Copper-Free Alternatives to Access Ketone Building Blocks from Grignard Reagents

Grignard reactions are an efficient way to form carbon-carbon bonds with widespread applications in large-scale processes. Classically, the electrophiles of choice to form ketones from Grignard reagents are acid chlorides. The reactions are typically catalyzed by additives such as CuCl to increase selectivity and yields. This work was focused on the use of acetic anhydride as an alternative to acetic chloride in the synthesis of 4-fluoro-2-(trifluoromethyl)acetophenone (3), a useful intermediate for the synthesis of active agricultural ingredients. The use of acetic anhydride as an electrophile not only equals but also surpasses acetic chloride in yield and selectivity, while also being more tolerable toward higher reaction temperatures. Furthermore, the reaction was performed in the absence of any additive, making it a highly attractive process for large-scale production. Computational mechanistic studies suggest that this advantageous behavior can be ascribed to the superior complexation of carboxylic acid anhydrides in the transition state.