Elucidating the mechanism of the asymmetric aza-Michael reaction.
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.
Phua
Pim Huat
PH
Department of Chemistry, Imperial College London, Exhibition Road, South Kensington, London, UK.
Mathew
Suju P
SP
White
Andrew J P
AJ
de Vries
Johannes G
JG
Blackmond
Donna G
DG
Hii
King Kuok Mimi
KK
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
D000814:Aniline Compounds; D001372:Aza Compounds; D007094:Imides; D008024:Ligands; D009942:Organometallic Compounds; D010165:Palladium; C023650:aniline