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

Abstract

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 19 F 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.