If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.



Making Heterocycles Behave In C–H Activation

Organic Chemistry: Reaction overcomes traditional selectivity issues when applied to complex, druglike molecules

by Carmen Drahl
November 10, 2014

A reaction scheme showing a Pd-catalyzed cyclization.
Heterocyclic substrates would typically experience C–H activation adjacent to the heteroatom. Yu and Dai’s method overcomes this selectivity limitation, activating the C–H bond next door to a powerful directing group (red bonds).

Heterocycles make great drugs, but they tend to be lousy substrates for C–H activation, a class of reactions that transforms traditionally inert C–H bonds into more useful moieties. The very same sulfur and nitrogen atoms that improve druglike properties such as solubility in water also poison the palladium catalysts typically used in C–H activation. Heteroatoms can also direct the C–H transformation to a bond that’s not of interest to a medicinal chemist. Now, a multi-institution team reports overcoming those limitations by adjusting the catalyst and employing a powerful directing group (Nature 2014, DOI: 10.1038/nature13885).

“Every time I visit a pharmaceutical company and talk about C–H activation, I get asked the same question: Can you do that with a heterocycle?” says Jin-Quan Yu of Scripps Research Institute, in La Jolla, Calif.. He’s been exploring ways to address that request for some time, in collaboration with his former postdoc Hui-Xiong Dai, now on the faculty at China’s Shanghai Institute of Organic Chemistry.

Even with one of their best directing groups, an N-methoxy amide, the researchers couldn’t get the reaction to work initially. But then they switched from a palladium(II) catalyst to palladium(0). Palladium(II) is so electron-poor, Yu says, that it coordinates strongly, even to neutral moieties, such as heterocycles, that have electron pairs to spare. Palladium(0) coordinates with neutral heterocycles weakly by comparison, but it coordinates with anions readily. So Yu and Dai surmised that they could choose the right directing group as an anion surrogate and ensure that there are no other anions in the reaction mixture to coordinate to palladium(0). They could then position their active palladium species at the directing group instead of at the heteroatom and use C–H activation on heterocycles.

Sure enough, the team demonstrated C–H activation with structures typically found in drug candidates, including those with pyridine, oxazoline, indole, furan, thiazole, and phosphoryl moieties. Usually, when C–H activation works with heterocycles at all, the bond that’s modified is adjacent to the heteroatom. Yu and Dai’s reaction overcomes this selectivity pattern. The process uses the team’s favored N-methoxy amide group as the directing group, and it uses air as the sole oxidant. Only free amine groups substantially lower the reaction’s yield.

The work is “a clever approach to a very relevant problem in drug discovery,” say Merck Research Laboratories chemists Timothy Cernak, an associate principal scientist, and Daniel DiRocco, a senior scientist. Any reaction that works on real-world substrates is a welcome addition to the toolbox, they say. But it remains to be seen how general the reaction will be, they caution, because the chemistry generates “an esoteric, albeit versatile,” product.

The reaction products are imidate heterocycles that can be converted to a number of other structures, including hard-to-make lactams, Yu points out. The team is working with Bristol-Myers Squibb to apply the chemistry to a heterocyclic drug candidate.

“This is truly an elegant example of identifying the ideal directing group that can dial in the appropriate level of coordination to circumvent competing, nonproductive pathways,” says Lawrence G. Hamann, executive director of global discovery chemistry at Novartis. “This will surely see widespread uptake among medicinal chemists.”


This article has been sent to the following recipient:

Chemistry matters. Join us to get the news you need.