Hemiaminals formed by the addition of azoles to aldehydes can be trapped via acylation. Previously, such O-acylated hemiaminals have been applied as prodrugs for bioactive NH-azoles. Here, we show that azole hemiaminal derivatives can be repurposed as versatile substrates for nickel-catalyzed reductive couplings by the incorporation of a redox-active mixed oxalate group. The method enables the modular and regioselective synthesis of azoles bearing branched alkyl substituents from readily available NH-azoles, aldehydes, and haloarenes, or carboxylic acid anhydrides. Density functional theory calculations provide insight into the scope and limitations of the transformation, including how the heterocycle structure influences the formation and reactivity of the putative azolylmethyl radicals.
Zambri et al. (Wed,) studied this question.