Synthesis of functionalized chiral ammonium, imidazolium, and pyridinium-based ionic liquids derived from ()-ephedrine using solvent-free microwave activation. Applications for the asymmetric Michael addition

Article abstract of DOI:10.1016/j.tet.2010.03.101

An efficient procedure for the synthesis of functionalized chiral ammonium, imidazolium, and pyridinium-based ionic liquids derived from (IR, 2S)-ephedrine using solvent-free microwave activation has been described. Good yields were obtained in very short reaction time. These chiral ionic liquids were used as chiral reaction media for the asymmetric Michael addition, giving good yields and moderate enantioselectivities.

Full text of DOI:10.1016/j.tet.2010.03.101

Tetrahedron 66 (2010) 5277e5282
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Tetrahedron
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Synthesis of functionalized chiral ammonium, imidazolium, and pyridinium-
based ionic liquids derived from (ꢀ)-ephedrine using solvent-free microwave
activation. Applications for the asymmetric Michael addition
*
Thi-Kim-Thu Truong, Giang Vo-Thanh
Laboratoire de Catalyse Moléculaire, Institut de Chimie Moléculaire et des Matériaux d’Orsay, UMR 8182, Université Paris-Sud 11, 91405 Orsay Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient procedure for the synthesis of functionalized chiral ammonium, imidazolium, and pyr-
idinium-based ionic liquids derived from (1R, 2S)-ephedrine using solvent-free microwave activation has
been described. Good yields were obtained in very short reaction time. These chiral ionic liquids were
used as chiral reaction media for the asymmetric Michael addition, giving good yields and moderate
enantioselectivities.
Received 1 February 2010
Received in revised form 25 March 2010
Accepted 28 March 2010
Available online 8 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
microwave irradiation conditions.11 Recently, Cravotto et al.12
described an effective and rapid one-pot procedure to synthesize
Over the past decade, ionic liquids (ILs) have received consid-
erable attention thanks to their ability to serve as effective reaction
media for a wide range of organic reactions and other applications
in chemistry.1 By modifying the structure of the cations or anions of
ionic liquids, it has been shown that their properties can be altered
in order to influence the outcomes of reactions. Advances in ILs
have made development of chiral ionic liquids (CILs), a subject of
intense study in recent years.2 Although a limited number of CILs
have been designed and synthesized, they have already found
promising applications in asymmetric synthesis,3 stereoselective
polymerization,4 chiral chromatography,5 liquid crystals,6 chiral
resolution, and as a NMR shift reagents.7 Nowadays, the design and
synthesis of novel CILs is growing rapidly. The study of CILs appli-
cations in asymmetric synthesis presents a challenge and an
opportunity to researchers. It is, therefore, essential if not in-
teresting to synthesize different kinds of CILs from various starting
materials, especially derived from a chiral pool.
Microwave (MW) activation, a non-conventional energy source,
has emerged as a powerful technique for promoting a variety of
chemical reactions and has become a useful technology in organic
chemistry.8 The combination of solvent-free conditions and MW
irradiation considerably reduces reaction time, enhances conver-
sions as well as selectivity and presents certain environmental
advantages.9 This method has been successfully applied to the
synthesis of several imidazolium-based ILs.10
a second-generation ionic liquid using combined microwave/ul-
trasound irradiation.
In view of the emerging importance of the ILs as reaction media
in organic synthesis and our general interests in MW-assisted
chemical processes, we report here the synthesis of functionalized
chiral ammonium, imidazolium, and pyridinium-based ILs using
solvent-free reactions under MW activation. These ILs were used as
chiral reaction media in the asymmetric Michael addition.
2. Result and discussion
2.1. Solvent-free microwave-assisted synthesis of
functionalized chiral ammonium, imidazolium, and
pyridinium-based ionic liquids
Our synthesis was initiated by the synthesis of (1R, 2S)-N-
methylephedrine 2 by reductive amination of (1R, 2S)-ephedrine
using solvent-free microwave irradiation. The compound 2 was
isolated with good yield (90%) for only 4 min, using 1 equiv of
formaldehyde along with formic acid in stoichiometric quantity
(Scheme 1). It should be noted that using classical procedure,13 the
H
N
N
HO
HO
In 2004, we reported the first synthesis of chiral ionic liquids
HCHO (1 equiv), HCO2H (1 equiv)
MW, no solvent, 80°C, 4 min.
possessing
a chiral ephedrinium cation using solvent-free
2
1
* Corresponding author. Tel.: þ33 1 69157891; fax: þ33 1 69154680; e-mail
Scheme 1. Solvent-free microwave synthesis of (1R, 2S)-N-methylephedrine.
address: giang.vo-thanh@u-psud.fr (G. Vo-Thanh).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.101

5278
T.-K.-T. Truong, G. Vo-Thanh / Tetrahedron 66 (2010) 5277e5282
Table 2
reaction must take longer time (around 5 h) and the use of large
excess of reagents is necessary.
Solvent-free microwave-assisted synthesis of chiral ionic liquids 4 using a two-step
one-pot sequence reaction. Conditions: 2:RCl¼1/1.2
We proceeded to our synthesis by direct alkylation of N-meth-
ylephedrine 2 using solvent-free microwave irradiation conditions
as previously reported by our group.11 2-(Chloromethyl)- and 3-
(chloromethyl)pyridine were used as alkylating agents for this
study. All the MW reactions were performed in the CEM Discover
monomode system with a strict control of power and temperature
during the course of the reaction. Generally speaking, excellent
yields were obtained in very short reaction time. Experiments using
a thermostatted oil bath (conventional heating) were executed
under identical reaction conditions (time, temperature, vessel,
profile of rise in temperature, without solvent). A drop in yield was
observed in all cases (Scheme 2, Table 1).
Entry
RCl
Temperature (ꢁC)
Isolated yield (%)
1
100a/75b
84 (37)c
Cl
Cl
N
N
2
85a/95b
78 (41)c
a
Temperature for the first step.
Temperature for the second step.
Yields obtained under conventional heating given in brackets.
b
c
bonding formation. Using the same strategy previously described
in Scheme 3, CILs 6 and 7 were obtained, respectively, in 45% and
49% overall yield in three steps, from (ꢀ)-N-methylephedrine.
Lower yields (25% for 6 and 18% for 7) were observed under con-
ventional heating. Scheme 4 summarizes the synthesis of these
new CILs.
R
N
Cl
N
HO
HO
3a: R=
3b: R=
N
RCl
MW, no solvent, 10 min.
N
N
N
Cl
3
2
HO
HO
Scheme 2. Solvent-free microwave-assisted synthesis of ephedrinium salts 3.
Cl-(CH2)4Br
MW, 85°C, 15 min
76%
Br
Table 1
2
H
N
5
Solvent-free microwave-assisted N-alkylation of (1R, 2S)-methylephedrine with 2-
(chloromethyl) or 3-(chloromethyl)pyridine. Conditions: 2:RCl¼1/1.2. Time: 10 min
1.
MW, 90°C, 20min
2. LiNTf2, H2O, 60°C, 3h
1.
N
N
N
N
MW, 90°C, 30min
Entry
RCl
Temperature (ꢁC)
Isolated yield (%)
2. LiNTf2, H2O, 60°C, 3h
1
2
90
100
90
98 (47)b
NTf2
HO
Cl
Cl
NTf2
HO
N
N
N
N
N
N
N
NTf2
H
3
85
85
83
NTf2
4a
90 (43)b
6
7
a
3-(Chloromethyl)pyridine (1.3 equiv) was used.
Yields obtained under conventional heating given in brackets.
b
Scheme 4. Synthesis of CILs 6 and 7.
The next step in the synthesis involves an anion exchange of
To sum up, we have developed an efficient procedure for the
synthesis of ammonium, imidazolium, and pyridinium-based ionic
liquids using a two-step one-pot reaction under solvent-free mi-
crowave activation. These chiral salts can be used as catalysts for
the asymmetric Michael addition.
ephedrinium chloride salts 3 with LiNTf2. Generally, this step was
carried out at reflux in a large excess of acetone as solvent for
several hours or even some days.14 Good yields were generally
obtained in all cases.
As already reported by Varma and Polshettiwar9d an anion ex-
change metathesis is easily performed under MW activation using
2.2. Chiral ionic liquids-based (L)-ephedine as catalysts for
the asymmetric Michael addition
a
domestic oven. In this way, 1,3-dialkylimidazolium tetra-
fluoroborate salts were prepared in good yields after only a few
minutes of reaction time.
In order to simplify the overall procedure, we carried out the
synthesis of chiral ammonium-based ionic liquids using a two-step
one-pot sequence reaction as developed previously by our group.11
All products (not isolated) resulting from the quaternisation step
(first step) were directly submitted to an anion exchange step
(Scheme 3). All the MW reactions were conducted in the absence of
any solvent. The more significant results are given in Table 2.
The conjugate addition of nucleophiles, usually called Michael
addition, is one of the fundamental bond-forming processes in or-
ganic chemistry15 and its asymmetric version offers an extremely
powerful tool for the synthesis of a variety of useful chiral function-
alized organic molecules.16 Efforts toward achieving asymmetric
conjugate addition of malonates to a,b-unsaturated ketones in the
presence of chiral catalyst have been the subject of several reports. As
a result, a variety of chiral metal catalysts17 as well as organo-
R
catalysts18 including imidazoline catalysts,19
L-proline-derived cata-
N
N
lysts,20 phase-transfer catalysts,21 pyrrolidylalkyl ammonium
hydroxide,22 and chiral ammonium salts.23 have been developed for
this transformation. There are also publications reporting Michael
addition reaction catalyzed by chiral ionic liquids.3k,18a,24 However,
these reactions employ highly activated Michael acceptors, such as
nitroalkenes. Enantioselective catalytic conjugate addition of ketones
with enones remains a challenging reaction.
NTf2
HO
HO
4a: R=
1. RCl, MW, no solvent, 10 min
2. LiNTf2, MW, no solvent, 20 min
N
2
4b: R=
4
N
Scheme 3. Solvent-free microwave-assisted synthesis of chiral ionic liquids 4.
After achieving the synthesis of CILs containing a chiral moiety,
a free hydroxyl group and a basic function, we were interested in
testing their potential for asymmetric induction. Initially, the Michael
addition reaction of diethyl-2-acetamidomalonate 9 to chalcone 8
(Ar1/Ph, Ar2/Ph) was selected for catalyst evaluation (Scheme 5).
We then proceeded to synthesize some other functionalized
CILs 6, possessing the imidazolium skeleton, and 7, having the
methylaminopyridinium function. These secondary basic groups
could serve as activator function of the substrates via a hydrogen

T.-K.-T. Truong, G. Vo-Thanh / Tetrahedron 66 (2010) 5277e5282
5279
Table 4
O
O
Ar2
CO2Et
CO2Et
Substrates scope for the asymmetric Michael addition reaction of diethyl-2-acet-
amidomalonate 9 to chalcone derivatives 8, using CIL 3b as a catalyst
CO2Et
CO2Et
CIL
Ar1
Ar2
AcHN
9
*
Ar1
KOH
Entry
Ar1
Ar2
Yield 10 (%)a
55 (56, 55, 56)c
67
67
73
60
80
61
10 ee (%)b
70 (70, 72, 70)c
10
25
4
42
4
NHAc
8
10
1
C6H5
C6H5
C6H5
C6H5
4-CH3OeC6H4
4-CleC6H4
C6H5
C6H5
2c
3
4-CH3OeC6H4
4-NO2eC6H4
4-ClC6H4
C6H5
C6H5
2-CleC6H4
Scheme 5. Asymmetric Michael addition reaction.
4d
5d
6d
7
A screening of CILs was examined as shown in Table 3. The re-
action was conducted in the presence of 1 equiv of CIL, without any
organic solvent, using catalytic amount of KOH (6 mol %) as co-basic
catalyst, at 60 ꢁC for 1 h. Optimization of reaction conditions was
carried out and the main results obtained were listed in Table 3.
56
a
Isolated yield.
ee determined by chiral HPLC.
Results obtained by reaction with recycled IL are given in brackets.
Toluene (0.3 mL) was added.
b
c
Table 3
d
Screening of CIL for the asymmetric Michael addition reaction of diethyl-2-acet-
amidomalonate 9 to chalcone 8
Entry
CIL
Yield 10 (%)
(S)-10 ee (%)a
The organic phase was dried over anhydrous MgSO4, filtered, and
evaporated in vacuo to afford the recycled ionic liquid. Spectra data
(IR, 1H, and 13C) were identical to the initial ionic liquid sample. The
CIL 3b could be recycled and reused for three times, maintaining
similar activity and stereoselectivity (Table 4, entry 1). Loss of ac-
tivity was observed in the fourth reuse.
1
2
3
4
5
6
4a
4b
7
60
51
58
52
51
55
52
51
76
58
64
47
40
70
70
66
59
52
6
3a
3b
3b
3b
3b
7b
8c
9d
3. Conclusion
a
ee determined by chiral HPLC25 and configuration (S)-10 was determined by
comparison of optical rotation with the literature value.21c
In summary, we have designed and synthesized novel func-
tionalized chiral ammonium, imidazolium, and pyridinium-based
ionic liquids derived from (ꢀ)-ephedrine as a chiral pool. The
synthesis of these ionic liquids is easy and practical using solvent-
free reaction under MW activation. Applications of these new CILs
as chiral catalyst for the asymmetric Michel addition reaction of
diethyl acetylaminomalonate to chalcone derivatives have been
studied. Moderate to good yields and enantioselectivities (up to
80% yield and 70% ee) were observed. Based on these preliminary
results, the design of novel CILs, which is expected to afford higher
levels of enantioselectivities for asymmetric induction, is currently
underway in our laboratory.
b
CIL: 10 mol %.
Temperature: 40 ꢁC.
Toluene (0.3 mL) was added.
c
d
As illustrated in Table 3, the structural variation of cations has
significant impact on the asymmetric induction. The best ee (up to
70%) was observed by using CIL 3a and 3b. The bis-cation CILs 6 and
7 catalyzed the reaction with lower enantioselectivities (entries 3
and 4). In all cases, moderate yields (up to 76%) were obtained. It can
be explained by a bad stirring of the reaction medium, which was not
homogeneous. The reaction worked better when using toluene as
solvent, but a drop in ee was observed (entries 6 and 9). Some other
optimization parameters were investigated. The reaction tempera-
ture was not critical in this reaction (entries 6 and 8), affording the
same yield with only 59% ee. Catalyst loading did not really affect the
studied reaction. When using 10 mol % CIL 3b in lieu of 1 equiv,
a slight drop in yield and ee was observed (entries 6 and 7).
The scope of the Michael addition reaction was next explored
under the optimized reaction conditions described above (1 equivof
3b, 6 mol % KOH, 60 ꢁC, 1 h). A range of chalcone derivatives bearing
either electron-withdrawing or electron-donating substitutes were
applicable in the reaction with diethyl acetylaminomalonate 9
(Scheme 6). The reaction smoothly proceeded to afford the corre-
sponding products 10 with moderate to good yields. Substitutes on
C4 position of benzene demonstrated dramatic effect on the enan-
tioselectivity. In all cases, lower until poor ee was observed with
these chaconne derivatives (Table 4).
4. Experimental section
4.1. General information
Microwave experiments were conducted using a CEM Discover
Synthesis Unit (monomode system) operating at 2450 MHz moni-
tored by a PC computer.
Melting points were measured on a Kofler bank. The NMR
spectra were recorded in CDCl3, MeOD-d4 or in acetone-d6. 1H NMR
spectra were recorded at 360 MHz. The chemical shifts (d) are
reported in part per million, relative to TMS as internal standard. J
values are given in hertz. 13C NMR spectra were recorded at
90 MHz. IR spectra were recorded on a FTIR PerkineElmer in-
strument. TLC experiments were carried out in 0.2 mm thick silica
gel plates (GF254) and visualization was accomplished by UV light or
phosphomolybdic acid solution. The columns were hand-packed
with silica gel 60 (200e300 mesh).
O
O
Ar2
CO2Et
CO2Et
CO2Et
CO2Et
CIL 3b
Ar1
Ar2
AcHN
9
Ar1
*
KOH (6 mol %)
All reagents and solvents were purchased from commercial
sources (Acros, Aldrich) and were used without further purification.
NHAc
8
10
10a: Ar1 = Ph; Ar2 = Ph
10e: Ar1 = 4-MeO-C6H4-; Ar2 = Ph
10b: Ar1 = Ph; Ar2 = 4-MeO-C6H4- 10f: Ar1 = 4-Cl-C6H4-; Ar2= Ph
10c: Ar1 = Ph; Ar2 = 4-NO2-C6H4- 10g: Ar1 = 2-Cl-C6H4-; Ar2 = Ph
10d: Ar1 = Ph; Ar2 = 4-Cl-C6H4-
4.2. General procedure for the solvent-free N-alkylation of 2
under microwaves activation
Scheme 6. Substrates scope for the asymmetric Michael addition reaction.
A mixture of (1R, 2S)-N-methylephedrine 2 (1.79 g, 10 mmol)
and 2-(chloromethyl) pyridine (or 3-(chloromethyl) pyridine)
(12 mmol), beforehand neutralized with K2CO3, was irradiated
under MW for 10 min at the temperature given in Table 1. The re-
action mixture was brought to room temperature and washed with
The recyclability and reusability of CILs were briefly tested. After
reaction, the catalyst could be easily recycled by dilution in
dichloromethane (5 mL) and then washed with water (2ꢂ2 mL).

5280
T.-K.-T. Truong, G. Vo-Thanh / Tetrahedron 66 (2010) 5277e5282
dichloromethane (2ꢂ10 mL) to afford the solid, which did not need
further purification.
77.1, 125.5, 125.8, 127.4, 129.5, 130.0, 142.3, 142.8, 153.1, 155.1. HRMS
(MꢀNTf2) m/z (%) calcd for [C17H23N2O]: 271.1805, found: 271.1813.
4.2.1. (1R, 2S)-N-2-Chloromethylpyridyl-N,N-dimethylephedrinium
4.3.3. (1R, 2S)-N-4-Chlorobutyl-N,N-dimethylephedrinium bromide
5. A mixture of (1R,2S)-N-methylephedrine 2 (2.69 g,15 mmol) and
1-bromo-4-chlorobutane (1.73 mL, 22.5 mmol) was irradiated un-
der microwaves at 85 ꢁC for 15 min. The reaction mixture was
brought to room temperature and washed with diethylether
(3ꢂ10 mL). The crude product was purified by flash chromatogra-
phy on alumina (CH2Cl2/MeOH¼98/2) to give the 5 as a white solid
25
chloride 3a. White solid. Mp 195 ꢁC. [
a
]
ꢀ13.2 (c¼1.98; MeOH).
D
IR (neat)
(360 MHz, MeOD-d4)
n
¼3313, 3153, 1584, 1133, 997, 786, 718, 614. 1H NMR
d
1.37e1.39 (d, J¼7.2 Hz, 3H), 3.32e3.42 (2s,
6H), 4.08e4.10 (m, 1H), 4.82e4.86 (d, J¼13.7 Hz, 1H), 5.03e5.06
(d, J¼13.3 Hz, 1H), 5.84 (s, 1H), 7.32e7.52 (m, 5H), 7.57e7.60 (m,
1H), 7.81e7.83 (d, J¼7.9 Hz, 1H), 7.98e8.03 (m, 1H), 8.79e8.80 (d,
J¼4.7 Hz, 1H). 13C NMR (90 MHz, MeOD-d4)
d
6.1, 49.2, 49.4, 66.4,
in 76% yield. Mp 132 ꢁC. [
a
]
D
25 ꢀ5.3 (c¼2; acetone). IR (neat)
n
¼3333,
69.3, 73.9, 124.9, 125.5, 127.5, 127.8, 128.2, 137.7, 141.5, 149.4,
149.9. HRMS: (MꢀCl) m/z (%): calcd for [C17H23N2O]: 271.1805,
found: 271.1811.
2817, 1593, 1410, 1328, 1250, 1140, 1074, 798, 708, 630. Rf¼0.25. 1H
NMR (360 MHz, MeOD-d4)
d
1.27e1.29 (d, J¼6.5 Hz, 3H), 1.94e2.14
(m, 4H), 3.32e3.43 (2s, 6H), 3.60e3.84 (m, 5H), 5.67 (s, 1H),
7.33e7.57 (m, 5H) 13C NMR (90 MHz, MeOD-d4)
d
6.4, 20.2, 29.2,
4.2.2. (1R, 2S)-N-3-chloromethypyridyl-N,N-dimethylephedrinium
41.1, 48.9, 49.2, 62.9, 68.9, 73.4, 125.8, 127.7, 128.4, 141.5. HRMS
(MꢀBr) m/z (%) calcd for [C15H25ClNO]: 270.1630, found: 270.1623.
25
chloride 3b. Pale yellow solid. Mp 230 ꢁC. [
a
]
ꢀ9.1 (c¼1.98;
D
MeOH). IR (neat)
NMR (360 MHz, MeOD-d4)
n
¼3159, 1590, 1169, 1003, 852, 718, 665, 607. 1H
d
1.44e1.45 (d, J¼6.5 Hz, 3H), 3.26e3.27
4.4. General procedure for the synthesis of compounds
6 and 7
(2s, 6H), 3.87e3.89 (m, 1H), 4.82e4.86 (d, J¼14.0 Hz,1H), 4.99e5.02
(d, J¼13.3 Hz,1H), 5.78 (s,1H), 7.33e7.54 (m, 6H), 7.63e7.67 (m,1H),
8.20e8.22 (d, J¼7.9 Hz, 1H), 8.75e8.77 (dd, J¼1.1 Hz, 1H), 8.86e8.87
A
mixture of (1R, 2S)-N-4-chlorobutyl-N,N-dimethylephe-
(d, J¼2.2 Hz, 1H). 13C NMR (90 MHz, MeOD-d4)
d
8.3, 49.9, 65.1, 71.3,
drinium bromide 5 (1.76 g, 5 mmol) and 3-methylaminopyridine
(or 1-methylimidazol) (6.5 mmol) in toluene (0.3 mL) was irradi-
ated under microwave at 90 ꢁC for 30 min (or 20 min.). The reaction
mixture was brought to room temperature and washed with ether
(3ꢂ5 mL). Solvent was evaporated and the obtained solid was
dissolved in water (5 mL). LiNTf2 (15 mmol) was added. After stir-
ring for 3 h at 60 ꢁC, the reaction mixture was brought again to
room temperature. CH2Cl2 (30 mL) was added and the resulting
mixture was washed with water (3ꢂ5 mL). The organic phase was
dried over anhydrous MgSO4, and then concentrated under re-
duced pressure. Purification by flash column chromatography on
silica gel (CH2Cl2/MeOH¼99/1) gave 6 (or 7) as a yellow viscous oil.
77.1,125.5, 125.8,127.4,129.5,130.0, 142.3, 142.8,153.1,155.1. HRMS:
(MꢀCl) m/z (%): calcd for [C17H23N2O]: 271.1805, found: 271.1807.
4.3. General procedure for the solvent-free ‘two-step
sequence’ preparation of chiral ionic liquids 4 from 2 under
microwave irradiation
A mixture of (1R, 2S)-N-methylephedrine 2 (1.79 g, 10 mmol)
and 2-(chloromethyl) pyridine (or 3-(chloromethyl) pyridine)
(12 mmol) was irradiated under MW at the temperature and for the
time given in Table 2. LiNTf2 (3.45 g, 12 mmol) was added and the
resulting mixture was then placed under MW irradiation for an
additional period of time and temperature as reported in Table 2.
The reaction mixture was brought to room temperature. CH2Cl2
(30 mL) was added, and the mixture was washed with water
(2ꢂ10 mL). The organic phases were dried over anhydrous MgSO4,
and then concentrated under reduced pressure. Purification by
flash column chromatography on silica gel (CH2Cl2/MeOH¼97/3)
gave the salt 4 as a white solid.
25
4.4.1. Compound 6. [
n
a
]
ꢀ3.44 (c¼2.09; acetone). IR (neat)
D
¼3522, 3159, 2923, 1580, 1451, 1350, 1192, 1130, 1056, 790, 741,
615, 571. Rf¼0.22. 1H NMR (360 MHz, acetone-d6)
d 1.35e1.36 (d,
J¼5.0 Hz, 3H), 2.15e2.19 (m, 4H), 3.40e3.46 (2s, 6H), 3.77e3.85
(m, 3H), 4.03 (s, 3H), 4.49e4.52 (t, 2H, J¼5.5 Hz), 5.19e5.20 (d,
J¼3.6 Hz, 1H), 5.78 (s, 1H), 7.32e7.49 (m, 5H), 7.69e7.70 (d,
J¼1.8 Hz, 1H), 7.74e7.75(d, J¼1.8 Hz, 1H), 8.97 (s, 1H). 13C NMR
Reactions under conventional heating were carried out with
exactly the same vessel and under similar conditions of time and
temperature (see Table 2) but in a preheated oil bath.
(90 MHz, acetone-d6) d 7.9, 21.3, 28.5, 37.4, 50.6, 50.8, 64.5, 71.1,
75.6, 124.1, 125.7, 127.4, 129.4, 130.0, 138.5, 142.9. HRMS (M-NTf2)
m/z (%) calcd for [C21H31F6N4O5S2]: 597.1640, found: 597.1641.
25
4.3.1. (1R, 2S)-N-2-(Chloromethylpyridyl)-N,N-dimethylephedrinium
4.4.2. Compound 7. [
a
]
ꢀ2.1 (c¼2; acetone). IR (neat) ¼3404,
n
D
25
bis (trifluoromethanesulfonyl)imide 4a. Mp 62 ꢁC.
[
a
]
ꢀ14.3
3096, 1662, 1626, 1594, 1539, 1353, 1207, 1138, 1055. Rf¼0.15. 1H
D
(c¼2.24; CHCl3). IR (neat)
n
¼3512, 3060, 1591, 1475, 1350, 1193,
NMR (360 MHz, acetone-d6)
d
1.29e1.31 (d, J¼6.5 Hz, 3H),
1055, 997, 615. 1H NMR (360 MHz, CDCl3)
d
1.26e1.28 (d, J¼6.5 Hz,
1.93e2.31 (m, 4H), 2.89e2.90 (d, J¼4.7 Hz, 3H), 3.41e3.45 (2s,
6H), 3.72e4.04 (m, 5H), 4.76e4.80 (t, 2H, J¼5.6 Hz), 5.91e5.93 (d,
J¼5 Hz, 1H), 6.87e6.88 (d, J¼5.4 Hz, 1H), 7.30e7.50 (m, 5H),
7.74e7.76(m, 2H), 8.26e8.27 (d, J¼4.7 Hz, 1H), 8.42 (s, 1H). 13C
3H), 3.14e3.25 (2s, 6H), 3.93e3.97 (m, 1H), 4.52e4.55 (d, J¼13.0 Hz,
1H), 4.82e4.86 (d, J¼14.4 Hz, 1H), 5.71 (s, 1H), 7.25e7.33 (m, 5H),
7.38e7.42 (m, 1H), 7.58e7.60 (d, J¼7.9 Hz, 1H), 7.76e7.80 (m, 1H),
8.60e8.61 (d, J¼4.7 Hz, 1H). 13C NMR (90 MHz, MeOD-d4)
d
6.9,
NMR (90 MHz, acetone-d6) d 6.4, 19.5, 27.8, 29.0, 49.0, 49.5, 60.6,
50.0, 50.3, 66.7, 69.8, 73.9, 125.2, 125.5, 127.7, 128.1, 128.7, 138.0,
140.2, 148.7, 150. HRMS (MꢀNTf2) m/z (%) calcd for [C17H23N2O]:
271.1805, found: 271.1809.
62.4, 68.7, 73.9, 125.9, 126.4, 127.6e127.8, 131.0, 141.7, 149.5.
HRMS (MꢀNTf2) m/z (%) calcd for [C25H33F6N4O5S2]: 623.1802,
found: 623.1805.
4.3.2. (1R, 2S)-N-3-(Chloromethylpyridyl)-N,N-dimethylephedrinium
4.5. General procedure for asymmetric Michael addition
reaction of diethyl-2-acetamidomalonate to chalcone
derivatives
25
bis(trifluoromethanesulfonyl)imide 4b. Mp 95 ꢁC.
[
a
]
þ2.7
D
(c¼1.99; acetone). IR (neat)
n
¼3159, 1590, 1169, 1003, 852, 718, 665,
607. 1H NMR (360 MHz, acetone-d6)
d
1.56e1.58 (d, J¼7.2 Hz, 3H),
3.48e3.49 (2s, 6H), 4.05e4.08 (m,1H), 4.98e5.02 (d, J¼13.0 Hz,1H),
5.12e5.16 (d, J¼13.3 Hz, 1H), 6.02 (s, 1H), 7.36e7.61 (m, 6H),
8.17e8.20 (m, 1H), 8.78e8.79 (dd, J¼1.8 Hz, 1H), 8.91e8.92 (d,
A mixture of chalcone 8 (2 mmol) and diethyl-2-acet-
amidomalonate 9 (434 mg, 2 mmol), ionic liquid 3b (37 mg,
0.12 mmol), KOH (6.7 g, 0.12 mmol) was stirred at 60 ꢁC for 1 h. The
reaction mixture was dissolved in dichloromethane (5 mL) and
J¼2.5 Hz, 1H). 13C NMR (90 MHz, acetone-d6)
d 8.3, 49.9, 65.1, 71.3,

T.-K.-T. Truong, G. Vo-Thanh / Tetrahedron 66 (2010) 5277e5282
5281
filtered. After evaporation of the solvent, the residue was purified
by flash chromatography on silica gel (n-pentane/AcOEt¼75/25).
2.13 (s, 3H), 3.27e3.38 (dd, J¼11.4 Hz, J¼17.0 Hz, 1H), 3.81 (s, 3H),
3.97e4.12 (m, 5H), 4.47e4.52 (dd, J¼2,0 Hz, J¼11.4 Hz, 1H), 6.68 (s,
1H), 6.85e6.88 (d, J¼12.2 Hz, 2H), 7.17e7.27 (m, 5H), 7.90e7.93 (d,
4.5.1. Diethyl-2-acetamido-2-(3-oxo-1,3-diphenylpropyl)malonate
J¼13.0 Hz, 2H). 13C NMR (62.5 MHz, CDCl3)
d 13.9, 14.0, 23.4, 40.6,
10a. White solid. Mp 113e115 ꢁC. IR (KBr)
n
¼3393, 3254, 2361,
46.6, 62.3, 63.0, 68.7, 113.6, 127.6, 128.3, 128.8, 130.0, 130.5, 138.2,
163.2, 166.7, 167.7, 169.6, 197.7. MS (MþH) m/z [C25H30NO7]: 456.
The ee value was determined by chiral HPLC analysis. Separation
conditions: AD-H column (thermostatted column 25 ꢁC); elution
with a mixture of hexane/ethanol 90/10; flow rate 1 mL/min; rt1:
1745, 1680, 1648, 1497, 1372, 1252, 1200, 1018, 755, 694. Rf¼0.25. 1H
NMR (300 MHz, CDCl3)
d 1.21e1.28 (m, 6H), 2.15 (s, 3H), 3.35e3.44
(dd, J¼11.4 Hz, J¼17.4 Hz, 1H), 4.02e4.30 (m, 5H), 4.50e4.54 (dd,
J¼2.4 Hz, J¼11.4 Hz, 1H), 6.66 (s, 1H), 7.21e7.27 (m, 5H), 7.38e7.53
(m, 3H), 7.91e7.93 (d, J¼6.9 Hz, 2H). 13C NMR (90 MHz, CDCl3)
31.9 min, rt2: 37.6 min;
l¼266 nm.
d
13.6, 13.8, 23.1, 40.7, 46.1, 62.0, 62.8, 68.6, 127.4, 127.9e128.6,
132.6, 136.7, 138.0, 166.4, 167.4, 169.4, 197.7. MS (MþH) m/z
[C24H28NO6]: 426. The ee value was determined by chiral HPLC
analysis. Separation conditions: (S,S)-Whelk-01 column (thermo-
statted column 10 ꢁC); elution with a mixture of hexane/ethanol
90/10; flow rate 1 mL/min.; retention time 40.8 min for (R)-10a and
4.5.6. Diethyl-2-acetamido-2-[3-(4-chlorophenyl)-3-oxo-1-phenyl-
propyl]malonate 10f. White solid. Mp 149 ꢁC. IR (KBr)
¼3295,
n
2984, 2342, 1749, 1695, 1652, 1517, 1368, 1249, 1202, 1013, 985, 830,
727, 600. Rf¼0.20. 1H NMR (250 MHz, CDCl3)
d 1.20e1.28 (m, 6H),
2.14 (s, 3H), 3.27e3.38 (dd, J¼11.5 Hz, J¼17.3 Hz, 1H), 3.98e4.30 (m,
5H), 4.45e4.51 (dd, J¼2.6 Hz, J¼11.8 Hz, 1H), 6.70 (s, 1H), 7.18e7.24
(m, 5H), 7.35e7.39 (d, J¼8.8 Hz, 2H), 7.86e7.89 (d, J¼8.5 Hz, 2H). 13C
45.2 min for (S)-10a;
l¼254 nm.
4.5.2. Diethyl-2-acetamido-2-(1-(4-methoxyphenyl)-3-oxo-3-phe-
nylpropyl)malonate 10b. White solid. Mp 123e128 ꢁC. IR (KBr)
NMR (62.5 MHz, CDCl3) d 13.9, 14.0, 23.4, 41.0, 46.4, 62.4, 63.1, 68.8,
127.8, 128.4, 128.8, 129.7, 135.2, 137.9, 139.2, 166.6, 167.6, 169.8,
196.9. MS (MþH) m/z [C24H27ClNO6]: 460.2. The ee value was de-
termined by chiral HPLC analysis. Separation conditions: (S,S)-
Whelk-01 column (thermostatted column 25 ꢁC); elution with
a mixture of hexane/ethanol 85/15; flow rate 1 mL/min; rt1:
n
¼3385, 2346, 1735, 1682, 1500, 1368, 1251, 1209, 1013, 858, 670.
Rf¼0.15. 1H NMR (360 MHz, CDCl3)
d 1.22e1.28 (m, 6H), 214 (s, 3H),
3.28e3.36 (dd, J¼11.5 Hz, J¼17.3 Hz, 1H), 3.74 (s, 3H), 4.00e4.29 (m,
5H), 4.45e4.49 (dd, J¼2.9 Hz, J¼11.5 Hz, 1H), 6.64 (s, 1H), 6.74e6.76
(d, J¼9.4 Hz, 2H), 7.09e7.11 (d, J¼8.6 Hz, 2H), 7.38e7.50 (m, 3H),
13.1 min, rt2: 15.5 min;
l¼250 nm.
7.91e7.93 (d, J¼8.3 Hz, 2H). 13C NMR (90 MHz, CDCl3)
d 13.6, 13.7,
23.0, 40.9, 45.3, 54.8, 61.9, 62.7, 68.8, 113.5, 127.9, 129.6, 129.8, 132.5,
136.7, 158.6, 165.5, 167.4, 169.5, 197.9. MS (MþH) m/z [C25H30NO7]:
456. The ee value was determined by chiral HPLC analysis. Sepa-
ration conditions: AD-H column (thermostatted column 20 ꢁC);
elution with a mixture of hexane/ethanol 80/20; flow rate 1 mL/
4.5.7. Diethyl-2-acetamido-2-[1-(2-chlorophenyl)-3-oxo-3-phenyl-
propyl]malonate 10g. White solid. Mp 132 ꢁC. IR (KBr)
¼3256,
2983,1744,1695,1650,1533,1447,1369,1258,1204,1095,1001, 860,
n
1
758, 693. Rf¼0.15. H NMR (250 MHz, CDCl3)
d 1.10e1.22 (m, 6H),
2.08 (s, 3H), 3.17e3.28 (dd, J¼11.8 Hz, J¼17.0 Hz, 1H), 3.85e3.92 (m,
1H), 4.12e4.33 (m, 4H), 5.04e5.10 (dd, J¼3.0 Hz, J¼11.8 Hz, 1H),
6.66 (s, 1H), 7.05e7.10 (m, 2H) 7. 21e7.43 (m, 5H), 7.87e7.90 (d,
min.; rt1: 14.3 min., rt2: 21.6 min;
l¼230 nm.
4.5.3. Diethyl-2-acetamido-2-[1-(4-nitrophenyl)-3-oxo-3-phenyl-
J¼7.3 Hz, 2H). 13C NMR (62.5 MHz, CDCl3)
d 13.7, 14.0, 23.4, 41.3,
propyl]malonate 10c. White solid. Mp 85e90 ꢁC. IR (KBr)
¼3408,
n
42.0, 62.4, 63.2, 68.2, 126.8, 128.3, 128.5, 128.6, 128.8, 130.0, 132, 9,
135.2, 136.1, 136.6, 166.6, 167.6, 169.8, 197, 9. MS (MþH) m/z
[C24H27ClNO6]: 460.2. The ee value was determined by chiral HPLC
analysis. Separation conditions: (S,S)-Whelk-01 column (thermo-
statted column 25 ꢁC); elution with a mixture of hexane/ethanol
2983, 2375, 1739, 1689, 1648, 1522, 1348, 1259, 1206, 858, 691.
Rf¼0.18. 1H NMR (300 MHz, CDCl3)
d 1.24e1.29 (m, 6H), 2.17 (s, 3H),
3.36e3.46 (dd, J¼11.4 Hz, J¼18.0 Hz, 1H), 4.06e4.38 (m, 5H),
4.62e4.67 (dd, J¼2.7 Hz, J¼11.4 Hz, 1H), 6.66 (s, 1H), 7.40e7.53 (m,
5H), 7.88e7.91 (d, J¼9.6 Hz, 2H), 8.10e8.13 (d, J¼8.4 Hz, 2H). 13C
90/10; flow rate 1 mL/min; rt1: 25.8 min, rt2: 31.4 min;
l¼254 nm.
NMR (90 MHz, CDCl3)
d 13.8, 13.9, 23.2, 40.7, 45.9, 62.5, 63.3, 68.2,
123.3, 128.0, 129.7, 133.1, 136.3, 146.3, 147.2, 166.1, 167.2, 169.9, 197.3.
MS (MþH) m/z [C24H27N2O8]: 471. The ee value was determined by
chiral HPLC analysis. Separation conditions: AD-H column (ther-
mostated column 10 ꢁC); elution with a mixture of hexane/ethanol
Acknowledgements
We are grateful to the ‘Ministère de l’Enseignement Supér-
ieur’du Vietnam for a doctoral fellowship to T.K.T.T., the CNRS (UMR
8182) and the Université Paris-Sud 11 for financial supports.
85/15; flow rate 1 mL/min.; rt1: 27.9 min., rt2: 52.6 min.;
l¼243 nm.
4.5.4. Diethyl-2-acetamido-2-[1-(4-chlorophenyl)-3-oxo-3-phenyl-
References and notes
propyl]malonate 10d. White solid. Mp 83e85 ꢁC. IR (KBr)
n
¼3400,
2936, 2980, 2362, 2343, 1735, 1683, 1490, 1370, 1258, 1208, 1095,
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rate 1 mL/min; rt1: 17.7 min, rt2: 26.6 min;
l¼224 nm.
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nylpropyl]malonate 10e. White solid. Mp 148 ꢁC. IR (KBr)
¼3292,
n
2989, 2343, 1750, 1686, 1651, 1601, 1511, 1371, 1251, 1169, 1013, 839,
676, 593. Rf¼0.18. 1H NMR (360 MHz, CDCl3)
d 1.20e1.29 (m, 6H),

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