Abstract
Since the discovery of Grignard reagents in 1900, the nucleophilic addition of magnesium-based carbon nucleophiles to various electrophiles has become one of the most powerful, versatile, and well-established methods for the formation of carbon−carbon bonds in organic synthesis. Grignard reagents are typically prepared via reactions between organic halides and magnesium metal in a solvent. However, this method usually requires the use of dry organic solvents, long reaction times, strict control of the reaction temperature, and inert-gas-line techniques. Despite the utility of Grignard reagents, these requirements still represent major drawbacks from both an environmental and an economic perspective, and often cause reproducibility problems. Here, we report the general mechanochemical synthesis of magnesium-based carbon nucleophiles (Grignard reagents in paste form) in air using a ball milling technique. These nucleophiles can be used directly for one-pot nucleophilic addition reactions with various electrophiles and nickel-catalyzed cross-coupling reactions under solvent-free conditions.
Highlights
Since the discovery of Grignard reagents in 1900, the nucleophilic addition of magnesiumbased carbon nucleophiles to various electrophiles has become one of the most powerful, versatile, and well-established methods for the formation of carbon−carbon bonds in organic synthesis
Yang, Dai, and co-workers reported magnesium-mediated reductive radical homo-coupling reactions of polyhaloarenes[28]. These pioneering studies are highly remarkable, neither successful examples of the use of magnesium-based carbon nucleophiles prepared by ball milling for the formation of carbon−carbon bonds with various electrophiles[29], nor direct spectroscopic evidence for the formation of carbon−magnesium bonds under mechanochemical conditions have been reported so far
The key to the success of this protocol is the addition of small amounts of tetrahydrofuran (THF) or cyclopentyl methyl ether (CPME), which facilitates the formation of organomagnesium nucleophiles and their addition to electrophiles
Summary
Since the discovery of Grignard reagents in 1900, the nucleophilic addition of magnesiumbased carbon nucleophiles to various electrophiles has become one of the most powerful, versatile, and well-established methods for the formation of carbon−carbon bonds in organic synthesis. We report the general mechanochemical synthesis of magnesium-based carbon nucleophiles (Grignard reagents in paste form) in air using a ball milling technique These nucleophiles can be used directly for one-pot nucleophilic addition reactions with various electrophiles and nickel-catalyzed cross-coupling reactions under solvent-free conditions. These requirements still represent major drawbacks from both an environmental and an economic perspective, and often cause reproducibility problems for unreactive organic halides In this context, the use of ball milling techniques[16,17,18,19,20,21,22,23,24] for the solvent-free preparation of Grignard reagents via reactions between aryl halides and magnesium metal has been studied by several research groups (Fig. 1b). The present study provides a new platform centered on magnesium-based carbon nucleophiles, which has the potential to update modern organic synthesis with a more cost-effective and environmental-friendly procedure for Grignard reactions
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