Recent advances in the synthesis of benzimidazol(on)es via rearrangements of quinoxalin(on)es

This is the ﬁ rst review describing all the quinoxaline – benzimidazole rearrangements as a whole and the new quinoxalinone – benzimidazol(on)e rearrangements in particular when exposed to nucleophilic rearrangements for the synthesis of various biheterocyclic motifs. The scope of the rearrangements is illustrated by way of numerous examples of their application, and in doing so, the review contains over 131 references and covers all of the literature, from the ﬁ rst report of the rearrangement of 2,3-diphenylquinoxaline by Ogg and Bergstrom in 1931 up to more recent examples in the past few years. The mechanisms for the selected transformations are also discussed.


Introduction
Benzimidazole, rstly described by Hobrecker in 1872, 1 is an important privileged heterocyclic motif [2][3][4][5] and one of the most widely investigated scaffolds by synthetic chemists because of its medicinal importance. The benzimidazole scaffold acts as an important class of heterocyclic compounds with a wide range of biological properties. 6 Benzimidazole derivatives are structural isosteres of naturally occurring nucleotides, which allow them to easily interact with the biopolymers of the living systems and different kinds of biological activity have been obtained. 2-Aminobenzimidazoles proved useful for acid/base catalysis and can substitute guanidinium groups in receptor molecules designed as phosphoryl transfer catalysts. 7 Some 2-aminobenzimidazoles displayed an appreciable antimicrobial effect and their corresponding carbamate derivatives have been synthesized for their signicant antilarial activity in vivo. 8 As to their high affinity towards a variety of enzymes and protein receptors, they could be considered as pivotal structures in drug design. 9 The optimization of benzimidazole-based structures has resulted in marketed drugs, e.g. omeprazole 10 and pimobendan 11 which are used as therapeutic agents in the treatment of peptic ulcer and congestive heart failure respectively. Benzimidazole derivatives proved of great interest because of their wide range of biological functions 12 and pharmacological applications. 13 They are an integral part of various clinical medicines 14 as well, for example 2-substituted benzimidazole, esomeprazole 15 is an anti-ulcer drug and albendazole 16 is used to treat parasitic diseases, whereas, 1,2-substituted benzimidazole, astemizole is an antihistamine drug (Fig. 1). 17 Many derivatives of benzimidazoles are well known for their antimicrobial, 18 anthelmintic, 19 antiviral, 20 and antifungal 21 activities. The antifungal agent benomyl was rst reported as a fungicide against a wide range of agricultural fungal diseases. 22 Later on, it proved to be a potent antiproliferative agent against the Hela cancer cell line and could be partly used in cancer chemotherapy. 23 Benzimidazole derivatives with ester groups on the benzene ring possessed antifungal, insecticidal and herbicidal activities. 24 Besides, many dichlorobenzimidazoles appeared very effective against methicillin resistant Staphylococcus aureus (MRSA). 25 Since 1985, benzimidazole containing compounds have been reported as well known anticancer agents. 26 The role of mammalian DNA topoisomerases as molecular targets for anticancer drugs received appreciation. Some benzimidazoles have been reported as topoisomerase inhibitors e.g. Hoechst 33258 and Hoechst 33342 (Fig. 1). 27 Some widely used anticancer drugs such as RAF265 (CHIR-265; Novartis Pharmaceuticals, Basel, Switzerland) and AZD6244 (ARRY-142886; AstraZeneca, London, England) are known to contain a benzimidazole moiety. RAF265 resulted in the reduction of tumor cell growth and in tumor cell apoptosis. 28 Compound AZD6244 suppresses the growth of melanoma cells through the induction of cytostasis. 29 2-Arylbenzimidazole moiety proved to be a pharmacophore for a new class of DNA intercalating agents. 30 The importance of naphthalene benzimidazole compounds as antioxidants on hepatic cytochrome has been explored since 1997. 31 On the other hand, the antiviral activity of 5-chloro and 5,6-dichloro-2-substituted benzimidazole derivatives against several viruses, e.g. inuenza, human cytomegalovirus, hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeciency retrovirus (HIV-1) was reported. 32 These compounds proved to be anticancer agents against breast and prostate cancer cell lines 33 as well as potential topoisomerase II inhibitors. 34 In 2010, a new series of 2-substituted benzimidazole derivatives with a 5-chloro or 5underivatized carboxylic acid group exhibited antitumor activity against hepatocellular carcinoma (HEPG2), human breast adenocarcinoma (MCF7) and human colon carcinoma (HCT 116) cell lines. 35 Telmisartan is a potent angiotensin II receptor antagonist in the treatment of essential hypertension. 36 It is one of the most efficient drugs in its class, boasting the longest half-life, a high protein binding affinity, and a low daily dosage. 37 The drug is currently marketed under the brand name of Micardis and provides additional benets against vascular and renal damage caused by diabetes and cardiovascular disease. 38 Bis-heterocyclic compounds offer better binding opportunities with a enzyme active site due to its three dimensional special arrangement and consequently possess many intrinsic biological properties. 39 In particularly, bis-heterocycles comprising pyridobenzimidazoles (I) are ligands for the BZD site on GABA-A receptors and are therefore used for the  treatment of disorders of the central nervous system including convulsion such as epileptic seizures, anxiety, depression, muscular spasm, and attention decit hyperactivity disorder (Fig. 2). 40 Polycyclic bis-heterocycles with imidazopyridine or imidazoisoindole moieties (II) prove the basic structural frameworks of potent inhibitors of respiratory syncytical virus while some imidazoisoindoles (III) exhibit antiviral activity. 41 Benzimidazoles in combination with the pyrrolo-isoidolones (IV) exhibit anticancer activity via the inhibition of the ATPase-type catalytic activity of the Hsp90 chaperone protein. 42 The drug reference books by Mashkovskiy 43 and Negwer 44 comprise 92 benzimidazole derivatives used in medicine. However, only 13 of them (Fig. 3) include other heterocyclic rings directly connected with the benzimidazole system. This is apparently due to the fact that such compounds are mostly inaccessible. The analysis of the literary data shows that the methods of the synthesis of such compounds involve many steps, i.e. they are laborious, and the total yields of products never exceed 20% AE 25%.
There are two classical methods for benzimidazole synthesis, i.e. coupling of 1,2-diaminobenzenes (1,2-DABs) with carboxylic acids and of 1,2-DABs with aldehydes and ketones (the Phillips-Ladenburg and the Weidenhagen reactions, respectively). 45 The classical version of these reactions are limited by the use of high temperatures (sometimes, 250-300 C) and by the low yields of products. 46 Actually, all the methods of benzimidazole synthesis which currently exist represent modications of the reactions mentioned. 47 The analysis of the data published has shown that the main drawback of these methods involve the impossibility to use them for synthesizing various types of benzimidazole derivatives. For example, it is no so easy task to enter any given heterocycle in position 2 of benzimidazole ring using of these methods. In addition to the methods mentioned, examples of the formation of benzimidazole derivatives by rearrangement of heterocyclic systems have been documented. Despite the fact that the publications on these reactions are much fewer as compared with the Phillips-Ladenburg and Weidenhagen reactions, they are more diverse but unfortunately not general. The generalization and systematization of the data published on the rearrangement reactions will considerably facilitate the quest of organic chemists for the methods of the synthesis of benzimidazole derivatives inaccessible by the Phillips-Ladenburg and Weidenhagen reactions. In this review, we will focus mainly on recent advances in the synthesis of benzimidazoles and benzimidazolones via new rearrangements of quinoxalinones when exposed to nucleophilic reagents and earlier works of importance will also be discussed.
2 Synthesis of benzimidazoles 2.1 Rearrangement of quinoxalines (historical background) First example. In 1931, Ogg and Bergstrom published a serious of papers aimed to demonstrate possible analogies between heterocyclic systems and their acyclic and alicyclic counterparts. 48 Quinoxaline, for example, was described as an "ammono glyoxal" and 2,3-diphenylquinoxaline 1 was considered to be the heterocyclic equivalent of benzyl. In an attempt to justify this hypothesis, the authors carried out the reaction of 2,3-diphenylquinoxaline 1 with potassium amide in liquid ammonia, anticipating a reaction similar to the benzyl / benzilic rearrangement, which would lead to the formation of 2,2-diphenyl-3-aminoquinoxaline 2 (Scheme 1). In fact the reaction lead to a new product -2-phenylbenzimidazole 3 in an approximately 30% yield and the recovery of about 60% of unchanged 2,3-diphenylquinoxaline 1. 49 The formation of 2-phenylbenzimidazole 3 from 2,3-diphenylquinoxaline 1 and potassium amide involves the initial addition of an amide ion at the C(2) carbon atom, according to Ogg and Bergstrom had postulated, but with subsequent ring contraction, presumably with the elimination of benzylidenimine. This would result in the observed product 3, rather than the phenyl migration of the benzyl acid-rearrangement type (Scheme 2). Attempts to accomplish the ring contraction of 2,3-diphenylquinoxaline 1 to 2-phenylbenzimidazole 3 with other bases (KOH in H 2 O or EtOH, NaOH in MeOH, NaH in toluene) were unsuccessful. The efficiency of KNH 2 appears to be specic.
Second example. Quinoxaline-2,3(1H,4H)-dione 4a with 1,2-DAB dihydrochloride was shown to interact with the formation of the highly labile compound 6a. As a result of "ammonolysis" this compound was spontaneously dehydrated and cyclised to form compound 7a (Scheme 3). 50 This reaction sequence has been used for the preparation of an unsymmetrically substituted 2,2 0 -bibenzimidazole, since 2,3dihydroxy-6-methylquinoxaline 4b and 1,2-DAB dihydrochloride reacted to form 5-methyl-2,2 0 -bibenzimidazole 7b (Scheme 4). 50 Third example. Exposure to sunlight of a methanolic solution of 2-benzoyl-3-phenylquinoxaline di-N-oxide 8 in a Pyrex ask for 12 h, resulted in the precipitation of 1,3-dibenzoylbenzimidazolone 9 in 70% yield. 51 This rearrangement can be considered to involve two nitrone functions in one molecule. It is generally accepted that the irradiation of nitrones leads to oxazirane intermediates with further thermal and photochemical rearrangements. 52 Hence, it is reasonable to assume that, on irradiation, 8 is transformed into the isomeric oxazirane A. Considering the mechanism for the formation of 9 from oxazirane A, the authors favor intermediate B arising from the thermal heterolytic N-O bond ssion of the oxirane ring, as suggested by Splitter and Calvin 52c for the thermal decomposition of 2,3-diaryloxaziranes. In this case the positive charge on the nitrogen is delocalized by resonance with the adjacent aromatic ring, and then be assumed to undergo 1,2-benzoyl migration to an electron-decient nitrogen C. The driving force for this shi is supplied by the negative charge on the oxygen (Scheme 5). When this mechanism is applied to the nitrone system at positions 3 and 4 the observed product 9 would be formed by ring contraction.
Fih example. In every the cases when the 2-chloroquinoxaline 17a-c was heated with potassium amide in liquid ammonia at low temperature, benzimidazole 19 as well as the corresponding 2-aminoquinoxalines 18a-c were formed (Scheme 8). 54 This indicates that the presence of a substituent at position 3 (Me or Ph) does not prevent ring contraction and that it is the carbon atom 3 in the quinoxaline ring which is eliminated. Considering the mechanism of this ring contraction it seems likely that there occurs an initial attack of the amide ion at position 3, which results in the intermediate 20 (Scheme 9). 54 At present, it is yet unclear whether isonitrile 21 (Scheme 9, route a) or iminochloride 22 (Scheme 9, route b) is involved in the course of this reaction. It is tentatively suggested that this ring contraction occurs as shown below (Scheme 9). The formation of a nitrile has been conrmed by the fact that with 17a it is possible to isolate benzamidine, which is probably formed by the addition of potassium amide to benzonitrile.
It should be pointed out that with 2-chloroquinoxaline the main product is benzimidazole, and only some 2-aminoquinoxaline is formed. Under these conditions 2-bromo-(17d) and 2-iodo-(17e) quinoxaline are almost exclusively converted Scheme 18 New one-pot two step process for the synthesis of benzimidazolylquinoxalines starting from glycerol.  into benzimidazole, whereas with 2-uoroquinoxaline 17f only a trace of benzimidazole is formed. 54 Sixth example. The hydrazinolysis of quinoxalin-2(1H)-one 23 in boiling 50% aqueous hydrazine lead to the formation of 2methylbenzimidazole 26. 55 This reaction has once again demonstrated the strong tendency of hydrazine to bring about ring transformation. This is assumed to occur by an initial addition of hydrazine at the C]N bond of 24, resulting in the 3,4-addition analogues to addition reactions in 6-and 7-oxopteridines with nucleophilic reagents. 56 As above, the ring contraction into 25, and the reductive conversion of the -HC] N-NH 2 into a methyl group by a Wolff-Kishner type process, together with dehydration, produced 26 (Scheme 10).
Seventh example. Photolysis of the quinoxalin-2-ylcarbamate N-oxides 27 and 28 in various solvents (e.g., methanol) gives the benzimidazol-2-ylcarbamates 30 and 31. Under acidic conditions the 1-oxide 27 yields the isonitrile 29 (Scheme 11). 57 Eighth example. A further case of ring contraction has been reported on the thermolysis of 2-azidoquinoxaline 1-oxide 32 when 2-cyano-1-hydroxybenzimidazole 33 is formed (Scheme 12). 58 Oxidation of 2-phenylquinoxaline-4-oxide 34 with a 30% aqueous hydrogen peroxide in acetic acid 59 or formic acid 60 results in the 1,4-dioxide, which on reduction with sulfurous acid in methanol yields 2-phenylquinoxaline-1-oxide. However, treatment of the 4-oxide 34 with a 30% aqueous hydrogen peroxide in methanol and the presence of potassium hydroxide brings about 2-phenylbenzimidazole-3-oxide 35. This is a general reaction of 2-alkyl-and 2-alkoxyquinoxaline 4-oxide (Scheme 13). 61 As evident from the above eight examples of recycling of quinoxaline derivatives, the rst two and the sixth one lead to the 2-substituted benzimidazoles, and the third and fourth ones result in the N-substituted benzimidazolones. All of them except the last one are special cases, i.e. implemented as the special representatives of the benzimidazole derivatives. As for the fourth example, the possibility of this reaction is limited to the synthesis of the derivatives of benzimidazolones with substituents only on the benzene ring. As a result of rearrangement they are eliminated as substituents at position 3 of the starting compounds. Thus, none of these methods of the synthesis of benzimidazole derivatives can compete with the classical Phillips-Ladenburg and Weidenhagen reactions.

Principles of the method
Quinoxalin-2(1H)-ones 37 can be converted into substituted benzimidazoles 40 following the reaction sequence, rst reported in 2000, 62 and shown in Scheme 14. Firstly, 3-a-chloro (or bromo)benzylquinoxalin-2(1H)-ones 36 are oxidized with the Kornblum type reactions 63 or the direct oxidation of 3-benzyl (or alkyl) quinoxalin-2(1H)-ones 36 with the help of GrO 3 in acetic acid with water 62d,64 to give 3-aroyl-or 3-alkanoylquinoxalin-2(1H)-ones 37. 3-Aroyl-or 3-alkanoylquinoxalin-2(1H)-ones 37 react with 1,2-DABs 5 to give the spiro-quinoxalinone derivative 38. The spiro-quinoxalinone derivative 38 is then heated in acetic acid to give the benzimidazole derivative 40 through the proceeding cascade reactions involving: (a) acid-catalyzed ringopening of spiro-compound 38 with the formation of quinoxaline derivative 39, (b) the intramolecular nucleophilic attack by the amino moiety on the carbonyl group leading to the formation of the nal product 40 with the elimination of water. Practically for every case the spiro-compound 38 can be isolated and individually characterized, but the quinoxaline derivative 39 can only be rarely isolated. The sequence is thus based on the combination of the following facts: (i) The presence of the carbonyl group at position 3 of quinoxalin-2(1H)-ones 37, according to the principle of Ogg and Bergstrom 48 allows to consider them as the hetero analogues of a-diketones (see Sections 4 and 10).
(ii) The susceptibility of these systems to the reactions of the usual a-diketones, according to the Hinsberg reaction 65 involves spiro-quinoxaline derivatives with at least one mobile hydrogen atom in the spiro-forming component. 62 (iii) The susceptibility of the spiro-quinoxaline derivatives 38 towards the acid-catalyzed ring-opening with the formation of quinoxaline derivatives 39, and the intramolecular ring closure reaction with the formation of benzimidazole derivatives 40.

Advantages of the method
The present method for the synthesis of substituted benzimidazoles starting from quinoxalin-2(1H)-one derivatives has the following characteristics or distinct advantages over the previously used routes (the Phillips-Ladenburg and the Weidenhagen reactions) or their numerous variations.
(A) Firstly, the acid-catalyzed rearrangement of spiroquinoxalinone derivative 38 through the o-aminoanylide quinoxaline 2-carboxylic acid 39 involves a milder reaction condition and provides almost quantitative yields of the benzimidazole derivative 40 (Scheme 14). Most of the popular approaches generally involve the condensation of an arylenediamine with a carbonyl equivalent (Scheme 15). For example, the reaction of 1,2-DABs with carboxylic acid or acid chloride results in intermediate amide 43. In order to produce benzimidazole 46 the latter in turn could undergo a cyclodehydration reaction at elevated temperatures under strong acidic or alternatively under harsh dehydrating conditions, (Scheme 15, route a). Similarly, esters, lactones and anhydrides could generate benzimidazoles via the cyclization of amide 43, although given the rather harsh reaction conditions required and the poor diversity prole of the nal products their scope might be limited. For instance, the reaction of 1,2-DABs with aliphatic esters and lactones involves the use of strong mineral acids such as hydrochloric acid, sulfuric acid, hot glacial acetic acid or polyphosphoric acid under very high temperatures, i.e. the conditions are not absolutely compatible with a broad range of functional groups and desirable substrates. Aromatic esters require temperatures of up to 250-300 C, thus rendering the synthesis of 2-arylbenzimidazoles almost impractical. 46a However, the reaction of aromatic esters with 1,2-DABs under the Weinreb conditions could provide access to 2-arylbenzimidazoles. 46b In the class of acid anhydrides of monobasic acids, only acetic anhydride has been practically used in the preparation of 2-methylbenzimidazoles. Cyclic anhydrides of dibasic acids have also been used in the synthesis of benzimidazoles, although high temperatures and strong acids are usually necessary to convert the intermediate N-(o-aminophenyl)-imide into the desired benzimidazole. 47a,b Besides, a mixture of regioisomeric benzimidazoles could result from the reaction of nonsymmetric anhydrides with arylenediamines.
In the presence of HCl the reaction of 1,2-DABs with amides 66 and nitriles 67 at 200-250 C could also afford 2substituted benzimidazoles with the general structure 46 via the cyclization of intermediate amidine 44a (Scheme 15, route b). Alternatively, upon the formation and subsequent cyclization of amidine 44a under milder conditions 68 the reaction of 1,2-DABs with an imidate could afford benzimidazole 46 as well. Although the imidate route could provide access to a diverse set of 2-substituted benzimidazoles starting from several commercially available aliphatic and aromatic nitriles, the hydroscopic nature of the intermediate imidates might be of concern, particularly in a high throughput set-up. The palladium catalyzed intramolecular N-arylation reaction of the o-bromophenylamidine precursors of type 44b, resulting from the assisted POCl 3 condensation of bromoaniline 41 and an amide, has been recently developed providing entry to Nsubstituted benzimidazoles with the general structure 47. 69 Despite the somewhat harsh conditions required to generate the intermediate amidine precursors, this method proves successful in the regioselective synthesis of N-substituted benzimidazoles which is a current limitation as regards many other approaches.
Aldehydes and, to a lesser extent, ketones can also afford benzimidazoles when condensed with 1,2-DABs (Scheme 15, route c). Although the reaction of ketones with 1,2-DABs in the presence of HCl at 250-300 C can yield benzimidazole 46 due to the aromatization of intermediate benzimidazoline 45a, their use has been rather limited. 1b,70 Furthermore, since the aromatization of benzimidazoline 45a occurs via the elimination of an alkyl group, a mixture of benzimidazoles could result from non-symmetric ketones. Alternatively, aldehydes have been used more extensively in the preparation of 2-substituted benzimidazoles according to the Weidenhagen's method. 71 For example, condensation of 1,2-DABs with an aldehyde, followed by the oxidation of the intermediate benzimidazoline 45b could afford benzimidazole 46 as well. While the oxidation can proceed spontaneously by disproportionation, this can lead to some of side products. Oxidative methods usually require heating in nitrobenzene or DMF at elevated temperatures, as well as the use of metal ions, iodine, organic oxidants or inorganic sultes when heated. 72 However, for the synthesis of Nsubstituted and N-H benzimidazoles one mild set of oxidation conditions utilizing oxone has been recently described. 72 Method of reductive cyclization of N-benzylidene-2nitroanilines 48 (R 2 ¼ Ar), prepared from o-nitroaniline 42 and benzaldehydes (Scheme 15, route d) could be a viable alternative to the widely used 1,2-DAB based synthetic methods. But according to our knowledge, it was not as yet been studied to date. Triethylphosphite, 73 triruthenium dodecacarbonyl 74 in the presence of carbon monoxide, and recently, phenylmagnesium chloride 75a have been successfully utilized as the reducing agents for this transformation. The reaction presumably proceeds via an in situ aryl nitro reduction, followed by an intramolecular cyclization, 75 and results in benzimidazole 46 (R 2 ¼ Ar). This strategy requires the preparation and isolation of the corresponding N-benzylidene-2-nitroanilines 48 before subjecting them to cyclization conditions though it could obviate the preparation and isolation of the intermediate 1,2-DABs in particular those that are water-soluble or prone to airoxidation.
(B) Secondly, the synthesis of substituted benzimidazoles can be accomplished starting from the quinoxalin-2(1H)-one derivative 36 easily available with the use of various preparatively simple ways under mild conditions from corresponding substituted 1,2-DABs and pyruvates. In doing so as a result of the rearrangement substituents of the benzene ring of the quinoxalinone system appeared to be on the benzene ring of the benzimidazole ring. As a result of the rearrangement the substituent R 2 at position N(1) of the quinoxalin-2(1H)-one system are transferred to the N atom of benzimidazole system.
(C) The route 36 to 40 clearly shows that a benzyl (or haloalkyl) group can be converted (by use of the Kornblum reaction) into a ketone group necessary for the introducing of quinoxaline ring in to position 2 of quinoxalinone 37 according to the Hinsberg reaction. 65 In this reaction compound 37 formally acts as the hetero analogue of a-diketone.
(D) As can be seen from the reaction depicted in Scheme 14, the key step in this case is the formation of spiro-compound 38. As a result of the cascade reaction this compound is transformed into a benzimidazole derivative 40, with a heterocyclic system. This system acts as a spiro-fragment in the intermediate compound 38. The result makes it possible to propose the main principle for this rearrangement. Any of the spiro-derivatives of 1,2,3,4-tetrahydroquinoxalin-3-one with at least one mobile hydrogen atom in their spiro-forming components can be converted into the benzimidazole derivative with the spiroforming component at position 2 (Scheme 16). 76 (E) The understanding of the reaction mechanism makes it possible for us to make a bold assumption as seen from Fig. 4, all the reactions of aroyl-and alkanoylquinoxalines when interacting with 1,2-DABs at the initial stage behave as hetero analogues of a-diketones, i.e., as iminoketones (see Sections 4 Scheme 26 Conversion of Ugi adduct into quinoxaline 85a via intermediates 86a and 87a. Scheme 27 Study of the reaction scope. and 10). Then the problem appears, why other quinoxaline derivatives with certain substituents do not behave like a-haloketones 49 (see Section 5), b-diketones 50 (see Section 6), aaminoketones 51 (see Section 7), methyl ketones 52 (see Section 8), o-aminoaldehydes (or ketones) 53 (see Section 9), etc.

From glycerol and 1,2-diaminobenzenes with use of gold catalysis
Methods for the synthesis of these hetarylquinoxalines are limited. An option involves the reaction of the 1,2-DAB 5a with 3-hydroxyimino-2-butanone 54 and bromine in a one-pot reaction (Scheme 17a). 77 Another possibility is to react 1,2-DABs 5ag with quinoxalin-2-carboxylic acid 56, but this synthetic route needs to be performed in a polyphosphoric acid media at 200 C (Scheme 17b). 78 A third route is to react the 1,2-DAB 5a with quinoxalin-2-carboxaldehyde 58 in benzene at reux temperature (Scheme 17c). 79 In all the three cases the yield of the target product remains very low.
A gold catalyst (Au/CeO 2 ) was used to synthesize benzimidazolylquinoxalines by two novel methods in a multistep one-pot methodology. 80 The rst method involved the oxidative coupling of glycerol 60 with 1,2-DAB 5a performed at 140 C using diglyme as a solvent and lead to the benzimidazolylquinoxaline compound 63a through the formation of intermediates 61a and 62a (Scheme 18). Herein, the benzimidazolylquinoxaline possesses the same substituents in both heterocycles. Aer that to expand the synthetic scope, an alternative route that allows Table 1 Acid-catalyzed rearrangement of quinoxalin-2-ones when exposed to 1,2-DAB 5a combining different substituents in both heteroaromatic moieties was designed. However, at the beginning of the reaction, the quinoxalin-2ylmethanol 61a, formed by oxidative coupling between glycerol 60 and 1,2-DAB 5a, and the 1-(1H-benzo-[d]imidazol-2-yl)ethane-1,2-diol 62a, which could be produced through the oxidation of one of the primary alcohol groups of glycerol and subsequent coupling with 1,2-DAB 5a, were the predominant products (Scheme 18). Both compounds (61a and 62a) exhibited a primary and unstable character and aer one hour of reaction, the concentrations of both intermediates began to decrease, due to their conversion into 2-(1H-benzo[d]imidazol-2-yl) quinoxaline 63a, produced through oxidation-cyclization of  Acid-catalyzed rearrangement of quinoxalin-2-ones when exposed to 3,4-diaminotoluene 5d and 4-nitro-1,2-DAB 5h In Scheme 20, good yields of benzimidazolylquinoxaline derivatives were obtained. However, with electron-withdrawing substituents such as nitro, chloro or nitrile groups, the yields of quinoxaline derivatives were slightly lower with respect to those of 1,2-DAB or with respect to 1,2-DABs with electrondonating substituents such as methyl and methoxy. In all these cases the reactions proceed with the formation of regioisomers of benzimidazolylquinoxalines.
To develop a method for the synthesis of the 2-benzimidazolylquinoxaline derivatives with different substituents in the benzimidazole and quinoxaline fragments the conditions for the formation of the assumed intermediate products of the reaction, i.e. hydroxymethylquinoxaline 61a, 1-(1H-benzo[d] imidazol-2-yl)ethane-1,2-diol 62a, and its protected derivative 80 were investigated (Scheme 21). 80 Following the optimization of the reaction conditions with different substrates, the results presented in Scheme 22 showed that only the reaction between glyceraldehyde and 1,2-DAB (Scheme 21, route c) in the presence of Au/CeO 2 , oxygen pressure, and at room temperature, produced the benzimidazole intermediate 62 with a high selectivity with complete conversion. Consequently, the synthesis of the benzimidazole intermediate from glyceraldehyde and 1,2-DAB derivative was chosen as the optimum rst step of the reaction.
This second process involves two sequential steps with very different reaction conditions. In the rst one, glyceraldehyde is coupled with an 1,2-DAB derivative in the presence of Au/CeO 2 Aer the complete conversion of glyceraldehyde, a solution of the second 1,2-DAB molecule 5d in diglyme is added, and the temperature is increased to 140 C while the water is removed by a Dean-Stark system. The main product observed under these conditions is the benzimidazolylquinoxalines 63g (Scheme 22), which is formed by oxidative coupling between the intermediate 62 and the 1,2-DAB molecule 5d. 80 Both routes were applied to the synthesis of different benzimidazolylquinoxalines derivatives, obtained in yields between 60 and 80%.
As can be seen from the reaction mechanism (Scheme 23) and from the data in the Scheme 20, this method cannot be used effectively in the case of the synthesis of substituted derivatives of 2-benzimidazolylquinoxalines, as the reactions of mono-substituted derivatives of 1,2-DAB proceed with the formation of the mixtures of regioisomers, which are difficult to separate. The problem is further complicated with the diversely substituted derivatives of 1,2-DAB. Expensive (Au) and environmentally unsafe (CeO 2 ) catalyst also limits the possibilities of this method.

Via the isocyanide based multi-component reactions (IMCRs)
IMCRs are considered as a principal eld of study for the generation of both new chemo type diversity and preferred methodologies to produce known heterocycles. 81 In particular, the Ugi reaction, is extremely versatile enabling access to the numerous of small molecules through a various strategies that include post-condensation modications of the Ugi adduct and use of variety of nucleophiles, which can trap nitrilium intermediate both intra-and intermolecularly (Scheme 24). Several groups have developed concise methodologies that enable access to diazepines, 82 ketopiperazines, 83 imidazolines, 84 b-lactams 85 hydantoins, etc. 86 The nal ring closure is accomplished Scheme 34 The general scheme of the synthesis of 3-benzimidazoylquinoxalin-2(1H)-one 37s starting with quinoxalin-2(1H)-one derivative 103 according to the references 95,97 The geometry of C]C double bond for quinoxaline derivative 107 is strongly supported by gauge-independent atomic orbital calculations. 99 Scheme 35 The reaction of 3-ethoxycarbonylmethylene-3,4-dihydroquinoxalin-2(1H)-one 103 with the Vilsmeier reagent.
through the amide bond formation in the Ugi/deprotect/cyclize strategies. 81e,f When 3-bromophenyl glyoxaldehyde 82 and N-Boc-(4,5dimethyl)-1,2-DAB 5k were used instead of amine and aldehyde components in the above reaction the process proceeded smoothly in methanol at ambient temperature resulting in the Ugi adduct 84 in a 70% yield (Scheme 25). The treatment of 84 with TFA provides 85a in good yield, which is the rst reported synthesis of quinoxalines derived in one step with the use of the Ugi reaction, assuming to proceed unexpectedly through intermediates 86 and 87 with the elimination of a benzoyl group (Scheme 26). 82 The nal product is appreciably different from the Ugi precursor, which provides a unique opportunity to achieve such a difference.
One pot procedure results in a higher overall yield of 85a (46%) when compared to that of the two step process (34%) (Scheme 26). 87 As to the scope of the reaction, various aldehydes, 1,2-DABs and isonitriles were used to produce a set of diversied quinoxalines and, the transformation worked equally well for all inputs (Scheme 27). 87 In the same reaction conditions, it was assumed that the use of isonitrile 86 (o-N-Boc-phenylisonitrile) 88 usually facilitates access to 2-benzimidazolylquinoxalines 88.
The Ugi reaction proceeded smoothly and upon microwave irradiation of Ugi products 87 with a 20% TFA/DCE, 2-benzimidazolylquinoxalines 88a-c were obtained in good yield (Scheme 28). 87 2-Benzimidazolylquinoxaline products 89 were observed with bulky o-substituted aromatic acids which had retained the benzoyl group through an internal acyl-transfer from the nitrogen obtained from the original Ugi amine input to the adjacent benzimidazole. Low yields of the desired products (39-49% in the cases of quinoxaline derivatives, and 37-46% in the case of 2-benzimidazolylquinoxalines) and the limited availability of mono-and di-variously-substituted derivatives of o-N-Boc-phenylisonitrile 86 and N-Boc-1,2-DAB limits the possibility of this approach to the synthesis of bicyclic derivatives of quinoxalines and 2-benzimidazolylquinoxalines variously substituted by quinoxaline and benzimidazole.

Synthesis of 2-(benzimidazol-2-yl)quinoxalines and their aza-analogues
One of the common reactions of a-diketones in the chemistry of heterocycles is the Hinsberg reaction, 65 i.e., the synthesis of quinoxalines by the interaction of 1,2-DABs with a-dicarbonyl compounds.
Thus a series of reactions according to Hinsberg were carried out.
The reaction of quinoxalin-2-one 37a (see Subsection 2.2) with 1,2-DAB 5a in boiling acetic acid leads to the corresponding 2-benzimidazolylquinoxaline 40a in a 97% yield (Scheme 29). 62a Tables 1 and 2 show that a variety of quinoxalinones 37a-r and 1,2-DABs 5a, d, h are compatible with these reaction conditions, with diverse 2-benzimidazolyl substituted quinoxalines in good yields. The reactions of 3-phenylacetylquinoxalin-2(1H)-one 37g with 3,4-diaminotoluene 5d, or 4-nitro-1,2-DAB 5h, produce a mixture of two isomers in almost equal amounts (Table 2), 62d,89 as evident from the 1 H NMR spectra of the crude products. This is because the fact that the probability of an initial attack of the amino group on the C(3) atom of the quinoxalin-2(1H)-one system and on the aroyl-or alkanoyl group during the rearrangement is nearly the same (Table 1). 62a,b,d,e,90 Table 1, shows that it makes no deference for the reaction whether or not there is a substituent of quinoxalin-2(1H)-ones at position 1. The same process is successful with N-alkylated derivatives of quinoxalin-2(1H)-ones, producing N-alkylated derivatives of benzimidazole as well. All these reactions involve the formation of 2-(benzimidazol-2-yl)quinoxalines almost in quantitative yields.
The reaction proceeds with the compounds with two quinoxalin-2(1H)-one moieties in their composition, and, what kind of spacer connects these two fragments makes no difference. In all cases the reactions proceed smoothly with the formation of benzimidazolemonopodands with the terminal quinoxaline fragments (Table 3). 62c,d, 91 When the reaction of 1,5-bis(3-benzoyquinoxalin-2(1H)-on-1yl)pentane 93f with the 3,4-diaminotoluene 5d was carried out under the same conditions the formation of a single product mainly the benzimidazolemonopodand 94f with the terminal 6and 7 0 -dimethylquinoxaline rings in a 77% yield actually occurs (Scheme 30). 62c These systems contain methyl groups at C(6) and C(7 0 ), and not at the C(6), C(6 0 ) and C (7), C(7 0 ) positions. The probability of an initial attack on the amino group on the C(3) atom or on the benzoyl group is roughly the same. Otherwise, the formation of three products of rearrangement could be observed in approximately equal amounts.
Scheme 38 A possible alternative mechanism for the formation of benzodiazepin-2(1H)-one derivative 105.

Synthesis of 2,3-bis(benzimidazol-2-yl)quinoxalines
It is not a simple task to obtain high results in the synthesis of heterocyclic systems with two directly connected benzimidazole fragments with the known methods (by Phillips-Ladenburg 3a,46b,47c,92b-e and Weidenhagen 71,72,74,92e-g reactions). At least twice as many labor-consuming classical methods of the synthesis of benzimidazoles are involved. It should be pointed out that there was only one paper 94 in which the formation of 2,3-bis(benzimidazol-2-yl)quinoxaline 100a as a by product in the reaction of tetrachloropyridazine 98 and 1,2-DAB 5a in N-methylpyrrolidone at 115 C for 17 h has been described (Scheme 31). The yield of the main product of this reaction 5,6,7,8,13,14-hexaazapentaphene 99 obtained as a free base aer treatment of the corresponding hydrochloride with aqueous sodium hydroxide is 15%. The yield of the byproduct -2,3-bis(benzimidazol-2-yl)quinoxaline 100a has not been given in this paper. Therefore this method cannot be used as a preparative one for the synthesis of 2,3-bis(benzimidazol-2yl)quinoxalines. The synthesis of other heterocyclic systems with two benzimidazole fragments cannot be used either.
It was suggested that the quinoxaline residue of the product 100a was formed by the initial nucleophilic attack on position 4 and 5 of tetrachloropyridazine 98 by 1,2-DAB. Further the aerial oxidation, resulting in an intermediate 1,4-dichloropyridazino [4,5-b]quinoxaline 101 which might react with two more molecules of 1,2-DAB to give the pyridazine-ring-opened system 100a (Scheme 32).
Scheme 43 Acid-catalyzed rearrangement.   Since this is contrary to the above ndings on the reactions of aroylquinoxalin-2(1H)-ones with 1,2-DAB, 62,96 proceeding with the formation of 2-benzimidazolylquinoxaline derivative it was decided to examine the results described in paper. 95 To this end, it was planned to synthesize 3-benzimidazoylquinoxalinone according to the following Scheme 34 described by Kurasawa. 95,97 As depicted in Scheme 34 compound 103 at the very rst stage to react with the Vilsmeier reagent [DMF-POCl 3 , 1 : 1], at a temperature on water bath for 2 h, to give 3-(N,N-dimethylaminocarbonyl)furo [2,3-b]quinoxaline hydrochloride 104 (83%). 97a Aer a detailed study of the structure of the reaction product, with the involvement of IR data 98 it was concluded that there was no compound 104, but its isomer -1-N,N-dimethylaminomethylene-1,2-dihydrofuro [2,3-b]quinoxalin-2-one 108 (Scheme 35).
Apparently the formation of the furo[2,3-b]quinoxalin-2-one derivative 108 proceeds via the initial formation of compound A according to the rst stage of the aliphatic Vilsmeier reaction, performed on the methylene group of the substituent at position 3 of quinoxalin-2(1H)-one 103. The latter undergoes intramolecular cyclization with the subsequent elimination of EtOH and HCl, results in the nal product 108 (Scheme 36).
Heating at reux of the benzodiazepine derivative 105 in the aqueous acetic acid solution affected ring transformation as has been shown in paper 95 to give 106, the treatment of which with a 5% sodium hydroxide yielded a free base 107 (Scheme 34). The nal stage of the synthesis of 3-benzimidazoylquinoxalin-2(1H)one 37s according to Scheme 34 involves the oxidation of compound 107 with m-chloroperbenzoic acid (m-CPBA). 95 According to this method the yield of the desired product is approximately 40%, therefore it was used the method of oxidation for the synthesis of 3-benzimidazoylquinoxalin-2(1H)one 37s, which has been recently developed for similar compounds. This includes the treatment of 3-(a-bromobenzyl) quinoxalin-2(1H)-ones with DMSO. 63b The reaction of 3-(benzimidazol-2-yl)methylenequinoxalin-2(1H)-one 107 with an equimolar amount of bromine in DMSO at room temperature for 24 h results in ketone 37s with a quantitative yield. According to the Kornblum oxidation 100 the formation of the latter can be represented as an oxo-dehydrohalo-bisubstitution 101 formed in situ 3-(a-bromomethylimidazol-2-yl)quinoxalin-2-(1H)-one (Scheme 39).
Thus, the results of the reaction of 3-(benzimidazo-2-yl)quinoxalin-2(1H)-one 37s with a variety of 1,4-di-N-nucleophiles conrm the hypothesis, which has been proposed earlier (Scheme 16). 76 Thus, we have developed a simple, mild and high yielding one-pot method to prepare quinoxalines and tethered quinoxaline-benzimidazoles. In this case the scope of the rearrangement was extended to other 1,4-di-N-nucleophiles, which enables a simple and efficient method for the preparation of a series of 2,3-bis(benzimidazol-2-yl)quinoxalines as well as of di(benzimidazol-2-yl)-furo[3,4-f]-, thieno[3,4-f]-and pyrazino [2,3-f]quinoxalines. This was accomplished by the rearrangement of 3-benzimidazoylquinoxalin-2(1H)-one on exposure to 1,2-DAB and its substituted and condensed derivatives. Considering the well documented medicinal utility of benzimidazoles and quinoxalines, these compounds consisting from the combination of the two scaffolds afford new opportunities to investigate their biological activity.

Synthesis of 2-(pyrazin-2-yl)benzimidazoles
Further exploration of the above strategy with the use of diaminomaleonitrile instead of 1,2-DABs has led to the development of a novel, simple method for the synthesis of 2benzimidazolylpyrazines. In this case the results of study on a novel rearrangement of 3-aroyl-and alkanoylquinoxalin-2(1H)ones and 2,3-diaminomaleonitrile as a N-nucleophile under the acid catalysis condition are presented. 103 Regardless of the molar ratio of the reagents (1 : 1, 1 : 1.1, 1 : 2; 37a : 121) and reaction time (3, 9 or 17 h) the reaction of 3benzoylquinoxalin-2(1H)-one (3-BQ) 37a with 2,3-diaminomaleonitrile 121 proceeded in the same way with the formation of a $45% yield of the rearrangement product 122a (Scheme 43), whereas 50% of 3-benzoylquinoxalin-2(1H)-one 37a reverted. Diaminomaleonitrile 121 apparently undergoes polymerization. Adding a second equivalent of diaminomaleonitrile 121 to the reaction mixture obtained aer boiling the equimolar ratio of reagents in acetic acid for 5 h did not lead to an increased yield of the desired product. Neither did the boiling for an additional 5 h.
In order to improve the yield of the rearrangement product there were used the principles of the previously proposed hypothesis (Scheme 16). 76 In accordance with this hypothesis here appeared the problem of the synthesis of the spiro[pyrazine-2,2 0 -quinoxalin]-3 0 (4 0 H)-one derivative. For this purpose the necessary pyrazine ring system at position 2 of quinoxalin-2(1H)-one 37a via the modied Körner and Hinsberg 104 reaction Table 10 3-Aroylquinoxalin-2(1H)-one derivatives as hetero analogues of a-diketones in the synthesis of functionalized imidazoles (the synthesis of quinoxalines by condensation of a-dicarbonyl compounds with 1,2-DAB) has been installed. This was achieved by the reaction of 37a with diaminomaleonitrile 121 in a boiling solution of MeOH in the presence of a catalytic amount of H 2 SO 4 . In this reaction the 3-BQ 37a was considered as an heteroanalogue of an a-dicarbonyl compound. The reaction proceeded smoothly for 2 h to give the desired spiro-compound, 5,6-dicyano-3R-1H,1 0 H-spiro[pyrazine-2,2 0 -quinoxalin]-3 0 (4 0 H)one 123a in 96% yield ( Table 6, entry 1). The optimum molar ratio of reagents 37a:121 was 1.0 : 1.1. Under these conditions other 3-aroyl-(37a-e, t, u) and 3-alkanoyl-(37g, i) derivatives of quinoxalin-2(1H)-ones behaved similarly resulting in high (75-96%) yields of the corresponding spiro-derivatives on reaction with diaminomaleonitrile 121 (Table 6). These examples of the reactions of 37a, d with 121 showed that increasing the reaction time up to 10 h resulted in a mixture of the products of rearrangement of 122a, d and spiro-derivatives of quinoxalinones 123a, d in a ratio of $1 : 3 (yield 89%), and up to 20 h in a ratio of $1 : 1 (yield 97%). When carrying out the reactions of quinoxalines 37a-e, g, j, t, u with diaminomaleonitrile 121 for 6 h in the presence of p-TsOH (20 mol%) as a catalyst the formation of spiro-compounds 123a-i occurred in yields of 60-85% ( Table  6). The reactions of quinoxalin-2(1H)-ones 37a, b with 121 show that in the presence of catalytic amounts of HCl, spirocompounds 123a-b are formed in 2 h and the yields of products were 91% and 88%, respectively ( Table 6, entries 1 and 2). Spiro-compounds 123a-e, h, i without substituents on the benzene ring of the quinoxaline system were quantitatively transformed into the desired 2-(pyrazin-2-yl)benzimidazole 122a-e, h, i in boiling AcOH in 10 min (Table 7, entries 1-5, 8,9). The substituted spiro-derivatives of quinoxalin-2(1H)-ones 123f, g underwent the rearrangement only aer 3 h in boiling AcOH (Table 7, entries 6, 7).
It is worthy of note that the products of the reaction of 3aroyl(alkanoyl)quinoxalin-2(1H)-ones 37a-e, g, i, t, u and Nalkyl-3-BQs 37o, v, w with diaminomaleonitrile 121 in DMSO-d 6 exist solely in spiro-cyclic-forms 123a-l, whereas in the crystalline state they exist only as open chain forms 123 0 a-l. 103 Based of the chemistry of quinoxalinones, 105 diaminomaleonitrile, 106 and the above data, it is reasonable to assume that as the rst step the formation of 2-(pyrazin-2-yl) benzimidazoles 122 involves addition of the amino group of diaminomaleonitrile 121 to the C(3) atom of quinoxalin-2(1H)one 37. The next step involves a nucleophilic attack of the second amino group of 121 on the benzoyl carbonyl group to form the spiro-quinoxaline derivative 123. Rearrangement of the spiro-quinoxalinone 123 is then assumed to occur according to Scheme 46, which proceeds via cascade reactions involving: An efficient and versatile metal-free method for the preparation of a series of 2-(pyrazin-2-yl)benzimidazoles has been developed. This was accomplished by the novel rearrangement of 3R-5,6-dicyano-1H,1 0 H-spiro[pyrazine-2,2 0 -quinoxalin]-3 0 (4 0 H)-ones easily obtained from 3-aroyl-and 3-alkanoylquinoxalin-2(1H)-ones on exposure to diaminomaleonitrile.
The key advantages are the simplicity of the operation, high yields, easy availability of 3-aroyl-and alkanoylquinoxalin-2(1H)-ones, as well as the simple work-up and purication of the products.

Synthesis of 2-(imidazol-4-yl)benzimidazoles
In continuation of the efforts to develop quinoxalin-2(1H)one. 62c,f,107 based on synthetic methodologies, a simple, mild and expeditious synthesis of 2,4,5-trisubstituted imidazoles in high yields with 3-aroylquinoxalin-2(1H)-ones as hetero analogues of a-diketones has been developed ( Table 9). 108 To determine the scope and generality of this reaction, various substituted aldehydes and 3-pyridinecarboxaldehyde were utilized. The desired products were obtained and the results are summarized in Table 10.
The presence of the o-iminoanilide substituent at position 4 of imidazoles 127 makes it possible to use them in further syntheses. Based on the four imidazole derivatives 127a, c, e, h it was shown that the reaction of these compounds with Scheme 47 The rearrangement of spiro-quinoxalinones 132. ammonium acetate in acetic acid proceeds with the formation of 2-(imidazol-4-yl)benzimidazoles 129a-d in almost quantitative yields (Table 11). A plausible mechanism for the synthesis of imidazoles, imidazo[1,5-a]quinoxalin-4(5H)-ones and benzimidazoles has been proposed (Scheme 45). The formation of the diamine intermediate A takes place during the initial stage of the reaction. Intermediate A condenses with the 3-benzoylquinoxalin-2(1H)-one 37s followed by dehydration to afford the imino intermediate B, which is transformed in two different ways (pathway I and pathway II). Pathway I proceeds by cascade reactions involving: (a) acid-catalyzed ring-closure of intermediate C with the formation of spiro-compound D, (b) acidcatalyzed ring-opening of spiro-compound E with the formation of the imidazole derivative F, which is rearranged into the imidazole derivative G via a [1,5] hydrogen shi, and (c) reaction of the latter with the aldehyde to form compound 127. Pathway II involves the tautomerism of intermediate B with the formation of compound H, which under acid catalysis undergoes intramolecular cyclization to give I. The nal product 128 is formed following the elimination of ammonia through intermediates J and K.
It is apparent that the formation of 2-(imidazol-4-yl) benzimidazoles 129a-d involves the ammonolysis of imidazoles 127a, c, d, g to form the corresponding o-aminoanilide derivative G as the rst step. The next step involves an intramolecular nucleophilic attack by the amino group on the carbonyl group with the formation of the intermediate hydroxyderivative L, and then the elimination of water. This leads to the formation of the nal product 129 (Scheme 46). This was accomplished by the novel ring-opening of 3aroylquinoxalin-2(1H)-ones on exposure to diaminoarylmethanes intermediately generated from arylaldehydes and ammonium acetate. The introduction of the o-iminoanilide fragment at position 4 of the imidazole derivatives with the help of this method makes it possible to synthesize 2-(imidazol-4-yl) benzimidazoles. The simplicity of this method, high yields, easy work-up and purication of compounds by crystallization are the key advantages.

Synthesis of 2-(3-arylindolizin-2-yl) benzimidazole
One of the common reactions of a-haloketones in the chemistry of heterocycles is the Chichibabin reaction, that is, the synthesis of indolizines by interaction of a-picoline with ahaloketones. It was carried out in a series of reactions according to Chichibabin. Thus, the reaction of quinoxalin-2-one 49 (see Subsection 2.3E) with a-picoline 130 at reux results in high yields of the corresponding 2-(indolizinyl)benzimidazoles 131 (Table 12). As is evident from the structure of compounds 131, the C(2)-C(3)-C(Cl)Ar and N]C-Me fragments of quinoxaline 49 and a-picoline 130 are involved in constructing the two new heterocyclic rings. 89,107a,109 Initially, a complete dissolution of compounds 49 is observed in reuxing the a-picoline solution. Aer that there rapidly occurs an abundant precipitation of crystals which gradually dissolve during the course of the reaction. The yield of crystalline products with a precise melting point, are obtained, for example, aer reuxing quinoxalin-2(1H)-one 49c in apicoline 130 for 1 h, and the yield is 41% (Table 13).
A rst-stage product resulting from the nucleophilic displacement of the Cl atom by the pyridine N atom of apicoline under milder reaction conditions than are required for the formation of a spiro-compound or its rearrangement into a benzimidazole derivative was isolated and characterized. For instance, when 3-(a-chlorobenzyl)quinoxalin-2(1H)one 49a was stirred in a-picoline 130 at 50 C for 3 h (Scheme 48), it was possible to obtain the rst stage product of the reaction, that is, compound 133, which in boiling acetic acid is transformed into a rearrangement product 132 in quantitative yields. 89 The formation of the rearrangement product can be represented by Scheme 49. According to this scheme, the initial step involves the nucleophilic displacement of the Cl atom by the pyridine N atom, which is followed by a cascade transformation. The latter involves: (a) dehydrochlorination with the abstraction of a methyl H atom of a-picoline, (b) intramolecular nucleophilic addition of the methylidene C atom of the apicoline fragment to the azomethine C atom of the quinoxaline system (spiro-compound B), (c) cleavage of the C(3)-N(4) bond Scheme 50 Proposed mechanism of the rearrangement with the initial attack on the aroyl carbonyl group.
Scheme 51 Proposed mechanism of the rearrangement with the initial attack on the C(3) atom of the quinoxalin-2(1H)-one.
According to this scheme, the initial step involves the nucleophilic displacement of the Cl atom by the pyridine N atom, which is followed by a cascade transformation. The latter involves: (a) dehydrochlorination with the abstraction of a methyl H atom of a-picoline, (b) intramolecular nucleophilic addition of the methylidene C atom of the a-picoline fragment to the azomethine C atom of the quinoxaline system (spiro compound B), (c) cleavage of the C(3)-N(4) bond (N-substituted 1,2-DAB C), (d) closure of a ve-membered ring (benzimidazoline D), and (e) elimination of water.
Thus, both the formation of spiro-quinoxalinones 134a-f and their rearrangement into the corresponding pyrazolylbenzimidazoles 135a-f proceed in high yields (Table 14 and 15). As is evident from the structure of compounds 135a-f, the C(2)-C(3)]CH-C(O)-Ar fragment of quinoxalines 50a-f and hydrazine hydrate are involved in the formation of the heterocyclic systems.
On the basis of the known chemistry of hydrazines, 111 ketones, 112 and quinoxalinones 105 it is reasonable to assume that the rst stage of the reaction mechanism involves the addition of the hydrazine to the carbonyl group of the 3-arylacylidene fragment of quinoxalin-2(1H)-one 50 with the formation of intermediate A capable of reversible tautomerization to intermediate B. The next step involves a nucleophilic attack of the amino group on the C(3) atom of the quinoxalin-2(1H)-one to form the spiro-quinoxaline derivative 134. Rearrangement of the spiro-quinoxaline is then assumed to occur according to Scheme 50, which proceeds by cascade reactions involving: (a) acid-catalyzed ring-opening in spiro-compound C with the intermediate formation of pyrazolo derivative D, (b) intramolecular nucleophilic attack by the amino group on the carbamoyl carbonyl group with the intermediate formation of hydroxy-derivative E, and (c) elimination of water leading to the formation of the nal product 135. It was shown that the reaction does not proceed in neutral or aprotic solvents.
It should be pointed out that the formation of spiroquinoxaline derivative 134 could be due to the Michael addition of hydrazine to the partially positive C(3) atom of the quinoxalin-2(1H)-one 50 in the rst stage of the reaction mechanism with the formation of intermediate A 0 capable of reversible tautomerization to intermediate B 0 . Then cyclization involves the nucleophilic attack of the amino group on the carbonyl group of the 3-arylacylidene fragment of quinoxalin-2(1H)-one (Scheme 51).
This was accomplished via a novel quinoxalinonebenzimidazole rearrangement of 3-arylacylidene-3,4-dihydroquinoxalin-2(1H)-ones on exposure to hydrazine hydrate and phenylhydrazine. The reaction is readily applicable to large scale synthesis.

Synthesis of 2-(pyrrol-3-yl) benzimidazole
One of the most popular reactions of a-aminoketones in heterocyclic chemistry is another Knorr reaction, that is, the synthesis of pyrroles by the interaction of a-aminoketones with b-dicarbonyl compounds. Assuming that 3-(a-aminobenzyl) quinoxalin-2-(1H)one is the very analog of a-amineketones we have carried out the reaction of 3-(a-aminobenzyl)quinoxalin-2-(1H)-one hydrochloride 51 (see Subsection 2.3E) with acetoacetic ester 138 in the boiling acetic acid. Reaction proceeds with the contraction of the pyrazine ring system as a result of the rearrangement involving C(2)-C(3)-C(NH 2 )Ph and the C(2)-C(3) fragments of the quinoxalinone system and acetoacetic ester, respectively, with the formation of 2-(5-methyl-2-phenyl-4ethoxycarbonyl-pyrrol-3-yl)benzimidazole 139 (Scheme 53). 76b Instead of the 3-(a-aminobenzyl)quinoxalin-2-(1H)-one 51 hydrochloride in the reaction with acetoacetic ester 138 its free base is used. This has no signicant effect on the yield of the product of the rearrangement, which is apparently associated with the occurrence of various acid catalyzed side reactions involving acetoacetic ether.
To improve the yield of the product of the rearrangement the main principle of this rearrangement, proposed above was used (see Subsection 2.3D). In accordance with the above principle the spiro[4-pyrrolyne-3,2 0 -quinoxalin]-3 0 (4 0 H)-one 140 was synthesized. The 3-(a-aminobenzyl)quinoxalin-2(1H)-one 51, was considered to be the hetero analogue of a-aminocarbonyl compound according to the Knorr reaction 113 (i.e. obtaining pyrroles by the condensation of a-aminoketones with ketones containing an activated methylene group). Thus, at position 2 of quinoxalinone 51 the necessary pyrrolidine system has been set up with the help of the reaction of the compound 51 with acetoacetic ester 138 in EtOH in the presence of KOH. The reaction proceeds smoothly with the formation of the desired spirocompound -5-methyl-2-phenyl-4-ethoxycarbonyl-1 0 H-spiro[4pyrrolyne-3,2 0 -quinoxalin]-3 0 (4 0 H)-one 140 with high yields (88%) (Scheme 54). It should be noted that the reaction proceeds well enough both at room temperature (12 h) and by reux (4 h).
Boiling the compound 140 in acetic acid for 1 h leads to the expected benzimidazole 139 in quantitative yields (Scheme 55).
The formation of the rearrangement product in the reaction of 3-(a-aminobenzyl)quinoxalin-2(1H)-one 51 with acetoacetic ester can be represented as shown below in Scheme 58. According to the scheme, the formation of spiro-compound 140 occurs at the initial stage. In reaction conditions it further undergoes acid-catalyzed rearrangement. The latter involves the disclosure of the pyrazine ring of the quinoxalin-2(1H)-one system on the N(1)-C(2) bond in the intermediate salt A and the closure of the imidazole ring of the benzimidazole system with the newly formed amino group and the carbonyl group of carbamoyl fragment in the pyrrole derivative B (Scheme 56).
It should be pointed out that other substituted derivatives of 3-(a-aminobenzyl)quinoxalin-2(1H)-one also successfully react not only with acetoacetic ester but with other esters of b-oxoacids, resulting in corresponding derivatives of 2-(pyrrol-3-yl) benzimidazole in high yields.

Synthesis of 2-(benzimidazol-2-yl) quinolines
One of the most popular reactions of usual ketones in the heterocyclic chemistry is the Friedländer reaction, that is, the Scheme 56 Proposed mechanism of the rearrangement.
To investigate the reaction mechanism, the reduction of 3-(b-2-nitrostyryl)-6,7-dimethylquinoxalin-2(1H)-one 141h with hydrogen using a 10 mol% Pd/CaCO 3 as the catalyst in methanol has been performed and the corresponding 3-(b-2-aminostyryl)-6,7-dimethylquinoxalin-2(1H)-one 143h obtained. When boiled in AcOH for 3 h the latter was transformed into 2-(benzimidazol-2-yl)quinoline 142h (Scheme 59).   The known chemistry of aniline, 114 azadienes, 115 and quinoxalinones, 105,116 allows to assume that the rst stage of this reaction involves the nucleophilic attack of the amine group on the C(3) atom of the quinoxalin-2(1H)-one of A to form the spiroquinoxaline derivative B. Rearrangement of the spiroquinoxaline is then assumed to occur according to Scheme 60 by cascade reactions involving: (a) acid-catalysed ring-opening with cleavage of the C(3)-N(4) bond in the spiro-compound C leading to the formation of the quinoline derivative D, and (b) intramolecular nucleophilic attack by the amino group on the carbamoyl carbonyl group with the formation of the nal product 142 following the elimination of water.
This protocol includes a novel acid-catalyzed rearrangement of 3-(b-2-aminostyryl)quinoxalin-2(1H)-ones. The simplicity of the reaction design and the possibility of introducing a variety of substituents at any position of both the benzimidazole and quinoline ring systems makes this method a useful tool for constructing these medicinally and technically (organic emitting materials) relevant compounds. The reaction is readily applicable to large-scale synthesis.
The structure of the compound 142 shows that the o-aminostyryle substituent and the C(2), C(3) atoms of the amide and imine fragments of the pyrazine ring of quinoxalin-2(1H)-one 143 (Scheme 59) are involved in the construction of two new heterocyclic systems. In this case, the formation of the pyridine ring of the quinoline system occurs as a result of the proceeding new rearrangement. 96,117,118 As seen from the Table 16, the atoms C(2) and C(3) of the quinoxalin-2(1H)-one system become the atoms C(2 0 ) and C(2) of the benzimidazole and quinoline systems of the compounds 142 respectively.
Following the line of logics demonstrated in the papers 62c-f,76,102,103,107,108a and specically in the paper 107c on the new rearrangement of the quinoxalin-2(1H)-one derivatives, it was proposed that in the latter reaction 3-(2-aminophenyl)quinoxalin-2(1H)-one derivatives 53 can be used instead of 3methylquinoxalin-2(1H)-one 52 and o-nitrobenzaldehyde 126 derivatives as the hetero analogues of o-amino aromatic aldehydes and ketones bearing an active a-methylene functionality. The ketones can be condensed with compounds 53 capable of providing a two-carbon fragment in the construction of the quinoline system, which makes it possible to synthesize the 4-(benzimidazol-2-yl)quinolines 145,147,149 isomeric to the 2-(benzimidazol-2-yl)quinolines 142.
Based on the known chemistry of amines, 121 enolizable ketones, 122 enamines, 123 quinoxalinones, 105,116 and the previous reports 62e,f,102,103,107,108a a plausible mechanism for the reaction of the formation of 4-(benzimidazol-2-yl)quinolines 147 has been proposed (Scheme 62). The reaction starts with the condensation of ketones with 3-(2-aminophenyl)quinoxalin-2(1H)-one 53a to form imine A, which is transformed to intermediate B by tautomerization. Subsequently intermediate B is easily cyclized through the intramolecular nucleophilic addition to give the spiro-quinoxaline derivative C. The rearrangement of the spiro-quinoxalinone C is then assumed to occur according to Scheme 64, which proceeds by cascade reactions involving: (a) the ring-opening with the cleavage of the C(3)-N(4) bond in the spiro-compound D with the intermediate formation of the quinoline derivative E, (b) the intramolecular nucleophilic attack by the amino group on the carbonyl group with the intermediate formation of the hydroxyl-derivative F, and (c) the elimination of water leading to the formation of the nal product 147. All the stages of the reaction involve acid-catalyzed processes.
This chemistry is not limited to mono-and disubstituted systems, and a compound with two acetyl fragments, namely 1,3-diacetylbenzene 148 is an acceptable substrate as well (Scheme 63).
The scope of this chemistry was also expanded on the compounds with two same and two different carbonyl groups in their compositions. The 3-(2-aminophenyl)quinoxalin-2(1H)ones 53a, b were allowed to react with 1,3-pentanedione 150 and ethyl acetoacetate 138, in AcOH, but in these cases with acetyl and ester groups at position 3 of the quinoline system there occurs the formation of benzimidazolo[2,1-a]pyrrolo [3,4-c] quinoline derivatives 153a,b and 154a,b instead of the expected 4-(benzimidazol-2-yl)quinolines 151a,b and 152a,b correspondingly (Scheme 64). 102 Thus, an efficient synthesis for structurally diverse 4-(benzimidazol-2-yl)quinolines via reactions of 3-(2-aminophenyl)quinoxalin-2(1H)-ones and ketones, including acetone, acetophenones, 1,3-pentanedione and ethyl acetoacetate has been developed. The selective formation of the very different quinoline derivatives depends on the structure of ketones. The key steps are assumed to involve the new acid-catalyzed rearrangement of the spiro-quinoxalinone derivatives formed in situ from the reaction of 3-(2-aminophenyl)quinoxalin-2(1H)-ones and ketones under the modied Friedländer reaction.
It should be pointed out that in an attempt to prepare 3-(2hydrazinophenyl)quinoxalin-2(1H)-one 157 by reduction of corresponding diazonium salt from 3-(2-aminophenyl)quinoxalin-2(1H)-ones 53 with sodium sulte instead of the intended product 157 a compound with the molecular formula C 14 H 10 N 4 O has been isolated, which the authors 124 considered to be 6Hquinoxalino[1, 6-c][1,2,3]benzotriazin-13(12H)-one 158. However, later 125 it proved that the structure proposed by the authors 124 was incorrect. By NMR spectroscopy 125 and by X-ray analysis 126 it was shown that the correct structure is 1-(1H-indazol-3-yl)-1H-benzimidazol-2(3H)-one 155 (Scheme 65). The formation of the 1H-benzimidazol-2(3H)-one derivative 155 as a consequence of the principle suggested above proceeds through the spirocompound 156 without any mobile hydrogen atom in their spiro-forming component.  the pyrazine ring of the quinoxalin-2-one system. It was also shown that the necessary condition for the rearrangement is the presence of at least one mobile hydrogen atom in the spiroforming fragment, which is responsible for the elimination of water. As can be seen from Scheme 16 the formation of water takes place with the involvement of the oxygen atom of the carbonyl group. We assumed that if the spiro-quinoxalinone derivative with no mobile hydrogen atom in the spirofragment was subjected to rearrangement, there might probably be two options. The rst one is that the rearrangement would not occur at all, the second one is that another rearrangement would take place without any water elimination and with the preservation of the carbonyl oxygen atom, probably quinoxalinone-benzimidazolone. To conrm this assumption it was necessary to synthesize a spiro-derivative so the quinoxalinone without any mobile hydrogen atoms. To this end, aer analyzing all the possible nucleophilic reagents, we have chosen the enamines as CN-nucleophiles. The reaction of 3-aroyl-and alkanoylquinoxalin-2(1H)-ones with the commercially available enamines (methyl-(159a) and ethyl-(159b) 3-aminocrotonates) as CN-nucleophiles under the acid catalysis condition proceeds so fast that it appears impossible to allocate the expected spiro-compound which are immediately subjected to the rearrangement with the formation of the corresponding N-(pyrrol-3-yl)benzimidazol-2-ones (160) as major and N-(pyrrol-2-yl)benzimidazol-2-ones (161) as minor products with the overall 89-99% yields (Table 18). 127 A plausible reaction mechanism for the formation of Npyrrolylbenzimidazol-2-ones 160 and 161 has been proposed (Scheme 66). The formation of N-pyrrolylbenzimidazol-2-ones occurs in two different ways (pathway I and pathway II), differing at their initial stage of the process. In the case of the formation of N-(pyrrol-3-yl)benzimidazol-2-ones 160 the reaction starts (Scheme 68) with the acid catalyzed subsequent Michael type of the reaction 128 between 37a and 159a involving a nucleophilic attack by the enamino double bond (of 159a) on the electron decient double bond (of 37a), which leads to the formation of A. The intramolecular cyclization of A involving the attack by the imine nitrogen on the nearby -C(O)Ph moiety affords the spiro-quinoxaline derivative B. The rearrangement of the spiro-quinoxalinone B is then assumed to occur according to Scheme 68, which proceeds by cascade reactions involving: (a) the intramolecular nucleophilic attack by the amino group on the carbonyl group with the intermediate formation of the hydroxy-derivative C, (b) the ring-opening with the cleavage of the C(2)-C(3) bond in the hydroxy-derivative C with the elimination of water leading to the formation of the nal product 160a.
In the case of the formation of N-(pyrrol-2-yl)benzimidazol-2ones 161 at its initial stage there occurs a nucleophilic attack by the enamino double bond (of 159a) on the electron decient benzoyl carbonyl group (of 37a) which leads to the formation of D (Scheme 68, pathway II). This brings about the rearrangement product via intermediates E and F (Scheme 67).
In this case 3-(benzimidazo-2-yl)quinoxalin-2(1H)-one 37s, supplying two carbon atoms in the formation of the pyrrole ring is subjected to a rearrangement (Scheme 69) different from that discussed above (see Section 4.2).
Enamines for the rearrangement can be generated from decomposition of azides. The above rearrangement was observed earlier in our group on the example of the selfcondensation of 3-(a-azidophenylalkyl)quinoxalin-2(1H)-ones 167a-c (Scheme 71) (see D. F. Saina thesis pages 89-93 in chapter 4). 89 In this version of the rearrangement the enamines for the rearrangement can be generated in situ by the decomposition of azides. The nal products 168a-c are formed as a result of the intermolecular condensation of an enamine J and the corresponding ketone K formed in situ under the reaction conditions. In this case the new rearrangement of quinoxalinones makes it possible to simultaneously construct two various new heterocyclic systems under one-pot reaction conditions.
The above reactions of 3-benzoyl-, 3-alkanoyl-quinoxalinones proceed equally well with enamines generated in situ from the ketones with an activated methylene group and amines. Table 19 reports the structural variations which are tolerated by these three-component reactions of 3-aroylquinoxalinones with various ketones and ammonium acetate.
Acetophenones (electron-withdrawing and electrondonating substituents) and heteroaromatic ketones have resulted in the corresponding products in good to excellent yields (Table 19). The same is true for the different 3-BQs with various substituents with the exception of the PhC(O) group (Table 19, entry 14) in the benzene ring of the quinoxalin-2(1H)one system.
The replacement of the commercially available acetophenone 146a with 1,3-diacetylbenzene 148, bearing an additional acetyl group, would allow the anticipated cascade process with two MCR modications in one pot with the formation of compound 172, with two 1-(pyrrol-2-yl)benzimidazolone cores in the benzene ring as a major product and compound 171 as a minor product with one 1-(pyrrol-2-yl)benzimidazolone core. It has been shown that acetophenone 171 with 3-BQ 37a in the presence of NH 4 OAc (the ratio of reagents is given in the Scheme 74) can also be transformed to 172 with a 30% yield (Scheme 73).
The known chemistry of ketones, 122 imines, 121 quinoxalines 105 and enamines 123 allows to propose a plausible reaction course (Scheme 74), although the exact mechanism of this reaction is yet unclear. Intermediate L formed at the initial stage of the processes reacts with the 3-BQ 37a in two different ways (pathway I and pathway II) with the formation of an isomeric spiro[pyrrol-3,2 0 -quinoxalin]-3-one derivative O and a spiro [pyrrol-2,2 0 -quinoxalin]-3-one derivative Q through the intermediate M and N. The latter are formed by the initial attack of enamine on the benzoyl carbonyl carbon atom (pathway I) and on the C(3) atom of the quinoxalinone system (pathway II), respectively. Then, both pathway I and pathway II proceed by cascade reactions involving: (a) the consecutively acid-catalyzed ring-closure of quinoxaline derivatives M, N to spiro-derivatives Q, O followed by formation of intermediates R, P with the aziridine ring system; (b) the acid-catalyzed ring-opening in intermediates R, P with the formation of the nal 1-(pyrrol-2-yl)-169 and 1-(pyrrol-3-yl)benzimidazolone 170 derivatives.
An important three component reaction of 3-benzoylquinoxalinones, various methylaryl-(hetaryl)ketones and ammonia has been developed. The method allows the preparation of substituted 1-(pyrrolyl)benzimidazolone derivatives via multicomponent reaction conditions from easily available 3-benzoylquinoxalinone precursors in the presence of various methylaryl(hetaryl)ketones and ammonia with good to excellent yields. Enamines could be generated in situ from ketones and ammonia, which smoothly react with 3-benzoylquinoxalinones to provide 1-(pyrrolyl)benzimidazolone derivatives. An important aspect of this method is that it can be used for the synthesis of a wide range of benzimidazolone derivatives, since various methylketones are commercially available and can easily be obtained through the various simple reactions.

Conclusion
Benzimidazol(on)es have taken a leading role in the recent literature because of their wide variety of applications in various disciplines like medicinal chemistry, organometallics, and material science. Several novel synthetic routes have been developed to achieve these skeletons. These newer synthetic routes are based on the combination of several interesting strategies such as tandem sequences, multicomponent reactions, and rearrangements. As is evident from the discussion in this review, these synthetic procedures offered easy access to benzimidazol(on)es from simple and readily available precursors. The development of these synthetic procedures is very useful especially for medicinal and material chemists. In this review we mainly focused our attention to two fundamentally new rearrangements of quinoxalinones and their aza-analogues discovered by us.
The rst one can be schematically represented as TYPE 1 on the Scheme 75: "Any of the spiro-derivatives of 1,2,3,4tetrahydroquinoxalin-3-one with at least one mobile hydrogen atom in their spiro-forming component are on their way to the benzimidazole derivative with the spiro-forming component at position 2".
The second one can be schematically presented as TYPE 2 on the Scheme 76: "Any of the spiro-derivatives of 1,2,3,4tetrahydroquinoxalin-3-one without any mobile hydrogen atom in their spiro-forming component are on their way to the benzimidazolone derivative with the spiro-forming component at position 1".