Highly selective preparation of a chiral quaternary allyl aryl piperidinedione by palladium-catalyzed asymmetric allylation under solid-liquid phase-transfer catalysis

Article abstract of DOI:10.1002/ejoc.200700670

The combination of a chiral palladium catalyst and a solid-liquid phase-transfer catalyst provides an effective method for the chemo- and enantioselective preparation of the chiral quaternary center of an allyl aryl piperidinedione. Wiley-VCH Verlag GmbH

Full text of DOI:10.1002/ejoc.200700670

FULL PAPER
DOI: 10.1002/ejoc.200700670
Highly Selective Preparation of a Chiral Quaternary Allyl Aryl
Piperidinedione by Palladium-Catalyzed Asymmetric Allylation Under Solid–
Liquid Phase-Transfer Catalysis
Audrey Nowicki,[a] Jérôme Keldenich,[b] and Francine Agbossou-Niedercorn*[b]
Keywords: Palladium / Alkylation / Synthetic methods / Allylic compounds / Heterocycles
The combination of a chiral palladium catalyst and a solid–
liquid phase-transfer catalyst provides an effective method
for the chemo- and enantioselective preparation of the chiral
quaternary center of an allyl aryl piperidinedione.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Here, we report on the preparation of chiral intermediate
1 by AAA of 2 (Scheme 1). The latter was prepared in a
few steps starting from (3,4-dichlorophenyl)acetonitrile (3;
Scheme 2).
Introduction
The construction of organic molecules containing chiral
all-carbon quaternary stereocenters by enantioselective ca-
talysis represents a very challenging area in organic synthe-
sis.[1] Among the many suitable reactions, asymmetric allylic
alkylation (AAA) is a very attractive and powerful synthetic
strategy, as it enables the direct and stereocontrolled forma-
tion of chiral quaternary centers bearing a diversity of func-
tionalities available for further structural elaboration.[2] In
intermolecular palladium-catalyzed AAA, success in pre-
paring chiral quaternary stereocenters has been obtained
with prochiral enolates as the nucleophiles, which were gen-
erated from, for instance, β-diketones,[3] β-keto esters,[4] α-
acetamido-β-keto esters and related derivatives,[5] imino-
esters,[6] cyclic ketones,[7] and lactams.[8]
Scheme 1. Retrosynthesis of 1.
We have an interest in the preparation of intermediates
containing a chiral quaternary center.[9] We prepared allyl
aryl cyano esters with moderate selectivity by AAA.[9] We
pursued our investigations with the purpose to prepare chi-
ral aryl allyl glutarimide[10] by direct alkylation of glutar-
imide enolate. Chiral glutarimide contains a quaternary ste-
reocenter, and it is of interest for further elaboration of this
compound into piperidine intermediates, which are building
blocks of high synthetic utility that are present in biolo-
gically active compounds.[11] Imides have been applied in
the AAA reaction. Nevertheless, essentially intramolecular
N-alkylation has been used in total synthesis.[2c]
Scheme 2. Synthesis of 2. Reagents and conditions: (i) NaOMe,
dimethylcarbonate, toluene, reflux, 93%; (ii) methyl acrylate, Triton
B, THF, reflux, 85%; (iii) LiOH, THF, reflux, 85%; (iv) AcOH,
H2SO4 (10 mol-%), reflux, 86%.
[a] Synthèse Organique et Systèmes Organisés, Laboratoire de Sci-
ences Chimiques de Rennes UMR CNRS 6226, ENSCR,
Avenue Général Leclerc, Campus de Beaulieu, 35700 Rennes,
France
[b] Unité de Catalyse et Chimie du Solide UMR CNRS 8181,
ENSCL (CHIMIE),
Results and Discussion
B. P. 90108, Bât C7, 59652 Villeneuve d’Ascq Cedex, France
Fax: +33-3-20470599
Our synthesis (Scheme 2) began with the substitution at
the benzylic position of 3 through reaction with dimethyl-
E-mail: francine.agbossou@ensc-lille.fr
6124
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6124–6127

Preparation of a Chiral Quaternary Allyl Aryl Piperidinedione
carbonate in the presence of sodium methoxide in toluene yield of 9% and with 15% ee (determined by 13C NMR
(2 equiv.).[12] Michael addition was carried out next in the spectroscopy in the presence of a chiral shift reagent).
presence of methyl acrylate and benzyltrimethylammonium
The use of identical reaction conditions in the presence
hydroxide (Triton B) to afford 5 in 85% isolated yield. of Trost auxiliaries L2 and L3 (Scheme 4) resulted in a mix-
Then, 5 was transformed into γ-cyano ester 6 through de- ture of 1 and 7 (Table 1, Entries 2 and 3). Interestingly, the
methoxycarbonylation performed in THF under reflux in enantioselectivity introduced into 1 increased from 15 to 40
the presence of lithine. Compound 6 was isolated in 85% and then to 80% ee when ligands L1, L2, and L3 were used,
yield.
respectively. Several bases were used (LDA, Cs2CO3, and
Finally, γ-cyano ester 6 was converted into imide 2 KH) (Table 1, Entries 4–6) without providing higher selec-
through heating in glacial acetic acid in the presence of a tivities of 1 in the presence of L3.
catalytic amount of H2SO4,[13] and 2 was isolated, after pu-
rification, in 86% yield. Compound 2 was next used in pal-
ladium-catalyzed AAA (Scheme 3). The results are reported
in Table 1. With substrate 2, we encountered a selectivity
problem during the AAA as C- as well as N-alkylation can
occur. Indeed, preliminary experiments carried out in the
presence of allyl acetate, NaH (1.5 equiv.), and a catalytic
amount of [Pd(η3-C3H5)Cl]2 (0.5 mol-%) and (R)-BINAP
(L1, 1 mol-%) provided a mixture of mono- and bis(allyl)
products 1 and 7 (60% conversion, 1/7, 1:1), respectively, as
determined by 1H NMR spectroscopy (Table 1, Entry 1).
After workup, expected product 1 was isolated in a low
Scheme 4. Chiral auxiliaries.
In order to increase the selectivity of 1, we attempted to
bring into solution a more reactive C-nucleophile that was
also deprotonated at the imide position, which would thus
favor C-allylation over N-allylation. We performed the
AAA in the presence of a catalytic amount of nHex4NBr
(10 mol-%). The conversion and the isolated yield of 1 were
higher (Table 1, Entry 7), even if the selectivity was still not
satisfactory (88% conversion, 45% isolated yield of 1).
When the amount of base was increased to two equivalents,
imide 2 was converted totally into the insoluble bis(anion).
Again, the latter was brought into solution under solid–
liquid phase-transfer catalysis in the presence of a catalytic
amount of nHex4NBr (10 mol-%) allowing the most reac-
tive C-nucleophile to react selectively.[14] We were delighted
to observe high conversion of the substrate accompanied by
Scheme 3. Palladium-catalyzed alkylation.
total selectivity into the mono C-alkyl product 1. Product
Table 1. Enantioselective allylation of 2 catalyzed by chiral palladium complexes.[a]
Entry
Chiral ligand
Base[b]
[equiv.]
Additive[b]
[equiv.]
Conversion[c]
[%]
Yield 1[d]
ee of 1
[%]
[%] (configuration)[e]
1
2
3
4
5
6
7
8
9
L1
L2
L3
L3
L3
L3
L2
L3
L3
NaH (1.5)
NaH (1.5)
NaH (1.5)
LDA (1.5)
Cs2CO3 (1.5)
KH (1.5)
NaH (1.5)
NaH (1.5)
NaH (2)
–
–
–
–
–
–
60
50
59
55
60
60
75
88
95
9
15 (R)
40 (R)
80 (R)
50 (R)
80 (R)
79 (R)
40 (R)
80 (R)
80 (R)
10
30
25
29
30
35
45
95
nHex4NBr (0.1)
nHex4NBr (0.1)
nHex4NBr (0.1)
[a] AAA reactions were carried out in THF with Pd/chiral auxiliary/2, 1:1:100. [b] Amount of base and additive with respect to 2. [c]
Determined by 1H NMR spectroscopic analysis of the crude reaction mixtures. [d] Determined after isolation of 1 through silica gel
chromatography. [e] Determined by 13C NMR spectroscopy in the presence of Eu(hfc)3. Configuration attributed according to the negative
sign of rotation measured by polarimetry.[10]
Eur. J. Org. Chem. 2007, 6124–6127
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6125

A. Nowicki, J. Keldenich, F. Agbossou-Niedercorn
FULL PAPER
oily residue was dissolved in ethyl acetate (100 mL) and washed
with water (75 mL). The aqueous phase was washed with ethyl ace-
tate (3ϫ50 mL). The combined organic phase was washed with
brine (3ϫ75 mL) and dried with anhydrous MgSO4. The solvent
was removed under reduced pressure. The product was purified by
flash silica gel column chromatography (petroleum ether/ethyl ace-
tate, 9:1 then 4:1). Derivative 5 was isolated as a yellow solid
(14.41 g, 84%). Rf = 0.44 (ethyl acetate/petroleum ether, 1:4). 1H
NMR (300 MHz, CDCl3): δ = 2.35–2.71 (m, 4 H, 2 CH2), 3.65 (s,
1 was isolated in 95% yield and with 80% optical purity.
Thus, C-alkylation is kinetically favored under our experi-
mental conditions. The added ammonium salt acts as a
phase-transfer catalyst, which brings the insoluble enolate
into solution to favor the kinetic process of C-alkylation.
Under such conditions, no N-alkylation is detectable.
3
4
Conclusions
3 H, OCH3), 3.80 (s, 3 H, OCH3), 7.38 (dd, JH,H = 8.3 Hz, JH,H
3
= 2.2 Hz, 1 H, HAr), 7.49 (d, JH,H = 8.3 Hz, 1 H, HAr), 7.62 (d,
We developed an efficient method for the selective alky-
lation of an aryl glutarimide enolate providing an allyl de-
rivative bearing a sterically congested quaternary stereocen-
ter with the aid of two catalytic processes (organometallic
and phase-transfer). This methodology is of interest to
solve some selectivity issues in AAA reactions. This com-
bined catalysis is under investigation for the preparation of
other chiral intermediates of interest bearing a quaternary
carbon and results will be reported soon.
4JH,H = 2.3 Hz, 1 H, HAr) ppm. 13C NMR (75 MHz, CDCl3): δ =
30.0 (CH2), 33.0 (CH2), 52.0 (OCH3), 52.3 (CCN), 54.4 (OCH3),
116.9 (CN), 125.5, 128.3, 131.2, 133.6, 133.7, 13.9 (CAr), 166.8
(CO), 171.6 (CO) ppm. C14H13Cl2NO4 (330.17): calcd. C 51.40, H
4.00, N 3.36; found C 51.25, H 3.89, N 3.40.
Methyl 4-Cyano-4-(3,4-dichlorophenyl)butyrate (6): To a 250-mL
round-bottom flask equipped with a condenser and a stir bar was
added 5 (7.664 g, 23.2 mmol) dissolved in THF (110 mL) followed
by lithium hydroxide (1.05 g, 25 mmol). The reaction mixture was
heated at reflux for 18 h, and the evolution of the reaction was
followed by GC. If necessary, more lithium hydroxide was added
(0.25-equiv. portions) until total conversion. After cooling, THF
was removed under reduced pressure. The oily residue was dis-
solved in ethyl acetate (100 mL) and washed with HCl (1 ,
3ϫ50 mL). The aqueous phase was washed with ethyl acetate
(3ϫ50 mL). The combined organic phase was washed with brine
(3ϫ100 mL) and dried with anhydrous MgSO4. After evaporation
of the solvent under reduced pressure, the product was purified by
flash silica gel chromatography (petroleum ether/ethyl acetate, 9:1
then 4:1). Derivative 6 was isolated as a yellow crystalline solid
(5.43 g, 86%). M.p. 106 °C. Rf = 0.45 (ethyl acetate/petroleum
ether, 1:4). 1H NMR (300 MHz, CDCl3): δ = 2.13–2.20 (m, 2 H,
CH2COOMe), 2.40–2.59 (m, 2 H, CNCHCH2), 3.67 (s, 3 H,
Experimental Section
All melting points were measured with an Electrothermal IA9300
melting point apparatus and are uncorrected. 1H and 13C NMR
spectra were recorded with a BRUKER AC300 spectrometer at
25 °C. Chemical shifts are reported in ppm downfield of internal
tetramethylsilane. GPC analyses were conducted with a CHROM-
PACK CP 9000 apparatus equipped with a BPX5 capillary column
(25ϫ0.32 mm). All reagents are commercially available and were
used without further purification. The organic syntheses were car-
ried out under classical conditions unless otherwise stated. The re-
actions were performed under an atmosphere of nitrogen. THF was
dried with CaCl2, filtered through basic alumina and distilled from
Na/K under an atmosphere of nitrogen. Diethyl ether was distilled
from sodium under an atmosphere of nitrogen.
3
3
OCH3), 4.0 (t, JH,H = 7.8 Hz, 1 H, CHCN), 7.18 (d, JH,H
=
8.3 Hz, 1 H, HAr), 7.43–7.47 (m, 2 H, HAr) ppm. 13C NMR
(75 MHz, CDCl3): δ = 30.6 (2CH2), 35.5 (CHCN), 52.0 (OCH3),
119.3 (CN), 126.6, 129.3, 131.2, 132.8, 133.4, 135.2 (CAr), 17.22
(CO) ppm. C12H11Cl2NO2 (272.13): calcd. C 52.96, H 4.07, N 5.15;
found C 52.51, H 3.95, N 5.12.
Methyl Cyano(3,4-dichlorophenyl)acetate (4): To a 200-mL round-
bottom flask equipped with a condenser and a stir bar was added
sodium methoxide (3.45 g, 64 mmol), (3,4-dichlorophenyl)acetoni-
trile (3; 10.2 g, 55 mmol), and dimethylcarbonate (18 mL,
212 mmol) followed by toluene (25 mL). The reaction mixture was
heated to 85 °C for 3 h during which time a slurry formed. Toluene
was distilled from the reaction medium under reduced pressure.
Then, the reaction mixture was hydrolyzed with HCl (1 ). Cyano-
ester 4 was extracted with diethyl ether (100 mL and then
2ϫ70 mL). The combined organic layer was washed with water
(2ϫ100 mL), brine (100 mL), and dried with anhydrous MgSO4.
After evaporation of the solvent under reduced pressure, the prod-
uct was isolated as a brown solid (12.48 g, 93%). 1H NMR
(300 MHz, CDCl3): δ = 3.82 (s, 3 H, CH3), 4.69 (s, 1 H, CHCN),
7.31 (dd, 3JH,H = 2.3 and 8.3 Hz, 1 H, HAr), 7.50 (d, 3JH,H = 8.3 Hz,
3-(3,4-Dichlorophenyl)piperidinedione (2): To a 100-mL round-bot-
tom flask equipped with a condenser and a stir bar was added 6
(3 g, 11.1 mmol) dissolved in acetic acid (15 mL). Then, concen-
trated sulfuric acid (600 µL) was added dropwise. The reaction mix-
ture was heated at reflux for 18 h. After cooling, the reaction mix-
ture was hydrolyzed with a saturated solution of NaHCO3. The
medium was extracted with dichloromethane (2ϫ75 mL). The
combined organic phase was washed with brine (3ϫ75 mL) and
dried with anhydrous MgSO4. After evaporation of the solvent un-
der reduced pressure, the product was crystallized from dichloro-
methane and isolated as white crystals (2.26 g, 92%). M.p. 207 °C.
1H NMR (300 MHz, DMSO): δ = 1.96–2.01 (m, 1 H, CHdione),
2.01–2.27 (m, 1 H, CHdione), 2.49–2.54 (m, 1 H, CHdione), 2.62–
3
1 H, HAr), 7.56 (d, JH,H = 2.3 Hz, 1 H, HAr) ppm. 13C NMR
(75 MHz, CDCl3): δ = 42.5 (CHCN), 54.3 (OCH3), 114.7 (CN),
127.3, 129.6, 130.0, 131.3, 133.6, and 134.0 (CAr), 164.6 (CO) ppm.
C10H7Cl2NO2 (244.08): calcd. C 49.20, H 2.89, N 5.74; found C
49.18, H 2.81, N 5.67.
3
4
2.68 (m, 1 H, CHdione), 3.96 (dd, JH,H = 12.4 Hz, JH,H = 4.6 Hz,
1 H, CHCONH), 7.23–7.28 (m, 1 H, HAr), 7.56–7.62 (m, 2 H, HAr),
10.91 (s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.4
(CH2), 31.6 (CH2), 46.5 (CH), 129.3, 129.6, 130.2, 130.4, 130.8,
140.2 (CAr), 171.5 (CO), 172.1 (CO) ppm. C11H9Cl2NO2 (258.10):
calcd. C 51.19, H 3.51, N 5.43; found C 50.88, H 3.47, N 5.43.
Dimethyl 2-Cyano-2-(3,4-dichlorophenyl)pentanedioate (5): To a
250-mL round-bottom flask equipped with a condenser and a stir
bar was added 4 (13.42 g, 55 mmol) and THF (125 mL) with Triton
B (1.94 mL, 11 mmol) followed by methyl acrylate (13.5 mL,
148.5 mmol). The reaction mixture was heated at reflux for 23 h.
After cooling and evaporation of THF under reduced pressure, the
3-(S)-Allyl-3-(3,4-dichlorophenyl)piperidine-2,6-dione (1): In
a
Schlenk tube, glutarimide 2 (258.1 mg, 1 mmol) was dissolved in
THF (4 mL). The solution was cooled to –78 °C and NaH (48 mg,
6126
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Eur. J. Org. Chem. 2007, 6124–6127

Preparation of a Chiral Quaternary Allyl Aryl Piperidinedione
2 mmol) was added. The solution was stirred at –78 °C for 1 h and
then charged with a solution containing [Pd(η3-C3H5)Cl]2 (1.8 mg,
0.005 mmol), chiral auxiliary L3 (7.9 g, 0.01 mmol), allyl acetate
(220.6 mg, 2.2 mmol), and tetrabutylammonium bromide (32.2 mg,
0.1 mmol) in THF (2 mL). The cold bath was removed, and the
reaction mixture was stirred at 0 °C for 4 h. The reaction mixture
was quenched with saturated NH4Cl (5 mL) and then water
(10 mL). The organic phase was extracted with ethyl acetate
(3ϫ15 mL), washed with brine (3ϫ20 mL), dried with MgSO4,
and concentrated under reduced pressure. The crude product was
purified by flash silica gel column chromatography (petroleum
ether/ethyl acetate, 2:1). Product 1 was isolated as a white crystals
(283.3 mg, 95%). M.p. 137 °C. Rf = 0.6 (ethyl acetate/petroleum
ether, 1:2). 1H NMR (300 MHz, CDCl3): δ = 2.22–2.41 (m, 3 H,
CHdione), 2.48–2.65 (m, 2 H, CHHЈCH= and CHdione), 2.75–2.81
(m, 1 H, CHHЈCH=CH2), 5.05–5.13 (m, 2 H, CH=CH2), 5.59 (m,
thank Sanofi-Aventis for financial support (grant to A. N. and
J. K.). We thank Catherine Méliet for NMR assistance.
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3
4
1 H, CH=CH2), 7.13 (dd, JH,H = 8.5 Hz, JH,H = 2.2 Hz, 1 H,
4
3
HAr), 7.38 (d, JH,H = 2.2 Hz, 1 H, HAr), 7.43 (d, JH,H = 8.3 Hz,
1 H, HAr), 8.5 (s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 27.1 (CH2), 29.0 (CH2), 44.3 (CH2), 50.0 (C), 120.2 (CH=CH2),
125.7 (CH=CH2), 128.4, 131.0, 132.2, 133.4, 138.7 (CAr), 172.0
(CO), 173.9 (CO) ppm. C14H13Cl2NO2 (298.17): calcd. C 56.39, H
4.39, N 4.70; found C 56.16, H 4.44, N 4.54.
1,3-Diallyl-3-(S)-(3,4-dichlorophenyl)piperidine-2,6-dione (7): In a
Schlenk tube, glutarimide 2 (258.1 mg, 1 mmol) was dissolved in
THF (4 mL). The solution was cooled to –78 °C and NaH (48 mg,
2 mmol) was added. The solution was stirred at –78 °C for 1 h and
then charged with a solution containing [Pd(η3-C3H5)Cl]2 (1.8 mg,
0.005 mmol), chiral auxiliary L3 (7.9 g, 0.01 mmol), and allyl ace-
tate (300 mg, 2.5 mmol) in THF (2 mL). The cold bath was re-
moved, and the reaction mixture was stirred at 0 °C for 4 h. The
reaction mixture was quenched with saturated NH4Cl (5 mL) and
then water (10 mL). The organic phase was extracted with ethyl
acetate (3ϫ15 mL), washed with brine (3ϫ20 mL), dried with
MgSO4 and concentrated under reduced pressure. The crude prod-
uct was purified by flash silica gel column chromatography (petro-
leum ether/ethyl acetate, 2:1). Product 7 was isolated as a yellow
oil (270 mg, 80%). Rf = 0.82 (ethyl acetate/petroleum ether, 1:2).
1H NMR (300 MHz, CDCl3): δ = 2.20–2.23 (m, 2 H, CH2dione),
2.36–2.54 (m, 2 H, CH2dione), 2.71 (m, 1 H, CCHHЈCH=CH2), 2.77
(m, 1 H, CCHHЈCH=CH2), 4.4 (m, 2 H, NCH2CH=CH2), 5.01–
5.16 (m, 4 H, CH2CH=CH2), 5.52–5.69 (m, 1 H, CH2CH=CH2),
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3
4
5.7–5.81 (m, 1 H, CH2CH=CH2), 7.03 (dd, JH,H = 8.52 Hz, JH,H
= 1.95 Hz, 1 H, HAr), 7.29 (d, 4JH,H = 1.95 Hz, 1 H, HAr), 7.39 (d,
3JH,H = 8.52 Hz, 1 H, HAr) ppm. 13C NMR (75 MHz, CDCl3):
δ = 26.1 (CH2dione), 29.5 (CH2dione), 42.2 (CCH2CH=CH2), 45.2
(NCH2CH=CH2), 50.4 [C(CO)(CH2)(CH2)], 118 (CH2=CH), 120
(CH2=CH), 125.7 (CH2=CH), 128.5 (CH2=CH), 130,9; 131,8;
131.9, 132.5, 133.3, 139.3 (CAr), 171 (C=O), 173.4 (C=O) ppm.
C17H17Cl2NO2 (338.23): calcd. C 60.37, H 5.07, N 4.14; found C
60.01, H 4.97, N 4.34.
[12] P. Cann, V. Levacher, J. Bourguignon, G. Dupas, Lett. Org.
Chem. 2004, 1, 129–133.
[13] R. W. Hartmann, C. Batzl, T. M. Pongratz, A. Mannschreck,
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Acknowledgments
[14] G. D. Yadav, S. A. Purandare, J. Mol. Catal. A 2005, 237, 60–
66, and references cited therein.
We thank Prof. Bertrand Castro, Dr. Gino Ricci (Sanofi-Aventis),
Received: July 20, 200
and Prof. André Mortreux for stimulating discussions, and we also
Published Online: October 18, 2007
Eur. J. Org. Chem. 2007, 6124–6127
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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