7‑Azaindole N‑Oxide (7-AINO) Mediated Cu-Catalyzed N‑Arylation: Mechanistic Investigation into the Role of Fluoride Ions

A Cu(II) fluoride-catalyzed N-arylation of 7-azaindole N-oxides (7-AINO) has been developed using boronic acid under base-free conditions. During the process, a combination of spectroscopy and crystallography techniques has identified the exact formulation of key reaction intermediates that allowed to propose a complete mechanistic description establishing the role of 7-AINO as a ligand and deducing the crucial role of fluoride ions (F^–) in the entire catalytic cycle. A monomeric Cu(II)-7-AINO complex (4) has been detected as a reaction intermediate along with isolation of its dimeric analog (4a) and confirmed by X-ray analysis and mass spectroscopy. The subsequent conversion of Cu(II)-7-AINO complex (4/4a) to catalytically active monomeric fluorinated Cu(II)-complex (I) has been confirmed by ¹⁹F NMR, mass, and EPR spectroscopy, reiterating the vital role of fluoride ions in forming the active catalyst. Further, the synthesized Cu(II)-7-AINO complex (4a) in combination with TBAF has been established as an alternative catalytic system for CEL coupling, and its efficiency has been demonstrated for N-arylation of various N-containing nucleophiles. Moreover, a general attempt has been made to promote F^– as complementary to the base as well as a CEL catalyst promoter. The role of 7-azaindole-N-oxide (7-AINO) as a ligand was further evaluated, where it acts as an apposite promoter for the Cu-catalyzed N-arylation of azoles in Ullmann-type coupling. The synthetic potential of this methodology is further demonstrated through the synthesis of various pharmaceutically important 7-azaindole annulated derivatives.