Synthesis of piperidinones incorporating an amino acid moiety as potential SP antagonists

Article abstract of DOI:10.1016/j.crci.2010.08.005

Substituted (±)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3- carboxamides (type I) and the acylated derivatives of (±)-trans-5-amino- 1-benzyl-6-phenylpiperidin-2-one (type II) were prepared by the reaction of (±)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-c

Full text of DOI:10.1016/j.crci.2010.08.005

C. R. Chimie 13 (2010) 1443–1449
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´
Full paper/Memoire
Synthesis of piperidinones incorporating an amino acid moiety as
potential SP antagonists
*
Nikola Burdzhiev, Elena Stanoeva
Department of Organic Chemistry, Faculty of Chemistry, St. Kliment Ohridski University of Sofia, 1, J. Bourchier Avenue, 1164 Sofia, Bulgaria
A R T I C L E I N F O
A B S T R A C T
Article history:
Substituted (Æ)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-carboxamides (type I) and the
acylated derivatives of (Æ)-trans-5-amino-1-benzyl-6-phenylpiperidin-2-one (type II) were
prepared by the reaction of (Æ)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-carboxylic acid
and some common reagents to provide the products in satisfactory yields. Newly synthesized
compounds share the same moiety with common SP antagonists and thus similar activities
might be expected.
Received 12 May 2010
Accepted after revision 20 August 2010
Available online 14 October 2010
Keywords:
Piperidinones
´
ß 2010 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Peptide bond
Hofmann Rearrangement
Configuration determination
SP antagonists
1. Introduction
into the piperidinone ring gave rise to the so-called
constraint pseudopeptides. Some of them have been
The naturally occurring Substance
P
(SP) is an
shown to possess ACE inhibitory activity [11,12]. Our
interest was focused on substituted piperidinones of type I
and II (Fig. 1), because of their structural similarity with
the already known SP antagonists.
Although the disubstituted piperidine framework has
shown various pharmaceutical activities, the pattern of
disubstitutedpiperidinesof typesI and II is less explored[5].
The purpose of the present investigation is to incorpo-
rate a moiety of an amino acid via a peptide bond to the
piperidinone ring leading to 3-carboxamides of type I and
5-(acylated amino)piperidinones of type II. This structural
modification would allow the investigation of the binding
ability of the newly synthesized compounds with the
undecapeptide belonging to the tachykinine family of
peptides, with very important biological activities [1,2]. It
was established that the release of SP is related to the
transmission of pain and the induction of neurogenic
inflammatory response [2–4]. SP evokes the release of such
neurotransmitters as acetylholine, histamine and GABA
[5]. The low degree of receptor selectivity combined with
the metabolic instability of peptides limit their use as
pharmacological tools [1]. This stimulated the search for
potent nonpeptide antagonists of the human neurokinin-1
(NK1) receptor to which SP preferentially binds [6]. It has
recently been reported that 3-amino- or 3-hydroxypiper-
idine derivatives such as CP-99994 and L-733060 respec-
tively, exhibit excellent affinity and selectivity with human
NK1 receptor [1,2,6–8]. Piperidinones are also useful
advanced intermediates in the preparation of piperidines
human NK1 receptor. Glycine and L-a-phenylalanine were
used, because they are components of the structure of SP.
Protected L-tryptophan was selected as well, because
esters of N-acetyl-L-tryptophan are shown to possess high
binding affinity towards human NK1 receptor [1,13,14].
[9] and scaffolds in the synthesis of
b
-turn peptide
mimetics [10]. Incorporation of an
a-amino acid residue
2. Results and discussion
The first step in the preparation of compounds of type I
and II is the formation of the piperidinone ring. The
* Corresponding author.
E-mail address: estanoeva@chem.uni-sofia.bg (E. Stanoeva).
1631-0748/$ – see front matter ß 2010 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.crci.2010.08.005

1444
[()TD$FIG]
N. Burdzhiev, E. Stanoeva / C. R. Chimie 13 (2010) 1443–1449
Table 1
Compounds 4–6 and their yields.
Compound number
R
Yield, %
4
5
6
-CH3
70
52
74
-CH2Ph
-CH2Ind
in Table 1. Their structures were confirmed by means of
elemental analysis, IR and 1H NMR spectra.
Compounds 4–6 derived from the acid 1 are 1:1 mixtures
of
a
-S, (Æ)-trans diastereomers as evidenced by their 1H NMR
spectra. We did not manage to separate the two diastereomers
of compounds 4–6 by means of column chromatography. After
fractional recrystallization, compound 4 was separated into
two portions, which have close melting points. The 1H NMR
spectra of the two portions revealed that the first portion
consisted of diastereomers in 20:1 ratio and for the second one
the respective ratio was 1:4, determined by the integral for the
doublet signals of methyl groups. This allowed us to
distinguish the signals of eachdiastereomer. It was established
by this experiment that signals for the same protons in the
different diastereomers are not shifted in one and the same
direction. With this in mind, in the experimental section we
noted the signals for the same protons which have higher
chemical shift with ‘‘*’’ symbol. Relative trans configuration of
the substituents at the piperidinone ring of peptide derivatives
3–6 was assigned on the basis of the value of coupling
constants 3J2,3, which is in the interval of 6.6–8.3 Hz.
Fig. 1. Substituted piperidinones of types I and II.
reaction of glutaric anhydride with N-arylidene-N-alkyla-
mines provides a straightforward path to the synthesis of
the piperidinone ring, affording many racemic trans-1-
alkyl-2-aryl-6-oxopiperidine-3-carboxylic acids in one step
We investigated the formation of (Æ)-trans-5-amino-1-
benzyl-6-phenylpiperidin-2-one (7) from the acid 1 using the
Hofmann rearrangement protocol [20] from amide 8 [19]. We
investigated several types of reaction conditions: the
oxidative rearrangement by means of lead tetraacetate
[21], the application of diacetoxyiodobenzene [22,23] and
the classical protocol, by treatment with bromine in aqueous
sodium hydroxide solution [20]. The latter reagent proved to
work well in our hands especially when 1–2 mmol of the
starting amide 8 were used. When more than 2 mmol of 8
were employed, the reaction rate was slower and the yield of
the amine 7 was greatly reduced. The target amine 7, which
was obtained as a single diastereomer, is an uncrystallizable
oil. However, the purification of 7 by column chromatogra-
phy was difficult because of its great polarity so in the
subsequent acylation reactions it was used without further
[15–18]. The synthesis of
(Æ)-trans-1-benzyl-6-oxo-2-
phenylpiperidine-3-carboxylic acid (1) and its acid chloride
2 was previously described [15,17,19]. Acid 1 is a suitable
starting compound for carboxylic group transformations into
either 3-carboxamido compounds or into 5-amino derivatives.
As was already mentioned, acid 1 is obtained as a racemic
mixture of enantiomers and only one of them will be shown
throughout the text for clarity. Two reaction pathways were
explored, and they are depicted on Scheme 1. The reactions
shown do not affect the chiral centres of the heterocycle and
thus the trans relative configuration of the products follows
directly from the configuration of the starting acid 1.
The synthesis of compounds of type I involves a peptide
bond construction between acid 1 as an acylation agent
purification. Amine
7 was characterized by elemental
and methyl esters of glycine, L-
nine and L-tryptophan. Since the acid 1 was shown to give
readily the acid chloride 2 [19], we attempted first N-
a
-alanine, L-
a
-phenylala-
analysis as a crystalline hydrobromide salt. 1H NMR spectrum
of amine 7 was taken and compared to 1H NMR data of trans-
3-substituted-1-benzyl-2-phenylpiperidin-6-ones investi-
gated previously by us [19]. Amine 7 is characterized by a
doublet signal at 4.54 ppm with 3J5,6 = 3.8 Hz for H-6 in its 1H
NMR spectrum. Similar values of 3J for disubstituted
piperidinones have been previously observed and they are
attributed to an equiliblium between two conformations in
solution - one with axial-pseudoaxial protons, and the other–
with equatorial-pseudoequatorial protons at the chiral
centres of the ring [18,19]. This equilibrium appears to be
more shifted to the latter conformation. On this ground we
attributed trans relative configuration of the substituents at
the chiral C-5 and C-6 carbon atoms of the piperidinone ring
of 7. Such a conclusion is in agreement with already
acylation of the selected L-
a-amino acid esters with the aid
of 2. Methyl esters of L- -tryptophan and L-
a
a
-phenylala-
nine, were first converted from hydrochlorides to free
bases and then treated with the acid chloride 2. Methyl L-
a-alaninate was used as a hydrochloride and its acylation
by means of 2 was performed in the presence of excess of
triethylamine (TEA) as a base to bind hydrogen chloride.
Methyl glycinate hydrochloride was treated with the acid 1
in presence of dicyclohexylcarbodiimide (DCC) and TEA.
Thus compounds 3–6 were obtained in very good yields
after purification by means of column chromatography
followed by a recrystallization. Compounds 4–6 are shown

N. Burdzhiev, E. Stanoeva / C. R. Chimie 13 (2010) 1443–1449
1445
[()TD$FIG]
Scheme 1. Synthesis of compounds of type I and II (only one enantiomer is shown).
established retention of the configuration of the migrating
carbon atom during the Hofmann rearrangement [20].
As additional proofs for the structure of 7, methylcar-
bamate 9 and acetamide 10 were also prepared by
acylation of 7 with methyl chloroformate and acetic
anhydride, resp. (Scheme 2) Derivatives 9 and 10 are
crystalline solids, which were characterized by means of
mps, elemental analysis and 1H NMR spectra. The trans
relative configuration of 9 and 10 was assigned on the base
of the singlet signals of H-2 protons in 1H NMR spectra,
which can be explained with a preferred conformation
with equatorial-pseudoequatorial protons at the chiral
centres. This conclusion seems to be relevant, having in
mind that compounds 9 and 10 are directly derived from
the amine 7. We attempted the preparation of carbamate 9
by a Curtius rearrangement as well [24]. Thus, hydrazide
11 was prepared and treated with nitrous acid at 0 8C
(Scheme 3).
The formation of acyl azide 12 was confirmed by its IR
spectrum which exhibited an intensive band for the N3
group at 2130 cmÀ1. Azide 12 was not stable and without
further purification was refluxed in dry methanol. The

[()TD$FIG]
1446
N. Burdzhiev, E. Stanoeva / C. R. Chimie 13 (2010) 1443–1449
Scheme 2. Synthesis of compounds 9 and 10 (only one enantiomer is shown).
[()TD$FIG]
Scheme 3. Synthesis of compound 9 via Curtius rearrangement (only one enantiomer is shown).
yield of methyl carbamate 9 is comparable to that obtained
via the Hofmann rearrangement. The latter is however
more straightforward and on this ground Curtius rear-
rangement of acyl azide 12 was no longer explored for the
purposes of this investigation.
symbol, similarly to compounds 4–6. In the 1H NMR spectra
of compounds 13–15 the signal for =-2 appears as a doublet
3
with J2,3 in the interval 3.1–3.8 Hz, while for compound 16
the signal for the same proton was singlet. On this base we
assigned trans relative configuration of substituents attached
to chiral C-2 and C-3 atoms of the piperidinone ring of
compounds 13–16.
Biological screening of newly synthesized compounds
is now in course.
Further amine 7 was reacted with N-protected L-
amino acids – Cbz-Glycine, N-trifluroacetyl L- -phenylal-
anine, Boc-L-tryptophane and Boc-L- -alanine using the
a-
a
a
carbodiimide method (Scheme 1) [5,25]. In this way
compounds 13–16 were obtained in good yields after
column chromatography purification (Table 2).
3. Experimental
As in the case of compounds 4–6, compounds 14–16
were 1:1 mixtures of
a
-S, (Æ)-trans-diastereomers, accord-
Meltingpoints(mps) weretakenona ‘‘Boetius’’PHMK05
micro hot-stage apparatus and are not corrected. IR spectra
were recorded on a Specord 75 instrument. 1H NMR spectra
(250.13 MHz) were obtained on a Bruker Avance DRX-250
ing to their 1H NMR spectra. In spite of our efforts, we could
not separate the diastereomeric couples of compounds 14–16
by means of column chromatography. This made difficult the
description of 1H NMR spectral data in the Experimental part,
because the signals for the same protons in the different
diastereomers are not shifted in one and the same direction.
For this reason in the experimental part the signals for the
same protons with higher chemical shift are noted with ‘‘*’’
spectrometer. The chemical shifts are given in ppm (d)
relative to tetramethylsilane as internal standard and
coupling constants (J) are given in Hz. The microanalyses
were performed on VarioEL III CHNS/O, Elementar Analy-
sensysteme GmbH at the Faculty of Chemistry, University of
Sofia. Thin layer chromatography (tlc) was performed on
Merck 1.05554 silica gel 60F254 aluminum plates. Column
chromatography purifications were carried out using
Riedel-de Hae¨n silica gel S (0.063–0.100 mm).
Table 2
Compounds 13–16 and their yields.
Compound number
R
Yield, %
Compounds 1, 2 and 8 are prepared according to the
procedures given in reference [19].
Methyl [((Æ)-trans-1-benzyl-6-oxo-2-phenylpiperi-
dine-3-carbonyl)amino]acetate (3). To a solution of acid
1 [19] (0.309 g, 1 mmol) in dry dichloromethane (5 mL),
13
14
15
16
-H
42
31
50
61
-CH2Ph
-CH2Ind
-CH3

N. Burdzhiev, E. Stanoeva / C. R. Chimie 13 (2010) 1443–1449
1447
triethylamine (0.14 mL, 1 mmol) and methyl 2-aminoace-
tate hydrochloride (0.126 g, 1 mmol) were added. The
reaction mixture was cooled (-10 8C) and DCC (0.275 g,
1.3 mmol) was added in portions. The mixture was stirred
for 2 h at -10 8C and then 12 h at room temperature. The
resulting precipitate of 1,3-dicyclohexylurea was filtered
and discarded. The filtrate was evaporated under reduced
pressure and the resulting oil was dissolved in ethyl
acetate (30 mL). The solution was successively washed
with 10% HCl, water, 10% Na2CO3 and brine. Organic layer
was dried (Na2SO4) and the solvent was removed in vacuo.
Recrystallization from light petroleum/ethyl acetate
yielded 0.167 g (44%), mp 130–131 8C; IR (Nujol): 1610,
acetate (50 mL) and the organic solution was washed with
water (3 20 mL). Organic layer was dried (Na2SO4). Crude
products were purified by means of column chromatogra-
phy and/or recrystallization from ethyl acetate.
Methyl (2S)-2-(((Æ)-trans-1-benzyl-6-oxo-2-phenyl-
piperidine-3-carbonyl)amino)-3-phenylpropanoate (5).
Synthesized from acid chloride 2 and L-a-phenylalanine
methyl ester. Recrystallization from ethyl acetate yielded
0.245 g (52%) of 5 as white crystals, mp 148–150 8C; IR
(Nujol): 1640, 1670 and 1700 (E = ?), 3380 (NH) cmÀ1; 1H
x
NMR (CDCl3):
d 1.79–2.12 (m, 4H, 2xH-4, 2xH-4*), 2.45–
2.76 (m, 7H, H-3, H-3*, 2xH-5, 2xH-5*, CHCH2Ph), 2.82 (dd,
1H, CHCH2Ph*, J = 6.8, 13.9 Hz), 2.91 (dd, 1H, CHCH2Ph,
J = 4.9, 13.8 Hz), 3.09 (dd, 1H, CHCH2Ph*, J = 5.6, 13.9 Hz),
3.36 (d, 1H, CH2Ph, J = 14.8 Hz), 3.37 (d, 1H, CH2Ph*,
J = 14.8 Hz), 3.65 (s, 3H, OCH3), 3.66 (s, 3H, OCH3*), 4.62–
4.81 (m, 4H, H-2, H-2*, CHNH, CHNH*), 5.45 (d, 1H, CH2Ph,
J = 14.8 Hz), 5.48 (d, 1H, CH2Ph*, J = 14.8 Hz), 5.58–5.73 (m,
2H, NHCO, NHCO*), 6.39–6.50 (m, 2H, Ph, Ph*), 6.88–7.43
(m, 28H, Ph, Ph*). Anal. Calcd. for C29H30N2O4: C, 74.02; H,
6.43; N, 5.95; Found: E, 74.60; =, 6.41; N, 5.92.
1680 and 1750 (C = O), 3280 (NH) cmÀ1; 1H NMR (CDCl3):
d
1.91–2.13 (m, 2H, H-4), 2.50–2.82 (m, 3H, H-3, 2xH-5), 3.35
(d, 1H, CH2Ph, J = 14.7 Hz), 3.69 (dd, 1H, CH2NH, J = 5.1,
18.2 Hz), 3.69 (s, 3H, OCH3), 3.84 (dd, 1H, CH2NH, J = 5.6,
18.2 Hz), 4.69 (d, 1H, H-2, J = 6.6 Hz), 5.54 (d, 1H, CH2Ph,
J = 14.7 Hz), 5.65 (t, 1H, NHCO, J = 5.0 Hz), 7.07–7.42 (m,
10H, Ph). Anal. Calcd. for C22H24N2O4: C, 69.46; H, 6.36; N,
7.36; Found: E, 69.70; =, 6.37; N, 7.31.
Methyl (2S)-2-[((Æ)-trans-1-benzyl-6-oxo-2-phenyl-
Methyl (2S)-2-(((Æ)-trans-1-benzyl-6-oxo-2-phenyl-
piperidine-3-carbonyl)amino)-3-(1H-indol-3-yl)pro-
panoate (6). Synthesized from acid chloride 2 and L-
tryptophan methyl ester. Column chromatography with
light petroleum:ethyl acetate (1:2, v/v) and further recrys-
tallization from ethyl acetate afforded 0.378 g (74%) of 6 as
white crystals, mp 112–114 8C; IR (Nujol): 1620, 1650 and
piperidine-3-carbonyl)amino]-propanoate (4). A solu-
tion of acid chloride
dichloromethane (3 mL) was cooled (0 8C) and triethyla-
mine (0.41 mL, 3 mmol) was added to it. Solution of L-
2
[19] (1.5 mmol) in dry
a
-
alanine methyl ester hydrochloride (0.206 g, 1.5 mmol) in
dry dichloromethane (3 mL) was added and the reaction
mixture was stirred for 0.5 h at room temperature. The
solvent was removed under reduced pressure and the
residue was dissolved in ethyl acetate (50 mL). Organic
;
1750 (E = ?), 3190 and 3410 (NH) cmÀ1 1H NMR (DMSO-
d6): 1.55–1.91 (m, 4H, 2xH-4, 2xH-4*), 2.26–2.57 (m, 4H,
d
2xH-5, 2xH-5*), 2.66–3.01 (m, 5H, H-3, H-3*, 2xCH2Ind,
CH2Ind*), 3.10 (dd, 1H, CH2Ind*, J = 5.4, 14.5 Hz), 3.31 (d, 1H,
CH2Ph, J = 15.4 Hz), 3.33 (d, 1H, CH2Ph*, J = 15.4 Hz), 3.49 (s,
3H, OCH3), 3.51 (s, 3H, OCH3*), 4.34–4.49 (m, 2H, CHNH,
CHNH*), 4.62 (d, 1H, H-2, J = 6.6 Hz), 4.65 (d, 1H, H-2*,
J = 6.6 Hz), 5.15 (d, 1H, CH2Ph, J = 15.4 Hz), 5.17 (d, 1H,
CH2Ph*, J = 15.4 Hz), 6.70–7.47 (m, 30H, Ph, Ph*), 8.32 (d, 1H,
NHCO, J = 7.5 Hz), 8.35 (d, 1H, NHCO*, J = 8.0 Hz), 10.77 (d,
1H, indolic NH, J = 1.7 Hz), 10.85 (d, 1H, indolic NH*,
J = 1.8 Hz). Anal. Calcd. for C31H31N3O4: C, 73.06; H, 6.13;
N, 8.25; Found: E, 73.26; =, 6.10; N, 8.08.
solution was washed with water (3 20 mL) and dried
x
(Na2SO4). Recrystallization from ethyl acetate afforded
0.189 g (32%) of 20:1 diastereomeric mixture of 4, mp 197–
199 8C. Concentration of the filtrate yielded 0.228 g (38%)
of 1:4 diastereomeric mixture of 4, mp 199–201 8C. The
total yield was 0.417 g (70%) of 4 as white crystals. IR
(Nujol): 1635, 1675 and 1735 (E = ?), 3425 (NH) cmÀ1; 1H
NMR (CDCl3):
d 1.02 (d, 3H, CHCH3, J = 7.2 Hz), 1.19 (d, 3H,
CHCH3*, J = 7.2 Hz), 1.91–2.18 (m, 4H, 2xH-4, 2xH-4*),
2.48–2.83 (m, 6H, H-3, H-3*, 2xH-5, 2xH-5*), 3.37 (d, 1H,
CH2Ph, J = 14.7 Hz), 3.39 (d, 1H, CH2Ph*, J = 14.7 Hz), 3.66 (s,
3H, OCH3), 3.69 (s, 3H, OCH3*), 4.40 (dq, 2H, CHCH3,
CHCH3*, J = 7.2 Hz), 4.64 (d, 1H, H-2, J = 8.3 Hz), 4.71 (d, 1H,
H-2*, J = 6.3 Hz), 5.48 (d, 1H, CH2Ph, J = 14.7 Hz), 5.53 (d, 1H,
CH2Ph*, J = 14.7 Hz), 5.61 (d, 1H, NHCO, J = 7.9 Hz), 5.53 (d,
1H, NHCO*, J = 7.2 Hz), 7.03–7.42 (m, 20H, Ph, Ph*). Anal.
Calcd for C23H26N2O4: C, 70.03; H, 6.64; N, 7.10; Found: E,
70.67; =, 6.65; N, 7.40.
Synthesis of (Æ)-trans-5-amino-1-benzyl-6-phenyl-
piperidin-2-one (7). To a cooled (-5 8C) solution of NaOH
(0.480 g, 12 mmol) in water (6 mL), bromine (0.12 mL,
2.3 mmol) was added. The mixture was stirred for 0.5 h and
(Æ)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-carboxa-
mide 8 [19] (0.616 g, 2 mmol) was added. The reaction mixture
was stirred at 60 8C for 1.5 h until completion of the reaction
(tlc). After extraction with ethyl acetate combined organic
layers were washed with 1:1 HCl (25 mL). The water layer was
then alkalized with 10% NaOH and extracted with ethyl
acetate. Organic phase was dried (Na2SO4) and solvent was
evaporated under vacuo. The oily product 0.410 g (73%) was
used for further transformations without additional purifica-
General procedure for the synthesis of (Æ)-trans-1-
benzyl-6-oxo-2-phenylpiperidine-3-carboxamides
5
and 6. Hydrochloride of the methyl ester of the corre-
sponding L- -amino acid (3 mmol) is transformed into a
a
base and extracted with dichloromethane. The organic
solution was dried (Na2SO4). The solvent was removed and
the residue was dissolved in dry dichloromethane (2 mL).
This solution was added dropwise to a cooled (0 8C)
solution of acid chloride 2 [19] (1 mmol) in dry dichlor-
omethane (3 mL). Reaction mixture was stirred for 0.5 h at
room temperature and solvent was removed under
reduced pressure. The residue was dissolved in ethyl
tion. IR (Nujol): 1620 (C = O), 3360 and 3480 (NH2) cmÀ1
Synthesis of (Æ)-trans-5-amino-1-benzyl-6-phenyl-
piperidin-2-one hydrobromide. Amine (0.450 g,
.
7
1.6 mmol) was dissolved in dry methanol (5 mL) and
48% hydrobromic acid was added until pH = 3. Dry diethyl
ether was added (1 mL) and crystallized solid was collected
by filtration. Yield 0.448 g (78%), mp 175–178 8C; IR

1448
N. Burdzhiev, E. Stanoeva / C. R. Chimie 13 (2010) 1443–1449
(Nujol): 1595 (NH), 1620 (C = O), 2450–3250 (NH3+) cmÀ1
1H NMR (DMSO-d6):
1.70–1.86 (m, 1H, H-4), 1.87–2.04
(m, 1H, H-4), 2.55–2.71 (m, 2H, H-3), 3.42 (d, 1H, CH2Ph,
J = 15.1 Hz), 3.49–3.60 (m, 1H, H-5), 4.54 (d, 1H, H-6,
J = 3.8 Hz), 5.15 (d, 1H, CH2Ph, J = 15.1 Hz), 7.06–7.48 (m,
10H, Ph), 8.06 (br. s, 3H, NH3+). Anal. Calcd. for
;
hydrazide 11 (0,323 g, 1 mmol), water (2.8 mL) and 38%
hydrochloric acid (0.75 mL), a solution of NaNO2 (0.200 g,
3 mmol) in water (0.3 mL) was slowly added. After that the
reaction mixture was stirred 15 min at 0 8C and extracted
with dichloromethane. The organic solution was dried
(Na2SO4) and the solvent was evaporated at reduced
pressure to give 0.240 g (72%) azide 12 as an oily product.
d
C
18H20N2O.HBr: C, 59.84; H, 5.86; N, 7.75; Found:
E, 60.28; =, 5.84; N, 7.84.
Methyl
Æ)-trans-1-benzyl-6-oxo-2-phenylpiperi-
IR (Nujol): 1620 and 1705 (E = ?), 2130 (N3) cmÀ1
Methyl
Æ)-trans-1-benzyl-6-oxo-2-phenylpiperi-
.
(
(
din-3-ylcarbamate (9). To a cooled (0 8C) solution of
amine 7 (0.311 g, 1.1 mmol) in dichloromethane (5 mL),
triethylamine (0.21 mL, 1.5 mmol) and methyl chlorofor-
mate (0.1 mL, 1.3 mmol) were added. Reaction mixture was
stirred for 0.5 h at room temperature until completion of the
reaction (tlc). The mixture was diluted with ethyl acetate
(40 mL) and washed with water, 10% Na2CO3 and water till
pH = 7. Organic phase was dried (Na2SO4) and the solvent
was evaporated under reduced pressure. Column chroma-
tography with light petroleum:2-propanol (20:1, v/v)
yielded 0.277 g (75%) of 9 as white amorphous product,
mp 60–65 8C; IR (CHCl3): 1630, 1640 and 1715 (E = ?), 3435
din-3-ylcarbamate (9) via Curtius rearrangement.
A solution of azide 12 (0.167 g, 0.5 mmol) in dry methanol
(3 mL) was refluxed for 5 h and then the solvent was
evaporated at reduced pressure. The residue was dissolved
in dichloromethane (40 mL) and washed successively with
2.5% HCl, 10% Na2CO3 and water. The organic solution was
dried (Na2SO4) and the solvent was evaporated. Column
chromatography with light petroleum:ethyl acetate (2:1,
v/v) of the residue yielded 0.236 g (72%) of 9 as white
amorphous product, identical in all respects with methyl
carbamate 9, prepared via Hofmann protocol.
General procedure for the synthesis of acylated
derivatives of (Æ)-trans-5-amino-1-benzyl-6-phenylpi-
peridin-2-one (13–16). Solution of amine 7 (0.280 g,
1 mmol) and corresponding N-protected amino acid
(1 mmol) in dichloromethane (5 mL) was cooled to -15 8C.
DCC (1.3 mmol) was added portionwise and the reaction
mixture was stirred for 1 h until completion of the reaction
(tlc). The precipitated 1,3-dicyclohexylurea was filtered and
filtrate was evaporated. Resulting oily residue was dissolved
in ethyl acetate (50 mL) and washed with 1:1 HCl, water,
10% Na2CO3 and water. Organic phase was dried (Na2SO4)
and the solvent was removed. Crude products were purified
by means of column chromatography and/or recrystalliza-
tion.
(NH) cmÀ1; 1H NMR (CDCl3):
d1.63–1.77 (m, 1H, H-4), 1.85–
2.02(m, 1H, H-4), 2.49–2.74(m, 2H, H-5), 3.35(d, 1H, CH2Ph,
J = 14.6 Hz), 3.55 (s, 3H, OCH3), 3.83–3.99 (m, 1H, H-3), 4.57
(s, 1H, H-2), 4.87–5.03 (m, 1H, NHCO), 5.67 (d, 1H, CH2Ph,
J = 14.6 Hz), 7.12–7.45 (m, 10H, Ph). Anal. Calcd. for
C20H22N2O3: C, 70.99; H, 6.55; Found: C, 70.57; H, 6.55.
N-((Æ)-Trans-1-benzyl-6-oxo-2-phenylpiperidin-3-
yl)acetamide (10). To a solution of amine 7 (0.258 g,
1 mmol) in dry dichloromethane (21 mL), triethylamine
(0.17 mL, 1.2 mmol) and acetic anhydride (0.1 mL, 1 mmol)
were added. Reaction mixture was stirred for 24 h at room
temperature, diluted with ethyl acetate (50 mL) and
washed with water (3 15 mL). Organic phase was dried
x
(Na2SO4) and the solvent was evaporated. Recrystallization
from methanol/water yielded 0.120 g (40%) of 10 as white
crystals, mp 186–188 8C; IR (Nujol): 1640 (C = O), 3330
Benzyl 2-((Æ)-trans-1-benzyl-6-oxo-2-phenylpiperi-
din-3-ylamino)-2-oxoethylcarbamate (13). The com-
pound was synthesized from amine 7 and Cbz-Glycine.
Repeated recrystallization from ethyl acetate/light petro-
leum yielded 0.199 g (42%), mp 161–163 8C; IR (Nujol):
1620, 1670 and 1720 (E = ?), 3250 and 3315 (NH) cmÀ1; 1H
(NH) cmÀ1; 1H NMR (CDCl3):
d 1.56–1.70 (m, 1H, H-4), 1.81
(s, 3H, CH3CO), 1.82–1.95 (m, 1H, H-4), 2.41–2.65 (m, 2H,
H-5), 3.35 (d, 1H, CH2Ph, J = 14.4 Hz), 4.14–4.24 (m, 1H, H-
3), 4.62 (s, 1H, H-2), 5.63 (d, 1H, CH2Ph, J = 14.4 Hz), 5.99 (d,
1H, NHCO, J = 7.2 Hz), 7.18–7.46 (m, 10H, Ph). Anal. Calcd.
for C20H22N2O2: C, 74.51; H, 6.88; Found: E, 74.40; =, 6.97.
NMR (DMSO-d6):
d 1.43–1.93 (m, 2H, H-4), 2.51–2.62 (m,
1H, H-5), 2.68–2.89 (m, 1H, H-5), 3.22–3.57 (m, 2H, CH2Ph,
CH2NH), 3.69 (dd, 1H, CH2NH, J = 5.9, 16.8 Hz), 3.90–4.02 (m,
1H, H-3), 4.48 (d, 1H, H-2, J = 3.1 Hz), 5.03 (s, 2H, OCH2Ph),
5.32 (d, 1H, CH2Ph, J = 15.4 Hz), 6.87–7.57 (m, 16H, NHCOO,
Ph), 8.26 (d, 1H, NHCO, J = 7.0 Hz). Anal. Calcd. for
(
Æ)-Trans-1-benzyl-6-oxo-2-phenylpiperidin-3-car-
bohydrazide (11). A solution of methyl (Æ)-trans-1-benzyl-
6-oxo-2-phenylpiperidin-3-carboxylate [19] (0.161 g,
0.5 mmol) and hydrazine hydrate (0.25 g, 5 mmol) in dry
methanol (1 mL) was refluxed for 5 h. The solvent was
evaporated and the residue was dissolved in dichloro-
methane and dried (Na2SO4). The solvent was removed
and the residue was recrystallized from ethyl acetate, which
yielded 0.137 g (85%) of 11 as white crystals, mp 143–144 8C;
C28H29N3O4: C, 71.32; H, 6.20; N, 8.91; Found: C, 71.70;
H, 6.38; N, 9.20.
(2S)-N-((Æ)-trans-1-benzyl-6-oxo-2-phenylpiperi-
din-3-yl)-3-phenyl-2-(2,2,2-trifluoroacetamido)propa-
namide (14). The compound was synthesized from amine
7 and N-trifluroacetyl L-a-phenylalanine. Repeated re-
crystallization from ethyl acetate yielded 0.161 g (31%), mp
IR (Nujol): 1640 and 1660 (E = ?), 3200 and 3330 (NH) cmÀ1
;
1H NMR (CDCl3): d 1.89–2.20 (m, 2H, H-4); 2.46–2.86 (m, 3H,
H-3, 2xH-5); 3.40 (d, 1H, CH2Ph, J = 14.7 Hz); 3.68 (broad s,
2H, NH2); 4.66 (d, 1H, H-2, J = 7.6 Hz); 5.53 (d, 1H, CH2Ph,
J = 14.7 Hz); 6.47 (broad s, 1H, NH); 7.06–7.45 (m, 10H, Ph).
Anal. Calcd. for C19H21N3O2: C, 70.57; H, 6.55; N, 12.99;
Found: C, 70.87; H, 6.42; N, 12.52.
221–223 8C; IR (Nujol): 1625, 1665 and 1715 (C = O), 3225
(NH) cmÀ1; 1H NMR (DMSO-d6):
d 1.43–1.85 (m, 4H, 2xH-
4, 2xH-4*), 2.51–3.03 (m, 8H, 2xH-5, 2xH-5*, 2xCHCH2Ph,
2xCHCH2Ph*), 3.26 (d, 1H, CH2Ph, J = 14.7 Hz), 3.36 (d, 1H,
CH2Ph*, J = 14.7 Hz), 3.87–3.99 (m, 1H, H-3), 3.99–4.10 (m,
1H, H-3*), 4.44 (d, 1H, H-2, J = 3.8 Hz), 4.48 (d, 1H, H-2*,
J = 3.6 Hz), 4.59 (dt, 1H, CHNH, J = 5.2, 9.1 Hz), 4.78 (dt, 1H,
CHNH*, J = 5.0, 9.6 Hz), 5.30 (d, 1H, CH2Ph, J = 14.7 Hz), 5.36
(
Æ)-Trans-1-benzyl-6-oxo-2-phenylpiperidin-3-car-
bonylazide (12). To a stirred and cooled (0 8C) mixture of

N. Burdzhiev, E. Stanoeva / C. R. Chimie 13 (2010) 1443–1449
1449
(d, 1H, CH2Ph*, J = 14.7 Hz), 6.97–7.52 (m, 30H, Ph, Ph*),
Acknowledgment
8.56 (d, 1H, NHCO, J = 7.3 Hz), 8.63 (d, 1H, NHCO*,
J = 7.1 Hz), 9.56 (d, 1H, NHCOCF3, J = 9.1 Hz), 9.60 (d, 1H,
NHCOCF3*, J = 8.8 Hz). Anal. Calcd. for C29H28F3N3O3: C,
66.53; H, 5.39; N, 8.03; Found: C, 67.14; H, 5.31; N, 8.20.
Tert-butyl (2S)-1-((Æ)-trans-1-benzyl-6-oxo-2-phe-
nylpiperidin-3-ylamino)-3-(1H-indol-3-yl)-1-oxopro-
pan-2-ylcarbamate (15). The compound was synthesized
from amine 7 and Boc-L-tryptophan. Repeated recrystalli-
zation from ethyl acetate yielded 0.285 g (50%) mp 206–
208 8C; IR (Nujol): 1610, 1655 and 1685 (E = ?), 3310 and
The financial support of the University of Sofia Science
Fund (project 142/2007), National Science Fund of Bulgaria
at the Ministry of Education and Science (project TK-X-
1706/07) and project UNION (DO-02-82/2008) is gratefully
acknowledged.
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3425 (NH) cmÀ1 1H NMR (DMSO-d6):
; d 1.28 (s, 9H,
C(CH3)3), 1.33 (s, 9H, C(CH3)3*), 1.40–1.93 (m, 4H, 2xH-4,
2xH-4*), 2.53–2.98 (m, 8H, 2xH-5, 2xH-5*, 2xCH2Ind,
2xCH2Ind*), 3.28–3.45 (m, 2H, CH2Ph, CH2Ph*), 3.83–3.95
(m, 1H, H-3), 3.95–4.09 (m, 1H, H-3*), 4.14–4.37 (m, 2H,
CHNH, CHNH*), 4.46 (d, 2H, H-2, H-2*, J = 3.2 Hz), 5.29 (d,
2H, CH2Ph, CH2Ph*, J = 15.1 Hz), 6.53 (d, 1H, indolic H,
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30H, Ph, Ph*, NHCO, NHCO*), 8.14 (d, 1H, NHCOO,
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indolic NH, indolic NH*). Anal. Calcd. for C34H38N4O4: C,
72.06; H, 6.76; N, 9.89; Found: C, 72.54; H, 6.72; N, 9.99.
Tert-butyl (2S)-1-((Æ)-trans-1-benzyl-6-oxo-2-phe-
nylpiperidin-3-ylamino)-1-oxopropan-2-ylcarbamate
(16). The compound was synthesized from amine 7 and
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petroleum:ethyl acetate (1:1, v/v) yielded 0.275 g (61%)
of 16 as amorphous product, mp 95–98 8C; IR (Nujol):
1625, 1665 and 1705 (E = ?), 3300 and 3420 (NH) cmÀ1; 1H
NMR (CDCl3):
d 1.10 (d, 3H, CHCH3, J = 7.0 Hz), 1.18 (d, 3H,
CHCH3*, J = 7.1 Hz), 1.44 (s, 9H, C(CH3)3), 1.50 (s, 9H,
C(CH3)3*), 1.56–1.76 (m, 2H, H-4, H-4*), 1.82–2.01 (m, 2H,
H-4, H-4*), 2.49–2.71 (m, 4H, 2xH-5, 2xH-5*), 3.30 (d, 1H,
CH2Ph, J = 14.5 Hz), 3.32 (d, 1H, CH2Ph*, J = 14.5 Hz), 3.86–
4.21 (m, 4H, H-3, H-3*, CHCH3, CHCH3*), 4.52 (s, 1H, H-2),
4.54 (d, 1H, NHCO, J = 7.7 Hz), 4.63 (s, 1H, H-2*), 4.93 (d, 1H,
NHCO*, J = 7.7 Hz), 5.67 (d, 2H, CH2Ph, CH2Ph*, J = 14.5 Hz),
6.88 (br. s, 2H, NHCOO, NHCOO*), 7.16–7.52 (m, 20H, Ph,
Ph*). Anal. Calcd. for C26H33N3O4: C, 69.16; H, 7.37; Found:
C, 69.04; H, 7.30.
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Conflict of interest statement
The authors state that there is no conflict of interest.
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