Cu-Catalyzed Tandem C-N and C-C Bond Formation Leading to 4(1H)-Quinolones: A Scaffold with Diverse Biological Properties from Totally New Raw Materials in a Single Step.

A novel Cu-catalyzed tandem C-N and C-C bond-formation reaction has been developed to furnish 2-substituted-4-(1H)-quinolones. 4-(1H)-quinolones play an important role in medicinal chemistry. Many 2-aryl(alkyl)-4(1H)-quinolones are found to exhibit diverse biological properties. While traditional methods have inherent issues [like starting materials with incompatible functional groups (NH2 and keto groups)], many modern methods either require activated starting materials (like Ynones) or employ expensive metals (Pd, Rh, Au, etc.) involving carbonylation using CO or metal complexes. Our protocol presents an environmentally friendly one-step method for the construction of these useful 2-substituted-4-(1H)-quinolones from easily available aryl boronic acid (or pinacolate ester) and nitriles as new raw materials, using a cheap Cu-catalyst and O2 (air) as a green oxidant. We further extended its application to the synthesis of various natural products, including the first formal total synthesis of punarnavine. A plausible mechanism involving an aryl nitrilium ion (formed due to the intermolecular C-N bond-forming coupling between aryl boron species and the nitrile group) followed by tandem intramolecular C-C bond formation has been proposed.

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

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.