H2O2/Fe(NO3)3-promoted synthesis of 2-arylbenzimidazoles and 2-arylbenzothiazoles

Article abstract of DOI:10.1055/s-0028-1087911

A new, convenient synthesis of 2-substituted benzimidazoles and benzothiazoles is described. Short reaction time, easy and quick isolation of the products, environmentally friendly procedure, excellent chemoselectivity and excellent yields are main advantages of this procedure. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087911

LETTER
569
H2O2/Fe(NO3)3-Promoted Synthesis of 2-Arylbenzimidazoles and
2-Arylbenzothiazoles
H
O
/Fe(N
O
)
3 3-Priomoted
u
Synthesis
o
m
2-Arylbenzimidaz
o
les and 2-A
r
r
ylbenz
s
othiazoles Bahrami,*a,b Mohammad Mehdi Khodaei,*a,b Fardin Naalia
2
2
a
Department of Chemistry, Razi University, Kermanshah, 67149 Iran
Nanoscience and Nanotechnology Research Center (NNRC), Razi University, Kermanshah, 67149 Iran
Fax +98(831)4274559; E-mail: kbahrami2@hotmail.com; E-mail: mmkhoda@razi.ac.ir
b
Received 17 August 2008
R
R
NH2
XH
N
X
H2O2, Fe(NO3)3
solvent-free
Abstract: A new, convenient synthesis of 2-substituted benzimida-
zoles and benzothiazoles is described. Short reaction time, easy and
quick isolation of the products, environmentally friendly procedure,
excellent chemoselectivity and excellent yields are main advantages
of this procedure.
+
Ar
ArCHO
X = NH, S
R = H, Me, NO2
Scheme 1
Key words: 2-arylbenzimidazole, 2-arylbenzothiazole, hydrogen
peroxide, chemoselectivity, aryl aldehydes, solvent-free
result was achieved by carrying out the reaction with 1,2-
phenylenediamine, benzaldehyde, H2O2 and Fe(NO3)3
(1:1:4:0.1) at 50 °C for two minutes under solvent-free
conditions.
The benzimidazole and benzothiazole structural motifs
are found in numerous pharmaceutical agents with a di-
verse range of biological properties.1–6 Consequently, the
synthesis of the heterocyclic nucleus contained in such
compounds has gained importance. Many synthetic meth-
ods for the synthesis of benzimidazoles7 and
benzothiazoles8 are now available. Despite their tremen-
dous success, however, some drawbacks still remain. For
example, some of the catalysts are expensive, complex or
not readily available and organic solvents are always
used. As a consequence, the introduction of new methods
and/or further work on technical improvements to over-
come the limitations is still an important experimental
challenge.
Table 1 Effect of Increasing Amount of H2O2 and Fe(NO3)3 on the
Preparation of Benzimidazole Derivatives at Different Reaction
Temperaturesa
NH2
N
+
PhCHO
Ph
N
H
NH2
Entry H2O2 (mmol) Fe(NO3)3 (mmol) Temp (°C) Yield (%)b
1
2
3
4
5
4
3
3
4
4
0.05
0.07
0.1
30
40
50
50
50
44
53
75
98
98
Evolution of organic synthesis involving environmentally
clean protocols and under solvent-free conditions has
emerged as an area of great interest from both environ-
mental and economical points of view.9,10 A dilute solu-
tion of hydrogen peroxide is an ecologically clean and
convenient reagent for different oxidations in the liquid
phase.11–13
In continuation of our work14 on the development of use-
ful synthetic methodologies, in this study we wish to re-
port the use of a catalytic redox cycling approach to the
synthesis of various benzimidazole derivatives, based on
Fe(III)/Fe(II)-redox-mediated oxidation of the Schiff base
intermediates derived from differently substituted aromat-
ic 1,2-phenylenediamines and a variety of aromatic alde-
hydes (Scheme 1).
0.1
0.25
a Reaction conditions: The reactions were performed with benzalde-
hyde (1 mmol) and 1,2-phenylenediamine (1 mmol) under solvent-
free conditions.
b Yields refer to pure isolated products.
In order to study the generality of this procedure, the ap-
plicability of the H2O2 with Fe(NO3)3 system was then ex-
amined for the reactions of a series of aromatic aldehydes
with 1,2-phenylenediamines under the optimized reaction
conditions (Table 2). As shown, a variety of substituted
aromatic aldehydes, bearing either electron-donating or
electron-withdrawing substituents, afforded the products
in excellent yields and high purities. In addition, hetero-
cyclic aldehydes could also be used for efficient prepara-
tion of various 2-heterocyclic-substituted benzimidazoles
(Table 2, entries 9 and 10). It was pleasing to observe the
remarkable stability of a variety of functional groups such
as ether, nitro, hydroxyl, halides, formyl and conjugated
carbon–carbon double bond under the reaction conditions.
We performed a set of preliminary experiments on benzal-
dehyde and 1,2-phenylenediamine in the presence of dif-
ferent amount of H2O2 and Fe(NO3)3 at different reaction
temperatures. The results are depicted in Table 1. The best
SYNLETT 2009, No. 4, pp 0569–0572
x
x.
x
x.
2
0
0
9
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087911; Art ID: D30108ST
© Georg Thieme Verlag Stuttgart · New York

570
K. Bahrami et al.
LETTER
This procedure is also applicable to substituted 1,2-phe- That the actual oxidant is Fe(NO3)3 and not H2O2 was con-
nylenediamines, which produced the corresponding 2- firmed in control experiments where the presence of just
arylbenzimidazoles smoothly and in excellent yields (Ta- H2O2 did not accelerate the reaction. Starting material re-
ble 2, entries 11–16).
mained unreacted after more than six hours. In contrast,
the addition of a substoichiometric amount of Fe(NO3)3
typically resulted in completion of reactions within 2 to 31
minutes.
Table 2 Results of the H2O2 and Fe(NO3)3 System Promoted Syn-
thesis of 2-Arylbenzimidazoles
R
NH2
R
N
A comparison of the efficiency of this method with select-
ed previous methods is collected in Table 3. The results
show that this method is superior to some previously re-
ported methods in terms of yields and reaction times.
+
ArCHO
Ar
N
H
NH2
Entry
1
Ar
Ph
R
Time (min) Yield (%)a,b
Table 3 Comparison of Methods for the Synthesis of 2-Arylbenz-
imidazoles and 2-Arylbenzothiazoles
H
2
31
9
98
90
98
87
95
97
98
92
94
95
95
97
94
92
96
97
2
4-MeOC6H4
4-MeC6H4
4-(Me)2NC6H4
4-HOC6H4
2-ClC6H4
3-O2NC6H4
PhCH=CH
2-furyl
H
XH
X
+
ArCHO
Ar
3
H
N
H
NH2
4
H
28
9
X = NH, S
5
H
Entry Ar
XH Conditions
Time Yield
(%)
6
H
3
1
Ph
NH2 H2O2, Fe(NO3)3,
solvent-free, 50 °C
DDQ, MeCN, r.t.15
Me2S+Br+Br–, MeCN,
r.t.16
2 min 98
7
H
4
6 h
5 h
90
85
8
H
4
9
H
10
8
PS-PPh3, CCl3CN,
15 min 79
9 min 98
10
11
12
13
14
15
16
2-thienyl
Ph
H
MeCN, MW, 150 °C17
Me
Me
Me
Me
NO2
NO2
3
2
4-MeC6H4 NH2 H2O2, Fe(NO3)3,
solvent-free, 50 °C
4-MeC6H4
4-MeOC6H4
4-ClC6H4
Ph
6
pyridine, SOCl2, CH2Cl2, 18 h
80
0–20 °C18
10
2
I2, KI, K2CO3, H2O,
90 °C19 PhNO2, SiO2,
MW, 110 °C20
45 min 75
10 min 84
12
10
3
4
Ph
SH H2O2, Fe(NO3)3,
solvent-free, 50 °C
MnO2, SiO2, MW,
140 °C21
4 min 97
5 min 86
4-FC6H4
a The products were characterized by comparison of their spectro-
scopic and physical data with authentic samples synthesized by
reported procedures.
H3PO4, solvent-free,
4 h
90
250 °C22
b Yields refer to pure isolated products.
4-MeOC6H4 SH H2O2, Fe(NO3)3,
solvent-free, 50 °C
PhNO2, SiO2, MW23
MnO2, SiO2, MW,
22 min 91
We have also developed this synthetic method for the
preparation of additional extended bisbenzimidazole de-
rivatives in a 2:1:4:0.1 molar ratio of 1,2-phenylene-
diamine derivative to 1,4-benzenedicarboxaldehyde to
H2O2 and Fe(NO3)3 as depicted in Scheme 2.
8 min 61
4 min 91
140 °C21
2-Aminothiophenol also underwent the reaction, under
conditions similar to those used for 1,2-phenylenedi-
amines, affording the corresponding 2-arylbenzothiazoles
in excellent yields (Scheme 1, Table 4).
NH2
N
N
(a)
95%
N
H
N
H
NH2
NH2
Nevertheless, this protocol has its limitations. Butyralde-
hyde, an aliphatic aldehyde, only provided 45% yield of
the desired product.
N
N
(b)
93%
N
N
NH2
H
H
In conclusion, the H2O2 with Fe(NO3)3 system has been
employed as a novel, mild, and highly efficient reagent for
the convenient preparation of benzimidazoles and
benzothiazoles24 in excellent yields from 1,2-phenylene-
diamines and 2-aminothiophenol and a wide variety of
Scheme 2 Reagents and conditions: (a) 1,4-Ph(CHO)2, H2O2,
Fe(NO3)3, solvent-free, 50 °C, 30 min; (b) 1,4-Ph(CHO)2, H2O2,
Fe(NO3)3, solvent-free, 50 °C, 25 min.
Synlett 2009, No. 4, 569–572 © Thieme Stuttgart · New York

LETTER
H2O2/Fe(NO3)3-Promoted Synthesis of 2-Arylbenzimidazoles and 2-Arylbenzothiazoles
571
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Table 4 Results of the H2O2 with Fe(NO3)3 System Promoted Syn-
thesis of 2-Arylbenzothiazoles
NH2
N
S
+
ArCHO
Ar
SH
Entry
1
Ar
Ph
Time (min)
Yield (%)a,b
4
22
7
97
91
96
95
98
95
98
95
95
97
98
95
2
4-MeOC6H4
4-MeC6H4
2-HOC6H4
4-ClC6H4
3-BrC6H4
4-FC6H4
3
4
6
5
6
6
5
7
4
8
OHCC6H4
4-NO2C6H4
4-NCC6H4
2-furyl
7
9
4
10
11
12
6
6
2-thienyl
5
a The products were characterized by comparison of their spectros-
copic and physical data with authentic samples synthesized by
reported procedures.
b Yields refer to pure isolated products.
aryl aldehydes. In addition, low cost and ready availability
of reagents, an environmentally benign procedure and ex-
cellent chemoselectivity make this methodology a useful
contribution to the existing procedures available for the
synthesis of benzimidazole and benzothiazole derivatives.
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Acknowledgment
We are grateful to the Razi University Research Council for partial
support of this work.
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(14) Bahrami, K.; Khodaei, M. M.; Kavianinia, I. Synthesis 2007,
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Synlett 2009, No. 4, 569–572 © Thieme Stuttgart · New York

572
K. Bahrami et al.
LETTER
119.4, 122.1, 123.1, 127.8, 130.3, 130.7, 131.6, 132.4,
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(24) Ferric nitrate, hydrogen peroxide (30%) as well as all the
aromatic aldehydes, 1,2-phenylenediamine derivatives and
2-aminothiophenol employed as substrates are commer-
cially available and were used without further purification.
The concentration of the commercial 30% H2O2 solution
was checked iodometrically prior to use.
2-(4-Hydroxyphenyl)-1H-benzimidazole: mp 276–278 °C
(lit.25 279 °C). 1H NMR (200 MHz, DMSO-d6): d = 5.04 (br,
1 H, OH), 6.91 (d, J = 8.7 Hz, 2 H), 7.12–7.21 (m, 2 H),
7.48–7.57 (m, 2 H), 7.97 (d, J = 8.7 Hz, 2 H), 10.02 (br, 1 H,
NH). 13C NMR (50 MHz, DMSO-d6): d = 120.1, 121.4,
125.9, 127.6, 133.9, 144.2, 157.2, 165.
General procedure for the Synthesis of Benzimidazoles
and Benzothiazoles: A mixture of 1,2-phenylenediamine (1
mmol), aryl aldehyde (1 mmol), H2O2 (30%, 4 mmol, 0.4
mL) and Fe(NO3)3·9 H2O (0.1 mmol, 0.04 g) was heated at
50 °C for the appropriate time as mentioned in Table 2. After
completion of the reaction, the reaction mixture was
dissolved in EtOH (10 mL) and then poured into ice-water
(30 mL). The pure solid product was filtered, washed with
ice-water and subsequently dried. An identical procedure
was employed using 2-aminothiophenol (1 mmol), aryl
aldehyde (1 mmol) in the presence of 30% H2O2 (4 mmol)
and Fe(NO3)3.9 H2O (0.1 mmol) for the synthesis of
benzothiazoles (Table 4).
2-(3-Bromophenyl)benzothiazole: mp 91–93 °C. 1H NMR
(200 MHz, DMSO-d6): d = 7.34–7.66 (m, 4 H), 7.91–8.12
(m, 3 H), 8.29–8.31 (m, 1 H). 13C NMR (50 MHz, DMSO-
d6): d = 122.1, 123.5, 123.8, 126, 126.6, 126.9, 130.6, 130.9,
134.2, 135.4, 135.8, 154.3, 166.5. Anal. Calcd for
C13H8NSBr: C, 53.81; H, 2.70; N, 4.83; S, 11.05. Found: C,
54.00; H, 2.70; N, 5.20; S, 11.10.
2-(4-Formylphenyl)benzothiazole: mp 135–136 °C. 1H
NMR (200 MHz, DMSO-d6): d = 7.39–7.56 (m, 2 H), 7.90–
8.26 (m, 6 H), 10.06 (s, 1 H).13C NMR (50 MHz, DMSO-d6):
d = 122.2, 124.1, 126.0, 126.3, 127.1, 128.4, 130.7, 135.8,
138.0, 139.1, 154.5, 191.9. Anal. Calcd for C14H9NSO: C,
70.27; H, 3.79; N, 5.85; S, 13.41. Found: C, 70.00; H, 3.70;
N, 6.10; S, 13.20.
Spectroscopic and Physical Data for Selected
Compounds:
2-(4-Methylphenyl)benzothiazole: mp 85–86 °C (lit.26 85–
86 °C). 1H NMR (200 MHz, DMSO-d6): d = 2.41 (s, 3 H),
7.24–7.48 (m, 4 H), 7.86–8.04 (m, 4 H). 13C NMR (50 MHz,
DMSO-d6): d = 22.0, 122.0, 123.5, 125.5, 126.7, 127.9,
130.2, 131.3, 135.4, 141.9, 154.6, 168.7.
2-Phenyl-1H-benzimidazole: mp 290–291 °C (lit.18 292
°C). 1H NMR (200 MHz, DMSO-d6): d = 7.19–7.23 (m, 2
H), 7.51–7.61 (m, 5 H), 8.16–8.21 (m, 2 H), 12.91 (br, 1 H,
NH). 13C NMR (50 MHz, DMSO-d6): d = 120.1, 123.0,
127.0, 127.3, 129.8, 130.8, 131.0, 152.1.
(25) Charlton, P. T.; Mlalipliant, G. K.; Oxley, P.; Peak, D. A.
J. Chem. Soc. 1951, 485.
(26) George, B.; Papadopoulos, E. P. J. Org. Chem. 1977, 42,
2-(2-Chlorophenyl)-1H-benzimidazole: mp 232–234 °C
(lit.18 234 °C). 1H NMR (200 MHz, DMSO-d6): d = 7.26–
7.32 (m, 2 H), 7.56–7.73 (m, 5 H), 7.93–7.96 (m, 1 H), 12.78
(br, 1 H, NH). 13C NMR (50 MHz, DMSO-d6): d = 112.1,
441.
Synlett 2009, No. 4, 569–572 © Thieme Stuttgart · New York

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