Alternative strategies for the stereoselective synthesis of enantioenriched 6-arylated piperidin-2-ones

Article abstract of DOI:10.1016/j.tetasy.2012.06.024

Two alternative synthetic approaches to a variety of enantioenriched 6-arylated piperidin-2-ones have been developed. The first one is based on the hydrogenation of suitably arylated chiral cyclic enehydrazides. The second approach relies on the asymmetric catalytic hydrogenation of the corresponding N-alkylated precursors. 2012 Elsevier Ltd.

Full text of DOI:10.1016/j.tetasy.2012.06.024

Tetrahedron: Asymmetry 23 (2012) 998–1004
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Tetrahedron: Asymmetry
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Alternative strategies for the stereoselective synthesis of enantioenriched
6-arylated piperidin-2-ones
Romain Sallio a,b, Stéphane Lebrun a,b, Francine Agbossou-Niedercorn a,c,d, Christophe Michon a,c,d,
,
⇑
Eric Deniau a,b,
⇑
a Université Lille Nord de France, 59000 Lille, France
b Université Lille 1, Laboratoire de Chimie Organique Physique, EA CMF 4478, Bâtiment C3(2), 59655 Villeneuve d’Ascq Cedex, France
c CNRS, UCCS UMR 8181, F-59655 Villeneuve d’Ascq Cedex, France
d ENSCL, CCM-CCCF, Bât C7, BP 90108, 59652 Villeneuve d’Ascq Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 May 2012
Accepted 29 June 2012
Two alternative synthetic approaches to a variety of enantioenriched 6-arylated piperidin-2-ones have
been developed. The first one is based on the hydrogenation of suitably arylated chiral cyclic enehydraz-
ides. The second approach relies on the asymmetric catalytic hydrogenation of the corresponding N-
alkylated precursors.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
OH
Ph
O
Me
H
N
O
Piperidines and their derivatives have attracted much attention
from the scientific community since they represent the core unit of
a wide range of alkaloids and biologically active compounds.1
Although less prominent in nature,2 the corresponding lactams
(piperidinones) have received increasing interest as they serve a
key role as advanced intermediates prior to their conversion to
piperidines.3
Simple enantiopure 6-(het)aryl substituted compounds have
been studied extensively and play an important role as key targets
for the pharmaceutical industry. Typical examples are shown in Fig-
ure 1 and include the spiro indane 1, which is an antagonist of CGRP
receptors involved in the treatment or prevention of migraine;4 the
indoloisoquinolinone 2 which displays antimalarial activity,5 the
NK1 antagonist 36 and the acylpiperidone 4 which has been re-
N
N
N
O
NH
N
H
H
O
O
1
2
O
HN
N
Me
CF3
N
O
F
O
O
N
H
CF3
F
·HCl
3
4
Figure 1. Examples of pharmacologically active enantiopure 6-(het)arylated
piperidinones.
ported as an
a1a receptor antagonist for the treatment of benign
prostatic hypertrophy.7 Consequently, the development of short,
versatile, and efficient procedures for the stereocontrolled prepara-
tion of these aza-heterocycles and their oxo derivatives constitutes
an area of current interest and alternative methods are currently the
object of intensive synthetic endeavor. Organic chemists have at
their disposal a variety of synthetic strategies for the asymmetric
synthesis of 6-arylated piperidin-2-ones, but varying degrees of
success have been achieved with regard to their stereoselectivities.
The control of the stereogenic center alpha to nitrogen in these
lactams can be achieved by different chemical processes such as
(i) the diastereoselective nucleophilic additions to chiral sulfini-
mines8 or SAMP hydrazones;9 (ii) the diastereoselective aza-Mi-
chael addition of a chiral lithium amide to an
a,b-unsaturated
Weinreb amide;10 (iii) the Ir-catalyzed enantioselective hydrogena-
tion of N-arylimines;11 (iv) the enantioselective catalytic vinylogous
Mannich reaction of sulfonylimines;12 and (v) the diastereoselective
a
-amidoalkylation reaction of Meyers’ bicyclic lactams.13
2. Results and discussion
⇑
Corresponding authors. Tel.: +33 (0)3 20 43 48 93; fax: +33 (0)3 20 43 65 85
(C.M.); tel.: +33 (0)3 20 33 71 48; fax: +33 (0)3 20 33 63 09 (E.D.).
E-mail addresses: Christophe.michon@ensc-lille.fr (C. Michon), Eric.Deniau@
univ-lille1.fr (E. Deniau).
We have developed two alternative and conceptually new syn-
thetic approaches to a variety of 6-arylated piperidinones that rely
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.024

R. Sallio et al. / Tetrahedron: Asymmetry 23 (2012) 998–1004
999
on the asymmetric reduction of endocyclic enamides 7 as the key
step (Scheme 1). These highly conjugated models could be ob-
tained via a two step sequence involving a Suzuki cross coupling
reaction from the N-protected imides 8. The stereoselectivities of
the transformations should be controlled either by the use of a
(S)-methylprolinol chiral auxiliary (Z = SMP, path a)14 or by the li-
gand/catalyst chirality (Z = Bn, path b). The N-deprotection of the
saturated compounds 6 should then result in the formation of
the desired enantiopure lactam heterocycles 5.
diverse enol phosphates in a variety of cross-coupling reactions.17
Exposure of compound 9 to KHMDS in THF at ꢀ78 °C provided the
corresponding potassium enolate, which was intercepted by reac-
tion with diphenyl phosphoryl chloride. Standard work-up gave
the sensitive vinyl phosphate 10, which was then used for the next
step without further purification. Hence, compound 10 was al-
lowed to react in refluxing THF with a variety of boronic acids
11a–e in the presence of Pd(PPh3)4 catalyst and Na2CO3, which
led to the formation of a series of cyclic enehydrazides 12a–e,
which were substituted with different aryl groups alpha to the
nitrogen. With a reliable route to these enehydrazides in hand,
studies addressing the enantioselective preparation of substituted
piperidinones 14a–e were initiated.
R1
R1
R2
O
N
Z
O
N
H
Based on the efficient method developed in our laboratory for
the asymmetric synthesis of 5-arylmethylpirrolidin-2-ones,18 we
anticipated that a high level of diastereoselectivity in the reduction
of the unsaturated compounds 12a–e could be ensured by the use
of Pd on C with ammonium formate. As can be seen from Table 1,
the formation of compounds 12a–e occurs with a high level of dia-
stereoselection. According to our previously reported results,18 one
can reasonably assume that the high facial selectivity might be as-
cribed to the addition of hydrogen on the preferred conformer of
the enehydrazides 12a–e. Hence, antiperiplanar addition of hydro-
gen should occur preferentially from the less hindered face of 12a–
e, providing the diastereomers 13a–e with a high level of selectiv-
R2
5
6
path a
path b
Z
Z
= SMP
R1
R2
O
N
Z
O
N
Z
O
= Bn
7
8
Scheme 1. Retrosynthetic analysis of chiral 6-arylated piperidinones.
The new synthetic route, depicted in Scheme 2, required the
ity. This hypothesis was corroborated by the comparison of the 1
H
preliminary elaboration of the chiral hydrazide 9, which was easily
prepared by a condensation between glutaric anhydride and (S)-
AminoMethylProlinol (SAMP).15 We assumed that these cyclic imi-
des would possess the appropriate functionality required for the
connection of an additional aryl unit through a palladium-medi-
ated Suzuki–Miyaura cross-coupling reaction. Since the pioneering
work of Oshima et al.,16 several groups have used constitutionally
and 13C NMR spectra of 6-phenylpiperidin-2-one 13a with its pre-
viously described epimer.9a
Finally, removal of the auxiliary was achieved cleanly under
oxidizing conditions by the treatment of hydrazides 13a–e with
magnesium mono-peroxyphthalate hexahydrate (MMPP)19 to af-
ford the targeted 6-arylpiperidin-2-ones 14a–e free of the chiral
auxiliary. The absolute configuration of 14a–e was inferred by
comparison of the specific rotation with the literature data, for
example ½a D
ꢁ
¼ ꢀ58:0 for (S)-14a (c 0.54, CHCl3), lit.10 +58.2 for
OMe
(R)-14a (c 1.0, CHCl3).
1)
N
O
N
N
O
For the alternative synthetic approach based on the catalytic
hydrogenation of the structurally related N-alkylated models, com-
pound 18 was initially chosen as the model study. In order to check
the scope and limitations (Table 3 and below), we subsequently ex-
tended our study to N-Boc and N-CO2Ph enamines 19 and 20. Pre-
cursors 18–20 could be a priori assembled through a variety of
procedures,20 but we opted for a two step sequence involving a Su-
zuki–Miyaura cross coupling reaction from the N-protected imide
15 and lactams 16–17 (Scheme 3).
NH2
2) AcONa, Ac2O
Δ, 5 h
O
O
O
MeO
9
83%
O
P
OPh
OPh
KHMDS, ClP(O)(OPh)2
THF, -78 °C to rt
O
N
N
O
Asymmetric hydrogenations of cyclic enamides studied and fo-
cused mainly on structures containing an exocyclic C@C bond.21
However, to the best of our knowledge, the asymmetric hydroge-
nation of 6-arylated dihydropyridin-2-ones has not been previ-
ously reported on. Hence, we started our catalytic study with the
preparation of racemic samples. Whereas the Pd/C catalyzed
hydrogenation of enamides 18–20 gave the racemic amides 21–
23 quantitatively (Table 2, entries 1, 6, 11), the screening of other
catalysts led to rather disappointingly results. Poor yields were ob-
served upon hydrogenation of compounds 18–20 using an Ir(I) cat-
alyst. Thus compound 21 was obtained in poor yield and without
enantioselectivity whereas substrates 19 and 20 could not be
hydrogenated (entries 2, 7, 12, 13). These results are in strong con-
trast with those reported by Zhou et al. who hydrogenated N-alkyl-
ated five-membered cyclic enamines by making use of Ir(I)
catalysts with high yields and enantioselectivities.22 Hydrogena-
tion of enamides 18 and 20 using Ru(II) catalysts also proved to
be unsuccessful, with 18 being hydrogenated in low yields and
enantioselectivity and 20 remaining unreacted (entries 3, 4, 15).
The use of Rh(I) catalysts enabled better hydrogenation reactions
for enamides 18–20. Whereas the combined use of (R)-BINAP
MeO
10
H
H
(OH)2B
O
N
R2
11a-e
R1
HCO2NH4
N
Pd/C
MeOH, Δ
81-92%
Na2CO3, H2O
Pd(PPh3)4, Δ
65-76%
OMe
R2
R1
12a-e
R1
R2
O
N
N
R1
R2
MMPP
O
N
MeOH, rt
83-90%
H
MeO
13a-e
14a-e
Scheme 2. Asymmetric synthesis of 6-arylated piperidinones 14a–e.

1000
R. Sallio et al. / Tetrahedron: Asymmetry 23 (2012) 998–1004
Table 1
Compounds 12a–e, 13a–e, 14a–e prepared
Entry
R1
R2
Compound
Yielda (%)
Compound
Yielda (%)
deb (%)
Compound
Yield (%)a
eec (%)
1
2
3
4
5
H
H
H
H
F
OMe
OMe
12a
12b
12c
12d
12e
72
65
70
76
75
13a
13b
13c
13d
13e
89
86
87
92
81
>96
>96
>96
>96
>96
14a
14b
14c
14d
14e
88
85
83
90
86
>96
>96
>96
>96
>96
OMe
OCH2O
a
b
c
After purification.
Determined by 1H NMR spectroscopy.
In correlation to the de value of the corresponding hydrazides 13a–e assuming that the deprotection step takes place without detectable racemization.9a
1) KHMDS, ClP(O)(OPh)2
H2, catalyst
THF, -78 °C to rt
Y
N
Z
O
Y
N
Z
Y
N
solvent, time
heating
2) PhB(OH)2, base, solvent
Z
Pd(PPh3)4, Δ
21-23
15-17
18-20
Scheme 3. Synthesis of compounds 18–23.
Table 2
Compounds 18–23 prepared
Entry
Z
Y
Compound
Base
Solvent
Time (h)
Yield (%)
Compound
1
2
3
Bn
Boc
CO2Ph
O
H2
H2
18
19
20
Ba(OH)2
Na2CO3
Na2CO3
1,4-Dioxane
THF
DME
12
2
0.5
78
81
85
21
22
23
Table 3
Screening of catalysts for the hydrogenation of enamides 18–20 into 21–23.
Entry
Reagent
Catalyst
Solvent
P(H2) (bar)
T (°C)
Time (h)
Yielda (%)
eeb (%)
1c
18
18
18
18
18
19
19
19
19
19
20
20
20
20
20
10% Pd/C
EtOH
THF
1
20
55
55
50
1
50
100
65
115
1
20
20
50
50
60
20
20
70
70
70
20
20
20
70
50
16
16
16
16
16
16
16
64
16
64
16
16
16
64
64
100
10
10
5
22
100
0
50
15
30
100
0
—
2d
3
(R)-(S)-Josiphos (2.2 mol %) + [IrCODCl]2 (2.2 mol %)
(S)-BINAP-Ru(OAc)2 (2 mol %)
(S)-BINAP-Ru(OAc)2 (2 mol %)
(R)-BINAP (1 mol %) + [RhCOD]2BF4 (1 mol %)
10% Pd/C
(R)-(S)-Josiphos (2.2 mol %) + [IrCODCl]2 (2.2 mol %)
(R)-BINAP (1 mol %) + [RhCOD]2BF4 (1 mol %)
(R)-BINAP (5 mol %) + [Rh(OH)COD]2 (1 mol %)
(R)-(R)-Walphos (5 mol %) + [Rh(OH)COD]2 (1 mol %)
10% Pd/C
(R)-(S)-Josiphos (2.2 mol %) + [IrCODCl]2 (2.2 mol %)
(R)-PHOX-IrCODBARF (1 mol %)
(R)-BINAP (1 mol %) + [RhCOD]2BF4 (1 mol %)
(S)-BINAP-Ru(OAc)2 (2 mol %)
<5
<5
<5
<5
—
MeOH
CH2Cl2
MeOH
EtOH
THF
iPrOH
EtOH
iPrOH
EtOH
THF
4
5e
6c,f
7g
—
8f
<5
<5
<5
—
—
—
9
10h
11c
12g
13i
14
15
20
50
50
45
CH2Cl2
iPrOH
MeOH
0
60
0
<5
—
a
b
c
d
e
f
Isolated yield.
measured by chiral HPLC on Regis™ (S,S)-Whelk 01, (80/20) n-hexane/i-PrOH, 1 ml/min, 200 nm.
Forty milligrams of Pd/C for 0.4 mmol of substrate and 20 ml EtOH.
Performed with 5 mol % I2.
Performed with 60 mol % Cs2CO3; same result without.
Same result for seven-membered ring compounds.
same result at 60 °C or with CH2Cl2.
g
h
i
Performed with 60 mol % Cs2CO3.
Same result at 70 °C in TCE.
and [RhCOD]2BF4 led to hydrogenation of compound 18 in a mod-
est 22% yield (entry 5), the use of the same catalyst with close reac-
tion conditions enabled compounds 19 and 20 to be hydrogenated
in 50% and 60% yields, respectively (entries 8, 14). However, in
each case, almost no enantioselectivity was obtained. For the
hydrogenation of enamide 19, the change for [Rh(OH)COD]2 and
Walphos ligand (Fig. 2) decreased the yield of 22 to 30% and did
not improve the enantioselectivity (Table 3, entries 9, 10).
O
N
(Ph)2P
P(Ph)2
P(Cy)2
Me
Fe
(Ph)2P
H
Me
Fe
(Ph)2P
H
Ir
COD
BARF
(R)-PHOXIrCODBARF
(R)-(S)-Josiphos
(R)-(R)-Walphos
Figure 2. Some ligands and catalyst used herein.

R. Sallio et al. / Tetrahedron: Asymmetry 23 (2012) 998–1004
1001
Calcd for C11H18N2O3: C, 58.39; H, 8.02; N, 12.38. Found: C, 58.43;
H, 8.26; N, 12.59.
3. Conclusion
In conclusion, two alternative synthetic approaches for the ster-
eoselective synthesis of 6-arylated piperidin-2-ones have been
developed. The first one is based on an intramolecular chirality
transfer from a variety of models equipped with a methoxymethyl-
pyrrolidine temporary activating agent. This methodology enriches
the repertoire of asymmetric methods relying on the Enders chiral
auxiliary, since high yields and enantioselectivities were observed
upon hydrogenation of the arylated endocyclic enehydrazide pre-
cursors. Rather disappointing results were however observed
through the alternative catalytic hydrogenation process applied
to structurally related N-alkyl or acyl precursors. These compounds
were hydrogenated with varying degrees of success but always
with low enantioselectivity and there is still a strong incentive
for the development of this conceptually different synthetic ap-
proach to the target compounds.
4.3. Typical procedure for the preparation of enehydrazides
12a–e
To a solution of imide 9 (2 mmol, 450 mg) and diphenyl phos-
phoryl chloride (0.62 mL, 3 mmol) in anhydrous THF (30 mL)
cooled at ꢀ78 °C and under a nitrogen atmosphere, was added
dropwise under stirring a solution of KHMDS (6 mL, 0.5 M in tolu-
ene, 3 mmol). After 30 min at ꢀ78 °C, water (20 mL) was added
and the resulting mixture was extracted with Et2O (2 ꢂ 50 mL)
and dried over MgSO4. Evaporation of the solvent under vacuum
yielded 10 as a yellow oil, which was directly used for the next
coupling step.
To a stirred solution of crude 10 (2 mmol) in THF (20 mL) main-
tained under a nitrogen atmosphere, were added a 2 M aqueous
Na2CO3 solution (2 mL, 4 mmol), Pd(PPh3)4 (120 mg, 5 mol %),
and aromatic boronic acid 11a–e (3 mmol). The mixture was stir-
red for 2 h at reflux, and then it was diluted with water (2 mL)
and extracted with Et2O (3 ꢂ 50 mL). The combined organic layers
were dried over MgSO4 and concentrated under vacuum to give an
orange oil, which was purified by flash column chromatography
using EA/hexanes (40:60) as eluent to afford 6-arylated dihydropy-
ridinones 12a–e.
4. Experimental
4.1. General
Melting points were determined on a Reichert-Thermopan
apparatus and are uncorrected. NMR spectra were recorded on a
Bruker AM 300 spectrometer. They were referenced against inter-
nal tetramethylsilane; coupling constants (J) are given in Hz and
rounded to the nearest 0.1 Hz. IR absorption spectra were run on
a Perkin-Elmer 881. Optical rotations were recorded on Perkin El-
mer 343 digital polarimeter at 589 nm. HPLC analyses were per-
4.3.1. (S)-1-(2-Methoxymethylpyrrolidin-1-yl)-6-phenyl-3,4-
dihydro-1H-pyridin-2-one 12a
Mp 100–101 °C; ½a D20
ꢁ
¼ ꢀ99:3 (c 1.12, CHCl3); 1H NMR (CDCl3):
1.21–1.32 (m, 1H), 1.41–1.56 (m, 1H), 1.88–2.05 (m, 2H), 2.12–2.27
(m, 1H), 2.38–2.61 (m, 3H), 2.80–2.88 (m, 1H), 3.02–3.11 (m, 2H),
3.20 (s, 3H, OCH3), 3.48–3.55 (m, 1H), 3.72–3.84 (m, 1H), 5.18 (t,
J = 7.0 Hz, 1H), 7.27–7.33 (m, 5H, Harom); 13C NMR (CDCl3): C
169.8 (CO), 146.6, 137.5, CH 127.9 (2CH), 127.4, 127.3 (2 ꢂ CH),
107.3, 60.8, CH2 76.1, 51.9, 34.0, 28.2, 22.9, 19.7, CH3 58.6. Anal.
Calcd for C17H22N2O2: C, 71.30; H, 7.74; N, 9.78. Found: C, 71.35;
H, 7.83; N, 9.60.
formed on
a Hitachi-VWR LaChromElite L-2000. Elemental
analyses were obtained using a Carlo-Erba CHNS-11110 equip-
ment. Flash chromatography was performed on Sorbent Technolo-
gies 32–63 lm 60 Å silica gel. Reactions were monitored by thin
layer chromatography with Sorbent Technologies 0.20 mm silica
gel 60 Å plates. Dry glassware was obtained by oven-drying and
assembly under an inert gas. Dry nitrogen was used as the inert
atmosphere. The glassware was equipped with rubber septa and
reagent transfer was performed by syringe techniques. Tetrahydro-
furan (THF) was distilled from sodium benzophenone ketyl prior to
use. Methanol (MeOH), ethanol (EtOH), and isopropanol (iPrOH)
were distilled over magnesium turnings, CH2Cl2 over CaH2, and tol-
uene over sodium.
4.3.2. 6-(4-Fluorophenyl)-1-((S)-2-methoxymethyl-pyrrolidin-
1-yl)-3,4-dihydro-1H-pyridin-2-one 12b
Mp 125–126 °C;
½
a 2D0
ꢁ
¼ ꢀ120:8 (c 1.54, CHCl3); 1H NMR
(CDCl3): 1.19–1.36 (m, 1H), 1.45–1.57 (m, 1H), 1.89–2.08 (m, 2H),
2.17–2.31 (m, 1H), 2.35–2.71 (m, 3H), 2.88 (dd, J = 6.1, 9.3 Hz,
1H), 2.94–2.99 (m, 1H), 3.04 (dd, J = 5.9, 9.3 Hz, 1H), 3.20 (s, 3H,
OCH3), 3.43–3.53 (m, 1H), 3.74–3.85 (m, 1H), 5.16 (dd, J = 3.1,
6.4 Hz, 1H), 6.96–7.04 (m, 2H, Harom), 7.22–7.33 (m, 2H, Harom);
13C NMR (CDCl3): C 169.7 (CO), 162.1 (d, J = 255 Hz), 145.6,
133.5, CH 129.5 (d, J = 8.0 Hz, 2 ꢂ CH), 114.3 (d, J = 21.5 Hz,
2 ꢂ CH), 107.3, 60.7, CH2 76.0, 52.0, 34.0, 28.1, 22.9, 19.7, CH3
58.8. Anal. Calcd for C17H21FN2O2: C, 67.09; H, 6.95; N, 9.20. Found:
C, 67.18; H, 7.06; N, 9.10.
4.2. Typical procedure for the preparation of imide 9
(S)-1-Amino-2-methoxymethylpyrrolidine
(SAMP,
5.2 g,
0.04 mol) was added to suspension of glutaric anhydride
a
(0.04 mol, 4.56 g) in CH2Cl2 (100 mL). The mixture was then stirred
at room temperature for 1 h. Acetic anhydride (5.6 mL, 0.06 mol)
and a catalytic amount of sodium acetate (30 mg) were subse-
quently added and the mixture was refluxed for 5 h. The reaction
mixture was cooled to 0 °C and stirred with a 5% aqueous NaHCO3
solution (50 mL) for 30 min. The aqueous layer was separated and
extracted with CHCl3 (3 ꢂ 30 mL). The combined organic layers
were dried over MgSO4. After evaporation of the solvent, the crude
product was purified by flash chromatography on silica gel using
EA/hexanes (50:50) as eluent to afford 9 as an oil.
4.3.3. 6-(4-Methoxyphenyl)-1-((S)-2-methoxymethylpyrrolidin-
1-yl)-3,4-dihydro-1H-pyridin-2-one 12c
Oil; ½a 2D0
ꢁ
¼ ꢀ56:2 (c 2.27, CHCl3); 1H NMR (CDCl3): 1.20–1.29
(m, 1H), 1.32–1.56 (m, 1H), 1.84–2.02 (m, 2H), 2.11–2.23 (m,
1H), 2.28–2.66 (m, 3H), 2.84 (dd, J = 6.4, 9.2 Hz, 1H), 2.94–3.07
(m, 2H), 3.16 (s, 3H, OCH3), 3.42–3.53 (m, 1H), 3.71–3.78 (m,
1H), 3.76 (s, 3H, OCH3), 5.09 (dd, J = 3.1, 6.4 Hz, 1H), 6.81 (d,
J = 8.7 Hz, 2H, Harom), 7.18 (d, J = 8.7 Hz, 2H, Harom); 13C NMR
(CDCl3): C 169.9 (CO), 158.9, 146.2, 130.0, CH 129.2, 112.8, 106.6,
60.7, CH2 76.1, 51.9, 34.1, 28.2, 22.8, 19.7, CH3 58.6, 55.2. Anal.
Calcd for C18H24N2O3: C, 68.33; H, 7.65; N, 8.85. Found: C, 68.20;
H, 7.67; N, 8.97.
4.2.1. 1-((S)-2-Methoxymethylpyrrolidin-1-yl)-piperidine-2,6-
dione 9
Oil; ½a 2D0
ꢁ
¼ þ3:9 (c 1.52, CHCl3); 1H NMR (CDCl3): 1.41–1.51 (m,
1H), 1.69–1.95 (m, 5H), 2.52–2.56 (m, 4H), 3.02–3.23 (m, 7H),
3.51–3.60 (m, 1H); 13C NMR (CDCl3): C 172.5 (CO), 171.4 (CO),
CH 59.5, CH2 76.4, 50.9, 34.2, 33.3, 27.1, 22.4, 16.6, CH3 58.6. Anal.

1002
R. Sallio et al. / Tetrahedron: Asymmetry 23 (2012) 998–1004
4.3.4. 6-(3,4-Dimethoxyphenyl)-1-((S)-2-methoxy-methylpyrro-
J = 8.6 Hz, 2H, Harom), 7.13 (d, J = 8.6 Hz, 2H, Harom); 13C NMR
(CDCl3): C 169.4 (CO), 158.8, 134.6, CH 128.4 (2 ꢂ CH), 113.5
(2 ꢂ CH), 60.9, 59.5, CH2 75.1, 50.7, 33.6, 32.0, 27.7, 23.2, 16.6,
CH3 58.3, 55.4. Anal. Calcd for C18H26N2O3: C, 67.90; H, 8.23; N,
8.80. Found: C, 67.78; H, 8.12; N, 8.98.
lidin-1-yl)-3,4-dihydro-1H-pyridin-2-one 12d
Mp 85–86 °C; ½a 2D0
ꢁ
¼ ꢀ105:2 (c 1.97, CHCl3); 1H NMR (CDCl3):
1.18–1.23 (m, 1H), 1.37–1.52 (m, 1H), 1.81–1.98 (m, 2H), 2.06–
2.19 (m, 1H), 2.35–2.64 (m, 3H), 2.72–2.83 (m, 1H), 2.93–3.08
(m, 2H), 3.17 (s, 3H, OCH3), 3.38–3.51 (m, 1H), 3.65–3.73 (m,
1H), 3.82 (s, 6H, 2 ꢂ OCH3), 5.16 (t, J = 7.1 Hz, 1H), 6.72–6.85 (m,
3H, Harom); 13C NMR (CDCl3): C 169.8 (CO), 148.3, 147.6, 146.2,
130.2, CH 120.4, 111.3, 110.0, 106.7, 60.6, CH2 76.0, 51.8, 34.0,
28.1, 22.8, 19.6, CH3 58.6, 55.8, 55.7. Anal. Calcd for C19H26N2O4:
C, 65.87; H, 7.56; N, 8.09. Found: C, 65.85; H, 7.46; N, 8.21.
4.4.4. (S)-6-(3,4-Dimethoxyphenyl)-1-((S)-2-methoxymethyl-
pyrrolidin-1-yl)piperidin-2-one 13d
Mp 96–97 °C; ½a 2D0
ꢁ
¼ ꢀ67:3 (c 1.64, CHCl3); 1H NMR (CDCl3):
1.48–1.60 (m, 3H), 1.68–1.89 (m, 3H), 2.05–2.18 (m, 2H), 2.35–
2.56 (m, 4H), 2.94 (s, 3H, OCH3), 3.05–3.11 (m, 2H), 3.44–3.53
(m, 1H), 3.83 (s, 6H, 2 ꢂ OCH3), 4.65 (t, J = 5.2 Hz, 1H), 6.67 (s,
1H, Harom), 6,73 (d, J = 8.2 Hz, 2H, Harom), 6.82 (d, J = 8.2 Hz, 2H, Har-
om); 13C NMR (CDCl3): C 169.6 (CO), 148.8, 148.2, 135.2, CH 119.3,
110.7, 110.3, 61.3, 59.7, CH2 75.5, 51.0, 33.4, 32.2, 27.6, 23.5, 16.6,
CH3 58.6, 55.9, 55.8. Anal. Calcd for C19H28N2O4: C, 65.49; H, 8.10;
N, 8.04. Found: C, 65.22; H, 8.12; N, 7.98.
4.3.5. 6-Benzo[1,3]dioxol-5-yl-1-((S)-2-methoxy-methylpyrroli-
din-1-yl)-3,4-dihydro-1H-pyridin-2-one 12e
Mp 148–149 °C; ½a D20
ꢁ
¼ ꢀ83:0 (c 0.53, CHCl3); 1H NMR (CDCl3):
1.23–1.35 (m, 1H), 1.48–1.61 (m, 1H), 1.90–2.06 (m, 2H), 2.13–2.25
(m, 1H), 2.32–2.67 (m, 3H), 2.94 (dd, J = 6.3, 9.3 Hz, 1H), 2.98–3.06
(m, 1H), 3.10 (dd, J = 5.6, 9.3 Hz, 1H), 3.22 (s, 3H, OCH3), 3.43–3.52
(m, 1H), 3.72–3.84 (m, 1H), 5.14 (dd, J = 2.9, 6.4 Hz, 1H), 5.96 (d,
J = 3.3 Hz, 1H), 5.98 (d, J = 3.3 Hz, 1H), 6.74–6.78 (m, 3H, Harom);
13C NMR (CDCl3): C 169.9 (CO), 146.9, 146.7, 146.0, 131.5, CH
121.4, 108.5, 107.4, 107.1, 60.8, CH2 101.0, 76.1, 52.0, 34.1, 28.3,
22.9, 19.6, CH3 58.7. Anal. Calcd for C18H22N2O4: C, 65.44; H,
6.71; N, 8.48. Found: C, 65.26; H, 6.83; N, 8.23.
4.4.5. (S)-6-Benzo[1,3]dioxol-5-yl-1-((S)-2-methoxymethyl-
pyrrolidin-1-yl)piperidin-2-one 13e
Oil; ½a 2D0
ꢁ
¼ ꢀ53:9 (c 0.49, CHCl3); 1H NMR (CDCl3): 1.54–1.63 (m,
3H), 1.73–1.87 (m, 3H), 2.04–2.18(m, 2H), 2.36–2.60 (m, 4H), 3.07(s,
3H, OCH3), 3.09–3.18 (m, 2H), 3.58–3.63 (m, 1H), 4.64 (t, J = 4.4 Hz,
1H), 5.95 (d, J = 3.0 Hz, 1H), 5.97 (d, J = 3.0 Hz, 1H), 6.68–6.83 (m,
3H, Harom); 13C NMR (CDCl3): C 169.5 (CO), 147.8, 146.8, 136.5, CH
120.4, 107.9, 107.7, 60.8, 59.7, CH2 101.1, 75.3, 50.9, 33.4, 31.9,
27.5, 23.4, 16.6, CH3 58.3. Anal. Calcd for C18H24N2O4: C, 65.04; H,
7.28; N, 8.43. Found: C, 65.18; H, 7.36; N, 8.60.
4.4. Typical procedure for the preparation of cyclic hydrazides
13a–e
A suspension of compounds 12a–e (2 mmol) in MeOH (30 mL)
was stirred with activated Pd/C (10%, 30 mg) and a solution of
HCO2NH4 (500 mg, 8 mmol) in distilled water (5 mL) was then
added. The reaction mixture was refluxed for 4 h, filtered on Cel-
ite™, and diluted with water. Extraction with CH2Cl2 (3 ꢂ 20 mL),
drying over MgSO4, and concentration under vacuum gave an oily
product, which was purified by chromatography on silica gel using
EA/hexanes (60:40) as eluent to give 13a–e.
4.5. Typical procedure for the preparation of piperidinones 14a–
e
To a solution of lactam 13a–e (1 mmol) in MeOH (40 mL) was
added MMPP (2.5 mmol, 1.24 g). The reaction mixture was stirred
at room temperature until no starting material remained (TLC
monitoring). The mixture was then poured into CH2Cl2 (150 mL)
and treated with a saturated aqueous NaHCO3 solution (100 mL).
The aqueous layer was extracted with CH2Cl2 (3 ꢂ 50 mL) and
the combined extracts were washed successively with water
(30 mL), brine (30 mL) and finally dried over MgSO4. Evaporation
of the solvent furnished an oily product, which was purified by
flash column chromatography using EA as eluent. The product
was finally recrystallized from Et2O to give 14a–e.
4.4.1. 1-((S)-2-Methoxymethylpyrrolidin-1-yl)-(S)-6-phenylpi-
peridin-2-one 13a
Oil, ½a 2D0
ꢁ
¼ ꢀ56:2 (c 2.89, CHCl3); 1H NMR (CDCl3): 1.51–1.68
(m, 3H), 1.71–1.92 (m, 3H), 2.07–2.25 (m, 2H), 2.35–2.61 (m,
4H), 2.96 (s, 3H, OCH3), 3.08–3.17 (m, 2H), 3.51–3.63 (m, 1H),
4.71 (t, J = 5.3 Hz, 1H), 7.19–7.46 (m, 5H, Harom); 13C NMR (CDCl3):
C 169.5 (CO), 142.8, CH 128.3 (2 ꢂ CH), 127.4, 127.3 (2 ꢂ CH), 61.0,
59.8, CH2 75.2, 51.0, 33.5, 32.0, 27.5, 23.3, 16.5, CH3 58.5. Anal.
Calcd for C17H24N2O2: C, 70.80; H, 8.39; N, 9.71. Found: C, 70.86;
H, 8.12; N, 9.69.
4.5.1. (S)-6-Phenylpiperidin-2-one 14a
Mp 116–117 °C, lit.10 115–117 °C; ½a D20
¼ ꢀ58:0 (c 0.54, CHCl3),
ꢁ
lit.10
½
a 2D0
ꢁ
¼ þ58:2 (c 1.1, CHCl3) for the (R)-enantiomer; 1H NMR
(CDCl3): 1.57–1.66 (m, 1H), 1.69–1.78 (m, 1H), 1.81–1.98 (m, 1H),
2.03–2.17 (m, 1H), 2.37–2.52 (m, 2H), 4.55 (dd, J = 4.5–9.1 Hz,
1H), 6.14 (br s, 1H, NH), 7.27–7.39 (m, 5H, Harom); 13C NMR (CDCl3):
C 172.5 (CO), 142.5, CH 128.8 (2 ꢂ CH), 127.9, 126.1 (2 ꢂ CH), 57.7,
CH2 32.1, 31.2, 19.6.
4.4.2. (S)-6-(4-Fluorophenyl)-1-((S)-2-methoxy-methylpyrro-
lidin1-yl)piperidin-2-one 13b
Oil; ½a 2D0
ꢁ
¼ ꢀ45:2 (c 1.43, CHCl3); 1H NMR (CDCl3): 1.53–1.66
(m, 3H), 1.71–1.88 (m, 3H), 2.10–2.23 (m, 2H), 2.38–2.65 (m,
4H), 3.03 (s, 3H, OCH3), 3.08–3.16 (m, 2H), 3.53–3.65 (m, 1H),
4.69 (t, J = 4.8 Hz, 1H), 7.03–7.11 (m, 2H, Harom), 7.18–7.27 (m,
4.5.2. (S)-6-(4-Fluorophenyl)piperidin-2-one 14b
2H,
H
arom); 13C NMR (CDCl3):
C
169.6 (CO), 162.0 (d,
Mp 98–99 °C; ½a 2D0
ꢁ
¼ ꢀ47:2 (c 0.60, CHCl3); 1H NMR (CDCl3):
J = 250.0 Hz), 138.5 (d, J = 7.4 Hz), CH 128.9 (d, J = 7.6 Hz, 2CH),
115.1 (d, J = 21.5 Hz, 2CH), 61.0, 59.8, CH2 75.3, 51.0, 33.5, 32.0,
27.6, 23.5, 16.6, CH3 58.6. Anal. Calcd for C17H23FN2O2: C, 66.64;
H, 7.57; N, 9.14. Found: C, 66.76; H, 7.41; N, 9.20.
1.51–1.63 (m, 1H), 1.66–1.77 (m, 1H), 1.79–1.91 (m, 1H), 1.97–
2.06 (m, 1H), 2.27–2.48 (m, 2H), 4.47 (dd, J = 4.6, 9.0 Hz, 1H), 5.95
(br s, 1H, NH), 6.94–7.03 (m, 2H, Harom), 7.16–7.25 (m, 2H, Harom);
13C NMR (CDCl3): C 171.4 (CO), 161.5 (d, J = 247.0 Hz), 136.9 (d,
J = 3.2 Hz), CH 126.7 (d, J = 7.2 Hz, 2 ꢂ CH), 114.7 (d, J = 2 1.6 Hz,
2 ꢂ CH), 56.3, CH2 32.1, 30.8, 19.4. Anal. Calcd for C11H12FNO: C,
68.38; H, 6.26; N, 7.25. Found: C, 66.48; H, 6.37; N, 7.15.
4.4.3. (S)-6-(4-Methoxyphenyl)-1-((S)-2-methoxymethylpyrro-
lidin-1-yl)piperidin-2-one 13c
Mp 94–95 °C; ½a 2D0
ꢁ
¼ ꢀ27:4 (c 1.29, CHCl3); 1H NMR (CDCl3):
1.50–1.62 (m, 3H), 1.75–1.88 (m, 3H), 2.06–2.21 (m, 2H), 2.35–
2.60 (m, 4H), 3.05 (s, 3H, OCH3), 3.07–3.13 (m, 2H), 3.51–3.59
(m, 1H), 3.82 (s, 3H, OCH3), 4.63 (t, J = 4.5 Hz, 1H), 6,86 (d,
4.5.3. (S)-6-(4-Methoxyphenyl)piperidin-2-one 14c
Mp 135–136 °C, lit.12 134–136 °C; ½a D20
¼ ꢀ58:8 (c 1.90, CHCl3),
ꢁ
lit.12
½
a 2D0
ꢁ
¼ þ58:0 (c 0.5, CHCl3) for the (R)-enantiomer; 1H NMR

R. Sallio et al. / Tetrahedron: Asymmetry 23 (2012) 998–1004
1003
(CDCl3): 1.57–1.72 (m, 1H), 1.74–1.82 (m, 1H), 1.85–1.97 (m, 1H),
2.01–2.12 (m, 1H), 2.32–2.51 (m, 2H), 3.80 (s, 3H, OCH3), 4.49
(dd, J = 4.2, 9.0 Hz, 1H), 6.08 (br s, 1H, NH), 6,89 (d, J = 8.6 Hz, 2H,
atmosphere and a solution of the selected catalyst in the same sol-
vent (2 mL) was then added. The autoclave was purged 3 times
with H2 gas and finally pressurized at the chosen pressure. Heating
(water bath) and stirring (magnetic stirring plate) were started and
the reaction time was counted since the desired temperature was
reached. After 16 h or 64 h of reaction, the autoclave was cooled
and then the H2 gas pressure was released. The reaction mixture
was filtered on a pad of Celite™ and then washed with EA
(2 ꢂ 10 mL). The combined organic layers were concentrated un-
der vacuum to leave an oily product which was purified by chro-
matography on silica gel using EA/hexanes mixtures as eluent.
HPLC analyses were performed by using Regis™ (S,S)-Whelk 01
H
arom), 7.22 (d, J = 8.6 Hz, 2H, Harom); 13C NMR (CDCl3): C 172.5
(CO), 159.2, 134.6, CH 127.3 (2 ꢂ CH), 114.1 (2 ꢂ CH), 57.3, CH2
32.2, 31.2, 19.7, CH3 55.3.
4.5.4. (S)-6-(3,4-Dimethoxyphenyl)piperidin-2-one 14d
Mp 124–125 °C; ½a D20
ꢁ
¼ ꢀ43:1 (c 2.16, CHCl3); 1H NMR (CDCl3):
1.55–1.64 (m, 1H), 1.68–1.76 (m, 1H), 1.81–1.88 (m, 1H), 1.94–2.07
(m, 1H), 2.27–2.49 (m, 2H), 3.78 (s, 3H, OCH3), 3.80 (s, 3H, OCH3),
4.42 (dd, J = 4.3, 9.0 Hz, 1H), 6.32 (br s, 1H, NH), 6.68–6.81 (m, 3H,
H
arom); 13C NMR (CDCl3): C 172.6 (CO), 149.1, 148.5, 135.0, CH
chiral column n-hexane/i-PrOH, 80:20, flow rate 1 mL minꢀ1
,
118.3, 111.1, 108.9, 57.4, CH2 32.2, 31.1, 19.7, CH3 55.9 (2 ꢂ OCH3).
Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C,
66.48; H, 7.17; N, 5.80.
detection: UV 200 nm. Retention times were: 38.0 and 55.0 min
for compound 21,25 7.6 and 31.5 min for compound 22,27 30.7
and 43.9 min for compound 23.
4.5.5. (S)-6-Benzo[1,3]dioxol-5-ylpiperidin-2-one 14e
4.9. 1-Benzyl-6-phenylpiperidin-2-one 21
Mp 136–137 °C; ½a D20
ꢁ
¼ ꢀ59:1 (c 0.33, CHCl3); 1H NMR (CDCl3):
Oil; 1H NMR (CDCl3): 2.45–2.56 (m, 4H), 3.27–3.35 (m, 2H), 4.36
(s, 2H), 5.61 (br d, 1H), 7.05–7.32 (m, 10 H, Harom); 13C NMR
(CDCl3): C 170.8 (CO), 141.1, 137.3, CH 128.6 (2 ꢂ CH), 128.4
(2 ꢂ CH), 128.1 (2 ꢂ CH), 127.6, 127.3, 126.7 (2 ꢂ CH), 59.6, CH2
47.7, 32.3, 31.8, 19.6.
1.55–1.68 (m, 1H), 1.72–1.80 (m, 1H), 1.84–1.94 (m, 1H), 1.99–2.08
(m, 1H), 2.37–2.46 (m, 2H), 4.46 (dd, J = 4.4, 9.0 Hz, 1H), 5.97 (s,
2H), 6.22 (br s, 1H, NH), 6.72–6.81 (m, 3H, Harom); 13C NMR (CDCl3):
C 172.4 (CO), 148.0, 147.2, 136.5, CH 119.4, 108.3, 106.5, 57.5, CH2
101.2, 32.2, 31.2, 19.6. Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98;
N, 6.39. Found: C, 65.57; H, 5.89; N, 6.58.
4.9.1. 2-Phenylpiperidine-1-carboxylic acid phenyl ester 23
Mp 63–64 °C; 1H NMR (CDCl3): 1.72–2.23 (m, 6H), 2.95–3.03
(m, 1H), 4.02–4.18 (m, 1H), 5.63 (t, J = 6.3 Hz, 1H), 7.03–7.32 (m,
10 H, Harom); 13C NMR (CDCl3): C 154.9 (CO), 151.7, 139.7, CH
129.4 (2 ꢂ CH), 128.9 (2 ꢂ CH), 126.9 (2 ꢂ CH), 126.7, 125.3,
121.9 (2 ꢂ CH), 54.2, CH2 41.2, 28.2, 25.6, 19.4. Anal. Calcd for
4.6. Procedures for the preparation of 15, 16, 17
Imide 15,23 and acylated lactams 1624 and 1717a were prepared
according to previously described procedures.
4.7. Procedures for the preparation of 18, 19, 20
C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C, 76.70; H, 6.89;
N, 4.81.
To a solution of compounds 15, 16, 17 (2 mmol) and diphenyl
phosphoryl chloride (0.62 mL, 3 mmol) in anhydrous THF (30 mL)
cooled at ꢀ78 °C and under nitrogen atmosphere, was added drop-
wise with stirring a solution of KHMDS (6 mL, 0.5 M in toluene,
3 mmol). After 30 min at ꢀ78 °C, water (20 mL) was added and
the resulting mixture was extracted with Et2O (2 ꢂ 50 mL) and
dried over MgSO4. Evaporation of the solvent under vacuum
yielded the vinyl phosphates as yellow oils, which were used di-
rectly in the next coupling step.
To a stirred solution of crude vinyl phosphates (2 mmol) in 1,4-
dioxane for 18, THF for 19 or DME for 20 (20 mL) maintained under
a nitrogen atmosphere, were added Ba(OH)2 (685 mg, 4 mmol) for
18 or 2 M aqueous Na2CO3 (2 mL, 4 mmol) for 19 and 20, Pd(PPh3)4
(120 mg, 5 mol %) and phenyl boronic acid (365 mg, 3 mmol). The
mixture was stirred at reflux for 12 h for 18, 2 h for 19 or 0.5 h for
20, and then it was diluted with water (2 mL) and extracted with
Et2O (3 ꢂ 50 mL). The combined organic layers were dried over
MgSO4 and concentrated under vacuum to give an orange oil which
was purified by flash column chromatography using EA/hexanes
(40:60) as eluent to afford compounds 18,25 19,26 20.17a
Acknowledgments
The French ‘Ministère de la Recherche et des Nouvelles Technol-
ogies’ is gratefully acknowledged for a Ph.D. fellowship (R.S.). Sup-
port from CNRS and Université Lille 1 is warmly acknowledged.
Fundings from Région Nord-Pas de Calais with ‘Projet Prim: Etat-
Région’ and with ‘Fonds Européen de Développement Régional
(FEDER)’ are also greatly appreciated. Ms. C. Delabre (UCCS) is
thanked for GC–MS analyses. Ms. M. Dubois (CMF) is thanked for
technical assistance and Dr. A. Couture for helpful comments on
the manuscript.
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