Chemistry of Nitroquinolones and Synthetic Application to Unnatural 1-Methyl-2-quinolone Derivatives

Abstract: The 1-methyl-2-quinolone (MeQone) framework is often found in alkaloids and recently attention was drawn to unnatural MeQone derivatives with the aim of finding new biologically active compounds, however, low reactivity of the MeQone framework prevents the syntheses of versatile derivatives. A nitro group is one of the useful activating groups for this framework that enables a concise chemical transformation. Among nitroquinolones, 1-methyl-3,6,8-trinitro-2-quinolone (TNQ) exhibits unusual reactivity favoring region-selective cine-substitutions that afford 4-substituted 1-methyl-6,8-dinitro-2-quinolones upon treatment with nucleophilic reagents. Contrary to this, 1-methyl-3,6-dinitro-2-quinolone (3,6-DNQ) does not undergo any reaction under the same conditions. The unusual reactivity of TNQ is caused by steric repulsion between the methyl group at the 1-position and the nitro group at the 8-position, which distorts the MeQone framework. As a result, the pyridone ring of TNQ loses aromaticity and acts rather as an activated nitroalkene. Indeed, the pyridone moiety of TNQ undergoes cycloaddition with electron-rich alkenes or dienes under mild conditions, whereby a new fused ring is constructed on the [c]-face of the MeQone. Consequently, TNQ can be used as a new scaffold leading to versatile unnatural MeQone derivatives.