Synthesis of Benzimidazoles

Attempts to effect the ring contraction of 2,3-diphenylquinoxaline 1 to 2-phenylbenzimidazole 3 with other bases (KOH in H2O or EtOH, NaOH in MeOH, NaH in toluene) were unsuccessful. The efficacy of KNH2 appears to be specific. 

This reaction sequence has been used for the preparation of an unsymmetrically substituted 2,2 -bibenzimidazole, since 2,3-dihydroxy-6-methylquinoxaline 4b and 

Fourth example Quinoxaline 1-oxides 12a-i, bearing a substituent at C(2), a carbonyl at C(3), and a free hydrogen at N(4), when heated with acetic anhydride, are transformed into l-acetyl-3-acetyl-2-benzimidazolinones or l,3-diacetyl-2-benzimi- 

1- acetyl-2(3//)-benzimidazolones 14a and 15 with 4-nitrobenzoic acid. Similarly, 

2- cyano-3-hydroxyquinoxaline 1-oxide 121 failed to react with acetic anhydride under ordinary conditions of reflux. However, in a sealed tube at 180 °C, it gave l,3-diacetyl-2-benzimidazolone 14a as well. 

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However, there are differences between o-phenylenediamine and 4,5-diaminopyrazoles in the synthesis of [5.5] systems. For example, the formation of pyrazolo[3,4-d]-[l,2,3]triazole (550) is similar to that of benzotriazole, but all attempts to extend the synthesis of benzimidazoles to the preparation of the imidazo[4,5-c]pyrazole system (551) have failed (78TH40400). 

The use of diamine 27, bearing a fluorous-Boc protecting group, has been used with microwave irradiation in an Ugi/de-Boc/cyclization strategy for the synthesis of benzimidazoles 28 and quinoxalinones 29 [64]. Compared to the original procedures, which take 1-2 days, this approach avoids the use of... 

Microwave Assisted Multicomponent Reactions for the Synthesis of Heterocycles Synthesis of benzimidazoles 28 ... 

Following the pioneering work by Alterman, several microwave-assisted palladium-catalyzed aminations have been reported for a number of different substrates, using different types of palladium sources and ligands. The examples shown in Scheme 6.59 include bromoquinolines [124], aryl triflates [125], and intramolecular aminations in the synthesis of benzimidazoles [126]. In all cases, the use of micro-wave irradiation dramatically reduced the required reaction times and in many cases also improved the yields. Several authors have also found that the microwave-driven reaction required significantly less catalyst than its conventionally heated counterpart [126]. 

Utilizing the same aryl fluoride linker on conventional MeOPEG polymer, these authors also presented a microwave-accelerated liquid-phase synthesis of benzimidazoles (Scheme 7.70) [79]. This bicydic pharmacophore is an important and valuable structural element in medicinal chemistry, showing a broad spectrum of pharmacological activities, such as antihistaminic, antiparasitic, and antiviral effects. 

VOURLOUMIS, D., Takahashi, M., SiMONSEN, K., Ayida, B., Barluenga, S., WiNTERSA, G., and Hermann, T. Solid-phase synthesis of benzimidazole libraries biased for RNA targets. Tetrahedron Lett. 2003, 44, 2807-2811. 

A variety of methods have been developed for the preparation of substituted benzimidazoles. Of these, one of the most traditional methods involves the condensation of an o-phenylenediamine with carboxylic acid or its derivatives. Subsequently, several improved protocols have been developed for the synthesis of benzimidazoles via the condensation of o-phenylenediamines with aldehydes in the presence of acid catalysts under various reaction conditions. However, many of these methods suffer from certain drawbacks, including longer reaction times, unsatisfactory yields, harsh reaction conditions, expensive reagents, tedious work-up procedures, co-occurrence of several side reactions, and poor selectivity. Bismuth triflate provides a handy alternative to the conventional methods. It catalyzes the reaction of mono- and disubstituted aryl 1,2-diamines with aromatic aldehydes bearing either electron-rich or electron-deficient substituents on the aromatic ring in the presence of Bi(OTf)3 (10 mol%) in water, resulting in the formation of benzimidazole [119] (Fig. 29). Furthermore, the reaction also works well with heteroaromatic aldehydes. 

Fig. 29 Synthesis of benzimidazole derivative from aromatic 1,2-diamines...

Benzimidazoles and their derivatives possess varied pharmacological activities59 60 and have therefore been targets of intense synthetic efforts using both solution- and solid-phase methods. In one of the pioneering studies on the assembly of benzofused heterocycles via SvAr reactions of o-fluoro-ni-troarenes, Phillips and Wei reported a solid-phase synthesis of benzimidazoles from 3-fluoro-4-nitrophenol, amines, and ethyl benzimidates (Scheme 13).61... 

Brain, C.T. and Steer, J.T., An improved procedure for the synthesis of benzimidazoles, using palladium-catalysed aryl-animation reaction chemistry,. Org. Chem., 2003,68, 6814-6816. 

As part of an efficient, facile and practical liquid-phase combinatorial synthesis of benzimidazoles under microwave irradiation, the reduction of a polymer bound o -nitroaniline with zinc metal in methanol was completed in a very short time (2 min)61 (Scheme 4.33). However, no detailed reaction conditions were given. 

Scheme 20 Synthesis of benzimidazoles using soluble PEG matrix...

Orthophenylene diamine is the starting point fbr the synthesis of benzimidazoles. 

Syntheses of perimidine 109 and naphtho[l,8-<7, ]triazine 110 derivatives usually start from 1,8-diaminonaphthalene by procedures which are quite similar to the synthesis of benzimidazoles and benzotriazoles from 1,2-diaminobenzene <1995AQ151>. For example, 2-alkyl and 2-arylperimi-dines 112 can be readily obtained in good yield by heating carboxylic acids with 1,8-naphthalenediamine 111 under microwave conditions (Scheme 54) <2005ASJ2411>. 

Although deprotonation of NHC salts have proven to be an efficient synthetic route, the basic reaction conditions can prove incompatible with certain complex synthesis in a one-pot procedure. Thus, other synthetic strategies to generate free carbene have been developed. Khun reported the synthesis of imidazol-2-ylidenes bearing a small alkyl group on the NHC backbone by potassium reduction of the corresponding thiones (10) (equation 5). This method has also been applied in the synthesis of benzimidazole derivatives, by reduction of the corresponding sulfones with Na/K alloy at room temperature. Synthesis of unsymmetrically substituted... 

Several different methods of synthesis of benzimidazoles have been reported. Intramolecular aryl guanidinylation of aryl bromides 103 with copper- and palladium-catalyzed methods led to... 

Cheng-Ting et al. [13] developed a simple and efficient method for the synthesis of benzimidazole linked quinoxalinones (i) on soluble polymer support using microwave conditions. The key steps involved in the implemented linear synthesis are the acid catalyzed condensation of 4-fluoro-3-nitrobenzoic acid with polymer... 

Xu and Xong [28] developed a microwave-assisted tracer rapid synthesis of benzimidazoles (xxi) on a polymer support. The arylation of benzylammonia, followed by treatment with N-chlorosulfonyl isocyanate and subsequent hydrolysis gave primary ureas. The Pd-catalysed cyclization of resin bound primary ureas followed by cleavage with TFA-H2O yielded the desired product in good yield and high purities. 

Under this heading fall some approaches to the synthesis of benzimidazole A-oxides which are formed when -nitro- or -nitrosoanilines react with aldehydes. Undoubtedly these reactions involve cyclization of an initially formed... 

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