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May 12, 2008
Volume 86, Number 19
p. 10

Organic synthesis

New Carbonyl Allylations

Reactions sidestep allyl-metal reagents, need for preliminary oxidation

Bethany Halford

IN AN EFFORT to build molecules via greener and less expensive processes, chemists at the University of Texas, Austin, have developed two new carbonyl allylation reactions (J. Am. Chem. Soc., DOI: 10.1021/ja802001b and 10.1021/ja801213x). Their novel approach eschews the need to use stoichiometric amounts of allyl-metal reagents in such reactions, and it enhances the versatility of such syntheses by making it possible to couple allyl moieties with aldehydes generated in situ from alcohols, something that couldn't be done before.

In an organic chemist's toolbox of carbon-carbon bond forming reactions, carbonyl allylation is a handy resource for constructing complex molecules. The transformation provides quick and easy access to homoallylic alcohols, which are important intermediates en route to medicinally relevant compounds such as polyketides.

The new carbonyl allylation methods, invented by chemistry professor Michael J. Krische and colleagues, employ allyl acetate or 1,3-dienes as surrogates for allyl-metal reagents. In the presence of an iridium or a ruthenium catalyst, respectively, these reagents will combine with primary alcohols to generate homoallylic alcohols. In the case of the iridium-catalyzed reaction, the process is enantioselective.

Previous examples of carbonyl allylation worked only with aldehydes, but Krische's method works with both aldehydes and alcohols. That's because the transformations capitalize on transfer hydrogenative coupling chemistry—a redox process in which a hydrogenation reaction instigates carbon-carbon bond formation. In the new reactions, an alcohol supplies the hydrogen. When the target of allylation is a primary alcohol, the catalyst oxidizes it to an aldehyde, which then undergoes carbon-carbon bond formation. When the target is already an aldehyde, an alcohol must be added to the reaction to serve as the hydrogen source; isopropanol is ideal because its oxidation by the reaction system yields a ketone, which cannot form a carbon-carbon bond under the conditions.

In addition to the greener chemistry that comes from sidestepping a preliminary oxidation reaction that has been needed in previous carbonyl allylation reactions, Krische points out that the new reactions don't generate metal salts found in classic carbonyl allylations. Instead, the reactions are either by-product-free or simply produce acetic acid. And they also use far less expensive starting materials than other carbonyl allylation reactions.

"I am really impressed by the ingenuity of the design of these reactions and the extensive capacity for application," adds David W. C. MacMillan, a chemistry professor at Princeton University. "At a time when methodologists often get caught up in the practice of taking obscure starting materials to make obscure products, the Krische transformations provide a new reaction that will allow rapid access to highly valuable products from relatively simple, readily accessible starting materials."

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Chemical & Engineering News
ISSN 0009-2347
Copyright © 2009 American Chemical Society


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