Novel method for the syntheses of 2-substituted benzimidazoles using Ti(IV) isopropoxide and cumene hydroperoxide

Article abstract of DOI:10.1080/00397911.2011.571803

Various 2-substituted benzimidazoles were prepared in one pot by condensation of o-phenylenediamine with an appropriate aldehyde in good to excellent yields using a mixture of Ti(IV) isopropoxide and cumene hydroperoxide. Copyright

Full text of DOI:10.1080/00397911.2011.571803

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Novel Method for the Syntheses of 2-
Substituted Benzimidazoles Using Ti(IV)
Isopropoxide and Cumene Hydroperoxide
Freddy H. Havaldar a , Ganesh Mule a & Bhushan Dabholkar a
a Nadkarny-Sacasa Research Laboratory, St. Xavier's College,
Department of Chemistry, Mumbai, India
Published online: 25 May 2011.
To cite this article: Freddy H. Havaldar , Ganesh Mule & Bhushan Dabholkar (2011) Novel Method for
the Syntheses of 2-Substituted Benzimidazoles Using Ti(IV) Isopropoxide and Cumene Hydroperoxide,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:15, 2304-2308, DOI: 10.1080/00397911.2011.571803
To link to this article: http://dx.doi.org/10.1080/00397911.2011.571803
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Synthetic Communications1, 41: 2304–2308, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.571803
NOVEL METHOD FOR THE SYNTHESES OF
2-SUBSTITUTED BENZIMIDAZOLES USING Ti(IV)
ISOPROPOXIDE AND CUMENE HYDROPEROXIDE
Freddy H. Havaldar, Ganesh Mule, and Bhushan Dabholkar
Nadkarny-Sacasa Research Laboratory, St. Xavier’s College,
Department of Chemistry, Mumbai, India
GRAPHICAL ABSTRACT
Abstract Various 2-substituted benzimidazoles were prepared in one pot by condensation of
o-phenylenediamine with an appropriate aldehyde in good to excellent yields using a
mixture of Ti(IV) isopropoxide and cumene hydroperoxide.
Keywords Aldehydes; catalysis; condensation; cumene hydroperoxide; 2-substituted
benzimidazoles
INTRODUCTION
Benzimidazole and its derivatives find applications as fungicides,
antihelmintics, immunosuppressants, and anticonvulsant drugs.[1–3] Biological
activity including antiulcer, antitumor, and antiviral effects[4,5] of benzimidazole
nucleus depends on substitution at different positions. A general method, therefore,
to rapidly synthesize benzimidazoles would be of great advantage. Methods of ben-
zimidazole synthesis include condensation of o-arylenediamines and aldehydes in
refluxing nitrobenzene[6,7] or condensation of o-arylenediamines and carboxylic acids
or their derivatives (esters, amides, imidate esters, chlorides, and anhydrides) in the
presence of strong acids such as polyphosporic acid or mineral acid.[8] More recently,
polymer-bound esters have been treated with 1,2-phenylenediamines and Lewis acid
in refluxing toluene in a solid-supported route to benzimidazoles.[9] Direct condensa-
tion of o-arylenediamines and aldehydes is not a good synthetic reaction as it yields a
complex mixture-1, 2-disubstituted benzimidazole and bis-dihydrobenzimidazole as
Received October 12, 2009.
Address correspondence to Bhushan Dabholkar, Nadkarny-Sacasa Research Laboratory, St.
Xavier’s College, Department of Chemistry, Mumbai 400 001, India. E-mail: bhushan_dabholkar@
hotmail.com
2304

2-SUBSTITUTED BENZIMIDAZOLES
2305
the main side products.[10] However, the addition of transition metals, namely,
cooper(II) acetate and lead tetra-acetate,[11] allows a partial synthesis of benzimida-
zoles. Kondo et al. prepared 2-substituted benzimidazoles by ruthenium-catalyzed
reaction of o-phenylenediamine with alcohols, which presumably proceeds through
the corresponding aldehyde generated in situ.[12]
A literature survey shows the use of catalytic redox cycling approach to synthe-
size various benzimidazole derivatives based on [Fe(III)=Fe(II)] redox–mediated oxi-
dation of Schiff’s base intermediates derived from differently substituted aromatic
o-phenylenediamine and various aromatic and heterocyclic aldehydes.[13] Recently,
in a solid-phase approach, bismuth chloride–catalyzed benzimidazole cyclization
on soluble polymer support by microwave irradiation has been reported.[14] In
addition, a solid-phase solvent-free synthesis of benzimidazole using rare-earth metal
triflates [Yb (OTf)3] has been reported.[15]
These reported procedures for the preparation of 2-substituted benzimidazole
derivatives were neither versatile nor compatible with differently substituted starting
materials and also posed practical difficulties in the form of laborious reaction
workup protocols; for example, the use of very high temperatures appears manda-
tory for the polyphosphoric acid (PPA)–mediated condensation reaction. A high
temperature and strong acidic condition lead to formation of by-products, which
result in poor yields of benzimidazoles. The higher temperature reactions require
special conditions and the use of autoclaves, which reduce the process feasibility
on a larger scale. The transition metal–catalyzed reactions involve the use of
rare-earth metals such as Yb, which decreases the cost-effectiveness of the product.
The higher boiling solvents such as nitrobenzene, at high temperature, increase
safety risks and are difficult to remove from the product.
Our aim was to find a simple and cost-effective commercially viable process for
preparation of 2-substituted benzimidazoles starting from aldehydes using an oxidat-
ive cyclization of Schiff’s base approach. As a part of our study to explore the utility
of transition metal catalysis involving benzimidazole formation, we have investigated
the use of Ti(IV) isopropoxide and cumene hydroperoxide as catalyst for the prep-
aration of various 2-substituted benzimidazoles. The aldehydes were condensed with
o-phenylenediamine to give Schiff’s base followed by oxidative cyclization using a
mixture of Ti(IV) isopropoxide and cumene hydroperoxide complex (Scheme 1).
Our method initially involves generation of Schiff’s base by the reaction of
o-phenylenediamine and aromatic aldehyde. The final aromatization step to benzi-
midazoles could be mediated by the use of transition metal ions as catalyst and ulti-
mate oxidant that could possibly be generated in situ with cumene hydroperoxide.
Our initial set of experiments with benzaldehyde and o-phenylenediamine
using less stoichiometric amounts [Ti(IV) isopropoxide 5% w=w and cumene
Scheme 1.

2306
F. H. HAVALDAR, G. MULE, AND B. DABHOLKAR
hydroperoxide 2.0 mol equiv.] yielded benzimidazole in >90% yield, free of titanium
contamination after silica chromatography. This provided us the input for develop-
ing this method further as a versatile and convenient one-pot procedure for the prep-
aration of a variety of known and unknown benzimidazole derivatives. The actual
oxidant in this reaction is Ti(IV) isopropoxide, which was confirmed by various con-
trol experiments. When the reaction was carried out without Ti(IV) isopropoxide,
the reaction did not accelerate as monitored by thin-layer chromatography (TLC).
In contrast, the addition of a catalytic amount of Ti(IV) isopropoxide typically
resulted in completion of the reaction in less than 5 h. The optimum amounts of
Ti(IV) isopropoxide and cumene hydroperoxide required for completion of reaction
were determined from several trial runs and applied to develop a general protocol for
the reaction on a small scale.
To test this procedure, substituted benzaldehydes with electron-withdrawing
and electron-donating substituents were employed to prepare the benzimidazole
derivatives. The products were confirmed by analytical methods such as infrared
1
(IR), gas chromatography–mass spectrometry (GC-MS), H NMR, and 13C NMR.
A convenient procedure followed by a simple workup, mild reaction
conditions, and use of sterically hindered benzaldehyde derivatives makes our
methodology a valid contribution to the existing methodologies for preparation of
2-substituted benzimidazoles from benzaldehyde derivatives.
EXPERIMENTAL
Typical Process
A solution of substituted benzaldehyde (3.2 mmol) in acetonitrile was added to
a stirred solution of o-phenylenediamine (3.2 mmol) in acetonitrile (25 ml), and the
solution was stirred for 2 h at 90–100 ꢀC. The mixture was then evaporated to dry-
ness. The resulting Schiff’s base was suspended in acetonitrile (30 ml) and cooled
to 15–20 ꢀC, and Ti(IV) isopropoxide (5% w=w) and cumene hydroperoxide
(2.0 mol equiv.) were added. The mixture was then heated to 90–110 ꢀC for 2–3 h
and depending on the course of completion the reaction was monitored on TLC.
The solvent was evaporated completely under vacuum, and the residue was
quenched into water. After stirring for a while, the product was extracted in dichlor-
omethane. The resulting organic layer was washed with two portions of water. After
complete removal of the solvent, the residue was triturated with petroleum ether.
The solid obtained was filtered and dried to give benzimidazole analogs in the indi-
cated yields (Table 1). For analytical purpose, small samples were purified using
silica-gel flash chromatography (gradient elution from n-hexane to ethyl acetate–
n-hexane (1:1) solvent mixture). Compounds 1–8 were identified by comparison with
commercial samples.
2-(4-Methoxy-2,3,6-trimethylphenyl)-1H-benzimidazole (4)
Off white solid; 1H NMR (300 MHz, DMSO-d6): d ¼ 1.94 (s, 3H), 2.04 (s, 3H),
2.10 (s, 3H), 3.83 (s, 3H), 7.16–7.20 (m, 2H), 7.45–7.47 (m, 1H), 7.63–7.65 (m, 1H),
12.39 (s, 1H (NH-exchangeable with D2O).

2-SUBSTITUTED BENZIMIDAZOLES
2307
Table 1. Ti(IV) isopropoxide–catalyzed formation of benzimidazole analogs 1–8
Amine
Aldehyde
Product
Yield (%)a
92
89
83
90
88
90
86
75
aYield of pure isolated products, characterized by IR, GC-MS, 1H NMR, and 13C NMR.
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