Combining Isocyanides with Carbon Dioxide in Palladium-Catalyzed Heterocycle Synthesis: N3-Substituted Quinazoline-2,4(1H,3H)-diones via a Three-Component Reaction

We report a Pd-catalyzed three-component reaction of 2-bromoanilines, carbon dioxide, and isocyanides. The combingtion of these two readily available C-1-reactants, featuring a huge difference in kinetic and thermodynamic stability, is hitherto unprecedented in transition-metal catalysis. With this one-pot three-component reaction, N3-substituted quinazoline-2,4(1H,3H)diones are obtained in moderate to high yields in a completely regioand chemoselective manner. Our approach easily allows variation of the arene and N3-substitution pattern of the desired heterocycle. The formal synthesis of different APIs illustrates its practical applicability. In addition, the methodology also allows for a convenient and selective C-13-labeling through the use of (CO2)-C-13. This is illustrated for [2-C-13]-2,4-dichloro-6,7-dimethoxyquinazoline synthesis, a key intermediate for several APIs.