Benzimidazole was discovered during research on vitamin B12. The benzimidazole nucleus was found to be a stable platform on which drugs could be developed.[3] Benzimidazole is produced bycondensation ofo-phenylenediamine withformic acid,[4] or the equivalenttrimethyl orthoformate:
C6H4(NH2)2 + HC(OCH3)3 → C6H4N(NH)CH + 3 CH3OH
2-Substituted derivatives are obtained when the condensation is conducted withaldehydes in place of formic acid, followed byoxidation.[5]
Benzimidazole derivatives are among the most frequently used ring systems forsmall molecule drugs listed by the United StatesFood and Drug Administration.[9] Many pharmaceutical agents belong to the benzimidazole class of compounds. For example:
^Walba, Harold; Isensee, Robert W. (1961). "Acidity Constants of Some Arylimidazoles and Their Cations".The Journal of Organic Chemistry.26 (8):2789–2791.doi:10.1021/jo01066a039.
^R. Jackstell; A. Frisch; M. Beller; D. Rottger; M. Malaun; B. Bildstein (2002). "Efficient telomerization of 1,3-butadiene with alcohols in the presence of in situ generated palladium(0)carbene complexes".Journal of Molecular Catalysis A: Chemical.185 (1–2):105–112.doi:10.1016/S1381-1169(02)00068-7.
^H. V. Huynh; J. H. H. Ho; T. C. Neo; L. L. Koh (2005). "Solvent-controlled selective synthesis of a trans-configured benzimidazoline-2-ylidene palladium(II) complex and investigations of its Heck-type catalytic activity".Journal of Organometallic Chemistry.690 (16):3854–3860.doi:10.1016/j.jorganchem.2005.04.053.
^Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J Med Chem 2014, 57, 5845.>
