Mechanistic Studies on the Copper-Catalyzed N-Arylation of Alkylamines Promoted by Organic Soluble Ionic Bases

Experimental studies on the mechanism of copper-catalyzed amination of aryl halides have been undertaken for the coupling of piperidine with iodobenzene using a Cu(I) catalyst and the organic base tetrabutylphosphonium malonate (TBPM). The use of TBPM led to high reactivity and high conversion rates in the coupling reaction, as well as obviating any mass transfer effects. The often commonly employed O,O-chelating ligand 2-acetylcyclohexanone was surprisingly found to have a negligible effect on the reaction rate and, based on NMR, calorimetric and kinetic modelling studies, the malonate dianion in TBPM is instead postulated to act as an ancillary ligand in this system. Kinetic profiling using reaction progress kinetic analysis (RPKA) methods show the reaction rate to have a dependence on all of the reaction components in the concentration range studied, with first order kinetics with respect to [amine], [aryl halide] and [Cu]total. Unexpectedly negative first order kinetics in [TBPM] was observed. This negative rate dependence in [TBPM] can be explained by the formation of an off-cycle copper(I) dimalonate species, which is also argued to undergo disproportionation and is thus responsible for catalyst deactivation. The key role of the amine in minimizing catalyst deactivation is also highlighted by the kinetic studies. An examination of the aryl halide activation mechanism using radical probes was undertaken which are consistent with an oxidative addition pathway. Based on these findings a more detailed mechanistic cycle for the C-N coupling is proposed, including catalyst deactivation pathways.