Benzimidazole libraries

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. 

Thomas JB, Fall MJ, Cooper JB, Burgess JP, Carroll FI, Rapid in-plate generation of benzimidazole libraries and amide formation using EEDQ, Tetrahedron Lett., 38 5099-5102, 1997. 

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. 

We next explored the applications of liquid-phase synthesis of benzofused heterocycles from a common building block PEG-bound nitro-activated aryl fluoride (Fig. 8). In these synthetic strategies, we created multiple accesses to the structurally diverse core molecules based on a fundamental scaffold 10. We focused on the construction of a variety of benzimidazole libraries starting from a versatile synthon 4-fluoro-3-nitrobenzoic acid via liquid-phase nucleo-... 

In order to investigate the further application of immobilized 4-fluoro-3-nitro benzoic acid synthon, we expanded our methodology to prepare 1,2-disubstituted benzimidazoles 23-25. Figure 11 shows our detailed efforts toward the preparation of a benzimidazole library. To achieve this goal, one pot cyclization of PEG-bound diamine 12 with trimethylorthoformate in TEA/... 

The structures of six standards (and QC compounds) of a 1,2,5-trisubstituted benzimidazole library and a 4,5,6-trisubstituted pyrimidine library are shown in Figs. 1 and 2. 

Quantitative Anaiyses of QC Compounds in 1,2,3-Trisubstituted Benzimidazole Library... 

Determine the concentration of compounds by comparing the fluorine resonance area of the sample to the calibration curve of the standard. Fluorine NMR spectra of all the synthetic samples revealed one major fluorine resonance for TFA at -77.7 ppm. From F-qNMR data, it is clear that a significant amount of TFA is present in the 1,2,5-trisubstituted benzimidazole library. Make a second qualification library by incorporating a more thorough base washing procedure that reduces the amount of TFA carryover. 

A "traceless" solid-phase S5mthesis for the generation of benzimidazole library with diversity on tiie benzene moiety was developed by Huang et al. [25]. During the final step of the synthesis, a reactive carbon fragment is added, followed by stepwise cleavage and cyclization/elimination in solution (Scheme 4). 

Vourloumis et al. [31] have utilized Wang resins as well as Rink amide resins for the SPOS of benzimidazole libraries biased for RNA-targets. Their work was focused on creating two libraries. A, witir two points of diversity at... 

W. Huang, R.M. Scarborough, A new "traceless" solid-phase s)mthesis strategy synthesis of a benzimidazole library. Tetrahedron Lett. 40 (1999) 2665-2668. 

Carroll and co-workers [13] reported on the preparation of benzimidazole libraries from anilines and carboxylic acids using 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. 

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