Basic functionalized ionic liquid catalyzed One-pot mannich-type reaction: Three component synthesis of β-Amino carbonyl compounds

Article abstract of DOI:10.1007/s00706-007-0767-2

Three-component Mannich-type reaction of cyclohexanone, aromatic aldehydes, and aromatic amines was catalyzed by a basic functionalized ionic liquid, 1-butyl-3-methylimidazolium hydroxide ([bmim][OH]), at room temperature to give various β-amino carbonyl compounds in high yields. The ionic liquid, which is environmentally friendly, can be recycled at least 5 times without significant loss of activity.

Full text of DOI:10.1007/s00706-007-0767-2

Monatshefte fu¨r Chemie 138, 1195–1198 (2007)
DOI 10.1007/s00706-007-0767-2
Printed in The Netherlands
Basic Functionalized Ionic Liquid Catalyzed One-pot Mannich-type
Reaction: Three Component Synthesis of b-Amino Carbonyl Compounds
ꢀ
Kai Gong, Dong Fang, Hua-Lan Wang, and Zu-Liang Liu
School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, P.R. China
Received April 13, 2007; accepted May 8, 2007; published online October 17, 2007
# Springer-Verlag 2007
Summary. Three-component Mannich-type reaction of cy-
clohexanone, aromatic aldehydes, and aromatic amines was
catalyzed by a basic functionalized ionic liquid, 1-butyl-3-
methylimidazolium hydroxide ([bmim][OH]), at room temper-
ature to give various ꢀ-amino carbonyl compounds in high
product separation, sometimes long reaction time,
and low yield, etc. Hence, there is high interest in
developing new convenient methods for the synthe-
sis of ꢀ-amino carbonyl compounds.
Fortunately, ionic liquids have recently attracted
increasing interest in the context of green synthe-
sis nowadays, of which functionalized ionic liquids
have been one of the hottest topics [7]. Basic func-
tionalized ionic liquids have aroused unprecedented
interest because they showed more advantages, such
as convenient recycling and high catalytic efficiency
than the mixture of inorganic base and ionic liquid
for some base-catalyzed processes [8]. A basic func-
tionalized ionic liquid [bmim][OH] has been success-
fully applied to catalyze the Michael addition of
active methylene compounds to conjugated ketones,
carboxylic esters, and nitriles [9], the Markonikov
addition of N-heterocycles to vinyl esters [10], and
the three-component condensation reaction of aro-
matic aldehydes, malononitrile, and ꢁ- or ꢀ-naphthol
for the synthesis of 2-amino-2-chromenes [11]. The
versatility of this ionic liquid encouraged us to study
its utility for three-component Mannich-type reac-
tion. To the best of our knowledge in the open lit-
erature, one-pot Mannich-type reactions catalyzed
by the basic ionic liquid [bmim][OH] have not yet
been reported. Herein, we have discovered that this
basic functionalized ionic liquid effectively promot-
ed Mannich-type reaction of cyclohexanone, aromat-
ic aldehydes, and aromatic amines under relatively
mild conditions (Scheme 1).
yields. The ionic liquid, which is environmentally friendly,
can be recycled at least 5 times without significant loss of
activity.
Keywords. Mannich-type reaction; Ionic liquid; Catalyst;
One-pot reaction.
Introduction
The Mannich-type reactions are very important car-
bon–carbon bond-forming reactions in organic syn-
thesis and have been one of the most basic and
useful methods for the preparation of ꢀ-amino car-
bonyl compounds for its use in various pharma-
ceuticals, natural products, and versatile synthetic
intermediates [1]. Mannich reactions have gained
popularity in synthetic chemistry over the past de-
cades. The most frequently used promoters like Lewis
acid catalysts [2], Brønsted acid catalysts [3], Lewis
base catalysts [4], rare metal salt catalysts [5], and
organo catalysts [6] have been reported to catalyze
the Mannich reaction. Most of these methods suf-
fer from severe drawbacks including the use of
large amount of catalysts, expensive reagents or cat-
alysts, harsh reaction conditions and difficulty in
ꢀ
Corresponding author. E-mail: liuzl@mail.njust.edu.cn

1196
K. Gong et al.
Scheme 1
Table 2. The Mannich reaction catalyzed by [bmim][OH] in
different solventsa
Results and Discussion
In the initial experiments, we screened different
basic functionalized ionic liquids for their ability
to catalyze three-component Mannich-type reac-
tions. Herein the reaction of cyclohexanone, benz-
aldehyde, and aniline was selected as model. The
results are summarized in Table 1. No products were
observed in the absence of ionic liquids (Table 1,
entry 1). Among the basic functionalized ionic liq-
uids, such as [H3NCH2CH2OH][CH3COO], [H2N-
(CH2CH2OH)2][CH3COO], [HN(CH2CH2OH)3]
[CH3COO], [emim][OH], and [bmim][OH] studied
for this reaction, [bmim][OH] was found to be the
most effective catalyst for this conversion since it
resulted in the highest conversion to the desired
product (Table 1, entry 7). We also observed that
10 mol% of [bmim][OH] (based on cyclohexanone)
could most effectively catalyze the reaction (Table 1,
entry 7), and increasing the amount of [bmim][OH] to
20 mol% showed no substantial improvement in the
yield (Table 1, entry 8). In conclusion, [bmim][OH]
Entry
Solvents
Yield=%b
1
2
3
4
5
Water
EtOH
CH3CN
CH2Cl2
None
52
85
81
60
61
a
Reaction conditions: cyclohexanone (10 mmol), benzalde-
hyde (10 mmol), aniline (10 mmol), [bmim][OH] (1 mmol) as
catalyst, solvent (5 cm3), r.t., 10 h
b
Isolated yield
is an effective catalyst for the Mannich-type reaction
of cyclohexanone, benzaldehyde, and aniline.
Similarly, the model reaction of cyclohexanone,
benzaldehyde, and aniline catalyzed by [bmim][OH]
at room temperature was chosen for investigating
the effect of solvents. The effect of solvents on
the yield of ꢀ-amino carbonyl compounds is given
in Table 2. The model reaction proceeded smooth-
ly in polar organic solvents, such as ethanol and
acetonitrile (Table 2, entries 2, 3), which afford-
ed better yields than others (Table 2, entries 1, 4,
5), and ethanol was found to be the most effective
solvent.
Table 1. The Mannich reaction catalyzed by different basic
functionalized ionic liquidsa
Entry
Ionic liquids (mmol)
Yield=%b
1
2
3
4
5
6
7
8
–
0
59
55
50
76
55
85
81
Next, we examined the scope of the reaction
by using various aromatic aldehydes and aromatic
amines. The results are summarized in Table 3. In
general, the three-component Mannich-type reaction
proceeded in presence of 10 mol% of [bmim][OH]
smoothly to give the corresponding products in high
yields at room temperature in ethanol for 10 h. It
should be noted that benzaldehydes and anilines car-
rying either electron-donating or electron-withdraw-
ing substituents all reacted well. Particularly, aryl
[H3NCH2CH2OH][CH3COO] (1)
[H2N(CH2CH2OH)2][CH3COO] (1)
[HN(CH2CH2OH)3][CH3COO] (1)
[emim][OH] (1)
[bmim][OH] (0.5)
[bmim][OH] (1)
[bmim][OH] (2)
a
Reaction conditions: cyclohexanone (10 mmol), benzalde-
hyde (10 mmol), aniline (10 mmol), EtOH (5 cm3), r.t., 10 h
Isolated yield
b

Basic Functionalized Ionic Liquid
1197
Table 3. Three-component Mannich-type reaction of cyclohexanone, aromatic aldehydes, and aromatic amines catalyzed by
[bmim][OH]a
Entry
R1
R2
Product
Yield=%b
m.p.=ꢁC
m.p.=ꢁC Ref.
1
2
3
4
5
6
7
8
9
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
85
91
83
86
78
75
88
91
90
95
92
116–117
117–118
137–138
97–98
122–123
130–131
133–134
98–99
115–116 [2c]
116–118 [5b]
137–138 [5b]
98–99 [2c]
122–123 [2c]
131–132 [2c]
135–136 [2c]
96–97 [2c]
4-CH3
4-Cl
4-Br
4-Cl
4-Br
H
4-Cl
4-Br
4-Cl
4-CH3
H
4-CH3O
4-CH3O
4-Cl
4-Cl
4-Cl
3-NO2
4-NO2
135–136
127–128
137–138
134–135 [2c]
125–126 [2c]
137–138 [2c]
10
11
4j
4k
a
Reaction conditions: cyclohexanone (10 mmol), aromatic aldehydes (10 mmol), aromatic amines (10 mmol), [bmim][OH]
(1 mmol), EtOH (5 cm3), r.t., 10 h
Isolated yield
b
lytic activity. This approach could make a valuable
contribution on the synthesis of ꢀ-amino carbonyl
compounds.
Experimental
Melting points were determined in open capillaries. 1H NMR
spectra were obtained from solution in CDCl3 with TMS as
internal standard using a Bruker DRX 300 (300 MHz) spec-
trometer. IR spectra were recorded on a Nicolete spectrometer
using KBr discs.
The functionalized ionic liquids, [bmim][OH] and [emim]-
[OH] (1-ethyl-3-methyl-imidazolium hydroxide), [H3NCH2-
CH2OH][CH3COO], [H2N(CH2CH2OH)2][CH3COO], and
Fig. 1. Reusability of [bmim][OH]=EtOH
[HN(CH2CH2OH)3][CH3COO] were prepared by the pro-
cedures given in Refs. [9, 12]. All other chemicals and re-
aldehydes bearing an electron-withdrawing group
are favorable for the transformation while anilines
agents were of analytical grade and used as obtained.
with electron-donating groups are beneficial for these
reactions.
The recycling of the ionic liquid was also investi-
gated. In the model reaction among cyclohexanone,
benzaldehyde, and aniline, the products were isolat-
ed from ethanol media by filtration. The filtrate was
reused in the next run without further purification.
As shown in Fig. 1, the catalyst can be recycled up to
5 times without significant decrease in catalytic ac-
tivity, the yields ranged from 88 to 82%.
In conclusion, we developed a simple, green, and
efficient protocol for the three-component Mannich-
type reactions catalyzed by the basic functionalized
ionic liquid, [bmim][OH]. The most attractive part
of this work is that [bmim][OH] is easily recycled
and can be reused without obvious loss of the cata-
General Procedure for the Synthesis of ꢀ-Amino Carbonyl
Compounds
To a mixture of 0.98g cyclohexanone (10mmol), 10 mmol
aromatic aldehyde, 10mmol aniline derivative, and 5 cm3 eth-
anol as the solvent, 1 mmol ionic liquid [bmim][OH] was added
and stirred at room temperature for the appropriate time.
When the reaction was completed as indicated by TLC,
the products were filtered off to get crude products, which
were then purified by recrystallization from ethanol to give
the corresponding compounds. The ionic liquid is remain-
ing in the ethanol and could be reused in the next run
without further purification.
2-(Phenyl(phenylamino)methyl)cyclohexanone
(4a, C19H21NO)
1
White solid; mp 116–117ꢁC; H NMR (300MHz, CDCl3):
ꢂ ¼ 7.37–7.33 (m, 2H), 7.31–7.26 (m, 2H), 7.24–7.19 (m,
1H), 7.05–7.02 (m, 2H), 6.60 (m, 1H), 6.54–6.51 (m, 2H),

1198
K. Gong et al.: Basic Functionalized Ionic Liquid
4.80–4.78 (d, 1H), 4.61–4.61 (d, 1H), 2.75–2.73 (m, 1H),
2.42–2.31 (m, 2H), 1.90–1.84 (m, 4H), 1.72–1.57 (m, 2H)
hedron 57: 2537; c) Akiyama T, Takaya J, Kagoshima H
(2001) Tetrahedron Lett 42: 4025
[4] a) Hata S, Lguchi M, Tomioka K (2004) Org Lett 11:
1721; b) Takahashi E, Fujisawa H, Mukaiyama T (2004)
Chem Lett 33: 936
ppm; IR (KBr): ꢃꢀ¼ 3330, 1705, 1600, 1498 cmꢂ1
.
Acknowledgements
[5] a) Wang L, Han J, Sheng J, Tian H, Fan Z (2005) Catal
Commun 6: 201; b) Yi WB, Cai C (2006) J Fluorine
Chem 127: 1515
[6] a) Ibrahem I, Zou W, Casas J, Cordova A (2006)
Tetrahedron 62: 357; b) Kantam ML, Rajasekhar CV,
Gopikrishna G, Reddy KR, Choudary BM (2006) Tet-
rahedron Lett 47: 5965
We are grateful to Nanjing University of Science and
Technology for financial support.
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