Completely N¹-Selective Palladium-Catalyzed Arylation of Unsymmetric Imidazoles: Application to the Synthesis of Nilotinib

The completely N¹-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 Pd₂(dba)₃ and <b>L1</b>. From these findings, it is clear that while imidazoles can prevent binding of <b>L1</b> 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

Me₃(OMe)<i>t</i>BuXPhos: A Surrogate Ligand for Me₄<i>t</i>BuXPhos in Palladium-Catalyzed C–N and C–O Bond-Forming Reactions

A new biarylphosphine ligand, Me₃(OMe)<i>t</i>BuXPhos (<b>L3</b>), was designed as a surrogate for Me₄<i>t</i>BuXPhos (<b>L1</b>). The Me₃(OMe)<i>t</i>BuXPhos could be prepared in a chromatography-free manner from inexpensive and readily available 2,3,6-trimethylphenol. Comparative studies demonstrated that a catalyst based on Me₃(OMe)<i>t</i>BuXPhos displayed the same reactivity as a catalyst based on Me₄<i>t</i>BuXPhos for Pd-catalyzed C–N and C–O bond-forming processes