Simple sonochemical protocols for fast and reproducible Grignard reactions

Abstract

The Grignard reaction is one of the most common synthetic pathways in organic chemistry and has widely been used in the preparation of fine chemicals and pharmaceutical intermediates. The reaction's reproducibility can be affected by several factors (metal purity, degree of association in solution, Schlenk equilibrium) and its activation with chemical, mechanical, sonochemical or electromagnetic treatments is practically essential. In this study we demonstrate that ultrasound-assisted Grignard reactions are safe, efficient and reproducible. The activation of the Mg surface, the single electron transfer (SET) from the metal to organic halide, and the subsequent nucleophilic addition of ArMgX to carbonyl substrates, fall into the larger domain of sonochemistry. As expected for a radical mechanism the best sonochemical conditions were observed at 300 kHz (cup horn). An efficient one-pot protocol with poorly-reactive aryl halides and the subsequent quenching with a hindered ketone are reported.