Advances in the Synthesis of Ring-Fused Benzimidazoles and Imidazobenzimidazoles

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.

One or two-electron reductases are responsible for bioreductive activation. NADPHcytochrome c (P450) reductase is predominant under hypoxic conditions with the oneelectron reduction reversed by oxygen [19]. Many solid tumors also over-express the obligatory two-electron reductase NAD(P)H:quinone oxidoreductase 1 (NQO1, also known as DT-diaphorase), which is a popular target for anti-cancer studies [20]. Many anti-cancer agents do not contain conventional DNA damaging functionality, and cytotoxicity may be due to the formation of reactive oxygen species. Pyrido[1,2-a]benzimidazolequinone 1 ( Figure 4) is more than 300 times more cytotoxic under hypoxic conditions than the clinical drug, MMC ( Figure 3), with cytotoxicity for alicyclic ring-fused benzimidazoles correlated to reductive potentials [21,22]. Highly conjugated naphthyl fused benzimidazolequinone 2 leads to increased stability of reduced intermediates leading to specificity towards human cancer cell lines over-expressing NQO1 [23].

Available Synthetic Methods
The categories of syntheses of ring-fused benzimidazoles 6 are according to the cyclization reaction (Scheme 1). Oxidative cyclizations from aniline or anilide derivatives is the most studied route (Route A) and is presented in context with the plethora of other syntheses that build the benzimidazole moiety (Routes B-D). The section on Route A is sub-divided into syntheses of benzimidazole and imidazobenzimidazole scaffolds. Lastly, there is a section on syntheses, which begin with the benzimidazole moiety (Route E), subdivided according to reaction (type) conditions. This is not an exhaustive review, and the reader should consult reviews on polycyclic benzimidazoles for comprehensive lists of syntheses [30][31][32][33]. Since the late 1990s, Aldabbagh et al. have worked on the discovery of new ring-fused benzimidazoles and synthetic methods, and the collated articles related to their research are reviewed herein. A reviewer recommended a Scifinder n search of "benzimidazole-fused", which was completed, and significant references are incorporated. For brevity, full papers are cited and not the preceding communication article. A historical perceptive is taken and analysis of the most significant contributions to the field is carried Ring-fused imidazo [4,5-f ]benzimidazolequinones 3a and 3b are NQO1 substrates [24,25], with 3a, at the National Cancer Institute (NCI), showing specificity towards the killing of melanoma cell lines ( Figure 5) [24]. Our group was the first to provide viable synthetic protocols for accessing ring-fused imidazo [5,4-f ]benzimidazoles, enabling evaluation of quinone and iminoquinone derivatives for toxicity against cancer cell lines [26][27][28][29]. Compared to alicyclic ring-fused analogues 4a and 4b, the oxygen atom of the 1,4-oxazino ring was found to increase toxicity of 4c [27]. Iminoquinone 5a isolated from the Fremy oxidation to prepare 4b, was unexpectedly the most potent imidazobenzimidazole, with more than 12 times greater cytotoxicity towards a prostate cancer cell line (DU145) than a normal fibroblast cell line (GM00637) [26]. More intensive cytotoxicity assays, computational docking, and NCI COMPARE analysis on 5a, revealed good correlation with NQO1 [28]. In contrast, isomeric imidazo[4,5-f ]benzimidazole 5b was inactive against the NCI 60 cell line panel [29].  Figure 4) is more than 300 times more cytotoxic under hypoxic conditions than the clinical drug, MMC ( Figure 3), with cytotoxicity for alicyclic ring-fused benzimidazoles correlated to reductive potentials [21,22]. Highly conjugated naphthyl fused benzimidazolequinone 2 leads to increased stability of reduced intermediates leading to specificity towards human cancer cell lines over-expressing NQO1 [23]. Ring-fused imidazo [4,5-f]benzimidazolequinones 3a and 3b are NQO1 substrates [24,25], with 3a, at the National Cancer Institute (NCI), showing specificity towards the killing of melanoma cell lines ( Figure 5) [24]. Our group was the first to provide viable synthetic protocols for accessing ring-fused imidazo [5,4-f]benzimidazoles, enabling evaluation of quinone and iminoquinone derivatives for toxicity against cancer cell lines [26][27][28][29]. Compared to alicyclic ring-fused analogues 4a and 4b, the oxygen atom of the 1,4oxazino ring was found to increase toxicity of 4c [27]. Iminoquinone 5a isolated from the Fremy oxidation to prepare 4b, was unexpectedly the most potent imidazobenzimidazole, with more than 12 times greater cytotoxicity towards a prostate cancer cell line (DU145) than a normal fibroblast cell line (GM00637) [26]. More intensive cytotoxicity assays, computational docking, and NCI COMPARE analysis on 5a, revealed good correlation with NQO1 [28]. In contrast, isomeric imidazo[4,5-f]benzimidazole 5b was inactive against the NCI 60 cell line panel [29].

Available Synthetic Methods
The categories of syntheses of ring-fused benzimidazoles 6 are according to the cyclization reaction (Scheme 1). Oxidative cyclizations from aniline or anilide derivatives is the most studied route (Route A) and is presented in context with the plethora of other syntheses that build the benzimidazole moiety (Routes B-D). The section on Route A is sub-divided into syntheses of benzimidazole and imidazobenzimidazole scaffolds. Lastly, there is a section on syntheses, which begin with the benzimidazole moiety (Route E), subdivided according to reaction (type) conditions. This is not an exhaustive review, and the reader should consult reviews on polycyclic benzimidazoles for comprehensive lists of syntheses [30][31][32][33]. Since the late 1990s, Aldabbagh et al. have worked on the discovery of new ring-fused benzimidazoles and synthetic methods, and the collated articles related to their research are reviewed herein. A reviewer recommended a Scifinder n search of "benzimidazole-fused", which was completed, and significant references are incorporated. For brevity, full papers are cited and not the preceding communication article. A historical perceptive is taken and analysis of the most significant contributions to the field is carried

Available Synthetic Methods
The categories of syntheses of ring-fused benzimidazoles 6 are according to the cyclization reaction (Scheme 1). Oxidative cyclizations from aniline or anilide derivatives is the most studied route (Route A) and is presented in context with the plethora of other syntheses that build the benzimidazole moiety (Routes B-D). The section on Route A is sub-divided into syntheses of benzimidazole and imidazobenzimidazole scaffolds. Lastly, there is a section on syntheses, which begin with the benzimidazole moiety (Route E), sub-divided according to reaction (type) conditions. This is not an exhaustive review, and the reader should consult reviews on polycyclic benzimidazoles for comprehensive lists of syntheses [30][31][32][33]. Since the late 1990s, Aldabbagh et al. have worked on the discovery of new ring-fused benzimidazoles and synthetic methods, and the collated articles related to their research are reviewed herein. A reviewer recommended a Scifinder n search of "benzimidazole-fused", which was completed, and significant references are incorporated. For brevity, full papers are cited and not the preceding communication article. A historical perceptive is taken and analysis of the most significant contributions to the field is carried out. In particular, methodology that forms a variety of ring-fused benzimidazoles is of interest, rather than procedures that give mainly the benzimidazole core. out. In particular, methodology that forms a variety of ring-fused benzimidazoles is of interest, rather than procedures that give mainly the benzimidazole core.

Scheme 1.
Categorizing available synthetic methods according to the cyclization reaction A-E.

Oxidations of o-Cycloaminoanilines and Anilide derivatives (Route A)
There are distinct differences in the reaction mechanisms and conditions for ringfused benzimidazole and imidazobenzimidazole formation warranting sub-division. Benzimidazoles form by oxidative cyclization of anilines via nitrosobenzene intermediates; in contrast, cyclization to give the ring-fused imidazobenzimidazole must begin from anilides and proceed via amine N-oxide intermediates under acidic conditions.

Forming Ring-Fused Benzimidazoles
In 1908, Spiegel and Kaufmann reported that Caro's acid (peroxymonosulfuric acid, H2SO5) oxidized 5-nitro-2-(piperidin-1-yl)aniline to 7-nitro-1,2,3,4-tetrahydropyrido[1,2a]benzimidazole [34]. In the absence of the nitro-substituent, no oxidative cyclization occurred. Caro's acid was already known to oxidize anilines to nitrosobenzenes [35], so supporting the idea of a nitroso intermediate. The prominent 20th century chemist and creator of Adam's catalyst, Roger Adams with Nair refined this methodology, and accessed a range of five to seven-membered ring-fused benzimidazoles in good to high yields using peroxytrifluoroacetic acid generated in situ from H2O2 and trifluoroacetic acid (TFA) (Scheme 2) [36]. Six-membered cyclization yields were higher, when the anilines contained a nitro-substituent. Meth-Cohn and Suschitzky [37] soon refuted the observation made by Nair and Adams that acyl derivatives do not undergo cyclization to give benzimidazoles. These workers showed a range of anilide derivatives (formyl, acetyl and benzoyl) underwent oxidative cyclizations using peroxytrifluoroacetic acid or performic acid (H2O2 and HCO2H). Meth-Cohn preferred the use of o-cyclic amine substituted anilides as substrates for making ring-fused benzimidazoles [37,38]. Meth-Cohn commented that Nair and Adams [36] had possibly formed the anilide in situ, due to the initial addition of TFA followed by H2O2 [38]. Mechanisms were proposed for benzimidazole formation from anilide, via an amine-N-oxide rather than the nitroso intermediate (see Section 2.1.2). Scheme 1. Categorizing available synthetic methods according to the cyclization reaction A-E.

Oxidations of o-Cycloaminoanilines and Anilide Derivatives (Route A)
There are distinct differences in the reaction mechanisms and conditions for ring-fused benzimidazole and imidazobenzimidazole formation warranting sub-division. Benzimidazoles form by oxidative cyclization of anilines via nitrosobenzene intermediates; in contrast, cyclization to give the ring-fused imidazobenzimidazole must begin from anilides and proceed via amine N-oxide intermediates under acidic conditions.
Preparations of ring-fused benzimidazoles using o-cyclic amine substituted anilines with performic acid compare favorably with the derivative anilide reaction, with Smalley et al. reporting moderate to good yields for five-to seven-membered adducts (Scheme 4a) [42]. In a more recent study, recyclable ethyl acetate (EtOAc) replaced formic acid, with aqueous effluent, organic-aqueous extraction and chromatography avoided for the preparation of pyrrolo[1,2-a]benzimidazoles from commercial o-(pyrrolidin-1-yl)anilines Scheme 2. Nair and Adams oxidative cyclizations of anilines [36].
Although, the presence of strong electron-withdrawing substituents (NO 2 , CN) and the six-membered cyclization required methanesulfonic acid (MsOH) to reach high yields. However, MsOH is a green acid undergoing biodegradation by forming CO 2 and sulfate [44]. (Scheme 4b) [43]. Although, the presence of strong electron-withdrawing substituents (NO2, CN) and the six-membered cyclization required methanesulfonic acid (MsOH) to reach high yields. However, MsOH is a green acid undergoing biodegradation by forming CO2 and sulfate [44].
Alternatives to peroxide-based oxidizing systems, include MnO2 in cold chloroform, but yields of ring-fused benzimidazoles from o-cycloaminoanilines were 15-20% due to presumed formation of azo-compounds [45]. Möhrle and Gerloff reported the use of a Hg(II) EDTA complex to deliver ring-fused benzimidazoles, in quantitative yield, apart from the morpholino compound, synthesized in 47% yield (Scheme 5) [46]. The cross dehydrogenative coupling (CDC) involves forming the C-N bond directly from C-H and N-H bonds under oxidative conditions with a formal loss of H2, in a process often catalyzed by transition metals. CDC is used to describe pentamethylcyclopentadienyl Ir(III)dichloride ([Cp*IrCl2]2) catalyzed oxidative cyclization of o-tetrahydroisoquinoline substituted aniline derivatives (Scheme 6a) [47]. The bulk around the primary amine dictated regioselectivity. The o-cyclic amine substituted aniline gave the benzimidazo[2,1a]isoquinoline 12, while the more hindered acetamide derivative gave the alternative kinetic product 13. The formamide has less steric bulk than the acetamide forming a mixture of the thermodynamic and kinetic products. The reaction was extended to the synthesis of pyrrolo-, pyrido-, and azepino-[1,2-a]benzimidazoles, without the requirement for a ligand (Scheme 6b), but was less successful for making morpholino-and piperazino-ringfused analogues [48]. Scheme 4. Aniline cyclizations using (a) performic acid [42] and (b) acid-free conditions [43].
Alternatives to peroxide-based oxidizing systems, include MnO 2 in cold chloroform, but yields of ring-fused benzimidazoles from o-cycloaminoanilines were 15-20% due to presumed formation of azo-compounds [45]. Möhrle and Gerloff reported the use of a Hg(II) EDTA complex to deliver ring-fused benzimidazoles, in quantitative yield, apart from the morpholino compound, synthesized in 47% yield (Scheme 5) [46]. (Scheme 4b) [43]. Although, the presence of strong electron-withdrawing substituents (NO2, CN) and the six-membered cyclization required methanesulfonic acid (MsOH) to reach high yields. However, MsOH is a green acid undergoing biodegradation by forming CO2 and sulfate [44].
Alternatives to peroxide-based oxidizing systems, include MnO2 in cold chloroform, but yields of ring-fused benzimidazoles from o-cycloaminoanilines were 15-20% due to presumed formation of azo-compounds [45]. Möhrle and Gerloff reported the use of a Hg(II) EDTA complex to deliver ring-fused benzimidazoles, in quantitative yield, apart from the morpholino compound, synthesized in 47% yield (Scheme 5) [46]. The cross dehydrogenative coupling (CDC) involves forming the C-N bond directly from C-H and N-H bonds under oxidative conditions with a formal loss of H2, in a process often catalyzed by transition metals. CDC is used to describe pentamethylcyclopentadienyl Ir(III)dichloride ([Cp*IrCl2]2) catalyzed oxidative cyclization of o-tetrahydroisoquinoline substituted aniline derivatives (Scheme 6a) [47]. The bulk around the primary amine dictated regioselectivity. The o-cyclic amine substituted aniline gave the benzimidazo[2,1a]isoquinoline 12, while the more hindered acetamide derivative gave the alternative kinetic product 13. The formamide has less steric bulk than the acetamide forming a mixture of the thermodynamic and kinetic products. The reaction was extended to the synthesis of pyrrolo-, pyrido-, and azepino-[1,2-a]benzimidazoles, without the requirement for a ligand (Scheme 6b), but was less successful for making morpholino-and piperazino-ringfused analogues [48]. The cross dehydrogenative coupling (CDC) involves forming the C-N bond directly from C-H and N-H bonds under oxidative conditions with a formal loss of H 2 , in a process often catalyzed by transition metals. CDC is used to describe pentamethylcyclopentadienyl Ir(III)dichloride ([Cp*IrCl 2 ] 2 ) catalyzed oxidative cyclization of o-tetrahydroisoquinoline substituted aniline derivatives (Scheme 6a) [47]. The bulk around the primary amine dictated regioselectivity. The o-cyclic amine substituted aniline gave the benzimidazo[2,1a]isoquinoline 12, while the more hindered acetamide derivative gave the alternative kinetic product 13. The formamide has less steric bulk than the acetamide forming a mixture of the thermodynamic and kinetic products. The reaction was extended to the synthesis of pyrrolo-, pyrido-, and azepino-[1,2-a]benzimidazoles, without the requirement for a ligand (Scheme 6b), but was less successful for making morpholino-and piperazino-ring-fused analogues [48]. Molecules 2021, 26, x FOR PEER REVIEW 7 of 29 Scheme 6. Ir(III)-mediated cyclizations (a) with ligand [47] and (b) without ligand [48].
Aniodic oxidation gave the required iminium ion 14 for cyclization (Scheme 8) [51]. The electrolyte was n-Bu4NPF6 (20 mol%), and the anode is reticulated vitreous carbon (RVC), and Pt is the cathode in an undivided cell at a constant current of 10 mA. A Russian team reported the electrochemical oxidative cyclization with reduction of nitrobenzene for cyclization onto an o-piperidinyl-substituent to give pyrido[1,2-a]benzimidazoles [52]. The isoindoline and tetrahydroisoquinoline substrates are the easiest to oxidize at high temperatures, including in the presence of TEMPO in air (Scheme 7a) [49], and catalytic iron(III) [50]. The latter gave the highest yields for the benzimidazo[2,1-a]isoquinoline systems (Scheme 7b). The isoindoline and tetrahydroisoquinoline substrates are the easiest to oxidize at high temperatures, including in the presence of TEMPO in air (Scheme 7a) [49], and catalytic iron(III) [50]. The latter gave the highest yields for the benzimidazo[2,1-a]isoquinoline systems (Scheme 7b). Scheme 7. Thermal oxidative cyclizations mediated by (a) TEMPO/air [49] and (b) Fe(III) [50].
Aniodic oxidation gave the required iminium ion 14 for cyclization (Scheme 8) [51]. The electrolyte was n-Bu4NPF6 (20 mol%), and the anode is reticulated vitreous carbon (RVC), and Pt is the cathode in an undivided cell at a constant current of 10 mA. A Russian team reported the electrochemical oxidative cyclization with reduction of nitrobenzene for cyclization onto an o-piperidinyl-substituent to give pyrido[1,2-a]benzimidazoles [52]. Aniodic oxidation gave the required iminium ion 14 for cyclization (Scheme 8) [51]. The electrolyte was n-Bu 4 NPF 6 (20 mol%), and the anode is reticulated vitreous carbon (RVC), and Pt is the cathode in an undivided cell at a constant current of 10 mA. A Russian team reported the electrochemical oxidative cyclization with reduction of nitrobenzene for cyclization onto an o-piperidinyl-substituent to give pyrido[1,2-a]benzimidazoles [52]. In the early 1970s, o-cyclic amine substituted anilines reacted in neat sulfuryl chloride in an oxidative cyclization with concomitant tetrachlorination of the activated aromatic nucleus (Scheme 9) [53]. The attempt to tetrachlorinate the o-pyrrolo substituted aniline analogue led to an inseparable mixture of mono-, di-, and trichloro ring-fused benzimidazoles. Scheme 9. Synthesis of polychlorinated ring-fused benzimidazoles using SO2Cl2 [53].
More recently, we heralded the use of H2O2 with hydrohalic acid (HX), as a convenient oxidizing and halogenation system for organic synthesis [54][55][56]. The system allows in situ generation of Cl2 and Br2, with the only by-product, being water (Scheme 10). The salt of hypochlorous acid (HOCl) is the active ingredient in domestic bleach and is the intermediate of the reaction between H2O2 and HCl. Domestic bleach gave cyclization and dichlorination of aniline 15 in 56% yield (Scheme 11a), with the lower yield attributed to the requirement for chromatography to separate the additives in the bleach [54]. Moreover, using H2O2/HX a library of selectively dichlorinated and dibrominated ring-fused benzimidazoles was prepared in high yields from commercial o-cyclic amine substituted anilines, with most cases not requiring chromatography (Scheme 11b,c). 5-Fluoro-2-piperidinylaniline was an exception, giving significant amounts of cyclization with monochlorination or monobromination. Bromination tended to be slower than chlorination, and tribrominated product 16 was isolated for the Scheme 8. Electrochemical oxidative cyclizations [51].
In the early 1970s, o-cyclic amine substituted anilines reacted in neat sulfuryl chloride in an oxidative cyclization with concomitant tetrachlorination of the activated aromatic nucleus (Scheme 9) [53]. The attempt to tetrachlorinate the o-pyrrolo substituted aniline analogue led to an inseparable mixture of mono-, di-, and trichloro ring-fused benzimidazoles. In the early 1970s, o-cyclic amine substituted anilines reacted in neat sulfuryl chloride in an oxidative cyclization with concomitant tetrachlorination of the activated aromatic nucleus (Scheme 9) [53]. The attempt to tetrachlorinate the o-pyrrolo substituted aniline analogue led to an inseparable mixture of mono-, di-, and trichloro ring-fused benzimidazoles. Scheme 9. Synthesis of polychlorinated ring-fused benzimidazoles using SO2Cl2 [53].
More recently, we heralded the use of H2O2 with hydrohalic acid (HX), as a convenient oxidizing and halogenation system for organic synthesis [54][55][56]. The system allows in situ generation of Cl2 and Br2, with the only by-product, being water (Scheme 10). The salt of hypochlorous acid (HOCl) is the active ingredient in domestic bleach and is the intermediate of the reaction between H2O2 and HCl. Domestic bleach gave cyclization and dichlorination of aniline 15 in 56% yield (Scheme 11a), with the lower yield attributed to the requirement for chromatography to separate the additives in the bleach [54]. Moreover, using H2O2/HX a library of selectively dichlorinated and dibrominated ring-fused benzimidazoles was prepared in high yields from commercial o-cyclic amine substituted anilines, with most cases not requiring chromatography (Scheme 11b,c). 5-Fluoro-2-piperidinylaniline was an exception, giving significant amounts of cyclization with monochlorination or monobromination. Bromination tended to be slower than chlorination, and tribrominated product 16 was isolated for the Scheme 9. Synthesis of polychlorinated ring-fused benzimidazoles using SO 2 Cl 2 [53].
More recently, we heralded the use of H 2 O 2 with hydrohalic acid (HX), as a convenient oxidizing and halogenation system for organic synthesis [54][55][56]. The system allows in situ generation of Cl 2 and Br 2 , with the only by-product, being water (Scheme 10). The salt of hypochlorous acid (HOCl) is the active ingredient in domestic bleach and is the intermediate of the reaction between H 2 O 2 and HCl. In the early 1970s, o-cyclic amine substituted anilines reacted in neat sulfuryl chloride in an oxidative cyclization with concomitant tetrachlorination of the activated aromatic nucleus (Scheme 9) [53]. The attempt to tetrachlorinate the o-pyrrolo substituted aniline analogue led to an inseparable mixture of mono-, di-, and trichloro ring-fused benzimidazoles. Scheme 9. Synthesis of polychlorinated ring-fused benzimidazoles using SO2Cl2 [53].
More recently, we heralded the use of H2O2 with hydrohalic acid (HX), as a convenient oxidizing and halogenation system for organic synthesis [54][55][56]. The system allows in situ generation of Cl2 and Br2, with the only by-product, being water (Scheme 10). The salt of hypochlorous acid (HOCl) is the active ingredient in domestic bleach and is the intermediate of the reaction between H2O2 and HCl. Domestic bleach gave cyclization and dichlorination of aniline 15 in 56% yield (Scheme 11a), with the lower yield attributed to the requirement for chromatography to separate the additives in the bleach [54]. Moreover, using H2O2/HX a library of selectively dichlorinated and dibrominated ring-fused benzimidazoles was prepared in high yields from commercial o-cyclic amine substituted anilines, with most cases not requiring chromatography (Scheme 11b,c). 5-Fluoro-2-piperidinylaniline was an exception, giving significant amounts of cyclization with monochlorination or monobromination. Bromination tended to be slower than chlorination, and tribrominated product 16 was isolated for the Scheme 10. Molecular halogen (X 2 ) generated from H 2 O 2 and HX [54][55][56].
Domestic bleach gave cyclization and dichlorination of aniline 15 in 56% yield (Scheme 11a), with the lower yield attributed to the requirement for chromatography to separate the additives in the bleach [54]. Moreover, using H 2 O 2 /HX a library of selectively dichlorinated and dibrominated ring-fused benzimidazoles was prepared in high yields from commercial o-cyclic amine substituted anilines, with most cases not requiring chromatography (Scheme 11b,c). 5-Fluoro-2-piperidinylaniline was an exception, giving significant amounts of cyclization with monochlorination or monobromination. Bromination tended to be slower than chlorination, and tribrominated product 16 was isolated for the o-(pyrrolidin- 3,6-Dimethoxy-2-(cycloamino)anilines underwent 6-electron oxidations to afford a variety of ring-fused halogenated benzimidazolequinones, when using higher amounts of HCl or HBr relative to H2O2 (Scheme 12a) [55]. The active species is the elemental halogen (X2) with water required for quinone formation (Scheme 12b). When less in situ halogen was generated, using [H2O2] > [HX], the 4-electron oxidation occurred, to give ring-fused halogenated benzimidazoles (Scheme 12c).
The use of hydroiodic acid (HI) is preferred when oxidative cyclization is required without halogenation [56], due to the relatively smaller electrophilicity of iodine [57]. Five-and seven-membered cyclizations of 3,6-dimethoxy-2-(cycloamino)anilines with H2O2 and a catalytic amount of HI in EtOAc proceeded in high yield (Scheme 13a), but 1,4,6,9-tetramethoxyphenazine 17, was unexpectedly formed, as an orange precipitate from six-membered cyclizations (Scheme 13a,b) [56]. The absence of phenazine 17 from the five-and seven-membered cyclizations was consistent with previous observations that six-membered oxidative cyclizations are more difficult [36,43]. The formation of 17 was optimized by reducing the amount of EtOAc (the reaction solvent) by four-fold and by decreasing the reaction temperature to room temperature (Scheme 14). Moreover, the iso- 3,6-Dimethoxy-2-(cycloamino)anilines underwent 6-electron oxidations to afford a variety of ring-fused halogenated benzimidazolequinones, when using higher amounts of HCl or HBr relative to H 2 O 2 (Scheme 12a) [55]. The active species is the elemental halogen (X 2 ) with water required for quinone formation (Scheme 12b). When less in situ halogen was generated, using [H 2 O 2 ] > [HX], the 4-electron oxidation occurred, to give ring-fused halogenated benzimidazoles (Scheme 12c).
The use of hydroiodic acid (HI) is preferred when oxidative cyclization is required without halogenation [56], due to the relatively smaller electrophilicity of iodine [57]. Fiveand seven-membered cyclizations of 3,6-dimethoxy-2-(cycloamino)anilines with H 2 O 2 and a catalytic amount of HI in EtOAc proceeded in high yield (Scheme 13a), but 1,4,6,9tetramethoxyphenazine 17, was unexpectedly formed, as an orange precipitate from sixmembered cyclizations (Scheme 13a,b) [56]. The absence of phenazine 17 from the five-and seven-membered cyclizations was consistent with previous observations that six-membered oxidative cyclizations are more difficult [36,43]. The formation of 17 was optimized by reducing the amount of EtOAc (the reaction solvent) by four-fold and by decreasing the reaction temperature to room temperature (Scheme 14). Moreover, the isolation of 17 was indicative of a nitrosobenzene intermediate in the conversion of o-(cycloamino)anilines to ring-fused benzimidazoles via the so-called t-amino effect [58]. Syntheses of phenazines involve nitroso intermediates [56,59,60]. Recent evidence in the synthesis of ring-fused benzimidazoles, included GC-MS of the reaction mixture (Scheme 14), after 1 h, which revealed EI-MS fragmentation pattern consistent with intermediate 18 [56].  [58]. Syntheses of phenazines involve nitroso intermediates [56,59,60]. Recent evidence in the synthesis of ring-fused benzimidazoles, included GC-MS of the reaction mixture (Scheme 14), after 1 h, which revealed EI-MS fragmentation pattern consistent with intermediate 18 [56].
Anilide reactant and acidic conditions are a prerequisite for oxidation to the imidazobenzimidazole, with attempts to cyclize 4,6-di(piperidin-1-yl)-1,3-phenylenediamine (24) giving an intractable mixture ( Figure 6) [61]. Meth-Cohn proposed the oxidative cyclization of acetamides to benzimidazole derivatives occurs via the amine-N-oxide intermediate 25 [38]. Isolated amine-N-oxides undergo acid-mediated benzimidazole and imidazobenzimidazole formation [27,61]. Anilide reactant and acidic conditions are a prerequisite for oxidation to the imidazobenzimidazole, with attempts to cyclize 4,6-di(piperidin-1-yl)-1,3-phenylenediamine (24) giving an intractable mixture ( Figure 6) [61]. Meth-Cohn proposed the oxidative cyclization of acetamides to benzimidazole derivatives occurs via the amine-N-oxide intermediate 25 [38]. Isolated amine-N-oxides undergo acid-mediated benzimidazole and imidazobenzimidazole formation [27,61]. The diamine-N-oxide intermediate 26 for imidazo [5,4-f]benzimidazole formation was isolated by Fagan [27]. The X-ray crystal structure of 26 showed hydrogen bonding between the amide NH and the amine N-oxide residues, supporting the absence of the amide NH peaks in the 1 H NMR spectra of solutions of amine N-oxides [27,38,61]. This is contrary to the orientation of the amine-N-oxide 25 adopted in Meth-Cohn's Polonovski- The diamine-N-oxide intermediate 26 for imidazo [5,4-f ]benzimidazole formation was isolated by Fagan [27]. The X-ray crystal structure of 26 showed hydrogen bonding between the amide NH and the amine N-oxide residues, supporting the absence of the amide NH peaks in the 1 H NMR spectra of solutions of amine N-oxides [27,38,61]. This is contrary to the orientation of the amine-N-oxide 25 adopted in Meth-Cohn's Polonovski-type reaction mechanism [38]. Our proposed mechanism begins with oxidation of the cyclic amines of diacetamide 27 to the Fagan amine-N-oxide orientation 26 (Scheme 18). Protonation in acidic media gives the imidols, upon loss of water. The double intramolecular nucleophilic imidol addition onto the iminum ion leads to the ring-fused imidazo [5,4-f ]benzimidazole [27]. type reaction mechanism [38]. Our proposed mechanism begins with oxidation of the cyclic amines of diacetamide 27 to the Fagan amine-N-oxide orientation 26 (Scheme 18). Protonation in acidic media gives the imidols, upon loss of water. The double intramolecular nucleophilic imidol addition onto the iminum ion leads to the ring-fused imidazo [5,4f]benzimidazole [27].

Reductions of Nitrobenzene-o-Cycloamines (Route B)
The reduction under acidic conditions of the aromatic nitro-group with cyclization onto the adjacent cycloamine substituent dates to the 1960s and employ ZnCl 2 /Ac 2 O [16,64,65], TiCl 3 /HCl [66], and Fe/AcOH [67]. There are cyclizations using Pd-catalysis with CO [68] or H 2 [69]. Recent metal-free conditions use visible light, phenylthiourea as catalyst and PhSiH 3 as reductant [70], and electrochemical cyclizations [52]. Thermal annulation using nitrobenzene substrates are possible with neat 1,2,3,4-tetrahydroisoquinoline (THIQ) (Scheme 20a) [71], and cyclizations occur using I 2 /HCO 2 H [72] (Scheme 20b). For the former reaction, the authors speculated on THIQ acting as a hydride donor after the initial S N Ar and redox cyclization, while HI generated in situ, is the active catalytic species in the latter reaction, acting as a strong Brønsted acid and reductant [71,72]. the initial SNAr and redox cyclization, while HI generated in situ, is the active catalytic species in the latter reaction, acting as a strong Brønsted acid and reductant [71,72].

Annulations onto Benzimidazoles (Route E)
A widely reported category for the synthesis of ring-fused benzimidazoles is annulations onto the 1-and 2-positions of benzimidazoles. This section reviews syntheses over the past 20 years, sub-divided according to the employed reaction (type) conditions.

Transition Metal and Lewis Acid Catalyzed Methods
InCl3-catalyzed the synthesis of benzimidazole-fused 1,4-oxazepines by intramolecular addition of a pendant alcohol onto an in situ-generated imine (Scheme 26) [87].

Annulations onto Benzimidazoles (Route E)
A widely reported category for the synthesis of ring-fused benzimidazoles is annulations onto the 1-and 2-positions of benzimidazoles. This section reviews syntheses over the past 20 years, sub-divided according to the employed reaction (type) conditions.

Annulations onto Benzimidazoles (Route E)
A widely reported category for the synthesis of ring-fused benzimidazoles is annulations onto the 1-and 2-positions of benzimidazoles. This section reviews syntheses over the past 20 years, sub-divided according to the employed reaction (type) conditions.

Transition Metal and Lewis Acid Catalyzed Methods
InCl3-catalyzed the synthesis of benzimidazole-fused 1,4-oxazepines by intramolecular addition of a pendant alcohol onto an in situ-generated imine (Scheme 26) [87].

Transition Metal and Lewis Acid Catalyzed Methods
InCl 3 -catalyzed the synthesis of benzimidazole-fused 1,4-oxazepines by intramolecular addition of a pendant alcohol onto an in situ-generated imine (Scheme 26) [87].

Annulations onto Benzimidazoles (Route E)
A widely reported category for the synthesis of ring-fused benzimidazoles is annulations onto the 1-and 2-positions of benzimidazoles. This section reviews syntheses over the past 20 years, sub-divided according to the employed reaction (type) conditions.

Conclusions
Over the past 20 years, significant advances in the synthesis of ring-fused benzimidazoles have occurred, notably using dehydrogenative coupling and radical cyclization. Transition metal catalysts achieve intramolecular and intermolecular aminations with benzimidazoles, with enantioselectivity for the former. Ring-fused benzimidazoles are

Conclusions
Over the past 20 years, significant advances in the synthesis of ring-fused benzimidazoles have occurred, notably using dehydrogenative coupling and radical cyclization. Transition metal catalysts achieve intramolecular and intermolecular aminations with benzimidazoles, with enantioselectivity for the former. Ring-fused benzimidazoles are Scheme 38. Synthesis of analogues of (a) cyclopropamitosenes [22,115,116] and (b) aziridinomitosene [14].

Conclusions
Over the past 20 years, significant advances in the synthesis of ring-fused benzimidazoles have occurred, notably using dehydrogenative coupling and radical cyclization. Transition metal catalysts achieve intramolecular and intermolecular aminations with benzimidazoles, with enantioselectivity for the former. Ring-fused benzimidazoles are prepared using hypervalent iodine(III) reagents and elemental iodine under metal-free conditions. There is an increasing use of sustainable and non-metal-mediated protocols, including photochemical, electrochemical, and thermal methods. Mild oxidative conditions tend to be more effective for preparing isoindoline and tetrahydroisoquinoline-fused scaffolds. There are effective methods for incorporating heteroatoms into the fused-ring, including N, O, and S atoms, and forming alicyclic rings with additional fused cyclopropane or delicate oxetane and aziridine rings. In terms of versatility, green chemistry, and value for money, it is difficult to beat the use of H 2 O 2 in traditional oxidative cyclizations of o-(cycloamino)anilines. H 2 O 2 in combination with HX generates the ordinarily inconvenient elemental halogen (X 2 ) in situ, to mediate one-pot oxidative cyclization with halogenation. The latter includes one-pot approaches to potential antitumor ring-fused benzimidazolequinones from readily accessible anilines. Oxone is a cheap alternative, with technical and environmental benefits, including the circumvention of organic waste by-products. Our present work generates X 2 in situ, by combining Oxone with benign NaX, to carry out onepot halogenation with oxidative demethylation to give the dimeric quinones of ring-fused dimethoxybenzimidazole-benzimidazolequinones (DMBBQs) [118]. The DMBBQ scaffold offers unique regioselective functionalization opportunities for bis-quinone motifs, and these unique dimeric structures require investigation as bioreductive anti-tumor agents.
Mechanisms for ring-fused benzimidazole and imidazobenzimidazole formation via the t-amino effect are now better defined. Recent studies have shown that acid and heat are unnecessary for oxidative cyclization via a nitrosobenzene intermediate using o-(cycloamino)anilines as substrates for benzimidazole formation. This offers opportunities for further investigations into the synthesis of ring-fused benzimidazoles under nonaggressive ambient conditions using commercial anilines as starting materials. While use of anilide derivatives results in a different mechanism via an amine-N-oxide intermediate. The anilide derivative and acidic conditions are mandatory for peroxide-mediated ringfused imidazobenzimidazole preparations. To date ring-fused imidazobenzimidazoles have only been prepared via oxidative cyclizations of anilides and radical cyclizations onto imidazobenzimidazoles, surely new synthetic methods will merge for this interesting scaffold.