Phua Pim Huat, Mathew Suju P, White Andrew J P, de Vries Johannes G, Blackmond Donna G, Hii King Kuok Mimi
Department of Chemistry, Imperial College London, Exhibition Road, South Kensington, London, UK.
Chemistry. 2007;13(16):4602-13. doi: 10.1002/chem.200601706.
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.
运用包括X射线晶体学、质谱、核磁共振、紫外/可见光谱以及动力学研究等多种技术手段，从多个方面对钯催化苯胺与α,β-不饱和N-酰亚胺的不对称氮杂-Michael加成反应机理进行了研究。发现苯胺与二价钯（II）金属中心的结合分两个连续步骤进行：第一个苯胺的结合快速且可逆，而第二个苯胺的结合较慢且不可逆。这一过程与N-酰亚胺的结合相互竞争，N-酰亚胺与金属中心形成一个平面六元螯合环；通过1,3-二羰基部分进行配位。同位素标记显示，N-H的加成以高度立体选择性的方式发生，从而能够合成光学活性的β(2)-和β(2,3)-氨基酸衍生物。加成反应的立体化学被推测为顺式。原位动力学研究提供了产物抑制的证据。发现N-酰亚胺与催化剂的结合是限速步骤。还发现苯胺是预催化剂的抑制剂。该研究最终设计出了一种新的反应方案。通过在反应过程中保持苯胺底物的低浓度，可以显著提高产率和对映选择性。
