Tetrabutylammonium fluoride (TBAF) catalysed synthesis of 2-arylbenzimidazole in water under ultrasound irradiation

Article abstract of DOI:10.1002/jccs.201000181

One-pot multistep reactions involving a new environmentally friendly catalytic procedure have been developed for the synthesis of benzimidazole. The reaction of the substituted aldehyde with o-phenylenediamine in water under ultrasonic irradiation at ambient temperature for appropriate time using 5 mol%of TBAF furnish the desired product in good to excellent yield. The process is green, mild, inexpensive, excellent chemo selectivity, and excellent yields are the main advantages of this procedure.

Full text of DOI:10.1002/jccs.201000181

Journal of the Chinese Chemical Society, 2010, 57, 1227-1231
1227
Communication
Tetrabutylammonium Fluoride (TBAF) Catalysed Synthesis of
2-Arylbenzimidazole in Water under Ultrasound Irradiation
Ratnadeep S. Joshi, Priyanka G. Mandhane, Sanjay K. Dabhade and Charansingh H. Gill*
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad (M.S.) 431 004, India
One-pot multistep reactions involving a new environmentally friendly catalytic procedure have been
developed for the synthesis of benzimidazole. The reaction of the substituted aldehyde with o-phenylene-
diamine in water under ultrasonic irradiation at ambient temperature for appropriate time using 5 mol% of
TBAF furnish the desired product in good to excellent yield. The process is green, mild, inexpensive, ex-
cellent chemo selectivity, and excellent yields are the main advantages of this procedure.
Keywords: Tetrabutylammonium fluoride (TBAF); Water; 2-Benzimidazole; Ultrasonication;
Green synthesis.
INTRODUCTION
Benzimidazole compounds have a wide range of bio-
However, it is noticed that all these methods are not
straightforward and involve various disadvantages such as
low yields, prolonged reaction times, and expensive cata-
lyst. In view of the conservation of the environment com-
bining with economic aspects, literature demands the ap-
plication of metal ion free, environmentally safe, and con-
venient reagents in the multicomponent reactions.
logical activities, ranging from widely used human and vet-
erinary anthelmintic1-2 to anticancer properties.3 The spec-
trum of the pharmacological activity of benzimidazole has
been reviewed by several authors.4-7 Along with this, benz-
imidazole derivatives with different pharmacological prop-
erties such as, anti ulcer,8-10 cardiotonic,11 antihyperten-
sive12 etc., have already been reported. The literature pre-
cedence reveals that the substitution at 1, 2 and 5, positions
of the benzimidazole moiety is crucial in point of view the
medicinal chemistry to exhibit wide range of pharmacolog-
ical activities.
Ultrasound accelerated chemical reactions are well
known and proceed via the formation and adiabatic col-
lapse of transient cavitations bubbles. Ultrasound irradia-
tion has been demonstrated as an alternative energy source
for organic reactions ordinarily accomplished by heating.
Many homogeneous and heterogeneous reactions can be
conducted smoothly by sonication to provide improved
yields and increased selectivities therefore ultrasound irra-
diation has been established as an important technique in
organic synthesis.
There are two general methods for the synthesis of 2-
substituted benzimidazole. One is coupling of o-phenyl-
enediamines and carboxylic acids13 or their derivatives
(nitriles, imidates, or orthoesters),14 which often requires
strong acidic conditions, and sometimes combines with
very high temperature or the use of microwave irradia-
tion.15 The other way involves a two-step procedure that is
oxidative cyclodehydrogenation of aniline schiff’s bases,
which are often generated in situ from the condensation of
o-phenylenediamines and aldehydes. Various oxidative re-
agents such as nitrobenzene,16 1,4-benzoquinone,17 DDQ,18
RESULTS AND DISCUSSION
We herein, report an eco-friendly, facile and efficient
methodology for the synthesis of 2-benzimidazole by using
the Tetrabutylammonium fluoride (TBAF).28 It is well
known that TBAF is a cheap and non-toxic reagent. Qua-
ternary ammonium fluoride salts are gaining increasing im-
portance in chemistry as organic-soluble sources of fluo-
ride ion. Of these, tetra-n-butylammonium fluoride (TBAF)
has found widespread use as a reagent to promote various
tetracyano ethylene,19 benzofuroxan,20 MnO2,21 Pb(OAc)4
22
oxone,23 NaHSO3,24 and Na2S2O5,25 DMP,26 and NH4VO3
27
have been employed.
* Corresponding author. Tel: +91-240-2403313; Fax: +91-240-2400491; E-mail: prof_gill@rediffmail.com

1228 J. Chin. Chem. Soc., Vol. 57, No. 6, 2010
Joshi et al.
Table 1. Screening of catalyst concentration on model reactiona
silylation/desilylation reactions, often under aprotic or an-
hydrous conditions.28 It is therefore of almost important to
evolve simple and its derivatives that cover the concept of
“Green Chemistry”. The uses of environmentally benign
solvents like water represent green solvent being economi-
cally and eco-friendly fro synthetic transformations. How-
ever, low solubility of reactant, incompatibility of certain
intermediate or competition between the desired reaction
and hydrolysis restrict the use of H2O as a common solvent,
although many reactions have been studied in H2O using
different catalyst.
Entry
Catalyst (mol %)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
0
1
2
3
4
5
6
30
30
30
30
30
30
30
No reaction
23
32
56
76
93
93
a Reaction of benzaldehyde with o-phenylene diamine in presence
of TBAF (5 mol%) under ultrasonic waves for 30 minute. b Iso-
lated yield.
Our research group devoted particular attention to the
development of environmentally friendly and efficient pro-
tocols by using water as the reaction medium or by working
under solventless conditions.29 Here, we wish to report the
use of a catalytic Tetrabutylammonium fluoride (TBAF) is
an efficient catalyst synthesis of various benzimidazole de-
rivatives from 1,2-phenylendiamines and variety of aro-
matic aldehydes in water under ultrasonic irradiation This
methodology gives the milder condition for synthesis of
2-substituted benzimidazole (Scheme I).
rized in the Table 1.
We kept catalyst concentration constant and used dif-
ferent solvents like dichloromethane, acetonitrile, metha-
nol, ethanol-water and water under ultrasonic irradiations.
Firstly, we have tried this reaction under solvent free condi-
tion, but the result of the reaction was reaction goes slug-
gish and a yield of the product was very low. In protic sol-
vent the reaction go smoothly as comparatively aprotic sol-
vent because the when the reaction carried out in the
aprotic solvent such as acetonitrile, DCM it takes longer re-
action time and the yields are comparatively low. Due to we
have concluded that the reaction go smoothly at protic sol-
vent such as methanol, ethanol, ethanol-water. After screen-
ing different solvents, it was found that the best solvent in
terms of fast conversion, non-toxic and quantified yield is
water. The obtained results summarized in (Table 2, entries
1–8).
Scheme I
We also performed a set of preliminary experiments
on benzaldehyde and 1,2-phenylendiamine in the presence
of different amounts TBAF and different solvent under ul-
trasonic irradiation. Firstly, in search of an efficient reac-
tion condition, the reaction of benzaldehyde (10 mol 1a and
o-phenylenediamine (10 mol) 2 in presence of TBAF at ul-
trasonic irradiation at ambient temperature the influence of
has been considered as model reaction at ambient tempera-
ture.
We have studied the different reaction conditions on
model reaction. The result revealed that, when the reaction
was carried at room temperature and reflux condition it
gave lower yield of product even after prolonged reaction
time. But at the same time the reaction was carried out un-
der ultrasonication we have got the excellent yields of
product in short span.
It was found that the ultrasonic irradiation was very
simple and convenient for the synthesis of 2-substituted
benzimidazole using ultrasonic cleaner with a frequency of
40 KHZ and a nominal power 100W. In experiment the ul-
trasonic technique represented a better procedure in terms
of time and yields (Table 2).
We have optimized catalyst concentration on model
reaction the best result was obtained on the 5mol% of the
TBAF in water at ultrasonic irradiations at ambient temper-
ature.
The lower amount of the catalyst effect on the yields
of product longer time span for the reaction and on further
increasing the amount of catalyst, the yield of the corre-
sponding product decreased, ascribable to increased acid-
ity. Even absence of the catalyst, reaction did not precede
the after extensive reaction time. The results are summa-
The effect of the electron donating group on the alde-
hyde having gives the better result as compare to the elec-
tron withdrawing. The time requires for the completion of
reaction for heteroaryl aldehyde as high and yields are low.

TBAF Catalysed Benzimidazole Synthesis
J. Chin. Chem. Soc., Vol. 57, No. 6, 2010 1229
On investigating the reaction mechanism it was no-
ticed that when aldehyde and o-phenylenediamine reacted
in presence of TBAF in water under ultrasonication. The
reaction led to the formation of intermediates as schiff
base. This intermediate was isolated and characterised by
spectroscopy method. However, extends of reaction irradi-
ate to gave the mix of product and intermediate (monitor by
TLC). After 30 min only product was detected and charac-
terised by spectroscopic method. According to observation
the mechanistic part shows TBAF when dissolved in water,
which activates the aldehyde towards elctrophillic attack of
o-phenylenediamine to generate schiff base as intermedi-
ate. Later on air oxidation of schiff base furnished desired
2-arylbenzimidazole.
Table 2. Optimization of solvent effect on the model reaction
With USa
Without USb
Time
(min)
Yieldc Time Yieldc
Entry
Solvent
(%)
(min)
(%)
1
2
3
4
5
6
7
8
Solvent free
Toluene
30
30
30
30
30
30
30
30
15
30
25
31
56
75
83
93
150
150
150
150
150
150
150
150
10
26
20
27
47
70
67
80
Dichloromethane
Acetonitrile
Methanol
Ethanol
Ethanol-water
Water
a Reaction of benzaldehyde with o-phenylene diamine in presence
of TBAF (5 mol%) under ultrasonic waves for 30 minute. b Reac-
tion of benzaldehyde with o-phenylene diamine in presence of
TBAF (5 mol%) under room temperature condition for 150
minutes. c Isolated yield.
EXPERIMENTAL
Melting points were determined on a Veego apparatus
and are uncorrected. Infrared spectra were recorded on a
Bruker spectrophotometer in a KBr disc, and the absorp-
tion bands are expressed in cm-1. 1H NMR spectra were re-
corded on a Varian AS 400 MHz spectrometer in CDCl3/
DMSO-d6, chemical shifts (d) are in ppm relative to TMS,
and coupling constants (J) are expressed in Hertz (Hz).
Mass spectra were taken on a Macro mass spectrometer
(Waters) by electro-spray method (ES). Bandelin Sonorex
(with a frequency of 40 KHz and a nominal power 100 W)
ultrasonic bath was used for ultrasonic irradiation The re-
action vessel placed in side the ultrasonic bath containing
Furthermore, effect of catalyst load on reaction time and
yield is explored in Table 1. The best result is obtained with
5 mol% of the catalyst. After optimizing the conditions, the
generality of this method was examined by the reaction of
several substituted aryl aldehydes with o-phenylene di-
amine. The results are shown in Table 3. The newly synthe-
sized compounds were compared (Melting point, MS,
NMR, and IR) with literature method.27 This comparison
revealed that the compounds synthesized by this newly de-
veloped method were exactly similar in all aspects to the
reference compounds.
Table 3. Characterization dataa of 2-substituted benzimidazole 3(a-m)
Entry
Aldehyde
Benzaldehyde
Time (min)
Isolated yielda
M.P. oC
3a
3b
3c
3d
3e
3f
30
40
40
45
45
50
60
60
60
94
90
92
88
84
82
85
82
85
289-29131
224-22631
224-22531
291-29331
245-24631
265-26631
285-28731
218-21931
245-24831
Anisaldehyde
4-methyl benzaldehyde
4-chlorobezaldehyde
4-flurobenzaldehyde
3-bromobenzaldehyde
Furan-2carbaldehyde
Piconaldehyde
3g
3h
3i
Nicotinaldehyde
4-(1H-1,2,4-trizol-1-
yl)benzaldehyde
3j
60
87
104-10630
3k
3l
Napthaldehyde
60
65
60
83
87
85
270-27232
199-20132
309-31032
Cinnamaldehyde
3m
3-nitrobanzaldehyde
a Reaction of aldehyde with o-phenylene diamine in presence of TBAF (5 mol%) in water
under ultrasonic waves. b Isolated yield. c All the compound characterized by IR. 1H NMR,
Mass and compared with reference compounds.

1230 J. Chin. Chem. Soc., Vol. 57, No. 6, 2010
Joshi et al.
water.
tuted benzimidazole in water under ultrasonic irradiation.
The advantages of this procedure are operational simplic-
ity, wide substrate scope, availability of catalyst, cost effec-
tive and high yields. In many cases, the products crystal-
lized directly from the reaction mixture in high purity. We
believe that this method presents a practical alternative to
existing procedures for the synthesis of 2-substituted benz-
imidazole.
General procedure for the synthesis of benzimidazole
A mixture of aldehyde (10 mmol), o-phenylene di-
amine (10 mmol) and TBAF (5 mol%) was dissolved in
minimum quantity of water with constant stirring. Further
the reaction mass was irradiated under ultrasonic irradia-
tion at ambient temperature for appropriate time (Table 3).
The progress of reaction was monitored by TLC. After the
completion of reaction, mixture was extract with ethyl ace-
tate (2 ´ 25 mL) and dried under vacuum. The residue was
subjected to column chromatography (60-120 mesh size
silica gel, eluted with hexane-ethyl acetate (80:20) to ob-
tain the pure product. The compounds 3(a-j) were prepared
by following the above procedure and their percentage
yield and physical constants were recorded in Table 3.
Their structures have been confirmed by 1H NMR, IR and
Mass spectra.
ACKNOWLEDGMENT
The authors are thankful to University Grants Com-
mission, New Delhi, for awarding the RFSMS Fellowship
and the Head, Department of Chemistry, Dr. Babasaheb
Ambedkar Marathwada University, Aurangabad, provida-
ing laboratory facility.
Received July 28, 2010.
Spectral data of representative compounds
Compound (3d): 1H NMR (400 MHz, DMSO-d6, d
ppm): 12.55 (br s, -NH), 8.14 (d, 2H), 7.61 (m, 1H), 7.23-
7.28 (m, 3H), 7.12-7.04 (m 2H); IR (KBr): 3053 (NH),
1682 (C=N), cm-1; MS: m/z: 229.0 (M+1), 231 (M+3);
Anal. Calcd for C13H9N2Cl: C, 68.28; H, 3.97; N, 12.25.
Found: C, 68.40; H, 3.89; N, 12.48%.
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