Elucidating the Mechanism of the Asymmetric Aza-Michael Reaction

• Published in: Chemistry : a European journal Vol. 13; no. 16; pp. 4602 - 4613
• Main Authors: Phua, Pim Huat, Mathew, Suju P., White, Andrew J. P., de Vries, Johannes G., Blackmond, Donna G., Hii, King Kuok (Mimi)
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01-01-2007; WILEY‐VCH Verlag
• Subjects: Aniline Compounds - chemistry; asymmetric catalysis; Aza Compounds - chemistry; Catalysis; Crystallography, X-Ray; Imides - chemical synthesis; Imides - chemistry; Kinetics; Ligands; Michael addition; Models, Molecular; Molecular Structure; Organometallic Compounds - chemistry; palladium; Palladium - chemistry; reaction mechanism; Stereoisomerism; Time Factors
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200601706

The mechanism of the palladium‐catalysed asymmetric aza‐Michael addition of aniline to α,β‐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 β2‐ and β2,3‐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.
A combination of several techniques was used to elucidate the mechanism of the palladium‐catalysed asymmetric aza‐Michael addition of aniline to α,β‐unsaturated N‐imide, that is, X‐ray crystallography, mass spectrometry, NMR and UV/Vis spectroscopies, as well as reaction progress kinetic analysis.