Predicting Regioselectivity in Cross-Coupling of Polyhaloheteroaromatics

Significance

A simple predictive tool for the re­gioselectivity of the widely used transition-metal-catalyzed cross-coupling reactions of polyhaloheteroaromatics based on ¹H NMR spectroscopy of parent heteroaromatic compounds is proposed. An analysis of the extensive literature data of cross-coupling regioselectivity in 5- and 6-membered ring heterocycles and their ¹H NMR spectra suggest that the initial site of coupling is always at the more electron-deficient center which correlates with the larger proton chemical shift. Interesting sequential reactions by variations of conditions (e.g., Negishi followed by Kumada-Corriu couplings) were established. Application of this tool to non-heteroaromatic polyhalo systems also led to predictable results.