One-Pot Synthesis of Chromone-2-carboxylate Scaffold: An Important Pharmacophore with Diverse Biological Properties

Abstract

Chromone-2-carboxylate scaffold is growing as an important pharmacophore in medicinal chemistry with diverse biological properties. We have developed a facile one-pot transformation of 2-fluoroacetophenone directly to chromone-2-carboxylate scaffold in a single step via a tandem C–C and C–O bond formation. The majority of the previously reported medicinal chemistry synthetic protocols primarily used only one procedure which follows a two-step strategy that needs to start with “2-hydroxyacetophenone”. Our methodology not only serves as an alternative one-pot methodology but also allows chemists to start from different raw materials (2-fluoroacetophenone) other than the traditional ortho-hydroxyacetophenone for maintaining the regioselectivity in the cyclization step. We further demonstrated the utility of our protocol by successfully extending the application to the synthesis of two natural products (Halenic acids A and B), various bis-chromones including drug molecules (DSCG, cromoglicic acid), and potent anti-Alzheimer compound (F-cromolyn). This methodology can serve as a promising alternative tool for finding new bioactive chromones with diverse modifications due to the opportunity to use new raw materials in the synthesis of chromones.