Novel Process for the Synthesis of Class I Antiarrhythmic Agent (±)-Cibenzoline and Its Analogs

Abstract

Synthesis of (±)-cibenzoline and its analogs has been achieved by a simple sequence of reactions. The diaryl cyanoolefin intermediate 3 could be prepared by Knoevenagel condensation of benzophenone with ethylcyanoacetate to form the tetra-substituted olefin intermediate 2 followed by Krapcho deethoxycarbonylation or from β-hydroxynitrile intermediate 2′ followed by the elimination of hydroxyl group respectively. The 2,2-diphenylcyclopropanecarbonitrile 4 was synthesized from intermediate 3 by cyclopropanation, which was converted to (±)-2-(2,2-diphenylcyclopropyl)-2-imidazoline 5 by reaction with ethylenediamine in the presence of a catalytic amount of sulfur. Moreover, the obtained 2-imidazolines were smoothly oxidized to the corresponding imidazoles 6 in good to moderate yields.

Keywords:

• Benzophenone
• cibenzoline
• cyclopropanation
• diaryl cyanoolefin

ACKNOWLEDGMENT

We acknowledge the Director of National Chemical Laboratory for in-house project funding. A. R. G. thanks Council of Scientific and Industrial Research, New Delhi, for the award of a senior research fellowship.