Mechanochemical synthesis of magnesium-based carbon nucleophiles in air and their use in organic synthesis

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.

Mechanochemistry‐Driven Construction of Aza‐fused π‐Conjugated Networks Toward Enhanced Energy Storage

“…[30][31][32][33] Besides the well-developed mechanochemical construction of CMPs via oxidative coupling of electron-rich monomers (e.g., arenes) in the presence of Lewis acids (e.g., FeCl 3 or AlCl 3 ), [34][35][36][37][38] magnesium (Mg) could catalyze the reductive C-C bond formation between aromatic halides driven by mechanochemistry, which has been demonstrated as a complementary methodology to realize the coupling of electron-deficient arene units via the Grignard reagent intermediates formation during the mechanochemical treatment process. [39][40] As an initial assessment, 3,8-dibromo-1,10-phenanthroline (Phen-Br) was taken as the only starting material, and Mg powder was used both as the catalyst and potential coordination reagent with the Phen-Br monomer (Figure 1). The mixture (mass ratio of 1:1) was then treated by high-speed vibrating ball milling for 3 h. After the mechanochemical treatment process, the product (denoted as Phen-CMP) was collected as a black powder with 75% yield after being thoroughly washed with dilute acid, water, and organic solvents to remove the residual metal species and unreacted Phen-Br precursor, indicating the successful cross-linking of the bromide monomer with a linear structure.…”

Access to a Labile Monomeric Magnesium Radical by Ball‐Milling

“…This clearly illustrates the much higher reactivity of the more electropositive Mg 0 species when compared to Be 0 (CAAC) 2 which is stable up to 180–190 °C [24] . The instability of 2 motivated a ball‐milling approach, an increasingly popular technique that recently also entered group 2 metal chemistry [29, 30] . Highly concentrated solid‐solid reactions are much faster than solution reactions and have the advantage to deliver the product in the solid state, in which it is “frozen” from further decomposition.…”

“…[24] The instability of 2 motivated a ball-milling approach, an increasingly popular technique that recently also entered group 2 metal chemistry. [29,30] Highly concentrated solid-solid reactions are much faster than solution reactions and have the advantage to deliver the product in the solid state, in which it is "frozen" from further decomposition.…”

Mechanochemistry: New Tools to Navigate the Uncharted Territory of “Impossible” Reactions

“…With the aim of facilitating the approach to chemistry, trying to set in the best reaction conditions and avoiding a whole series of complicated combinations, Ito and co‐workers have developed an innovative and extremely versatile method for the preparation of Grignard reagents and their consequent reactions on various electrophiles [165] . Grignard's reaction has always been a helpful tool for preparing certain intermediates and products within well‐defined retrosynthetic pathways.…”

“…With the aim of facilitating the approach to chemistry, trying to set in the best reaction conditions and avoiding a whole series of complicated combinations, Ito and co-workers have developed an innovative and extremely versatile method for the preparation of Grignard reagents and their consequent reactions on various electrophiles. [165] Grignard's reaction has always been a helpful tool for preparing certain intermediates and products within well-defined retrosynthetic pathways. However, if this is true, it is equally valid that these reactions are often difficult to implement, requiring inert and anhydrous atmospheres without considering the preparation of complicated setups (Figure 17), discouraging their use.…”