Zirconocene catalyzed synthesis of 2-substituted benzimidazole derivatives

Article abstract of DOI:10.1007/s11164-016-2534-7

Abstract: Zirconocene dichloride (Cp₂ZrCl₂) in the presence of ethanol is found to be a highly efficient catalyst for the one-pot synthesis of structurally diverse 2-substituted benzimidazole derivatives by reaction of o-phenylenedia

Full text of DOI:10.1007/s11164-016-2534-7

Res Chem Intermed
DOI 10.1007/s11164-016-2534-7
Zirconocene catalyzed synthesis of 2-substituted
benzimidazole derivatives
1
1
•
Shrikrishna Karhale
Chandrakant Bhenki
Vasant Helavi
•
Kiran Patil
Gajanan Rashinkar
1
2
•
•
1
Received: 1 February 2016 / Accepted: 29 March 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract Zirconocene dichloride (Cp ZrCl ) in the presence of ethanol is found to be
2
2
a highly efficient catalyst for the one-pot synthesis of structurally diverse 2-substituted
benzimidazole derivatives by reaction of o-phenylenediamine and aromatic aldehydes at
ambient temperature.
Graphical Abstract
CHO
NH2
N
Cp ZrCl2
2
+
NH2
Ethanol, RT
N
H
Keywords Zirconocene dichloride Á o-Phenylenediamine Á Aromatic aldehydes Á
-Substituted benzimidazole derivatives Á Ambient temperature
2
Introduction
Organozirconocenes represent an important class of metallocenes that have
garnered intensive research interest on account of their fascinating sandwich
structure and unusual properties. Zirconocene dichloride is an air and moisture
0
stable, non-hazardous, 16 electron, d organozirconocene that has been the
&
Vasant Helavi
vbhelavi@gmail.com
1
2
Department of Chemistry, Rajaram College, Kolhapur, Maharashtra 416004, India
Department of Chemistry, Shivaji University, Kolhapur, Maharashtra 416004, India
123

S. Karhale et al.
subject of an intense research competition in the industrial sector. It is one of
the most widely used metallocene-based catalysts for ethylene polymerization
[
1]. The catalytic activity of Cp ZrCl and other structurally related
2 2
metallocenes are attributed to their Lewis acidic character [2, 3]. Despite the
interesting catalytic potential of Cp ZrCl , its applications in organic synthesis
are scarcely reported [4–6]. The catalytic phenomena occurring with Cp ZrCl
2
2
2
2
include the formation of unsaturated di-and polycyclic aluminacarbocycles [7],
quinozolin-4(3H)-ones [8], 1-amidoalkyl-2-naphthols [9], 1,5-benzodiazepines
[
10], cyclobutenylphosphaonates [11], 5-hydroxy-1-alkenyboronates [12],
intramolecular cyclization [13], pinacol coupling of aromatic aldehydes and
ketones [14], and direct amide bond formation between carboxylic esters and
amines [15]. The impressive catalytic potential of Cp ZrCl prompted us to
2
2
exploit its usefulness in the synthesis of medicinally privileged heterocyclic
scaffolds.
Benzimidazole and their derivatives have attracted considerable interest as they
represent promising building blocks with potential applications in diverse fields.
They are a privileged core in natural products, which exhibit illustrious biological
[
16–18] and pharmacological properties [19–21] such as ulcerative, anti-cancer,
anti-diabetic, anti-bacterial, anti-microbial, anti-hypertensive, anti-viral, anti-in-
flammatory, anti-convulsant, and anti-parasitic as well as FXa inhibitory activity
[
22, 23]. In addition, they display significant activity against many viruses including
influenza [24], HIV [25], human cytomegalovirus (HCMV) [26], etc. Moreover,
they act as topoisomerase-I inhibitors [27], angiotensin-II inhibitors [28], and
selective neuropeptide YY1 receptor antagonists [29] as well as selective 5-HT3
antagonists in the isolated guinea pig ileum [30]. The multifarious biological
applications of substituted benzimidazoles have stimulated the development of
numerous methodologies for their synthesis. The most popular approach for
synthesis of 2-substituted benzimidazoles involves condensation of o-phenylenedi-
amine with aromatic aldehydes. A variety of catalysts such as TiO NPs [31], UHP/
2
I [32], CeCl Á7H O [33], saccharose [34], imidazolium trifluoroacetate protic ionic
2
3
2
liquid [35], carbon disulfide [36], CAN/methanol [37], solid acid scolecite [38],
CoCl Á6H O [39], heteropoly acid [40], zeolite [41], etc. have been reported to
2
2
catalyze this reaction. Nevertheless, most of these methodologies are associated
with drawbacks such as low yields, harsh reaction conditions, use of excess catalyst,
formation of undesirable products, high temperature conditions, prolonged reaction
time, and tedious workup procedure. Thus, there is a scope for improvement
towards developing a simple and an efficient protocol for the synthesis of
2-substituted benzimidazoles especially using metallocene-based catalyst at ambient
temperature.
In continuation of our research in the development of highly convenient
methodologies for the synthesis of bioactive heterocyclic moieties [10, 42], we
report herein the zirconocene dichloride catalyzed synthesis of 2-substituted
benzimidazole derivatives by condensation of o-phenylenediamine with various
aromatic aldehydes at ambient temperature (Scheme 1).
1
23

Zirconocene catalyzed synthesis of 2-substituted…
O
H
NH2
Cp ZrCl
N
2
2
+
NH2
Solvent, rt
N
H
2 2
Scheme 1 Cp ZrCl catalyzed synthesis of 2-phenyl-1H-benzimidazole
Experimental
All the chemicals were obtained from Sigma Aldrich and Spectrochem and used
without further purification. Melting points were determined in an open capillary
and are uncorrected. All the reactions were carried out under open atmosphere in
dried glassware. IR spectra were recorded on a Perkin-Elmer Spectrum one FTIR
1
13
spectrometer. H NMR and C NMR spectra were recorded on a Bruker Avanche
13
1
(
300 MHz for H NMR and 75 MHz for C NMR) spectrometer using CDCl or
3
DMSO-d6 as solvent and Tetramethylsilane (TMS) as an internal standard.
Chemical shifts (d) are expressed in parts per million (ppm) values with TMS as
the internal reference, and coupling constants are expressed in hertz (Hz). Mass
spectra were recorded on a Shimadzu QP2010 GCMS.
General procedure for the synthesis of 2-substituted benzimidazole
derivatives
A mixture of o-phenylenediamine (1 mmol), aryl aldehyde (1 mmol), and
zirconocene dichloride (5 mol%) in ethanol (5 mL) was stirred at room temperature
till the completion of the reaction as monitored by thin layer chromatography
(
TLC). After the completion of the reaction, cold water was added to quench the
reaction mixture. The resultant solution was extracted with ethyl acetate and
combined organic layers were dried over anhydrous Na SO . After the evaporation
2
4
of solvent, crude solid obtained was purified by silica gel column chromatography
Merck, 60–120 mesh, ethyl acetate: petroleum ether as an eluent) to afford the pure
product, which was characterized by spectroscopic techniques.
(
Spectral data of representative compounds
2
-Phenyl-1H-benzimidazole (Table 3, entry 1)
1
Mp: 290–292 °C, H NMR (300 MHz, CDCl ): d (ppm) 7.88–7.91 (m, 1H,
3
0
benzimidazole-H ), 7.69–7.73 (m, 2H, Ph-H , H ), 7.47–7.49 (t, 2H, J = 3.65 Hz,
0
4
2
2
benzimidazole-H , H ), 7.42–7.63 (m, 3H, Ph-H , H , H ), 7.12–7.15 (t, 1H,
5
6
3
1
3
4
3
J = 3.9 Hz, benzimidazole-H ), 5.49 (s, 1H, NH); C NMR (75 MHz, CDCl ): d
7
3
1
10.5 (benzimidazole-C ), 120.0 (benzimidazole-C ), 123.0 (benzimidazole-C ),
5 6 4
0
1
C ), 129.9 (Ph-C ), 130.1 (Ph-C ), 136.4 (benzimidazole-C ), 143.1 (benzimidazole-
1
C ), 154.1 (benzimidazole-C ); IR (KBr) (cm ): 3374, 3053, 2922, 1518, 1393,
25.9 (benzimidazole-C ), 127.7 (Ph-C ), 128.7 (Ph-C ), 129.0 (Ph-C ), 129.2 (Ph-
0
7
4
2
2
3
3
1
3a
-
7
a
2
?
343, 1276, 970, 820, 741, 670; MS(EI): m/z 194 [M] .
1
123

S. Karhale et al.
2
-(4-Nitrophenyl)-1H-benzimidazole (Table 3, entry 2)
1
Mp: [300 °C, H NMR (300 MHz, CDCl ): d (ppm) 8.33–8.36 (d, 2H, J = 9 Hz,
3
0
0
Ph-H , H ), 8.05–8.11 (m, 2H, Ph-H , H ), 7.13–7.17 (m, 2H, benzimidazole-H ,
1
H ), 6.79–6.84 (m, 2H, benzimidazole-H , H ), 4.35 (bs, 1H, NH); C NMR
3
3
2
2
4
3
7
5
6
(
75 MHz, CDCl ): d 115.8 (benzimidazole-C ), 116.8 (benzimidazole-C ), 118.4
3
7
4
0
benzimidazole-C ), 120.6 (benzimidazole-C ), 124.1 (Ph-C ), 127.6 (Ph-C ),
5 6 3 3
(
0
29.1 (Ph-C ), 135.6 (Ph-C ), 141.9 (benzimidazole-C ), 143.7 (benzimidazole-
2 2 3a
1
-
1
C ), 149.0 (Ph-C ), 153.7 (benzimidazole-C ), 158.9 (Ph-C ); IR (KBr) (cm ):
4
7
a
1
2
3
461, 3073, 2918, 1594, 1339, 1262, 958, 892, 844, 709, 686; MS(EI): m/z 239
?
M] .
[
2
-(4-Chlorophenyl)-1H-benzimidazole (Table 3, entry 3)
1
Mp: 300–302 °C, H NMR (300 MHz, CDCl ): d (ppm) 8.35 (t, 2H, J = 6.9 Hz,
3
0
Ph-H , H ), 7.83–7.92 (m, 4H, benzimidazole-H , H , H , H ), 7.65–7.75 (m, 2H,
13
Ph-H , H ), 5.86 (s, 1H, NH); C NMR (75 MHz, CDCl ): d 112.8 (benzimida-
zole-C , C ), 114.3 (benzimidazole-C , C ), 118.4 (Ph-C ), 124.6 (Ph-C , C ),
0
29.5 (Ph-C , C ), 144.7 (benzimidazole-C , C ), 150.6 (Ph-C ), 156.9 (benzim-
2 2 3a 7a 4
3
3
4
5
6
7
0
2
2
3
0
4
7
5
6
1
3
3
1
-
1
idazole-C ); IR (KBr) (cm ): 3443, 3017, 1625, 1572, 976, 848, 749; MS(EI): m/z
2
?
28 [M] .
2
2
-(4-Bromophenyl)-1H-benzimidazole (Table 3, entry 4)
1
Mp: 281–283 °C, H NMR (300 MHz, CDCl ): d (ppm) 8.15 (dd, 2H, J = 6.8,
3
0
1
.6 Hz, Ph-H , H ), 7.73–7.96 (m, 4H, benzimidazole-H , H , H , H ), 7.63–7.77
13
3
3
4
5
6
7
0
(
(
m, 2H, Ph-H , H ), 5.98 (s, 1H, NH); C NMR (75 MHz, CDCl ): d 114.2
2
2
3
benzimidazole-C , C ), 115.3 (benzimidazole-C , C ), 119.4 (Ph-C ), 125.6 (Ph-
0
4
7
5
6
4
0
C , C ), 130.5 (Ph-C , C ), 145.7 (Ph-C ), 153.6 (benzimidazole-C ), 157.9
3a
2
2
3
3
1
-
1
(
benzimidazole-C ), 158.2 (benzimidazole-C ); IR (KBr) (cm ): 3431, 3057,
7a 2
?
675, 1577, 1499, 978, 898, 840, 748, 699; MS(EI): m/z 273 [M] .
1
2
-(4-Hydroxyphenyl)-1H-benzimidazole (Table 3, entry 5)
1
Mp: 252–255 °C, H NMR (300 MHz, CDCl ): d (ppm) 10.63 (bs, 1H, OH),
3
0
7.80–7.82 (dd, 2H, J = 9 Hz, Ph-H , H ), 7.52–7.76 (m, 4H, benzimidazole-H ,
13
H , H , H ), 7.43–7.46 (m, 2H, Ph-H , H ), 5.94 (bs, 1H, NH); C NMR (75 MHz,
2
2
4
0
5
6
7
3
3
0
CDCl ): d 114.3 (benzimidazole-C , C ), 115.9 (Ph-C , C ), 121.6 (benzimidazole-
3
4
7
3
3
0
C , C ), 126.4 (Ph-C , C ), 128.6 (Ph-C ), 142.8 (benzimidazole-C ), 145.1
-
5
6
2
2
1
3a
1
(
benzimidazole-C ), 152.4 (benzimidazole-C ), 158.9 (Ph-C ); IR (KBr) (cm ):
7a 2 4
?
567, 3396, 3034, 1618, 912, 834, 789, 642; MS(EI): m/z 210 [M] .
3
2
-(4-Methoxyphenyl)-1H-benzimidazole (Table 3, entry 6)
1
Mp: 223–225 °C, H NMR (300 MHz, CDCl ): d (ppm) d 7.62 (t, 2H, J = 5.4 Hz,
3
0
benzimidazole-H , H ), 7.48 (d, 2H, J = 3.0 Hz, Ph-H , H ), 7.19 (d, 2H,
4
7
2
2
1
23

Zirconocene catalyzed synthesis of 2-substituted…
0
J = 2.4 Hz, Ph-H , H ), 7.11–7.18 (m, 2H, benzimidazole-H , H ), 5.73 (s, 1H,
3
3
5
6
1
3
NH), 3.82 (s, 3H, OCH3); C NMR (75 MHz, CDCl ): d 53.3 (OCH ), 111.3 (Ph-
C , C ), 114.5 (benzimidazole-C ), 118.8 (benzimidazole-C ), 122.8 (Ph-C ), 124.7
0
benzimidazole-C ), 125.1 (benzimidazole-C ), 128.4 (Ph-C ), 128.9 (Ph-C ),
5 6 2 2
3
3
0
3
3
4
7
1
(
1
48.9 (benzimidazole- C , C ), 151.4 (benzimidazole-C ), 160.1 (Ph-C ); IR
3a 7a 2 4
-
KBr) (cm ): 3596, 3381, 2965, 1641, 1528, 817, 754, 601; MS(EI): m/z 224 [M] .
1
?
(
2
-(3-Methoxyphenyl)-1H-benzimidazole (Table 3, entry 7)
1
Mp: 212–214 °C, H NMR (300 MHz, CDCl ): d (ppm) 7.89 (t, 2H, J = 5.5 Hz,
3
benzimidazole-H , H ), 7.48 (d, 2H, J = 3.4 Hz, benzimidazole-H , H ), 7.11–7.18
0 0
m, 4H, Ph-H , H , H , H ), 5.83 (s, 1H, NH) 3.74 (s, 3H, OCH ); C NMR
2 2 3 4 3
4
7
5
6
13
(
(
75 MHz, CDCl ): d 51.3 (OCH ), 110.3 (benzimidazole-C , C ), 111.5 (Ph-C ),
3
3
4
7
2
0 0
13.5 (Ph-C ), 119.8 (Ph-C ), 123.8 (benzimidazole-C , C ), 126.1 (Ph-C ), 129.4
4 2 5 6 3
1
(
zole-C ), 159.1 (Ph-C ); IR (KBr) (cm ): 3546, 3343, 2962, 1638, 1531, 845, 741;
Ph-C ), 142.9 (benzimidazole-C ), 148.9 (benzimidazole-C ), 152.4 (benzimida-
1 3a 7a
-
1
2
3
?
MS(EI): m/z 224 [M] .
2
-(4-Methylphenyl)-1H- benzimidazole (Table 3, entry 8)
1
Mp: 268–270 °C, H NMR (300 MHz, CDCl ): d (ppm) 8.16–8.18 (d, 2H,
3
J = 6.9 Hz, benzimidazole-H , H ), 7.54–7.44 (m, 2H, benzimidazole-H , H ),
4
7
5
6
13
C
0
0
7
.34–7.40 (m, 4H, Ph-H , H , H , H ), 5.80 (bs, 1H, NH), 2.32 (s, 3H, CH );
3
2
2
3
3
NMR (75 MHz, CDCl ): d 23.2 (CH ), 111.8 (benzimidazole-C , C ), 115.7
3
3
4
7
0
benzimidazole-C , C ), 122.6 (Ph-C ), 124.3 (Ph-C ), 127.4 (Ph-C ), 129.4 (Ph-
5 6 2 2 1
(
0
C , C ), 138.7 (Ph-C ), 143.2 (benzimidazole-C ), 152.4 (benzimidazole-C ),
3
3
4
3a
7a
-
1
156.3 (benzimidazole-C ); IR (KBr) (cm ): 3446, 3022, 1632, 858, 761, 681;
2
MS(EI): m/z 208 [M] .
?
2
-(2-Hydroxyphenyl)-1H-benzimidazole (Table 3, entry 9)
1
Mp: 238–240 °C, H NMR (300 MHz, CDCl ): d (ppm) 12.61 (bs, 1H, OH),
3
0
7.73–7.82 (d, 2H, J = 9 Hz, benzimidazole-H , H ), 7.52–7.69 (m, 4H, Ph-H , H ,
13
H , H ), 7.38–7.49 (m, 2H, benzimidazole-H , H ), 5.84 (bs, 1H, NH); C NMR
4
7
3
3
0
4
2
5
6
(
75 MHz, CDCl ): d 111.3 (benzimidazole-C , C ), 113.9 (benzimidazole-C , C ),
3
4
7
5
6
0 0
14.6 (Ph-C ), 118.2 (Ph-C ), 122.5 (Ph-C ), 126.7 (Ph-C ), 127.6 (Ph-C ), 143.7
3 1 3 2 4
1
(
(
[
benzimidazole-C ), 145.8 (benzimidazole-C ), 153.4 (benzimidazole-C ), 155.4
3a 7a 2
-
Ph-C ); IR (KBr) (cm ): 3533, 3436, 3054, 1658, 854, 769, 632; MS(EI): m/z 210
1
2
?
M] .
2
-(3, 4, 5-Trimethoxyphenyl)-1H-benzimidazole (Table 3, entry 10)
1
Mp: 212–214 °C, H NMR (300 MHz, DMSO-d ): d (ppm) 12.85 (bs, 1H, NH),
6
7.63–7.66 (m, 2H, benzimidazole-H , H ), 7.51–7.54 (dd, 2H, J = 6, 1.8 Hz,
4 7
benzimidazole-H , H ), 7.43 (s, 2H, Ph-H , H ), 3.92 (s, 9H, OCH ); C NMR
0
13
5
6
2
2
3
(
75 MHz, DMSO-d ): d 56.1 (OCH ), 61.2 (OCH ), 105.8 (benzimidazole-C ),
6
3
3
4
123

S. Karhale et al.
1
1
1
1
11.4 (benzimidazole-C ), 119.7 (benzimidazole-C ), 122.7 (benzimidazole-C ),
7
5
6
0
24.4 (Ph-C ), 125.8 (Ph-C , C ), 138.9 (benzimidazole-C , C ), 147.9 (Ph-C ),
4
1
2
2
3a
-1
51.3 (benzimidazole-C ), 156.2 (Ph-C , C ); IR (KBr) (cm ): 3447, 3078, 1620,
7a
0
2
3
3
?
540, 823, 768, 691; MS(EI): m/z 284 [M] .
2
-(Furan-2-yl)-1H-benzimidazole (Table 3, entry 11)
1
Mp: 283–284 °C, H NMR (300 MHz, CDCl ): d (ppm) 7.87–7.90 (dd, 2H,
3
J = 6.0, 1.8 Hz, benzimidazole-H , H ), 7.71–7.84 (d, J = 9 Hz, 2H, benzimida-
1
zole-H , H ), 7.52–7.66 (m, 3H, furan-H , H , H ), 5.91 (bs, 1H, NH); C NMR
4
7
3
5
6
3
4
5
(
C ), 124.5 (benzimidazole-C , C ), 138.3 (benzimidazole-C , C ), 147.7 (benz-
75 MHz, CDCl ): d 111.8 (furan-C ), 114.3 (furan-C ), 119.7 (benzimidazole-C ,
3
4
5
4
7
5
6
3a
7a
-
imidazole-C ), 149.2 (furan-C ), 156.1 (furan-C ); IR (KBr) (cm ): 3411, 3023,
1
2
3
1
?
634, 1312, 812, 721, 617; MS(EI): m/z 184 [M] .
1
2
-(Thiophen-2-yl)-1H-benzimidazole (Table 3, entry 12)
1
Mp: [300 °C, H NMR (300 MHz, CDCl ): d (ppm) 7.81–7.84 (dd, 2H, J = 6,
3
3 Hz, benzimidazole-H , H ), 7.76–7.78 (d, 2H, J = 7.8 Hz, benzimidazole-H ,
4 7 5
H ), 7.56–7.68 (m, 3H, thiophene-H , H , H ), 5.98 (bs, 1H, NH); C NMR
1
3
6
3
4
5
(
(
75 MHz, CDCl ): d 110.1 (benzimidazole-C ), 116.5 (benzimidazole-C ), 123.9
3
4
7
benzimidazole-C ), 124.6 (benzimidazole-C ), 127.8 (thiophene-C ), 128.3 (thio-
5
6
3
phene-C ), 129.8 (thiophene-C ), 136.9 (benzimidazole-C , C ), 145.0 (benzim-
4
5
3a
7a
-
1
idazole-C ), 148.6 (thiophene-C ); IR (KBr) (cm ): 3418, 3033, 1614, 815, 727,
2
1
?
86; MS(EI): m/z 200 [M] .
6
2
-(Ferrocenyl)-1H-benzimidazole (Table 3, entry 13)
1
Mp: 208–210 °C, H NMR (300 MHz, DMSO-d ): d (ppm) 12.29 (s, 1H, NH), 7.47
6
(
s, 2H, benzimidazole-H , H ), 7.09–7.12 (m, 2H, benzimidazole-H , H ), 5.03 (s,
4 7 5 6
1
3
2
H, C H ), 4.42 (s, 2H, C H ), 4.07 (s, 5H, C H ); C NMR (75 MHz, DMSO-d6):
5 4 5 4 5 5
d 60.09 (C H ), 67.6 (C H ), 69.7 (C H ), 70.0 (C H ), 74.5 (C H ), 78.7 (C H ,
5
4
5
4
5
5
5
5
5
5
5 4
Cipso), 114.3 (benzimidazole-C , C ), 121.6 (benzimidazole-C , C ), 139.2 (benz-
4
7
5
6
-
imidazole-C , C ), 153.4 (benzimidazole-C ); IR (KBr) (cm ): 3413, 3047, 1635,
1
3
a
7a
2
?
579, 926, 818, 729; MS(EI): m/z 302 [M] .
1
Result and discussion
Our initial efforts were focused on optimization of reaction conditions. The reaction
between o-phenylenediamine and benzaldehyde was considered as a model reaction
for investigating the effectiveness of different polar and non polar solvents using a
catalytic amount of the Cp ZrCl (5 mol%). Solvent optimization clearly suggested
2
2
that ethanol is the best solvent for the desired transformation due to a fast reaction
rate and a high yield (Table 1, entry 9). The other polar protic solvents such as water
and methanol gave the desired product in lower yields (Table 1, entries 7–8) while
1
23

Zirconocene catalyzed synthesis of 2-substituted…
Table 1 Optimization of the reaction conditions using different solvents
O
H
NH2
Cp ZrCl2
N
2
+
NH2
Solvent, rt
N
H
a
Entry
Solvent
Reaction time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
1, 4-Dioxane
Toluene
2.0
2.5
3.5
3.5
4.5
4.0
5.0
2.0
1.5
35
38
45
50
70
75
55
56
94
Chloroform
Ethylene dichloride
THF
Acetonitrile
Water
Methanol
Ethanol
2 2
Reaction conditions: o-phenylenediamine (1 mmol), benzaldehyde (1 mmol), and Cp ZrCl (5 mol%) in
solvent (5 mL) were stirred at room temperature
a
Isolated yields after column chromatography
polar aprotic solvents like EDC, THF, and acetonitrile displayed slow reaction rates
leading to moderate yields of the product (Table 1, entries 4–6). On the other hand,
nonpolar solvents such as 1–4 dioxane, toluene, and chloroform afforded the desired
condensation products in lower yields (Table 1, entries 1–3). The higher reaction
rate in ethanol can be attributed to the coordination between ethanol and Cp ZrCl2
2
that causes enhancement in Lewis acidity of the zirconium centre thereby improving
its catalytic efficiency [43].
We have carried out the model reaction using different stoichiometric amounts of
catalyst. The catalyst screening results are summarized in Table 2. It was observed
that the excellent yield was achieved by using 5 mol% of Cp ZrCl (Table 2, entry
2
2
3). Further increase in catalyst quantity beyond 5 mol% did not increase the yield of
the product significantly (Table 2, entry 4–5).
After investigating the influence of different reaction parameters on the model
reaction, we turned our attention towards the synthesis of benzimidazole derivatives
using o-phenylenediamine and a variety of substituted aromatic aldehydes, and the
results are summarized in Table 3. In all the cases, 2-substituted benzimidazoles
were the sole products and no anomalies, such as 1, 2-disubstitued benzimidazole,
were noted. With the both electron-poor and electron-rich benzaldehydes (Table 3,
entries 2–4 and 5–8), the corresponding 2-substituted benzimidazole derivatives
were obtained in good to excellent yields. The sterically hindered aldehydes such as
salicylaldehyde as well as 3, 4, 5-trimethoxy benzaldehyde (Table 3, entries 9 and
10) were also tolerated with equal chemical efficiency although yields were
comparatively moderate. Remarkably, heterocyclic aldehydes such as furfural and
123

S. Karhale et al.
2 2
Table 2 Optimization study for the amount of Cp ZrCl
O
H
NH2
Cp ZrCl
N
2
2
+
NH2
Solvent, rt
N
H
a
Entry
Amount of catalyst (mol%)
Reaction time (h)
Yield (%)
1
2
3
4
5
01
02
05
10
20
1.5
1.5
1.5
1.5
1.5
40
72
94
94
94
2 2
Reaction conditions: o-phenylenediamine (1 mmol), benzaldehyde (1 mmol), and Cp ZrCl in ethanol
(5 mL) were stirred at room temperature
a
Isolated yields of purified products
thiophene-2-aldehyde (Table 3, entries 11 and 12) reacted smoothly with o-
phenylenediamine furnishing the anticipated products in excellent yields. Further-
more, organometallic aldehyde such as ferrocenecarboxyldehyde also reacted
efficiently with o-phenylenediamine affording the desired product in excellent
yields (Table 3, entry 13).
The plausible mechanism of Cp ZrCl catalyzed synthesis of 2-substituted
2
2
benzimidazoles from o-phenylenediamine and benzaldehyde with the probable
sequence of events is shown in Scheme 2. In the beginning, Cp ZrCl coordinates
2
2
with the carbonyl group of benzaldehyde causing its electrophilic activation, which
facilitates nucleophilic attack of the amino group from o-phenylenediamine leading
to formation of the intermediate (II) which loses a water molecule and undergoes
subsequent air oxidation to form the desired product.
In order to show the advantages of Cp ZrCl in comparison with other catalysts
2
2
used for similar reaction, we have summarized several results for the preparation of
-phenyl-1H-benzimidazole from o-phenylenediamine and benzaldehyde in
Table 4. It is clear that Cp ZrCl is highly effective catalyst for the synthesis of
2
2
2
2
-substituted benzimidazole derivatives at ambient temperature.
Conclusion
We have described a one-pot, simple, and efficient method for the synthesis of
benzimidazole derivatives using o-phenylenediamine and a variety of aryl
aldehydes at ambient temperature by using a catalytic amount of Cp ZrCl . The
2
2
present protocol offers several advantages such as high yield, operational simplicity,
shorter reaction times, mild reaction conditions, and a simple experimental and
workup procedure.
1
23

Zirconocene catalyzed synthesis of 2-substituted…
Table 3 Cp ZrCl catalyzed reaction of o-phenylenediamine and aryl aldehydes
2
2
O
H
NH2
Cp ZrCl
N
2
2
+
NH2
Ethanol, rt
N
H
R
R
Entries Aryl aldehyde
Product
Time
(
Yield
a
%
Mp (°C) [References]
min)
1
CHO
N
90
94
290–292 (290–293)
[
44]
N
H
2
3
4
CHO
CHO
N
80
75
80
92
94
85
[300 (322–323) [44]
300–302 (301) [45]
281–283 (283–284)
NO2
Cl
N
H
O2N
Cl
N
N
H
CHO
N
Br
[
46]
N
H
Br
CHO
N
5
6
7
110
90
88
90
87
252–255 (254–256)
47]
OH
[
N
H
HO
CHO
CHO
N
223–225 (223–226)
49]
OCH3
[
N
H
H3CO
OCH3
95
212–214 (214–215)
[50]
N
H3CO
N
H
CHO
N
8
9
95
87
82
268–270 (270) [50]
238–240 (242) [48]
CH3
H
3
C
N
H
CHO
HO
100
N
OH
N
H
H3CO
H3CO
H3CO
OCH3
OCH3
OCH3
10
110
75
260
N
CHO
N
H
1
1
2
N
85
90
82
86
283–284 (284–286)
[51]
CHO
CHO
O
S
N
H
O
1
N
[300 (330) [49]
N
H
S
123

S. Karhale et al.
Table 3 continued
Entries Aryl aldehyde
a
Product
Time (min)
90
Yield %
85
Mp (°C) [References]
N
13
208–210
CHO
N
H
Fe
Fe
2 2
Reaction conditions: o-phenylenediamine (1 mmol), aryl aldehyde (1 mmol), and Cp ZrCl (5 mol%) in
ethanol (5 mL) were stirred at room temperature
a
Isolated yields of purified products
Cl
Zr
Cl
Cl
Zr
Cl
O
O
H N
2
H
H
+
H N
2
(I)
Cl
H
N
H
O
Zr
Cl
N
NH2
[O]
- H O
2
N
H
N
H
N
H
(
III)
(II)
Scheme 2 Plausible mechanistic pathway for the formation of 2-phenyl-1H-benzimidazole
Table 4 Comparison of a variety of catalysts for the reaction of o-phenylenediamine and aryl aldehyde
Sr. no.
Catalyst used
Amount of catalyst
Temp (°C)
Time
Yield (%)
References
1
2
3
4
5
6
7
8
UHP/I
CeCl
Á7H
Saccharose
CoCl
Á6H
Zeolite
NH OAc
MgCl
Á6H
Cp ZrCl
2
20 mol%
0.3 eqvt.
20 mol%
10 mol%
800 mg
70
30 min
2.5 h
1 h
87
87
80
81
54
95
93
94
[32]
3
2
O
RT
45
[33]
[34]
2
2
O
RT
130
75
4 h
[39]
10 h
[41]
4
100 mol%
10 mol%
5 mol%
4.5 h
100 min
1.5 h
[48]
2
2
O
60
[52]
2
2
RT
This work
Acknowledgments SSK is thankful to the University Grants Commission, New Delhi, for Teacher
Fellowship [F. No. 30-35/14 (WRO) dated: 11th June 2014] under the Faculty Development
Programme.
1
23

Zirconocene catalyzed synthesis of 2-substituted…
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