Reusable porphyrinatoiron(III) complex supported on activated silica as an efficient heterogeneous catalyst for a facile, one-pot, selective synthesis of 2-arylbenzimidazole derivatives in the presence of atmospheric air as a "green" oxidant at ambient temperature

Article abstract of DOI:10.1002/ejoc.200800351

An efficient and highly selective synthesis of 2-arylbenzimidazoles by condensation of a wide range of aryl aldehydes bearing electron-donating or -withdrawing substituents and phenylenediamines in a single pot using a catalytic amount of (meso-tetrakis(o-chlorophenyl)porphyrinato)iron(III) chloride (5 mol-%) in excellent isolated yields is described. The reactions were performed in the presence of atmospheric air as a "green" oxidant at ambient temperature in ethanol without any additives. To benefit from the recovery and reuse of the catalyst, a new iron(III) porphyrin-silica heterogeneous catalyst was prepared by simple and successful impregnation of (meso-tetrakis(o-chlorophenyl)porphyrinato)iron(III) chloride onto activated commercial chromatographic silica gel. The silica was modified by treatment with HCl solution followed by NaOH solution, giving rise to the transformation of -O- strained siloxane atoms and silanol-OH groups into terminal negatively charged silanol-O^- groups. The heterogeneous catalyst was characterized by powdered X-ray diffraction (XRD), scanning electronic microscopy (SEM), atomic force microscopy (AFM), thermogravimetry (TG) to analyse for nitrogen adsorption, and Raman and FTIR spectroscopy. Leaching experiments showed that the catalyst is most strongly anchored to the activated support after 10 cycles. T(o-Cl)PPFe^III-SiO₂ was successfully used for all runs performed by the homogeneous catalyst and exhibited high isolated yields, selectivity, reusability, and the potential for large-scale synthesis. Mechanistically, the high-valent oxidoiron(IV)-porphyrin could be the key intermediate in this efficient and highly selective synthesis of benzimidazole derivatives. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800351

FULL PAPER
DOI: 10.1002/ejoc.200800351
Reusable Porphyrinatoiron(III) Complex Supported on Activated Silica as an
Efficient Heterogeneous Catalyst for a Facile, One-Pot, Selective Synthesis of
2-Arylbenzimidazole Derivatives in the Presence of Atmospheric Air as a
“Green” Oxidant at Ambient Temperature
Hashem Sharghi,*[a] Mohammad Hassan Beyzavi,[a] and Mohammad Mahdi Doroodmand[a]
Keywords: Iron / Porphyrinoids / Benzimidazoles / Heterogeneous catalysis / Activated silica gel / Oxidation
An efficient and highly selective synthesis of 2-arylbenzimid-
azoles by condensation of a wide range of aryl aldehydes
bearing electron-donating or -withdrawing substituents and
phenylenediamines in a single pot using a catalytic amount
of (meso-tetrakis(o-chlorophenyl)porphyrinato)iron(III) chlo-
ride (5 mol-%) in excellent isolated yields is described. The
reactions were performed in the presence of atmospheric air
as a “green” oxidant at ambient temperature in ethanol with-
out any additives. To benefit from the recovery and reuse of
the catalyst, a new iron(III) porphyrin–silica heterogeneous
catalyst was prepared by simple and successful impregnation
of (meso-tetrakis(o-chlorophenyl)porphyrinato)iron(III) chlo-
ride onto activated commercial chromatographic silica gel.
The silica was modified by treatment with HCl solution fol-
lowed by NaOH solution, giving rise to the transformation
of –O– strained siloxane atoms and silanol–OH groups into
terminal negatively charged silanol–O– groups. The hetero-
geneous catalyst was characterized by powdered X-ray dif-
fraction (XRD), scanning electronic microscopy (SEM),
atomic force microscopy (AFM), thermogravimetry (TG) to
analyse for nitrogen adsorption, and Raman and FTIR spec-
troscopy. Leaching experiments showed that the catalyst is
most strongly anchored to the activated support after 10 cy-
cles. T(o-Cl)PPFeIII–SiO2 was successfully used for all runs
performed by the homogeneous catalyst and exhibited high
isolated yields, selectivity, reusability, and the potential for
large-scale synthesis. Mechanistically, the high-valent oxido-
iron(IV)–porphyrin could be the key intermediate in this ef-
ficient and highly selective synthesis of benzimidazole deriv-
atives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
amines (o-PDs) and carboxylic acids[16] or their derivatives
(nitriles, imidates, or orthoesters),[17] which often requires
strong acidic conditions such as polyphosphoric acid[18] or
mineral acids,[19] PS–PPh3/CCl3CN[20] sometimes combined
with very high temperatures (i.e., PPA, 180 °C) or the acid-
promoted cyclization of N-(N-arylbenzimidoyl)-1,4-benzo-
quinoneimines,[21] or the use of microwave irradiation.[22]
The other way involves a two-step procedure that includes
the oxidative cyclo-dehydrogenation of aniline Schiff bases,
which are often generated in situ from the condensation of
phenylenediamines and aldehydes. Various oxidative rea-
gents such as nitrobenzene (high-boiling-point oxidant/
solvent),[23] 1,4-benzoquinone,[24] DDQ,[25] tetracyano-
ethylene,[26] benzofuroxan,[27] MnO2,[28] Pb(OAc)4,[29]
Oxone®,[30] NaHSO3,[31] I2,[32] sulfamic acid,[33] IBD,[34]
Introduction
The benzimidazole ring is an important pharmacophore
in modern drug discovery.[1] Benzimidazole derivatives exhi-
bit significant activity against several viruses such as HIV,[2]
herpes (HSV-1),[3] RNA,[4] influenza,[5] and human cyto-
megalovirus (HCMV).[2a] Substituted benzimidazole deriv-
atives have found commercial applications in several thera-
peutic areas such as in antiparasitic,[6] antitumor,[7] antimi-
crobial,[8] and anti-inflammatory[9] agents as well as in anti-
helminthic agents in veterinarian medicine.[10] Furthermore,
benzimidazoles are very important intermediates in organic
reactions[11] and also can act as ligands to transition metals
for modeling biological systems.[12] Therefore, the prepara-
tion of benzimidazoles has gained considerable attention in
recent years.[13–15] Despite their importance from pharma-
cological, industrial, and synthetic points of view, there are
only two general methods for the synthesis of 2-substituted
benzimidazoles. One is the coupling of o-phenylenedi-
H2O2/HCl,[35] Me2SBr2,[36] IL,[37] Sc(OTf)3,[38] Yb(OTf)3,[39]
[41]
In(OTf)3,[40] and Na2S2O5
have been employed. Partly
due to the availability of a vast number of aldehydes, the
latter method has been extensively used. The direct conden-
sation of o-aryldiamines and aldehydes at room tempera-
ture is less developed.[42–46] However, many of these meth-
ods have some drawbacks such as low isolation yields, long
reaction times, high reaction temperature, tedious work-up
procedures, air-sensitive catalysts, toxic solvents, the
[a] Department of Chemistry, College of Science, Shiraz Univer-
sity,
Shiraz 71454, Iran
Fax: +98-711-2280926
E-mail: shashem@chem.susc.ac.ir
hashemsharghi@gmail.com
4126
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Eur. J. Org. Chem. 2008, 4126–4138

Reusable Oxidation Catalyst
requirement of a stoichiometric or excess amount of oxi-
dants, and the occurrence of several side-reactions. In some
cases more than one step is involved in the synthesis of
these compounds. Moreover, the main disadvantage of al-
most all the existing methods is that the catalysts are de-
stroyed in the work-up procedure and cannot be recovered
or reused. Therefore, the search continues for a better cata-
lyst for the synthesis of benzimidazoles in terms of opera-
tional simplicity, reusability, economic viability, and greater
selectivity. Metalloporphyrins have been the subject of
many studies because these complexes show wide applica-
bility[47] and in the past two decades the biomimetic cataly-
sis of metalloporphyrins has increasingly attracted con-
siderable attention.[48] Metalloporphyrins are chosen as the
catalytic platform for several reasons. First, they are impor-
tant catalysts in both biological and synthetic transforma-
tions. Secondly, they can tolerate many functional groups
and solvents. Common polar groups such as hydroxy
groups, amides, and ethers do not interfere with their cata-
lytic activity. Thirdly, the phenyl groups in tetraphenylpor-
phyrin are nearly perpendicular to the porphyrin plane, and
introduction of functional groups with predictable spatial
orientation on the phenyl rings is possible. Among them,
porphyrinatoiron complexes, an important class of transi-
tion-metal complexes, continue to attract considerable at-
tention because of their importance in biology and as cata-
lysts. The roles played by these complexes in electron-trans-
fer processes, metabolic control, transport, and versatile
catalytic processes in vitro are surprisingly diverse. These
compounds can also promote substrate oxidation by using
molecular oxygen as the oxygen atom source[49–51] [Equa-
tion (1)]. High-valent oxido-iron–porphyrin complexes (2)
have been recognized as the active intermediates in shunt
cycles,[52] and the mechanism of oxygen-atom transfer from
iron to substrates has been the subject of extensive investi-
gation from various points of view, including kinetics,[53]
stereoselectivity,[54] molecular rearrangement,[55] and deute-
rium isotope effects.[56]
Scheme 1.
In order to establish the optimum conditions for this re-
action, initially, various metalloporphyrin complexes were
examined in a model reaction between o-PD and benzalde-
hyde in ethanol as solvent at room temperature with atmo-
spheric air used as a “green” oxidant. Porphyrinatoiron(III)
was found to be the most effective catalyst in terms of reac-
tion rate, selectivity, and isolated yield of the product
(Table 1, entry 1).
Table 1. Investigation of various metalloporphyrins (5 mol-%) in
the synthesis of 2-phenylbenzimidazole from o-PD (1 mmol) and
benzaldehyde (1 mmol) in ethanol at room temperature.
Entry Catalyst
Yield[a] of
product 3 [%]
Time
[h]
Yield[a] of
byproduct[b] 4 [%]
1
2
3
4
FeTPPCl[c]
CoTPP(OAc)
CrTPPCl
MgTPP
92
80
82
30
65
30
40
35
80
45
60
45
20
0
0.6
0.8
1
2
2
1.5
2
2
1
1.5
2
0
0
5
10
0
5
5
10
0
10
20
10
20
0
5
6
MnTPP(OAc)
ZnTPP
7
8
SnTPPCl2
NiTPP
9
CuTPP
HgTPP
CdTPP
PbTPP
10
11
12
13
14
2
24
24
FeCl3
[d]
–
[a] Isolated yield. [b] Byproduct: 2-phenyl-1-phenylmethyl-1H-1,3-
benzimidazole. [c] TPP = meso-tetraphenylporphyrinato dianion.
[d] Under the same conditions but without catalyst.
(1)
In this paper, we report a practical, facile, and selective
synthesis of 2-arylbenzimidazoles starting from o-PDs and
aromatic aldehydes in ethanol in the presence of catalytic
amounts of porphyrinatoiron(III) in homogeneous and
heterogeneous forms with molecular oxygen as the sole
“green” oxidant without any additives at ambient tempera-
ture.
Results and Discussion
As a part of our ongoing project devoted towards the
development of a practical synthesis of heterocyclic mole-
Then the effect of the structure of various porphyrin li-
cules of biological interest,[57] we have explored the possibil- gands was investigated using a number of porphyrin-
ity of synthesizing benzimidazole derivatives using metallo- atoiron(III) complexes (Table 2). As shown in Table 2,
porphyrins as catalyst (Scheme 1).
(entry 2), meso-tetrakis(o-chlorophenyl)porphyrin–FeIIICl
Eur. J. Org. Chem. 2008, 4126–4138
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H. Sharghi, M. H. Beyzavi, M. M. Doroodmand
FULL PAPER
Table 2. Investigation of various ligand structures of the porphyrinatoiron complexes (5 mol-%) on the synthesis of 2-phenylbenzimidazole
from o-PD (1 mmol) and benzaldehyde (1 mmol) in ethanol at room temperature.
Entry
Porphyrinatoiron(III) chlorides
Yield[a] of product 3 [%]
Time [min]
Yield[a] of byproduct[b]
4 [%]
1
2
3
4
5
6
7
8
meso-tetraphenylporphyrin–Fe
92
97
81
85
60
60
75
95
36
30
40
–
–
–
–
–
–
–
–
meso-tetrakis(2-chlorophenyl)porphyrin–Fe
meso-tetrakis(4-hydroxyphenyl)porphyrin–Fe
meso-tetrakis(3-hydroxyphenyl)porphyrin–Fe
meso-tetrakis(2-thiophenylphenyl)porphyrin–Fe
meso-tetrakis(9-anthracyl)porphyrin–Fe
meso-tetrakis(2-hydroxynaphthyl)porphyrin–Fe
meso-tetrakis(2,6-dichlorophenyl)porphyrin–Fe
40
100
120
40
40
[a] Isolated yield. [b] Byproduct = 2-phenyl-1-phenylmethyl-1H-1,3-benzimidazole.
[T(o-Cl)PPFeIIICl] proved to be the most suitable catalyst
and sterically crowded meso-tetrakis(9-anthracyl)porphy-
rin–FeIIICl the least reactive complex (entry 6).
During our optimization studies, various solvents were
examined and it was found that the solvent plays a signifi-
cant role in terms of reaction rate, isolated yield, and selec-
tivity (Table 3). Ethanol clearly stands out as the solvent
of choice with its fast reaction rate, high yield, selectivity,
cheapness, and environmental acceptability.
Table 3. Investigation of the effect of various solvents on the syn-
thesis of 2-phenylbenzimidazole from o-PD (1 mmol), benzalde-
hyde (1 mmol), and T(o-Cl)PPFeIIICl (5 mol-%) at room tempera-
ture.
Entry Solvent
Yield[a] of
product 3 [%]
Time
[h]
Yield[a] of
byproduct[b] 4 [%]
Figure 1. Plots of the yield of 2-phenylbenzimidazole and the TON
versus the amount of T(o-Cl)PPFeIIICl used as catalyst in the reac-
tion of o-PD (1 mmol) and benzaldehyde (1 mmol) in ethanol at
room temperature.
1
2
3
4
5
6
7
8
9
10
acetonitrile
10
15
97
10
40
5
30
10
25
15
2
2
0.5
2
3
2
2
2
2
5
5
10
0
5
15
5
10
5
10
10
dioxane
ethanol
diethyl ether
chloroform
dmf
xylene
water
Immobilization of metalloporphyrin catalysts on insolu-
ble organic and inorganic supports appears to be a good
way to render them practicable and to improve their sta-
bility, selectivity, and the control of their reactivity through
the microenvironment created by the support. There are
also other advantages relating to the ease of catalyst re-
moval from the reaction mixture and subsequent reuse.
THF
DMSO
[a] Isolated yield. [b] Byproduct = 2-phenyl-1-phenylmethyl-1H-
1,3-benzimidazole.
It should be noted that the optimal catalyst loading in Supported metalloporphyrins also provide a physical sepa-
the synthesis of 2-arylbenzimidazole is at a concentration ration of active sites, thus minimizing catalyst self-destruc-
of 5 mol-%. The product yields and catalyst TONs obtained tion and the dimerization of unhindered metalloporphyrins.
under the optimal operating parameters are shown in Fig- Furthermore, in the era of “environmental amity chemis-
ure 1. The plot of the yield of 2-arylbenzimidazole versus try”, heterogeneous catalytic oxidation reactions have be-
the amount of catalyst has a turning point at a catalyst come an important target as these processes are used in
concentration of 20 mol-%. The self-polymerization of the industry, helping to minimize the problems of industrial
porphyrinatoiron might account for this phenomenon.[58,59] waste treatment and disposal.[60–64]
Using the optimized conditions, the effect of oxygen was
Five general methods have been used to anchor metallo-
investigated. Instead of a static atmosphere of air, a con- porphyrins onto solid surfaces, namely, covalent bind-
tinuous flow of O2 was bubbled through the reaction mix- ing,[65] coordinative binding,[66] ionic interactions,[67] inter-
ture, but the reaction rate was not accelerated showing that calation,[67b,68] and entrapment.[69] Each of these has poten-
the O2 dissolved in solvent and adsorbed by the surface of tial advantages depending on factors such as the strength
the reaction mixture is sufficient for an efficient reaction. of the attachment to the support, the ease of preparation,
Then, as a continuation of our study, the homogeneous cat- the general applicability to different metalloporphyrins, sta-
alyst was immobilized on a solid support in an effort to bility, and selectivity.
develop a heterogeneous catalyst that could be recovered
and reused.
The use of inorganic solids has some advantages over
other types of supports. The chemical and thermal stability
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Reusable Oxidation Catalyst
of inorganic supports make them compatible with the wid-
est range of reagents and experimental conditions. Also,
mechanical resistance of the solids makes these inorganic
particles less prone to attrition due to stirring and solvent
attack during their use in a chemical reactor under con-
tinuous operation. Another advantage relates to their inert-
ness in oxidizing media. Besides the advantages mentioned
above, silica has a high surface area (5–800 m2 g–1) com-
pared with other inorganic supports, ranking these materi-
als at the top of the list of high-surface area solids.[70] Be-
cause of its high surface area and porosity, silica gel is a
common sorbent for the chromatographic separation of or-
ganic compounds. Furthermore, silica gel has found in-
creasing application in organic synthesis.[71] Its surface con-
tains silanol–OH groups, which are mainly responsible for
adsorption, and –O– strained siloxane atoms.[72]
Figure 2. SEM image of T(o-Cl)PPFeIII supported on activated sil-
ica gel.
As T(o-Cl)PPFeIIICl proved to be the best catalyst
among the porphyrinatoiron complexes for benzimidazole
synthesis, we set out to prepare a new heterogeneous cata-
lyst by simple impregnation of activated commercial chro-
matographic silica gel with T(o-Cl)PPFeIIICl.
In order to activate the silica gel, before direct use of the
silica, its surface was modified by heating it at reflux with
37% hydrochloric acid to increase the terminal silanol–OH
groups by transformation of the strained –O–siloxane
atoms into these functional groups.[73] Then the support
was heated at reflux with an aqueous solution of 0.04 
NaOH to change the terminal silanol–OH groups into neg-
atively charged silanol–O– groups (Scheme 2) to produce
the desired activated silica to be impregnated by porphyrin-
atoiron(III) and thus form the heterogeneous catalyst (see
the Exp. Sect. for details).
Scheme 2. Activation of chromatography-grade silica with aqueous
HCl followed by treatment with NaOH solution.
In order to examine the effect of the first step of the
activation (refluxing with hydrochloric acid), a standard ba-
sic solution of NaOH (0.093 , pH = 12.97) was prepared
and added to silica treated with HCl and stirred for
24 hours in a sealed flask; a decrease in the pH of the aque-
ous solution from 12.97 to 10.56 was observed. The same
procedure was used with unactivated silica. Calculations
showed that the number of terminal silanol–OH in silica
activated by HCl increases 13.18% in comparison with un-
activated silica.
Preparation of the Silica Gel Supported T(o-Cl)PPFeIII
Catalyst
Immobilization of the catalyst was undertaken by stirring
a refluxing ethanolic solution of T(o-Cl)PPFeIIICl with acti-
Figure 3. AFM Images of T(o-Cl)PPFeIII supported on activated
vated silica. The anchoring process was monitored by UV/ silica gel. Part A: 2D image, part B: 3D image, C: voltage profile.
Eur. J. Org. Chem. 2008, 4126–4138
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H. Sharghi, M. H. Beyzavi, M. M. Doroodmand
FULL PAPER
Vis spectrophotometry and a decrease in intensity of the
Soret band at λmax = 412.2 nm (ethanol) of the supernatant
solution was observed. Removal of the solvent by rotary
evaporation at 50 °C afforded the heterogeneous Fe catalyst
as a pale-brown solid (see the Exp. Sect. for details). The
FT-Raman analysis of T(o-Cl)PPFeIII–SiO2 showed that
the νSi–O stretches at 795 and 877 cm–1 and also the varia-
tions in wavenumber are related to the straightening of the
tetrahedral chains and the corresponding changes in the Si–
O bond lengths and O–Si–O angles caused by substitution
of Na for Fe, which leads to broad bands. To evaluate the
Fe content, the supported catalyst was treated with concen-
trated HCl and concentrated nitric acid to digest the metal
complex and then analyzed by inductively coupled plasma
(ICP) analysis. The Fe content was determined to be
0.600% w/w (see Exp. Sect. for details).
Figure 4. XRD pattern of T(o-Cl)PPFeIII supported on activated
silica gel.
To obtain a visual image of the supported catalyst, scan-
ning electron microscopy (SEM) and atomic force micro- ing oxygen (Si–O) stretching vibration of silanol. In Fig-
scopy (AFM) of T(o-Cl)PPFeIII–SiO2 were carried out. Ac- ure 5, the band at 570.9 cm–1 is associated with the stretch-
cording to the SEM (Figure 2) and AFM images (Figure 3, ing vibration of Fe–O differentiated from the absorption of
see parts A and B), very different channels of porphy- activated silica as substrate. Note that the intensity of the
rinatoiron particles are dispersed molecularly on the sili- Fe–O band strongly depends on the weight percentage of
cone substrate.
Fe3+ in the T(o-Cl)PPFeIII sample. This implies that T(o-
The diameters of the complex were estimated to be sev- Cl)PPFeIII is well developed in this phase.[74] This result
eral microns according to the voltage profile image of Fe strongly supports the observed XRD patterns and shows
catalysts (Figure 3, C). From the width of the band at half that the porphyrinatoiron(III) complex is immobilized on
height of the peak, the diameter of particles was estimated the support by electrostatic interaction between the nega-
to be about 1.15 µm.
tively charged surface of the activated inorganic solid and
The XRD pattern of the heterogeneous catalyst (Fig- the positively electrically charged complex through the for-
ure 4) shows a single-phase complex of a porphyrinatoiron mation of a coordinative bond with the metal. To prove
structure and the amorphous nature of the SiO2 substrate. this kind of interaction, the T(o-Cl)PP ligand was similarly
The strongest peaks of the XRD pattern correspond to the loaded onto the activated silica. A loading of about only
SiO2 plane with the other peaks indexed as the (220), (311), 15% was achieved compared with that of T(o-Cl)PPFeIIICl,
(400), (422), (511), and (440) planes of the porphyrinatoiron which indicates the important role of the metal.
complex.
The adsorption behavior of nitrogen gas on both acti-
The FTIR transmission spectrum of the supported cata- vated silica gel and on activated silica gel impregnated with
lyst shows bands at around 1072, 802, and 470 cm–1, which T(o-Cl)PPFeIII was investigated by thermogravimetric
are presumably due to asymmetric stretching (νas), symmet- analysis (TGA) under nitrogen (Figure 6). The results show
ric stretching (νs), and bending modes of Si–O–Si, respec- that support of the Fe complex on activated silica gel re-
tively. The weak band at 1002 cm–1 is due to the nonbridg- duces the adsorption of nitrogen gas by about 0.07 wt.-%.
Figure 5. The FTIR spectrum of T(o-Cl)PPFeIII–SiO2 differentiated from activated silica as substrate.
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Reusable Oxidation Catalyst
From this value it is estimated that the activated surface of Homogeneous and Heterogeneous Catalytic Benzimidazole
silica gel is reduced by about 0.56 cm3 when T(o-Cl)- Synthesis
PPFeIIICl is supported.
Finally, under the optimized conditions, the condensa-
tion of o-PDs and aryl aldehydes was carried out in the
presence of homogeneous and heterogeneous catalysts at
room temperature and a ratio of 1:1 of o-PDs and aryl alde-
hydes was found to be optimum to give exclusively the cor-
responding 2-aryl-substituted benzimidazoles 3 in high
yields (Scheme 3).
Figure 6. Comparison of adsorption of nitrogen on activated silica
gel (B) and T(o-Cl)PPFeIII supported on activated silica gel (A) at
25 °C.
Scheme 3. Condensation of o-PDs and aromatic aldehydes under
The principle advantages of this immobilization tech-
the optimized conditions.
nique include the absence of any complexity in the immobi-
lization process, the widespread availability of silica inor-
To test the generality and versatility of this procedure in
ganic supports (chromatography grade silica), the lack of the direct synthesis of 2-substituted benzimidazoles via the
any laborious need to alter the catalyst to facilitate the im- formation of Schiff bases, we examined the reactions of a
mobilization, the rapidity and experimental simplicity of number of substituted aromatic aldehydes and o-PDs under
the procedure by which the immobilization can be com- the optimized conditions in the presence of both homogen-
pleted, and the fact that the purity of the immobilized com- eous and heterogeneous catalysts. As shown in Table 4, al-
plex can be better assessed.
dehydes bearing electron-donating or -withdrawing substit-
Table 4. Selective synthesis of 2-arylbenzimidazoles from various o-PDs (1.0 mmol) and benzaldehydes (1.0 mmol) in the presence of
homogeneous and heterogeneous T(o-Cl)PPFeIII catalyst (5 mol-%) in ethanol solvent at room temperature.
Entry
o-PDs (R)
Aldehydes
Compound 3
Method A[a]
Method B[b]
Yield[c] of product
Time
[min]
Yield[c] of product Time
3 [%]
3 [%]
[h]
1
2
3
4
5
6
7
8
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
benzaldehyde
3a
3b
3c
3d
3e
3f
3g
3h
3i
97
96
95
94
95
95
95
94
94
94
95
91
92
90
96
93
91
90
90
90
90
30
45
55
55
55
90
80
190
220
105
115
95
230
300
65
105
50
110
60
95
91
90
90
91
92
90
88
89
87
90
85
88
86
91
85
86
84
85
89
86
1.5
1.8
2.0
2.2
2.0
2.6
2.5
4.0
3.8
3.0
3.2
3.0
4.5
4.9
2.1
2.8
2.0
2.9
2.4
2.7
3.4
2-chlorobenzaldehyde
3-chlorobenzaldehyde
4-chlorobenzaldehyde
4-methylbenzaldehyde
4-methoxybenzaldehyde
4-isopropylbenzaldehyde
4-cyanobenzaldehyde
2-hydroxybenzaldehyde
3-hydroxybenzaldehyde
4-hydroxybenzaldehyde
2,6-dichlorobenzaldehyde
3-nitrobenzaldehyde
4-nitrobenzaldehyde
2-naphthaldehyde
2-thiophenecarbaldehyde
2-pyridinecarbaldehyde
2-furancarbaldehyde
4-methylbenzaldehyde
4-methylbenzaldehyde
benzaldehyde
9
10
11
12
13
14
15
16
17
18
19
20
21
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
–
CH3
COC6H5
CO2H
75
180
3u
[a] Reaction performed in the presence of homogeneous T(o-Cl)PPFeIIICl. [b] Reaction performed in the presence of heterogeneous T(o-
Cl)PPFeIII–SiO2 containing 5 mol-% of catalyst (see the Exp. Sect. for details). [c] Isolated yield.
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H. Sharghi, M. H. Beyzavi, M. M. Doroodmand
FULL PAPER
uents gave the desired benzimidazoles in high yields with
As shown in Figure 7, the catalytic activity of T(o-Cl)-
both catalysts. Heteroaryl aldehydes, such as 2-thienyl, 2- PPFeIII–SiO2 remained largely unchanged for 10 successive
pyridyl, acid-sensitive 2-furyl (Table 4, entries 16–18), and runs. The heterogeneous catalyst was also recycled up to 20
the sterically hindered 2-naphthaldehyde (Table 4, entry 15) times without any significant reduction in activity in the
tolerated these mild conditions. The method tolerates other synthesis of benzimidazoles in ethanol as solvent with a to-
functional groups such as hydroxy, methoxy, halides, nitro, tal of 388 turnovers being achieved.
and nitrile on the aryl aldehyde (Table 4, entries 2–14) and
methyl, carbonyl, and carboxylic acid on o-PD (Table 4, en-
tries 19–21). As expected, the carboxylic substituent on the
o-PD did not participate in the reaction, resulting in the
clean formation of 2-phenylbenzimidazole-6-carboxylic
acid (Table 4, entry 21) with none of the dimeric derivative
5, potentially formed from the participation of the carbox-
ylic acid substituent, detected.
Figure 7. Recyclability of T(o-Cl)PPFeIII–SiO2 in the synthesis of
2-phenylbenzimidazole.
Note that the anchoring of T(o-Cl)PPFeIIICl onto unac-
tivated silica or silica activated by only HCl resulted in 42
and 34% leaching, respectively, after one run, which shows
The reactivity of the heterogeneous catalyst in compari- the importance of the whole activation process for the suc-
son with the homogeneous catalyst is slightly reduced, pre- cessful immobilization of the catalyst.
sumably because of its limited solubility in reaction media,
To assess the feasibility of applying this method on a
but the selectivity remained unchanged (Table 4). The silica- preparative scale, we coupled o-PD with benzaldehyde on a
supported porphyrinatoiron(III) complex was recovered by 100 mmol scale in the presence of the heterogeneous cata-
filtration after each experiment and could be reused for the lyst. As expected, the reaction proceeded similarly to the
benzimdazole synthesis in more than 10 successive reac- smaller-scale reaction (Table 4, entry 1), and the desired 2-
tions. After 10 consecutive reactions, the recovered T(o-Cl)- phenylbenzimidazole was obtained in 92% isolated yield in
PPFeIII–SiO2 was found to contain 0.586% (w/w) of Fe 1.8 h. Continuous bubbling of O2 through the reaction mix-
based on ICP analysis, which is comparable to the initial ture instead of the static atmosphere of air did not acceler-
value of 0.600 % (w/w), indicative of less than 2% leaching ate the reaction rate, as mentioned above for the smaller-
during the reaction cycles (see the Exp. Sect. for details).
scale reaction.
Scheme 4. Proposed mechanism for the porphyrinatoiron-catalyzed synthesis of benzimidazole.
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Reusable Oxidation Catalyst
To explore the mechanism of the reaction, aldehyde con- PPFeII Soret band at λmax = 427.7 nm (ethanol) in several
sumption was monitored by GC analysis and we found that minutes (Figure 8). In 1984, Balch and co-workers iden-
the Schiff base is formed very rapidly (within the first tified the irreversible oxidation of (TMP)FeII (TMP = meso-
3 minutes of the beginning of reaction) and the rate-de- tetramesitylporphyrin dianion) by molecular oxygen at a
termining step (RDS) was found to be the oxidative cycliza- low temperature[77] and confirmed the previous proposal.[78]
tion step. Furthermore, we found that it is not necessary to The oxygen-bound porphyrinatoiron complex reacts with
prepare Schiff bases in advance. We can directly use equi- another T(o-Cl)PPFeII to give the µ-peroxo complex. Sub-
molar amounts of o-PDs and aromatic aldehydes as starting sequent O–O bond cleavage gives the high-valent oxo
materials in the presence of porphyrinatoiron(III) com- iron(IV) porphyrin complex, T(o-Cl)PPFeIV=O (Scheme 6).
plexes, which should be synthetically useful and practical.
The subsequent oxidative dehydrogenation of adduct B in
A plausible pathway for the formation of benzimidazoles the presence of the porphyrin–iron(IV)-oxido complex af-
involves the formation of intermediate Schiff bases A from fords the desired 2-arylbenzimidazoles (Scheme 4).
which the cyclic adduct B (hydrobenzimidazole) is produced
by intramolecular participation of the o-amino group
(Scheme 4).[35,75] In the initial step of the catalytic reaction,
we propose that T(o-Cl)PPFeIIICl is reduced to the T(o-
Cl)PPFeII state by an outer-sphere electron transfer from
hydrobenzimidazole B to the porphyrin periphery (a pe-
Scheme 6.
ripheral π transfer). Both the N–H and α-C–H positions in
compound B are essential for this reduction (Scheme 5).[76]
To validate our proposal, the reaction progress was moni-
Conclusions
tored from the beginning of the reaction by UV/Vis spectro-
photometry under strictly anaerobic conditions and the
T(o-Cl)PPFeIII Soret band at λmax = 412.2 nm (ethanol) was
observed to gradually shift to the corresponding T(o-Cl)-
In summary, we have presented the first example of a
porphyrinatoiron-catalyzed synthesis of benzimidazoles un-
der mild conditions. This new and efficient catalytic method
provides a protocol that enables the synthesis of 2-aryl-
benzimidazoles in a regioselectively pure form while dis-
playing good functional group tolerance. The advantage of
this procedure is the employment of atmospheric air as the
oxidant. No toxic reagent(s) or byproduct(s) was involved
and no laborious purifications were necessary. This pro-
cedure is ideally suited to automated applications because
the entire synthetic sequence can be carried out at room
temperature in the presence of a reusable heterogeneous cat-
alyst. These conditions are also environmentally friendly,
cost effective, and possess high generality, which makes our
methodology suitable for industrialization as a valid contri-
bution to the existing processes in the field of benzimid-
azole synthesis, an important class of heterocycles.
Scheme 5.
Experimental Section
General: NMR spectra were recorded with a Bruker Avance DPX-
250 spectrometer (1H NMR 250 MHz and 13C NMR 62.9 MHz)
in pure deuteriated solvents with tetramethylsilane (TMS) as the
internal standard. Scanning electron micrographs were obtained by
SEM (SEM, XL-30 FEG SEM, Philips, at 20 KV). An atomic
forced microscope (AFM, DME-SPM, version 2.0.0.9) was also
used to obtain AFM images. Spectroscopic methods including Ra-
man spectrometry (Thermo Nicolet AlmegaY dispersive, Raman
Spectrometer) and X-ray diffraction (XRD, D8, Advance, Bruker,
axs) data were used to characterize the heterogeneous catalyst.
TGA of the samples was performed with a laboratory-made TGA
instrument. Infrared spectra were obtained using a Shimadzu FT-
IR 8300 spectrophotometer. Metal contents were obtained with an
ICP analyzer (Varian, vista-pro). Mass spectra were determined
with a Shimadzu GCMS-QP 1000 EX instrument at 70 or 20 eV.
Melting points were determined in open capillary tubes in a Buchi-
535 circulating oil melting point apparatus. UV/Vis spectra were
Figure 8. The UV/Vis spectra change from (a) T(o-Cl)PPFeIII Cl
(λmax = 412.2 nm) to (b) T(o-Cl)PPFeIICl (λmax = 427.7 nm) due to
electron transfer under strictly anaerobic conditions in the presence
of o-PD and benzaldehyde in a 1:1 ratio in ethanol as solvent at
25 °C (t = 10 min). (c) Absorbtion spectrum of intermediate Schiff
base A (λmax = 404.9 nm) separately prepared in the absence of the
catalyst in ethanol solvent. Spectrum (c) overlays spectra (a) and
(b).
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H. Sharghi, M. H. Beyzavi, M. M. Doroodmand
FULL PAPER
obtained with an Ultrospec 3000 UV/Vis spectrometer. Elemental
analyses were performed with a Thermo Finnigan CHNS-O 1112
series analyzer. The purity determination of the substrates and re-
action monitoring were accomplished by TLC on silica gel coated
(PolyGram SILG/UV254) plates or by GC with a Shimadzu Gas
Chromatograph GC-10A instrument with a flame-ionization detec-
tor using a column of 15% carbowax 20  chromosorb-w acid
washed 60–80 mesh. Column chromatography was carried out on
short columns of silica gel 60 (70–230 mesh) in glass columns (2–
3 cm diameter) using 15–30 gram of silica gel per gram of the crude
mixture. Chemicals were either prepared in our laboratories or pur-
chased from Fluka, Aldrich, or Merck.
with distilled CH2Cl2 (100 mL), aryl aldehyde (1 mmol), and pyr-
role (0.07 mL, 1 mmol). The resulting solution was magnetically
stirred at room temperature. After stirring the solution for 5–
10 min, an appropriate amount of CF3SO2Cl (0.1 mL, 1 mmol) was
added through a syringe. After 1 h, the yield of the porphyrinogen
was a maximum. Then the gas inlet line was switched to filtered
house air and the mixture was aerated for 4 h (39 °C). During this
time, the mixture became dark purple, and the porphyrinogen un-
der aerobic oxidation was converted into the product. The solution
was concentrated by rotary evaporation and purified by
chromatography (silica gel; with CH2Cl2/petroleum ether, 1:1) to
give the product in 35% yield.
Preparation of Activated Silica Gel: Silica gel 60 (5.00 g, 0.063–
0.200 mm, 70–230 mesh ASTM, CAS No. 60740, Fluka) was
heated at reflux with 37% hydrochloric acid (30 mL) for 8 h to
change the –O– strained siloxane atoms into terminal silanol–OH
groups. Then the silica was thoroughly washed with diionized water
until the pH of the eluent reached 6. As the final step, the silica
was heated at reflux with an aqueous solution of 0.04  NaOH
(30 mL) for 8 h to transform the terminal silanol–OH groups into
negatively charged silanol–O– groups. Then it was washed with di-
ionized water until a constant pH8 to afford a white solid powder
that was dried at 110 °C in an oven overnight under vacuum.
Preparation of [meso-Tetrakis(o-chlorophenyl)porphyrinato]iron(III)
Chloride: A three-necked round-bottomed flask equipped with a
thermometer, reflux condenser, and magnetic force stirrer was
charged with DMF (20 mL), T(o-Cl)PP (0.27 mmol), and anhy-
drous FeCl3 (0.30 mmol). The mixture was stirred under reflux for
2 h at 165 °C. TLC revealed the complete disappearance of the
starting material. Deionized water (20 mL) and 10% HCl (30 mL)
were added to the cooled mixture, and a crystalline product
formed. After overnight deposition, followed by filtration and dry-
ing in a vacuum, the crude product (180 mg) was obtained. This
was dissolved in CH2Cl2 and purified by column chromatography
(neutral Al2O3, CH2Cl2 as eluent), and T(o-Cl)PPFeIII(Cl) was ob-
tained as a powder (160 mg). Other metalloporphyrin complexes
were prepared by reported procedures, and their spectroscopic and
physical data were compared with those reported in the litera-
ture.[80]
Preparation of the Silica-Supported T(o-Cl)PPFeIII Catalyst: Immo-
bilization of the catalyst was undertaken by stirring a refluxing eth-
anolic solution (15 mL) of T(o-Cl)PPFeIII (0.10 g) with activated
silica (1.00 g) for 8 h. The anchoring process was monitored by UV/
Vis spectrophotometry and a decrease in the intensity of the Soret
band at λmax = 412.2 nm (ethanol) of supernatant solution was
observed. Removal of the solvent by rotary evaporation at 50 °C
afforded the heterogeneous T(o-Cl)PPFeIII–SiO2 catalyst as a pale-
brown solid. In order to remove any physisorbed complex, the re-
sulting heterogeneous catalyst was purified by Soxhlet extraction
with ethanol for 8 h.
General Procedure for the Synthesis of 2-Substituted Benzimidazoles
in the Presence of a Catalytic Amount of the T(o-Cl)PPFeIIICl Com-
plex: For each reaction, o-PD (1 mmol) and aryl aldehyde (1 mmol)
were stirred in EtOH (5 mL) in the presence of catalyst (5 mol-%)
at room temperature. The reactions were monitored by TLC using
n-hexane/ethyl acetate (8:1). After completion of the reaction the
solvent was evaporated to give the crude product, which was puri-
fied by silica gel column chromatography employing n-hexane/ethyl
acetate (8:1) as the eluent.
General Procedure for the Synthesis of 2-Substituted Benzimidazoles
in the Presence of a Catalytic Amount of T(o-Cl)PPFeIII–SiO2 and
Recycling of the Heterogeneous Catalyst: The gel-supported T(o-
Cl)PPFeIII catalyst was subjected to 10 successive reuses under the
reaction conditions: For each reaction, o-PD (1 mmol) and aryl
aldehyde (1 mmol) was stirred in EtOH (96%, 5 mL) in the pres-
ence of the heterogeneous catalyst (5 mol-%, 0.470 g) at room tem-
perature. According to the ICP analysis, the Fe content in the
heterogeneous catalyst was determined to be 0.600% (w/w). There-
fore, each gram of heterogeneous catalyst includes 0.000107 mmol
of iron or porphyrinatoiron complex. For 1 mmol of reactants,
0.05 mmol of catalyst is needed, which is equal to 0.470 g of the
heterogeneous catalyst. The reactions were monitored by TLC
using n-hexane/ethyl acetate (8:1). After the reaction was complete
the whole reaction mixture was centrifuged and the supernatant
solution was decanted to separate the catalyst, which was washed
several times with ethanol. The reaction vessel containing the
heterogeneous catalyst was recharged with o-PD, aryl aldehyde, and
ethanol for another reaction run. The combined supernatant and
organic washings were purified by silica gel column chromatog-
raphy employing n-hexane/ethyl acetate (8:1) as the eluent.
All the benzimidazoles produced were characterized in detail by
1
IR, H and 13C NMR, mass spectroscopy, and elemental analysis.
2-Phenyl-1H-benzimidazole (3a): Colorless solid; 97% yield
(0.188 g). M.p. 290–292 °C (ref.[81] m.p. 292 °C). IR (KBr): ν =
˜
1620 (C=N), 3444 (NH) cm–1. 1H NMR ([D6]DMSO, 250 MHz):
δ = 7.14–7.25 (m, 2 H), 7.44–7.61 (m, 5 H), 8.20 (d, J = 7.2 Hz, 2
H), 12.94 (s, 1 H) ppm. 13C NMR ([D6]DMSO, 62.9 MHz): δ =
122.1, 126.4, 128.4, 128.9, 129.2, 129.8, 130.1, 151.2 ppm. MS: m/z
(%) = 194 (97.4) [M]+, 149 (45.6), 115 (20.2), 97 (27.2), 73 (46.5),
57 (100.0). C13H10N2 (194.235): C 80.39, H 5.19, N 14.42; found
C 80.30, H 5.25, N 14.39.
2-(2-Chlorophenyl)-1H-benzimidazole (3b): Colorless solid; 96%
yield (0.219 g). M.p. 233–234 °C (ref.[81] m.p. 234 °C). IR (KBr): ν
˜
= 1620 (C=N), 3445 (NH) cm–1. 1H NMR ([D6]DMSO, 250 MHz):
δ = 7.20–7.24 (m, 2 H), 7.48–7.51 (m, 2 H), 7.54–7.68 (m, 3 H),
7.89–7.93 (m, 1 H), 12.74 (s, 1 H) ppm. 13C NMR ([D6]DMSO,
62.9 MHz): δ = 111.7, 119.0, 121.7, 122.7, 127.3, 129.9, 130.3,
131.1, 131.6, 132.0, 134.6, 143.1, 149.1 ppm. MS: m/z (%) = 230
(2.3) [M + 2]+, 229 (13.5) [M + 1]+, 228 (44.6) [M]+, 167 (24.2),
149 (68.5), 129 (20.4), 112 (19.2), 91 (41.2), 57 (100.0). C13H9ClN2
(228.681): C 68.28, H 3.97, N 12.25; found C 68.31, H 4.07, N
12.20.
General Procedure for the Synthesis of meso-Tetrakis(o-chlo-
rophenyl)porphyrin: Our recent methods for the synthesis of meso-
tetraarylporphyrins were used.[79] A standard reaction was per-
formed in a 150-mL three-necked round-bottomed flask fitted with
a septum port, a reflux condenser, and a gas inlet port. The inlet
port consisted of a glass disk immersed in solution with nitrogen
flow rates maintained at about 2 mL/min. The flask was charged
2-(3-Chlorophenyl)-1H-benzimidazole (3c): Colorless solid; 95%
yield (0.217 g). M.p. 230–232 °C. IR (KBr): ν = 1623 (C=N), 3445
˜
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Reusable Oxidation Catalyst
1
(NH) cm–1. H NMR ([D6]DMSO, 250 MHz): δ = 7.21 (m, 2 H), 250 MHz): δ = 6.97–7.04 (m, 2 H), 7.25–7.45 (m, 3 H), 7.63–7.67
7.49–7.64 (m, 4 H), 8.13 (dd, J1 = 6.6, J2 = 1.8 Hz, 1 H), 8.21 (s,
1 H), 13.04 (s, 1 H) ppm. 13C NMR ([D6]DMSO, 62.9 MHz): δ =
111.5, 119.0, 122.0, 122.9, 125, 126, 129.5, 130.9, 132.1, 133.7,
143.5, 149.7 ppm. MS: m/z (%) = 230 (16.1) [M + 2]+, 229 (25.0)
(m, 2 H), 8.02 (d, J = 7.8 Hz, 1 H), 13.07 (s, 2 H) ppm. 13C NMR
([D6]DMSO, 62.9 MHz): δ = 111.5, 112.5, 117.1, 117.9, 119.1,
122.4, 123.2, 126.1, 131.7, 151.6, 157.9 ppm. MS: m/z (%) = 211
(60.5) [M + 1]+, 210 (84.1) [M]+, 181 (43.2), 149 (52.7), 129 (16.8),
[M + 1]+, 228 (38.6) [M]+, 167 (20.5), 149 (62.8), 111 (19.6), 94 94 (42.3), 73 (39.5), 57 (100.0). C13H10N2O (210.234): C 74.27, H
(99.8), 71 (37.3), 55 (100.0). C13H9ClN2 (228.681): C 68.28, H 3.97,
N 12.25; found C 68.21, H 4.09, N 12.18.
4.79, N 13.33; found C 74.24, H 4.82, N 13.28.
3-(1H-Benzimidazol-2-yl)phenol (3j): Colorless solid; 94% yield
2-(4-Chlorophenyl)-1H-benzimidazole (3d): Colorless solid; 94%
(0.197 g). M.p. 182–183 °C (ref.[84] m.p. 181–184 °C). IR (KBr): ν
˜
yield (0.214 g). M.p. 292–293 °C (ref.[81] m.p. 292 °C). IR (KBr): ν = 1620 (C=N), 3261 (OH, NH) cm–1. 1H NMR ([D6]DMSO,
˜
= 1626 (C=N), 3445 (NH) cm–1. 1H NMR ([D6]DMSO, 250 MHz):
δ = 7.18–7.21 (m, 2 H), 7.60 (m, 4 H), 8.17 (d, J = 8.6 Hz, 2 H),
12.99 (s, 1 H) ppm. 13C NMR ([D6]DMSO, 62.9 MHz): δ = 111.4,
118.9, 121.9, 122.7, 128.1, 129, 134.5 150.1 ppm. MS: m/z (%) =
250 MHz): δ = 6.86–6.89 (m, 1 H), 7.16–7.19 (m, 2 H), 7.32 (t, J
= 8.1 Hz, 1 H), 7.55–7.58 (m, 4 H), 9.81 (s, 1 H) ppm. 13C NMR
([D6]DMSO, 62.9 MHz): δ = 112.6, 117.0, 117.2, 122.1, 129.6,
131.2, 151.4, 157.7 ppm. MS: m/z (%) = 212 (1.5) [M + 2]+, 211
230 (21.1) [M + 2]+, 229 (36.3) [M + 1]+, 228 (54.9) [M]+, 193 (8.2) [M + 1]+, 210 (14.6) [M]+, 150 (9.9), 137 (15.2), 111 (19.0), 97
(13.5), 167 (7.0), 149 (25.0), 129 (11.1), 111 (15.4), 85 (33.2), 57
(100.0). C13H9ClN2 (228.681): C 68.28, H 3.97, N 12.25; found C
68.23, H 4.05, N 12.24.
(38.6), 83 (56.4), 70 (23.7), 55 (100.0) C13H10N2O (210.234): C
74.27, H 4.79, N 13.33; found C 74.19, H 4.85, N 13.32.
4-(1H-Benzimidazol-2-yl)phenol (3k): Pale-yellow solid; 95% yield
(0.199 g). M.p. 254–255 °C (ref.[85] m.p. 254.1–256.6 °C). IR (KBr):
˜
2-(4-Methylphenyl)-1H-benzimidazole (3e): Colorless solid; 95%
yield (0.197 g). M.p. 270–272 °C (ref.[82] m.p. 270–272 °C). IR ν = 1620 (C=N), 3256 (OH, NH) cm–1. 1H NMR ([D6]DMSO,
1
(KBr): ν = 1620 (C=N), 3649 (NH) cm–1. H NMR ([D ]DMSO, 250 MHz): δ = 6.93 (dd, J1 = 8.5, J2 = 1.2 Hz, 2 H), 7.10–7.22 (m,
˜
6
250 MHz): δ = 2.35 (s, 3 H), 7.15–7.20 (m, 2 H), 7.33 (d, J = 8.1 Hz,
2 H), 7.52–7.53 (m, 2 H), 8.02 (d, J = 8.6 Hz, 2 H), 10.07 (s, 1 H),
2 H), 7.46–7.56 (m, 2 H), 8.07 (d, J = 8.1 Hz, 2 H), 12.84 (s, 1 12.65 (s, 1 H) ppm. 13C NMR ([D6]DMSO, 62.9 MHz): δ = 115.7,
H) ppm. 13C NMR ([D6]DMSO, 62.9 MHz): δ = 20.9, 121.9, 126.3,
127.4, 128.9, 129.4, 139.5, 151.3 ppm. MS: m/z (%) = 208 (66.5)
[M]+, 149 (49.1), 111 (18.0), 83 (44.9), 57 (100.0). C14H12N2
(208.262): C 80.74, H 5.81, N 13.45; found C 80.69, H 5.90, N
13.38.
121.0, 121.6, 128.1, 151.8, 159.1 ppm. MS: m/z (%) = 211 (55.2)
[M + 1]+, 210 (100.0) [M]+, 181 (24.8), 105 (20.9), 64 (26.4).
C13H10N2O (210.234): C 74.27, H 4.79, N 13.33; found C 74.19, H
4.85, N 13.32.
2-(2,6-Dichlorophenyl)-1H-1,3-benzimidazole (3l): Colorless solid;
2-(4-Methoxyphenyl)-1H-benzimidazole (3f): Colorless solid; 95%
91% yield (0.239 g). M.p. 279 °C. IR (KBr): ν = 1627 (C=N), 3447
˜
1
yield (0.213 g). M.p. 226 °C (ref.[83] m.p. 226–227 °C). IR (KBr): ν (NH) cm–1. H NMR (CDCl3, 250 MHz): δ = 7.11–7.30 (m, 7 H),
˜
= 1612 (C=N), 3422 (NH) cm–1. 1H NMR ([D6]DMSO, 250 MHz):
δ = 3.78 (s, 3 H), 7.10 (d, J = 8.8 Hz, 2 H), 7.16 (q, J = 3.01 Hz, 2
H), 7.50 (m, 2 H), 8.12 (d, J = 8.8 Hz, 2 H), 12.76 (s, 1 H) ppm.
13C NMR ([D6]DMSO, 62.9 MHz): δ = 55.2, 111.0, 114.3, 118.4,
121.5, 122.0, 122.6, 128.0, 151.3, 160.5 ppm. MS: m/z (%) = 225
(86.4) [M + 1]+, 224 (92.4) [M]+, 210 (51.8), 182 (51.0), 149 (30.9),
129 (17.8), 97 (30.4), 69 (100.0). C14H12N2O (224.261): C 74.98, H
5.39, N 12.49; found C 74.93, H 5.42, N 12.45.
7.54 (s, 1 H) ppm. 13C NMR ([D6]DMSO, 62.9 MHz): δ = 115.4,
122.2, 128.3, 130.4, 132.4, 135.0, 137.0, 146.6 ppm. MS: m/z (%) =
265 (7.0) [M + 2]+, 263 (100.0) [M]+, 228 (58.0), 193 (71.0).
C13H8Cl2N2: C 59.34, H 3.06, N 10.65; found C 59.16, H 3.15, N
10.63.
2-(3-Nitrophenyl)-1H-benzimidazole (3m): Pale-yellow solid; 92%
yield (0.219 g). M.p. 206–207 °C (ref.[86] m.p. 207–208 °C). IR
(KBr): ν = 1346, 1516 (NO ), 1620 (C=N), 3368 (NH) cm–1. 1H
˜
2
2-(4-Isopropylphenyl)-1H-benzimidazole (3g): Colorless solid; 95%
NMR ([D6]DMSO, 250 MHz): δ = 7.21 (m, 2 H), 7.61 (m, 2 H),
7.74–7.84 (m, 1 H), 8.23–8.32 (m, 1 H), 8.52–8.57 (m, 1 H), 8.95
(s, 1 H), 13.24 (s, 1 H) ppm. 13C NMR ([D6]DMSO, 62.9 MHz):
δ = 116.0, 120.8, 122.7, 124.2, 130.6, 131.6, 132.4, 136.9, 148.3,
yield (0.224 g). M.p. 250–251 °C. IR (KBr): ν = 1620 (C=N), 3417
˜
(NH) cm–1. 1H NMR ([D6]DMSO, 250 MHz): δ = 1.22 (d, J =
6.9 Hz, 6 H), 2.93 (m, 1 H), 7.17 (m, 2 H), 7.40 (d, J = 8.15 Hz, 2
H), 7.51–7.62 (m, 2 H), 8.10 (d, J = 8.2 Hz, 2 H), 12.83 (s, 1 149.0 ppm. MS: m/z (%) = 239 (3.3) [M]+, 209 (14.4), 167 (10.5),
H) ppm. 13C NMR ([D6]DMSO, 62.9 MHz): δ = 23.6, 33.3, 111.2,
118.6, 121.5, 122.3, 126.4, 127.7, 150.3, 151.3 ppm. MS: m/z (%) =
237 (40.1) [M + 1]+, 236 (67.3) [M]+, 221 (100.0), 194 (11.6), 110
(17.6), 92 (29.5), 65 (31.2). C16H16N2 (236.316): C 81.32, H 6.82,
N 11.85; found C 81.25, H 6.90, N 11.78.
149 (25.4), 129 (13.9), 111 (12.7), 84 (29.7), 55 (100.0). C13H9N3O2
(239.232): C 65.27, H 3.79, N 17.56; found C 65.22, H 3.83, N
17.49.
2-(4-Nitrophenyl)-1H-benzimidazole (3n): Yellow solid; 90% yield
(0.215 g). M.p.312–314 °C (ref.[81] m.p. 316 °C). IR (KBr): ν =
˜
1
4-(1H-Benzimidazol-2-yl)benzonitrile (3h): Colorless solid; 94%
1338, 1516 (NO2), 1620 (C=N), 3421 (NH) cm–1. H NMR ([D6]-
yield (0.206 g). M.p. 262 °C (ref.[82] m.p. 261–262 °C). IR (KBr): ν DMSO, 250 MHz): δ = 7.22–7.26 (m, 2 H), 7.62 (m, 2 H), 8.38 (m,
˜
= 1612 (C=N), 2230 (CN) cm–1. 1H NMR ([D6]DMSO, 250 MHz): 4 H), 13.27 (s, 1 H) ppm. 13C NMR ([D6]DMSO, 62.9 MHz): δ =
δ = 7.22–7.24 (m, 2 H), 7.50–7.70 (m, 2 H) 7.97 (d, J = 8.3 Hz, 2
111.7, 119.3, 122.3, 123.4, 124.1, 127.2, 135.9, 147.6, 148.9 ppm.
H), 8.31 (d, J = 8.3 Hz, 2 H), 13.17 (s, 1 H) ppm. 13C NMR ([D6]- MS: m/z (%) = 240 (4.3) [M + 1]+, 210 (7.9), 181 (3.5), 150 (6.6),
DMSO, 62.9 MHz): δ = 111.8, 118.5, 119.3, 122.2, 123.2, 126.4,
123 (10.2), 97 (32.6), 57 (100.0). C13H9N3O2 (239.232): C 65.27, H
126.9, 132.9, 134.2, 149.3 ppm. MS: m/z (%) = 220 (9.7) [M + 1]+, 3.79, N 17.56; found C 65.19, H 3.86, N 17.52.
219 (14.1) [M]+, 149 (18.6), 97 (19.6), 69 (100.0), 57 (82.1).
C14H9N3 (219.245): C 76.70, H 4.14, N 19.17; found C 76.63, H
4.21, N 19.11.
2-(2-Naphthyl)-1H-1,3-benzimidazole (3o): Colorless solid; 96%
yield (0.234 g). M.p. 217 °C. IR (KBr): ν = 1625 (C=N), 3445
˜
1
(NH) cm–1. H NMR (CDCl3, 250 MHz): δ = 7.19 (dd, J1 = 6.0,
2-(1H-Benzimidazol-2-yl)phenol (3i): Yellow solid; 94% yield
J2 = 3.0 Hz, 2 H), 7.37–7.40 (m, 2 H), 7.59–7.77 (m, 5 H), 8.11
(0.197 g). M.p. 240–242 °C (ref.[81] m.p. 242 °C). IR (KBr): ν =
(dd, J1 = 8.6, J2 = 1.7 Hz, 1 H), 8.49 (s, 1 H) ppm. 13C NMR
˜
1620 (C=N), 3247 (OH, NH) cm–1. 1H NMR ([D6]DMSO, (CDCl3, 62.9 MHz): δ = 115.2, 123.2, 123.6, 126.5, 126.8, 127.2,
Eur. J. Org. Chem. 2008, 4126–4138
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4135

H. Sharghi, M. H. Beyzavi, M. M. Doroodmand
FULL PAPER
127.8, 128.5, 129.0, 134.2, 138.1, 145.9, 151.6 ppm. MS: m/z (%) =
245 (43) [M + 1]+, 244 (100) [M]+, 153 (58). C17H12N2: C 83.58, H
4.95, N 11.47; found C 83.40, H 4.97, N 11.42.
DMSO, 62.9 MHz): δ = 122.7, 123.5, 124.0, 125.0, 126.7, 128.3,
129.2, 129.6, 130.3, 142.4, 153.7, 168.0 ppm. MS: m/z (%) = 239
(8.6) [M + 1]+, 238 (9.2) [M]+, 221 (7.1), 193 (1.9), 152 (5.6), 111
(16.2), 83 (41.4), 57 (100.0). C14H10N2O2 (238.244): C 70.58, H
4.23, N 11.76; found C 70.52, H 4.28, N 11.72.
2-(2-Thienyl)-1H-benzimidazole (3p): Yellow solid; 93% yield
(0.186 g). M.p. 329–331 °C (ref.[87] m.p. 330 °C). IR (KBr): ν =
˜
1620 (C=N), 3447 (NH) cm–1. 1H NMR ([D6]DMSO, 250 MHz):
δ = 7.16–7.22 (m, 3 H), 7.48–7.58 (m, 2 H), 7.73 (d, J = 3.1 Hz, 1
H), 7.82 (d, J = 2.7 Hz, 1 H), 12.96 (s, 1 H) ppm. 13C NMR ([D6]-
DMSO, 62.9 MHz): δ = 111.0, 118.4, 121.7, 122.6, 126.6, 128.2,
128.7, 133.6, 134.6, 147.0 ppm. MS: m/z (%) = 201 (2.4) [M + 1]+,
200 (5.4) [M]+, 167 (5.6), 149 (29.9), 123 (11.4), 94 (23.6), 73 (49.1),
57 (100.0). C11H8N2S (200.258): C 65.98, H 4.03, N 13.99; found
C 65.95, H 4.09, N 13.92.
Acknowledgments
We gratefully acknowledge the support of this work by the Shiraz
University Research Council.
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˜
(C=N), 3444 (NH) cm–1. 1H NMR ([D6]DMSO, 250 MHz): δ =
7.16–7.24 (m, 2 H), 7.47–7.71 (m, 3 H), 7.98 (dd, J1 = 7.7, J2
=
1.7 Hz, 1 H), 8.30–8.34 (m, 1 H), 8.71 (d, J = 6.9 Hz, 1 H), 13.01
(s, 1 H) ppm. 13C NMR ([D6]DMSO, 62.9 MHz): δ = 112.0, 119.2,
121.4, 121.9, 123.1, 124.6, 134.8, 137.5, 143.7, 148.4, 149.3,
150.7 ppm. MS: m/z (%) = 196 (42.8) [M + 1]+, 195 (100.0) [M]+,
167 (25.1), 105 (11.8), 78 (31.6), 51 (28.3). C12H9N3 (195.223): C
73.83, H 4.65, N 21.52; found C 73.77, H 4.72, N 21.48.
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˜
1627 (C=N), 3447 (NH) cm–1. 1H NMR ([D6]DMSO, 250 MHz):
δ = 6.69 (dd, J1 = 3.4, J2 = 1.7 Hz, 1 H), 7.16–7.20 (m, 4 H), 7.53
(d, J = 3.1 Hz, 1 H), 7.56 (d, J = 3.1 Hz, 1 H), 7.89 (s, 1 H) ppm.
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˜
126, 223.
250 MHz): δ = 2.21 (s, 3 H), 2.34 (s, 3 H), 6.99–7.08 (m, 3 H), 7.48
(s, 1 H), 7.54 (d, J = 8.1 Hz, 1 H), 8.15 (d, J = 8.1 Hz, 2 H), 12.65
(s, 1 H) ppm. 13C NMR (CDCl3, 62.9 MHz): δ = 21.4, 21.5, 113.9,
114.4, 124.1, 125.5, 127.3, 129.8, 134.1, 134.6, 135.9, 141.7,
150.8 ppm. MS: m/z (%) = 223 (40.1) [M + 1]+, 222 (62.3) [M]+,
221 (42.0), 170 (2.5), 149 (35.2), 110 (17.3), 105 (17.9), 83 (33.3),
55 (100.0). C15H14N2 (222.285): C 81.05, H 6.35, N 12.60; found
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[2-(4-Methylphenyl)-1H-benzimidazol-6-yl](phenyl)methanone (3t):
Colorless solid; 90% yield (0.280 g). M.p. 234 °C. IR (KBr): ν =
˜
1612 (C=N), 1643 (C=O), 3244 (NH) cm–1. 1H NMR ([D6]DMSO,
250 MHz): δ = 2.05 (s, 3 H), 7.37 (d, J = 7.4 Hz, 2 H), 7.55 (d, J
= 7.4 Hz, 2 H), 7.61–7.75 (m, 5 H), 7.94 (s, 1 H), 8.09 (d, J =
7.4 Hz,
2 H), 8.29 (s, 1
H) ppm. 13C NMR ([D6]DMSO,
62.9 MHz): δ = 20.9, 79.1, 114.6, 117.6, 124.3, 126.2, 126.8, 128.3,
129.4, 129.6, 131.1, 131.9, 138.0, 138.3, 140.6, 141.9, 153.8, 195.4.
MS: m/z (%) = 314 (16.1) [M + 2]+, 313 (87.6) [M + 1]+, 312 (66.6)
[M]+, 311 (34.0), 250 (2.8), 237 (32.1), 236 (100.0), 235 (91.4), 207
(23.3), 181 (13.9) 149 (19.5), 97 (37.0), 71 (43.3) ppm. C21H16N2O
(312.365): C 80.75, H 5.16, N 8.97; found C 80.71, H 5.19, N 8.92.
2-Phenyl-1H-benzimidazole-6-carboxylic Acid (3u): Colorless solid;
90% yield (0.214 g). M.p. 325 °C. IR (KBr): ν = 1628 (C=N), 1655
˜
1
(C=O), 2450–3250 (OH), 3549 (NH) cm–1. H NMR ([D6]DMSO,
250 MHz): δ = 7.47–7.66 (m, 4 H), 7.84 (d, J = 8.4 Hz, 1 H), 8.17–
8.20 (m, 3 H), 12.79 (s, 1 H), 13.19 (s, 1 H) ppm. 13C NMR ([D6]-
4136
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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