Choline chloride/urea as a deep eutectic solvent/organocatalyst promoted three-component synthesis of 3-aminoimidazo-fused heterocycles via Groebke-Blackburn-Bienayme process

Article abstract of DOI:10.1016/j.tetlet.2015.12.014

The catalytic activity of urea-, metal- and organic acid-based/choline chloride deep eutectic solvents/organocatalysts was investigated for the synthesis of 3-aminoimidazo-fused heterocycles via a one-pot domino reaction of an aldehyde, an isocyanide and 2-aminoheterocycles. The urea-based/choline chloride system exhibited significant catalytic activity for the reaction and could be reused in four consecutive reactions with no considerable loss in catalytic activity.

Full text of DOI:10.1016/j.tetlet.2015.12.014

Accepted Manuscript
Choline chloride/urea as a deep eutectic solvent/organocatalyst promoted three-
component synthesis of 3-aminoimidazo-fused heterocycles via Groebke-
Blackburne-Bienayme process
Ahmad Shaabani, Seyyed Emad Hooshmand
PII:
S0040-4039(15)30429-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.014
TETL 47061
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 April 2015
1 November 2015
2 December 2015
Please cite this article as: Shaabani, A., Hooshmand, S.E., Choline chloride/urea as a deep eutectic solvent/
organocatalyst promoted three-component synthesis of 3-aminoimidazo-fused heterocycles via Groebke-
Blackburne-Bienayme process, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.12.014
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Choline chloride/urea as a deep eutectic solvent/organocatalyst
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promoted three-component synthesis of 3-aminoimidazo-fused
heterocycles via Groebke-Blackburne-Bienayme process
Ahmad Shaabani* and Seyyed Emad Hooshmand

1
Tetrahedron Letters
Choline chloride/urea as a deep eutectic solvent/organocatalyst promoted three-
component synthesis of 3-aminoimidazo-fused heterocycles via Groebke-Blackburne-
Bienayme process
Ahmad Shaabani* and Seyyed Emad Hooshmand
a Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran Email: a-shaabani@sbu.ac.ir
ARTICLE INFO
ABSTRACT
The catalytic activity of urea-, metal- and organic acid-based/choline chloride deep
eutectic solvents/organocatalysts were investigated for the synthesis of 3-
aminoimidazo-fused heterocycles via a one-pot domino reaction of an aldehyde, an
isocyanide and 2-aminoheterocycles. The urea-based/choline chloride system exhibited
significant catalytic activity for the reaction and could be reused in four consecutive
reactions with no considerable loss in catalytic activity.
Article history:
Received
Received in revised form
Accepted
Available online
2015 Elsevier Ltd. All rights reserved.
Keywords:
Deep eutectic solvents
GBB reaction
Multicomponent reactions
Isocyanide chemistry
The synthesis of organic compounds using new chemical
strategies and activation processes is used to highlight the
power of organic transformations. The development of
strategies to accomplish reactions are of fundamental interest
to chemists. A class of solvents with physical properties and
phase behaviours very similar to those of room temperature
ionic liquids (RTILs) are deep eutectic solvents (DESs). A
series of DESs based on choline chloride and metal
chlorides, polyols, sugars, carboxylic acids or urea have been
reported.1 The charge delocalization occurring through
hydrogen bonding between the electronegative component,
such as a halide ion, and the hydrogen-donor moiety, is
responsible for the decrease in the melting points of the
mixture relative to the melting points of the individual
components.2, 3 DESs are attractive alternatives to RTILs, as
they are less expensive, more synthetically accessible,
nontoxic and biodegradable.4,5 To date, DESs have been
applied to many chemical processes such as extraction,6,7
polymerization,8 biomass processing,9 as sustainable media
for the controlled synthesis of nanoscale and functional
materials 10 and various organic reactions.11-23
involving the formation of multiple bonds in a single
reaction with high atom efficiency.24 The Groebke-
Blackburne-Bienayme (GBB) reaction which was
independently disclosed by three research groups25-27
involves the reaction between an aldehyde, 2-aminoazine
and an isocyanide in the presence of a suitable acid catalyst,
affording highly substituted, fused imidazole derivatives.28
Imidazopyridine, an imidazole moiety fused with a pyridine
ring, is an important class of biologically active nitrogen
containing heterocycle. Among the various imidazopyridine
derivatives, the imidazo[1,2-a]pyridine moiety is one of the
most important in terms of natural products and
pharmaceuticals and has recently been reviewed.29
Figure 1. Selected imidazo[1,2-a]pyridine-based drugs.
These derivatives show a wide range of biological
activities with anti varicella-zoster,30 antibacterial,31
Multicomponent reactions (MCRs) have emerged as
powerful tools to construct complex molecular architectures

2
Tetrahedron Letters
antifungal32 and anthelmintic33 applications. Several drugs
such as zolpidem ( 2,
, treatment of insomnia),34 alpidem (
Table 2. 3-Aminoimidazo-fused heterocycle synthesis using
choline chloride:urea
1
anxiolytic agent)34 and zolimidine (
3, treatment of peptic
ulcers)35 are available which contain the imidazo[1,2-
a]pyridine moiety (Figure 1).
The synthesis of 3-aminoimidazo-fused heterocycles
yield 4
time
(min)
Entry
1
2
3
(%)a
such
as
3-aminoimidazo[1,2-a]pyridines
and
3-
aminoimidazo[1,2-a] pyrazines have been reported in
various solvents, however the use of hazardous and toxic
solvents in chemical processes is considered an issue with
regard to health and safety as well as environmental
pollution. In addition, although the advantages of catalysts
for organic transformations are plentiful, in many cases extra
steps are needed to recycle the catalyst and/or remove it
from the reaction medium. Very recently, the GBB reaction
has been carried out in the presence of Lewis36-38 or Brønsted
acid27 catalysts. In order to comply with the principles of
1
2
4a, 8843
55
50
4b, 8643
3
4
5
4c, 80
4d, 85
4e, 8636
120
80
70
green chemistry, alternative media, such as water,39
41
poly(ethyleneglycol) (PEG),40,
ionic liquids42 and also
solvent-free conditions43 have been reported for the synthesis
of 3-aminoimidazo-fused heterocycles.
6
7
4f, 9451
4g, 8640
45
70
Results and discussion
Based on our continued interest in isocyanide-based
multicomponent reactions (IMCRs)44-47 especially the
synthesis of imidazo[1,2-a]pyridines,42, 48-52 we describe the
efficiency of various choline chloride-based deep eutectic
solvents in the synthesis of 3-aminoimidazo-fused
heterocycles via the GBB three-component domino reaction.
Initially, in order to determine the best deep eutectic solvent,
the catalytic activities of various DESs were evaluated in the
model reaction of benzaldehyde (0.20 mmol), 2-
aminopyridine (0.20 mmol), and cyclohexyl isocyanide (0.20
mmol).53 As indicated in Table 1, the best conditions for the
GBB reaction were determined as choline chloride and urea
(1 mmol choline chloride:2 mmol urea) at 80 °C (Entry 3).
8
9
4h, 9041
4i, 9050
4j, 8448
50
50
60
10
11
12
13
4k, 8836
4l, 8838
55
50
45
4m,
9236
Table 1. GBB reaction in various DES based on choline chloride
Temp. Yield
14
15
16
4n, 9036
4o, 8638
4p, 85
40
50
80
Entry
DES
(oC)
25
50
80
80
80
80
80
80
(%)
30a
55
90
60
68
45
25
35
1
2
3
4
5
6
7
8
choline chloride:urea (1:2)
choline chloride:urea (1:2)
choline chloride:urea (1:2)
choline chloride:malonic acid (1:1)
choline chloride:citric acid (2:1)
choline chloride:PTSA (1:1)
choline chloride:ZnCl2 (1:2)
choline chloride:SnCl2 (1:2)
a Isolated yield.
a Yield after 4 h
As indicated in Table 2, 2-aminoazine derivatives such as
2-aminopyrazines, 2-amino-6-methylpyridine, 2-amino-5-
bromopyridine and 2-aminopyridines were successfully
applied to this reaction and afforded the corresponding 3-
aminoimidazo-fused heterocycles in excellent yields.
The scope of this reaction was investigated using different 2-
amino heterocycles, aldehydes and isocyanides (Table 2).
Accordingly,
2-aminobenzimidazole
and
2-
aminobenzothiazole (Table 1, 4g and 4p) were treated with
other pairs of components. To our delight, tricyclic scaffolds
(imidazo- fused benzoimidazole and imidazo-fused

3
benzothiazoles) were obtained. Additionally, aromatic
aldehydes containing both electron-donating and
synthesise 3-aminoimidazo-fused heterocycles are shown
in Figure 2.
withdrawing groups on the phenyl ring were found to react
equally well using this protocol. Heteroaromatic and
polycyclic aromatic aldehydes (furfural and 2-
naphthaldehyde) were also suitable substrates in this
protocol (Table 1, 4b and 4h). We also found that the
reaction proceeded in high yields using with alkyl
isocyanides such as cyclohexyl isocyanide, tert-butyl
isocyanide,
toluenesulfonylmethyl isocyanide.
2-morpholinoethyl
isocyanide
and
p-
Figure 2. From left to right A: mixture of choline chloride:urea
(1:2), white solid; B: preparation of DES after heating at 80 C,
o
colourless liquid; C: synthesis of 3-aminoimidazo-fused heterocycles
in DES, a coloured viscous oil; D: reaction mixture after addition of
water.
Recently Gámez-Montañ and co-workers reported a method
for the synthesis of imidazo[1,2-a]pyridin-chromones using
relatively harsh reaction conditions including an organic solvent
in the presence of a metal-based catalyst and chloroacetic acid
under microwave irradiation (MW) at 85 °C.54 In order to
investigate the possibility of the synthesis under metal-free
catalysis and mild reaction conditions, we extended our reaction
to 3-formylchromone derivatives to give compounds 4q-t
(Scheme 1). These products were obtained in relatively high
yields without the need for MW irradiation, under metal-free
catalysis and without organic solvents.
One of the advantages of using DES is their ability to act
as a recyclable reaction media. The reaction mixture,
including DES and products, was dissolved in water and the
crude product obtained by extraction with EtOAc. The DES
was recovered from the aqueous phase by evaporation at 80
°C under vacuum and was recycled for the next reaction
(Figure 3).
100
90
80
70
60
50
40
30
20
10
0
First
2
3
4
Figure 3. The recyclability of the DES
In conclusion, we have described an effective and rapid
system for the GBB reaction using an eco-friendly and
biodegradable deep eutectic solvent based on the choline
chloride–urea mixture. The advantages of this method are
operational simplicity, green medium, DES recoverability,
short reaction times and high yields.
Acknowledgments
We gratefully acknowledge financial support from the Iran
National Science Foundation (INSF), the Research Council of
Shahid Beheshti University and Catalyst Center of Excellence
Scheme 1. Synthesis of imidazo[1,2-a]pyridin-chromones
(CCE) at Shahid Beheshti University.
The experimental procedure is simple and the reaction
times are short. The steps for the preparation of DES to
5
6
7
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Tetrahedron Letters
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5-methyl-2-phenyl-imidazo[1,2-a]pyridine-3-amine 4d Light yellow
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CH), 3.14 (1H, s, NH), 7.31-7.42 (2H, m, H-Ar), 7.60 (3H, m, H-Ar),
7.99-8.19 (2H, td, Ja = 21.6 and Jb = 6.6 Hz, H-Ar). 13C NMR (75 MHz,
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126.8, 128.3, 128.7, 129.6, 130.6, 131.3, 131.6, 131.9, 133.0, 134.2,
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imidazo[1,2-a]pyridin-2-yl)-4H-chromen- 4-one 4q Orange powder; m.p.
155-158 °C. IR (KBr) cm-1: 3411, 2939, 2854, 1734, 1621, 1543, 1431.
1H NMR (300 MHz, DMSO-d6) : δ (ppm) 1.07 (5H, m, cyclohexyl),
1.46-1.76 (5H, m, cyclohexyl), 2.69 (1H, s, CH), 3.11 (1H, s, NH), 6.90-
6.94 (1H, m, H-Ar), 7.19-7.24 (1H, m, H-Ar), 7.47-7.50 (1H, m, H-Ar),
7.83-7.94 (1H, m, H-Ar), 8.19 (1H, m, H-Ar), 8.96 (1H, s, =CH). 13C
NMR (75 MHz, DMSO-d6) : δ (ppm) 21.3, 24.9, 25.6, 55.9, 112.2, 117.2,
120.3, 121.5, 123.6, 124.4, 124.9, 125.0, 129.1, 130.8, 134.8, 141.4,
154.5, 157.7, 174.9. Anal. Calcd for C22H20ClN3O2: C, 67.09; H, 5.12; N,
10.67; found C, 67.29 H, 4.89, N, 10.96.
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53 Preparation of choline chloride-based deep eutectic solvents: Choline
chloride-based deep eutectic solvents were prepared according to the
literature,2-3 and was used without further purification.
Typical procedure for preparation of 3-aminoimidazo-fused
heterocycles: 2-aminopyridine (0.25 mmol), benzaldehyde (0.25 mmol),
and cyclohexyl isocyanide (0.25 mmol) were added to DES (choline
chloride:urea 1 mmol:2 mmol). The resulting mixture was stirred for the
o
specified time (Table 2) at 80 C. After reaction completion, (TLC, ethyl
acetate/n-hexane, 2:1), the reaction mixture was washed with water (10
mL) and the solid residue recrystallized from ethyl acetate to obtain the
pure product. (In the case of imidazo[1,2-a]pyridin-chromones, the
reaction progress was monitored by TLC using CH2Cl2/n-hexane, 1:1).