Completely N<sup>1</sup>-Selective Palladium-Catalyzed
Arylation of Unsymmetric Imidazoles: Application to the Synthesis
of Nilotinib
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Abstract
The completely N<sup>1</sup>-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<sub>2</sub>(dba)<sub>3</sub> 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
