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Synthesis

Catalyst activates tertiary C–H bonds

Dirhodium agent functionalizes specific bonds without need for nearby directing groups

by Stu Borman
November 21, 2017 | APPEARED IN VOLUME 95, ISSUE 47

Credit: Nature
A rhodium catalyst developed last year (left) or the new one (right) add substituents at secondary (blue) or tertiary (red) C–H sites. The substrates (center) are a variety of acyclic and cyclic compounds.

In recent years, chemists have devised powerful synthetic tools that activate C–H bonds to allow them to install new substituents. But many C–H bonds still cannot be functionalized selectively. Researchers have now expanded the C–H activation toolkit by developing a way to add groups to specific tertiary C–H bonds, carbon atoms bonded to three other carbons, without the usual need for directing groups to control selectivity.

Alkyl compounds often contain many fairly unreactive C–H bonds that are difficult to distinguish. Chemists can install chemical groups in the molecules to direct addition of desired substituents at adjacent carbons, but this process adds to the complexity of a synthesis.

Last year, Huw M. L. Davies of Emory University and coworkers developed a dirhodium catalyst with triarylcyclopropylcarboxylate ligands that uses steric and electronic forces to functionalize the most accessible secondary C–H bond in an alkane or terminally substituted alkyl compound. The catalyst could do so without a directing group because its ligands block most secondary and tertiary C–H bonds from reaching the catalyst surface, except for the most accessible secondary C–H bond.

This team has now developed a dirhodium catalyst with tetrachlorophthalimido adamantyl acetic acid ligands that targets the most accessible tertiary C–H bond (Nature 2017, DOI: 10.1038/nature24641). Yields were up to 93% and enantioselectivities as high as 92%. They used the approach to modify several natural products, including steroids and a vitamin E derivative, suggesting the catalyst could be used for late-stage functionalization of complex molecules.

The study “shows the power of ligands bound to an active metal-catalyst center to touch C–H bonds otherwise difficult or impossible to access selectively,” comments Kenichiro Itami of Nagoya University. John F. Hartwig of the University of California, Berkely, adds that the new technique is remarkable for its ability to form C–C bonds at tertiary C–H positions with control of both regioselectivity and absolute configuration.


CORRECTION: This story was updated on Nov. 22, 2017, to correct the figure caption and the name of the ligands used in the new catalyst.

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