An efficient one-pot two catalyst system in the construction of 2-substituted benzimidazoles: Synthesis of benzimidazo[1,2-c]quinazolines

Article abstract of DOI:10.1039/c5ob01777g

The benzimidazole core is a common moiety in a large number of natural products and pharmacologically active small molecules. The synthesis of novel benzimidazole derivatives remains a main focus in medicinal research. In continuation of the efforts towards Ce(iii) catalysts for organic transformations, we observed for the first time the activity of the iodide ion and copper cation in activating CeCl₃·7H₂O in the selective formation of prototypical 2-substituted benzimidazoles. The one-pot CeCl₃·7H₂O-CuI catalytic system procedure includes the cyclo-dehydrogenation of aniline Schiff's bases, generated in situ from the condensation of 1,2-phenylenediamine and aldehydes, followed by the oxidation with iodine, which works as a hydrogen sponge. Mild reaction conditions, good to excellent yields, and clean reactions make the procedure a useful contribution to the synthesis of biologically active fused heterocycles containing benzimidazoquinazolines.

Full text of DOI:10.1039/c5ob01777g

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ARTICLE
Efficient one-pot two catalyst system in the construction of 2-
substituted benzimidazoles: synthesis of benzimidazo[1,2-
c]quinazolines
Received 00th January 20xx,
Accepted 00th January 20xx
a
a,§
a,c,§
b
Cristina Cimarelli, Matteo Di Nicola, Simone Diomedi, Riccardo Giovannini, Dieter
DOI: 10.1039/x0xx00000x
c
a,§
a,c,§
a
Hamprecht, Roberta Properzi, Federico Sorana, and Enrico Marcantoni,*
www.rsc.org/
The benzimidazole core is a common moiety in a larger number of natural products and pharmacologically active small
molecules. The synthesis of novel benzimidazole derivatives remains a main focus of medicinal research. In continuation of
the efforts towards Ce(III) catalysts for organic transformations, we observed for the first time the activity of the iodide ion
and copper cation in activating CeCl
3 2
.7H O in the selective formation of prototypical 2-substituted benzimidazoles. The
one-pot CeCl .7H O-CuI catalytic system procedure includes the cyclo-dehydrogenation of aniline Schiff’s bases, generated
3
2
in situ from condensation of 1,2-phenyldiamine and aldehydes, followed by oxidation with iodine, which works as an
hydrogen sponge. Mild reaction conditions, good to excellent yields, and clean reactions make the procedure a useful
contribution to the synthesis of biologically active fused heterocycles containing benzimidazoquinazolines.
6
.
better activator for CeCl 7H O than NaI. Although not
3
2
Introduction
studied by the authors, it appears likely that lithium acts as a
Lewis acid co-catalyst of the Ce(III) salt in the proposed
reaction.
Catalytic processes provide a means to improve the
economic and environmental aspects by allowing organic
chemists to minimise the use of chemicals, waste production
and process energy consumption. A powerful tool in applied
organic chemistry is represented by the use of heterogeneous
catalysts, and in the last years, one-pot two catalyst systems
allowing complex organic transformations to take place in
cleaner and more efficient one-pot processes. The
simultaneous presence of both catalysts needed to complete
the chemical reaction sequences poses the problem of
compatibility. However, the ease with which they operate,
compared to metal co-catalyst systems, makes the one-pot
catalyst system a useful methodology that may find
applications in both academia and in industry.
Cerium is the most abundant element in the series of
lanthanides, and represents one of the more widely used
ones in organic chemistry. The most stable cerium salts
Even if we observed that different catalytic inorganic
7
.
iodides (M I ) increase the Lewis acidity of CeCl 7H O, the
x y
3
2
above results prompted us to examine how the nature of the
y+
metal ion M promotes the Lewis acidity of Ce(III) salt. Simple
and inexpensive copper catalysts play an important role in
8
numerous organic reactions, and very recently Z. Wang and
co-workers have developed a methodology through which it
is possible to construct functionalised cyclic structures using
9
copper catalysis together with gold catalysis. Therefore, in
the course of our program aimed at developing general
methods for the synthesis of nitrogen-containing
1
1
0
heterocycles, we decided to explore the potential of
1
1
.
CeCl 7H O in combination with CuI in Lewis acid catalysed
3
2
12
heterocyclocondensation reactions. In this paper we report
a facile methodology for the synthesis of 2-substituted
2
.
benzimidazoles by one-pot CeCl 7H O-CuI catalysed
3
2
heterocyclocondensation without copper contamination of
the products. The methodology was successfully applied to a
synthesis of pharmaceutically relevant compounds such as
benzimidazo[1,2-c]quinazolines, a new class of antiviral and
belong to the trivalent oxidation state such as CeCl , which is
a most useful compound for organic chemistry applications.
3
3
CeCl is a Lewis acid tolerant to water, even if moderate
3
activation of reaction has been experienced when hydrated
13
4
antitumor compounds.
CeCl is used on its own. In contrast, we observed recently
3
.
2-Substituted benzimidazoles are important moieties in
many biologically relevant molecules in the drug discovery
that the activity of CeCl 7H O as a Lewis acid can be
3
2
enhanced by the combination with an iodide source such as
14
5
field, thus a range of methodologies have been developed in
pharmaceutical industry for syntheses of this important
family of heterocyclic molecules. The most common strategy
involves the condensation of aryl amines with carbonyl
NaI. In 2009 Yadav and co-workers have found that LiI is a
a.
b.
School of Science and Technology, Chemistry Division, University of Camerino, via
S. Agostino 1, I-62032 Camerino (MC), Italy.
Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397
15
moieties followed by oxidative cyclisation. Nevertheless,
Biberach an der Riss, Germany.
BI Research Italia S.a.s. of BI IT S.r.l., Via Lorenzini 8, I-20139 Milano, Italy
Electronic Supplementary Information (ESI) available.
c.
†
See DOI: 10.1039/x0xx00000x
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ARTICLE
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most of these methodologies have been associated with result and was selected as solvent for further optimisation of
View Article Online
DOI: 10.1039/C5OB01777G
drawbacks such as harsh reaction conditions, use of expensive this reaction.
catalysts, formation of undesirable products, requirement of
1
6
an excess amount of solvents, low yields, etc. For these Table 1 Optimisation of conditions for the synthesis of 2-substituted
reasons, the interest in developing environmentally friendly benzimidazoles.
reactions for traditional chemical transformations suggested
to study the heterocyclocondensation between o-
phenylendiamine and aldehydes under oxidative conditions
(Scheme 1), avoiding the use of costly structurally complex
catalysts, favouring in particular simplicity and practical
17
applicability. The use of the alternative one-pot two catalyst
system in the aforementioned heterocyclocondensation will
surely be benefitial to the synthesis of 2-substituted
benzimidazoles.
c
a
Conv. 3a:4a
Entry
CeCl ∙7H O NaI
CuI
I2
b
3
2
(
%)
10
70
68
72
80
85
30
10
9
1
2
3
4
5
6
7
8
9
-
-
0.1
0.2
0.3
0.3
0.3
-
-
-
-
-
48:52
0.1
0.2
0.3
0.3
0.3
-
45:55
34:68
52:48
44:56
62:38
58:42
52:48
62:38
68:32
75:25
95:5
Scheme
1 Catalysed heterocyclocondensation to 2-substituted
-
-
benzimidazoles.
-
-
-
0.3
2.0
2.0
-
Results and discussion
-
-
The condensation of ortho-diamine
1
with p-
-
-
0.3
0.3
0.3
0.3
0.3
0.3
methoxybenzaldehyde (2a) was selected as the model
reaction to test our idea (Table 1). We first examined the
condensation of o-phenylendiamine with 2a at room
temperature, and very low benzimidazole formation was
observed even after prolonged treatment (Table 1, entry 1).
-
-
2.0
-
1
1
0
1
0.3
0.3
0.3
0.3
-
78
70
75
91
-
0.3
2.0
2.0
d
12
13
-
.
e
Introduction of the CeCl 7H O-NaI system as catalyst greatly
3
2
-
96:4
increased conversion, but yields of 2-substituted
benzimidazole 3a were limited due to the competing
formation of 1,2-disubstituted benzimidazole 4a (Table 1,
entries 2, 3 and 4). It should be noted that in all these cases
target compound 3a was the minority product compared to
a
All reactions were carried out at 0.05 M in aldehyde, at room
temperature for 3 hours, in acetonitrile, and values reported in the
b
Table are referred to one aldehyde equivalent. Conversion
c
percentages refer to aldehyde. 3a:4a Ratio determined by GC-MS
1
,2-disubstituted 4a. Although the latter is an important
d
analysis of the reaction mixture. The reaction was checked also
18
branch of benzimidazole derivatives too, we considered it
appropriate to check that our procedure is suitable for
controlling regioisomeric selectivity, increasing efficiency, and
improving generality towards the synthesis of 2-
monosubstituted benzimidazoles. As from our experience
addition of I2 to the CeCl 7H O-NaI system results in a
remarkable improvement of the activity as Lewis acid, the
reaction was carried out introducing molecular iodine to the
reaction mixture (Table 1, entry 5). This, however, only
e
after
2
days, observing no changes. 1.5 Equivalents of o-
phenylenediamine
1
were used.
19
On the basis of the above experimental results, we propose
the major reaction pathways as depicted in Scheme 2. The
high coordinating ability of the Ce(III) species towards oxygen
atoms of the carbonyl moiety promotes the formation of
.
3
2
20
imine
cyclisation (pathway A) is slow, the situation could favour the
condensation of the intermediate with another molecule of
aldehyde (pathway B). This leads to di-imine , central
intermediate towards the formation of 1,2-substituted
product . The cyclo-dehydrogenation of aniline Schiff’s bases
could be fostered by the addition of an at least
5, the key reactive intermediate. If intramolecular
resulted in
a
very modest further increase in
heterocyclocondensation. To determine the appropriate
conditions for the desired catalyst system, we screened a
variety of different solvents, temperatures, and reaction
times. Several different solvents were screened in our model
reaction, including dioxane, tetrahydrofuran, ethanol, N,N-
dimethylformamide, 1,2-dichloroethane, ethyl acetate, and
5
2
7
4
5
stoichiometric amount of oxidants. In agreement with this,
we have observed a 62:38 ratio between 3a and 4a in the
presence of 2 equivalents of I (Table 1, entry 6), which is an
2
1
nitromethane. The desired product 3a was isolated in
moderate yields in all cases, but acetonitrile gave the best
2
2
| J. Name., 2012, 00, 1-3
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Journal Name
efficient oxidant. Molecular iodine, which is environmentally aldehydes
ARTICLE
22
2
to intermediate
5
. For this reason we conducted
View Article Online
rather benign compared to metal catalysts, can act as the reaction in the presence of variabDleOIa: m10o.10u3n9t/sC5oOfB20,167-7d7Gi-
hydrogen sponge favouring the aromatisation of intermediate tert-butyl-4-methylpyridine, a hindered base that should be
6
to 2-monosubstituted benzimidazole 3. In contrast to the capable of neutralising traces of HX that might contaminate
23
.
results of Konwar and co-workers, only low conversion was the reaction mixture, without deactivating the CeCl 7H O-
observed when I was employed in the absence of the binary CuI-I system. However, also under these conditions a slight
catalyst system CeCl 7H O-NaI (Table 1, entry 7). For excess of
3
2
26
2
2
.
1
has proven necessary to obtain a satisfactory
3
2
rendering the C=N π-system in
intramolecular nucleophilic attack resulting in cyclisation, we To further explore the versatility of the CeCl 7H O-CuI-I
2
5 more susceptible to the percentage conversion and favourable product ratio.
.
3
2
have decided to replace NaI with another inorganic iodide.
catalysed heterocyclocondensation we performed an
aldehyde substrate survey under optimised reaction
conditions (Table 2). Using substituted benzaldehydes, we
observed that substituents with different electronic
properties have little effect on the outcome of the reaction.
Only a moderate acceleration occurs in the presence of
electron-withdrawing groups (Table 2, entries 3, 4 and 5).
Good yields were also obtained for aliphatic and α,β-
unsaturated aldehydes (Table 2, entries 6 and 7, respectively).
We did not observe by-products arising from intermolecular
additions. When performing the reaction with chiral
functionalised aldehyde 2h, the PMB-ether protecting group
was stable under the conditions employed. Only when
carrying out the reaction in refluxing acetonitrile, after 1.5 h a
small amount of the corresponding deprotected hydroxy
27
benzimidazole was observed. In any case, we did not
2
8
observe racemisation of the stereogenic center in 3h
.
Another interesting aspect of our catalytic system was its
ability to promote heterocyclocondensation with glyoxylate
derivatives (Table 2, entries 9 and 10). This kind of reaction
does not have much precedence in literature, presumably due
to the high reactivity of aldehydes 2i and 2j. Benzimidazoles
29
30
3
i and 3j are useful building blocks due to the presence of
the 2-carboxy- or 2-carbonylbenzimidazole moiety.
As for the copper salt to be used, cuprous iodide was found
to be the best co-catalyst when compared to other cuprous
Scheme 2 Plausible mechanism.
salts such as CuBr, CuCl, and Cu O (Table 3). Cu(II) salts are
2
31
more azaphilic than Cu(I) salts, however they are not
Starting from the idea that recently the CuI/I combination available as iodide salt, and it is worth mentioning that cupric
2
has found use in organic chemistry as promoter system in the salts, such as CuBr , CuCl , and Cu(OAc) work for this
2
2
2
alkyne-carbonyl metathesis reaction for the synthesis of heterocyclocondensation, but with lower yields (Table 3) and
24
heterocyclic rings from acyclic precursors, we investigated formation of more complex reaction mixtures hardly
.
the use of a catalytic amount of CeCl 7H O-CuI system. We separable by column chromatography. These issues could be
3
2
observed an increased ratio in favour of the desired 2- in agreement with the one-pot Cu(II)/Ce(III)-mediated
monosubstituted benzimidazole 3a (Table 1, entry 10), in multistep transformations discovered by Evans and co-
accordance with a contribution of the known copper- workers in their macrocycle construction of tetracycline
2
5
32
catalysed carbon-nitrogen bond formation. Encouraged by antibiotics, where they found it necessary to utilise
.
.
Cu(OAc) H O in combination with Ce(OAc) nH O rather than
2 2 2
.
these results we further investigated a CeCl 7H O-CuI-I
combination (Table 1, entries 11, 12, and 13). While no CeCl .7H O for satisfactory results. It should also be noted
3
2
2
3
3
2
further improvement was observed when the three that the involvement of single electron transfer processes can
33
components were present in equal amounts, a 95:5 ratio of not be excluded. However, upon introducing BHT (2,6-di-
3
a
:
4a resulted when 2 equivalents of I were employed (Table tert-butyl-4-methylphenol) as radical scavenger into the
2
1
,
entry 12). Finally, the slight excess of the o- reaction, no changes were observed. At the same time, no
phenylendiamine required in the reaction for complete Cu(0) powder was observed on the glass bottom of the
conversion, can readily be recovered unchanged (Table 1, reaction flask as further confirmation that single electron
entry 13). We hypothesised that an internal production of redox changes of copper are not involved in the reaction. One
Brönsted acid (such as HCl or HI) might block the o- would think that Cu(0) species could be reoxidised to Cu(I)
phenylendiamine, preventing the complete conversion of
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34
Table 2 Synthesis of 2-substituted benzimidazoles by one-pot two under the reaction conditions as they are formed, but
View Article Online
DOI: 10.1039/C5OB01777G
catalyst system.
certainly the same should be ruled out for Ce(III). In fact, on
the basis of the calculated Ce(III) / Ce(II) redox potential (-2.90
35
V vs NHE), the species Ce(II) is sufficiently reducing to be
unstable in common organic solvents. It is known that for
lanthanides such as La, Ce, Pr, Gd, Tb, Ho, and Er, the
corresponding ions in the +2 oxidation state would be too
reactive to be isolable in molecular species in our reaction
36
conditions. It should be noted that, in accordance to what
Buchwald and co-workers proposed, the observed copper-
a
Time
h)
Yield
(%)
mediated carbon-nitrogen bond-forming cyclisation in
5
may
Entry
1
aldehyde
Product
b
(
37
proceed through a copper(I)/copper(III) couple. Finally,
3
8
unlike what was reported by Nagarajan, the reaction of o-
phenylenediamine with aldehydes in the presence of copper
salt only showed no formation of benzimidazole derivatives in
appreciable yields in the reaction mixture. We were pleased
3.0
2.5
3.0
1.0
1.0
91
87
85
88
80
3a
2a
2
3
4
5
to find that an excellent yield of
3
was obtained also by use of
3.
2
3b
a combination of our CeCl 7H
O-CuI-I system at a substrate
2
2b
concentration of 0.5 M. Under these conditions there was no
evidence of competing intermolecular coupling, despite the
39
relatively high concentration employed, and this implies
3c
that the intramolecular process is significantly more
favourable.
2c
Regarding the potential of our one-pot two catalyst
CeCl .7H O-CuI system in organic chemistry, it is another
3
2
2d
3d
example of how Lewis acid catalysed organic transformations
40
have tremendous impact in organic synthesis, and many
41
have been applied in pharmaceutical industry. However, the
impact of metals should be considered not only for their
3e
2e
42
active role in any chemical reaction, but may also pose a
problem of toxicity. For this reason, in medicinal chemistry
great care is applied to avoid the presence of metal traces in
final products. Various measures are undertaken in the light
6
7
8
1.5
1.5
1.5
83
85
80
2
f
3f
4
3
of the recent reports on metal impurity effects, amongst
which transition metal-free synthesis. Even if caution is
44
needed when handling CeCl3, it has a moderate toxicity that
2g
3g
also allows its use in the synthesis of pharmaceutically active
4
5
ingredients. However, the need for the Cu(I) catalyst in our
4
6
procedure could be limiting. The cytotoxicity, in fact, of
47
copper ions can cause oxidative damage including DNA
c
d
2h
3h
48
degradation.
Thus, traces of copper are especially
problematic in the pharmaceutical sector where levels must
4
9
remain below 15 ppm. For this reason, after proving the
9
1.5
1.5
75
81
.
applicability of the one-pot two catalyst system CeCl 7H O-
CuI in the synthesis of 2-monosubstituted benzimidazoles, we
turned our attention to potential copper impurities in the
products 3. Due to the good coordinating ability of the
nitrogen heterocycles formed in our heterocyclocondensation
reaction, copper contamination of the benzimidazole
products could be expected. We determined the copper
content in benzimidazole 3a by using Atomic Absorption
Spectroscopy after column chromatographic purification.
The analysis showed that the product obtained from the
reaction catalysed by our CeCl .7H O-CuI system was
3
2
2
i
3i
3j
10
2j
a
50
The reaction was conduct with o-phenylenediamine (1.5 equiv),
aldehyde 2 (1 equiv), CeCl 7H
equiv), CH CN (0.05 M), and was monitored by GC-MS and TLC. All
3
yields are referred to products after isolation by flash
chromatography, and they were characterised by IR, NMR, and Mass
analysis. Aldehyde 2h was obtained starting from ethyl (L)-Lactate.
Configuration retention was determined by polarimetric analysis of
deprotected alcohol.
3.
2
O (0.3 equiv), CuI (0.3 equiv), I
2
(2
b
51
c
3
2
d
contaminated with only 11 ppm of copper, a value much
below what can be obtained in other methods of synthesis of
N-heterocycles by copper catalysts.
52
4
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5
9
With an efficient procedure in hand for obtaining 2- nitrobenzaldehyde with o-phenylendiamine. Subsequent
View Article Online
58
DOI: 10.1039/C5OB01777G
provided chloroethyl quinazoline 10
substituted benzimidazoles, we decided to explore the acylation of
9
.
Finally,
synthetic application of our methodology. We believe that the nucleophilic substitution with N-methylpiperazine afforded
.
new CeCl 7H O-CuI-I promoting system in the preparation of the target benzimidazo derivative 11 in good yield.
3
2
2
heterocyclic compounds can find useful application in the
As a further demonstration of the potential of the
53
.
synthesis of biologically active small molecules, amongst CeCl 7H O-CuI-I
system
others also from the perspective of economic and heterocyclocondensation of
to
promote
the
3
2
2
o-phenylendiamine
and
54
environmental considerations.
aldehydes, we were able to develop a simple synthesis of 2,2’-
bis-benzimidazoles starting from adduct 3j. At this point we
have some encouraging results; due to the importance of bis-
60
benzimidazole scaffolds in cancer treatment a complete
study will be reported in due course.
Conclusions
In conclusion, with regard to the effectiveness of the
.
CeCl 7H O-CuI system in promoting organic reactions for the
3
2
assembly of N-heterocyclic structures, the results obtained
demonstrate once again the important role that this Lewis
acid plays in the synthesis of biologically active small
molecules. The exploration of a new one-pot two catalyst
.
system that involves the use of CeCl 7H O and an iodide
3
2
source different from NaI has opened a new approach in the
use of Ce(III) salts in organic transformations. We believe that
this first example of an efficient catalyst system composed of
.
iodine-activated CeCl 7H O and CuI may be an example to
3
2
Scheme 3 Synthesis of benzoimidazo[1,2-c]quinazoline 11
.
the development of multiple catalyst systems in the
preparation of a variety of important heterocycles. Simple
61
In fact, it is known that benzimidazole derivatives are crucial workup, mild reaction conditions, good to excellent yields,
structural elements in many biologically active small and clean reactions make our methodology an attractive and
5
5
molecules, and for this reason they represent a fruitful useful contribution to the repertoire of procedures for the
template for further pharmaceutical research and synthesis of 2-monosubstituted benzimidazoles that have an
62
development. Thus, in recent years great efforts have been important place in medicinal chemistry.
directed towards the synthesis of biologically active
We have developed a new dual catalytic system that
heterocyclic compounds containing benzimidazoquinazoline allowed us to efficiently obtain benzimidazoles, a feat not
56
moieties. The recent efficient strategy of Wang and co- accessible using either of the catalysts alone.
5
7
workers for the synthesis of these heterocycles, and the Heterocyclocondensation to benzimidazoles is a fairly well
studies of some of us in the preparation of polycyclic established methodology and represents a classical reaction
compounds
such
as
benzoimidazo[1,2-c]quinazoline for obtaining N-heterocyclic compounds widely employed
derivatives suggested to us applying our catalytic system in today, as in past decades. However, following the convergent
such preparations that generally would require rather drastic strategy described in this work for the preparation of
conditions with existing methods. These compounds benzimidazo[1,2-c]quinazoline 11, it has been possible to
characterised by a planar conformation representemerging show how transformations originally developed in response
58
potent antiviral agents. They are capable, in fact, of to questions of academic interest can find space in the
intercalating into DNA, thus inhibiting viral activity. For these synthetic armamentarium of medicinal chemists in the
reasons, a practical and efficient way for their synthesis is pharmaceutical industry. Extension of our work on one-pot
.
useful, also in vision of preparations of further analogues. CeCl 7H O-CuI catalyst systems are currently being
3
2
Although formidable syntheses have been reported, most of investigated in our laboratories, and further utilisation of this
the more useful synthetic approaches involve the preparation flexible methodology in the synthesis of other biologically
of the key intermediate
9 (Scheme 3) from 2-aminobenzoic active nitrogen-containing heterocycles will be reported in
acid under harsh conditions, such as the use of due course. Furthermore, due to the convenient nature of the
polyphosphoric acid at high temperature. Even if 2-amino operation, versatility, and environmental friendliness of our
benzaldehyde cannot used as a starting material due to its procedure for
tendency to polymerise, we found that intermediate was benzimidazoles, we hope that the newly developed
easily prepared by reduction of the nitro group of the CeCl 7H O-M I catalytic system could be applied not only in
the
preparation of
2-substituted
9
.
3
2
x y
benzimidazole derivative 3d. This intermediate is easily the laboratory but also in large-scale production of
accessible by our methodology via the known reaction of 2- substituted heterocycles.
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1
H-NMR (400 MHz, DMSO-d ) δ 7.19 (bs, 2H), 7.45-7.55 (m,
Experimental
General information
6
View Article Online
DOI: 10.1039/C5OB01777G
4
H), 7.66 (d, 1H, J = 6.84 Hz), 8.17 (d, 2H, J = 7.69 Hz), 12.89
13
(s, 1H); C-NMR (100 MHz, DMSO-d ) δ 111.3, 118.9, 121.7,
6
All reagents and solvents were purchased from commercial 122.5, 126.4, 128.9, 129.1 129.8, 130.1, 135.0, 143.8, 151.2;
+
suppliers and used without further purification, unless EI-MS m/z 194 [M] , 193, 105, 91, 77, 51, and 39; IR (nujol) ν
-1
mentioned otherwise. Purification of the reaction products 3650, 3186, 3113, 1666, 1534, 754 cm . C13
was carried out by column flash-chromatography using silica 80.39, H 5.19, N 14.42; found: C 80.05, H 5.07, N 14.52.
gel (0,040-0,063 mesh). All reactions were monitored by thin-
H N : calcd C
10 2
2-(4-Nitrophenyl)-1H-benzimidazole 5(3c). Analytical data
6
layer chromatography using EMD/Merck silica gel 60 pre- well matched with reported values. Yellow solid (85%
1
coated plates (0.25 mm), and the compounds were visualised yield), m.p. 258-260 °C (7:3 cyclohexane/ethyl acetate); H-
either by UV illumination (254 nm), and/or by dipping the NMR (400 MHz, DMSO-d
plates into iodine vapour and Von’s reagent.
8.40 (bs, 4H), 13.29 (bs, 1H); C-NMR (100 MHz, DMSO-d
H and C NMR spectra were recorded on a Varian Mercury 123.6, 124.9, 128.0, 136.7, 148.4, 149.7; EI-MS m/z 239 [M] ,
) δ 7.24-7.26 (m, 2H), 7.65 (s, 2H),
6
1
3
) δ
6
1
13
+
3
4
00 or Varian Mercury plus 400 MR, and were recorded at 209, 193, 166, 77, 63, and 39; IR (nujol) ν 3651, 3180, 1635,
-
1
00 MHz or 300 MHz, and at 100 MHz or 75 MHz, 1550, 1517, 1335, 754 cm . C13H N O : calcd C 65.27, H 3.79,
9 3 2
respectively. The spectra were reported as chemical shifts N 17.56; found: C 65.15, H 3.69, N 17.42.
quoted in ppm and referenced to residual H in deuterated
2-(2-Nitrophenyl)-1H-benzimidazole
solvent as the internal standard. Infrared spectra were well matched with reported values. Yellow solid (88%
(
3d). Analytical data
6
6
recorded on a Perkin-Elmer FTIR Paragon 500 spectrometer as yield), m.p. 232-235 °C (7.5:3.5 cyclohexane/ethyl acetate);
1
a thin films on a NaCl plates. Mass spectra were recorded on a
H-NMR (400 MHz, DMSO-d ) δ 7.29-7.20 (m, 2H), 7.60 (dd,
6
gas chromatograph with a mass-selective detector, utilising 2H, J = 6.47 and 10.85 Hz), 7.74 (dd, 1H, J = 6.70 and 10.91
electron ionisation (EI) at an ionising energy of 70 eV, or on a Hz), 7.85 (t, 1H, J = 7.61 Hz), 7.96 (d, 1H, J = 7.70 Hz), 8.02 (d,
13
LC-MS utilising an electrospray ionisation (ESI) source. 1H, J = 8.05 Hz), 13.10 (bs, 1H). C NMR (100 MHz, DMSO-d )
6
Microanalyses were performed with a EA1108 CHNS-D Fisons δ 122.5, 124.1, 124.3, 131.0, 130.9, 132.6, 147.3, 148.9; EI-
+
Instrument. Optical rotations were recorded on a polarimeter MS m/z 239 [M] , 222, 192, 166, 104, 91, 63; IR (nujol) ν 3641,
-1
with a path length of 1 dm and are given in units of 10-1 deg 3190, 1639, 1565, 1524, 1332, 755 cm . C13H N O : calcd C
9 3 2
cm2 g-1. Concentrations are quoted in g/100 mL. Melting 65.27, H 3.79, N 17.56; found: C 65.10, H 3.57, N 17.50.
points were determined in open capillary tubes on a Büchi 2-[4-(Trifluoromethyl)phenyl]1H-benzimidazole
(3e).
6
7
5
35 melting point apparatus and are uncorrected.
Typical Procedure for Synthesis of 2-Substituted oil (7:3 cyclohexane/ethyl acetate) (80% yield); H-NMR (400
Analytical data well matched with reported values. Yellow
1
.
Benzimidazoles 3a-j. A mixture of CeCl 7H O (0,3 mmol), CuI MHz, DMSO-d
) δ 7.21-7.25 (m, 2H), 7.56 (d, 1H, J = 6.84 Hz),
6
3
2
(
0,3 mmol) and I (2 mmol) in CH CN (20 mL) was stirred at 7.69 (d, 1H, J = 7.27 Hz), 7.92 (d, 2H, J = 8.12 Hz), 8.37 (d, 2H, J
2
3
13
room temperature for 30 minutes. Then the starting aldehyde = 8.10 Hz), 13.15 (bs, 1H). C NMR (100 MHz, DMSO-d ) δ
6
1
(
2a-j) (1 mmol) was added, and the solution was stirred for 111.6, 119.2, 122.0, 123.2, 124,1 (q, JCF = 269,8Hz), 125.9,
2
further 10 min. Then o-phenylenediamine (
1
) (1.5 mmol) was 126.0, 126.2, 127.0, 129,4 (q, JCF = 31,8Hz), 133.9, 135.1,
+
added. After the completion of the reaction, the mixture was 143.8, 149.7; EI-MS m/z 262 [M] , 243, 223, 193, 131, 90, 39;
-
1
diluted with CH Cl (35 mL), and the organic layer was washed IR (neat) ν 3662, 3165, 1629, 1524, 753 cm . C14
H
F N
9 3
: calcd
2
2
2
twice with 10% Na S O (20 mL), and subsequently washed C 64.12, H 3.46, N 10.68; found: C 64.09, H 3.56, N 10.60.
2
2 3
with brine, and finally dried on Na SO The solvent was
2-(2-Phenylethyl)-1H-benzimidazole (3f). Analytical data
2
4.
68
evaporated under reduced pressure and the residue was well matched with reported values. Pale pink oil (8:2
1
purified by column flash-chromatography on silica gel with cyclohexane-ethyl acetate) (88% yield); H-NMR (400 MHz,
cyclohexane/ethyl acetate as eluent to afford the CDCl
corresponding 2-substituted benzimidazole products 3a-j
5H), 7.52-7.54 (m, 2H). C-NMR (100 MHz, CDCl
-(4-Methoxyphenyl)-1H-benzimidazole
3a). Analytical 34.5, 114.9, 122.4, 126.6, 128.4, 128.8, 133.5, 140.6, 154.4;
) δ 3.17-3.22 (m, 4H), 7.12-7.14 (m, 2H), 7.19-7.24 (m,
3
1
3
.
) δ 31.4,
3
2
(
6
3
+
data well matched with reported values. White solid (91% EI-MS m/z 222 [M] , 221, 131, 91, 77, 63; IR (neat) ν 3660,
yield), m.p. 220-221 °C (7:3 cyclohexane/ethyl acetate); H- 3160, 1617, 1514, 759 cm . C15
1
-1
H N : calcd C 81.05, H 6.35, N
14 2
NMR (400 MHz, DMSO-d ) δ 3.82 (s, 3H), 7.09 (d, 2H, J = 8.5 12.60; found: C 80.99, H 6.32, N 12.50.
6
Hz), 7.12-7.18 (m, 2H), 7.47 (d, 1H, J = 6.83Hz), 7.60 (d, 1H, J =
7
2-[(E)-2-Phenylvinyl]-1H-benzimidazole
.27 Hz), 8.10 (d, 2H, J = 8.5 Hz), 12.73 (s, 1H); C-NMR (100 well matched with reported values. Dark yellow oil (7:3
MHz, DMSO-d ) δ 55.3, 110.1, 114.4, 118.5, 121.8, 122.7, cyclohexane-ethyl acetate) (85% yield); H NMR (400 MHz,
(
3g). Analytical data
13
69
1
6
+
1
2
25.3, 128.0, 128.2, 128.9, 151.4, 160.6; EI-MS m/z 224 [M] , CDCl
) δ 7.20 (d, 1H, J = 16.47 Hz), 7.25-7.31 (m, 5H), 7.40-
3
-
1
09, and 181; IR (nujol) ν 3636, 3186, 1645, 1524, 754 cm . 7.62 (m, 2H), 7.63-7.68 (m, 2H), 7.70 (d, 2H, J = 16.48 Hz), 9.1
13
C H N O: calcd C 74.98, H 5.39, N 12.49; found: C 74.62, H (bs, 1H); C-NMR (100 MHz, CDCl ) δ 115.2, 116.5, 123.4,
14 12 2
3
5
.31, N 12:35.
-Phenyl-1H-benzimidazole
127.3, 129.1, 129.3, 135.7, 136.2, 138.9, 151.3; EI-MS m/z
+
2
(
3b). Analytical data well 220(M ), 219, 128, 109, 91, 77, 63, 39; IR (neat) ν 3638, 3175,
64
-1
matched with reported values. Dark yellow solid (87% 1659, 1544, 750 cm . C15
H N : calcd C 81.79, H 5.49, N
12 2
yield), m.p. 287-289 °C (7.5:3.5 cyclohexane/ethyl acetate); 12.72; found: C 81.68, H 5.43, N 12.69.
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx

Page 7 of 9
Organic & Biomolecular Chemistry
Journal Name
-{(1S)-1-[(4-Methoxybenzyl)oxy]ethyl}-1H-benzimidazole
ARTICLE
+
2
148.9, 153.2; EI-MS m/z 209 [M] , 181, 143, 118, 104, 91, 77.
View Article Online
DOI: 10.1039/C5OB01777G
(3h). White solid
(80% yield), m.p. 238-240 °C (7:3 C H N : calcd C 74.62, H 5.30, N 20.08; found: C 76.57, H
13 11 3
24
1
cyclohexane/ethyl acetate), [α] = - 24.3° (c 0.01, CHCl ); H 5.19, N 20.07.
D
3
NMR (400 MHz, CDCl ) δ 1.65 (d, 3H, J = 6.41Hz), 3.79 (s, 3H),
6-(Chloroethyl)benzimidazo[1,2-c]quinozoline
.46 (d, 1H, J = 11.13 Hz), 4.54 (d, 1H, J = 11.13 Hz), 4.93 (q, stirred solution of [2-(1H-benzimidazol-2-yl)phenyl]amine (
H, J = 6.41 Hz), 6.86 (d, 2H, J = 8.12 Hz), 7.23-7.27 (m, 4H), (0.21 g, 1 mmol) in glacial acetic acid (5 mL), was added
(10). To a
3
4
1
7
7
9)
1
3
.59-7.61 (m, 2H). C-NMR (100 MHz, CDCl ) δ 21.3, 55.5, dropwise 3-chloropropanoyl chloride (0.126 mL, 1.57 mmol)
3
1.4, 72.1, 114.1, 115.4, 122.8, 129.8, 156.2, 159.6; ESI-MS under nitrogen atmosphere. Temperature of reaction mixture
+
+
m/z 283 [M+1] , 587 [2M+Na] ; IR (nujol) ν 3638, 3155, 1619, was raised to 50 °C. After 15 minutes the mixture was cooled
1
9
-
1
544, 1145, 746 cm . C H N O : calcd C 72.32, H 6.43, N to 0°C. Cold water was added to reaction mixture to obtain
17 18 2 2
.92; found: C 72.28, H 6.40, N 9.88.
white precipitate. The precipitate was filtered and washed
Ethyl 1H-benzimidazole-2-carboxylate
well matched with reported values.
cyclohexane-ethyl acetate) (75% yield); H NMR (300 MHz, obtaining quinazoline 10 (0.24 g, 0,87 mmol) in 87 % isolated
(
3i). Analytical data with water until the filtrate reach to neutral pH. The white
Yellow oil (7:3 solid was dried and purified with crystallisation in acetone
7
0
1
1
CDCl ) δ 1.49 (t, J=7.1; 3H), 4.54 (q, J=7.0; 2H), 7.45-7.34(m, yield as a white solid, m.p. 169-171 °C; H NMR (400 MHz,
3
2
1
9
7
6
H), 7.54 (d, J=9.3Hz; 1H), 7.92 (d, J=8.9Hz; 1H), 10.05 (bs, CDCl ) δ 8.73 (d, 1H, J = 7.89 Hz), 8.06 (m, 2H), 7.89 (d, 1H, J =
3
+
+
H); ESI-MS m/z 191 [M+1] ; EI-MS m/z 190 [M] , 144, 118, 8.12 Hz), 7.78 (t, 1H, J = 7.64 Hz), 7.66 (t, 1H, J = 7.58 Hz), 7.58
0, 63; IR (neat) ν 3638, 3175, 1765, 1659, 1544, 1147, 1092, (t, 1H, J = 7.69), 7.49 (t, 1H, J = 7.81 Hz), 4.29 (t, 2H, J = 7.39
-
1
+
54 cm . C H N O : calcd C 63.15, H 5.30, N 14.73; found: C Hz), 3.90 (t, 2H, J = 7.37 Hz). ESI-MS m/z 282 [M+H] .
1
0 10 2 2
3.08, H 5.25, N 14.70.
H-Benzimidazole-2-carboxaldehyde dimethyl acetale
C H ClN : calcd C 68.21, H 4.29, N 14.91; found: C 68.15, H
16 12 3
1
(
3j). 4.28, N 14.88.
Analytical data well matched with reported values. Light 6-[2-(4-Methylpiperazin-1-yl)ethyl]benzimidazo[1,2-
yellow oil (7:3 cyclohexane-ethyl acetate) (81% yield); H c]quinazoline 11). To a stirred solution of chloroethyl
NMR (300 MHz, CDCl ) δ 3.46 (s, 6H), 5.66 (s, 1H), 7.30-7.26 quinazoline 10 (0.20 g, 0,72 mmol) in methanol (20 mL), was
30
1
(
3
(
m, 2H), 7.46-7.31 (m, 1H), 7.8-7.78 (m, 1H), 9.39 (bs, 1H); ESI- added N-methylpiperazine (0.216 g, 2.16 mmol) and the
+
+
MS m/z 193 [M+1] ; EI-MS m/z 192 [M] , 161, 147, 131, 118, resulting solution was refluxed. After 2 h, water (20 ml) was
9
-1
1, 77, 64; IR (neat) ν 3668, 3158, 1654, 1547, 1085, 756 cm . added to obtaining a white solid. Solid was filtered and
C H N O : calcd C 62.49, H 6.29, N 14.57; found: C 62.40, H washed with water. Purification was done by crystallisation in
10 12 2 2
6
.21, N 14.55.
-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-1H-
isopropanol to give 6-[2-(4-methylpiperazin-1-yl)ethyl]-
benzimidazol[1,2-c]quinazoline (11) in 87 % isolated yield
1
benzimidazole
(
4a). Analytical data well matched with (0.174 g) as a white solid. Analytical data well matched with
71
58
1
reported values. Yellow oil (7:3 cyclohexane-ethyl acetate); reported values. M.p. 170-172 °C; H NMR (400 MHz,
1
H-NMR (400 MHz, CDCl ) δ 3.66 (s, 3H), 3.80 (s, 3H), 5.47 (s, CD OD): δ 2.35 (s, 3H) 2.69 (bs, 8H), 3.16 (t, 2H, J = 5.45 Hz),
3
3
2
2
3
5
1
3
1
7
H), 6.82 (d, 2H, J = 8.5 Hz), 6.92 (d, 2H, J = 8.50 Hz), 7.06 (d, 3.57 (t, 2H, J = 5.56 Hz), 7.42 (t, 1H, J = 7.79 Hz), 7.51 (t, 1H, J
H, J = 8.50 Hz), 7.16-7.22 (m, 2H), 7.40-7.42 (m, 1H), 7.66 (d, = 7.66 Hz), 7.58 (t, 1H, Hz), 7.71 (t, 1H, J = 8.07 Hz), 7.77 (d,
13
H, J = 8.50 Hz); C-NMR (100 MHz, DMSO-d ) δ 46.9, 55.0, 1H, J = 7.82 Hz), 7.82 (d, 1H, J = 8.11 Hz), 8.06 (d, 1H, J = 8.28
6
13
5.3, 111.0, 114.1, 114.2, 119.0, 122.0, 122.3, 122.4, 128.4, Hz), 8.43 (d, 1H, J = 7.96 Hz); C NMR (100 MHz, CD OD) δ
3
28.8, 130.5, 135.8, 142.7, 153.2, 158.5, 160.7. EI-MS m/z 34.1, 46.0, 55.0, 55.8, 116.1, 118.6, 120.3, 124.8, 124.8,
+
44[M] , 237, 210, 167, 121, 77; IR (neat) ν 3095, 1675, 1474, 127.0, 128.7, 129.1, 130.2, 133.2, 143.4, 144.7, 149.0, 150.7.
-
1
+
156 cm . C H N O : calcd C 76.72, H 5.85, N 8.13; found: C ESI-MS m/z 346.3 [M+H] . C H N : calcd C 73.02, H 6.71, N
22
20
2
2
21 23 5
6.65, H 5.81, N 8.05.
2-(1H-Benzimidazol-2-yl)phenyl]amine (9). To a stirred
20.27; found: C 72.97, H 6.65, N 20.25.
[
solution on the 2-(2-nitrophenyl)-1H-benzoimidazole 3d (0.35
mg, 1.46 mmol) in methanol (20 mL) was added Pd/C 5% (94
mg). The reaction mixture was stirred for 18 hours under
hydrogen atmosphere. Progress of reaction was monitored by
TLC (5:5 cyclohexane-ethyl acetate). After completion of
reaction, the reaction mixture was filtered through a short
pad of Celite. Filtrate was concentrated to obtain 0.286 mg
Acknowledgements
This work was carried out under the framework of the
University Research Project ‘Design, synthesis and biological
evaluation of novel chemical entities as potential anticancer
drugs and for the control of the metastatic process’
supported by the University of Camerino (FAR 2011-2012). S.
D. and F. S. gratefully acknowledge BI Research Italia for
doctoral fellowships. We thank for doctoral fellowships Pfizer
Global Supply – Ascoli Piceno Site and delta Company for
granting doctoral fellowships to R. P. and M. D. N.,
respectively.
(1.36 mmol) of the title product
9 in 94% isolated yield as a
white solid. Analytical data well matched with reported
5
9a
1
values. M.p. 210-213 °C (5:5 cyclohexane-ethyl acetate); H
NMR (400 MHz, DMSO-d ) δ 6.63 (t, 1H, J = 7.49 Hz), 6.82 (d,
6
1
7
1
1
H, J = 8.18 Hz), 7.18 (m, 3H), 7.22 (s, 1H), 7.49 (d, 1H, J =
.55 Hz), 7.63 (d, 1H, J = 7.63 Hz), 7.83 (d, 1H, J = 7.79 Hz),
13
2.69 (s, 1H). C NMR (100 MHz, DMSO-d ) δ 110.7, 111.4,
6
15.6, 116.8, 118.8, 122.0, 123.0, 127.9, 131.0, 134.2, 143.6, Notes and references
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7

Organic & Biomolecular Chemistry
Page 8 of 9
ARTICLE
Journal Name
§
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