Arylation of morpholine

N-Arylmorpholines and N-arylpiperazines are found in many drugs. 4-(4-Methylphenyl)morpholine is difficult to prepare by nucleophilic aromatic substitution, because the ring of 4-chlorotoluene is not activated.

With a palladium catalyst and a bulky dialkylbiarylphosphine such as XPhos, and sodium tert-butoxide as the base, the aryl chloride couples with morpholine in hot toluene to give the arylamine in good yield. With first-generation ligands, the bromide or iodide had to be used.