Synthesis of some new benzimidazole derivatives of pharmaceutical interest

Article abstract of DOI:10.1155/2011/723421

Reaction of 2-(aminomethyl)benzimidazole dihydrochloride (1) with ethyl acetoacetate was studied to give diazepinone-benzimidazole derivative (2), while, treatment of 1 with phenylhydrazono ethylacetoacetate afforded phenylhydrazino diazepinone derivative

Full text of DOI:10.1155/2011/723421

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(2), 748-752
http://www.e-journals.net
Synthesis of Some New Benzimidazole
Derivatives of Pharmaceutical Interest
FAWZIA ZAKARIA EL-ABLACK
Chemistry Department, Damietta Faculty of Science
Mansoura University, Egypt
fawzia@mans.edu.eg
Received 27 March 2010; Accepted 20 May 2010
Abstract: Reaction of 2-(aminomethyl)benzimidazole dihydrochloride (1)
with ethyl acetoacetate was studied to give diazepinone-benzimidazole
derivative (2), while, treatment of 1 with phenylhydrazono ethylacetoacetate
afforded phenylhydrazino diazepinone derivative (3). On the other hand,
reaction of 1 with acetyl acetone resulted in the formation of diazepine
derivative (4). The reaction of 1 with ethyl cyanoacetate was studied to give 3-
aminodiazepinone derivative (5). Also the reaction of 1 with acetophenone
and/or benzophenone has been investigated to give the fused imidazolines 6 and
7
respectively, while the reaction of 1 with cyclopentanone gave
benzimidazolyl derivative (8). Treatment of 1 with chloroacetyl chloride gave
the fused pyrazinone (9). The treatment of 1 with benzoin gave the derivative
(10). The structures of the hitherto unknown compounds have been confirmed
from analytical and spectral data. The newly synthesized compounds were
screened for antibacterial and antifungal activity
Keywords Diazepino-Benzimidazole, Pyrazino -benzimidazole and midazolo {1.5-a}benzimidazole,
Antibacterial, Antifungal activity
Introduction
Benzimidazole derivatives have been reported to have a wide range of pharmacological and
biochemical activity; It consider to be CNS depressant, anti-Parkinson, antiviral activity, anti
ulcerative, antihypertensive, antifungal, antitumor, antihistaminic, anti-bacterial and anti-
helminthes agents1-4
.
Following the above findings and continuous to our previous work5-8 directed towards
the synthesis of fused heterocyclic compounds of potential biological activities the utilizing
of 2-aminomethyl benzimidazole9 as a title compound for the synthesis of some new
benzimidazole derivatives was studied.

Synthesis of Some New Benzimidazole Derivatives
749
Due to the wide range of pharmacological activity and synthetic application of
benzimidazoles in this study it was planned to synthesize benzimidazole derivatives
using 2-aminomethyl benzimidazole9 (1). Thus the reaction of 2-aminomethyl
benzimidazole (1) with ethyl acetoacetate gave diazepinone derivative (2). IR
spectrum revealed the disappearance of NH2 absorption band at 3400-3550 cm-1 and
the appearance of absorption band at 1680 cm-1 CO group. NMR spectra established
the presence of a signals at δ 3.78(s, 2H, CH2) and at δ 2.6 (s, 2H, CH2) so it not
present as tautomeric enaminone structure (2). Treatment of 1 with phenylhydrazeno
ethyl acetoacetate afforded (1,4-diazepino [1,2-a] benzimidazole derivative (3), the
1
structure of 3 was based on the analytical and spectral data, the H NMR spectrum
reveal the presence of a signal at δ 8.12 (s, 1H, NH) and δ 2.89 (s, 2H,CH2). While
the treatment of 1 with acetyl acetone in 1 N sodium hydroxide solution resulted in
the formation of 3,5-dimethyl-[1,3]diazipene[1,2-a]benzimidazole derivative (4), the
structure of 4 was inferred from the obtained analytical and spectral data. IR spectrum
revealed the disappearance of NH2 absorption band and the presence of absorption
band at 1625 cm-1 for C=N.
When 1 was treated with ethyl cyanoacetate in ethanol containing a catalytic amount of
piperdene gave 3-amino diazepinone derivative (5). The structure of 5 was based on the
1
analytical and spectral data. IR spectrum reveal the presence of (NH2) at 3345 cm-1, the H
NMR spectrum revealed the presence of signal at δ 6.5 (s, 2H, NH2), δ 7.2 - 7.7 (m, 4H,
ArH), δ 2.73 (s, 2H, CH2) and δ 2.85 (s, 2H, CH2) so it not present in its tautomeric
enaminone structure (5). .
The reaction of 1 with acetophenone and benzophenone resulted in the formation
of 1H-imidazol[1,5-a]benzimidazole derivatives (6,7) respectively. The structure of
6 was confirmed from the obtained analytical and spectral data. IR spectrum of 6
displayed absorption band at 3330 cm-1 (NH), 1H NMR spectrum displayed signals at
δ 2.1 (s, 1H, NH) (Table 3).
As a further extension of the above studies, the reaction of 1 with cyclopentanone gave
benzimidazole derivative (8). The structure of 8 was assigned from the analytical and
spectral data. 1H NMR spectrum displayed signal at δ 2.3 (s, 1H, NH).
Treatment of 1 with chloroacetyl chloride gave pyrazino{1,2-a}benzimidazol-3(4H)-
one derivative (9). The structure of 9 was established from the obtained analytical and
spectral data. IR spectrum revealed absorption band at 3335 cm-1 NH. On the other hand, the
reaction of 1 with benzoin in ethanol containing catalytic amount of piperdene gave 3, 4-
1
diphenyl-1,4-dihydropyrazino[1,2-a]benzimidazole (10). H NMR revealed signal at δ 5.01
(s, H, CH olefinic) and at δ 4.78 (s, 2H, CH2) (Scheme 1& 2).
Experimental
Melting points (uncorrected) were determined on Fisher-Johns melting point apparatus.
Elemental analysis was performed in the microanalysis unit, Cairo University. IR spectra
were recorded by means of pressed KBr on a Perkin-Elmer 883 infrared spectrophotometer.
1H NMR spectra were recorded on a Varian 90 MHz in CDCl3.

750
F. Z. EL-ABLACK et al.
O
O
CH3
N
N
NH
NH
N
NH
N
N
N
C6H5
NH
(2\)
(9)
O
(8)
C6H5
N
CH3
CL-CO-CH2-CL
Cl-CO-CH2-Cl
N
N
N
cyclopentanone
N
E.A.A
benzophenone
(7)
(2)
H
N
N
N-NHAr
acetophenone
dye
E.A.A
NH2
CH3
NH
O
C6H5
N
(1)
CH3
N
N
N
E.C.A
A.A
N
(6)
(3)
CH3
CH3
O
NH2
N
N
N
N
N
N
(4)
(5)
O
N
N
NH2
NH
(5’)
Scheme 1
C6H 5
C 6H5
H
N
N
N
N
NH2
N
(1)
(10)
Scheme 2
Formation of 3-methyl-1,4-dihydro-5H{1,4}diazepino{1,2-a}benzimidazol-5-one (2)
To a solution of 1 (0.01 mol) in NaOH solution (1 N, 25 mL) ethyl acetoacetate (0.01 mol) was
added. The reaction mixture was heated on water bath for 3 h, left to cool and the solid product
was separated, filtered off and recrystallized from the appropriate solvent ( Table 1).
Formation of (4E)-3-methyl-4-(2-phenylhydrazinylidene)-1,4-dihydro-5H-[1,4]diazepino
[1,2-a]benzimidzol-5-one (3)
To a 0.01 mol solution of 1 in NaOH solution (1 N, 25 mL), phenylhydrazino ethyl
acetoacetate (0.01 mol) was added. The reaction mixture was heated on water-bath with
continuous stirring and cooled. The obtained product was filtered off and recrystallized from
the proper solvent (Table 1).

Synthesis of Some New Benzimidazole Derivatives
751
Formation of 3,5-dimethyl-1H-{1,4}diazepino{1,2-a}benzimidazole (4)
A mixture of 1 (0.01 mol) and acetyl acetone (0.01 mol) in 30 mL ethanol containing a
catalytic amount of piperidene (1 mL) was heated under reflux for 3-4 h. The solid product
was cooled, filtered off and recrystallized from ethanol (Table 1).
Formation of 3-amino-1,4-dihydro-5H{1,4}diazepino{1,2-a}benzimidazol-5-one (5)
To a solution of 1 (0.01 mole) in ethanol (30 mL) containing a catalytic amount of
piperidene (0.5 mL), ethyl cyanoacetate (0.01 mole) was added. The reaction mixture was
heated to reflux for 4 h, cooled, poured onto ice-cold water. The obtained products were
filtered off and crystallized from ethanol (Table 1).
Formation of 1-methyl-1-phenyl-2,3-dihydro-1H-imidazol[1,5-a]benzimidazole (6),
and 1,1-diphenyl-2,3-dihydro-1H-imidazol[1,5-a]benzimidazole (7)
A mixture of 1 (0.01 mol) and acetophenone and/or phenzophenone (0.01 mol) in ethanol
(30 mL) containing a catalytic amount of piperidene (1 mL) was heated to reflux for 3-4 h,
cooled and poured onto ice-cold water then acidified with dil HCl. The solid product that
separated was filtered off and crystallized from the appropriate solvent (Table 1).
Formation of 6\,7\-dihydrospiro[ cyclopentane-1,5\-imidazo[1,5a] benzimidazole] (8)
A mixture of 1 (0.005 mol) and cyclopentanone (0.005 mol) was heated under reflux for 3-4 h in
ethanol (30 mL) containing piperidene (1 mL). The reaction mixture was cooled, poured onto acidified
ice-cold water. The product was filtered off and recrystallized from the proper solvent (Table 1).
Formation of 1,2-dihydro pyrazino{1,2-a}benzimidazol-3(4H)-one (9)
A mixture of 1 (0.01 mol) and chloroacetyl chloride (0.03 mol) was heated in water bath for
3 h, the solid product was cooled, filtered off, washed with ethanol and recrystallized from
the proper solvent (Table 1).
Formation of 3,4-diphenyl-1,4-dihydropyrazino[1,2-a]benzimidazole (10)
A mixture of 1 (0.01 mol) and benzoin (0.01 mol) in 50 mL ethanol containing a catalytic
amount of piperdine (1 mL) was heated under reflux for 4 h, cooled, poured into ice-cooled
water and acidified. The precipitated was filtered off and recrystallized from ethanol (Table 1).
Table 1. Characterization data of the compounds
Compound Yield, M.P
Colour Solvent Formula
(M.Wt).
EtOH/ C12H11N3O 67.59
Calc./Found
%C %H %N
%
92
oC
170
2
3
Dark
brown
brown
5.2
5.0
4.76
4.52
6.20
6.0
4.71
4.25
6.06
5.83
5.50
5.12
7.1
6.85
4.85
4.52
5.26
4.96
19.71
19.51
22.07
21.96
19.89
18.94
26.16
25.45
16.86
16.24
13.5
AcOH (213.23) 67.01
EtOH C18H15N5O 68.12
(317.34) 67.99
77.77
60
145
197
178
4
Pale
brown
Brown
EtOH C13H13N3 73.91
(211.25) 73.54
5
89.2
65.9
89.7
73.9
63.04
70.2
EtOH C11H10N4O 61.67
(214.22) 61.15
202 Reddish EtOH C16H15N3 77.1
6
brown
White
(249.3)
EtOH C21 H17N3 81.0
(311.37) 80.54
76.09
7
245
145
180
120
12.93
19.7
8
Brown
White
EtOH C13H15N3 73.21
(213.27) 72.95
EtOH C10H9N3O 64.16
(187.192) 63.95
19.54
22.45
22.01
13.00
12.80
9
10
Yellow EtOH C22H17N3 81.73
323.390 81.01

752
F. Z. EL-ABLACK et al.
Pharmacology
A solution of the tested compounds in acetone (1 mg/mL) was added to the nutrient agar (for
bacteria) or medium (for fungi) mixed well and poured on plates, the tested organism was
then streaked on the surface of agar or medium was incubated at 37 ºC for 24 h (bacteria)
and 28 ºC for 48 h (fungi) and the growth was recorded the organism used were S. Aurous,
S. Albus, E. Coli in addition to yeast (Table 2).
Table 2. In vitro biological activity of the compounds (2, 6, 7, 8, 9)
Compound
S. Albus
S.aureus
50
E.coli
-
Yeast
-
50
β
.subtities
-
50
50
-
-
50
2
6
7
8
9
-
100
100
-
-
100
50
100
100
100
100
100
50
100
100
Table 3. Spectral data of synthesized compounds
IR. cm-1 (KBr)
1H NMR. δ(ppm)
Compd
3095(CH aromatic), 2965 (CH3), 2890
(CH2), 1675 (C=O), 1620 (C=N).
3410(NH); 2995 (CH aromatic);2885(CH2) 2.03 (s, 3H. CH3); 2.89 (s, 2H. CH2); 7.43-
1.05 (s, 3H. CH3); 3.78 (s, 2H. CH2); 2.6 (s,
2H. CH2).7.24 (m, 4H, ArH).
2
3
4
2930( CH3);1680(C=O); 1620(C=N).
3042 (CH aromatic); 2965-2980 (CH3);
2890 (CH2); 1625 (C=N); 1610 (C=C).
3050 (CH aromatic); 3345 (NH2); 2895
(CH2); 1680 (C=O); 1628 (C=N).
7.65 (m, 9H, ArH), 8.81 (s, H, NH)
1.13(s, 6H. CH3); 2.65(s, 2H. CH2); 7.1-7.7
(m, 4H, ArH)); 5.1 (s, H, CH olefinic)
2.4(s, 2H. CH2); 2.8 (s, 2H, CH2) 7.1-7.7 (m,
4H. ArH); 6.5 (s, 2H, NH2)
5
3330(NH); 3095(CH aromatic);2930(CH3); 2.03(s, 3H. CH3); 3.8 (s, 2H. CH2); 7.1-7.6
6
2896(CH2); 1626(C=N);1200-1250(C-N-C).
3415 (NH); 3096 (CH aromatic); 2875
(CH2); 1620 (C=N).
(m, 9H. ArH); 2.1 (s, 1H, NH).
7.12-7.67 (m, 14H, ArH); 3.8 (s, 2H, CH2);
2 (s, 1H, NH).
7
3445 (NH), 3095 (CH Aromatic), 2870 7.23-7.63( m, 4H, ArH); 3.43 (s, 2H, CH2);
(CH2), 1624 (C=N) 2.3 (s, 1H, NH);1.56-2.2 (CH2 cyclopetane)
3335 (NH); 3045 (CH aromatic);2899(CH3); 3.4(S, 2H, 2CH2); 4.46 (S, 2H, CH2); 7.26-
8
9
2880(CH2); 1680(C=O);1620 (C=N).
3100 (ArH), 2910 (CH2), 3085 (=C-H),
1628 ( C=N).
7.65 ( m, 4H, ArH); 8.15 (S, 1H, NH)
7.06-7.62 ( m, 14H, ArH), 5.01 (s, 1H, CH
olefinic), 4.79 (s, 2H, CH2)
10
References
1.
2.
3.
Menon M K, Clark W G and Ures D A, Eur J Pharmacol.,1972, 19, 43-51.
Pandey V K and Agarwat A K, J Indian Chem Soc., 1981, 58, 306-307.
Spasov A A, Yozhitsa I N, Bugaeva L I and Anisimova V A, Pharm Chem J., 1999,
33, 232-243.
4.
a) Gravatt G L, Baguley B C, Wilson W R and Denny W A, J Med Chem., 1994, 37,
4338-4345;. b) Jayashankara B and Rai K M L, ARKIVOC, 2008, 11, 75.
El-Ablack F Z, Etmann H A, Metwally M A and Amer F A, Pharmzie, 1995, 50(3), 222-224.
El-Ablack F Z, Etman H A and Metwally M A, Boll Chim Farmaceutico.,1995, 134, 77-79.
Mohareb R M, Wardakhan W W and El-Ablack F Z, J Chem Res (M), 1994, 747-760.
El-Ablack F Z, Boll Chi Farmac., 2003, 9, 142.
5.
6.
7.
8.
9.
Reddy B S, Reddy R B, Chandramouli G V P and Reddy Y D, J Indian Chem Soc.,
1988, 65, 853-854.

International Journal of
Advances in
Organic Chemistry
International
International Journal of
International Journal of
Photoenergy
Medicinal Chemistry
Analytical Chemistry
Physical Chemistry
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
Volume 2014
International Journal of
Carbohydrate
Chemistry
Journal of
Quantum Chemistry
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
http://www.hindawi.com
Volume 2014
Volume 2014
Submit your manuscripts at
http://www.hindawi.com
Journal of
The Scientific
Analytical Methods
in Chemistry
World Journal
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
http://www.hindawi.com
Volume 2014
Volume 2014
International Journal of
Journal of
Journal of
International Journal of
Bioinorganic Chemistry
Spectroscopy
Inorganic Chemistry
Electrochemistry
Applied Chemistry
and Applications
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
Journal of
Journal of
International Journal of
Chromatography
Journal of
Theoretical Chemistry
Catalysts
Research International
Chemistry
Spectroscopy
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
Volume 2014
Volume 2014
Volume 2014