Mechanochemical Pd-Catalyzed Cross-Coupling of In-Situ Generated Reformatsky Zn-Enolates

Abstract

Transition-metal-catalyzed α-arylations of carbonyl compounds have shown to be a useful strategy for the late-stage synthesis of α-arylesters. However, the use of strong basic conditions and difficult handling necessary for the in-situ preparation of enolates is a major disadvantage. On the other hand, using Reformatsky zinc-enolates can overcome these challenges. Moreover, mechanochemical in-situ activation of zinc is even more beneficial. Herein, we report mechanochemical Pd-catalyzed cross-coupling between in-situ generated Reformatsky Zn-enolates and aryl halides. This operationally simple procedure affords α-arylated esters or amides using an affordable catalytic system. Reactions were carried under air and ambient conditions using granulated zinc without the need for its pre-activation. Less reactive and commercially more affordable aryl bromides afforded the desired products in good to excellent yields in comparison to aryl iodides. The optimized conditions were applied in scale-up reaction and in the synthesis of α-arylated esters, amides, and derivatives of natural products.