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C-H Activation

C–H activation template opens door to less-accessible carbons

Multiple catalysts do complex chemistry to give a simple product

by Leigh Krietsch Boerner
March 3, 2020 | A version of this story appeared in Volume 98, Issue 9


The reaction of a heterocycle with an aryl iodide with a palladium catalyst, an amino acid ligand, a template, and a norbornene gives the product arylated at the C6 position

C–H bonds, activate! Reactions that allow chemists to cleave off hydrogen and replace it with something functional are some of the most important in organic chemistry. Chemists use C–H activation to systematically build molecules, including drugs from simple starting materials, such as heterocycles. Now researchers have made these reactions even more useful, making it possible to selectively activate C–H bonds at multiple positions on a heterocycle—even if those bonds are not electron rich or close to a functional group.

Jin-Quan Yu and coworkers at Scripps Research in California and University of California, Los Angeles have found a way to selectively activate C–H bonds on the electron-poor, previously inaccessible side of a heterocycle (Nat. Chem. 2020, DOI: 10.1038/S41557-020-0424-5). Their method, which uses the cooperation of a directing template, a transient mediator, and an amino acid ligand, has yields of up to 93%, and is applicable to quinolines, isoquinolines, and phenylpropanoic acid derivatives.

Activating C–H bonds that are far away from a functional group, or electron poor, has long been challenging—especially if several of those C–H bonds are electronically similar to each other, Yu says. “We previously developed a U-shaped template that can target these remote C–H bonds,” he says. But if two C–H bonds are both close together and relatively inaccessible, “then you have a big problem,” he says. “How do you tell them apart?” The answer is to use a set of catalysts and other reactants that can pin the heterocycle in place, exposing the group of interest, activating the C–H bond, and swapping in a substituent.

The reaction involves multiple steps. The group starts with a palladium pyridine-2,6-dicarboxamide compound, a “template” catalyst that holds the heterocycle in place and allows the second Pd compound to bind to the C5 position (see scheme). Then, one after another, three more actors—a second Pd compound, norbornene, and aryl iodide—insert into the C5 and C6 bonds. Finally, the researchers release the resulting C6 arylated heterocycle.

Because of the precision targeting enabled by this complex reaction, Yu likens it to molecular editing. He hopes it will be used by medicinal and biological chemists, who often must use multistep syntheses to make complex natural products and drugs. Yu says this kind of highly targeted approach might be particularly useful when chemists want to functionalize their compound—for example, to create a new binding site—without risking changes to its biological activity.

“This will be very useful in small-scale, late-stage functionalization applications that will accelerate access to potential biologically active molecules,” says Matthew Gaunt, an organic chemist at the University of Cambridge. “It’s a really nice example of synthetic design.”



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