Aryl-heteroaryl coupling via double C-H activation is a powerful transformation that avoids the installation of activating groups. A double C-H activation of privileged biological scaffolds, 2-coumarins and 2-pyrones, is reported. Despite the rich chemistry of these molecular frameworks, the yields are very good. Excellent regioselectivity was achieved on the pyrones. This methodology was applied to the synthesis of flemichapparin C in three steps. Isotope effect experiments were carried out, and a mechanism is proposed.
Direct arylation represents a favourable alternative to traditional cross‐coupling reactions and has found widespread use with simple aryls and robust heterocycles. Herein a direct arylation protocol has been optimised and applied to more delicate, privileged biological motifs. The intramolecular direct arylation of 2‐pyrones, 2‐coumarins, 2‐pyridones and 2‐quinolones occurs in very good to excellent yields using a Pd0 source and pivalic acid as a crucial additive. Preliminary mechanistic investigations were also carried out.
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.
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