Palladium-Catalyzed α-Heteroarylation Route to 4-, 5-, 6- and 7-Azaindoles

Significance

On their way to IkB kinase β inhibitors, BMS scientists developed a convenient route to azaindoles as reported herein. The first approach involving a Sonogashira coupling and ­subsequent annulation required isolation of intermediates. In this route with no C2-substitution complex mixtures were obtained; furthermore, ­trying to follow with direct C2-arylation was unsuccessful. Additionally, the palladium-catalyzed enamine Heck coupling was only successful with ethyl pyruvate, and the palladium-catalyzed tandem coupling of gem-dichloroolefins was only successful with substrates having few or no ­substituents. Therefore, the direct arylation of enolates with 2-amino-3-bromopyridine was explored. After optimization, the use of Nolan’s N-heterocyclic carbene catalyst and Na- or LiHMDS as base resulted in complete conversions. The desired 7-azaindoles were isolated in moderate to excellent yields. Extension of the methodology to 4-, 5- and 6-azaindoles (and the synthesis of the desired kinase inhibitor) was successful, albeit in lower yields. Both aryl and alkyl ketones were successful in the reaction.