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Ketones Couple With Olefins In Alkylation Advance

Organic Synthesis: Bifunctional catalyst weds reluctant partners

by Bethany Halford
July 3, 2014 | A version of this story appeared in Volume 92, Issue 27

A bifunctional catalyst weds ketones to olefins in a by-product-free strategy.
A reaction scheme showing a bifunctional catalyst being used to merge ketones with olefins.
A bifunctional catalyst weds ketones to olefins in a by-product-free strategy.

Matchmaking between ketones and olefins has never been easy. Although ketones readily pair up with many reagents, thanks to their ability to deprotonate and form nucleophilic enolates, olefins typically rebuff advances from such nucleophilic suitors. Now, chemists at the University of Texas, Austin, have found a catalyst capable of forging a carbon-carbon bond between this unlikely pair.

“Ketones are very common compounds. Olefins are even more common—they’re readily available feedstocks,” says Guangbin Dong, the chemistry professor who spearheaded the work. “We thought if we could find a good way to couple these two together, it would be very useful.”

Dong and postdoc Fanyang Mo determined that the ideal matchmaker would be a bifunctional catalyst that contains both a secondary amine, 7-azaindoline, and a low-valent rhodium complex (Science 2014, DOI: 10.1126/science.1254465). The amine part of the catalyst activates the ketone by forming an enamine, which is amenable to oxidative addition by the rhodium part of the catalyst. The resulting rhodium hydride coordinates with the olefin, followed by migratory insertion and reductive elimination to generate an alkylated enamine. Hydrolysis produces an α-alkylated ketone and regenerates the catalyst.

Dong notes that the reaction has several advantages over traditional ketone alkylations, which typically are done by deprotonating the α-carbon of a ketone and using the resulting enolate to attack an alkyl halide. For example, he says, the new reaction tolerates a broad range of functional groups and is regioselective for alkylating the less hindered side of the ketone.

“This is a very cool piece of chemistry,” comments David W. C. MacMillan, an organic synthesis expert at Princeton University. “The capacity to use simple olefins as alkylating reagents for carbonyls is a transformation that is appreciated by the community to be valuable. Although a number of other groups have successfully demonstrated the use of olefins to perform the equivalent of enolate alkylation, this new variant is unique and could find broad application.”

Dong hopes to optimize the catalyst so that he might replace rhodium with a less expensive transition metal.



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