Catalytic Concerted SNAr Reactions of Fluoroarenes by an Organic Superbase

Abstract

We herein propose that the catalytic concerted SNAr reaction is a powerful method to prepare functionalized aromatic scaffolds. Classic stepwise SNAr 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 SNAr 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 SNAr 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.