Dimethylurea/citric acid as a highly efficient deep eutectic solvent for the multi-component reactions

Article abstract of DOI:10.1007/s12039-014-0624-x

Dimethylurea/citric acid deep eutectic solvent was used as a dual catalyst and a green reaction medium for the efficient synthesis of bis(indolyl)methanes, quinolines and aryl-4, 5-diphenyl-1H-imidazoles. Ease of recovery and reusability of DES with high

Full text of DOI:10.1007/s12039-014-0624-x

c
J. Chem. Sci. Vol. 126, No. 3, May 2014, pp. 881–887. ꢀ Indian Academy of Sciences.
Dimethylurea/citric acid as a highly efficient deep eutectic solvent
for the multi-component reactions
BEHNAZ BAFTI and HOJATOLLAH KHABAZZADEH∗
Department of Chemistry, Shahid Bahonar University of Kerman, Kerman, 76169, Iran
e-mail: hkhabazzadeh@uk.ac.ir
MS received 27 October 2013; revised 13 January 2014; accepted 17 January 2014
Abstract. Dimethylurea/citric acid deep eutectic solvent was used as a dual catalyst and a green reaction
medium for the efficient synthesis of bis(indolyl)methanes, quinolines and aryl-4, 5-diphenyl-1H-imidazoles.
Ease of recovery and reusability of DES with high activity makes this method efficient and eco-friendly.
Keywords. Deep eutectic; citric acid; dimethylurea; bis(indolyl)methane; quinoline; aryl-4, 5-diphenyl-1H-
imidazole.
1. Introduction
organic salt and a suitable organic complexant, typically
a hydrogen-bond donating species such as a polyol or
urea derivatives.
Solvents play an essential role in chemical processes
serving to put reactants into contact by dissolution and
also affecting rates of the reactions. Solvents are also
used in the later stages of a reaction for extraction and
purification of the products.
Organic solvents are extensively used in organic syn-
thesis and for this reason they are a matter of much
concern due to characteristics such as high flammabi-
lity, volatility, hazardness, and toxicity. Thus the search
for environmentally benign substitutes for organic sol-
vents has recently gained more attention in view of the
increasing importance of Green Chemistry.
DESs exhibit similar physico-chemical properties
to the traditionally used ionic liquids, while being
much cheaper and environmentally friendlier. Rela-
tive to conventional ILs, DESs have significant advan-
tages, such as being easier and cheaper to prepare, non-
reactive with water and many are biodegradable, but
still exhibit chemical stability, non-flammability and
conductivity.8 ,9
In recent years DES were used in synthetic organic
chemistry due to their ability to serve as catalysts as
well as solvents.10–12
Room-temperature ionic liquids (ILs) are potential
green alternatives to organic solvents1 for extractions,2
chemical reactions3 and biotransformations.4 Ionic liq-
uids are non-volatile, thermally stable and their solva-
tion properties vary by changing the cation and anion.
However, most ILs have the disadvantage of high cost
for large-scale production and some of them are envi-
ronmentally unsafe. Moreover, the preparation of ILs
often requires the use of organic solvents, and heat
supply,5 and cost can be high.
In this investigation a new method for the synthe-
sis of bis(indolyl)methanes, quinolines and aryl-4, 5-
diphenyl-1H-imidazole in the presence of dimethyl-
urea/citric acid deep eutectic solvent (DES) as an effi-
cient, low cost and homogeneous catalytic medium will
be described (scheme 1).
2. Experimental
Another new versatile reaction medium has emerged,
known as deep eutectic solvents (DESs). Abbott et al.6,7
pioneered the development of these solvents which are
low-melting liquids derived from the mixture of a solid
All chemicals were purchased from Merck chemical
company and were used without further purification.
All products are known and were identified by compar-
ison of their spectral data and physical properties with
those of the authentic samples. Melting points were
obtained in open capillary tubes and were measured on
an Electrothermal-9100 and 9200 apparatus. 1H and 13C
NMR spectra were determined on a Bruker 300-DRX
Avance instrument at 300 and 75 MHz.
∗For correspondence
881

882
Behnaz Bafti and Hojatollah Khabazzadeh
1
2
R R
O
DES
1
R
2
R
+
100 oC
N
N
N
z
z
z
3
2
1
Ph
Ph
N
Y
O
R'
R
Y
O
DES
R'
+
R
100 oC
NH2
4
5
6
Ph
Ph
O
O
DES
N
Ar CHO
NH OAc
+
+
4
100 oC
Ph
Ph
Ar
N
H
7
8
9
Scheme 1. Synthesis of bis(indolyl)methane, quinoline and imidazole derivatives in presence of DES.
2.1 Preparation of deep eutectic solvent
2.3 General procedure for the preparation
of quinolines
The deep eutectic solvent (DES) was prepared as fol-
lows: a mixure of dimethylurea/citric acid with 6:4 ratio 2-Amino aryl ketone 4 (1 mmol) was added to 1.1 mmol
was heated at 100◦C in air with stirring until a clear ketone 5 and were reacted in the same conditions for the
colourless liquid was obtained. Then the mixture was preparation of bis(indolyl)methanes.
used.
2.4 General procedure for the preparation of aryl-4,
5-diphenyl-1H-imidazole
2.2 General procedure for the preparation
of bis(indolyl)methanes
Benzil (1 mmol), aldehyde (1 mmol), ammonium
acetate (3 mmol) were reacted in the same conditions
for the preparation of bis(indolyl)methanes.
A mixture of an aldehyde 1 (1 mmol), indole deriva-
tive 2 (2 mmol) and 1 g of DES was heated at 100◦C
for a period of time as indicated in table 1. The
reactions were followed by thin-layer chromatography
(TLC). After completion of the reaction, 10 mL of
water was added to the mixture and the resulting pre-
2.5 Spectral data
cipitate was filtered off. The product was recrystalyzed 2.5a 3, 3ꢁ-Bis-indolyl phenylmethane (table 1, entry
from ethanol and the filtered solution was evaporated to 6):13 1H NMR (300 MHz, CDCl3): δ 5.92 (s, 1H),
recover the DES.
6.60 (d, J = 15 Hz, 2H), 7.05 (d, J = 7.9 Hz, 2H), 7.20

Dimethylurea/citric acid deep eutectic solvent
883
Ref.
17
Table 1. Synthesis of bis(indolyl)methanes in dimethylurea/citric acid DES.
Entry
Aldehyde
Product
Time (min)
Yield (%)
86
Mp (observed)
74–76
Mp (reported)
70–71
CHO
Cl
Cl
1
2
N
N
H
H
Cl
CHO
17
2
3
2
4
95
90
77–79
97–99
76–77
93–94
N
H
N
H
Cl
CH3
CHO
17
CH3
N
H
N
H
Cl
CHO
Cl
Cl
14
4
4
96
102–105
103–106
Cl
N
H
N
H
NO2
CHO
18
14
5
6
4
2
85
90
224–226
127–130
220–223
125–127
N
H
N
H
NO2
CHO
N
H
N
H
NO2
CHO
NO2
13
7
6
88
210–211
215–217
N
N
H3C
CH3
2.5b 3, 3ꢁ-Bis-(N-methylindolyl)-(4-nitro phenyl-
methane) (table 1, entry 7):14 1H NMR (300 MHz,
CDCl3): δ (ppm) 3.79 (6H, s, 2CH3), 6.10 (1H, s),
6.68 (2H, s), 7.14 (2H, t, J = 7.3 Hz), 7.34 (2H, t, J =
7.7 Hz), 7.45 (4H, m), 7.61 (2H, d, J = 8.5 Hz), 8.23
(2H, d, J = 8.5 Hz). 13C NMR (75 MHz, CDCl3): δ
(d, J = 7.9 Hz, 2H, Ar–H), 7.23–7.28 (m, 1H, Ar–H),
7.29–7.35 (m, 3H, Ar–H), 7.36–7.40 (m, 3H, Ar–H),
7.42 (d, J = 79 Hz, 2H, Ar–H), 7.82 (s, 2H, N–H). 13
C
NMR (75 MHz, CDCl3): δ 40.1, 111.1, 119.2, 119.7,
121.0, 121.9, 123.8, 126.1, 127.1, 128.2, 128.8, 136.6,
144.1.

884
Behnaz Bafti and Hojatollah Khabazzadeh
(ppm) 32.8, 40.2, 109.4, 116.7, 119.1, 119.7, 121.9, (1H, t, J = 8.0 Hz, arom), 7.47 (2H, d, J = 2.0 Hz,
123.6, 127.1, 128.4, 129.5, 137.5, 146.5, 152.4.
arom), 7.48 (1H, d, J = 1.6 Hz, arom), 7.58 (1H, d, J
= 8.0 Hz, arom), 7.72 (1H, d, J = 6.8 Hz, arom), 8.08
(1H, d, J = 8.4 Hz, arom). 13C NMR (75 MHz, CDCl3):
δ (ppm) 13.6, 23.8, 61.3, 125.1, 126.4, 126.5, 127.4,
128.2, 128.4, 128.8, 129.3, 130.2, 135.7, 146.2, 147.7,
154.6, 168.4.
2.5c Ethyl-6-chloro-2-methyl-4-phenylquinoline-3-
carboxylate (table 2, entry 1):15 1H NMR (300 MHz,
CDCl3): δ (ppm) 0.95 (3H, t, J = 7.2 Hz, CH3), 2.77
(3H, s, CH3), 4.06 (2H, q, J = 7.2 Hz, CH2), 7.33 (1H,
d, J = 2 Hz, arom), 7.35 (1H, d, J = 3.6 Hz, arom),
7.49 (2H, d, J = 2.4 Hz, arom), 7.50 (1H, s, arom), 7.54 2.5e 2-(4-Chloro-phenyl)-4, 5-diphenyl-1H-imidazole
(1H, d, J = 2.4 Hz, arom), 7.65 (1H, dd, J = 8.8 Hz, (table 3, entry 2):16 1H NMR (300 MHz, DMSO-d6)δ
J = 2.4 Hz, arom), 8.01 (1H, d, J = 8.8 Hz, arom). (ppm): 7.21–7.48 (10H, m), 7.54 (2H, d, J = 8.5 Hz),
13C NMR (75 MHz, CDCl3): δ (ppm) 13.6, 23.7, 61.4, 8.09 (2H, d, J = 8.5 Hz), 12.76 (1H, s). 13C NMR
125.2, 125.9, 128.2, 128.4, 128.7, 129.3, 130.5, 131.1, (75 MHz, DMSO-d6)δ (ppm): 126.5, 126.8, 127.0,
132.3, 135.0, 145.4, 146.1, 155.0, 168.1.
127.8, 128.1, 128.4, 128.6, 128.7, 129.1, 130.8, 132.7,
134.9, 137.2, 144.3.
2.5d Ethyl-2-methyl-4-phenylquinoline-3-carboxylate
(table 2, entry 2):15 1H NMR (300 MHz, CDCl3): 2.5f 2-(3-Nitro-phenyl)-4, 5-diphenyl-1H-imidazole
δ (ppm) 0.95 (3H, t, J = 7.2 Hz, CH3), 2.79 (3H, s, (table 3, entry 5):16 1H NMR (300 MHz, DMSO-
CH3), 4.06 (2H, q, J = 7.2 Hz, CH2), 7.36 (1H, d, d6) δ (ppm): 7.21–7.57 (10H, m), 7.77 (1H, t, J =
J = 2.0 Hz, arom), 7.37 (1H, d, J = 4.0 Hz, arom), 7.43 8.0 Hz), 8.18-8.22 (1H, m), 8.50 (1H, d, J = 8.0 Hz),
Table 2. Synthesis of quinolines in dimethylurea/citric acid DES.
Entry
1
Carbonyl
Product
Time (min)
10
Yield (%)
92
Mp (observed)
102–104
Mp (reported)
106–107
Ref.
Ph
O
O
O
O
O
Cl
OEt
20
OEt
OEt
N
Ph
O
OEt
20
21
20
21
21
2
3
4
5
15
25
15
15
30
90
88
93
90
90
96–98
100–101
150–151
208–210
185–186
164–165
N
Ph
N
O
Cl
O
O
145–147
202–205
180–183
160–162
Ph
O
O
O
O
Cl
N
Ph
O
O
Cl
N
Ph
O
O
Cl
6
7
N
Ph
21
25
85
151–153
156–157
N

Dimethylurea/citric acid deep eutectic solvent
885
Table 3. Synthesis of aryl-4, 5-diphenyl-1H-imidazole in dimethylurea/citric acid DES.
Entry
Aldehyde
Product
Time (min)
Yield (%)
Mp (observed)
Mp (reported)
280–281
Ref.
Ph
CHO
N
22
1
25
90
275–278
Ph
N
H
CHO
Ph
N
2
3
Ph
22
16
N
30
30
92
88
260–265
260–262
263–265
264–266
H
Cl
Br
Cl
CHO
Ph
N
Ph
N
H
Br
CHO
Ph
N
4
5
22
16
50
30
86
92
228–230
290–295
230–232
301–302
Ph
N
H
OMe
NO2
OMe
CHO
Ph
N
Ph
N
H
NO2
8.95 (1H, m), 13.08 (1H, s).13C NMR (75 MHz,
DMSO-d6)δ (ppm): 119.3, 122.5, 126.7, 127.1, 128.2,
128.4, 128.6, 129.1, 130.4, 130.6, 131.1, 131.8, 134.7,
137.6, 143.3, 147.0, 148.3.
indole were investigated. In order to show the general
applicability of this method, various aldehydes were
efficiently reacted with two equivalents of indole
derivatives in the same conditions. As shown in table 1
yields are good to excellent in most cases.
After successfully synthesizing
a
series of
bis(indolyl)methanes, we turned our attention towards
the synthesis of quinoline derivatives in the presence
of dimethylurea/citric acid (6:4) DES under similar
reaction conditions.
As shown in table 2, this method is equally effec-
tive for both cyclic and acyclic ketones. This reaction
is very clean and free from side reactions such as self-
condensation of ketones, which is normally observed
under basic conditions.
3. Results and discussion
Initially, we chose indole (2 mmol) and benzaldehyde
(1 mmol) as standard starting materials to establish the
best conditions for the reaction.
Best results were obtained with (6:4) dimethyl-
urea/citric acid DES at 100◦C.
After setting up the optimized reaction conditions,
the reaction of a series of carbonyl compounds with
Table 4. Reaction of indole with carbonyl compounds in the presence of different catalysts.
Product
Catalyst
Conditions
Solvent
Time (min)
Yield (%)
80
Ref.
23
Cl
Fe(HSO4)3
R.T.
CH2Cl2
Solvent-free
Solvent-free
Dimethylurea/citric acid
30
15
6
[BTBAC]Cl-FeCl13
[bnmim][HSO4]
–
60◦C
Microwave
100◦C
95
95
95
24
25
2
–
N
N
H
H
1Benzyl tributylammonium chloride

886
Behnaz Bafti and Hojatollah Khabazzadeh
Table 5. Reaction of ethylacetoacetate with 2-amino-5-chloro benzophenone in the presence of different catalysts.
Product
Catalyst
Conditions Solvent
Time (min) Yield (%) Ref.
O
19
Cellulose sulphuric acid
100◦C
60◦C
Solvent-free
Solvent-free
Solvent-free
Dimethylurea/citric acid
15
120
20
92
80
96
92
Cl
15
26
OEt
I2
Dodecylphosphonic acid
–
90◦C
N
100◦C
10
–
Table 6. Reaction of benzil with benzaldehyde in the presence of different catalysts.
Product
Catalyst
Conditions
Solvent
Time (min)
Yield (%)
Ref.
Ph
21
22
27
–
poly(AMPS-co-AA)1
H2SO4.SiO2
–
110◦C
110◦C
110◦C
100◦C
PEG-400
Solvent-free
Solvent-free
Dimethylurea/citric acid
90
25
50
25
88
92
90
90
N
Ph
N
H
–
1Poly acrylamido-2-methyl-1-propane sulphonic acid-acrylic acid
In the next step, dimethylurea/citric acid (6:4) DES 4. Conclusion
was used for the synthesis of 2-aryl-4, 5-diphenyl-1H-
In conclusion, we have developed an environmentally
friendly, and practical procedure for the synthesis of
bis(indolyl)methane, quinoline and aryl-4, 5-diphenyl-
1H-imidazole derivatives in the presence of a deep
eutectic solvent and readily available starting materials
in high yields. This method offers several advantages
including using of a green DES instead of organic sol-
vents, high yields, short reaction times, and a simple
work-up procedure, and reusability of DES.
imidazole derivatives under similar reaction conditions.
The results are summarized in table 3.
In order to show the merit of dimethylurea/citric acid
DES catalytic system in comparison with the other cata-
lytic systems used for the similar reactions, some of
the results have been given in tables 4, 5 and 6. As it
is evident from the results, the present method is very
efficient for the synthesis of bis(indolyl) methanes and
quinolines.
3.1 Recyclability of deep eutectic solvent
Acknowledgements
The deep eutectic solvent medium was recycled and re-
used up to three times. Reaction of 4-nitro benzalde-
hyde with N-methyl indole was selected as the model
reaction. Deep eutectic solvent that recycled from the
previous run was re-used for the next run without fur-
ther purification. Only a slight decrease in yields was
observed as shown in table 7. This indicates the fact that
DES reserves its activity even after three runs.
Financial support received from Research Council of
Shahid Bahonar University of Kerman for this work is
acknowledged.
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86

Dimethylurea/citric acid deep eutectic solvent
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