Development of highly enantioselective asymmetric aldol reaction catalyzed by 1-glycyl-3-methyl imidazolium chloride-iron(III) complex

Article abstract of DOI:10.1016/j.molcata.2013.08.029

A novel, effective asymmetric 1-glycyl-3-methyl imidazolium chloride-iron(III) [[Gmim]Cl-Fe(III)] complex was synthesized and studied as organocatalyst in asymmetric aldol addition under solvent free condition at 25 C. The hydrophobic group of amino acid

Full text of DOI:10.1016/j.molcata.2013.08.029

Journal of Molecular Catalysis A: Chemical 379 (2013) 333–339
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journal homepage: www.elsevier.com/locate/molcata
Development of highly enantioselective asymmetric aldol reaction
catalyzed by 1-glycyl-3-methyl imidazolium chloride–iron(III)
complex
Parasuraman Karthikeyan, Prashant Narayan Muskawar, Sachin Arunrao Aswar,
Suresh Kumar Sythana, Pundlik Rambhau Bhagat∗
Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632 014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2012
Received in revised form 28 August 2013
Accepted 30 August 2013
Available online 10 September 2013
A novel, effective asymmetric 1-glycyl-3-methyl imidazolium chloride–iron(III) [[Gmim]Cl–Fe(III)] com-
plex was synthesized and studied as organocatalyst in asymmetric aldol addition under solvent free
condition at 25 ◦C. The hydrophobic group of amino acid favors reagent diffusion toward the chloroglycine
moiety increasing the catalytic activity of supported iron complex. This method contains simplified prod-
uct isolation and catalyst recycling, affording substituted aromatic aldehydes imparting high yield of aldol
with excellent stereo-selectivity. This recyclable heterogeneous catalyst provides a simple strategy for
the generation of a variety of new C C bonds under environmentally benign condition.
© 2013 Elsevier B.V. All rights reserved.
Keywords:
Asymmetric reaction
Ionic liquid
Iron complex
Amino acid
1. Introduction
and small peptide derivatives as well as some other small chiral
molecules used as catalysts allow the synthesis of complex poly
Asymmetric aldol addition is an important reaction due to its
wide range of applications in both laboratory and industry. The
significance of these aldol resides in the synthesis of carbohydrates,
amino sugars, steroids, pharmaceutically active chiral compounds
and various potential synthons [1]. As a rule, the major reaction
products have anti-configuration, whereas syn-aldols are formed
exclusively in native aldolase catalyzed aldol reaction [2].
In recent years, chiral ionic liquids have emerged as a set of
green solvent with unique properties such as tunable polarity,
high thermal stability and immiscibility with a number of organic
solvents, negligible vapor pressure and recyclability. Their non-
volatile character and thermal stability make the metal complexes
potentially attractive alternatives to environmentally unfavorable
organic co-solvents, notably chlorinated hydrocarbons. In particu-
lar, they show promising role as solvents for the immobilization of
transition metal catalysts, Lewis acids and enzymes [3,4].
functional compounds of high enantiomeric purity from simple
achiral precursors. Although the natural amino acid functionalized
metal complexes are cheap, recycling of organocatalysts can be an
issue if one think in terms of large scale production or of green
chemistry.
During the last two years, iron complex has been used for sev-
eral organic transformations such as the epoxidation of styrene [6],
oxidation of alcohol [7], asymmetric synthesis [8], amination [9]
and also for the Michel addition [10] reactions. Recently, Wu et al.
[11] have reported the simple and recyclable O-acylation serine
derivatives catalyzed for the large-scale asymmetric direct aldol
reaction in the presence of water. However, Calogero et al. [12]
was described the l-proline supported zirconium phosphate cat-
alyzed for direct asymmetric aldol addition. Siyutkin et al. [5] and
Khan et al. [13] used the ionic liquid modified by hydroxy-␣-amino
acid or tagged organocatalysts moieties, for asymmetric aldol reac-
tion in the presence of water. All the above mentioned methods
provide a good yield whereas, some of these reactions are sluggish
requiring at least 24 h for the reaction completion, harsh reaction
conditions (organic co-solvents) and require absolutely dry and
inert media. From these literatures no report was found in asym-
metric aldol addition catalyzed by 1-glycyl-3-methyl imidazolium
chloride–iron(III) complex (Fig. 1). Hence, we felt it would be inter-
esting to investigate the alternative method for the synthesis of
aldols. In this regard, we have developed an easy and a selective
Furthermore, the asymmetric metal complex is an intensively
developing area of modern organic chemistry. It was ascertained
that the reaction could be performed at a higher rate and selectiv-
ity under the action of some more elementary organic molecules
[5]. These contain amino acid derivatives, other natural amino acid,
∗
Corresponding author. Tel.: +91 9047289073; fax: +91 416 22404119.
E-mail address: drprbhagat111@gmail.com (P.R. Bhagat).
1381-1169/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molcata.2013.08.029

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P. Karthikeyan et al. / Journal of Molecular Catalysis A: Chemical 379 (2013) 333–339
2.2. Preparation of [Gmim]Cl–Fe(III) complex
The chiral [Gmim]Cl–Fe(III) complex was synthesized according
to literature [20,21] while the other ionic liquids were synthesized
using the literature procedure reported elsewhere [22–25]. The
optical rotations for [Gmim]Cl–Fe(III) is [˛]2D5 = −28.2 (c 1, MeOH).
2.3. Procedure for asymmetric aldol addition
A mixture of cyclohexanone (1.2 mmol), p-nitrobenzaldehyde
(1 mmol) and chiral [Gmim]Cl–Fe(III) (0.01 mmol) was added and
stirred at 25 ◦C for 6 h. The product and excess of cyclohexanone
were extracted with ethyl acetate (2 × 3 mL). The organic phase was
separated and dried over anhydrous Na2SO4 and evaporated. The
resulting crude was purified by column chromatography to give the
desired pure product with excellent enantioselectivities.
2.4. Recycling of the catalyst for the model reaction of
p-nitrobenzaldehyde with cyclohexanone using [Gmim]Cl–Fe(III)
under solvent free condition
Fig.
1. 1-Glycyl-3-methyl
imidazolium
chloride–iron(III)
complex
([Gmim]Cl–Fe(III)).
p-Nitrobenzaldehyde (1 mmol) was reacted with cyclohex-
anone (1.2 mmol) in the presence of [Gmim]Cl–Fe(III) (0.01 mmol)
at ambient temperature. After completion of the reaction (TLC), the
product was extracted as stated in the preceding general method.
The brownish yellow solid [Gmim]Cl–Fe(III) was isolated by cen-
trifugation. The recovered complex was washed with diethyl ether
and dried with nitrogen. The resulting catalyst was charged to
another batch of the similar reaction. This was repeated for eight
runs to complete the reaction in 6 h, to give the desired product
with 90–98% enantioselectivities (Table 7).
synthetic route, expand an operationally simple, safe and widely
used eco-friendly method.
However, recovery and leaching can occur in the extractive work
up leading to a loss of the catalyst in the reaction mixture on the one
hand and requests additional effort to purify the extracted product.
To overcome such problems, novel complex was developed [14] by
covalent linking of organic catalytic units with an ionic liquid moi-
ety (often chloroglycine). This imparts a low solubility of catalyst in
the solvents used for extraction of the product on the one hand and
high solubility in the reaction medium on the other hand [15–19].
This strategy was also applied to aldol reaction providing high yield
and stereoselectivities and good recyclability of the organocatalyst.
The objectives of the present study are: (i) preparation of
hexacoordinated 1-glycyl-3-methyl imidazolium chloride–iron(III)
complex and its application as a catalyst system, (ii) develop-
ment of competent synthetic process for the facile conversion of
asymmetric aldol addition. The present method developed for the
asymmetric aldol addition offer many advantages including high
stereoselectivity and conversion, short duration and the involve-
ment of non-toxic reagents.
3. Results and discussion
3.1. Characterization of iron complex
[Gmim]Cl–Fe(III) catalyst has been characterized by FT-IR and
XRD.
3.2. FT-IR analysis
Compounds
C
N
C
O
Fe
O
Fe
N
O
–
3429s
3378s
H
N H
[Gmim]Cl–Fe(III)
[Gmim]Cl
Chloroglycine
1394s
1382s
1392s
1723s
1626s
1625s
480m
–
–
407m
–
–
3342m
3372m
3335m
2. Experimental
FT-IR spectra of [Gmim]Cl–Fe(III) at different dissociation
degrees are shown in Fig. 2. For carboxylate ion, the absorption
band at 1723 cm−1 corresponds to carbonyl symmetric stretching.
The asymmetric stretching of carboxylate was shifted to 1626 cm−1
[Gmim]Cl in contrast with the shift to 1625 cm−1 in chloroglycine,
which appeared when [Gmim] Cl was treated with FeCl3 and thus
the carbonyl stretching was decreased. However, the plane of
2.1. Materials and methods
All solvents and chemicals were commercially available and
used without further purification unless otherwise stated. The
[Gmim]Cl–Fe(III) complex was characterized by powder X-ray
diffraction (P-XRD) diffractometry with a Bruker D8 (advance
model), Germany and lynx eye detector operating with nickel fil-
tered Cu-K radiation. The 1H-NMR spectra were recorded on a
Bruker 500 MHz using CDCl3/DMSO-d6 as the solvent and mass
spectra were recorded on JEOL GC MATE II HRMS (EI) spectrom-
eter. FT-IR spectra were recorded on an AVATRA 330 spectrometer
with DTGS detector. Column chromatography was performed
on silica gel (200–300 mesh). Analytical thin-layer chromatogra-
phy (TLC) was carried out on precoated silica gel GF-254 plates.
Analytical high performance liquid chromatography (HPLC) was
carried out on Agilent 1200 instrument using Chiralpak OJ-H
(4.6 mm × 250 mm), optical rotations were measured on a JASCO
P-1010 Polarimeter at ꢀ = 589 nm.
C
OH at 3378, 3429 cm−1 was present in chloroglycine, [Gmim]Cl,
respectively, but when the network was treated with FeCl3 no sig-
nal was observed for the OH group, indicates the formation of
Fe O (480 cm−1) bond. Although, the NH2 signal in chloroglycine,
[Gmim]Cl was detected in 3335, 3372 cm−1 with doublet, but in the
case of [Gmim]Cl–Fe(III), we also found the doublet at 3342 cm−1
,
this also shows the formation of Fe NH (407 cm−1) bond in the
catalyst [27]. In all spectra, stretching of C N was observed at
1394, 1382 and 1392 cm−1, respectively. Notably, the FT-IR spectra
revealed that a series of new iron complex with ionizable groups
had been synthesized.

P. Karthikeyan et al. / Journal of Molecular Catalysis A: Chemical 379 (2013) 333–339
335
100
90
(c)
80
70
60
50
40
30
20
(b)
(a)
10
0
3500
3000
2500
2000
1500
1000
500
400
Wavenumber (cm-1)
Fig. 2. FT-IR of (a) chloroglycine, (b) 1-glycyl-3-methyl imidazolium chloride ([Gmim]Cl) and (c) 1-glycyl-3-methyl imidazolium chloride–iron(III) complex
([Gmim]Cl–Fe(III)).
3.3. Powder XRD analysis
influenceofdifferentbasesto themodelreactionwas studied;these
results are summarized in Table 1. It was observed that, base free
condition found to be the most effective and thus chosen as the pre-
ferred for the reaction, although organic and inorganic bases can be
used. This may be due to the blocking of free coordination sites on
the iron center. Although, the effect of the base in the aldol reac-
tion is still imperfectly understood and many recent works were
concerned on this subject. Recently, Wu et al. [11] have studied
the role of the base in the aldol reaction using O-acylation serine
as catalytic precursors and concluded that the oxidative addition
step (when performed from aromatic aldehyde) becomes slower
and the carbanion step turn into faster in the absence of the base.
Furthermore, we have screened several solvents for the reac-
tion between cyclohexanone and p-nitrobenzaldehyde (Table 2).
According to publications from Siyutkin et al. [5] and Calogero et al.
The formation of the Fe(III) catalyst was also supported by the
XRD patterns with those of glycine, chloroglycine, Fe(III) complex.
In comparison with glycine, chloroglycine, Fe(III) complex which
showed major peaks, respectively, in 20.55, 28.98, 25.12, 31.80 and
45.82 (confirming iron peak with JCPDS Data Care No.: 99-101-1980
for Fe(III)), the [Gmim]Cl–Fe(III) pattern was in good agreement
with peak at 31.80 and 45.82 (Fig. 3).
The iron complex catalyzed aldol reaction was carried out using
cyclohexanone and p-nitrobenzaldehyde as a model reaction to
investigate different parameters, such as effect of solvent, diverse
bases, catalysts and concentration of the catalyst. Initially, the
31.80
45.82
Table 1
Effect of the base on asymmetric aldol addition reaction.a
(c)
Yieldb (%)
Anti/sync
ee of antic
25.12
Entry
Base
Time (h)
1
2
3
4
5
6
7
8
9
K2CO3
KOH
NaOH
Py
Imidazole
Et3N
–
–
–
–
–
–
24
24
24
24
24
24
24
18
12
6
Trace
50
47
51
68
70
94
95
95
95
90
88
Trace
65/35
73/27
60/40
75/25
73/27
93/7
93/7
94/6
94/6
90/10
90/10
Trace
60
70
67
70
75
98
98
98
98
94
92
(b)
20.55
28.98
10
11
12
(a)
3
1
0
30
60
90
a
Reaction condition: p-Nitrobenzaldehyde (1 mmol), cyclohexanone (1.2 mmol),
2 theta (deg.)
different base (0.1 mmol) and [Gmim]Cl–Fe(III) (0.01 mmol) stirring at 25 ◦C for 6 h.
b
Isolated yield by flash chromatography.
Determined by chiral HPLC analysis (OJ-H).
Fig. 3. Powder X-ray diffraction patterns of (a) glycine, (b) chloroglycine and (c)
1-glycyl-3-methyl imidazolium chloride–iron(III) complex ([Gmim]Cl–Fe(III)).
c

336
P. Karthikeyan et al. / Journal of Molecular Catalysis A: Chemical 379 (2013) 333–339
Table 2
Table 4
Effect of the solvent on asymmetric aldol addition reaction.a
Effect of the catalyst loading on asymmetric aldol addition reaction.a
Entry Solvent
Temp. (◦C) Time (h) Yieldb (%) Anti/sync
ee of
antic
Entry
[Gmim]Cl–Fe(III)
(mmol)
Time (h)
Yieldb
Anti/sync
ee of antic
1
2
3
4
5
6
7
8
9
DCM
CHCl3
THF
Methanol
Ethanol
CH3CN
DMF
PhMe
Solvent free
Solvent free
Solvent free
Water (5 mL)
35
50
50
50
65
60
130
90
25
20
35
90
24
24
24
24
24
24
24
24
6
38
43
40
50
53
50
60
63
95
95
93
40
52/48
60/40
56/44
65/35
60/40
58/42
64/36
67/33
94/6
50
54
47
60
63
54
60
57
98
97
98
65
1
2
3
4
5
6
7
8
–
0.1
24
6
6
6
6
6
6
6
Trace
96
96
96
96
96
94
93
Trace
94/6
94/6
94/6
94/6
94/6
90/10
86/14
Trace
98
98
98
98
98
96
90
0.075
0.050
0.025
0.01
0.0075
0.005
a
Reaction condition: p-Nitrobenzaldehyde (1 mmol), cyclohexanone (1.2 mmol)
10
11
12
6
6
24
92/8
95/5
60/40
and [Gmim]Cl–Fe(III) (0.01 mmol) stirring at 25 ◦C for 6 h.
b
Isolated yield by flash chromatography.
Determined by chiral HPLC analysis (OJ-H).
c
a
Reaction condition: p-Nitrobenzaldehyde (1 mmol), cyclohexanone (1.2 mmol),
different solvent (5 mL) and [Gmim]Cl–Fe(III) (0.01 mmol) stirring at 25 ◦C for 6 h.
b
observed acceptable rate in the aldol reaction of alcohols. Among
the previous reports, increasing the quantity of the catalyst can
improve the reaction yield and shorten reaction time (Table 4).
First, aldol reaction was carried out in absence of catalyst at ambi-
ent temperature; it was found that no product formed even after
24 h. Even though amount of the catalyst decreased from 0.1 to
0.025 mmol, no change in the yields, whereas using 0.01 mmol
[Gmim]Cl–Fe(III), in model reaction generated 96% product. Almost
dissimilar yield was obtained when decreasing the catalyst amount
from 0.01 to 0.005 mmol. Therefore, the aldol addition reaction
was carried out at the molar ratio of p-nitrobenzaldehyde, cyclo-
hexanone and [Gmim]Cl–Fe(III) 1:1.2:0.01 mmol under solvent free
condition at ambient temperature.
In order to test the substrate generality of [Gmim]Cl–Fe(III)
complex catalyzed direct aldol reaction, the condensation of var-
ious aromatic aldehydes with cyclohexanone were studied under
the optimized conditions. The results are summarized in Table 5.
It can be noticed that a wide range of aromatic aldehydes can
efficiently contribute in the aldol reactions. However, the reac-
tion between cyclohexanone and aromatic aldehydes bearing
electron-withdrawing substituents furnished ␤-hydroxy carbonyl
aldol products with excellent yields (80–98%) and enantioselec-
tivities (93–98% ee for anti-isomer) within 6–12 h, particularly
the p-nitrobenzaldehyde and o-nitrobenzaldehyde. On the other
hand, longer reaction times (15 h) were required for aromatic alde-
hydes containing an electron-donating group to give comparatively
inferior yields (70–75%), without lacking of enantioselectivities,
in particular the p-toulaldehyde. This can be explained that
electron-withdrawing groups improve the electrophilicity of car-
bonyl carbons in aldehydes, which facilitates the reaction, while
electron-donating groups reduce the electrophilicity. Moreover,
the direct aldol reaction of neutral aldehydes catalyzed by the iron
complex also afforded the aldol products with high enantioselec-
tivities and diastereoselectivities. All the condensation reactions
of cyclohexanone with aromatic aldehydes afford the subsequent
products with excellent yield (70–98%) and enantioselectivities
(93–98% ee of anti-isomers).
Isolated yield by flash chromatography.
Determined by chiral HPLC analysis (OJ-H).
c
[12] polar, aprotic solvents tend to give the best results for the
aldol reaction, while Fu et al. [11] obtained high-activity catalysts
in water solvent. We employed several solvents in the aldol model
reaction. Among the previous reports, reaction under solvent free
condition was the most productive, as compared with the polar
and non-polar solvents. The catalyst was easily coordinating with
organic co-solvents. It has also been reported that H2O molecule
sometimes is required to activate the Fe(III) catalyst. In our case,
carrying out the reaction in H2O (5 mL) 90 ◦C gave a negative effect
on the product yield in comparison with solvent free condition and
this lower yield could be due to the delocalization of the complex
under aqueous condition.
Next, in order to optimize the reaction conditions for a particu-
lar catalyst the condensation reaction was executed using different
catalysts and the results are given in Table 3. When the reaction was
carried out using various catalysts such as glycine, chloroglycine,
1-carboxyethyl-3-methylimidazoliumbromide ([Cemim]Br) [26],
1-aminoethyl-3-methylimidazoliumbromide ([Aemim]Br) [26],
FeCl3/[Cemim]Br, FeCl3/[Aemim]Br and FeCl3/[Gmim]Cl in absence
of solvent, it gave trace to 80% of enantioselectivities product. How-
ever, when the same reaction was conducted with [Gmim]Cl–Fe(III)
as a catalyst it gave remarkable yield of product in short duration.
Almost similar yield was obtained when increasing the duration.
The catalytic reaction which can be carried out with a small
amount of expensive complexes is the most useful feature of syn-
thetic reaction involving iron complex. According to literature,
Jankowska et al. [28] obtained good yield in the Mukaiyama-aldol
reaction of benzaldehyde with Z-enol silyl ether using 20 mol% of
air and water stable FeCl2·4H2O in the presence of EtOH/H2O. Using
Fe(CO)3 in the range between 1 mol% and 5 mol%, Gree et al. [29]
Table 3
Effect of the various catalysts on asymmetric aldol addition reaction.a
Entry
Catalyst
Time (h)
Yieldb
Anti/sync
ee of
antic
Finally, condensation of cyclopentanone with different aro-
matic aldehydes was investigated. In these reactions, variety of
aldehyde were treated with cyclopentanone in the presence of
[Gmim]Cl–Fe(III) at room temperature in absence of solvent. The
reaction proceeded smoothly with the formation of aldols with
87–93% enantioselectivities. In addition, it was found that substi-
tuted group of aromatic aldehydes have an effect on aldol; aromatic
aldehydes with withdrawing group was observed to be more reac-
tive than that of electron donating group (Table 6).
1
2
3
4
5
6
7
8
9
Glycine
Chloroglycine [Cl-gly] 24
[Cemim]Br
[Aemim]Br
FeCl3/[Cemim]Br
FeCl3/[Aemim]Br
FeCl3/[Gmim]Cl
[Gmim]Cl–Fe(III)
[Gmim]Cl–Fe(III)
24
Trace
50
42
44
60
71
75
96
97
Trace
–
Trace
–
24
24
24
24
24
6
–
–
–
60/40
70/30
75/25
94/6
93/7
52
75
80
98
98
7
Isolation of the heterogeneous catalyst was easily performed
by separation or centrifugation. The isolated catalyst was washed
with ethyl acetate and dried in air. The regenerated cata-
lyst was used for the reaction of p-nitrobenzaldehyde with
a
Reaction condition: p-Nitrobenzaldehyde (1 mmol), cyclohexanone (1.2 mmol)
and different catalyst (0.01 mmol) stirring at 25 ◦C for 6 h.
b
Isolated yield by flash chromatography.
Determined by chiral HPLC analysis (OJ-H).
c

P. Karthikeyan et al. / Journal of Molecular Catalysis A: Chemical 379 (2013) 333–339
337
Table 5
Table 6
Asymmetric aldol addition reaction of different aromatic aldehydes with cyclohex-
Asymmetric aldol addition reaction of different aromatic aldehydes with cyclopen-
anone in the presence [Gmim]Cl–Fe(III) under solvent free condition.a
tanone in the presence [Gmim]Cl–Fe(III) under solvent free condition.a
Entry
Product (R)
Time (h)
Yieldb (%)
Anti/sync
ee of antic
Entry Product
1
Time (h) Yieldb (%) Anti/sync ee of antic
1
2
3
4
5
6
H
NO2
Cl
Br
OCH3
CH3
8
6
12
12
12
15
75
94
85
85
70
68
85/15
90/10
83/17
85/15
90/10
80/20
87
95
93
93
90
90
8
6
80
96
90/10
94/6
93
98
a
Reaction
condition:
Aldehydes
(1 mmol),
ketone
(1.2 mmol)
and
2
[Gmim]Cl–Fe(III) (0.01 mmol) stirring at 25 ◦C for 6 h.
b
Isolated yield by flash chromatography.
c
Determined by chiral HPLC analysis (OJ-H) and comparison of the retention
times with literature data [11].
3
4
5
6
6
6
97
97
98
85
95/5
97/3
97/3
92/8
98
98
98
94
Table 7
Recycling of the catalyst for the reaction of p-nitrobenzaldehyde with
cyclohexanone.a
Entry
Run
Yieldb (%)
Anti/sync
ee of antic
1
2
3
4
5
6
7
8
0
1
2
3
4
5
6
7
96
96
96
94
93
93
92
90
94/6
93/7
93/7
93/7
92/8
92/8
90/10
90/10
98
98
95
95
95
92
92
90
6
12
a
Reaction condition: p-Nitrobenzaldehyde (1 mmol), cyclohexanone (1.2 mmol)
and [Gmim]Cl–Fe(III) (0.01 mmol) stirring at 25 ◦C for 6 h.
b
Isolated yield by flash chromatography.
Determined by chiral HPLC analysis (OJ-H).
c
7
8
12
15
85
75
92/8
95
93
chemical and structural changes, thus proving its surface catalytic
activity toward the condensation reaction of p-nitrobenzaldehyde
with cyclohexanone. On the other hand, presence of peaks due
to metallic iron is noted in the powder XRD pattern of the com-
plex in the case of ‘Fe(III)’ (Fig. 4a and b). Furthermore, Fe leaching
was also studied by inductively coupled plasma atomic emis-
sion spectroscopy (ICP-OES) analysis, indicating that the product
mixture contained 0 ppm of iron accounting for 0.1 mmol of the
initially added amount of Fe. From those experimental results,
91/9
9
15
70
90/10
95
a
Reaction
condition:
Aldehydes
(1 mmol),
ketone
(1.2 mmol)
and
[Gmim]Cl–Fe(III) (0.01 mmol) stirring at 25 ◦C for 6 h.
b
Isolated yield by flash chromatography.
c
Determined by chiral HPLC analysis (OJ-H) and comparison of the retention
times with literature data [11].
31.80
cyclohexanone for eight runs to afford (S)-2-((R)-hydroxy(4-
nitrophenyl)methyl)cyclohexanone with 98–90% enantioselectivi-
ties (Table 7).
(b)
31.89
For practical application in the asymmetric aldol reaction, the
life time of the heterogeneous catalysts and their reusability are
very important factors. For the comparative study, asymmetric
aldol reaction was carried out with model reaction at the optimized
conditions in presence of Fe/C catalyst. However, a significant dif-
ference in Fe leaching was observed. Without exclusion of air about
26% of the total iron amount were lost from the Fe/C and found in
solution (AAS) compared to [Gmim]Cl–Fe(III) where no leaching
detected.
For those conformation, [Gmim]Cl–Fe(III) catalyst was collected
after the completion of the reaction and analyzed by powder X-ray
diffraction method and the diffraction patterns are given in Fig. 4.
The analysis specifies that the [Gmim]Cl–Fe(III) do not undergo any
(a)
0
30
60
90
2 theta (deg.)
Fig. 4. Powder X-ray diffraction patterns of the [Gmim]Cl–Fe(III)complex: (a) before
reaction and (b) after reaction (8th run).

338
P. Karthikeyan et al. / Journal of Molecular Catalysis A: Chemical 379 (2013) 333–339
(S)-2-((R)-(4-bromophenyl)(hydroxy)methyl)cyclohexanone
(Table 5, entry 7): The diastereomeric anti/syn ratio was deter-
mined by 1H-NMR analysis of the crude product: ı 5.30 (d,
J = 2.6 Hz, 1H, syn, minor), 4.75 (d, J = 8.5 Hz, 1H, anti, major). Enan-
tiomeric excess was determined by HPLC with a Chiralpak (OJ-H)
(4.6 mm × 250 mm) column (n-hexane/i-PrOH 4/1, 1.0 mL/min,
ꢀ = 254 nm, 25 ◦C): tR = 14.1 min (minor) and 16.4 min (major).
(S)-2-((R)-hydroxy(4-methoxyphenyl)methyl)cyclohexanone
(Table 5, entry 8): The diastereomeric anti/syn ratio was deter-
mined by 1H-NMR analysis of the crude product: ı 5.32 (m, 1H, syn,
minor), 4.74 (d, J = 8.8 Hz, 1H, anti, major). Enantiomeric excess was
determined by HPLC with a Chiralpak (OJ-H) (4.6 mm × 250 mm)
column (n-hexane/i-PrOH 4/1, 1.0 mL/min, ꢀ = 254 nm, 25 ◦C):
tR = 43.2 min (minor) and 34.4 min (major).
(S)-2-((R)-hydroxy(phenyl)methyl)cyclopentanone (Table 6,
entry 1): The diastereomeric anti/syn ratio was determined by 1H-
NMR analysis of the crude product: ı 5.31 (m, 1H, syn, minor),
4.71 (d, J = 8.7 Hz, 1H, anti, major). Enantiomeric excess was deter-
mined by HPLC with a Chiralpak (OJ-H) (4.6 mm × 250 mm) column
(n-hexane/i-PrOH 4/1, 1.0 mL/min, ꢀ = 254 nm, 25 ◦C): tR = 20.8 min
(minor) and 16.5 min (major).
(S)-2-((R)-hydroxy(4-nitrophenyl)methyl)cyclopentanone
(Table 6, entry 2): The diastereomeric anti/syn ratio was deter-
mined by 1H-NMR analysis of the crude product: ı 5.42 (m, 1H, syn,
minor), 4.85 (d, J = 8.9 Hz, 1H, anti, major). Enantiomeric excess was
determined by HPLC with a Chiralpak (OJ-H) (4.6 mm × 250 mm)
column (n-hexane/i-PrOH 4/1, 1.0 mL/min, ꢀ = 254 nm, 25 ◦C):
tR = 77.4 min (minor) and 81.6 min (major).
Scheme 1. Proposed catalytic mechanism.
we believe that the no Fe leaching observed in asymmetric aldol
reaction, it’s due to immobilized iron in amino acid functional-
ized ionic liquid binding site located on the surface, which acts
as a ligand through metal–ligand interaction. The anchoring of Fe
species by amino acid sites supported on ionic liquid minimizes
catalyst deterioration and no metal leaching and therefore allows
efficient catalyst recycling. The precise mechanism of the catalytic
reaction needs to be elucidated, but it is noticeable that the mech-
anism is strongly modified depending of the substituted aromatic
aldehydes employed, obtaining highly enantioselective asymmet-
ric aldols (anti) as the main product (Scheme 1).
The [Gmim]Cl–Fe(III) complex stumble on superiority over most
of the reported catalysts with many advantages: facile synthesis,
thermal stability and structural versatility, easy handling, catalytic
performance in air at 25 ◦C, without any additives, no inert atmo-
sphere required without leaching of catalyst.
(S)-2-((R)-hydroxy(phenyl)methyl)cyclohexanone (Table 5,
entry 1): The diastereomeric anti/syn ratio was determined by
1H-NMR analysis of the crude product: ı 5.39 (d, J = 2.3 Hz, 1H, syn,
minor), 4.79 (d, J = 8.8 Hz, 1H, anti, major). Enantiomeric excess was
determined by HPLC with a Chiralpak (OJ-H) (4.6 mm × 250 mm)
column (n-hexane/i-PrOH 4/1, 1.0 mL/min, ꢀ = 254 nm, 25 ◦C):
tR = 22.5 min (minor) and 20.8 min (major).
4. Conclusions
In conclusion, the results from the investigation demonstrate
that the 1-glycyl-3-methyl imidazolium chloride–iron(III) complex
was efficient catalyst for highly enantioselective aldol addition
reaction. The procedure is easy and does not require special pre-
cautions. All the reaction was conducted in the air without the
use of an organic co-solvent. Noteworthy features of this catalysis
system are: (1) synthesized a novel green 1-glycyl-3-methyl imid-
azolium chloride–iron(III) complex; (2) its catalytic activity was
tested in direct aldol reaction; (3) 0.01 mmol of catalyst was suf-
ficient to furnish the aldol products with excellent yields (up to
98%) and enantioselectivities (up to 98%); (4) the catalyst can be
readily recovered and reused without significant loss of its activ-
ity and stereo selectivity; notably, (5) this organo catalyzed direct
asymmetric aldol reaction can be performed on a large-scale with
the enantio selectivity being maintained at the same level, which
offers a great possibility for applications in industry.
(S)-2-((R)-hydroxy(4-nitrophenyl)methyl)cyclohexanone
(Table 5, entry 2): The diastereomeric anti/syn ratio was deter-
mined by 1H-NMR analysis of the crude product: ı 5.48 (d,
J = 1.8 Hz, 1H, syn, minor), 4.89 (d, J = 8.8 Hz, 1H, anti, major). Enan-
tiomeric excess was determined by HPLC with a Chiralpak (OJ-H)
(4.6 mm × 250 mm) column (n-hexane/i-PrOH 4/1, 1.0 mL/min,
ꢀ = 254 nm, 25 ◦C): tR = 26.3 min (minor) and 34.9 min (major).
1H-NMR (500 MHz, CDCl3): ı 2.12–1.31 (m, 6H), 2.49–2.32 (m,
2H), 2.63–2.57 (m, 1H), 4.07 (s, 1H), 4.89 (d, J = 8.4 Hz, 1H), 7.50 (d,
J = 8.7 Hz, 2H), 8.20 (d, J = 8.6 Hz, 2H). 13C-NMR: ı 24.7, 27.7, 30.8,
42.7, 57.2, 74.0, 123.5, 127.9, 147.6, 148.4, 214.8.
Acknowledgments
We greatfully acknowledge the SIF VIT-DST-FIST, VIT University
– Vellore, and SAIF (IITM) for providing the spectral data.
Appendix A. Supplementary data
Supplementary material related to this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.molcata.2013.
08.029.
(S)-2-((R)-hydroxy(3-nitrophenyl)methyl)cyclohexanone
(Table 5, entry 3): The diastereomeric anti/syn ratio was deter-
mined by 1H-NMR analysis of the crude product: ı 5.50 (m, 1H, syn,
minor), 4.92 (d, J = 8.4 Hz, 1H, anti, major). Enantiomeric excess was
determined by HPLC with a Chiralpak (OJ-H) (4.6 mm × 250 mm)
column (n-hexane/i-PrOH 4/1, 1.0 mL/min, ꢀ = 254 nm, 25 ◦C):
tR = 47.0 min (minor) and 35.5 min (major).
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