1:1 MeOH/EtOH (70 mL),
treated with decolorizing carbon for 15 min, and then filtered
through Celite and concentrated to give an off-white solid. The
solid was then dissolved in a minimal quantity of warm methanol,
diluted with 50 mL of hot EtOAc, and stirred at rt for 4 h. The
resultant precipitate was isolated via filtration rinsing with EtOAc
2473, 1574, 1437, 1416, 1336, 1142, 1111, 1068, 765, 704 cm-1
.
Anal. Calcd for C14H22NO2Cl: C, 61.87; H, 8.16; N, 5.15. Found:
C, 61.60; H, 8.34; N, 5.05. A sample was converted into the free
base for NMR analysis by partitioning between satd NaHCO3 and
1
CDCl3: H NMR (free base, 400 MHz, CDCl3, δ) 7.67 (d, J ) 8
Hz, 2H), 7.29 (app. t, J ) 8 Hz, 2H), 7.24-7.21 (m, 1H), 4.06 (s,
1H), 3.18 (s, 3H), 3.10 (s, 3H), 2.62 (m, 1H), 2.02-1.85 (comp,
3H), 1.60 (m, 1H), 1.28 (m, 1H), 0.98 (d, J ) 6.6 Hz, 3 H); MS
m/z (ion) 204 (M - OMe).
rel-(2S,6S)-6-Ethyl-2-phenylpiperidin-3-one Oxime Hydrochlo-
ride (24). A mixture of trans-6-ethyl-3,3-dimethoxy-2-phenylpip-
eridine 23 (1.00 g, 3.51 mmol) and hydroxylamine hydrochloride
(968 mg, 14.3 mmol) was dissolved in an ice-cold solution of 4 M
HCl (9 mL). The resultant solution was warmed to rt for 1 h, and
the pH was then raised from to ∼2 by the addition of saturated
sodium acetate to accelerate oxime formation. After being stirred
for 30 min, the mixture was basified carefully with NaHCO3, dil-
uted with water, and extracted three times with CH2Cl2. The
combined extracts were dried and concentrated. 1H NMR analysis
revealed the presence of the desired cis and trans oxime isomers
in an approximate 1:1 ratio, along with ca. 7% of a single undesired
epimer. The material was dissolved in ethyl acetate, and a solution
of 12 M HCl (292 uL, 3.5 mmol) in MeOH (1 mL) was added.
The mixture was stirred for 3 h, and the resultant precipitate was
isolated via filtration to provide 455 mg (51%) of a mixture
consisting of the desired cis/trans oximes and the undesired epimer
in a ∼3:3:1 ratio, respectively: mp 187-188 °C. 1H NMR
resonances corresponding to the desired oxime hydrochlorides are
as follows: IR (DRIFTS) 2940, 2639, 2471, 2436, 1583, 1556, 1461,
1439, 1373, 752, 697 cm-1; 1H NMR (400 MHz, D2O, δ) 7.51 (d,
J ) 8.3 Hz, 4H), 7.34-7.36 (comp, 6H), 7.28 (m, 4H), 7.16 (d, J
) 8.3 Hz, 4H), 5.95 (s, 1H), 5.16 (s, 1H), 3.53 (m, 1H), 3.37 (m,
1H), 2.99 (dt, J ) 16.6, 4.9 Hz, 1H), 2.52-2.57 (comp, 2H), 2.39
(m, 1H), 2.19 (s, 6H), 1.90-2.01 (comp, 2H), 1.60 (m, 2H), 1.24
(d, J ) 6.2 Hz,, 3H), 1.16 (d, J ) 6.2 Hz, 3H); MS m/z (ion) 218
(M - HCl); HRMS calcd for C13H19N2O M + H 219.1491, obsd
219.1500. Anal. Calcd for C13H18N2O·HCl: C, 61.29; H, 7.52; N,
11.00. Found: C, 61.20; H, 7.70; N, 10.95.
1
to supply 1.57 g (63%) of a white powder. H NMR revealed the
presence of the title compound 1a as well as ∼8% of the
rel-(2S,3R,6S)-isomer 3a: IR (DRIFTS) 2939, 2835, 2632, 2020,
1611, 1573, 1527, 1501, 1456, 1391, 754, 748, 703 cm-1. A portion
was converted into the free base for NMR analysis: 1H NMR (400
MHz, CDCl3, δ) 7.2-7.4 (comp, 5H), 4.25 (d, J ) 2.5 Hz, 1H),
3.48-3.53 (m, 1H), 3.00-3.03 (m, 1H), 2.01-2.15 (m, 2H),
1.75-1.80 (m, 1H), 1.30-1.40 (m, 1H), 1.28 (d, J ) 6.8 Hz, 3H);
13C NMR (DMSO-d6, δ) 133.2, 129.8, 129.6, 129.0, 54.0, 50.1,
22.9, 21.6, 15.3, 14.5; MS m/z (relative intensity, ion) 191 (76, M
+ H), 174 (100, M - NH2); HRMS calcd for C12H19N2 M + H
191.1542, obsd 191.1538. Anal. Calcd for C12H18N2 ·2HCl·0.25
H2O: C, 53.84; H, 7.72; N, 10.46. Found: C, 53.88; H, 7.80; N,
10.55.
cis-Benzyl 6-Ethyl-3-nitro-2-phenyl-3,4-dihydropyridine-1(2H)-
carboxylate (30). To a solution of cis-6-ethyl-3-nitro-2-phenyl-
2,3,4,5-tetrahydropyridine (12-cis) (404 g, 1.00 mol) in methylene
chloride (1.6 L) was added carefully satd NaHCO3 (2.4 L). To the
vigorously stirred mixture was added rapidly dropwise benzyl
chloroformate (202 g, 1.18 mol). The mixture was heated to reflux
with vigorous stirring for ∼2 h and was then cooled back to rt.
The layers were separated, and the aqueous layer was extracted
with CH2Cl2. The combined organic layers were dried via passage
through a cotton plug and concentrated to an oil. The residue was
diluted with ∼1.5 L of isopropyl ether and stirred in an ice bath
for several hours to induce crystallization. The resultant solids were
collected via filtration to yield 267 g (73%) of the title compound
rel-(2S,6S)-6-Methyl-2-phenylpiperidin-3-one Oxime p-Toluene-
sulfonate (24a). To trans-3,3-dimethoxy-6-methyl-2-phenylpiperi-
dine (23a) was added ice-cold 4 N HCl (60 mL) followed by
hydroxylamine hydrochloride (5.80 g, 84 mmol). The solution was
warmed to rt and stirred for 2.5 h. Ammonium acetate was added
(28.4 g, 369 mmol) to raise the pH and accelerate oxime formation.
1
as a pale yellow powder: mp105-106 °C; H NMR (CDCl3, 400
MHz, δ) 7.4-7.1 (br m, 10H), 6.22 (d, J ) 5 Hz, 1H), 5.25-5.05
(br m, 2H), 4.96 (br t, 1H), 4.90 (m, 1H), 2.8-2.5 (m, 4H), 1.0 (t,
3H); 13C NMR (DMSO-d6, δ) 153.8, 139.8, 136.6, 136.3, 129.3,
4534 J. Org. Chem. Vol. 74, No. 12, 2009

DiastereoselectiVe Synthesis of 2,3,6-Trisubstituted Piperidines
129.12, 129.08, 128.8, 128.6, 127.8, 107.3, 81.3, 68.3, 57.7, 28.0,
23.3, 13.1; MS m/z (ion) 367 (M + H); HRMS calcd for
C21H23N2O4 M + H 367.1652, obsd 367.1648.
Chiral Resolution of 1. A mixture of 1 (1.17 g, 5.7 mmol) and
(-)-dibenzoyltartaric acid (2.05 g, 5.7 mmol) in 2-propanol (30
mL) and water (15 mL) was heated to reflux with stirring. The
solution was allowed to cool to rt with stirring overnight. The
resultant solid was collected via filtration, washed with 2:1
2-propanol/water (6 mL), and dried to yield (2S,3S,6S)-6-ethyl-2-
phenylpiperidin-3-ylamine (1) (1.65 g, 49%) as a white solid in
96% ee as determined by chiral HPLC (chiralpak AD, 5% EtOH,
rel-(2S,3S,6S)-6-Ethyl-3-nitro-2-phenylpiperidine-1-carboxylic Acid
Benzyl Ester (32). To cis-benzyl-6-ethyl-3-nitro-2-phenyl-3,4-
dihydropyridine-1(2H)-carboxylate (30) in methylene chloride (1.8
L) at -30 °C was added triethylsilane (239 mL, 1.50 mol), and
the solution was stirred for 10 min. Trifluoroacetic acid (130 mL,
3.00 mol) was added over 3 h, maintaining an internal temperature
of -25 to -30 °C (Caution! After a brief latency period during
the early part of the TFA addition, the reaction becomes exother-
mic.) The resultant clear yellow solution was stirred for an
additional 5 h at -25 to -30 °C and was finally warmed to rt for
12 h. n-Butanol (880 mL) was added, and the methylene chloride
was removed via distillation under reduced pressure. Ethanol (880
mL) and water (880 mL) were added, and the resultant suspension
was stirred with cooling for several hours. The solids were collected
via filtration, rinsed with 50% aqueous ethanol (100 mL), and dried
under at flow of nitrogen to afford 265 g (72%) of a white solid:
mp 78-79 °C; 1H NMR (400 MHz, CDCl3, δ) 7.08-7.32 (m, 10H),
5.99 (d, J ) 5.1 Hz, 1H), 5.13 (d, J ) 12.4 Hz, 1H), 5.04 (d, J )
12.4 Hz, 1H), 4.97-4.99 (m, 1H), 5.02 (dddd, J ) 5.4, 6.8, 10.2
Hz, 1H), 1.44-2.25 (m, 6H), 0.93 (t, J ) 7.5 Hz, 3H); MS m/z
(ion) 369 (M + H).
1
95% heptane, 0.2% Et2NH): mp 163-164 °C; H NMR (DMSO-
d6, 400 MHz, δ) 7.87 (d, J ) 7.2 Hz, 4H), 7.59 (t, J ) 5.7 Hz,
2H), 7.43 (t, J ) 8.0, 11.6 Hz, 4H), 7.42-7.20 (comp, 5H), 5.59
(s, 2H), 4.19 (d, J ) 1.8 Hz, 1H), 3.25 (br m, 1H), 2.90 (br m,
1H), 1.90 (m, 1H), 1.75 (m, 2H), 1.54 (dq, J ) 7.4, 2H), 1.25 (m,
1H), 0.73 (t, J ) 7.6 Hz, 3H); 13C NMR (DMSO-d6, δ) 169.2,
165.6, 138.8, 133.9, 130.5, 129.9, 129.3, 129.2, 128.4, 127.8, 73.8,
54.2, 53.7, 50.1, 23.5, 22.3, 20.4, 11.4; [R]22 +20.7 (c 4.5,
D
CH3OH).
rel-(2S,3R,6S)-6-Ethyl-3-nitro-2-phenylpiperidine Hydrochloride
(35). rel-(2S,3S,6S)-6-Ethyl-3-nitro-2-phenylpiperidine hydrobro-
mide (34) (1.07 g, 3.40 mmol) was converted into the free base by
partitioning between CH2Cl2 and satd NaHCO3. The organic phase
was dried through a plug of cotton and concentrated. The residual
oil was dissolved in triethylamine (4 mL) for 6.5 h and concentrated.
Residual triethylamine was removed via azeotropic evaporation with
chloroform to yield a colorless oil consisting of the 2,3-trans epimer
rel-(2S,3S,6S)-6-Ethyl-3-nitro-2-phenylpiperidine Hydrobromide
(34). rel-(2S,3S,6S)-6-Ethyl-3-nitro-2-phenylpiperidine-1-carboxylic
acid benzyl ester (32) (40 g, 108 mmol) was dissolved in 80 mL
of 30% HBr in propionic acid at rt with efficient stirring. Rapid
evolution of gas occurred, and the desired product precipitated after
3-5 min. Stirring was continued at rt for 16 h, at which point the
off-white precipitate was collected, washed with ether, and dried
in vacuo to afford 29.0 g (85%) of the title compound as a off-
1
and starting material in a 40:1 ratio, respectively, by H NMR
analysis. The material was dissolved in ethyl acetate (8 mL) and
treated with a slight excess of HCl (added as 935 uL of a 4 N
solution in methanol). The slurry was stirred for 4 days, and the
precipitate was collected via filtration to yield 656 mg (72%) of
the title compound as a white powder: 1H NMR (400 MHz, CDCl3,
δ) 7.4-7.2 (comp, 5 H), 4.63 (ddd, J ) 4.1, 4.2, 8.7 Hz, 1H), 4.33
(d, J ) 8.7 Hz, 1 H), 2.95-2.93 (m, 1H), 2.33-2.26 (m, 1H),
2.21-2.17 (m, 1H), 1.94-1.71 (comp, 2 H), 1.76-1.71 (m, 1 H),
1.62-1.55 (m, 1H), 0.92 (t, J ) 7.5 Hz, 3 H); 1H NMR (400 MHz,
D2O, δ) 7.40 - 7.31 (comp, 5 H), 5.25 (dt, J ) 5.0, 10.4 Hz, 1H),
4.87 (d, J ) 10.0 Hz, 1H), 3.46 (m, 1 H), 2.37 (comp, 2 H),
1.99-1.86 (comp, 4H), 1.75 (m, 1H), 0.86 (t, J ) 7.0 Hz, 3H);
13C NMR (DMSO-d6, δ) 132.9, 130.7, 129.9, 129.5, 85.5, 55.7,
55.0, 24.9, 22.0, 20.8, 11.1; MS m/z (ion) 235 (M + H); HRMS
calcd for C13H19N2O2 M + H 235.1441, obsd 235.1451.
rel-(2S,3R,6S)-6-Ethyl-2-phenylpiperidin-3-ylamine Dihydro-
chloride (3). To a slurry of rel-(2S,3R,6S)-6-ethyl-3-nitro-2-phe-
nylpiperidine (35) (585 mg, 2.17 mmol) in water (5 mL) was added
6 M HCl (10 mL) followed by zinc powder (2.00 g, 30.8 mmol)
added in three portions over 1 h. After being stirred overnight, the
mixture was diluted with water (25 mL) and cooled in an ice bath.
The solution was basified with ice-cold 6 N NaOH and stirred for
15 min. The resultant cloudy mixture was then filtered through
Celite, and the filter cake was rinsed with copious water. The
combined filtrate was extracted three times with chloroform, and
the extracts were dried via filtration through cotton and concentrated.
The resultant oil was dissolved in a solution of ethyl acetate (23
mL) and methanol (7 mL), and a solution of 12 M HCl (380 µL,
4.56 mmol) in methanol (1 mL) was added with stirring. The
mixture was stirred for 2 days, and the precipitate was collected
via filtration and rinsed with ethyl acetate to yield 575 mg (96%)
of the title compound as a white powder: mp 298-300 °C; 1H NMR
(500 MHz, D2O, δ) 7.41-7.34 (comp, 5H), 4.27 (d, J ) 11.2 Hz,
1H), 3.72 (app. dt, J ) 4.1, 11.6 Hz, 1H), 3.48 (m, 1H), 3.14 (s,
amine protons), 2.09-1.79 (comp, 5H), 1.70 (M, 1H), 0.83 (t, J )
7.5 Hz, 3H); 13C NMR (DMSO-d6, δ) 133.2, 130.1, 130.0, 129.7,
55.4, 55.0, 50.7, 23.0, 22.0, 20.5, 10.9; IR (DRIFTS) 3366, 2815,
2724, 2550, 2000, 1655, 1634, 1574, 1538, 1464, 1059, 1018, 700
cm-1; MS m/z (relative intensity, ion) 205 (29, M + H), 188 (100,
M - NH2); HRMS calcd for C13H21N2 M + H 205.1699, obsd
205.1698. Anal. Calcd for C13H22N2Cl2 ·0.75H2O: C, 53.70; H, 8.15;
N, 9.63. Found: C, 53.79; H, 8.34; N, 9.63.
1
white powder: mp 219-220 °C; H NMR (400 MHz, D2O, δ)
7.30-7.19 (br m, 5 H), 5.22 (q, J ) 4.1 Hz, 1H), 4.92 (d, J ) 3.7
Hz, 1 H), 3.65 (br. m.), 2.4-2.3 (m, 1H), 2.28 - 2.17 (m, 1H),
2.9-1.98 (m, 1H), 1.85-1.75 (comp, 2H), 1.66-1.59 (m, 1H), 0.85
(t, 3H); 1H NMR (CD3OD, 400 MHz) δ 7.48-7.43 (m, 5H), 5.27
(q, J ) 8.3 Hz, 1H), 5.10 (d, J ) 3.7 Hz, 1H), 3.71 (br. m, 1H),
2.61-2.51 (m, 1H), 2.32 (app dq, J ) 3.6, 15.6 Hz, 1H), 2.23 (m,
1H), 2.10 (m, 1H), 1.99 (app dq, J ) 3.6, 15.2 Hz, 1H), 1.81 (m,
1H), 1.07 (t, J ) 7.5 Hz, 3H); 13C NMR (DMSO-d6, δ) 133.2,
129.9, 129.4, 128.1, 83.5, 54.3, 53.1, 21.8, 21.3, 19.8, 10.8; IR
(DRIFTS) 2967, 2898, 2755, 2726, 2686, 2624, 1547, 1434, 1406,
1374, 1257, 1130, 697 cm-1; MS m/z (ion) 235 (M + H); HRMS
calcd for C13H19N2O2 M + H 235.1441, obsd 235.1436. Anal. Calcd
for C13H18N2O2 ·HBr: C, 49.54; H, 6.08; N, 8.89. Found: C, 49.48;
H, 6.22; N, 8.80.
rel-(2S,3S,6S)-6-Ethyl-2-phenylpiperidin-3-ylamine (1). Approxi-
mately 1.0 g of commercial Raney nickel was rinsed with deionized
water until the supernatant registered neutral pH. The wet slurry
was then added to a 259 mL Parr Bottle followed by a solution of
rel-(2S,3S,6S)-6-ethyl-3-nitro-2-phenylpiperidine hydrobromide (34)
(1.00 g, 3.18 mmol) in methanol (60 mL). The mixture was
hydrogenated in a Parr shaker at ∼42 psi for 4 h and was then
carefully filtered through Celite and concentrated under vacuum.
The residue was partitioned twice between CH2Cl2 and 1 N NaOH.
The combined organic portions were washed with brine, dried, and
evaporated to afford 470 mg (72%) of the title compound: 1H NMR
(400 MHz, CDCl3) δ 7.4-7.2 (br m, 5 H), 4.05 (d, 1H), 3.0 (br t,
1H), 2.90 (m, 1H), 1.98 (m, 1H), 1.75 (m, 2H), 1.6-1.4 (m, 3H),
0.80 (t, 3H). A sample was converted into the hydrochloride salt
by treatment with an excess of HCl in methanol. The mixture was
concentrated under vacuum and the residue was recrystallized from
methanol/EtOAc: IR (DRIFTS) 2930, 2837, 1614, 1573, 1527,
1
1505, 1456 cm-1; H NMR (D2O) δ 7.59-7.40 (comp, 5H), 4.89
(d, J ) 5.8, 1H), 3.90 (ddd, J ) 7.5, 13.9 Hz, 1H), 3.64-3.49 (m,
1H), 2.24 (m, 1H), 2.16 (m, 2H), 1.67-1.50 (comp, 3H), 0.88 (t,
J ) 7.5 Hz, 3H); MS m/z (ion) 205 (M + H); HRMS calcd for
C13H21N2 M + H 205.1699, obsd 205.1705.
J. Org. Chem. Vol. 74, No. 12, 2009 4535

Humphrey et al.
1
Acknowledgment. We thank Carbogen AMCIS AG, Swit-
zerland, for assistance in running kilogram-scale reactions and
conducting the high-pressure hydrogenation reaction of 32. We
thank Syncom BV Groningen, The Netherlands, for conducting
the chiral salt screen to enable resolution of 1. We thank Jon
Bordner for single-crystal X-ray determination of 12-trans, 13a,
30a, and 34.
Supporting Information Available: H NMR spectra and
crystallographic information files including ORTEP diagrams.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO9003184
4536 J. Org. Chem. Vol. 74, No. 12, 2009