Intramolecular Direct Arylation of 3-Halo-2-pyrones and 2-Coumarins

Direct arylation represents a favorable alternative to traditional cross-coupling and has found widespread use with simple aryls and robust heterocycles. Herein a direct arylation protocol has been optimized and applied to 2-pyrones, which are delicate and privileged biological motifs. Regioselective halogenation at the 3-position allows intramolecular coupling by activation of a pyrone C-Br or C-Cl bond and a phenoxy C-H bond. Importantly, electron-poor phenoxy substrates also worked well. The methodology was extended to 2-coumarins and applied to the synthesis of flemichapparin C and a novel analogue. Deuterium isotope effects, typical of a concerted metalation-deprotonation (CMD) mechanism, were observed in the case of a bromopyrone, but a highly unusual, inverse kinetic isotope effect was evident using a chlorocoumarin, implying that a different mechanism is operating.