*5.1.2.2. Comparison of the different sulfonyl moieties in the ATH of alkyl-3,4-dihydroisoquinolines*

The role of sulfoonamide moiety of Noyori-based catalysts [Ru(II)Cl(η6 *p* cymene)(*S,S*)-(*N*arylsulfonyl-DPEN) in the asymmetric transfer hydrogenation of two cyclic imine substrates (1-methyl-3,4-dihydroisoquinoline and 6,7 dimethoxy-1-methyl-3,4-dihydroisoquinoline) was also investigated [24]. All together, nine complexes, differing in substitution of the aromatic ring of the ligand, were synthesized and characterized, most of which have not been previously reported and the majority of the corresponding ligands have not been described in imine ATH.

As the standard, Noyori's original catalysts bearing N-*p*-toluenesulfonyl-DPEN ligand was selected, which served as the benchmark for the kinetic study. The substitution of the sulfonyl part of the catalyst was divided into several parts. The first were the ligands with bulky groups (*p*-(*tert*-butyl)phenyl, mesityl and 1-naphtyl), the second aromatic ring bearing electron donating methoxy groups differing in their position on the aromatic ring. Others were ligands with (3,4-dichloro)phenyl substituent as the representative of halogenated aromatic ring. The last two complexes contained: first, a very bulky and electron-poor 3,5-bis(trifluoromethyl)phenyl group, and the second, a heteroatom-containing ring, thiophene, chosen as an alternative to the common aromatic substituents.

The results obtained in this study showed that the change of aryl substituent on the sulfonyl part of the catalyst had a great influence on the reaction rate in ATH of 3,4 dihydroisoquinolines. Especially, the halogenated and hetero-aromatic substituents delivered reasonable reactivity only for one of the two substrates. The sterically demanding naphthyl containing ligand was the least preferred one.

#### **5.2. Structural effects of the substrate**

Isoquinoline-based molecules belong to the most important naturally-occurring alkaloids encompassing a significant group of biologically active species. These compounds have various pharmacological effects, which are enabled by their structural similarity with endogenous neurotransmitters. Therefore, a kinetic NMR study of ATH of five different 3,4 dihydroisoquinolines (**Figure 8**) was performed [25]. Four of them differed in various methoxysubstitutions of the dihydroisoquinoline skeleton, while the fifth examined substrate was a precursor for the production of mivacurium, a muscle relaxant. With 7 methoxy derivates (**3, 4, 5**), the reaction rate was significantly higher than in the case where no methoxy group was present in the position 7. The ATH of 6-methoxy-1-methyl-3,4-dihydroisoquinoline (**2**), bearing the 6-methoxy group, proceeded with a considerably lower reaction rate. However, the positive influence of the 7-methoxy group seemed to have overcome the detrimental effect of the 6-methoxy substituent when these two were present together, as it was for instance in the case of 6,7-dimethoxy-1-methyl-3,4-dihyroisoquinoline. Similarly, the bulky 1 (3',4',5' trimethoxybenzyl) moiety of the last substrate (**5**) further enhanced the reaction performance.

**Figure 8.** List of model substrates used to determine the effect of different substitution at the aromatic ring.

The substitution of the dihydroisoquinoline substrate with methoxy groups is followed by a much higher reaction rate and enantioselectivity than in the case of 1-methyl-3,4-dihydroisoquinoline (**1**). The presence of one methoxy group in the substrate molecule (**2** and **3**) led to an *ee* increase of 4–5 percentage points (89% (**2**) and 88% (**3**) versus 84% with the substrate **1**). With more methoxy groups affording *ees* higher by 9–10 percentage points (93% (**4**) and 94% (**5**) versus 84% with the substrate **1**). This observation could be attributed to substituent effects on the aromatic ring of the substrate, which affected the CH/π attraction between the catalyst and the substrate.

These experimental observations were supported by examining all involved substrates using molecular modeling, especially, the charge distribution (calculated Mulliken charges, NPA charges and grid-based Bader analysis) on the C = N double bond (**Figure 9**). However, no expected correlations were found.

**5.2. Structural effects of the substrate**

50 New Advances in Hydrogenation Processes - Fundamentals and Applications

the substrate.

Isoquinoline-based molecules belong to the most important naturally-occurring alkaloids encompassing a significant group of biologically active species. These compounds have various pharmacological effects, which are enabled by their structural similarity with endogenous neurotransmitters. Therefore, a kinetic NMR study of ATH of five different 3,4 dihydroisoquinolines (**Figure 8**) was performed [25]. Four of them differed in various methoxysubstitutions of the dihydroisoquinoline skeleton, while the fifth examined substrate was a precursor for the production of mivacurium, a muscle relaxant. With 7 methoxy derivates (**3, 4, 5**), the reaction rate was significantly higher than in the case where no methoxy group was present in the position 7. The ATH of 6-methoxy-1-methyl-3,4-dihydroisoquinoline (**2**), bearing the 6-methoxy group, proceeded with a considerably lower reaction rate. However, the positive influence of the 7-methoxy group seemed to have overcome the detrimental effect of the 6-methoxy substituent when these two were present together, as it was for instance in the case of 6,7-dimethoxy-1-methyl-3,4-dihyroisoquinoline. Similarly, the bulky 1 (3',4',5' trimethoxybenzyl) moiety of the last substrate (**5**) further enhanced the reaction performance.

**Figure 8.** List of model substrates used to determine the effect of different substitution at the aromatic ring.

The substitution of the dihydroisoquinoline substrate with methoxy groups is followed by a much higher reaction rate and enantioselectivity than in the case of 1-methyl-3,4-dihydroisoquinoline (**1**). The presence of one methoxy group in the substrate molecule (**2** and **3**) led to an *ee* increase of 4–5 percentage points (89% (**2**) and 88% (**3**) versus 84% with the substrate **1**). With more methoxy groups affording *ees* higher by 9–10 percentage points (93% (**4**) and 94% (**5**) versus 84% with the substrate **1**). This observation could be attributed to substituent effects on the aromatic ring of the substrate, which affected the CH/π attraction between the catalyst and

These experimental observations were supported by examining all involved substrates using molecular modeling, especially, the charge distribution (calculated Mulliken charges, NPA

**Figure 9.** Partitions of total electron density on C and N atoms of imine bond of substrates containing one methoxy group.

To sum up, changing the position of single methoxy group resulted in drastic differences on the reaction performance in terms of both, the reaction rate and enantioselectivity. The presence of methoxy groups remarkably increased the reaction's enantioselectivity. Finally, an interesting conclusion could be drawn that less basic substrates were hydrogenated with higher reaction rates.
