Diversity oriented synthesis of benzimidazole-based biheterocyclic molecules by combinatorial approach: a critical review

Abstract

Heterocyclic compounds play a major role in drug discovery processes as these are the common structural motif for 80% of the marketed drugs by US retail sales in 2014. Benzimidazole and its derivatives are regarded as important heterocyclic motifs that exhibit a wide range of pharmaceutical applications including anticancers, antihypertensives, antivirals, antifungals and anti-HIVs. In view of their wide ranging bioactivities, it is imperative to focus on the synthesis of heterocyclic molecules containing benzimidazole as one of the moieties. This review focuses on the application of solid supports for the synthesis of different classes of benzimidazole-based biheterocyclic molecules in the last decade. In this review paper, detailed synthetic steps involved for the synthesis of benzimidazole-based biheterocyclic molecules, are shown in the schemes. The synthesis covers linear, angular and fused benzimidazole-based biheterocyclic molecules by a combinatorial approach. In addition, in the introduction section we shed some light on the use of biheterocyclic molecules as current drugs and open a new avenue for the utilization of these biheterocyclic molecules for pharmaceutical applications.

---

Barnali Maiti

Dr Barnali Maiti, obtained her MSc in organic chemistry from Vidyasagar University, West Bengal India in 2003. She subsequently worked as a Research Fellow in Chemgen Pharma International India, from 2003–2006. In 2011, she finished her PhD in Applied Chemistry from National Chiao Tung University under the guidance of Prof Chung Ming Sun on the topic of Ionic Liquid supported green synthesis. In 2011, she moved to Department of Chemical Engineering, National Tsing Hua University, Taiwan for an NSC-postdoctoral fellowship with Prof Hsing Wen Sung. Now she is working as an Assistant Professor in Department of Chemistry, VIT University, Vellore. She is the recipient of DST young scientist award 2015. Her research interests include green synthesis, asymmetric synthesis, drug delivery, and gene delivery.

Kaushik Chanda

Dr Kaushik Chanda, obtained his MSc in Organic Chemistry from Gauhati University, Assam India in 2001. He subsequently worked as a Senior Research Fellow in an ICAR-NATP funded project in St Anthony’s College, Shillong, India from 2002–2005. In 2010, he finished his PhD in Applied Chemistry from National Chiao Tung University under the guidance of Prof Chung Ming Sun on a topic of Combinatorial Chemistry. In 2010, he moved to Department of Chemistry, National Tsing Hua University, Taiwan for an NSC-postdoctoral fellowship with Prof Michael H Y Huang. Now he is working as an Assistant Professor in Department of Chemistry, VIT University, Vellore. His research interests include diversity oriented synthesis, anticancer drug design, drug delivery and nanocatalysis.

---

Introduction

In drug discovery research, heterocyclic compounds play a major role as these are the common structural motifs for 80% of the marketed drugs by US retail sales in 2014.¹ Owing to their importance in drug discovery research, a significant effort has been devoted to their construction by both solid phase and solution-phase combinatorial approaches.² In general scientists have discovered combinatorial libraries contain one heterocyclic scaffold where the diversity can be achieved through the variation of different R groups (such as Me, Et, Pr etc.). However, these types of libraries are limited by the presence of only one R group, which may limit their potential bioproperties. The problem faced by monoheterocyclic scaffolds can be overcome by the introduction of different heterocyclic R groups which will pave the way for the synthesis of biheterocyclic scaffolds as depicted in Fig. 1.

Fig. 1 Combinatorial approach to biheterocyclic libraries.

Recently it has been noticed that among the combinatorial libraries of derivatized heterocycles, the most active members of the libraries have a biheterocyclic structures.³ Moreover, increased structural complexity is also observed in current drugs. In view of the structural complexity, the number of biheterocyclic molecules entering into US-FDA approved prescription drugs are slowly increasing, as is evident from Fig. 2. Among the list of current top 50 drugs there are 10 approved nitrogen-, oxygen- and sulfur-based biheterocycles (crizotinib, ponatinib, axitinib, ibrutinib, pomalidomide, olaparib, idelalisib, ceritinib, palbociclib, dabrafenib) reported for their antitumor properties.⁴ Compared to monoheterocycles, biheterocyclic compounds provide greater chemical space and better binding opportunities. Although the medicinal chemistry community has put up a brave effort to design the synthesis of biheterocyclic compounds and study their bioproperties, yet many libraries of biheterocyclic compounds have not been extensively studied. Considerable efforts have been made for biheterocyclic compounds, yet there is much to investigate for structurally and functionally modified biheterocyclic compounds linked directly, rather than through a spacer or linker.

Fig. 2 Biheterocyclic drugs approved by US FDA for their anti-tumor properties (2010–2015).

In the past ten years, a large number of scientific publications have appeared in the literature depicting the synthesis of biheterocycles which clearly shows the importance of this type of molecule in the pharmaceutical industry for drug development. However, as yet, there is no single review which describes the synthesis and the biological evaluation of various biheterocycles which have been developed and published in the literature.

The present review deals with the main innovations regarding the synthesis of nitrogen-, oxygen- and sulfur-based biheterocyclic scaffolds through solid-phase as well as solution-phase approaches. Moreover, this review article will pave the way for the access of numerous strategies leading to the synthesis of biheterocyclic molecules with substantial potential to become possible drug candidates. The benzimidazole-based biheterocyclic molecules described here are highly diverse entities formed by the combination of different heterocyclic cores with skeletal diversity. This review will highlight the key developments and challenges to the future design of biheterocyclic scaffolds.

Linear benzimidazole-linked biheterocyclic molecules

Benzimidazole is a heterocyclic aromatic organic compound with diverse pharmaceutical properties which includes antiviral, antifungal, antimicrobial, antiprotozoal, anti-inflammatory, anticancer, antioxidant, anticoagulant, antidiabetic and antihypertensive activities.⁵ Moreover, it is one of the key components in vitamin B₁₂.⁶ There are numerous synthetic strategies for the synthesis of benzimidazole derivatives which commences with condensation of acid chlorides/carboxylic acids or aldehydes with o-phenylenediamine derivatives with or without the presence of catalyst installing only one diversity. Our objective is to discuss the efficient methodologies involved for the solid-phase synthesis of benzimidazole-linked biheterocyclic libraries formed by the combinatorial assembly of two heterocyclic systems. For this purpose, initially we will discuss the solid supported synthesis of benzimidazole derivatives with two points of structural diversity by various groups. In 1999, Schotten et al. synthesized the polyethylene glycol (PEG) immobilized biaryl aldehydes by coupling aryl halides with substituted formyl benzene boronic acid 2 followed by the condensation with o-phenylene diamine derivatives 4 to obtain the biaryl benzimidazole derivatives. Finally the cleavage of the polymer support with NaOMe in MeOH led to the biaryl benzimidazole derivatives 5 with excellent yields as shown in Scheme 1.⁷

Scheme 1 PEG supported synthesis of biaryl benzimidazole derivatives.

Most of the cases in the solid-phase synthesis of the benzimidazole nucleus involves the utilization of o-fluoronitrobenzene derivatives for functional group interconversion and cyclisation strategy to develop this privileged scaffold.⁸

In 2000, Sun et al. described the rapid parallel synthesis of a benzimidazole derivative on a soluble polymer support as outlined in Scheme 2.⁹ Commercially available 4-fluoro-3-nitrobenzoic acid 6 was immobilized on PEG support via a linker strategy to obtain the o-fluoronitrobenzene conjugates 7 which underwent SnAr reactions with diverse primary amines via ipso fluoro displacement followed by Zn/NH₄Cl mediated nitro group reduction to obtain the polymer conjugated o-phenylenediamine derivatives 8. Further cyclisation of polymer conjugates 8 to benzimidazole derivatives was achieved by trimethyl orthoformate/TFA (0.5 eq.) in CH₂Cl₂ solution at room temperature. Finally cleavage of the polymer support with NaOMe in MeOH provided the benzimidazole derivatives 9 with one point of structural diversity.

Scheme 2 PEG synthesis of benzimidazole derivatives with single diversity.

Soon after the synthesis of benzimidazole derivatives with one structural diversity the same group had also reported the synthesis of 2-alkylthio-2-arylaminobenzimidazole derivatives with two points of structural diversity.¹⁰ In 2001, Tumelty et al. synthesized the highly substituted benzimidazole derivatives via a traceless solid-phase strategy using a base cleavable linker.¹¹ In 2002, Fukase et al. developed the solid-phase synthesis of benzimidazole derivatives which is outlined in Scheme 3.¹² The key reaction in the synthetic scheme involves the selective monoalkylation of o-phenylenediamine derivatives with polymer-supported alkyl halides 12 followed by the condensation with substituted aldehydes to obtain the polymer immobilized benzimidazole derivatives.

Scheme 3 Tentagel S RAM supported synthesis of benzimidazole derivatives.

Subsequent cleavage from the polymer support generated the benzimidazole derivatives 14 with three points of structural diversity. In 2003, Vourloumis et al. synthesized the trisubstituted benzimidazole derivatives 19 utilizing the Rink Amide Resin 15 as solid support following the protocol developed by Sun et al. for targeting RNA as depicted in Scheme 4.¹³

Scheme 4 Rink Amide Resin supported synthesis of benzimidazole derivatives for RNA targets.

Our next target is to discuss the synthesis of benzimidazole-linked linear biheterocyclic molecules achieved by different groups. In 2004, Sun et al. utilized the soluble polymer support PEG for the synthesis of bisbenzimidazole derivatives.¹⁴ As shown in Scheme 5, polymer immobilized o-phenylenediamines were synthesized under microwave irradiation. The polymer immobilized diamines 8 were continuously N-acylated with 4-fluoro-3-nitrobenzoic acid 6 at the primary amine functionality followed by nucleophilic aromatic substitution with primary amines. The resulting polymer conjugates 20 were cyclized in acidic solution to obtain the benzimidazole derivatives 21 which further underwent reduction and subsequent cyclization with various aldehydes and isothiocyanates to obtain the bisbenzimidazole derivatives 22 and 23, respectively, with three points of structural diversity in good yields and high purity.

Scheme 5 PEG supported synthesis of bisbenzimidazole derivatives with three points of structural diversity.

In 2004, Kamal et al. utilized a solution-phase approach for the synthesis of C8-linked pyrrolo[2,1-c][1,4]benzodiazepine–benzimidazole conjugates 31 which showed good DNA-binding affinity as shown in Scheme 6.¹⁵

Scheme 6 Solution-phase approach to benzimidazole-linked pyrrolo[2,1-c][1,4]molecularbenzodiazepine derivatives.

In 2006, Sun et al. achieved the synthesis of amino bisbenzimidazoles via microwave irradiation. In this case the polymer immobilized diamines 8 were continuously N-acylated with 4-fluoro-3-nitrobenzoic acid 6 to obtain 32.¹⁶ The conversion of the polymer conjugates 32 to the monobenzimidazole derivatives was obtained in two pathways as shown in Scheme 7. In the first case, various amines were reacted to obtain the polymer conjugates followed by intramolecular cyclization by using an acidic solution under MW irradiation leading to the polymer bound 2-arylbenzimidazole derivatives 33. The second pathway was arrived by the reverse sequence of reactions such as the initial cyclization and the SNAr reaction with primary amines to obtain the polymer bound 2-arylbenzimidazole derivatives 33. Reduction of the nitro group in polymer bound 2-arylbenzimidazole derivatives 33 was accomplished under MW conditions to obtain the polymer conjugates 21. The polymer bound 2-amino bisbenzimidazole derivatives were generated by the [4 + 1] approach with CNBr under microwave irradiation followed by the cleavage of polymer support, to obtain the amino bisbenzimidazoles 34 derivatives in good yields.

Scheme 7 PEG supported synthesis of amino bisbenzimidazole derivatives.

Further in 2008, Sun et al. developed a multistep synthetic protocol to generate 2-alkylthiobisbenzimdiazole derivatives as shown in Scheme 8.¹⁷ Polymer conjugates 21 were reacted with 1,1′-thiocarbonyldiimidazole in 1,2-dichloroethane to generate the bisbenzimidazole-2-thione derivatives 36 at room temperature for 15 h. In order to reduce the time, the same set of reactions carried out in refluxing dichloromethane gave rise to an unexpected product, which was confirmed after cleavage from the polymer support as bisbenzimidazole-2-chloromethyl sulfide derivatives 37. The ¹³C NMR analysis of compound 37 indicated the presence of a signal at 43.2 ppm instead of 60 ppm which further confirmed the absence of an N–CH₂–Cl group. The third point of structural diversity was achieved by the N-alkylation of polymer conjugates 35. In accordance with the literature report available, alkylation of polymer conjugates 35 can yield either N- or S-alkylated product. However, under room temperature conditions, reaction with different alkyl halides and triethyl amine resulted in the S-alkylated products, as confirmed upon cleavage of the polymer support to generate the 2-alkylthiobisbenzimidazole derivatives 38 with three points of structural diversity.

Scheme 8 PEG supported synthesis of 2-alkylthiobisbenzimidazole derivatives.

In the same year, Sun et al. reported the synthesis of diverse benzimidazolyl benzimidazolones on PEG support as shown in Scheme 9.¹⁸ Polymer bound o-phenylenediamine conjugates 21 with two in-built diversity aspects were reacted with triphosgene in 1,2-dichloroethane to generate the bisbenzimidazole-2-one derivatives 39 at room temperature for 12 h. Furthermore to introduce the third diversity function, N-alkylation of polymer conjugates 39 were affected by deprotonation of the cyclic ureide using NaH in dichloromethane at room temperature to obtain the conjugates 40. However, it was observed that the hydride ion did not attack the ester carbonyl to induce polymeric cleavage.

Scheme 9 PEG supported synthesis of benzimidazolyl benzimidazolone derivatives.

Because of the nucleophilicity of the cyclic ureide moiety, no O-alkylated product was obtained. Finally the cleavage of polymer support led to the benzimidazolyl benzimidazolones 41 with three diversity points.

In 2008, Vanden Eynde et al. synthesized bisbenzimidazole derivatives 44 structurally similar to bisbenzamidines for antileshmanial effectiveness as shown in Scheme 10.¹⁹

Scheme 10 Synthesis of bisbenzimidazoles for antileshmanial activity.

In 2008, Krchňák et al. demonstrated the solid-phase synthetic strategies for three biheterocyclic libraries of benzimidazolothiazoles that differ by the position of the thiazole ring on the benzimidazole moiety as shown in Fig. 3.²⁰ To achieve this strategy, they utilized the BAL-resin or HMPB-resin to obtain the resin bound substituted nitroanilines 48 as shown in Scheme 11.

Fig. 3 Benzimidazolothiazole analogues.

Scheme 11 Resin bound synthesis of substituted benzimidazolothiazole biheterocyclic structures with multiple diversity.

It of note to mention that all three benzimidazolothizole-biheterocyclic libraries are synthesized from common intermediate 47 with two diversity points. The first biheterocyclic structure 51 was synthesized according to Scheme 11. The resin bound nitroanilines 48 with R¹ as an amino substituent were reacted with freshly prepared Fmoc-NCS in dry THF followed by deprotection of the Fmoc group with 50% piperidine to obtain the resin bound thiourea 49 which further reacted with haloketones and upon subsequent reduction of the nitro group led to the amine functionalized thiazole derivatives 50. The benzimidazolothiazole biheterocyclic derivatives 51 were obtained by acylation reaction followed by cleavage from the resin using TFA in DCM and subsequent cyclization in AcOH at elevated temperature. The next biheterocyclic structures 54 and 57 were obtained using the same set of reactions with the only difference being the use of 1,2-dichloro-4-fluoro-5-nitrobenzene and 4-fluoro-3-nitrobenzoic acid as primary substituents.

In 2009, Sun et al. developed the enantioselective synthesis of benzimidazolylquinoxalinones on a PEG support via focused microwave irradiation.²¹ It is a well established fact that stereoselectivity is a vital component in drug design.²² In view of this property, a chiral library of benzimidazolylquinoxalinones has been synthesized to increase the molecular complexity. The key step in this multistep sequence involves the ipso-fluoro displacement with various chiral amino esters on the polymer conjugates 58 by microwave irradiation for 10 min as compared to 20 h for refluxing dichloromethane to obtain the intermediate 59 as shown in Scheme 12. The intermediate 59 underwent NO₂ group reduction under neutral conditions to generate the polymer immobilized conjugates 60 via intramolecular cyclisation. The chiral libraries of benzimidazolylquinoxalinones 61 were obtained from the polymer cleavage by 1% KCN in MeOH in good yields. Moreover, it is interesting to observe that the under harsh microwave conditions, racemization of the chiral centre did not occur significantly. High enantiomeric excesses (80–98%) were observed for the biheterocyclic benzimidazolylquinoxalinone derivatives 61.

Scheme 12 PEG supported synthesis of chiral libraries of benzimidazolylquinoxalinone derivatives.

In 2010, Reddy et al. developed a new series of benzimidazolyl-thiadiazepine biheterocyclic analogs 66 and tested their antibacterial activity as shown in Scheme 13.²³

Scheme 13 Solution-phase approach to benzimidazolyl-thiadiazepine biheterocyclic analogs.

In 2011, Sun et al. introduced the parallel synthesis of substituted benzimidazolylbenzoxazoles using focused microwave irradiation on a soluble polymer support.²⁴ Here 4-hydroxy-3-nitrobenzoic acid 67 was used as a key component for the synthesis of benzoxazoles. The polymer immobilized conjugates 8 were continuously N-acylated at the primary amine functionality with 4-hydroxy-3-nitrobenzoic acid 67 followed by acid mediated ring closure to obtain the conjugates 68. The NO₂ group in conjugates 68 was further reduced by 10% Pd/C in HCOONH₄ followed by heterocyclisation with various alkyl, aryl and heteroaryl isothiocyanates to generate the polymer bound benzimidazolylbenzoxazoles 69 as shown in Scheme 14. The biheterocyclic benzimidazolylbenzoxazole library with two sites of structural diversity, 70, was finally cleaved from the polymer support using 1% KCN in MeOH for 12 h. Further, the designed biheterocyclic libraries were studied against receptor tyrosine kinase VEGFR-3 involved in lymphogenesis, and showed moderate to high inhibition levels with IC₅₀ values ranging from 0.56 to 1.42 μm.

Scheme 14 PEG supported synthesis of benzimidazolylbenzoxazole derivatives.

In the same year, Sun et al. utilized the Pictet–Spengler reaction for the construction of the benzimidazole-pyrrolo[1,2-a]quinoxaline core of medicinal interest.²⁵ As shown in Scheme 15, instead of typically attaching the primary amine moiety, for the first time a secondary amine such as pyrrole was utilized for aromatic nucleophilic substitution reaction (SnAr) with the polymer immobilized substrate 58. Moreover, this was the first report to introduce the electron-rich pyrrole moiety 71 via aromatic nucleophilic substitution reaction on to the electron-withdrawing benzimidazole ring, which was achieved by the use of a judicious choice of base such Cs₂CO₃ in DMF solvent. The polymer conjugates 72 were obtained in 95% yield under focused microwave irradiation for 10 min at 135 °C.

Scheme 15 PEG supported synthesis of benzimidazole-pyrrolo[1,2-a]quinoxalines.

The next effort was to increase the structural diversity for the target library; the nitro group ortho to the pyrrole moiety of polymer ester conjugates 72 was reduced with zinc dust in methanol buffered with ammonium formate under microwave irradiation for 10 min to obtain the intermediate 73. The next step was to utilize the amine functionality of intermediate 73 for the ring closure using Pictet–Spengler reaction with various ketones 74. The traditional Pictet–Spengler reaction involves reactive aldehydes with the aliphatic amine connected to the carbon of an activated aromatic moiety whereas the use of ketones in Pictet–Spengler reaction of aromatic amines with a pyrrole moiety in the current skeleton is a variation. Accordingly, the intermediates 73 were treated with various symmetrical and unsymmetrical ketones using TFA as an acid catalyst in chloroform as solvent under focussed microwave irradiation at 85 °C within 12 min, to obtain the polymer bound conjugates 75. The designed biheterocyclic benzimidazole-pyrrolo[1,2-a]quinoxaline library with two sites of structural diversity 76 was finally cleaved from the polymer support using 1% KCN in MeOH at room temperature for 24 h.

In the same year, Sun et al. have synthesised benzimidazole-linked four annulated rings in one scaffold by the application of Pictet–Spengler cyclisation strategy on a soluble polymer support as depicted in Scheme 16.²⁶ Polymer bound intermediate 58 underwent aromatic nucleophilic substitution reaction with indoline moiety 77 under refluxing CH₃CN solution to obtain the intermediate 78. The reduction of the NO₂ functionality in intermediate 78 to 79 was achieved by use of zinc dust in methanol buffered with ammonium formate, followed by the Pictet–Spengler cyclisation with various aldehydes and ketones, to obtain the polymer immobilized intermediate. The cleavage of polymer conjugates using 1% KCN in MeOH at room temperature for 12 h led to the benzimidazole-linked tetrahydroindolodiazepine library 80 along with oxidized benzimidazole-linked dihydroindolodiazepine analogue 80′. It is interesting to note that reduction of the NO₂ group in polymer conjugates 78 using Pd/C and cyclohexene in refluxing ethanol yielded indole-substituted polymer conjugates 81 by reducing the nitro group and dehydrogenating the indoline to indole in one step. The same intermediate 81 could be obtained by the DDQ oxidation of polymer conjugates 79. Treatment of polymer conjugates 81 with various aldehydes or ketones in refluxing CHCl₃ solution using TFA as acid catalyst and MgSO₄ as dehydrating agent followed by polymer cleavage led to the benzimidazole-linked indoloquinoxalinones 82 along with the more stable aromatic skeleton 82′.

Scheme 16 PEG supported synthesis of benzimidazole-linked four annulated rings in one scaffold.

After successfully synthesizing the pyrrole and indole fused biheterocyclic synthon, Sun et al. introduced the imidazole into an aromatic moiety.²⁷ As shown in Scheme 17, polymer bound intermediate 58 underwent aromatic nucleophilic substitution reaction with imidazole moiety 83 under microwave irradiation to obtain the intermediate 84. The nitro group in compound 84 was reduced into an amine by neutral reduction with Zn/HCOONH₄. The polymer bound compound 85 then underwent unconventional regioselective Pictet–Spengler cyclization with the C-2 position on the imidazole ring system under sealed tube conditions for 6 h to obtain the intermediates 86 and 87.

Scheme 17 PEG supported synthesis of novel benzimidazole-linked imidazo[1,2-a]quinoxalines.

However, it was observed that aldehydes bearing electron-donating groups generated the 4,5-dihydroimidazoquinoxalines 88 after polymer cleavage which then auto-aromatize into benzimidazole-linked imidazo[1,2-a]quinoxalines 89. By contrast, Pictet–Spengler cyclisation with electron-withdrawing aldehydes directly provided the aromatized benzimidazole-linked imidazo[1,2-a]quinoxalines 87 which after polymer cleavage with 1% KCN in MeOH at room temperature gave the novel methoxylated benzimidazole-linked imidazo[1,2-a]quinoxalines 90.

Subsequently, Sun et al. reported the microwave assisted approach to benzimidazole-linked quinoxalinones on PEG support with two diversity positions.²⁸ As depicted in Scheme 18, polymer immobilized intermediates 21 with two in-built diversity positions, were reacted with chloroacetyl chloride 91 in the presence of Et₃N followed by cyclization to obtain the intermediate 92 under microwave heating. The cleavage of intermediate 92 with NH₃ in MeOH at room temperature for 48 h led to two products 93, and 93′ which was confirmed after careful analysis of HPLC data. Based on the analysis of the spectroscopic data it was confirmed that product 93′ was obtained from product 93 by auto-oxidation as shown in Scheme 18.

Scheme 18 PEG supported synthesis of novel benzimdazole-linked quinoxalinones.

Owing to the heterogeneous nature of solid-phase synthesis and low loading capacity of soluble polymer supports such as PEG, researchers have recently implemented the ionic liquid supported synthesis of small molecules which retains the advantages over solution-phase chemistry.²⁹ Generally the readily available 3-hydroxyethyl(1-methylimidazolium) tetrafluoroborate [HEMIm]BF₄ 94 is selected as a suitable ionic liquid (IL) support for multistep combinatorial synthesis. In 2011, Sun et al. successfully coupled 4-fluoro-3-nitrobenzoic acid 6 with [HEMIm]BF₄ 94 via esterification followed by the ipso-fluoro substitution of primary amines and subsequent reduction of the nitro-group, and obtained the IL immobilized o-phenylenediamine 95 by microwave irradiation as shown in Scheme 19.³⁰ Compound 95 was continuously N-acylated at the primary amine functionality with 4-fluoro-3-nitrobenzoic acid 6 in the presence of pyridine using microwave heating for 10 min to obtain the IL immobilized amide 96. Compound 96 was further cyclized to benzimidazole derivative 97 using TFA as acid catalyst and magnesium sulfate under microwave irradiation for 5 min at 100 °C. In order to introduce the second diversity, IL-supported o-fluoronitrobenzoate 97 was further treated with various primary amines in microwave conditions for 5 min, followed by nitro group reduction with zinc and ammonium formate to furnish IL immobilized diamine 98. IL immobilized diamine 98 was used as a common scaffold to generate the targeted biheterocyclic molecules by one-pot tandem transformation using various 3- and 4-ketoacids 99 to obtain pyrrolo- and pyrido-fused tricyclic benzimidazolones. Accordingly, IL conjugate 98 was treated with 3- or 4-keto acids 99 in the presence of TFA under microwave irradiation. In this key step the role of TFA is very important with the use of a catalytic quantity of TFA leading to the 2-alkyl substituted bisbenzimidazoles 100, whereas the use of 30 equiv. of TFA under focused microwave irradiation for 10 min, led to the desired tricyclic framework 101, respectively. The synthesis to tricyclic framework 101 through one pot cascade reactions involve the amino-alkylation of ionic liquid immobilized benzimidazole-linked diamine 98 with ketoacids 99 followed by intramolecular cyclization through attack of secondary amine toward pentacyclic aza-ring formation, and intramolecular cyclization to deliver the second cyclic amine ring. The ionic liquid support was cleaved from 101 using NaOMe in methanol solution under microwave irradiation for 10 min to obtain benzimidazole-linked pyrrolo/pyrido-benzimidazolone derivatives 102 and 103.

Scheme 19 Ionic liquid supported synthesis of benzimidazole-linked tricyclic frameworks.

In 2012, Sun et al. reported the diversity-oriented synthetic approach to benzo[d]oxazol-5-yl-1H-benzo[d]imidazole on ionic liquid support via microwave irradiation.³¹ As shown in Scheme 20, 4-hydroxy-3-nitrobenzoic acid 67 was successfully able to couple on to the ionic liquid immobilized o-phenylenediamine 95 followed by acid mediated ring closure reaction toward the generation of benzimidazole derivatives 104.

Scheme 20 Ionic liquid supported synthesis of thio-analogs of benzimidazole-linked benzoxazoles.

After hydrogenating the nitro group to amines, the resulted ionic liquid conjugates underwent efficient heterocyclization with 1,1-thiocarbonyldiimidazoles to provide the biheterocycles 105 on the ionic liquid support. Final skeletal diversity of the present scaffold 106 was achieved by S-alkylation with substituted bromides followed by cleavage from the support with sodium methoxide in methanol under microwave irradiation with good functional group tolerance and broad substrate scope.

In 2013, Sun et al. developed a one-pot multicomponent approach to benzimidazole-linked 2-aminothiophenes under solution-phase chemistry.³² As revealed in Scheme 21, substituted methyl-3,4-diaminobenzoate 107 underwent condensation reaction with cyanoacetic acid 108 at the primary amine functionality to give cyanoacetamide, which was subsequently cyclised using TFA, to give 2-cyanomethyl benzimidazole 109 in good yields. The intermediate 109, treated with aldehydes 74 containing an active methylene group and sulfur powder, under refluxing condition gave biologically relevant benzimidazole-linked 2-aminothiophene 110 in good yields. Subsequently this methodology has also been applied on an ionic liquid support with good yield and high purity.

Scheme 21 Solution-phase approach to benzimidazole-linked 2-aminothiophenes.

Recently, Sun et al. have explored the cascade synthesis of novel benzimidazole-linked alkyloxypyrrolo[1,2-a]quinoxalinones on a soluble polymer support under microwave irradiation.³³ As depicted in Scheme 22, the desired benzimidazole-linked methyl 1-(2-nitrophenyl)-1H-pyrrole-2-carboxylate 112 was obtained in 10 min under microwave irradiation. Polymer immobilized N-hydroxypyrroloquinoxalinones 113 were obtained by partial reductive cyclization for 7 min at 60 °C, and the synthesis of polymer conjugated pyrroloquinoxalinones 114 was accomplished by full reductive cyclization at 85 °C for 12 min under microwave irradiation followed by N-or O-alkylation with alkyl bromide.

Scheme 22 PEG supported synthesis of novel benzimidazole-linked alkyloxypyrrolo[1,2-a]quinoxalinones.

Compounds 115 and 116 were obtained after cleavage from the polymer support using 1% KCN in MeOH solution for 16 h with high purity and good yield.

In 2015, Kamal et al. designed and synthesized benzimidazole-linked imidazopyridine/imidazopyrimidine conjugates under solution-phase chemistry for the evaluation of antiproliferative activity against a panel of cancer cell lines.³⁴ The synthetic strategy depicted in Scheme 23 was commenced with the synthesis of the imidazopyridine/imidazopyrimidine 120 moiety followed by the condensation with substituted o-phenylenediamine derivative 4 to obtain the bis-heterocyclic scaffolds 121 for antiproliferative assay studies.

Scheme 23 Solution-phase approach to benzimidazole-linked imidazopyridine/imidazopyrimidines.

In the same year, Kamal et al. developed benzimidazole-linked arylpyrazole–benzimidazole conjugates 125 as potential microtubule disruptors.³⁵ As shown in Scheme 24, substituted acetophenones 122 were reacted with diethyl oxalate followed by hydrazine hydrate to obtain the pyrazole derivatives 123, which after functional group transformation, delivered the intermediate 124.

Scheme 24 Solution-phase approach to benzimidazole-linked arylpyrazole conjugates.

The intermediates 124 were cyclised with substituted o-phenylenediamine derivative 4 to generate the benzimidazole-linked arylpyrazole conjugates 125 which were studied for potential microtubule disruptor activity.

Angular benzimidazole-linked biheterocyclic molecules

After the successful synthesis of linear benzimidazole-linked biheterocyclic molecules, the second part of this review describes the design and synthesis of angularly oriented biheterocycles in which the substituents are positioned strategically on which the construction of a second angularly tilted heterocycle can be carried out. Moreover the heteroatoms in angular biheterocyclic molecules are more favorably oriented for binding electron deficient sites of the receptors or an in situ metal chelation in biomolecules.

In 2006, Chen et al. developed a solution-phase methodology for the synthesis of angular bisbenzimidazole, and bisbenzoxazole derivatives for potential anticancer evaluation.³⁶ The benzimidazole derivatives 126 were reacted with substituted phenylenediamine derivative 127 using SOCl₂ and pyridine in refluxing CH₂Cl₂ solution, followed by the cyclization in AcOH medium, to obtain the angular bisbenzimidazole derivative 129, which after functional group manipulation, led to the derivatives 130 and 131. Similarly, the bisbenzoxazole derivatives 135 were synthesized using the same protocol as depicted in Scheme 25.

Scheme 25 Solution-phase approach to bisbenzimidazole and bisbenzooxazoles.

In 2009, Sun et al. synthesized angular bisbenzimidazoles with three appendages on soluble polymer support using microwave irradiation.³⁷ As depicted in Scheme 26, polymer bound o-phenylenediamine conjugate 8 was reacted with 2-chloro-3-nitrobenzoic acid 136 for the installation of the angular moiety followed by cyclization to obtain the intermediate 137.

Scheme 26 PEG supported synthesis of trisubstituted angular bisbenzimidazole derivatives.

The second diversity was installed through ipso-chloro displacement with various primary amines followed by the reduction of the nitro group to generate the intermediate 138. The intermediate 138 underwent heterocyclisation with aldehydes or isothiocyanates or orthoformates to provide a more efficient route to angular bisbenzimidazole derivatives 139. Finally, PEG support was cleaved in KCN solution to deliver trisubstituted angular bisbenzimidazoles 140 in good yield.

In 2013, the same group reported the solution-phase synthesis of angular benzimidazole-linked benzoxazoles/benzothiazoles via Cu-catalysed domino annulation.³⁸ As shown in Scheme 27, the methyl ester of o-phenylenediamine derivative 107 was reacted with 2-chloro-3-nitrobenzoic acid 136 as the primary building block via an amide linkage, followed by cyclization using TFA to obtain the compound 141. The Cl and NO₂ groups in compound 141 were positioned strategically on which the construction of angularly oriented benzoxazoles and benzothiazoles could be easily carried out.

Scheme 27 Solution-phase approach to benzimidazole-linked benzoxazoles/benzothiazoles via Cu(I) catalysed domino reaction.

The reduction of the NO₂ group to an amino group was carried out under neutral condition using Zn and ammonium formate in MeOH solution to obtain the intermediate 142. The intermediate 142 underwent heterocyclisation using substituted acid chloride or isothiocyanates by intramolecular cross coupling reaction in a domino one-pot manner to obtain the angularly oriented benzimidazole-linked benzoxazoles 143 or benzothiazoles 144 in good yields.

In 2012, Sun, et al. synthesized biprivileged molecular scaffolds with three diversity points.³⁹ Pictet–Spengler cyclization was used as a key step to construct angularly oriented benzimidazole-linked tetracyclic scaffolds such as indolobenzodiazepines 146 and indoloquinoxalines 148 as shown in Scheme 28.

Scheme 28 Solution-phase approach to angularly oriented benzimidazole-linked indolobenzodiazepines and indoloquinoxalines.

In 2013, the same group reported the synthesis of benzimidazolylimidazo[1,2-a]pyridine under solvent-free microwave irradiation with three points of structural diversity.⁴⁰ As shown is Scheme 29, the methyl ester of o-phenylenediamine derivative 107 was reacted with 2-aminonicotinic acid 149 as the primary building block via an amide linkage, followed by cyclisation using TFA to obtain the benzimidazole-linked aminopyridine 150. The key step in the present scaffold is to accomplish the three-component Groebke–Blackburn–Bienaymé reaction involving benzimidazole-linked aminopyridine 150, aldehyde 74 and isonitrile 151 using Sc(OTf)₃ as acid catalyst under neat microwave conditions to afford the angularly oriented biheterocyclic scaffolds 152 in good yield.

Scheme 29 Solution-phase approach to angularly oriented benzimidazolyl imidazo[1,2-a]pyridine.

Fused benzimidazole-linked biheterocyclic molecules

Since the privileged structures offer an ideal foundation for drug discovery research due to their intrinsic affinity for diverse biological targets, a wide variety of fused heterocyclic structures has been designed with a view to occupy empty or sparingly occupied regions of chemical space, which eventually increase their chances of finding uses as new drug candidates with completely different modes of actions.

In pursuit of fused benzimidazole-based fused heterocyclic structures, Houghten et al. described the parallel synthesis of 2-imino-4-oxo-1,3,5-triazino[1,2-a]benzimidazoles 157 on a solid support as shown in Scheme 30.⁴¹ The synthetic methodology involves the generation of iminophosphorone derivatives 156 using Mitsunobu reaction from supported 2-aminobenzimidazole 155, which subsequently underwent Aza–Wittig reaction with isocyanates followed by intramolecular heterocyclisation, to generate the fused heterocycles 157 in good yield.

Scheme 30 Solid-phase approach to benzimidazole-linked fused heterocycles.

In 2007, Kurth et al. utilized microwave assisted cycloaddition of azomethine ylides as the key step for the efficient synthesis of pyrrolidino[2′,3′:3.4]pyrrolidino[1,2-a]benzimidazoles 160 in good yield.⁴²

As observed in Scheme 31, the substituted carbaldehydes 158 underwent condensation with secondary amino esters followed by 1,3-dipolar cycloaddition under microwave irradiation to deliver the benzimidazole-linked fused polycyclic pyrrolidines 160.

Scheme 31 Microwave assisted synthesis of fused polycyclic pyrrolidines.

In 2008, Yan et al. discovered a one-pot four-component reaction using pyridine 163, chloroacetonitrile 162, malononitrile 161 and aromatic aldehyde 74 to deliver the polysubstituted pyrido[1,2-a]benzimidazoles 164 in refluxing acetonitrile with good yield.⁴³ The reaction sequence involves the formation of a benzene ring followed by substitution and annulation reaction of pyridine in Scheme 32.

Scheme 32 One-pot four-component synthesis of pyrido[1,2-a]benzimidazoles.

In 2009, Huang et al. reported the solid-phase synthesis of benzo-fused tricycles using 3-(2-aminophenylamino)-2-selenoester as support.⁴⁴ As depicted in Scheme 33, the resin bound diamines 165 were reacted with various isothiocyanates and DIC as coupling agent to form the aminobenzimidazoles which subsequently cyclised in the presence of K₂CO₃ to obtain the fused tricycles 166 after cleavage from the solid support. Simultaneously, the intermediates 165 were reacted with Fmoc amino acid under usual coupling conditions to obtain the intermediates 167 which underwent Fmoc deprotection and subsequent cleavage to form benzimidazole fused tricycles 168 in good yields.

Scheme 33 Solid-phase synthesis of benzo-fused tricycles using 3-(2-aminophenylamino)-2-selenoester.

In 2010, Zhang et al. developed the 2,3-diarylpyrimido[1,2-a]benzimidazoles 171 by one-step cyclocondensation of 2-aminobenzimidazole 169 with isoflavones 170 in refluxing methanol in good yield as shown in Scheme 34.⁴⁵

Scheme 34 Solution-phase approach to 2,3-diarylpyrimido[1,2-a]benzimidazoles.

In view of the important bioactivities shown by fluorene and aza fluorenes, Sun et al. have developed a multidisciplinary synergetic approach to a triaza fluorene library on soluble polymer support using microwave irradiation.⁴⁶ As shown in Scheme 35, polymer immobilized o-phenylenediamine derivatives 8 underwent heterocyclisation with CNBr reagent under microwave irradiation to obtain the PEG immobilized benzimidazole derivatives 172. To furnish the triaza fluorine derivatives on PEG support, the benzimidazole derivatives 172 underwent multicomponent reaction with substituted aldehydes 74 and 1,3-diones or 3-oxoesters 173 under both microwave heating and classical heating conditions. The reaction took just 30 min for completion in microwave conditions as compared to 18 h in refluxing toluene solution. However, the stoichiometry of the reagents played an important role with excess of aldehyde leading to imine derivatives whereas an excess of 1,3-diones or 3-oxoesters resulted in amide derivatives as the byproducts. In order to obtain the triaza fluorine derivatives 174 with high yields, an equimolar mixture of benzimidazole derivatives 172, aldehydes 74, 1,3-diones or 3-oxoesters 173 and 10 mol% of piperidine in MeOH solution were subjected to microwave irradiation at 100 °C for 15–20 min followed by cleavage from the polymer support. The mechanism of the multicomponent cyclisation involves the Knoevenagel condensation of aldehydes with 1,3-diketones to obtain the unsaturated diones which underwent Michael addition with benzimidazole derivatives followed by proton transfer and subsequent intermolecular cyclization with dehydration to obtain the triaza fluorene library 174.

Scheme 35 Soluble polymer supported synthesis of triaza fluorene library.

Li et al. have developed an efficient iodocyclization strategy for a tandem route to the synthesis of iodoisoquinoline-fused benzimidazole derivatives in the presence of CuI as catalyst.⁴⁷ As shown in Scheme 36, substituted o-phenylenediamine derivatives 4 underwent tandem reaction with 2-ethynylbenzaldehydes 175 and iodine to afford the corresponding iodoisoquinoline-fused benzimidazoles 176 in good yields. This methodology has been extended to bromoisoquinoline-fused benzimidazole derivatives 177 using NBS as brominating agent in the presence of CuI as catalyst. However with NCS as the chlorinating agent, the yield was very much lower owing to the apparent lower reactivity associated with NCS.

Scheme 36 Synthesis of iodoisoquinoline-fused benzimidazole derivatives.

In 2011, Sun et al. have established a polymer supported approach to novel regioselective imidazo[1,2-a]benzimidazoles using microwave irradiation.⁴⁸ Polymer immobilized benzimidazole derivatives 172 underwent nucleophilic bromo-substitution with α-bromo ketones 178 followed by intramolecular cyclisation and subsequent aromatization to obtain the polymer immobilized imidazo[1,2-a]benzimidazole derivatives in Scheme 37. Finally the polymer was cleaved using 1% KCN in MeOH solution to obtain the imidazo[1,2-a]benzimidazoles 179 regioselectively.

Scheme 37 PEG supported regioselective synthesis of imidazo[1,2-a]benzimidazoles 179.

In the same year, Sun et al. demonstrated the synthesis of dihydropyrimidobenzimidazoles on a soluble polymer support by an unusual 1,3-sigmatropic rearrangement.⁴⁹

As depicted in Scheme 38, 2-aminobenzimidazole derivatives 180 underwent imination reaction with substituted aldehyde 74 using piperidine as base under microwave irradiation. The resultant benzimidazole-2-imine 181 was further reacted with methyl propiolate as electron deficient dienophile 182 and piperidine as base in an attempt to obtain the anticipated Povarov reaction product 183. However an unprecedented [1,3]sigmatropic rearrangement of the Povarov reaction product 183 led to the dihydropyrimido[1,2-a]benzimidazoles 184 regioselectively, using a solution-phase strategy. Moreover, the same reaction strategy was applied to polymer immobilized benzimidazole derivatives 172 with substituted aldehyde 74, and electron deficient dienophile 182 in the presence of piperidine as base under microwave irradiation to obtain the polymer cleaved dihydropyrimido[1,2-a]benzimidazoles 184 through a multicomponent Povarov reaction and in situ [1,3]sigmatropic rearrangement.

Scheme 38 Base-catalysed Povarov reaction on soluble support.

In 2011, Chibele et al. investigated pyrido[1,2-a]benzimidazoles using a solution-phase strategy for the evaluation of antiplasmodal activity.⁵⁰ In Scheme 39, 2-benzimidazole acetonitrile 187 underwent condensation with ethyl(4-alkanoyl/aroyl)acetate 188 to obtain the pyrido[1,2-a]benzimidaoles 189. Further diversification of the latter scaffold was obtained by treating with secondary amine to obtain the substituted pyrido[1,2-a]benzimidazoles 190 in high yields.

Scheme 39 Solution-phase approach to substituted pyrido[1,2-a]benzimidazoles.

Kaim et al. reported the efficient synthesis of benzimidazole fused piperizines using four-component Ugi–Smiles reaction.⁵¹ In this methodology, aminoacetaldehyde dimethyl acetal 191, substituted 2-nitrophenol 192, isocyanide 151 and substituted aldehydes 74 underwent four-component Ugi–Smiles reaction followed by an acid-catalyzed cyclization to obtain the intermediate 194. The intermediate 194 further underwent an intramolecular reductive cyclization, followed by oxidation to generate the privileged scaffold 195 as shown in Scheme 40.

Scheme 40 Ugi–Smiles approach to benzimidazole fused piperizines.

In 2012, Kraćhnak et al. demonstrated the stereoselective synthesis of benzimidazolinopiperazinones on a solid phase.⁵² As shown in Scheme 41, the synthetic strategy was carried out on Rink Amide Resins using bromoacetic acid followed by reaction with aminoacetaldehyde dimethyl acetal to form intermediate 197. The intermediate 197 was further reacted with different amino acids to obtain intermediates 198. After deprotecting the Fmoc moiety in intermediates 198, they were further treated with substituted or unsubstituted o-fluoronitrobenzene followed by a sequence of reactions to obtain the benzimidazolinopiperazinones 200 in good yield.

Scheme 41 Solid-supported synthesis of benzimidazolinopiperazinones.

In 2013, Sun et al. achieved the synthesis of complex pentacyclic heterocycles through piperidine-mediated Groebke–Bienayme–Blackburn multicomponent reaction.⁵³ As depicted in Scheme 42, 2-aminobenzimidazole 180, methyl 2-formyl benzoate 201, and isocyanides 151 react together, using piperidine as base, to obtain the isoquinolinone embedded imidazo[1,2-a]benzimidazoles 202 in good yields.

Scheme 42 Piperidine mediated solution-phase multicomponent approach to isoquinolinone embedded imidazo[1,2-a]benzimidazoles.

Further inspired by the above results, Sun et al. have developed a multicomponent approach to pyrrolo[1,2-a]benzimidazoles on an ionic liquid support via Knoevenagel condensation and a [4 + 1]-cycloaddition reaction.⁵⁴

The key intermediate 204 was reacted with substituted aldehydes 74 and isocyanides 151 in the presence of Et₃N as base to obtain the pyrrolo[1,2-a]benzimidazole derivatives 206 followed by cleavage of the ionic liquid support under microwave irradiation as shown in Scheme 43.

Scheme 43 Ionic-liquid supported synthesis of pyrrolo[1,2-a]benzimidazole derivatives.

In 2013, Sun et al. again accomplished the synthesis of imidazo[1,2-a]benzimidazoles via a one-pot two-step multicomponent (4 + 1) cycloaddition reaction under solution-phase strategy.⁵⁵ As designed in Scheme 44, 2-aminobenzimidazole derivatives 180 underwent initial condensation with substituted aldehydes 74 to form imine 207 using piperidine as base under microwave irradiation for 10 min. Subsequently the imines were isolated from the reaction mixture and ¹H NMR study indicated the existence in s-cis conformation which favored the subsequent (4 + 1) cycloaddition with substituted isocyanides. The imines 207 further underwent (4 + 1) cycloaddition reaction with isocyanides 151 to obtain the imidazo[1,2-a]benzimidazoles 208 with three structural diversity features in good yields.

Scheme 44 Microwave-assisted telescoped synthesis of imidazo[1,2-a]benzimidazoles.

Li et al. have developed an one-pot synthetic route to benzo[4.5]imidazo[2.1-a]isoquinolones with high yields.⁵⁶ The synthetic methodology consists of nucleophilic addition of 2-arylbenzimidazole 209 to substituted alkynyl bromide 210, followed by the intramolecular Pd-catalyzed C–H vinylation reaction to generate the privileged scaffold 211, as shown in Scheme 45.

Scheme 45 Pd-catalysed one-pot approach to benzo[4.5]imidazo[2.1-a]isoquinolones.

In the same year, Sun et al. reported the synthesis of pyrimido[1,2-a]benzimidazoles via a Michael/heteroannulation strategy, on an ionic liquid support.⁵⁷ As reported in Scheme 46, treatment of ionic liquid supported o-phenylenediamine derivative 95 with cyanogen bromide in refluxing dichloromethane led to the IL-immobilized 2-aminobenzimidazoles 212. The intermediate 212 underwent Michael addition with in situ generated 1,1-dicyano-2-aryl ethylenes 213 from malononitrile 161 and substituted aldehydes 74, followed by intramolecular heteroannulation to obtain regioselectively pyrimido[1,2-a]benzimidazoles 214 on the ionic liquid support. Finally, the ionic liquid was cleaved using CH₃ONa in methanol solution for 8 h at room temperature to obtain the tricyclic skeleton 215 in excellent yields.

Scheme 46 Ionic liquid supported synthesis of tricyclic skeletons.

In 2014, Sun’s group reported the synthesis of fused tricyclic triazenes via tandem imination–isocyanate-mediated annulation reactions on an ionic liquid support.⁵⁸ As reported in Scheme 47, synthetic modifications on the IL-immobilized 2-aminobenzimidazoles 212 were carried out using piperidine-mediated imination reaction of 2-aminobenzimidazoles 212 with aldehydes 74, followed by substituted isocyanate 216 backed annulation reaction to obtain the triazene derivatives 217.

Scheme 47 Ionic liquid supported synthesis of fused tricyclic triazenes.

Finally the ionic liquid was cleaved using a solution of ammonia in methanol at room temperature for 8 h to obtain the trisubstituted triazenes 218 in excellent yields.

Sun et al. further reported the synthesis of benzimidazo[1′,2′:1,5]pyrrolo[2,3-c]isoquinolines by a three-component coupling reaction on ionic liquid support.⁵⁹ As shown in Scheme 48, ionic liquid immobilized 2-cyanomethyl benzimidazole 204 underwent Knoevenagel condensation reaction with methyl-2-formylbenzoate 201 using piperidine as basic catalyst in refluxing CH₃CN solution to obtain the intermediate 219. Further the intermediate 219 reacted with an isocyanide 151 via [4 + 1] cycloaddition to obtain the pentacyclic scaffolds 220 in high yields, followed by cleavage of the ionic liquid support under microwave irradiation.

Scheme 48 Ionic liquid supported rapid two-step synthesis of fused pentacyclic scaffolds.

Wang et al. have developed an inexpensive and efficient Cu(I) catalysed domino method for the synthesis of benzoimidazo-1,2,4-benzothiadiazine 1,1-dioxide 223 using solution-phase methodology.⁶⁰ As depicted in Scheme 49, benzimidazole 221 reacted with substituted sulfonamides 222 via Ullmann-type N-arylation followed by intramolecular C–H amination reaction using base and atmospheric oxygen as oxidant to achieve the desired scaffolds 223 in good yields.

Scheme 49 Cu(I) catalyzed domino approach to benzoimidazo-1,2,4-benzothiadiazine 1,1-dioxide.

In 2016, Sotelo et al. have utilized the three-component Biginelli condensation reaction for the construction of benzo[4,5]imidazo[1,2-a]pyrimidines 225.⁶¹ In this methodology, chloroacetic acid was used as a catalyst for the three-component coupling of 2-aminobenzimidazole 169, substituted aldehyde 74 and ethyl acetoacetate 224 under microwave irradiation as shown in Scheme 50. Further the synthesized compounds were found to be active as an A₂B adenosine receptor antagonist.

Scheme 50 Microwave assisted approach to benzo[4,5]imidazo[1,2-a]pyrimidines.

Xu et al. have employed the Ugi multicomponent approach to architecturally beautiful benzimidazoisoquinolinone with high yields.⁶² In this methodology, isonitrile 226, aldehyde 227, primary amine 228, and carboxylic acid 229 underwent Ugi multicomponent reaction in MeOH solution at room temperature to afford the intermediate 230. The intermediate 230 subsequently underwent acid-mediated cyclisation using 10% TFA in DCE at 150 °C to afford the benzimidazoisoquinolinone 231 as depicted in Scheme 51.

Scheme 51 Ugi multicomponent approach to benzimidazoisoquinolinone.

In 2016, Sun, et al. developed the ultrasound promoted three-component coupling reaction towards the synthesis of benzimidazo[2,1-a]quinazolin-1(1H)-ones 234, shown in Scheme 52.⁶³ In this methodology, substituted 2-aminobenzimidazoles 180, aldehydes 74 and 1,3-diones 232 underwent three-component coupling reaction using piperidine as catalyst under green synthetic condition.

Scheme 52 Ultrasound promoted multicomponent approach to benzimidazo[2,1-a]quinazolin-1(1H)-ones.

The key step in this methodology involved the nucleophilic attack by 2-aminobenzimidazole on the in situ generated Michael adduct 233 of 1,3-diones and substituted aldehydes, followed by the electrocyclic ring closure to generate the target compound. As predicted initially, reaction of 2-aminobenzimidazole 180 with the piperidine-catalyzed Knoevenagel product did not yield the desired scaffold 234.

Conclusion and outlook

Nowadays, the medicinal chemistry community is showing a great interest to obtain biheterocyclic small molecules to understand the biological processes which can act as chemical modulators and analyzers of signaling pathways. Biheterocyclic small molecules are in great demand for better understanding of normal and disease-related biological processes which could be a useful starting point in drug discovery research. Although a number of important synthetic advances have been made in the synthesis of benzimidazole-based linear, angular and fused biheterocyclic molecules, new chemistry is being developed on a solid phase support which does not have any solution-phase counterpart. In this review, efforts have been made to highlight the latest information available on the syntheses and applications of benzimidazole-based biheterocyclic derivatives from 1999 to 2016. However, in many cases, the biological evaluation of these novel biheterocyclic small molecules is not fully realized yet and this is an area that will be given careful scrutiny in the years to come. In future the first major step towards reaching the goals of novel biheterocyclic molecules as analyzers for all the signaling networks lies in the development of new synthetic methods with the potential of generating bioactive compounds in a high-throughput manner. The combination of modern concepts such as green chemistry, as exemplified by microwave assisted ionic liquid supported synthesis, will help in developing more economic and more likely routes to generate new therapeutic scaffolds to abridge the ‘valley of death’. The present synthetic methodologies incorporated in this review article will help to improve the status of these biheterocyclic scaffolds in future syntheses and drug discovery applications.

Acknowledgements

The authors thank the Chancellor and Vice Chancellor of VIT University for providing an opportunity to carry out this study. Further the authors wish to thank the management of this university for providing seed money as a research grant. Barnali Maiti thanks DST-Govt of India for funding through DST-SERB-YSS/2015/00450. The authors thank the reviewers for giving constructing comments for the overall improvement of the manuscript.

References

1. Top Prescription Drugs by U.S. Sales 2014|Statistic, http://www.statista.com/statistics/258010/top-branded-drugs-based-on-retail-sales-in-the-us/, accessed on 28 May 2015.
2. (a) R. E. Dolle, B. L. Bourdonnec, A. J. Goodman, G. A. Morales, C. J. Thomas and W. Zhang, J. Comb. Chem., 2008, 10, 753–802; (b) J. P. Nandy, M. Prakesch, S. Khadem, P. T. Reddy, U. Sharma and P. Arya, Chem. Rev., 2009, 109, 1999–2060.
3. (a) R. E. Dolle, J. Comb. Chem., 2005, 7, 739–798; (b) C. R. Kodihalli, M. V. Hosadu and V. P. Vaidya, ARKIVOC, 2008, 1–10.
4. New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products, http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/default.htm, accessed 1 June 2015.
5. (a) K. C. Achar, K. M. Hosamani and H. R. Seetharamareddy, Eur. J. Med. Chem., 2010, 45, 2048–2054; (b) J. Bauer, S. Kinast, A. Burger-Kentischer, D. Finkelmeier, G. Kleymann, W. A. Rayyan, K. Schroppel, A. Singh, G. Jung, K. H. Wiesmuller, S. Rupp and H. Eickhoff, J. Med. Chem., 2011, 54, 6993–6997; (c) H. B. El-Nassan, Eur. J. Med. Chem., 2012, 53, 22–27; (d) B. Garudachari, M. N. Satyanarayana, B. Thippeswamy, C. K. Shivakumar, K. N. Shivananda, G. Hegde and A. M. Isloor, Eur. J. Med. Chem., 2012, 54, 900–906; (e) A. Mavrova, D. Vuchev, K. Anichina and N. Vassilev, Eur. J. Med. Chem., 2010, 45, 5856–5861; (f) C. S. Mizuno, A. G. Chittiboyina, F. H. Shah, A. Patny, T. W. Kurtz, H. A. Pershadsingh, R. C. Speth, V. T. Karamyan, P. B. Carvalho and M. A. Avery, J. Med. Chem., 2010, 53, 1076–1085; (g) C. G. Neochoritis, T. Zarganes-Tzitzikas, C. A. Tsoleridis, J. Stephanatou, C. A. Kontogiorgis, D. J. Hadjipavlou-Litina and T. CholiPapadopoulou, Eur. J. Med. Chem., 2011, 46, 297–306; (h) R. V. Patel, P. K. Patel, P. Kumari, D. P. Rajani and K. H. Chikhalia, Eur. J. Med. Chem., 2012, 53, 41–51.
6. Y. Bansal and O. Silakari, Bioorg. Med. Chem., 2012, 20, 6208–6236.
7. C. G. Blettner, W. A. König, G. Rühter, W. Stenzel and T. Schotten, Synlett, 1999, 307–310.
8. (a) A. Mazurov, Bioorg. Med. Chem. Lett., 2000, 10, 67–70; (b) Z. Wo, P. Rea and G. Wickham, Tetrahedron Lett., 2000, 41, 9871–9874; (c) J. P. Kilburn, J. Lau and R. C. F. Jones, Tetrahedron Lett., 2000, 41, 5419–5421; (d) V. Krachnák, J. Smith and J. Vágner, Tetrahedron Lett., 2001, 42, 1627–1630.
9. Y. C. Chi and C. M. Sun, Synlett, 2000, 591–594.
10. (a) C. M. Yeh and C. M. Sun, Tetrahedron Lett., 1999, 40, 7247–7250; (b) C. M. Yeh and C. M. Sun, Synlett, 1999, 810–812; (c) C. M. Yeh, C. L. Tung and C. M. Sun, J. Comb. Chem., 2000, 2, 341–348; (d) P. M. Bendale and C. M. Sun, J. Comb. Chem., 2002, 4, 359–361; (e) C. Y. Wu and C. M. Sun, Tetrahedron Lett., 2002, 43, 1529–1533; (f) K. T. Huang and C. M. Sun, Bioorg. Med. Chem. Lett., 2002, 12, 1001–1003.
11. D. Tumelty, K. Cao and C. P. Holmes, Org. Lett., 2001, 3, 83–86.
12. H. Akamatsu, K. Fukase and S. Kusumoto, J. Comb. Chem., 2002, 4, 475–483.
13. D. Vourloumis, M. Takahashi, K. B. Simonsen, B. K. Ayida, S. Barluenga, G. C. Winters and T. Hermann, Tetrahedron Lett., 2003, 44, 2807–2811.
14. (a) M. J. Lin and C. M. Sun, Synlett, 2004, 663–666; (b) W. B. Yeh, M. J. Lin and C. M. Sun, Comb. Chem. High Throughput Screening, 2004, 7, 251–255.
15. A. Kamal, P. Ramulu, O. Srinivas, G. Ramesh and P. P. Kumar, Bioorg. Med. Chem. Lett., 2004, 14, 4791–4794.
16. C. H. Wu and C. M. Sun, Tetrahedron Lett., 2006, 47, 2601–2604.
17. C. M. Chang, M. V. Kulkarni, C. H. Chen, C. H. Wang and C. M. Sun, J. Comb. Chem., 2008, 10, 466–474.
18. H. Y. Chen, M. V. Kulkarni, C. H. Chen and C. M. Sun, Tetrahedron, 2008, 64, 6387–6394.
19. A. Mayence, A. Pietka, M. S. Collins, M. T. Cushion, B. L. Tekwani, T. L. Huang and J. J. Vanden Eynde, Bioorg. Med. Chem. Lett., 2008, 18, 2658–2661.
20. M. Soural, I. Bouillon and V. Krachňăk, J. Comb. Chem., 2008, 10, 923–933.
21. K. Chanda, J. Kuo, C. H. Chen and C. M. Sun, J. Comb. Chem., 2009, 11, 252–260.
22. (a) G. A. Molander and L. A. Felix, J. Org. Chem., 2005, 70, 3950–3956; (b) S. Fioravanti, L. Pellacani, P. A. Tardella, A. Morreale and G. D. Signore, J. Comb. Chem., 2006, 8, 808–811.
23. V. M. Reddy and K. R. Reddy, Chem. Pharm. Bull., 2010, 58, 1081–1084.
24. K. Chanda, B. Maiti, G. S. Yello, M. H. Chien, M. L. Kuo and C. M. Sun, Org. Biomol. Chem., 2011, 9, 1917–1926.
25. B. Maiti and C. M. Sun, New J. Chem., 2011, 35, 1385–1396.
26. L. H. Chen, C. C. Mao, D. B. Salunke and C. M. Sun, ACS Comb. Sci., 2011, 13, 391–398.
27. C. H. Chen, J. Kuo, G. S. Yellol and C. M. Sun, Chem.–Asian J., 2011, 6, 1557–1565.
28. C. T. Chou, Y. S. Yellol, C. W. Jin, M. L. Sun and C. M. Sun, Tetrahedron, 2011, 67, 2110–2117.
29. (a) W. Miao and T. H. Chan, Org. Lett., 2003, 5, 5003–5005; (b) W. S. Miao and T. H. Chan, Acc. Chem. Res., 2006, 39, 897–908; (c) B. Ni and A. D. Headley, Chem.–Eur. J., 2010, 16, 4426–4436.
30. S. Thummanagoti, G. S. Yello and C. M. Sun, Tetrahedron Lett., 2011, 52, 2818–2822.
31. K. Chanda, B. Maiti, C. C. Tseng and C. M. Sun, ACS Comb. Sci., 2012, 14, 115–123.
32. L. H. Chen, Y. S. Chuang, B. D. Narhe and C. M. Sun, RSC Adv., 2013, 3, 13934–13943.
33. S. Dhole, M. Selvaraju, B. Maiti, K. Chanda and C. M. Sun, ACS Comb. Sci., 2015, 17, 310–316.
34. A. Kamal, G. B. Kumar, V. L. Nayak, V. S. Reddy, A. B. Shaik, Rajender and M. K. Reddy, Med. Chem. Commun., 2015, 6, 606–612.
35. A. Kamal, A. B. Shaik, S. Polepalli, G. B. Kumar, V. S. Reddy, R. Mahesh, S. Garmella and N. Jain, Bioorg. Med. Chem., 2015, 23, 1082–1095.
36. S. T. Huang, I. J. Hsei and C. Chen, Bioorg. Med. Chem., 2006, 14, 6106–6119.
37. C. H. Chen, M. H. Chien, M. L. Kuo, C. T. Chou, J. J. Lai, S. F. Lin, S. Thummanagoti and C. M. Sun, J. Comb. Chem., 2009, 11, 1038–1046.
38. J. Y. Liao, M. Selvaraju, C. H. Chen and C. M. Sun, Org. Biomol. Chem., 2013, 11, 2473–2481.
39. I. Barve, C. Y. Chen, D. B. Salunke, W. S. Chung and C. M. Sun, Chem.–Asian J., 2012, 7, 1684–1690.
40. B. Maiti, K. Chanda, M. Selvaraju, C. C. Tseng and C. M. Sun, ACS Comb. Sci., 2013, 15, 291–297.
41. C. E. Hoesl, A. Nefzi and R. A. Houghten, J. Comb. Chem., 2003, 5, 155–160.
42. L. Meng, J. C. Fettinger and M. J. Kurth, Org. Lett., 2007, 9, 5055–5098.
43. C. G. Yan, Q. F. Wang, X. K. Song and J. Sun, J. Org. Chem., 2009, 74, 710–718.
44. X. Huang, J. Cao and J. Huang, J. Comb. Chem., 2009, 11, 515–518.
45. Z. T. Zhang, L. Qiu, D. Xue, J. Wu and F. F. Xu, J. Comb. Chem., 2010, 12, 225–230.
46. Y. S. Hsiao, G. S. Yellol, L. H. Chen and C. M. Sun, J. Comb. Chem., 2010, 12, 723–732.
47. H. C. Ouyang, R. Y. Tang, P. Zhong, X. G. Zhang and J. H. Li, J. Org. Chem., 2011, 76, 223–228.
48. L. H. Chen, Y. S. Hsiao, G. S. Yellol and C. M. Sun, ACS Comb. Sci., 2011, 13, 112–119.
49. C. H. Chen, G. S. Yellol, P. T. Lin and C. M. Sun, Org. Lett., 2011, 13, 5120–5123.
50. A. J. Ndakala, R. K. Gessner, P. W. Gitari, N. October, K. L. White, A. Hudson, F. Fakorede, D. M. Shackleford, M. Kaiser, C. Yeates, S. A. Charman and K. Chibale, J. Med. Chem., 2011, 54, 4581–4589.
51. L. E. Kaïm, L. Grimaud and S. R. Purumandla, J. Org. Chem., 2011, 76, 4728–4733.
52. N. Cankařová and V. Krachňăk, J. Org. Chem., 2012, 77, 5687–5689.
53. C. H. Lee, W. S. Hsu, C. H. Chen and C. M. Sun, Eur. J. Org. Chem., 2013, 2201–2208.
54. W. S. Hsu, V. Paike and C. M. Sun, Mol. Diversity, 2013, 17, 285–294.
55. Y. S. Hsiao, B. D. Narhe, Y. S. Chang and C. M. Sun, ACS Comb. Sci., 2013, 15, 551–555.
56. J. Peng, G. Shang, C. Chen, Z. Miao and B. Li, J. Org. Chem., 2013, 78, 1242–1248.
57. M. Selvaraju, W. S. Shiu, M. V. Kulkarni and C. M. Sun, RSC Adv., 2013, 3, 22314–22318.
58. I. J. Barve, C. H. Chen, C. H. Kao and C. M. Sun, ACS Comb. Sci., 2014, 16, 244–249.
59. B. D. Narhe, M. H. Tsai and C. M. Sun, ACS Comb. Sci., 2014, 16, 421–427.
60. D. Yang, B. An, W. Wei, L. Tian, B. Huang and H. Wang, ACS Comb. Sci., 2015, 17, 113–119.
61. A. E. Maatougui, J. Azuaje, M. G. Gómez, G. Miguez, A. Crespo, C. Carbajales, L. Escalante, X. García-Mera, H. Gutierrez-de-Terán and E. Sotelo, J. Med. Chem., 2016, 59, 1967–1983.
62. W. L. Liao, S. Q. Li, J. Wang, Z. Y. Zhang, Z. W. Yang, D. Xu, C. Xu, H. T. Lan, Z. Z. Chen and Z. G. Xu, ACS Comb. Sci., 2016, 18, 65–69.
63. L. H. Chen, T. W. Chung, B. D. Narhe and C. M. Sun, ACS Comb. Sci., 2016, 18, 162–169.

---