DOI: 10.1002/cssc.201100228
An Inorganic Iodine-Catalyzed Oxidative System for the Synthesis of
Benzimidazoles Using Hydrogen Peroxide under Ambient Conditions
Chenjie Zhu and Yunyang Wei*[a]
Benzimidazoles are very useful building blocks for the develop-
ment of molecules of pharmaceutical or biological interest.[1]
Benzimidazole derivatives exhibit significant activity against
several viruses, such as HIV,[2] herpes (HSV-1),[3] DNA,[4] RNA,[5]
influenza,[6] and human cytomegalovirus (HCMV).[2a] Bis-benzi-
midazoles are being developed as DNA minor-groove binding
agents with antitumor activity[7] and can act as ligands with
transition metals for modeling biological systems.[8] In addition,
benzimidazoles are very important intermediates in organic re-
actions.[9] The widespread interest in benzimidazole-containing
structures has promoted extensive studies on their synthesis.[10]
There are two general methods for the synthesis of benzimid-
azoles. One is the coupling of a carboxylic acid or derivative
(nitrile, imidate, or orthoester) with phenylenediamine, which
is usually performed under strongly acidic conditions,[11] harsh
dehydrating conditions that often require high tempera-
tures,[12] or via the use of agents such as phosphorus anhy-
drides,[13] sometimes in combination with microwave irradia-
tion.[14] The other method is oxidative cyclo-dehydrogenation
of aniline Schiff base, which is often generated in situ from the
condensation of phenylenediamine and aldehyde. Various oxi-
dative reagents, such as MnO2,[15] Pb(OAc)4,[16] PhI(OAc)2,[17]
Oxone,[18] DDQ,[19] I2,[20] 1,4-benzo-quinone,[21] tetracyanoethy-
lene,[22] benzofuroxan,[23] NaHSO3,[24] Na2S2O5,[25] (NH4)2S2O8,[26]
and nitrobenzene or DMF (high-boiling oxidant/solvent)[27]
have been employed to effect the dehydrogenation step. Al-
though many of these methods are practical, some have prob-
lems such as the use of dangerous or toxic reagents, or the
formation of N-benzylbenzimidazole side products resulting
from further reaction of the aldehyde with benzimidazoline
prior to oxidation.
help of harmful reagents such as H2S;[13d,30a,b] and (iv) complex
routes for the synthesis of ionic liquids. From an economic and
environmental perspective, the development of a new catalytic
oxidation system with both a more ecofriendly oxidant and
catalyst is attractive.
Recently, hypervalent iodine reagents have drawn considera-
ble attention as mild and highly chemoselective oxidizing re-
agents for various organic transformations.[32] As a result of
their nontoxic nature, affordability, and safety profile, hyperva-
lent iodine reagents are nowadays popular reagents for the
formation of carbon–carbon bonds, carbon–heteroatom
bonds, and heteroatom–heteroatom bonds. The activation of
carbon–hydrogen bonds, rearrangements, and fragmentations
can also be induced by these reagents.[33] However, the use of
stoichiometric amounts of hypervalent iodine reagents leads
to the production of equimolar amounts of organic iodine
waste, such as PhI, which is difficult to recover and reuse be-
cause of its high volatility and solubility in organic solvents. A
recent significant breakthrough in the field of organoiodine
chemistry was the development of catalytic systems based on
hypervalent iodine.[34] In 2007, Kirihara and co-workers report-
ed the in situ-generated hypoiodite-catalyzed oxidative cou-
pling of thiols to disulfides with hydrogen peroxide.[35] In 2010,
Ishihara and co-workers reported a mild and efficient catalytic
method for oxidative cycloetherification using Bu4NI, and its
enantioselective version using chiral quaternary ammonium
iodide.[36] Very recently, the method of (hypo)iodite-catalyzed
a-oxyacylation of carbonyl compounds was also reported by
Ishihara.[37]
In continuation of our efforts to develop new applications of
hypervalent iodine reagents,[38] we report herein a simple and
efficient catalytic oxidative system for the synthesis of benzimi-
dazole derivatives using H2O2 as a green and economic termi-
nal oxidant in the presence of catalytic amounts of Bu4NI.
Initial experiments were carried out with phenylenediamine
and benzaldehyde as model substrates. When phenylenedia-
mine and benzaldehyde were treated with H2O2/Bu4NI in
MeCN at room temperature for 4 h, the desired 2-phenylbenzi-
midazole was isolated in 64% yield (Table 1, entry 1). As con-
trol experiments, the same reaction was carried out in the ab-
sence of Bu4NI and H2O2 (entries 2 and 3, respectively). The
yield of 2-phenylbenzimidazole was either much lower, or null.
Moreover, other tetrabutylammonium halogenides, such as
Bu4NBr and Bu4NCl, were tested for this reaction. All of them
were unsatisfactory except for Bu4NI (entries 4 and 5). Encour-
aged by these results, we examined the effects of solvents on
the reaction, which showed that EtOH was the most efficient
solvent, giving the highest yield (entries 6–10). To optimize the
reaction conditions, the role of H2O2 was studied: 2.0 equiv of
H2O2 was the better choice for this reaction (entries 11–13).
In view of the drawbacks of existing routes and the impor-
tance of green chemistry, a few green syntheses of benzimida-
zoles have recently been reported, employing air,[28] HClO (gen-
erated in situ from H2O2 and HCl),[29] metal ions,[30] and ionic
liquid.[31] However, even these methods still have several draw-
backs from a practical point of view. These are: (i) the need for
a high temperature (often>1008C) and long reaction time (up
to 44 h); (ii) the use of strongly acidic conditions that may be
detrimental to some sensitive substrates; (iii) the use of metal
ions which, in addition to environmental concerns, often re-
quires decomplexation of the metal from the product with the
[a] C. Zhu, Prof. Y. Wei
School of Chemical Engineering
Nangjing University of Science and Technology
Nanjing 210094 (PR China)
Fax: (+86)25-84315514
Supporting Information for this article is available on the WWW under
1082
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2011, 4, 1082 – 1086