**1. Introduction**

Synthesis of biologically active chiral compounds such as drugs or pesticides goes hand in hand with the necessity of a high optical purity. Chiral molecules play an important role in many basic functions of living organisms, e.g., molecular recognition in biological systems is achieved by chiral environment (e.g., receptors), and thus the response induced by one enantiomer can be completely different from the other enantiomer of the same compound.

Commonly used synthetic approaches are not stereoselective and lead to a racemic mixture of the products from which the desired enantiomer is to be separated using specific separation methods, such as racemic cleavage. This method is relatively broadly applied in the chemical

industry but it can hardly be considered as ideal. Frequently, the yield of this process is limited only to 50% since the second (undesired) enantiomer is not recyclable and ends up as a waste. This fact represents a significant limitation, especially, during the synthesis of fine chemicals, e.g., drugs, where every loss can have a significant impact on profitability of the production process. These economical aspects are one of the most important reasons why the methods of enantioselective (asymmetric) synthesis are still in the forefront of modern synthetic chemistry.

From a historical point of view, the first described enantioselective reaction was asymmetric hydrogenation (AH). Mainly homogenous catalysts, represented by coordinated compounds with optically pure ligands, carrying asymmetric information, have been used in this type of reaction. These catalysts can be divided into several subgroups, e.g., according to the ligand structure, function groups, central atom, or mechanistic aspects. Nevertheless, the hydrogen source plays most prominent role. Meanwhile the classical asymmetric hydrogenation used gaseous hydrogen, while asymmetric transfer hydrogenation (ATH) focused on utilizing substances contained in the reaction mixture, such as propane-2-ol or azeotropic mixture of formic acid and triethylamine. The absence of gaseous hydrogen in the case of ATH enabled to skip the requirement of pressure reactors, which lowered the overall cost of the process and minimized the explosion hazard.

First, homogeneous catalysts to be applied in ATH of prochiral ketone and imine compounds were introduced by the group of professor Noyori between 1995 and 1996 [1, 2] (**Figure 1**). The catalysts contained ruthenium(II) as the central atom, enantioenriched chiral diamine ligand, such as *N* (2-amino-1,2-diphenylethyl)-4-toluenesulfonylamide, in short TsDPEN and η6 aromatic ligand (e.g., benzene, *p*-cymene or mesitylene). The main advantage of these complexes lied in their high modularity. The structure of these complexes can be relatively easily modified in order to enhance their catalytic properties to better fit the hydrogenated substrate.

**Figure 1.** A scheme of asymmetric transfer hydrogenation of 1-methyl-3,4-dihydroisoquinoline.

This work is predominantly focused on the ATH of compounds with C=N and C=O double bonds in its structure using Noyori's ruthenium catalytic complexes. Additionally, several related topics are discussed such as the mechanism of asymmetric transfer hydrogenation of imines and ketones, the modification of the catalyst structure, the influence of the reaction conditions, and its application to the chemical industry and the synthesis of pharmaceutical substances.

#### **2. Mechanism of ATH catalyzed by [RuCl(η6 -arene)TsDPEN]**

industry but it can hardly be considered as ideal. Frequently, the yield of this process is limited only to 50% since the second (undesired) enantiomer is not recyclable and ends up as a waste. This fact represents a significant limitation, especially, during the synthesis of fine chemicals, e.g., drugs, where every loss can have a significant impact on profitability of the production process. These economical aspects are one of the most important reasons why the methods of enantioselective (asymmetric) synthesis are still in the forefront of modern synthetic chemistry. From a historical point of view, the first described enantioselective reaction was asymmetric hydrogenation (AH). Mainly homogenous catalysts, represented by coordinated compounds with optically pure ligands, carrying asymmetric information, have been used in this type of reaction. These catalysts can be divided into several subgroups, e.g., according to the ligand structure, function groups, central atom, or mechanistic aspects. Nevertheless, the hydrogen source plays most prominent role. Meanwhile the classical asymmetric hydrogenation used gaseous hydrogen, while asymmetric transfer hydrogenation (ATH) focused on utilizing substances contained in the reaction mixture, such as propane-2-ol or azeotropic mixture of formic acid and triethylamine. The absence of gaseous hydrogen in the case of ATH enabled to skip the requirement of pressure reactors, which lowered the overall cost of the process and

38 New Advances in Hydrogenation Processes - Fundamentals and Applications

First, homogeneous catalysts to be applied in ATH of prochiral ketone and imine compounds were introduced by the group of professor Noyori between 1995 and 1996 [1, 2] (**Figure 1**). The catalysts contained ruthenium(II) as the central atom, enantioenriched chiral diamine ligand, such as *N* (2-amino-1,2-diphenylethyl)-4-toluenesulfonylamide, in short TsDPEN and

 aromatic ligand (e.g., benzene, *p*-cymene or mesitylene). The main advantage of these complexes lied in their high modularity. The structure of these complexes can be relatively easily modified in order to enhance their catalytic properties to better fit the hydrogenated

**Figure 1.** A scheme of asymmetric transfer hydrogenation of 1-methyl-3,4-dihydroisoquinoline.

This work is predominantly focused on the ATH of compounds with C=N and C=O double bonds in its structure using Noyori's ruthenium catalytic complexes. Additionally, several related topics are discussed such as the mechanism of asymmetric transfer hydrogenation of imines and ketones, the modification of the catalyst structure, the influence of the reaction conditions, and its application to the chemical industry and the synthesis of pharmaceutical

minimized the explosion hazard.

η6

substrate.

substances.

The first study regarding mechanistic aspects of the reaction was performed by Noyori et al. in 2001 [3]. This work was focused on the ATH of ketones. By means of molecular modeling methods, it was demonstrated that the reaction proceeds *via* a six-membered cyclic transition state. For the purpose of these calculations, formaldehyde as the substrate and simplified structure of the catalytic complex, i.e., Ru(H)(η6 -benzene)(ethylenediamine) were used (**Figure 2**). According to their findings, the substrate primarily formed C=O⋅⋅⋅H-N intermediate with the ruthenium complex and then evolved into six-membered cyclic transition state. Simultaneously, a proton transfer from the NH group took place to the carbonyl oxygen and hydride transfer onto the C=O carbon atom.

**Figure 2.** The original mechanistic concept published by Noyori et al. [3].

However, in 2013 Dub and Ikariya extended the previous Noyori's study and reported the detailed density functional theory (DFT) study [4], which showed that the hydrogenation of ketones occurred *via* a two-step pathway including the solvent as an important part of the hydrogen transfer mechanism.

From this perspective, the catalyst containing a ligand with (*S, S*) configuration provided (*S*) product. Nevertheless, Wills et al. [5] pointed out that this concept was not applicable on the ATH of imines, since the reaction was catalyzed by the catalyst with (*S, S*) configuration of the ligand providing (*R*)-product. An interesting fact was reported by Åberg et al. [6], who, in their study, proved that ATH of imines could be performed only in the presence of acids (for instance, an azeotropic mixture of formic acid and triethylamine), whereas ketones were possible to be hydrogenated also in alkaline medium. Imine, contrary to the ketone, enters the reaction in a protonated form and thus to perform the reaction itself, an acid addition is necessary. Consequently, Wills et al. [5] proposed several transition state structures, the socalled ionic mechanism, and presented their own experimental data.
