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Synthesis

Adding two functional groups to an aliphatic alcohol in one shot

The simple reaction could be an easy way to synthesize new molecules for drug discovery

by Fernando Gomollón-Bel, special to C&EN
March 25, 2020 | APPEARED IN VOLUME 98, ISSUE 12

 

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Shining visible light on a one-pot reaction adds two functional groups to an aliphatic alcohol in a single step.
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Shining visible light on a one-pot reaction adds two functional groups to an aliphatic alcohol in a single step.

Aliphatic alcohols are cheap, widely available, and very stable building blocks for chemical synthesis and drug discovery. Now, a team of chemists has found a way to add functional groups to them in two different positions in just one step. This novel strategy could lead to new biologically active molecules (J. Am. Chem. Soc. 2020, DOI: 10.1021/jacs.0c01318).

Carbon chains bearing different types of heteroatoms are very attractive in medicinal chemistry, but they are very hard and expensive to prepare. Directly functionalizing carbon–hydrogen bonds in aliphatic alcohols typically requires metal catalysts and the presence of directing groups, or chemists first need to oxidize the alcohol to an alkene before starting the synthesis.

“Our approach is way simpler,” says organic chemist David A. Nagib of the Ohio State University, who led the study. By combining three main reagents—an alcohol, a nitrile, and iodine—and shining visible light on the reaction, Nagib and his team can produce an aliphatic alcohol with an amine and iodine on adjacent carbons. Iodine is a good leaving group, making that carbon an easy site for adding a range of other nucleophilic groups. By being able to add two functional groups to the alcohol at the same time, “we kill two birds with one stone,” Nagib says.

The researchers found this reactivity by chance while trying to doubly functionalize the same carbon, Nagib says. They immediately realized that decorating two neighboring carbon atoms had tremendous potential.

By substituting other functional groups for the iodine, the researchers created aliphatic alcohols bearing azide and thiol groups—ideal substrates for click reactions—and biotin, a compound widely used in biochemical assays.

Marion H. Emmert, a chemist specializing in drug discovery at Merck & Co., believes this new approach “is a clear breakthrough both from a fundamental point of view and in terms of applications in synthesis.” Direct functionalization of aliphatic C–H bonds is “extremely challenging,” she says, especially in complex molecules where other functional groups may hinder reactivity. She especially values the potential of this approach to modify molecules at the final stages of a synthetic route. “This is key for drug discovery,” she says. “The number of accessible molecules is only limited by the diversity of nucleophiles you can use.”

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