Catalytic effect and recyclability of imidazolium-tagged bis(oxazoline) based catalysts in asymmetric Henry reactions

Article abstract of DOI:10.1039/c2ob06434k

Functional imidazolium ionic liquids have been developed as a new class of versatile catalysts. C₂-symmetric imidazolium-tagged bis(oxazoline) ligands were prepared, and the anions of the ligands were altered. The catalysts based on the new lig

Full text of DOI:10.1039/c2ob06434k

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PAPER
Catalytic effect and recyclability of imidazolium-tagged bis(oxazoline) based
catalysts in asymmetric Henry reactions†
Zhi-Ming Zhou,*a,b Zhi-Huai Li,a Xiao-Yan Hao,a Jun Zhang,a Xiao Dong,a Ying-Qiang Liu,a
Wen-Wen Sun,a Dan Caoa and Jin-Liang Wanga
Received 22nd August 2011, Accepted 5th December 2011
DOI: 10.1039/c2ob06434k
Functional imidazolium ionic liquids have been developed as a new class of versatile catalysts.
C2-symmetric imidazolium-tagged bis(oxazoline) ligands were prepared, and the anions of the ligands
were altered. The catalysts based on the new ligands and Cu(OAc)2·H2O were applied in asymmetric
Henry reactions between various aldehydes 3 and CH3NO2 4. The catalysts achieved a high level of
enantioselectivity; product (R)-5n was attained at 94% ee in MeOH. Moreover, the catalyst could be
recycled 6 times without an obvious loss of activity or enantioselectivity. In addition, a theoretical
mechanistic study was conducted to explain the origin of the enantioselectivity.
Chiral 2-nitro-1-arylalkanols, which are key intermediates and
Introduction
building blocks16 for the synthesis of β-adrenergic drugs17 and
Chiral bis(oxazolines) have proven to be very effective ligands
that afford high levels of activity and enantioselectivity in many
reactions.1–8 Because most catalysts are expensive and because
the metal as well as the ligands are highly toxic to the environ-
ment and humans, the recycling of catalysts now assumes an
even greater importance. However, the activity of the catalyst
often dramatically decreases after several runs, and such
decreases are usually caused by the catalysts leaching from the
reaction system during product extraction or by the catalysts
abating during the purification of the catalyst-containing phase
before recycling.9 A number of approaches to prevent the
expensive chiral metal complex from running off during the
recovery and/or recycling process have been investigated.10
The limitations of a catalyst or ligand may be minimised by the
presence of an ion tag on the frame of the ligand. The ionic
nature could ideally render the catalyst or ligand insoluble in
non-polar solvents such that the product could be extracted to
leave a recyclable phase that contains the catalyst.9,11 In addition,
the properties of ionic liquids, such as low volatility, immiscibil-
ity with non-polar organic solvents and stability, make them
excellent candidates for solvents in green processes.12–15 The
ion-tagging strategy has attracted more attention in recent years.
natural products, such as polyamino alcohols and polyhydroxy-
lated amides,18 are generally prepared via the Henry (nitroaldol)
reaction.19 Since the first asymmetric Henry reaction was
reported by Shibasaki and co-workers using a series of heterobi-
metallic catalysts,19–21 various effective catalytic systems have
been developed. Many researchers, including Evans, have
reported that bis(oxazoline) complexes derived from
Cu(OAc)2·H2O were found to be promising catalysts for the
Henry reaction at mild conditions.22 To date, there are only a
handful of reports about the immobilisation and recycling of a
catalyst in asymmetric Henry reactions. Lee16 immobilised a
bis(oxazoline) ligand onto a magnetically separable hierarchi-
cally ordered mesocellular mesoporous silica (M-HMMS), and
this new catalytic system was examined in the asymmetric Henry
reaction between various aldehydes and nitromethane at ambient
temperature. Up to 86.0% ee was observed when the free silanol
groups of the mesoporous silica were capped by trimethylsilyl
group. This catalyst was separated magnetically and reused 5
times with little loss of reactivity or enantioselectivity. Khan23
reported the catalyst derived from C2-symmetric chiral secondary
bis-amines based on a 1, 2-diaminocyclohexane structure with
copper acetate and its application in the asymmetric Henry reac-
tion in the presence of different ionic liquids, with a focus on
[Emim]BF4. Up to 94% ee was achieved, and the catalyst could
be reused 5 times with retention of enantioselectivity. However,
to the best of our knowledge, none of the ionic-tagged box com-
pounds have been used as ligands in the asymmetric Henry reac-
tion nor has their recyclability been evaluated in this reaction.
Our group has designed and prepared imidazolium-tagged
bis(oxazoline) compounds (Scheme 1). Their performance in
the copper-catalysed asymmetric Diels–Alder reaction between
aR&D Centre for Pharmaceuticals, School of Chemical Engineering
and the Environment, Beijing Institute of Technology, Beijing, PR China,
100081. E-mail: zzm@bit.edu.cn; Fax: +86 010 68912664; Tel: +86
010 68912664
bState Key Laboratory of Explosion Science and Technology, Beijing
Institute of Technology, Beijing, PR China, 100081
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob06434k
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Table 1 Screening of ligand/metal ratio for the asymmetric Henry
reaction under catalysis of the complex based on 1
Entry
Ligand:metal
Yield/%a
ee/%b
1
2
3
4
5
1 : 0.5
1 : 0.8
1 : 1
1 : 1.25
1 : 2
98
97
97
98
98
20 (R)
38 (R)
41 (R)
43 (R)
42 (R)
a Yields were calculated based on benzaldehyde. The ligand’s loading
was 15 mol%. b ee values were determined by HPLC analysis using a
Chiralcel® OD-H column, hexane/iPrOH 85 : 15, 0.8 ml min−1
.
Scheme 1 Ligands applied in asymmetric Henry reaction.
N-acryloyloxazolidinones and 1,3-cyclohexandiene in the ionic
liquid 1-butyl-3-methylimidazolium bis[(trifluoromethyl)sulfo-
nyl]-imide [Bmim]NTf2 yielded up to 98% conversion with a
97% ee.24 The catalyst could be recycled 20 times. Aiming at
expanding the scope of application of the imidazolium-tagged
bis(oxazoline), we evaluated their performance in the asym-
metric Henry reaction. Up to 94% ee was obtained when using a
catalyst based on 2a. More importantly, the catalyst in the reac-
tion system could be recycled 6 times without obvious loss of
activity and enantioselectivity.
Fig. 1 Effects of reaction time and temperature on the asymmetric
Henry reaction using the catalyst based on 1.
or decreasing of the ratio led to lower activity or enantioselectiv-
ity (Table 1, entries 1–3, entry 5). The ligand/metal ratio of
1 : 1.25 was chosen as the optimised reaction condition. The
effects of reaction time and temperature on the asymmetric
Henry reaction using the catalyst based on 1 was investigated,
and the results are shown in Fig. 1. The reaction was carried out
at 0 °C for 72 h, after which the temperature increased at a rate
of 10 °C 24 h−1. It can be observed that the reaction was almost
complete within 48 h at 0 °C. The ee value was not affected sig-
nificantly by the reaction time, but the amount of the by-product
(dehydration of the main product) increased as time passed.
Once the temperature was increased, the by-product formation
increased rapidly, and the ee value decreased from 59% to 50%.
Next, we examined the effect of various solvents, including
ionic liquids, on the asymmetric Henry reaction of benzaldehyde
with nitromethane using 3 ligands. The results are summarised
in Table 2. As can be seen in Table 2, using traditional 1 as the
ligand, the solvents affect the reaction activity and enantioselec-
tivity. Protic solvents (alcohols) are superior to aprotic solvents.
For alcohols, the activity and enantioselectivity increased in the
following order: iPrOH < EtOH < MeOH (Table 2, entries 1–3).
Reaction in CH2Cl2 was not observed at all (Table 2, entry 5).
For the coordinating THF, the reaction reached completion;
however, the enantioselectivity was only 27% (Table 2, entry 4).
The imidazolium-tagged bis(oxazoline) compounds 2a and 2e
Results and Discussion
Preparation of C2-symmetric imidazolium-tagged bis(oxazoline)
New ligands 1 and 2 were prepared from 6a and 6b according to
methods in our previous report.24 C2-symmetric imidazolium-
tagged bis(oxazoline) ligands were prepared successfully and
efficiently. The anions of the ligands could be altered by ion
exchange.
Asymmetric Henry reaction
For a preliminary study, the asymmetric Henry reaction was cata-
lysed by the catalyst based on 1. Benzaldehyde was taken as a
representative aldehyde, and the effect of the ligand/metal ratio
was tested at room temperature. The results are shown in
Table 1. It was found that the activity and enantioselectivity of
the asymmetric Henry reaction were the best when the ratio of
ligand to metal was 1 : 1.25 (Table 1, entry 4), while increasing
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Table 2 Effects of solvent on the asymmetric Henry reaction
most cases (Table 3, entries 3–4, entries 8–9). The catalyst
derived from 2a yielded the product at 75% conversion and 78%
ee in MeOH (Table 3, entry 3), whereas the catalyst derived from
2b yielded 60% ee (Table 3, entry 8). The anions of the ligands
affect the enantioselectivity and activity. The tosyl-anion ligand
2a yielded better enantioselectivities and activities than hex-
afluorophosphoric, chloride or iodide salts (Table 3, entries 3–6).
The opposite result was found for tert-butyl-substituted counter-
parts (Table 3, entries 8–9). On the other hand, the imidazolium-
tagged bis(oxazoline) compounds 2a and 2e performed better
than the traditional ligand 1 and 6a (Table 3, entries 1–2, entries
3–4), which demonstrated that our ligands have potential for the
asymmetric Henry reaction.
Ligand 2a was selected as the best ligand, and the efficiency
of 2a was evaluated for various aldehydes under the optimised
conditions. As summarised in Table 4, in general, benzaldehydes
with electron-withdrawing nitro substituents gave better yields
than substrates with weak electron-withdrawing or even electron-
donating properties (Table 4, entries 1–8). However, benzal-
dehydes with electron-donating substituents gave better ee
values than substrates with electron-withdrawing substituents,
especially for 3, 4-dimethoxybenzaldehyde, which had ee values
of 78% and 94% at 20 °C and 0 °C, respectively (Table 4, entry
14, entry 17). As can be seen in Table 4, temperature affects the
activity and the enantioselectivity to a great extent. The ee value
Entrya
Ligand
Solvent
Yield/%b
ee/%b
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
2e
2e
2e
2e
2e
2a
2a
2a
2a
2a
MeOH
EtOH
iPrOH
THF
CH2Cl2
[Bmim]PF6
[Bmim]BF4
iPrOH
EtOH
MeOH
[Bmim]PF6
[Bmim]BF4
iPrOH
EtOH
MeOH
[Bmim]PF6
[Bmim]BF4
96
98
98
100
—
97
98
61
65
71
94
95
67
72
77
97
98
61 (R)
49 (R)
37 (R)
27 (R)
—
0
0
67 (R)
75 (R)
77 (R)
0
9
10
11
12
13
14
15
16
17
0
68 (R)
76 (R)
78 (R)
0
0
a The ratio of benzaldehyde : CH3NO2 : ligand : Cu(OAc)2·H2O is
1.0 : 50.0 : 0.15 : 0.18, and the reactions were carried out at 0 °C for
24 h. b Yields were calculated based on benzaldehyde. % ee values were
determined by HPLC analysis using a Chiralcel OD-H column, hexane/
iPrOH 85 : 15, 0.8 ml min−1
.
Table 4 Enantioselective Henry reaction of nitromethane with various
aldehydes catalysed by a complex based on 2a
yielded better results than ligand 1, and the effect of the solvents
was consistent with that of 1. 2a yielded the best result among
the 3 ligands (Table 2, entries 13–15). Reactions in ionic liquids
achieved yields of more than 94%; however, there was no enan-
tioselectivity (Table 2, entries 6–7, entries 11–12, entries 16–17).
MeOH was then chosen as the optimised solvent.
Entry
R
T/°C Time/h Yield/%a ee/%b
We further screened the ligands to evaluate their catalytic per-
formance using the optimised conditions at 0 °C (Table 3).
Phenyl-substituted bis(oxazoline) was the optimum ligand and
yielded higher ees than its tert-butyl-substituted counterpart in
1
2
3
4
5
6
7
8
Ph (3a)
20
20
20
20
20
20
20
20
20
20
20
20
20
20
0
0
0
0
0
0
0
0
0
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
48
48
48
48
48
48
48
48
84
17
30
62
100
89
32
37
40
85
35
82
77
54
75
10
34
29
95
83
20
42
23
37
27
61
64 (R)
63 (R)
73 (R)
71 (R)
67 (R)
59 (R)
53 (R)
55 (R)
42 (R)
47 (R)
61 (R)
69 (R)
23 (R)
78 (R)
78 (R)
65 (R)
94 (R)
80 (R)
30 (R)
77 (R)
82 (R)
73(R)
92(R)
75(R)
73(R)
64(R)
2-OMeC6H4 (3b)
3-OMeC6H4 (3c)
4-OMeC6H4 (3d)
4-NO2C6H4 (3e)
2-NO2C6H4 (3f)
2-ClC6H4 (3g)
4-ClC6H4 (3h)
3-BrC6H4 (3i)
4-BrC6H4 (3j)
2-FC6H4 (3k)
Table 3 Screening of ligands for the asymmetric Henry reaction of
nitromethane and benzaldehyde
9
10
11
12
13
14
15
16
17
18
19
20
21
22c
23c
24c
25c
26c
4-FC6H4 (3l)
1-naphthyl (3m)
3,4-diOMeC6H3 (3n)
Ph (3a)
2,4-diClC6H3 (3o)
3,4-diOMeC6H3 (3n)
3,5-diOMeC6H3 (3p)
4-pyridyl (3q)
Entry
Ligand
Time/h
Yield/%a
ee/%b
1
2
3
4
5
6
8
9
1
24
24
24
24
24
24
24
24
96
86
75
71
70
67
38
35
61 (R)
45 (S)
78 (R)
77 (R)
49 (R)
43 (R)
60 (S)
78 (S)
6b
2a
2e
2c
2d
2b
2f
2-furyl (3r)
3,4,5-triOMeC6H2 (3s)
2-OMeC6H4 (3b)
3,4-diOMeC6H3 (3n)
3,5-diOMeC6H3 (3p)
3,4,5-triOMeC6H2 (3s)
4-NO2C6H4 (3e)
0
0
0
a Yields were calculated based on benzaldehyde. b ee values were
a Yields were calculated based on aldehyde. b ee values were determined
by HPLC analysis using Chiralcel OD-H, Chiralpak AD-H and Chiralcel
OJ-H columns. c Catalyst based on 2e.
determined by HPLC analysis using a Chiralcel OD-H column, hexane/
iPrOH 85 : 15, 0.8 ml min−1
.
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Table 5 Effects of Lewis acid on the asymmetric Henry reaction of 3,
4-dimethoxybenzaldehyde under the catalysis of complex based on 2a
Table 6 Effects of base on the asymmetric Henry reaction of 3, 4-
dimethoxybenzaldehyde under the catalysis of complex based on 2a
Entry Base
Solvent
Time/h Yield/%a ee/%b
Entry
Metal
Solvent
Time/h
Yield/%a
ee/%b
1
2
3
4
5
6
7
Et3N(5 mol%)
Et3N(5 mol%)
Et3N(5 mol%)
Et3N(15 mol%) MeOH
KOAc(5 mol%) MeOH
DMF (5 mol%) MeOH
MeOH
MeOH
MeOH
24
48
60
24
24
24
24
42
50
57
55
35
37
41
92 (R)
93 (R)
92 (R)
90 (R)
73 (R)
91 (R)
88 (R)
1
2
3
4
5
6
7
Cu(OTf)2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
24
24
48
48
48
48
48
0
34
0
0
3
0
0
—
Cu(OAc)2·H2O
Pd(OAc)2·H2O
TiCl4
Co(OAc)2·4H2O
AlCl3
94 (R)
—
—
47 (R)
—
—
CsOAc(5 mol
MeOH
Ti(iPrO)4
%)
—
—
8c
9
MeOH
MeOH/DMF
(1 : 1)
MeNO2/MeOH 24
(7 : 1)
24
24
54
8
93 (R)
88 (R)
a Yields were calculated based on 3, 4-dimethoxybenzaldehyde. b ee
values were determined by HPLC analysis using a Chiralcel OD-H,
hexane/iPrOH 85 : 15, 0.8 ml min−1
.
10
—
0
—
a Yields were calculated based on 3, 4-dimethoxybenzaldehyde. b ee
increased up to 18% when the temperature decreased from 20 °C
to 0 °C (Table 4, entry 1, entries 14–15, entry 17). Moderate to
good enantioselectivities could be achieved in most cases when
the reaction was carried out at 0 °C (Table 4, entry 1, entries
15–21). Once the reaction temperature was decreased, the yield
dropped sharply, and a longer time was required to complete the
reaction. In the cases of other aromatic aldehydes, such as 1-
naphthaldehyde, isonicotinaldehyde and 2-furanaldehyde, lower
or comparable enantioselectivities and good yields relative to
benzaldehyde were obtained. Next, the catalyst based on 2e was
applied to asymmetric Henry reaction with several substrates
(Table 4, entries 22–26), it can be seen from the results that the
tosyl-anion ligand 2a yielded better enantioselectivities than hex-
afluorophosphoric ligand 2e in most cases. Consistent with litera-
ture,25 the moderate catalytic activity of our catalyst may be
attributed to the anionic and electron-rich nature of the imidazo-
lium-tagged bis(oxazoline) ligand, and their better performance
in MeOH may also result from this nature.
To examine the role of Lewis acids on the asymmetric Henry
reaction, several metal salts were investigated in the presence
of ligand 2a (Table 5). As reported previously, air stable
Cu(OAc)2·H2O could act as a suitable Lewis acid for the asym-
metric Henry reaction (Table 5, entry 2). Additionally,
Co(OAc)2·4H2O facilitated the reaction and afforded the product
in poor yield with moderate ee value (Table 5, entry 5). Other
Lewis acids investigated, such as Cu(OTf)2, Pd(OAc)2·H2O,
TiCl4, AlCl3 and Ti(iPrO)4, made no contribution to the reaction
(Table 5, entry 1, entries 3–4, entries 6–7).
values were determined by HPLC analysis using a Chiralcel OD-H,
hexane/iPrOH 85 : 15, 0.8 ml min−1 c 50 mol% of ligand used.
.
Moreover, using 1 : 1 of MeOH/DMF as solvent, the ee value
decreased to 88% with a trace yield (Table 6, entry 6, entry 9).
Inorganic bases, such as KOAc and CsOAc, affect the reaction
more than organic base. The presence of these two bases in the
reaction system resulted in ee values lower than 90% (Table 6,
entry 5, entry 7). The use of 7 : 1 of CH3NO2/MeOH as solvent
provided no product (Table 6, entry 10). Presumably the pres-
ence of a strong base could perturb the catalyst structure.16
The optimized catalyst system was also applied to the asym-
metric Henry reaction with nitroethane as the nucleophile. The
reaction could form two chiral centers and provide diasteroi-
somers, the corresponding results were summarized in Table 7.
The reaction of nitroethane provided the adduct with good anti-
selectivity (entries 1–2), and needed more time to give the pro-
ducts than nitromethane. Though the enantioselectivity was
moderate, the catalyst has potential in the diasteroselective
Henry reaction.
Table 7 Diasteroselective Henry reaction of nitroethane with
aldehydes catalysed by a complex based on 2a
We also attempted to improve the efficacy of these transform-
ations in MeOH using 5 mol% of an organic or inorganic base,
such as Et3N, DMF, KOAc, CsOAc or CH3NO2, as the additive
(Table 6). It can be observed that the addition of base decreased
the enantioselectivity of the catalyst. When 5 mol% of Et3N was
added, the yield of the asymmetric Henry reaction increased
while the ee value decreased from 94% to 92% (Table 6, entries
1–3). Once the amount of Et3N increased from 5 mol% to
15 mol%, the ee value decreased to 90% (Table 6, entry 4). The
ee value also decreased using 5 mol% of DMF as additive.
Entry
R
Yield/%a
Anti/synb
ee of anti
1
2
Ph (3a)
4-NO2C6H4 (3e)
27
91
72 : 28
81 : 19
63%
68%
a Reactions were carried out at 0 °C for 60 h. Yields were calculated
based on aldehyde. b Anti/syn and ee values were determined by HPLC
analysis using Chiralcel OD-H and Chiralpak AD-H columns, hexane/
iPrOH.
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Recyclability of the catalysts
Theoretical mechanistic study
To evaluate the recyclability of the catalysts generated from our
new ligands 2a and 2e, we performed the asymmetric Henry
reaction in MeOH. After completion of the reaction, MeOH was
removed under reduced pressure, and the residue was extracted
with diethyl ether and transferred. The residual catalyst was sub-
jected to vacuum to remove traces of diethyl ether, flushed with
inert gas and charged with further portions of MeOH, aldehyde
and CH3NO2. The activity and enantioselectivity were main-
tained even after the catalyst was reused 6 times. The asymmetric
Henry reaction using the catalyst based on 2a and 3,4-dimethox-
ybenzaldehyde as substrate provided conversion of 41% and an
ee value of 91% on the 6th cycle; a conversion of 80% and ee
value of 78% were obtained using same catalyst and benzal-
dehyde as substrate. The asymmetric Henry reaction using the
catalyst based on 2e and 2-methoxybenzaldehyde as substrate
provided a conversion of 59% and an ee value of 74% on the 6th
cycle; a conversion of 70% and an ee value of 75% were
obtained using the same catalyst and benzaldehyde as substrate. It
was found that the conversion and enantioselectivity were better
in the second cycle in most cases. Presumably, in the second
cycle, the ligand and metal reached a better coordination, which
resulted in better conversion and enantioselectivity (Fig. 2).
In contrast, a conversion of 35% and ee value of 47% were
obtained using catalyst based on 7 with 2-methoxybenzaldehyde
as substrate, the catalyst was reused only 4 times, provided a low
yield of 35% and an poor ee value of 19% on the 4th cycle. It
can be seen that, in our case, it is the ionic tag of the catalyst
which assured the good recyclability.
A theoretical mechanistic study was conducted to explain the
origin of the enantioselectivity at the molecular level. Compu-
tational calculations of the geometry of the complex Cu(OAc)2
2a were performed with the B3LYP/6-31G(d) scheme in the
Gaussian03 software package. The optimal geometry is pre-
sented in Fig. 3. Because of the imidazolium salt tagged to the
long alkyl chains on the carbon bridge between the two oxazo-
lines, the steric environment was enhanced. The most probable
transition structure for the asymmetric Henry reaction was also
illustrated in Fig. 3. According to the model proposed by
Evans,20,22 the most reactive transition structure was in a mode
such that the CH3NO2, as a nucleophile, is perpendicular to the
ligand plane and the aldehyde, as electrophile, is in the ligand
Fig. 2 Variations in percentage conversion (1) and percentage ee (2)
upon recycling of the catalyst. a: Ligand is 2e, substrate is benzaldehyde;
b: ligand is 2e, substrate is 2-methoxybenzaldehyde; c: ligand is 2a,
substrate is benzaldehyde; d: ligand is 2a, substrate is 3, 4-
dimethoxybenzaldehyde.
Fig. 3 Computational geometry of complex Cu(OAc)2-2a (H was
omitted for clarity) and possible transition structure for the asymmetric
Henry reaction.
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plane. This transition structure was favorable on the basis of both
steric and electronic considerations. Because one of the long
alkyl chains on the carbon bridge was more curved than the
other, and with the imidazolium salt tagged to it, the bulky
[OTs]− anion was closely coordinated to the Cu(II); this
increased the steric bulk, made it more difficult for the nitronate
to attack from the si-face thereby increasing the enantioselectiv-
ity. Cu(OAc)2-2a afforded adducts with an (R)-configuration,
indicating that the nitronate attacks the re-face of the aldehyde.
column chromatography on silica gel (Merck, 60–120 mesh,
(ethyl acetate/hexane, 3 : 7) to afford the pure 2-nitroalcohol.
Acknowledgements
The National Technological Project of the Manufacture and
Innovation of Key New Drugs (2009ZX09103-143) and the
Major Projects Cultivating Special Program in Technology Inno-
vation Program (Grant NO. 2011CX01008) of the Beijing Insti-
tute of Technology are gratefully acknowledged for their
financial support.
Conclusions
In conclusion, catalysts based on the new imidazolium-tagged
bis(oxazoline) ligands and Cu(OAc)2·H2O were applied to the
asymmetric Henry reaction between various aldehydes 3 and
CH3NO2 4. The catalyst derived from 2a yielded adduct (R)-5n
at 94% ee in MeOH. Furthermore, the catalyst based on 2a could
be recycled at least 6 times without an obvious loss of activity or
enantioselectivity. At the same time, a theoretical mechanistic
study was conducted to explain the origin of the enantioselectiv-
ity. The synthetic utility of the catalytic enantioselective Henry
reaction could be demonstrated by the application of a short-step
synthesis of a telmisartan analogue, a type of angiotensin II
receptor antagonists. Our process, which was simple and easy to
operate, possesses potential as an environmentally friendly
process in the chemical industry. Further research on C2-sym-
metric imidazolium-tagged bis(oxazoline) ligands and their per-
formance in asymmetric reactions is ongoing in our laboratory.
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Experimental section
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1
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To an oven-dried 10 mL two necked round-bottomed flask, a sol-
ution of ligand (0.05 mmol) and Cu(OAc)2·H2O (12.4 mg,
0.063 mmol) in MeOH (1 mL) was stirred for 2 h at 25 °C.
Then the aldehyde (0.34 mmol) and nitromethane (17 mmol)
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appropriate time. After completion, as monitored by TLC, the
solvent was removed, and the resulting residue was purified by
2118 | Org. Biomol. Chem., 2012, 10, 2113–2118
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