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