Mechanisms asymmetric transfer hydrogenation

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. 

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. 21. General synthesis of p-CD-linked ruthenium complexes asymmetric transfer hydrogenation is described as a metal-ligand bifunctional mechanism according to 31).

Figure 1.24. Metal-ligand bifunctional mechanism in asymmetric transfer hydrogenation of...

Figure 1.25 exemplifies the strucmres of certain efficient precatalysts for asymmetric transfer hydrogenation of ketones. Precatalysts C1-C3 use the NH effect described above. A turnover frequency, defined as moles of product per mol of catalyst per hour, of 30,000 h is achieved by using of C2 and an alkaline base in 2-propanol. A Rh complex C3 is an isolobal to the corresponding arene-Ru complex (see Figure 1.23). The Ru complexes C4 " and C5 without NH group in ligand catalyze the reaction by different mechanisms. A higher than 90% optical yield is achieved by using C5 in reduction of certain aliphatic ketones.

Asymmetric transfer hydrogenation of imines catalyzed by chiral arene-Ru complexes achieves high enantioselectivity (Figure 1.34). Formic acid in aprotic dipolar solvent should be used as a hydride source. The reaction proceeds through the metal-ligand bifunctional mechanism as shown in the carbonyl reduction (Figure 1.24). 

Asymmetric transfer hydrogenation catalytic properties and mechanism... 

The real catalytic species 42 and key reactive intermediate 43 in asymmetric transfer hydrogenation with a chiral ligand 13-Ru(II) complex were isolated and characterized (Scheme 35) [120]. Examination of the reactivities of the two complexes as well as the kinetic study fully revealed the reaction mechanism. When the purple complex 42 is treated with 2-propanol at room temperature in the absence of any base, rapid elimination of acetone took place to produce the yellow Ru hydride species 43. The treatment of this 18-electron species 43 with... 

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. 

Wills and co-workers later suggested (48) that the reaction mechanism of the formic acid decomposition in a HCOOH/EtsN azeotrope to hydrogen and carbon dioxide, using a Rh-TsDPEN (where TsDPEN = AT-(4-toluenesulfonyl)-l,2-diphenylethylenediamine) tethered catalyst, is closely related to that of asymmetric transfer hydrogenations of ketones (Scheme Scheme 1). 

Scheme 1. Proposed mechanism for hydrogen formation from formic acid. It is anticipated to be closely related to that of asymmetric transfer hydrogenation reactions. Reprinted from Ref 48, copyright 2009, with kind permission from the American Chemical...

Scheme 1.46 A revised catalytic cycle for the asymmetric transfer hydrogenation of aromatic ketones in propan-2-ol by the Noyori-Ikariya (pre)catalyst 2 demonstrates crossover of the reaction pathways the product is obtained via a H"/H+ outer-sphere hydrogenation mechanism and/or step-wise metal-ligand bifunctional mechanism (see text). Formation of the major enantiomeric product is shown. (Adapted from Dub, P. A. et al., /. Am. Chem. Soc., 135, 2604-2619. Copyright 2013 American Chemical Society.)...

The catalytic alcohol racemization with diruthenium catalyst 1 is based on the reversible transfer hydrogenation mechanism. Meanwhile, the problem of ketone formation in the DKR of secondary alcohols with 1 was identified due to the liberation of molecular hydrogen. Then, we envisioned a novel asymmetric reductive acetylation of ketones to circumvent the problem of ketone formation (Scheme 6). A key factor of this process was the selection of hydrogen donors compatible with the DKR conditions. 2,6-Dimethyl-4-heptanol, which cannot be acylated by lipases, was chosen as a proper hydrogen donor. Asymmetric reductive acetylation of ketones was also possible under 1 atm hydrogen in ethyl acetate, which acted as acyl donor and solvent. Ethanol formation from ethyl acetate did not cause critical problem, and various ketones were successfully transformed into the corresponding chiral acetates (Table 17). However, reaction time (96 h) was unsatisfactory. 

In the case of isomerization which proceeds according to the 7c-allyl mechanism, 1,3-hydrogen transfer takes place. These reactions are catalyzed by palladium(II) complexes which easily form 7r-allyl complexes from 7r-olefin compounds. Also, compounds of nickel, rhodium, iron, etc., are utilized as catalysts. Effective isomerization is possible if the hydrogen addition to both terminal carbon atoms of the 7r-allyl asymmetric grouping takes place. 

Mechanistic studies of Ru-catalyzed asymmetric hydrogenations and transfer hydrogenations began shortly after the discovery of catalysts 1 and 2 and were based on three main approaches stoichiometric NMR studies, kinetic analyses including measurements of kinetic isotope effects (KlE s), and gas-phase computations. All of these methods are indeed ubiquitously used by chemists to study reaction mechanisms and analyze catalytic cycles. 

Kejrwords Dynamic kinetic asymmetric transformation (DYKAT) Dynamic kinetic resolution (DKR) Hydrogenation Imine reduction Ketone reduction Mechanism of carbonyl reduction Mechanism of imine reduction Mechanism of dUiydrogen activation Ruthenium catalysis Shvo s catalyst Transfer hydrogenation... 

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