Asymmetric transfer hydrogenations

Asymmetric reduction of prochiral ketones using TH is an effective and mild route for the formation of optically active secondary alcohols. Generally, NHC-based systems display good catalytic activity but the obtained ee values are low to moderate. 

Rh and Ir NHC derived from amino acids such as 71 were found to be promising catalysts. Finally, Ru complexes prepared from chiral oxazolines containing imidazol-2-ylidenes were used for ATH of acetophenone and alkyl ketones in refluxing KOH/i-PrOH. However, 72 only exhibited a moderate activity and no chiral induction.  

Very recently, Chen and Deng reported the synthesis of the chiral dendrimer 1,2-diaminocyclohexane (DACH) by using a very similar synthetic approach 

In 2003, two other series of chiral dendrimer hgands based on (1S,2R)-norephedrine were reported by Deng and Tu, which were used in ruthenium- 

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Asymmetric transfer hydrogenation reducing agents react with 2-aryl azirines to give aziridines in good yields but with moderate enantiomeric excesses (Scheme 4.42) [62],... 

On the other hand, one of the first chiral sulfur-containing ligands employed in the asymmetric transfer hydrogenation of ketones was introduced by Noyori el al Thus, the use of A-tosyl-l,2-diphenylethylenediamine (TsDPEN) in combination with ruthenium for the reduction of various aromatic ketones in the presence of i-PrOH as the hydrogen donor, allowed the corresponding alcohols to be obtained in both excellent yields and enantioselectivities, as... 

As another successful application of Noyori s TsDPEN ligand, Yan et al. reported the synthesis of antidepressant duloxetine, in 2008. Thus, the key step of this synthesis was the asymmetric transfer hydrogenation of 3-(dime-thylamino)-l-(thiophen-2-yl)propan-l-one performed in the presence of (5,5)-TsDPEN Ru(II) complex and a HCO2H TEA mixture as the hydrogen donor. The reaction afforded the corresponding chiral alcohol in both high yield and enantioselectivity, which was further converted in two steps into expected (5)-duloxetine, as shown in Scheme 9.17. 

Even if chiral S/N ligands have proved their efficiency for promoting metal-catalysed asymmetric transfer hydrogenation, up to now they do not compete with the N/N ligands, at least in terms of enantioselectivity. ... 

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. 

Apart from the Meerwin-Ponndorf-Verley (MPV) reaction,16 18catalytic asymmetric transfer hydrogenation has remained quite primitive,111,112 with successful examples of reduction of activated olefins, using alcohols or formic acid as hydrogen source, being reported only recently.113,114... 

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... 

Asymmetric transfer hydrogenation can be employed in the asymmetric hydrogenation of prochiral ketones with a ruthenium complex of bis(oxazolinylmethyl) amine ligand 110. Enantioselectivities are greater than 95%.643... 

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... 

A number of excellent reviews have recently been published [1] consequently, this chapter will consider mainly the practical aspects of asymmetric transfer hydrogenation by reviewing each of the components of the reaction, namely catalyst, hydrogen donor, substrate, product and other elements such as solvent, reaction conditions and scale-up. 

In broad terms there are three types of catalyst for transfer hydrogenation dehydrogenases heterogeneous and homogenous metal catalysts. Here, the first two are mentioned for completeness, and the main focus of this chapter will be asymmetric transfer hydrogenation with homogenous metal catalysts. 

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]. 

Fig. 35.6 Synthesis of chiral amines by an improved procedure for making diphenylphosphinylimines, followed by asymmetric transfer hydrogenation.

The synthesis of amines by the in-situ reductive amination of ketones is termed the Leuckart-Wallach reaction. Recently, an asymmetric transfer hydrogenation version of this reaction has been realized [85]. Whilst many catalysts tested give significant amounts of the alcohol, a few produced almost quantitative levels of the chiral amine, in high enantiomeric excess. 

Scheme 36.7 Parallel ruthenacycle preparation and screening in asymmetric transfer hydrogenation.

Table 41.15 Recycling of 9- and 10-Ru in the asymmetric transfer hydrogenation of acetophenone with the azeotrope in [BMIM][PF6] [110].

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]. 

Evans et al.106 report an asymmetric transfer hydrogenation of ketones using samarium(III) complex (108) as the catalyst at ambient temperature in 2-propanol. The products showed ee comparable with those obtained through enantioselective borane reduction (Scheme 6-48). 

Increasing effort has been applied to develope asymmetric transfer hydrogenations for reducing ketones to alcohols because the reaction is simple to perform and does not require the use of reactive metal hydrides or hydrogen. Ruthenium-catalyzed hydrogen transfer from 2-propanol to ketones is an efficient method for the preparation of secondary alcohols. 

Complex 109 can also be used for the asymmetric transfer hydrogenation... 

TABLE 6-10. Asymmetric Transfer Hydrogenation of a Variety of Imines... 

Scheme 6-51. Asymmetric transfer hydrogenation of acetophenone in the presence of 119. Reprinted with permission by Am. Chem. Soc., Ref. 112.

Jiang et al.113 synthesized another tridentate ligand 121 for asymmetric transfer hydrogenation. Ru-121-catalyzed asymmetric transfer hydrogenation gives comparable enantioselectivity to Noyori s catalyst 109 but shows more... 

Transition metal complexes with chiral phosphorous and nitrogen ligands have also been used for promoting asymmetric transfer hydrogenation. Moderate to good results have been obtained.114... 

The asymmetric transfer hydrogenation of ketones is further described elsewhere.117... 

I. S. 3/ >.4/ >j-2-AZANORBORNYLMETIIANOL, AN EFFICIENT LIGAND FORRUTHENIUM-CATALYSED ASYMMETRIC TRANSFER HYDROGENATION OF AROMATIC KETONES... 

Ruthenium-catalysed asymmetric transfer hydrogenation of acetophenone 133... 

In this chapter and in Chapters 10-12, we will review and validate some methods for asymmetric (transfer) hydrogenation of carbon-oxygen and carbon-carbon double bonds catalysed by non-metallic systems, homogeneous transition metal catalysts and biocatalysts. Reduction of carbon-nitrogen double bond systems will be reported in another volume of this series. 

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