Hydrogenation Noyori transfer

With transfer hydrogenation Noyori et al. were not only able to hydrogenate C-0 double bonds but also the C-N double bonds of prochiral imines. As hydrogen donor they used a formic acid-triethylammonium mixture. With the chiral Ru(II)-catalyst systems shown in Scheme 4 they achived ee s up to 96 % in hydrogenating various prochiral imines. [19]... 

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. 

The Noyori transfer hydrogenation is operationally simple, and the achieved enantioselectivities are generally very high. For example, when a O.IM solution of acetophenone in 2-propanol containing [ RuClj(ri -p-cymene) J, (lS,2S)-A-p-toluenesulfonyl-l,2-diphenylethylenediamine, and KOH (ketone Ru diamine KOH=200 1 1 2 molar ratio) was... 

Vedejs E, Trapencieris P, Suna E. Substituted isoquinohnes by Noyori transfer hydrogenation enantioselective synthesis of chiral diamines containing an aniline subunit. J. Org. Chem. 1999 64(18) 6724-6729. 

These transition-metal catalysts contain electronically coupled hydridic and acidic hydrogen atoms that are transferred to a polar unsaturated species under mild conditions. The first such catalyst was Shvo s diruthenium hydride complex reported in the mid 1980s [41 14], Noyori and Ikatiya developed chiral ruthenium catalysts showing excellent enantioselectivity in the hydrogenation of ketones [45,46]. 

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. 

Liese el al. attached a transfer-hydrogenation catalyst to a soluble polymer and applied this system in a continuously operated membrane reactor.[60] A Gao-Noyori catalyst was bound to a soluble polysiloxane polymer via a hydrosilylation reaction (Figure 4.41). 

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. 

An interesting catalytic ruthenium system, Ru(7/5-C5Ar4OH)(CO)2H based on substituted cyclopentadienyl ligands was discovered by Shvo and coworkers [95— 98]. This operates in a similar fashion to the Noyori system of Scheme 3.12, but transfers hydride from the ruthenium and proton from the hydroxyl group on the ring in an outer-sphere hydrogenation mechanism. The source of hydrogen can be H2 or formic acid. Casey and coworkers have recently shown, on the basis of kinetic isotope effects, that the transfer of H+ and TT equivalents to the ketone for the Shvo system and the Noyori system (Scheme 3.12) is a concerted process [99, 100]. 

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]. 

Typically, heterogeneous transfer hydrogenations are carried out at higher temperatures. The Noyori-Ikariya ruthenium arene catalysts are stable up to temperatures around 80 °C, whilst the rhodium and iridium CATHy catalysts are... 

Besides Ir-diphosphines, two more catalyst systems have shown promise for industrial application. As mentioned in Section 37.5.2, the Rh-Josiphos-cata-lyzed hydrogenation of unprotected /1-dehydro amino acid derivatives by Merck actually involves the hydrogenation of a C=N and not a C=C bond (see Fig. 37.10) [3, 51]. Noyori s Ru-PP-NN catalyst system seems also suitable for C=N hydrogenation [129], and was successfully applied in a feasibility study by Dow/Chirotech for the hydrogenation of a sulfonyl amidine [130]. Avecia also showed the viability of its CATHy catalyst for the transfer hydrogenation of phosphinyl imines [115] (see Fig. 37.34). 

Vedejs et al. reported catalyst inhibition during a study on the enantioselective transfer hydrogenation of dihydro-isoquinolines using Noyori s catalyst (Scheme 44.2) [27]. Here, the problem is caused by the bidentate nature of the substrate. Whereas the bromo compound 1 a could be rapidly reduced, the tosylamide-sub-stituted compound lb could not be reduced, and although the problem could be alleviated somewhat by alkylation of the sulfmamide to 1 c, hydrogenation of this was still sluggish. Although the authors propose this to be a case of product... 

Whereas most hydrogenation catalysts function very well in water (see for example Chapter 38 for two-phase aqueous catalysis), scattered instances are known of inhibition by water. Laue et al. attached Noyori s transfer hydrogenation catalyst to a soluble polymer and used this in a continuous device in which the catalyst was separated from the product by a membrane. The catalyst was found to be inhibited by the presence of traces of water in the feed stream, though this could be reversed by continuously feeding a small amount of potassium isopropoxide [60]. A case of water inhibition in iridium-catalyzed hydrogenation is described in Section 44.6.2. 

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