Elucidating the Mechanism of the Asymmetric Aza‐Michael Reaction

Abstract

The mechanism of the palladium-catalysed asymmetric aza-Michael addition of aniline to alpha,beta-unsaturated N-imide was examined from several aspects using a combination of techniques, including X-ray crystallography, mass spectrometry, NMR, UV/Vis spectroscopy, and kinetic studies. The binding of aniline to the dicationic palladium(II) metal centre was found to occur in two consecutive steps: The binding of the first aniline is fast and reversible, whereas the binding of the second aniline is slower and irreversible. This occurs in competition with the binding of the N-imide, which forms a planar six-membered chelate ring with the metal centre; coordinating through the 1,3-dicarbonyl moiety. Isotopic labelling revealed that the addition of N-H occurs in a highly stereoselective manner, allowing the synthesis of optically active beta(2)- and beta(2,3)-amino acid derivatives. The stereochemistry of the addition is postulated to be syn. In situ kinetic studies provided evidence for product inhibition. The binding of the N-imide to the catalyst was found to be the rate-limiting step. Aniline was found to be an inhibitor of the pre-catalyst. The study culminated in the design of a new reaction protocol. By maintaining a low concentration of the aniline substrate during the course of the reaction, significant enhancement of yield and enantioselectivity can be achieved.

Nonlinear Effects in Asymmetric Catalysis

“…A linear relationship was found between ee binap and ee prod (reactions performed in THF), but a (+)-NLE was observed in toluene because of the insolubility of some of the diastereomeric complexes (see Section 5). [60] Hayashi and co-workers found a (À)-NLE in the Rh/ binap-catalyzed asymmetric 1,4-addition of PhB(OH) 2 to 2-cyclohexenone [Eq. (13), Scheme 2].…”

Palladium(II)-Catalyzed Alkene Functionalization via Nucleopalladation: Stereochemical Pathways and Enantioselective Catalytic Applications

“…116,117,118 Because the reaction appears to proceed by a Lewis-acid catalyzed mechanism, 119 as opposed to a nucleopalladation mechanism, further discussion of this reaction is not included here; however, the interested reader is directed to recent reviews detailing this topic. 120 …”

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

“…In order to find means to overcome the low enantioselectivities observed when electron-rich anilines are used in their protocol for aza-Michael additions, Hii and co-workers performed a detailed mechanistic study of this reaction [ 241 ]. Based on this study, the rate-limiting step of the aza-Michael addition was the coordination of the catalyst to the 1,3-dicarbonyl moiety of the Michael acceptor.…”