Palladium-catalyzed cross-coupling of alcohols with olefins by positional tuning of a counteranion

Transition metal–catalyzed cross-couplings have great potential to furnish complex ethers; however, challenges in the C(sp3)–O functionalization step have precluded general methods. Here, we describe computationally guided transition metal–ligand design that positions a hydrogen-bond acceptor anion at the reactive site to promote functionalization. A general cross-coupling of primary, secondary, and tertiary aliphatic alcohols with terminal olefins to furnish gt;130 ethers is achieved. The mild conditions tolerate functionality that is prone to substitution, elimination, and epimerization and achieve site selectivity in polyol settings. Mechanistic studies support the hypothesis that the ligand’s geometry and electronics direct positioning of the phosphate anion at the π-allyl-palladium terminus, facilitating the phosphate’s hydrogen-bond acceptor role toward the alcohol. Ligand-directed counteranion positioning in cationic transition metal catalysis has the potential to be a general strategy for promoting challenging bimolecular reactivity. Chemists still frequently forge the carbon-oxygen bonds in ethers using a nucleophilic displacement reaction dating back to Williamson’s work in the mid-19th century. A major drawback to this reaction is that it is largely restricted to unhindered carbon centers. Kaster et al. report a broadly versatile alternative involving palladium-catalyzed oxidative coupling of olefins with alcohols. Simulations helped to optimize the ligand design to best orient the alcohol for reaction through hydrogen bonding to a phosphate counterion. —Jake S. Yeston