Completely N[superscript 1]-Selective Palladium-Catalyzed Arylation of Unsymmetric Imidazoles: Application to the Synthesis of Nilotinib

Abstract

The completely N[superscript 1]-selective Pd-catalyzed arylation of unsymmetric imidazoles with aryl halides and triflates is described. This study showed that imidazoles have a strong inhibitory effect on the in situ formation of the catalytically active Pd(0)–ligand complex. The efficacy of the N-arylation reaction was improved drastically by the use of a preactivated solution of Pd[subscript 2](dba)[subscript 3] and L1. From these findings, it is clear that while imidazoles can prevent binding of L1 to Pd, once the ligand is bound to the metal, these heterocycles do not displace it. The utility of the present catalytic system was demonstrated by the regioselective synthesis of the clinically important tyrosine kinase inhibitor nilotinib.