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.