Mechanochemical synthesis of magnesium-based carbon nucleophiles in air and their use in organic synthesis
Rina Takahashi, Anqi Hu, Pan Gao, Yunpeng Gao, Yadong Pang, Tamae Seo, Julong Jiang, Satoshi Maeda, Hikaru Takaya, Koji Kubota* and Hajime Ito*
*Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan, Email: kbteng.hokudai.ac.jp, hajitoeng.hokudai.ac.jp
R. Takahashi, A. Hu, P. Gao, Y. Gao, Y. Pang, T. Seo, J. Jiang, S. Maeda, H. Takaya, K. Kubota, H. Ito, Nat. Commun., 2021, 12, 6691-6701.
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The prepartion of Grignard reagents normally requires dry organic solvents, long reaction times, strict control of the reaction temperature, and inert-gas-line techniques. A general mechanochemical synthesis of magnesium-based carbon nucleophiles followed by nucleophilic addition with various electrophiles or Ni-catalyzed cross-coupling can be performed in air using ball milling.
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formation of magnesium-based carbon nucleophiles
Representative procedure for the solvent-less synthesis of magnesium-based carbon nucleophiles and their reactions with electrophiles
Mg turnings (0.75 mmol, 1.5 equiv) were placed in a jar (stainless steel; 5 mL) with a ball (stainless steel; 10 mm, diameter) in air. An organic bromide (0.75 mmol, 1.5 equiv) and THF (123 μL, 1.5 mmol, 3.0 equiv) were added to the jar using a syringe. After the jar was closed without purging with inert gas, the jar was placed in a ball mill (Retsch MM 400, 60 min, 30 Hz). After grinding for 60 min, the jar was opened in air and charged with an electrophile (0.50 mmol). The jar was then closed without purging with inert gas, and was placed in the ball mill (Retsch MM 400, 60 min, 30 Hz). After grinding for 60 min, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with CH2Cl2 (30 mL×3). The solution was washed with brine and dried over Na2SO4. After the removal of the solvents under reduced pressure, the crude material was purified by flash column chromatography (SiO2, hexane/ethyl acetate, 100:0 to 80:20) to give the corresponding product.
Grignard reaction, alcohols, mechanochemistry