Dumping directing groups means synthesis shortcut

Installing directing groups, tiny signposts that tell a functional group where to attach to a molecule, is time consuming, but usually necessary. Ming Joo Koh and colleagues at the National University of Singapore, together with researchers at the University of Maryland, have figured out a way to make new carbon-carbon bonds without this extra step. Using a nickel catalyst with a bulky carbene as a ligand, they were able to add two types of carbon functional groups across alkenes, while controlling where each new carbon group ended up (Nat. Chem. 2021, DOI: 10.1038/s41557-021-00836-6). This new procedure can potentially shorten syntheses of organic compounds, saving time and money. Koh’s team’s catalyst can aid in adding a variety of functional groups regioselectively across unactivated alkenes. Unactivated means the alkene doesn’t have substituents pulling the bond’s electrons one way or the other, so both carbons in the double bond look similar to incoming functional groups. That’s why chemists have needed to use directing groups, Koh explains. “But then you have to remove them at the end of the day, or transform them to something else,” he says. “So now we can just use any alkene we desire to do the reaction directly.”

The group incorporated an N-heterocyclic carbene to the Ni catalyst, which is key in two ways. First, the carbene drives an efficient C-Ni addition across the alkene. “Second, because it is staggeringly large,” Koh says, it forces the Ni catalyst to bind the alkene so that the toluol group adds first (shown in red), followed by the phenyl group (shown in black). The group made over 50 compounds, by starting with a variety of alkenes, including ones with aromatic and aliphatic groups as well as alkenes with biologically active compounds obtained from a Vitamin E derivative and the lipid drug gemfibrozil.

Koh thinks the concept will work for other types of alkene addition reactions and will be important for chemists producing drug-like compounds and building blocks, “because we can generate molecular complexity in a much faster way.”