Benzimidazole synthesis

The scope of the silver cyanide-catalyzed reaction of difunctional nucleophiles with alkyl isocyanides has been described in the earlier section on imidazoles an example of the use of this simple approach in benzimidazole synthesis is illustrated in Scheme 105.169... 

Furthermore, multicomponent reactions can also be performed under fluorous-phase conditions, as shown for the Ugi four-component reaction [96], To improve the efficiency of a recently reported Ugi/de-Boc/cyclization strategy, Zhang and Tempest introduced a fluorous Boc group for amine protection and carried out the Ugi multicomponent condensation under microwave irradiation (Scheme 7.84). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid/tet-rahydrofuran under microwave irradiation. The resulting quinoxalinones were purified by a second F-SPE to furnish the products in excellent purity. This methodology was also applied in a benzimidazole synthesis, employing benzoic acid as a substrate. 

Grimmett, M. R. Imidazole and Benzimidazole Synthesis Academic Press London, 1997. 

A facile method for the synthesis of N-substituted 2-benzimidazolinones 142 has been developed by Romero et al. (96TL2361) using A-substituted ureas 139, which are cyclized to 142 with IBTA as an oxidant. The reaction probably proceeds via intermediates 140 and 141. Besides the iV-alkyl or aryl substituent, presence of the 1-methoxy group is necessary for the success of this cyclization. Another benzimidazoles synthesis involves cycli-zation of N-phenyl-C-alkyl formimidamides with IBD [95JCS(P1)615]... 

An alternative strategy towards benzimidazole synthesis relies on the palladium-catalysed cyclisation of (2-bromophenyl)amidines. This chemistry has been reported to take place under aqueous reaction conditions, in the presence of sodium hydroxide in sealed microwave vials. The products were isolated by a catch and release method using a strongly acidic ion exchange resin, thereby avoiding conventional chromatographic purification (Scheme 3.14)23. Selectively, N-functionalised benzimidazoles were conveniently prepared by this method. 

M.R. Grimmett, Imidazole and Benzimidazole Synthesis, Academic Press, San Diego, (1997)... 

X = leaving group, eg. Cl- see benzimidazole synthesis. Chapter 1 R x end isoquinoline synthesis, Chapter 6)... 

Probably the best method for synthesizing 2-substituted benzimidazoles makes use of the cyclodehydration reaction between a carboxylic acid or derivative and 1,2-arylenediamines under acidic conditions (81HC6). Both 2-(pyridyl)-l//-benzimidazoles 72, 73 and l-alkyl-(l//-benzimidazol-2-yOpyridinium salts 74 shown in Eq.(l 1) have been efficiently synthesized by Hein s benzimidazole synthesis (92S395, 92UP1 93CPB614) [Eq.(16) and (17)]. 

Several quaternary salts of type 39, 43-46 have been prepared either by Hein s benzimidazole synthesis [see Eqs.(17) and (18)] or using an acylchloride, instead of the carboxylic acid or derivative, as shown in Eq.(19) (Table IV). 

Syntheses of various types of quaternary salts 2 containing a 2-benzimidazole ring are summarized in Table IV the best results have been achieved using the modified protocol of Hein s benzimidazole synthesis. 

In contrast to the pyrazoles, there is no single method of wide application for the synthesis of imidazoles, although the use of o-phenylenediamine and related compounds in benzimidazole synthesis might merit such a description. The common synthetic methods are divided into those which build up the imidazole ring from largely acyclic precursors, and transformations of other heterocyclic species. Ring-synthetic procedures can entail the formation of between one and four bonds. 

Benzimidazole synthesis has been reviewed in detail in Preston s volumes [7J which contain a wealth of tabular material. Other review material has been less heavily oriented towards synthesis [1-6, 8-15J. 

Synthetic procedures which fall under this heading apply to both imidazoles and benzimidazoles, and some are closely related to those methods which involve formation of both the 1,2 and 2,3 bonds. This section should therefore be read closely with Section 3.1.2, particularly with regard to benzimidazole synthesis. 

One of the more common methods of benzimidazole synthesis is that which cyclizes o-arylenediamines in which one of the amino groups has been acylated or thioacylated. The starting material must be functionalized in such a way that an aromatic product can be formed when cyclization takes place. It is more common with analogous aliphatic diamine derivatives for reduced imidazoles to be formed, but there are a number of synthetically useful processes which cyclize monoacylated alkylenediamines. One example involves niono-acylated diaminomaleonitrile (see below), which can be dehydrated to form imidazoles fl5]. 

This is an uncommon synthetic approach to imidazoles, being largely confined to examples in which an active methylene group cyclizcs on to a nitrile carbon. There are, naturally, no such examples of benzimidazole synthesis. 

A recent, efficient, one-pot benzimidazole synthesis treats an o-nitroaniline with an allyl, benzyl or alkyl halide in the presence of sodium hydride as a base. The products are l-alkyloxy-2-alkyl-, l-benzyloxy-2-aryl- and l-al]yloxy-2-vinylbenzimidazoles in 75-98% yields. This novel sequence combines jV-alkylation, helerocyclization and 0-alkylations in the reaction vessel [137, 138]. 

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