Deep eutectic solvent catalyzed eco-friendly synthesis of imines and hydrobenzamides

Article abstract of DOI:10.1007/s00706-015-1447-2

The urea-choline chloride-based deep eutectic solvent was found to be an efficient catalyst and reaction media for the additive-free synthesis of imines (Schiff bases) and hydrobenzamides by the reaction of aldehydes with amines and ammonia in good to high yields. Outstanding features of this protocol were the general and atom-economical reaction, absence of external catalysts and additives, simple workup, and availability and recycling of urea-choline chloride as a green solvent. Graphical abstract: (Chemical Equation Presented).

Full text of DOI:10.1007/s00706-015-1447-2

Monatsh Chem
DOI 10.1007/s00706-015-1447-2
ORIGINAL PAPER
Deep eutectic solvent catalyzed eco-friendly synthesis of imines
and hydrobenzamides
•
Najmedin Azizi Mahtab Edrisi
Received: 24 December 2014 / Accepted: 25 February 2015
Ó Springer-Verlag Wien 2015
Abstract The urea–choline chloride-based deep eutectic
solvent was found to be an efficient catalyst and reaction
media for the additive-free synthesis of imines (Schiff
bases) and hydrobenzamides by the reaction of aldehydes
with amines and ammonia in good to high yields. Out-
standing features of this protocol were the general and
atom-economical reaction, absence of external catalysts
and additives, simple workup, and availability and recy-
cling of urea–choline chloride as a green solvent.
Graphical abstract
hazardous organic solvents. Deep eutectic solvents are mix-
tures that are exclusively composed of cations and anions,
and have low melting point, negligible vapor pressure, and
fabulous thermal and chemical stability. Deep eutectic sol-
vents have allocated a great deal of concern in green
chemistry due to their comfortable availability, absence of
purification problems, reusability, and biodegradability [1–8].
The synthesis of nitrogen containing compounds in the
moderate and safe reaction media without additive and
catalyst, which is characterized by eco-friendly degrada-
tion, plays an important role in organic synthesis as well as
medicinal chemistry [9–12]. The condensation reaction of
primary amines with active carbonyl compounds in the
presence of acid catalyst was first reported by Hugo Schiff
in 1864, and the products are often referred to as Schiff
bases or imines [13].
The promising applications of imines and their deriva-
tives as key intermediates in the synthesis of various novel
nitrogen heterocyclic compounds and alkaloids that have
shown considerable biological actions, have attracted a
great deal of attention in contemporary organic and med-
icinal chemistry [14–16]. Furthermore, they found
tremendous applications as antibiotics, antifungal drugs,
antiviral drugs, anthelmintics, and essential pharmaceutical
compounds [17, 18].
Keywords Deep eutectic solvent ꢀ Green chemistry ꢀ
Schiff bases ꢀ Hydrobenzamides ꢀ Urea–choline chloride
Introduction
The condensation reaction of ammonia or equivalents
with carbonyl compounds produces N,N0-bis(arylmethyli-
dene)arylmethanes called hydrobenzamides [19]. Due to
the unique arrangement of nitrogen atoms with unsaturated
bonds in the hydrobenzamide derivatives, they have been
recognized as excellent synthetic nitrogen key intermedi-
ates for the synthesis of a variety of biologically active
nitrogen heterocyclic compounds [20–23]. Because of the
widespread applications of hydrobenzamides, great efforts
have been made to the synthesis of this pivotal intermediate
As a new stream in organic synthesis, deep eutectic solvents
(DESs) have attracted much attention as advanced ionic
liquids. They are ideal systems of solvents due to their sus-
tainable and appropriate reaction have to be compared to
N. Azizi (&) ꢀ M. Edrisi
Chemistry & Chemical Engineering Research Center of Iran,
P.O. Box 14335-186, Tehran, Iran
e-mail: azizi@ccerci.ac.ir
123

N. Azizi, M. Edrisi
in the most affordable way using different solvents and
catalysts [24–35]. Although some of these procedures are
so influential and proper in small scale, developing a clean
and efficient way for the synthesis of this versatile inter-
mediate, which is not burdened by environmental and
safety problems as encountered for large-scale prepara-
tions, is most desirable.
same mixture at room temperature for 5 h produced the
corresponding products in very low yield (28 %).
Under above reaction condition, to elaborate the scope and
generality of this DES, various aromatic and heterocyclic
aldehydes were examined and the details of the result are
summarized in Table 1. Aromatic aldehydes bearing electron-
donating as well as electron-withdrawing groups undergo
condensation with ammonia to afford hydrobenzamides 3 in
moderate to good yields. Aromatic aldehydes, such as ben-
Results and discussion
zaldehyde,
3-nitrobenzaldehyde,
4-bromobenzaldhyde,
4-chlorobenzaldehyde, and 4-methoxybenzaldehyde proved
to be effective substrates and produced hydrobenzamides 3 in
good to excellent yields (58–85 %). Furfural as a heteroaryl
aldehyde reacted efficiently with ammonia to result in the
related hydrobenzamides 3d in good yields (Table 1, entry 4).
However, aliphatic aldehydes did not participate in the
reaction.
In conjunction with our interest in developing an efficient
and a green procedure for organic reactions in DESs [36–
41] herein we report the straightforward and mild prepa-
ration of N,N0-bis(arylmethylidene)arylmethane diamines
and imines from the reaction of aromatic aldehydes with
ammonia and a variety of amines in choline chloride-based
deep eutectic solvent under the safe and eco-friendly
conditions.
Based on this remarkable efficiency of DES as green
reaction media, and to study the scope of this green pro-
tocol, we next extended our study to various aromatic and
aliphatic amines for the preparation of imines and the re-
sults are listed in Table 2. Under optimized reaction
condition, it was observed that simple mixing of aldehyde
(1 mmol), aniline (1 mmol) in DES (0.2 cm3) at 60 °C for
2 h gives product 5a in 95 % isolated yield. A range of
functionalized aromatic and aliphatic aldehydes as well as
various aromatic and aliphatic amines were employed for
the preparation of imines. These results show that the re-
action is general with respect to starting material and
nature of aldehyde or amine which has little effect on the
yields and reaction times.
In the model reaction, the synthesis of hydrobenzamides
was studied with the reaction of ammonia (3.2 mmol) and
benzaldehyde (3 mmol) in urea–choline chloride as the
solvent (0.5 cm3). The desired product was obtained with
an isolated yield of 85 % after 2 h at 60 °C. To develop an
environmentally benign procedure, foul smelling and toxic
ammonia was replaced with HMDS as a green source of
ammonia in this protocol. However, a low yield was ob-
tained while the reaction was performed with aldehyde
(3 mmol) and HMDS (3 mmol) in DES (0.5 cm3) at 60 °C
in 2 h which afforded the corresponding product 3a in
45 % isolated yield. Furthermore, it was observed that the
Table 1 Synthesis of N,N0-bis(arylmethylidene)arylmethane diamines in DES
Entry
Ar
Product
Yield/%
M.p./°C
Found
Reported
1
2
3
4
5
6
7
8
Ph
3a
3b
3c
3d
3e
3f
85
68
72
58
68
62
76
74
98–100
86–88
104–105 [33]
88–90 [33]
128–129 [34]
116 [35]
4-Cl–C6H4
3-MeO–C6H4
2-Furanyl
126–127
114–116
180–182
136–138
120–121
128–129
3-NO2–C6H4
4-(MeOCO)–C6H4
4-Br–C6H4
4-MeO–C6H4
178 [31]
140–142 [33]
120 [33]
3h
3i
127 [30]
123

Eco-friendly synthesis of imines and hydrobenzamides
Table 2 Synthesis of imines in DES
Entry
R
Ar
Product
Yield/%a
M.p./°C
Found
Reported
1
Ph
Ph
5a
5b
5c
5d
5e
5f
95
95
74
72
75
81
95
82
80
78
70
68
80
72
68
65
52–54
62–63
61–62
64–65
88–89
Oil
52–54 [21]
62–64 [21]
63 [22]
2
4-Cl–C6H4
4-MeO–C6H4
2,4-(MeO)2–C6H3
4-NO2–C6H4
3-i-Pr–C6H4
3-Br–C6H4
4-MeO–C6H4
3-Br–C6H4
4-NO2–C6H4
Ph
3
4
65 [21]
5
89–90 [23]
Oil [25]
Oil [25]
41 [23]
6
7
5g
5h
5i
Oil
8
PhCH2
41–42
37–38
55–57
Oil
9
38 [23]
10
11
12
13
14
15
16
a
5j
56 [21]
3-Cl-C6H4
5k
5l
Oil [22]
55–56 [23]
47 [20]
4-MeO–C6H4
3-Cl–C6H4
4-Cl–C6H4
3-Br–C6H4
4-Cl–C6H4
54
5m
5n
5o
5p
46–48
66–67
Oil
67 [22]
n-Bu
Oil [24]
Oil [24]
Oil
Isolated yield
To test the industrial applicability of the procedure,
scale-up experiments were done, 4-chlorobenzaldehy-
de (20 mmol) with aniline (20 mmol) in DES (4 cm3)
was performed under the above conditions and the N-
benzylideneaniline in 92 % isolated yield was
obtained.
outstanding features of this green synthesis are the use of
DES, absence of any external catalyst and additive, short
reaction time, simple separation and purification.
Experimental
The recycling of DES was examined using the reaction
of benzaldehyde and aniline. After the completion of the
reaction, water was added to the mixture and shaked vig-
orously. After simple filtration, the product was purified by
recrystallization with ethanol as effectual solvent. The
soluble DES in the water was recovered by evaporating the
water at 80 °C under vacuum, and it was reused for the
next run and recycled again without decreasing the yield.
All starting materials, reagents, and solvents are commer-
cially available and were used as purchased. All products
were confirmed by melting point or boiling point, FT-IR
spectroscopy. Water and other extraction solvents were
distilled before using. All the reactions were monitored by
thin layer chromatography (TLC) carried out on 0.25 mm
silica gel with UV light as detecting agent. Melting points
and boiling points were recorded on Bu¨chi 535 melting
point apparatus. FT-IR spectra were determined on a
BrukerVector-22 infrared spectrometer using KBr disks.
1H NMR spectra were recorded at r.t. on a FT-NMR Bruker
UltraShieldTM (500 MHz) or Bruker AC 80 MHz instru-
ment in CDCl3 or DMSO-d6 as solvent, chemical shifts are
expressed in ppm.
Conclusion
In conclusion, a fast and green method for the formation of
carbon–nitrogen bond is achieved using DES as a cost-
effective and eco-friendly solvent. The proposed reaction
proceeds under mild conditions and gives the products in
good and quantitative yields between 58 and 95 % with
exhaustive eco-friendly procedure. The attractive and
Choline chloride–urea deep eutectic solvent was pre-
pared according to the literature [1]. The obtained deep
eutectic solvent was used without any further purification.
123

N. Azizi, M. Edrisi
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In a dried test tube, 3.0 mmol aldehyde, 0.4 cm3 ammonia
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60 °C until the reaction was complete. The reaction mix-
ture was then diluted with water and extracted with ethyl
acetate. After evaporation of the solvent, the resulting solid
or viscous liquid was recrystallized from solvents such as
n-hexane, ethanol, diethyl ether; in some cases column
chromatography (n-hexane–ethyl acetate) was applied to
give pure products. All compounds were characterized by
melting points that were found to be identical with the ones
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General procedure for the synthesis of imines in DES
(Table 2)
In a dried test tube, 1.0 mmol aldehyde, 1.0 mmol amine,
and 0.2 cm3 DES were added and the mixture was heated
at 60 °C until the reaction was completed. After the reac-
tion time, water was added to the mixture, and the residue
collected by filtration. The resulting solid was washed with
water and was purified by flash column chromatography or
recrystallization with ethanol to give pure products. The
viscous oil/semi-solid products were extracted with ethyl
acetate. All compounds were characterized by melting
points that were found to be identical with the ones de-
scribed in literature.
Acknowledgments Financial support of this work by Chemistry
and Chemical Engineering Research Center of Iran is gratefully
appreciated.
36. Azizi N, Amiri AK, Ghafuri H, Bolourtchian M (2011) Mol
Divers 15:157
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