**5. Structural effects of the catalyst and the cyclic imine substrate**

The main result, regarding ATH of dihydroisoquinolines, depends either on individual structural fragments of the catalyst itself or substitution on the molecule of the substrate. Even a small change either in the structure of catalyst or substrate can have a significant impact on the enantioselectivity, reaction rate or even feasibility of the process.

## **5.1. Modification of the structure of Noyori's catalysts**

As previously mentioned, one of the main advantages of Noyori's [Ru(Cl)(η6 arene)(*S, S)* TsDPEN] catalysts is their structural flexibility. The structure of these complexes can be divided into three components, while each of them can be synthetically modified to increase the catalytic activity and enantioselectivity of the reaction in ATH of specific substrates (**Figure 6**).

**Figure 6.** Scheme showing individual parts of the catalyst.

#### *5.1.1. Modification of the coordinated η6 -arene*

method was successfully validated and nowadays is used for the analysis of many tetrahy-

Chiral solvation by Pirkle's alcohol ((*R*)-(-)-1-(anthracen-9-yl)-2,2,2-trifluoroethanol) was used to determine *ee* at tetrahydroisoquinoline derivatives with a high boiling point. The method is based on the fact that the products of ATH provide diastereomeric solvates by the reaction

The main result, regarding ATH of dihydroisoquinolines, depends either on individual structural fragments of the catalyst itself or substitution on the molecule of the substrate. Even a small change either in the structure of catalyst or substrate can have a significant impact on

As previously mentioned, one of the main advantages of Noyori's [Ru(Cl)(η6 arene)(*S, S)* TsDPEN] catalysts is their structural flexibility. The structure of these complexes can be divided into three components, while each of them can be synthetically modified to increase the catalytic activity and enantioselectivity of the reaction in ATH of specific substrates (**Figure 6**).

droisoquinoline derivatives with a sufficiently low boiling point to GC analysis.

with Pirkle's alcohol and each product can be distinguished by NMR analysis.

**5. Structural effects of the catalyst and the cyclic imine substrate**

the enantioselectivity, reaction rate or even feasibility of the process.

**5.1. Modification of the structure of Noyori's catalysts**

**Figure 6.** Scheme showing individual parts of the catalyst.

*4.2.2. Determination of ee by chiral solvation by Pirkle's alcohol*

46 New Advances in Hydrogenation Processes - Fundamentals and Applications

The core of enantioselectivity of asymmetric transfer hydrogenation lies in the weak bond between the hydrogen atom of η6 -arene of the catalyst and π electrons of the aromatic ring of the substituted 3,4-dihydroisoquinoline substrate, e. g., CH/π interactions [7]. This interaction can assure the desired stabilization, providing the substrate molecule adopts a specific orientation permitting its formation. This interaction has also been one of the key reasons that gradually led to a certain abandoning of ketone-analogous mechanisms and formulations of the so-called ionic mechanism [5, 6, 13].

The work focused on the field of experimental testing of the Noyori based catalysts differentiated in their η6 -arene in ATH of various substituted 3,4-dihydroisoquinolines, accompanied by a computational study [14]. For the evaluation of the effect of η6 -arene ligand, a set of kinetic experiments was performed, followed by the determination of the enantiomeric purity of the products. For the purpose of this study, six cyclic imines (6, 7-dimethoxy-1-methyl-3,4 dihydroisoquinoline, 1-methyl-3,4-dihydroisoquinoline, 6 methoxy-1-methyl-3,4-dihydroisoquinoline, 7-methoxy-1-methyl-3,4-dihydroisoquinoline, 1-phenyl-3,4-dihydroisoquinoline, and 1-(4-trifluormethylphenyl)-3,4-dihydroisoquinoline) were tested in asymmetric transfer hydrogenation using four catalysts differing in their η6 arene ligand (*i.e*., benzene, mesitylene, *p*-cymene and hexamethylbenzene). According to the results, catalysts bearing mesitylene and *p* cymene (**Figure 7**), could deliver higher *ee* values than the catalyst containing benzene as η6 arene ligand. The explanation of this fact was found out by authors during the molecular modeling. The calculation of transition states of the ATH with catalyst containing *p*-cymene and mesitylene suggested that for those two, it was possible to form a double CH/π interaction, whereas for the catalysts with a benzene ligand, only a single CH/π interaction could be formed that resulted in lower *ee* values.

**Figure 7.** The so-called favorable transition state that occurred during the ATH of 1-methyl-3,4-dihydroisoquinoline.

Apart from the enantioselectivity, the modification of η6 -arene ligand affects also other reaction parameters. These include the turnover frequency (TOF), e.g., for the catalysts with hexamethylbenzene ligand, the TOF value was the smallest of all tested catalysts. Since homogeneous catalysis is involved, the solubility of the catalyst also plays a very important part of the synthesis. The modification of η6 -arene ligand significantly changes the solubility of the complex. The catalysts bearing mesitylene, *p* cymene and hexamethylbenzene were soluble in almost all polar solvents, whereas the catalyst with the benzene ligand was more or less soluble only in highly boiling solvents as dimethyl sulfoxide or *N, N* dimethylformamide.

#### *5.1.2. Modification of the sulfonyl moiety*

As mentioned in one of the previous sections, sulfonyl moiety of the catalyst, especially its oxygen atoms are important during the anticipated reaction mechanism where they serve as the active sites of the catalysts by interacting with both the protonated base and the protonated substrate with the use of hydrogen bonds. However, over a certain period of time, *N*-R-sulfonyl fragment was a target to a series of changes. Originally published catalysts [1, 2] contained *N*-aryl- or *N* alkylsulfonyl moieties of the TsDPEN ligand, typically mesityl (Mes), tosyl (Ts) or 1 naphthyl (Np). Later, the catalyst bearing methanesulfonyl fragment was found to be highly active in asymmetric hydrogenation of ketones and imines using gaseous hydrogen [15]. Among others, Wills and co-workers reported series of novel *N*-alkylated derivatives and tethered complexes, linking the arene and diamine ligand of the catalyst together [5, 16].

More profound modifications of *N*-R-sulfonyl fragment have been showed, aiming at substantial changes in catalyst's properties, e. g., for immobilization, or for conducting ATH in different media (water, ionic liquid, etc.) [17]. It is evident that the literature contains many interesting examples of structural variations. Nevertheless, the scope of available ligands is difficult to compare due to inconsistent reaction conditions.

#### *5.1.2.1. Asymmetric transfer hydrogenation of 1-phenyl dihydroisoquinolines*

Asymmetric transfer hydrogenation of 1-phenyl dihydroisoquinolines [18], represents a considerable challenge since the catalyst bearing the ligand of *N*-*p*-toluenesulfonyl-1, 2-diphenylethylenediamine (TsDPEN) failed to catalyze this reaction under standard reaction conditions. Although the original Noyori-type ATH catalysts always bore *N* arylsulfonyl as the substituent, several studies showed that Ir and Ru catalysts, containing methanesulfonyl-DPEN (MsDPEN), hydrogenated various aryl-*N*-benzyl imines, *N* sulfonylimines and aryl ketones with molecular hydrogen [5, 15, 19–21]. The ligand of methanesulfonyl DPEN is a part of a rather small group of ligands finding their use as a component of catalysts applicable for asymmetric (transfer) hydrogenation. Rather recently, another ligand bearing alkyl group, *N*-(camphor-10-sulfonyl)-DPEN (CsDPEN), was reported for its high efficiency in the ATH of a series of carbonyl compounds [22, 23]. However, no alkylsulfonyl diamines, such as 3,4 dihydroisoquinoline derivatives, have been applied in ATH of imines.

In addition, several Noyori-based Ru catalysts bearing *N*-naphtalene-1-sulfonyl-DPEN (NpsDPEN) and *N*-((*1S, 2S*-borneol-10-sulfonyl)-DPEN (CsDPEN) were tested in ATH of series of 1-phenyl-3,4-dihydroisoquinolines. The change of the original *N*-arylsulfonyl-DPEN from *p*-toluenesulfonyl-DPEN to naphthalene-1-sulfonyl in the catalysts structure, thus, enabled the catalytic activity in the ATH of aryl substituted 3,4-dihydroisoquinolines. The camphor fragment itself was indeed specific. The reaction which provided the desired catalytic complex was also an enantioselective reaction by itself. The preparation of the catalytic complex was performed in propane-2-ol, which also served as the hydrogen donor for ATH of ketones and thus the prepared complex also underwent transfer auto hydrogenation of the carbonyl group. The isolated crystalline material contained only one isomer. This isolated complex was tested in ATH of several 1-phenyl-3,4-dihydroisoquinolines derivates. Interestingly enough, in the reduction of aryl substrates containing electron-donating groups, the catalyst's performance was comparable with that measured with catalyst bearing naphthalene-1-sulfonyl-DPEN fragment. On the contrary, aryl substrates lacking electron-donating groups or even containing an electron withdrawing group displayed a very low catalytic activity. In the ATH of alkyl substrates, 1-methyl-3,4 dihydroisoquinoline and 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline, the reactivity was much higher than with naphthalene-1-sulfonyl-DPEN, and slightly exceeding the activity of original Noyori's catalyst with toluenesulfonyl-DPEN ligand.

Apart from the enantioselectivity, the modification of η6

48 New Advances in Hydrogenation Processes - Fundamentals and Applications

difficult to compare due to inconsistent reaction conditions.

*5.1.2.1. Asymmetric transfer hydrogenation of 1-phenyl dihydroisoquinolines*

part of the synthesis. The modification of η6

*5.1.2. Modification of the sulfonyl moiety*

thylformamide.

action parameters. These include the turnover frequency (TOF), e.g., for the catalysts with hexamethylbenzene ligand, the TOF value was the smallest of all tested catalysts. Since homogeneous catalysis is involved, the solubility of the catalyst also plays a very important

ty of the complex. The catalysts bearing mesitylene, *p* cymene and hexamethylbenzene were soluble in almost all polar solvents, whereas the catalyst with the benzene ligand was more or less soluble only in highly boiling solvents as dimethyl sulfoxide or *N, N* dime-

As mentioned in one of the previous sections, sulfonyl moiety of the catalyst, especially its oxygen atoms are important during the anticipated reaction mechanism where they serve as the active sites of the catalysts by interacting with both the protonated base and the protonated substrate with the use of hydrogen bonds. However, over a certain period of time, *N*-R-sulfonyl fragment was a target to a series of changes. Originally published catalysts [1, 2] contained *N*-aryl- or *N* alkylsulfonyl moieties of the TsDPEN ligand, typically mesityl (Mes), tosyl (Ts) or 1 naphthyl (Np). Later, the catalyst bearing methanesulfonyl fragment was found to be highly active in asymmetric hydrogenation of ketones and imines using gaseous hydrogen [15]. Among others, Wills and co-workers reported series of novel *N*-alkylated derivatives and tethered complexes, linking the arene and diamine ligand of the catalyst together [5, 16].

More profound modifications of *N*-R-sulfonyl fragment have been showed, aiming at substantial changes in catalyst's properties, e. g., for immobilization, or for conducting ATH in different media (water, ionic liquid, etc.) [17]. It is evident that the literature contains many interesting examples of structural variations. Nevertheless, the scope of available ligands is

Asymmetric transfer hydrogenation of 1-phenyl dihydroisoquinolines [18], represents a considerable challenge since the catalyst bearing the ligand of *N*-*p*-toluenesulfonyl-1, 2-diphenylethylenediamine (TsDPEN) failed to catalyze this reaction under standard reaction conditions. Although the original Noyori-type ATH catalysts always bore *N* arylsulfonyl as the substituent, several studies showed that Ir and Ru catalysts, containing methanesulfonyl-DPEN (MsDPEN), hydrogenated various aryl-*N*-benzyl imines, *N* sulfonylimines and aryl ketones with molecular hydrogen [5, 15, 19–21]. The ligand of methanesulfonyl DPEN is a part of a rather small group of ligands finding their use as a component of catalysts applicable for asymmetric (transfer) hydrogenation. Rather recently, another ligand bearing alkyl group, *N*-(camphor-10-sulfonyl)-DPEN (CsDPEN), was reported for its high efficiency in the ATH of a series of carbonyl compounds [22, 23]. However, no alkylsulfonyl diamines, such as 3,4 dihydroisoquinoline derivatives, have been applied in ATH of imines.


