ONSH: Optimization of Oxidative Alkylamination Reactions through Study of the Reaction Mechanism

Oxidative alkylamination of electron-deficient (hetero)aromatic compounds, via the nucleophilic substitution of hydrogen, is a methodology that has made significant progress since the introduction of AgPy₂MnO₄ as oxidant. This oxidant generally gives good conversions and yields, whereas the use of KMnO₄ only sometimes works equally well. In order to rationalize this, the reaction mechanism of oxidative alkylamination has been studied. 3-Nitropyridine (1), 1,3-dinitrobenzene (2), and quinazoline (3) were chosen as model substrates and n-butylamine and pyrrolidine as model alkylamines. The rate-limiting step of the mechanism for these substrate/alkylamine combinations was determined. With the use of ¹H NMR spectroscopy thermodynamic properties of σ^Η-adduct formation were deduced and the effect of additives on the adduct formation was investigated. The fundamental insights resulting from these studies led to the identification of a cheap additive (tetrabutylammonium chloride), which in combination with the standard and cheap oxidant KMnO₄ generally gave excellent yields, similar to the ones previously obtained with more expensive AgPy₂MnO₄.