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Reversing rules of arene chemistry

New norbornene compound overcomes ring substitution limitation

by Tien Nguyen
July 1, 2018 | A version of this story appeared in Volume 96, Issue 27


Structure of a norbornene cofactor.

Electronics reign in the realm of electrophilic aromatic substitutions. In these reactions, six-membered rings with electron-rich substituents point reactants to adjacent or opposing positions on the ring, while compounds with electron-poor groups place them on the carbon in between. Medicinal chemists have long sought methods to free themselves from these conventions. Reactions using a palladium catalyst combined with a norbornene cofactor offer reversed site selectivity in aryl iodides, but they come with caveats. Guangbin Dong’s lab at the University of Chicago has developed a novel norbornene compound (shown) that lifts one of those limitations (Nat. Chem. 2018, DOI: 10.1038/s41557-018-0074-z). Called the ortho constraint, a substituent had to occupy the ortho—in other words, adjacent—position on the ring next to iodine to avoid overreaction or norbornene getting stuck on the ring. The researchers were able to forgo this substituent by incorporating a floppy alkyl chain at the bridgehead position of norbornene, which they suggest disfavors the side reactions. Dong and coworkers demonstrated the reaction’s complementary site selectivity by adding amine, acyl, and aryl electrophiles in tandem with various nucleophiles, including hydride, to arene substrates possessing a variety of electron-donating and electron-withdrawing groups. In one example, the researchers accomplished a late-stage amination of the pesticide strychnine that had previously taken seven steps in only two steps.


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