Robust route for carbonyl-olefin metathesis

When organic chemists want to construct six-membered carbon rings, their go-to method is that old stalwart, the Diels-Alder reaction. But when they want to make five-membered rings, the route is less obvious.

Chemists at the University of Michigan, Ann Arbor, now report a carbonyl-olefin ring-closing metathesis reaction catalyzed by iron that creates such pentagonal structures with ease.

The reaction, says chemistry professor Corinna S. Schindler, who spearheaded the work, has the potential to become a classic reaction in the organic chemist’s repertoire. “It’s easy to do. You don’t need fancy reagents. You can do it in air,” she says. Also the transformation can produce a wide variety of five-membered, and even some six-membered, rings.

Although carbonyl-olefin metathesis reactions—in which a CO bond and a CC bond switch bonding partners to make a new carbonyl and a new olefin—have been known for decades, most require stoichiometric amounts of transition metal reagents, which adds to the cost and environmental impact of the transformation. The new reaction developed by Schindler, along with Jacob R. Ludwig, Paul M. Zimmerman, and Joseph B. Gianino, requires only a catalytic amount of an inexpensive and abundant iron chloride catalyst (Nature 2016, DOI: 10.1038/nature17432). It also tolerates functional groups, such as amides and esters, and can even be used to construct rings that contain quaternary carbons—a challenging synthetic motif.

The researchers believe the reaction proceeds through an oxetane intermediate that’s coordinated to iron from the FeCl3 catalyst. To verify this metathesis mechanism, Zimmerman, a chemistry professor who specializes in computation, used a reaction discovery method he developed called ZStruct. “We theoretically investigated several thousand possible reaction paths,” he says. The analysis suggested the oxetane mechanism was the most likely because it had the lowest energy barrier of the bunch.

“This work represents a major development in the area of carbonyl-olefin metathesis,” comments Tristan H. Lambert, a chemist at Columbia University, who works on metathesis chemistry. “The Schindler group has taken a significant leap forward in demonstrating catalysis and ring-closing carbonyl-olefin metathesis on a much broader range of substrates than in previous work.”