Synthesis, anti-bacterial, anti-asthmatic and anti-diabetic activities of novel N-substituted-2-(benzo[d]isoxazol-3-ylmethyl)-1H-benzimidazoles

Article abstract of DOI:10.1002/jhet.5570440327

(Chemical Equation Presented) Synthesis of a series of novel class of N-substituted-2-(benzo[d]isoxazol-3-ylmethyl)-1H-benzimidazoles (4) by the condensation of o-phenylenediamine (1) with benzo[d]isoxazol-3-yl-acetic acid (2) and subsequent reactions wit

Full text of DOI:10.1002/jhet.5570440327

May-Jun 2007
685
Synthesis, Anti-bacterial, Anti-asthmatic and Anti-diabetic
Activities of Novel N-Substituted-2-(benzo[d]isoxazol-3-ylmethyl)-
1H-benzimidazoles
Sanjay Dashrath Vaidyaa, Bobba Venkata Siva Kumara, Ramanatham Vinod Kumar*a
Umesh Nanasaheb Bhisea and Uday Chandrakant Mashelkar* b†
(a) Glenmark Research Center, Plot No. A-607, T.T.C.Industrial Area,
M.I.D.C. Mahape Navi Mumbai-400 709, India
(b) Oraganic Research Laboratory, Patkar College, S. V. Road,
Goregaon(West), Mumbai-400 062, India.
udaymashelkar@yahoo.com; rvinodk@yahoo.com
Received October 26, 2006
HOOC-H2C
N
N
NH2
4N HCl
R-X or Ar-X
Base
+
N
N
H
N
R
Reflux/ 6h
O
NH2
N
N
O
O
( 3 )
( 1 )
( 2 )
( 4a -4w )
( 65 - 92 % )
Synthesis of a series of novel class of N-substituted-2-(benzo[d]isoxazol-3-ylmethyl)-1H-benzimida-
zoles (4) by the condensation of o-phenylenediamine (1) with benzo[d]isoxazol-3-yl-acetic acid (2) and
subsequent reactions with different types of electrophiles have been reported. Some compounds exhibited
promising anti-bacterial activity against Salmonella typhimurium, however poor activity against
Staphylococcus aureus. The compound 4t was found to have high activity even at 1 μg/ml compared to
Cephalexin against S. aureus. The biological activity against PDE-IV for potential anti-asthmatic effect
and against DP-IV and PTP-1B for potential anti-diabetic effects was disappointing.
J. Heterocyclic Chem., 44, 685 (2007).
INTRODUCTION
RESULTS AND DISCUSSION
Benzimidazole and its derivatives are marked as
prominent heterocyclic compounds that exhibit a large
number of biological activities [1]. Significantly, the
benzimidazole moiety is a constituent part of Vitamin-B12
core structure [2]. Some, like thiabendazole, mebendazole
and albendazole, are widely used as antihelmintic drugs [3]
(Figure 1). Similarly, 2-substituted benzimidazoles and their
derivatives have been found to be potent biologically active
compounds as well [4]. The activity and structural diversity
exhibited by compounds containing the benzimidazole
moiety has led to the discovery and development of novel
and useful bioactive benzimidazole libraries [5]. We have
been interested in the synthesis of novel benzimidazole ring
systems in connection with our on-going project on
benzimidazoles [6]. In continuation of our work on bioactive
benz-imidazole libraries, we herein describe our efforts
towards the synthesis of a novel class of benzimidazole
derivatives and their biological activity screening studies.
Condensation of o-phenylenediamine 1 (OPDA) with
benzo[d]isoxazol-3-yl-acetic acid [7], 2 under Phillips'
condition [8] in refluxing 4 N HCl for 6 hr and
subsequent work-up resulted in the formation of a white
solid having m.p.174-176 °C and in 80% yield. Based on
the spectral and analytical data the compound was
assigned to be 2-(benzo[d]isoxazol-3-ylmethyl)-1H-benz-
imidazole 3 [9] (Scheme 1).
Scheme-1
HOOC-H2C
NH2
N
4N HCl
+
N
Reflux/ 6h
80%
N
H
O
NH2
N
( 1 )
( 2 )
( 3 )
O
Compound 3 was also synthesized by the condensation
of 1 with 2 in the presence of Eaton's reagent [10] (1:10
mixture of phosphorous pentoxide - methanesulfonic acid,
O
S
H
N
N
N
N
NH
NH
O
N
H
O
S
N
N
H
O
O
Albendazole
Mebendazole
Thiabendazole
Figure -1

686
S. D. Vaidya, B. V. S. Kumar, R. V. Kumar, U. N. Bhise and U. C.Mashelkar
Vol 44
an efficient and convenient alternative to polyphosphoric
acid (PPA) [11] for cyclodehydration reactions). In order to
reduce the reaction time, the condensation of 1 and 2 was
carried out in PPA under microwave irradiation [12] for 3
minutes that also yielded compound 3 in comparable and
sometimes in higher yield than conventional methods. The
alkylation and acylation of 3 with various electrophilic
reagents yielded the N-alkylated/ acylated derivatives
(Scheme 2). The physical and spectral data of the
compounds 4a-4w is presented in Table 3.
Biological Activity. All the compounds prepared
herein were screened for their potential biological
activities such as, anti-bacterial activity against
Staphylococcus aureus (gram positive) and Salmonella
typhimurium (gram negative) bacterial strains.
Cephalexin was used as a reference standard. The results
of the antibacterial activity screening of the tested
compounds are summarized in Table 1. Most of the
compounds tested were found to have good anti-bacterial
activity against Salmonella typhimurium, however, they
Scheme-2
O
O
N
Alkylating / acylating
agent
N
N
N
R--X
+
N
R
N
H
Base / Solvent
( 3 )
(4 a- w)
(4a, R = -CH3 ), (4b, R = -CH2-CH3 ), (4c, R = -CO-O-Ethyl), (4d, R = -CO-O-CH(Cl)-CH3),
(4e, R = -CO-O-Butyl), (4f, R = -CO-O-Iso-butyl), (4g, R=-CO-O-benzyl),
(4h, R = -CO-O-C6H4-NO2(p), (4i, R = -CO-CH3), (4j, R = -CO-CH2-CH3)
(4k ,R = -CO-CH2-CH2-CH3), (4l, R = -CO-Ph), (4m, R =-CO-C6H4-(tert.butyl-(p)),
(4n, R = -SO2-CF3), (4o, R =-SO2-CH2-CH2-CH2-Cl), (4p, R =-SO2-Ph)
(4q, R = -SO2-C6H4-CH3), (4r, R= -CH2-Ph), (4s, R =-CH2-C6H4-F(p),
(4t, R = -CH2-C6H4-Br(p), (4u, R = -CH2-C6H4-CH3(p), (4v, R = -CH2-C6H4-t.butyl-(p)),
(4w, R = -CO-O-C(CH3)3
In an alternate route compound 4a has also been
were found to have poor activity against Staphylococcus
aureus. The compound 4t was found to have high activity
even at 1μg/ml compared to Cephalexin against
Staphylococcus aureus. Also they were tested against
synthesized by direct condensation of N-methyl-OPDA
dihydrochloride [13] (5) with 2 in refluxing 4 N HCl as in
the case of preparation of compound 3 described above.
Table 1
Antibacterial activity of compounds against Staphylococcus aureus.
Compound No.
Concentration
0.1μg/ml
++
++
++
++
++
++
++
+
1μg/ml
++
++
++
++
++
++
++
+
10μg/ml
100μg/ml
200μg/ml
500μg/ml
APP.MIC
100 μg/ml
200 μg/ml
200 μg/ml
500 μg/ml
500 μg/ml
500 μg/ml
500 μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
500 μg/ml
500 μg/ml
100 μg/ml
500 μg/ml
200 μg/ml
500 μg/ml
1μg/ml
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
+
++
+
++
++
+
+
P
P
P
++
+
+
+
P
+
P
+
+
--
+
P
+
+
+
+
P
P
P
+
P
P
+
P
P
--
P
P
+
--
+
+
+
--
--
--
--
P
P
P
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
P
--
--
--
--
--
--
P
P
P
--
P
--
P
++
++
++
++
++
++
+
++
+
++
++
++
+
+
++
++
+
+
++
+
+
+
+
++
++
--
++
++
++
++
++
--
++
+
++
--
--
P
P
P
--
++
++
++
++
500 μg/ml
500 μg/ml
500 μg/ml
10 μg/ml
4v
4w
Cephalexin

May-Jun 2007
Novel N-Substituted-2-(benzo[d]isoxazol-3-ylmethyl)-1H-benzimidazoles
687
1
Perkin-Elmer Spectrum One FT-IR spectrometer. H-NMR and
13C-NMR spectra were recorded on a Varian Mercury Vx
SWBB 300 MHz spectrometer. Elemental analysis was
PDE - IV for potential anti-asthmatic effect, and against
DP-IV and PTP-1B for potential anti-diabetic effects.
Unfortunately, the results were disappointing.
Table 2
Antibacterial activity of compounds against Salmonella typhimurium.
Compound No.
Concentration
0.1μg/ml
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
1μg/ml
++
++
++
++
++
++
++
+
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
10μg/ml
++
++
++
++
++
+
++
+
+
100μg/ml
200μg/ml
500μg/ml
APP.MIC
200 μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
500 μg/ml
200 μg/ml
500 μg/ml
100 μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
100 μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
100μg/ml
200 μg/ml
200 μg/ml
200 μg/ml
200μg/ml
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
P
P
+
+
+
P
+
--
P
P
P
P
+
+
+
+
--
P
+
+
--
+
P
P
P
--
--
--
--
P
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
+
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
++
++
++
+
+
++
++
++
+
++
++
++
+
4v
4w
Cephalexin
++
P
+
Symbols: Total Inhibition, no growth of organism
Poor growth compared to controls
= --
= P
Medium growth compared to controls
Confluent growth, no inhibition
= +
= ++
carried out on a Perkin-Elmer Series-II CHNS/O Analyzer
2400. o-Phenylenediamine, alkylating, acylating and aroylating
agents were obtained from commercial suppliers. Benzo[d]-
isoxazol-3-yl-acetic acid was prepared by the reported procedure
[7]. All the solvents used were of commercial grade only.
CONCLUSION
In conclusion, we have demonstrated the synthesis of a
series of novel benzimidazole derivatives by the
condensation of OPDA with benzo[d]isoxazol-3-yl-acetic
acid and subsequent reactions at the benzimidazole -NH
with different electrophilic reagents under different
conditions. Some of the compounds were found to have
good anti-bacterial activity against S. typhimurium,
however they were found to have less activity against S.
aureus. The compound 4t was found to have high activity
even at 1μg/ml compared to Cephalexin against S. aureus.
These compounds were also tested against PDE-IV for
potential anti-asthmatic effect, and against DP-IV and
PTP-1B for potential anti-diabetic effects. Unfortunately,
the results were disappointing.
Synthesis of 2-(benzo[d]isoxazol-3-ylmethyl)-1H-benzimi-
dazole (3). A mixture of OPDA (1.08 g, 10 mmoles), 2 (1.77g,
10 m moles) was taken in a solution of 4 N HCl (10 ml) and
refluxed in a water bath for 6 hr (tlc monitoring). The reaction
mixture was then cooled to room temperature and neutralized
with aq. NaHCO3 (10%), till neutral to pH. A sticky solid was
obtained, which on further stirring for 30 minutes yielded a solid
suspension that was free flowing. The solid was collected by
filtration, washed with water (2 x 25 ml) and dried under
vacuum to obtain 3 (1.99 g, 80 %). A part of the crude product
was recrystallized from hot aq. ethanol to obtain a white
crystalline compound. (M.P.-174-176[9] °C).
Synthesis of compound (3) via Eaton's Reagent. A mixture
of OPDA (1.08g, 10 mmole), 2 (1.77g, 10 m mole), and P2O5-
MSA (1: 10 mixture) (Eaton's Reagent) was heated with stirring
at 100 °C for 5 hrs. The reaction was then quenched with aq.
saturated bicarbonate (2 x 25 ml) and extracted with ethyl
acetate (3 x 50 ml). The organic layer was washed with water (2
x 25 ml), brine (2 x 25 ml and dried over anhydrous magnesium
sulfate and evaporated to get compound 3 (1.99 g, 80%), which
EXPERIMENTAL
Melting points are uncorrected and were recorded on a
MRVIS Series, Lab India Instrument. TLC analysis was
carried out using pre-coated silica gel plates and visualization
was done using Iodine/UV lamp. IR spectra were recorded on a

688
S. D. Vaidya, B. V. S. Kumar, R. V. Kumar, U. N. Bhise and U. C.Mashelkar
Vol 44
Table 3
Physical and Analytical Data of Compounds 3, 4a - 4w ꢀ
Compound
R
Time
hours
Mp
(°C)
Yield
%
Molecular
Formula
Analysis %
Calcd./Found
H
C
N
3
4a
4b
4c
4d
4e
4f
H
6
2
24
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
5
5
5
5
5
3
174-176
141-142
145-150
146-147
152-153
108-109
115-116
122-123
171-172
165-166
185-187
144-145
117-118
144-145
140-141
107-108
140-141
135-136
148-149
148-150
174-175
175-176
146-147
115-116
80
90
92
72
87
71
85
65
90
77
80
80
84
80
91
91
77
86
87
90
85
85
88
78
C15H11N 3O
C16H13N3O
17H15N3O
72.28
72.30
72.99
72.86
73.63
73.37
67.28
67.19
60.77
60.85
68.75
68.67
68.75
68.58
72.05
71.86
63.77
63.59
70.09
69.81
70.81
70.62
71.46
71.30
74.78
74.43
76.26
76.05
50.40
50.43
55.46
55.24
64.77
64.66
65.49
65.46
77.86
77.80
73.94
73.95
63.17
63.04
78.16
78.00
78.96
79.05
68.75
68.62
4.45
4.56
4.98
5.27
5.45
5.27
4.71
4.93
3.97
4.10
5.48
5.74
5.48
5.68
4.47
4.67
3.41
3.57
4.50
4.77
4.95
5.19
5.37
5.64
4.28
4.50
5.66
5.97
2.64
2.51
4.14
4.25
3.88
3.98
4.25
4.24
5.05
5.20
4.51
4.62
3.86
3.93
5.42
5.54
6.37
6.50
5.48
5.66
16.86
16.85
15.96
15.90
15.15
15.23
13.08
12.96
11.81
11.90
12.03
11.93
12.03
12.01
10.96
10.79
13.52
13.23
14.42
14.41
13.76
13.60
13.16
12.93
11.89
11.72
10.26
10.12
11.02
11.00
10.78
10.71
10.79
10.62
10.41
10.26
12.38
12.47
11.76
11.80
10.05
10.00
11.89
11.87
10.62
10.56
12.03
11.92
Methyl
Ethyl
C
Ethyl-O-CO-
C18H15N3O3
C18H14ClN3O3
C20H19N3O3
C20H19N3O3
C23H17N3O3
C22H14N4O5
C17H13N3O2
C18H15N3O2
C19H17N3O2
C22H15N3O2
C26H23N3O2
C16H10 F3N3O3S
C18H16 ClN3O3S
C21H15N3O3S
C22H17N3O3S
C22H17N3O
CH3-CH(Cl)-O-CO-
Butyl-O-CO-
Iso-butyl-O-CO-
Benzyl-O-CO-
4-nitro-phenyl-O-CO-
CH3-CO-
4g
4h
4i
4j
CH3-CH2-CO-
CH3-CH2-CH2-CO-
C6H5-CO-
4k
4l
4m
4n
4o
4p
4q
4r
4s
(4)-Tert-butyl-C6H4-CO-
CF3-SO2-
Cl-CH2-CH2-CH2-SO2-
Ph-SO2-
(4)-CH3-C6H4-SO2-
Benzyl
(p)F-C6H4-CH2-
(p)Br-C6H4-CH2-
(p)CH3-C6H4-CH2-
(p)Tert.butyl-C6H4-CH2-
(CH3)3C-O-CO-
C22H16FN3O
C22H16BrN3O
C23H19N3O
4t
4u
4v
4w
C26H25N3O
C20H19N3O3
ꢀ All products were recrystallized from hot aq. ethanol.
was recrystallized from aq. ethanol to obtain the pure compound
3. M.P.-174-176 °C.
g, 78%). The crude product was recrystallized from aq. ethanol
to obtain the pure compound 3. M.P.-174-176 °C.
General Procedure for the synthesis of compounds 4a and
4b. To a solution of compound 3 (2 mmoles) in acetone (50 ml)
was added finely grounded anhydrous K2CO3 (4 mmoles),
triethylbenzylammonium bromide (TEBAB, 1 mmole) followed
by the addition of alkylating agent (3 mmoles). The reaction
mixture was then refluxed for 5 hrs in case of 4a and 24 hrs in
case of 4b (tlc monitoring). Acetone from the reaction mixture
was evaporated under vacuum, water (50 ml) was added to the
residue and extracted with ethyl acetate. The ethyl acetate layer
Synthesis of compound (3) via Microwave Irradiation. A
mixture of OPDA (1.08 g, 10 mmole) and 2 (1.77 g, 10 mmole),
in polyphosphoric acid (10 ml) were stirred and irradiated in a
microwave oven at 100 W for 3 min at 170 °C. The reaction
mixture was then cooled to room temperature and the reaction
mass was neutralized with ice-cold concentrated potassium
hydroxide solution (50 ml) to obtain neutral pH. The solid that
separated out was collected by filtration, washed with water (3 x
50 ml) and dried under vacuum afforded an off-white solid (1.94

May-Jun 2007
Novel N-Substituted-2-(benzo[d]isoxazol-3-ylmethyl)-1H-benzimidazoles
689
was washed with water (2x50 ml), brine (20 ml) and dried over
anhydrous sodium sulfate. Evaporation of the solvent yielded the
corresponding alkylated product 4a or 4b (for details please see
Table 3).
2-((Benzo[d]isoxazol-3-yl)methyl)-1-methyl-1H-benzimida-
zole (4a). ir (KBr): 3020 (CH) cm-1. 1H-nmr (CDCl3): ꢀ 3.84 (s,
3H, N-CH3), 4.79 (s, 2H, -CH2-), 7.14-7.26 (m, 2H, Ar-H), 7.36
(t, J=7.35 Hz, 1H, Ar-H), 7.54 (d J=7.8Hz, 2H, Ar-H), 7.65 (t,
J=7.6Hz, 1H, Ar-H), 7.74-7.78 (m, 2H, Ar-H).13C-
nmr(CDCl3)(75 MHz): 25.66 (-CH2-), 30.21(N-CH3), 109.25,
109.73, 119.63, 120.96, 122.21, 122.25, 122.76, 123.75, 130.16,
136.09, 142.33, 148.87, 153.99, 163.38. (aromatic carbons). EI-
MS: 264 (M++1).
2-((Benzo[d]isoxazol-3-yl)methyl)-1-ethyl-1H-benzimida-
zole (4b). ir (KBr): 3043(CH) cm-1 1H-nmr (CDCl3): ꢀ 1.23 (t,
J=7.2Hz, 3H, -CH3), 4.26 (q, J=7.2Hz, 2H, N-CH2), 4.72 (s, 2H,
-CH2-), 7.19-7.32 (m, 4H, Ar-H), 7.47-7.55 (m, 2H, Ar-H), 7.76-
7.80 (m, 2H, Ar-H ). 13C-nmr (CDCl3) (75 MHz): 14.72(CH3),
25.69(CH2), 38.79(N-CH2), 109.49, 109.68, 119.72, 120.98,
122.12, 122.42, 122.68, 123.73, 130.14, 134.96, 142.55, 148.22,
154.15, 163.34(aromatic carbons). EI-MS: 278 (M++1).
Ethyl 2-((benzo[d]isoxazol-3-yl) methyl)-1H- benzimida-
zole-1-carboxylate (4c). ir (KBr): 2999(CH), 1742(C=O)cm-1.
1H-nmr (CDCl3): ꢀ 1.42 (t, J=6.9Hz, 3H, -CH3), 4.49 (q,
J=6.9Hz, 2H, O-CH2), 4.97 (s, 2H, -CH2-), 7.23-7.28 (m, 1H,
Ar-H), 7.35-7.40 (m, 2H, Ar-H), 7.50-7.62 (m, 3H, Ar-H),
7.72-7.76 (m, 1H, Ar-H), 7.96-7.99 (m, 1H, Ar-H).13C-nmr
(CDCl3) (75 MHz): 13.97(CH3), 28.56(CH2), 64.29(O-CH2),
109.79, 114.99, 119.98, 121.28, 121.56, 123.39, 124.47, 125.04,
129.76, 132.95, 141.93, 149.95, 150.07, 154.30 (C=O),
163.06.EI-MS: 322 (M++1).
1-Chloroethyl-2-((benzo[d]isoxazol-3-yl)methyl)-1H-benz-
imidazole-1-carboxylate (4d). ir(KBr): 1755(C=O)cm-1.1H-
nmr (CDCl3): ꢀ 1.93 (d, J=5.7Hz, 3H, CH3), 4.95 (s, 2H, CH2),
6.72 (q, J=6Hz, 1H, CH), 7.24-7.29 (m, 1H, Ar-H), 7.37-7.47
(m, 2H, Ar-H), 7.50-7.63 (m, 3H, Ar-H), 7.72-7.75 (m, 1H, Ar-
H), 7.96-7.99 (m, 1H, Ar-H) .13C-nmr(CDCl3)(75 MHz):
24.96(CH3), 28.63(CH2), 83.72(CH), 109.94, 115.07, 120.31,
121.23, 121.49, 123.54, 125.08, 125.54, 129.94, 132.68, 142.00,
147.78, 149.97, 154.11 (C=O), 163.16. EI-MS: 356 (M++1).
Butyl 2-((benzo[d]isoxazol-3-yl)methyl)-1H-benzimida-
zole-1-carboxylate (4e). ir (KBr): 1758(C=O)cm-1. 1H-nmr
(CDCl3): ꢀ 0.94 (t, J=7.2Hz, 3H, CH3), 1.36-1.48 (m, 2H, CH2),
1.71-1.84 (m, 2H, CH2), 4.43 (t, J=7.2Hz, 2H,O-CH2), 4.96 (s,
2H,-CH2), 7.22-7.27 (m, 1H, Ar-H), 7.32-7.39 (m, 2H, Ar-H),
7.49-7.61 (m, 3H, Ar-H), 7.72-7.75 (m, 1H, Ar-H), 7.94-7.97
(m, 1H, Ar-H).13C-nmr(CDCl3) (75 MHz): 13.55(CH3),
19.01(CH2), 28.61(CH2), 30.35(CH2), 68.16(O-C), 109.87,
114.98, 120.08, 121.34, 121.59, 123.43, 124.52, 125.10, 129.80,
132.99, 142.00, 150.16, 154.35 (C=O), 163.13 EI-MS: 350
(M++1).
Alternate synthesis of compound 4a. A mixture of N-
methy1-o-phenylenediamine dihydrochloride, 5 (1.95 g, 10
mmoles), 2 (2.12 g, 12 mmoles) was taken in a solution of 4 N
HCl (10 ml) and refluxed in a water bath for 6 hr (tlc
monitoring) The reaction mixture was then cooled to room
temperature and neutralized with aq. NaHCO3 (10%), till basic
pH to obtain a sticky oily mass which was then extracted with
ethyl acetate and was washed with aq. NaHCO3 (10%, 2 x 25
ml), water (2 x 50 ml), brine (15 ml) and dried over anhydrous
sodium sulfate. After evaporation of the solvent 4a was obtained
in 83% yield (2.18 g).
General Procedure for the synthesis of compounds 4c –
4q. To a solution of compound 3 (2 mmoles) in pyridine (5 ml)
was added acyl/aroyl chloride (3 mmoles) drop-wise at 0 °C. After
the addition was complete, the temperature of the reaction mixture
was slowly raised to room temperature and stirred at this
temperature for 2 hrs (tlc monitoring). A solution of 2 N HCl was
added to the reaction mixture until pH at which point a solid
separated out and was collected by filtration, washed with water (2
x 30 ml) and dried under vacuum to obtain the corresponding acyl
or aroyl derivatives 4c-4 (for details see Table 3).
General Procedure for the synthesis of compounds 4r - 4v.
To a solution of compound 3 (2 mmoles) in acetonitrile (20 ml)
was added aqueous sodium hydroxide solution (10%, 5 ml) and
the mixture was stirred for 15 minutes. Benzyl bromide (2.4
mmole) was then added slowly with stirring to the reaction
mixture at 0 °C. After the addition was complete, the
temperature of the reaction mixture was allowed to slowly rise
to room temperature and was stirred at this temperature for 24
hrs (tlc monitoring). After the completion of the reaction,
acetonitrile from the reaction mixture was evaporated under
vacuum to obtain a residue. The residue was then extracted with
ethyl acetate and the organic layer was washed with water (2 x
50 ml), brine (2 x 20 ml) and dried over anhydrous sodium
sulfate. Evaporation of the solvent under vacuum gave the
corresponding N-substituted derivatives 4r - 4v respectively.
The crude compounds were recrystallized from hot aq. ethanol
to obtain pure products (For details see Table 3).
Synthesis of compound 4w. To a solution of compound 3 (2
mmoles) in THF (10 ml) was added aq. NaOH (10%, 10 ml),
Boc anhydride (2 mmoles) in THF (5 ml) drop-wise at 0 °C.
After the addition was complete, the temperature of the reaction
mixture was slowly raised to room temperature and stirred at
this temperature for 2 hrs (tlc monitoring). The reaction mixture
was then diluted with water (30 ml) and extracted with ether.
The ethereal layer was washed with 1 N HCl (50 ml), brine (30
ml) and dried over anhydrous sodium sulfate. Evaporation of the
solvent yielded an off white solid 4w (for details see Table 3).
Isobutyl 2-((benzo[d]isoxazol-3-yl)methyl)-1H-benzimida-
zole carboxylate (4f). ir (KBr): 1751(C=O) cm-1. 1H-nmr
(CDCl3): ꢀ1.01 (s, 3H,CH3), 1.03 (s, 3H, CH3), 2.12-2.17 (m,
1H, CH2), 4.24 (d, J=6.6Hz, 2H, -O-CH2), 4.97 (s, 2H, -CH2),
7.23-7.29 (m, 1H, Ar-H), 7.35-7.39 (m, 2H, Ar-H), 7.53-7.62
(m, 3H, Ar-H), 7.72-7.75 (m, 1H, Ar-H), 7.95-7.98 (m, 1H, Ar-
H). 13C-nmr (CDCl3) (75 MHz): 19.03(CH3), 27.61(CH),
28.55(CH2), 74.30(O-CH2), 109.86, 114.93, 120.11, 121.36,
121.60, 123.41, 124.51, 125.09, 129.78, 132.91, 142.01, 150.28,
154.33 (C=O), 163.12. EI-MS: 350 (M++1)
Benzyl-2-((benzo[d]isoxazol-3-yl)methyl)-1H-benzimida-
zole-1-carboxylate (4g). ir (KBr): 1758(C=O)cm-1.1H-nmr
(CDCl3): ꢀ 4.93 (s, 2H, -CH2-), 5.48 (s, 2H, O-CH2-), 7.32-7.39
(m, 6H, Ar-H), 7.44-7.48 (m, 2H, Ar-H), 7.61-7.68 (m, 2H, Ar-
H), 7.73-7.80 (m, 2H, Ar-H), 7.92-7.95 (m, 1H, Ar-H). 13C-nmr
Spectral and Analytical Data for Compounds 3, 4a-4w.
2-((Benzo[d]isoxazol-3-yl)methyl)-1H-benzimidazole (3).
1
ir(KBr): 2900(-NH) cm-1. H-nmr (DMSO-d6): ꢀ 4.67 (s, 2H,-
CH2-), 7.10-7.19 (m, 2H, Ar-H), 7.35 (t, J=6.9Hz, 1H, Ar-H),
7.45 (t, J=6.6Hz,1H, Ar-H), 7.54 (t, J=7.2Hz,1H, Ar-H), 7.61-
7.67 (m,1H, Ar-H), 7.73-7.77 (m, 2H, Ar-H), 12.58 (s, 1H, -
NH). 13C-nmr (DMSO-d6) (75 MHz): 26.11(-CH2-), 109.77,
120.91, 121.59, 122.62, 123.90, 130.41, 148.81, 154.48, 163.07
(aromatic carbons). EI-MS: 250 (M++1).

690
S. D. Vaidya, B. V. S. Kumar, R. V. Kumar, U. N. Bhise and U. C.Mashelkar
Vol 44
(CDCl3) (75 MHz): 28.67(-CH2-), 69.85 (O-CH2), 109.90,
115.07, 120.10, 121.32, 121.58, 123.46, 124.62, 125.22, 128.80,
128.88, 129.07, 129.82, 132.97, 133.85, 141.99, 149.97, 150.11,
154.36 (C=O), 163.13. EI-MS: 384 (M++1).
nmr (CDCl3): ꢀ 4.86 (s, 2H, -CH2-), 7.27-7.33 (m, 1H, Ar-H),
7.40-7.47 (m, 2H, Ar-H), 7.53-7.64 (m, 3H, Ar-H), 7.68-7.73
(m, 1H, Ar-H), 7.83-7.86 (m, 1H, Ar-H).13C-NMR(CDCl3) (75
MHz): 26.76(-CH2-), 110.12, 113.56, 117.31, 121.09, 121.43,
121.60, 123.67, 126.33, 126.55, 130.05, 132.72, 141.51, 149.21,
153.16, 163.40. (aromatic and CF3 carobons). EI-MS: 382
(M++1).
2-((Benzo[d]isoxazol-3-yl)methyl)-1-(3-chloropropanesul-
fonyl)-1H-benzimidazole (4o). ir (KBr): 1054(S=O) cm-1. 1H-
nmr (CDCl3): ꢀ 2.18-2.27 (m, 2H, CH2), 3.53-3.64 (m, 4H,
CH2), 4.95 (s, 2H, -CH2-), 7.32-7.44 (m, 3H, Ar-H), 7.57-7.58
(m, 2H, Ar-H), 7.74-7.79 (m, 2H, Ar-H), 7.83-7.86 (m, 1H, Ar-
H). 13C-nmr (CDCl3) (75 MHz): 25.74(CH2), 26.92(-CH2-),
41.89(CH2), 51.96 (CH2Cl), 109.97, 113.07, 120.61, 121.01,
121.58, 123.84, 125.04, 125.60, 130.33, 133.12, 141.62, 148.76,
154.76, 163.19. (aromatic carbons). EI-MS: 390(M++1).
2-((Benzo[d]isoxazol-3-yl) methyl)-1-benzenesulfonyl-1H-
benzimidazole (4p). ir (KBr): 3059(CH), 1054(S=O) cm-1.1H-
nmr(CDCl3): ꢀ 4.98 (s, 2H,-CH2-), 7.19-7.24 (m, 1H, Ar-H),
7.34-7.42 (m, 4H, Ar-H), 7.48-7.57 (m, 4H, Ar-H), 7.68 (d,
J=7.2Hz, 1H, Ar-H), 7.84 (d, J=7.5Hz, 2H, Ar-H), 8.03 (d,
J=7.8Hz, 1H, Ar-H). 13C-nmr(CDCl3) (75 MHz): 27.03 (-CH2-),
109.89, 113.53, 120.52, 121.24, 121.78, 123.52, 124.91, 125.48,
126.73, 129.50, 129.88, 133.16, 134.66, 137.83, 141.68, 148.86,
153.81, 163.26 (aromatic carbons). EI-MS: 390(M++1).
2-((Benzo[d]isoxazol-3-yl)methyl)-1-(4-methylbenzenesul-
fonyl)-1H-benzimidazole (4q). ir (KBr): 3058(CH),1050 (S=O)
cm-1.1H-nmr (CDCl3): ꢀ 2.36 (s, 3H,CH3), 5.09 (s, 2H, -CH2-), 7.32-
7.45 (m, 5H, Ar-H), 7.62-7.78 (m, 3H, Ar-H), 7.77 (d, J=8.4Hz, 1H,
Ar-H), 7.96 (d, J=7.5Hz, 1H, Ar-H), 8.02 (d, J=8.4Hz, 2H, Ar-H).
13C-nmr (CDCl3) (75 MHz): 21.55(CH3), 26.98(-CH2-), 109.78,
113.53, 120.40, 121.22, 121.79, 123.44, 124.75, 125.34, 126.75,
129.77, 130.05, 133.12, 134.80, 141.64, 146.02, 148.81, 153.82,
163.21(aromatic carbons). EI-MS: 404(M++1).
4-Nitrophenyl 2-((benzo[d]isoxazol-3-yl)methyl)-1H-benz-
imidazole-1-carboxylate (4h). ir (KBr): 1765(C=O)cm-1.1H-
nmr (CDCl3): ꢀ 5.02 (s, 2H,-CH2), 7.28-7.31 (m, 1H, Ar-H),
7.42-7.45 (m, 4H, Ar-H), 7.55 (d, J=6.6Hz, 2H, Ar-H), 7.67 (d,
J=8.1Hz, 1H, Ar-H), 7.79-7.82 (m, 1H, Ar-H), 8.01-8.04 (m,
1H, Ar-H), 8.34 (d, J=6.6Hz, 2H, Ar-H).13C-nmr (CDCl3) (75
MHz): 28.76(CH2), 110.03, 115.03, 120.56, 121.15, 121.46,
122.38, 123.73, 125.42, 125.53, 125.84, 130.16, 132.79 (C=O),
142.10, 147.56, 149.95, 153.86, 154.08, 163.19 (aromatic
carbons & carbonyl carbon) EI-MS: 415 (M++1).
1-(2-((Benzo[d]isoxazol-3-yl)methyl)-1H-benzimidazole-1yl)-
ethanone (4i). ir (KBr): 1720(C=O)cm-1 .1H-nmr(CDCl3): ꢀ
2.87 (s, 3H, CH3), 4.95 (s, 2H, CH2), 7.31-7.42(m, 3H, Ar-H),
7.60-7.68 (m, 2H, Ar-H), 7.74-7.82 (m, 2H, Ar-H), 7.96 (d,
J=8.1Hz, 1H, Ar-H). 13C-nmr (CDCl3) (75 MHz): 26.80(CH3),
29.19(-CH2), 109.90, 113.54, 120.78, 121.42, 121.54, 123.45,
124.56, 125.00, 129.85, 132.45, 142.55, 150.89, 154.54, 163.06,
169.00 (C=O). EI-MS: 292 (M++1).
1-(2-((Benzo[d]isoxazol-3-yl)methyl)-1H-benzimidazole-1-
yl)propan-1-one (4j). ir (KBr): 2982(CH), 1728(C=O) cm-1.1H-
nmr (CDCl3): ꢀ 1.32 (t, J=7.2Hz, 3H, CH3), 3.14 (q, J=7.2Hz, 2H,
CO-CH2), 4.98 (s, 2H, -CH2-), 7.26-7.31 (m, 1H, Ar-H), 7.36-7.40
(m, 2H, Ar-H), 7.54-7.56 (m, 2H, Ar-H), 7.64-7.71 (m, 2H, Ar-
H), 7.75-7.79 (m, 1H, Ar-H).13C-nmr(CDCl3) (75 MHz):
8.41(CH3), 29.37(-CH2-), 32.20(CH2), 109.92, 113.77, 120.82,
121.46, 121.60, 123.44, 124.46, 124.93, 129.84, 132.20, 142.64,
151.04, 154.61, 163.09, 173.02 (C=O). EI-MS: 306 (M++1).
1-(2-((Benzo[d]isoxazol-3-yl)methyl)-1H-benzimidazole-1-
1
yl)butan-1-one (4k). ir (KBr): 2965(CH), 1714(C=O)cm-1. H-
NMR (CDCl3): ꢀ 0.99 (t, J=7.2Hz, 3H, CH3), 1.82 (q, J=7.2Hz,
2H, CH2), 3.05 (t, J=7.2Hz, 2H, -CH2-CO), 4.97 (s, 2H,-CH2-),
7.24-7.29 (m, 1H, Ar-H), 7.33-7.40 (m, 2H, Ar-H), 7.49-7.57
(m, 2H, Ar-H), 7.62-7.67 (m, 2H, Ar-H), 7.74-7.77 (m, 1H, Ar-
H).13C-nmr(CDCl3) (75 MHz): 13.40(CH3), 17.52(CH2), 29.27(-
CH2-), 40.39(CH2), 109.86, 113.69, 120.76, 121.43, 121.55,
123.41, 124.39, 124.87, 129.81, 132.16, 142.59, 151.00, 154.57,
163.05, 172.17 (C=O). EI-MS: 320 (M++1).
2-((Benzo[d]isoxazol-3-yl)methyl)-1-benzyl-1H-benzimida-
zole (4r). ir (KBr): 3026(CH) cm-1.1H-nmr (CDCl3): ꢀ 4.61 (s,
2H,-CH2-), 5.40 (s, 2H, N-CH2-), 6.91 (s, 2H, Ar-H), 7.17-7.28
(m, 7H, Ar-H), 7.47 (s, 2H, Ar-H), 7.71 (d, J=7.5Hz,1H, Ar-H),
7.82 (d, J=7.2Hz, 1H, Ar-H).13C-NMR(CDCl3) (75 MHz):
25.73(-CH2-), 47.01(N-CH2), 109.60, 109.75, 119.72, 120.95,
122.13, 122.30, 122.99, 123.56, 126.02,127.68, 128.68, 129.97,
135.27, 135.79, 142.35, 148.93, 153.82, 163.21(aromatic
carbons).EI-MS: 340(M++1).
1-(4-Fluorobenzyl)-2-((benzo[d]isoxazol-3-yl)methyl)-1H-
benzimidazole (4s). ir (KBr): 3033(CH)cm1. 1H-nmr (CDCl3): ꢀ
4.64 (s, 2H, -CH2-), 5.34 (s, 2H, N-CH2), 6.80-6.82 (m, 4H, Ar-
H), 7.18-7.44 (m, 4H, Ar-H), 7.44 (s, 2H, Ar-H), 7.68 (d,
J=7.8Hz, 1H, Ar-H), 7.83 (d, J=7.5Hz, 1H, Ar-H) .13C-nmr
(CDCl3) (75 MHz): 25.75(-CH2-), 46.34(N-CH2), 109.56,
109.59, 109.62, 115.33, 115.61, 119.77, 120.85, 122.02, 122.38,
123.07, 123.56, 127.62, 127.73, 129.99, 130.89, 130.93, 135.64,
142.30, 148.76, 153.70, 160.31, 163.15, 163.58(aromatic
carbons).EI-MS: 358(M++1).
1-(4-Bromobenzyl)-2-((benzo[d]isoxazol-3-yl)methyl)-1H-
benzimidazole (4t). ir (KBr): 3055(CH) cm-1.1H-nmr(CDCl3): ꢀ
4.65 (s, 2H, -CH2-), 5.33 (s, 2H, N-CH2), 6.68 (d, J=8.1Hz, 2H,
Ar-H), 7.15-7.32 (m, 6H, Ar-H), 7.43-7.50 (m, 2H, Ar-H), 7.66
(d, J=8.1Hz, 1H, Ar-H), 7.83 (d, J=7.8Hz, 1H, Ar-H).13C-nmr
(CDCl3) (75 MHz): 25.87(-CH2-), 46.52(N-CH2), 109.59,
109.70, 119.88, 120.88, 121.56, 122.03, 122.52, 123.22, 123.64,
127.62, 130.05, 131.64, 134.16, 135.71, 142.32, 148.77, 153.69,
163.21(aromatic carbons).EI-MS: 418(M++1).
(2-((Benzo[d]isoxazol-3-yl)methyl)-1H-benzimidazole-1-yl)-
(phenyl)methanone (4l). ir (KBr): 3065(CH), 1688(C=O) cm-1.
1H-NMR (CDCl3): ꢀ 4.95 (s, 2H, -CH2-), 6.62 (d, J=8.4Hz, 1H,
Ar-H), 7.10 (t, J=7.2Hz, 1H, Ar-H), 7.26-7.31 (m, 2H, Ar-H),
7.46-7.50 (m, 4H, Ar-H), 7.65-7.77 (m, 5H, Ar-H).13C-
NMR(CDCl3) (75 MHz): 27.28(-CH2-), 109.89, 113.32, 120.18,
121.15, 121.39, 123.50, 124.00, 124.14, 128.91, 129.93, 130.05,
132.82, 133.92, 134.05, 142.15, 150.80, 154.36, 163.07, 168.64
(C=O). EI-MS: 354 (M++1).
(4-tert-Butylphenyl)(2-((benzo[d]isoxazol-3-yl)methyl)-1H-
benzimidazole-1-yl)methanone(4m). ir (KBr): 1697(C=O)
cm-1.1H-nmr (CDCl3): ꢀ 1.36 (s, 9H, CH3), 4.93 (s, 2H, -CH2-),
6.74 (d, J=8.4Hz, 1H, Ar-H), 7.12 (t, J=7.05Hz, 1H, Ar-H),
7.25-7.31 (m, 2H, Ar-H), 7.47-7.53 (m, 4H, Ar-H), 7.64-7.69
(m, 3H, Ar-H), 7.76 (d, J=7.2Hz, 1H, Ar-H). 13C-nmr (CDCl3)
(75 MHz): 27.20(-CH2-), 31.01(CH3), 35.33(C-), 109.89,
113.35, 120.14, 121.21, 121.46, 123.49, 123.88, 124.09, 125.91,
129.84, 129.90, 130.21, 134.09, 142.16, 150.75, 154.40, 158.32,
163.09, 168.50 (C=O). EI-MS: 410 (M++1).
2-((Benzo[d]isoxazol-3-yl)methyl)-1-trifluoromethanesul-
1
fonyl-1H-benzimidazole (4n). ir (KBr): 1044(S=O) cm-1. H-

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Novel N-Substituted-2-(benzo[d]isoxazol-3-ylmethyl)-1H-benzimidazoles
691
[3] Kohler P. Int. J. Parasitol., 2001, 31, 336.
[4] Preston, P. N. Chem. Rev., 1974, 74, 279.
1-(4-Methylbenzyl)-2-((benzo[d]isoxazol-3-yl)methyl)-1H-
benzimidazole (4u). ir (KBr): 3056(CH) cm-1.1H-nmr (CDCl3):
ꢀ 2.24 (s, 3H, CH3), 4.63 (s, 2H, -CH2-), 5.33 (s, 2H, N-CH2-),
6.80 (d, J=7.8Hz, 2H, Ar-H), 6.95 (d, J=7.8Hz, 2H, Ar-H), 7.14-
7.28 (m, 4H, Ar-H), 7.44-7.45 (m, 2H, Ar-H), 7.68 (d, J=7.8Hz,
1H, Ar-H), 7.81 (d, J=7.8Hz, 1H, Ar-H).13C-nmr (CDCl3) (75
MHz): 20.91(CH3), 25.73(-CH2-), 46.83(N-CH2-), 109.54,
109.77, 119.66, 120.96, 122.15, 122.21, 122.92, 123.51, 126.04,
129.30, 129.89,132.24, 135.80, 137.38, 142.32, 148.90, 153.83,
163.19 (aromatic carbons). EI-MS: 354(M++1).
1-(4-tert-Butylbenzyl)-2-((benzo[d]isoxazol-3-yl)methyl)-1H-
benzimidazole (4v). ir (KBr): 3058(CH) cm-1.1H-nmr (CDCl3 ):
ꢀ 1.25 (s, 9H, CH3), 4.65 (s, 2H, -CH2-), 5.36 (s, 2H, N-CH2),
6.86 (d, J=7.5Hz, 2H,Ar-H), 7.17-7.28 (m, 6H, Ar-H), 7.43 (s,
2H, Ar-H), 7.69 (d, J=7.8Hz, 1H, Ar-H), 7.84 (d, J=7.5Hz, 1H,
Ar-H) . 13C-nmr (CDCl3) (75 MHz): 25.67(-CH2-), 31.08(CH3),
34.26(C), 46.61(N-CH2), 109.49, 109.72, 119.61, 120.94,
122.07, 122.17, 122.86, 123.43, 125.48, 125.70, 129.82, 132.21,
135.80, 142.27, 148.87, 150.52, 153.75, 163.11(aromatic
carbons). EI-MS: 396(M++1).
[5a] Breslin, H. J.; Miskowski, T. A.; Kukla, M. J.; De Winter, H.
L.; Somers, M. V. F.; Roevens, P. W. M.; Kavash, R. W. Bioorg. &
Med. Chem. Lett., 2003, 13, 4467; [b] Spasov, A. A.; Yozhitsa, L. N.;
Bugaeva, L. I.; Anisimova, V. A. Pharmaceutical Chem. Journal, 1999,
33, 232; [c] Valdez, J.; Cedillo, R.; Hernandez-Campos, A.; Yepez, L.;
Hernandez-Luis, F.; Navarrete-Vazquez, G.; Tapia, A.; Cortes, R.;
Hernandezc, M.; Castillo, R. Bioorg. & Med. Chem. Lett., 2002, 12,
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[6a] Vinod Kumar, R.; Raja Gopal, K. and Seshu Kumar, K. V. S.
R. J. Heterocycl.
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Kumar, R.; Bhirud, S. B.; Mane, R. B. Euro. J. Med. Chem., 2006, 41,
599 .
[7a] Mustafa, A.; Hsihmat, O. H.; Zayed, S. M. A. D.; Nawar, A.
A. Tetrahedron,
1963, 19, 1831; [b] Casini, G.; Gualtieri, F.; Stein, M. L. J. Heterocycl.
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Heterocycl. Chem. 1969, 6, 279.
[8] Phillips, M. A. J. Chem. Soc., 1928, 2393.
[9] For a preliminary communication of this work please see.
Vaiday, S. D.; Siva Kumar, B. V.; Vinod Kumar, R.; Bhirud, S. B.;
Mashelkar, U. C. Indian J. Heterocycl. Chem, 2005, 14, 197.
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38, 4071.
tert-Butyl-2-((benzo[d]isoxazol-3-yl)methyl)-1H-benzimi-
dazole-1-carboxylate (4w). ir (KBr): 1751(CO) cm-1.1H-nmr
(CDCl3 ): ꢀ 1.62 (s, 9H, CH3), 4.96 (s, 2H, -CH2-), 7.22-7.38
(m, 3H, Ar-H), 7.50-7.56 (m, 3H, Ar-H), 7.70-7.73 (m, 1H, Ar-
H), 7.93-7.96 (m, 1H, Ar-H). 13C-NMR (CDCl3) (75 MHz):
27.84(-CH2-), 28.56(CH3), 86.09(O-C), 109.81, 114.95, 119.92,
121.36, 121.64, 123.38, 124.22, 124.82, 129.74, 133.15, 141.87,
148.50, 150.13, 154.41 (C=O), 163.06. EI-MS: 350 (M++1).
[11] Kauffman, J. M.; Khalaj, A.; Litak, P. T.; Novinski, J. A.;
Bajwa, G. S. J. Heterocycl. Chem., 1994, 31, 957.
[12] Reviews on microwave chemistry include: [a] Gabriel, C.;
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Texier-Boullet, F.; Jacquault, P.; Mathé, D. Synthesis, 1998, 9, 1213;
[e] Galema, S. A. Chem. Soc. Rev., 1997, 26, 233; [f] Caddick, S.;
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Danks, T. N. Tetrahedron. Lett., 1999, 40, 3957; (h) Microwaves in
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[*†] Author to whom all correspondence should be addressed. E-
mail: udaymashelkar@yahoo.com
[1a] Wright, J. B. Chem. Rev., 1951, 48, 397; [b] Amari, M.;
Fodili, M.; Nedjar-Kolli, B. J. Heterocycl. Chem., 2002, 39, 811.
[2] The Merck Index, 13th Edition, Ed. M. J. O'Neil; M. Smith; P.
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