Mechanochemically Generated Calcium-Based Heavy Grignard Reagents and Their Application to Carbon-Carbon Bond-Forming Reactions

In sharp contrast to the use of conventional magnesium-based Grignard reagents (R-MgX), the application of calcium-based heavy Grignard reagents (R-CaX) in organic synthesis remains poorly explored. This is mainly due to the lack of experimentally simple ways to access such organocalcium nucleophiles from readily available starting materials under mild conditions. Here, we show that a mechanochemical technique using ball milling allows the generation of calcium-based heavy Grignard reagents from aryl halides and commercially available calcium metal without complicated pre-activation processes. Notably, all experimental operations can be carried out in air. Our operationally simple protocol enables the rapid development of novel cross-electrophile-coupling reactions mediated by arylcalcium nucleophiles, which are rather difficult using conventional Grignard reagents. This method will allow synthetic chemists to readily access the novel and unique reactivity of organocalcium nucleophiles.

Automated summary

The use of calcium-based heavy Grignard reagents (R-CaX) in organic synthesis is not well-explored compared to conventional magnesium-based Grignard reagents (R-MgX). This is mainly due to the lack of a simple method to access organocalcium nucleophiles from readily available starting materials. In this study, the researchers demonstrate a mechanochemical technique using ball milling to generate calcium-based heavy Grignard reagents without complicated pre-activation processes. The method allows for the development of novel cross-electrophile-coupling reactions mediated by arylcalcium nucleophiles, which is difficult using conventional Grignard reagents.