Ruthenium catalysts asymmetric transfer hydrogenation

We therefore quickly turned our attention to the ruthenium-catalyzed asymmetric transfer hydrogenation recently reported by Noyori. Without any optimization, 95% yield and 96% e.e. were obtained with 0.25 mol% catalyst and formic acid-triethylamine 5 2 azeotropic mixture (2.5 mL/g) in CH2CI2 at room temperature for 8 h (Scheme 6.17). - Apart from the high yield, enantiomeric excess, and turnover, this procedure is particularly simple to carry out. It also allows an easy recovery of the optically active amine by filtration, as its formiate salt at the end of the reaction, if needed, would offer an additional improvement in optical purity. 

The use of chiral ruthenium catalysts can hydrogenate ketones asymmetrically in water. The introduction of surfactants into a water-soluble Ru(II)-catalyzed asymmetric transfer hydrogenation of ketones led to an increase of the catalytic activity and reusability compared to the catalytic systems without surfactants.8 Water-soluble chiral ruthenium complexes with a (i-cyclodextrin unit can catalyze the reduction of aliphatic ketones with high enantiomeric excess and in good-to-excellent yields in the presence of sodium formate (Eq. 8.3).9 The high level of enantioselectivity observed was attributed to the preorganization of the substrates in the hydrophobic cavity of (t-cyclodextrin. 

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... 

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... 

The mechanism of the Meerwein-Pondorf-Verley reaction is by coordination of a Lewis acid to isopropanol and the substrate ketone, followed by intermolecular hydride transfer, by beta elimination [41]. Initially, the mechanism of catalytic asymmetric transfer hydrogenation was thought to follow a similar course. Indeed, Backvall et al. have proposed this with the Shvo catalyst [42], though Casey et al. found evidence for a non-metal-activation of the carbonyl (i.e., concerted proton and hydride transfer [43]). This follows a similar mechanism to that proposed by Noyori [44] and Andersson [45], for the ruthenium arene-based catalysts. By the use of deuterium-labeling studies, Backvall has shown that different catalysts seem to be involved in different reaction mechanisms [46]. 

Carpentier and coworkers studied the asymmetric transfer hydrogenation of /f-keloeslers using chiral ruthenium complexes prepared from [(// -p-cyrriene)-RuC12]2 and chiral aminoalcohols based on norephedrine. During this study, these authors became aware of substrate inhibition when ketoesters carrying 4-halo-substituents were used. It transpired that this was caused by formation of a complex between the substrate and the catalyst [28]. 

An excellent review describing asymmetric transfer hydrogenation has been published156. Many excellent results have been achieved in recent studies of acrylic acid reductions employing the same catalysts of ruthenium or rhodium with a chiral diphosphine as were used in the hydrogen gas process1331157. In this case, however, the most common hydrogen source is the combination of formic acid with an amine. The choice of amine is often critical in the reduction shown in Scheme 30, the use... 

Dissymmetric ferrocenyldiphosphines have been synthesized from (R)-(+)-N, N -dimethylaminoethylferrocene. The diphosphines have been used as ligands in asymmetric transfer hydrogenation of acetophenone in the presence of ruthenium catalysts.297 Asymmetric transfer hydrogenation of a,/S-unsaturated aldehydes with Hantzsch dihydropyridines and a catalytic amount of MacMillan imidazolidinone salt (12) leads to the saturated carbonyl compounds in high yields and excellent chemo-and enantio-selectivities.298 ... 

Asymmetric transfer hydrogenation of acetylpyridines is possible in the presence of chiral ruthenium catalysts and... 

Preferential chirality can also be imposed on the sp2 carbon of the azirine through the asymmetric transfer hydrogenation protocol. Thus, the azirine 191 was converted to the scalemic aziridine 192 in 83% yield and 72% ee in the presence of a ruthenium catalyst and the chiral auxiliary 190 in an isopropanol medium <02CC1752>. 

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). 

Among the various chiral catalysts reported for asymmetric transfer hydrogenation, the most notable has been the ruthenium complex with N-(p-toluenesulfonyl)-... 

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... 

E., King, F. and Xiao, J. (2004) Organic Letters, 5, 3321. The asymmetric transfer hydrogenation of various acetophenones was catalyzed in water by a ruthenium complex of PEG-TsDPEN (0.1-1.0mol%) with sodium formate, and the polymeric catalyst was readily recovered via precipitation, and reused 14 times without significant loss of either catalytic activity or stereoselectivity. 

There have been multiple efforts toward supported catalysts for asymmetric transfer hydrogenation, and the 4 position on the aryl sulfonate group of 26 has proven a convenient site for functionalization. Thus far, this ligand has been supported on dendrimers [181,182], polystyrenes [183], silica gel [184], mesoporous siliceous foam [185], and mesoporous siliceous foam modified with magnetic particles [186]. The resulting modified ligands have been used in combination with ruthenium, rhodium, and iridium to catalyze the asymmetric transfer of imines and, more commonly, ketones. 

This example illustratively shows that inorganic materials are well suited for continuous flow processes in column-like reactors. Thus, covalently immobilized NH-benzyl-(li, 2S)-(-)-norephedrine 10 on silica inside a column was doped with ruthenium. This setup was used to carry out continuous asymmetric transfer hydrogenation reactions (Scheme 10) [38]. Remarkably,no catalyst deactivation occurred over a period of one week, which the authors ascribed to the successful site isolation of the catalyst on the support. 

Other chiral diamine-( -arene)ruthenium catalysts were developed by Noyori where the chirality was centred at the metal (see Figure 3.18). These complexes were effective catalysts for asymmetric transfer hydrogenation of carbonyl compounds and a mechanism involving a metal-ligand bifunctional process was proposed. 

Asymmetric transfer hydrogenation of ketones in the presence of soluble transition metal catalysts has been developed [8-10], enantioselectivities up to 99% ee being obtained using a ruthenium catalyst bearing mono-N-tosylated diphenyl-ethylenediamine as a ligand. Iridium complexes associated with fluorous chiral diimines 3a-3c or diamines 4a—4b have also been shown to be effective catalysts in hydrogen-transfer reduction of ketones [11,12]. 

The reduction of the carbonyl group (and related functionalities) by catalytic methods has been successfully achieved by a number of methods. Rhodium and ruthenium complexes are the most popular catalysts used in the hydrogenation of ketones. While most catalyst systems of this type require the presence of additional chelating functionality on the substrate the recent development of highly active ruthenium(diamine) complexes allows the reduction of simple unfunctionalised ketones. Ruthenium catalysts have also been applied, with much success, to the catalytic asymmetric transfer hydrogenation of ketones in the presence of alcohols or formate. 

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