7-Azaindole N-Oxide (7-AINO) Mediated Cu-Catalyzed N-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 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.

Supporting coordination through hydrogen bonding in lanthanide complexes of 7-azaindole-N-oxide

“…Das and co-workers found that these dimeric species tend to be solvent dependent, and tended to observe a discrete CuL 2 complex crystallised from methanol (using copper( ii ) fluoride) and selective crystallisation of the axially-coordinated dimer 1 only when recrystallised from dichloromethane/hexane. 13 In our hands, using copper acetate as the copper source we observed only the axially bridged dimer and minute quantities of the methoxide bridged species.…”

“…16 Recently, Das and co-workers reported the room-temperature structure of a triclinic hydrate of HL crystallised from dichloromethane/hexane, which exhibited similar angled hydrogen-bonded dimers between HL units. 13 Despite the less hydrophilic crystallisation solvent, association of water was still observed in that case, giving a hemihydrate HL ·0.5H 2 O.…”

“…A recent study by Das and co-workers also observed direct deprotonation of HL on reaction of copper( ii ) fluoride in methanol in the absence of base. 13 The predominant phase [Cu L 2 ] 1 is crystallised as green plates from methanol after combining with methanolic copper acetate at room temperature. In some batches, a minute quantity of a second blue phase was obtained, with the formula [Cu 2 (OMe) 2 L 2 ] (ESI†), but this phase was difficult to reproduce; both PXRD and elemental analysis confirmed that 1 is formed essentially exclusively under these conditions.…”

“…Surprisingly, however, to date the only report examining the structural chemistry of 7-azaindole- N -oxide, either as an organic building block itself or in any coordination compounds, has been a contemporary report by Das and co-workers examining its role in copper-catalysed N -arylation reactions ( vide infra ). 13 Here, we explore 7-azaindole- N -oxide HL as a ligand capable of simultaneously coordinating to oxophilic lanthanide ions while facilitating hydrogen bonding to support the coordination sphere and influence the local and extended structure.…”

Preparation of 2,5‐Disubstituted Tetrazoles using a Copper‐Catalysed Regioselective Direct Coupling of Tetrazoles with Free NH Groups and Boronic Acid Derivatives

“…Several coordinating ligands, such as N,N'-dimethylethylenediamine (DMEDA)and N,N,N',N'-tetramethylethylenediamine (TMEDA), [33] pyridine N-oxide, [34] thiophene-2carboxylate (TC), [35] 1,10-phenanthroline (phen) [36] and 4-(Dimethylamino)pyridine (DMAP), [37][38][39] have been found promoting various copper catalysed CÀ N bond forming [40][41][42] reactions. These ligands help in preventing copper aggregation, enhancing solubility, stimulate milder conditions and stabilise active catalyst species during the catalysis process.…”