BF3·Et2O promoted selective synthesis of benzimidazoles

Article abstract of DOI:10.1002/jhet.5570440529

(Chemical Equation Presented) Benzimidazoles 3, 6 and 9 have been synthesized selectively in excellent yields by cyclocondensation of β-(3-methyl-5-styryl-4-isoxazolyl amido) benzoic acids, acrylic acids and propionic acids with 1,2-phenylene diamines by employing BF₃· Et₂O as the catalyst. When the same reaction was carried out in pyridine it resulted in mixture of products in each case (3 & 4, 6 & 7 and 9 & 10). Other methods tried by using polyphosphoric acid, HCl, TFA also led to mixtures of 3 & 4, 6 & 7 and 9 & 10 in each case, similar to that of pyridine reaction.

Full text of DOI:10.1002/jhet.5570440529

Sep-Oct 2007
1153
BF3ꢀEt2O Promoted Selective Synthesis of Benzimidazoles
E. Rajanarendar*, P. Ramesh, E .Kalyan Rao, G. Mohan and A. Siva Rami Reddy
Department of Chemistry, Kakatiya University, Warangal – 506 009 (AP), India.
Email : eligeti_rajan@yahoo.co.in
Received June 1, 2006
O
NH
C
H3C
O
C
N
St
O
N
NH
R
H3C
NH
N
HO2 C
St
O
R
NH2
NH2
1
R
3
O
C
. DCM
R
O
NH
H3C
H3C
NH
C
2
N
St
O
N
NH
R
N
HO2 C
St
O
BF3.Et2O rt, 7-10 hr
5
R
O
C
6
O
H3C
NH
NH
C
H3C
N
HO2 C
St
O
N
St
O
N
NH
R
8
HC CH Ar
St =
R = H, Cl
Ar = C6H5, 4-CH3-C 6H4, 4-CH3OC6H4
R
9
Benzimidazoles 3, 6 and 9 have been synthesized selectively in excellent yields by cyclocondensation of
ꢁ-(3-methyl-5-styryl-4-isoxazolyl amido) benzoic acids, acrylic acids and propionic acids with 1,2-
phenylene diamines by employing BF3ꢀEt2O as the catalyst. When the same reaction was carried out in
pyridine it resulted in mixture of products in each case (3 & 4, 6 & 7 and 9 & 10). Other methods tried by
using polyphosphoric acid, HCl, TFA also led to mixtures of 3 & 4, 6 & 7 and 9 & 10 in each case, similar
to that of pyridine reaction.
J. Heterocyclic Chem., 44, 1153 (2007).
INTRODUCTION
Isoxazoles have been found to posses marked biological
effects as CAN stimulants [13], anti-inflammatory and
analgesic [14], antimicrobial [15], antitumor [16], in
chemotherapy [17] and found to possess vasodilating
effect [18] similar to that of nifedipine.
Benzimidazole is an important nucleus that has been
extensively used in medicinal chemistry, notable
examples being the antihistaminic astemizole and the
antiulcerative omeprazole [1]. Benzimidazoles are also
known for their anti-inflammatory [2], antibiotic [3],
antihelmintic [4], anticancer [5] and antiviral activities
[6]. In recent years benzimidazoles have been reported to
act as topoisomerase I inhibitors [7], selective neuro-
peptide “Y Y 1” receptor antagonists [8], angiotensin II
(A II) inhibitors [9], potential antitumor agents [10],
smooth muscle cell proliferation inhibitors [11], and in
diverse areas of chemistry [12].
Literature survey revealed that when one biodynamic
heterocyclic system was coupled with another, a molecule
with enhanced biological activity was produced [19-20].
The chemistry of these linked biheterocycles has been a
fascinating field of investigation in medicinal chemistry
as they have been found to exhibit enhanced biological
profile [21]. In view of this, we undertook the synthesis
of isoxazolyl substituted benzimidazoles.

1154
E. Rajanarendar, P. Ramesh, E .Kalyan Rao, G. Mohan and A. S. R. Reddy
Vol 44
A number of synthetic methods have been developed in
anhydride, maleic anhydride and succinic anhydride
separately in a mortar for 2 h. The reaction was
monitored with TLC. It was extracted with NaHCO3
solution. The clear filtrate on neutralization gave the
corresponding products phthalic mono amide 1, maleic
monoamide 5 and succinic monoamide 8, which were
characterized by spectral data [25].
recent years to uncover a variety of new reagents for the
synthesis of substituted benzimidazoles [22]. However,
these methods suffer drawback with regard to yields and
involvement of multi steps and some other factors.
Therefore the introduction of new efficient methods is
still in demand.
As a sequel to our work on development of new
methodologies for the synthesis of substituted isoxazoles
[23], we now report a selective synthesis of isoxazolyl
substituted benzimidazoles in presence of BF3ꢀEt2O.
In a typical case, a mixture of 1 equiv. of phthalic
monoamide 1 or maleic monoamide 5 or succinic
monoamide 8 and 1 equiv. of 1,2-phenylene diamine 2
in dichloromethane were stirred for 15 min. at room
temp., then BF3ꢀEt2O in dichloromethane was added to it
dropwise and reaction mixture was stirred at room
temperature for 10 hr. After the usual process, 2-
isoxazolyl substituted benzimidazole 3, 6 and 9,
respectively, was obtained as sole product in each case,
in excellent yield (80-95%) (Scheme 1).
RESULTS AND DISCUSSION
The required starting materials viz., phthalic mono-
amide 1, maleic monoamide 5 and succinic monoamide
8 have been prepared by grinding the 4-amino-3-
methyl-5-substituted styrylisoxazole [24] with phthalic
Scheme 1
NH2
R
O
C
O
C
,
DCM
H3C
NH
St
NH2
H3C
R
NH
2
N
N
BF3.Et2O, rt, 7-10 hr
HO2C
O
St
O
N
NH
R
St =
HC CH Ar
1
NH2
NH2
R
R
R
, pyridine
3
120oC, 3 hr
O
H3C
N
N
O
+
3
St
O
4
NH2
NH2
R
O
C
O
,
DCM
H3C
NH
H3C
R
NH
C
2
N
N
BF3.Et2O rt, 7-10 hr
St
HO2C
O
St
O
N
NH
St =
HC CH Ar
(trans)
5
NH2
NH2
R
R
R
R
, pyridine
6
120oC 3 hr
O
H3C
N
+
6
N
O
St
O
7

Sep-Oct 2007
BF3ꢀEt2O Promoted Selective Synthesis of Benzimidazoles
1155
Scheme 1 (continued)
NH2
R
O
C
O
C
. DCM
NH2
H3C
NH
St
H3C
R
NH
2
N
N
BF3.Et2O, rt, 7-10 hr
O
St HO2C
O
N
NH
R
St =
HC CH Ar
(trans)
8
NH2
NH2
R
R
R
9
, pyridine
120oC, 3 hr
3a / 6a / 9a : R = H, Ar = C6H5
O
3b / 6b / 9b : R = H, Ar = 4-CH3C6H4
3c / 6c / 9c : R = H, Ar = 4-CH3OC6H4
3d / 6d / 9d : R = Cl, Ar = C6H5
H3C
N
3e / 6e / 9e : R = Cl, Ar = 4-CH3C6H4
3f / 6f / 9f : R = Cl, Ar = 4-CH3OC6H4
+
9
N
O
St
O
10
The reaction was extended to phthalic monoamides 1
(Ar = 4-CH3C6H4, 4-CH3OC6H4), maleic monoamides 5
(Ar = 4-CH3C6H4, 4-CH3OC6H4), succinic monoamides 8
(Ar = 4-CH3C6H4, 4-CH3OC6H4) which are reacted with
1,2-phenylenediamines 2 (R = H, Cl) to afford the
corresponding 2-isoxazolyl substituted benzimidazoles 3,
6 and 9 respectively, in excellent yields (Table 1).
When the same reaction was carried out in pyridine at
120 °C, cyclodehydration to imide [25] (4, 7, 10) as well
as cyclocondensation with 1,2-phenylene diamines took
place resulting in the formation of mixture of products 3
& 4, 6 & 7 and 9 & 10 (40:60 ratio) (Scheme-1). In this
context, we envisaged that, exclusive formation of desired
2-isoxazole substituted benzimidazoles could be achieved
Scheme 2
+
:
O
-
O
BF3
R'
C
OH
BF3.Et2O
R'
C
OH
1)
2)
+
+
-
O
C
BF3
..
H2N
+
:
R'
OH
-
R
R
O
BF3
OH
H
H
..
H2N
N
R'
C
H2N
R
R
-
-
O
C
BF3
O
C
BF3
R'
R'
H
H
N
NH
..
H2N
N
H
H3C
NHCO
St
R
R
R' =
R
R
N
O
-H2O
-BF3
H3C
H3C
NHCO
St
=
N
R
N
O
R'
NHCO
St
N
R
=
H
N
O

1156
E. Rajanarendar, P. Ramesh, E .Kalyan Rao, G. Mohan and A. S. R. Reddy
Vol 44
Table 1
Synthesis of Benzimidazoles Catalysed by Pyridine and BF3ꢀEt2O
Compd No.
Ar
R
m.p.
(°C)[a]
Pyridine[c]
Reaction time Yield (%)[b] Reaction time
BF3.Et2O
Yield (%)[b]
(hr)
(hr)
3a
3b
3c
3d
3e
3f
6a
6b
6c
6d
6e
6f
9a
9b
9c
9d
9e
9f
C6H5
H
H
H
Cl
Cl
Cl
H
H
H
Cl
Cl
Cl
H
181-183
172-174
169-170
191-193
197-199
203-204
178-179
165-166
175-176
188-190
194-196
208-210
155-158
142-144
149-151
185-187
200-202
213-215
14
12
12
15
16
13
13
12
11
14
13
11
12
13
12
14
12
14
35
42
40
30
36
41
37
41
40
32
42
43
36
42
44
38
40
45
10
8
8
9
8
7
9
8
7
10
9
7
10
9
8
9
8
8
82
87
94
89
94
95
89
80
91
83
92
94
85
90
95
81
89
92
4-CH3C6H4
4-CH3OC6H4
C6H5
4-CH3C6H4
4-CH3OC6H4
C6H5
4-CH3C6H4
4-CH3OC6H4
C6H5
4-CH3C6H4
4-CH3OC6H4
C6H5
4-CH3C6H4
4-CH3OC6H4
C6H5
4-CH3C6H4
4-CH3OC6H4
H
H
Cl
Cl
Cl
[a] All of the products were characterized by 1H NMR, IR and mass spectral and elemental analysis data. [b] Isolated yields after column
chromatography. [c] Yields of 4, 7 and 10 are in nearly 40%.
aqueous bicarbonate solution. The clear filtrate on acidification
gave the crude solid, which was recrystallized from absolute
ethanol to afford isoxazolyl substituted phthalic monoamides,
maleic monoamides and succinic monoamides respectively in
excellent yields.
2-[({3-Methyl-5-[(E)-2-(4-methylphenyl)-1-ethenyl]-4-isox-
azolyl}amino)carbonyl]benzoic acid (1b). This compound
was obtained as colourless crystals, yield 82%; mp. 182-184°C;
1H NMR (300 MHz, CDCl3): ꢁ 2.21 (s, 3H, isoxazole-CH3), 2.53
(s, 3H, CH3), 6.80 (d, J=12 Hz, 1H, CH=CH), 7.04 (d, J=12 Hz,
1H, CH=CH), 7.22-7.85 (m, 8H, Ar-H), 9.21 (bs, 1H, NHCO,
D2O exchangeable), 11.60 (bs, 1H, COOH, D2O exchangeable);
MS (EI) m/z 362 (M+); IR (KBr): cm-1 1692, 1712 (C=O), 3055
(OH), 3179 (NH). Anal. Calcd for C21H18N2O4: C, 69.61, H,
4.97; N, 7.73%; found: C, 69.55; H, 4.99; N, 7.69%.
by using only BF3ꢀEt2O. Other methods tried by using
polyphosphoric acid, HCl and TFA also led to the mixture
of two products in each case.
So, selective intermolecular cyclocondensation has
been achieved by utilizing BF3ꢀEt2O only. Moreover,
BF3ꢀEt2O is an efficient catalyst and tolerant towards
chloro, methyl and methoxy groups on the aromatic ring.
We have successfully demonstrated the usage of BF3ꢀEt2O
as selective cyclocondensation catalyst, by avoiding the
intramolecular cyclodehydration of the substrate itself. A
single selective and desired product has been achieved in
excellent yields.
EXPERIMENTAL
2-[({5-[(E)-2-(4-Methoxyphenyl)-1-ethenyl]-3-methyl-4-
isoxazolyl}amino)carbonyl]benzoic acid (1c). This compound
was obtained as colourless crystals, yield 88%; m.p. 175-178°C;
1H NMR (300 MHz, CDCl3): ꢁ 2.15 (s, 3H, isoxazole-CH3), 3.70
(s, 3H, OCH3), 6.77 (d, J=12 Hz, 1H, CH=CH), 6.92 (d, J=12
Hz, 1H, CH=CH), 7.20-7.75 (m, 8H, Ar-H), 9.90 (bs, 1H,
NHCO, D2O exchangeable), 11.22 (bs, 1H, COOH, D2O
exchangeable); MS (EI) m/z 378 (M+), IR (KBr): cm-1 1685,
Melting points were determined on a Cintex melting point
apparatus and are uncorrected. The purity of the compounds
was checked by TLC. IR spectra were recorded in KBr on a
Perkin Elmer spectrum BX series FT-IR spectrometer. 1H NMR
spectra on a Varian Gemini 300 MHz spectrometer using
tetramethylsilane as internal standard and mass spectra on Jeol
JMC D-300 spectrometer. The silicagel (0.040 x 0.063 mm)
used for column chromatography was purchased from Merck.
Elemental analyses (C, H and N) were carried out on Carlo Erba
106 and Perkin Elmer model 240 analysers.
General procedure for synthesis of isoxzolyl substituted
phthalic monoamides (1b, c) maleic monoamides (5b, c) and
succinic monamides (8b, c). 4-Amino-3-methyl-5-substituted
styrylisoxazole (10 mmol) and phthalic anhydride / maleic
anhydride / succinic anhydride (10 mmol) were mixed well in a
mortar and ground for 2 hrs at room temperature. The mixture
was kept at room temperature for another 2 hrs for the
completion of reaction. The resulting solid was extracted with
1723 (C=O), 2990 (OH), 3220 (NH).
Anal. Calcd for
C21H18N2O5: C, 66.66; H, 4.76; N, 7.40%; found: C, 66.61; H,
4.79; N, 7.34%.
4-({3-Methyl-5-[(E}-2-(4-methylphenyl)-1-ethenyl]-4-isox-
azolyl}amino)-4-oxo-2-butenoic acid (5b). This compound was
obtained pale yellow colour crystals, yield 79%; m.p. 184-
1
185°C; H NMR (300 MHz, CDCl3): ꢁ 2.06 (s, 3H, isoxazole –
CH3), 2.45 (s, 3H, CH3), 6.30 (d, J=12 Hz, 1H, CH=CH), 6.65
(d, J=12 Hz, 1H, CH=CH), 7.02-7.76 (m, 4H, Ar-H & 2H,
CH=CH), 10.21 (bs, 1H, NHCO, D2O exchangeable), 11.44 (s,
1H, COOH, D2O exchangeable); MS (EI) m/z 312 (M+); IR
(KBr): cm-1 1652, 1705 (C=O), 3059 (OH), 3272 (NH). Anal.

Sep-Oct 2007
BF3ꢀEt2O Promoted Selective Synthesis of Benzimidazoles
1157
Calcd for C17H16N2O4: C, 65.38; H, 5.12; N, 8.97%; found: C,
65.31; H, 5.17; N, 8.94%.
N-(3-Methyl-4-isoxazolyl-5-styryl)-succinimide (10). This
compound was obtained as colourless crystals, yield 52%; m.p.
95°C, 1H NMR (300 MHz, CDCl3): 2.25 (s, 3H, isoxazole-CH3),
3.25 (t, 4H, -CH2-CH2-), 6.80 (d, J=12 Hz, 1H, CH=CH), 7.08-
7.92 (m, 6H, Ar-H & CH=CH); MS (EI): m/z 282 (M+). IR
(KBr): cm-1 1672, 1725 (C=O). Anal. Calcd for C16H14N2O3: C,
68.08; H, 4.96; N, 9.92%; found: C, 68.12; H, 4.92; N, 9.88%.
General procedure for synthesis of 2-isoxazolyl substituted
benzimidazoles (3 / 6 / 9). To a well stirred solution of
compound 1 / 5 / 8 (10 mmol) and 1,2-phenylene diamines (10
mmol) in dichloromethane (20 ml), BF3ꢀEt2O (10 mmol) in
dichloromethane (20 ml) was added dropwise with stirring and
the reaction continued for 7-10 hr at room temperature (reaction
monitored by TLC). After completion of the reaction, the
solvent was evaporated under reduced pressure. The crude solid
was purified by column chromatography over silicagel, elution
with ethylacetate: n-hexane (1:9) afforded benzimidazoles
(3/6/9) in 81-95% yields.
4-({5-[(E)-2-(4-Methoxyphenyl)-1-ethenyl]-3-methyl-4-
isoxazolyl}amino)-4-oxo-2-butenoic acid (5c). This compound
was obtained as pale yellow colour crystals, yield 74%; m.p.
152-154°C; 1H NMR (300 MHz, CDCl3): ꢁ 2.15 (s, 3H,
isoxazole-CH3), 3.60 (s, 3H, OCH3), 6.45 (d, J=12 Hz, 1H,
CH=CH), 6.71 (d, J=12 Hz, 1H, CH=CH), 6.90-7.76 (m, 4H,
Ar-H
& 2H, CH=CH), 10.67 (bs, 1H, NHCO, D2O
exchangeable), 11.80 (s, 1H, COOH, D2O exchangeble), MS
(EI) m/z 328 (M+); IR (KBr): cm-1 1675, 1712 (C=O), 3110
(OH), 3315 (NH). Anal. Calcd for C17H16N2O5: C, 62.19; H,
4.87; N, 8.53%; found: C, 62.24; H, 4.82; N, 8.50%.
4-({3-Methyl-5-[(E)-2-(4-methylphenyl)-1-ethenyl]-4-isoxa-
zolylamino)-4-oxobutanoic acid (8b). This compound was
1
obtained as colourless crystals, yield 72%; m.p. 121-124°C; H
NMR (300 MHz, CDCl3): ꢁ 2.05 (s, 3H, isoxazole –CH3), 2.31 (s,
3H, CH3), 2.73 (m, 4H, CH2-CH2), 6.70 (d, J=12 Hz, 1H, CH=CH),
6.90 (d, J=12 Hz, 1H, CH=CH), 7.25-7.88 (m, 4H, Ar-H), 9.92 (bs,
1H, NHCO, D2O exchangeable), 11.32 (s, 1H, COOH, D2O
exchangeable); MS (EI) m/z 314 (M+); IR (KBr): cm-1 1670, 1715
(C=O), 3035 (OH), 3257 (NH). Anal. Calcd for C17H18N2O4: C,
64.96; H, 5.73; N, 8.91%; found: C, 64.91; H, 5.70; N, 8.94%.
4-({5-[(E)-2-(3-Methoxyphenyl)-1-ethenyl]]-3-methyl-4-
isoxazolyl}amino)-4-oxobutanoic acid (8c). This compound
was obtained as colourless crystals, yield 78%; m.p. 112-116°C;
1H NMR (300 MHz, CDCl3): ꢁ 2.14 (s, 3H, isoxazole-CH3), 2.62
(m, 4H, CH2-CH2), 3.65 (s, 3H, OCH3), 6.80 (d, J=12 Hz, 1H,
CH=CH), 7.03 (d, J=12 Hz, 1H, CH=CH), 7.25-7.78 (m, 4H,
Ar-H), 10.32 (bs, 1H, NHCO, D2O exchangeable) 11.65 (s, 1H,
COOH, D2O exchangeble): MS (EI) m/z 330 (M+): IR (KBr):
cm-1 1681, 1710 (C=O), 3010 (OH), 3325 (NH). Anal. Calcd.
For C17H18N2O5: C, 61.81; H, 5.45; N, 8.58%; found: C, 61.74;
H, 5.49; N, 8.59%.
General procedure for synthesis of isoxazolyl substituted
phthalimide (4), maleimide (7) and succinimides (10).
Isoxazolyl substituted monoamides 1/5/8 (10 mmol) and 1,2-
phenylene diamines (10 mmol) were dissolved in pyridine and
refluxed for 24 hrs in the oil bath at 120°C. After completion of
the reaction (monitored with TLC) the reaction mixture was
allowed to cool and poured into ice cold water with stirring. The
separated solid was collected by filtration and washed with
water. Crude solid was purified by column chromatography by
eluting with ethylacetate and hexane in 3:7 ratio and ethyl
acetate and hexane in a 5:5 ratio respectively. 2-isoxazolyl
substituted benzimidazoles (3/6/9) and undesired imides 4/7/10
are obtained in 2:3 ratio respectively from eluted solvent.
N-(3-Methyl-4-isoxazolyl-5-styryl)-phthalimide (4). This
compound was obtained as colourless crystals, yield 40%; m.p.
185-187°C. 1H NMR (300 MHz, CDCl3): 2.22 (s, 3H,
isoxazole-CH3), 6.82 (d, J=12 Hz, 1H, CH=CH), 7.04-7.94 (m,
10, Ar-H & CH=CH); MS (EI) m/z 330 (M+) : IR (KBr): cm-1
1725, 1785 (C=O). Anal. Calcd for C20H14N2O3: C, 72.72; H,
4.24; N, 8.48%; found: C, 72.76; H, 4.20; N, 84.2%.
N1-{3-Methyl-5[(E)-2-phenyl-1-ethenyl]-4-isoxazolyl}-2-
(1H-benzo[d]imidazol-2-yl)benzamide (3a). This compound
1
was obtained as colourless crystals; m.p. 181-183°C; H NMR
(300 MHz, CDCl3): ꢁ 2.40 (s, 3H, CH3), 6.65 (d, J=12 Hz, 1H,
CH=CH), 6.82 (d, J=12 Hz, 1H, CH=CH), 7.05-7.86 (m, 13H,
Ar-H), 9.72 (bs, 1H, NHCO, D2O exchangeable), 11.03 (bs, 1H,
benzimidazole-H, D2O exchangeable); MS (EI) m/z 420 (M+);
IR (KBr): cm-1 1708 (NHCO), 3380 (NHCO), 3460 (NH). Anal.
Calcd. for C26H20N4O2: C, 74.28; H, 4.76; N, 13.33%; found: C,
75.34; H, 4.81; N, 13.39%.
N1-{3-Methyl-5[(E)-2-(4-methylphenyl)-1-ethenyl]-4-isoxa-
zolyl}-2-(1H-benzo[d]imidazol-2-yl)benzamide (3b). This
compound was obtained as colourless crystals; m.p. 172-174°C; 1H
NMR (300 MHz, CDCl3): ꢁ 2.14 (s, 3H, isoxazole-CH3), 2.62 (s,
3H, CH3), 6.70 (d, J=12 Hz, 1H, CH=CH), 6.93 (d, J=12 Hz, 1H,
CH=CH), 7.20 - 7.85 (m, 12H, Ar-H), 10.02 (bs, 1H, NHCO,
D2O exchangeable), 11.24 (bs, 1H, benzimidazole-H, D2O
exchangeable); MS (EI) m/z 434 (M+); IR (KBr): cm-1 1689
(NHCO), 3320 (NHCO), 3480 (NH). Anal. Calcd. for C27H22N4O2:
C, 74.65; H, 5.06; N, 12.90%; found: C, 74.69; H, 5.11; N, 12.98%.
N1-{3-Methyl-5[(E)-2-(4-methoxyphenyl)-1-ethenyl]-4-isox-
azolyl}-2-(1H-benzo[d]imidazol-2-yl)benzamide (3c). This
compound was obtained as colourless crystals; m.p. 169-170°C; 1H
NMR (300 MHz, CDCl3): ꢁ 2.22 (s, 3H, CH3), 3.75 (s, 3H, OCH3),
6.61 (d, J=12 Hz, 1H, CH=CH), 6.82 (d, J=12 Hz, 1H, CH=CH),
7.10-7.90 (m, 12H, Ar-H), 10.55 (bs, 1H, NHCO, D2O
exchangeable), 11.52 (bs, 1H, benzimidazole-H, D2O
exchangeable); MS (EI) m/z 450 (M+); IR (KBr): cm-1 1685
(NHCO), 3360 (NHCO), 3452 (NH). Anal. Calcd. for C27H22N4O3:
C, 72.00; H, 4.88; N, 12.44%; found: C, 72.09; H, 4.81; N, 12.39%.
N1-{3-Methyl-5[(E)-2-phenyl-1-ethenyl]-4-isoxazolyl}-2-
(5,6-dichloro-1H-benzo[d]imidazol-2-yl)benzamide (3d). This
compound was obtained as colourless crystals; m.p. 191-193°C;
1H NMR (300 MHz, CDCl3): ꢁ 2.24 (s, 3H, CH3), 6.62 (d, J=12
Hz, 1H, CH=CH), 6.85 (d, J=12 Hz, 1H, CH=CH), 7.02-8.05
(m, 11H, Ar-H), 9.91 (bs, 1H, NHCO, D2O exchangeable),
10.95 (bs, 1H, benzimidazole-H, D2O exchangeable); MS (EI)
m/z 488 (M+); IR (KBr): cm-1 1660 (NHCO), 3150 (NHCO),
3200 (NH). Anal. Calcd. for C26H18Cl2N4O2: C, 63.81; H, 3.71;
N, 11.45%; found: C, 63.97; H, 3.74; N, 11.40%.
N-(3-Methyl-4-isoxazolyl-5-styryl)-maleimide (7). This
compound was obtained as pale yellow crystals, yield 55%; m.p.
150-152°C. 1H NMR (300 MHz, CDCl3): 2.16 (s, 3H,
isoxazole-CH3), 6.62 (d, 2H, imide, CH=CH), 6.82 (d, J=12 Hz,
1H, CH=CH), 7.04-7.78 (m, 6H, Ar-H & CH=CH); MS (EI) m/z
279 (M+); IR (KBr): cm-1 1660, 1730 (C=O). Anal. Calcd. For
C16H12N2O3: C, 68.57; H, 4.28; N, 10.00; found: C, 68.50; H,
4.32; N, 10.05.
N1-{3-Methyl-5[(E)-2-(4-methylphenyl)-1-ethenyl]-4-isox-
azolyl}-2-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)benzamide
(3e). This compound was obtained as colourless crystals; m.p.
197-199°C; 1H NMR (300 MHz, CDCl3): ꢁ 2.05 (s, 3H,

1158
E. Rajanarendar, P. Ramesh, E .Kalyan Rao, G. Mohan and A. S. R. Reddy
Vol 44
isoxazole-CH3), 2.73 (s, 3H, CH3), 6.75 (d, J=12 Hz, 1H,
CH=CH), 6.93 (d, J=12 Hz, 1H, CH=CH), 7.12-8.05 (m, 10H,
Ar-H), 9.23 (bs, 1H, NHCO, D2O exchangeable), 10.8 (bs, 1H,
benzimidazole-H, D2O exchangeable); MS (EI) m/z 502 (M+);
IR (KBr): cm-1 1675 (NHCO), 3252 (NHCO), 3345 (NH). Anal.
Calcd. for C27H20Cl2N4O2 : C, 64.54; H, 3.98; N, 11.15%;
Found: C, 64.61; H, 3.91; N, 11.22%.
N1-{3-Methyl-5[(E)-2-(4-methylphenyl)-1-ethenyl]-4-isox-
azolyl}-(E)-3-(5,6-dichloro-2,3-dihydro-1H-benzo[d]imidazol-
2-yl)-2-propenamide (6e). This compound was obtained as
colourless crystals; m.p. 194-196°C; 1H NMR (300 MHz,
CDCl3): ꢀ 2.14 (s, 3H, isoxazole-CH3), 2.62 (s, 3H, CH3), 6.82
(d, J=12 Hz, 1H, CH=CH), 7.05 (d, J=12 Hz, 1H, CH=CH),
7.22-8.15 (m, 8H, Ar-H & CH=CH), 9.02 (bs, 1H, NHCO, D2O
exchangeable), 10.12 (bs, 1H, benzimidazole-H, D2O
exchangeable); MS (EI) m/z 452 (M+); IR (KBr): cm-1 1685
N1-{3-Methyl-5[(E)-2-(4-methoxyphenyl]-1-ethenyl]-4-isox-
azolyl}-2-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)benzamide
(3f). This compound was obtained as colourless crystals; m.p.
(NHCO), 3225 (NHCO), 3382 (NH).
Anal. Calcd. for
1
203-204°C; H NMR (300 MHz, CDCl3): ꢀ 2.12 (s, 3H, CH3),
C23H18Cl2N4O2: C, 61.06; H, 3.98; N, 12.38%; Found: C, 61.14;
H, 4.05; N, 12.32%.
3.65 (s, 3H, OCH3), 6.61 (d, J=12 Hz, 1H, CH=CH), 6.84 (d,
J=12 Hz, 1H, CH=CH), 7.10-7.90 (m, 10H, Ar-H), 9.92 (bs, 1H,
NHCO, D2O exchangeable), 10.91 (bs, 1H, benzimidazole-H,
D2O exchangeable); MS (EI) m/z 518 (M+); IR (KBr): cm-1 1682
(NHCO), 3288 (NHCO), 3375 (NH). Anal. Calcd. for
C27H20Cl2N4O3: C, 62.54; H, 3.86; N, 10.81%; Found: C, 62.61;
H, 3.81; N, 10.89%.
N1-{3-Methyl-5[(E)-2-phenyl-1-ethenyl]-4-isoxazolyl}-(E)-
3-(1H-benzo[d]imidazol-2-yl)-2-propenamide (6a). This
compound was obtained as colourless crystals; m.p. 178-179°C;
1H NMR (300 MHz, CDCl3): ꢀ 2.23 (s, 3H, CH3), 6.65 (d, J=12
Hz, 1H, CH=CH), 6.80 (d, J=12 Hz, 1H, CH=CH), 7.02-8.05
(m, 11H, Ar-H & CH=CH), 9.92 (bs, 1H, NHCO, D2O
exchangeable), 10.98 (bs, 1H, benzimidazole-H, D2O
exchangeable); MS (EI) m/z 370 (M+); IR (KBr): cm-1 1685
(NHCO), 3200 (NHCO), 3350 (NH). Anal. Calcd. for
C22H18N4O2 : C, 71.35; H, 4.86; N, 15.13%; Found: C, 71.41; H,
4.80; N, 15.17%.
N1-{5[(E)-2-(4-Methoxyphenyl)-1-ethenyl]-3-methyl-4-
isoxazolyl}-(E)-3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-2-
propenamide (6f). This compound was obtained as colourless
1
crystals; m.p. 208-210°C; H NMR (300 MHz, CDCl3): ꢀ 2.35
(s, 3H, CH3), 3.62 (s, 3H, OCH3), 6.64 (d, J=12 Hz, 1H,
CH=CH), 6.87 (d, J=12 Hz, 1H, CH=CH), 7.02-7.86 (m, 8H,
Ar-H & CH=CH), 8.82 (bs, 1H, NHCO, D2O exchangeable),
10.45 (bs, 1H, benzimidazole-H, D2O exchangeable); MS (EI)
m/z 468 (M+); IR (KBr): cm-1 1673 (NHCO), 3245 (NHCO),
3372 (NH). Anal. Calcd. for C23H18Cl2N4O3: C, 58.97; H, 4.05;
N, 11.96%; Found: C, 58.90; H, 4.11; N, 11.92%.
N1-{3-Methyl-5[(E)-2-(2-phenyl)-1-ethenyl]-4-isoxazolyl}-
3-(1H-benzo[d]imidazol-2-yl)-propanamide (9a). This
compound was obtained as colourless crystals; m.p. 155-158°C;
1H NMR (300 MHz, CDCl3): ꢀ 2.33 (s, 3H, CH3), 3.02 (t, 2H,
CH2CH2), 3.35 (t, 2H, CH2CH2), 6.62 (d, J=12 Hz, 1H,
CH=CH), 6.82 (d, J=12 Hz, 1H, CH=CH), 7.05-7.64 (m, 9H,
Ar-H), 7.82 (bs, 1H, NHCO, D2O exchangeable), 9.88 (bs, 1H,
benzimidazole-H, D2O exchangeable); MS (EI) m/z 372 (M+);
IR (KBr): cm-1 1675 (NHCO), 3265 (NHCO), 3290 (NH). Anal.
Calcd. for C22H20N4O2: C, 70.96; H, 5.37; N, 15.05%; Found: C,
70.90; H, 5.41; N, 15.11%.
N1-{3-Methyl-5[(E)-2-(4-methylphenyl)-1-ethenyl]-4-isox-
azolyl}-3-(1H-benzo[d]imidazol-2-yl)propanamide (9b). This
compound was obtained as colourless crystals; m.p. 142-144°C;
1H NMR (300 MHz, CDCl3): ꢀ 2.05 (s, 3H, isoxazole-CH3), 2.82
(s, 3H, CH3), 3.13 (t, 2H, CH2CH2), 3.45 (t, 2H, CH2CH2), 6.76
(d, J=12 Hz, 1H, CH=CH), 6.91 (d, J=12 Hz, 1H, CH=CH),
7.13-7.95 (m, 8H, Ar-H), 8.25 (bs, 1H, NHCO, D2O
exchangeable), 10.16 (bs, 1H, benzimidazole-H, D2O
exchangeable); MS (EI) m/z 386 (M+); IR (KBr): cm-1 1698
N1-{3-Methyl-5[(E)-2(4-methylphenyl)-1-ethenyl]-4-isox-
azolyl}-(E)-3-(1H-benzo[d]imidazol-2-yl)-2-propenamide (6b).
This compound was obtained as colourless crystals; m.p. 165-
1
166°C; H NMR (300 MHz, CDCl3): ꢀ 2.15 (s, 3H, isoxazole-
CH3), 2.70 (s, 3H, CH3), 6.73 (d, J=12 Hz, 1H, CH=CH), 6.92
(d, J=12 Hz, 1H, CH=CH), 7.20-8.12 (m, 10H, Ar-H &
CH=CH), 9.12 (bs, 1H, NHCO, D2O exchangeable), 10.25 (bs,
1H, benzimidazole-H, D2O exchangeable); MS (EI) m/z 384
(M+); IR (KBr): cm-1 1672 (NHCO), 3240 (NHCO), 3385 (NH).
Anal. Calcd. for C23H20N4O2: C, 71.87; H, 5.20; N, 14.58%;
Found: C, 71.82; H, 5.27; N, 14.52%.
N1-{5[(E)-2-(4-Methoxyphenyl)-1-ethenyl]-3-methyl-4-
isoxazolyl}-(E)-3-(1H-benzo[d]-imidazol-2-yl)-2-propenamide
(6c). This compound was obtained as colourless crystals; m.p.
1
(NHCO), 3289 (NHCO), 3310 (NH).
Anal. Calcd. for
175-176°C; H NMR (300 MHz, CDCl3): ꢀ 2.33 (s, 3H, CH3),
C23H22N4O2: C, 71.50; H, 5.69; N, 14.50%; Found: C, 71.57; H,
5.61; N, 14.58%.
3.85 (s, 3H, OCH3), 6.82 (d, J=12 Hz, 1H, CH=CH), 7.01 (d,
J=12 Hz, 1H, CH=CH), 7.24-8.32 (m, 10H, Ar-H & CH=CH),
9.25 (bs, 1H, NHCO, D2O exchangeable), 10.46 (bs, 1H,
benzimidazole-1H, D2O exchangeable); MS (EI) m/z 400 (M+);
IR (KBr): cm-1 1691 (NHCO), 3255 (NHCO), 3395 (NH). Anal.
Calcd. for C23H20N4O3: C, 69.00; H, 5.00; N, 14.00%; Found: C,
69.08; H, 5.05; N, 13.92%.
N1-{5[(E)-2-(4-Methoxyphenyl)-1-ethenyl]-3-methyl-4-isox-
azolyl}-3-(1H-benzo[d]imidazol-2-yl)propanamide (9c). This
compound was obtained as colourless crystals; m.p. 149-151°C;
1H NMR (300 MHz, CDCl3): ꢀ 2.20 (s, 3H, CH3), 3.22 (t, 2H,
CH2CH2), 3.45 (t, 2H, CH2CH2), 3.76 (s, 3H, OCH3), 6.82 (d,
J=12 Hz, 1H, CH=CH), 7.02 (d, J=12 Hz, 1H, CH=CH), 7.25-
7.96 (m, 8H, Ar-H), 8.72 (bs, 1H, NHCO, D2O exchangeable),
10.45 (bs, 1H, benzimidazole-H, D2O exchangeable); MS (EI)
m/z 402 (M+); IR (KBr): cm1 1705 (NHCO), 3252 (NHCO),
3398 (NH). Anal. Calcd. for C23H22N4O3: C, 68.65; H, 5.47; N,
13.93%; Found: C, 68.59; H, 5.52; N, 13.87%.
N1-{3-methyl-5[(E)-2-phenyl-1-ethenyl]-4-isoxazolyl}-(E)-
3-(5,6-dichloro-2,3-dihydro-1H-benzo[d]imidazol-2-yl)-2-
propenamide (6d). This compound was obtained as colourless
1
crystals; m.p. 188-190°C; H NMR (300 MHz, CDCl3): ꢀ 2.45
(s, 3H, CH3), 6.70 (d, J=12 Hz, 1H, CH=CH), 6.92 (d, J=12 Hz,
1H, CH=CH), 7.12-7.92 (m, 9H, Ar-H & CH=CH), 9.45 (bs,
1H, NHCO, D2O exchangeable), 9.82 (bs, 1H, benzimidazole-H,
D2O exchangeable); MS (EI) m/z 438 (M+); IR (KBr): cm-1 1690
N1-{3-Methyl-5[(E)-2-(2-phenyl)-1-ethenyl]-4-isoxazolyl}-
3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)propanamide (9d).
This compound was obtained as colourless crystals; m.p. 185-
(NHCO), 3200 (NHCO), 3350 (NH).
Anal. Calcd. for
1
187°C; H NMR (300 MHz, CDCl3): ꢀ 2.50 (s, 3H, CH3), 2.92
C22H16Cl2N4O2: C, 60.27; H, 3.65; N, 12.78%; Found: C, 60.32;
H, 3.69; N, 12.71%.
(t, 2H, CH2CH2), 3.11 (t, 2H, CH2CH2), 6.65 (d, J=12 Hz, 1H,

Sep-Oct 2007
BF3ꢀEt2O Promoted Selective Synthesis of Benzimidazoles
1159
[7] (a) Wu, Z.; Jin, S.; Yang, J.M.; Xiao, H.; Sim, S.P.; Liu, A.;
Liu, L.F.; Lavoie, E. Abstracts of the American Chemical Society,
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IL Aug 2001, pp. 26-29; American Chemical Society; Washington-DC.
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Schober, D.A.; Bruns, R.F. Bioorg. Med. Chem. Lett., 1999, 9, 647. (b)
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M.B.; Schober, D.A.; Gackenheimer, S.L.; Bruns, R.F.; Hipskind, P.A.;
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CH=CH), 6.82 (d, J=12 Hz, 1H, CH=CH), 7.02-7.85 (m, 7H,
Ar-H), 9.12 (bs, 1H, NHCO, D2O exchangeable), 10.25 (bs, 1H,
benzimidazole-H, D2O exchangeable); MS (EI) m/z 440 (M+);
IR (KBr): cm-1 1685 (NHCO), 3295 (NHCO), 3400 (NH). Anal.
Calcd. for C22H18Cl2N4O2: C, 60.00; H, 4.09; N, 12.72%;
Found: C, 60.09; H, 4.14; N, 12.80%.
N1-{3-Methyl-5[(E)-2-(4-methylphenyl)-1-ethenyl]-4-isox-
azolyl}-3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)propan-
amide (9e). This compound was obtained as colourless crystals;
1
m.p. 200-202°C; H NMR (300 MHz, CDCl3): ꢁ 2.12 (s, 3H,
isoxazolyl-CH3), 2.75 (s, 3H, CH3), 3.02 (t, 2H, CH2CH2), 3.25
(t, 2H, CH2CH2), 6.76 (d, J=12 Hz, 1H, CH=CH), 6.92 (d, J=12
Hz, 1H, CH=CH), 7.15-8.05 (m, 6H, Ar-H), 8.45 (bs, 1H,
NHCO, D2O exchangeable), 10.52 (bs, 1H, benzimidazole-H,
D2O exchangeable); MS (EI) m/z 454 (M+); IR (KBr): cm-1 1710
(NHCO), 3305 (NHCO), 3350 (NH).
Anal. Calcd. for
C23H20Cl2N4O2: C, 60.79; H, 4.40; N, 12.33%; Found: C, 60.84;
H, 4.46; N, 12.39%.
[13] Eugster, Prog. Chem. Org. Nat. Prod., 1969, 27, 261.
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E.M.; Stephen, F.F. J. Med. Chem., 1988, 31, 473.
N1-{5[(E)-2-(4-Methoxyphenyl)-1-ethenyl]-3-methyl-4-isox-
azolyl}-3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)propan-
amide (9f). This compound was obtained as colourless crystals;
1
m.p. 213-215°C; H NMR (300 MHz, CDCl3): ꢁ 2.35 (s, 3H,
CH3), 3.12 (t, 2H, CH2CH2), 3.34 (t, 2H, CH2CH2), 3.74 (s, 3H,
OCH3), 6.92 (d, J=12 Hz, 1H, CH=CH), 7.15 (d, J=12 Hz, 1H,
CH=CH), 7.35-8.27 (m, 6H, Ar-H), 8.92 (bs, 1H, NHCO, D2O
exchangeable), 10.75 (bs, 1H, benzimidazole-H, D2O
exchangeable); MS (EI) m/z 470 (M+); IR (KBr): cm-1 1688
[19] Boschail, C.; Cana, A.; Disftilo, R.; Frutlero, A.; Gasco,
Bioorg. Med. Chem. Lett., 2000, 7, 1727.
[20] Moloney Gerard, P.; Martin Graemer, Mathew. J. Chem. Soc.
Perkin Trans, 1999, 19, 2725.
(NHCO), 3329 (NHCO), 3295 (NH).
Anal. Calcd. for
C23H20Cl2N4O3: C, 58.72; H, 4.25; N, 11.91%; Found: C, 58.79;
H, 4.31; N, 11.99%.
Acknowledgements. The authors are thankful to Prof. S.
SriHari, Head, Department of Chemistry, Kakatiya University,
Warangal for providing facilities. The authors are grateful to
Director, Indian Institute of Chemical Technology, Hyderabad
for 1H NMR and Mass spectra.
[21] Clark, R.D.; Carron, J.H.; Kloge, A.F.; Repke, D.B.;
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