Reaction between glutaric anhydride and N-benzylidenebenzylamine, and further transformations to new substituted piperidin-2-ones

Article abstract of DOI:10.1016/j.tet.2006.06.054

The reaction between glutaric anhydride (1) and N-benzylidenebenzylamine (3) was studied in detail by ¹H NMR spectroscopy under different reaction conditions. The major product was (±)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-carboxylic acid (

Full text of DOI:10.1016/j.tet.2006.06.054

Tetrahedron 62 (2006) 8318–8326
Reaction between glutaric anhydride and
N-benzylidenebenzylamine, and further transformations
to new substituted piperidin-2-ones
*
Nikola T. Burdzhiev and Elena R. Stanoeva
St. Kliment Ohridski University of Sofia, Faculty of Chemistry, Department of Organic Chemistry,
1, J. Bouchier Ave., 1164 Sofia, Bulgaria
Received 7 March 2006; revised 30 May 2006; accepted 15 June 2006
Available online 10 July 2006
Abstract—The reaction between glutaric anhydride (1) and N-benzylidenebenzylamine (3) was studied in detail by 1H NMR spectroscopy
under different reaction conditions. The major product was (ꢀ)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-carboxylic acid (2), which was
converted into new substituted piperidin-2-ones via transformations of the carboxylic group. The final products are expected to possess
pharmaceutical activities, and the relevant screenings are in course.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Schiff base was converted to an aza analog of tetrahydro-
cannabinol by Grignard addition to the carboxylic group in
the key step.16 The aim of the present paper is to investigate
other possible transformations of the carboxylic group in
order to achieve its replacement by carboxamido or by amino-
methyl groups. In this way two types of target structures,
A and B, can be obtained. The carboxamides, represented by
structure A, contain a b-alanine subunit (the fragment given
in bold). The (aminomethyl)piperidinone derivatives are
related to structure B, which can be considered as inverse
amide analogs of g-aminobutyric acid (GABA).17–19 The
two sets of piperidinone derivatives may be designed to
incorporate an amino group in the side chain as a part of
another heterocycle such as 4-substituted piperazine, morpho-
line, piperidine, etc. Such heterocyclic moieties are well
known pharmacophore substituents.20–22 The combination
of the piperidinone ring with different heterocyclic moieties
in the side chain would result in a series of compounds with
potential biological activities. For the purposes of this
The piperidine ring is an important core structure in organic
chemistry because of its presence in many natural prod-
ucts.1–4 Substituted piperidines display a wide spectrum of
physiological activities such as analgesic and anti-inflam-
matory,5 anticonvulsant,6 aromatase inhibiting,7 etc. Piper-
idines possessing an amino substituent show cytotoxicity,8
and are selective human neurokinin-1 antagonists.9 Piperidi-
nones are often useful advanced intermediates in the prepa-
ration of piperidines4 and scaffolds in the synthesis of b-turn
peptide mimetics.10 Piperidinones possessing piperazino
substituents exhibit antihistaminic and antianaphylactic
activities.11 The diverse biological activities of substituted
piperidines have provoked numerous synthetic studies.
Several reviews dealing with the recent progress in the syn-
thesis of substituted piperidines and piperidinones have been
published.4,12–14 The reaction of glutaric anhydride (1) with
N-arylidene-N-alkylamines provides a straightforward path
to the synthesis of the piperidinone ring. It affords many
trans-1-alkyl-2-aryl-6-oxopiperidine-3-carboxylic acids in
one step.5,7,15,16 However, less attention has been paid to
the functional group transformations in the piperidinones
obtained. For instance, trans-1-methyl-2-(2-methoxy-
phenyl)-6-oxopiperidine-3-carboxylic acid obtained bycyclo-
condensation of glutaric anhydride and the appropriate
Keywords: Piperidin-2-ones; Glutaric anhydride; Piperazine; Stereo-
chemistry.
* Corresponding author. Tel.: +359 2 8161 225; fax: +359 2 962 5438;
e-mail: estanoeva@chem.uni-sofia.bg
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.054

N. T. Burdzhiev, E. R. Stanoeva / Tetrahedron 62 (2006) 8318–8326
8319
investigation we needed a great amount of trans-1-benzyl-2-
phenyl-6-oxopiperidine-3-carboxylic acid (2). That made us
study the reaction of 1 and N-benzylidenebenzylamine (3) in
order to determine the optimal conditions for a fast and easy
approach to acid 2.
every signal. They are measured relatively to the doublet sig-
nal for H-2 (d 4.81 ppm) in the molecule of the acid 2. The
determination of the relative quantity of the monoamide 4
was done using the doublet signal at 4.25 ppm for the two
benzylic CH2 protons, arbitrarily marked as H-7. Thus, the
1H NMR spectrum after 0.5 h showed the presence of the
acid trans-2 and the monoamide 4 in ca. 1:4 ratio. The reac-
tion mixtures also contained benzaldehyde from hydrolysis
of the corresponding Schiff base 3 as evidenced by the sin-
glet for CHO at 10.0 ppm. A certain amount of benzalde-
hyde is lost probably during the evaporation of p-xylene
under reduced pressure. Signals of glutaric anhydride (1)
could not be detected due to overlap with other signals. After
the longest reaction time the ratio of 2 to 4 reached 5:1 and
the quantity of the aldehyde was significantly reduced. For-
mation of other compounds besides 2 and 4 was not detected,
which gave rise to the conclusion that compound 4 was
converted into 2. Recently, a similar reactivity of the mono-
amide of homophthalic acid toward aldehydes to furnish cis-
2,3-disubstituted 1-oxotetrahydroisoquinoline-4-carboxylic
acids has been observed.23 However, in the latter case the
reaction took place in the presence of Al salts and yielded
the cis-product.23 In order to shed more light whether the
amide 4 is an intermediate in the reaction, an equimolar
mixture of the amide 4 and benzaldehyde was refluxed in
p-xylene (Scheme 2).
2. Results and discussion
The required starting trans-1-benzyl-6-oxo-2-phenylpiperi-
dine-3-carboxylic acid (2) was first prepared by Shetty
et al. by refluxing a mixture of glutaric anhydride (1) and
N-benzylidenebenzylamine (3) in xylene for 10 h in 80%
yield5 (Scheme 1). Chan et al. prepared trans-2 by refluxing
1 and 3 in toluene for 50 h.15 It was shown that trans-2
formed a non-stoichiometric channel inclusion complex
with acetonitrile as evidenced by X-ray analysis.15 The sig-
nificant difference in the reaction times5,15 prompted us to
investigate the relationship between the temperature and
the time needed for the completion of the reaction. To
achieve this we chose to fix the reaction time, in order to
estimate the difference in the yields. Mixtures of 1 and 3
were refluxed in aprotic solvents with different boiling
points. The solvents used and the yields of trans-2 after 6 h
are shown in Table 1.
1H NMR analysis of the reaction mixture after 6 h at reflux
showed a complex mixture and the presence of the acid
trans-2 in very low quantity. In order to increase the yield
of trans-2, we prolonged the reflux to 40 h and isolated 2
in 11% yield. This experiment shows that the acid 2 can
be formed by reaction of 4 and benzaldehyde in boiling
p-xylene. The catalytic effect of other reaction components
present in the reaction mixture of 1 and 3 is probably essen-
tial and it could explain the low yield of 2 from the reaction
of 4 and benzaldehyde. Thus, the acyclic monoamide 4
seems to be an intermediate in the formation of trans-2
in the reaction of 1 and 3. The question whether the reaction
pathway via 4 is the only one or more reaction pathways are
possible, remains open and requires further investigations.
Scheme 1. Synthesis of compound 2.
The results indicate that the yield of trans-2 increases with
the rise of the temperature. Thus p-xylene appears to be
the most suitable solvent for this reaction. That was the rea-
son for using p-xylene as the solvent in our further research.
A detailed investigation of the reaction mixture by TLC
showed that glutaric anhydride (1) disappeared after 1 h at
reflux and the reaction mixture contained along with the
acid trans-2, also glutaric acid mono-N-benzylamide 4. Up
to now, there are no literature data about the concomitant
formation of acyclic monoamides of glutaric acid during
the reaction of the glutaric anhydride (1) with imines.5,15,16
This made us follow the course of the reaction in p-xylene by
1H NMR spectroscopy. We prepared four reaction mixtures
each containing the same equimolar amounts of the reagents
1 and 3 in p-xylene and heated them at different times—0.5,
1, 3 and 6 h. Aliquots were taken and investigated by
1H NMR spectroscopy. The corresponding spectra are pre-
sented in Figure 1. The integral intensities are shown below
Scheme 2. Reaction between 4 and benzaldehyde.
The preparation of carboxamides 5 from trans-2 is shown in
Scheme 3. The acid 2 was refluxed with thionyl chloride and
the corresponding acid chloride without further purification
was treated with an excess of the corresponding amine. The
compounds 5a–n thus obtained were purified by recrystalli-
zation or column chromatography. Compound 5o was
synthesized by BOC cleavage of 5n and purified by column
chromatography and subsequent recrystallization. The
methyl ester 6 was obtained by esterification of the acid 2
with CH3OH–H2SO4. The reduction of the ester 6 with
Table 1. The yield of trans-2 in the cases of different solvents, after 6 h
at reflux
Solvent
bp, ꢁC
Yield, %
THF
65
80
110
138
4.4
9.2
53.2
78.0
Benzene
Toluene
p-xylene

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N. T. Burdzhiev, E. R. Stanoeva / Tetrahedron 62 (2006) 8318–8326
Figure 1. 1H NMR spectra of the reaction mixture, where a—trans-2, b—imine 3, c—monoamide 4, d—benzaldehyde.
LiBH4 proceeded selectively at the ester group to give trans-
5-(hydroxymethyl)-6-phenylpiperidin-2-one (7). The latter
was converted with p-toluenesulfonyl chloride (p-TosCl)
into the tosylate 8. The reaction of 8 with an excess of the
selected secondary heterocyclic amines was carried out in
refluxing toluene. The resulting aminomethyl derivatives
9a–g were purified by means of recrystallization or column
chromatography (Scheme 4). The compounds 5 and 9 are
new. Their structure and trans relative configuration were
established by means of 1H NMR spectral data, which were
compared with the data of the previously described structur-
ally similar diastereomeric 1,2-disubstituted 6-oxopiperi-
dine-3-carboxylic acids and their methyl esters16,24 as well
as with the spectral data of the acid 2.
It is known that the reaction of the anhydride 1 with different
N-arylidenealkylamines in refluxing xylene affordsa mixture
of trans- and cis-1,2-disubstituted 6-oxopiperidine-3-car-
boxylic acids, with the strong predominance for the trans-
isomers.16,24 It has been shown that the trans-isomers are
thermodynamically more stable and their predominant
formation is evidently favored by the reaction conditions
(long reflux at ca. 140 ꢁC).24 The previously reported
X-ray analysis of the inclusion complex of the acid trans-2
with acetonitrile, shows that the piperidinone ring is in
a highly distorted chair conformation due to the presence
of the planar amide fragment and protons HA and HB occupy
an axial–pseudoaxial position.15 However, on the basis of 1H
NMR spectroscopy it is accepted that the conformation in

N. T. Burdzhiev, E. R. Stanoeva / Tetrahedron 62 (2006) 8318–8326
8321
Figure 2.
coupling constant 3J 5.0 Hz. It is known that six-membered
rings in chair conformation are characterized with 3J of the
vicinal axial protons in 8–13 Hz range and 3J of the vicinal
1
equatorial protons in 1–4 Hz range in their H NMR spec-
tra.25 In analogy to the literature data, we assume that in
solution trans-2 spends more time in a conformation with
pseudoequatorial HA and equatorial HB16,25 (Fig. 2). In the
1H NMR spectrum of the methyl ester 6, HA exhibits a dou-
3
3
blet with JA,B 3.9 Hz. This value of JA,B is in agreement
with trans configuration and preferred pseudoequatorial–
equatorial solution conformation of HA and HB of the ester
6. Such conformation of the ester 6 is also preferred in solid
state, which is evidenced by X-ray analysis.15 The subse-
quent reactions of 2 and the intermediate ester 6 do not affect
the two stereogenic centers. The trans relative configurations
of the alcohol 7, the tosylate 8 as well as the target amides 5,
and aminomethyl derivatives 9 follow directly from the con-
figuration of the starting compounds, trans-2 and the ester 6.
In the case of the amides 5, 3J is in the range of 6.8–9.3 Hz,
which can be explained by the conformational equilibrium
shifted to a greater extent to the conformer with diaxial pro-
tons. This can be due to the planarity of the carboxamido
group, which leads to a smaller steric hindrance with the
Scheme 3. Synthesis of compounds 5a–n.
1
neighboring phenyl moiety. In the H NMR spectra of the
aminomethyl derivatives 9 the signal of HA appears as a sin-
glet, which is again in agreement with the trans configuration
of compounds 9 and equatorial–pseudoequatorial orienta-
tion of HA and HB, influenced by the bigger effective volume
of the aminomethyl substituent (Fig. 2). It should be noted
that the ring numbering of compounds 7–9 is different
from that of compounds 2, 5, 6 and the HA and HB protons
have a different number, which is reflected in Section 3.
The pharmacological screening of compounds 5 and 9 is in
course.
3. Experimental
3.1. General
Melting points were taken on a Kofler hot stage apparatus
and are uncorrected. IR spectra were recorded on a Specord
75 instrument. 1H NMR spectra (250.13 MHz) and 13C
NMR spectra (62.90 MHz) were obtained on a Bruker
Avance DRX-250 spectrometer. The chemical shifts are
given in parts per million (d) relative to tetramethylsilane
as internal standard. Assignments were made using a combi-
nation of 1D and 2D spectra (DEPT, COSY). The micro-
analyses were done at the Faculty of Chemistry, University
of Sofia. Thin layer chromatography (TLC) was performed
on Merck 1.05554 silica gel 60F254 aluminum plates.
Chromatographic filtration and column chromatography
were carried out using Acros silica gel (0.060–0.200 mm).
Scheme 4. Synthesis of compounds 9a–g.
solution with a pseudoaxial phenyl, respective pseudoequa-
torial HA is more favorable because of the smaller A1,2 strain
between the phenyl group and the N-substituent16 (Fig. 2). In
our experiments the acid 2 was isolated always as a single
diastereomer. The formation of the cis-isomer was not de-
tected, even when the reaction of 1 and 3 was followed by
1
means of H NMR spectroscopy. The signal of HA in the
1H NMR spectrum of 2 appears as a doublet with vicinal

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Electrospray ionization (ESI) mass spectra were recorded by
flow injection of acetonitrile solution into an ESI source
attached to Varian Prostar 240 instrument.
benzene (4 mL) was heated at 70 ꢁC for 1 h. The volatile
products were evaporated under reduced pressure and the
slightly yellow oil was dissolved in CH2Cl2 (4 mL). The
solution was cooled at ꢂ5 ꢁC and 3 mmol of the correspond-
ing amine was added dropwise. In the case of the amide 5a,
dry ammonia was bubbled through the solution at ꢂ5 ꢁC.
The mixture was stirred at room temperature. After the
completion of the reaction (TLC), the reaction mixture
was dissolved in ethyl acetate (50 mL) and washed with
water (3ꢃ20 mL). The organic phase was dried (Na2SO4)
and the solvent was evaporated under reduced pressure.
The resulting oil was purified by recrystallization or column
chromatography and subsequent recrystallization from ethyl
acetate–hexane. In this way the following compounds were
prepared:
3.2. Preparation of ( )-trans-1-benzyl-6-oxo-2-phenyl-
piperidine-3-carboxylic acid (2)
To a solution of N-benzylidenebenzylamine (3, 1.71 g,
8.8 mmol) in dried p-xylene (18 mL), glutaric anhydride
(1, 1.0 g, 8.8 mmol) was added. The reaction mixture was
refluxed for 6 h. The crystals separated were filtered and re-
crystallized from ethyl acetate–methanol to yield the acid 2
as white needles (2.12 g, 78%). Mp 168–171 ꢁC. According
to lit.,5 mp of 2 is 171–174 ꢁC. IR (Nujol): 3200–2500 (OH),
1705 (COOH), 1590 (CON) cmꢂ1. 1H NMR d (DMSO-d6):
1.78–1.96 (2H, m, H-4), 2.42–2.65 (2H, m, H-5), 2.76–2.88
(1H, m, H-3), 3.38 (1H, d, H-7, J¼15.2 Hz), 4.81 (1H, d,
H-2, J¼5.0 Hz), 5.19 (1H, d, H-7, J¼15.2 Hz), 7.06–7.43
(10H, m, arom. H), 12.40 (1H, br s, COOH). 13C NMR
d (DMSO): 20.2 (1C, C-4), 29.8 (1C, C-5), 46.5 (1C, C-3),
47.5 (1C, C-7), 61.7 (1C, C-2), 127.0 (2C, Ph), 127.7 (2C,
Ph), 127.9 (2C, Ph), 128.4 (2C, Ph), 128.9 (2C, Ph), 137.2
(1C, Ph), 140.5 (1C, Ph), 169.2 (1C, C-6), 173.5 (1C,
COOH). Anal. Calcd for C19H19NO3: C 73.77%, H 6.19%;
found: C 73.79%, H 6.33%.
3.5.1.1. ( )-trans-1-Benzyl-6-oxo-2-phenylpiperidine-
3-carboxamide (5a). White solid; yield: 78%, mp 101–
103 ꢁC. IR (Nujol): 3400 (NH), 1680, 1665 (CON) cmꢂ1
.
1H NMR d (DMSO): 1.73–1.92 (2H, m, H-4), 2.41–2.58
(2H, m, H-5), 2.60–2.73 (1H, m, H-3), 3.33 (1H, d, H-7,
J¼15.3 Hz), 4.68 (1H, d, H-2, J¼6.9 Hz), 5.18 (1H, d,
H-7, J¼15.3 Hz), 6.87 (1H, s, NH), 7.04–7.41 (11H, m,
NH, arom. H). 13C NMR d (DMSO): 22.5 (1C, C-4), 30.8
(1C, C-5), 46.8 (1C, C-7), 47.8 (1C, C-3), 62.0 (1C, C-2),
126.9 (1C, Ph), 127.2 (2C, Ph), 127.5 (2C, Ph), 127.7 (1C,
Ph), 128.4 (2C, Ph), 128.8 (2C, Ph), 137.3 (1C, Ph), 141.0
(1C, Ph), 169.5 (1C, C-6), 173.5 (1C, CONH2). Anal. Calcd
for C19H20N2O2: C 74.00%, H 6.54%; found: C 73.65%, H
6.60%.
3.3. Preparation of 5-(benzylamino)-5-oxopentanoic
acid (4)
To a solution of 1 (0.228 g, 2 mmol) in CH2Cl2 (4 mL),
benzylamine (0.22 mL, 2 mmol) was added. The mixture was
stirred at room temperature for 15 min and then the solvent
was evaporated. The resulting oil was triturated with ethyl
acetate, the crystals were collected and recrystallized from
water, to give monoamide 4 as colorless platelets (0.333 g,
75%). Mp 105–106 ꢁC. IR (Nujol): 3300 (NH), 3200–2500
3.5.1.2. ( )-trans-1-Benzyl-2-phenyl-3-(pyrrolidine-1-
carbonyl)-piperidin-6-one (5b). White needles; yield:
1
64%, mp 137–139 ꢁC. IR (CHCl3): 1620 (CON) cmꢂ1. H
NMR d (CDCl3): 1.43–1.96 (5H, m, H-4, 4CH2), 2.00–
2.20 (1H, m, H-4), 2.39–2.69 (2H, m, 2H-5), 2.74–2.93
(2H, m, H-3, CH2N), 3.07–3.39 (3H, m, CH2N), 3.44 (1H,
d, H-7, J¼14.8 Hz), 4.67 (1H, d, H-2, J¼8.6 Hz), 5.49
(1H, d, H-7, J¼14.8 Hz), 7.02–7.38 (10H, m, arom. H).
MS m/z: 363 (M+, 100), 338 (8), 256 (20), 201 (10), 196
(95), 168 (24), 130 (45). Anal. Calcd for C23H26N2O2:
C 76.21%, H 7.23%; found: C 76.05%, H 7.12%.
(OH), 1690 (COOH), 1635 (CON), 1540 (CONH) cmꢂ1
.
1H NMR d (DMSO): 1.64–1.81 (2H, m, H-3), 2.12–2.26
(4H, m, H-2, H-4), 4.25 (2H, d, H-7, J¼5.8 Hz), 7.17–7.43
(5H, m, arom. H), 8.34 (1H, t, NH, J¼5.8 Hz). 13C NMR
d (CDCl3+DMSO): 20.8 (1C, CH2), 33.2 (1C, CH2COOH),
34.8 (1C, CH2CON), 42.6 (1C, CH2N), 126.8 (1C, Ph),
127.3 (2C, Ph), 128.2 (2C, Ph), 139.0 (1C, Ph), 172.4 (1C,
CON), 174.7 (1C, COOH). Anal. Calcd for C12H15NO3: C
65.14%, H 6.83%; found: C 64.86%, H 7.11%.
3.5.1.3. ( )-trans-1-Benzyl-2-phenyl-3-(piperidine-1-
carbonyl)-piperidin-6-one (5c). Colorless crystals; yield:
1
58%, mp 129–131 ꢁC. IR (CHCl3): 1625 (CON) cmꢂ1. H
3.4. Reaction of 4 and benzaldehyde in boiling p-xylene
NMR d (CDCl3): 0.61–0.79 (1H, m, CH2), 1.11–1.33 (2H,
m, CH2), 1.34–1.49 (3H, m, CH2), 1.81–1.93 (1H, m, H-4),
1.97–2.17 (1H, m, H-4), 2.51–2.68 (1H, m, H-5), 2.73–2.86
(1H, ddd, H-5, J¼4.7, 4.7, 17.6 Hz), 2.93–3.12 (3H, m,
H-3, 2CH2N), 3.13–3.27 (1H, m, CH2N), 3.42 (1H, d, H-7,
J¼14.8 Hz), 3.48–3.63 (1H, m, CH2N), 4.72 (1H, d, H-2,
J¼8.3 Hz), 5.45 (1H, d, H-7, J¼14.8 Hz), 7.02–7.38 (10H,
m, arom. H). Anal. Calcd for C24H28N2O2: C 76.56%,
H 7.50%; found: C 76.80%, H 7.69%.
To a solution of 4 (0.222 g, 1 mmol) in p-xylene (2 mL),
benzaldehyde (0.1 mL, 1 mmol) was added. After 40 h of
reflux, the reaction mixture was cooled and diluted with
ethyl acetate (20 mL). It was extracted with 5% aq NaHCO3
(3ꢃ15 mL) and the combined water layers were acidified
with 15% HCl to pH¼2. The precipitated solid was filtered
and dried, yielding 0.034 g (11%) of colorless crystalline
trans-2, identical in all respects with trans-2, prepared as
above.
3.5.1.4. ( )-trans-1-Benzyl-3-(morpholine-4-carbonyl)-
2-phenylpiperidin-6-one (5d). White powder; yield:
1
3.5. Preparation of amides 5a–o
73%, mp 143–145 ꢁC. IR (CHCl3): 1630 (CON) cmꢂ1. H
NMR d (CDCl3): 1.83–1.96 (1H, m, H-4), 2.02–2.22 (1H,
m, H-4), 2.53–2.95 (4H, m, 2H-5, 2CH2N), 2.94–3.21 (2H,
m, H-3, CH2N), 3.22–3.46 (4H, m, H-7, CH2N, 2CH2O),
3.47–3.73 (2H, m, CH2O), 4.65 (1H, d, H-2, J¼8.5 Hz),
3.5.1. Preparation of ( )-trans-1-benzyl-6-oxo-2-phenyl-
piperidine-3-carboxylic acid amides 5a–n. A mixture of
2 (0.309 g, 1 mmol) and SOCl2 (0.15 mL, 2 mmol) in

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8323
5.48 (1H, d, H-7, J¼14.8 Hz), 6.96–7.41 (10H, m, arom. H).
13C NMR d (CDCl3): 23.2 (1C, C-4), 31.5 (1C, C-5), 42.1
(1C, CH2N), 44.9 (1C, C-7), 45.9 (1C, CH2N), 46.7 (1C,
C-3), 63.2 (1C, C-2), 66.0 (1C, CH2O), 66.5 (1C, CH2O),
127.2 (3C, Ph), 128.2 (2C, Ph), 128.4 (3C, Ph), 129.0 (2C,
Ph), 136.5 (1C, Ph), 139.6 (1C, Ph), 170.0 (1C, C-6),
170.3 (1C, CON). Anal. Calcd for C23H26N2O3: C
72.99%, H 6.92%; found: C 72.73%, H 6.92%.
H-4, CH2N), 2.27 (3H, s, CH3), 2.33–2.46 (1H, m, CH2N),
2.51–2.68 (2H, m, H-5, CH2N), 2.73–2.87 (1H, m, H-5),
2.95–3.22 (3H, m, H-3, CH2N), 3.30–3.48 (3H, m, H-7,
CH2N), 3.71–3.92 (1H, m, CH2N), 4.64 (1H, d, H-2,
J¼8.6 Hz), 5.45 (1H, d, H-7, J¼14.8 Hz), 6.99–7.42 (10H,
m, arom. H). 13C NMR d (CDCl3): 23.1 (1C, C-4), 31.5
(1C, C-5), 41.6 (1C, CH2N), 45.0 (1C, C-7), 45.3 (1C,
CH2N), 45.6 (1C, CH3), 46.8 (1C, C-3), 54.2 (1C, CH2N),
54.4 (1C, CH2N), 63.1 (1C, C-2), 127.2 (3C, Ph), 128.2
(3C, Ph), 128.3 (2C, Ph), 128.9 (2C, Ph), 136.6 (1C, Ph),
139.8 (1C, Ph), 170.1 (2C, C-6, CON). Anal. Calcd for
C24H29N3O2: C 73.63%, H 7.47%; found: C 73.82%, H
7.32%.
3.5.1.5. ( )-trans-1-Benzyl-N,N-diisopropyl-6-oxo-2-
phenylpiperidine-3-carboxamide (5e). Chromatographic
purification (hexane–ethyl acetate¼1:1) and recrystalliza-
tion yielded 5e as white powder (44%). Mp 75–77 ꢁC. IR
1
(CHCl3): 1620 (CON) cmꢂ1. H NMR d (CDCl3): 0.54
(3H, d, CH3, J¼6.5 Hz), 1.01 (3H, d, CH3, J¼6.6 Hz),
1.11 (3H, d, CH3, J¼6.8 Hz), 1.27 (3H, d, CH3,
J¼6.8 Hz), 1.72–1.89 (1H, m, H-4), 1.99–2.19 (1H, m,
H-4), 2.50–2.68 (1H, m, H-5), 2.72–2.84 (1H, m, H-5),
2.90–3.03 (1H, m, H-3), 3.14–3.37 (1H, br s, CHN), 3.45
(1H, d, H-7, J¼14.8 Hz), 3.53–3.71 (1H, m, CHN), 4.81
(1H, d, H-2, J¼9.3 Hz), 5.43 (1H, d, H-7, J¼14.8 Hz),
7.00–7.37 (10H, m, arom. H). Anal. Calcd for C25H32N2O2:
C 76.50%, H 8.22%; found: C 76.45%, H 8.41%.
3.5.1.9.
( )-trans-1-Benzyl-3-(4-(2-hydroxyethyl)pi-
perazine-1-carbonyl)-2-phenylpiperidin-6-one (5i). White
needles; yield: 75%, mp 136–138 ꢁC. IR (Nujol): 3355 (OH),
1620 (CON) cmꢂ1. 1H NMR d (CDCl3): 1.80–1.94 (1H, m,
H-4), 1.99–2.29 (4H, m, H-4, 3CH2N), 2.31–2.45 (3H, m,
CH2N), 2.51–2.69 (1H, m, H-5), 2.73–2.87 (1H, m, H-5),
2.88–3.22 (3H, m, H-3, 2CH2N), 3.27–3.37 (1H, m,
CH2N), 3.41 (1H, d, H-7, J¼14.8 Hz), 3.55 (2H, t, CH2O,
J¼5.3 Hz), 3.58–3.64 (1H, m, CH2N), 4.67 (1H, d, H-2,
J¼8.5 Hz), 5.47 (1H, d, H-7, J¼14.8 Hz), 7.01–7.40 (10H,
m, arom. H). 13C NMR d (CDCl3): 23.0 (1C, C-4), 31.4
(1C, C-5), 41.7 (1C, CH2N), 44.9 (1C, C-7), 45.4
(1C, CH2N), 46.8 (1C, C-3), 52.2 (1C, CH2N), 52.5 (1C,
CH2N), 57.6 (1C, CH2N), 59.0 (1C, CH2O), 63.1 (1C,
C-2), 127.2 (3C, Ph), 128.2 (3C, Ph), 128.4 (2C, Ph), 129.0
(2C, Ph), 136.5 (1C, Ph), 139.7 (1C, Ph), 170.1 (2C, C-6,
CON). Anal. Calcd for C25H31N3O3: C 71.23%, H 7.41%;
found: C 69.88%, H 7.77%.
3.5.1.6. ( )-trans-1-Benzyl-N,N-dicyclohexyl-6-oxo-2-
phenylpiperidine-3-carboxamide (5f). Chromatographic
purification (hexane–ethyl acetate¼3:2) and recrystalliza-
tion yielded 5f as white powder (44%). Mp 161–163 ꢁC.
IR (CHCl3): 1625 (CON) cmꢂ1. 1H NMR d (CDCl3): 0.83–
1.88 (20H, m, 10CH2), 2.00–2.21 (1H, m, H-4), 2.21–2.48
(1H, br s, CHN), 2.49–2.80 (2H, m, H-4, H-5), 2.71–2.85
(1H, m, H-5), 2.91–3.15 (2H, m, H-3, CHN), 3.44 (1H, d,
H-7, J¼14.8 Hz), 4.74 (1H, d, H-2, J¼8.9 Hz), 5.43 (1H,
d, H-7, J¼14.8 Hz), 6.97–7.37 (10H, m, arom. H). MS m/z:
472 (M+, 100), 281 (8). Anal. Calcd for C31H40N2O2: C
78.77%, H 8.53%; found: C 78.85%, H 8.68%.
3.5.1.10.
piperazine-1-carbonyl)piperidin-6-one (5j). White needlꢂes1;
yield: 84%, mp 181–183 ꢁC. IR (CHCl3): 1645 (CON) cm
( )-trans-1-Benzyl-2-phenyl-3-(4-phenyl-
.
1H NMR d (CDCl3): 1.85–1.96 (1H, m, H-4), 2.04–2.26 (2H,
m, H-4, CH2N), 2.54–2.82 (3H, m, 2H-5, CH2N), 2.82–2.94
(1H, m, CH2N), 3.02–3.15 (3H, m, H-3, 2CH2N), 3.23–3.45
(1H, m, CH2N), 3.38–3.52 (2H, m, H-7, CH2N), 3.69–3.81
(1H, m, CH2N), 4.68 (1H, d, H-2, J¼8.6 Hz), 5.49 (1H, d,
C-7, J¼14.8 Hz), 6.74–6.81 (2H, m, arom. H), 6.85–6.92
(1H, m, arom. H), 7.03–7.08 (2H, m, arom. H), 7.13–7.39
(10H, m, arom. H). 13C NMR d (CDCl3): 23.3 (1C, C-4),
31.6 (1C, C-5), 41.7 (1C, CH2N), 45.2 (1C, C-7), 45.4 (1C,
CH2N), 46.8 (1C, C-3), 49.0 (1C, CH2N), 49.2 (1C, CH2N),
63.2 (1C, C-2), 116.5 (2C, Ph), 120.5 (1C, Ph), 127.2 (3C,
Ph), 128.2 (2C, Ph), 128.3 (1C, Ph), 128.4 (2C, Ph), 129.0
(1C, Ph), 129.1 (1C, Ph), 136.6 (1C, Ph), 139.8 (1C, Ph),
150.5 (1C, Ph), 170.0 (1C, C-6), 170.2 (1C, CON). MS m/z:
454 (M+, 100), 347 (12), 294 (7), 292 (39), 251 (20), 197
(18), 196 (90), 189 (67), 163 (8), 130 (54). Anal. Calcd for
C29H31N3O2: C 76.79%, H 6.89%; found: C 76.74%, H
7.16%.
3.5.1.7. ( )-trans-N-(2-(1H-indol-3-yl)ethyl)-1-benzyl-
6-oxo-2-phenylpiperidine-3-carboxamide (5g). White
powder; yield: 61%, mp 178–180 ꢁC. IR (Nujol): 3240
(NH), 1630, 1615 (CON) cmꢂ1 1H NMR d (DMSO):
.
1.69–1.92 (2H, m, H-4), 2.38–2.72 (5H, m, H-3, 2H-5,
2CH2), 3.12–3.27 (2H, dt, CH2N, J¼7.1, 13.2 Hz), 3.33
(1H, d, H-7, J¼15.3 Hz), 4.70 (1H, d, H-2, J¼6.8 Hz),
5.22 (1H, d, H-7, J¼15.3 Hz), 6.91–7.47 (15H, m, 1CH,
14 arom. H), 7.94 (1H, t, NHCO, J¼5.6 Hz), 10.75 (1H, d,
NH, J¼1.0 Hz). 13C NMR d (DMSO): 22.3 (1C, C-4),
25.0 (1C, CH2), 30.7 (1C, C-5), 39.4 (1C, CH2N), 46.7
(1C, C-7), 48.0 (1C, C-3), 62.2 (1C, C-2), 111.4 (1C, indole),
111.6 (1C, indole), 118.2 (2C, indole), 120.9 (1C, indole),
122.6 (1C, indole), 126.9 (1C, Ph), 127.0 (2C, Ph), 127.1
(1C, indole), 127.5 (2C, Ph), 127.7 (1C, Ph), 128.3 (2C,
Ph), 128.7 (2C, Ph), 136.2 (1C, indole), 137.2 (1C, Ph),
140.7 (1C, Ph), 169.5 (1C, C-6), 171.3 (1C, CON). Anal.
Calcd for C29H29N3O2: C 77.14%, H 6.47%; found: C
77.49%, H 6.81%.
3.5.1.11.
piperazine-1-carbonyl)-2-phenylpiperidin-6-one
( )-trans-1-Benzyl-3-(4-(4-fluorophenyl)-
(5k).
3.5.1.8. ( )-trans-1-Benzyl-3-(4-methylpiperazine-1-
carbonyl)-2-phenylpiperidin-6-one (5h). Chromatographic
purification (ethyl acetate–methanol¼4:1 containing 1%
aq ammonia) and recrystallization yielded 5h as white solid
(52%). Mp 100–103 ꢁC. IR (CHCl3): 1630 (CON) cmꢂ1. 1H
NMR d (CDCl3): 1.81–1.95 (1H, m, H-4), 2.00–2.19 (2H, m,
White needles; yield: 55%, mp 153–155 ꢁC. IR (CHCl3):
1
1635 (CON) cmꢂ1. H NMR d (CDCl3): 1.84–1.98 (1H,
m, H-4), 2.02–2.22 (2H, m, H-4, CH2N), 2.53–2.71 (2H,
m, H-5, CH2N), 2.73–2.89 (2H, m, H-5, CH2N), 2.91–3.03
(1H, m, CH2N), 3.03–3.17 (2H, m, H-3, CH2N) 3.23–3.36
(1H, m, CH2N) 3.37–3.51 (2H, m, H-7, CH2N), 3.69–3.83

8324
N. T. Burdzhiev, E. R. Stanoeva / Tetrahedron 62 (2006) 8318–8326
(1H, m, CH2N), 4.68 (1H, d, H-2, J¼8.5 Hz), 5.49 (1H, d,
H-7, J¼14.8 Hz), 6.67–6.80 (2H, m, arom. H), 6.88–7.00
(2H, m, arom. H), 7.01–7.11 (2H, m, arom. H), 7.13–7.40
(8H, m, arom. H). 13C NMR d (CDCl3): 23.3 (1C, C-4),
31.5 (1C, C-5), 41.8 (1C, CH2N), 45.1 (1C, C-7), 45.4
(1C, CH2N), 46.8 (1C, C-3), 50.0 (1C, CH2N), 50.3 (1C,
CH2N), 63.2 (1C, C-2), 115.6 (2C, d, Ph, J¼22.2 Hz),
118.4 (2C, d, Ph, J¼7.8 Hz), 127.3 (3C, Ph), 128.3 (3C,
Ph), 128.4 (2C, Ph), 129.0 (2C, Ph), 136.6 (1C, Ph), 139.8
(1C, Ph), 147.2 (1C, d, Ph, J¼2.3 Hz), 157.5 (1C, d, CF,
J¼240.2 Hz), 170.0 (1C, C-6), 170.2 (1C, CON). MS m/z:
472 (M+, 100), 342 (1.75), 279 (3.75), 261 (3.50), 217
(4.25). Anal. Calcd for C29H30FN3O2: C 73.86%, H
6.41%; found: C 74.18%, H 6.56%.
CH2N), 3.14–3.30 (2H, m, CH2N), 3.31–3.45 (2H, m, H-7,
CH2N), 3.53–3.66 (1H, m, CH2N), 4.66 (1H, d, H-2,
J¼8.5 Hz), 5.47 (1H, d, H-7, J¼14.8 Hz), 7.01–7.40 (10H,
m, arom. H). 13C NMR d (CDCl3): 23.3 (1C, C-4), 28.3
(3C, 3CH3), 31.6 (1C, C-5), 41.7 (2C, CH2N), 45.3 (3C,
C-7, 2CH2N), 46.8 (1C, C-3), 63.2 (1C, C-2), 80.3 (1C,
OC(CH3)3), 127.2 (2C, Ph), 127.3 (1C, Ph), 128.3 (2C,
Ph), 128.4 (3C, Ph), 129.0 (2C, Ph), 136.6 (1C, Ph), 139.7
(1C, Ph), 154.2 (1C, NCOO), 170.0 (1C, C-6), 170.4 (1C,
CON). Anal. Calcd for C28H35N3O4: C 70.42%, H 7.39%;
found: C 70.45%, H 7.32%.
3.5.2. ( )-trans-1-Benzyl-2-phenyl-3-(piperazine-1-car-
bonyl)piperidin-6-one (5o). A mixture of 5n (0.220 g,
0.5 mmol) and F3CCOOH (0.53 mL, 7 mmol) was sonicated
for 15 min. The mixture was neutralized with 10% aq
Na2CO3 and extracted with ethyl acetate (30 mL). The
organic phase was dried (Na2SO4) and the solvent was evapo-
rated under reduced pressure. The resulting oil was recrys-
tallized from ethyl acetate to yield 5o as white crystals
(0.118 g, 68%). Mp 144–146 ꢁC. IR (CHCl3): 1635 (CON)
3.5.1.12.
piperazine-1-carbonyl)-2-phenylpiperidin-6-one
( )-trans-1-Benzyl-3-(4-(3-chlorophenyl)-
(5l).
Chromatographic purification (hexane–ethyl acetate¼1:1)
and recrystallization yielded 5l as pale pink spheres (41%).
Mp 152–154 ꢁC. IR (CHCl3): 1630 (CON) cmꢂ1. 1H NMR
d (CDCl3): 1.83–1.97 (1H, m, H-4), 2.03–2.23 (2H, m,
H-4, CH2N), 2.53–2.82 (3H, m, 2H-5, CH2N), 2.83–2.95
(1H, m, CH2N), 3.00–3.16 (3H, m, H-3, 2CH2N), 3.20–
3.34 (1H, m, CH2N), 3.35–3.48 (2H, m, H-7, CH2N), 4.67
(1H, d, H-2, J¼8.6 Hz), 5.49 (1H, d, H-7, J¼14.8 Hz),
6.64 (1H, dd, arom. H, J¼2.1, 8.3 Hz), 6.72 (1H, t, arom.
H, J¼2.1 Hz), 6.83 (1H, dd, arom. H, J¼1.7, 7.8 Hz),
7.01–7.40 (11H, m, arom. H). Anal. Calcd for
C29H30ClN3O2: C 71.37%, H 6.20%; found: C 71.71%, H
6.36%.
1
cmꢂ1. H NMR d (CDCl3): 1.58 (1H, s, NH), 1.80–2.19
(3H, m, 2H-4, CH2N), 2.42–2.81 (5H, m, 2H-5, 3CH2N),
2.81–2.98 (1H, m, CH2N), 2.99–3.17 (2H, m, H-3, CH2N),
3.21–3.35 (1H, m, CH2N), 3.41 (1H, d, H-7, J¼14.8 Hz),
3.48–3.61 (1H, m, CH2N), 4.68 (1H, d, H-2, J¼8.5 Hz),
5.47 (1H, d, H-7, J¼14.8 Hz), 7.01–7.41 (10H, m, arom.
H). Anal. Calcd for C23H27N3O2: C 73.18%, H 7.21%;
found: C 73.07%, H 6.83%.
3.6. Preparation of methyl ( )-trans-1-benzyl-6-oxo-2-
phenylpiperidine-3-carboxylate (6)
3.5.1.13. ( )-trans-1-Benzyl-2-phenyl-3-(4-(3-(trifluoro-
methyl)phenyl)piperazine-1-carbonyl)piperidin-6-one
(5m). Chromatographic purification (hexane–ethyl
acetate¼2:3) and recrystallization yielded 5m as colorless
needles (40%). Mp 136–138 ꢁC. IR (CHCl3): 1645 (CON)
A mixture of 2 (5.89 g, 19 mmol), methanol (30 mL), and
concd H2SO4 (2 mL) was refluxed for 2 h. The cooled reac-
tion mixture was poured into water (100 mL). The suspen-
sion was neutralized with 10% aq Na2CO3 and extracted
with ethyl acetate (3ꢃ30 mL). The organic phase was dried
(Na2SO4) and the solvent was evaporated under reduced
pressure. The crude product was recrystallized from ethyl
acetate to give 6 as colorless platelets (4.53 g, 77%). Mp
125–127 ꢁC. IR (Nujol): 1730 (COOCH3), 1630 (CON)
1
cmꢂ1. H NMR d (CDCl3): 1.85–1.97 (1H, m, H-4), 2.04–
2.22 (2H, m, H-4, CH2N), 2.54–2.83 (3H, m, 2H-5,
CH2N), 2.84–2.98 (1H, m, CH2N), 3.04–3.18 (3H, m, H-3,
2CH2N), 3.24–3.35 (1H, m, CH2N), 3.36–3.49 (2H, m, H-
7, CH2N), 3.73–3.85 (1H, m, CH2N), 4.67 (1H, d, H-2,
J¼8.6 Hz), 5.50 (1H, d, H-7, J¼14.8 Hz), 6.89–6.97 (2H,
m, arom. H), 7.02–7.09 (2H, m, arom. H), 7.09–7.40 (10H,
m, arom. H). 13C NMR d (CDCl3): 23.3 (1C, C-4), 31.6
(1C, C-5), 41.6 (1C, CH2N), 45.2 (2C, C-7, CH2N), 46.8
(1C, C-3), 48.5 (1C, CH2N), 48.8 (1C, CH2N), 63.2 (1C,
C-2), 112.6 (1C, q, Ph, J¼3.8 Hz), 116.7 (1C, q, Ph,
J¼3.8 Hz), 119.3 (1C, Ph), 124.1 (1C, q, CF3, J¼
272.6 Hz), 127.3 (3C, Ph), 128.3 (2C, Ph), 128.4 (1C, Ph),
128.5 (2C, Ph), 129.1 (2C, Ph), 129.6 (1C, Ph), 131.4 (1C,
q, CCF3, J¼31.8 Hz), 136.6 (1C, Ph), 139.8 (1C, Ph),
150.7 (1C, Ph), 170.0 (1C, C-6), 170.3 (1C, CON). MS
m/z: 522 (M+, 100), 292 (12), 202 (9), 196 (47), 130 (39),
120 (7). Anal. Calcd for C30H30F3N3O2: C 69.08%, H
5.80%; found: C 68.79%, H 5.67%.
1
cmꢂ1. H NMR d (CDCl3): 1.83–2.10 (2H, m, H-4), 2.52–
2.66 (1H, m, H-5), 2.69–2.84 (2H, m, H-3, H-5), 3.34 (1H,
d, H-7, J¼14.7 Hz), 3.48 (3H, s, CH3), 4.89 (1H, d, H-2,
J¼3.9 Hz), 5.60 (1H, d, H-7, J¼14.7 Hz), 7.10–7.43 (10H,
m, arom. H). 13C NMR d (CDCl3): 19.0 (1C, C-4), 29.3
(1C, C-5), 46.2 (1C, C-7), 47.7 (1C, C-3), 51.8 (1C,
OCH3), 60.6 (1C, C-2), 126.5 (2C, Ph), 127.2 (1C, Ph),
127.9 (1C, Ph), 128.2 (2C, Ph), 128.4 (2C, Ph), 128.9 (2C,
Ph), 136.6 (1C, Ph), 139.6 (1C, Ph), 169.7 (1C, C-6),
171.9 (1C, COO). Anal. Calcd for C20H21NO3: C 74.28%,
H 6.55%; found: C 74.04%, H 6.82%.
3.7. Preparation of ( )-trans-1-benzyl-5-(hydroxy-
methyl)-6-phenylpiperidin-2-one (7)
3.5.1.14. tert-Butyl-4-(( )-trans-1-benzyl-6-oxo-2-phe-
nylpiperidine-3-carbonyl)piperazine-1-carboxylate (5n).
White crystals; yield: 58%, mp 134–136 ꢁC. IR (CHCl3):
To a stirred suspension of LiCl (1.78 g, 42 mmol) and KBH4
(2.27 g, 42 mmol) in THF (10 mL) was added dropwise a
solution of 6 (4.53 g, 14 mmol) in THF (20 mL) for 20 min.
The reaction mixture was stirred at room temperature for 5 h.
The solvent was removed under reduced pressure and the
residue was poured in water (100 mL). The suspension
1680 (COOC(CH3)3), 1635 (CON) cmꢂ1
.
1H NMR
d (CDCl3): 1.42 (9H, s, 3CH3), 1.81–2.20 (3H, m, 2H-4,
CH2N), 2.27–2.45 (1H, m, CH2N), 2.53–2.71 (1H, m, H-
5), 2.74–2.98 (2H, m, H-5, CH2N), 2.98–3.13 (2H, m, H-3,

N. T. Burdzhiev, E. R. Stanoeva / Tetrahedron 62 (2006) 8318–8326
8325
was extracted with ethyl acetate (3ꢃ30 mL) and the organic
phase was dried (Na2SO4). After removal of the solvent, the
residue was purified by recrystallization from ethyl acetate,
to give 7 as white powder (3.71 g, 90%). Mp 134–136 ꢁC. IR
(Nujol): 3300 (OH), 1600 (CON) cmꢂ1. 1H NMR d (CDCl3):
1.52–1.70 (1H, m, H-4), 1.82–2.08 (2H, m, H-4, H-5), 2.58
(2H, t, 2H-3, J¼6.9 Hz), 3.31 (1H, d, H-7, J¼14.6 Hz),
3.41–3.55 (2H, m, CH2OH), 4.37 (1H, d, H-6, J¼4.9 Hz),
5.59 (1H, d, H-7, J¼14.6 Hz), 7.09–7.45 (10H, m, arom.
H). 13C NMR d (CDCl3): 19.7 (1C, C-4), 29.7 (1C, C-3),
43.3 (1C, C-5), 47.5 (1C, C-7), 61.0 (1C, C-6), 62.6 (1C,
CH2O), 126.9 (2C, Ph), 127.3 (1C, Ph), 127.7 (1C, Ph),
128.2 (2C, Ph), 128.5 (2C, Ph), 128.7 (2C, Ph), 137.1 (1C,
Ph), 140.6 (1C, Ph), 170.7 (1C, C-2). Anal. Calcd for
C19H21NO2: C77.26%, H 7.17%;found:C 77.59%, H7.00%.
m, 2H-3, H-4, H-5, 2H-8, 2CH2N), 2.41–2.63 (2H, m,
CH2N), 3.28 (1H, d, H-7, J¼14.4 Hz), 4.64 (1H, s, H-6),
5.61 (1H, d, H-7, J¼14.4 Hz), 7.10–7.43 (10H, m, arom.
H). Anal. Calcd for C24H30N2O: C 79.52%, H 8.34%; found:
C 79.18%, H 8.20%.
3.9.2. ( )-trans-1-Benzyl-5-(morpholinomethyl)-6-
phenylpiperidin-2-one (9b). White powder; yield: 92%,
1
mp 115–117 ꢁC. IR (Nujol): 1640 (CON) cmꢂ1. H NMR
d (CDCl3): 1.39–1.54 (1H, m, H-4), 1.86–2.03 (4H, m,
H-4, H-5, 2CH2N), 2.08–2.26 (2H, m, H-8, CH2N), 2.26–
2.41 (2H, m, H-8, CH2N), 2.41–2.65 (2H, m, 2H-3), 3.24
(1H, d, H-7, J¼14.3 Hz), 3.43–3.60 (4H, m, CH2O), 4.66
(1H, s, H-6), 5.67 (1H, d, H-7, J¼14.3 Hz), 7.10–7.44
(10H, m, arom. H). Anal. Calcd for C23H28N2O2: C
75.79%, H 7.74%; found: 75.69%, H 7.59%.
3.8. Preparation of (( )-trans-1-benzyl-2-oxo-6-phenyl-
piperidin-5-yl)methyl 4-methylbenzenesulfonate (8)
3.9.3. tert-Butyl-4-((( )-trans-1-benzyl-2-oxo-6-phenyl-
piperidin-5-yl)methyl)piperazine-1-carboxylate (9c).
White powder; yield: 90%, mp 162–163 ꢁC. IR (Nujol):
p-Toluenesulfonyl chloride (4.41 g, 23.1 mmol) was added
in portions, with stirring, to a solution of 7 (3.41 g,
11.6 mmol) in pyridine (30 mL) maintained at ꢂ5 ꢁC. The
reaction mixture was allowed to warm to room temperature
and the stirring continued for further 4 h. The mixture was
poured into ice-water and the product was extracted with
ethyl acetate (3ꢃ30 mL). The organic layer was dried
(Na2SO4) and evaporated. The resulting oil was recrystal-
lized from ethyl acetate to yield 8 as colorless needles
(4.1 g, 79%). Mp 98–100 ꢁC. IR (Nujol): 1630 (CON),
1680 (COOC(CH3)3), 1625 (CON) cmꢂ1 1H NMR d
.
(CDCl3): 1.45 (10H, s, H-4, 9CH3), 1.83–2.02 (4H, m,
H-4, H-5, 2CH2N), 2.05–2.15 (1H, m, H-8), 2.18–2.33
(3H, m, H-8, 2CH2N), 2.38–2.63 (2H, m, 2H-3), 3.13–3.31
(5H, m, H-7, 4CH2N), 4.65 (1H, s, H-6), 5.67 (1H, d, H-7,
J¼14.3 Hz), 7.11–7.45 (10H, m, arom. H). 13C NMR
d (CDCl3): 19.4 (1C, C-4), 28.3 (4C, C-3, 3CH3), 37.6
(1C, C-5), 47.8 (1C, C-7), 52.9 (3C, CH2N), 58.8 (2C,
CH2N), 61.0 (1C, C-6), 79.4 (1C, OC(CH3)3), 126.5 (2C,
Ph), 127.3 (1C, Ph), 127.4 (1C, Ph), 128.3 (2C, Ph), 128.7
(2C, Ph) 128.8 (2C, Ph), 137.5 (1C, Ph), 141.5 (1C, Ph),
154.6 (1C, NCOO), 170.0 (1C, C-2). Anal. Calcd for
C28H37N3O3: C 72.54%, H 8.04%; found: C 72.32%, H
7.95%.
1
1180 (OSO2) cmꢂ1. H NMR d (CDCl3): 1.58–1.74 (1H,
m, H-4), 1.79–1.95 (1H, m, H-4), 2.08–2.22 (1H, m, H-5),
2.46 (3H, s, CH3), 2.54 (2H, t, H-3, J¼6.8 Hz), 3.28 (1H,
d, H-7, J¼14.7 Hz), 3.76–3.90 (2H, m, CH2O), 4.18 (1H,
d, H-6, J¼6.1 Hz), 5.49 (1H, d, H-7, J¼14.7 Hz), 6.93–
7.08 (4H, m, arom. H), 7.22–7.35 (8H, m, arom. H), 7.59–
7.65 (2H, m, arom. H). 13C NMR d (CDCl3): 20.1 (1C,
C-4), 21.6 (1C, CH3), 29.8 (1C, C-3), 41.0 (1C, C-5), 47.3
(1C, C-7), 60.8 (1C, C-6), 69.5 (1C, CH2O), 126.9 (2C,
Ph), 127.4 (1C, Ph), 127.8 (2C, Ph), 128.1 (1C, Ph), 128.2
(2C, Ph), 128.5 (2C, Ph), 128.9 (2C, Ph), 129.8 (2C, Ph),
132.4 (1C, CS), 136.6 (1C, Ph), 139.4 (1C, Ph), 145.0 (1C,
CCH3), 169.8 (1C, C-2). Anal. Calcd for C26H27NO4S: C
69.44%, H 6.05%; found: C 69.74%, H 6.22%.
3.9.4. ( )-trans-1-Benzyl-6-phenyl-5-((4-phenylpiper-
azin-1-yl)methyl)piperidin-2-one (9d). Chromatographic
purification (hexane–ethyl acetate¼3:2) and recrystalliza-
tion yielded 9d as white powder (35%). Mp 117–119 ꢁC.
1
IR (Nujol): 1635 (CON) cmꢂ1. H NMR d (CDCl3): 1.40–
1.55 (1H, m, H-4), 1.86–2.06 (2H, m, H-4, H-5), 2.08–
2.22 (3H, m, H-8, 2CH2N), 2.30 (1H, dd, H-8, J¼9.8,
12.4 Hz), 2.40–2.65 (4H, m, 2H-3, 2CH2N), 2.93–3.09
(4H, m, CH2N), 3.25 (1H, d, H-7, J¼14.3 Hz), 4.68 (1H, s,
H-6), 5.66 (1H, d, H-7, J¼14.3 Hz), 6.80–6.93 (3H, m,
arom. H), 7.12–7.44 (12H, m, arom. H). 13C NMR
d (CDCl3): 19.5 (1C, C-4), 28.4 (1C, C-3), 37.7 (1C, C-5),
48.0 (1C, C-7), 49.1 (2C, CH2N), 53.2 (2C, CH2N), 58.8
(1C, CH2N), 61.2 (1C, C-6), 115.9 (2C, Ph), 119.6 (1C,
Ph), 126.6 (2C, Ph), 127.3 (1C, Ph), 127.4 (1C, Ph), 128.4
(2C, Ph), 128.7 (2C, Ph) 128.9 (2C, Ph), 129.0 (2C, Ph),
137.6 (1C, Ph), 141.7 (1C, Ph), 151.2 (1C, Ph), 170.1 (1C,
C-2). Anal. Calcd for C29H33N3O: C 79.23%, H 7.57%;
found: C 79.49%, H 7.83%.
3.9. Preparation of ( )-trans-5-aminomethylpiperidin-
2-ones 9a–g
To a solution of 8 (0.90 g, 2 mmol) in toluene (5 mL) was
added the corresponding amine (6 mmol). The reaction
mixture was refluxed until the completion of the reaction de-
termined by TLC. The mixture was allowed to cool down to
room temperature and ethyl acetate (50 mL) was added. The
organic layer was washed with water (4ꢃ20 mL) and then
dried (Na2SO4). The solvent was removed under reduced
pressure. The resulting oil was recrystallized or purified by
column chromatography and subsequent recrystallization
from ethyl acetate–hexane, if not stated otherwise. In this
way the following compounds were prepared:
3.9.5. ( )-trans-1-Benzyl-5-((4-(4-fluorophenyl)piper-
azin-1-yl)methyl)-6-phenylpiperidin-2-one (9e). Colorless
crystals; yield: 69%, mp 149–151 ꢁC. IR (CHCl3): 1615
(CON) cmꢂ1 1H NMR d (CDCl3): 1.40–1.55 (1H, m,
.
3.9.1. ( )-trans-1-Benzyl-6-phenyl-5-((piperidin-1-yl)
methyl)piperidin-2-one (9a). White powder; yield: 57%,
H-4), 1.86–2.06 (2H, m, H-4, H-5), 2.08–2.23 (3H, m, H-8,
2CH2N), 2.31 (1H, dd, H-8, J¼9.8, 12.4 Hz), 2.39–2.65
(4H, m, 2H-3, 2CH2N), 2.85–3.01 (4H, m, CH2N), 3.25
(1H, d, H-7, J¼14.3 Hz), 4.68 (1H, s, H-6), 5.66 (1H, d,
1
mp 95–97 ꢁC. IR (CHCl3): 1635 (CON) cmꢂ1. H NMR
d (CDCl3): 1.24–1.55 (7H, m, H-4, 6CH2), 1.81–2.37 (8H,

8326
N. T. Burdzhiev, E. R. Stanoeva / Tetrahedron 62 (2006) 8318–8326
H-7, J¼14.3 Hz), 6.78–7.01 (4H, m, arom. H), 7.12–7.44
(10H, m, arom. H). Anal. Calcd for C29H32FN3O: C
76.12%, H 7.05%; found: C 76.44%, H 7.14%.
References and notes
1. Felpin, F.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693–3712.
2. Lee, H.; Chun, J.; Pak, C. Tetrahedron 2003, 59, 6445–6454.
3. Dragull, K.; Yoshida, W.; Tang, C. Phytochemistry 2003, 63,
193–198.
4. Weintraub, P.; Sabol, J.; Kane, J.; Borcherding, D. Tetrahedron
2003, 59, 2953–2989.
5. Shetty, B.; McFadden, A.; Hofer, P. U.S. Patent 4,476,311,
1984; Chem. Abstr. 1985, 102, 583.
6. Hill, M.; Reddy, P.; Covey, D.; Rothman, S. J. Pharmacol. Exp.
Ther. 1998, 285, 1303–1309.
7. Baroudi, M.; Robert, J.; Luu-Duc, C. Heterocycl Commun.
1996, 2, 255–260.
8. Trost, B.; Fandrick, D. Org. Lett. 2005, 7, 823–826.
9. Bodas, M.; Upadhyay, P.; Kumar, P. Tetrahedron Lett. 2004, 45,
987–988.
10. Verbist, B.; De Borggraeve, W.; Toppet, S.; Compernolle, F.;
Hoornaert, G. Eur. J. Org. Chem. 2005, 2941–2950.
11. de Meglio, P. G.; Corradi, F.; Revenna, F.; Gentili, P.; Tempra-
Gabbiati, G.; Cristina, T.; Riva, M. Il Farmaco 1987, 42,
359–382.
3.9.6. ( )-trans-1-Benzyl-5-((4-(3-chlorophenyl)piper-
azin-1-yl)methyl)-6-phenylpiperidin-2-one (9f). Chromato-
graphic purification (hexane–ethyl acetate¼3:2) and
recrystallization yielded 9f as white crystalꢂs1(66%). Mp
155–157 ꢁC. IR (CHCl3): 1615 (CON) cm
.
1H NMR
d (CDCl3): 1.39–1.54 (1H, m, H-4), 1.86–2.05 (2H, m, H-4,
H-5), 2.06–2.21 (3H, m, H-8, 2CH2N), 2.30 (1H, dd, H-8,
J¼9.8, 12.4 Hz), 2.39–2.66 (4H, m, 2H-3, 2CH2N), 2.91–
3.09 (4H, m, CH2N), 3.25 (1H, d, H-7, J¼14.3 Hz), 4.67
(1H, s, H-6), 5.67 (1H, d, H-7, J¼14.3 Hz), 6.70–6.84 (3H,
m, arom. H), 7.11–7.44 (11H, m, arom. H). 13C NMR
d (CDCl3): 19.5 (1C, C-4), 28.4 (1C, C-3), 37.6 (1C, C-5),
47.9 (1C, C-7), 48.6 (2C, CH2N), 52.9 (2C, CH2N), 58.7
(1C, CH2N), 61.2 (1C, C-6), 113.7 (1C, Ph), 115.5 (1C,
Ph), 119.1 (1C, Ph), 126.6 (2C, Ph), 127.3 (1C, Ph), 127.4
(1C, Ph), 128.4 (2C, Ph) 128.8 (2C, Ph), 128.9 (2C, Ph),
129.9 (1C, Ph), 134.8 (1C, CCl), 137.6 (1C, Ph), 141.6 (1C,
Ph), 152.2 (1C, Ph), 170.1 (1C, C-2). Anal. Calcd for
C29H32ClN3O: C 73.48%, H 6.80%; found: C 73.21%, H
6.71%.
12. Wang, C.; Wuonola, M. Org. Prep. Proced. Int. 1992, 24,
583–621.
13. Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1729.
14. Mitchinson, A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1 2000,
2862–2892.
15. Chan, T.; Kwong, S.; Mak, T.; Kwok, R.; Chen, X.; Shi, K.
J. Inclusion Phenom. 1988, 6, 507–513.
16. Cushman, M.; Castagnoli, N. J. Org. Chem. 1974, 39, 1546–
1550.
17. Bonnaud, B.; Carlessi, A.; Bigg, D. J. Heterocycl. Chem. 1993,
30, 257–265.
18. Kozekov, I.; Koleva, R.; Palamareva, M. J. Heterocycl. Chem.
2002, 39, 229–235.
19. Stoyanova, M.; Kozekov, I.; Palamareva, M. J. Heterocycl.
Chem. 2003, 40, 795–803.
20. Pessoa-Mahana, H.; Gajardo, G.; Araya-Maturana, R.;
Carcamo, J.; Pessoa-Mahana, C. Synth. Commun. 2004, 34,
2513–2521.
3.9.7. ( )-trans-1-Benzyl-6-phenyl-5-((4-(3-(trifluoro-
methyl)phenyl)piperazin-1-yl)methyl)piperidin-2-one (9g).
White powder; yield: 79%, mp 151–153 ꢁC (methanol). IR
(CHCl3): 1615 (CON) cmꢂ1. 1H NMR d (CDCl3): 1.40–1.55
(1H, m, H-4), 1.87–2.06 (2H, m, H-4, H-5), 2.07–2.23 (3H,
m, H-8, 2CH2N), 2.32 (1H, dd, H-8, J¼9.9, 12.3 Hz), 2.40–
2.66 (4H, m, 2H-3, 2CH2N), 2.96–3.14 (4H, m, CH2N), 3.25
(1H, d, H-7, J¼14.3 Hz), 4.68 (1H, s, H-6), 5.67 (1H, d,
H-7, J¼14.3 Hz), 6.98–7.44 (14H, m, arom. H). 13C NMR
d (CDCl3): 19.5 (1C, C-4), 28.4 (1C, C-3), 37.7 (1C, C-5),
48.0 (1C, C-7), 48.7 (2C, CH2N), 53.0 (2C, CH2N), 58.7
(1C, CH2N), 61.2 (1C, C-6), 112.0 (1C, q, Ph, J¼3.8 Hz),
115.7 (1C, q, Ph, J¼3.8 Hz), 118.6 (1C, Ph), 124.3 (1C, q,
CF3, J¼272.3 Hz), 126.6 (2C, Ph), 127.4 (1C, Ph), 127.5
(1C, Ph), 128.4 (2C, Ph) 128.8 (2C, Ph), 128.9 (2C, Ph),
129.5 (1C, Ph), 131.3 (1C, q, CCF3, J¼31.7 Hz), 137.6 (1C,
Ph), 141.6 (1C, Ph), 151.3 (1C, Ph), 170.1 (1C, C-2). Anal.
Calcd for C30H32F3N3O: C 70.99%, H 6.35%; found: C
71.21%, H 6.63%.
€
21. Mensonides-Harsema, M.; Liao, Y.; Bottcher, H.; Bartoszyk,
G. D.; Greiner, H. E.; Harting, J.; De Boer, P.; Wikstrom,
€
H. V. J. Med. Chem. 2000, 43, 432–439.
22. Kinoyama, I.; Taniguchi, N.; Yoden, T.; Koutoku, H.; Furutani,
T.; Kudoh, M.; Okada, M. Chem. Pharm. Bull. 2004, 52,
1330–1333.
Acknowledgements
23. Azizian, J.; Mohammadi, A.; Karimi, A.; Mohammadizadeh,
M. J. Org. Chem. 2005, 70, 350–352.
We would like to thank to: Johnson & Johnson, R&D,
Janssen Pharmaceutica, Belgium; St. Kliment Ohridski
University of Sofia; Ministry of Education and Science of
Republic of Bulgaria for the kind financial support.
24. Cushman, M.; Castagnoli, N. J. Org. Chem. 1973, 38, 440–
448.
25. Abraham, R.; Fisher, J.; Loftus, P. Introduction to NMR
Spectroscopy; Wiley: New York, NY, 1988.