A comparative mechanistic study of Cu-catalyzed oxidative coupling reactions of N-phenyltetrahydroisoquinoline with different nucleophiles was conducted. Two previously reported combinations of catalyst and oxidant were studied, CuCl(2)·2H(2)O/O(2) and CuBr/tert-butyl hydroperoxide (TBHP). On the basis of a synthetic study with different nucleophiles, the electrophilicity of the intermediate iminium ion was estimated and differences between the two methods were revealed. The key intermediate in the aerobic method is shown to be an iminium ion, formed through oxidation by copper(II), which can react with any nucleophile of sufficient reactivity. The role of oxygen is the reoxidation of the reduced catalyst. In the CuBr/TBHP system, an α-amino peroxide is proposed as a true intermediate within the catalytic cycle, formed from the amine and TBHP by a Cu-catalyzed radical reaction pathway and acting as a precursor to the iminium ion intermediate.

The mechanism of an aerobic copper-catalyzed oxidative coupling reaction with N-phenyl tetrahydroisoquinoline was investigated. The oxidized species formed from the reaction of the amine with the copper catalyst were analyzed by NMR-spectroscopy. An iminium dichlorocuprate was found to be the reactive intermediate and could be structurally characterized by X-ray crystallography. The effect of methanol to effectively stabilize the iminium ion was investigated and shown to be beneficial in an oxidative allylation reaction.

The question of whether hydrogen atom transfer (HAT) or electron transfer (ET) is the key step in the activation of N-aryl tetrahydroisoquinolines in oxidative coupling reactions using CuBr as catalyst and tert-butyl hydroperoxide (tBuOOH) has been investigated. Strong indications for a HAT mechanism were derived by using different para-substituted N-aryl tetrahydroisoquinolines, showing that electronic effects play a minor role in the reaction. Hammett plots of the Cu-catalyzed reaction, a direct time-resolved kinetic study with in situ generated cumyloxyl radicals, as well as density functional calculations gave essentially the same results. We conclude from these results and from kinetic isotope effect experiments that HAT is mostly mediated by tert-butoxyl radicals and only to a lesser extent by tert-butylperoxyl radicals, in contrast to common assumptions. However, reaction conditions affect the competition between these two pathways, which can significantly change the magnitude of kinetic isotope effects

The results from a kinetic investigation of a Cu-catalyzed oxidative coupling reaction between N-phenyl tetrahydroisoquinoline and a silyl enol ether using elemental oxygen as oxidant are presented. By using reaction progress kinetic analysis as an evaluation method for the obtained data, we discovered information regarding the reaction order of the substrates and catalysts. Based on this information and some additional experiments, a refined model for the initial oxidative activation of the amine substrate and the activation of the nucleophile by the catalyst was developed. The mechanistic information also helped to understand why silyl nucleophiles have previously failed in a related Cu-catalyzed reaction using tert-butyl hydroperoxide as oxidant and how to overcome this limitation.