New route for the synthesis of benzimidazoles by a one-pot multistep process with mono and bifunctional solid catalysts

Article abstract of DOI:10.1016/j.tet.2009.11.048

One-pot multistep reactions involving a new environmentally friendly catalytic procedure have been developed for the synthesis of benzimidazoles. Benzimidazole derivatives with biological and pharmaceutical interest have been prepared by a one-pot four step process with a solid catalyst containing basic and oxidation sites. The four steps refer to: (a) oxidation of the alcohol; (b) cyclocondensation of the aldehyde formed with ortho-phenylenediamines, (c) oxidation of the carbon-nitrogen bond, (d) N-alkylation reaction. The process is illustrated by the synthesis of 1,2-disubstituted benzimidazole derivative with antiviral activity.

Full text of DOI:10.1016/j.tet.2009.11.048

Tetrahedron 66 (2010) 730–735
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New route for the synthesis of benzimidazoles by a one-pot multistep process
with mono and bifunctional solid catalysts
*
*
´
Violeta R. Ruiz, Avelino Corma , Marıa J. Sabater
Instituto de Tecnolog´ıa Qu´ımica UPV-CSIC, Avenida Los Naranjos s/n, 46022 Valencia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
One-pot multistep reactions involving a new environmentally friendly catalytic procedure have been
developed for the synthesis of benzimidazoles. Benzimidazole derivatives with biological and pharma-
ceutical interest have been prepared by a one-pot four step process with a solid catalyst containing basic
and oxidation sites. The four steps refer to: (a) oxidation of the alcohol; (b) cyclocondensation of the
aldehyde formed with ortho-phenylenediamines, (c) oxidation of the carbon–nitrogen bond, (d) N-al-
kylation reaction. The process is illustrated by the synthesis of 1,2-disubstituted benzimidazole derivative
with antiviral activity.
Received 1 October 2009
Received in revised form
10 November 2009
Accepted 11 November 2009
Available online 14 November 2009
Keywords:
One-pot
Ó 2009 Elsevier Ltd. All rights reserved.
Benzimidazole
Heterogeneous
Aerobic oxidation
Gold
Palladium
1. Introduction
a diamine, and in a second reaction process, the carbon–nitrogen
bond is oxidized to afford the imidazole cycle. When the stability or
Benzimidazoles are important organic molecules, which find
applications as antiulcers, antihypertensives, antivirals, antifungals,
anticancer, and antihistaminics among others.1–3 Owing to their
interesting properties, great attention has been paid to the
synthesis of benzimidazole derived compounds and two main
synthesis methods have been developed. One of them involves the
coupling of phenylenediamines and carboxylic acids or their
derivatives, a process that requires strong acidic conditions and
sometimes combines very high temperatures or the use of micro-
wave.4–6 The other synthesis route involves a two-step procedure
that includes the cyclo-dehydrogenation of aniline Schiff’s bases,
which are often generated in situ from the condensation of phe-
nylenediamines and aldehydes, followed by oxidation with
stoichiometric oxidants, as for instance, nitrobenzene, 1,4-benzo-
quinone, MnO2, Oxone, NaHSO3, or I2/KI/K2CO3/H2O, and more
recently with air.7,8
the handling of the aldehyde is an issue, the catalyst presented here
allows to start the reaction from the corresponding alcohols that
will be oxidized to generate ‘in situ’ the aldehyde. Working on these
bases it will be presented here that it is possible to afford the
synthesis of
a disubstituted benzimidazole derivative, 1(2,6-
difluorobenzyl)-2-phenylbenzimidazole, which is a molecule with
inhibitory activity against human immunodeficiency virus
type-1 (HIV-1), through a one-pot four step process, by using
a bifunctional base oxidation catalyst.
2. Results and discussion
2.1. The one-pot process and catalysts involved
In order to see if the synthesis route presented above could be
used to produce benzimidazoles with good conversions and selec-
tivities we reacted benzyl alcohol and o-phenylenediamine using
gold and palladium-based catalysts that have shown to be active
and selective aerobic oxidative catalysts.9–18 In this case the global
process will require: (i) a metal catalyzed aerobic oxidation to afford
benzaldehyde, (ii) the cyclocondensation reaction with o-phenyl-
enediamine and (iii) the catalytic aerobic oxidation of the C–N bond
to give the final substituted benzimidazole according to Scheme 1.
We present here, a one-pot multistep catalytic process for the
synthesis of benzimidazoles starting form alcohols or aldehydes. If
one can start with the aldehyde, then this can be coupled with
* Corresponding authors. Tel.: þ34 96 3877800, fax: þ34 96 3877809.
E-mail addresses: acorma@itq.upv.es (A. Corma), mjsabate@itq.upv.es (M.J.
Sabater).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.048

V.R. Ruiz et al. / Tetrahedron 66 (2010) 730–735
731
formation of the intermediate compound 1 (see Scheme 1). In
striking contrast, the intermediate 2 reacts very fast and was not
detected under our experimental conditions (see Scheme 1).
It is important to remark that both reaction steps (oxidation and
cyclization)havetobecarriedoutunderoxygenpressure(PO2¼5 bar),
since in the absence of oxygen (or even under air) the yield of ben-
zimidazolic compound 3 decreases and product 4 can be isolated by
column chromatography (in some cases as the major product) to-
gether with compound 5 (see entries 4–8 in Table 1 and Scheme 2).
Scheme 1. Schematic representation of the synthesis of benzimidazole heterocycle 3
in a single pot with gold and/or palladium catalyst and oxygen as terminal oxidant.
CHO
Since preliminary experiments showed that the oxidation of
benzyl alcohol did notoccur in the presence of the diamine, probably
due to a strong competitive adsorption of the latter on the metal, the
one-pot three-step synthesis was devised in such a way that the
diamine was incorporated when almost all benzyl alcohol was oxi-
dized. Thus, with few exceptions, the oxidation of benzyl alcohol to
benzaldehyde proceeds rapidly at 90 ꢀC under oxygen in the pres-
ence of palladium and gold supported catalysts (see entries 1–10,
Table 1),19 and good yields of the desired 2-phenyl-1-H-benzimid-
azole 3 were obtained with Pd on carbon or MgO, as well as with gold
on nanoparticulated CeO2 (see entries 1–3 in Table 1).19
H
Ph
N
N
N
NH2
NH2
N
Ph
Ph
+
+
+
N
H
NH2
Ph
5
3
4
Scheme 2. Product distribution obtained after the cyclization step under inert
atmosphere.
2.2. The formation of byproducts 4 and 5
The formation of compound 4 is associated to a catalytic
transfer hydrogenation reaction. In general, the transfer hydro-
genation methodology involves the use of an alcohol (or any
other donor molecule) that should be dehydrogenated with the
aid of a metal catalyst to give an oxidized compound and a metal
hydride (metal monohydride and/or dihydride intermediate),
which would selectively hydrogenate a multiple bond, in this
case the imine.21 Taking into account that the aromatic alcohol
has been almost completely transformed into benzaldehyde
before adding the diamine, benzyl alcohol cannot be the hydro-
gen donor and therefore there is only one compound that may
behave as potential donor molecule for this reaction. That is, the
intermediate benzimidazoline 2, a heterocyclic precursor formed
by a benzene ring fused with an imidazoline, which may undergo
oxidative removal of hydrogen to afford our target product
benzimidazole together with a metal hydride.22 This metal
hydride can hydrogenate the imine 1 to afford 4 as byproduct as
depicted in the Figure 1.
Table 1
Synthesis of 2-phenyl-1H-benzimidazole 3 using heterogeneous gold and palla-
dium-based catalystsa
Entry
Catalyst
Convb(%)
step a
Convc(%)
step b
Yd(%)
3
4
5
1
2
3
4
5
6
7
8
9
Pd–MgO
Pd–C
93
97
89
89
93
96
67
70
30
11
100
100
100
99
97
96
99
99
100
75
85
90
85
62
37
36
27
33
29
8
d
d
d
2
51
5
traces
d
d
d
d
2
d
Au–CeO2
Au–CeO2
e
12
traces
20
40
6
Pd–MgOe
Pd–Ce
Pd-HAPe,f
Au/Pd–TiO2
Au–TiO2
Au–Fe2O3
e
d
H
N
H
N
R
R
10
d
2
3
Pd
R
a
1
Reaction conditions: 1 mmol benzyl alcohol, 1 mmol diamine, catalyst
N
H
(0.05 mmol metal), 1 ml trifluorotoluene, T¼90 ꢀC, PO2¼5 bar.
NH
2
b
Calculated by GC on the basis of the amount of benzyl alcohol transformed.
Calculated by GC on the basis of the amount of benzaldehyde transformed.
Isolated yield.
Cyclocondensation step carried out under N2.
2
4
c
d
R
N
2
e
N
R
1
f
Pd-HAP refers to palladium supported on hydroxyapatite.
N
H
R
3
NH
Pd-H
2
With respect to gold based catalysts, we have found significant
differences in reactivity and yield of benzimidazole derivatives
depending on the support. The highest activity and selectivity have
been achieved when gold was deposited onto CeO2 (entry 3, Table
1) under oxygen, whereas benzyl alcohol hardly reacts when Au
was supported on TiO2 or Fe2O3 (see entries 9–10 in Table 1).
Similarly, the yield of the hydrogenated product 4 was lower with
Au–CeO2 than with Pd–MgO (see entries 4–5, Table 1) working
under inert atmosphere. The reason for this relies in the lower
tendency of gold to form hydrides together with their lower sta-
bility and reactivity as compared to palladium hydrides.20
It has to be emphasized that the desired compound 3 (see
Scheme 1) precipitates in the reaction medium, while being pro-
duced, making very easy its isolation. The reaction sequence in
Scheme 1 was verified by disrupting or decreasing the reaction
temperature immediately after adding the diamine. In this case, it
was possible to stop the synthetic sequence and to detect the
1
3
Figure 1. Schematic representation of the Pd–MgO catalyzed hydrogenation transfer
reaction for the formation of compound 4 with benzimidazoline as hydrogen donor.
The formation of 5 takes also place in the absence of catalyst
and, in accordance to this, the 1,2-disubstituted benzimidazole 5 is
again formed with moderate yields when using an inert support
like Pd–C under inert atmosphere (entry 6, Table 1). Formation of
compound 5 through an intermediate diimine has been proposed
in the literature.23 Nevertheless, and as was said above, it is possible
to obtain high yields of the desired compound 3 with gold and
palladium supported catalysts and working under oxygen pressure
(see entries 1–3 in Table 1).
In close connection to this, it is interesting to note that recently
a synthesis of benzazoles by hydrogen transfer catalysis from al-
cohols has been reported. Nonetheless, the use of hydrogen transfer

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V.R. Ruiz et al. / Tetrahedron 66 (2010) 730–735
effectively requires the presence of a convenient acceptor for the
generation of the aldehyde in the presence of Ru and Ir
complexes.22b
Starting from piperonyl alcohol and ortho-phenylenediamine,
moderate yields of the corresponding benzimidazole derivative
could be obtained (entry 7, Table 2).
With electron-acceptor substituents on the aromatic diamine
the cyclization/oxidation reaction proceeds more slowly and, ac-
cordingly, lower yields of the desired benzimidazole were obtained
after prolonged heating (entry 5, Table 2). The same effect was
observed when the electronwithdrawing substituent was at the
aromatic alcohol (entry 6, Table 2).
On the other hand, 1-butanol afforded very poor yields of the
corresponding heterocycle provided this aliphatic alcohol hardly
converted to the corresponding aldehyde (entry 8, Table 2). In
striking contrast the conjugated alcohol 2-octen-1-ol converted up
to 80%tothe corresponding aldehyde, albeit the latterhardlyreacted
with the diamine to afford the desired heterocycle (entry 9, Table 2).
2.3. Scope of the reaction
To test the general scope and versatility of this synthetic pro-
cedure a number of differently substituted aryl alcohols and phe-
nylenediamines were examined. For doing this, stoichiometric
amounts of ortho-phenylenediamines were incorporated to the
reaction vessel after completing the alcohol transformation to al-
dehyde at 90 ꢀC in the presence of Au–CeO2 under oxygen. Con-
versions and yields of isolated benzimidazole derivatives are
indicated in Table 2.
As described previously, all benzimidazole derivatives were in-
soluble in the reaction media, thus being isolated by filtration. It was
found thatintroductionofa donor methoxygroup atthe para position
of the aromatic alcohol speeds up the oxidation reaction to obtain the
aromatic aldehyde, being the yields of the benzimidazole heterocy-
cles from moderate to high (see entries 2–3, Table 2). With a methyl
group at the para position the yields were moderate (entry 4, Table 2).
2.4. Synthesis of a target molecule in a one-pot four step
synthesis
Since in general, the experimental procedure described is
chemoselective and operates under mild reaction conditions, we
Table 2
Au–CeO2 catalyzed synthesis of benzimidazole derivatives from aromatic alcohols and phenylenediamines under oxygena
Entry
1d
Alcohol
Diamine
Product
Cb (%)
Yc(%)
85
N
NH2
CH2OH
89 (>99%)
N
H
NH2
N
CH2OH
NH2
NH2
OCH3
2e
> (>99%)
91
N
H
H3CO
NC
CH2OH
N
NC
NH2
NH2
3f
4e
5g
6h
7i
8
94 (>99%)
70
60
55
40
53
13j
OCH3
N
H
H3CO
H3C
N
CH2OH
CH2OH
CH2OH
CH2OH
NH2
NH2
CH3
84
N
H
O2N
O2N
N
NH2
NH2
OCH3
>99 (>99%)
N
H
H3CO
N
NH2
Cl
O
>99
87
N
NH2
Cl
H
N
O
O
NH2
NH2
N
H
O
N
NH2
NH2
40
OH
N
H
N
NH2
NH2
9
80
22
OH
N
H
a
Reactions were performed at 90 ꢀC by using 1 mmol of alcohol, 1 mmol diamine, Au–CeO2 (0.5% mmol), 1 ml of trifluorotoluene, and oxygen (PO2¼5 bar).
b
c
d
e
f
Calculated on the amount of transformed alcohol ; selectivity is given in parenthesis.
Isolated yields.
Ref 24a.
Ref 24b.
Ref 24c.
Ref 24d.
Ref 24e.
Ref 24f.
Calculated by GC.
g
h
i
j

V.R. Ruiz et al. / Tetrahedron 66 (2010) 730–735
733
thought that the same protocol could be applied to the synthesis
of benzimidazoles with pharmaceutical and biological interest as
can be the synthesis of non-nucleoside antivirals. Effectively, a key
target in the search for effective drugs useful for AIDS therapy is
the search of viral enzymes that play key roles in the life cycle of
the human immunodeficiency virus type-1 (HIV-1). One such es-
sential enzyme is reverse transcriptase (RT), an enzyme that
contains both a DNA polymerase activity (which can use either
RNA or DNA as a template), and a ribonuclease H activity.25,26
Inhibition of RT provides an effective means of blocking HIV-1
replication.27,28 In close connection to this, a number of inhibitors
have been developed for antiviral chemotherapy and among them
it can be pointed out the non-nucleoside RT inhibitor with N-
benzylbenzimidazole structure 1-(2,6-difluorobenzyl)-2-phenyl
benzimidazole, that it is synthesized in 40% yield through a mul-
tistep process.3
A priori, the challenge of adapting the one-pot methodology
described above to the synthesis of this antiviral becomes apparent
when considering the retrosynthetic analysis of this molecule. In-
deed, we thought that the molecule could be synthesized via
a N-alkylation reaction of the corresponding 2-arylbenzimidazole
structure, which in turn should be obtained by coupling the di-
amine and benzaldehyde through the previously described one-pot
sequence.
synthetic approach afforded the highest yields (88 and 85%) of the
target compound 1-(2, 6-difluorobenzyl)-2-phenylbenzimidazole
(see entries 2, 3 in Table 3).
Table 3
Synthesis of 1-(2,6-difluorobenzyl)-2-phenylbenzimidazole through different syn-
thetic strategiesa
Entry Route
Catalyst
Oxidationb (%) Cyclizationc (%) Yieldd (%)
1
2
3
4
5
6
route-1 Pd–MgO
route-2 Pd–MgO
route-2 Au–CeO2
95
93
89
d
91
95
95
d
40
88
85
44
86
82
MCR
Pd–MgO
e
route-2 Pd–MgO2
90
88
90
96
e
route-2 Au–CeO2
a
Reaction conditions: 1 mmol of alcohol, 1 mmol diamine, 1 mmol 2,6-difluor-
obenzylbromide, 0.5% mmol metal (Au–CeO2 or Pd–MgO), 1 ml of trifluorotoluene,
oxygen (PO2¼5 bar), T¼90 ꢀC and 0.2 ml of DMF as co-solvent to carry out the N-
alkylation step.
b
Conversion calculated by GC on the bases of benzyl alcohol transformed.
Conversion calculated by GC on the bases of benzaldehyde transformed.
Isolated yield.
Recovered and reused catalysts.
c
d
e
Finally, in the search for a synthetic strategy to build up the best
cascade reaction, the final product was assembled through a re-
action in which the three starting materials benzaldehyde, ortho-
phenylenediamine and the alkyl bromide were simultaneously
reacted (Scheme 3). The reaction was performed in the presence of
Pd–MgO, and moderated yields of the target product were obtained
(see entry 4 in Table 3), that were in the same order that in pre-
viously reported synthesis procedure through a multistep process.28
It has to be pointed out the excellent reusability of both catalysts
for which no metal leaching or deactivation was observed, main-
taining its initial activity and selectivity after two uses (see entries
5, 6 in Table 3).
In a first approach we selected palladium deposited on a basic
support as catalyst. The use of this basic solid could allow the
introduction of a N-alkylation reaction to the original one-pot
sequence described before, resulting in a oxidation/cyclization/
N-alkylation global sequence (Scheme 3).
O
OH
H
NH2
NH2
N
3. Conclusions
An effective strategy has been developed for the rapid and ef-
ficient one-pot synthesis of benzimidazoles from easily available
alcohols and diamines. This strategy allows access to a structurally
diverse array of products. The one-pot process in which a first al-
cohol oxidation is combined with further formation of imidazoline
ring, takes place in several steps wherein each product becomes the
substrate for the next reaction. The one-pot reactions are controlled
by means of the sequential addition of diamines after ensuring the
almost complete consumption of the starting alcohol. After amine
addition, the formation of a Schiff base intermediate takes place,
which will cyclize to the benzimidazoline (not detected) and is
oxidized to afford the benzimidazole derivative, hence minimizing
the number of operations to be performed.
N
H
F
O
OH
H
Br
route-1
H
F
O
+
N
NH2
MCR
route-2
N
NH2
F
F
NH2
F
+
F
N
H
Br
6
F
F
1-(2, 6-difluorobenzyl)-2-phenylbenzimidazole
Scheme 3. Diverse synthetic strategies for the synthesis of 2-arylbenzimidazole an-
tiviral 1-(2, 6-difluorobenzyl)-2-phenylbenzimidazole [Ref. 29].
The main side reactions were: catalytic hydrogenation reaction
of the imine 1 to afford 4, and the formation of 1,2-dialkylated
benzimidazole 5. Both reactions were completely inhibited under
oxygen pressure affording high yields of the desired product 3.
The deposition of the metal on a solid basic support allows
planning diverse multistep routes for the synthesis of a 2-aryl
substituted benzimidazole, a molecule with inhibitory activity
against human immunodeficiency virus type-1 (HIV-1).
For achieving this, Pd–MgO was used to afford the 2-phenyl-
benzimidazole heterocycle above mentioned (see details of their
preparation in the Experimental section) and once the formation of
2-phenylbenzimidazole was completed, the N-alkylation reaction
with 2,6-difluorobenzylbromide afforded the desired target prod-
uct, i.e., 1-(2, 6-difluorobenzyl)-2-phenylbenzimidazole, with
moderate yields (entry 1, Table 3 and Scheme 3).
A closely related one-pot procedure was alternatively developed
using the same bifunctional catalysts Pd–MgO, as well as Au–CeO2
via route 2 in Scheme 3. For achieving this, the monoalkylated
diamine N-(2,6-difluorobenzyl)benzene-1,2-diamine (6) was
obtained in parallel (see details of its preparation in the Experi-
mental section), being incorporated after the aromatic alcohol
transformation to benzaldehyde (see Scheme 3). This convergent
4. Experimental section
4.1. Materials
Commercial Pd–C was purchased from Aldrich; Au–TiO2 and
Au–Fe2O3 catalysts were obtained from Gold World Council Co. and
used without further purifications.

734
V.R. Ruiz et al. / Tetrahedron 66 (2010) 730–735
17b
16a
Au–CeO2
,
AuPd–TiO2
and Pd-HAP29 were prepared
4.5. Experimental procedure for the MCR synthesis of 1-(2,6-
according to previous reported procedures.
Solvent trifluorotoluene and all commercially available alcohols
and phenylenediamines were employed without further
purification.
difluorobenzyl)-2-phenyl-1-H-benzimidazole
Stoichiometric amounts of benzaldehyde (0.2 mmol), o-phenyl-
enediamine (0.2 mmol), and 2,6-difluorobenzylbromide (0.2 mmol),
wereincorporatedintoareactorcontaining0.5 mloftrifluorotoluene
and Pd–MgO (0.002 g, 0.4%) under oxygen (PO2¼5 bar). The mixture
was stirred at 90 ꢀC for 24 h. The reaction was monitored by GC.
4.2. Typical procedure for synthesis of benzimidazole
derivatives (Tables 1 and 2)
4.6. SynthesisofN-(2,6-difluorobenzyl)benzene-1,2-diamine(6)
1 mmol of aromatic alcohol and palladium or gold catalyst (0.5%
mol) were added to a autoclave containing 1 ml of trifluorotoluene.
The reaction mixture was heated at 90 ꢀC under continuous stirring
under oxygen (PO2¼5 bar). In most cases the aromatic aldehyde was
produced with high yield. Nonetheless, since benzyl benzoate ester
was detected at high alcohol conversion, the o-phenylenediamine
was incorporated before the ester formation, in order to scavenge
benzaldehyde and avoid the overoxidation to benzoic acid and the
subsequent esterification reaction. Then, after almost complete
consumption of the starting alcohol, stoichiometric amounts of 1,
2-phenylenediamine (1 mmol) were added and heating was pro-
longed to total diamine consumption. The progress of the one-pot
reaction was monitored by GC. All benzimidazole derivatives were
insoluble in the reaction medium and precipitated being isolated by
filtration.
A
100 mL round bottom flask was charged with 0.108 g
(1 mmol) of 1,2-ortho-phenylenediamine, 0.207 g (1 mmol) of 2,6-
difluorobenzylbromide, 0.101 g (1 mmol) NEt3 and 5 ml of THF. The
mixture was stirred at reflux temperature for 24 h. The solvent was
evaporated under vacuum and the solid was purified by column
chromatography using an eluent mixture of Cl2CH2:MeOH. (99:1)
to get 0.140 g (60% yield) of the compound N-(2,6-difluoro-
benzyl)benzene-1,2-diamine and showing the following elemental
composition: C, 66.93%; H, 5.35%; N, 11.45%; C13H12N2F2 requires C,
66.66%; H, 5.16%; N, 11.96%. 1H NMR (300 MHz, DMSO-d6);
d
¼7.41
(m, 1H), 7.11 (t, J¼8.1 Hz, 2H), 6.50 (m, 4H), 4.56 (t, J¼5.5 Hz, 1H),
4.69 (br s, 2H), 4.26 (d, J¼5.8 Hz, 2H) ppm 13C NMR (300 MHz,
DMSO-d6); 75 MHz, DMSO-d6: d¼163.0, 159.7, 135.4, 135.1, 129.7,
117.6, 117.3, 115.2, 114.8, 111.7, 111.5, 110.0, 35.4 ppm.
4.3. Experimental procedure for the one-pot 1 synthesis of 1-
(2,6-difluorobenzyl)-2-phenyl 1-H-benzimidazole (route 1)
Acknowledgements
´
´
Financial support by the Direccion General de Investigacion
1 mmol of benzyl alcohol and 0.043 g Pd–MgO were in-
corporated into a reactor containing 1 ml of trifluorotoluene. The
reaction mixture was heated at 90 ꢀC under continuous stirring
and oxygen (PO2¼5 bar). After almost complete oxidation of the
starting alcohol to aldehyde (before detecting the formation of
the benzoic acid ester derivative), stoichiometric amounts of 1,2-
ortho-phenylenediamine (1 mmol, 0.108 g) were added and
heating was prolonged to total diamine consumption. After this,
stoichiometric amounts of 2,6-difluorobenzylbromide (1 mmol,
0.207 g) and 0.2 ml of DMF were added and heating was pro-
longed under inert atmosphere. The reaction was monitored by
TLC. After completing the reaction, the solvent was evaporated
under vacuum and the final product was purified by column
chromatography by using Cl2CH2:MeOH (99:1) as eluent to get
0.13 g (40% yield) of 1-(2,6-difluorobenzyl)-2-phenyl-1H-
benzimidazole.
´
´
Cientıfica y Tecnica of Spain (Project MAT2006-14274-C02-01) and
Generalitat Valenciana (PROMETEO) is gratefully acknowledged.
V.R. thanks to Consejo Superior de Investigaciones Cientıficas for
´
I3-P fellowships.
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acid), stoichiometric amounts of
6 (0.117 g, 0.5 mmol) were
added and heating was prolonged to total diamine
consumption.
The reaction was monitored by TLC. After completing the re-
action, the solvent was evaporated under vacuum and the final
product was purified by column chromatography by using
Cl2CH2:MeOH (99:1) as eluent to get 0.282 g of 1-(2,6-difluoro-
benzyl)-2-phenyl-1H-benzimidazole (88% yield using Pd–MgO as
catalyst) and 0.272 g of the same compound (85% yield using
Au–CeO2 as catalyst).
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