Synthesis and characterization of some new benzimidazole derivatives

Article abstract of DOI:10.1080/00397910903296045

Synthesis of nine new benzimidazole derivatives was reported. The products were identified by ¹H NMR, mass spectroscopy, and infrared spectroscopy. Taylor & Francis Group, LLC.

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Synthesis and Characterization of Some
New Benzimidazole Derivatives
Pingili Ramchandra Reddy a b , Ganta Madhusudan Reddy a , Ghanta
Mahesh Reddy a & Vurimidi Himabindu b
a Research and Development, Integrated Product Development, Dr.
Reddy's Laboratories Ltd., Andhra Pradesh, India
b Center for Environment Sciences, Institute of Science and
Technology, Jawaharlal Nehru Technological University, Kukatpally,
Hyderabad, India
Published online: 05 Aug 2010.
To cite this article: Pingili Ramchandra Reddy , Ganta Madhusudan Reddy , Ghanta Mahesh Reddy &
Vurimidi Himabindu (2010) Synthesis and Characterization of Some New Benzimidazole Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:17, 2610-2616, DOI: 10.1080/00397910903296045
To link to this article: http://dx.doi.org/10.1080/00397910903296045
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Synthetic Communications1, 40: 2610–2616, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903296045
SYNTHESIS AND CHARACTERIZATION OF SOME NEW
BENZIMIDAZOLE DERIVATIVES
Pingili Ramchandra Reddy,1,2 Ganta Madhusudan Reddy,1
Ghanta Mahesh Reddy,1 and Vurimidi Himabindu2
1Research and Development, Integrated Product Development,
Dr. Reddy’s Laboratories Ltd., Andhra Pradesh, India
2Center for Environment Sciences, Institute of Science and Technology,
Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, India
Synthesis of nine new benzimidazole derivatives was reported. The products were identified
by 1H NMR, mass spectroscopy, and infrared spectroscopy.
Keywords: Anti-inflammatory; anti-ulcerative; derivatives of benzimidazoles; synthesis and
characterization
INTRODUCTION
Benzimidazole derivatives have been found to possess a wide range of
biological activities, such as anticonvulsant,[1] antidepressant,[2] antihistamine,[3,4]
antifungal,[5] antihypertensive,[6] anticancer,[7] anti-inflammatory,[8] anthelmintic,[9,10]
and antiallergic[11] properties. The biological activities of the compounds containing
this basic moiety have been well documented.[12] Some of them (such as thiabenda-
zole, mebendazole, and albendazole) are widely used as antihelmintic drugs.[13]
Similarly, benzimidazole-2-thiol and its derivatives have also been reported to have
potent biological activities, such as proton pump inhibitory activity,[14] antiulcer
activity,[15] and potassium-activated ATPase (Hþ=Kþ-ATPase) inhibitory activity.[16]
The therapeutic agents that have been commonly used for the treatment of
ulcers are antacids for neutralizing gastric acid, antipepsin agents for protecting
the gastric mucous membrane, and anticholinergic agents for inhibiting gastric acid
secretion.
At the present time, histamine-H2 receptor antagonists have been widely used
for treating gastric and duodenal ulcers. More recently, proton pump inhibitors are
gaining importance because they block the proton pump of the Hþ=Kþ-ATPase
enzyme specifically present in the parietal cells of the stomach and inhibit the gastric
acid secretion at the final stage.
Received June 24, 2009.
Address correspondence to Ghanta Mahesh Reddy, Research and Development, Integrated
Product Development, Dr. Reddy’s Laboratories Ltd., Plot No. 21, Road No. 4, Jawahar Colony,
Hyderabad, Andhra Pradesh, India. E-mail: ram2reddy@rediffmail.com
2610

SYNTHESIS OF BENZIMIDAZOLE DERIVATIVES
2611
Scheme 1. Synthesis of benzimidazole derivatives.
Ganser and Forte were the first to demonstrate that parietal cell membranes
contain a Hþ=Kþ-ATPase enzyme, which operates as a proton pump. Substituted
benzimidazoles are capable of blocking gastric acid secretion in response to known
stimuli. It is reported that benzimidazole sulfide is capable of inhibiting gastric acid
secretion in vivo.
In view of the biological and pharmacological importance of both pyridine and
benzimidazole moieties, it was thought worthwhile to synthesize new benzimidazole
derivatives coupled with both pyridine and benzimidazole moieties.

2612
P. R. REDDY ET AL.
RESULTS AND DISCUSSION
Three series of benzimidazole derivatives containing both pyridine and
benzimidazole moieties are prepared. One series of benzimidazole derivatives was
prepared as follows:
The reaction of 2-mercapto-1H-benzimidazole (1) with 40-bromomethyl-
biphenyl-2-tetrazole (2) in aqueous sodium hydroxide at room temperature gives
product 3. Compound 3 is reacted with 2-chloromethyl pyridine derivatives 4a–d
in the presence of aqueous sodium hydroxide at room temperature to afford com-
pounds 5a–d. The compounds 5a–d are treated with aqueous hydrochloric acid in
the presence of methanol to give products characterized as compounds 6a–d on
the basis of spectral and analytical data. Thus, IR spectra showed characteristic
absorptions at 3400 cmꢀ1 (assignable to the tautomeric NH-group of the imidazole),
3050 cmꢀ1 (assignable to the aromatic CꢀH stretching), around 1630 and 1580
=
=
(assignable to the aromatic C C, C N stretching), 1460 strong band (assignable
to the aliphatic CꢀH bending), and 1070 (assignable to the CꢀO stretching). The
1
IR, H NMR, and mass spectra are mentioned in the Experimental section.
The other series of benzimidazole was prepared by sulfoxidation of 3 with
meta-chloroperbenzoic acid (m-CPBA) in dichloromethane (DCM) to give
compound 7. The compound 7 is deprotected with aqueous hydrochloric acid in
the presence of methanol to yield compound 8, which was characterized on the basis
of its spectral and analytical data. Thus, its IR spectrum showed characteristic
absorption at 3420 cmꢀ1 (assignable to the tautomeric NH group of the imidazole
ring), 3050 cmꢀ1 (assignable to the aromatic CꢀH stretching), around 1600 and
=
1
=
1580 (assignable to the aromatic C C, C N stretching), and 1476 (assignable to
the aliphatic CꢀH bending). Its IR, H NMR, and mass spectra are mentioned in
the Experimental section.
The another series of benzimidazoles were prepared by treating of 9 with 4a–d
in the presence of aqueous sodium hydroxide at 50 ꢁC for 15 h at room temperature
to give the products characterized as compounds 10a–d on the basis of spectral and
analytical data. The IR spectra showed absorption around 3050 cmꢀ1 (assignable to
the aromatic CꢀH stretching), around 1580 and 1560 (assignable to the aromatic
=
=
C C, C N stretching), 1460 (assignable to the aliphatic CꢀH bending), and 1035
(assignable to the CꢀO stretching). Its IR, 1H NMR, and mass spectra are
mentioned in the Experimental section. See Scheme 1.
EXPERIMENTAL
The IR spectra were recorded in the solid state as KBr dispersion media
using a Perkin-Elmer Spectrum One Fourier transform (FT)–IR spectrophot-
1
ometer. H NMR was recorded in dimethylsulfoxide (DMSO) using a 400-MHz
Varian Mercury Plus 400-MHz FT NMR spectrometer in DMSO-d6. The 1H
chemical shift values were reported on the d scale in parts per million, relative
to tetramethylsilane (TMS; d ¼ 0.00 ppm). The liquid chromatography–mass
spectrometry (LC-MS) was performed on a AB-4000 Q-trap LC-MS=MS mass
spectrometer. Compounds 1, 2, and 4a–d were procured from Dr. Reddy’s
Laboratories Ltd., Hyderabad, India.

SYNTHESIS OF BENZIMIDAZOLE DERIVATIVES
2613
Preparation of 6a–d from 1 and 2 (General Procedure)
2-Mercapto-1H-benzimidazole (1) (14 g, 0.093 mol) and 1-bromomethyl
biphenyl tetrazole (2) (50 g, 0.089 mol) were added to a solution of sodium hydroxide
(30 g, 0.75 mol) in water (150 mL) and acetone (1000 mL) at 25–30 ꢁC. The reaction
mass was stirred for 15 h and concentrated, followed by isolation of the product 3 in
water (200 mL). Yield 48 g (85%).
Compounds 3 (40 g, 0.063 mol) and 4a–d (0.063 mol) were added to a solution
of sodium hydroxide (24 g, 0.6 mol) in water (120 mL) and acetone (800 mL) at
25–30 ꢁC. The reaction mass was stirred for 15 h and concentrated, followed by
isolation of the products 5a–d from water (160 mL). Yield: 85%.
A solution of 36% HCl (50 mL, 15 mol) was added to a solution of compounds
5a–d (25 g) in methanol (200 mL) at 10–15 ꢁC and stirred for 1 h. The separated
by-product (trityl chloride) was filtered and charged with water (500 mL). The result-
ing solution was stirred for solid separation and filtered to yield the hydrochloride
salts 6a–d. Yield: 65%.
Data for Compounds 6a–d
Compound 6a. 1H NMR d 7.96 (s, 1H), 7.59 (d, J ¼ 8 Hz, 1H), 7.52 (d,
J ¼ 6.8 Hz, 1H), 7.31 (m, 4H), 7.18 (d, J ¼ 8 Hz, 1H), 7.12 (m, 4H), 7.02 (d, J ¼ 7.6 Hz,
Hz, 1H), 5.38 (s, 2H), 4.49 (s, 2H), 3.71 (s, 3H), 2.24 (s, 3H), 2.13 (s, 3H); MS m=z 534
(Mþ þ H); FT-IR (KBr, cmꢀ1): 3435 (NꢀH stretching), 3050 (aromatic CꢀH
=
=
stretching), 2960 (aliphatic CꢀH stretching), 1638, 1580 (aromatic C C, C N
stretching), 1460 (aliphatic CꢀH bending), 1071 (CꢀO stretching), 760, 744
(aromatic CꢀH bending).
Compound 6b. 1H NMR d 8.03 (d, J ¼ 5.6 Hz, 1H), 7.57 (d, J ¼ 6.8 Hz, 1H),
7.52 (d, J ¼ 5.2 Hz, 1H), 7.29 (m, 6H), 7.15 (m, 4H), 7.03 (d, J ¼ 5.6 Hz, 1H), 5.41
(s, 2H), 4.53 (s, 2H), 3.86 (s, 3H), 3.73 (s, 3H); MS m=z 536 (Mþ þ H); FT-IR
(KBr, cmꢀ1): 3392 (NꢀH stretching), 3058 (aromatic CꢀH stretching), 2974 (aliphatic
=
=
CꢀH stretching), 1637, 1585 (aromatic C C, C N stretching), 1459 (aliphatic CꢀH
bending), 1070 (CꢀO stretching), 762, 748 (aromatic CꢀH bending).
1
Compound 6c. H NMR d 8.16 (d, J ¼ 6 Hz, 1H), 7.56 (m, 6H), 7.33 (d,
J ¼ 8.4 Hz, 1H), 7.26 (m, 4H), 7.12 (d, J ¼ 6 Hz, 1H), 7.03 (d, J ¼ 8 Hz, 1H), 5.59 (s,
2H), 4.93 (q, J ¼ 8.4 Hz, 16.8 Hz, 2H), 4.63 (s, 2H), 2.25 (s, 3H); MS m=z 588
(Mþ þ H); FT-IR (KBr, cmꢀ1): 3421 (NꢀH stretching), 3053 (aromatic CꢀH stretch-
=
=
ing), 2970 (aliphatic CꢀH stretching), 1630, 1583 (aromatic C C, C N stretching),
1477 (aliphatic CꢀH bending), 1169 (CꢀO stretching), 760, 745 (aromatic CꢀH
bending).
Compound 6d. 1H NMR d 8.03 (d, J ¼ 5.6 Hz, 1H), 7.56 (m, 6H), 7.32 (d,
J ¼ 8 Hz, 1H), 7.11 (m, 4H), 7.01 (d, J ¼ 8.4 Hz, 1H), 6.88 (d, J ¼ 5.6 Hz, 1H), 5.40
(s, 2H), 4.54 (s, 2H), 4.08 (t, J ¼ 6.4 Hz, 2H), 3.48 (t, J ¼ 6.4 Hz, 2H), 3.24 (s, 3H),
2.19 (s, 3H), 1.96 (m, 2H); MS m=z 578 (Mþ þ H); FT-IR (KBr, cmꢀ1): 3421
(NꢀH stretching), 3058 (aromatic CꢀH stretching), 2929 (aliphatic CꢀH stretch-
=
=
ing), 1630, 1582 (aromatic C C, C N stretching), 1478 (aliphatic CꢀH bending),
1087 (CꢀO stretching), 760, 743 (aromatic CꢀH bending).

2614
P. R. REDDY ET AL.
Preparation of Compound 8
A solution of m-CPBA (11 g, 0.063 mol) in methylene chloride (100 mL) was
added to a solution of compound 3 (20 g, 0.031 mol) in methylene chloride
(100 mL) at 10–15 ꢁC. The reaction mass was stirred for 1 h and filtered to yield
the separated by-product (m-chlorobenzoic acid). The organic layer was washed
the with 5% aqueous sodium hydroxide solution (2 ꢂ 100 mL). The organic layer
was concentrated to dryness, and the product was isolated from acetone (20 mL)
to give the compound 7. Yield: 75%.
A solution of 36% HCl (20 mL, 0.2 mol) was added to a solution of compound
7 (10 g, 0.015 mol) in methanol (80 mL) at 10–15 ꢁC. The reaction was stirred for 1 h,
and the separated by-product (trityl chloride) was filtered. The reaction mass was
concentrated to dryness, and water (200 mL) was charged. The resulting solution
was stirred for solid separation, filtered, and dried in a vacuum oven to afford 8.
Yield: 65%.
Data for Compound 8
1H NMR d 7.64 (m, 4H), 7.57 (d, J ¼ 6.4 Hz, 1H), 7.51 (d, J ¼ 8 Hz, 1H), 7.35
(m, 4H), 7.16 (d, J ¼ 8.4 Hz, 1H), 7.03 (d, J ¼ 8.4 Hz, 1H), 4.68 (d, J ¼ 13.2 Hz, 1H),
4.49 (d, J ¼ 13.2 Hz, 1H); MS m=z 312 (Mþ þ H); FT-IR (KBr, cmꢀ1): 3421 (NꢀH
stretching), 3058 (aromatic CꢀH stretching), 2964 (aliphatic CꢀH stretching), 1604,
=
=
1586 (aromatic C C, C N stretching), 1476 (aliphatic CꢀH bending), 1019 (CꢀO
stretching), 748 (aromatic CꢀH bending).
Preparation of Compounds 10a–d (General Procedure)
Compound 9 (25 g, 0.082 mol) and compound 4a–d (0.082 mol) were added to a
solution of sodium hydroxide (15 g 0.37 mol) in water (75 mL) and acetone (500 mL).
The reaction mass was stirred for 15 h at 50 ꢁC and concentrated. Water was charged
(100 mL), followed by acetone (50 mL), and the mixture was then stirred for solid
separation and filtered to yield 10a–10d. Yield: 85%.
Data for Compounds 10a–d
1
Compound 10a. H NMR d 7.97 (s, 1H), 7.58 (m, 2H), 7.57 (s, 1H), 7.41 (s,
1H), 7.23 (m, 2H), 5.59 (s, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 2.76 (t, J ¼ 7.2 Hz, 2H),
2.62 (s, 3H), 2.32 (s, 3H), 2.14 (s, 3H), 1.75 (m, 2H), 0.95 (t, J ¼ 7.2Hz, 3H); MS m=z
454 (Mþ þ H); FT-IR (KBr, cmꢀ1): 3061 (aromatic CꢀH stretching), 2963 (aliphatic
=
=
CꢀH stretching), 1588, 1568 (aromatic C C, C N stretching), 1459 (aliphatic CꢀH
bending), 1079 (CꢀO stretching), 834, 734 (aromatic CꢀH bending).
Compound 10b. 1H NMR d 8.07 (d, J ¼ 5.6 Hz, 1H), 7.68 (s, 1H), 7.64 (d,
J ¼ 7.6 Hz, 1H), 7.57 (d, J ¼ 7.2 Hz, 1H), 7.44 (s, 1H), 7.25 (m, 2H), 7.05 (d, J ¼ 5.6 Hz,
1H), 5.57 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 2.91 (t, J ¼ 7.2 Hz, 2H), 2.59
(s, 3H), 1.79 (m, 2H), 0.98 (t, J ¼ 7.6 Hz, 3H); MS m=z 456 (Mþ þ H); FT-IR (KBr,
cmꢀ1): 3048 (aromatic CꢀH stretching), 2964 (aliphatic CꢀH stretching), 1583,
=
=
1527 (aromatic C C, C N stretching), 1451 (aliphatic CꢀH bending), 1071 (CꢀO
stretching), 823, 745 (aromatic CꢀH bending).

SYNTHESIS OF BENZIMIDAZOLE DERIVATIVES
2615
Compound 10c. 1H NMR d 8.10 (d, J ¼ 5.2 Hz, 1H), 7.60 (s, 1H), 7.58 (m,
2H), 7.42 (s, 1H), 7.23 (m, 2H), 7.03 (d, J ¼ 6.0 Hz, 1H), 5.66 (s, 2H), 4.89 (q,
J ¼ 8.8 Hz, 17.2 Hz, 2H), 3.81 (s, 3H), 2.76 (t, J ¼ 7.6 Hz, 2H), 2.62 (s, 3H), 2.31
(s, 3H), 1.75 (m, 2H), 0.94 (t, J ¼ 6.8 Hz, 3H); MS m=z 508 (Mþ þ H); FT-IR
(KBr, cmꢀ1): 3056 (aromatic CꢀH stretching), 2963 (aliphatic CꢀH stretching),
=
=
1579, 1527 (aromatic C C, C N stretching), 1458 (aliphatic CꢀH bending), 1166
(CꢀO stretching), 834, 744 (aromatic CꢀH bending).
Compound 10d. 1H NMR d 8.03 (d, J ¼ 6.0 Hz, 1H), 7.61 (d, J ¼ 7.2 Hz, 1H),
7.58 (s, 1H), 7.55 (d, J ¼ 7.2 Hz, 1H), 7.41 (s, 1H), 7.23 (m, 2H), 6.88 (d, J ¼ 5.2 Hz,
1H), 5.60 (s, 2H), 4.09 (t, J ¼ 6.0 Hz, 2H), 3.80 (s, 3H), 3.48 (t, J ¼ 6.0 Hz, 2H), 3.24
(s, 3H), 2.77 (t, J ¼ 7.6 Hz, 2H), 2.62 (s, 3H), 2.27 (s, 3H), 1.97 (m, 2H), 1.75 (m, 2H),
0.95 (t, J ¼ 7.2 Hz, 3H); MS m=z 498 (Mþ þ H); FT-IR (KBr, cmꢀ1): 3038 (aromatic
=
=
CꢀH stretching), 2960 (aliphatic CꢀH stretching), 1579, 1524 (aromatic C C, C N
stretching), 1459 (aliphatic CꢀH bending), 1090 (CꢀO stretching), 832, 730
(aromatic CꢀH bending).
ACKNOWLEDGMENT
The authors thank the colleagues of the Analytical Research Department and
Dr. Reddy’s Laboratories Ltd., Integrated Product Development, Bachupally,
Hyderabad, India.
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