One-pot synthesis of quinoline derivatives using choline chloride/tin (II) chloride deep eutectic solvent as a green catalyst

Article abstract of DOI:10.1016/j.molliq.2016.04.094

In this work, various quinoline derivatives were prepared efficiently through a one-pot, three component synthesis using choline chloride/tin(II) chloride (ChCl·2SnCl2) deep eutectic solvent (DES) as a green catalyst. The procedure is free of using toxic solvents or catalyst and it could be categorized as a green method. In this procedure, aniline derivatives, aromatic aldehydes and enolizable aldehydes were mixed in the presence of DES that plays both roles of solvent and the reaction catalyst. Using this methodology, quinoline derivatives were synthesized simply at 60 °C in 2-3 h with high yields (54-97%). All products were purified by chromatography and recrystallization in ethanol. The employed DES have been recycled 4 time without important loss of its activity.

Full text of DOI:10.1016/j.molliq.2016.04.094

Journal of Molecular Liquids 220 (2016) 324–328
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
One-pot synthesis of quinoline derivatives using choline chloride/tin (II)
chloride deep eutectic solvent as a green catalyst
⁎
Dana Shahabi, Hossein Tavakol
Department of Chemistry, Isfahan University of Technology, Isfahan 84156-83111, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
In this work, various quinoline derivatives were prepared efficiently through a one-pot, three component synthe-
sis using choline chloride/tin(II) chloride (ChCl·2SnCl2) deep eutectic solvent (DES) as a green catalyst. The pro-
cedure is free of using toxic solvents or catalyst and it could be categorized as a green method. In this procedure,
aniline derivatives, aromatic aldehydes and enolizable aldehydes were mixed in the presence of DES that plays
both roles of solvent and the reaction catalyst. Using this methodology, quinoline derivatives were synthesized
simply at 60 °C in 2–3 h with high yields (54–97%). All products were purified by chromatography and recrystal-
lization in ethanol. The employed DES have been recycled 4 time without important loss of its activity.
© 2016 Elsevier B.V. All rights reserved.
Received 28 November 2015
Accepted 22 April 2016
Available online xxxx
Keywords:
Catalyst
Deep eutectic solvent
Multi-component
Quinolines
1. Introduction
and during these years, coal tar has been remained as a major source
of commercial quinoline [28]. However, because of the limitations in
Quinoline (and its derivatives) is one of the most important
nitrogen-containing heterocyclic aromatic compounds because of its bi-
ological activities [1–6]. Although, quinoline derivatives have shown an-
tiviral [7], antimalarial [8–10], antibacterial [11–13], anticancer [14],
antifungals [15], anti-inflammatory and antihypertensive [16,17] activ-
ities. Quinolines are well known not only for their significant biological
activities, but also because of their applications in the formation of con-
jugated molecules and polymers [18]. These materials combined en-
hanced electronic, optoelectronic, or nonlinear optical properties with
excellent mechanical properties [19–21]. Quinoline derivatives have
been used in the synthesis of fungicides, biocides and flavoring agents
[22,23]. Furthermore, these compounds are useful in chemistry of tran-
sition metal catalysts, uniform polymerization and luminescence chem-
istry [24,25], in addition to their applications as antifoaming agent in
refineries [26]. Therefore, quinoline derivatives have been attracted
much attention because of their broad range of activities and wide
applications.
The main sources of quinoline are petroleum, coal processing, wood
preservation and shale oil. The quinoline derivatives could be observed
in various natural products. In this line, several quinoline derivatives
have been isolated from natural resources or prepared synthetically. In
1820, quinine (a derivative of quinoline) was isolated from the bark of
the cinchona tree and it has been used in the treatment of malaria for
many years. After this discovery, many quinoline derivatives have
been isolated from different plants and used in various applications
[27]. In addition, quinoline was extracted from the coal tar in 1834
the use of natural resources, the syntheses of quinolines have been the
subject of great focus in by synthetic organic chemists.
The first synthesis of quinoline was reported by Skraup over a cen-
tury ago. After the Skraup synthesis, many synthetic methods such as
Doebner-Von Miller, Friedlander [29] and Combes reactions have been
developed for the preparation of quinolines. In addition, many catalysts
have been used involving a variety of metal catalysts and Lewis acids.
However, many of these procedures are not fully acceptable because
of some problems in their operational simplicity, cost and toxicity of
the reagents, reaction time and isolated yields. Thus, it is necessary to
find new methodologies for the synthesis of quinolines. More impor-
tantly, the main disadvantage of the most of reported methods is the
poor recoverability of the employed catalyst and in the cases where
the catalyst could be recovered, the preparation of the catalyst needs
to hazardous or expensive materials and hard procedures [30–34].
Therefore, presenting a simple synthesis of quinolines that involves eco-
nomic and environmental friendly chemical processes could be useful.
In this line, in continuation of our interests on the use of deep eutectic
solvents (DESs) as a green media in organic synthesis [35,36] the at-
tempts have been made for the syntheses of quinolines using DES
(also known as deep eutectic ionic liquids (DEILs)), low-melting mix-
tures (LMMs) or low transition temperature mixtures (LTTMs). DESs
are a green class of common organic solvents that mostly avoid their
problems such as high flammability, volatility, hazardness, and toxicity.
During last decades, the search for environmentally-friend substitutes
for organic solvents has recently gained more attention in green chem-
istry. DESs have become more and more attractive in recent years due to
their interesting properties and benefits, such as low cost of compo-
nents, easy to prepare, tunable physicochemical properties, negligible
⁎
Corresponding author.
E-mail addresses: H_tavakol@cc.iut.ac.ir, h_tavakol@yahoo.com (H. Tavakol).
http://dx.doi.org/10.1016/j.molliq.2016.04.094
0167-7322/© 2016 Elsevier B.V. All rights reserved.

D. Shahabi, H. Tavakol / Journal of Molecular Liquids 220 (2016) 324–328
325
Scheme 1. The general reaction for the synthesis of quinoline derivatives in presence of DES.
vapor pressure, non-toxicity, non-reactivity with water, non-
flammability, conductivity, bio renewability and biodegradability [37,
38]. In addition, when they are consisted of common catalyst (such as
Lewis acid or base), they could play a role of catalyst, in addition to
their solvent role. These DESs have been widely used as green and sus-
tainable media as well as catalysts in many chemical processes.
In this study, we wish to report a new, simple and efficient method
for the synthesis of quinoline derivatives from aniline, aromatic alde-
hydes and enolizable aldehydes in presence of choline chloride/tin(II)
chloride DES as an efficient media. Moreover, the catalytic recoverability
of the DES were investigated to show its high potency. The results ob-
tained in this work and the employed methodologies will be discussed
in the next sections.
1H), 8.32 (d, 1H), 8.94 (d, 1H) ppm·13C NMR (125 MHz, CDCl3): δ =
120.2, 125.5, 127.0, 127.4, 128.5, 128.6, 134.9, 147.5, 149.5 ppm.
1-phenyl-2-(quinolin-2(1H)-ylidene) ethanone (the tautomer form
of the expected quinoline derivative): Pale yellow solid, mp =
108–110 °C, FT-IR (KBr): νmax = 3428, 3059, 1628, 1580, 1549, 849,
824, 797, 752, 727, 690 cm−1 1H NMR (400 MHz, CDCl3): δ = 6.06
·
(s, 1H), 6.79 (d, 1H), 7.02 (t, 1H), 7.45 (m, 4H), 7.49 (m, 2H), 7.56 (d,
1H), 7.96 (m, 2H), 15.69 (bs, 1H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 89.9, 118.1, 122.3, 123.3, 123.7, 126.7, 127.6, 128.3, 130.4, 131.0,
136.2, 137.8, 139.8, 154.1, 183.9 ppm.
3. Results and discussion
Initially, we chose the model reaction between aniline (1 mmol),
benzaldehyde (1 mmol) and acetaldehyde (1 mmol) in the presence
of DES to optimize the reaction parameters and obtain the best condi-
tions for the general reaction according to Scheme 1. Different reaction
conditions such as the amount of DES (5, 10 and 20 mol%), reaction tem-
perature (r.t, 40, 60, 80 °C) and the reaction time (0.5, 1, 2, 5 h) were
changed and the preparation of product was monitored. The results
were listed in Table 1 that showed the best yield of the product could
be obtained by carrying out the reaction at 60 °C in the presence of
5 mol% of catalyst at 2 h (Table 1, entry 8). Therefore, we employed
these conditions to prepare other derivatives of quinoline according to
the general reaction (Scheme 1) but in preparation of some derivatives,
the time was increased to 3 h to improve the yield of the reaction.
The details of all prepared quinolines and obtained products were
shown in Table 2. In one especial case (entry 16 of the table), instead
of quinoline derivatives, its tautomeric form was obtained. According
2. Experimental
Chemicals were purchased from Merck and Sigma-Aldrich compa-
nies. Progress of the reactions was followed by thin layer chromatogra-
phy (TLC) using silica gel 60 PF254 plates. Melting points were measured
in capillary tubes using Gallen Kamp melting point instrument without
correction. IR spectra were recorded with KBr pellets on JASCO FT-IR
spectrophotometers in the range of 400 to 4000 cm−1·1H and 13C
NMR (respectively in 400 and 125 MHz) spectra were recorded on a
Bruker Ultrashield 400 MHz spectrometer in CDCl3 solution.1H and 13
chemical shifts are referenced to TMS as an internal standard.
C
2.1. Preparation of DES
A mixture of choline chloride/tin(II) chloride with 1:2 ratio was
heated with stirring until a clear colorless liquid was obtained. The mix-
ture was used without further purification.
to this table,
a variety of arylaldehydes containing electron-
withdrawing and electron-donating groups at the ortho, meta or para
position were used.
In addition, aniline and its 4-chloro and 4-bromo derivatives were
used as aromatic amine source, in attendant with various enolizable al-
dehydes (ethanal, propanal, butanal and heptanal) to show the versatil-
ity of the reaction. It is important to note that some of the optimization
reactions were also carried out without the presence of DES as a catalyst
and solvent (Table 1, entries 1–4). Under these conditions, the desired
2.2. General procedure for the synthesis of quinoline derivatives
Aniline derivative (1 mmol), aromatic aldehyde (1 mmol),
enolizable aldehyde (1 mmol) and ChCl·2SnCl2 (5 mol%) was mixed
in a 25 mL round-bottom flask equipped with a condenser on the top.
The reaction mixture has been stirred for 2–3 h and during stirring, it
was warmed slowly on the oil bath to 60 °C. The progress of the reaction
was monitored by TLC (eluent phase = n-hexane: EtOAc = 3:1). After
completion of the reaction, the mixture was diluted with water
(5 mL) and Et2O (2 × 5 mL) and shaken vigorously. The organic layer
was separated from the aqueous layer (consisted of DES) by simple
liquid-liquid extraction. The deep eutectic solvent was dried at 60–70
°C to remove water and reused. The organic layer was dried over
MgSO4 and its solvent was evaporated. The crude product was recrystal-
lized in ethanol to give the pure product or purified by column chroma-
tography over silica gel (hexane: ethyl acetate ratio: 3:1). All products
were known compounds and their physical and spectroscopic data
(mp, IR, 1H NMR, 13C NMR) were compared with those of authentic
samples in the references [39–46]. The physical and spectroscopic
data for selected compounds are as follows.
Table 1
Optimization of Reaction Conditions for the Synthesis of the model reactiona.
Entry
Catalyst
T (°C)
Cat (Mol %)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
ChCl·2SnCl2
ChCl·2SnCl2
ChCl·2SnCl2
ChCl·2SnCl2
ChCl·2SnCl2
ChCl·2SnCl2
ChCl·2SnCl2
ChCl·2SnCl2
ChCl·2SnCl2
ChCl·2ZnCl2
ChCl·2Urea
r.t.
40
60
80
60
60
60
60
60
60
60
20
20
20
20
10
5
5
5
5
5
5
5
5
5
5
5
2
1
0
30
94
90
96
96
96
62
45
73
10
9
10
11
30 min
2
2
5
Quinoline: Pale yellow oil, FT-IR (KBr): νmax = 3057, 3035, 1595,
1570, 1550, 1534, 1500, 868, 805, 786, 759, 738 cm−1·1H NMR
(400 MHz, CDCl3): δ = 7.09 (t, 1H), 7.35 (t, 1H), 7.58 (m, 2H), 7.82 (d,
a
The model reaction: aniline (1 mmol), benzaldehyde (1 mmol) and acetaldehyde (1
mmol).
b
Isolated yield.

326
D. Shahabi, H. Tavakol / Journal of Molecular Liquids 220 (2016) 324–328
Table 2
a
One-pot, three-component synthesis of quinoline derivatives catalyzed by ChCl·2SnCl2
.
Entry
1
R1
R2
R3
Product
Time (h)
2
Yield(%)b
95
Mp
Ref
4-Br
3-NO2-C6H4
C5H11
128–129
[39]
2
3
4-Br
4-Br
4-Cl-C6H4
C5H11
3
3
96
95
102–104
100–102
[39]
[39]
4-OCH3-C6H4
C5H11
4
5
4-Br
4-Br
Naphthyl
C5H11
2
3
72
63
110–112
198–200
[39]
[39]
3,4-OCH3-C6H4
C5H11
6
7
H
H
H
H
H
2
2
92
96
Oil
Oil
[39]
[39]
C6H5
8
9
H
H
C6H5
C2H5
2
2
93
54
Oil
Oil
[39]
[39]
4-OCH3-C6H4
C5H11
10
11
H
H
4-(Me)2N-C6H4
4-OCH3-C6H4
CH3
CH3
2
3
97
87
100–102
104–106
[39]
[43]
12
13
H
Naphthyl
C6H5
CH3
CH3
4
2
64
76
109–111
104–107
[43]
[43]
4-Cl
14
H
2-OH-C6H4
CH3
2
82
113–116
[44]
15
16
H
H
4-Cl-C6H4
CH3
H
2
3
68
95
95–97
[45]
[46]
CH2COC6H4
108–110
a
Reaction conditions: a mixture of aniline derivatives (1 mmol), aryl aldehyde derivatives (1 mmol), aliphatic aldehyde derivatives (1 mmol) and DES (5mol%) were heated in an oil
bath at 60 °C.
b
Isolated yield.
quinolines were obtained between 0 and 71% yields. These results
clearly show that the present DES catalyst is necessary for the synthesis
of quinolines. By comparison between aniline and its derivatives and al-
though between various enolizable aldehyde, any significant difference
in their reactivities was not observed. However, aromatic aldehydes
with electron withdrawing groups produced the products in the higher
yields. To define the role of employed DES in the reaction, a reliable
mechanism was proposed according to Scheme 2. The DES could be con-
sidered as choline cation and SnCl3 anion that plays the both roles of
Lewis acid (to activate the aldehyde or imine versus nucleophilic addi-
tion) and base (to get the proton of enolizable aldehyde and produce
enolate anion).

D. Shahabi, H. Tavakol / Journal of Molecular Liquids 220 (2016) 324–328
327
Scheme 2. Proposed mechanism for the synthesis of quinolines catalyzed by ChCl·2SnCl2.
At the final step of this study, the reusability of DES, which is much
4. Conclusion
important for industrial purposes and recommended for green pro-
cesses [47,48], has also been explored in the model reaction. To test
the reusability of the catalyst, after accomplishment of the reaction,
the mixture was diluted with 5 mL of water and the organic phase
was extracted using 2 × 5 mL of diethyl ether. The water of aqueous
layer (consisted of DES) was evaporated to obtain the pure DES, it was
dried at 60–70 °C and reused (for next three times) without further pu-
rification. All of these steps were performed quickly to avoid hydrolyz-
ing tin chloride. The results were listed in Table 3 and they showed
that the employed DES could be used at least four times without any sig-
nificant loss in the yield of the product. It is more valuable when we
know that simple SnCl2 salt could be hydrolyzed in the excess values
of the water. However, because of the nature of our DES and producing
SnCl−3 , it could be reused without hydrolyzing in the water.
In summary, we have developed an environmentally-friend and
green approach for the synthesis of quinoline derivatives via a one-
pot, multi-component reaction between aniline derivatives, aryl alde-
hydes and enolizable aldehydes in the presence of ChCl2·SnCl2 DES as
a green catalyst and solvent. This method offers several advantages in-
cluding using of a green DES instead of toxic organic solvents or cata-
lysts (or both), high yields, short reaction times, simple work-up
procedure and reusability of DES.
Acknowledgement
The partial support of this work by the research council of Isfahan
University of Technology is gratefully acknowledged.
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