L-proline-catalyzed asymmetric direct aldol reaction of heteroaromatic aldehydes and acetone: Improvement of catalytic efficiency in ionic liquid bmim [BF4]

Article abstract of DOI:10.1080/00397910701575574

L-proline in bmim [BF4] ionic liquid has been successfully used as an efficient and reusable catalyst for the direct asymmetric aldol reaction of acetone with different heteroaromatic aldehydes to afford higher selectivity of the aldol products with good enantioselectivity. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701575574

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L‐Proline‐Catalyzed Asymmetric Direct Aldol
Reaction of Heteroaromatic Aldehydes and
Acetone: Improvement of Catalytic Efficiency
in Ionic Liquid bmim [BF4]
K. Rajender Reddy a , L. Chakrapani a , T. Ramani a & C. V. Rajasekhar a
a Inorganic and Physical Chemistry Division , Indian Institute of Chemical
Technology , Hyderabad, India
Published online: 14 Dec 2007.
To cite this article: K. Rajender Reddy , L. Chakrapani , T. Ramani & C. V. Rajasekhar (2007)
L‐Proline‐Catalyzed Asymmetric Direct Aldol Reaction of Heteroaromatic Aldehydes and Acetone:
Improvement of Catalytic Efficiency in Ionic Liquid bmim [BF4], Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:24, 4301-4307, DOI:
10.1080/00397910701575574
To link to this article: http://dx.doi.org/10.1080/00397910701575574
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Synthetic Communicationsw, 37: 4301–4307, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701575574
L-Proline-Catalyzed Asymmetric Direct
Aldol Reaction of Heteroaromatic Aldehydes
and Acetone: Improvement of Catalytic
Efficiency in Ionic Liquid bmim [BF4]
K. Rajender Reddy, L. Chakrapani, T. Ramani, and
C. V. Rajasekhar
Inorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology, Hyderabad, India
Abstract: L-proline in bmim [BF4] ionic liquid has been successfully used as an
efficient and reusable catalyst for the direct asymmetric aldol reaction of acetone
with different heteroaromatic aldehydes to afford higher selectivity of the aldol
products with good enantioselectivity.
Keywords: asymmetric aldol, enantiomeric excess, heteroaromatic aldehlydes
b-hydroxy carbonyl compounds, ionic liquid, L-proline
INTRODUCTION
The aldol reaction constitutes a fundamental synthetic methodology for
forming carbon–carbon bonds, and nature itself seems to prefer this
reaction in its biosynthetic processes, for example, in the prebiotic
formation of saccharides.[1] Its great synthetic utility in organic synthesis
has promoted a rapid development of numerous highly enantioselective
catalysts.[2] Synthetic methodologies involving both aldolase and catalytic
antibodies have been extensively developed for accomplishing aldol
reactions with high efficiency and selectivity.[3]
Received in India May 9, 2007
Address correspondence to K. Rajender Reddy, Inorganic and Physical Chemistry
Division, Indian Institute of Chemical Technology, Hyderabad, India. E-mail:
rajender@iict.res.in or rajenderkallu@yahoo.com
4301

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K. R. Reddy et al.
Pioneered by List, Barbas, and their coworkers, L-proline has been a very
popular organocatalyst for aldol and other reactions involving an enamine
intermediate in their transition state.[4] However, the reactivity and selectivity
of some of these proline-catalyzed aldol reactions have serious limitations
because of the difficulty in modifying the structure of proline. Furthermore,
a substoichiometric amount of proline is often necessary to achieve reasonable
yields in the direct aldol reaction of aldehydes with acetone.
Most of the reported aldol reactions were carried out in polar organic
solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF),
chloroform (CHCl3), tetrahydrofuran (THF), or acetonitrile (CH3CN).
Moreover, proline is known to undergo decarboxylation when it is reacted
with electron-deficient aromatic aldehydes.[5] In the past few years, room-
temperature ionic liquids (RTILs, usually organic onium salts) have been
proposed as environmentally benign alternatives to conventional organic
solvents.[6] These ionic liquids have been used largely as solvents in
organic synthesis, biocatalysis, and electrochemistry separation processes.[7]
Moreover, they are reusable, allow for simple isolation of products, and
enable the easy recovery of catalysts. More interesting is the enhancement
of reaction efficiency by using ionic liquids as solvents.[8] Thus, the employ-
ment of an ionic liquid as the solvent for an atom-economical reaction such as
the asymmetric direct aldol reaction will make the process more environmen-
tally benign and economical. Aldol reactions in the presence of L-proline in
ionic liquids have been documented earlier.[9]
Regarding the aldol reactions with heteroaromatic aldehydes, Chimni
et al. reported the pyrrolidine-catalyzed direct aldol reaction of heteroaromatic
aldehydes with acetone, in which they documented the less catalytic efficiency
of proline compared to pyrrolidine.[10a] Maruoka et al. designed an artificial
amino acid catalyst for the direct asymmetric aldol reaction of heteroaromatic,
olefinic, and aromatic aldehydes, in which decarboxylation was not
observed.[10b]
Herein, we present the L-proline-catalyzed asymmetric direct aldol reaction
of heteroaromatic aldehydes with acetone in ionic liquids, which leads to a
remarkable improvement of the reaction in comparison to organic solvents. To
the best of our knowledge, this is the first demonstration of asymmetric direct
aldol reaction of heteroaromatic aldehydes and acetone in ionic liquids.
RESULTS AND DISCUSSION
We initially screened the reaction of acetone with substituted pyridine
aldehydes in different solvents at room temperature (Table 1). In general,
aldol adducts in very low yields with good enantioselectivity are obtained
1
in polar solvents such as DMSO, NMP, and DMF. The H NMR spectra
revealed that part of the proline and the aldehyde under anhydrous conditions
condensed to form a bicyclic oxazolidinone.[5] The aldol reaction is very clean

L-Proline-Catalyzed Asymmetric Direct Aldol Reaction
4303
Table 1. Direct catalytic asymmetric aldol reaction of acetone with different hetero-
aromatic aldehydes in different solventsa
Entry
Aldehyde
Solvent
Time (h)
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1c
1c
1c
DMSO
NMP
H2O
24
24
12
24
24
36
24
24
12
,10
,10
84
70
70
18
68
73
10
55
46
0
DMSO
NMP
H2O
,10
,10
42
DMSO
NMP
H2O
,5
,10
59
aAll reactions were carried out with 20 mol% catalyst, aldehyde (1 mmol), acetone
(1 mL), and solvent (2 mL).
1
bYields based on H NMR.
cThe ee is determined by chiral HPLC using Diacel Chiralpak AS-H, OJ-H.
in water as the solvent (Table 1, entries 3, 6, and 9) but has poor enantioselec-
tivity. This could be because of the hydrolysis of oxazolidinone in water. To
improve the rate as well as the enantioselectivity, a mixed-solvent system with
different mol% of water in DMSO was screened for pyridine-2-carbox-
aldehyde reaction (Table 2). An acceleration in the rate of aldol reaction is
observed as the percentage of water content is increased but at the expense
of enantioselectivity.
Based on the enhancement of the rate of reaction in polar solvents such as
water, we made an attempt to observe the reactivity in room-temperature ionic
Table 2. Effect of water on proline-catalyzed direct asymmetric aldol reaction of
acetone with pyridine-2-carboxaldehyde at room temperaturea
Entry
Solvent
H2O (vol%)
Yieldb (%)
Eec (%)
1
2
3
4
5
DMSO
DMSO
DMSO
DMSO
—
0
5
10
29
37
41
60
55
50
48
5
10
50
100
0
aAll reactions were carried out with 20 mol% catalyst, aldehyde (1 mmol), acetone
(1 mL), and solvent (2 mL).
1
bYields based on H NMR.
cThe ee is determined by chiral HPLC with Diacel Chiralpak AS-H, OJ-H.

4304
K. R. Reddy et al.
liquids (RTILs, usually organic onium salts). In the presence of 20 mol% of
L-proline, the direct aldol reaction of acetone with pyridine-4-carboxaldehyde
was examined in ionic liquid ([bmim] [BF4]). Surprisingly, the reactions in
ionic liquids are very clean and much faster than those in DMSO and NMP.
The enantioselectivities are also retained. Moreover, oxazolidinone, which
was the major adduct in the case of proline-catalyzed direct aldol reactions,
is not observed. The improved catalytic performance in ionic liquid might
be due to the stabilization of the imminium intermediate formed from the
ketones and the secondary amine of the proline or because of the enhanced
nucleophilicity of the enamine. Further, we have done the aldol reaction of
other pyridine aldehydes in [bmim][BF4], which resulted in higher yields
compared to the organic solvents (Table 3).
The possibility of recycling the catalyst was finally examined by
employing the direct aldol reaction of pyridine-4-carboxaldehyde with
acetone in [bmim] [BF4]. The data shown in Table 4 illustrate that the
catalyst can be reused at least three times without sacrificing the yield and
enantioselectivity.
EXPERIMENTAL
General
The heteroaromatic aldehydes and proline were purchased from Aldrich and
used without further purification. Acetone and other solvents were
purchased from S. D. Fine Chemicals, India. ACME silica gel (100–200
mesh) was used for column chromatography, and thin-layer chromatography
(TLC) was performed on Merck precoated silica-gel 60-F254 plates. All the
other solvents and chemicals were obtained from commercial sources and
purified using standard methods.
Table 3. Direct asymmetric aldol reaction of acetone with heteroaromatic aldehydes
in bmim [BF4]a
Entry
R-CHO
Time (h)
Yieldb (%)
Eec (%)
1
2
3
2-pyridyl
3-pyridyl
4-pyridyl
12
6
50
95
98
56
74
70
6
aAll reactions were carried out with 20 mol% catalyst, aldehyde (1 mmol), acetone
(1 mL), bmim[BF4] (1 mL).
1
bYields based on H NMR.
cThe ee is determined by chiral HPLC using Diacel Chiralpak AS-H, OJ-H.

L-Proline-Catalyzed Asymmetric Direct Aldol Reaction
4305
Table 4. Studies on catalyst recyclinga
Entry
Cycle
Yieldb (%)
Eec (%)
1
2
3
4
98
98
98
96
70
70
70
68
1
2
3
aA reaction mixture of pyridine-4-carboxaldehyde (1 mmol) and acetone (1 mL)
catalyzed by 20 mol% L-proline in ionic liquid (1 mL) at room temperature.
1
bYields based on H NMR.
cDetermined by HPLC using Diacel Chiralpak AS-H.
Preparation of bmim [BF4] Ionic Liquid
The RTIL bmim [BF4] was synthesized according to the general procedure
reported in the literature.[9]
General Reaction Procedure and Reusability Protocol for
Asymmetric Aldol Reaction
To a dry 25-mL, round-bottomed flask charged with L-proline (0.20 mmol,
23 mg), bmim-BF4 (1 mL) was added, followed by acetone (1 mL) and
aldehyde (1 mmol, 0.1 mL) at room temperature. The reaction mixture was
stirred for 6 h before extraction with ether (4 ꢀ 10 mL). The combined
ether layers were concentrated in vacuum to give the pure aldol addition
product. The residual ionic liquid containing L-proline was further concen-
trated in vacuum to remove ether or acetone before use.
CONCLUSION
In conclusion, the asymmetric direct aldol reactions of heteroaromatic aldehydes
with acetone in imidazolium-based ionic liquid are investigated. Higher yields
and good ees are obtained under the optimal conditions. Further study
regarding the recycling of the catalyst has revealed that L-proline in an ionic
liquid can be reused with comparable yields and enantioselectivities. The possi-
bilityofcarryingoutasymmetricreactionsusingachiralcatalystinanionicliquid
greatly enhances the synthetic value of ionic liquids as green reaction media.
ACKNOWLEDGMENT
We thank the Council of Scientific and Industrial Research (CSIR) for
financial support under the Task Force Project CMM-0005. L. C. P., T. R.,
and C. V. R. thank the CSIR, India, for research fellowships.

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K. R. Reddy et al.
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