Directing group lets chemists reach remote C–H bonds

Because of their ubiquity in organic compounds, C–H bonds have long tantalized chemists as synthetic handles. But these bonds are both relatively inert and virtually indistinguishable to reagents, synthetic challenges that have spawned an entire field of research known as C–H activation. One such strategy in this area, known since the 1970s, is to treat a heteroatom-containing molecule with a palladium catalyst, which hooks onto the heteroatom and the neighboring carbon atom to form a thermodynamically favored five-membered palladacycle. But this approach activates only C–H bonds in the β position, the second carbon away from the heteroatom. Now, researchers led by Jin-Quan Yu at Scripps Research have extended the reaction’s reach by one carbon (Nat. Chem. 2019, DOI: 10.1038/s41557-019-0245-6). Because C–H bonds defy the typical tools for controlling selectivity via metal insertion, such as tweaking a catalyst’s electronics or sterics, Yu says, the team turned to ring strain. They proposed that capping alcohol-containing substrates with an imine or pyridone directing group would favor the less-strained 6,5 bicyclic palladacycle over the 5,5 bicyclic intermediates. Using its directing group method, the team preferentially plucked off γ-C–H bonds to install a variety of aryl molecules (example shown). Directing groups were removed by standard hydrogenation or reduction. Now the researchers have their sights set on the seven-membered palladacycle.