Asymmetric Transfer Hydrogenation of Ketones and Imines

Noyori and coworkers reported well-defined ruthenium(II) catalyst systems of the type RuH( 76-arene)(NH2CHPhCHPhNTs) for the asymmetric transfer hydrogenation of ketones and imines [94]. These also act via an outer-sphere hydride transfer mechanism shown in Scheme 3.12. The hydride transfer from ruthenium and proton transfer from the amino group to the C=0 bond of a ketone or C=N bond of an imine produces the alcohol or amine product, respectively. The amido complex that is produced is unreactive to H2 (except at high pressures), but readily reacts with iPrOH or formate to regenerate the hydride catalyst. 

Palmer and Wills in 1999 reviewed other ruthenium catalysts for the asymmetric transfer hydrogenation of ketones and imines [101]. Gladiali and Mestro-ni reviewed the use of such catalysts in organic synthesis up to 1998 [102]. Review articles that include the use of ruthenium asymmetric hydrogenation catalysts cover the literature from 1981 to 1994 [103, 104], the major contributions... 

Chan et al. synthesized first- and second-generation dendrimers containing up to 12 chiral diamines at the periphery (Fig. 8) [29]. Their ruthe-nium(II) complexes displayed high catalytic activity and enantioselectivity in the asymmetric transfer hydrogenation of ketones and imines. Quantitative yields, and in some cases a slightly higher enantioselectivity compared to those of the monomeric systems (up to 98.7% ee), were obtained. 

Vaclavik, J. Kacer, R Kuzma, M. Cerveny, L. Opjxjrtimities offered by chiral n6-arene/N-arylsulfonyl-diamine-RuII catalysts in the asymmetric transfer hydrogenation of ketones and imines. Molecules 2011,16,5460-5495. 

Noyori Asymmetric Transfer Hydrogenation Noyori s well-designed chiral Ru -arene complexes catalyze the asymmetric transfer hydrogenation of ketones and imines (not shown) with stable organic hydrogen donors such as 2-propanol [69]. The reaction is reversible, and the involved chiral ruthenium species and the proposed transition state are depicted in Scheme 2.140. 

Precursor of Useful Chiral Ligands. OPEN is widely used for the preparation of chiral ligands. Organometallic compounds with these ligands act as useful reagents or catalysts in asymmetric induction reactions such as dihydroxylation of olefins, transfer hydrogenation of ketones and imines, Diels-Alder and aldol reactions, desymmetrization of meso-diols to produce chiral oxazolidinones, epoxidation of simple olefins, benzylic hydroxylation, and borohydride reduction of ketones, imines, and a,p-unsaturated carboxylates. ... 

In order to facilitate recycling of the multiple TsDPEN-functionalized dendrimer catalysts, the same group recently reported the synthesis of a novel form of hybrid dendrimer ligands by coupling polyether dendrons with peripherally TsDPEN-functionahzed Newkome-type poly(ether-amide) dendrimer (Figure 4.28) [90]. The solubility of these hybrid dendrimers was found to be affected by the generation of the polyether dendron. The ruthenium complexes produced were applied in the asymmetric transfer hydrogenation of ketones, enones, imines and activated... 

Following the development of successful catalytic hydrogenation of olefins, recent attention is directed to catalytic hydrogenation and transfer hydrogenation of ketones and imines [77]. Because of requirement of production of various pharmaceutical compounds of importance, further development is expected in asymmetric catalytic hydrogenation. 

One place to look for good alcohol racemization catalysts is in the pool of catalysts that are used for hydrogen transfer reduction of ketones. One class of complexes that are excellent catalysts for the asymmetric transfer hydrogenation comprises the ruthenium complexes of mono sulfonamides of chiral diamines developed by Noyori and coworkers [20, 21]. These catalysts have been used for the asymmetric transfer hydrogenation of ketones [20] and imines [21] (Fig. 9.9). 

Other aminophosphines have also been sought and applied in different enantio-selective transformations, e. g., allylic substitution [56] (up to 95 % ee), and Ir-based imine hydrogenation (88% ee) [57]. Chiral aminophosphines have also been investigated in the asymmetric transfer hydrogenation of ketones (up to 84 % ee for the reduction of aryl ketones) [58],... 

Asymmetric Transfer Hydrogenation of Ketones. The first reports on asymmetric transfer hydrogenation (ATH) reactions catalyzed by chiral metallic compounds were published at the end of the seventies. Prochiral ketones were reduced using alcohols as the hydrogen source, and Ru (274,275) or Ir (276) complexes were used as catalysts. Since then, many chiral catalytic systems for homogeneous ATH of ketones, imines, and olefins have been developed (37,38,256,257,277-289). The catalytic systems are usually based on ruthenium, rhodium, or iridium, and the ATH of aryl ketones is by far the most studied. Because of the reversibility of this reaction, at high conversions, a gradual erosion of the ee of the product has been frequently reported. An azeotropic 5 2 mixture of formic acid/triethylamine can be used to overcome this limitation. 

Zuo, W. Tauer, S. Prokopchuk, D. E. Morris, R. H. Iron catalysts containing amine(imine)diphosphine P-NH-N-P ligands catalyze both the asymmetric hydrogenation and asymmetric transfer hydrogenation of ketones. Organometallics 2014,33,5791-5801. 

Among the most active catalysts for the asymmetric transfer hydrogenation of prochiral ketones and imines to chiral alcohols and amines are arene-ruthenium(II) amino-alcohol (or primary/ secondary 1,2-diamine)-based systems, with an inorganic base as co-catalyst, developed by Noyori139-141 and further explored by others (Scheme 27).142-145... 

The catalytic, asymmetric hydrogenations of alkenes, ketones and imines are important transformations for the synthesis of chiral substrates. Organic dihydropyridine cofactors such as dihydronicotinamide adenine dinucleotide (NADH) are responsible for the enzyme-mediated asymmetric reductions of imines in living systems [86]. A biomimetic alternative to NADH is the Hantzsch dihydropyridine, 97. This simple compound has been an effective hydrogen source for the reductions of ketones and alkenes. A suitable catalyst is required to activate the substrate to hydride addition [87-89]. Recently, two groups have reported, independently, the use of 97 in the presence of a chiral phosphoric acid (68 or 98) catalyst for the asymmetric transfer hydrogenation of imines. 

Asymmetric Transfer Hydrogenation of Imines. In spite of the great importance of optically active amines for pharmaceutical and agrochemical industries, the ATH of C=N imine bonds has been much less studied than that of ketone bonds (278,280,284,289,340). Cyclic imines are reduced with greater ee values than their acyclic counterparts. The existence of geometrical isomers for the latter is based on the encountered difference in selectivity. 

Vdclavik, J. L Kuzma, M. Pfech, J. Kader, P. Asymmetric transfer hydrogenation of imines and ketones using chiral RuIICl(T 6-p-cymene)[(S, S)-N-TsDPEN] as a catalyst A computational study. Organometallics 2011, 30, 4822-4829. 

Transfer hydrogenation is particularly good for the reduction of ketones and imines that are somewhat more difficult to reduce with Hj than are C—C bonds. BSckvall and co-workers have shown how RuCl fPPhj) is effective at 80°C with added base as catalyst promoter. The role of die base is no doubt to form the isopropoxide ion. which presumably coordinates to Ru and by elimination forms a hydride and acetone. Noyori and co-workers have has a remarkable asymmetric catalytic hydrogen transfer that goes without direct coordination of the C=0 bond to the metal. Instead, the metal donates a hydride to the C=0 carbon while the adjacent RU-NH2R group donates a proton to the C=0 oxygen. 

Asymmetric hydrogen transfer shows promise for use at industrial scale because ruthenium complexes that contain chiral vicinal diamino 164 or amino alcohol 165 ligands allow the reductions of substrates such as aryl ketones and imines to be achieved under mild conditions.13 207... 

Hypothesizing that primary amine catalysts, due to their reduced steric requirements, might be suitable for the activation of ketones, we studied various salts of a-amino acid esters. (For pioneering use of primary amine salts in asymmetric iminium catalysis involving aldehyde substrates, see Ishihara and Nakano 2005 Sakakura et al. 2006 for the use of preformed imines of a, 3-unsaturated aldehydes and amino acid esters in diastereoselective Michael additions, see Hashimot et al. 1977.) We have developed a new class of catalytic salts, in which both the cation and the anion are chiral. In particular, valine ester phosphate salt 35 proved to be an active catalyst for the transfer hydrogenation of a variety of a, 3-unsaturated ketones 36 with commercially available Hantzsch ester 11 to give saturated ketones 37 in excellent enantiose-lectivities (Scheme 28 Martin and List 2006). 

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