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C-H Activation

Losing the metal to make organoboron bonds

New synthesis with BBr 3 opens a door to the arene backbone of indoles

by Leigh Krietsch Boerner
October 3, 2019 | A version of this story appeared in Volume 97, Issue 39


The borylation of an acyl-substituted indole proceeds via a chelated intermediate to give the desired compound with the new boron-carbon bond at the C-7 position.

Creating new carbon-carbon bonds is the backbone of synthesizing drugs and natural products. Ultimately, many chemists do this through a Suzuki coupling reaction, which marries an organohalide to an organoboron to beget the desired C–C bond. Now, two independent groups have come up with a simpler way to insert the necessary B atoms, an advance that could make it easier to make organoboron compounds (Angew. Chem., Int. Ed. 2019, DOI:10.1002/anie.201909786 and Nature 2019, DOI: 10.1038/s41586-019-1640-2). Both groups used indoles, bicyclic compounds made up of a benzene ring fused to a pyrrole ring, to figure out their new coupling reactions.

Indoles are important precursors to many biomolecules and drugs, and their chemistry is well understood. Chemists know how to get a boron atom onto the pyrrole’s C-2 and C-3 positions of an indole, but they have had a harder time cracking the benzyl backbone. “Reactivity in the pyrrolic unit has lower barriers,” says Michael Ingleson, a chemist from the University of Edinburgh and an author on the Angewandte Chemie International Edition paper. “It’s been historically challenging to get the other side,” he says.

Chemists have traditionally made indoles substituted on the benzyl ring from aryllithiums via lithium-halogen exchange or directed ortho metalation, says Nanjing University chemist Zhuangzhi Shi, an author on the Nature paper. Expensive transition-metal catalysts can install a boron in a C–H bond, but they are a source of contamination and have to be removed to create, for example, pure batches of pharmaceuticals. Both groups sought to remove these metals.

Each team found that it could eliminate the catalysts by using BBr3 as a boron source on a variety of N-pivaloyl indoles. The acyl oxygen attached to the pyrrole ring directs the boron group to the C-7 position to make a chelate-supported intermediate (shown). The chemists then added pinacol to remove the bromine groups, yielding the borylated indole. In addition, the researchers found that this reaction also works well with analines, a class of aromatic amines.

The new method is elegant and can compete with many transition-metal systems, says Frédéric-Georges Fontaine, a green-catalysis chemist from Laval University. He says the method’s efficient selection of boron sites is impressive and opens a new door to the benzyl end of an indole, which has always been elusive.



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