Deep Eutectic Solvent as a Recyclable Catalyst for Three-Component Synthesis of β-Amino Carbonyls

Article abstract of DOI:10.1007/s10562-014-1471-6

We have reported one-pot, three-component Mannich type reaction of aldehyde, amines and ketone (acetone and acetophenones), catalyzed by deep eutectic solvent (choline chloride/zinc chloride) at room temperature to give β-amino carbonyls in good yields. The catalyst could be recycled at least four times without remarkable decrease in its catalytic activity. The general method is easy, fast and environmental friendly.

Full text of DOI:10.1007/s10562-014-1471-6

Catal Lett
DOI 10.1007/s10562-014-1471-6
Deep Eutectic Solvent as a Recyclable Catalyst for
Three-Component Synthesis of b-Amino Carbonyls
Fariba Keshavarzipour Hossein Tavakol
•
Received: 3 December 2014 / Accepted: 20 December 2014
Ó Springer Science+Business Media New York 2014
Abstract We have reported one-pot, three-component
Mannich type reaction of aldehyde, amines and ketone
product. Since the first report of Mannich reaction, several
studies have published to optimize the reaction conditions
and present new and efficient catalysts for this reaction. In
this line, using microwave [4, 5] and ultrasound irradiation
[6], Lewis acids [7–10], Lewis bases [11] and metal salts
[12] have reported as catalyst for this reaction. Although a
large number of methods have been reported for the
Mannich reaction, some of these methods have a series of
limitations. To overcome these problems, ionic liquids
(
acetone and acetophenones), catalyzed by deep eutectic
solvent (choline chloride/zinc chloride) at room tempera-
ture to give b-amino carbonyls in good yields. The catalyst
could be recycled at least four times without remarkable
decrease in its catalytic activity. The general method is
easy, fast and environmental friendly.
Graphical Abstract
(ILs) have introduced as new and green media for the
Mannich reaction as well as their applications in many
organic reactions [13–16]. ILs have desired properties such
as thermal stability (some of them), wide range solubility
for chemical (both organic and inorganic) compounds and
low vapor pressure. However, using ILs has been restricted
by some unfavorable properties such as high cost, degra-
dation and toxicity [17]. Therefore, a new category of ILs,
known as deep eutectic solvents (DESs), have presented.
DESs were first described by Abbot et al. which consisted
of the composition of two salts using simple procedure to
prepare the mixture with low meting point [18]. In this line,
choline chlorides (ChCl) have been extensively used as a
green, biodegradable and non-toxic structure in DESs [17–
H
NH2
CH
3
ChCl.2 ZnCl
2
(
5 mol%)
NH R3
R1
O
R
3
O
R
2
R2
Water, 4h, r.t
R1
O
Keywords Choline chloride Á Mannich Á Green Á Eutectic
solvent Á b-Amino carbonyl
1
Introduction
Multicomponent reactions are one of the most important
class of reactions in organic synthesis, which have been
used for the synthesis of various structures [1]. The first
reaction of this class is three-component synthesis of b-
amino carbonyl, discovered by Carl Mannich [2], which
presents a simple method consisted of carbon–carbon bond
formation. The Mannich reaction uses aldehyde, ketone
and amine in the presence of catalyst [3] to prepare desired
2
4] in composition with many organic and inorganic
molecules.
Therefore, In the course of our previous efforts in
multicomponent synthesis [25–27] it seems to be useful to
use ChCl in combination of a Lewis acid (i.e. zinc chloride)
in a multicomponent Mannich reaction. This mixture have
been successfully used as a green media in many organic
reactions. In this paper, we report the three-component
Mannich reaction using ChClÁ2ZnCl as both catalyst and
2
F. Keshavarzipour Á H. Tavakol (&)
solvent to prepare b-amino carbonyls. The employed
methodology and results obtained in this research will be
discussed in the next sections.
Department of Chemistry, Isfahan University of Technology,
84156-83111 Isfahan, Iran
e-mail: h_tavakol@cc.iut.ac.ir
123

F. Keshavarzipour, H. Tavakol
13
1
2
Experimental
points, elemental analysis, FT-IR, HNMR and CNMR
spectra data with those of authentic samples [29–37].
All chemical compounds have purchased from Sigma-
Aldrich and Merck companies and used without further
purifications. Melting points were determined using Gallen
Kamp melting point apparatus. Thin layer chromatography
was used to monitor the reaction and check purities. IR
spectra (KBr) were recorded by JASCO FT-IR and
2.3 Selected Spectral Data
-
1
Choline chlorideÁ2ZnCl : IR (KBr, cm ): 3,550, 3,500,
2
1,609, 1,473, 1,081, 952, 866. Elemental Anal. for (C,
14.75; H, 3.42; N, 3.4) Found: (C, 14.54; H, 4.037; N,
3.48).
1
13
HNMR spectra and CNMR spectra were recorded by
-
1
Brucker Ultrashield 400 MHz. NMR chemical shifts were
expressed in ppm versus the chemical shift of tetrameth-
ylsilane (TMS) as internal reference.
4a: White solid, mp 169–170 °C, IR (KBr, cm ):
3,383, 3,020, 1,669, 1,598, 1,510, 1,298, 1,219, 1,073,
1
1,026, 997, 859, 710, 510. HNMR (400 MHz, CDCl ):
3
7
.93 (d, 2H, J = 8.6 Hz), 7.59 (t, 1H, J = 7.2 Hz), 7.47
m, 4H), 7.35 (m, 2H), 7.28 (m, 1H), 7.11 (m, 2H), 6.68 (t,
H, J = 7.6 Hz), 6.58 (d, 2H, J = 7.6 Hz), 5.03 (dd, 1H,
J = 5.2, 7.6 Hz), 4.58 (s, 1H), 3.53 (dd, 1H, J = 5.2,
(
2
.1 Preparation of Deep Eutectic Solvent
1
The employed DES (ChClÁ2ZnCl ) have synthesized
2
13
15.4 Hz), 3.44 (dd, 1H, J = 7.6, 15.4 Hz). CNMR
according to the reported method [28]. The preparation
method involved reaction of ChCl (1 mol) with ZnCl2
(100 MHz, CDCl ): 45.3, 54.8, 113.8, 117.8, 126.4, 127.4,
3
1
1
8
28.2, 128.7, 128.8, 129.1, 133.4, 135.4, 136.7, 142.9,
(2 mol) at 100 °C (Scheme 1) to obtain a clear solution
that will be used without further purification.
44.7, 146.9, 198.2. Elemental Anal. for C H NO (C,
21 19
3.72; H, 6.31; N, 4.65) Found: C, 84.05; H, 6.07; N, 4.72.
1
-
4
e: Colorless solid, mp 149–151 °C, IR (KBr, cm ):
1
3,381, 1,674, 160, 1,509, 1,259, 1174,835, 510. HNMR
2
.2 General Procedure for Preparation of b-Amino
Carbonyls
(400 MHz, CDCl ): 7.97 (d, 2H, J = 7.6 Hz), 7.90 (d, 2H,
3
J = 8.8 Hz), 7.47 (d, 2H, J = 7.6 Hz), 7.34 (t, 2H,
J = 7.2 Hz), 7.10 (t, 2H, J = 7.6 Hz), 6.95 (t, 2H,
J = 9.2 Hz), 6.67 (t, 1H, J = 7.2 Hz), 6.58 (d, 2H,
J = 7.6 Hz), 4.97 (dd, 1H, J = 5.2, 7.6 Hz), 3.89 (s, 3H),
In a round bottom flask, to a mixture ChClÁ2ZnCl
2
(
5 mol%) in 1 ml water (to reduce the viscosity and pro-
vide proton source), aldehyde (2 mmol), amine (2 mmol),
and ketone (2 mmol) were added. The mixture was stirred
at room temperature for a certain time (Scheme 2). After
completion (confirmed by TLC), the precipitated crude
product was collected by filtration and recrystallized from
ethanol to obtain the pure product. The filtrate, containing
catalyst, was recycled and directly used in the next run
without further purification. The structures of all the pro-
ducts were determined by comparison of their melting
1
3
3.45 (dd, 2H, J = 5.2, 15.8 Hz). CNMR (100 MHz,
CDCl ):45.9, 55.06, 55.49, 113.7, 117.67, 126.35, 127.27,
3
127.47, 128.35, 128.55, 128.78, 128.93, 129.05, 130.31,
130.45, 130.55, 130.82, 143.19, 147.11, 163.5, 163.76,
196.74; Elemental Anal. for C H NO (C, 79.76; H, 6.34;
2
2
21
2
N, 4.23) Found: C, 80.14; H, 6.65; N, 4.12.
3
Results and Discussion
The reaction of benzaldehyde, aniline and acetophenone
model reaction) to prepare b-amino carbonyl was exam-
Cl
OH
.
ZnCl2
Heated at 100°C
N
(
OH
2
ZnCl2
N
ined first without using ChClÁ2ZnCl (eutectic solvent) that
2
Cl Zn-Cl
2
any product has not been observed after 20 h. Therefore all
Choline Chloride Zinc chloride
mol
2 mol
reactions should be performed using ChClÁ2ZnCl . To
2
1
Deep eutectic solvent
obtain the best reaction conditions, several experiments,
based on the model reaction have designed using 5, 10, 15
Scheme 1 Preparation of deep eutectic solvent
and 20 % of ChClÁ2ZnCl in different times and temper-
2
atures. The results of optimization processes were listed in
Table 1.
H
NH2
CH3
O
ChCl.2 ZnCl
2
The data listed in Table 1 show that using 5 mol% of the
(
5 mol%)
NH R3
R1
O
R3
R2
catalyst (ChClÁ2ZnCl ) give the highest yield for the
2
R2
Water, 4h, r.t
R1
O
reaction. When the amount of catalyst increased to more
than 5 mol%, the yield was decreased. Moreover, the best
time for the model reaction is 4 h. To optimize the
1
2
3
4a-r
Scheme 2 Mannich-type reaction catalyzed by the ChCl-2ZnCl
2
1
23

Deep Eutectic Solvent for Synthesis of b-Amino Carbonyls
Table 1 The effects of reaction time, temperature and catalyst
loading on the reaction yield for the reaction of benzaldehyde, aniline
and acetophenone
the results obtained in these reactions were listed in
Table 2. These experiments prove that ChClÁ2ZnCl could
2
be employed as a general, green and effective catalyst for
three-component Mannich synthesis of various b-amino
carbonyl. The reaction proceeded effectively to give pro-
ducts with acceptable yields in the range of 52–98 %. The
data listed in Table 2 show that aldehydes with an electron-
donor substituent give higher yield than the others.
Therefore, 4-nitrobenzaldehyde has the least yield and
Entry
Catalyst (mol%)
Temp.
Time (h)
Yield
1
2
3
4
5
6
7
8
9
–
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
80
20
1
0
5
30
96
96
96
83
75
62
\50
5
4
5
10
20
4
5
4-hydroxy benzaldehyde has the highest yield in this
10
15
20
10
reaction (entries 4b and 4f of the Table). Moreover, the
yields of reactions using acetone are nearly the same with
those values for acetophenone or 4-hydroxy acetophenone
4
4
4
(comparing 4a, 4h and 4o). Therefore, substituents on
ketone have not important effect on the reaction yield. In
some reactions, an amine with electron-withdrawing sub-
stituent (4-nitroaniline) was also investigated that a little
smaller yields were observed in these reactions, involved
with electron deficient amines. Mannich reactions were
carried out for several aliphatic aldehydes (such as butanal,
propanal and 2-methyl propanal) and because they are e-
nolizable (they have a hydrogen), several products were
observed that showed this reaction could not performed
using aliphatic aldehydes.
temperature, the model reaction has examined at various
temperatures (one case was added to the end of Table 1). It
was observed that with the increasing of reaction temper-
ature, side reactions would be increased and the yield was
decreased. Therefore, room temperature was obtained as
best temperature for the reaction. All of these optimized
conditions were used in next experiments for the synthesis
of other b-amino carbonyls (Scheme 2) from the Mannich
reaction.
This should be noticed that by previous reports,
acceptable yields were obtained when the Mannich type
was using neat ZnCl as catalyst. However, neat ZnCl is
To examine the versatility of the reaction and showing
its ability to prepare various b-amino carbonyls, different
substituted benzaldehyde were used with aniline or 4-ni-
troanilines (as amine sources) and acetone, acetophenone
and 4-methoxy acetophenone as ketone sources at the
optimized conditions (presented in previous paragraph) and
2
2
sometimes non-recoverable, corrosive and this process
should use toxic solvents that do not represent green pro-
tocols [38, 39]. Therefore, we employed ChClÁ2ZnCl
2
instead of neat ZnCl as both catalyst and green solvent to
2
Table 2 Three component
reaction of various aldehydes,
anilines, and ketones catalyzed
Structure
R1
R2
R3
Yield %
Ref
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
Ph
H
Ph
96
52
73
98
91
98
64
98
70
52
64
60
98
82
96
95
84
75
[29]
[30]
[30]
[30]
[30]
[31]
[32]
[33]
[34]
[35]
[34]
[36]
[36]
[36]
[37]
[37]
[37]
[37]
2
by ChClÁ2ZnCl at the
4-NO
2
-C
6
H
5
H
Ph
optimized conditions (5 mol%
eutectic solvent, 4 h and r.t)
4-Cl-C
2-Naphthyl
4-OMe-C
6
H
5
H
Ph
H
Ph
6
H
5
H
Ph
4-OH-C
6
H
5
H
Ph
g
h
i
H
H
Ph
Ph
Ph
Ph
H
4-OCH
4-OCH
Ph
3
-C
6
H
5
5
4-NO
4-NO
4-NO
4-NO
4-NO
4-NO
H
2
2
2
2
2
2
-C
3 6
H
j
k
l
4-Cl-C
4-OCH
3,4-OCH
6
H
5
Ph
3
-C
-C
N-C
6
H
5
Ph
m
n
o
p
q
r
3
6
H
5
Ph
4-(Me)
Ph
2
6
H
5
Ph
CH
CH
CH
CH
3
3
3
3
4-OCH
4-OH-C
4-Cl-C
3
-C
6
H
5
H
6
H
5
H
6
H
5
H
123

F. Keshavarzipour, H. Tavakol
Scheme 3 Proposed
mechanism for the synthesis of
b-amino carbonyls
O
H
NH
O
OH
N
N
OH ZnCl3
ZnCl3
H N
2
O
H
-
H O
2
N
-
ZnCl3
O
ZnCl
3
H
N
O
N
O
H
N
H
N
H
O
H
ZnCl3
H
N+
O
H
H C
2
H
O-
O
N
ZnCl3
acetophenone could be facilitated. On the basis of these
assumptions, the experimental results and reported studies,
possible mechanism for the formation of b-amino carbonyl
using ChClÁ2ZnCl was proposed in Scheme 3.
2
To complete this work, the recovering ability of
ChClÁ2ZnCl in the model reaction using optimized con-
2
ditions was examined and the results were shown in Fig. 1.
After each run, the eutectic solvent (ChClÁ2ZnCl ) was
2
isolated from the product and used without further purifi-
cation in the next run. As shown in Fig. 1, ChClÁ2ZnCl
2
could be reused at least four runs without remarkable loss
of its activity.
Fig. 1 Reusability of the catalyst
4
Conclusions
overcome these problems. The important role of
In summary, an effective, green, and simple procedure
ChClÁ2ZnCl in multicomponent reactions have been
2
have presented for the synthesis of b-amino carbonyl
described previously [28, 40]. It was reported that the
presence of choline chloride enhance the catalytic proper-
ties of zinc chloride. Abbott showed that the actual species
reaction using deep eutectic solvents (ChClÁ2ZnCl ) as
2
both catalyst and solvent. The advantages of this method
are simplicity, easy separation, recoverability of catalyst
and high yields. In addition, the employed deep eutectic
solvent is cheap, green (biodegradable and non-toxic) and
could be easily prepared.
-
-
presented in ChClÁ2ZnCl , could be [ZnCl ] , [ZnCl ] ,
2
3
5
-
-
[
ZnCl ] . [ZnCl ] . These species may act as Lewis base
7 3
to adsorb a proton of acetophenone to give anionic species.
Moreover, ChClÁ2ZnCl can form an acceptor–donor
2
complex with the aldehyde and the imine in the first stage.
Therefore, addition of the enol (or enolate) form of
Acknowledgments We are grateful to Professor Akbar Heydari
(Tarbiat Modarres University, Tehran, Iran) for his valuable
1
23

Deep Eutectic Solvent for Synthesis of b-Amino Carbonyls
assistance. This work was supported by the research affairs of Isfahan
University of Technology.
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