Mapping Regioisomer-Dependent Buchwald–Hartwig C-N Coupling: Bromoimidazo[1,5-a]pyridines as a Model Electrophile Series

Buchwald–Hartwig C-N coupling is a central method for constructing (hetero)aryl–nitrogen bonds. Yet condition translatability is often problematic from one substrate to another, even among closely related substrates, especially for heteroaryl halides. In this work, we demonstrate an approach to solving this task using the six available bromoimidazo[1,5-a]pyridine regioisomers and a representative nucleophile panel comprising benzamide, aniline, morpholine, and benzylamine as a model study. A limited-scale HTE campaign was conducted with an in-house ligand set, a fixed palladium source, and two bases. Reaction performance was assessed by LCMS with internal standard calibration, and targeted hits were verified by preparative re-runs and NMR-confirmed product assignment. The resulting conversion and product yield maps reveal strong dependence on bromide position, nucleophile class, and ligand/base selection. The 6- and 8-bromo isomers show the broadest productive reactivity profiles, whereas the 5- and 7-isomers are active in narrow condition windows. The imidazole–ring 1- and 3-bromo isomers react readily but do not provide isolable, structurally confirmed target products. Methodologically, this work demonstrates that a compact HTE workflow can rapidly define useful ligand/base combinations for heteroaryl bromides while preventing misleading conclusions from conversion-only analysis. The same approach can be applied as an early-stage reactivity screen for other heteroaryl halide series.