Gao Pan, Jiang Julong, Maeda Satoshi, Kubota Koji, Ito Hajime
Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Hokkaido 060-8628, Japan.
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan.
Angew Chem Int Ed Engl. 2022 Oct 10;61(41):e202207118. doi: 10.1002/anie.202207118. Epub 2022 Aug 3.
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.
与传统镁基格氏试剂（R-MgX）的使用形成鲜明对比的是，钙基重格氏试剂（R-CaX）在有机合成中的应用仍未得到充分探索。这主要是因为缺乏在温和条件下从易得的起始原料制备此类有机钙亲核试剂的实验简单方法。在此，我们表明，使用球磨的机械化学技术能够从芳基卤化物和市售钙金属生成钙基重格氏试剂，而无需复杂的预活化过程。值得注意的是，所有实验操作均可在空气中进行。我们操作简单的方案能够快速开发由芳基钙亲核试剂介导的新型交叉亲电偶联反应，而使用传统格氏试剂进行此类反应相当困难。该方法将使合成化学家能够轻松利用有机钙亲核试剂新颖独特的反应性。
