Time and Temperature Dependent Palladium-Catalyzed Stereo- and Regioselective Alkoxy-arylation of Triple Bonds: Synthesis of ()/()-1,1-Disubstituted-3-(1-Phenylalkylidene)-1,3-dihydroisobenzofurans.

The development of synthetic strategies enabling the - and selective synthesis of organic molecules is indispensable in the pharmaceutical industry. This work describes a and selective synthesis of ()/()-1,1-disubstituted-3-(1-arylalkylidene)-1,3-dihydroisobenzofurans catalyzed by palladium. The DHIBFs are achieved from readily available aryl bromides and alkyne tertiary alcohols intermolecular aryl Heck coupling and intramolecular -cyclization of the suitably situated hydroxyl group. Significantly, it was demonstrated that a -isomer was formed as a substantial isomer at 80 °C for 6 h, whereas the stable -isomer was the predominant one at slightly vigorous conditions (100 °C for 12 h). In addition, careful observation has also led to the realization that this double isomerization from - to -isomer was triggered in the NMR tube itself in CDCl at room temperature. Significantly, this protocol, for the first time, enabled the synthesis of heavily substituted dihydroisobenzofurans, especially, bearing a tetra-substituted double bond.