Fast and efficient access to a family of multifunctional 1,3,5-trisubstituted piperidines

Article abstract of DOI:10.1080/00397910701877608

A collection of new 1,3,5-trisubstituted piperidines has been synthesized starting from the commercially available 5-bromonicotinic acid. A unified, diastereoselective strategy allows the controlled access to both cis and trans stereochemistries. The heterocyclic compounds thus prepared bear multiple functional groups suitable for structural diversification and combichem protocols. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701877608

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Fast and Efficient Access to a
Family of Multifunctional 1,3,5-
Trisubstituted Piperidines
José Luis Díaz a , Dolors Fernández-Forner b , Jordi
Bach b & Rodolfo Lavilla a
a Institute for Research in Biomedicine, Barcelona,
Spain
b Department of Medicinal Chemistry, Laboratorios
Almirall, Barcelona, Spain
Version of record first published: 25 Aug 2010.
To cite this article: José Luis Díaz, Dolors Fernández-Forner, Jordi Bach & Rodolfo
Lavilla (2008): Fast and Efficient Access to a Family of Multifunctional 1,3,5-
Trisubstituted Piperidines, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:16, 2799-2813
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Synthetic Communications1, 38: 2799–2813, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701877608
Fast and Efficient Access to a Family of
Multifunctional 1,3,5-Trisubstituted Piperidines
1
Jose Luis Dıaz, Dolors Fernandez-Forner, Jordi Bach, and
2
2
´
´
ꢀ
Rodolfo Lavilla1
1Institute for Research in Biomedicine, Barcelona, Spain
2Department of Medicinal Chemistry, Laboratorios Almirall, Barcelona, Spain
Abstract: A collection of new 1,3,5-trisubstituted piperidines has been synthe-
sized starting from the commercially available 5-bromonicotinic acid. A unified,
diastereoselective strategy allows the controlled access to both cis and trans
stereochemistries. The heterocyclic compounds thus prepared bear multiple func-
tional groups suitable for structural diversification and combichem protocols.
Keywords: Piperidines, protecting groups, pyridines, scaffolds, stereoselective
synthesis
INTRODUCTION
The potential for structural diversification offered by combinatorial
methods may reach higher levels if new scaffolds are contemplated,
especially when orthogonal protection and automated protocols are com-
patible with the chemical methodology. This is particularly important in
medicinal chemistry, where the classical scaffolds have suffered almost
exhaustive exploitation. On the other hand, the use of privileged struc-
tures[1] greatly increases the chances of finding bioactive compounds.
In this context, we envisaged the practical access to a collection of 5-
arylnipecotic acid derivatives as new scaffolds for combinatorial chemistry.
There is a limited number of approaches suitable for the preparation
of 3,5-disubstituted piperidines.[2,3] We planned the synthesis of the
Received October 26, 2007
Address correspondence to Rodolfo Lavilla, Institute for Research in Biomedi-
cine, Barcelona Science Park, Josep Samitier, 1-5, 08028 Barcelona, Spain.
E-mail: rlavilla@pcb.ub.es
2799

´
J. L. Dıaz et al.
2800
Figure 1. Retrosynthesis of the 1,3,5-trisubstituted piperidine targets.
required compounds starting from the commercially available 5-
bromonicotinic acid, 1. The key reactions would involve the aryl moiety
introduction (through a Pd-mediated coupling), reduction of the pyridine
ring, functional group transformations (affecting the carboxylic acid),
and protective group chemistry (NH and=or other functionalities) as
outlined in Fig. 1. The stereochemical control would arise as the result
of a thermodynamic epimerization at the carbonyl a-position.
RESULTS AND DISCUSSION
According to Scheme 1, the methyl 5-bromonicotinate was obtained from
the acid 1 (SOCl2 and then MeOH) in 96% yield. The Suzuki coupling [4]
was achieved following a previously described procedure,[5] using
Pd(PPh3)4 and PhB(OH)2 in an aqueous Na2CO3 solution. The 5-
arylnicotinate 2 can be conveniently obtained (89%). Using Jeffery
(phosphine-free) conditions (K3PO4, Bu4NþBrꢀ, DMF),[6] 2 was
isolated in 64% yield.
Reduction of the pyridine ring was achieved by hydrogenation over a
mixture of catalysts consisting of Pd=C and PtO2 in AcOH at room tem-
perature and atmospheric pressure. In this way, a stereoisomeric mixture
of piperidines 3a,b (cis=trans 1:2) was obtained in 90% yield. Unexpect-
edly, overreduction on the aryl substituent was also observed in 5–10%.
Attempts of reduction using only the Adam’s catalyst in AcOH or
aqueous HCl (in the absence of palladium) yielded the cyclohexyl-type
products (4a,b, 90%) as the major components of the crude mixture.
Base-promoted epimerization of the 3a,b mixture (tBuOK=MeOH)
(4c) afforded a useful cis=trans 5:1 ratio of epimers. MMF94 and semiem-
pirical AM1 calculations show the cis epimer being around 2 kcal=mol
more stable than the trans epimer. Diequatorial disposition of the substi-
tuents on the former (confirmed by NMR spectroscopic analysis of
related derivatives) seems to be in good agreement with the theoretical
predictions. 5-Arylnipecotic acid is obtained sometimes as a minor
by-product, but it can be recovered carrying out a Fischer esterification

Multifunctional 1,3,5-Trisubstituted Piperidines
2801
Scheme 1. Reagents and conditions: (a) SOCl2, 85 ꢁC and then MeOH, CH2Cl2
60 ꢁC (96%); (b) Pd(PPh3)4, PhB(OH)2, toluene, MeOH, Na2CO3 2 M, 80 ꢁC
(89%); (c) H2, Pd=C, PtO2, AcOH, rt, 1 atm (90%); (d) KtBuO, MeOH,
60 ꢁC; (e) LiAlH4, THF, rt (85%); (f) H2O reflux (96%) and then FmocCl,
Na2CO3, dioxane, 0 ꢁC to rt (85%); (g) NH3-MeOH, KCN, sealed tube,
100 ꢁC (79%); (h) LiAlH4, THF (80%); (i) Boc2O, THF, NaHCO3, rt (99%);
(j) Boc2O, CH2Cl2, Et3N, rt, and then NaOH 10%, MeOH, rt (90%, two steps);
(k) DPPA, Et3N, benzene, and then PhCH2OH, 80 ꢁC (65%); (l) H2, Pd=C,
MeOH, rt, 1 atm (90%).

´
J. L. Dıaz et al.
2802
Figure 2. Diagnostic features for the stereochemical assignment.
(MeOH, H2SO4). The chromatographic separation of 3a and 3b was not
practical, and the mixture was used throughout the scheme.
The first building block, the hydroxymethyl derivative 5b (85%), was
prepared by reduction of 3a,b with LiAlH4 in tetrahydrofuran (THF). In this
case, the trans epimer was efficiently separated by flash chromatography.
Spectral NMR analysis (1H, 13C, correlation spectroscopy (COSY), and
heteronuclear single quantum coherence (HSQC) experiments) secured the
cis stereochemistry. The stereochemical assignment is based on the following
diagnostic features: the cis isomers display an apparent quadruplet for
1
H-4ax in the H NMR spectra, because of its three (almost equal) large
coupling constants, whereas the trans isomers show for this hydrogen the
expected broad and complex multiplet. On the other hand, the aryl substi-
tuted carbon atom, C-5, is considerably shielded (ꢂ5ppm) in the trans series,
probably through a c-gauche effect (Fig. 2).
The Fmoc-protected b-aminoacids 6a and 6b were obtained from the
epimeric mixture of the methyl 5-aryl nipecotinate (3a,b) in a two-step
process. After hydrolysis in neat water, probably through a self-catalyzed
mechanism, the subsequent protection[7] furnished the two carboxylic
acids (trans-6a and cis-6b), which could be conveniently separated by
crystallization with Et2O (the trans isomer nicely precipitated under these
conditions). 5-Phenyl-nipecotic acid has been previously obtained but
without stereocontrol. See Ref. 2a.
The 5-arylnipecotamide framework was accessible from the epimer-
ized mixture 3a,b by reaction with methanol saturated with ammonia
and KCN as a catalyst[8] in a sealed tube at 100 ꢁC (7a,b, 79%). NH3
in acetonitrile yielded the desired amides 7a,b but reaction times were
longer (72 h) and the yields somewhat lower. Recrystallization in EtOAc
affords the cis epimer 7b in 40%. Protection of the piperidine nitrogen
(Boc) afforded the corresponding derivatives (8a,b) in almost quantitative
yield. The carboxamides 7a,b can be directly reduced with LiAlH4 in
THF to the corresponding primary amines, which upon recrystallization
from EtOAc furnished the pure cis epimer 9b (80%).

Multifunctional 1,3,5-Trisubstituted Piperidines
2803
Scheme 2. Reagents and conditions: (a) H2, PtO2, AcOH, rt, 1 atm (90%); (b)
KtBuO, MeOH, 60 ꢁC (85%, cis=trans 5:1); (c) Boc2O, CH2Cl2, Et3 N, rt, and
then NaOH 10%, MeOH, rt (86%, two steps).
The next goal was the synthesis of the 3-amino-5-arylpiperidine
building block through a rearrangement from a carbonyl precursor.
The first attempt was carried out starting from the protected nipecota-
mides 8a,b; a Hofmann rearrangement was tested using PIFA [iodo-
benzene bis(trifluoroacetate)] as the halogen source without positive
results.[9] The related Curtius rearrangement was studied next. The
required carboxylic acid derivative was readily prepared through a
high-yielding, selective sequence. Starting again from the 3a,b mixture,
the necessary protection of the piperidine nitrogen was carried out
(Boc2O), and the subsequent basic hydrolysis of the ester moiety (NaOH
in MeOH)[10] afforded the N-Boc acids 10a,b (90% from 3a,b). Treatment
of these carboxylic acids with DPPA (diphenylphosphoryl azide) and
benzyl alcohol yielded the mixture of 3-N-Cbz-1-N-Boc-piperidines
11a,b with complete retention of configuration.[11] The two epimers thus
obtained were conveniently separated by flash chromatography. A sol-
ution of the diprotected cis isomer in MeOH was subjected to hydrogeno-
lysis (H2, Pd=C) to afford the Cbz-free aminopiperidine 12b (55% overall
yield).
In a series of related transformations, the cyclohexyl derivatives 4a,b
(cis=trans 1:2, obtained in the reduction of the 5-phenylnicotinate 2) were
purified by flash chromatography, and after the epimerization step, the
cis-enriched mixture (cis=trans 5:1) was N-Boc protected and subse-
quently hydrolyzed to furnish the carboxylic acids 13a and 13b (1:5,
86% overall yield) (Scheme 2).
CONCLUSIONS
In conclusion, the diastereoselective syntheses of several piperidine
derivatives were accomplished from a common, commercially available
starting material in a few steps, using Suzuki coupling, pyridine hydro-
genation, routine functional group (FG) transformations, and protecting
group chemistry as the key reactions. This unified protocol allows the

´
J. L. Dıaz et al.
2804
synthesis of cis and trans scaffolds in a practical (multigram scale) man-
ner and is suitable for a wide range of structural diversification using
standard combinatorial chemistry techniques, amenable for solid-phase
methods. All new compounds are racemates, but the resolution of these
materials, if convenient or desirable at a later stage, may be routinely
addressed (for instance, by chiral HPLC or through derivatization, being
amines and carboxylic acids).
EXPERIMENTAL
Unless otherwise stated, all reactions were carried out using dry solvent
under argon atmosphere in dried glassware. Commercially available reac-
tants were used without further purification. Thin-layer chromatography
(TLC) was conducted with Merck silica-gel 60 F254 sheets and visualized
via UV, KMnO4, and ninhydrine solution. Silica gel (particle size 35–
1
70 mm) was used for flash-column chromatography. H and 13C NMR
spectra were recorded on Varian Gemini 200 and 300 spectrometers (at
200, 300 MHz and 50.3, 75.4 MHz respectively). Unless otherwise quoted,
NMR spectra were recorded in CDCl3 solution with TMS as an internal
reference. Melting points were determined in a capillary tube and are
uncorrected. IR spectra were recorded on a Thermo Nicolet Nexus spec-
trometer, and only noteworthy absorptions are listed. The mass spectra
(MS) were recorded on a Hewlett-Packard 5989 A (70 eV, low resolution)
and Autospec-EQ (high resolution).
5-Phenylnicotinic Acid Methyl Ester (2)
A mixture of 5-bromonicotinic acid (1, 10.0 g, 49.4 mmol) and thionyl
chloride (18.0 mL, 124.0 mmol) was stirred at reflux temperature for
24 h. The excess SOCl2 was removed by distillation under reduced press-
ure, and the resulting residue was cooled in an ice bath. A mixture of
MeOH (20 mL) and CH2Cl2 (30 mL) was slowly added. The resulting
mixture was heated to reflux temperature for 1 h, then cooled, and parti-
tioned between an aqueous 2 M NaOH solution and CH2Cl2. The organic
extracts were dried, filtered, and concentrated under reduced pressure to
yield methyl 5-bromonicotinate (10.7 g, 96%). An aqueous 2 M solution
of Na2CO3 (37 mL) and a solution of phenylboronic acid (5.4 g,
44.4 mmol) in MeOH (20 mL) were added to a stirred solution of methyl
5-bromonicotinate (8.0 g, 37.2 mmol) and Pd(PPh3)4 (1.3 g, 1.2 mmol) in
toluene (80 mL) under a nitrogen atmosphere. The stirred mixture was
warmed at 80 ꢁC for 4 h, then cooled, and partitioned between CH2Cl2
and 2 M aqueous Na2CO3 containing concentrated NH3. The organic

Multifunctional 1,3,5-Trisubstituted Piperidines
2805
layer was dried and filtered, and the solvent was removed under reduced
pressure. Flash chromatography on silica gel of the residue (hexa-
nes=EtOAc 7:3) afforded pure 2 (7.9 g, 89%); mp 44.5–45.0 ꢁC. 1H
NMR (200 MHz, CDCl3) d 9.19 (d, J ¼ 2.3 Hz, 1H), 9.01 (d, J ¼ 2.3 Hz,
Hz, 1H), 8.48 (t, J ¼ 2.3 Hz, 1H), 7.65–7.47 (m, 5H), 3.99 (s, 3H).
Trans- and Cis-5-phenylpiperidine-3-carboxylic Acid Methyl
Esters (3a,b)
Pd=C [500 mg, 10% (w=w)] and PtO2 (750 mg) were added to a solution
of ester 2 (5.0 g, 23.5 mmol) in acetic acid (125 mL), and the mixture was
hydrogenated at room temperature and atmospheric pressure. When the
hydrogen uptake was complete (monitored by TLC, CH2Cl2=MeOH=
diethylamine 90:9:1), the catalysts were removed by filtration over a short
pad of Celite1 and washed with acetic acid and CH2Cl2. The filtrates
were evaporated under reduced pressure, and H2O was added to the resi-
due. NH3 (aqueous solution, 20%) was added dropwise to reach pH 10,
and the mixture was extracted several times with CH2Cl2. The collected
organic layers were dried, filtered, and concentrated. A crude mixture of
4.65g was obtained containing (by 1H NMR analysis) 5-phenylpiperidine-
3-carboxylic acid methyl esters (3a,b, trans=cis 2:1) and 5-cyclohexylpi-
peridine-3-carboxylic acid methyl esters (4a,b, trans=cis 2:1) in a 9:1 ratio.
A solution of 1.86 g of this mixture and potassium tert-butoxide (5.0 g,
44.6 mmol) in anhydrous MeOH (300 mL) was stirred at reflux tempera-
ture for 12 h. The major part of MeOH was removed under reduced
pressure, and the residue was poured into an ice=CH2Cl2 mixture and
extracted with CH2Cl2. The combined organic layers were dried, filtered,
and concentrated under reduced pressure to afford 1.60 g (85%) of
a brown oil. Flash chromatography (CH2Cl2=MeOH=Et2NH 90:9:1) on
silica gel afforded a mixture of 5-phenylpiperidine-3-carboxylic acid
methyl esters 3a,b (1.41 g, 75%, trans=cis 1:5).
IR (NaCl): 3324, 2952, 1728 cmꢀ1 1H NMR (200 MHz, CDCl3) d
7.18–7.35 (m, 5H), 3.76 (s, COOCH3 trans, 3H), 3,69 (s, COOCH3 cis,
3H), 3.36 (d, 1H), 3.17 (d, 1H), 2.56–2.80 (m, 5H), 2.30 (m, 1H), 1.80
(q, 1H). 13C NMR (75 MHz, CDCl3) d 174.5, 142.9, 128.6, 128.5,
126.9, 126.6, 52.0, 46.0, 41.7, 39.5, 39.1, 34.0, 32.5. MS (EI, m=z, %):
219 (Mþ , 18), 128 (32), 87 (100). HRMS calcd. for C13H17NO2 [Mþ ]
219.1259; found 219.1263. Further elution with CH2Cl2=MeOH=Et2NH
85:14:1 afforded the cyclohexyl derivatives 4a,b (0.18 g, 10%, trans=cis
1:5). 1H NMR (200 MHz, CDCl3) d 3.71 (s, COOCH3 trans, 3H),
3.67 (s, COOCH3 cis, 3H), 3.34–3.25 (m, 1H), 3.06 (m, J ¼ 12.8 Hz,
1H), 2.77–2.11 (m, 5H), 1.74–1.70 (m, 5H), 1.31–0.96 (m, 8H). MS

´
J. L. Dıaz et al.
2806
(EI, m=z, %): 225 (Mþ, 30), 143 (M-82, 100). HRMS calcd. for
C13H23NO2 [Mþ ] 225.1729; found 225.1738.
Cis-(5-phenylpiperidin-3-yl)-methanol (5b)
A solution of LiAlH4 (350 mg, 9.22 mmol) in anhydrous THF (60 mL)
was slowly added via cannula to a solution of esters 3a,b (1.0 g, 4.6 mmol,
trans=cis 1:5) in anhydrous THF (25 mL), and the resulting mixture was
stirred at room temperature for 4 h. The reaction was quenched by
addition of a saturated solution of Rochelle’s salt, and the resulting
mixture was extracted with EtOAc. The organic layer was washed with
brine, dried, and concentrated under reduced pressure to give an oil,
which was purified by flash chromatography on silica gel. Elution
with EtOAc=MeOH=Et2NH (65:30:5) afforded pure cis-alcohol 5b
(554 mg, 85%).
IR (KBr): 3360, 3285, 2916, 1039 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d 7.28–7.17 (m, 5H), 3.48 (m, 2H), 3.43 (bs, 2H), 3.36 (m, 2H), 2.75 (m,
J ¼ 3.3 Hz, J ¼ 12.0 Hz, J ¼ 12.3 Hz, 1 H), 2.59 (m, J ¼ 11.7 Hz,
J ¼ 12.0 Hz, 1 H), 2.36 (t, J ¼ 11.7 Hz, 1 H), 1.98 (bd, J ¼ 12.0 Hz,
1H), 1.88 (m, 1 H), 1.31 (m, J ¼ 12.3 Hz, J ¼ 12.3 Hz, J ¼ 12.3 Hz, 1H).
13C NMR (75 MHz, CDCl3) d 143.8, 128.4, 126.9, 126.4, 65.6, 53.2,
49.9, 43.3, 40.1, 34.9. MS (EI, m=z, %): 191 (Mþ , 24), 104 (100). HRMS
calcd. for C12H17NO [Mþ ] 191.1310; found 191.1321.
Trans- and-Cis-N-Fmoc-5-phenylpiperidine-3-carboxylic Acids (6a,b)
A suspension of esters 3a,b (1.5 g, 6.8 mmol, trans=cis 1:5) in H2O (20 mL)
was stirred at reflux temperature for 24 h. The solvent was removed under
reduced pressure to afford the corresponding 5-phenylpiperidine-3-
carboxylic acids (1.4 g, 96%) as white powder. A degassed solution of this
mixture of acids (1.35 g, 6.6 mmol) and Na2CO3 (1.75 g, 16.5 mmol) in
H2O (18 mL) and dioxane (15 mL) was slowly added to a cooled flask
(0 ꢁC) containing Fmoc-Cl (1.71 g, 6.6 mmol). The mixture was stirred
at 0 ꢁC for 1 h and then at room temperature for 24 h. Water was added,
and the mixture was extracted with Et2O. The aqueous phase was acidi-
fied to pH 2 with 1 M HCl and extracted with EtOAc. The organic phase
was dried and concentrated under reduced pressure to afford a mixture of
the epimeric acids 6a,b. (2.4 g, 85%). The mixture was treated with Et2O,
which caused the precipitation of a white solid, which was filtered (the
procedure was repeated three times) to afford pure trans-Fmoc-acid
trans-6a (0.40 g, 14%).

Multifunctional 1,3,5-Trisubstituted Piperidines
2807
IR (NaCl): 3037, 2912, 1732, 1647, 1450, 1189 cmꢀ1
.
1H NMR
(200 MHz, CDCl3) d 7.74 (d, J ¼ 7 Hz, 2H), 7.58 (bs, 2H), 7.42–7.25
(m, 9H), 4.56–4.20 (m, 4H), 3.13–3.00 (m, 4H), 2.80 (t, J ¼ 3.8 Hz,
1H), 2.42 (bd, J ¼ 13.8 Hz, 1H), 1.92 (m, 1H). 13C NMR (50 MHz,
CDCl3) d 175.5, 143.9, 142.2, 141.1, 141.8, 128.5, 127.6, 127.1, 127.0,
126.7, 125.0, 119.9, 67.7, 49.9, 47.2, 45.0, 38.8, 38.3, 32.4. MS (EI, m=z,
%). 428 (Mþ þ 1, 34), 178 (100).
The isomeric cis-acid 6b (1.99 g, 71%) was isolated from the solution
after evaporation of the solvent under reduced pressure. Cis-acid 6b:
IR (NaCl): 3064, 3026, 2925, 1703, 1477, 1449, 1255 cmꢀ1. 1H NMR
(200 MHz, CDCl3) d 7.75 (d, J ¼ 7.4 Hz, 2H), 7.58 (d, J ¼ 6.2 Hz, 2H),
7.43–7.16 (m, 9H), 4.51–4.25 (m, 4H), 2.88–2.50 (m, 5H), 2.34 (bd,
J ¼ 13.2 Hz, 1H), 1.82 (m, J ¼ 12.6 Hz, J ¼ 12.4 Hz, 1H). 13C NMR
(75 MHz, CDCl3) d 178.0, 155.2, 144.3, 141.6, 128.9, 127.9, 127.9,
127.3, 127.3, 125.2, 120.3, 67.4, 50.6, 47.6, 45.6, 41.8, 34.3, 26.7. MS
(EI, m=z, %): 428 (Mþ þ 1, 3), 178 (100). HRMS calcd. for
C27H25NO4 [Mþ þ 1] 428.1862; found 428.1875.
Cis-5-phenylpiperidine-3-carboxamide (7b)
KCN (150 mg, 2.30 mmol, caution) was added to a stirred solution of
esters 3a,b (2.1 g, 9.60 mmol, trans=cis 1:5) in NH3-saturated MeOH
(200 mL) in a sealed tube. The mixture was stirred at 100 ꢁC for 48 h (cau-
tion, internal pressure). The excess of NH3 was Ar-degassed, and meth-
anol was removed under reduced pressure. The residue was partitioned
between CH2Cl2 and water. The organic phase was dried, filtered, and
concentrated under reduced pressure to yield the epimeric mixture of
amides 7a,b (1.58 g, 79%, trans=cis 1:5). Pure cis-isomer 7b can be
obtained as a white foam by successive EtOAc washings of the mixture.
IR (KBr): 3304, 3048, 1667, 1559 cmꢀ1 1H NMR (200 MHz,
.
CD3OD) d 7.29–7.19 (m, 5H), 3.15 (d, J ¼ 11.2 Hz, 1H), 3.04 (d,
J ¼ 11.2 Hz, 1H), 2.75–2.52 (m, 4H), 2.05 (m, 1H), 1.87 (q, J ¼ 11.8 Hz,
J ¼ 12.4 Hz, 1H). 13C NMR (50 MHz, CD3OD) d 176.5, 142.2, 129.7,
128.3, 128.0, 50.0, 46.5, 42.3, 41.6, 35.3. MS (EI, m=z, %): 204 (Mþ,
8), 72 (100). HRMS calcd. for C12H16N2O [Mþ ] 204.1263; found
204.1270.
Cis-N-Boc-5-phenylpiperidine-3-carboxamide (8b)
A stirred solution of carboxamides 7a,b (500 mg, 2.40 mmol, trans=cis
1:5) in a 1:1 mixture of aqueous saturated NaHCO3 solution and THF
(300 mL) was cooled to 0 ꢁC, and (Boc)2O (4.28 g, 19.6 mmol) was added.

´
J. L. Dıaz et al.
2808
The resulting mixture was stirred at room temperature for 24 h and
extracted with CH2Cl2. The combined organic extracts were dried, fil-
tered, and concentrated under reduced pressure. The resulting residue
was purified by chromatography (SiO2, CH2Cl2) to yield the mixture of
epimers 8a,b (740 mg, 99%, trans=cis 1:5). Pure cis-isomer 8b was
obtained as a white foam by successive EtOAc=MeOH washings of the
mixture.
1
IR (NaCl) 3300, 2928, 1666 cmꢀ1. H NMR (300 MHz, CDCl3) d
7.35–7.21 (m, 5H), 5.96 (bs, 1H), 4.40–4.09 (m, 2H), 2.90–2.46 (m, 4H),
2.18 (bd, 1H), 1.96 (m, J ¼ 12.9 Hz, J ¼ 10.8 Hz, 1H), 1.46 (s, 9H). 13C
NMR (75 MHz, CDCl3) d 175.2, 154.6, 142.1, 128.5, 127.0, 126.9, 80.1,
46.0, 42.9, 42.1, 41.8, 34.8, 28.4. MS (EI, m=z, %): 304 (Mþ , 10), 203
(50), 57 (100). HRMS calcd. for C17H24N2O3 [Mþ ] 304.1787; found
304.1781.
Cis-(5-phenylpiperidin-3-yl)-methylamine (9b)
A solution of LiAlH4 (645 mg, 17.03 mmol) in anhydrous THF (40 mL)
was slowly added via cannula to a 0 ꢁC cooled solution of carboxamides
7a,b (650 mg, 3.19 mmol, trans=cis 1:5) in anhydrous THF (110 mL). The
resulting mixture was stirred at 60 ꢁC for 4 h, and then a saturated
solution of Rochelle’s salt was carefully added. The mixture was
extracted with EtOAc, and the organic phase was washed with brine,
dried, filtered, and concentrated under reduced pressure to afford the
amine 9b (575 mg, 80%) as a white foam.
1
IR (NaCl): 3285, 2922 cmꢀ1. H NMR (200 MHz, CD3OD) d 7.32–
7.17 (m, 5H), 3.10 (bt, 2H), 2.87–2.48 (m, 5H), 2.24 (t, J ¼ 12.2 Hz,
1H), 2.04 (bd, J ¼ 12.6 Hz, 1H), 1.70 (m, 1H), 1.31 (q, J ¼ 12.2 Hz,
1H). 13C NMR (50 MHz, CDCl3) d 144.1, 128.4, 127.0, 126.4, 53.5,
50.3, 46.2, 43.8, 40.8, 36.5. MS (EI, m=z, %): 190 (Mþ, 4), 173 (47),
104 (100). HRMS calcd. for C12H18N2 [Mþ ] 190.1470; found 190.1478.
Trans- and-Cis-N-Boc-5-phenylpiperidine-3-carboxylic Acids (10a,b)
Et3N (290 ml, 2.05 mmol) and (Boc)2O (450 mg, 2.05 mmol) were added to
a solution of esters 3a,b (300 mg, 1.37 mmol, trans=cis 1:5) in CH2Cl2
(25 mL). The mixture was stirred at room temperature for 18 h, poured
onto a cold saturated aqueous NH4Cl solution, and extracted with
Et2O. The combined organic extracts were dried, filtered, and concen-
trated under reduced pressure. The resulting residue was purified by chro-
matography (SiO2, EtOAc) to yield the corresponding N-Boc methyl
esters (396 mg, 95%). To a solution of this material (375 mg, 1.22 mmol)

Multifunctional 1,3,5-Trisubstituted Piperidines
2809
in MeOH (2 mL), 10% aqueous NaOH solution (2 mL) 10%, was added.
The mixture was stirred at room temperature for 5 h, and MeOH was
removed under reduced pressure. The residue was carefully acidified first
by addition of 3 M HCl to pH 6 and then adjusted to pH 4 with citric
acid. The aqueous phase was extracted with EtOAc, and the organic
extracts were dried, filtered, and concentrated to afford the N-Boc acids
10a,b (341 mg, 95%, trans=cis 1:5) as a white foam. Recrystallization in
EtOAc=hexanes afforded the pure cis isomer 10b.
1
IR (NaCl) 2977, 2930, 1693, 1428, 1168 cmꢀ1. H NMR (200 MHz,
CDCl3) d 7.37–7.20 (m, 5H), 4.45 (bs, 1H), 4.25 (bs, 1H), 2.83–2.60 (m,
4H), 2.35 (bd, J ¼ 13.6 Hz, 1H), 1.81 (q, J ¼ 12.4 Hz, 1H), 1.47( s, 9H).
13C NMR (50 MHz, CDCl3) d 178.2, 154.5, 141.9, 128.6, 127.0, 126.9,
80.3, 50.1, 45.3, 41.5, 34.4, 28.5. MS (EI, m=z, %): 305 (Mþ, 1), 249
(6), 57 (100).
Trans- and Cis-N-Boc-3-benzylcarbamate-5-phenylpiperidines (11a,b)
Diphenylphosphorazidate (2.63 mL, 12.2 mmol) and Et3N (1.70 mL,
12.2 mmol) were added to a stirred solution of carboxylic acids 10a,b
(3.0 g, 10.2 mmol, trans=cis 1:5) in anhydrous benzene (250 mL). The
resulting mixture was stirred at reflux temperature for 2 h, and then ben-
zyl alcohol (2.15 mL, 20.5 mmol) was added. Stirring at reflux tempera-
ture was continued for 12 h, the reaction was cooled to room
temperature, and the volatiles were removed under reduced pressure.
The resulting residue was partitioned between EtOAc and saturated
aqueous NaHCO3. The layers were separated, and the organic phase
was washed with brine, dried, filtered, and concentrated under reduced
pressure. The resulting residue (2.73 g, 65%) was purified by chromato-
graphy over silica gel. Elution with hexanes=EtOAc (9:1) afforded the
cis-carbamate 11b (2.20 g, 53%) as a white foam.
1H NMR (300 MHz, 50 ꢁC, CDCl3) d 7.36–7.19 (m, 10H), 5.11 (s,
2H), 4.87 (bs, 1H), 4.39 (bd, J ¼ 8.7 Hz, 1H), 4.21 (bd, J ¼ 10.5 Hz,
1H), 3.69 (m, 1H), 2.77 (m, 1H), 2.61 (t, J ¼ 12.3 Hz, 1H), 2.45 (t,
J ¼ 11.7 Hz, 1H), 2.27 (bd, J ¼ 12.3 Hz, 1H), 1.48 (m, 10H). 13C NMR
(50 MHz, CDCl3) d 155.5, 154.5, 141.7, 136.3, 128.6, 128.5, 128.1,
127.0, 126.9, 80.1, 66.8, 49.6, 47.8, 41.4, 38.7, 28.4, 26.5. MS (EI,
m=z, %): 410 (Mþ, 2), 309 (M ꢀ 101, 2), 57 (100). HRMS calcd. for
C24H30N2O4 [Mþ ] 410.2206; found 410.2218.
Further elution gave the trans-carbamate 11a (496 mg, 11%).
1H NMR (200 MHz, CDCl3) d 7.32–7.15 (m, 10H), 5.62 (bs, 2H),
4.21–4.04 (m, 2H), 2.98 (dd, J ¼ 2.7 Hz, J ¼ 14.1 Hz, 1H), 2.91–2.73
(m, 2H), 2.23 (bd, J ¼ 13.8 Hz, 1H), 1.88–1.80 (m, J ¼ 3.9 Hz,

´
J. L. Dıaz et al.
2810
J ¼ 14.1 Hz, 1H), 1.72–1.65 (m, 1H), 1.45 (s, 9H). 13C NMR (75 MHz,
CDCl3) d 155.7, 151.2, 141.5, 135.3, 129.6, 128.6, 128.6, 128.5, 128.4,
126.9, 80.4, 70.6, 50.0, 47.4, 46.5, 35.1, 28.3, 26.4. MS (EI, m=z, %):
410 (Mþ, 4), 341 (43), 290 (60), 203 (100).
Further elution afforded the N,N0-bis-(1-Boc-5-phenylpiperidin-3-
yl)urea.
1
IR (NaCl) 3321, 2972, 1705, 1616, 1579, 1419, 1249, 1149 cmꢀ1. H
NMR (200 MHz, CDCl3) d 7.27–7.22 (m, 10H), 4.32 (m, 5H), 3.74 (m,
2H), 2.82–2.27 (m, 8H), 1.47 (m, 19H). 13C NMR (75 MHz, CDCl3)
d 157.0, 154.8, 141.8, 128.5, 126.8, 126.7, 80.3, 48.7, 46.4, 41.3, 38.9, 28.2.
Cis-N-Boc-3-amino-5-phenylpiperidine (12b)
Pd=C (100 mg, 10%) was added to a solution of cis-carbamate 11b
(150 mg, 0.37 mmol) in MeOH (15 mL). The resulting suspension was
hydrogenated at room temperature and atmospheric pressure. When
hydrogenation was complete (monitored by TLC), the catalysts were
removed by filtration over a short pad of Celite1 and washed with
MeOH. The filtrates were dried, filtered, and concentrated under reduced
pressure to give the cis-3-aminopiperidine 12b (90 mg, 55% overall yield).
1
IR (NaCl) 3346, 2976, 2929, 1693, 1165 cmꢀ1. H NMR (200 MHz,
CDCl3) d 7.35–7.19 (m, 5H), 4.40–4.17 (m, 2H), 2.99–2.44 (m, 6H),
2.23 (bd, J ¼ 13.6 Hz, 1H), 1.57–1.39 (m, 10H). 13C NMR (100 MHz,
CDCl3) d 154.8, 142.1, 128.8, 127.3, 127.1, 80.3, 49.9, 49.8, 48.1, 41.8,
39.9, 28.6. MS (EI, m=z, %): 276 (Mþ, 5), 259 (6), 203 (25), 57 (100).
HRMS calcd. for C16H24N2O2 [Mþ ] 276.1838; found 276.1849.
Trans- and-Cis-N-Boc-5-cyclohexylpiperidine-3-carboxylic Acids (13a,b)
Et3N (2.80 mL, 19.9 mmol) and (Boc)2O (4.34 g, 19.9 mmol) were added
to a solution of cyclohexyl derivatives 4a,b (3.0 g, 13.3 mmol, trans=cis
1:5) in CH2Cl2 (250 mL). The mixture was stirred at room temperature
for 18 h and then poured onto a cold saturated aqueous NH4Cl solution
and extracted with Et2O. The combined organic extracts were dried, fil-
tered, evaporated, and purified by chromatography (SiO2, EtOAc) to
yield a light brown oil that was taken up in MeOH (20 mL). This solution
was added to a 10% NaOH aqueous solution (20 mL), and the resulting
mixture was stirred at room temperature for 5 h. MeOH was removed
under reduced pressure, and the residue was carefully acidified first by
adding 3 M HCl to pH 6 and then adjusted to pH 4 with citric acid.
The resulting suspension was extracted with EtOAc, and the organic
layer was dried, filtered, and concentrated under reduced pressure to

Multifunctional 1,3,5-Trisubstituted Piperidines
2811
afford acids 13a,b (3.42 g, 86%, trans=cis 1:5) as a white foam. Recrystal-
lization in EtOAc=hexane afforded the major cis isomer 13b.
1H NMR (200 MHz, CDCl3) d 4.31 (bs, 1H), 4.14 (bs, 1H), 2.68 (t,
J ¼ 12.0 Hz, 1H), 2.46–2.18 (m, 3H), 1.74 (bs, 5H), 1.46 (s, 9H), 1.31–
1.01 (m, 8H). 13C NMR (75 MHz, CDCl3) d 178.8, 154.6, 79.9, 47.1,
44.5, 41.7, 40.8, 31.4, 30.1, 29.9, 28.4, 26.5, 26.5. MS (EI, m=z, %): 311
(Mþ, 2) 255 (7), 129 (24), 57 (100).
ACKNOWLEDGMENT
Support from Laboratorios Almirall (Barcelona, Spain), Barcelona
Science Park, and DGICYT (Spain, Project BQU2006-03794) is grate-
fully acknowledged.
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