Multicomponent domino reactions in deep eutectic solvent: An efficient strategy to synthesize multisubstituted cyclohexa-1,3-dienamines

Article abstract of DOI:10.1016/j.molliq.2017.09.049

The multicomponent domino reactions of ketones, aldehydes and malononitrile in a deep eutectic solvent (DES) were developed. Urea-choline chloride based DES is effective dual solvents/organocatalysts and affording a series of multisubstituted cyclohexa-1,

Full text of DOI:10.1016/j.molliq.2017.09.049

Accepted Manuscript
Multicomponent domino reactions in deep eutectic solvent: An
efficient
strategy
to
synthesize
multisubstituted
cyclohexa-1,3-dienamines
Najmedin Azizi, Tahereh Soleymani Ahooie, Mohammad
Mahmoudi Hashemi
PII:
DOI:
Reference:
S0167-7322(17)32380-2
doi: 10.1016/j.molliq.2017.09.049
MOLLIQ 7886
To appear in:
Journal of Molecular Liquids
Received date:
Revised date:
Accepted date:
31 May 2017
9 August 2017
14 September 2017
Please cite this article as: Najmedin Azizi, Tahereh Soleymani Ahooie, Mohammad
Mahmoudi Hashemi , Multicomponent domino reactions in deep eutectic solvent: An
efficient strategy to synthesize multisubstituted cyclohexa-1,3-dienamines, Journal of
Molecular Liquids (2017), doi: 10.1016/j.molliq.2017.09.049
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ACCEPTED MANUSCRIPT
Multicomponent domino reactions in deep eutectic solvent: an efficient strategy to synthesize
multisubstituted cyclohexa-1,3-dienamines
Najmedin Azizi,a* Tahereh Soleymani Ahooie,b Mohammad Mahmoudi Hashemib
a Chemistry & Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran
b Department of Chemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran
Tel: +98-21-44580-775; e-mail: azizi@ccerci.ac.ir
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Abstract:
The multicomponent domino reactions of ketones, aldehydes and malononitrile in a deep eutectic solvent
(DES) were developed. Urea-choline chloride based DES is effective dual solvents/organocatalysts and
affording a series of multisubstituted cyclohexa-1,3-dienamines in good to excellent yields under mild
conditions. The DES could be easily recycled several times without appreciable loss of activity. The
present protocol offers advantages in terms of environmental sustainability and efficient utilization of
natural resources, operational simplicity and short reaction times.
Keywords: multicomponent domino reactions, deep eutectic solvent, multisubstituted cyclohexa-1,3-
dienamines, green chemistry
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1. Introduction
Recently, a new generation of green solvents, namely deep eutectic solvents (DESs) had emerged an
environmentally-benign media alternative to hazardous organic solvents in a variety of applications [1-4].
In fact, DESs are liquid systems formed from an eutectic mixture, and due to the similar common
properties of ionic liquids (ILs) serve as a low-cost alternative to ILs [5-9]. DESs can be prepared in a pure
state by the combination of hydrogen bond donors and hydrogen bond acceptors by simply mixing of
cheaper and biodegradable components [10-14]. DES have some advantages, such as negligible vapor
pressure (reduced air pollution), non-flammability (process safety), simple reaction workup,
biodegradability and renewability. All the factors discussed above, have made DESs as a hot topic and
many researchers recently have focused on their syntheses and properties and particularly their applications
in organic synthesis, polymer chemistry, analytical chemistry and biomass valorization [15-21].
Heterocyclic motifs such as multisubstituted cyclohexa-1,3-dienamines and their derivatives represent
diverse biological and pharmacological activities and well distributed in naturally-occurring compounds as
well as a key synthetic intermediate [22-26]. Because of their immense pharmacological and commercial
importance, considerable studies of the synthesis of substituted cyclohexa-1,3-dienamines and their
derivatives have been reported [27,28]. While these studies have led to remarkable improvements in the
yields of reaction, these processes are usually time and energy-consuming and involve using various
volatile organic solvents, unavailable reactants or catalysts. In view of the toxicological effects of any
organic solvent to the environment as well as human developing more environmentally friendly method for
N-heterocyclic construction via multicomponent domino reactions is a challenging but important task on
the field of green chemistry [29-34]. The best of our knowledge, this is the first example of no other added
catalysts domino reaction in DES for regioselective synthesis of multisubstituted cyclohexa-1,3-dienamines
[35-39].
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2. Experimental section
2.1. Materials and instrumentation
2.2All chemicals and solvents were obtained from commercially available sources and used. All
products were confirmed by 1HNMR, FT-IR spectroscopy and mass spectrometry. 1H NMR spectra
were recorded on 500 or 300 MHz 1HNMR, 13C NMR 125.7 and 75 MHz NMR spectrometer using
DMSO- d6 as a solvent and chemical shifts have been expressed in (ppm) 40 downfield from TMS.
Melting points were recorded on Buchi 535 melting point apparatus and are uncorrected. FT-IR spectra
were determined on a Bruker Vector-22 infrared spectrometer using KBr disks.
2.2. Deep eutectic solvent preparation: Choline chloride based DES were prepared by heating with
stirring up to 60 °C for 40-100 min of the corresponding individual components (Table 1) until a
clear solution was obtained. The obtained deep eutectic solvent was used without any further
purification.
General Procedure: In a typical procedure, ketone (0.5 mmol), aromatic aldehyde (0.5 mmol),
malononitrile (1.0 mmol) was added to the dried test tube containg DES (0.5 mL).The resulting
mixture was stirred at 50 ºC for the required time monitored (that as the reaction mixture becomes
more viscous or solids when is completed) and then cooled to room temperature. Water was added
and the residue collected by filtration. The resulting solid was washed with water and recrystallized
from ethanol or ethyl acetate and diethyl ether to afford the pure products.
3. Results and discussion
As a part of our continued interest for eco-friendly solvents in organic synthesis, we recently succeeded in
developing the deep eutectic solvent as a green media in chemical reactions [40-43]. In this paper, we
would like to report a green and efficient multicomponent domino reaction of ketones, aldehydes and
malononitrile in urea-choline chloride based DESs. DES catalyzed one-flask tandem Knoevenagel-
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Michael-cyclocondensation reactions to the construction of multisubstituted cyclohexa-1,3-dienamines in
good to excellent yield.
A series of choline chloride-based deep eutectic solvents were prepared in the simplest manner according to
the reported procedure [25] and were used without further purification.
After preparation of DES, in order to optimize the reaction condition, benzaldehyde, (0.5 mmol),
cyclohexanone (0.5 mmol) and malononitrile (1.0 mmol) was chosen as a model reaction to evaluate
several choline chloride based DESs under various conditions (Table 1). Stirring the reaction mixture in
ChCl-urea as the solvent at room temperature gives fair conversion and yield (Table 1, entry 1). To
improve the reaction conditions, various critical parameters were examined. Further studies found that the
best results in terms of conversions and times were obtained by heating the reaction mixture in 50 °C in
various DES. One possible reason for this is that the lowering of the viscosity thanks to the increase of the
temperature. When performed in 50 °C, the reaction is complete in 40 min and a satisfactory conversion
was achieved and the yield could be increased to as high as 95 % for ChCl–urea. To our great delight, a
significant improvement was observed when the ChCl and glycerol DES was used (Table 1, entry 2). A
ChCl and metal halides based DESs (Table 1, entries 3-6) resulted in good conversion, but unsatisfactory
yield. The natural carboxylic acids as well as PTSA based DESs, was the least efficient reaction medium
among the DES studied and did not achieve full conversion. Due to the high acidic properties of these
DESs, side reactions were observed (Table 1, entries 7-10).
Table 1
Screening the ten DESs revealed that ChCl-urea emerges as the best catalyst for the synthesis of
multisubstituted cyclohexa-1,3-dienamines under mild conditions. Furthermore, ChCl-urea based DES has
low price, an operationally simple and efficient workup. With the optimal conditions in hand, we turned
our attention toward the scope and tolerance of the multicomponent domino reactions of various aldehydes,
clohexanone and malononitrile at 50 °C in DES. As summarized in Table 2, a wide range of aromatic
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aldehydes can be employed in construction of multisubstituted cyclohexa-1,3-dienamines compounds with
biological and chemical properties. A broad range of aromatic aldehydes bearing diverse functional groups
including halogen, methyl, methoxy, and ester proceeded smoothly and a series of multisubstituted
cyclohexa-1,3-dienamines were afforded in good to excellent yields (73–95%). Generally, substituents on
the para positions of aryl groups slightly influenced the yields of reaction. For example, aryl aldehydes
bearing both electron-withdrawing and electron-donating groups gave the desired products in excellent
yields. Marginally, good yields were achieved for ortho-substituted arylaldehydes due to the steric factors.
To further explore the potential of this protocol for domino reaction for the construction of highly
functionalized heterocyclic synthesis, we investigated one-pot reactions involving various ketones partner.
The reactions employing tetrahydro-4H-pyran-4-one with aromatic aldehydes and malononitrile, proceeded
smoothly and a variety of the desired products were obtained in good yields (Table 2).
Table 2
The present protocol is potentially useful in organic synthesis in industrial applications due to the
advantage of environmental sustainability and efficient utilization of natural resources. For this propose, the
model reaction was performed on a relatively large scale (5 mmol), the reaction to give good yields (92 %)
of 4a with simple work-up, which shows its potential for scale-up applications.
The recyclability of DES was important, which helps address both economical and environmental view
points in industrial scale. To demonstrate this issue, the recyclability of the DES was examined for
compound 4a between benzaldehyde (5 mmol), clohexanone (5 mmol) and malononitrile (10 mmol) under
the optimized conditions (Table 1, entry 1). It is worthwhile to mention that the DES was recycled up to
four times without any significant loss and diminution in its amount and efficacy. After completion of
reaction, water was added slowly to the reaction mixture and a precipitate was formed. DES is completely
recovered by using the water phase containing DES from solid products. The DES solvent easily was
recycled by evaporating of water under vacuum (reduced pressure) and washed with ethyl acetate and used
for the next run (Figure 1).
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Figure 1
Although the detailed mechanism and the role of DES in the present work have not been confirmed yet, the
possible mechanism is proposed in a manner similar to that described in the IL catalyzed reactions is
suggested by Lohar et al. [38]. We supposed that the DES had two functions: (1) to activate carbonyl
groups of aldehyde and ketone through hydrogen binding to start the nucleophilic addition of malononitrile;
(2) to provide a nucleophilic urea via capturing a proton of malononitrile to form corresponding
carbanions. Activation of both the starting ketones and the aldehyde by hydrogen bonding increases the
electrophilicity of the aldehyde and cyclohexanone and assists the formation of separate Knoevenagel
condensations aldehyde and cyclohexanone with malononitrile (Scheme 1). The resulting Knoevenagel
condensation products undergo the concerted stereospecific [4 + 2] Diels-Alder reaction and gave the final
desired product (4a).
Scheme 1
4. Conclusion
In summary, the present work describes DES-catalyzed multicomponent reactions for the easy access
of a wide range of multisubstituted cyclohexa-1,3-dienamines. The significant advantages of these
methodologies are high yields, the wide scope of substrates, easy preparation and lower cost of the DES,
simple work-up procedures, with good to high isolated yields.
Acknowledgements
The financial support of this work provided by Iran National Science Foundation (INSF) is
gratefully appreciated.
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Scheme 1. A supposed mechanism
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100
80
60
40
20
0
1
2
3
4
5
Run
Figure 1. Recyclability experiments of DES in the model reaction
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Table 1. Investigation of deep eutectic solvents in model reaction
Entry
1
DES
Yields (%)a,c
Choline chloride:urea (2:1) 0.5 mL
Choline chloride:glycerol (2:1) 0.5 mL
Choline chloride:SnCl2 (2:1) 2 drop
Choline chloride:ZnCl2 (2:1) 2 drop
Choline chloride:ZnCl2:SnCl2 (2:1) 2 drop
Choline chloride:LaCl3 (2:1) 2 drop
Choline chloride:PTSA (2:1) 0.5 mL
Choline chloride:malonic acid (1:1) 0.5 mL
Choline chloride:tartaric acid (1:1) 0.5 mL
Choline chloride:oxalic acid (1:1) 0.5 mL
Choline chloride (0.1 g)
95 (25)b
84
2
3
78
4
82
5
76
6
58
7
42
8
40
9
35
10
11
12
13
14
15
40
62
Glycerol (0.1 mL)
74
SnCl2 ( 10 mg)
25
ZnCl2 (10 mg)
70
LaCl3 (10 mg)
38
a isolated yields. b reaction in rt. c Reaction condition: benzaldehyde, (0.5 mmol), cyclohexanone
(0.5 mmol) and malononitrile (1.0 mmol) at 50 °C in DES (0.5 mL).
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Table 2. Synthesis of various multisubstituted cyclohexa-1,3-dienamines under optimum
conditions
Entry
Ar (Aldehyde)
Product
(4a-4o)
4a
Time
(min.)
40
50
45
50
50
60
60
80
60
70
80
Yields
(%)a,b
95
86
92
80
78
90
74
78
74
72
78
Ref.
1
2
3
4
5
6
7
8
9
C6H5
4-ClC6H4
4-MeC6H4
4-BrC6H4
3-OMeC6H4
3-BrC6H4
2-BrC6H4
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
37
38
38
38
39
37
38
39
38
38
39
36
4b
4c
4d
4e
4f
4g
4h
4i
4-OMeC6H4
3-NO2C6H4
2,4-Cl2C6H3
3,4-(OMe)2C6H3
10
11
12
4j
4k
4l
90
64
13
CH2
4m
90
68
36
14
15
4-Me-Ph
Ph
O
O
4n
4o
80
80
74
72
36
36
a Isolated yields. b The reaction mixture becomes more viscous or solids when is completed
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Graphical abstract
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Huighlights
►greener strategy under operational simplicity was reported.
► Good to excellent yields of the products..
► This approach eliminates the use of hazardous organic solvents and toxic catalysts.
► Biorenewable and recyclable solvent.
19