Development and efficient 1-glycyl-3-methyl imidazolium chloride-copper(II) complex catalyzed highly enantioselective synthesis of 3, 4-dihydropyrimidin- 2(1H)-ones

Article abstract of DOI:10.1016/j.jorganchem.2012.06.022

A novel, effective asymmetric 1-glycyl-3-methyl imidazolium chloride-copper(II) complex [[Gmim]Cl-Cu(II)] was synthesized and studied as organocatalyst for enantioselective Biginelli reaction under solvent free condition at 25°C. The hydrophobic group on

Full text of DOI:10.1016/j.jorganchem.2012.06.022

Journal of Organometallic Chemistry 723 (2013) 154e162
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Journal of Organometallic Chemistry
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Development and efficient 1-glycyl-3-methyl imidazolium chlorideecopper(II)
complex catalyzed highly enantioselective synthesis of 3, 4-dihydropyrimidin-
2(1H)-ones
Parasuraman Karthikeyan, Sachin Arunrao Aswar, Prashant Narayan Muskawar,
*
Pundlik Rambhau Bhagat , S. Senthil Kumar
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:
A novel, effective asymmetric 1-glycyl-3-methyl imidazolium chloride-copper(II) complex [[Gmim]Cl
eCu(II)] was synthesized and studied as organocatalyst for enantioselective Biginelli reaction under
solvent free condition at 25ꢀC. The hydrophobic group on amino acid favors reagent diffusion towards
the chloroglycine moiety increasing the catalytic activity of supported palladium complex. Spectroscopic
evidence of complex has been proved by Powder XRD, SEM, FT-IR and AFM. This method contains
simplified product isolation and catalyst recycling, affording substituted aldehydes imparting high yield
with excellent stereoselectivity. This recyclable heterogeneous catalyst provides a simple strategy for the
generation of a variety of new CeC bonds under environmentally benign condition.
Received 25 March 2012
Received in revised form
9 June 2012
Accepted 25 June 2012
Keywords:
3, 4-dihydropyrimidin-2(1H)-one
Ionic liquid
Copper complex
Amino acid
Ó 2012 Published by Elsevier B.V.
1. Introduction
Furthermore, asymmetric metal complex is an intensively devel-
oping area of modern organic chemistry. It was ascertained that the
Multicomponent reactions are very attractive tools to obtain the
complex molecules from one-pot procedures. Moreover, Dihy-
dropyrimidinones are vital synthons, pharmaceuticals or precur-
sors. Furthermore, these compounds have emerged as the integral
backbones of several calcium-channel blockers. However, some
marine alkaloids containing the dihydropyrimidine core unit to
interesting biological properties; batzelladine alkaloids have been
found to be potent HIV gp-120-CD4 inhibitors. Recently, dehydro
pyrimidinones have been considered as a new lead for the devel-
opment of new anticancer drugs [1e3].
In recent years, imidazolium functionalized 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 recy-
clability. Their non-volatile character and thermal stability makes
the metal complexes potentially attractive alternatives to envi-
ronmentally unfavorable organic co-solvents, notably chlorinated
hydrocarbons. They are particularly promising as solvents for the
immobilization of transition metal catalysts, Lewis acids and
enzymes [4,5].
reaction could be performed at higher rate and selectivity under the
action of some more elementary organic molecules [6]. These contain
amino acid derivatives, other natural amino acid, and small peptide
derivatives as well as some other small chiral molecules used as
catalysts which allow the synthesis of complex poly functional
compounds of high enantiomeric purity from simple achiral precur-
sors. Althoughthenaturalaminoacidfunctionalizedmetalcomplexes
are cheap, recycling of organocatalysts can be an issue if one thinks in
terms of large scale production or of green chemistry.
During the last two years, copper complex has been used for
several organic transformations such as the epoxidation of styrene
[7e10], oxidation of alcohol and alkane [11e16], asymmetric
synthesis [17e19], amination [20,21] and also for the Suzuki cross-
coupling [22e24] reactions. Recently, Chengjian Zhu and co-
workers have reported the highly enantioselective Biginelli reac-
tion using a new chiral ytterbium catalyst: asymmetric synthesis of
dihydropyrimidines [25]. However, Liu-Zhu Gong et al., was
described the highly enantioselective organocatalytic Biginelli
reaction [26]. Zhiwei Miao [27] and Shi-Wei Luo et al. [28], orga-
nocatalyst modified by 3,30-disubstituents of phosphoric acids or
chiral bifunctional primary amineethiourea catalysts: for enantio-
selective Biginelli reaction in the presence of organic co-solvent.
Furthermore; Li-Wen Xu et al., was achieved the high enantiose-
lective in presence of NbCl5/primary amine [29].
* Corresponding author. Tel.: þ91 9047289073; fax: þ91 416 22404119.
E-mail address: drprbhagat111@gmail.com (P.R. Bhagat).
0022-328X/$ e see front matter Ó 2012 Published by Elsevier B.V.
http://dx.doi.org/10.1016/j.jorganchem.2012.06.022

P. Karthikeyan et al. / Journal of Organometallic Chemistry 723 (2013) 154e162
155
Over all the methods provide good yield, but some have draw-
backs such as lengthy work-up procedure, harsh reaction condi-
tions (organic co-solvents) and require absolutely dry and inert
media. From these literature no report was found for enantiose-
lective Biginelli reaction catalyzed by 1-glycyl-3-methyl imidazo-
lium chloride-copper(II) complex (Fig. 1). Hence, we felt it would be
keen interest to investigate the alternative method for the
synthesis of high enantioselective Biginelli reaction. In this regard,
we have developed an easy and selective synthetic route, expand an
operationally simple, safe and widely usable 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 [30] by
covalent linking of organocatalytic unit with an ionic liquid moiety
(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 [31e35]. This
strategy was also applied to Biginelli reaction providing high yield
and enantioselective and good recyclability of the organocatalyst.
The objectives of the present study are indeed: (i) prepare tetra-
coordinated 1-glycyl-3-methyl imidazolium chloride-copper (II)
complex and to explore its application as catalyst system, (ii)
develop an efficient synthetic process for the facile conversion of
enantioselective Biginelli reaction. The present method developed
for the enantioselective Biginelli reaction offer many advantages
including high conversion, short duration and the involvement of
non-toxic reagents.
in an ice-water bath. Boc (8 mmol) was added and agitation
continued at 25ꢀC for 30 to 45 min. The resulting solution was
concentrated in vacuo, cooled in an ice-water bath, covered with
a layer of ethyl acetate (15 mL). Then, the reaction mixture was
acidified to pH 2e3 using KHSO4. The aqueous phase was extracted
with ethyl acetate (3 ꢁ 10 mL). The ethyl acetate layer washed with
water, dried over anhydrous Na2SO4 and evaporated in vacuo. The
residue was recrystallized using ethanol [36,37].
2.2.2. Protection of acid group using methyl ester
Boc-glycine (10 mmol) was suspended in 2, 2-di methoxypropane
(DMP) (50 mL) and concentrated HCl (5 mL) was added. The mixture
was allowed to stand at 25ꢀC over night. The volatile reactant was
removedinvacuo at 60 ꢀC, the residuedissolved ina minimum amount
of dry methanol and the solution diluted with dry ether (50 mL). The
crystalline methyl esterhydrochloridewas collected on a filter, washed
with ether and dried in vacuo over NaOH. Recrystallization from
methanoleether (9:1 mL) affords the analytically pure ester [38].
2.2.3. Chlorination of protected glycine
In 100 mL RB, Thionyl chloride (6 mmol) was added and cooled
in an ice-water bath. The protected glycine (4 mmol) was dissolved
in ethanol and added to RB drop wise at (0 ꢀC) and stirred at 25ꢀC
for 48 h. The resulting solution was concentrated under vacuo,
cooled in an ice-water bath to get the desired precipitate. Recrys-
tallization of the product using ethanoleether affords the analyti-
cally pure chloroglycine.
2.2.4. Removal of protecting group using hydrobromic acid in acetic
acid
2. Experimental
An about 33% (10 mL) solution of HBr in acetic acid is placed in
a 100 mL RB flask and protected chloroglycine (4 mmol) was added
with stirring. The flask was closed with a cotton filled drying tube
and swirled to effect complete dissolution of the protected chlor-
oglycine. The deprotection occurred with evolution of CO2 and heat.
When the gas evolution ceases, dry ether (50 mL) was added with
swirling and the reaction mixture was stored in an ice-bath. The
precipitated chloroglycine ester was collected on a filter, washed
with ether and dried over NaOH in vacuo.
2.1. Materials and methods
All solvents and chemicals were commerciallyavailable and used
without further purification unless otherwise stated. The [Gmim]
CleCu(II) 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 filtered CueK 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) spectrometer. FT-IR spectra were
recorded on an AVATRA 330 Spectrometer with DTGS detector.
Column chromatography was performed on silica gel (200e300
mesh). Analytical thin-layer chromatography (TLC) was carried out
on precoated silica gel GF-254 plates. AFM and SEM were recorded
on (Nano Surf Easy Scan-2 Switzerland), (Carl Zeiss EVO MA
15(model)) respectively. Analytical high performance liquid chro-
matography (HPLC) was carried out on Agilent 1200 instrument
using Chiralpak OJ-H (4.6 mm ꢁ 250 mm), optical rotations were
Furthermore, a solution chloroglycine ester (4 mmol) in meth-
anol (10 mL) was surrounded by water bath at ambient temperature
and NaOH (20 mL) was added with stirring. The mixture was stored
at 25 ꢀC for overnight. Dilute HCl (10 mL) was added and methanol
removed in vacuo. The aqueous solution was cooled in ice-water for
2 h. Chloroglycine was collected on a filter, washed with ether and
dried in air [39e42]. 1H NMR (500 MHz, DMSO-d6):
d 5.28 (s, 2H),
5.49 (s, 2H),10.83 (s,1H). HR-MS (EI): C2H4ClNO2 (found: 108.92), cal
(108.99). Micro analytical data: Cal (C: 21.94; N: 12.79; H: 3.68),
25
found: (C: 21.90; N: 12.76; H: 3.64). [
a
]
¼ þ152.77 (c 1, MeOH).
D
measured on a JASCO P-1010 Polarimeter at
l
¼ 589 nm.
2.2.5. Synthesis of 1-glycyl-3-methyl imidazolium chloride
[Gmim]Cl
Initially, chloroglycine (0.01 mol) reacted with N-Methyl-
imidazole (0.011 mol) in 50 mL acetonitrile at 70 ꢀC for 24 h to
generate chloroglycine ligand modified by imidazole salt (3-(ami-
2.2. Preparation of [Gmim]CleCu(II) complex
2.2.1. Protection of amino group using di. tert Butyl pyrocarbonate
(Boc)
A solution of the glycine (10 mmol) in a mixture of dioxane
(10 mL), water (5 mL) and 0.5 N NaOH (5 mL) was stirred and cooled
no(carboxy)methyl)-1-methyl-1H-imidazol-3-ium
chloride)
[Gmim]Cl. The solvent (acetonitrile) was removed under reduced
pressure at 80 ꢀC (water bath temperature). Then the residue was
mixed with 50 mL water and extracted with ethyl acetate
(3 ꢁ 5 mL). Further, the water phase was evaporated under reduced
pressure at 80 ꢀC until the mass of the residue did not change. 1H
NMR (500 MHz, DMSO-d6): d 2.2 (s, 1H), 3.3 (s, 3H), 5.0 (s, 2H), 6.92
(d, 1H), 7.0 (d, 1H), 7.6 (s, 1H), 9.1 (s, 1H). HR-MS (EI): C6H10ClN3O2
(found: 191.10), cal (191.05). FT-IR (KBr, cmꢂ1): 3429, 3372, 2933,
25
Fig. 1. 1-glycyl-3-methyl imidazolium chloride-Copper (II) complex [Gmim]CleCu (II).
2855, 1628, 1526 and 1382. [
a
]
¼ þ47.12 (c 1, MeOH).
D

156
P. Karthikeyan et al. / Journal of Organometallic Chemistry 723 (2013) 154e162
Table 1
Table 3
Effect of the base on asymmetric Biginelli reactiona.
Effect of the various catalysts on asymmetric Biginelli reactiona.
Entry
Base
Time (h)
Yieldb (%)
eec
Entry
Catalyst
-glycine
Chloroglycine [Cl-gly]
[Cemim] Br
Time (h)
Yieldb
eec
1
2
3
4
5
6
7
8
K2CO3
KOH
NaOH
Py
Imidazole
Et3N
e
24
24
24
24
24
24
24
12
9
Trace
40
37
41
58
60
94
95
92
90
85
82
Trace
60
70
67
70
75
98
98
98
92
90
88
1
2
3
4
5
6
7
8
9
L
24
24
24
24
24
24
24
12
13
Trace
35
42
44
60
71
75
96
97
Trace
40
48
50
52
65
70
98
98
[Aemim] Br
CuCl2/[Cemim] Br
CuCl2/[Aemim] Br
CuCl2/[Gmim]Cl
[Gmim]CleCu (II)
[Gmim]CleCu (II)d
e
9
e
10
11
12
e
6
3
1
a
Reaction condition: 4-metoxy benzaldehyde (1.0 mmol), ethyl acetoacetate
(1.0 mmol), urea (1.2 mmol) and [Gmim]CleCu (II) complex (0.01 mmol%) stirring at
25 ꢀC for 12 h.
e
e
a
b
Reaction condition: 4-metoxy benzaldehyde (1.0 mmol), ethyl acetoacetate
(1.0 mmol), urea (1.2 mmol) and [Gmim]CleCu (II) complex (0.01 mmol%) stirring at
25 ꢀC for 12 h.
Isolated yield by flash chromatography.
Determined by chiral HPLC analysis (OJ-H).
Reaction time 13 h.
c
d
b
Isolated yield by flash chromatography.
Determined by chiral HPLC analysis (OJ-H).
c
extracted as stated in the preceding general method. The pale blue
solid [Gmim]CleCu(II) was isolated by centrifugation. The recovered
complex was washed with diethyl ether and dried in air. The resulting
catalyst was charged to another batch of the similar reaction. This was
repeated for seven runs to complete the reaction in 12 h, to give the
desired product with 98e90% with enantioselectivities (Table 6).
2.2.6. Synthesis of 1-glycyl-3-methyl imidazolium chloride-
Copper(II) complex [Gmim]CleCu(II)
In RB, [Gmim]Cl (0.02 mmol) was treated with CuCl2
(0.01 mmol) in 100 mL methanol at 50 ꢀC for 12 h to deliver the
[Gmim]Cl modified by copper complex [Gmim]CleCu(II). The
solvent (methanol) was removed under reduced pressure at 80 ꢀC
(water bath temperature). Finally, pale blue solid [Gmim]CleCu(II)
4. Results and discussion
25
complex was obtained in 96% [42] [
a]
¼ þ45.44 (c 1, MeOH).
D
4.1. Characterization copper complex
3. General procedure for Biginelli reaction
[Gmim]CleCu(II) catalyst has been characterized by FT-IR, XRD,
SEM and AFM.
A mixture of substituted aldehyde (1.0 mmol), ethyl acetoace-
tate (1.0 mmol), urea (1.2 mmol) and [Gmim]CleCu(II) complex
(0.01 mmol%) was added to a 50 mL round-bottomed flask and
stirred at 25 ꢀC for the appropriate time (see Table 5) (The reaction
was monitored by TLC, until the aldehyde was disappeared). The
product was extracted with diethyl ether (3 ꢁ 5 mL) and dried over
MgSO4 and evaporated under reduced pressure. The resulting
crude was purified by flash chromatography to give the desired
pure product with excellent enantioselectivities.
4.1.1. FT-IR analysis
Compounds
CeN
C]O
CueO
CueN
OeH
NeH
[Gmim]CleCu (II)
[Gmim]Cl
Chloroglycine
1394 s
1382 s
1392 s
1723 s
1626 s
1625 s
521 m
e
407 m
e
e
3342 m
3372 m
3335 m
3429 s
3378 s
e
e
3.1. Recycling of the catalyst for model reaction using [Gmim]Cle
Cu(II) under solvent free condition
FT-IR spectra of [Gmim]CleCu(II) at different dissociation
degrees are shown in Fig. 2. For carboxylate ion, the absorption
band at 1723 cmꢂ1 corresponds to carbonyl symmetric stretching.
The asymmetric stretching of carboxylate was shifted to 1626 cmꢂ1
[Gmim]Cl in contrast with the shift to 1625 cmꢂ1 in chloroglycine,
which appeared when [Gmim]Cl was treated with CuCl2 and thus
the carbonyl stretching was decreased.
4-metoxy benzaldehyde (1.0 mmol), ethyl acetoacetate (1.0 mmol),
urea (1.2 mmol) and [Gmim]CleCu(II) complex (0.01 mmol%) stirring
at 25ꢀC. After completion of the reaction (TLC), the product was
Table 2
Optimization of solvent for the asymmetric Biginelli reactiona.
Entry
Solvent
Temp (ꢀC)
Time (h)
Yieldb (%)
eec
1
2
3
4
5
6
7
8
DCM
CHCl3
THF
1,4-dioxane
Ethanol
CH3CN
DMF
PhMe
Solvent free
Solvent free
Solvent free
Water (5 ml)
35
50
50
85
65
60
130
90
25
20
35
90
24
24
24
24
24
24
24
24
12
12
12
24
38
43
40
50
53
50
60
63
95
95
93
40
50
54
47
60
63
54
60
57
98
97
98
65
Table 4
Effect of the catalyst loading on asymmetric Biginelli reactiona.
Entry
[Gmim]CleCu (II) mmol%
Time (h)
Yieldb
eec
1
2
3
4
5
6
7
8
e
24
12
12
12
12
12
12
12
Trace
96
96
96
95
96
90
84
Trace
98
98
98
98
98
96
90
0.1
0.075
0.050
0.025
0.01
0.0075
0.005
9
10
11
12
a
a
Reaction condition: 4-metoxy benzaldehyde (1.0 mmol), ethyl acetoacetate
(1.0 mmol), urea (1.2 mmol) and [Gmim]CleCu (II) complex (0.01 mmol%) stirring at
25 ꢀC for 12 h.
Reaction condition: 4-metoxy benzaldehyde (1.0 mmol), ethyl acetoacetate
(1.0 mmol), urea (1.2 mmol) and [Gmim]CleCu (II) complex (0.01 mmol%) stirring at
25 ꢀC for 12 h.
b
b
Isolated yield by flash chromatography.
Determined by chiral HPLC analysis (OJ-H).
Isolated yield by flash chromatography.
Determined by chiral HPLC analysis (OJ-H).
c
c

P. Karthikeyan et al. / Journal of Organometallic Chemistry 723 (2013) 154e162
157
Table 5
Asymmetric Biginelli reaction of different aldehyde in the presence [Gmim]CleCu (II) under solvent free conditiona.
S. No
Reactant
Product
Time (h)
Yieldb (%)
eec (%)
1
12
94
97
2a,d
12
96
98
3
14
95
98
4
14
90
93
5
14
90
92
6
18
82
92
(continued on next page)

158
P. Karthikeyan et al. / Journal of Organometallic Chemistry 723 (2013) 154e162
Table 5 (continued )
S. No
Reactant
Product
Time (h)
Yieldb (%)
eec (%)
7
20
80
90
a
Reaction condition: Substituted aldehyde (1.0 mmol), ethyl acetoacetate (1.0 mmol), urea (1.2 mmol) and [Gmim]CleCu (II) complex (0.01 mmol%) stirring at 25 ꢀC for
12 h.
b
c
Isolated yield by flash chromatography.
Determined by chiral HPLC analysis (OJ-H) and comparison of the retention times with literature data [25e29].
Reaction condition: 4-metoxy benzaldehyde (10.0 mol), ethyl acetoacetate (10.0 mol), urea (12.0 mol) and [Gmim]CleCu (II) complex (0.01 mmol%) stirring at 25 ꢀC
d
for 12 h.
However, the plane of CeOH at 3378, 3429 cmꢂ1 was present in
image for 1-glycyl-3-methyl imidazolium chloride was present
10.2
m2 size of the particles. It can be seen that the surface was
chloroglycine, [Gmim]Cl respectively, but when the network were
treated with CuCl2 no signal was observed for the eOH group,
indicates the formation of CueO (521 cmꢂ1) bond. Although, the
NH2 signal in chloroglycine, [Gmim]Cl was detected at 3335,
3372 cmꢂ1 with doublet, but in the case of [Gmim]CleCu(II), we
also found the doublet at 3342 cmꢂ1, this also shows the formation
of Cu-NH (407 cmꢂ1) bond in the catalyst [43]. In all spectra,
m
very smooth crystalline ligand are notably different, the grain size
and the shape vary significantly (Fig. 5(a)). After doping the CuCl2 to
the [Gmim]Cl, Fig. 5(b) 3D AFM image was obtained. From this
image, the larger scan size also emphasizes the differences between
the [Gmim]Cl and [Gmim]CleCu(II). The surface of copper doped
ionic liquid, showed in the rough topography that confirmed the
stretching of CeN was observed at 1394, 1382 and 1392 cmꢂ1
,
formation of film with copper complex in the size of 3.92 m
m2.
respectively. Notably, the FT-IR spectra revealed that a series of new
copper complex with ionisable groups had been synthesized.
The copper complex catalyzed Biginelli reaction was carried out
using 4-metoxy benzaldehyde, ethyl acetoacetate and urea as
a model reaction to investigate different parameters, such as effect
of solvent, diverse bases, catalysts and concentration of the catalyst.
Initially, the influence of different bases to the model reaction was
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 preferred for the reaction, although organic and
inorganic bases can be used. This may be due to the blocking of free
coordination sites on the copper center. Although, the effect of the
base in the Biginelli reaction is still imperfectly understood and
many recent works were concern on this subject. Recently, Ruyu
Chen have studied the role of the base in the Biginelli reaction using
chiral bifunctional primary amine-thiourea catalysts (enamine
intermediate) and concluded that the oxidative addition step
(when performed from substituted aldehyde) becomes slower and
the carbanion step turn into faster in the absence of the base [27].
Furthermore, we have screened several solvents for the reaction
between 4-metoxy benzaldehyde, ethyl acetoacetate and urea
(Table 2). According to publications from Chengjian Zhu [25] and
co-workers and Liu-Zhu Gong [26] polar, aprotic solvents tend to
give the best results for the asymmetric Biginelli reaction, while
Shi-Wei Luo [28] obtained high-activity catalysts in Toluene
solvent. We employed several solvents in the 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 Cu(II) catalyst. It has also been reported
that H2O molecule is required in some cases to activate the Cu(II)
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.
4.1.2. Powder XRD analysis
The formation of the Cu(II) catalyst was also supported by the
XRD patterns with those of chloroglycine, CuCl2, Cu(II) complex. In
comparison with chloroglycine, CuCl2 and Cu(II) complex which
showed major peaks respectively at 16.37, 31.42 and 45.82 (con-
firming copper peak with JCPDS data care no: 99-100-1542 for
Cu(II), the [Gmim]CleCu(II) pattern was in good agreement with
peak at 31.42 (Fig. 3).
4.1.3. SEM analysis
The SEM image of the catalyst is shown in Fig. 4. From this image
it is clear that [Gmim] CleCu(II) has nano sphere like morphology
with particles of dimensions ca. 250e300 nm and these are
distributed uniformly throughout the material.
4.1.4. AFM analysis
The 3D AFM images of the 1-glycyl-3-methyl imidazolium
chloride and [Gmim]CleCu(II) complex is shown in Fig. 5. The 3D
Table 6
Recycling of the catalysta.
Entry
Run
Yieldb (%)
eec
1
2
3
4
5
6
7
0
1
2
3
4
5
6
96
95
94
94
93
93
92
98
96
95
95
95
92
92
a
Reaction condition: 4-metoxy benzaldehyde (1.0 mmol), ethyl acetoacetate
(1.0 mmol), urea (1.2 mmol) and [Gmim]CleCu (II) complex (0.01 mmol%) stirring at
25 ꢀC for 12 h.
Next, in order to optimize the reaction conditions for a partic-
ular catalyst the condensation reaction was executed using
b
Isolated yield by flash chromatography.
Determined by chiral HPLC analysis (OJ-H).
c

P. Karthikeyan et al. / Journal of Organometallic Chemistry 723 (2013) 154e162
159
Fig. 2. FT-IR of (a) chloroglycine (b) 1-glycyl-3-methyl imidazolium chloride [Gmim]Cl (c) 1-glycyl-3-methyl imidazolium chloride-Copper (II) complex [Gmim]CleCu (II).
different catalysts and the results are given in Table 3. When the
reaction was carried out using various catalysts such as -glycine,
reaction was carried out in absence of catalyst at ambient
L
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]CleCu(II), 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 asymmetric Biginelli
reaction was carried out at the molar ratio of 4-metoxy benzalde-
Chloroglycine, 1-carboxy ethyl-3-methyl imidazolium bromide
[Cemim] Br, 1-aminoethyl-3-methyl imidazolium bromide
[Aemim] Br, CuCl2/[Cemim] Br, CuCl2/[Aemim] Br and CuCl2/
[Gmim]Cl in absence of solvent, it gave trace to 70% of enantiose-
lectivities product. However, when the same reaction was con-
ducted with [Gmim]CleCu(II) as a catalyst it gave remarkable yield
of product in short duration. Almost similar yield was obtained
when increasing the duration.
hyde,
ethyl
acetoacetate,
urea
and
[Gmim]CleCu(II)
1:1:1.2:0.01 mmol% under solvent free condition at 25ꢀC.
The catalytic reaction which can be carried out with a small
amount of expensive complexes is the most useful feature of
synthetic reaction involving copper complex. According to litera-
ture, Li-Wen Xu [29] and co-workers obtained good yield in the
asymmetric Biginelli reaction using 10 mol% of air and water stable
Cu(OTf)2 in the presence of 1,4-dioxane. Among the previous
report, increasing the quantity of the catalyst can improve the
reaction yield and shorten reaction time (Table 4). First, Biginelli
In order to test the substrate generality of [Gmim]CleCu(II)
complex catalyzed asymmetric Biginelli reaction, the condensa-
tion of various aldehyde with ethyl acetoacetate and urea were
studied under the optimized conditions. The results are summa-
rized in Table 5. It can be noticed that a wide range of aldehyde can
efficiently contribute in the Biginelli reaction. However, the
Fig. 3. Powder X-ray diffraction patterns of (a) chloroglycine (b) CuCl2 (c) 1-glycyl-3-
methyl imidazolium chloride-copper (II) complex [Gmim] CleCu (II).
Fig. 4. SEM image of [Gmim]CleCu (II).

160
P. Karthikeyan et al. / Journal of Organometallic Chemistry 723 (2013) 154e162
Fig. 6. Powder X-ray diffraction patterns of the [Gmim]CleCu (II)complex a) before
reaction b) After reaction (7th run).
Fig. 5. (a) AFM image of 1-glycyl-3-methyl imidazolium chloride (b) AFM image of 3-
(amino (carboxy) methyl)-1-methyl-1H-imidazol-3-ium chloride supported copper
complex.
accounting for 0.01 mmol% of the initially added amount of Cu.
From those three experimental results, we believe that the no Cu
leaching observed in asymmetric Biginelli reaction, it’s due to
immobilized copper in amino acid functionalized ionic liquid
binding site located on the surface, which acts as a ligand through
metaleligand interaction. The anchoring of Cu species by amino
acid sites supported on ionic liquid minimizes catalyst deteriora-
tion and no metal leaching and therefore allows efficient catalyst
recycling. The copper(II) 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. The possible mecha-
nism for the reaction is shown in Fig. 8(a) (pathway-1). In the
transition state I (TS I), the amino acid moiety of [Gmim]CleCu
catalyst interacts through hydrogen bonding with the acyl group
of benzylidene urea while the neighboring primary amine activates
ethyl acetoacetate involving an enamine intermediate. The ob-
tained absolute configuration of DHPMs was explained by the
transition state I, in which the imine was predominantly
approached by the enamine intermediate generated from ethyl
acetoacetate and the primary amine group of the [Gmim]CleCu
benzaldehyde bearing electron-withdrawing substituents fur-
nished Biginelli reaction with excellent yields (90e96%) and
enantioselectivities (92e98% ee) within 12e14 h. On the other
hand, longer reaction times (18e20 h) were required for aldehyde
containing an electron-donating group to give comparatively
inferior yields (90e92%), without lacking of enantioselectivities.
This can be explained that electron-withdrawing groups improve
the electrophilicity of carbonyl carbons aldehyde, which facilitates
the reaction, while electron-donating groups reduce the electro-
philicity. Moreover, the asymmetric Biginelli reaction of neutral
aldehyde catalyzed by the copper complex also afforded the Bigi-
nelli product with high enantioselectivities and diaster-
eoselectivities. All the condensation reactions of substituted
aldehyde, ethyl acetoacetate, urea and [Gmim]CleCu(II) afford the
subsequent products with excellent yield (80e96%) and enantio-
selectivities (90e98% ee).
Isolation of the heterogeneous catalyst was easily performed by
separation or centrifugation. The isolated catalyst was washed with
ether and dried in air. The regenerated catalyst was used for the
reaction of 4-metoxy benzaldehyde with ethyl acetoacetate and
urea for seven runs to afford ethyl (R)-ethyl 4-(4-methoxy phenyl)-
6-methyl-2-oxo-1, 2, 3, 4-tetra hydropyrimidine-5-carboxylate
with 98-90% enantioselectivities (Table 6).
The [Gmim]CleCu(II) 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. 6 The analysis specifies
that the [Gmim]CleCu(II) do not undergo any chemical and struc-
tural changes, thus proving its surface catalytic activity towards the
condensation reaction of 4-metoxy benzaldehyde with ethyl ace-
toacetate and urea. On the other hand, presence of peaks due to
metallic copper is noted in the powder XRD pattern of the complex
in the case of ‘Cu(II)’ (Fig. 6(aeb)). Moreover, surface & size of that
reused catalyst was captured by AFM. The surface of recycled
copper complex showed in the rough topography evidence and
reduced size of the particle 2.15
m
m2 (Fig. 7).
Furthermore; Cu leaching was also studied by inductively
coupled plasma-atomic emission spectroscopy (ICP-AES) analysis,
indicating that the product mixture contained zero ppm of copper
Fig. 7. AFM image of 3-(amino (carboxy) methyl)-1-methyl-1H-imidazol-3-ium chlo-
ride supported copper complex after 7th run.

P. Karthikeyan et al. / Journal of Organometallic Chemistry 723 (2013) 154e162
161
found: (C: 62.25; N: 9.64; H: 5.87). FT-IR (KBr, cmꢂ1):
1707, 1648, 1593, 1486, 1324, 1274, 1189, 1093, 755, 694.
n
3157, 2996,
a
(Table 5, entry 4): Enantiomeric excess was determined by HPLC
with a Chiralpak (OJ-H) (4.6 mm ꢁ 250 mm) column (n-hexane/i-
PrOH 9/1, 1.0 mL/min,
l
¼ 254 nm, 25 ꢀC): tR ¼ 9.12 min (minor) and
7.53 min (major). 1H NMR (500 MHz, DMSO-d6):
d
1.10 (t, J ¼ 7.2 Hz,
3H), 2.26 (s, 3H), 3.40 (dd, J ¼ 7.2, 6.8 Hz, 2H), 5.15 (d, J ¼ 3.2 Hz,1H),
7.26 (d, J ¼ 8.8 Hz, 2H), 7.40 (d, J ¼ 8.4 Hz, 2H), 7.75 (s, 1H), 9.22 (s,
1H). Micro analytical data: Cal (C: 57.25; N: 9.54; H: 4.80), found:
(C: 57.21; N: 9.50; H: 4.77). FT-IR (KBr, cmꢂ1):
n 3422, 3215, 2980,
2928, 1707, 1652, 1570, 1465, 1194, 1179, 1099, 748.
(Table 5, entry 5): Enantiomeric excess was determined by HPLC
with a Chiralpak (OJ-H) (4.6 mm ꢁ 250 mm) column (n-hexane/i-
PrOH 9/1,1.0 mL/min,
l
¼ 254 nm, 25 ꢀC): tR ¼ 9.60 min (minor) and
7.72 min (major). 1H NMR (500 MHz, DMSO-d6):
d
1.08 (t, J ¼ 7.2 Hz,
3H), 2.25 (s, 3H), 3.99 (q, J ¼ 7.2 Hz, 2H), 5.13 (d, J ¼ 3.2 Hz, 1H), 7.17
(d, J ¼ 8.4 Hz, 2H), 7.53 (d, J ¼ 8.4 Hz, 2H), 9.25 (s, 1H). Micro
analytical data: Cal (C: 49.72; N: 8.28; H: 4.17), found: (C: 49.68; N:
b
8.24; H: 4.13). FT-IR (KBr, cmꢂ1):
1576, 1460, 1193, 1115, 770, 666.
n 3304, 3186, 2981, 2926, 1663,
(Table 5, entry 6): Enantiomeric excess was determined by HPLC
with a Chiralpak (OJ-H) (4.6 mm ꢁ 250 mm) column (n-hexane/i-
PrOH 9/1,1.0 mL/min,
l
¼ 254 nm, 25 ꢀC): tR ¼ 8.82 min (minor) and
7.50 min (major). 1H NMR (500 MHz, DMSO-d6):
d
1.11 (t, J ¼ 7.2 Hz,
3H), 2.25 (d, J ¼ 7.6 Hz, 6H), 3.98 (q, J ¼ 6.8 Hz, 2H), 5.3 (d, J ¼ 3.2 Hz,
1H), 7.10 (s, 4H), 9.13 (s, 1H). Micro analytical data: Cal (C: 65.92; N:
10.25; H: 6.27), found: (C: 65.88; N: 10.10; H: 6.23). FT-IR (KBr,
cmꢂ1):
n 3354, 2987, 1652, 1486, 1570, 1274, 1093, 800, 750.
(Table 5, entry 7): Enantiomeric excess was determined by HPLC
with a Chiralpak (OJ-H) (4.6 mm ꢁ 250 mm) column (n-hexane/i-
PrOH 9/1, 1.0 mL/min,
l
¼ 254 nm, 25 ꢀC): tR ¼ 13.43 min (minor)
and 10.82 min (major). 1H NMR (500 MHz, DMSO-d6):
d 1.14e1.10(t,
J ¼ 7.1 Hz, 3H), 2.04 (s, 3H), 4.14e4.10 (q, J ¼ 7.1 Hz, 2H), 5.20 (s, 1H),
6.50 (s, 1H), 6.72e6.65 (m, 2H), 6.78 (m, 1H), 7.04e6.99 (m, 1H).
Micro analytical data: Cal (C: 60.86; N: 10.14; H: 5.84), found: (C:
60.91; N: 10.11; H: 5.83). FT-IR (KBr, cmꢂ1):
1532, 1382, 1170, 650.
n 3310, 3228,1710,1550,
Fig. 8. (a) Plausible reaction mechanism (pathway-1) (b) Plausible reaction mecha-
nism (pathway-2).
5. Conclusions
catalyst. The attack of the enamine to the benzylidene urea was
restricted by the complex scaffold of the catalyst. The mechanism
indicates that the amino acid moiety and copper scaffold of the
copper catalyst play a significant role in controlling the regio and
diastereoselectivity of the Biginelli reaction. The precise mecha-
nism of the catalytic reaction needs to be elucidated, but it is
noticeable that the mechanism is strongly modified depending of
the copper catalyst employed, obtaining enantioselective 3, 4-
dihydropyrimidin-2(1H)-ones as the main product Fig. 8(b)
(pathway-2).
In conclusion, the results from the investigation demonstrate
that the 1-glycyl-3-methyl imidazolium chloride-copper (II)
complex was efficient catalyst for highly enantioselective asym-
metric Biginelli reaction. The procedure is easy and does not require
special precautions. 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 imidazolium chloride-copper (II) complex; (2) its catalytic
activity was tested in asymmetric Biginelli reaction; (3) 0.01 mmol%
of catalyst was sufficient to furnish the Biginelli products with
excellent yields (up to 96%) and enantioselectivities (up to 98%); (4)
The catalyst can be readily recovered and reused without signifi-
cant loss of its activity and stereoselectivity; Notably, (5) this
organo catalyzed asymmetric Biginelli 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.
(Table 5, entry 1): Enantiomeric excess was determined by HPLC
with a Chiralpak (OJ-H) (4.6 mm ꢁ 250 mm) column (n-hexane/i-
PrOH 9/1, 1.0 mL/min,
l
¼ 254 nm, 25 ꢀC): tR ¼ 7.46 min (minor) and
9.55 min (major). 1H NMR (500 MHz, DMSO-d6):
d
1.11 (t, J ¼ 7.2 Hz,
3H), 2.28 (s, 3H), 3.40 (dd, J ¼ 6.8 Hz, 7.2 Hz, 2H), 5.14 (d, J ¼ 3.2 Hz,
1H), 7.34e7.23 (m, 5H), 7.72 (s, 1H), 9.17 (s, 1H). Micro analytical
data: Cal (C: 64.85; N: 10.80; H: 5.83), found: (C: 64.81; N: 10.75; H:
5.80). FT-IR (KBr, cmꢂ1):
n 3186, 2981, 2926, 1663, 1710, 1474, 830.
(Table 5, entry 2): Enantiomeric excess was determined by HPLC
with a Chiralpak (OJ-H) (4.6 mm ꢁ 250 mm) column (n-hexane/i-
PrOH 9/1, 1.0 mL/min,
l
¼ 254 nm, 25 ꢀC): tR ¼ 13.12 min (minor)
Acknowledgments
and 9.45 min (major). 1H NMR (500 MHz, DMSO-d6):
d 1.11 (t,
J ¼ 7.2 Hz, 3H), 2.53 (s, 3H), 3.72 (s, 3H), 3.99 (q, J ¼ 6.8 Hz, 2H), 5.9
(d, J ¼ 3.2 Hz, 1H), 6.86 (d, J ¼ 8.8 Hz, 3H), 7.15 (d, J ¼ 8.8 Hz, 2H),
9.15 (s, 1H). Micro analytical data: Cal (C: 62.27; N: 9.68; H: 5.92),
We gratefully acknowledge the management of VIT University
for providing required facilities and SAIF (IITM) for providing the
spectral data

162
P. Karthikeyan et al. / Journal of Organometallic Chemistry 723 (2013) 154e162
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