Author: Wu, Jing
Title: Synthesis of novel chiral dipyridylphosphine ligands and their application in Ru- and Rh-catalyzed asymmetric hydrogenation reactions
Degree: Ph.D.
Year: 2003
Subject: Hong Kong Polytechnic University -- Dissertations
Ligands (Biochemistry)
Ruthenium compounds
Department: Department of Applied Biology and Chemical Technology
Pages: xvi, 361 leaves : ill. ; 30 cm
Language: English
Abstract: In contrast to the tremendous success achieved in the use or chiral arylphosphine Ligands in the Rh- and Ru-catalyzed asymmetric reactions, chiral phosphine Ligands containing heteroeyclic moieties such as pyridyl groups have been relatively unexplored even though the importance of the expansion of the scope of the metal phosphirie chemistry with the rich chemistry of heterocyclic functionalities is quite obvious. We have recently developed a chiral dipyridylphosphince ligand 2,2',6,6'-tetramethoxy-4,4'-bis(diphenyiphosphino)-3,3'-bipyridine (P-Phos, 64), which was found to be very effective in the Ru-catalyzed asymmetric hydrogenation of 2-(6'-methoxy-2'naphthyl)propenoic acid to give the nonstcroidal anti-inflammatory drug naproxen. It is well known that subtle changes in the geometric, steric, and electronic properties of chiral ligands can lead to dramatic variations of the reactivity and enantioselectivity of transition-metal complexes. In this study, we have designed and prepared two analogs of P-Phos (64), 2,2',6,6'-tetrarnethoxy-4,4'-bis[di(p-methyl-phenyl)phosphino]-3,3'-bipyridine (ToI-P-Phos, 65)and 2,2',6,6'-tetrarnethoxy-4,4'-bis[di-(3,5-dimethylphenyl)phosphino]-3,3'-bipyridine(Tyl-P-Phos, 66) by introducing various substituents (e.g., 4-methyl, 3,5-dimethyl) onto the four phenyl rings in P-Phos to tune its electronic and steric properties. In addition, we also designed another new type of P-Phos variant, 2.2',6,6'-tetramethoxy-4,4'-bis(dicyclohexylphosphino)-3,3'-bipyridine(Cy-P-Phos, 67), which bears four bulky, electron-donating cyclohexyl groups in the two phosphorus atoms, instead of the four arene groups of conventional P-Phos ligands. The structures of these ligands were confirmed by 1H, 13C, 31P NMR, mass spectrometry, elemental analysis and single crystal X-ray diffraction studies. The ruthenium complexes of these dipyridylphosphine ligands have been found to be highly active and enantioselective catalysts in the asymmetric hydrogenation of B-keto esters. The reactions proceeded smoothly at 70-90 oC and under 200-500 psi of H2 to give quantitative yield and up to 98.5% ee in 1-3 h. The chiral trans-[RuCI2(dipyridylphosphine)(1,2-diamine)]complex combined with (CH3)3COK in 2-propanol acted as a very effective catalyst system for the enantioselective hydrogenation of a diverse range of simple ketones including aromatic ketones, hetero-aromatic ketones, substituted benzophenones, alkenyl ketones as well as cyclopropyl ketones with high activities (substrate-to-catalyst ratio up to 100,000) and excellent enantiose lectivities (up to >99.9%). Besides the successful application of the dipyridylphosphine ligands in the Ru- catalyzed asymmetric hydrogenation of functionalized and simple ketones, the good efficacy of these chiral ligands in the Ru- and Rh-catalyzed asymmetric hydrogenation of methyl esters of a variety of(Z)-2-acetamido-3-arylacrylic acids and various B-alkyl-substituted B-(acylamino)acrylates was also demonstrated (up to 99.7% ee). We have also studied the application of the dipyridylphosphine ligands in the Ru-catalyzed asymmetric hydrogenation of 2-(6'-methoxy-2'-naphthyl)proprnoic acid leading to the popular anti-inflammatory drug (S)-naproxen. The best ee obtained was 95.2% when the reaction was carried out in methanol at 0 oC and under 1000 psi of H2. In addition, the effects of the backbones and the substituents on the phosphorous atoms of the chiral ligands were extensively investigated. The results showed that the electronic and steric properties of these ligands as well as the different transition metal ions have significant influences on the catalytic properties. Particularly noteworthy was the observation that the use of Xyl-P-Phos (66) as the chiral diphosphine ligand often provided far superior ee's to those obtainable with the parent ligand P-Phos (64) or Tol-P-Phos (65), which strongly supported our cognition for the design of efficient chiral ligands. In this study, it is of great interest to note that the Ru-P-Phos catalyst system is highly air-stable even in solution. In a simple stability test we found that even when the experimental procedures prior to the introduction of hydrogen were performed in air, the activity and enantioselectivity of the catalyst remained unchanged from the air-proved system. Even when the solution of the catalyst was exposed to air for 10 h, its efficiency remained essentially unchanged. The combination of desirable features, such as fast reaction rate, broad substrate scope, excellent enantioselectivity, high substrate-to-catalyst ratio and high air-stability of the catalysts in solution makes the studied catalyst system of high practical interest.
Rights: All rights reserved
Access: open access

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