Phillips-Ladenburg benzimidazole synthesis

What is Phillips-Ladenburg benzimidazole synthesis?

Although benzimidazole was first prepared by Hobrecker in 1872, it was Ladenburg who extensively explored the preparation of its derivatives through the condensation between ortho-amino aniline and carbonyl compounds (aldehydes and ketones) in 1875.

Phillips-Ladenburg benzimidazole synthesis - general reaction scheme - Ladenburg method - Phillips method - Phillips modification - Phillips-Ladenburg reaction
Phillips-Ladenburg benzimidazole synthesis
Phillips-Ladenburg benzimidazole synthesis - general reaction scheme - Ladenburg method - Phillips method - Phillips modification - Phillips-Ladenburg reaction
Phillips-Ladenburg benzimidazole synthesis

R = alkyl, aryl (see list of acronyms)

Later on, Phillips further extended Ladenburg’s method by using acetic acid to produce different carboxylic acids in the presence of dilute mineral acid. Therefore, the process of preparing benzimidazole from ortho-amino aniline is commonly known as the Ladenburg method, Phillips method, Phillips modification, or the Phillips-Ladenburg reaction.

The condensation between ortho-amino aniline and carbonyl compounds is believed to involve the formation of a Schiff base intermediate, whereas the condensation between ortho-amino aniline and acid proceeds via the N,N-diacyl and monoacyl intermediate. This method is generally suitable for aliphatic acids and can also be used for aromatic acids if the condensations are carried out above 180 ºC in sealed reaction vessels.

References

  • Hobrecker, F., Ber., 1872, 5, 920
  • Ladenburg, A., Ber., 1875, 8, 677
  • Ladenburg, A., Ber., 1877, 10, 1123
  • Ladenburg, A., Ber., 1878, 11, 590
  • Ladenburg, A., Ber., 1878, 11, 1648
  • Ladenburg, A. and Rügheimer, L., Ber., 1879, 12, 951
  • Phillips, M. A., J. Chem. Soc., 1928, 172
  • Phillips, M. A., J. Chem. Soc., 1928, 2395
  • Phillips, M. A., J. Chem. Soc., 1928, 3134
  • Phillips, M. A., J. Chem. Soc., 1929, 2820
  • Phillips, M. A., J. Chem. Soc., 1930, 1409
  • Phillips, M. A., J. Chem. Soc., 1930, 1416
  • Phillips, M. A., J. Chem. Soc., 1931, 1143
  • Phillips, M. A., J. Chem. Soc., 1931, 1151
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