Benzimidazoles, quaternization

Here, we envisage building the benzimidazole scaffold directly onto the linker and, by analogy with a regular tertiary amine synthesis on the REM linker, we can quaternize the resin-bound benzimidazole compounds by reaction with reactive bromides. The quaternary salt can then be liberated by a Hofmann elimination reaction upon treatment with base. 

To further elucidate this point, we were able to remove from the resin about four-fifths of the quaternized target compound that had been synthesized (this was judged using the double-linker approach mentioned above). The variability in the actual amount of target material synthesized on (and competent to be released from) the resin was dictated by the reaction (incompatibility of the three monomers comprising each individual benzimidazole compound. 

MO calculations predict that in unsubstituted imidazoles and benzimidazoles the 2-position should be the most susceptible to nucleophilic attack and quaternization of the heterocycle should enhance this orientation. The presence of electron-withdrawing groups elsewhere in the molecule can modify this preferred site of attack. 

N-Aryl substituents usually depress the basic properties of the imidazole or benzimidazole nucleus. The effects of substituents on the aryl group are evident from the data listed in Table 7 which also lists rate constants for quaternization with iodoethane, a reaction which is dependent upon the nucleophilic character of the pyridine-type nitrogen (70CHE194). A phenyl group withdraws electrons from the imidazole ring, but does so rather weakly. The p value of +0.753 for the protonation process is in accord with weak electron transfer from the phenyl substituent to the basic nitrogen. 

A study of the C NMR spectra of 2-(2 pyridyl)benzimidazoles and their quaternary salts has shown that tautomerism is blocked in the quaternized species, and that hydrogen bonding between the benzimidazole NH and the pyridine N can also render the benzene ring carbons non-equivalent... 

Aminobenzimidazoles, quaternized with l-bromoprop-2-yne and converted with ammonia into the 2-imines, cyclize on heating with a strong base the quaternary salt behaves similarly. The enzyme catalase promotes the cyclization of the amino-alkene (12.5) to a benzimidazole under comparatively mild conditions (review [B-53]). 

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