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14-year effort culminates in reaction that activates methylenes

Technique uses metal insertion to derivatize methylene C–H bonds catalytically and enantioselectively

by Stu Borman
September 5, 2016 | A version of this story appeared in Volume 94, Issue 35

Reaction scheme shows how a Pd catalyst and a ligand are used to activate one of two methylene C–H bonds to form a chiral aryl derivative.
Yu and coworkers use a Pd catalyst and a ligand to activate one of two methylene C–H bonds to form chiral aryl derivatives.

The ability to activate specific C–H bonds in organic compounds so they can be converted into C–C bonds or other derivatives has been a longtime goal in synthetic organic chemistry.

Over the past few decades, chemists have learned to activate several types of C–H bonds by inserting metal atoms into them. But the ability to activate the most common class of C–H bonds, those in methylene (CH2) groups, and to convert them into chiral centers has been a largely unsolved problem.

Jin-Quan Yu of Scripps Research Institute California and coworkers have now developed what could become a textbook reaction—the first that uses metal insertion to derivatize methylene C–H bonds catalytically and enantioselectively. It converts methylenes that are two carbon atoms away from amide and carboxyl groups into chiral centers (Science 2016, DOI: 10.1126/science.aaf4434).

Activating these so-called β-methylenes enantioselectively “was my first independent project, started in 2002, back in Cambridge University,” Yu says. “It took 14 years to finally achieve this goal.”

“Yu’s trailblazing group has managed to bring to reality what might have been considered seemingly impossible,” comments Erick Carreira, an expert on asymmetric synthesis at the Swiss Federal Institute of Technology (ETH), Zurich. “It represents a giant leap for the field that opens new vistas for the synthesis of optically active building blocks.”

Yu believes the approach can be extended to other classes of substrates besides those containing amides and carboxyls. A group at Bristol-Myers Squibb that he collaborates with is already using the new reaction to synthesize drug candidates.

Conjugate addition, a classical reaction that does not involve metal insertion, can also create chiral centers adjacent to carbonyl groups, but it requires that an alkene group be available or preinstalled at the β-position, and that is not always possible or easy to arrange.

In the new reaction, palladium and a simple bidentate ligand—one that coordinates with the substrate in two different ways—cause Pd to insert into one of the C–H bonds of a β-methylene. Chemists can then substitute aryl groups for the metal. The reactions have good yields and produce high ratios of products with specific chirality.

Although the ligand looks simple, engineering its structure so it worked just right took a considerable amount of effort and was key to developing the new reaction. Kendall N. Houk of the University of California, Los Angeles, and coworkers helped that effort by developing a computational model of ligand-substrate interactions.

This article has been translated into Chinese and can be found here.

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