Benzofurans are molecular motifs found in a wide variety of natural products and pharmaceutical compounds, such as dronedarone and amiodarone (antiarrhythmic), or naloxone (opioid antagonist). Due to the importance of benzofurans, multiple synthetic methods have been developed that focus on constructing the heterocyclic core. Among those, gold(I)-catalyzed cyclization of phenols onto alkynes has emerged as one of the leading methods of forming the fused bicyclic structure. Although robust, the general method is limited to 2-alkynyl aryl phenols (R-OH) and does not work well when gold(I)–NHC carbene complexes such as Au(IPr)OH are employed. Our previous work showed that 2-alkynyl thioanisoles (RSMe) readily undergo a Au(IPr)OH-catalyzed dealkylative cyclization to give benzothiophenes. More recently we showed that O-PMB derivatives (PMB = p-methoxybenzyl) can be employed in the same reaction although the transfer of the PMB group is not always selective which leads to a mixture of products. In this follow-up work, we show that the O-tetrahydropyran (ROTHP) derivatives of 2-alkynylaryl phenols undergo an efficient reaction catalyzed by Nolan’s gold dimer hydroxide catalyst. Cyclization followed by concomitant removal of the THP group gives the benzofuran heterocycle in high yields (up to 95%). Interestingly, under the same reaction conditions, free phenol is unreactive. To streamline substrate scope evaluation, we developed an qHNMR assay to determine the reaction yield. The details of reaction optimization and substrate scope survey will be presented.

Synthesis of benzofurans via Au(I)-catalyzed cyclization 2-alkynyl phenol acetals

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