Sequential oxidation and condensation of alcohols to benzimidazoles/ benzodiazepines by MoO3-SiO2 as a heterogeneous bifunctional catalyst

Article abstract of DOI:10.1016/j.catcom.2010.07.008

Sequential oxidation of alcohols to their corresponding aldehydes/ketones using H₂O₂ as a green oxidant and its further condensation with diamines to yield benzimidazoles/benzodiazepines with minimum side product formation under mild

Full text of DOI:10.1016/j.catcom.2010.07.008

Catalysis Communications 11 (2010) 1205–1210
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Catalysis Communications
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Sequential oxidation and condensation of alcohols to benzimidazoles/benzodiazepines
by MoO3–SiO2 as a heterogeneous bifunctional catalyst
⁎
Kalpesh D. Parghi, Radha V. Jayaram
Department of Chemistry, Institute of Chemical Technology, N. Parekh Marg, Matunga, Mumbai, 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 April 2010
Received in revised form 6 July 2010
Accepted 14 July 2010
Available online 8 August 2010
Sequential oxidation of alcohols to their corresponding aldehydes/ketones using H2O2 as a green oxidant and
its further condensation with diamines to yield benzimidazoles/benzodiazepines with minimum side
product formation under mild reaction conditions has been described. MoO3–SiO2 is explored as
a
heterogeneous bifunctional catalyst for both oxidation as well as condensation reaction thus making it a
versatile catalyst. The prepared catalysts were characterized using FT-IR, Raman spectroscopy, XRD, SEM and
NH3-TPD to study its surface properties. MoO3–SiO2 shows good catalytic activity and reusability for both the
reaction systems giving high yields of the desired products.
Keywords:
Sequential
Bifunctional
Oxidation
© 2010 Elsevier B.V. All rights reserved.
Condensation
Benimidazole
Benzodiazepine
1. Introduction
However, the traditional synthesis of benzimidazoles involves
reaction between OPDA and carboxylic acid or its derivatives (nitriles,
Benzimidazole structural motifs have attracted much interest in
diverse areas of medicinal chemistry. These heterocycles have shown
various pharmacological activities such as anti HIV [1], poli(ADP-
ribose)phosphorilase inhibitors [2], Histamine H4 receptor binders
[3], antiparasitic [4], cardiovascular [5], anticancers [6], and anti-
hypertensives [7]. In view of the tremendous biological activities of
benzimidazoles, their preparation has gained considerable attention
in recent years. Similarly, benzodiazepines are also used as inter-
mediates for the synthesis of fused ring compounds such as triazolo-
3,5-oxadiazolo- [8], oxazino- [9], and furano-benzadiazepines [10].
Despite their wide range of pharmacological, industrial and synthetic
applications, the synthesis of 1,5-benzodiazepines has received little
attention. Benzodiazepines have been synthesized by the condensa-
tion of o-phenylenediamine (OPDA) with α, β-unsaturated carbonyl
compounds, β-haloketones or with ketones. Many reagents have been
reported in the literature for this condensation, including BF3-
etherate [11], polyphosphoric acid [12], SiO2 [13], MgO/POCl3 [14],
Yb(OTf)3 [15], acetic acid under microwave conditions [16] and in
ionic liquids [17]. Many of these processes suffer from one or more
limitations, such as long reaction time, occurrence of several side
reactions, drastic reaction conditions, low yield of desired products
and tedious work-up procedures.
amidates, and orthoesters) under harsh dehydrating conditions [18–
23]. Some other strategies for their synthesis utilise o-nitroanilines as
intermediates or resort to direct N-alkylation of an unsubstituted
benzimidazole [24]. Condensation of OPDA with aldehyde in the
presence of oxidative reagents such as I2/KI/K2CO3/H2O [25], sodium
metabisulfite [26], Na2S2O5 under microwave irradiation [27], silica
sulfuric acid [28], iodobenzene diacetate (IBD) [29], HCl/H2O2 [30], air
in dioxane [31], bromodimethylsulfonium bromide (BDMS) [32], and
CAN/H2O2 [33] have also been reported.
Very recently, Corma et al. [34] have reported a new route for
synthesis of benzimidazole wherein the starting reactant alcohol is
oxidized to generate aldehyde in situ and then the diamines are added
to yield the corresponding benzimidazoles using Au/CeO2 and Pd/
MgO as bifunctional catalyst. Although this methodology shows
utilization of bifunctional catalysts to couple both the steps of
oxidation and cyclization there is enough scope to improve this
route as it suffers from drawbacks such as use of oxidant (O2) under
pressure conditions, long reaction time, use of expensive Au or Pd
based catalyst and complex reaction procedure.
In continuation of our endeavour to develop new synthetic
methodologies using bifunctional catalysts herein we report,
MoO3–SiO2 as a heterogeneous bifunctional catalyst for sequential
oxidation of alcohols to their corresponding aldehydes/ketones
using H2O2 as a green oxidant and its sequential condensation
with OPDA to yield benzimidazoles/benzodiazepines with mini-
mum side product formation under mild reaction conditions
(Scheme 1).
⁎
Corresponding author. Tel.: +91 22 3361 11 11; fax: +91 22 2269 21 02.
E-mail address: rv.jayaram@ictmumbai.edu.in (R.V. Jayaram).
1566-7367/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2010.07.008

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K.D. Parghi, R.V. Jayaram / Catalysis Communications 11 (2010) 1205–1210
2.4. Typical experimental procedure
2. Experimental
2.1. Materials
2.4.1. Synthesis of benzimidazoles
2 mmol of primary aromatic alcohol was added to the mixture of
6 mmol of 30% H2O2 and 20 wt.% of the catalyst in a 25 mL round bottom
flask fitted with a distillation condenser and were heated at 70 °C for 7 h.
The reaction mixture was further cooled till room temperature, to this
2 mmol of OPDA (in aliquots) and 2 mL ethanol was added. The
intermediate (aldehyde) was monitored by TLC/gas chromatography.
After completion of the reaction ethyl acetate (10 mL) was added, and
the organic solution was separated from catalyst by filtration. The
solvent was evaporated under reduced pressure, and the residue was
purified by column chromatography over silica gel eluting with hexane/
ethyl acetate 9:1 mixture, yielding the products. The products were
identified by GC–MS and confirmed by NMR.
All chemicals were procured from firms of repute. Various alcohols
were purchased from Sigma-Aldrich. All solvents used were pur-
chased from S. D. Fine Chem. India Ltd. All the chemicals were used
without any further purification.
2.2. Catalyst preparation
MoO3/SiO2 catalysts with varying molybdenum oxide molar
concentrations (5, 10, 15, 20, 25) were prepared. Ammonium
heptamolybdate (AHM) and tetraethyl orthosilicate (TEOS) were used
as molybdenum and silica sources, respectively. In a typical procedure
20 mol% MoO3/SiO2 catalyst was synthesized by dissolving 14.11 g AHM
in 40 mL distilled water at 80 °C. This hot solution was added drop wise
to the dry isopropyl alcohol solution of TEOS (48.0 g) with constant
stirring. The resultant transparent greenish gel was air dried and
calcined at 500 °C in air in a muffle furnace for 12 h. Similarly catalysts
with 5, 10, 15 mol% Mo loadings were prepared. The prepared catalysts
are further named as 5MoO3–SiO2, 10MoO3–SiO2, 15MoO3–SiO2 and
20MoO3–SiO2. Pure high surface area silica catalyst was prepared for
comparison by adding 52 g TEOS to 30 g dry isopropyl alcohol; to this
mixture0.02 g ammonia solution (25%) wasslowlyadded withconstant
stirring. The transparent white gel thus obtained was air dried and
calcined in a muffle furnace at 500 °C for 12 h [35].
2.4.2. Synthesis of benzodiazepines
2 mmol of secondary alcohol was added to the mixture of
6 mmol of 30% H2O2 and 20 wt.% of the catalyst in a 25 mL round
bottom flask fitted with a distillation condenser and were heated
at 70 °C for 7 h. The reaction progress was monitored by TLC/gas
chromatography analysis. The reaction mixture was further cooled
till room temperature and to this 1 mmol OPDA (in aliquots) and
2 mL of ethanol was added. After completion of the reaction ethyl
acetate (10 mL) was added, and the organic solution was
separated from catalyst by filtration. The solvent was evaporated
under reduced pressure, and the residue was purified by column
chromatography over silica gel eluting with hexane/ethyl acetate
9:1 mixture, yielding the products. The products were identified
by GC–MS and confirmed by NMR.
2.3. Characterization techniques
2.4.3. Reusability of catalyst
The FT-IR spectra were recorded using a Perkin Elmer (Spectra
100) spectrometer by KBr pellet technique. The laser Raman spectrum
was obtained on a Jobvin-Yvon-Horiba (HR800UV) Raman spectrom-
eter at ambient conditions equipped with laser supplying the
excitation line at 514.5 nm with 1–10 mW. Powder X-ray diffraction
(XRD) of the catalyst was recorded with a (Philips 1050) diffractom-
eter using graphite monochromatized Cu-Kα radiation over a 2θ
range of 10–90o. SEM images were recorded using a Tungsten source
on JEOL model JSM-6390 instrument. NH3-TPD technique was used to
assess the acidic strength of the catalyst using a conventional flow
reactor on Micrometrics microbalance using 20 mg sample of the
catalyst and a commercial 10% NH3 in He gas mixture. Gas
Chromatogram were recorded on Thermofisher GC-1000 equipped
with capillary column (30 m×0.32 mm1D–0.25 μm BP-10). GC–MS
spectra were recorded on Shimadzu (GCMS-QP 2010). 1H and 13C
NMR spectra were recorded on Joel-300 MHz NMR spectrometer
using TMS as an internal standard.
After completion of reaction, reaction mixture was filtered under
vacuum and the catalyst was washed with acetone (3 times) and then
kept for drying at 100 °C for 2 h, after which the catalyst was reused
for next cycle. The catalyst reusability was checked for first step of
oxidation and also for the sequential protocol.
3. Results and discussion
3.1. Characterization of MoO3–SiO2
3.1.1. FT-IR analysis
The FT-IR spectra of all the catalyst samples prepared by sol–gel
technique are presented in Fig. 1. The intensive bands at around 1090,
800 and 460 cm−1 are ascribed to Si–O vibration of SiO2, and the broad
band centered atabout 960 cm−1 witha shoulderatabout 920 cm−1 for
all the samples is the sign of supported molybdenum species. All the
above mentioned peaks were observed for Mo loaded catalystshowever,
peaks at 960 and 920 cm−1 were not observed for MoO3 (Fig. 1e) [36].
3.1.2. Raman spectral analysis
Raman spectrum for 15MoO3–SiO2 catalyst is shown in Fig. 2. The
spectrum shows presence of Mo species anchored to silica surface.
Bands for SiO2 matrix can be seen at 440–550 cm−1 and 609–615 cm−1
attributed to strained trisiloxane rings; Si–O stretches appear at 880–
925 cm−1, assigned to symmetrical stretching of the Si–O bonds of
geminal silanols and to the siloxane bridges (Si–O–Si). Raman spectrum
shows bands at 993, 820 and 630 cm−1 which may be assigned to the
stretching mode of terminal Mo=O groups, the asymmetric and
symmetric modes of Mo–O–Mo bridges in α-MoO3 respectively. Signal
at 960–970 cm−1 may be attributed to the symmetric stretching mode
of terminal Mo=O bonds with a possible contribution of Si–O stretching
of SiOH–OMo and of Si–O–Mo moieties. However, typical bands at 851
and 781 cm−1 ascribed for β-MoO3 were not present [37].
Scheme 1. Sequential oxidation and condensation for synthesis of benzimidazole and
benzodiazepine.

K.D. Parghi, R.V. Jayaram / Catalysis Communications 11 (2010) 1205–1210
1207
Fig. 1. FT-IR spectra of a) SiO2, b) 5 MoO3–SiO2, c) 10 MoO3–SiO2, d) 15 MoO3–SiO2, and
e) 20 MoO3–SiO2.
3.1.3. XRD studies
The XRDpatternsofall the catalysts prepared by sol–gel are shown in
Fig. 3. For comparison, the XRD pattern of pure silica is also included (Fig.
3). The patterns show the amorphous nature of the material at low Mo
loadings (Fig. 3b–d) indicating a very high dispersion of amorphous
molybdenum oxo species on amorphous silica support up to 15 mol%
loading of Mo. The XRD patterns of 20% Mo loaded catalyst (Fig. 3e)
exhibit sharp peaks on the broad underlying peaks characteristic of the
amorphous silica at 2θ=24°. These intense peaks observed at 2θ=12.9,
23.4, 25.8 and 27.4° are characteristic of the α-MoO3 orthorhombic
phase [38]. It is interesting to note that even though the MoO3 is in the
crystalline form at higher Mo loading, the silica support still retains its
amorphousnature leadingto thehigh surfaceareaof the catalysts [39]. It
appears from the XRD results that up to 15 mol% MoO3 loading there is a
uniform dispersion of amorphous molybdenum oxo species on silica
support, however at higher loading; MoO3 crystalline bulk phase is
formed on amorphous silica support (Fig. 3).
Fig. 3. X-ray diffraction of a) SiO2, b) 5 MoO3–SiO2, c) 10 MoO3–SiO2, d) 15 MoO3–SiO2,
and e) 20 MoO3–SiO2.
3.1.5. NH3-TPD analysis
Acidity measurements were carried out using NH3-TPD analysis
(Table 1), it was found that the acidity of SiO2 (entry 1) was very less
compared to the Mo loaded SiO2. This showed that the acidity of the
catalyst is majorly due to Mo species. It was observed that as the
percentage of Mo loading was increased acidity of the catalyst was
also increased (entries 2–4). However, the best results were obtained
with 15 mol% Mo loadings (entry 4) although 20% Mo loading had
higher acidity. Similar results were obtained by Wang et al. [40] where
the decreased activity of the MoO3–SiO2 catalyst at higher MoO3
loading was attributed to the aggregation of MoO3 particles on SiO2
surface. The aggregation of MoO3 at higher loading can also be
observed in XRD results in Fig. 3.
3.1.4. SEM analysis
The scanning electron microscope study provides an insight on the
morphological changes in MoO3–SiO2. SEM image of SiO2 shows
presence of smooth surface without any pores, however micrographs
for MoO3–SiO2 clearly shows marked difference in the morphology
from that of SiO2. The differences in SEM images thus, illustrate that
incorporation of MoO3 changes the morphological structure of SiO2
surface considerably (Fig. 4).
3.2. Influence of MoO3–SiO2 with different Mo loading
In order to study various reaction parameters for sequential
oxidation and condensation we chose sequential oxidation of benzyl
alcohol and condensation of the formed benzaldehyde with OPDA as a
test reaction. We started our investigation by using individual
component oxides SiO2 and MoO3 as the catalyst (Table 1; entries 1,
2). As expected SiO2 showed no product formation, however, MoO3
provided low yield of the desired 2-phenyl benzimidazole. Next, MoO3–
SiO2 with different Mo loadings were used and it was observed that as
Mo loading increased from 5–15 mol% the yield of 2-phenyl benzimid-
azole also increased (entries 3–5). However, on further increasing the
Mo loading till 25 mol% the yield decreased to 72%. Thus 15MoO3–SiO2
was used as the preferred catalyst for further studies.
3.3. Influence of catalyst concentration
The effect of catalyst concentration on the given reaction protocol
was studied. It was found that as the concentration of 15MoO3–SiO2 was
increased from 5 wt% to 20 wt% (Table 1; entries 5, 8–11) yield of the
desired benzimidazole also increased. On further increasing the
concentration to 25 wt% no change in yield was observed and hence
20 wt% of MoO3–SiO2 catalyst was chosen as the optimum
concentration.
Fig. 2. Raman spectrum of 15MoO3–SiO2.

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K.D. Parghi, R.V. Jayaram / Catalysis Communications 11 (2010) 1205–1210
Fig. 4. SEM images of a) SiO2 and b)15MoO3–SiO2.
3.4. Influence of solvent for oxidation of alcohols
3.5. MoO3–SiO2 catalyzed sequential oxidation and condensation
As first step is crucial in sequential synthesis, it was very
important to check the influence of solvent on reaction outcome.
Generally, chlorinated solvents are used for oxidation of alcohols
to aldehydes which limits their application from an environment
point of view and hence we intended to use an alternate solvent
system and compare it with effect of chlorinated solvent medium
(Table 2). When CH2Cl2 and CHCl3 (entries 1, 2) were used as a
solvent the yield of benzaldehyde was found to be . reaction using
acetonitrile as a solvent yielded desired product in 90% (entry 3).
However, reaction without any solvent provided excellent yield of
the desired product (entry 5) hence solvent free conditions were
applied for further studies.
In the second step i.e. condensation of formed benzaldehyde with
OPDA, solvent free conditions gave by products of bis-anils and 1,2-
disubstituted benzimidazoles. Thus in order to increase the yield of
our desired 2-phenyl benzimidazole solvent effect was studied where
solvent was added along with OPDA. Amongst the screened solvents
ethanol was used as the solvent of choice as it gave the maximum
yield of desired benzimidazole.
To test the general scope and versatility of this procedure for
synthesis of variety of substituted benzimidazoles, we examined various
substituted aryl alcohols. Thus, for the initial step of oxidation benzyl
alcohol (2 mmol) and 30% H2O2 (6 mmol) were heated to 70 °C for 7 h
which is then followed by addition of OPDA (2 mmol) and ethanol
(2 mL) and allow it to stir for next 3.5 h at room temperature (Table 4).
We were pleased to find high yields for the initial oxidation reaction as it
was a prerequisite for our sequential reaction protocol. As Table 3
shows, benzyl alcohol and substituted benzyl alcohols bearing electron-
donating group such as –CH3 and –OCH3 provided good yields of the
desired benzimidazoles (entries1–3). However, when electron-with-
drawing substituents like Cl− and Br− was attached to benzyl alcohol
marked difference was observed and yields of benzimidazoles were
decreased (entries 4, 5).
To extend the scope of this methodology, we also examined
sequential oxidation of secondary alcohols to ketones and its
condensation with OPDA to give their corresponding 1, 5-benzodiaz-
epine derivatives under same reaction conditions. To effect this
transformation, phenethyl alcohol and substituted phenethyl alcohols
were studied (Table 3, entries 6–10) and were found to give high
yields of benzodiazepines. Phenethyl alcohol reacted effectively
giving 94% of acetophenone which on further condensation with
diamine gave 82% of the desired benzodiazepine. Phenethyl alcohol
with electron-donating substituents like –CH3, –OCH3 and electron-
withdrawing group like Cl− gave good yields of their respective
benzodiazepines between 84–72% (entries 7–9).
Table 1
Influence of MoO3–SiO2 and its component oxides on sequential oxidation and
condensation.a
Entry
Catalyst
Catalyst
amount
(wt.%)
NH3 desorbed
(mmol/g)
Yieldb (%)
Cyclic alcohol like cyclohexanol (entry 10) also reacted smoothly
to give high yields up to 74% of the corresponding fused ring
benzodiazepines.
Effect of Mo loading
1
2
3
4
5
6
7
SiO2
MoO3
20
20
20
20
20
20
20
0.02
0.13
0.47
0.62
0.77
0.82
0.80
–
28
42
63
77
73
72
5 MoO3–SiO2
10 MoO3–SiO2
15 MoO3–SiO2
20 MoO3–SiO2
25 MoO3–SiO2
Table 2
Influence of solvent for oxidation of alcohols.a
Entry
Solvent
Yieldb (%)
Effect of catalyst loading
8
9
10
11
15 MoO3–SiO2
15 MoO3–SiO2
15 MoO3–SiO2
15 MoO3–SiO2
5
10
15
25
–
–
–
–
38
63
72
77
1
2
3
4
5
CH2Cl2
CHCl3
CH3CN
C2H5OH
–
84
85
90
72
91
a
Reaction conditions: benzyl alcohol (2 mmol), catalyst, H2O2 (6 mmol), 7 h at 70 °C.
OPDA (2 mmol) and ethanol (2 mL) added after 7 h and stirred at room temperature
further for 3.5 h.
a
Reaction conditions: benzyl alcohol (2 mmol), 15 MoO3–SiO2 (20 wt%), 30% H2O2
(6 mmol), solvent (2 mL), 7 h at 70 °C.
b
b
Isolated yield.
GC yield.

K.D. Parghi, R.V. Jayaram / Catalysis Communications 11 (2010) 1205–1210
1209
Table 3
Sequential oxidation and condensation for synthesis of benzimidazoles and benzodiazepines.a
Entry
1
Alcohol
Aldehyde/ketoneb
Benzimidazol/benzodiazepinec
Yieldb/c (%)
91/77
2
94/80
3
4
5
96/85
86/54
85/52
6
7
8
94/82
94/84
95/83
9
88/72
90/74
10
a
Reaction conditions: alcohol (2 mmol), 15 MoO3–SiO2 (20 wt%), H2O2 (6 mmol), 7 h at 70 0C. OPDA (2 mmol) and ethanol (2 mL) added after 7 h and stirred at room
temperature further for 3.5 h.
b
G.C yield.
Isolated yield.`
c

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K.D. Parghi, R.V. Jayaram / Catalysis Communications 11 (2010) 1205–1210
Table 4
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catalyst for sequential oxidation and condensation reaction of
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benzimidazoles/benzodiazepines. Environmentally viable H2O2 was
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The financial assistance from the University Grants Commission
(UGC), New Delhi, India is kindly acknowledged.