Introduction

Benzimidazole represents a key aromatic heterocyclic organic compound. Over recent decades,
pharmaceutical researchers have been captivated by the synthesis of benzimidazole-derived
poly heterocycles due to their significant role as a pharmacophore in medicinal chemistry and
pharmacology. Essentially, benzimidazole constitutes a bicyclic compound formed by the fusion
of benzene with imidazole, resulting in a structurally privileged framework. This distinctive
structure possesses numerous pharmacological attributes. Notably, the most renowned
benzimidazole moiety to date is N-ribosyl-dimethyl benzimidazole, occurring naturally and
serving as the axial ligand for cobalt in vitamin B[1]

Benzimidazole

Benzimidazole displays a plethora of biological activities, spanning antimicrobial, antifungal,

antihistaminic, anti-inflammatory, antiviral, antioxidant, anticancer, and anti-ulcerative properties.
This broad spectrum of functions underscores the importance of benzimidazole derivatives in
the development of pharmaceutical compounds with diverse therapeutic applications.[2-3]

The biological relevance of many heterocyclic building blocks lies in their structural similarity to
purine nucleobases. In particular, benzimidazole derivatives exhibit a selective ability to inhibit
endothelial cell growth, thereby exerting a suppressive effect on angiogenesis, both in vitro and
in vivo.[3]

In the 1990s, benzimidazole underwent significant modification, with fluorine, propylene,

tetrahydroquinoline, and cyclized molecules being substituted for various benzimidazole
derivatives. These alterations resulted in the production of compounds characterized by
enhanced bioavailability, stability, and notable biological activity. Moreover, studies
demonstrated that the addition of an electron-donating group to pyridine contributed to
increased activity. In 1991, advancements allowed for the creation of benzimidazole derivatives
through derivatization at the N-H position with electron-donating groups, accompanied by the
substitution of large chains such as propyl, acetamido, thio, thiazole-amino, and tetramethyl
piperidine on pyridine. These derivatives exhibited potent antiulcer activity.[4-5]
Several attempts have been made in the past to establish an efficient and low-cost process for
the synthesis of benzimidazole derivatives. There are three main techniques for synthesising 2-
substituted benzimidazoles. The first is the Phillips-Ladenburg reaction, which is based on the
relationship of diaminobenzenes with In addition, the second approach involves the
Weidenhagen reaction, which centres on the interaction between ortho-phenylenediamine and
aldehydes or ketones. However, the utilization of these methods in their conventional form is
hindered by the extreme temperature conditions, often ranging from 250 °C to 300 °C, and low
yields. As a result, all currently accessible benzimidazole synthesis techniques are essentially
variations of the Phillips-Ladenburg and Weidenhagen processes. Lastly, the third method,
known as the Mamedov heterocycle rearrangement, entails an acid-catalyzed transformation of
quinoxalinone derivatives into 2-heteroaryl-substituted benzimidazoles.[6-7]

Molecular Structure of Benzimidazole

 Improtance of benzimidazoles in medicinal chemistry

Broad Spectrum of Biological Activities

Benzimidazoles exhibit a wide range of biological activities, making them valuable scaffolds for
drug discovery. They have shown efficacy as antiparasitic agents against various helminths and
protozoa, including nematodes, cestodes, and trematodes. Additionally, benzimidazoles
possess antimicrobial properties against bacteria, fungi, and some viruses. Moreover, they have
demonstrated anticancer activity by targeting key cellular pathways involved in cancer
progression.

Benzimidazoles serve as versatile scaffolds in drug discovery due to their diverse

pharmacological activities, making them invaluable in the quest for new therapeutic agents.
Their efficacy spans multiple therapeutic areas, making them attractive candidates for
addressing a wide range of diseases and conditions.[8]

Antiparasitic Activity: Benzimidazoles have long been recognized for their effectiveness as
antiparasitic agents against a variety of parasitic infections. They are particularly notable for
their activity against helminths (worms) and protozoa. Benzimidazole drugs such as
albendazole and mebendazole are widely used in the treatment of nematode infections,
including those caused by intestinal parasites like Ascaris lumbricoides and hookworms.
Moreover, they are effective against cestodes (tapeworms) and trematodes (flukes), providing a
broad-spectrum approach to parasitic disease management.[8]

Antimicrobial Properties: In addition to their antiparasitic activity, benzimidazoles exhibit

antimicrobial properties against a range of microbial pathogens, including bacteria, fungi, and
certain viruses. They have demonstrated efficacy against both gram-positive and gram-negative
bacteria, making them potentially useful in the treatment of bacterial infections. Benzimidazole
derivatives also show antifungal activity against various fungal species, making them potential
candidates for the treatment of fungal infections. Furthermore, some benzimidazoles have
exhibited antiviral activity against certain viruses, although more research is needed to fully
elucidate their mechanisms of action and therapeutic potential in this regard.[8]

Anticancer Activity : Benzimidazoles have emerged as promising candidates for anticancer

therapy due to their ability to target key cellular pathways involved in cancer progression. They
exert their anticancer effects through various mechanisms, including inhibition of microtubule
polymerization, disruption of mitotic spindle formation, induction of apoptosis, and modulation of
signaling pathways associated with cell proliferation and survival. Benzimidazole derivatives
have shown efficacy against a wide range of cancer types, including solid tumors and
hematological malignancies, making them attractive candidates for further development as
anticancer drugs. Additionally, their potential for combination therapy with existing anticancer
agents holds promise for enhancing treatment outcomes and overcoming drug resistance in
cancer patients.[8]
 Therapeutic Versatility
Benzimidazoles are renowned for their therapeutic versatility, having been harnessed in the
development of drugs targeting a wide spectrum of diseases and conditions. This versatility
stems from their unique chemical structure and diverse pharmacological properties, making
them valuable tools in medicinal chemistry.[9]

Anthelmintic Activity : Among their most well-known therapeutic applications, benzimidazoles

are widely employed as anthelmintic agents for the treatment of parasitic worm infections.
Albendazole and mebendazole, two prominent benzimidazole derivatives, are cornerstone
drugs in the management of helminthiasis, targeting a broad range of parasitic worms including
nematodes, cestodes, and trematodes.
Their efficacy in clearing intestinal parasites and preventing disease transmission has
established them as essential components of public health programs aimed at controlling
parasitic infections, particularly in resource-limited settings.[9]

Antimicrobial Properties: Benzimidazole-based antibiotics represent another facet of the

therapeutic versatility of benzimidazoles. Compounds such as thiabendazole exhibit potent
antimicrobial activity against a diverse array of microbial pathogens, including bacteria, fungi,
and certain parasites. Thiabendazole, for instance, has demonstrated efficacy against bacterial
pathogens such as Staphylococcus aureus and Streptococcus species, as well as fungal
pathogens like Candida albicans.[9]

Its broad-spectrum antimicrobial activity makes it a valuable agent in the treatment of infectious
diseases, particularly those caused by multidrug-resistant pathogens.

Anticancer Potential: Benzimidazole derivatives have garnered considerable interest as

potential anticancer agents due to their ability to interfere with critical cellular processes involved
in cancer progression. One of the primary mechanisms underlying their anticancer activity is the
inhibition of microtubule polymerization, a process essential for cell division and proliferation. By
disrupting microtubule dynamics, benzimidazole derivatives impair mitotic spindle formation,
leading to mitotic arrest and subsequent apoptosis in cancer cells.[9]

Additionally, benzimidazole compounds have been shown to modulate signaling pathways

implicated in tumor growth and metastasis, further enhancing their potential as anticancer
therapeutics. Although their clinical development as anticancer drugs is ongoing, benzimidazole
derivatives hold promise for the treatment of various cancer types and may offer new avenues
for personalized cancer therapy.
Structural Features Amenable to Modification
The structural scaffold of benzimidazoles provides a robust foundation for medicinal chemists to
explore and manipulate, offering boundless opportunities for structural modification and
optimization. This inherent flexibility stems from the distinctive architecture of benzimidazole
molecules, characterized by a fused bicyclic ring system comprising a benzene ring fused to an
imidazole ring.

Highly Modifiable Structure : Benzimidazoles possess a modular structure that lends itself well
to structural modification. The benzimidazole core serves as a versatile scaffold onto which
various functional groups can be appended or substituted, allowing for the creation of diverse
analogs with tailored pharmacological properties.

This structural versatility facilitates the systematic exploration of structure-activity relationships

(SAR), wherein the effects of specific structural modifications on the biological activity of
benzimidazole derivatives can be systematically studied and optimized.

Impact on Pharmacological Properties: Substituent variations on the benzimidazole core can

exert profound effects on the pharmacological properties of the resulting compounds. By
strategically introducing substituents at different positions of the benzimidazole scaffold,
medicinal chemists can modulate the potency, selectivity, and pharmacokinetic profile of the
analogs, thereby fine-tuning their therapeutic utility and minimizing undesirable side effects.
These modifications may influence various aspects of drug behavior, including receptor binding
affinity, metabolic stability, solubility, and bioavailability, ultimately influencing the efficacy and
safety of the drug candidates.

Facilitation of SAR Studies: The structural flexibility of benzimidazoles enables comprehensive

structure-activity relationship (SAR) studies, which are essential for rational drug design and
optimization. Through systematic exploration of the effects of structural modifications on
biological activity,

Medicinal chemists can elucidate the underlying molecular mechanisms of action, identify key
structural features essential for activity, and optimize drug candidates for specific therapeutic
applications. This iterative process of SAR-guided optimization allows for the development of
benzimidazole derivatives with enhanced pharmacological properties and improved therapeutic
profiles.[10]
Drug Resistance Management
Benzimidazoles are pivotal in addressing the pressing challenge of drug resistance, especially
within the realm of antiparasitic therapy. As parasites develop resistance to conventional
anthelmintic drugs, including benzimidazoles, there arises an urgent need for innovative
strategies to combat this phenomenon and ensure effective treatment outcomes.
Benzimidazoles, with their established efficacy and widespread use, are at the forefront of
efforts to manage drug-resistant parasites and mitigate the impact of resistance on public
health.

1. **Emergence of Drug Resistance**: In recent years, the emergence of resistance to

conventional anthelmintic drugs, such as benzimidazoles, has become a significant concern in
parasitic worm control programs worldwide. Parasitic worm populations, including nematodes,
cestodes, and trematodes, have developed mechanisms to evade the effects of benzimidazoles,
rendering these drugs less effective or ineffective in treating infections.

This trend underscores the importance of developing alternative treatment strategies to

overcome drug resistance and maintain the efficacy of antiparasitic therapy.

2. **Need for Novel Compounds and Combination Therapies**: In response to the challenge of
drug resistance, there is a growing emphasis on the development of new compounds or
combination therapies that can circumvent resistance mechanisms and restore drug efficacy.
Researchers are actively exploring novel benzimidazole derivatives with enhanced potency,
improved pharmacokinetic profiles, or alternative mechanisms of action to counteract drug
resistance in parasitic worms.

Additionally, the use of combination therapies, which involve the simultaneous administration of
multiple drugs with different modes of action, is being investigated as a strategy to prevent or
delay the emergence of resistance and prolong the effectiveness of benzimidazole-based
treatments.

3. **Research into Alternative Mechanisms of Action**: A key aspect of managing drug

resistance involves exploring alternative mechanisms of action that can bypass or circumvent
resistance mechanisms observed in parasitic worms. Research into novel benzimidazole
derivatives with distinct modes of action, such as targeting different molecular targets or
disrupting essential biological processes in parasites, offers promising avenues for overcoming
resistance and enhancing the efficacy of antiparasitic therapy. By diversifying the arsenal of
antiparasitic agents and exploiting new therapeutic targets, researchers aim to stay one step
ahead of evolving resistance mechanisms and ensure continued success in parasite control
efforts.[11]
 Synthesis of Bendamedazole

Benzimidazole, a versatile heterocyclic compound, can be synthesized through various

methods, each offering its advantages and challenges. One common approach involves the
condensation reaction between o-phenylenediamine and carboxylic acids or their derivatives
under acidic conditions, yielding benzimidazoles. Another method utilizes the reaction between
o-phenylenediamine and aldehydes or ketones in the presence of ammonium acetate, leading
to the formation of benzimidazoles. Additionally, benzimidazoles can be synthesized via
cyclization reactions of o-phenylenediamine derivatives with carbonyl compounds under
oxidative conditions, providing a pathway to diverse benzimidazole derivatives. Furthermore,
transition metal-catalyzed reactions, such as C-H functionalization, have been employed to
construct benzimidazoles efficiently. These synthetic routes offer flexibility in accessing
benzimidazole derivatives, essential in the development of pharmaceuticals, agrochemicals,
and materials science.

Traditional Synthetic Methods

Scheme 1
The Phillips-Ladenburg reaction involves the condensation of 1,2-diaminobenzene derivatives
with carboxylic acids in the presence of a weak mineral acid, resulting in the formation of
benzimidazole derivatives. [10]

Scheme 1. Phillips-Ladenburg reaction

Scheme 2
An alternative classic method for synthesizing benzimidazoles is the Weidenhagen reaction.
This process entails the reaction of 1,2-diaminobenzene with aldehydes and ketones in water or
alcohol, facilitated by oxidizing agents like copper acetate or a similar bivalent copper salt.[10]

Scheme 2. Weidenhagen reaction

 (Scheme 3)
Hoebrecker synthesized benzimidazole through the reduction and dehydration of
2-nitro-4-methylacetanilide.[11]

Scheme 3. Preparation of benzimidazole from 2-nitro-4-methyl acetanilide

Modern Synthetic Strategies

1. From O-phenylenediamines (o-phenylenediamine)

Scheme 4
a. Phillips-Ladenburg reaction in benzimidazole synthesis
Various research findings indicate that benzimidazole derivatives can be synthesized by
employing o-phenylenediamine and carboxylic acids. The condensation reaction between
o-phenylenediamine and aromatic acids like salicylic acid, benzoic acid, or cinnamic acid at
temperatures ranging from 80°C to 90°C, utilizing ammonium chloride (NH4Cl) as a catalyst in
ethanol (EtOH), yields benzimidazole derivatives with yields ranging from 72% to 90%.[12]

Scheme 4. Benzimidazole preparation from carboxylic acids.

Scheme 5
Alam et al. identified that refluxing a 1:1 molar ratio of o-phenylenediamine and 4-aminobenzoic acid in
dimethylbenzene and polyphosphoric acid for only six hours resulted in the production of
2-(4-aminophenyl)-1H-benzimidazole with a yield of 51%.[13]

Scheme 5. Benzimidazole preparation from an aromatic carboxylic acid.

 Scheme 6
Nguyen et al. developed an efficient Fe/S catalytic redox condensation method for the synthesis of benzimidazole
derivatives from phenylacetic acid and 2-nitroaniline, yielding substantial quantities without any organic
by-products.[14]

Scheme 6. Benzimidazole preparation from Fe/S catalytic redox condensation method.

Scheme 7
The condensation reaction between o-phenylenediamine and 4-aminobenzoic acid in o-phosphoric acid at 200°C for
two hours results in a 70% yield of 4-(1H-benzimidazol-2-yl)benzenamine.[15]

Scheme 7. Preparation of benzimidazole from 4-aminobenzoic acid.

(Scheme 8)

According to the study when 4-methyl-1,2-phenylenediamine is reacted with formic acid in the
presence of nanoparticles of ZnO at 70 °C produces a 94% yield of
5-Methyl-1H-benzimidazole[16]

Scheme 8. Preparation of benzimidazole from formic acid.1

Scheme 9
The study indicates that when 4-methoxy-1,2-phenylenediamine is subjected to reaction with formic acid in the
presence of zinc oxide nanoparticles at 70°C, it results in a 98% yield of 5-Methoxy-1H-benzimidazole.[16]
 Scheme 9. Preparation of benzimidazole from formic acid.
Scheme 10
Benzimidazole derivatives were synthesized by coupling o-phenylenediamine with organic acids in solvent-free
conditions at 140 °C[17]

Scheme 10. Preparation of benzimidazole from aldehyde

(Scheme 11)
According to multiple studies, heating o-phenylenediamine with 4,4-dimethoxy-3-oxobutanoate
in the presence of 5 mol% of 1-butyl imidazolium trifluoroacetate (HBIm.TFA) for 4-12 hours at
80°C yields benzimidazole 2-carboxaldehyde dimethyl acetal with a 95% yield.[18]

Scheme 11. Preparation of benzimidazole from 4 4-dimethoxy 3-oxo butanoate with mechanism
 (Scheme 12).
The Reaction of o-phenylenediamine, aryl isothiocyanate, and methyl acetylene carboxylate in
CH2Cl2- toluene under reflux conditions for ten-hour produces benzimidazole derivatives with
65%–70% yield.[19]

Scheme 12. Preparation of benzimidazole from aryl isothiocyanate, and methyl acetylenecarboxylate with
mechanism.
 Weidenhagen reaction in benzimidazole synthesis

(Scheme 13).
Benzimidazole derivatives can be efficiently synthesized by condensing o-phenylenediamine with an aldehyde at
ambient temperature in methanol conditions. This process involves using Cu(OH)2 as a catalyst for 6 hours in an
open oxygen environment, resulting in a high yield of the desired products[20]

Scheme 13. Preparation of benzimidazole from aldehydes.

(Scheme 14).
The reactions were performed in 2 to 4 hours and yields ranged from 85% to 95%

Scheme 14. One-pot preparation of benzimidazole derivatives by LaCl3 catalysis.

(Scheme 15).
The reactions of o-phenylenediamine with aryl aldehydes in aqueous micellar media, using aqueous extract of Acacia
concinna pods at 25 °C give 1,2-disubstituted benzimidazole. The yield of the product depends on the concentration
of the aqueous extract of Acacia concinna pods when concentration increases like (10, 20, 30, 40) the mol% yield of
the product is also affected (89, 97, 95, 95)% respectively[21]

Table- Optimization of catalyst concentration

 Scheme 15. Preparation of benzimidazole derivatives with a surfactant catalyst (aqueous extract of Acacia
concinna pods).

(Scheme 16).
The condensation of o-phenylenediamine with 4-chlorobenzaldehyde for half an hour in the presence of tert-butyl
nitrite in tetrahydrofuran at 25°C yields an 80% yield of 2-(4-chlorophenyl)benzimidazole.[22]

Scheme 16. Preparation of benzimidazole from 4-chlorobenzaldehyde.

(Scheme 17).
Benzimidazole derivatives were synthesized by coupling o-phenylenediamine with an aldehyde in
solvent-free conditions at 140 °C. [23]

Scheme 17. Preparation of benzimidazole from aldehyde

(Scheme 18)
When 3,4-Toluenediamine is heated with methyl phenyl ketone for a while at 180 °C to produce 2-phenyl- 5(or
6)-methyl benzimidazole in this manner. In this instance, the methyl group is removed, resulting in benzimidazole[24]

Scheme 18. Preparation of benzimidazole using acetophenone.

 (Scheme 19)
Dhanalakshmi et al. produced high-quality yields of benzimidazole derivatives from
α,β-unsaturated ketones using either thermal or microwave irradiation.[25]

Scheme 19. Preparation of benzimidazole from α,β-unsaturated ketones.

Microwave-assisted benzimidazole synthesis

Benzimidazole synthesis from carboxylic acids/carboxylic acid derivatives and

1,2-diamino benzenes

(Scheme 1)
The first microwave-assisted benzimidazole synthesis reported in 1995 by Bougrin and
Soufaoui . They have described a benzimidazole synthesis method using 1,2-
diaminobenzene or 4-substituted-1,2-diaminobenzene and ethyl acetoacetate or ethyl
benzoylacetate on solid mineral supports in dry media under microwave irradiation in
domestic ovens.(26)
 (Scheme 2)
Bougrin et al. have described in dry media synthesis of 2-trifluoromethyl benzimidazoles
through cyclo condensation of N-(carbotrifluoromethyl)-ortho-arylenediamines on
montmorillonite K10 under domestic microwave oven with good yields (Scheme 2)[27]

(Scheme 3)
Bendale and Sun have described an efficient, facile, and practical liquid-phase combinatorial
synthesis of benzimidazoles under microwave irradiation in short time [28]
 (Scheme 4)
Getvoldsen et al. developed an in situ monitoring method for the reactions in a microwave
using UV/Vis spectroscopy. The benzimidazole synthetic reaction from 1,2-diaminobenzene
and formic acid has chosen as a model reaction. They have reported that the new method
would be an excellent analytical tool for monitoring the progress of a reaction,
determination of end points and derivation of quantitative and kinetic data [28]

(Scheme 5)
Boufatah et al. have reported the preperation of some new biologically active
benzimidazole-4,7-dione derivatives in 7 steps through the microwave irradiation for the
ring closing step to obtain benzimidazole derivative. [29]
 (Scheme 6)
Zhang and Tempest have improved the efficiency of the Ugi/de-Boc/cyclization synthesis
replaced the normal Boc group with the fluorous-Boc group to protect the diamine. They were
used fluorous component as a limiting agent in the Ugi reaction. Hence, they have easily
separated designed condensation product containing the F-Boc group from the reaction
mixture by fluorous SPE. Compared to the original Ugi/de-Boc/cyclization procedures, which
take 1-2 days, the fluorous/microwave approach which modified by Zhang and Tempest has
more favorable reaction and purification conditions: less than 20 min for each reaction and no
need of the double scavenging step.[30]

(Scheme 7)
Getvoldsen et al. have reported 2-([4-18F] fluorophenyl) benzimidazole synthesis from the
cyclocondensation reaction of 1,2-diaminobenzene with radiolabelled [4-18F]fluorobenzoic acid
in neat methanesulfonic and polyphosphoric acids under microwave[31]

(Scheme 8)
Martinez-Palou et al. have described 2-long alkyl chain substituted benzimidazole
synthesis from the reaction of 1,2-diaminobenzene and stearic acid via mono and multimode
microwave irradiation with high yields
 (Scheme 10)
Lin et al. have reported a microwave-assisted one-pot synthesis of several benzimidazole
derivatives from readily available starting compounds such as 1,2-diaminobenzene, 4,5-
diaminopyrimidine, cis-1,2-diaminocicylohexane and several carboxylic acids including
heteroaraomatic carboxylic acids. [32]

(Scheme 11)

Mobinikhaledi and co-workers described a selective synthesis of 2-aryl-1H-benzimidazoles

through the reaction of 1,2-diaminobenzene with arylcarboxylic acid using zeolite as an
efficient catalyst under microwave irradiation [33]

(Scheme 12)
Jing et al. have described a simple and rapid synthesis of benzimidazoles from 1,2-
diaminobenzene dihydrochloride and esters under microwave irradiation. This is also the first
report for microwave assisted benzimidazole synthesis from esters and 1,2-diaminobenzenes
[34]
 (Scheme 13)
Gellis et al. (53) have reported the synthesis of a series of variously substituted benzimidazole-
4,7-diones in seven steps and antitumor activity results of them. One of them exhibit excellent
cytotoxicity comparable to that of mitomycin C [35]

(Scheme 14)
Algül et al. have described the synthesis of some 2-substituted benzimidazole, benzothiazole,
and indole derivatives using on both microwave irradiation and conventional heating methods.
They have also evaluated hyaluronidase inhibitory activity of the compounds. [36]
 (Scheme 15)
Keri et al. have reported an expeditious, novel, and efficient method for the synthesis of
benzimidazole derivatives from o-phenylenediamines with different phenoxy acid using a Wells
Dawson H6P2W18O62.24 H2O catalyst [37]

(Scheme 16)
Similar to the Keri method, Hosamani and co-workers (55) described a convenient protocol for
the preparation of 5-nitro-2-arylsubstituted phenoxymethyl-1H-benzimidazole libraries in one
pot-synthesis both under microwave irradiation and conventional heating methods using
hydrochloride acid as catalyst[38]

(Scheme 17)
Hasaninejad et al. have reported the synthesis of some 2-substituted benzimidazole
derivatives from benzene-1,2-diamine with mono and dicarboxylic acids under microwave
irradiation using silphox [POCl3-n(SiO2)n] catalyst in highly yield and short reaction times
[39]
 (Scheme 18)
Sun and co-workers synthesized angular bis-benzimidazoles on the support with three
appendages with good yields and purities through soluble polymer-supported reaction. The
integration of microwave irradiation and a soluble polymer support strategy provided an
efficient and convenient approach for high throughput and diversity-oriented synthesis of drug
like molecules. Their preliminary screening results have shown that some of these compounds
exhibited moderately to good inhabitation against VEGFR 3, which is related to the invasion
and migration of cancer cells.[40]
 (Scheme 19)
Sun and co-workers reported a novel synthetic method for the substituted benzimidazole
derivatives from the starting compounds 1,2-diaminobenzene derivative on soluble polymer
support and 3-nitro-4-hydroxy/fluorobenzoic acid in a multistep process under focused
microwave irradiation [41-43]

(Scheme 20)
The same group has recently described the synthesis of bis-heterocyclic skeletal novel
benzimidazole-linked pyrrolo-/pyridobenzimidazolones and benzimidazole-linked isoindolo
benzimidazoleones on ionic liquid support under microwave irradiation by utilizing the cascade
cyclization[44]

Benzimidazole synthesis from aldehydes and 1,2-diaminobenzenes

 (Scheme 21)
Ben-Alloum et al. have described oxidative heterocyclization of aldehydes and o
phenylenediamine with nitrobenzene or dimethylsulfoxide impregnated on silica gel irradiated
with microwave in good yields and high purity.[45]

(Scheme 22)
Navarrete-Vazquez and co-workers described a simple, rapid, and efficient method for the
preparation of several 2-(alkyoxyaryl)-1H-benzimidazole compounds under solvent-free
conditions using readily available and inexpensive reagents utilizing microwave irradiation[46]

(Scheme 23)

Zahran and co-workers described the synthesis of new heterocyclic compounds containing
pyrazol-5-one coupled with benzimidazole under dry media and they also explored antitumor
activity of the newly synthesized heterocycles. Some of them were found to be more effective
than thalidomide [47]

Scheme 24
Dubey and Moorthy have reported comparative synthesis of 2-alkyl and 2-aryl substituted
benzimidazole derivative in the presence of polyphosphoric acid through microwave and
conventional methods and also studied the effect of salt form of reactant for completion of the
reaction. According to their report, the 2-substituted aryl and alkyl benzimidazole derivative
synthesized via microwave and it is beneficial, in respect of yield increases up to 10 to 50%)
and time (96 to 98% was reduced) than conventional method of synthesis. They also showed
some remarkable inferences while the use of salt form of the reactant (1,2-diaminobenzene
dihydrochloride). Navarrete-Vazquez et al.have synthesized several benzimidazole derivatives
which could be vasorelaxant and spasmolytic properties from the reaction of 1,2-
diaminobenzene with aromatic substituted aldehydes and sodium metabisulfite under
microwave irradiation. [48]

Jacob and co-workers described an improved methodology for the selective synthesis of
1,2-disubstituted benzimidazoles by the condensation of 1,2-diaminobenzene and aldehydes
using solid-supported catalyst (SiO2/ZnCl2) in a short time under microwave irradiation.

Mao et al. have reported intermittent microwave irradiation for the synthesis 2-
benzimidazole derivatives from aromatic aldehydes an 1,2-diaminobenzene only using
molecular oxygen as the oxidant and inexpensive KI as the catalyst.[47]

Rathod and co-workers described eco-friendly benzimidazole synthesis from aromatic

aldehydes and 1,2-diaminobenzene using MoO3/CeO2.ZrO2 as a catalyst under solvent-free
conditions both conventional and microwave heating. Azarifar et al. have [48]

Reported 2-aryl- 1-(arylmethyl)1H-benzimidazole synthesis from 1,2-diaminobenzene and

aldehydes through acetic acid-promoted condensation in air under microwave irradiatiom.
 (Scheme 26)
Krim et al. have reported efficient synthetic routes to prepare fluorescent compounds
containing benzimidazoles in the 5-position of pyrimidine nucleosides. Their synthesis is
based on the straightforward condensation of 5-formyl-2’-deoxyuridine and ethylenediamine
[49]

Miscellaneous benzimidazole syntheses

(Scheme 27)
Reddy et al. have reported microwave assisted synthesis of 5- or 5,6-disubstituted-2-
trifluoroacetonylbenzimidazole derivatives.[50]
 (Scheme 28)
Hulme and co-workers described a novel two-step solution phase protocol for the
synthesis of arrays of triazadibenzoazulenones using the Ugi reaction and two tandem ring
closing transfomations. They also used microwave irradiation for 5 or 10 min for the second
ring closing step[51]

(Scheme 29)

Wang et al. reported microwave-assisted solvent-dependent chemoselective reaction

dealing with 4-arylidene-2-phenyloxazol-5-ones and ortho-diamines to obtain benzimidazole
Scaffold.[52]
 (Scheme 30)
Shaw and et al. described a novel synthetic protocol for the synthesis of unique norstatine
analogs bearing benzimidazole moiety through Passerini reaction and following ring closing[53]

scheme30
Shaw and et al. described a novel synthetic protocol for the synthesis of unique norstatine
analogs bearing benzimidazole moiety through Passerini reaction and following ring
closing[54]
 (Scheme 31)
Wen et al. have reported on eco-friendly, one-pot efficient propylphosphonic anhydride
(T3P) mediated synthesis of benzimidazoles from various carboxylic acids and 1,2-
diaminobenzene under microwave irradiation.[55]
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