Benzimidazole library reactions

Among the multistep solution libraries prepared, Cheng et al. [17,18] reported a dipeptide mimetic template-based 78-member library prepared via four synthetic steps and purified with an excellent protocol based on acid-base extractions. Thomas et al. [19] presented a > 1000-member benzimidazole library prepared via three steps including a 2-ethoxy-1-ethoxycarbonyl- 1,2-dihydro-quinoline (EEDQ)-assisted cyclization. Boger et al. reported two 600-member C -symmetrical [20,21] and unsymmetrical [21] libraries prepared via four-five synthetic steps, based on iminodiacetic acid as a scaffold and using the olefin metathesis reaction. 

The principle of the split-split method is illustrated by an example of a three combinatorial step benzimidazole library that uses 24 amines, 12 o-fluoro-nitrobenzenes, and 48 acids, producing a library of 13,824 compounds (Scheme 1) (10), The first step can be performed in 24 La Marast reaction vessels, each containing 12 g of resin. For the second combinatorial step, resin from each La Marast reaction vessel is split into 24 syringes and the Domino Block synthesizer is used to handle the syringes. The last combinatorial step is performed in wells of 96-well plates, with the resin from each syringe being split into two rows (24 wells) of a plate. 

As in the case of benzimidazole, a parallel synthesis of benzoxazoles was described. The authors report that mixing directly differently substituted o-amino phenols 193 with acylating agents 194 and heating at 200 °C for 10-15 min under microwave irradiation, a collection of benzoxazoles 195 was obtained (Scheme 70). With this reaction, a 48-member library of benzoxazoles with different substituents on the aromatic rings was obtained [125]. 

Benzimidazoles are an interesting class of heterocycles which are incorporated into several therapeutic agents. There are several standard preparations of benzimidazoles, but many of them require high temperatures and strong acidic reaction conditions. In general, when adapting a solution-phase methodology into a solid-phase approach, very drastic conditions are to be avoided due to potential problems associated with the stability of the solid support. These criteria were taken into account by Philips and Wei in their approach towards the solid-phase synthesis of a benz-imidazole library. ... 

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