ZnCl2/urea as a deep eutectic solvent for the preparation of bis(indolyl)methanes under ultrasonic conditions

Article abstract of DOI:10.1080/15533174.2013.862828

This work describes the synthesis of bis(indolyl)methanes by using effective combination of ultrasound and deep eutectic solvent. This methodology offers momentous improvements over various options for the synthesis of bis(indolyl)methanes with regard to

Full text of DOI:10.1080/15533174.2013.862828

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ZnCl /Urea as a Deep Eutectic Solvent for the
2
Preparation of Bis(indolyl)methanes Under Ultrasonic
Conditions
a
b
c
Neda Seyedi , Hojatollah Khabazzadeh & Samira Saeednia
a
Department of Chemistry, University of Jiroft, Jiroft, I. R. Iran
b
c
Department of Chemistry, Shahid Bahonar University of Kerman, Kerman, I. R. Iran
Department of Chemistry, Faculty of Science, Vali-e-Asr University, Rafsanjan, I. R. Iran
Accepted author version posted online: 18 Feb 2015.
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To cite this article: Neda Seyedi, Hojatollah Khabazzadeh & Samira Saeednia (2015) ZnCl /Urea as a Deep Eutectic Solvent
2
for the Preparation of Bis(indolyl)methanes Under Ultrasonic Conditions, Synthesis and Reactivity in Inorganic, Metal-Organic,
and Nano-Metal Chemistry, 45:10, 1501-1505, DOI: 10.1080/15533174.2013.862828
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry (2015) 45, 1501–1505
Copyright © Taylor & Francis Group, LLC
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2013.862828
ZnCl /Urea as a Deep Eutectic Solvent for the Preparation
2
of Bis(indolyl)methanes Under Ultrasonic Conditions
1
2
3
NEDA SEYEDI , HOJATOLLAH KHABAZZADEH , and SAMIRA SAEEDNIA
1
Department of Chemistry, University of Jiroft, Jiroft, I. R. Iran
2
Department of Chemistry, Shahid Bahonar University of Kerman, Kerman, I. R. Iran
3
Department of Chemistry, Faculty of Science, Vali-e-Asr University, Rafsanjan, I. R. Iran
Received 13 July 2013; accepted 2 November 2013
This work describes the synthesis of bis(indolyl)methanes by using effective combination of ultrasound and deep eutectic solvent.
This methodology offers momentous improvements over various options for the synthesis of bis(indolyl)methanes with regard to
yield of products, simplicity in operation, and green aspects by avoiding toxic catalysts and solvents. Further, the deep eutectic
solvent can be reused and recovered for several times without loss of activity.
Keywords: deep eutectic, bis(indolyl)methanes, ultrasound, ZnCl , indole
2
Introduction
therefore the possibility of formation of by-products is
reduced, and the reaction workup is easier.
Bis(indolyl)methanes have been obtained by the reaction
[
8]
Deep eutectic solvents (DESs) are materials consisting of
components that form a low melting point much lower than of indoles with various carbonyl compounds in the presence
[
9,10]
each of the individual components. This system provides a of either protic or Lewis acids.
Most of the previously
unique substance for developing advanced materials and usu- reported methods suffer from several disadvantages such as
ally cheaper with less time-consuming than the development using of expensive and toxic catalysts or toxic solvents such
[
11]
of new materials.
as benzene.
Hence a more efficient and practical alternative method
[
1,2]
Abbott et al.
pioneered the development of these sol-
vents, which are low-melting liquids derived from the mixture using an inexpensive and environmentally friendly reagent
of a solid organic salt and a suitable organic complexant, typ- and solvent is still demanded.
ically a hydrogen-bond donating species such as a polyol or
urea derivatives.
In this investigation a green, convenient, mild, and effi-
cient procedure for the synthesis of bis(indolyl)methanes is
DESs exhibit similar physicochemical properties to the reported using a deep eutectic mixture of ZnCl /urea (1:3.5)
2
traditionally used ionic liquids, while being much cheaper as solvent in ultrasonic (US) conditions (Scheme 1).
and environmentally friendlier. Compared to ionic liquids
DESs have some significant advantages. They are easier and
cheaper to prepare, nonreactive with water and many are bio-
Experimental
degradable, but still exhibit chemical stability, nonflamma-
[3,4]
bility, and conductivity.
Carbonyl compounds, indole, ZnCl , urea, and organic solvents
2
Application of ultrasound in organic transformation has
proved to be an important tool in enhancing reaction rates
were purchased from Merck chemical company and used with-
out further purification. All products are known and identified
by comparison of their spectral data and physical properties with
those of the authentic samples. Melting points were recorded on
an Electrothermal-9100 apparatus and are uncorrected. All the
[5,6]
and improving yields.
It promotes the reaction under
milder conditions where drastic conditions are required
conventionally.
Ultrasound irradiation, by virtue of cavitational collapse,
[7]
is able to activate numerous organic reactions.
Compared to the thermal methods in this technique, the
reaction is carried out normally at lower temperature
Address correspondence to Hojatollah Khabazzadeh, Depart-
ment of Chemistry, Shahid Bahonar University of Kerman, Sch. 1. Ultrasound assisted synthesis of bis(indolyl)methane
6169, I. R. Iran. E-mail: hkhabazzadeh@uk.ac.ir derivatives using deep eutectic solvent as reaction medium.
7

1
502
Seyedi et al.
Table 1. Synthesis of bis(indolyl)methanes in DES under ultrasonic conditions
ꢀ
ꢀ
Time
(min)
10
Yield
(%)
92
Mp ( C)
Mp ( C)
Entry
1
Carbonyl compound
Indole
Product
observed
Reported [ref]
[
12]
142–145
140–142
[
13]
2
3
10
90
93
82–83
78–80
[
14]
8
220–224
221–223
264–265
[
9]
4
5
6
12
14
16
90
86
85
261–263
76–78
[
12]
74–76
95–97
[
12]
93–96
[
12]
7
16
80
183–186
185–187
(
Continued on next page)

Preparation of Bis(indolyl)methanes
1503
Table 1. Synthesis of bis(indolyl)methanes in DES under ultrasonic conditions (Continued)
ꢀ
ꢀ
Mp ( C)
Time
Yield
(%)
80
Mp ( C)
Entry
8
Carbonyl compound
Indole
Product
(min)
25
observed
Reported [ref]
160–164
163–165[12]
[
12]
9
12
10
93
90
244–246
186–189
247–248
[
15]
1
1
1
0
1
2
180–184
[
[
[
9]
10
14
92
80
237–240
170–173
241–243
12]
174–175
9]
1
1
3
4
8
8
90
92
202–205
216–218
201–203
[
12]
219–220
(
Continued on next page)

1
504
Seyedi et al.
Table 1. Synthesis of bis(indolyl)methanes in DES under ultrasonic conditions (Continued)
ꢀ
ꢀ
Time
Yield
(%)
86
Mp ( C)
Mp ( C)
Entry
Carbonyl compound
Indole
Product
(min)
10
observed
Reported [ref]
[
15]
1
5
150–153
145–148
reactions were studied using digital ultrasonic cleaner CD-4820.
NMR spectra were recorded on a Bruker DRX-500 Avance
(d, J D 7.9 Hz, 2H, Ar–H), 7.20 (d, J D 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 D 7.9 Hz, 2H, Ar–
NMR spectrometer using CDCl as solvent.
3
1
3
H), 7.82 (s, 2H, N–H). C NMR (CDCl ): d 40.1, 111.1,
3
1
19.2, 119.7, 121.0, 121.9, 123.8, 126.1, 127.1, 128.2,
Preparation of Deep Eutectic Solvent
1
28.8, 136.6, 144.1.
0
3
,3 -Bis-(N-methylindolyl)-(4-methylphenyl)methane (Table 1,
The DES was prepared as follows: ZnCl (1 mmol) was mixed
with urea (3.5 mmol) and heated at 80 C in air with stirring
until a clear colorless liquid was obtained. Then the mixture
was allowed to cool to room temperature and then was used.
2
ꢀ
1
entry 15): H NMR (CDCl ) d 2.32 (s, 3H, CH ), 3.68 (s,
3 3
6
7
7
H, 2CH ), 5.80 (s, 1H), 6.49 (s, 2H, Ar–H), 6.09 (d, J D
3
.8 Hz, 2H, Ar–H), 7.00 (d, J D 7.2 Hz, 2H, Ar–H),
.02¡7.20 (m, 4H, Ar–H), 7.23 (d, J D 7.3 Hz, 2H, Ar–
1
3
H), 7.42 (d, J D 7.4 Hz, 2H, Ar–H). C NMR (CDCl ) d
3
General Procedure for the Preparation of bis(indolyl)
methanes
21.2, 31.2, 38.3, 109.1, 116.0, 117.0, 119.2, 120.1, 126.4,
126.8, 127.2, 127.5, 134.7, 136.2, 140.3.
A mixture of a carbonyl compound (1 mmol), indole
(
2 mmol), and DES (1 eq) was irradiated in the water bath of
ꢀ
the ultrasonic cleaner at 60 C for a period as indicated in
Table 1. The reactions were followed by thin layer chroma-
tography (TLC). After completion of the reaction, 10 mL of
water was added to the mixture and the resulting precipitate
was filtered off. The product was recrystallyzed from ethanol
and the filleterd solution was evaporated to recover the DES.
Results and Discussion
Study of Significance of DES in Synthesis of Bis(indolyl)
methanes by Thermal and US Methods
The reaction parameters were optimized by the reaction of
benzaldehyde with indole. First deep eutectic solvent (ZnCl2/
urea) and common organic solvents such as ethanol, chloro-
Selected Spectral Data
form and acetonitrile in the presence of 1eq ZnCl as a cata-
2
lyst were used as reaction medium in thermal conditions.
0
1
3
,3 -Bis-indolyl phenylmethane (Table 1, entry 1): H NMR
Best results were obtained with ZnCl /urea. The efficiency of
2
(
CDCl ): d 5.92 (s, 1H), 6.60 (d, J D 1.5, 2H, Ar–H), 7.05
3
deep eutectic medium (ZnCl /urea) prompted us to explore
2
the scope for further improvement in results using ultrasound
method. This method gave improved yield in shorter reaction
time (Table 2).
Table 2. Synthesis of bis(indolyl)methanes in conventional ther-
mal and ultrasonic methods
As shown in Table 2, the combination of DES and US
showed marked improvements both in terms of reaction
times and yields. The impact of acoustic energy results in
rapid micromixing thus reducing the processing time.
Temperature Time Yield
ꢀ
Entry
Solvent
Conditions
( C)
(min) (%)
1
2
3
4
5
6
7
8
9
EtOH
CHCl3
thermal
thermal
thermal
thermal
thermal
US
US
US
US
reflux
reflux
reflux
30
50
30
50
60
64
40
50
30
30
20
25
15
10
10
65
50
70
50
75
55
80
92
92
CH CN
3
Table 3. The reaction of benzaldehyde with indole in DES
ZnCl /urea
2
ZnCl /urea
Entry
Cycle
Time (min)
Yield (%)
2
ZnCl /urea
2
1
2
3
First run
Second run
Third run
10
10
12
92
90
87
ZnCl /urea
2
ZnCl /urea
2
ZnCl /urea
2

Preparation of Bis(indolyl)methanes
1505
Ref.
Table 4. Reaction of indole with carbonyl compounds in the presence of different catalysts
Carbonyl compound
-Cl-C H CHO
Catalyst
Solvent
Condition
Time
Yield (%)
ꢀ
4
P O /SiO
2
Glycerin
Solvent-free
Glycerin
75 C
8 h
30 min
8 h
88
92
85
90
[12]
[16]
[17]
—
6
4
2
5
CeCl .7H O
R. T.
3
2
ꢀ
FePO4
75 C
ꢀ
ZnCl /Urea
ZnCl /Urea
60 C/US
10
2
2
This protocol accepts different carbonyl compounds and synthesis of bis(indolyl)methane derivatives. Ultrasonic irra-
produces respective bis(indolyl)methanes in excellent yields diation also showed a significant improvement in parameters
and the results are presented in Table 1. As shown in Table 1, such as reaction yield and time. DES was found to be more
aromatic aldehydes with electron-donating or electron-with- effective than conventional organic solvents. This method
drawing groups reacted successfully and gave the products in has several unique merits, such as high yields, very short reac-
high yields. As was expected the electron-donating and elec- tion time, efficiency, generality, the use of cheap and nontoxic
tron-withdrawing groups affect the activity of carbonyl group solvent and catalyst, and simplicity in operation.
and it was observed that, the aromatic aldehydes with elec-
tron-withdrawing groups such as 4-nitro benzaldehyde reacts
faster than the aromatic aldehydes with electron-donating
groups such as 4-methyl and 4-methoxy benzaldehyde. It
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