Reaction Progress Kinetic Analysis of a Copper-Catalyzed Aerobic Oxidative Coupling Reaction withN-Phenyl Tetrahydroisoquinoline

Abstract

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.

Highly Active Titanocene Catalysts for Epoxide Hydrosilylation: Synthesis, Theory, Kinetics, EPR Spectroscopy

“…Initial experiments were designed to examine the stability of the catalyst under synthetically relevant conditions. [9,10] The conversion of 4 into 5 in the presence of 10 mol %catalyst was monitored by following [5]a nd subsequently plotting [4]a s af unction of time ( Figure 3). Ah igher catalyst loading was employed to ensure reproducible detection of the titanocene species and to obtain fast turnover.…”

Reactions Catalysed by a Binuclear Copper Complex: Aerobic Cross Dehydrogenative Coupling of N‐Aryl Tetrahydroisoquinolines

“…In its absence, neither 5 nor 6 afforded any coupling product under the conditions used. The previously demonstrated simple copper salts, such as CuCl and CuCl 2 , could also catalyse the aerobic coupling, and showed similar activity in the absence or presence of TBAC (Table , entries 13–16). They are, however, much less effective than the combination of 1 and TABC, and afforded 4 a in <60 % yield in a prolonged time of 12 h under the conditions given in Table .…”

“…They also demonstrated that the coupling with nitroalkanes can be conducted with O 2 or electrochemically . Klussmann and co‐workers recently revealed that CuCl 2 also catalyses the CDC reaction of N ‐aryl tetrahydroisoquinolines with a number of nucleophiles and, more interestingly, oxygen can be used as the terminal oxidant for this wide range of nucleophiles . We note that with these simple copper salts, the catalyst loading is usually high, typically 5–10 mol %.…”

“…The role of the terminal oxidant O 2 is to oxidize the catalyst back to its starting oxidation state (Scheme A), with no bearing on the step of amine oxidation. In the last a few years, mechanistic studies by Klussmann et al . and Doyle et al .…”

“…In particular, the hypothetical iminium intermediate was isolated by Klussmann et al. in the aerobic CDC of N ‐phenyl tetrahydroisoquinolines catalysed by CuCl 2 ⋅ 2 H 2 O, and a systematic study led to the refined mechanism shown in Scheme B . The key feature of this mechanism is that the amine is oxidized by two molecules of the Cu II catalyst in a two‐electron oxidation process in which an iminium cation is formed and Cu II is reduced to a Cu I anion, namely, CuCl 2 − .…”