Catalytic asymmetric allylic alkylation of 3-arylated piperidin-2-ones

Article abstract of DOI:10.1002/ejoc.201300510

The preparation of optically active lactams from 3-aryl-2-piperidinone is reported. The quaternary carbon stereocentres were formed using palladium-catalysed asymmetric allylic alkylation reactions. The resulting enantioenriched compounds are useful inter

Full text of DOI:10.1002/ejoc.201300510

FULL PAPER
DOI: 10.1002/ejoc.201300510
Catalytic Asymmetric Allylic Alkylation of 3-Arylated Piperidin-2-ones
Christophe Michon,*[a,b,c] Aurélien Béthegnies,[a,b,c] Frédéric Capet,[a,b,d][‡]
Pascal Roussel,[a,b,d][‡] Arnault de Filippis,[e] Domingo Gomez-Pardo,[e] Janine Cossy,*[e] and
Francine Agbossou-Niedercorn*[a,b,c]
Dedicated to Professor Bertrand Castro
Keywords: Lactams / Heterocycles / Alkylation / Palladium / Asymmetric catalysis
The preparation of optically active lactams from 3-aryl-2-pip-
eridinone is reported. The quaternary carbon stereocentres
were formed using palladium-catalysed asymmetric allylic
alkylation reactions. The resulting enantioenriched com-
pounds are useful intermediates for the synthesis and devel-
opment of neurokinin antagonists.
pain transmission, and neurogenic inflammation. Thus, an-
tagonists of these NK receptors have attracted a great deal
of interest as potential therapeutic agents.[3] Some optically
active 3-aryl-2-piperidinone derivatives have been described
as pharmacologically relevant structures (Figure 1). The
neurokinin antagonist Osanetant SR-142801 (1) has been
described as active against depression, emesis, irritable
bowel syndrome, schizophrenia, and urinary trouble.[4]
Spiro indane 2, which is an NK1 antagonist, has been used
for the treatment of depression and anxiety.[5] Histamine
and tachykinin receptor antagonist 3 has been used for the
treatment of rhinitis and sinusitis.[6]
Introduction
Neurokinins, also known as tachykinins, are neuro-
transmittors, and examples include substance P (SP), neu-
rokinin A (NKA), and neurokinin B (NKB). These pept-
ides share the common carboxy-terminal sequence Phe-X-
Gly-Leu-Met-NH2 and are widely distributed in the central
and peripheral nervous systems.[1] Three distinct seven-
transmembrane G-protein-coupled receptor types have
been identified based on their affinities for natural neuroki-
nins: NK1 (SP-preferring), NK2 (NKA-preferring), and
NK3 (NKB-preferring).[2] The various forms of neurokinin
in the mammalian body affect a large number of biological
activities, including muscle contraction and relaxation, va-
sodilatation, secretion, activation of the immune system,
[a] Université Lille Nord de France
59000 Lille, France
[b] CNRS, UCCS UMR 8181
59655 Villeneuve d’Ascq, France
[c] ENSCL, CCCF (Chimie-C7)
B. P. 90108, 59652 Villeneuve d’Ascq Cedex, France
Fax: +33-3-20436585
E-mail: christophe.michon@ensc-lille.fr
francine.agbossou@ensc-lille
Homepage: http://uccs.univ-lille1.fr/index.php/annuaire/15-
fiches-personnels/221-michon-christophe
http://uccs.univ-lille1.fr/index.php/annuaire/15-
fiches-personnels/81-agbossou-niedercorn-francine
[d] ENSCL, CS (Chimie-C7)
B. P. 90108, 59652 Villeneuve d’Ascq Cedex, France
Fax: +33-3-20436814
E-mail: pascal.roussel@ensc-lille.fr
Figure 1. Examples of pharmacologically active enantiopure 3-
aryl-2-piperidinones.
[e] Laboratoire de Chimie Organique associé au CNRS, ESPCI,
10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax: +33-1-40794660
As a result of our interest in the preparation of interme-
diates for the synthesis of potent NK antagonists based on
2,2-disubstituted morpholines[7] and piperidinediones,[8] we
considered the palladium-catalysed asymmetric allylic alk-
ylation[9] of 3-aryl-2-piperidinones. Such a short, versatile,
E-mail: janine.cossy@espci.fr
Homepage: http://www.lco.espci.fr
[‡] Authors to whom correspondance about X-ray diffraction
should be addressed
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300510.
Eur. J. Org. Chem. 2013, 4979–4985
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Michon, J. Cossy, F. Agbossou-Niedercorn et al.
FULL PAPER
Aefficient, and stereocontrolled reaction can compete with
other synthetic methods[10] regularly used to introduce qua-
ternary carbon stereocentres into lactams or imides. As
we[7b] and others[11] have shown, the introduced allyl func-
tionality can be derivatized in a few steps to give key inter-
mediates for the synthesis of compounds of interest, such
as neurokinins based on piperidine scaffolds.
Results and Discussion
Lactam 4 was first protected by a deprotonation/trap-
ping sequence using nBuLi followed by the addition of
benzyl bromide, benzoyl chloride, or tosyl chloride
(Scheme 1). The resulting N-protected 2-piperidinones (i.e.,
5–7) were then α-arylated by initial conversion into the zinc
enolates, and subsequent palladium-catalysed coupling with
bromobenzene.[12] First, the reaction of compounds 5–7
with LiHMDS (Lithium hexamethyldisilazide; 1 equiv.)
gave the corresponding lithium enolates, and these were im-
mediately transmetallated with ZnCl2 (1.5 equiv.) to in-
crease their reactivity. The resulting zinc enolates were then
added to a combination of Pd(dba)2 (dba = dibenzylidene-
acetone; 2.5 mol-%), Davephos ligand (3.8 mol-%), and
bromobenzene (1 equiv.), and heated at reflux in THF for
36 h. After workup and flash chromatography, 3-aryl-piper-
idinones 8–10 were isolated in 25–52% yield.
Scheme 2. Ligands used in the asymmetric allylic alkylation of 3-
aryl piperidinones 8–10.
down the process (Table 1, Entry 4). While 11a could be
The asymmetric allylic alkylation of prochiral 3-aryl- obtained in 40% yield and with 57% ee using L2 (Table 1,
benzoylpiperidinone 8 was first studied using allylpalladium Entry 4); L3 gave 11a with a higher yield (52%) but a much
chloride dimer and Trost ligands L1–L3 (Scheme 2 and lower enantioselectivity (10% ee; Table 1, Entry 10). The
Table 1).
use of L2 also led to the best results for 12, with a 53%
The selectivity of the reaction proved to be dependent on yield and a 48% ee after 3 h (Table 1, Entry 6). A lower
several parameters, including the nature of the base and the yield (33%) and a better enantioselectivity (68% ee) could
phosphane ligand. When NaH was used as a base, L1 gave be obtained for 12 by using a longer reaction time (Table 1,
only compound 11a (Table 1, Entry 1); L2 led to the forma- Entry 7). Compound 12 proved to decompose over time,
tion of products 11a, 12, and 13 (Table 1, Entries 4 and 5); with partial conversion into 13. Compound 13 could be ob-
and L3 led to the formation of 11a and 13 (Table 1, En- tained in 27% yield and with 65% ee by using L3 and with
try 10). Under these conditions, the reaction time was criti- a reaction time of 12 h (Table 1, Entry 8). Other ligands led
cal in favouring the formation of one product over the to lower yields and enantioselectivities for 13 (Table 1, En-
others. Compound 11a could be formed in 1 or 2 h (Table 1, tries 3–10). Unfortunately, the use of other inorganic or or-
Entries 1 and 4), whereas longer reaction times, i.e., 3–6 h, ganic bases did not improve the yields of the products, as
promoted the formation of 12 and/or 13 (Table 1, Entries 2, the conversions were rather low (Table 1, Entries 11–17).
3, 6, and 7), although a lower temperature tended to slow Although the addition of a catalytic amount of NaBARF
Scheme 1. Syntheses of 3-aryl piperidinones 8–10.
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Eur. J. Org. Chem. 2013, 4979–4985

Catalytic Asymmetric Allylic Alkylation of Piperidin-2-ones
Table 1. Asymmetric allylic alkylation of 3-aryl-benzoylpiperidinone 8. BARF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate; DMAP =
4-(dimethylamino)pyridine; DABCO = 1,4-diazabicyclo[2.2.2]octane; DBN = 1,5-diazabicyclo[4.3.0]non-5-ene; DBU = 1,8-diazabicy-
clo[5.4.0]undec-7-ene; BSA = O,N-bistrimethylsilylacetamide.
Entry
Ligand
Base and additive
T
[°C]
Time
[h]
Yield [%][a]
Yield [%][a]
Yield [%][a]
(ee) of 11a[b]
(ee [%]) of 12[b]
(ee [%]) of 13[b]
1
2
3
4
5
6
7
8
9
(R,R)-L1
(R,R)-L1
(R,R)-L1
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
NaH (2.6 equiv.)
NaH (2.6 equiv.)
NaH (2.6 equiv.)
NaH (2.6 equiv.)
NaH (2.6 equiv.)
NaH (2.6 equiv.)
NaH (2.6 equiv.)
NaH (2.6 equiv.)
NaH (2.6 equiv.)
+ NaBARF (0.03 equiv.)
NaH (2.6 equiv.)
DMAP (1.3 equiv.)
DABCO (1.3 equiv.)
DBN (1.3 equiv.)
NaOtBu (2.6 equiv.)
DBU (1.3 equiv.)
BSA (1.3 equiv.)
20
20
20
0
20
20
20
20
20
1
3
6
2
1
3
5
12
5
28 (60)
10 (64)
0
0
0
0
7
4
20 (60)
4
18 (69)
19 (40)
28 (59)
27 (65)
17 (48)
40 (57)
11 (63)
18 (55)
31 (68)
53 (48)
33 (67)
0
0
0
0
6(c)
23 (58)
10
11
12
13
14
15
16
(R,R)-L3
(R,R)-L3
(R,R)-L3
(R,R)-L3
(R,R)-L2
(R,R)-L2
(R,R)-L2
20
20
20
20
0
20
20
5
4
4
4
2
4
20
52 (11)
0
6 (0)
17 (0)
17[c]
26 (0)
17 (0)
0
0
0
0
0
0
0
23 (26)
0
0
0
0
0
0
+ KOAc (0.08 equiv.)
LiHMDS (1.3 equiv.)
17
(R,R)-L2
20
4
0
28 (10)
12 (–)
[a] Isolated yields. [b] Measured by HPLC with Regis (S,S)-Whelk 01 CSP, n-hexane/iPrOH (9:1), 0.5 mL/min. [c] Isomerized product
11b.
improved the conversion,[13] we observed lower yields of 12 organic bases were far less efficient (Table 2, Entries 15–19).
and 13, and also the isomerization of 11a into 11b (Table 1, It is worth noting that better yields and enantioselectivities
Entry 9).
could be obtained by using an additional catalytic amount
The asymmetric allylic alkylation reactions of prochiral of NaBARF,[13] but the results were not reproducible (see
3-aryl-benzylpiperidinones 9a,b and 3-aryl-tosylpiperidin- Supporting Information). The use of NaOtBu might lead
one 10 were studied next (Scheme 2 and Table 2). The palla- to a weaker ion-pair with the allylpalladium intermediate,
dium catalysts using Trost ligands L1–L3 proved to be far and result in a higher enantioselectivity. Although the
more efficient than the iridium catalysts[14,15] based on li- asymmetric allylic alkylation of 9a proceeded smoothly, the
gands L4–L6 (Table 2, Entries 1–8 and 9–11). The different reaction of 9b led to a low enantioselectivity because of the
chiral backbone of ligand (R,R)-L3 led to a reversal of the additional chlorides on one of the phenyl groups (Table 2,
sense of enantioselectivity compared to (R,R)-L1 and Entry 20). Furthermore, the switch to a tosyl protecting
(R,R)-L2 (Table 2, Entries 5 and 7). THF turned out to be group resulted in low yields for the formation of 13 or 15,
the best solvent, as no reaction was observed in dichloro- along with decomposition of 3-aryl-tosylpiperidinone 10
methane (Table 2, Entry 12). When NaH was used as a (Table 2, Entries 21–22).
base, yields of around 75% were obtained, and enantio-
To check whether the asymmetric allylic alkylation of 3-
selectivities increased gradually to 64% ee by switching aryl-2-piperidinone could be achieved without the use of a
from L1 to L2 and then to L3 (Table 2, Entries 1–6). A protecting group, we prepared compound 16a in 47% yield
[16]
decrease of the reaction temperature resulted in better by deprotection of lactam 8 using SmI2
in methanol
enantioselectivities for the formation of 14a, provided the (Scheme 3). Interestingly, allylated compound 11a could be
reaction was run at 0 °C (Table 2, Entries 3–5). Even lower deprotected similarly, leading to 12 in 50% yield.
temperatures resulted in reduced yields (–10 °C), or even
We have previously shown that imide 16b could be con-
stopped the reaction (–20 °C; Table 2, Entries 7–8). Na- verted into allylated derivative 18 in 95% yield and with
OtBu proved to be the best base, as it gave 14a in 72% yield 80% ee by using a palladium catalyst and a quaternary am-
and with 72% ee (Table 2, Entry 13). The use of NaOtAm monium salt (Scheme 3).[7d] However, no reaction was ob-
(sodium tert-amylate) led to a better yield but a lower served with compound 16a under similar conditions. In the
enantioselectivity (Table 2, Entry 14). Other inorganic or absence of the ammonium salt, N-allylated product 17 was
Eur. J. Org. Chem. 2013, 4979–4985
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Michon, J. Cossy, F. Agbossou-Niedercorn et al.
FULL PAPER
Table 2. Asymmetric allylic alkylations of 3-aryl-benzylpiperidinones 9a,b and 3-aryl-tosylpiperidinone 10. TMEDA = tetramethylethyl-
enediamine.
Entry
Starting material
Ligand
Base
T [°C]
Time [h]
Product, yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9b
10
10
rac-L1
(R,R)-L1
(R,R)-L2
(R,R)-L2
(R,R)-L3
(S,S)-L3
(R,R)-L3
(R,R)-L3
(R)-L4
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaOtBu
NaOtAm
Cs2CO3
LiHMDS
DBU
25
0
25
0
0
0
–10
–20
15
24
15
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
5
14a, 74
14a, 42
14a, 75
14a, 80
14a, 78
14a, 75
14a, 45
14a, 0
0
22
44
51
–64[c]
64
–64[c]
0
9[e]
10[e]
11[e]
12
13
14
15
16
17
18
19
20
21
22
0 or 60
14a, 12 or 0
14a, 0
0
0
0
0
(R,R)-L5
(S,R,R)-L6
(S,S)-L3
(R,R)-L3
(R,R)-L3
(R,R)-L3
(R,R)-L3
(R,R)-L3
(R,R)-L3
(R,R)-L3
(R,R)-L3
rac-L1
0
0 or 60
14a, 0
0
0
0
0
0
0
0
0
0
14a, 0[d]
14a, 72
14a, 79
14a, 0
–72[c]
–67[c]
0
14a, 60
14a, 0
6
0
nBuLi + sparteine[f]
nBuLi + TMEDA[f]
NaH
14a, 11
14a, 39
14b, 90
13, 20
–4[c]
–14[c]
–15[c]
0
NaH
DBU
25
25
(R,R)-L2
5
15, 5
–
[a] Isolated yields. [b] Measured by HPLC with Daicel Chiralpak OJ-H CSP, n-hexane/iPrOH (9:1), 0.3 mL/min. [c] Opposite enantiomer.
[d] In dichloromethane. [e] Without [Pd(allyl)Cl]2 and with [Ir(COD)Cl]2 (0.016 equiv.) instead (COD = cyclooctadienyl). [f] 2.6 equiv. of
additive.
Scheme 3. Role of the protecting group.
formed in 20% yield, with compound 12 not being observed
(Scheme 3).
The absolute configurations of the products from the
catalytic asymmetric allylic alkylation reactions were inves-
tigated by X-ray diffraction analysis. Compounds 14a and
14b did not give any crystals. Slow diffusion of a chloro-
form solution of non-racemic compound 12[17] in n-hexane
gave monocrystals, which unfortunately proved to be race-
mic, with the mother liquor being slightly enantioenriched
(Figure 2). Moreover, regarding compound 8, although we
started from a racemic sample, some monocrystals proved Figure 2. X-ray diffraction analysis of racemic compound 12.[17]
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Eur. J. Org. Chem. 2013, 4979–4985

Catalytic Asymmetric Allylic Alkylation of Piperidin-2-ones
3-Allyl-1-benzoyl-3-phenylpiperidin-2-one (11a): From compound 8
(0.101 g, 0.36 mmol), according to the general procedure for a reac-
tion at 0 °C for 2 h. The resulting crude product was purified by
flash chromatography on silica gel (petroleum ether/ethyl acetate,
8:2) to give compound 11a (0.05 g, 40%) as a colourless oil. 1H
NMR (CDCl3): δ = 2.07 (m, 3 H), 2.61 (m, 3 H), 3.52 (m, 1 H),
3.83 (m, 1 H), 4.99 (m, 2 H), 5.50 (m, 1 H), 7.40 (m, 10 H) ppm.
13C NMR (CDCl3): δ = 19.4, 28.8, 45.4, 46.2, 52.1, 118.8, 126.7 (2
C), 127.5, 127.7 (2 C), 128.2 (2 C), 128.9 (2 C), 131.6, 134.0, 136.6,
to be chiral, and the absolute configuration of the chiral
centre proved to be (R) (see Supporting Information).[17–19]
Conclusions
We have developed a new route to enantioenriched 2-
aryl/allyl-piperidines, key intermediates for the synthesis of
neurokinin antagonists, containing a quaternary stereocen- 139.7, 175.4 (CO), 176.4 (CO) ppm. IR (KBr): ν = 2943, 1679,
˜
1599, 1496, 1447, 1387, 1282, 1147, 920, 796 cm–1. HRMS (ESI+):
tre. To access such quaternary carbon atoms, palladium-
calcd. for C21H22NO2 [M + H]+ 320.16450; found 320.16394.
catalysed asymmetric allylic alkylation proved to be a
powerful synthetic method, provided finely tuned reaction
conditions were used. Moreover, the nature of the lactam
protecting group tended to be crucial for the selectivity and
efficiency of the reaction. The resulting enantioenriched
lactams are useful intermediates for the synthesis and devel-
opment of neurokinin antagonists, which have attracted a
great deal of interest as therapeutic agents.
[α]2D0 = +101 (CH2Cl2, c = 3.1 mm, for 64% ee). HPLC [REGIS
(S,S)-WHELK-01 CSP, 20 °C, hexane/iPrOH (9:1), 0.5 mL/min,
200 nm]: tR = 76.3 and 83.9 min.
(E)-1-Benzoyl-3-phenyl-3-(prop-1-en-1-yl)piperidin-2-one
(11b):
From compound 8 (0.101 g, 0.36 mmol), according to the general
procedure but adding NaBARF (0.03 equiv.), for a reaction at
20 °C for 5 h. The resulting crude product was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate, 8:2) to
give compound 11b (0.007 g, 7%) as a colourless oil. 1H NMR
(CDCl3): δ = 1.61 (m, 1 H), 1.86 (m, 1 H), 2.19 (m, 1 H), 3.45 (m,
1 H), 3.60 (m, 1 H), 4.66 (m, 2 H), 5.16 (m, 2 H), 5.85 (m, 1 H),
6.21 (br. s, 1 H), 7.31 (m, 5 H), 7.47 (m, 3 H), 7.74 (m, 2 H) ppm.
13C NMR (CDCl3): δ = 27.6, 30.7, 39.6, 51.3, 65.5, 118.2, 126.9 (2
C), 127.4, 127.9 (2 C), 128.6 (2 C), 128.8 (2 C), 131.4, 131.9, 134.6,
138.7, 167.5 (CO), 173.6 (CO) ppm.
Experimental Section
General Remarks: All solvents were dried using standard methods.
All reactions were carried out under dry nitrogen. Analytical thin
layer chromatography (TLC) was performed on Merck pre-coated
0.20 mm silica gel Alugram Sil 60 G/UV254 plates. Flash
chromatography was carried out with Macherey silica gel 60 M. 1H
(300 MHz), 13C (75 MHz), and 31P (121 MHz) NMR spectra were
acquired with Bruker Avance spectrometers. Chemical shifts are
reported downfield of Me4Si, and coupling constants are expressed
in Hz. HPLC analyses were performed with a Hitachi LaChromEl-
ite apparatus using a micropump, a Peltier oven, and a DAD detec-
tor. Gas chromatography analysis was done with GC Varian 3900
and 430 instruments with FID detectors, using an Alltech Econo-
Cap EC-5TM column (30 m, 0.25 mm, 0.25 μm). GC–MS analysis
was performed with a Shimadzu QP2010+ instrument using a Sup-
elco column SLBTM-5ms (30 m, 0.25 mm, 0.25 μm). Infrared spec-
tra were recorded with a ThermoScientific–Nicolet 6700 spectrom-
eter, and the samples were prepared with KBr powder. HRMS-ESI
analysis was performed at CUMA-University Lille Nord de France.
See Supporting Information for other details.
3-Allyl-3-phenylpiperidin-2-one (12): From compound 8 (0.101 g,
0.36 mmol), according to the general procedure for a reaction at
20 °C for 3 h. The resulting crude product was purified by flash
chromatography on silica gel (petroleum ether/acetone, 8:2) to give
compound 12 (0.041 g, 53%) as a white solid. M.p. 102 °C. 1H
NMR (CDCl3): δ = 1.68 (m, 2 H), 2.04 (m, 1 H), 2.17 (m, 1 H),
2.52 (dd, J = 8.4, 8.2 Hz, 1 H), 2.88 (dd, J = 6.0, 5.9 Hz, 1 H), 3.28
(m, 2 H), 5.10 (m, 2 H), 5.76 (m, 1 H), 6.13 (br. s, 1 H), 7.22 (t, J
= 7.1 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H)
ppm. 13C NMR (CDCl3): δ = 18.8, 31.5, 42.6, 45.1, 50.8, 118.4,
126.7 (3 C), 129.7 (2 C), 134.1, 143.6, 174.8 (CO) ppm. IR (KBr):
ν = 2940, 1639, 1493, 1443, 1351, 1204, 1118, 911 cm–1. HRMS
˜
(ESI+): calcd. for C14H18NO [M + H]+ 216.1383; found 216.1379.
[α]2D0 = +47 (CH2Cl2, c = 9.6 mm, for 68% ee). HPLC [REGIS
(S,S)-WHELK-01 CSP, 20 °C, hexane/iPrOH = 9:1, 0.5 mL/min,
200 nm]: tR (major) = 34.4 min, tR (minor) = 42.9 min.
General Procedure for Allylic Alkylation of N-Protected and N-
Unprotected 3-Phenylpiperidin-2-ones: The substrate (101 mg,
0.36 mmol) was placed in a Schlenk tube and dried under vacuum.
NaH (2.6 equiv., 37.5 mg) and then anhydrous THF (1.5 mL) were
added under nitrogen, and the resulting solution was stirred at 0 °C
for 30 min, then at room temperature for 30 min. [Pd(allyl)Cl]2
(1.4 mol-% 0.92 mg) and the selected ligand (1.6 mol-%) were
placed in a second Schlenk tube and dried. Anhydrous THF (1 mL)
and then allyl acetate (3.8 equiv., 0.15 mL) were added to the sec-
ond Schlenk tube under nitrogen, and the mixture was stirred at
room temperature for 30 min. Then, the solution from the second
Schlenk tube was transferred by cannula to the first Schlenk tube,
and the resulting solution was stirred at the selected temperature
for the stated time. The reaction was then quenched with NH4Cl
(saturated aq.), and the mixture was extracted with ethyl acetate.
The organic extracts were dried with MgSO4 and concentrated un-
der vacuum. The resulting oil was purified by flash chromatog-
raphy on silica gel (ethyl acetate gradient in petroleum ether or
cyclohexane with 5% triethylamine when needed) to give the prod-
uct as an oily residue.
1,3-Diallyl-3-phenylpiperidin-2-one (13): From compound
8
(0.101 g, 0.36 mmol), according to the general procedure for a reac-
tion at 20 °C for 5 h. The resulting crude product was purified by
flash chromatography on silica gel (petroleum ether/ethyl acetate,
1
8:2) to give compound 13 (0.139 mg, 99%) as a colourless oil. H
NMR (CDCl3): δ = 1.68 (m, 2 H), 2.05 (m, 1 H), 2.18 (m, 1 H),
2.49 (dd, J = 8.4, 8.3 Hz, 1 H), 2.91 (dd, J = 6.0, 5.6 Hz, 1 H), 3.15
(m, 1 H), 3.27 (m, 1 H), 3.99 (dd, J = 5.9, 5.9 Hz, 1 H), 4.15 (dd,
J = 5.9, 5.9 Hz, 1 H), 5.11 (m, 4 H), 5.77 (m, 2 H), 7.22 (m, 1 H),
7.33 (m, 4 H) ppm. 13C NMR (CDCl3): δ = 19.0, 31.6, 45.7, 47.5,
50.0, 51.1, 117.3, 118.1, 126.6, 126.8 (2 C), 128.5 (2 C), 133.2, 135.5,
144.1, 173.1 (CO) ppm. IR (KBr): ν = 2870, 1640, 1492, 1441,
˜
1352, 1277, 1201 cm–1. HRMS (ESI+): calcd. for C17H22NO [M +
H]+ 256.1696; found 256.1689. [α]2D0 = +26 (CH2Cl2, c = 8.0 mm,
for 65 % ee). HPLC [REGIS (S,S)-WHELK-01 CSP, 20 °C, hexane/
iPrOH (9:1), 0.5 mL/min, 200 nm]: tR (major) = 31.7 min, tR
(minor) = 44.7 min.
3-Allyl-1-benzyl-3-phenylpiperidin-2-one (14a): From compound 9a
(0.096 g, 0.36 mmol), according to the general procedure for a reac-
Eur. J. Org. Chem. 2013, 4979–4985
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4983

C. Michon, J. Cossy, F. Agbossou-Niedercorn et al.
FULL PAPER
[2]
[3]
tion at 0 °C for 24 h. The resulting crude product was purified by
flash chromatography on silica gel (cyclohexane/ethyl acetate/NEt3,
7.0:2.5:0.5) to give compound 14a (0.079 g, 72%) as a colourless
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1
oil. H NMR (CDCl3): δ = 1.59 (m, 2 H), 2.01 (m, 1 H), 2.13 (m,
1 H), 2.48 (dd, J = 8.2, 8.2 Hz, 1 H), 2.92 (dd, J = 6.2, 6.2 Hz, 1
H), 3.12 (m, 2 H), 4.04 (s, 2 H), 5.06 (m, 2 H), 5.73 (m, 1 H), 7.24
(m, 10 H) ppm. 13C NMR (CDCl3): δ = 18.8, 31.3, 45.7, 47.4, 50.7,
51.1, 118.2, 126.5, 126.7 (2 C), 127.3, 128.2 (2 C), 128.4 (2 C), 128.6
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(2 C), 135.3, 137.5, 143.9, 172.3 (CO) ppm. IR (KBr): ν = 2943,
˜
1640, 1493, 1442, 1352, 1278, 1198, 1002, 916 cm–1. [α]2D0 = +181
(CH2Cl2, c = 6.9 mm, for 62% ee). HRMS (ESI+): calcd. for
C21H24NO [M
[DAICEL CHIRALPAK OJ-H CSP, 20 °C, hexane/iPrOH = 9:1,
+
H]+ 306.18520; found 306.18426. HPLC
0.3 mL/min, 200 nm]: tR (minor)
= 56.4 min, tR (major) =
100.3 min.
3-Allyl-1-benzyl-3-(3,4-dichlorophenyl)piperidin-2-one (14b): From
compound 9b (0.126 g, 0.36 mmol), according to the general pro-
cedure. The resulting crude product was purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate/NEt3,
7.0:2.5:0.5) to give compound 14b (0.126 g, 90%) as a colourless
1
oil. H NMR (CDCl3): δ = 1.59 (m, 2 H), 2.00 (m, 2 H), 2.41 (dd,
J = 8.1, 6.7 Hz, 1 H), 2.82 (dd, J = 6.5, 6.2 Hz, 1 H), 3.15 (m, 2
H), 4.50 (d, J = 14.6 Hz, 1 H), 4.67 (d, J = 14.6 Hz, 1 H), 5.01 (m,
2 H), 5.63 (m, 1 H), 7.22 (m, 7 H), 7.39 (d, J = 2.3 Hz, 1 H) ppm.
13C NMR (CDCl3): δ = 18.9, 31.3, 45.6, 47.6, 50.7, 50.9, 118.9,
126.4, 127.6, 128.2 (2 C), 128.8 (2 C), 129.1, 130.3, 130.7, 132.5,
[5]
[6]
134.5, 137.3, 144.3, 171.4 (CO) ppm. IR (KBr): ν = 2930, 1680,
˜
1488, 1450, 1352, 1241, 1193 cm–1. HRMS (ESI+): calcd. for
C21H22NOCl2 [M
+
H]+ 374.1073; found 374.1076. HPLC
[DAICEL CHIRALPAK OJ-H CSP, 20 °C, hexane/iPrOH = 9:1,
0.1 mL/min, 200 nm]: tR = 128.9 and 139.4 min.
[7]
1-Allyl-3-phenylpiperidin-2-one (17): From compound 16a (0.1 g,
0.57 mmol), according to the general procedure for a reaction at
20 °C for 4 h. The resulting crude product was purified by flash
chromatography on silica gel (petroleum ether/acetone, 8:2) to give
compound 17 (0.025 g, 20%) as a colourless oil. 1H NMR (CDCl3):
δ = 1.94 (m, 3 H), 2.21 (m, 1 H), 3.41 (m, 2 H), 3.74 (m, 1 H), 4.13
(m, 2 H), 5.26 (m, 2 H), 5.89 (m, 1 H), 7.27 (m, 3 H), 7.35 (m, 2
H) ppm. 13C NMR (CDCl3): δ = 20.9, 30.5, 47.6, 48.6, 49.8, 117.5,
126.5, 128.2 (2 C), 128.4 (2 C), 133.0, 141.8, 170.3 (CO) ppm. IR
[8]
[9]
(KBr): ν = 2942, 1648, 1492, 1443, 1351, 1282, 1252, 1192 cm–1.
˜
HRMS (ESI+): calcd. for C14H18NO [M + H]+ 216.13829; found
216.13833.
Supporting Information (see footnote on the first page of this arti-
cle): Additional data, all experimental procedures and characteriza-
tions, copies of 1H and 13C NMR spectra of all final products,
copies of HR mass spectra of new compounds.
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Acknowledgments
We are grateful to Sanofi–Aventis with Prof. Bertrand Castro and
Dr. Gino Ricci for supporting part of this work (grant to A. de F.
and financial support). Support from the Centre National de la
Recherche Scientifique (CNRS) and the Région Nord Pas de Calais
is also greatly appreciated. Dr. Régis Gauvin and Dr. Isabelle
Suisse (UCCS UMR 8181) are thanked for preliminary experi-
ments in Lille on some starting materials. Mrs. Nathalie Duhal
(CUMA, Pharm. Dept., Univ. Lille Nord de France) is thanked
for the mass spectrometry analysis.
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Received: April 9, 2013
Published Online: June 17, 2013
Eur. J. Org. Chem. 2013, 4979–4985
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4985