Synthesis of new trisubstituted 4-aminopiperidines as PAF-receptor antagonists

Article abstract of DOI:10.1002/ejoc.200700667

Two novel classes of 4-aminopiperidines substituted in the 3-position by groups bearing either a carbamate or a ureido function have been synthesized from ethyl 4-oxo-3-piperidinecarboxylate and 3,3′-iminobis(propanenitrile) , respectively. The key step in this synthesis, the reduction of the piperidinic β-enamino ester or nitrile, occurred readily. In contrast to published works, the free primary amines could be isolated from the corresponding β-amino ester or nitrile. Regioselective amidification of the amino group offered two pairs of diastereoisomers which were successfully separated and identified. Measurement of PAF-receptor antagonist activity gave interesting results with an IC₅₀ close to the micromolar. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700667

FULL PAPER
DOI: 10.1002/ejoc.200700667
Synthesis of New Trisubstituted 4-Aminopiperidines as PAF-Receptor
Antagonists
Houcine Benmehdi,[a,b] Aazdine Lamouri,[a] Nawal Serradji,[a] Frédérique Pallois,[a] and
Françoise Heymans*[a]
Keywords: Aminopiperidines / Diastereoisomers / Enamines / Antagonists / Reduction / Biological activity
Two novel classes of 4-aminopiperidines substituted in the 3-
position by groups bearing either a carbamate or a ureido
function have been synthesized from ethyl 4-oxo-3-piper-
Regioselective amidification of the amino group offered two
pairs of diastereoisomers which were successfully separated
and identified. Measurement of PAF-receptor antagonist ac-
idinecarboxylate and 3,3Ј-iminobis(propanenitrile), respec- tivity gave interesting results with an IC50 close to the micro-
tively. The key step in this synthesis, the reduction of the
piperidinic β-enamino ester or nitrile, occurred readily. In
contrast to published works, the free primary amines could
be isolated from the corresponding β-amino ester or nitrile.
molar.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
can also be blocked by co-incubation with PAF acetylhy-
drolase,[21] the main catabolic enzyme for PAF, or by a
PAF-receptor antagonist.[21] Blocking pathologic effects of
PAF may therefore be favourable in the treatment of HIV-
associated dementia and inflammatory syndrome.[23]
Introduction
After characterization[1–3] of the platelet activating factor
(PAF), elucidation of its structure by three independent re-
search groups[4–6] and its stereospecific synthesis,[7–11] suf-
ficient material was available to allow evaluation of the
pharmacology and physiopathology of this agent. PAF is
recognized as a potent phospholipidic inflammatory media-
tor and plays a physiopathological role in a variety of clin-
ical conditions such as asthma[12] and pulmonary dysfunc-
tion, acute inflammation, cardiac anaphylaxis, thrombosis,
gastrointestinal ulceration, endotoxic shock, allergic skin
diseases, transplanted organ rejection, ovoimplantation in
pregnancy and retinal and corneal diseases.[13–20] Moreover,
in the central nervous system, high PAF concentrations are
reported in the cerebrospinal fluid of patients suffering
from dementia and an altered immune system.[21] Since di-
rect infection of neurons by HIV is unlikely and because
TNF-α and PAF are both neurotoxic, there is a consensus
that neuronal dysfunction and apoptosis are mediated by
these soluble factors released by macrophages and micro-
glia in the CNS.[22] PAF is probably the key element in this
phenomenon since TNF-α mediated neuronal apoptosis
The search for molecules able to antagonize the effects
of PAF has been a part of our work for a while. A study of
natural and synthetic inhibitors through their 3D electro-
static potential maps, which take into account volume, con-
formation and electronic distribution, led us to propose first
a simple model for a PAF-receptor comprising a bi-
polarized cylinder[24,25] and then a tetrapolarized one.[26]
From these findings we chose piperazine as a support for
functionalized moieties, in accordance with the hypotheses,
and designed and synthesized potent antagonists.[27,28] Be-
sides this activity, some of these compounds showed inhibi-
tion of HIV-1 replication in monocyte-derived macrophages
(MDMs).[29–31] Following our interest in this field, we
undertook to replace the piperazine ring of compounds 1
and 2 (Figure 1), previously synthesized, by an aminopiper-
idine moiety to evaluate the influence of this ring on both
biological activities. These modifications aimed to reinforce
the dual anti-PAF and anti-HIV-1 activity of 1 and to in-
crease the anti-PAF potency of 2 (Table 1). Indeed, the ami-
nopiperidine moiety is beneficial in compounds showing
various biological activities such as narcotic analgesics,[32]
neurokin-1 receptor ligands,[33] 5-HT2A serotonin receptor
antagonists,[34] CCR5 chemokine receptor ligands,[35] hu-
man β3-adrenergic receptor antagonists,[36] potent cognition
enhancing drugs,[37] ORL 1 antagonists[38] and human-
cloned dopamine D4 receptor antagonists[39] and has been
used as a supporting structure for nitrogen-type antago-
[a] Unité de Pharmacochimie Moléculaire et Systèmes Membran-
aires (EA 2381), Université Paris 7 – Denis Diderot, case 7066,
2 Place Jussieu, 75251 Paris Cedex 05, France
Fax: +33-144275641
E-mail: heymans@ccr.jussieu.fr
[b] Laboratoire de Chimie Organique, Substances Naturelles et
Analyse (COSNA), Faculté des Sciences, Université Aboubakr
Belkaid,
B. P. 119, Tlemcen, Algeria
Eur. J. Org. Chem. 2008, 299–307
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299

F. Heymans et al.
FULL PAPER
nists.[40] By using substituted 4-aminopiperidines instead of
their piperazine analogues, three important parameters are
modified: (i) the flexibility, (ii) the distance between the two
nitrogen atoms and, therefore, (iii) the substituent-induced
electronic distribution. To the best of our knowledge, the
properties of trisubstituted aminopiperidines have been po-
orly investigated so far; only a few papers have dealt with
this topic.[41–49] This prompted us to develop a new and
convenient synthesis of trisubstituted aminopiperidine de-
rivatives and to study their biological activity. We have suc-
ceeded in synthesizing new 4-aminopiperidine derivatives
substituted in position 3 by groups bearing a carbamate
(see Scheme 3) or a ureido (see Scheme 4) function. In these
two classes of compounds, we reduced conjugated double
bonds by using NaBH3CN/HCl or CH3COOH as the re-
ducing agent. The interesting point was that we were able
to separate diastereoisomers in a later step.
Scheme 1. Reagents and conditions: (i) AcONH4, MeOH, room
temp., 1 h, 99%; (ii) NaNH2, THF, reflux, 2 h, 81%.
Several attempts were made to perform the N-alkylation
or N-acylation of this enamine 3 by using either benzyl
chloride or 3,4,5-trimethoxybenzoyl chloride (TMB-Cl) in
refluxing toluene (2 weeks) but none was satisfactory as
only traces of the final products were obtained. Three
hypotheses could explain these results: (i) a strong conju-
gated system between the amine function, the double bond
and the carbonyl of the ester group, (ii) the formation of a
six-membered ring stabilized by hydrogen bonding between
the amine and ester functions and finally (iii) an equilib-
rium displaced more towards the imine than the enamine
group under basic conditions. The high stability of the en-
amine 3 did not allow its reduction into the desired amine
under common conditions: NaBH3CN in MeOH, NaBH4
in EtOH or NaBH3CN in nBuOH. Published work has re-
vealed that β-enamino esters can easily be reduced into the
corresponding β-amino esters.[50–53] A few methods for the
reduction of piperidinic β-enamino esters have been de-
scribed,[38,47–49] but the free primary amines could not be
isolated from the corresponding piperidinic β-amino esters
or nitriles in any of the cases. As shown in Scheme 2, the
intermediate 3 was successfully reduced to the key com-
pound 4 after treatment with NaBH3CN in acidic condi-
tions (HCl or acetic acid) and EtOH at 50 °C, affording in
good yield a crude mixture of inseparable diastereoisomers.
However, the addition of 3,4,5-trimethoxybenzoyl chloride
led to the desired amides 7 as two pairs of diastereoisomers
which could be easily separated by silica gel column
chromatography. In accord with the results of Kawamoto
et al., we chose to use the stereodescriptor trans to charac-
terize the stereoisomers presenting the higher Rf on TLC
Figure 1. Piperazine derivatives 1 and 2 and their biological data.
Table 1. In vitro anti-PAF activity of 4-aminopiperidine derivatives.
Compound Ar1
Ar2
Z
Anti-PAF IC50
[μM]
1
2
TMB
TMB
TMB –CH2OCON(Et)2
TMB –CH2NHCONHC6H12
8
Ͼ100
0.28
2.63
2.28
0.63
trans-10
cis-10
cis-12
cis-14
PhCH2 TMB –CH2OCON(Et)2
PhCH2 TMB –CH2OCON(Et)2
TMB
TMB –CH2OCON(Et)2
PhCH2 TMB –CH2NHCONHC5H11
Results and Discussion
Chemistry
Carbamate Series
Scheme 2. Reagents and conditions: 3,4,7: Z = CO2Et, 5,6,8: Z =
CN. (i) for 4: NaBH3CN, EtOH, HCl, 50 °C, 3 h, 65%; for 6:
NaBH3CN, EtOH, HCl, 50 °C, 12 h, 81%; (ii) for cis- and trans-7:
TMB-Cl, NEt3, CH2Cl2, room temp., 4 h, 56.3 and 30.4%, respec-
tively; for cis- and trans-8: TMB-Cl, NEt3,THF, room temp., 1 h,
50 and 36%, respectively.
As described in Scheme 1, ethyl 1-benzyl-4-oxo-3-piper-
idinecarboxylate was treated with a large excess of ammo-
nium acetate in MeOH at room temperature to give the
corresponding enamine 3.[38]
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Synthesis of Trisubstituted Aminopiperidines
1
and cis, the ones with the smaller Rf (Scheme 2).[38] The H Ureido Series
NMR spectra revealed that each diastereoisomer exists as
a pair of enantiomers.
As outlined in Scheme 1, compound 5 was obtained in
good yield from 3,3Ј-[(phenylmethyl)imino]bis(propane-
nitrile)[57,58] after Thorpe intramolecular cyclization using
sodium amide in refluxing THF.[59] As for the correspond-
ing ester 3, several strategies to prepare N-acylated or N-
alkylated compounds were investigated but all failed, prob-
ably for the reasons we evoked in the ester 3 case. Com-
pound 5 was then reduced by using NaBH3CN in the pres-
ence of concentrated HCl in EtOH to give the correspond-
ing β-aminonitrile 6 as a mixture of inseparable diastereo-
isomers (Scheme 2). Treatment of its amine function with
TMB-Cl gave two pairs of diastereoisomers cis- and trans-
8 which were separated by silica gel column chromatog-
raphy in 50 and 36% yields, respectively.
The reduction of cis- and trans-7 with NaBH4/LiCl ac-
cording to the published procedure provided alcohols cis-
and trans-9 (Scheme 3), respectively,.[54] Treatment of
alcohols 9 with first NaH and then by diethylcarbamoyl
chloride afforded carbamates cis- and trans-10 respectively,
in quantitative yields.[55] Subsequent removal of the N-ben-
zyl protecting group using ammonium formate and the Pd/
C catalyst generated the derivatives cis- and trans-11.[56]
Our synthesis was completed by a final treatment with
3,4,5-trimethoxybenzoyl chloride to provide compounds
cis- and trans-12 in 88 and 71% yields, respectively.
In the next step (Scheme 4) the hydrogenation of the ni-
trile function of compounds 8 was carried out in acidic eth-
anol in the presence of the Raney nickel catalyst[60] and pro-
vided the corresponding amines cis- and trans-13 which re-
acted with pentyl isocyanate to give the ureido compounds
cis- and trans-14 in moderate yields. Debenzylation oc-
curred with HCO2NH4 and Pd/C in refluxing methanol and
gave cis- and trans-15 in 79 and 60% yields, respectively.
These compounds were then acylated with TMB-Cl to the
desired final products cis- and trans-16 in 61 and 74%
yields, respectively.
Biological Results
The inhibition of platelet aggregation was evaluated by
the method of Cazenave et al. by using platelet-rich plasma
(PRP) of New Zealand rabbits.[61] The intermediates were
tested for their ability to antagonize PAF-induced platelet
aggregation. All the results obtained are listed in Table 1.
In the case of the carbamate series, cis-12 and the reference
compound 1 present similar anti-PAF activities showing
that the piperazine ring of 1 can be replaced by an aminopi-
peridine moiety (cis-12) without any alteration of the bio-
logical activity. Replacement of one of the 3,4,5-trimeth-
oxybenzoyl groups of 1 by a benzyl substituent (trans- and
Scheme 3. Reagents and conditions: (i) NaBH4, LiCl, THF, EtOH,
room temp., 36 h, 57 and 83%, respectively; (ii) NaH, THF,
ClCON(Et)2, reflux, 90 min, 81 and 93%, respectively; (iii) Pd/C,
HCO2NH4, MeOH, reflux, 1 h, 81 and 43%, respectively; (iv)
3,4,5-(CH3O)3C6H2COCl, NEt3, THF, room temp., 90 min, 88 and
71%, respectively.
Scheme 4. Reagents and conditions: (i) H2, Ni, EtOH, concd. HCl (cat.), 60 °C, 12 h, 75 and 37%, respectively; (ii) C5H11N=C=O,
CH2Cl2, room temp., 2 h, 65%; (iii) Pd/C, HCO2NH4, MeOH, reflux, 1 h, 79 and 60%, respectively; (iv) 3,4,5-(CH3O)3C6H2COCl, NEt3,
THF, room temp., overnight, 61 and 74%, respectively.
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301

F. Heymans et al.
FULL PAPER
of 3,3Ј-[(phenylmethyl)imino]bis(propanenitrile)[58,59] (33 g, 0.15
mol) in THF (400 mL) . The solution was then stirred and refluxed
for 2 h. The sodium amide excess was destroyed with water at 0 °C
and the solvents were removed to dryness. The residue was dis-
solved in CH2Cl2, washed with water and dried with MgSO4. The
organic layer was then concentrated in vacuo. Compound 5 was
obtained as a yellow solid (27 g, yield 81%). M.p. 152 °C, Rf = 0.51
cis-10) leads to potent compounds and diastereoisomers:
trans-10 (IC50 = 0.28 μm) is nearly 10 times more active
than its analogue cis-10 (IC50 = 2.63 μm). In the ureido
series, cis-14 presents a good antagonism (IC50 = 0.63 μm)
towards the PAF-receptor in contrast to the piperazine ana-
logue 2 which is inactive. Evaluation of the HIV-1 activity
of our synthesized trisubstituted 4-aminopiperidine deriva-
tives is currently underway.
(CH Cl /MeOH, 90:10, v/v). IR (KBr): ν = 3427 (NH ), 2928, 2823
˜
2
2
2
(CH2), 1642 (C=C), 1615 (ArC=C), 2181 (CN) cm–1. 1H NMR
(CDCl3): δ = 7.25–7.32 (m, 5 H, ArH), 4.39 (s, 2 H, NH2), 3.58 (s,
2 H, ArCH2), 3.07 (s, 2 H, CH2 piperidine), 2.58–2.64 (t, J =
5.73 Hz, 2 H, CH2 piperidine), 2.2–2.3 (t, J = 5.71 Hz, 2 H, CH2
piperidine) ppm. 13C NMR (CDCl3): δ = 154.7 (C=C-NH2), 137.5,
128.4, 127.4 (ArC=C), 119.1 (CN), 72.6 (C=C-CN), 61.5, 50.7,
48.2, 28.0 (ArCH2 and CH2 piperidine) ppm.
Conclusions
In summary, an efficient synthesis of trisubstituted ami-
nopiperidine with ureido and carbamate functions has been
developed. Contrary to the previously published papers, we
succeeded in isolating the β-amino ester 4 and β-aminoni-
trile 6 which are the key intermediates in the preparation of
other compounds. Two pairs of diastereoisomers in each
General Procedure for the Synthesis of Compounds 4 and 6:
NaBH3CN (2 equiv.) and acetic acid or hydrochloric acid (3 equiv.)
were added to a solution of the enamine 3 or 5 in ethanol at room
temperature and the mixture was heated at 50 °C until the reaction
was complete (TLC monitoring). After cooling, the excess
NaBH3CN was destroyed with water. After evaporation of the sol-
vents, the residue was dissolved in CH2Cl2 and washed with a solu-
tion of NaHCO3 and water. The organic layer was dried with
MgSO4, filtered and concentrated in vacuo.
1
series were isolated and characterized by H NMR spec-
troscopy. Preliminary biological results are interesting as all
the compounds present anti-PAF activity in the micromolar
range. Anti-retroviral evaluation of the racemic mixtures of
cis-/trans-12 and cis-/trans-16 is currently under investiga-
tion and chiral resolution of these mixtures could be at-
tempted if interesting results are obtained in order to test
the two enantiomeric forms separately.
Ethyl 4-Amino-1-benzyl-3-piperidinecarboxylate (4): Compound 4
was prepared according to the general procedure using 3 (34 g,
130 mmol) in ethanol (500 mL), NaBH3CN (16.5 g, 262 mmol) and
acetic acid (18.5 mL, 323 mmol). Further purification by silica gel
column chromatography (CH2Cl2 then CH2Cl2/MeOH, 97:3, v/v)
gave the title compound as a green oil (18 g, yield 65%). Rf = 0.34
Experimental Section
(CH Cl /MeOH, 93:7, v/v). IR (film): ν = 3378 (NH ), 2925–2808
˜
2
2
2
Materials and Methods: All reactions were monitored by thin-layer
chromatography on TLC plastic sheets (silica gel 60F254, layer
thickness 0.2 mm) from Merck. Column chromatography purifica-
tion was carried out on silica gel 60 (particle size 0.063–0.200 mm)
from Merck without any special treatment. All melting points were
determined with a digital melting point apparatus (Electrothermal)
and are uncorrected. The structures of all compounds were con-
(CH2 and CH3), 1726 (CO2Et), 1601 (ArC=C) cm–1. 1H NMR
(CDCl3): δ = 7.22–7.30 (m, 5 H, ArH), 4.07–4.18 (q, J = 7.2 Hz, 2
H, OCH2CH3), 3.06–3.44 (m, 2 H, Ar-CH2), 2.36–3.08 (2m, 4 H,
CH2 and CH piperidine), 2.28 (s, 2 H, NH2), 1.41–2.14 (3 m, 4 H,
NCH2CH2), 1.19–1.26 (t, J = 7 Hz, 3 H, OCH2CH3) ppm. 13C
NMR (CDCl3): δ = 172.9 (C=O ester), 137.8 (ArC=C), 129.0,
128.7, 128.0, 126.9 (ArCH=CH), 62.2 (OCH2CH3), 60.3 (ArCH2),
53.8, 51.9, 33.4 (CH2 piperidine), 51.0, 50.2 (CH piperidine), 14.0
(OCH2CH3) ppm.
1
firmed by IR, H and 13C NMR spectra. IR spectra were recorded
with an ATI Mattson Genesis Series FTIR infrared spectrometer
(4000–600 cm–1). 1H and 13C NMR spectra were recorded in
CDCl3 with a Bruker AC 200 spectrometer. Chemical shifts (δ)
were measured in ppm and are reported relative to the solvent peak
of TMS. All elemental analyses were within Ϯ0.4% of theoretical
values.
4-Amino-1-benzyl-3-cyanopiperidine (6): Concentrated hydrochloric
acid (12 n, 4.5 mL, 140 mmol) was added to a mixture of 5 (10.6 g,
50 mmol) in ethanol (100 mL) and NaBH3CN (6.25 g, 100 mmol)
was added. The solution was heated at 50 °C for 12 h. Purification
by silica gel column chromatography eluted with CH2Cl2 and
CH2Cl2/MeOH (97:3, v/v) gave the title compound as a green oil
(8.6 g, yield 80%). Rf = 0.23 (CH2Cl2/MeOH, 97:3, v/v). IR (film):
Ethyl
4-Amino-1-benzyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate
(3): AcONH4 (51 g, 662 mmol) was added to a solution of 1-ben-
zyl-3-ethoxycarbonyl-4-piperidone (20 g, 67 mmol) in methanol
(400 mL) at room temperature and the reaction mixture was stirred
for 1 h and concentrated in vacuo. The residue was dissolved in
CH2Cl2 and washed successively with a solution of NaHCO3 and
water. The organic layer was dried with MgSO4, filtered and con-
centrated to dryness to give compound 3 as a colourless oil (16 g,
ν = 3371–3303 (NH ), 2941–2807 (CH ), 1599 (ArC=C), 2239
˜
2
2
1
(CN) cm–1. H NMR (CDCl3): δ = 7.16–7.27 (m, 5 H, ArH), 3.53
(d, J = 13.4 Hz, ArCH), 3.4 (d, J = 13.4 Hz, ArCH), 2.73–2.87 (m,
4 H, CH and CH2 piperidine), 2.13–2.06 (m, 2 H, CH2 piperidine),
1.71–1.64 (q, J = 3.9 Hz, 2 H, CH2 piperidine) ppm. 13C NMR
(CDCl3): δ = 137.4, 137.1 (ArC=C), 128.4, 128.2, 127.9, 126.9,
126.7 (ArCH=CH), 119.7, 119.2 (CN), 61.5, 61.3 (ArCH2), 53.1,
52.2, 51.3, 33.3, 31.8 (CH2 piperidine), 50.9, 48.7, 37.9, 37.2 (CH
piperidine) ppm.
yield 99%). R = 0.25 (CH Cl /MeOH, 95:5 v/v). IR (film): ν =
˜
f
2
2
3440–3331 (NH2), 2903–2803 (CH2 and CH3), 1671 (CO2Et), 1621
1
(C=C), 1548 (ArC=C) cm–1. H NMR (CDCl3): δ = 7.21–7.37 (m,
5 H, ArH), 6.00 (br. s, 2 H, NH2), 4.07–4.17 (q, J = 7 Hz, 2 H,
OCH2CH3), 3.61 (s, 2 H, ArCH2), 3.24 (s, 2 H, N-CH2 piperidine),
2.47–2.53 (t, J = 5.6 Hz, 2 H, N-CH2 piperidine), 2.26–2.31 (t, J =
General Procedure for the Synthesis of Compounds cis-7, trans-7,
cis-8, trans-8, cis-12, trans-12, cis-16 and trans-16: A solution of
3,4,5-trimethoxybenzoyl chloride (1.1 equiv.) in dichloromethane
or THF was added dropwise to a solution of 4, 6, cis-11, trans-11,
cis-15 or trans-15 in dichloromethane or THF and triethylamine
(3 equiv.). The solution was stirred at room temperature until the
5.6 Hz,
2 H, N-CH2CH2-), 1.20–1.27 (t, J = 7 Hz, 3 H,
OCH2CH3) ppm.
4-Amino-1-benzyl-3-cyano-1,2,5,6-tetrahydropyridine (5): A suspen-
sion of sodium amide (7.25 g, 18 mmol) was added to a solution
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Synthesis of Trisubstituted Aminopiperidines
reaction was complete (TLC monitoring). After washing with a
NaHCO3 solution and water, the organic layer was dried with
MgSO4, filtered and concentrated to dryness. The residue was puri-
fied by chromatography on a silica gel column as indicated.
[1-Benzyl-4-(3,4,5-trimethoxybenzoylamino)piperidin-3-yl]methyl
N,N-Diethylcarbamate (trans-10): NaH (0.12 g, 5 mmol) was added
to a solution of trans-9 (1 g, 2.4 mmol) in dry THF (60 mL). The
mixture was stirred at 60 °C for 0.5 h, then a solution of diethyl-
carbamoyl chloride (0.36 g, 2.65 mmol) was added dropwise. The
reaction mixture was stirred at 60 °C for 1 h. The excess NaH was
destroyed with water and the solvents were removed under reduced
pressure. The crude product was dissolved in CH2Cl2 and washed
with water. The organic layer was dried with MgSO4, filtered and
concentrated in vacuo. Purification by silica gel column chromatog-
raphy, eluting with CH2Cl2 and CH2Cl2/1% MeOH, gave the title
compound as a white solid (1 g, yield 81%). M.p. 133 °C, Rf = 0.43
(CH2Cl2/MeOH, 93:7, v/v). C28H39N3O6·¾H2O (526.5): C 63.75,
Ethyl 1-Benzyl-4-(3,4,5-trimethoxybenzoylamino)-3-piperidinecarb-
oxylate (trans- and cis-7): Compounds trans- and cis-7 were pre-
pared by using 4 (11.8 g, 45 mmol) in dichloromethane (150 mL),
triethylamine (19 mL, 135 mmol) and a solution of 3,4,5-trime-
thoxybenzoyl chloride (11.43 g, 49.58 mmol) in dichloromethane
(50 mL). The reaction mixture was stirred at room temperature for
4 h and after usual treatment a mixture of the two pairs of dia-
stereoisomers was obtained as a white solid. Separation by silica
gel column chromatography using (CH2Cl2 then CH2Cl2/MeOH,
9:1, v/v) as eluent afforded trans-7 (6.7 g, 30.4% yield), m.p. 163 °C,
Rf = 0.34 (CH2Cl2/MeOH, 97:3, v/v), and cis-7 (12.4 g, 56.3%
yield), m.p. 146 °C, Rf = 0.26 (CH2Cl2/MeOH, 97:3, v/v), as white
H 7.96, N 7.96; found C 63.91, H 7.65, N 7.95. IR (KBr): ν = 3307
˜
(NH amide), 2922 (CH2 and CH3), 1703 (C=O carbamate), 1626
(C=O amide), 1583 (ArC=C), 1128 (OCH3) cm–1 1H NMR
.
(CDCl3): δ = 7.6–7.7 (br. d, 1 H, NHCO), 7.26–7.33 (m, 5 H, ArH),
7.20 (s, 2 H, ArH), 4.2–4.51 (m, 2 H, CH2OH), 4.0–4.18 (m, 1 H,
CH piperidine), 3.87–3.93 [2 s, 9 H, (OCH3)3], 3.47–3.6 (dd, J =
10 Hz, 2 H, ArCH2), 3.0–3.4 [br. q, 4 H, N(CH2CH3)2], 1.50–2.83
(m, 7 H, CH and CH2 piperidine), 0.9–1.2 [br. t, 6 H, N(CH2-
CH3)2] ppm. 13C NMR (CDCl3): δ = 166.7 (C=O amide), 156.0
(C=O ureido), 152.9, 140.5, 138.1 (ArC=C), 129.7, 128.8, 128.1,
127.0, 104.3 (ArCH=CH), 64.9 [CH2OCON(Et)2], 62.7 (ArCH2),
60.7, 56.1 (OCH3), 57.0, 52.2, 32.1 (CH2 piperidine), 49.1, 42.4 (CH
piperidine), 41.7, 41.2 (NCH2CH3), 13.8, 13.3 (NCH2CH3) ppm.
solids. IR (KBr) (trans-7 diastereoisomer): ν = 3341 (NH amide),
˜
2903 (CH2 and CH3), 1725 (CO2Et), 1630 (C=O amide), 1581
(ArC=C) cm–1; (cis-7 diastereoisomer) : ν = 3240 (NH amide),
˜
2929–2802 (CH2 and CH3), 1733 (CO2Et), 1628 (C=O amide), 1582
(ArC=C) cm–1. 1H NMR (CDCl3) (trans-7 diastereoisomer): δ =
7.38–7.43 (d, J = 10 Hz, 1 H, NHCO), 7.23–7.28 (m, 5 H, ArH),
6.98 (s, 2 H, ArH), 4.2–4.4 (m, 1 H, CH piperidine), 4.07–4.17 (q,
J = 7.14 Hz, 2 H, OCH2CH3), 3.85–3.88 [2 s, 9 H, (OCH3)3], 3.32–
3.62 (dd, J = 13.3 Hz, 2 H, ArCH2), 2.20–3.32 (m, 7 H, CH and
CH2 piperidine), 1.13–1.20 (t, J = 7.14 Hz, 3 H, OCH2CH3); (cis-
7 diastereoisomer): δ = 7.26–7.32 (m, 5 H, ArH), 6.96 (s, 2 H,
ArH), 6.17–6.21 (d, J = 8 Hz, 1 H, NHCO), 4.03–4.10 (q, J = 7 Hz,
2 H, OCH2CH3), 4.10–4.14 (m, 1 H, CH piperidine), 3.86–3.88 [2 s,
9 H, (OCH3)3], 3.55 (s, 2 H, ArCH2), 1.5–3.1 (m, 7 H, CH and
CH2 piperidine), 1.12–1.19 (t, J = 7.14 Hz, 3 H, OCH2CH3) ppm.
13C NMR (CDCl3) (trans-7 diastereoisomer): δ = 173.5 (C=O es-
ter), 166.0 (C=O amide), 153.0, 140.7, 138.3, 130.0 (ArC=C), 128.7,
128.0, 126.9, 104.2 (ArCH=CH), 62.4 (ArCH2), 60.8, 56.2 (OCH3),
60.5 (OCH2CH3), 54.4, 53.0, 29.0 (CH2 piperidine), 47.1, 44.3 (CH
piperidine), 13.9 (OCH2CH3); (cis-7 diastereoisomer): δ = 173.5
(C=O ester), 166.0 (C=O amide), 153.1, 140.0, 138.3, 130.0
(ArC=C), 128.7, 128.0, 126.9, 104.2 (ArCH=CH), 62.4 (ArCH2),
56.2, 60.8 (OCH3), 60.5 (OCH2CH3), 54.4, 53.0, 29.0 (CH2 piper-
idine), 47.2, 44.3 (CH piperidine), 14.0 (OCH2CH3) ppm.
General Procedure for the Synthesis of Compounds cis-11, trans-11,
cis-15 and trans-15: Ammonium formate, triethylamine (3 equiv.)
and palladium on activated carbon were added to a solution of cis-
10, trans-10, cis-14 or trans-14 in methanol. The mixture was re-
fluxed until the reaction was complete (TLC monitoring). After
cooling at room temperature, filtration of Pd/C and evaporation of
the solvent to dryness, the residue was dissolved in CH2Cl2 and
washed with water. The organic layer was dried with MgSO4, fil-
tered and concentrated in vacuo. The residue was purified by silica
gel column chromatography as indicated.
[4-(3,4,5-Trimethoxybenzoylamino)piperidin-3-yl]methyl N,N-Dieth-
ylcarbamate (trans-11): This compound was prepared using a solu-
tion of trans-10 (1 g, 1.94 mmol) in methanol (80 mL), ammonium
formate (1.5 g, 23.8 mmol) and Pd/C (0.3 g). The reaction mixture
was refluxed for 1 h. After concentrating in vacuo, purification on
a silica gel column chromatography, eluting with (CH2Cl2/MeOH,
97:3 and 90:10, v/v), gave the title compound as a viscous solid
(0.35 g, yield 43 %). Rf = 0.38 (CH2Cl2/MeOH, 80:20, v/v). IR
1-Benzyl-3-hydroxymethyl-4-(3,4,5-trimethoxybenzoylamino)piper-
idine (trans-9): Dry LiCl (1.48 g, 34.84 mmol), NaBH4 (0.66 g,
17.36 mmol) and absolute EtOH (25 mL) were added successively
to a solution of trans-7 (2 g, 438 mmol) in anhydrous THF
(50 mL). The reaction mixture was stirred at room temperature for
36 h under argon. The excess NaBH4 and LiCl were destroyed with
water and the solvents were evaporated to dryness. The residue was
dissolved in CH2Cl2 and washed with water and brine. The organic
layer was dried with MgSO4, filtered and concentrated in vacuo.
Further purification by silica gel column chromatography (CH2Cl2
then CH2Cl2/MeOH) gave trans-9 as a white solid (1.5 g, yield
83%). M.p. 143 °C, Rf = 0.20 (CH2Cl2/1% MeOH, 5:5, v/v). IR
(film): ν = 3346 (NH, piperidine and NH amide), 2924–2855 (CH
˜
2
and CH3), 1676 (C=O carbamate), 1636 (C=O amide), 1583
1
(ArC=C), 1125 (OCH3) cm–1. H NMR (CDCl3): δ = 7.6–7.8 (br.
d, 1 H, NHCO), 7.1–7.25 (s, 2 H, ArH), 4.35–4.45 (d, J = 6 Hz, 1
H, HN piperidine), 4.15–4.3 (m, 1 H, CH piperidine), 3.75–4.00
[2 s, 9 H, (OCH3)3], 3.0–3.4 [br. q, 4 H, N(CH2CH3)2], 2.6–3.0 (m,
2 H, CH2OCO), 1.2–3.0 (m, 7 H, CH and CH2 piperidine), 1.01–
1.08 [t, J = 7 Hz, 6 H, N(CH2CH3)2] ppm. 13C NMR (CDCl3): δ
= 166.5 (C=O amide), 155.9 (C=O ureido), 152.9, 140.4, 129.6,
104.3 (ArC=C), 64.8 [CH2OCON(Et)2], 60.6, 56.0 (OCH3), 50.0,
45.2, 33.1 (CH2 piperidine), 49.2, 43.1 (CH piperidine), 41.7, 41.1
(NCH2CH3), 13.9, 13.2 [N(CH2CH3)] ppm.
(KBr): ν = 3409 (OH), 3308 (NH amide), 2921–2856 (CH and
˜
2
CH3), 1626 (C=O amide), 1580 (ArC=C), 1128 (OCH3) cm–1. 1H
NMR (CDCl3): δ = 7.27–7.33 (m, 5 H, ArH), 7.01 (s, 2 H, ArH),
6.80–6.85 (br. d, 1 H, NHCO), 4.22–4.42 (m, 1 H, CH piperidine),
3.87–3.91 [2 s, 9 H, (OCH3)3], 3.79–3.82 (m, 3 H, CH2OH), 3.53 (s, [1-(3,4,5-Trimethoxybenzoyl)-4-(3,4,5-trimethoxybenzoylamino)-
2 H, ArCH2), 1.98–2.7 (m, 7 H, CH and CH2 piperidine) ppm. 13
piperidin-3-yl]methyl N,N-Diethylcarbamate (trans-12): Compound
NMR (CDCl3): δ = 168.0 (C=O amide), 153.1, 141.1, 137.9 trans-12 was prepared using trans-11 (0.34 g, 0.8 mmol), triethyl-
C
(ArC=C), 129.1, 128.1, 127.0, 104.4 (ArCH=CH), 62.9 (ArCH2),
61.7 (CH2OH), 60.7, 56.2 (OCH3), 55.6, 52.5, 31.7 (CH2 piper-
idine), 48.2, 44.9 (CH piperidine) ppm.
amine (0.3 mL, 2.1 mmol) in THF (60 mL) and a solution of 3,4,5-
trimethoxybenzoyl chloride (0.20 g, 0.86 mmol) in THF (10 mL).
The reaction mixture was stirred at room temperature for 1.5 h.
Eur. J. Org. Chem. 2008, 299–307
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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303

F. Heymans et al.
FULL PAPER
Evaporation of THF to dryness and crystallization of the crude
product in methanol gave trans-12 as a white solid (0.35 g, yield
71 %). M.p. 240 °C, Rf = 0.33 (CH2Cl2/MeOH, 95:5, v/v).
C31H43N3O10 (617): C 60.27, H 7.01, N 6.80; found C 60.36, H
N(CH2CH3)2], 1.4–3.28 (m, 7 H, CH and CH2 piperidine), 2.38 (s,
1 H, HN piperidine), 1.05–1.12 [t, J = 7 Hz, 6 H, N(CH2-
CH3)2] ppm. 13C NMR (CDCl3): δ = 166.5 (C=O amide), 155.9
(C=O carbamate), 152.9, 140.4, 129.6, 104.4 (ArC=C), 64.8
[CH2OCON(Et)2], 60.6, 56.0 (OCH3), 50.0, 45.2, 33.1 (CH2 piper-
idine), 49.2, 43.1 (CH piperidine), 41.7, 41.1 [N(CH2CH3)], 13.9,
13.2 [N(CH2CH3)] ppm.
7.04, N 6.75. IR (KBr): ν = 3368 (NH amide), 2925–2856 (CH
˜
2
and CH3), 1695 (C=O carbamate), 1656 (C=O amide), 1585
(ArC=C), 1123 (OCH3) cm–1. 1H NMR (CDCl3): δ = 7.22 (s, 2 H,
ArH), 6.63 (s, 2 H, ArH), 4.25–4.5 (m, 2 H, NHCO and CH piper-
idine), 4.1–4.25 (m, 2 H, CH2OCO), 3.86–3.89 [2 s, 18 H,
(OCH3)6], 3.0–3.4 [br. q, 4 H, N(CH2CH3)2], 1.5–3.4 (m, 7 H, CH
and CH2 piperidine), 0.9–1.2 [br. t, 6 H, N(CH2CH3)2] ppm. 13C
NMR (CDCl3): δ = 170.8 (C=O amide), 166.5 (C=O amide), 153.3
(C=O ureido), 153.0, 130.8, 129.1, 148.4, 148.7, 104.5, 104.2
(ArC=C), 60.8, 56.2, 56.1 (OCH3 and CH piperidine), 41.9, 41.2,
28.1 (CH2 piperidine), 13.9, 13.3 [N(CH2CH3)] ppm.
[1-(3,4,5-Trimethoxybenzoyl)-4-(3,4,5-trimethoxybenzoylamino)-
piperidin-3-yl]methyl N,N-Diethylcarbamate (cis-12): Compound
cis-12 was prepared from cis-11 (0.35 g, 86 mmol), triethylamine
(0.36 mL, 2.56 mmol) and a solution of 3,4,5-trimethoxybenzoyl
chloride (0.25 g, 1 mmol) using the same process as for trans-12.
Compound cis-12 was obtained as a white solid (0.45 g, yield
88 %). M.p. 112 °C, Rf = 0.20 (CH2Cl2/MeOH, 95:05, v/v).
C31H43N3O10·H2O (635): C 57.76, H 7.14, N 6.52; found C 57.86,
1-Benzyl-3-hydroxymethyl-4-(3,4,5-trimethoxybenzoylamino)piper-
idine (cis-9): Compound cis-9 was prepared from cis-7 (3.17 g,
6.95 mmol), LiCl (1.18 g, 27.78 mmol) and NaBH4 (0.53 g,
13.94 mmol) using the procedure described for trans-9 and was ob-
tained as a white solid (1.5 g, yield 57%). M.p. 164 °C, Rf = 0.23
H 7.28, N 6.20. IR (KBr): ν = 3345 (NH amide), 3055
˜
(ArCH=CH), 2974–2836 (CH2 and CH3), 1695 (C=O carbamate),
1
1624 (C=O amide), 1585 (ArC=C), 1127 (OCH3) cm–1. H NMR
(CDCl3): δ = 7.18 (s, 2 H, ArH), 6.61 (s, 2 H, ArH), 4.47–4.54 (br.
d, J = 12.2 Hz, 1 H, NHCO), 3.85–3.92 [2 s, 18 H, (OCH3)6], 3.5–
3.92 (m, 3 H, CH2O and CH piperidine), 3.0–3.4 [br. q, 4 H,
N(CH2CH3)2], 1.0–3.1 (m, 7 H, CH and CH2 piperidine), 1.0–1.12
[br. t, 6 H, N(CH2CH3)2] ppm. 13C NMR (CDCl3): δ = 170.1 (C=O
amide), 166.8 (C=O amide), 153.2 (C=O ureido), 153.0, 140.8,
139.2, 130.8, 129.2, 104.4, 104.0 (ArC=C), 64.2 [CH2OCON(Et)2],
60.8, 56.1, 49.3 (OCH3), 41.9, 41.3, 21.1 (CH2 piperidine), 13.8,
13.3 N (CH2CH3) ppm.
(CH Cl /MeOH, 93:07, v/v). IR (KBr): ν = 3422 (OH), 3330 (NH
˜
2
2
amide), 2941–2836 (CH2 and CH3), 1633 (C=O amide), 1582
(ArC=C), 1128 (OCH3) cm–1. 1H NMR (CDCl3): δ = 7.25–7.30 (m,
5 H, ArH), 6.9 (s, 2 H, ArH), 6.20–6.24 (d, J = 8.48 Hz, 1 H,
NHCO), 3.90–3.98 (m, 2 H, CH piperidine and OH), 3.87 [2 s, 9
H, (OCH3)3], 3.60 (s, 2 H, ArCH2), 1.5–3.61 (m, 9 H, CH and CH2
piperidine and CH2OH) ppm. 13C NMR (CDCl3): δ = 167.0 (C=O
amide), 153.1, 137.2, 141.0 (ArC=C), 129.7, 128.9, 128.4, 127.4,
104.4 (ArCH=CH), 63.7 (ArCH2), 62.9 (CH2OH), 60.8, 56.3
(OCH3), 55.3, 51.6, 29.4 (CH2 piperidine), 47.6, 38.9 (CH piper-
idine) ppm.
1-Benzyl-3-cyano-4-(3,4,5-trimethoxybenzoylamino)piperidine (cis-8
and trans-8): Compounds cis- and trans-8 were prepared using 6
(13.3 g, 61.86 mmol), triethylamine (21.7 mL, 154.4 mmol) in THF
(150 mL) and a solution of 3,4,5-trimethoxybenzoyl chloride (15 g,
65 mmol) in THF (50 mL). The reaction mixture was stirred at
room temperature for 1 h. After evaporation of the solvent, the
residue was dissolved in CH2Cl2 and crystallized by adding meth-
anol to give 19.4 g (yield 78%) of a mixture of cis-8 and trans-8
diastereoisomers as a white powder. They were separated by silica
gel column chromatography using CH2Cl2 then CH2Cl2/MeOH
(98:2, v/v) as eluent to give 7 g of trans-8 (yield 36%), m.p. 200 °C,
Rf = 0.54 (CH2Cl2/MeOH, 95:5, v/v), and 9.7 g of cis-8 (yield 50%),
m.p. 195 °C, Rf = 0.29 (CH2Cl2/MeOH, 95:5, v/v)]. IR (KBr)
[1-Benzyl-4-(3,4,5-trimethoxybenzoylamino)piperidin-3-yl]methyl
N,N-Diethylcarbamate (cis-10): Compound cis-10 was prepared
from cis-9 (1.52 g, 3.48 mmol), NaH (0.17 g, 7.4 mmol) and dieth-
ylcarbamoyl chloride (0.52 g, 3.83 mmol) using the same procedure
as for trans-10 and was obtained as a white solid (1.65 g, yield
93 %). M.p. 186 °C, Rf = 0.33 (CH2Cl2/MeOH, 93:07, v/v).
C28H39N3O6 (513): C 65.47, H 7.65, N 8.18; found C 65.81, H 7.44,
N 7.79. IR (KBr): ν = 3317 (NH amide), 2936–2836 (CH and
˜
2
CH3), 1696 (C=O carbamate), 1626 (C=O amide), 1583 (ArC=C),
1127 (OCH3) cm–1 1H NMR (CDCl3): δ = 7.27–7.32 (m, 5 H,
.
(trans-8 diastereoisomer): ν = 3308 (NH amide), 3054 (ArC-H),
˜
ArH), 7.26 (s, 2 H, ArH), 7.00–7.11 (br. d, 1 H, NHCO), 4.40–4.45
(2 dd, 1 H, CH piperidine), 3.86–3.91 [2 s, 9 H, (OCH3)3], 3.62–
3.66 (m, 2 H, CH2O), 3.54 (s, 2 H, ArCH2), 3.00–3.35 [br. q, 4 H,
N(CH2CH3)2], 1.5–3.00 (m, 7 H, CH and CH2 piperidine), 0.90–
1.20 [br. t, 6 H, N(CH2CH3)2] ppm. 13C NMR (CDCl3): δ = 166.7
(C=O amide), 155.9 (C=O carbamate), 152.9, 140.4, 138.0
(ArC=C), 129.7, 128.8, 128.1, 126.9, 104.3 (ArCH=CH), 64.9
[CH2OCON(Et)2], 62.7 (ArCH2), 60.7, 56.0 (OCH3), 57.0, 52.2,
32.1 (CH2 piperidine), 49.1, 42.3 (CH piperidine), 41.7, 41.1
[N(CH2CH3)], 13.8, 13.3 [N(CH2CH3)] ppm.
2943–2810 (CH2), 2305–2241 (CN), 1632 (C=O amide), 1582
(ArC=C) cm–1; (cis-8 diastereoisomer): ν = 3334 (NH amide),
˜
2956–2815 (CH2 of piperidine), 2244 (CN), 1642 (C=O amide),
1
1585 (ArC=C) cm–1. H NMR (CDCl3) (trans-8 diastereoisomer):
δ = 7.23–7.35 (m, 5 H, ArH), 7.03 (s, 2 H, ArH), 6.71–6.75 (d, J =
7.62 Hz, 1 H, NHCO), 4.10–4.12 (m, 1 H, CH piperidine), 3.83–
3.88 [s, 9 H, (OCH3)3], 3.48–3.63 (dd, J = 3.56 Hz, 2 H, ArCH2),
3.40–3.41 (br. d, 1 H, CH piperidine), 2.90–3.14 (2 br. d, 1 H, CH
piperidine), 1.90–2.33 (m, 4 H, CH2 piperidine); (cis-8 diastereoiso-
mer): δ = 7.25–7.36 (m, 5 H, ArH), 6.99 (s, 2 H, ArH), 6.39–6.43
(d, J = 8.13 Hz, 1 H, NHCO), 4.17–4.22 (m, 1 H, CH piperidine),
3.86 [s, 9 H, (OCH3)3], 3.56 (s, 2 H, ArH), 2.81–3.10 (m, 3 H, CH
[4-(3,4,5-Trimethoxybenzoylamino)piperidin-3-yl]methyl N,N-Dieth-
ylcarbamate (cis-11): Compound cis-11 was prepared from cis-10
(1.35 g, 2.63 mmol), ammonium formate (1.66g, 26.32 mmol) and
Pd/C (0.5 g) using the procedure described for trans-11. Compound
cis-11 was obtained as a white solid (0.90 g, yield 81 %). M.p.
and CH2 piperidine), 1.72–2.45 (m, 4 H, CH2 piperidine) ppm. 13
C
NMR (CDCl3) (trans-8 diastereoisomer): δ = 167.0 (C=O amide),
153.0, 141.1, 137.5, 128.8 (ArC=C), 128.5, 128.3, 127.2, 104.5
(ArCH=CH), 119.6 (CN), 61.8 (ArCH2), 60.8, 56.2 (OCH3), 52.9,
51.9, 28.3 (CH2 piperidine), 48.0, 34.2 (CH piperidine); (cis-8 dia-
stereoisomer): δ = 166.9 (C=O amide), 153.0, 141.1, 137.5, 128.8
149 °C, R = 0.21 (CH Cl /MeOH, 80:20, v/v). IR (KBr): ν = 3328–
˜
f
2
2
3269 (NH of piperidine and NH amide), 2940 (CH2 and CH3),
1691 (C=O carbamate), 1625 (C=O amide), 1582 (ArC=C), 1127
(OCH3) cm–1. 1H NMR (CDCl3): δ = 7.12–7.18 (m, 3 H, ArH and (ArC=C), 128.5, 128.3, 127.2, 104.5 (ArCH=CH), 119.6 (CN), 61.7
NHCO), 4.40–4.45 (2 dd, 1 H, CH piperidine), 3.85–3.91 [2 s, 9 H,
(OCH3)3], 3.60–3.69 (m, 2 H, CH2O), 3.17–3.28 [q, J = 7 Hz, 4 H,
(ArCH2), 60.7, 56.2 (OCH3), 52.9, 51.9, 28.3 (CH2 piperidine),
48.0, 34.2 (CH piperidine) ppm.
304
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Eur. J. Org. Chem. 2008, 299–307

Synthesis of Trisubstituted Aminopiperidines
3-Aminomethyl-1-benzyl-4-(3,4,5-trimethoxybenzoylamino)piper- piperidine, NHCH2CH2-), 1.26–1.88 [m, 13 H, HN piperidine,
idine (trans-13): HCl (12 n, 0.5 mL, 16.16 mmol) and an activated
Raney nickel suspension (5 mL) were added to a solution of com-
pound trans-8 (4.62 g, 11.29 mmol) in absolute EtOH (80 mL). The
resulting mixture was hydrogenated under pressure (40 psi) with
shaking at 60 °C for 12 h. The catalyst was removed by filtration
and the ethanol was evaporated to dryness. The crude residue was
dissolved in dichloromethane and washed with a NaHCO3 solution
and water. The organic layer was then dried with MgSO4 and con-
centrated in vacuo. Silica gel column chromatography in CH2Cl2
then 97:3 and 93:7 (v/v) CH2Cl2/MeOH solutions afforded the pure
product trans-13 as a white solid (1.68 g, yield 37%). M.p. 70 °C,
(CH2)3, CH and CH2 piperidine], 0.85–0.91 (t, J = 6.7 Hz, 3 H,
CH3) ppm. 13C NMR (CDCl3): δ = 166.7 (C=O amide), 158.8
(C=O ureido), 153.0, 129.6, 104.7 (ArC=C), 60.8, 56.3 (OCH3),
47.0, 42.0 (CH2 piperidine), 44.7, 38.9 (CH piperidine), 40.6
(CH2NHCO), 29.8 (CONHCH2), 29.5 (CONHCH2CH2), 28.9
(NH (CH2)2CH2), 22.3 (CH2CH3), 13.9 (CH3) ppm.
1-Pentyl-3-[1-(3,4,5-trimethoxybenzoyl)-4-(3,4,5-trimethoxybenzoyl-
amino)piperidin-3-ylmethyl]urea (trans-16): Compound trans-16 was
prepared using trans-15 (0.47 g, 1.04 mmol), triethylamine
(0.41 mL, 2.96 mmol) in dichloromethane (60 mL) and a solution
of 3,4,5-trimethoxybenzoyl chloride (0.26 g, 1.13 mmol) in dichlo-
romethane (10 mL). The reaction mixture was stirred at room tem-
perature overnight. Purification by silica gel column chromatog-
raphy (CH2Cl2 and CH2Cl2/MeOH, 97:3 and 95:5, v/v) gave the
title compound as a white solid (0.43 g, yield 74%). M.p. 179 °C,
Rf = 0.50 (CH2Cl2/MeOH, 93:7, v/v). C32H46N4O9·¼H2O (634.5):
C 60.48, H 7.24, N 8.82; found C 60.13, H 7.30, N 8.47. IR (KBr):
R = 0.28 (CH Cl /MeOH, 80:20, v/v). IR (KBr): ν = 3368 (NH ),
˜
f
2
2
2
3277 (NH amide), 3054 (ArC–H), 2939–2836 (CH2 of piperidine),
1
1643 (C=O amide), 1583 (ArC=C), 1126 (OCH3) cm–1. H NMR
(CDCl3): δ = 7.24–7.35 (m, 5 H, ArH), 7.15 (2 s, 2 H, ArH), 6.97–
7.00 (d, J = 4.7 Hz, 1 H, NHCO), 4.22–4.24 (m, 1 H, CH piperi-
dine), 3.83–3.93 [s, 9 H, (OCH3)3], 3.48–3.63 (m, 4 H, ArCH2 and
NH2), 3.08–3.25 (2 br. d, 1 H, CH2 piperidine), 2.64–3.02 (2 br. d,
2 H, CH2NH2), 1.98–2.33 (m, 5 H, CH and CH2 piperidine) ppm.
13C NMR (CDCl3): δ = 167.3 (C=O amide), 153.0, 137.4, 136.8
(ArC=C), 129.3, 129.1, 128.3, 128.2, 127.4, 127.2, 104.8, 104.6
(ArCH=CH), 62.6 (ArCH2), 60.8, 56.2 (OCH3), 52.4, 50.2 (CH
piperidine), 41.8, 34.1, 31.6 (CH2 piperidine) ppm.
ν = 3343–3260 (NH), 2924–2858 (CH and CH3), 1634 (C=O),
˜
2
1581 (ArC=C), 1123 (OCH3) cm–1. 1H NMR (CDCl3): δ = 8.17–
8.23 (br. s, 1 H, NHCO), 7.29 (s, 2 H, ArH), 6.57 (s, 2 H, ArH),
5.90 (br. s, 1 H, CH2NHCO), 4.78–5.00 (m, 2 H, CH piperidine
and CONHCH2), 3.80–3.89 [2 s, 18 H, (OCH3)6], 2.90–3.78 (m, 4
H, CH2NHCO and CONHCH2), 2.15–2.65 (m, 5 H, CH and CH2
piperidine), 1.23–1.38 [m, 8 H, CH2 piperidine and -(CH2)3CH3],
0.81–0.87 (t, J = 6.4 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3): δ =
170.9, 166.2 (C=O amide), 159.4 (ureido), 153.4, 153.0, 130.5,
129.4, 104.7, 104.0 (ArC=C), 60.8, 56.2, 56.1 (OCH3), 47.9 (CH
piperidine), 40.4 (CH2 NHCO), 30.0 (CONHCH2 ), 29.0
(CONHCH2CH2), 22.3 (CH2CH3), 13.9 (CH3) ppm.
3-[1-Benzyl-4-(3,4,5-trimethoxybenzoylamino)piperidin-3-ylmethyl]-
1-pentylurea (trans-14): A solution of pentyl isocyanate (0.42 g,
3.71 mmol) in dry dichloromethane (10 mL) was added dropwise
to a solution of trans-13 (1.55 g, 3.7 mmol) in dry dichloromethane
(60 mL). The reaction mixture was then stirred at room tempera-
ture for 2 h and washed successively with water and brine. The
organic layer was dried with MgSO4 and the solvent was evapo-
rated to dryness. The crude product was purified by silica gel col-
umn chromatography (CH2Cl2/MeOH, 97:3 and 93:7, v/v) to give
trans-14 as a white solid (1.3 g, yield 65%). M.p. 133 °C, Rf = 0.38
(CH2Cl2/MeOH, 93:7, v/v). C28H39N3O6·½H2O (522): C 65.01, H
1-Benzyl-3-methylamino-4-(3,4,5-trimethoxybenzoylamino)piper-
idine (cis-13): This compound was prepared from cis-8 (1.75g,
4.3 mmol), HCl (12 n, 0.5 mL, 16.16 mmol) and an activated
Raney nickel solution (5 mL) using the same procedure as de-
scribed for trans-13. The crude product was purified by silica gel
column chromatography (CH2Cl2, CH2Cl2/MeOH, 97:3 and 93:7,
v/v) to give pure cis-13 as a white solid (1.45 g, yield 75%). M.p.
7.84, N 10.46; found C 65.05, H 8.10, N 10.81. IR (KBr): ν = 3283
˜
(NH amide and ureido), 3053 (ArC–H), 2936 (CH2 and CH3 of
piperidine and alkyl chain), 1648 (C=O of amide and ureido), 1583
(ArC=C), 1127 (OCH3) cm–1. 1H NMR (CDCl3): δ = 7.90 (br. s, 1
H, NHCO), 7.25–7.45 (m, 7 H, ArH), 5.1–5.4 (br. t, 1 H,
CH2NHCO), 4.60 (br. t, 1 H, CONHCH2), 4.08–4.29 (m, 1 H, CH
piperidine), 3.86–3.93 [s, 9 H, (OCH3)3], 3.67–3.80 (m, 1 H, CH2
piperidine), 3.40–3.57 (dd, J = 12.7 Hz, 2 H, ArCH2), 1.72–3.13
(m, 10 H, CH2NH, NHCH2, CH2 piperidine), 1.36–1.47 [m, 2 H,
CH2(CH2)2CH3], 1.22–1.28 [m, 4 H, (CH2)2CH3], 0.82–0.89 (t, J =
6.7 Hz, 3 H, CH2CH3) ppm. 13C NMR (CDCl3): δ = 166.5 (C=O
amide), 158.0 (C=O ureido), 153.0, 140.5, 129.6 (ArC=C), 128.9,
128.3, 127.3, 104.6 (ArCH=CH), 63.1 (ArCH2), 60.8, 56.2 (OCH3),
52.3, 47.1 (CH2 piperidine), 41.0, 40.7 (CH piperidine), 39.0
(CH2NHCO), 29.8 (NHCH2), 28.9 (NHCH2CH2), 29.1 (CH2
CH3), 22.3 (CH2CH3), 13.9 (CH3) ppm.
115 °C, R = 0.22 (CH Cl /MeOH, 80:20, v/v). IR (KBr): ν = 3313
˜
f
2
2
(NH2), 3309 (NH amide), 3053 (ArC-H), 2942 (CH2), 1640 (C=O
1
amide), 1584 (ArC=C) cm–1. H NMR (CDCl3): δ = 7.58–7.62 (d,
J = 7.69 Hz, 1 H, NHCO), 7.10–7.27 (m, 7 H, ArH), 4.69 (br. s, 3
H, CH2NH2 and CH piperidine), 3.84–3.85 [s, 9 H, (OCH3)3], 3.40–
3.57 (m, 2 H, ArCH2), 2.66–3.02 (m, 4 H, CH2NH2 and CH2 piper-
idne), 1.61–2.07 (m, 5 H, CH and CH2 piperidine) ppm. 13C NMR
(CDCl3): δ = 167.2 (C=O amide), 153.0, 137.4, 136.8 (ArC=C),
129.3, 129.1, 128.3, 128.2, 127.4, 127.2, 104.8, 104.6 (ArCH=CH),
62.6 (ArCH2), 60.8, 56.4, 56.3 (OCH3), 52.4, 51.7, 50.2 (CH piper-
idine), 42.0, 41.8, 34.2, 31.6 (CH2 piperidine) ppm.
3-[1-Benzyl-4-(3,4,5-trimethoxybenzoylamino)piperidin-3-ylmethyl]-
1-pentylurea (cis-14): Compound cis-14 was prepared from cis-13
(0.6 g, 1.47 mmol) and pentyl isocyanate (0.17 g, 1.5 mmol) using
the same procedure as for compound trans-14 and obtained in the
form of a white solid (0.5 g, yield 65%). M.p. 193 °C, Rf = 0.29
(CH2Cl2/MeOH, 93:7, v/v). C29H42N4O5·1͞3H2O (532): C 65.37, H
1-Pentyl-3-[4-(3,4,5-trimethoxybenzoylamino)piperidin-3-ylmethyl]-
urea (trans-15): Compound trans-15 was prepared using a solution
of trans-14 (1 g, 1.85 mmol) in methanol (60 mL), ammonium for-
mate (1.16 g, 184 mmol) and Pd/C (0.4 g) as the catalyst. The reac-
tion mixture was stirred at reflux for 1 h. After filtration and evapo-
ration of the solvent a white solid was obtained (0.5 g, yield 60%).
7.89, N 10.51; found C 65.20, H 8.30, N 10.36. IR (KBr): ν =
˜
3356–3292 (NH), 2932 (CH2), 1630 (C=O), 1584 (ArC=C), 1127
M.p. 175 °C, Rf = 0.27 (CH2Cl2/MeOH/NH4OH, 80:20:2, v/v/v). (CH3O) cm–1. 1H NMR (CDCl3): δ = 7.24–7.31 (m, 5 H, ArH),
IR (KBr): ν = 3311–3306 (NH), 2935–2864 (CH and CH ), 1634 7.14 (s, 2 H, ArH), 6.93–6.97 (d, J = 8 Hz, 1 H, NHCO), 5.28–5.30
˜
2
3
(C=O), 1581 (ArC=C), 1123 (OCH3) cm–1. 1H NMR (CDCl3): δ = (br. t, 1 H, CH2NHCO), 4.30–4.36 (br. t, 1 H, CONHCH2), 3.88–
7.77 (br. s, 1 H, NHCO), 7.26–7.36 (s, 2 H, ArH), 5.81 (br. s, 1 H, 3.93 [2 s, 9 H, (OCH3)3], 3.67–3.76 (m, 1 H, CH piperidine), 3.40–
CH2NHCO), 4.56 (br. t, 1 H, CONHCH2), 4.38–4.5 (m, 1 H, CH 3.62 (dd, J = 30.2 Hz, 2 H, ArCH2), 2.85–3.18 (m, 4 H, CH2NHCO
piperidine), 3.89–3.99 [2 s, 9 H, (OCH3)3], 2.85–3.18 (m, 5 H, CH and CONHCH2), 2.64–2.74 (m, 1 H, CH piperidine), 1.82–2.17 (m,
Eur. J. Org. Chem. 2008, 299–307
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
305

F. Heymans et al.
FULL PAPER
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6 H, CH and CH2 piperidine), 1.45–1.63 (m, 2 H, NHCH2CH2),
1.26–1.34 [m, 4 H, (CH2)2CH3], 0.87–0.94 (t, J = 6.7 Hz, 3 H,
CH3) ppm. 13C NMR (CDCl3): δ = 167.4 (C=O amide), 158.6
(C=O ureido), 153.0, 140.7, 137.5, 129.4, 129.1 (ArC=C), 128.2,
127.2, 104.5 (ArCH=CH), 62.6 (ArCH2), 60.8, 57.2 (OCH3), 56.2,
52.0, 40.2 (CH2 piperidine), 49.7, 43.2 (CH piperidine), 40.5
(CH2NHCO), 31.7 (CONHCH2), 29.8 (CONHCH2CH2), 29.0
(CONHCH2CH2CH2), 22.3 (CH2CH3), 13.9 (CH3) ppm.
1-Pentyl-3-[4-(3,4,5-trimethoxybenzoylamino)piperidin-3-ylmethyl]-
urea (cis-15): Compound cis-15 was prepared from cis-14 (0.4 g,
0.76 mmol), ammonium formate (0.8 g, 1.27 mmol) and Pd/C
(0.1 g) as the catalyst using the same procedure as for trans-15 and
gave the title compound in the form of a white solid (0.26 g, yield
79%). M.p. 184 °C, Rf = 0.24 (CH2Cl2/MeOH/NH4OH, 80:20:2,
v/v/v). IR (KBr): ν = 3317–3286 (NH), 2905 (CH ), 1629 (C=O),
˜
2
1583 (ArC=C), 1126 (CH3O) cm–1. 1H NMR (CDCl3): δ = 7.08–
7.19 (m, 3 H, ArH and NHCO), 5.52 (br. t, 1 H, CH2NHCO),
4.50–4.53 (br. t, 1 H,CONHCH2), 3.88–3.93 [2 s, 9 H,(OCH3)3],
3.56–3.66 (m, 1 H, CH piperidine), 2.11–3.24 (m, 9 H, CH2NHCO,
CH2 and HN piperidine, CONHCH2), 1.26–1.68 [m, 8 H, CH2
piperidine, NHCH2CH2, (CH2)2CH3], 0.85–0.92 (t, J = 6.7 Hz, 3
H, CH3) ppm. 13C NMR (CDCl3): δ = 166.7 (C=O amide), 158.8
(C=O ureido), 153.0, 129.6, 104.6 (ArC=C), 60.8, 56.2 (OCH3),
47.0, 42.0 (CH2 piperidine), 44.6, 38.9 (CH piperidine), 40.5
(CH2NHCO), 29.8 (CONHCH2), 29.5 (NHCH2CH2), 28.9
(CH2CH2CH3), 22.3 (CH2CH3),13.9 (CH3) ppm.
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[22]
[23]
61%). M.p. 110 °C, Rf
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C32H46N4O9·2͞3H2O (642): C 59.78, H 7.16, N 8.72; found C 59.50,
H 7.44, N 9.14. IR (KBr): ν = 3393–3331 (NH), 3053 (ArCH),
˜
[25]
[26]
[27]
2935–2867 (CH2 and CH3), 1631 (C=O), 1583 (ArC=C), 1128
(CH3O) cm–1. 1H NMR (CDCl3): δ = 8.92 (br. s, 1 H, NHCO),
7.38 (s, 2 H, ArH), 6.64 (s, 2 H, ArH), 5.63 (br. s, 1 H, CH2NHCO),
5.3 (br. s, 1 H, CONHCH2), 4.53 (m, 1 H, CH piperidine), 3.86–
3.95 [s, 9 H, (OCH3)3], 3.58–3.86 (m, 1 H, CH piperidine), 3.02–
3.17 (m, 4 H, CONHCH2, CH2NHCO), 1.27–1.99 [m, 12 H, CH2
piperidine, NHCH2CH2, (CH2)2CH3], 0.84–0.91 (t, J = 7 Hz, 3 H,
CH3) ppm. 13C NMR (CDCl3): δ = 170.9, 166.2 (C=O amide),
159.4 (C=O ureido), 153.4, 152.9, 130.5, 129.4, 104.7, 104.0
(ArC=C), 60.9, 60.8, 56.2, 56.1 (OCH3), 47.9 (CH piperidine), 40.4
(CH2NHCO), 30.0 (CONHCH2), 29.0 (CONHCH2CH2), 22.3
(CH2CH3), 13.9 (CH3) ppm.
[28]
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The authors express their appreciation to Dr. Wafa Sallem for as-
sistance in PAF-induced platelet aggregation measurements.
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Received: July 19, 2007
Published Online: November 12, 2007
Eur. J. Org. Chem. 2008, 299–307
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
307