Advances in the Synthesis of Ring-Fused Benzimidazoles and Imidazobenzimidazoles

Abstract

This review article provides a perspective on the synthesis of alicyclic and heterocyclic ring-fused benzimidazoles, imidazo[4,5-f]benzimidazoles, and imidazo[5,4-f]benzimidazoles. These heterocycles have a plethora of biological activities with the iminoquinone and quinone derivatives displaying potent bioreductive antitumor activity. Synthesis is categorized according to the cyclization reaction and mechanisms are detailed. Nitrobenzene reduction, cyclization of aryl amidines, lactams and isothiocyanates are described. Protocols include condensation, cross-dehydrogenative coupling with transition metal catalysis, annulation onto benzimidazole, often using CuI-catalysis, and radical cyclization with homolytic aromatic substitution. Many oxidative transformations are under metal-free conditions, including using thermal, photochemical, and electrochemical methods. Syntheses of diazole analogues of mitomycin C derivatives are described. Traditional oxidations of o-(cycloamino)anilines using peroxides in acid via the t-amino effect remain popular.

Keywords: green chemistry; halogen; heterocycle; hydrogen peroxide; imidazole; iodine; nitrosobenzene; oxone; palladium; quinone.

Figure 1

Benzimidazole in vitamin B₁₂ and biologically-active ring-fused systems [1,2,3,4,5,6,7,8,9].

Figure 2

Imidazole-based wakayin analogues [10].

Figure 3

Aziridinyl-functionalized antitumor agents [11,12,13,14,15,16,17,18].

Figure 4

Benzimidazolequinones targeting over-expressed reductases in solid tumors [21,22,23].

Figure 5

Imidazobenzimidazolequinones and iminoquinones [24,25,26,27,28,29].

Scheme 1

Categorizing available synthetic methods according to the cyclization reaction A-E.

Scheme 2

Nair and Adams oxidative cyclizations of anilines [36].

Scheme 3

Acetanilide cyclizations onto (a) azepino- and azocino- [39], and (b) spirocyclic oxetane- [40] derivatives.

Scheme 4

Aniline cyclizations using (a) performic acid [42] and (b) acid-free conditions [43].

Scheme 5

Hg(II)-mediated oxidative synthesis [46].

Scheme 6

Ir(III)-mediated cyclizations (a) with ligand [47] and (b) without ligand [48].

Scheme 7

Thermal oxidative cyclizations mediated by (a) TEMPO/air [49] and (b) Fe(III) [50].

Scheme 8

Electrochemical oxidative cyclizations [51].

Scheme 9

Synthesis of polychlorinated ring-fused benzimidazoles using SO₂Cl₂ [53].

Scheme 10

Molecular halogen (X₂) generated from H₂O₂ and HX [54,55,56].

Scheme 11

One-pot ring closure with selective halogenation using (a) domestic bleach or H₂O₂/HCl, (b) H₂O₂/HCl, and (c) H₂O₂/HBr, and (d) five to eight-membered ring-fused adducts [54].

Scheme 12

One-pot transformations of anilines to halogenated ring-fused benzimidazolequinones using (a) H₂O₂/HX, (b) Cl₂ and Br₂ with water, and (c) H₂O₂/HX without quinone formation [55].

Scheme 13

H₂O₂/HI-mediated (a) five- to seven-membered cyclizations and (b) six-membered cyclizations with phenazine formation [56].

Scheme 14

Optimizing the synthesis of 1,4,6,9-tetramethoxyphenazine 17 [56].

Scheme 15

Oxone-mediated ring-closure of 2-(morpholin-4-yl)aniline [61].

Scheme 16

Sequential aminations of nitrosoarenes to prepare (a) alicyclic ring-fused benzimidazoles, (b) naphthoimidazoles, and (c) the proposed mechanism [62].

Scheme 17

Oxidative syntheses of imidazo[4,5-f]benzimidazoles using (a) performic acid [24,25] and (b) Oxone [29], and (c) of imidazo[5,4-f]benzimidazoles using Oxone [27], and (d) with fused spirocyclic oxetane ring [61].

Figure 6

Key chemical structures in resolving the mechanism [27,37,38].

Scheme 18

Mechanism for oxidation o-(cycloamino)acetamide to imidazobenzimidazole [27].

Scheme 19

Acid-mediated cyclization of amine N-oxides to (a) benzimidazole [27] and (b) imidazo[4,5-f]benzimidazole [61].

Scheme 20

Reductive cyclizations using (a) thermal conditions [71] and (b) I₂/HCO₂H [72].

Scheme 21

Synthesis from (a) o-haloarylamidine [75], (b) a lactam derivative of o-phenyldiamine [76], and (c) a rearrangement of aryl isothiocyanates [77].

Scheme 22

Cyclization of aryl amidines using (a) phenyliodine(III) diacetate [78] and (b) Kosher’s reagent [79].

Scheme 23

Synthesis of pyrido[1,2-a] benzimidazoles via amidine intermediates [80].

Scheme 24

Acid-catalyzed condensation of 1,2-phenylenediamine with o-phthaldehyde and glutaraldehyde [82].

Scheme 25

Annulations [4 + 2] of benzimidazoles using bromoethylsulfonium salt [86].

Scheme 26

Synthesis of benzimidazole-fused 1,4-oxazepines [87].

Scheme 27

Pd(II)-catalyzed synthesis of benzimidazole-fused phenanthridines [88].

Scheme 28

Asymmetric pyrido[1,2-a]benzimidazole syntheses [91].

Scheme 29

Annulations [4+2] of benzimidazoles using Ru(II)-NH and CH activation [93].

Scheme 30

Pd-catalyzed dehydrogenative cross-couplings to give (a) 11H-isoindolo[2,1-a]benzimidazoles [94] and (b) benzimidazoquinazolines [95].

Scheme 31

CuI-catalyzed annulations onto N-1 of benzimidazole using (a) 1,1-dibromoalkenes [96] and (b) cyanamide [97].

Scheme 32

Pd-catalyzed macrocyclization to give benzimidazole-fused thiazocine [99].

Scheme 33

Radical initiator-free HAS using (a) UV-light [102] and (b) Barton ester intermediates [104].

Scheme 34

Bu₃SnH-mediated formation of ring-fused benzimidazoles using (a) chain reaction [23,105], and non-chain reaction (b) double [26] and (c) single [28] HAS.

Scheme 35

Di-tert-butyl peroxide (DTBP)-mediated oxidative HAS [110].

Scheme 36

Annulations onto N-1 of benzimidazole using (a) PIFA [112] and (b) aryl isocyanates [113].

Scheme 37

Condensation of 2-(benzimidazol-1-yl)anilines [114].

Scheme 38

Synthesis of analogues of (a) cyclopropamitosenes [22,115,116] and (b) aziridinomitosene [14].