Sustainable methine sources for the synthesis of heterocycles under metal- and peroxide-free conditions

Abstract

Alcohols and ethers were identified as sustainable methine sources for synthesizing quinazolinone and benzimidazole derivatives using a combination of TsOH·H₂O/O₂ and appropriate bis-nucleophiles for the first time. Deuterium labeling studies clearly proved that the C₂ hydrogen of the synthesized heterocycles came from the methine source. These unique reaction conditions were successfully applied to the synthesis of echinozolinone (2e′), 2f′ (a common precursor of rutaecarpine and (±) evodiamine), and dimedazole (6d). Notable features of this method include its low toxicity, use of commercial feedstocks as substrates, low cost, broad functional group tolerance and suitability for a wide range of bis-nucleophilic starting materials.