title: 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.
authors.affiliation: Department of Chemistry, Imperial College London, Exhibition Road, South Kensington, London, UK.
authors.forename: Pim Huat
authors.initials: PH
authors.lastname: Phua
authors.forename: Suju P
authors.initials: SP
authors.lastname: Mathew
authors.forename: Andrew J P
authors.initials: AJ
authors.lastname: White
authors.forename: Johannes G
authors.initials: JG
authors.lastname: de Vries
authors.forename: Donna G
authors.initials: DG
authors.lastname: Blackmond
authors.forename: King Kuok Mimi
authors.initials: KK
authors.lastname: Hii
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D001372:Aza Compounds / Q000737:chemistry*; D002384:Catalysis; D018360:Crystallography, X-Ray; D007094:Imides / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry; D010165:Palladium / Q000737:chemistry; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D000814:Aniline Compounds; D001372:Aza Compounds; D007094:Imides; D008024:Ligands; D009942:Organometallic Compounds; D010165:Palladium; C023650:aniline