Ball milling assisted solvent and catalyst free synthesis of benzimidazoles and their derivatives

Article abstract of DOI:10.3390/molecules21091111

Benzoic acid and o-phenylenediamine efficiently reacted under the green solvent-free Ball Milling method. Several reaction parameters were investigated such as rotation frequency; milling balls weight and milling time. The optimum reaction condition was milling with 56.6 g weight of balls at 20 Hz frequency for one hour milling time. The study was extended for synthesis of a series of benzimidazol-2-one or benzimidazol-2-thione using different aldehydes; carboxylic acids; urea; thiourea or ammonium thiocyanate with o-phenylenediamine. Moreover; the alkylation of benzimidazolone or benzimidazolthione using ethyl chloroacetate was also studied.

Full text of DOI:10.3390/molecules21091111

molecules
Article
Ball Milling Assisted Solvent and Catalyst Free
Synthesis of Benzimidazoles and Their Derivatives
Taghreed H. EL-Sayed 1,2, Asmaa Aboelnaga 1,2 and Mohamed Hagar 1,3,
*
1
Faculty of Science, Chemistry Department, Yanbu, Taibah University, Yanbu, Saudi Arabia;
taghreed.hussien@yahoo.com (T.H.E.); asmaa_aboelnaga77@yahoo.com (A.A.)
Faculty of Women for Arts, Science and Education, Chemistry Department, Ain Shams University,
Heliopolis, Cairo 11757, Egypt
Faculty of Science, Chemistry Department, Alexandria University, Alexandria 21321, Egypt
Correspondence: mhagar@taibahu.edu.sa or mohamedhaggar@gmail.com; Tel.: +966-54-552-7958
2
3
*
Academic Editors: Koichi Komatsu and Carsten Bolm
Received: 31 July 2016; Accepted: 15 August 2016; Published: 24 August 2016
Abstract: Benzoic acid and o-phenylenediamine efficiently reacted under the green solvent-free Ball
Milling method. Several reaction parameters were investigated such as rotation frequency; milling
balls weight and milling time. The optimum reaction condition was milling with 56.6 g weight
of balls at 20 Hz frequency for one hour milling time. The study was extended for synthesis of
a series of benzimidazol-2-one or benzimidazol-2-thione using different aldehydes; carboxylic acids;
urea; thiourea or ammonium thiocyanate with o-phenylenediamine. Moreover; the alkylation of
benzimidazolone or benzimidazolthione using ethyl chloroacetate was also studied.
Keywords: Ball Milling; mechanochemistry; green chemistry; combinatorial chemistry; benzimidazoles
1
. Introduction
Ball Milling is a green method where reagents are placed inside a vessel with grinding balls that
is shaken at high speeds in the absence of solvent [
a chemical reaction which makes an amorphous mixture of the reagents. Recently, this method has
been used in the generation of inorganic salts [ ] while this methodology is relatively new to organic
1–3]. The high speed is enough force to facilitate
4–7
synthesis. The mechanochemical process is a separate branch of chemistry because chemical reactions
that are caused by mechanical processes work directly and this kind of reaction is often different from
conventional heating.
Although ball milling organic synthesis is relatively new, the absence of solvents in the reaction is
one of the advantages of ball milling technology, a tool with fast growing fields of application.
One of the most biologically active classes of compounds is benzimidazoles and its derivatives,
which are well-documented in literature possessing a wide spectrum of activities. They show selective
neuropeptides YY1 receptor antagonists [
8
–
11], excellent inhibitors of TIE-2 and VEGFER-2 tyrosine
21], gamma-amino butyric acid (GABA) agonists,
kinase receptors [12 18], antitumor agents [19
–
–
and 5-HT3 antagonists [22–25].
Continuing of our interest [26
–28] in finding a facile, efficient and green method for preparation
of nitrogen heterocycles, herein, the aim of this work is to investigate an efficient green ball milling
solvent-free synthesis of a series of benzimidazoles in good yield. The outcome of a chemical reaction
in a ball mill mainly depends on the amount of energy that is supplied. Several reaction parameters
directly influence this energy input. Some of these parameters are rotation frequency, milling balls
weight and milling time.
Molecules 2016, 21, 1111; doi:10.3390/molecules21091111
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2
. Results and Discussion
2
.1. Influence of the Reaction Parameters
The reaction parameters influence the energy input directly and can be changed and controlled
during ball milling. These significant parameters include: variables frequency, milling balls weight
and milling time. It could be proven that these three factors are the main ones impacting organic
reactions in ball mills [29–31].
2
.1.1. Influence of Rotation Frequency
The effect of the rotation frequency was investigated in a range from 5–30 Hz. The results (Table 1,
Figure 1) are confirm that, as the rotation frequency rises, the yield of the reaction increases due to
increased kinetic energy of the molecules and increased collision between the substrates. The increase in
the yield of the reaction continues up to a point, “the optimum rotation frequency” (20 Hz), a maximum
yield of product (95%) beyond which any further increase in a rotation frequency causes a decrease in
the yield of the reaction.
Table 1. Milling of 2.5 g of o-phenylenediamine and 3 g of benzoic acid with 56.6 g of balls for 60 min.
Entry
Frequency (Hz)
% Yield
1
2
3
4
5
6
5
20
58
80
95
94
82
10
15
20
25
30
100
80
60
40
20
0
5
10
15
20
25
30
Frequency Hz
Figure 1. Milling of 2.5 g of o-phenylenediamine and 3 g of benzoic acid with 56.6 g of balls for 60 min.
2
.1.2. Influence of Milling Balls Weight
Technological parameters describe the engineering part of variables that can influence the outcome
of a reaction, one of these parameters is the weight of the milling balls. The results show that the yield
of the reaction product increases as the weight of milling balls increases (Table 2, Figure 2). A total
of 14.4 g of milling balls weight affords only 70% of bezamidazole product after 60 min milling time,
while 56.60 g increases the overall yield to 95%.
Table 2. Milling of 2.5 g of o-phenylenediamine and 3 g of benzoic acid at 20 Hz for 60 min.
Entry
Balls (g)
No of Balls (mm diameter)
% Yield
1
2
3
14.12
28.27
56.60
1 (12.7 mm), 1 (6.3 mm), 1 (3.2 mm)
2 (12.7 mm), 2 (6.3 mm), 2 (3.2 mm)
4 (12.7 mm), 4 (6.3 mm), 4 (3.2 mm)
70
89
95

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100
80
60
40
20
0
10
20
30
40
50
60
70
Ball (g)
Figure 2. Milling of 2.5 g of o-phenylenediamine and 3 g of benzoic acid at 20 Hz for 60 min.
2
.1.3. Influence of Milling Time
To obtain high yields of the product in a short reaction time, milling conditions were optimized.
The optimization of reaction time was necessary for completion of the reaction and to avoid by-products.
The reaction progress was evaluated by observing the reaction mixture at various times (Table 3,
Figure 3). The maximum yield of 95% was obtained by 60 min milling time at milling frequency 20 Hz
and using 56.60 g milling balls. The prolonged reaction time is not preferable (80 min), and the yield
decreased to 93% instead of 95% for a shorter time (60 min).
Table 3. Milling of 2.5 g of o-phenylenediamine and 3 g of benzoic acid with 56.6 g of balls at 20 Hz.
Entry
Time (min)
% Yield
1
2
3
4
20
40
60
80
64
90
95
93
100
8
0
0
0
0
0
6
4
2
10
20
30
40
50
60
70
80
90
Time min
Figure 3. Milling of 2.5 g of o-phenylenediamine and 3 g of benzoic acid with 56.6 g of balls at 20 Hz.
Several reactions were carried out on o-phenylenediamine and different organic substrate as
the model by varying the reaction time and finally the best result was obtained. The Milling of
o-phenylenediamine and benzaldehyde with 56.6 g of balls at 20 Hz gave a maximum yield (97%) at
6
0 min. Longer milling time does not cause any increase in the yield (Table 4).
Table 4. Milling of 2.5 g of o-phenylenediamine and 2.7 g of benzaldehyde with 56.6 g of balls at 20 Hz.
Entry
Time (min)
% Yield
1
2
3
4
20
40
60
80
41
88
97
97

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Also, the milling of o-phenylenediamine and of urea with 56.6 g of balls at 20 Hz causes the
overall yield of reaction to increase with increasing time until reaching maximum value (73%) at 80 min
(Table 5).
Table 5. Milling of 2.5 g of o-phenylenediamine and 1.5 g of urea with 56.6 g of balls at 20 Hz.
Entry
Time (min)
% Yield
1
2
3
4
20
40
60
80
20
55
72
73
Twenty minutes of milling time of benzimidazol-2-one, sodium hydride and ethyl chloroacetate
with 56.6 g of balls at 20 Hz affords the alkylating product at 96% yield. The increase in the milling
time to 30 min did not affect in the amount of yield (Table 6)
Table 6. Milling of 2.5 g of benzimidazol-2-one, 2 g sodium hydride and 5.0 g of ethyl chloroacetate
with 56.6 g of balls at 20 Hz.
Entry
Time (min)
% Yield
1
2
3
10
20
30
63
96
96
Optimum conditions was examined by subjecting different aldehydes, carboxylic acids, urea
thiourea or ammonium thiocyanate with o-phenylenediamine with 56.6 g of balls for 60 min at 20 Hz.
Various functionalized products (Schemes 1 and 2) were obtained in excellent selectivity and yields
(Table 7).
NH2
NH2
N
N
O
X
BM
+
R
Slovent free
R
2
3
1
H
a. X= H, R= Ph
a. R= Ph
b. X= H, R= p-ClC H4
b. R= p-ClC H4
6
6
c. X= H, R= p-OMeC H4
c. R= p-OMeC H4
6
6
d. X= H, R= p-NO2C H4
d. R= p-NO2C H4
6
6
e. X= OH, R= Ph
f. X= OH, R= H
g. X= OH, R= CH3
f. R= H
g. R= CH3
Scheme 1. Synthesis of various functionalized 2-substituted benzimidazole.
H
NH
2
X
BM
Solvent free
N
H N
2
NH SCN
4
+
X
NH
4
Cl
H N
2
NH2
N
H
BM
NH2
Solvent free H2N
4
5
X= O, S
X= O, S
Scheme 2. Synthesis of benzimidazol-2-one and benzimidazol-2-thione.

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Table 7. Milling of 2.5 g of o-phenylenediamine and 3 g of aldehyde, carboxylic acids, urea or
ammonium thiocyanate with 56.6 g of balls for 60 min at 20 Hz.
◦
Product
Reactant
m.p. ( C)
% Yield
Benzaldehyde
Benzoic acid
p-Chlorobenzaldehyde
p-Methoxybenzaldehyde
p-Nitrobenzaldehyde
Benzoic acid
97
95
91
80
96
95
89
80
72
67
64
3
a
294 [32]
3
b
302 [33]
225 [33]
312 [33]
294 [33]
170 [34]
177 [35]
100 [36]
3
c
3
d
3
3
e
f
Formic acid
Acetic acid
Urea
Thiourea
3
g
5
a
5
b
307 [36]
Ammonium thiocyanate
Milling of benzimidazol-2-one or benzimidazol-2-thione with ethyl chloroacetate in presence of
sodium hydride with 56.6 g of balls for 20 min at 20 Hz, affords the alkylating product (7a
,
b) in high
yield (Scheme 3, Table 8).
R
H
N
N
N
BM
Solvent free
X
+ 2 ClCH COOEt
X
2
NaH
N
H
5
6
7
R
a. X= O, R= CH COOEt
2
b. X= S, R= CH COOEt
2
Scheme 3. Alkylation of benzimidazol-2-one and benzimidazol-2-thione.
Table 8. Milling of 2.5 g of benzimidazol-2-one or benzimidazol-2-thione, 2 g of sodium hydride and
.2 equivalent of alkylating agent with 56.6 g of balls for 20 min at 20 Hz.
2
◦
Product
Substrate
Alkylating Agent
m.p. ( C)
% Yield
7
a
Benzimidazol-2-one
Benzimidazol-2-thione Ethyl chloroacetate
Ethyl chloroacetate
177 [37]
200 [37]
97
83
7
b
The ball milling method offers several advantages such as high conversions, shorter reaction
times, non-toxic cost efficiency providing, cleaner reaction profiles and simple experimental and
work-up procedures. In summary, a simple work-up procedure, mild reaction conditions and very
good yields make our methodology a valid contribution to the existing processes in synthesis of
benzimidazole derivatives.
3
. Materials and Methods
3
.1. General Method
3
The ball mill was a SPEX 8000 mixer with 250 cm stainless steel vials. TLC were performed on
Merck Kiesel gel; 60-F254 plates, and the spots were detected by UV light absorption.

Molecules 2016, 21, 1111
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3
.2. General Reaction of o-Phenylenediamine with Carboxylic Acids or Aldehydes
A mixture of 1,2-phenylenediamine (2.5 g, 23.1 mmol) and 27.2 mmol of the appropriate carboxylic
acid or aldehyde were introduced into stainless steel vials with appropriate weight of stainless
steel balls for the mentioned time. The reaction was poured into water and neutralized with solid
sodium carbonate. The formed precipitate was filtered, washed with water and recrystallized
from ethanol-water.
3
.3. General Reaction of o-Phenylenediamine with Ammonium Thiocyanate, Urea and Thiourea
A mixture of 1,2-phenylenediamine (2.5 g, 23.1 mmol) and 25.0 mmol of ammonium thiocyanate,
urea or thiourea was introduced into stainless steel vials with appropriate weight of stainless steel
balls for the mentioned time. The reaction was poured into water. The formed precipitate was filtered,
washed with water and recrystalized from ethanol.
3
.4. General Alkylation Reaction of Benzimidazol-2-one and Benzimidazol-2-thione
A mixture of (2.5 g) of benzo[d]imidazol-2-one or benzimidazol-2-thione, 2 g of sodium hydride
and 2.2 equivalent of ethyl chloroacetate was introduced into stainless steel vials with appropriate
weight of stainless steel balls for the mentioned time. The reaction mixture was added to 100 g of
ice-water. The precipitate was collected by filtration, washed with water and ethanol and recrystalized
from hot ethanol.
4
. Conclusions
In conclusion, a green solvent-free Ball Milling method for preparation of benzimidazole
derivatives was studied under variable reaction parameters. The best reaction condition was 56.6 g
weight of balls at 20 Hz frequency for one hour milling time to give ~95% of product yield. A high
yield (64–97%) of benzimidazol-2-one derivatives was synthesized from different aldehydes, carboxylic
acids, urea thiourea or ammonium thiocyanate with o-phenylenediamine. Moreover, dialkylation of
benzimidazolone or benzimidazolthione using ethyl chloroacetate proceeded to give the corresponding
product in 97% and 83%, respectively.
Acknowledgments: The authors highly acknowledge Alexandria University and Ain Shams University to give
us the opportunity to do this work.
Author Contributions: All authors are equally contributed in this article.
Conflicts of Interest: The authors declare no conflict of interest.
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2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
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