G Model
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N. Azizi et al. / C. R. Chimie xxx (2013) xxx–xxx
most investigated transformations during the past decade,
in conjunction with the enabling technologies, such as
high-throughput screening, combinatorial and assembling
complex pharmacologically important structures. The
classical Ugi reaction is carried out in solvents, such as
methanol and dichloromethane under stirring at room
temperature overnight [25–30]. In order to further comply
with the green chemistry, alternative green solvents, such
as water and trifluoroethanol or ionic liquids, were used in
an isocyanide-based multicomponent reaction [31–34].
complete. To consider the efficiency of DES relative to
conventional organic solvents, some protic and aprotic
solvents were performed with the optimized conditions of
DES; the results are summarized in Table 1. The results
confirmed that DES is the best solvent and catalyst for the
one-pot multicomponent Ugi reaction.
Under these reaction conditions, the evaluation of DESs
as solvents was tested for a wide range of carbonyl
compounds. A variety of structurally diverse aldehydes
and ketones, including saturated, unsaturated, aromatic
and heteroaryl aldehydes underwent green reaction
smoothly, without using any catalyst to afford the
corresponding Ugi products in good to excellent yields.
The results are summarized in Table 2. Aryl aldehydes
substituted with various electron-withdrawing and elec-
tron-donating groups, as well as heteroaryl aldehydes,
aliphatic aldehydes and simple ketones did not seem to
influence the reaction time and yields, as revealed by the
similarity of the results, and all the carbonyl groups readily
converted into their corresponding Ugi products in the
presence of a variety of functional groups.
Encouraged by this success, the reaction is also studied
for various aromatic amines, isocyanides, and carboxylic
acid. Benzaldehyde was reacted with aromatic amines,
such as 4-methylaniline, 4-methoxyaniline, 2-methylani-
line, 4-chloroaniline, and 4-bromoaniline in DES at room
temperature, giving good to excellent yields. To further
increase the diversity at this point, we next tested other
benzoic acid derivatives, which also produced the desired
2. Results and discussion
Throughout our investigations to develop green chem-
istry by using water and deep eutectic solvent as reaction
medium [35–39], in the present work, we report the first
example of an efficient and green procedure for a one-pot
multicomponent Ugi reaction in DES based on choline
chloride and urea as a novel and green catalyst and
reaction medium.
The experimental procedure is very simple and easy.
The deep eutectic solvent DES was prepared by simply
mixing choline chloride (100 mmol) with urea (200 mmol),
and heated to ca. 80 8C in air with stirring till a clear
solution was obtained, which was used without any
purification. Since this method forms eutectic mixture
with no by-product formation, it provides 100% atom
economy.
In a typical experiment, benzaldehyde (0.5 mmol),
aniline (0.5 mmol), benzoic acid (0.5 mmol), cyclohexyli-
socyanide (0.5 mmol) and deep eutectic solvent (1 mL)
were stirred at room temperature. After completion
(180 min), the reaction mixture was diluted with water,
and the white solid mass was separated by simple
filtration. The corresponding Ugi product 5 was formed
as the only detectable product and isolated in 90% yield
after washing with water and ethanol (Table 1).
The DES was recovered easily from the filtrate by
evaporating water under vacuum and reused for three
successions of the reaction without much loss in the
product yields. Furthermore, it was possible to monitor the
a
-aminoacyl amide derivatives in good yields. The scope of
the isocyanide component was then examined. The
reaction of benzaldehyde, aniline, benzoic acid and t-butyl
isocyanide, tosylmethyl isocyanide (TOSMIC) also gave the
desired products in moderate to good yields in this type of
process (Fig. 1).
The experimental procedure is easy and the reactions
went to completion at room temperature, within 2–5 h,
depending on the reactivity of the aldehydes and
carboxylic acids. The products were easily separated by
easy extraction of the deep eutectic solvent with water,
and were usually obtained in high purity.
reaction visually.
A
white suspension solution was
In general, the reactions are very mild and clean, and no
side-products were obtained between the starting materi-
als of the Ugi reaction with DES in any run. Furthermore, in
the separated model reaction, aniline as well as benzoic
obtained after addition of all the components to the deep
eutectic solvent, and the reaction mixture became an
orange viscous liquid or solid after the reaction is
Table 1
Comparison of conventional organic solvents with DES.
O
Ph
PhNH2
2
PhCHO
1
H
Solvent (1 mL)
rt, 3h
N
+
Ph
N
C6H11
H11C6-NC
PhCO2H
Ph
O
4
5
3
Entry
Solvent (1 mL)
Yields (%)
1
2
3
4
5
6
Urea–choline chloride
90
60
40
45
30
45
Neat (solvent free condition)
CH3OH
H2O
CH2Cl2
CH3CN
Please cite this article in press as: Azizi N, et al. A sustainable approach to the Ugi reaction in deep eutectic solvent. C. R.
Azizi, Najmedin
