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Innovative Way To Activate C–H Bonds

Organic Synthesis: Process converts amines into nitrogen heterocycles of interest for drug discovery

by Stu Borman
May 30, 2014 | A version of this story appeared in Volume 92, Issue 22

A reaction scheme showing a new C-H functionalization reaction with four-membered cyclopalladation intermediates instead of five- or six-membered ones.
New C–H functionalization reaction proceeds via virtually unprecedented four-membered cyclopalladation intermediates (bottom row) instead of conventional five-membered (shown, top row) or six-membered ones.

Chemists have developed a unique way to get specific carbon-hydrogen bonds in organic compounds to break so new carbon-based connections can be made. The technique could make it easier to create a range of nitrogen-based compounds for drug discovery and other applications.

C–H bonds are notoriously unreactive, but in recent years researchers have developed ways to coax them into being more cooperative. Typically, this is done by cyclometalation, in which a metal such as palladium coordinates to a polar functional group and then breaks into an adjacent C–H bond to form a five- or six-membered cyclic intermediate. The carbon-metal bond in the cyclic intermediate can then react with a range of reagents, releasing the metal and forming products in which the C–H bond’s carbon is functionalized.

Matthew J. Gaunt and coworkers at the University of Cambridge have now discovered a family of catalytic reactions in which palladium coordinates with a methyl group adjacent to a secondary amine group, yielding a four-membered palladacycle intermediate (Nature 2014, DOI: 10.1038/nature13389). Such four-membered rings have been virtually unprecedented in cyclometalations.

Gaunt and coworkers found that the palladacycles can be transformed into strained nitrogen heterocycles such as aziridines and β-lactams by reacting them with reagents such as an oxidant. Gaunt believes the resulting products “will enable medicinal chemists to extend the range of chemical space accessible around the ubiquitous amine function.”

C–H functionalization specialist Gong Chen of Pennsylvania State University says the reaction is important because the unfunctionalized secondary alkyl amines it uses as starting materials have been underutilized for organic synthesis. Such amines are often used as bases or coupling partners but are seldom used to construct drug pharmacophores, he notes.

John F. Hartwig of the University of ­California, Berkeley, who specializes in ­catalytic reactions involving metal complexes, comments that “the application of C–H bond functionalization to the synthesis of amines, as opposed to sulfonamides or amides, is rare, and the ability to do so while forming a strained ring is particularly ­surprising.”

Gaunt’s group is currently working on expanding the technique into a more general strategy. For example, right now the new method is restricted to fairly hindered amines—secondary amine groups bearing bulky substituents. But preliminary results reported in the paper suggest that less hindered amines can undergo similar reactions. Gaunt and coworkers are trying to make the new process viable for all classes of secondary amines.

They would also like to better understand the mechanism and selectivity of the reaction, develop an enantioselective version, and apply it to targeted synthesis of important drugs and natural products, among other projects.

“This is a sweet discovery, highlighting the great potential of using C–H functionalization to develop new organic transformations,” Chen adds.


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