Green synthesis of privileged benzimidazole scaffolds using active deep eutectic solvent

Article abstract of DOI:10.3390/molecules24162885

The exploitation and use of alternative synthetic methods, in the face of classical procedures that do not conform to the ethics of green chemistry, represent an ever-present problem in the pharmaceutical industry. The procedures for the synthesis of benzimidazoles have become a focus in synthetic organic chemistry, as they are building blocks of strong interest for the development of compounds with pharmacological activity. Various benzimidazole derivatives exhibit important activities such as antimicrobial, antiviral, anti-inflammatory, and analgesic activities, and some of the already synthesized compounds have found very strong applications in medicine praxis. Here we report a selective and sustainable method for the synthesis of 1,2-disubstituted or 2-substituted benzimidazoles, starting from o-phenylenediamine in the presence of different aldehydes. The use of deep eutectic solvent (DES), both as reaction medium and reagent without any external solvent, provides advantages in terms of yields as well as in the work up procedure of the reaction.

Full text of DOI:10.3390/molecules24162885

molecules
Article
Green Synthesis of Privileged Benzimidazole
Scaffolds Using Active Deep Eutectic Solvent
1
,
1
2,
3
Maria Luisa Di Gioia * , Roberta Cassano
, Paola Costanzo * , Natividad Herrera Cano ,
4
2
1
2
Loredana Maiuolo , Monica Nardi
and Antonio Procopio 2
, Fiore Pasquale Nicoletta , Manuela Oliverio
1
Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Dipartimento di Eccellenza L. 232/2016,
Edificio Polifunzionale, Università della Calabria, 87036 Rende (CS), Italy
Department of Health Sciences, Magna Græcia University, Viale Europa, 88100 Germaneto CZ, Italy
2
3
ICYTAC, CONICET and Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento.
Química Orgánica. Ciudad Universitaria, Bv. Juan Filloy s/n, 5000 Córdoba, Argentina
Dipartimento di Chimica e Tecnologie Chimiche, Via P. Bucci, cubo 12C, Università della Calabria,
4
8
7036 Rende (CS), Italy
*
Correspondence: ml.digioia@unical.it (M.L.D.G.); pcostanzo@unicz.it (P.C.);
Tel.: +39-0984-493095 (M.L.D.G.); +39-0961-3694120 (P.C.)
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Scott Handy
Received: 9 July 2019; Accepted: 7 August 2019; Published: 8 August 2019
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: The exploitation and use of alternative synthetic methods, in the face of classical procedures
that do not conform to the ethics of green chemistry, represent an ever-present problem in the
pharmaceutical industry. The procedures for the synthesis of benzimidazoles have become a focus
in synthetic organic chemistry, as they are building blocks of strong interest for the development
of compounds with pharmacological activity. Various benzimidazole derivatives exhibit important
activities such as antimicrobial, antiviral, anti-inflammatory, and analgesic activities, and some of
the already synthesized compounds have found very strong applications in medicine praxis. Here
we report a selective and sustainable method for the synthesis of 1,2-disubstituted or 2-substituted
benzimidazoles, starting from o-phenylenediamine in the presence of different aldehydes. The use
of deep eutectic solvent (DES), both as reaction medium and reagent without any external solvent,
provides advantages in terms of yields as well as in the work up procedure of the reaction.
Keywords: benzimidazoles; deep eutectic solvents; green chemistry; aromatic amines;
heterocyclic moiety
1
. Introduction
Among the heterocyclic pharmacophores, the benzimidazole ring is one of the most widespread
systems in nature. It is indicated as a “privileged nucleus” due to its occurrence in molecules essential
for the life cycle of organisms [ ]. The 5,6-dimethylbenzimidazole moiety in the structure of vitamin
1
B12 [2] is an important example (Figure 1).
Bioactive compounds with a benzimidazole nucleus are heterogeneous molecules in structure
and activity. This diversification is to be found in the derivatization of the basic core, followed
by a structure–activity relationship for each compound. The first example of a clinically available
benzimidazole-based drug is thiabendazole, capable of acting as a fungicide and antiparasitic [3]. Over
the years, many other derivatives have been developed: The antihistamine Clemizole, the anti-ulcerative
Omeprazole, the antihypertensive Telmisartan, antifungal Thiabendazol, analgesic Bezitramide,
antiviral Hoechst 33342, anticancer Bendastumide, and antiemetic KB-R-6933 (Figure 2) [4].
Molecules 2019, 24, 2885; doi:10.3390/molecules24162885
www.mdpi.com/journal/molecules

Molecules 2019, 24, 2885
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H NOC
2
Me Me
CN
CONH2
CONH2
H NOC
2
Me
Me
N
N
Co
H
Me
Me
N
N
H NOC
2
Me
CONH2
Me
N
Me
Me
O
NH
HO
N
O
Me
O
P
O
O
OH
O
Figure 1. Benzimidazole nucleus in vitamin B .
1
2
N
O
N
N
H
NH
N
N
Hoechst 33342
Antiviral and Antitumour)
Cl
N
N
(
N
S
N
N
2
H N
N
H
N
Thiabendazole
(Anthelminic)
KB-R 6933
(Antiemetic)
COOH
N
N
N
N
N
Cl
HOOC
N
N
H
N
N
Benzimidazole
nucleus
Telmisartan
Antihypertensive )
Cl
Bendamustine
(Anticancer)
(
N
COOEt
O
N
N
N
N
S
H
N
O
Cl
Benzitramide
Analgesic)
S
N
(
Clemizole
(Antitumor and Antiallergic)
N
H
O
Omeprazole
(Anti-ulcer)
O
Figure 2. Examples of important drugs containing a benzimidazole nucleus.
More recently, the treatment potency of benzimidazoles in diseases such as ischemia-reperfusion
injury or hypertension, have also been reported [5].
Due to their properties and roles in various diseases, special interest has been devoted to
benzimidazole-based chemistry [6–9]. A lot of synthetic methodologies are available for the preparation
of benzimidazole and its derivatives. Generally, the reaction between o-phenylenediamines and
carboxylic acids or their derivatives has been used [10,11].

Molecules 2019, 24, 2885
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A different and widely used procedure for the same synthesis is the condensation
of o-phenylenediamine with differently substituted aldehydes affording 2-substituted and
1,2-di-substituted benzimidazoles derivatives. However, these protocols suffer some drawbacks
such as long reaction times, expensive reagents, use of toxic organic solvents, difficulties in the
preparation of the catalyst, non-recoverability of the catalyst, and tedious work-up procedures.
Moreover, most of them lack selectivity [12
mild procedures with easily separable and recyclable catalysts, and in particular, greater selectivity is
still in demand. Recently, the use of water [18 21] or ionic liquids (ILs) as green media, and/or the use
–17]. Therefore, the introduction of simple, efficient, and
–
of readily available organometallic catalysts, have been exploited [22–28].
Although these protocols provide improvement, it is well-known that ILs are (eco)toxic and
harmful to the environment [29]. Further, their synthesis and purification is often expensive and
time-consuming [30].
In the last decade, the most important drug manufacturing industries have been influenced by
green chemistry principles introducing “greener” raw materials, less use of toxic organic solvents, cuts
in waste production, and alternative organic synthetic methods [31].
In this regard, as the pharmaceutical industry is known to use a large amount of solvents to
produce active pharmaceutical ingredient (API), most of the investigations are currently focusing
on the replacement of hazardous conventional solvents with more sustainable alternatives such
as water [32–40], supercritical fluids [41
biomass [51–53].
,42], ionic liquids [43–50], and solvents derived from
Deep eutectic solvents (DES) are considered the green solvents of the 21st century with tremendous
applicability in all areas of the chemical industry [54]. They can be defined as a mixture of two or more
compounds, that at certain molar ratios exhibit a high depression of the melting point, becoming liquid
at or near room temperature. At these conditions, the compounds that form the deep eutectic solvents
interact between themselves, mainly through hydrogen bonding, thus enabling the components to
behave as one single entity [55–57].
Because the production of these deep eutectic solvents relies solely on the physical mixture of two
or more natural components, their production has virtually no impact on the environment. Moreover,
because deep eutectic solvents do not need any complex processing and equipment, they are also
cheap alternatives to most common green solvents such as ionic liquids [55].
In our continuous efforts towards green organic chemistry, here we present a new synthetic route
to benzimidazole derivatives. The novel feature of the procedure proposed is that in the first step,
a DES is formed consisting of o-phenylendiamine (o-PDA) and choline chloride (ChCl). Therefore, we
explored a double role of the DES: Solvent and reactant.
2
. Results and Discussion
The pilot reaction between o-phenylenediamine and benzaldehyde, as reported in literature,
involves indiscriminately the formation of monosubstituted and disubstituted benzimidazole
derivatives: It is a nonselective synthesis [58].
Thus, we started our investigation conducting the model reaction with the most explored DES
choline chloride/urea (ChCl:urea) as an eco-alternative solvent.
Choline chloride is one of the most commonly used hydrogen bond acceptors (HBA) used for the
formation of DES [56] and its combination with a suitable HBD (usually sugars, natural organic acids,
amides, etc.) produces eutectic mixtures that are liquid at ambient temperature and have unusual
solvent properties [57].
It is an economic, biodegradable, nontoxic, and even edible quaternary salt that can be extracted
from biomass or easily synthesized from fossil reserves. Similarly, urea has a low cost, is easily
available, and is absolutely nontoxic. Both compounds are constitutively present in our body. Choline
is a ubiquitous molecule, mainly responsible for the structural integrity of cell membranes (it is a
component of membrane phospholipids) and for the synthesis of the neuronal chemical mediator

Molecules 2019, 24, 2885
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acetylcholine; urea is one of the products of protein metabolism, mainly developed by the liver and
kidneys, and eliminated by them. A solvent characterized by such a composition can only be defined
as absolutely nontoxic. It is noteworthy that to obtain the eutectic mixture, the two compounds are
simply mixed and left in the right heating conditions; urea, through the formation of hydrogen bonds,
is easily associated with choline chloride.
The model reaction was performed dissolving o-phenylenediamine (1 mmol) in 1.0 mL of
ChCl:urea DES and then adding benzaldehyde in an equimolar ratio. The reaction mixture was left
◦
◦
under magnetic stirring at 60 C or 80 C and monitored by thin layer chromatography (TLC) and gas
chromatography/mass spectrometry (GC/MS) analysis. The GC/MS analysis confirmed the complete
conversion of the reagents within 10 min affording, at the higher temperature, the 2-substituted
benzimidazole derivative 1a and the 1,2-disubstituted benzimidazole derivative 1b in 88% and 12%
yields respectively (entries 1 and 2 in Table 1).
Table 1. Optimization of the reaction conditions in pilot reaction.
Molar Ratio
o-PDA:Benzaldehyde
Yield (%) 3
a:b
◦
Entry
Solvent
T ( C)
Time (min)
1
1
2
3
4
ChCl:urea (1:2)
ChCl:urea (1:2)
ChCl:urea (1:2)
ChCl:urea (1:2)
1:1
1:2
1:1
1:2
60
60
80
80
15
15
10
10
67:33
30:70
88:12
13:87
2
1
2
1
General reaction conditions: o-phenylendiamine (1 mmol) and benzaldehyde (1 mmol) were dissolved in 1.0 mL
2
DES and stirred for 10–15 min at different temperatures. General reaction conditions: o-phenylendiamine (1 mmol)
and benzaldehyde (2 mmol) were dissolved in 1.0 mL DES and stirred for 10–15 min at different temperatures.
3
The complete conversion of the reagents was observed. Ratio (a:b) determined by GC/MS.
The reaction in DES was replicated by varying the molar ratios of the reagents using the diamine
and benzaldehyde in a 1:2 ratio. In this case, a selectivity towards the double-condensation product
b
was observed by GC/MS analysis. After 10 min of reaction the conversion of the reagents went almost
completely in favor of the product
b
that was obtained in 87% yield while
a
was afforded in 13% yield.
and
◦
The same reaction performed in DES at 60 C provided, after 15 min, a mixture of products
a
b
both in the case of a molar ratio diamine:benzaldehyde 1:1 and in the case of the molar ratio 1:2
(Table 1, entries 1 and 2).
The high selectivity observed in DES let us hope that we had developed one of the most promising
and green methods for obtaining benzimidazole derivatives. DESs as an alternative to ILs, not only
have similar characteristics to traditional imidazolium based ILs, but also have several benefits such as
ease of preparation and availability from bulk renewable resources. In addition, the use of choline
chloride/urea enables an easy work-up as the products can be recovered by simple extraction with
ethyl acetate, followed by separation and removal of the solvent under reduced pressure.
To further improve our green procedure, we decided at this stage to explore a double role of the
DES. In fact, the use of solvents as reagents is an efficient and widely explored way to minimize waste
formation [59]. The use of urea to form type III eutectic solvents where choline chloride is mostly taken
as quaternary ammonium cation has been known for a considerable time. This principle, however, is
not limited to amides, but can be applied to a wide variety of other hydrogen bond donors (HBDs)
such as organic acids, alcohols, and amines. To date, only a few example of DESs based on ChCl and
amine group bearing compounds have been reported [60,61] and only one example of DESs based on

Molecules 2019, 24, 2885
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ChCl and solid aromatic amines has been described [62]. Nevertheless, none of these DESs have been
used for organic synthetic applications.
In the light of the above statement, our approach was to explore o-phenylendiamine (o-PDA) as
HBD to combine with choline chloride, thus forming a eutectic mixture: The diamine would therefore
be part of the solvent and at the same time reactant.
Thus, a ChCl: o-PDA based DES was prepared by mixing the components in a molar ratio amine:
◦
ChCl 1:1 at ambient temperature and then heated up to 80 C for 2 h, to obtain a liquid product.
The final mixture was a light yellow colored liquid, gradually becoming green on air, and that after
preparation slightly increased its viscosity. A differential scanning calorimetry (DSC) analysis of the
mixture was performed, as well as for the individual components, to demonstrate the formation of the
◦
◦
DES. ChCl and o-phenylendiamine are solid components melting at 302 C and 102 C, respectively:
◦
The DSC analysis of the mixture resulted in a eutectic that melts at 32 C. This result demonstrated the
successful formation of a eutectic with a melting point significantly lower than that of its individual
components. The eutectic temperature for ChCl: o-PDA DES is shown in Table 2 and graphically in
Figure 3.
Figure 3. Eutectic temperature (T ) of ChCl with o-phenylendiamine (o-PDA). The melting point of
f
◦
pure ChCl is 302 C.

Molecules 2019, 24, 2885
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Table 2. Structure, composition, and eutectic temperature (T ) of the deep eutectic solvents (DES) with
f
the corresponding melting point (T
given in C.
m
*) of the pure hydrogen bond donor (HBD). The temperature is
◦
Tf
C)
Tm HBD
( C)
∆
ChCl
HBD
Molar Ratio
Appearance
◦
◦
◦
(
( C)
Light yellow liquid
that tends to become
greenish.
1
:1
32
102
70
◦
In the thermogram of o-phenylendiamine melting is observed with T
m
of 102 C. From the
thermogram of ChCl:o–PDA (1:1) DES shown in Figure 3 it is clear that the thermal behavior of
the DES is different from the behavior of the individual components, thus providing evidence of
interaction established between choline chloride and the diamine, which make the DES behave like a
different entity.
Abbott et al. suggested that the depression of the freezing point is dependent on the lattice
energies of the DESs and low melting mixtures (LMMs), the interaction of the anion and HBD, and the
entropy changes arising from forming a liquid [63
structure on the physical properties of ChCl/o-PDA can be interpreted based on available results for
DESs formed by ChCl mixtures with other aromatic hydrogen bond donors, such as phenols [62 66].
–65]. In our situation, the influence of the amine
,
In fact, Zhu et al. [66] showed that the structure of phenols is responsible for hydrogen bond formation
between the phenolic group and Cl anion of ChCl. In accordance, Spychaj et al. [62] assumed that
aromatic NH can interact with choline chloride, thus affecting the physicochemical properties of DES.
2
The obtained DES (ChCl:o–PDA) was studied as solvent and, at the same time, reactant in the
pilot reaction for the synthesis of benzimidazole derivatives. To this end, 1 mol of benzaldehyde with
◦
respect to the DES component o-PDA, was added and magnetically stirred for 10 min at 80 C.
GC/MS analysis of the mixture revealed the formation of compound 1a as the only product
of reaction (95% yield, Scheme 1). Employing 2 mol of benzaldehyde for the same reaction,
the 1,2-disubstituted benzimidazole 1b was selectively obtained in 97% yield as a single product
(
Scheme 1). The reaction conditions were finally optimized as follows: 1 mol benzaldehyde in
◦
ChCl:o–PDA (1:1) DES at 80 C to give the monosubstituted benzimidazole derivative 1a (Scheme 1);
2
mol benzaldehyde in the same reaction conditions to afford the 1,2-disubstituted benzimidazole 1b
(Scheme 1).
O
O
1
mol
H
H
NH2
H
N
2
mol
N
N
N
OH
NH2
80 °C, 10 min
N
80 °C, 10 min
Cl
1
a 95% yield
1
b 97% yield
CHCl:o-PDA DES
Scheme 1. Optimized conditions for the pilot reaction. GC/MS analysis showed the formation of
compound as the only product (95% yield) when using 1 mol of benzaldehyde and the formation of
a
compound b as the only product (97% yield) when using 2 mol benzaldehyde.
An important advantage of this solvent system is that the use of the new DES, enables an easy
work-up without using any chromatographic or other purification methods. In fact, the reaction
products were recovered by simple dilution of the mixture with water followed by extraction with
ethyl acetate.
The application scope of this reaction was then examined by subjecting different aldehydes to
the same protocol. By using this reactive DES solvent and varying the molar ratio of the aldehyde,

Molecules 2019, 24, 2885
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2-substituted or 1,2-disubstituted benzimidazoles with various functional groups can be obtained in
excellent selectivity and yields (Tables 3 and 4).
Table 3. Synthesis of 2-substituted benzimidazoles a.
O
1
mol
NH2
NH2
H
N
R
H
N
OH
R
80 °C, 10 min
Cl
N
a
DES Component
Yields b (%)
Entry
R
Product
1
Ph
1a
95 (93) c
H
N
2
3
4
5
p-MePh
2a
3a
4a
5a
97
92
95
96
N
H
N
p-MeOPh
O
N
CH CH2
3
CH3
H
N
6
CH Ph
6a
91
2
N
H
N
7
8
p-ClPh
Cl
7a
8a
90
89
N
H
N
p-NO Ph
NO2
2
N
a
General reaction conditions: 1 mmol of aldehyde was dissolved under stirring in ChCl: o-PDA (1:1) DES at 80
◦
b
C for 10 min. Percent yield calculated from GC/MS data. The corresponding monosubstituted benzimidazole
c
derivative was recovered as the sole product. The reaction was carried out in a scale of 20 mol and furnished 1a in
93% yield.
All reactions were complete and the reaction times were always short, generally between 8 and 10
min. The reaction yields related to the formation of the 2-substituted benzimidazoles derivative ranged
from 89% to 97%. The reaction yields related to the formation of the disubstituted benzimidazoles
derivative were between 91% and 98%.
As it can be seen from Table 3, good reaction yields were obtained with aldehydes containing
electron donor groups (entries 2–6), and also electron withdrawing groups (entries 7–8).

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Table 4. Synthesis of 1,2-disubstituted benzimidazoles a.
O
R
NH2
2 mol
R
H
N
N
N
OH
R
NH2
80 °C, 10 min
Cl
DES Component
b
Yields b (%)
Entry
R
Product
1
Ph
N
N
1b
2b
97
98
2
3
p-MePh
N
N
OCH
3
p-MeOPh
3b
93
N
N
OCH
3
4
5
CH CH2
4b
5b
90
91
3
N
N
N
CH3
N
6
CH Ph
6b
7b
8b
91
2
N
N
Cl
7 c
p-ClPh
0
N
N
Cl
NO
2
8 c
p-NO Ph
0
2
N
N
NO2
a
◦
General reaction conditions: 2 mol of aldehyde was dissolved under stirring in ChCl:o–PDA (1:1) DES at 80 C for
b
1
0 min. Percent yield calculated from GC/MS data. The corresponding disubstituted benzimidazole derivative
c
was recovered as the sole product. Product b was not detected. Only the corresponding 2-substituted derivative
(7a 93% yield and 8a 93% yield) was afforded.

Molecules 2019, 24, 2885
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The generality of the selective formation of 1,2-disubstituted benzimidazoles was demonstrated
through the reaction of o-phenylendiamine with 2 molar amount of various aldehydes (Table 4).
The expected 1,2-disubstituted products were obtained in 90%–98% yields. The reaction, as already
reported in the literature, proceeds through a bis-imine formation, a rearrangement, and a 1,3-hydride
shift pathway that finally afford the 1,2-disubstituted derivatives [67]. The DES formed by choline
chloride and the diamine possibly increases the electrophilic character at aldehyde carbon, which will
facilitate the nucleophilic addition of o-phenylenediamine to obtain the benzimidazole derivatives.
The intermediate formed could be stabilized through hydrogen bonding and electronic interaction
with DES components, thereby exalting the electrophilic character of the aldehydes.
However, the reactions performed with 2 molar amount of aldehydes containing electron
withdrawing groups such as p-chloro or p-nitro benzaldehyde (Table 4, entries 7–8) afforded exclusively
the corresponding 2-monosubstituted benzimidazoles (7a and 8a) in good yields, without observing
the formation of disubstituted derivative. This result is in accordance with the data reported in
the literature [21]. Electron deficient aldehydes, as they possess a lower density of negative charge
on the oxygen atom of the carbonyl group, do not simply coordinate with the DES components
to form the hydrogen bonding interaction. As a consequence, the formation of the disubstituted
product is not favored. Additionally, the highly electrophilic character of the carbonyl carbon of
aldehydes with a chloro or nitro substituent is responsible, after the formation of the mono-imine, for
the fast formation of the monosubstituted benzimidazole derivative 7a and 8a via the corresponding
intermediate imidazoline [67].
Finally, in order to demonstrate the potential industrial applicability of this green procedure,
the pilot reaction to give 1a was carried out in a scale of 20 mol (entry 1, Table 3, footnote c). The reaction
was completed in 30 min with 93% isolated yield after simple water addition (10 mL) and extraction
with 10 mL ethyl acetate.
In the development of a green procedure, solvent recyclability and reusability is an essential
feature. In this case, after completion of the reactions, ChCl is dissolved in water and can be recycled
easily by water distillation under vacuum. However, as water distillation consumes a lot of energy
and is not an advantageous process from an economical point of view and, since choline chloride is
a very cheap and nondangerous substance (500 g
aqueous solution can be simply thrown away.
€ 49.80 MERCK, 2019), at the end of reaction the
3
. Materials and Methods
3
.1. General Information
All chemicals and solvents were purchased from common commercial sources and were used
as received without any further purification. All reactions were monitored by GC/MS analysis and
TLC on silica Merck 60 F254 precoated aluminum plates (KGaA, Darmstadt, Germany). The GC-MS
Shimadzu workstation was constituted by a GC 2010 (equipped with a 30 m-QUADREX 007-5MS
capillary column (BGB Analytik AG, CH-4461 Boeckten, Switzerland) operating in “split” mode,
−
1
1
mL min flow of He as carrier gas) and a 2010 quadrupole mass-detector. Proton nuclear magnetic
1
resonance ( H NMR) spectra were recorded on a Brüker spectrometer (Auckland, New Zealand) at
300 MHz. Chemical shifts are reported in
δ units (ppm) with TMS as reference (δ 0.00). All coupling
constants (J) are reported in Hertz. Multiplicity is indicated by one or more of the following: s (singlet),
13
d (doublet), t (triplet), q (quartet), m (multiplet). Carbon nuclear magnetic resonance ( C NMR)
spectra were recorded on a Brüker at 75 MHz. Chemical shifts are reported in units (ppm) relative to
CDCl (δ 77.0) (more information see Supplementary Materials).
δ
3
3
.2. General Procedure for DESs Preparation
The ChCl:urea (1:2) DES was prepared as follows: Choline chloride (6.98 g, 50 mmol) and urea
6.00 g, 100 mmol) were added in a round-bottom flask under inert atmosphere. The mixture was
(

Molecules 2019, 24, 2885
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◦
magnetically stirred for 60 min at 80 C until a clear colorless liquid was obtained. The obtained DES
was used without need of purification.
For the preparation of ChCl:o–PDA (1:1) DES the following procedure was used: Choline chloride
(
6.98 g, 50 mmol) and o-phenylendiamine (5.40 g, 50 mmol) were mixed in a round-bottom flask under
◦
inert atmosphere. The mixture was magnetically stirred for 2 h at 80 C until a clear yellow liquid was
obtained. The obtained DES was characterized by DSC analysis and used without further purification.
3
.3. General Procedure for the Synthesis of 2-Substituted Benzimidazoles 1a–8a in the DES ChCl:o–PDA (1:1)
The appropriate aldehyde (1 mmol) was added to the ChCl:o–PDA (1:1) eutectic mixture (1 mL)
◦
under magnetic stirring. The resulting mixture was stirred at 80 C for 8–10 min. The reaction was
monitored by TLC and GC/MS analysis. After this time, 2 mL of H O were added. The resulting
2
aqueous suspension was then extracted with AcOEt (3
×
2 mL). The organic phases were dried over
8a
Na SO , followed by evaporation under reduced pressure to give the corresponding products 1a
–
.
2
4
Spectral data were in accordance with the literature [21].
3
.4. General Procedure for the Synthesis of 1,2-Substituted Benzimidazoles 1b–8b in the DES
ChCl:o–PDA (1:1)
The appropriate aldehyde (2 mmol) was added to the ChCl:o–PDA (1:1) eutectic mixture (1 mL)
◦
under magnetic stirring. The resulting mixture was stirred at 80 C for 8–10 min. The reaction was
monitored by TLC and GC/MS analysis. After this time, 2 mL of H O were added. The resulting
2
aqueous suspension was then extracted with AcOEt (3
×
2 mL). The organic phases were dried over
8b
Na SO , followed by evaporation under reduced pressure to give the corresponding products 1b
–
.
2
4
Spectral data were in accordance with the literature [21].
3
.5. Differential Scanning Analysis (DSC)
The ChCl:o–PDA DES mixture and raw chemicals were characterized by DSC analysis (model
◦
◦
◦
DSC NETZSCH 200) on the temperature range from
for 5 min at
−
80 C to 350 C, at 10 C/min, after equilibration
◦
−
80 C. The experiments were performed under nitrogen atmosphere (50 mL/min), with
1
5 mg of the sample in aluminum pans with covering lids.
4
. Conclusions
For the first time a type III DES based on ChCl as quaternary ammonium salt and a HBD such as
o-phenylendiamine (ChCl:o–PDA, 1:1) was prepared and used as medium, and at the same time as a
reagent, for the synthesis of benzimidazole derivatives.
The methodology proved to be complete in terms of eco-sustainability, ecotoxicity, reaction,
and economics.
In summary, it can be asserted that the high reaction yield, the selectivity of the process, the easy
preparation of the solvent, the economy, the short reaction times, and the absence of chromatographic
purification are the salient aspects of our approach.
The use of easy-to-handle and environment-friendly chemicals with low toxicity and without using
any external solvent makes this method a potential approach for obtaining benzimidazole derivatives,
even on a large scale, and perfectly fulfills several requirements, as formulated by Anastas et al. in the
twelve principles of green chemistry [68].
Supplementary Materials: The following are available online, MS(EI) spectra of products, DSC thermograms
and general synthetic procedures.
Author Contributions: Conceptualization, M.L.D.G. and P.C.; formal analysis, R.C., N.H.C., and F.P.N.; project
administration, M.L.D.G. and P.C.; validation, L.M., M.N., and M.O.; Supervision, A.P.
Funding: This research received funding from Dipartimento di Farmacia e Scienze della Salute e della Nutrizione,
Dipartimento di Eccellenza L. 232/2016, Arcavacata di Rende (CS).

Molecules 2019, 24, 2885
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Conflicts of Interest: The authors declare no conflict of interest.
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©
2019 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
CC BY) license (http://creativecommons.org/licenses/by/4.0/).
(