C–H Bond Functionalization Under Metalation–Deprotonation Process: Regioselective Direct Arylation of 3-Aminoimidazo[1,2-a]pyrazine

Abstract

Concerted metalation deprotonation (CMD) approach with appropriate proton shuttle precursor, base, and solvent (PivOH–K2CO3–toluene) has rendered a regioselective Pd-catalyzed C6-arylation of 3-aminoimidazo[1,2-a]pyrazine, a therapeutically relevant scaffold accessible by multicomponent reaction. The arylation of this heteroarene suffers from competing C5 and C2′-arylation reactions, while the developed process has virtually eliminated these competing arylations. Density functional calculations for CMD C–H activation at C6, C5, C8, and C2′ sites imply that the energy barrier with distortion energy penalty as major contributing component influences the regioselectivity.