Heteropoly acid in ionic liquid - An efficient and recyclable system for one-pot three-component Mannich reaction

Article abstract of DOI:10.1139/V06-176

This paper describes a one-pot three-component Mannich reaction, catalyzed by phosphotungstic acid (H₃PW₁₂O₄₀), a heteropoly acid in ionic liquid. The catalyst was found to be mild and efficient, and the protocol affords β-arnino ketones in good yields under ambient conditions. Several ionic liquids and conventional organic solvents were employed for the reaction. The ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF₄) offered the best results in terms of yield of the products. It was observed that a Homogeneous reaction medium proved beneficial for the yield of the reaction.

Full text of DOI:10.1139/V06-176

Pagination not final/Pagination non finale
1
COMMUNICATION / COMMUNICATION
Heteropoly acid in ionic liquid — An efficient and
recyclable system for one-pot three-component
Mannich reaction
Meghana S. Rasalkar, Sachin V. Bhilare, Amol R. Deorukhkar, Nitin B. Darvatkar,
and Manikrao M. Salunkhe
Abstract: This paper describes a one-pot three-component Mannich reaction, catalyzed by phosphotungstic acid
(H3PW12O40), a heteropoly acid in ionic liquid. The catalyst was found to be mild and efficient, and the protocol af-
fords β-amino ketones in good yields under ambient conditions. Several ionic liquids and conventional organic solvents
were employed for the reaction. The ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4) offered
the best results in terms of yield of the products. It was observed that a homogeneous reaction medium proved benefi-
cial for the yield of the reaction.
Key words: Mannich reaction, β-amino ketones, phosphotungstic acid, ionic liquid, recyclability.
Résumé : Dans ce travail on a réalisé une réaction de Mannich monotope à trois composants, catalysée par l’acide
phosphotungstique (H3PW12O40), un hétéropolyacide, dans un milieu ionique. On a trouvé que ce catalyseur est doux et
efficace et que la méthode conduit à la formation de $-aminocétones avec de bons rendements, en opérant dans des
conditions ambiantes. Pour réaliser cette réaction, on a utilisé plusieurs liquides ioniques ainsi que plusieurs solvants
organiques conventionnels. Le liquide ionique du nom de tétrafluoroborate de 1-butyl-3-méthylimidazolium
([bmim]BF4) est celui qui donne les meilleurs résultats en terme de rendement des produis. On a observé que le milieu
réactionnel homogène s’avère utile pour le rendement de la réaction.
Mots-clés : réaction de Mannich, β-aminocétones, acide phosphotungstique, liquide ionique, possibilité de recycler.
[Traduit par la Rédaction] Rasalkar et al.
4
Introduction
ports involve the use of HCl in H2O–SDS and HBF4 in
organic solvent – H2O systems (16, 17).
The Mannich reaction is very useful in the preparation of
nitrogen-containing compounds (1–4). The reaction essen-
tially proceeds via the condensation of an amine, an alde-
hyde, and a ketone to form β-amino carbonyl compounds.
These compounds are very important biologically active
molecules. Novel modifications of the Mannich reaction
have been attempted by other researchers (5–10).2 Some
groups have reported the reaction of silyl enol ethers with
imines in the presence of Lewis acids (11–13). Lanthanide
triflates are quite attractive catalysts for Mannich reaction
because of their high catalytic activity and low toxicity (14,
15). However, their high cost restricts their use. Other re-
Recently, the research in the field of heterogeneous catal-
ysis has experienced considerable growth. Heteropoly acids
(HPAs) are polyoxometalate inorganic cage structures be-
longing to a promising class of solid acid catalysts. They
may adopt the Keggin form (18) with the general formula
H3MX12O40, where M is the central atom and X is the
heteroatom. Typically, M can be either phosphorous (P) or
silicon (Si) and X can be tungsten (W) or molybdenum (Mo).
HPAs have an enormous potential in catalyzing various types
of synthetic organic transformations, which has not yet been
fully realized. The low cost, availability, and environment-
friendly nature make them suitable candidates for replacing
Received 13 September 2006. Accepted 20 November 2006. Published on the NRC Research Press Web site at
http://canjchem.nrc.ca on 5 January 2007.
M.S. Rasalkar, S.V. Bhilare, A.R. Deorukhkar, N.B. Darvatkar, and M.M. Salunkhe.1 Department of Chemistry, The Institute
of Science, 15 Madam Cama Road, Mumbai 400 032, India.
1Corresponding author (e-mail: mmsalunkhe@hotmail.com).
2During the preparation of this manuscript, a one-pot three-component Mannich reaction, employing heteropoly acids in water, was
reported; see ref. 10.
Can. J. Chem. 85: 1–4 (2007)
doi:10.1139/V06-176
© 2007 NRC Canada

Pagination not final/Pagination non finale
2
Can. J. Chem. Vol. 85, 2007
Scheme 1. One-pot three-component Mannich reaction catalyzed
by a heteropoly acid.
hazardous and expensive catalysts. HPAs are Brönsted ac-
ids, composed of heteropoly anions, with protons as the
counter cations. They are more efficient than many conven-
tional solid acid catalysts, such as mixed oxides, zeolites,
and so forth. Some reactions, e.g., Friedel–Crafts acylation
(19) and Fries rearrangement (20), are catalyzed by HPAs.
The HPA catalysts are easily separated from the reaction
mixture and recycled. The chemistry and general physical
properties of these catalysts have been extensively discussed
in a number of review articles (21, 22).
OMe
OMe
O
O
HN
O
10 mol% HPA
+
R1
+
H
R2
R1
R2
Org. solvent/
ionic liquid
R3
R3
NH2
3
1
2
R1 = aryl
R3
=
alkyl or H
In the past decade, a new approach has been adopted for
catalyst separation and recycling in catalytic reactions in-
volving the use of room-temperature ionic liquids, especially
those based upon 1-n-alkyl imidazolium cation. Ionic liq-
uids, also called “the designer solvents”, have been largely
successful in replacing obnoxious organic solvents. Their
high thermal stability and ability to solvate various sub-
strates have made them highly useful in a variety of organic
reactions (23, 24). Amongst other reports, an asymmetric
version of the Mannich reaction, employing L-proline in
ionic liquids, demonstrated by Barbas et al. (25) is worth
mentioning (26–28). For the past few years, our group has
been actively involved in exploring the field of ionic liquids
(29–31) and has investigated various aspects of the different
reactions using ionic liquid as solvents.
Realizing the growing significance of the use of heteroge-
neous solid acids as recyclable catalysts in organic synthesis,
we describe here, for the first time, the use of a heteropoly
acid in conjunction with an ionic liquid for a one-pot three-
component Mannich reaction (Scheme 1). Our technique
combines and maximizes the individual advantages of using
heteropoly acids and ionic liquids in organic syntheses while
satisfying the basic principles of green chemistry.
R2 = alkyl
Table 1. Comparison of different heteropoly acids (HPAs) em-
ployed for Mannich reaction between p-anisidine, benzaldehyde,
and acetone in [bmim]BF4 at room temperature.
Heteropoly acida
Time (h)
Yieldb (%)
H3PW12O40
H4SiW12O40
H3PMo12O40
18
18
18
70
61
45
a5 mol% of the HPA was used.
bIsolated yields.
These HPAs vary in their acidity, and hence, it was ex-
pected that this would affect the outcome of the reaction in
terms of the yield. Studies have proven that PW12 is the
strongest and most active heteropoly acid (32). It was ob-
served that the yield of the reaction was directly related to
the acid strength of the catalyst, as the yield for the various
catalysts decreased in the order of PW12 > SiW12 > PMo12.
Hence, the best yield of the product of the reaction, i.e., 4-
(4-methoxyphenylamino)-4-phenylbutan-2-one (70%), was
obtained in 18 h with the strongest of the three heteropoly
acids, i.e., phosphotungstic acid (PW12). Considering PW12
as the superior heteropoly acid for the present study, we em-
ployed it in further investigations. The results are presented
in Table 1.
Results and discussion
Because it is more efficient to perform a direct Mannich
reaction, which eliminates a separate step for imine prepara-
tion prior to the reaction, a one-pot reaction between
benzaldehyde, p-anisidine, and acetone with heteropoly acid
as the catalyst was carried out as a prototype. Initially, we
chose a hydrophilic ionic liquid 1-butyl-3-methylimidazo-
lium tetrafluoroborate ([bmim]BF4) for the reaction. A simple
procedure was used to carry out the Mannich reaction,
wherein all the substrates, namely, an amine (1 mmol), HPA,
an aldehyde (1 mmol), and a ketone (in excess) were mixed
with the ionic liquid, respectively. To begin with, we decided
to screen various heteropoly acids for the model reaction.
We employed three different heteropoly acids, namely,
phosphotungstic acid (H3PW12O40) (PW12), tungstosilicic
acid (H4SiW12O40) (SiW12), and phosphomolybdic acid
(H3PMo12O40) (PMo12) for the reaction. All the HPAs com-
pletely dissolved in the ionic liquid. 5 mol% of each of these
HPAs were used. The reaction mixture was stirred at room
temperature.
The amount of catalyst was optimized to improve the
yields. The yield was quite low (~40%) when phosphotung-
stic acid was used in low concentrations (1 mol%). Marked
improvement in yields (88%) and reduced reaction times
(12 h) were observed when the catalyst loading was in-
creased to 10 mol%.
We carried out the reaction in various other hydrophilic as
well as hydrophobic ionic liquids and conventional organic
solvents to compare the outcome of the reaction in terms of
the yield and the rate of the reaction. HPA dissolved in
organic solvents like DMSO, DMF, and acetonitrile and hy-
drophilic ionic liquids, such as 1-butyl-3-methylimidazolium
chloride ([bmim]Cl) and 1-methoxyethyl-3-methylimidazo-
lium methanesulphonate ([moemim]OMs), to produce a
homogenous system. However, HPA was insoluble in hydro-
phobic ionic liquids, such as 1-butyl-3-methylimidazolium
hexafluorophosphate ([bmim]PF6) and 1-hexyl-3-methyl-
imidazolium tetrafluoroborate ([hmim]BF4), and solvents
like toluene. Better yields were obtained when the catalyst
was soluble in the reaction medium compared with those ob-
tained when the catalyst was insoluble in the reaction sol-
vent. From these observations, it can be deduced that the
solubility of the catalyst in the medium plays an important
The reaction furnished the product 4-(4-methoxyphenyl-
amino)-4-phenylbutan-2-one. However, it was observed that
the substrates completely disappeared after 18 h only with
PW12. In case of other heteropoly acids, TLC showed the
presence of p-anisidine even after prolonged reaction times.
© 2007 NRC Canada

Rasalkar et al.
3
Table 2. Phosphotungstic acid (PW12) catalyzed Mannich reac-
tion involving p-anisidine, benzaldehyde, and acetone in various
solvents.
Table 3. Synthesis of various β-amino ketones via the Mannich
reaction, using phosphotungstic acid and employing different
aldehydes, ketones, and amines in [bmim]BF4.
Entry
Solvent
Time (h)
Yielda (%)
Aldehyde
Ketone
Producta
3
Yieldb
(%)
Entry
1
2
3
1
2
[bmim]BF4
[bmim]PF6
[hmim]BF4
12
12
12
88
62
64
O
NHPMPd
CHO
O
88
1
4
5
6
7
8
[bmim]Cl
[moemim]OMs
DMSO
DMF
Acetonitrile
Toluene
13
15
14
15
15
15
15
80
80
83
65
60
51
55
O
NHPMP
CHO
CHO
78c
O
2
3
O
O
NHPMP
NHPMP
9
10
Dichloromethane
65
Note: 10 mol% of PW12 was used.
aIsolated yields.
O
O
CHO
4
5
73c
56
role in enhancing the outcome of the reaction and that a ho-
mogeneous system produces better yields.
CHO
O
NHPMP
Amongst the various ionic liquids and organic solvents
that were employed for the present study (see Table 2), the
use of [bmim]BF4 and DMSO resulted in good yields. The
rate of the reaction was only slightly better in case of [bmim]BF4
compared with DMSO. However, DMSO is highly obnox-
ious and has a detrimental effect on the environment. Hence,
taking into account the various environmental constraints,
[bmim]BF4 was employed for further investigation.
O
O
O
NHPMP
CHO
NO2
77
6
O2N
CHO
O
NHPMP
O
Having ascertained the efficiency of the protocol for the
model reaction between p-anisidine, acetone, and benzalde-
hyde, we next turned our attention to its synthetic utility in
[bmim]BF4 (Table 3). All the reactions were stirred for 24 h.
At first, we decided to employ various aromatic aldehydes
(1), keeping the ketone (2) and the amine moieties constant.
Substituted benzaldehydes with electron-withdrawing or
electron-donating groups (Table 3, entries 6 and 7) re-
sponded well to the reaction conditions, as the correspond-
ing β-amino ketones (3) were obtained in 77% and 80%
yield, respectively. A heteroaromatic aldehyde, namely,
furfuraldehyde, was also chosen as a substrate, and it fur-
nished the product in 72% yield (Table 3, entry 8). On the
other hand, cinnamaldehyde, as an α,β-unsaturated aldehyde,
gave comparatively lower yield (Table 3, entry 5).
80
72
73
MeO
7
8
OMe
O
NHPMP
O
O
O
CHO
CHO
O
O
O
NHPh
9
NHPHPe
CHO
O
O
10
11
75
23
CH3(CH2)6CHO
O
NHPMPe
(CH2)6CH3
Likewise, we altered the ketone moiety. Aliphatic ketones,
such as 3-pentanone and cyclohexanone, and aromatic ke-
tones, such as acetophenone, were selected. 3-Pentanone
(Table 3, entry 2) gave better results than cyclohexanone
(Table 3, entry 4). On the other hand, acetophenone (Ta-
ble 3, entry 3) gave a moderate yield. Ketones were taken in
excess to avert the formation of bis-Mannich product. Fur-
ther, we chose two different amines, namely, aniline and p-
amino phenol. The results were quite similar to those
obtained with p-anisidine, albeit the yields were slightly
lower. To examine the applicability of the protocol to
aliphatic aldehydes, we decided to synthesize Mannich base
taking n-octanal (Table 3, entry 11). However, the reaction
yield was very low. The results are presented in Table 3.
The combination of the heteropoly acid and [bmim]BF4
provides a homogeneous system for the reaction; hence, this
prompted us to investigate the possibility of recycling the
complete system of HPA and ionic liquid. The result was
aRepresentative spectral data of some Mannich bases are given in the
experimental section.
bIsolated yields.
cA syn:anti ratio of 42:58 for entry 2 and 35:65 for entry 4 was ob-
1
tained and confirmed by H NMR spectroscopic analysis of the crude
product.
dPMP is p-methoxy phenyl.
ePHP is p-hydroxy phenyl.
quite fruitful. The entire product could be isolated from the
reaction mixture simply by ether extraction, and the system
of the catalyst and the ionic liquid could be recovered and
recharged with fresh substrates. We screened the system for
two subsequent runs; the product was obtained in 83% and
75% yields, respectively.
Conclusion
We have demonstrated an efficient one-pot methodology
© 2007 NRC Canada

Pagination not final/Pagination non finale
4
Can. J. Chem. Vol. 85, 2007
for the Mannich reaction using a combination of heteropoly
acid and ionic liquid in the syntheses of β-amino carbonyl
compounds. Both the catalyst and the ionic liquid could be
easily recovered and recycled. The absence of undesirable
side-products and ambient reaction conditions also enhanced
the synthetic utility of the reaction.
Acknowledgement
The authors gratefully acknowledge the financial support
provided by the Department of Science and Technology,
Government of India.
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© 2007 NRC Canada

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