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Green Aminations Without Palladium

Nucleophilic aromatic substitution of heteroaryl chlorides works just fine by using KF in water as an alternative to standard palladium-catalyzed methods

by Stephen K. Ritter
July 8, 2013 | A version of this story appeared in Volume 91, Issue 27

One of the largest classes of reactions used in medicinal chemistry is the palladium-catalyzed cross-coupling of aryl halides with amines to make N-arylamines. During the past 20 years, this efficient method has largely replaced the classical nucleophilic aromatic substitution (SNAr) approach to N-arylations. One team of researchers is now suggesting that chemists have become so dependent on palladium-catalyzed N-arylations that they blindly use the method without giving SNAr a chance. Katie Walsh and Christopher J. Moody at the University of Nottingham, in En­gland, and Helen F. Sneddon of GlaxoSmithKline note that heteroaryl substrates such as chloropyrimidines and chloropyrazines are highly reactive via SNAr, more so than chlorobenzene, and don’t need a palladium catalyst. With their thoughts on green chemistry, the researchers set out to optimize SNAr reactions of the heteroaryl chlorides (ChemSusChem 2013, DOI: 10.1002/cssc.201300239). They found that using potassium fluoride as a base and water as the solvent leads to N-arylamines in yields comparable with the palladium-catalyzed method and avoids the palladium catalyst, phosphine ligand, and organic solvent.


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