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

Abstract

A novel Cu-catalyzed tandem C−N and C−C bondformation 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 (NH 2 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 O 2 (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 bondforming coupling between aryl boron species and the nitrile group) followed by tandem intramolecular C−C bond formation has been proposed.

Using Quinolin-4-Ones as Convenient Common Precursors for a Metal-Free Total Synthesis of Both Dubamine and Graveoline Alkaloids and Diverse Structural Analogues

“…Additionally, Graveoline 1 has been identified as a stimulant of the CNS [15,16] and as phytotoxic [17], while Dubamine 2 has displayed antitumor activity, as shown in some previous studies [18]. Some synthetic approaches have previously been reported to construct the structures of alkaloids 1 [18][19][20][21][22][23][24][25][26] and 2 [11,[27][28][29][30][31][32][33][34][35][36]. Thus, Graveoline 1 and its derivatives were obtained through different strategies like the treatment of Dubamine 2 with a methylating agent and subsequent oxidation (Scheme 1a) [18].…”