Catalytic Concerted SNAr Reactions of Fluoroarenes by an Organic Superbase

Abstract

We herein propose that the catalytic concerted S_NAr reaction is a powerful method to prepare functionalized aromatic scaffolds. Classic stepwise S_NAr reactions involving addition/elimination processes require the use of electron-deficient aromatic halides to stabilize Meisenheimer intermediates, despite their widespread use in medicinal chemistry research. Recent efforts have been made to develop concerted S_NAr reactions involving a single transition state, allowing the use of electron-rich substrates based on the use of stoichiometric amounts of strong bases or reactive nucleophiles. This study demonstrates that, without the use of such reagents, the organic superbase t-Bu-P4 efficiently catalyzes the concerted S_NAr reactions of aryl fluorides regardless of their electronic nature. The key to establishing this system is the dual activation of aryl fluoride and anionic nucleophiles by the t-Bu-P4 catalyst. Furthermore, this catalysis allows excellent functional group tolerance, utilization of diverse nucleophiles, and late-stage functionalization of bioactive compound derivatives. These findings make possible diverse applications in chemical synthesis and pharmaceutical development.