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

Svitlana Sotnik; Svitlana Stetsenko; Illia Pavliei; Oleksii Brusylovets; Oleksandr Pokholenko; Galyna P. Grabchuk; Olexandr Ye. Pashenko; Dmytro M. Volochnyuk; Serhiy V. Ryabukhin

doi:10.26434/chemrxiv.15004199/v1

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

Тип публікації :

Препринт

Дата випуску :

2 червня 2026 р.

Автор(и) :

Svitlana Sotnik

Svitlana Stetsenko

Illia Pavliei

Oleksii Brusylovets

Oleksandr Pokholenko

Galyna P. Grabchuk

Olexandr Ye. Pashenko

Dmytro M. Volochnyuk

Serhiy V. Ryabukhin

eKNUTSHIR URL :

https://ir.library.knu.ua/handle/15071834/34300

DOI :

10.26434/chemrxiv.15004199/v1

Журнал :

ChemRxiv

Цитування :

[APA 7] Svitlana, S., Svitlana, S., Illia, P., Oleksii, B., Oleksandr, P., Galyna, P. G., Olexandr, Y. P., Dmytro, M. V., & Serhiy, V. R. (2026). Mapping Regioisomer-Dependent Buchwald-Hartwig C-N Coupling: Bromoimidazo[1,5-a]pyridines as a Model Electrophile Series. ChemRxiv,. https://doi.org/10.26434/chemrxiv.15004199/v1

[ДСТУ] Mapping Regioisomer-Dependent Buchwald-Hartwig C-N Coupling: Bromoimidazo[1,5-a]pyridines as a Model Electrophile Series / S. Svitlana та ін. ChemRxiv. 2026. DOI: 10.26434/chemrxiv.15004199/v1 (дата звернення: 11.09.2026).

Buchwald-Hartwig C-N coupling is a central method for constructing aryl- and heteroaryl-nitrogen bonds, yet condition translatability often fails for heteroaryl halides, even among closely related substrates. In this work, we examine the six available bromoimidazo[1,5-a]pyridine regioisomers using a representative nucleophile panel comprising benzamide, aniline, morpholine, and benzylamine. 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 selected 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 require 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.