Exploiting Metal–Ligand Bifunctional Reactions in the Design of Iron Asymmetric Hydrogenation Catalysts

This is an Account of our development of iron-based catalysts for the asymmetric transfer hydrogenation (ATH) and asymmetric pressure hydrogenation (AH) of ketones and imines. These chemical processes provide enantiopure alcohols and amines for use in the pharmaceutical, agrochemical, fragrance, and other fine chemical industries. Fundamental principles of bifunctional reactivity obtained by studies of ruthenium catalysts by Noyori's group and our own with tetradentate ligands with tertiary phosphine and secondary amine donor groups were applied to improve the performance of these first iron(II) catalysts. In particular the correct positioning of a bifunctional H-Fe-NH unit in an iron hydride amine complex leads to exceptional catalyst activity because of the low energy barrier of dihydrogen transfer to the polar bond of the substrate. In addition the ligand structure with this NH group along with an asymmetric array of aryl groups orients the incoming substrate by hydrogen-bonding, and steric interactions provide the hydrogenated product in high enantioselectivity for several classes of substrates. Enantiomerically pure diamines or diphenylphosphino-amine compounds are used as the source of the asymmetry in the tetradentate ligands formed by the condensation of the amines with dialkyl- or diaryl-phosphinoaldehydes, a synthesis that is templated by Fe(II). The commercially available ortho-diphenylphosphinobenzaldehyde was used in the initial studies, but then diaryl-phosphinoacetaldehydes were found to produce much more effective ligands for iron(II). Once the mechanism of catalysis became clearer, the iron-templated synthesis of (S,S)-PAr2CH2CH2NHCHPhCHPhNH2 ligand precursors was developed to specifically introduce a secondary amine in the precatalyst structures. The reaction of a precatalyst with strong base yields a key iron-amido complex that reacts with isopropanol (in ATH) or dihydrogen (in AH) to generate an iron hydride with the Fe-H bond parallel to the secondary amine N-H. In the AH reactions, the correct acidity of the intermediate iron-dihydrogen complex and correct basicity of the amide are important factors for the heterolytic splitting of the dihydrogen to generate the H-Fe-N-H unit; the acidity of dihydrogen complexes including those found in hydrogenases can be estimated by a simple additive ligand acidity constant method. The placement of the hydridic-protonic Fe-H···HN interaction in the asymmetric catalyst structure influences the enantioinduction. The sense of enantioinduction is predictable from the structure of the H-Fe-N-H-containing catalyst interacting with the ketone in the same way as related H-Ru-N-H-containing catalysts. The modular construction of the catalysts permits large variations in order to produce alcohol or amine products with enantiomeric excess in the 90-100% range in several cases.

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