Nitroarenes as versatile building blocks for the synthesis of unsymmetrical urea derivatives and N-Arylmethyl-2-substituted benzimidazoles

Article abstract of DOI:10.1007/s11696-021-01785-7

In this contribution, a fast and simple method for the synthesis of unsymmetrical urea derivatives and N-arylmethyl-2-substituted benzimidazoles was developed starting from nitroarenes. The reaction of nitroarenes and phenyl isocyanate or phenyl isothiocyanate in tin (II) chloride dihydrate/choline chloride eutectic mixture afforded the expected urea and thiourea derivatives, while the reaction of different aldehydes with o-nitroaniline or 4-methoxy-2-nitroaniline shows a markedly high preference for the obtention of N-arylmethyl-2-substituted benzimidazoles over the 2-substituted analogues. This method offers a straightforward alternative to obtain the target compounds in good to excellent yields with short reaction times employing an operationally simple experimental set-up. Graphic abstract: [Figure not available: see fulltext.] A series of unsymmetrical urea and thiourea derivatives together with 1,2-disubstituted benzimidazoles are easily obtained in good yields starting from nitroarenes employing the eutectic mixture tin (II) chloride dihydrate/choline chloride as reductive reaction media.

Full text of DOI:10.1007/s11696-021-01785-7

Chemical Papers
https://doi.org/10.1007/s11696-021-01785-7
ORIGINAL PAPER
Nitroarenes as versatile building blocks for the synthesis
of unsymmetrical urea derivatives and N‑Arylmethyl‑2‑substituted
benzimidazoles
Paula A. Rodríguez‑Huerto1 · Diana Peña‑Solórzano1 · Cristian Ochoa‑Puentes1
Received: 29 March 2021 / Accepted: 6 July 2021
© Institute of Chemistry, Slovak Academy of Sciences 2021
Abstract
In this contribution, a fast and simple method for the synthesis of unsymmetrical urea derivatives and N-arylmethyl-2-sub-
stituted benzimidazoles was developed starting from nitroarenes. The reaction of nitroarenes and phenyl isocyanate or phe-
nyl isothiocyanate in tin (II) chloride dihydrate/choline chloride eutectic mixture aforded the expected urea and thiourea
derivatives, while the reaction of diferent aldehydes with o-nitroaniline or 4-methoxy-2-nitroaniline shows a markedly high
preference for the obtention of N-arylmethyl-2-substituted benzimidazoles over the 2-substituted analogues. This method
ofers a straightforward alternative to obtain the target compounds in good to excellent yields with short reaction times
employing an operationally simple experimental set-up.
Graphic abstract
A series of unsymmetrical urea and thiourea derivatives together with 1,2-disubstituted benzimidazoles are easily obtained
in good yields starting from nitroarenes employing the eutectic mixture tin (II) chloride dihydrate/choline chloride as reduc-
tive reaction media.
Keywords Benzimidazoles · Deep eutectic solvents · Nitroarenes · Redox solvent · Urea derivatives
Introduction
Urea derivatives are widely found in diverse synthetic mole-
cules and natural products. Several bioactive compounds and
marketed drugs have the urea functionality in the structure
* Cristian Ochoa-Puentes
which, in many cases is responsible for the marked biologi-
cochoapu@unal.edu.co
cal activity due to the capability of this subunit to form sta-
1
ble multiple hydrogen bonds with receptors such as proteins.
Laboratorio de Síntesis Orgánica Sostenible, Departamento
de Química, Universidad Nacional de Colombia–Sede
Bogotá, Carrera 45 # 26–85, A.A. 5997, Bogotá, Colombia
The enhanced afnity of the urea fragment with diferent
Vol.:(0123456789)
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Chemical Papers
receptors is fundamental for drug development, and con-
sidering this, compounds with antiviral, anti-infammatory,
antimicrobial, anticonvulsant, anti-ulcerogenic and antitryp-
anosomal activities together with derivatives with potential
use in the treatment of pain and nervous system disorders
have been reported (Jagtap et al. 2017; Patil et al. 2019). In
addition, drugs for the treatment of diferent types of cancer,
HIV, Parkinson’s disease, schizophrenia and bipolar disor-
ders, migraine, allergic and infammatory states have been
developed and approved by the FDA (Fig. 1) (Ghosh and
Brindisi 2020).
remains as one of the most simple and accessible method
for the obtention of the desired molecules (Singh et al. 2019;
Kulkarni et al. 2017).
1,2-Disubstituted benzimidazoles are of immense impor-
tance in medicinal chemistry due to their diverse range of
biological and pharmacological properties (Keri et al. 2015;
Wang et al. 2015). Recognized marketed drugs such as
astemizole, tecastemizole, mizolastine (antihistamine drugs)
and candesartan, telmisartan (antihypertensives drugs) pos-
sess in their structure this heterocyclic skeleton (Fig. 2)
(Bansal and Silakari 2012).
Urea derivatives also play a fundamental role in the
construction of several urea-based receptors used for the
molecular recognition of anions, (Amendola et al. 2010)
and as versatile organocatalysts, (Zhang and Schreiner 2009;
Atashkar et al. 2018) where the use of chiral ureas have been
the platform to develop the asymmetric synthesis (Connon
2006; Limnios and Kokotos 2016).
Classical methods for the obtention of 1,2-disubstituted
benzimidazoles involve the N-alkylation of 2-substituted
benzimidazoles; (Hérault et al. 2007; Chakraborty et al.
2018) and the condensation of o-phenylenediamine with
aldehydes employing diferent catalysts.
Although 2-substituted and 1,2-disubstituted benzimi-
dazole derivatives can be obtained in this reaction, good
selectivity towards the 1,2-disubstituted analogue is usually
reported modulating the reaction conditions (Bahrami et al.
2010; Majumdar et al. 2015; Jin et al. 2014; Kokare et al.
2007; Herrera Cano et al. 2016). Other modern and alterna-
tive methods include the dehydrogenative coupling of ortho-
phenylenediamine and benzylic alcohols, (Das et al. 2018) di
N-alkylation oxidation-cyclization sequence, (Sharma et al.
2019) reaction of mono-N-alkyl-ortho-phenylenediamines
and carboxylic acids or aldehydes, (Blatch et al. 2006)
metal-catalyzed intramolecular amination/cyclization of
amidines, (Carvalho et al. 2011) intramolecular C(sp3)−H
imination (Bose et al. 2019), iron-catalyzed oxidative
Considering the importance of this scafold in diferent
areas, several approaches for the obtention of unsymmetrical
ureas have been developed including the direct carbonylation
of primary amines using carbon monoxide, (McCusker et al.
2000; Zhao et al. 2016) addition of amines to carbonyldiimi-
dazole, (Padiya et al. 2012) transition-metal-catalyzed reac-
tions, (Kim and Hong 2016; Vinogradova et al. 2012; Guan
et al. 2012) direct conversion of ketones to urea, (Sribalan
et al. 2017) rearrangement of N-fuoro-N-(phenylsulfonyl)
benzamides, (Zhao et al. 2020) among others. However,
conventional methods such as the reaction of amines with
commercially available or generated in situ isocyanates
Fig. 1 Biologically active
unsymmetrical urea derivatives
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Fig. 2 Structure of marketed
drugs containing the 1,2-disub-
stituted benzimidazole core
coupling of di-substituted ortho-phenylenediamines, (Thapa
et al. 2020) cascade arylamination/condensation of o-bromo-
or o-chloro-acetanilides, (Zou et al. 2007) N-arylation/con-
densation of benzamides (Xie et al. 2017) and the reduc-
tive intermolecular coupling/heterocyclization between
2-nitroaniline derivatives and aromatic aldehydes (Kim et al.
2002; Kim et al. 2004; Weires et al. 2012; Yang et al. 2005;
Kommi et al. 2012; Wu et al. 2000) (Scheme 1).
and Tavakol 2017). The low cost of the reagents, easy prep-
aration, storage and the reusability are some fundamental
characteristics of DES that have promoted their wide appli-
cation in synthetic chemistry and allowed the construction
of diverse molecular structures including biological active
compounds (Ghosh and Nagarajan 2016; Higuera et al.
2019; Massolo et al. 2016; Peña-Solóorzano et al. 2019).
Considering the benefts of using DES in organic chem-
istry, the broad spectrum of applications of urea derivatives
and benzimidazoles together with the easy access and large
number of commercially available nitroarenes, in this con-
tribution we report the use of nitroaromatic compounds as
starting materials for the synthesis of unsymmetrical urea
Deep eutectic solvents have emerged as a new platform
to perform several organic transformations in which the
eutectic mixture can play a role as catalyst, solvent and
starting material (Shahabi and Tavakol 2018; Abtahi and
Tavakol 2020; Keshavarzipour and Tavakol 2016; Shahabi
O
Scheme 1 Common strategies
Blatch et al. 2006
for the synthesis of 1,2-disubsti-
X
R1
Das et al. 2018
Sharma et al. 2019
or
tuted benzimidazoles
+
NH2
R
Br
or
R
OH
RCHO
R1
NH
or
+
NHR
NH2
NH2
N
X
et
RCHO
Bahrami et al. 2010
Carvalho
al. 2011
R
R
R
N
NH
R
N
R
N
N
N
H
or
R
Hérault et al. 2007
Chakraborty et al. 2018
NH
NH2
Bose et al. 2019
+
R
R1
R1
X
Thapa et al. 2020
O
R
NH
NHX
NO2
Kim et al. 2004
+
RNH2
Weires
et al. 2012
+
RCHO
H
N
R
Yang et al. 2005
Kommi et al. 2012
Wu et al. 2000
O
I
+
Zou et al. 2007
R
NH2
I
Xie et al. 2017
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Chemical Papers
derivatives and benzimidazoles employing tin (II) chloride
dihydrate/choline chloride deep eutectic solvent (DES) as
reductive reaction medium (Scheme 2).
General experimental procedure for the synthesis
of N‑arylmethyl‑2‑substituted benzimidazoles 14–21
and 22,22a‑28,28a
To an open headspace vial equipped with a magnetic stir bar,
o-nitroaniline or 2-nitro-4-methoxyaniline (1.0 mmol), the
.
Experimental section
corresponding aldehyde (3 mmol) and 1.9 g of SnCl2 2H2O/
ChCl (2:1 molar ratio) DES were added, and the resulting
solution was then stirred and heated at 110 °C. After running
the reaction to an appropriate time (45 min, TLC analysis),
the mixture was cooled to room temperature, neutralized
(pH 7) with aqueous NaOH (10% NaOH) and extracted with
AcOEt (3× 10 mL). After drying over anhydrous Na2SO4
and evaporating the solvent under reduced pressure, the
crude material was purifed by column chromatography on
silica gel to aford the desired product.
Chemistry
All the chemicals and solvents were purchased from com-
mercial suppliers (Aldrich, Merck). Melting points, reported
without correction, were measured using a Stuart SMP10
apparatus. The FT-IR spectra were obtained with a Shi-
madzu IR prestige 21 spectrophotometer (Columbia, MD,
USA). 1H and 13C NMR spectra were recorded with a Bruker
AVANCE III system operating at 400 MHz, using residual
and deuterated solvent peaks of CDCl3 (δH 7.26; δC 77.0)
and DMSO (δH 2.50; δC 39.5) as reference standards.
Results and discussion
.
2.1.1 SnCl2 2H2O/ChCl (2:1 molar ratio) DES Prepara-
.
tion. A mixture of SnCl2 2H2O (1451 mg, 6.43 mmol) and
Recently, we have reported the redox capability of tin (II)
chloride dihydrate/choline chloride eutectic mixture in the
conversion of several nitroarenes into the corresponding aro-
matic amines, N-arylacetamides and quinoxalines (Trujillo
et al. 2020). Our initial studies showed that nitrobenzene and
its analogues bearing electron donating and electron with-
drawing groups are easily reduced by the DES afording the
corresponding anilines in short reaction times with excellent
yields (Trujillo et al. 2020). Considering this, in this work
our initial eforts were directed at studying the reaction of
phenyl isocyanate and nitroarenes to aford unsymmetrical
urea derivatives employing the DES. Initially, nitrobenzene
was poured into the DES, and after its conversion to aniline
(5 min, TLC), phenyl isocyanate was added obtaining the
desired urea 1 in 93% isolated yield after 20 min. With these
interesting results in our hands, the reactivity of diferent
substituted nitroarenes in this reaction was also evaluated.
Results are depicted in Scheme 3.
ChCl (449 mg, 3.215 mmol) was poured in a glass vial. The
mixture was stirred and heated up to 80 °C until a homoge-
neous colourless liquid was obtained.
General experimental procedure for the synthesis
of unsymmetrical urea and thiourea derivatives 1–13
To an open headspace vial equipped with a magnetic stir
.
bar, the nitroarene (1.0 mmol) and 1.9 g of SnCl2 2H2O/
ChCl (2:1 molar ratio) DES were added, and the resulting
solution was then stirred and heated at 80 °C. After complete
reduction in the nitroarene (5 min, TLC), phenyl isocyanate
(1.2 mmol) was added, and heating was continued until the
reaction was complete (15–25 min, TLC analysis). Next,
the mixture was cooled to room temperature, neutralized
(pH 7) with aqueous NaOH (10% NaOH) and extracted with
AcOEt (5 X 2 mL), the organic layer was separated and dried
over anhydrous Na2SO4. After evaporating the solvent under
reduced pressure, the desired product was obtained in high
purity without further purifcation.
As seen in Scheme 3, nitroarenes bearing electron donat-
ing and electron withdrawing groups (methyl-, chloro- and
bromo-, respectively) aforded the target urea derivatives
2–8 in 85–93% yield. In addition, 4-bromophenyl isocyanide
Scheme 2 Nitroarenes in the
synthesis of unsymmetrical urea
and benzimidazole derivatives
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and phenyl isothiocyanate also reacted smoothly yielding the
urea (9 and 10) and thiourea (11–13) derivatives in excellent
yields (Scheme 3). No clear tendency on the reactivity was
observed regarding the diferent substituents located at the
nitroarene or the phenyl isocyanate derivative.
Next, we focused our eforts on the synthesis of 2-arylb-
enzimidazoles by reacting o-nitroaniline with diferent alde-
hydes; and for this, benzaldehyde was selected as starting
material in the model reaction (Table 1).
To our surprise, after running the reaction with 1 equiv.
of o-nitroaniline and 1 equiv. of benzaldehyde we found that
the desired 2-phenylbenzimidazole 14a was obtained in 22%
and the disubstituted analogue 14 was obtained in 66% yield
(Table 1 entry 1).
This result prompted us to redirect our synthesis towards
the access to the disubstituted analogue 14; and for this,
the equivalents of benzaldehyde were increased in 2, 2.5
and 3 folds (Table 1, entries 2 to 4). It was observed that
the amount of isolated benzimidazole 14a decreases with
the increase in benzaldehyde, and the reaction is selective
towards the obtention of the disubstituted analogue 14 when
3 equiv. of benzaldehyde are employed (Table 1, entry 4).
In addition, reactions performed at low temperatures
or prolonged reaction times did not improve the yield of
the reaction (Table 1, entries 5 and 6). A review of lit-
erature reveals that some authors also have studied the
same transformation starting from o-nitroaniline. Kim
and collaborators(Kim et al. 2002, 2004) found that this
Scheme 3 One-pot synthesis of unsymmetrical urea and thiourea
derivatives
Table 1 Optimization studies for the reaction of o-nitroaniline and benzaldehyde[a]
Yield[b]
14
Entry
Conditions: ratio amine/aldehyde, T (oC), t (min)
14a
1
2
3
4
5
6
7
8
9
1:1, 110 °C, 45 min
1:2, 110 °C, 45 min
1:2.5, 110 °C, 45 min
1:3, 110 °C, 45 min
1:3, 80 °C, 45 min
1:3, 110 °C, 75 min
6[c]
22[c]
9[d]
5[d]
0[d]
0[d]
0[d]
57
74[d]
77[d]
85[d]
72[d]
85[d]
33
1:2, Zn (10 equiv.), BNP (2 equiv.), MeOH/DCM (1/1), rt, 10 h(Kim et al. 2002)
1:2, In (5 equiv.), BNP (4 equiv.), MeOH/H2O (2/1), rt, 5 h(Kim et al. 2004)
70
43
10
43
1:2, NH4HCO2 (3.3 equiv.), Pd/C (0.05 mmol Pd), mont. K-10, toluene, refux, 16 h(Weires
et al. 2012)
.
[a] All reactions were performed in 1.9 g of tin (II) chloride dihydrate/choline chloride (SnCl2 2H2O/ChCl, 2:1 molar ratio) DES. [b] Isolated
yield. [c] Yields based on the amount of benzaldehyde. [d] Yields based on the amount of o-nitroaniline
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reductive intermolecular coupling/heterocyclization reac-
tion can be accomplished in the presence of Zn or In and
2-bromo-2-nitropropane (BNP); however a poor selectivity
is obtained when zinc is employed, and 2-phenylbenzimida-
zole 14a is obtained as major product when indium is used
(Table 1, entries 7 and 8). On the other hand, Weires et al.
(Weires et al. 2012) employed a mixture of two heteroge-
neous catalysts (montmorillonite-K10 and Pd/C), but this
strategy aforded an equimolar mixture of benzimidazoles 14
and 14a. (Table 1, entry 9). The poor selectivity towards the
disubstituted benzimidazole 14, low yields and long reaction
times found in the aforementioned procedures highlight the
novelty of our method. The scope and limitations of this
synthetic procedure was further studied in the reaction of
diferent aldehydes and o-nitroaniline. Results are illustrated
in Scheme 4.
As shown in Scheme 4, the electronic nature of the aro-
matic aldehydes does not infuence the outcome of the reac-
tion: aldehydes with electron donating groups (methoxy,
methyl, and methylenedioxy) aforded the target N-arylme-
thyl-2-substituted benzimidazoles 15–17 in 91, 90 and 89%
yield, while aldehydes with electron withdrawing groups
(o-chloro and p-chloro) yielded compounds 18 and 19 in 90
and 88%, respectively.
In addition, heterocyclic aldehydes such as 2-pyridine-
carboxyaldehyde aforded the compound 20 in good yield,
but aliphatic (n-decanal) and masked aldehydes (2,3-dihy-
drofuran and 2,3-dihydropyran) give a complex mixture of
products probably due to the enolizable character of these
aldehydes. Interestingly, when 2-hydroxybenzaldehyde was
employed in the reaction, only 2-arylbenzimidazole 21 was
obtained, which is most likely formed through an imine
intermediate where an intramolecular hydrogen bond sta-
bilizes the structure and promotes the nucleophilic attack
of the second nitrogen atom (see supporting information).
To further expand the scope of our method, and to evalu-
ate the regioselectivity of this reaction, 2-nitro-4-methoxy-
aniline was also employed as starting material. As depicted
in Scheme 4, this nitroaniline also reacted smoothly with
all aldehydes afording the corresponding derivatives; how-
ever a preference for the obtention of one regioisomer was
not observed and an equimolar mixture of both isomers
Scheme 4 One-pot synthesis of N-arylmethyl-2-substituted benzimi-
dazoles. Products 22–28 are 1:1 mixture of the 5- and 6-isomers
To get insights into the reaction mechanism, we decided
to perform two reactions starting from o-phenylenediamine
(see supporting information).
For the frst reaction, o-phenylenediamine (1 equiv.) was
reacted with benzaldehyde (3 equiv.) employing the DES
as solvent obtaining the compound 14a in 25% yield. Inter-
estingly compound 14 was not observed in this reaction.
The second reaction was achieved with the same starting
materials employing HCl (drops) in ethanol at refux, and
under these conditions, the 1,2-disubstituted benzimidazole
14 was obtained in 68% yield. The results obtained in these
reactions indicate that the DES do not catalyze the cyclocon-
densation to aford 14, and instead of this, HCl is capable of
promoting the desired transformation. With this information,
a plausible reaction mechanism is proposed in Scheme 5.
According to the mechanism, the reaction might fol-
low two paths for the frst: o-nitroaniline can be reduced
by the DES afording o-phenylenediamine A, which reacts
with benzaldehyde yielding the imine C. Alternatively, the
1
was obtained according to H-NMR. Diferent attempts
to separate such isomers by column chromatography were
unsuccessful.
The efciency and synthetic utility of this method was
next evaluated by performing a gram scale experiment.
According to this, o-nitroaniline (10 mmol) and benzalde-
hyde (30 mmol) were poured into the DES and the reac-
tion mixture was run for 45 min at 110 °C. After the proper
work-up and purifcation, the compound 14 was obtained
in 78% yield.
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Chemical Papers
.
Scheme 5 Plausible reaction mechanism for the synthesis of N-arylmethyl-2-substituted benzimidazoles in SnCl2 2H2O/ChCl DES
second path involves the condensation of o-nitroaniline with
benzaldehyde forming the azomethine B which is reduced
by the DES afording the compound C. Next, compound C,
which is responsible for the formation of 14a, react with a
second equivalent of benzaldehyde in acidic media (HCl,
which is formed during the reduction in o-nitroaniline and
compound B) yielding the bis imine D that undergoes an
intramolecular cyclization afording the intermediate E.
Finally, isomerization of E through a 1,3-hydride shift yields
the corresponding 1,2-disubstituted benzimidazole 14.
Finally, although this novel methodology allows the
access to N-arylmethyl-2-substituted benzimidazoles hav-
ing identical aromatic rings at positions 1 and 2, we also
explored the synthesis of derivatives with diferent substitu-
ents at the same positions, and thus increase the structural
diversity of such derivatives. To accomplish this, compound
29 was synthesized (Siddiqui et al. 2006) and it was reacted
with p-anisaldehyde; however a complex mixture was
obtained where compounds 14a, 15 and 30 were identifed
and obtained in a ratio of 1:1.3:2.5, respectively, according
to GCMS analysis (Scheme 6). The origin of regioselectiv-
ity for compounds 15 and 30 could be explained in terms of
relative stability of benzylic carbocations where the more
electron rich the arene aford the more stable carbocation.
Thus, after cyclization the corresponding benzimidazole 30
can be generated as the major isomer (Bose et al. 2019).
Scheme 6 Identifed com-
pounds in the reaction of com-
pound 29 and p-anisaldehyde in
.
SnCl2 2H2O/ChCl DES
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Chemical Papers
Carvalho LCR, Fernandes E, Marques MMB (2011) Developments
towards regioselective synthesis of 1,2-Disubstituted benzimida-
zoles. Chem - Eur J 17(45):12544–12555. https://doi.org/10.1002/
chem.201101508
Conclusion
In conclusion, we have developed a simple and straightfor-
ward method for the synthesis of unsymmetrical urea and
thiourea derivatives together with 1,2-disubstituted ben-
zimidazoles starting from nitroarenes. Diferent nitroaro-
matic compounds are efectively reduced employing the
Chakraborty A, Debnath S, Ghosh T, Maiti DK, Majumdar S (2018)
An efcient strategy for N-alkylation of benzimidazoles/imida-
zoles in SDS-aqueous basic medium and N-alkylation induced
ring opening of benzimidazoles. Tetrahedron 74(40):5932–5941.
https://doi.org/10.1016/j.tet.2018.08.029
.
SnCl2 2H2O/ChCl DES, and the formed anilines reacted
Connon SJ (2006) Organocatalysis mediated by (thio)urea deriva-
tives. Chem - Eur J 12(21):5418–5427. https://doi.org/10.1002/
chem.200501076
smoothly with phenyl isocyanate or phenyl isothiocyanate
affording the corresponding ureas or thioureas in good
yields. Similarly, the reaction of o-nitroaniline or 2-nitro-
4-methoxyaniline with several aromatic and heteroaromatic
aldehydes employing the same DES as a reductive reaction
medium yielded 1,2-disubstituted benzimidazole derivatives
in good yields; however, no regioselectivity was observed
when 2-nitro-4-methoxyaniline was used.
Das K, Mondal A, Srimani D (2018) Selective synthesis of 2-sub-
stituted and 1,2-disubstituted benzimidazoles directly from
aromatic diamines and alcohols catalyzed by molecularly
defined nonphosphine manganese(I) complex. J Org Chem
83(16):9553–9560. https://doi.org/10.1021/acs.joc.8b01316
Ghosh AK, Brindisi M (2020) Urea derivatives in modern drug dis-
covery and medicinal chemistry. J Med Chem 63(6):2751–2788.
https://doi.org/10.1021/acs.jmedchem.9b01541
Ghosh SK, Nagarajan R (2016) Deep eutectic solvent mediated syn-
thesis of quinazolinones and dihydroquinazolinones: synthesis
of natural products and drugs. RSC Adv 6(33):27378–27387.
https://doi.org/10.1039/C6RA00855K
Supplementary Information The online version contains supplemen-
tary material available at https://doi.org/10.1007/s11696-021-01785-7.
Guan Z-H, Lei H, Chen M, Ren Z-H, Bai Y, Wang Y-Y (2012) Palla-
dium-catalyzed carbonylation of amines: switchable approaches
to carbamates and N, N′-disubstituted ureas. Adv Synth Catal
354(2–3):489–496. https://doi.org/10.1002/adsc.201100545
Hérault D, Aelvoet K, Blatch AJ, Al-Majid A, Smethurst CA, Whit-
ing A (2007) Benzimidazole nitrogen-directed, regiocontrolled,
lithiation of ferrocenyl- and phenyl-N-n-butylbenzimidazoles.
J Org Chem 72(1):71–75. https://doi.org/10.1021/jo061639+
Herrera Cano N, Uranga JG, Nardi M, Procopio A, Wunderlin DA,
Santiago AN (2016) Selective and eco-friendly procedures for
the synthesis of benzimidazole derivatives. The role of the
Acknowledgements We gratefully acknowledge the fnancial support
from Universidad Nacional de Colombia. C. O-P. We sincerely thank
Prof. Humberto Zamora for providing some infrastructure facilities.
Declarations
Conflict of interest The authors declare that they have no known com-
peting fnancial interests or personal relationships that could have ap-
peared to infuence the work reported in this paper.
Er(OTf)3
catalyst in the reaction selectivity. Beilstein J Org
Chem 12:2410–2419. https://doi.org/10.3762/bjoc.12.235
Higuera NL, Pemña-Solóorzano D, Ochoa-Puentes C (2019) Urea–
zinc chloride eutectic mixture-mediated one-pot synthesis of
imidazoles: efcient and ecofriendly access to trifenagrel. Syn-
lett 30(2):225–229. https://doi.org/10.1055/s-0037-1610679
Jagtap AD, Kondekar NB, Sadani AA, Chern J-W (2017) Ureas:
applications in drug design. Curr Med Chem 24(6):622–651.
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thesis of 2-aryl-1-arylmethyl-1H-benzimidazoles in ball mill
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