Improved Direct 2-Trifluoromethylation of Quinoline Derivatives Using Me₂(CH₂Cl)SiCF₃

Abstract

This study addresses the critical need for efficient methods to synthesize 2-trifluoromethylated aromatic azacycles, which are pivotal targets in drug and agrochemical development. While direct C–H trifluoromethylation using trimethyl(trifluoromethyl)silane (TMSCF₃) offers a facile route for C2-regioselective incorporation, its limitations in yield and substrate scope present a significant challenge. To overcome this, we introduce a novel concept by modifying the reagent structure: utilizing Me₂(CH₂Cl)SiCF₃, a bifunctional silyl reagent that enhances its reactivity compared to existing silyl reagents. Under a modified Kanai & Kuninobu procedure involving sequential nucleophilic addition and oxidative aromatization, this approach demonstrates substantial theoretical and methodological progress. It successfully delivers an array of 2-CF₃ substituted quinoline derivatives (24 examples) in yields significantly superior to those of TMSCF₃ (with increments of ≥20% for 10 examples), while also expanding the scope to include naphthyridines and phenanthrolines. These results advance beyond current methodologies by establishing that polar modification of the silyl methyl group can generate more powerful reagents, thereby providing a robust framework for the selective and high-yielding synthesis of valuable fluorinated aromatic azacycles.

Keywords

Direct trifluoromethylation / Me₂(CH₂Cl)SiCF₃ / Aromatic azacycle / Quinoline / Pyridine / Silyl trifluoromethylating reagent / 2-CF₃ quinolines / Antimicrobial activity

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