• 10.1021/jo8014984
  • The Journal of Organic Chemistry
  • Volume 73
  • October 2008
  • pp 7841-7844

Slight adjustments will give more yields

Details


Summary:

This paper reports an efficient method for synthesising benzimidazoles through cascade reactions of o-haloacetoanilide derivatives with amidine hydrochlorides. 10 mol % CuBr was used as the catalyst and Cs2CO3 as the base. The reactions were carried out in DMSO solvent. The sequence of steps as pointed out by the authors is (i) coupling of o-haloacetoanilide derivatives with amidines, (ii) hydrolysis of the intermediates (amides), and (iii) intramolecular cyclization with the loss of NH3 to give 2-substituted 1H-benzimidazoles.

The Reactions of Interest:

Practical observations:

  • Applying the general procedure described for synthesis of 2-substituted benzimidazoles via cascade reactions of o-haloacetanilide derivatives with amidine hydrochlorides, decent yields were obtained. The lowest yield of 56% was obtained for entry 13 (Table 2) while the highest for entry 7 (88%).
  • The Table 1 for the identification of appropriate catalyst for synthesis of 2-Propyl-1H-benzimidazole (3b) and subsequently, for all entries in Table 1 and Table 2 seems to overlook the fact that copper compounds produce the 1,2-disubstituted benzimidazoles easily from methanol solutions. The one-pot two-step coupling of o-haloacetanilides, amidine hydrochlorides, and aryl iodides reported in Table 3 were found to be proceeding at room temperature in methanolic solutions.

Recommendations:

  • I would recommend using methanol as a solvent for the direct synthesis of 1,2-disubstituted benzimidazoles as it is easy to handle and the reaction products are easily separable.
  • I used copper nitrate in place of CuBr & found the results to be reproducible at room temperature. So, I would recommend it.


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