Abstract
In these days, asymmetric transfer hydrogenation (ATH) is a very attractive method for synthesis of enantioenriched chiral compounds, especially fine chemicals such as drugs or agrochemicals. In this review, several topics related to the asymmetric transfer hydrogenation of ketones and cyclic or acyclic imines are discussed. Initially, the reaction mechanism of the ATH of ketones and imines, mainly 3,4-dihydroisoquinoline derivates, is examined. Next, typical reaction conditions, structural effects of the catalyst and a substrate, and analytical methods used for ATH monitoring and practical applications of the ATH in the chemical industry are described.
Keywords
- ruthenium
- asymmetric hydrogenation
- imines
- dihydroisoquinolines
- catalysis
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
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]
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
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
From this perspective, the catalyst containing a ligand with (
2.1. Asymmetric transfer hydrogenation of cyclic imines (dihydroisoquinolines)
Theoretical work accompanied with the computational study with the application of DFT to investigate the ionic mechanism concept in ATH of 1-methyl-3,4-dihydroisoquinoline resulted in a series of interesting proposals. All calculations, having employed [Ru(Cl)(η6
It was assumed that a protonated substrate is attached to the molecule of the catalyst by the hydrogen bond between the hydrogen of the protonated substrate and the oxygen of the sulfonyl amide group of the catalyst and by that transition state is stabilized. Nonbinding interactions between π electrons of aromatic ring of the substrate and hydrogen atoms of
Besides, corresponding calculations allowed to suggest the pathway toward ATH of 1 methyl-3,4-dihydroisoquinoline using formic acid/triethylamine azeotrope as the source of hydrogen (Figure 3).
The proposed cycle starts with the transformation of the [Ru(Cl)(η6
2.2. Asymmetric transfer hydrogenation of acyclic imines (N -benzyl-1-phenylethan-1-imin)
Asymmetric transfer hydrogenation of acyclic imines proceeds rather differently than in the case of cyclic imines such as substituted 3,4-dihydroisoquinolines. ATH of
2.3. Influence of the base on the asymmetric transfer hydrogenation of imines
To clarify the role of the base in asymmetric transfer hydrogenation of cyclic imines using Noyori’s Ru(Cl)(η6-
The spectroscopic methods were applied to understand the influence of the base in depth. For the NMR examinations, the mixture of [Ru(Cl)(η6-
3. Influence of the reaction conditions
Similar to every chemical reaction, it is important to carry out asymmetric transfer hydrogenation under specific reaction conditions, particularly ratio between the reaction rate and the enantioselectivity optimized as much as possible. The first comprehensive parametric study [10] focused on the determination of the best possible reaction conditions for ATH of cyclic imines, especially 3,4-dihydroisoquinoline derivates. This study thus involved clarifying the best attainable value of temperature, reaction mixture concentration or substrate to catalyst molar ratio (S/C).
Primarily, the attention was paid to the concentration in the reaction mixture as one of the important parameters. Two experiments were performed with different S/C molar ratios, S/C = 100 and S/C = 200, and other crucial molar ratios set to: formic acid/TEA = 2.5, hydrogenation mixture/substrate = 8.8, and the temperature set to 30°C. The major difference was observed in reaction ratio. For S/C = 200 the reaction ratio was slightly lower and also the difference grew with an increasing concentration. Probably, this fact can be explained by a certain amount of the catalyst being blocked by the protonated base, resulting in a lower reaction rate than in the case of the experiment with S/C = 100. The final outcome of this first set of experiments is as follows: reaction rate increases with an increasing of the reaction mixture concentration. This can be probably explained that at higher concentrations, the reaction rate is no longer limited by the frequency of effective collisions between active ruthenium-hydride species and the protonated molecule of the substrate but by the total amount of ruthenium-hydride intermediate present in the reaction mixture. Furthermore, the differences of the reaction mixture, related to the mass of the catalyst with different S/C ratios, were examined afterward as the S/C ratio is parameter that generally affects the course of catalytic reactions. As a result, it was confirmed that modifying S/C ratio leads to different reaction rates, regardless of the influence of the catalyst amount.
The second basic important parameter for every chemical reaction is the temperature. For this reaction, the measurement of its effect on both, the reaction rate and the enantioselectivity was conducted in the range of 10–50°C (Figure 5). Increasing the reaction rate with an increasing temperature was expected and could be considered common. However, the decrease of enantioselectivity was observed with an increasing temperature. This fact can be explained by Yamakawa’s supported theory that two transition states exist. One would lead to the preferred configuration of the product; the other would lead to the other configuration. The so-called unfavorable transition state will prevail at a higher temperature and the nonpreferred product would become more abundant.
The amount of the hydrogenation mixture is also important for the process of ATH. The mixture of formic acid and TEA provides hydrogen for the hydrogenation itself. The most commonly used molar ratio for these two is 2:5. The variation of this amount was expected to have a major influence on the course of the reaction and thus several hydrogenation mixture/substrate ratios were tested, where the concentrations were set to 7%, as well as S/C = 100, formic acid/TEA = 2.5, and the temperature to 30°C. Contrary to the original expectation, increasing the amount of the hydrogenation mixture leads to a decrease in the initial reaction rate (Figure 5). Therefore, two working hypothesis were considered to explain such behavior. The first, under a strong acidic condition, the catalyst’s ligand became protonated, and subsequently deco-ordinated from the Ru atom, followed by the loss of catalytic activity and the second one, in a large excess of hydrogenation mixture, the protonated triethylamine is also in large excess over the protonated substrate and sterically hinders active site of the catalyst for substrate.
The variation of the ratio between formic acid and triethylamine, the two components of the hydrogenation mixture, could provide an insight into several subtle aspects of the reaction mechanism. Also, several visual differences between reaction mixtures containing different molar ratios of TEA and formic acid were observed, yellow color for mixtures containing higher molar ratio between formic acid and triethylamine and orange color for the mixture with higher amount of base. This fact indicates that the catalytic complex undergo some significant changes in excess of acid followed by loss of activity of the catalyst. Although, using higher amount of the TEA also showed that the reaction perform much more slowly than usual. Explanation for this phenomenon could be really simple; the excess of TEA probably neutralizes all of the formic acid and by this disable the reaction itself. However, according to the results obtained during the study, azeotropic mixture of formic acid/TEA (molar ratio 5:2) seems to be an optimal as the source of hydrogen for the purpose of ATH (Figure 5).
4. Analytical methods tailored to asymmetric transfer hydrogenation
For the purpose of monitoring of the reaction and determination of
4.1. In situ kinetic study using NMR spectroscopy
Implementation of the kinetic measurements of ATH of imines in flask brings some drawbacks. One of them is relatively complicated preparation of the sample for the following gas chromatography analysis. This preparation includes alkalinization of the reaction mixture for the release of the basic product and salt from formic acid, extraction of organic compounds into the diethyl ether, evaporating of the ether and dissolving of the sample with acetonitrile and analysis itself. For the practical reasons it is not possible to perform efficient enough kinetic measurements. To remove these drawbacks practical
4.2. Determination of the enantiomeric excess (ee ) of ATH
Typical instrumental method for determination of optical purity at products of reaction is gas or liquid chromatography, using columns with chiral stationary phase. However, these columns are relatively expensive. Another disadvantage is that these columns is higher sensitivity, which manifest itself during GC analysis by lower temperature limit and at LC analysis by impossible analysis of any chemicals or are limited by certain pH. Hence, alternative methods using derivatization or chiral solvatation of the product are expedient.
4.2.1. Determination of ee by derivatization with (R)-menthyl-chloroformate
This method is based on a quantitative reaction of the product with (
4.2.2. Determination of ee by chiral solvation by Pirkle’s alcohol
Chiral solvation by Pirkle’s alcohol ((
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)(
5.1.1. Modification of the coordinated η6-arene
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 (
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,
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,
More profound modifications of
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
In addition, several Noyori-based Ru catalysts bearing
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
As the standard, Noyori’s original catalysts bearing N-
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 methoxy-substitutions of the dihydroisoquinoline skeleton, while the fifth examined substrate was a precursor for the production of mivacurium, a muscle relaxant. With 7 methoxy derivates (
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 (
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.
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.
6. Practical industrial applications of asymmetric transfer hydrogenation
Even though asymmetric transfer hydrogenation was originally merely a subject of academic interest, nowadays this reaction finds its use also in several sectors of chemical industry. There are a large number of optically active amines and alcohols used as active substances and a suitable method for ATH preparation. As any method or technology, ATH inclusively has its pros and cons. The indisputable advantages, compared to asymmetric hydrogenation by gaseous hydrogen, are primarily the catalyst stability under air conditions (AH catalyst typically contains phosphine ligands, which easily undergo oxidation by atmospheric oxygen) and second, avoiding the use of gaseous hydrogen. These two facts actually permit testing many structurally different catalysts in a relatively short period of time. Eliminating the use of pressure hydrogen and thus the demanding apparatus for reactions at a high pressure noticeably simplifies the production facilities, which is an important aspect from the economical point of view.
Relatively small values of turnover frequencies (TOF) present one of the major drawbacks compared to AH catalysts. Extending the reaction time or using a higher amount of the catalyst represent potential solutions (since the catalysts for ATH are inexpensive compared to AH, this solution is economically acceptable). Increasing the reaction temperature is, however, not the optimal solution, since enantioselectivity is decreasing with a higher temperature. Eliminating metal residues from the product is not an issue in these days as applying commercially available methods allows reducing the number of residues to units of
In 1997, Avencia Company patented rhodium catalysts bearing diamine, aminoalcohol ligands, respectively, for asymmetric transfer hydrogenation of imines and ketones. These Rh complexes are analogues to original Noyori’s ruthenium catalysts. However, except for the central atom, these catalysts also differ in their aromatic ligand, which is in the most cases η5-pentamethylcyclopentadienyl. These catalysts are used for the production of several different types of chiral alcohols and amines. To name some examples, one of the running processes is ATH of tetralone to (
Asymmetric transfer hydrogenation has the potential to find use also in the production of fine chemicals such as drugs, where a high optical purity of the final products is demanded. To provide an example, the preparation of the precursor for the synthesis of muscle relaxant, mivacurium-chloride, can be mentioned [27]. In this case, the application of ATH for the preparation of mivacurium-chloride seems to be a more favorable, since the cleavage used in the classical preparation, capitalizing on using
7. Conclusion
The main purpose of this study was to describe selected parts of the asymmetric transfer hydrogenation of ketones and particularly imines. Our attention was predominantly aimed to the importance of the mechanistic aspects of the ATH or structural effects influencing the reaction course. All parts of this work show that the asymmetric transfer hydrogenation is the reaction which can find its use across all branches of the chemical industry.
Acknowledgments
This work was realized within the Operational Program Prague – Competitiveness (CZ.2.16/3.1.00/22197) and “National Program of Sustainability“ (NPU I LO1215) MSMT - 34870/2013); The Operational Program Prague–Competitiveness (CZ.2.16/3.1.00/21537) and “National Program of Sustainability“ (NPU I LO1601) MSMT-43760/2015); The Operational Program Prague–Competitiveness (CZ.2.16/3.1.00/24501) and “National Program of Sustainability“ (NPU I LO1613) MSMT-43760/2015) and GACR (GA15-08992S).
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