InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Chemistry » Organic Chemistry » "Hydrogenation", book edited by Iyad Karamé, ISBN 978-953-51-0785-9, Published: October 10, 2012 under CC BY 3.0 license. © The Author(s).

Chapter 2

Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones

By Bogdan Štefane and Franc Požgan
DOI: 10.5772/47752

Article top


Simple ketones in chemoselective AH catalyzed by bifunctional catalysts of type C1
Figure 1. Simple ketones in chemoselective AH catalyzed by bifunctional catalysts of type C1
Ruthenabicyclic vs. standard Noyori catalyst for the AH of structurally different ketones
Figure 2. Ruthenabicyclic vs. standard Noyori catalyst for the AH of structurally different ketones
Highly active ruthenium catalysts
Figure 3. Highly active ruthenium catalysts
AH of sterically congested and poorly reactive ketones
Figure 4. AH of sterically congested and poorly reactive ketones
Rh-catalyzed AH of simple and fluorinated ketones
Figure 5. Rh-catalyzed AH of simple and fluorinated ketones
Ir-catalyzed AH
Figure 6. Ir-catalyzed AH
Selected ligands for ATH
Figure 7. Selected ligands for ATH
ATH catalyst systems
Figure 8. ATH catalyst systems
Selected iron catalysts
Figure 9. Selected iron catalysts
Ligands for Cu-mediated hydrogenation and Os-complexes
Figure 10. Ligands for Cu-mediated hydrogenation and Os-complexes
Selected ligands and complexes for aqueous hydrogenation
Figure 11. Selected ligands and complexes for aqueous hydrogenation
Hydrogenation in ionic liquids
Figure 12. Hydrogenation in ionic liquids
Outer-sphere hydridic route for bifunctional catalysts
Figure 13. Outer-sphere hydridic route for bifunctional catalysts
Enantiodifferentiation in the bifunctional-catalyzed hydrogenation of acetophenone
Figure 14. Enantiodifferentiation in the bifunctional-catalyzed hydrogenation of acetophenone
Schematic presentation of chiral porous Zr-phosphonate-Ru-(R)-C24 in Ru-(R)-C25 heterogeneous catalysts
Figure 15. Schematic presentation of chiral porous Zr-phosphonate-Ru-(R)-C24 in Ru-(R)-C25 heterogeneous catalysts
Heterogeneous RuII mesoporous silica-supported catalysts
Figure 16. Heterogeneous RuII mesoporous silica-supported catalysts
Ir and Ru mesoporous silica-supported catalysts
Figure 17. Ir and Ru mesoporous silica-supported catalysts
Magnetic Ir and Rh chiral catalysts
Figure 18. Magnetic Ir and Rh chiral catalysts
Chiral RuCl2-diphosphine-diamine complexes immobilized on mesoporous silica nanospheres
Figure 19. Chiral RuCl2-diphosphine-diamine complexes immobilized on mesoporous silica nanospheres
Self-supported Noyori-type catalysts C37-C40 for the AH of ketones
Figure 20. Self-supported Noyori-type catalysts C37-C40 for the AH of ketones
Enantio-selective hydrogenation of a keto-functionalized ionic liquid
Figure 21. Enantio-selective hydrogenation of a keto-functionalized ionic liquid
Enantio-selective hydrogenation of activated ketones.
Figure 22. Enantio-selective hydrogenation of activated ketones.
Enantioselective hydrogenation of activated ketones.
Figure 23. Enantioselective hydrogenation of activated ketones.
Schematic representation of the adsorption mode of CD on the metal surface and interactions between the half-hydrogenated state of the activated ketone and the basic quinuclidine-N atom of the chiral modifier.
Figure 24. Schematic representation of the adsorption mode of CD on the metal surface and interactions between the half-hydrogenated state of the activated ketone and the basic quinuclidine-N atom of the chiral modifier.

Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones

Bogdan Štefane and Franc Požgan

1. Introduction

Optically active alcohols are important building blocks in the synthesis of fine chemicals, pharmaceuticals, agrochemicals, flavors and fragrances as well as functional materials (Arai & Ohkuma, 2011; Klingler, 2007). Furthermore, molecular hydrogen is without doubt the cleanest reducing agent, with complete atom efficiency. Therefore, the catalytic, asymmetric hydrogenation (AH) of prochiral ketones is the most practical and simplest method to access enantiomerically enriched secondary alcohols, on both the laboratory and industrial scales. Asymmetric transfer hydrogenation (ATH), on the other hand, represents an attractive alternative or complement to hydrogenation because it is easy to execute and a number of cheap chemicals can be used as hydrogen donors. For practical use and to address environmental issues a high catalyst activity (low loadings) and selectivity is preferable, as well as the employment of ‘’greener’’ solvents, mild operating conditions and recyclable catalyst systems. High turnover numbers (TONs) and turnover frequencies (TOFs), and satisfactory stereo- and chemoselectivities are attainable only with a combination of well-defined metal catalysts and suitable reaction conditions. The reactivity and selectivity can be finely tuned by changing the bulkiness, chirality and electronic properties of the auxiliaries on the metal center of the catalyst.

2. Homogenous, asymmetric hydrogenation and transfer hydrogenation

Since the application of very efficient, chiral BINAP-derived ruthenium complexes in the AH of functionalized ketones (β-keto esters) at a high enantioselectivity level in the homogenous phase (Noyori et al., 1987), the development of more robust and reactive molecular catalysts is still highly desirable. Furthermore, because of the structural and functional diversity of organic substrates, no universal catalysts exist. Ruthenium complexes bearing chiral ligands are among the most commonly used catalysts for AH and ATH, following by rhodium and iridium, although in recent times other transition metals, like Fe, Cu, or Os have rapidly penetrated this field.

2.1. Ru-, Rh- and Ir-catalyzed hydrogenation and transfer hydrogenation

A major breakthrough in the wide-scope AHs of ketones was the discovery by Noyori and co-workers of the conceptually new and extremely efficient ruthenium bifunctional catalysts. They found that simple ketones like 1-5, which lack anchoring heteroatoms capable of interacting with a metal center, can be reduced enatioselectively with H2 (1-8 atm) in i-PrOH using a ternary catalyst system comprising a chiral BINAP-RuCl2 precursor, a chiral 1,2-diamine ligand (L1−L3) and an alkaline base (e.g., KOH) in a 1:1:2 molar ratio (Fig. 1) (Ohkuma et al., 1995a, 1995b). This catalyst system chemoselectively afforded the corresponding chiral alcohols in almost quantitative yields and up to 99% optical yields. Since then, a number of AHs catalyzed by Ru(II) complexes, like C1 bearing chiral diphosphine, and diamine ligands for structurally diverse substrates, like alkyl-aryl ketones, heteroaromatic ketones, unsymmetrical benzophenones, aliphatic and α,β-unsaturated ketones, has been reported (Noyori & Ohkuma, 2001; Ohkuma, 2010). Furthermore, proper matching of a chiral ruthenium diphosphine with the correct enantiomer of diamine leads to exceptionally enantioselective catalysts, which are also highly chemoselective for C=O group vs. C=C and C≡C bonds, and tolerate many functionalities, like NO2, CF3, halogen, acetal, CO2R, NH2, NHCOR, etc.


Figure 1.

Simple ketones in chemoselective AH catalyzed by bifunctional catalysts of type C1

The XylBINAP-complex C2 proved to be very effective for the stereoselective hydrogenation of heteroaromatic ketones (2-furyl, 2- and 3-thienyl, 2-thiazolyl, 2-pyrrolyl, 2-, 3- and 4-pyridinyl) as well as aromatic-heteroaromatic and bis-heteroaromatic ketones (phenyl-thiazolyl, phenyl-imidazolyl, phenyl-oxazolyl, phenyl-pyridinyl, pyridinyl-thiazolyl) thus providing a plethora of structurally interesting heterocyclic alcohols (C. Chen et al., 2003; Ohkuma et al., 2000). In fact, the complex C2 has been established as one of the most efficient and selective pre-catalysts for the AH of a variety of ketones (Ohkuma et al., 1998) until the discovery of novel ruthenabicyclic complexes (Matsumura et al., 2011). The hydrogenation of acetophenone catalyzed by the ruthenabicyclic complex C3 with a substrate-to-catalyst molar ratio (S/C) 10000 under 50 atm of H2 in a i-PrOH/EtOH/t-BuOK mixture was completed in one minute to give (R)-1-phenylethanol in more than 99% ee, thus achieving a TOF of about 3.5 104 min-1. For comparison, the pre-catalyst C2 provided a similar outcome in four hours. This ruthenabicyclic pre-catalyst is better than all previous catalyst systems in terms of efficiency, enenatioselectivity and the scope of the ketone substrates (aromatic, aliphatic, cyclic and bicyclic ketones; 6-9) (Fig. 2).


Figure 2.

Ruthenabicyclic vs. standard Noyori catalyst for the AH of structurally different ketones

Since the Noyori’s standard Ru(II) complexes of the type C1 require the presence of a strong base as a co-catalyst to in situ generate an active catalyst, i.e., RuH2 species, some unwanted side reactions (e.g., transesterification with an alcohol product in the case of 10) may occur. Ohkuma et al. succeeded in preparing a relatively stable [RuH(η1-BH4)(BINAP)(1,2-diamine)] catalyst C4, which allowed for the base-free AH of otherwise base-sensitive ketone substrates 10−13 in almost quantitative yields and excellent ee values (Fig. 3) (Ohkuma et al., 2002).

The extremely high reactivity and enantio-selectivity of [TunesPhos-Ru(II)-(1,2-diamine)] complexes combined with t-BuOK enabled the AH of ring-substituted acetophenones, 2-acetylthiophene, 2-acetylfuran, 1- and 2-acetylnaphthalen, and cyclopropyl methyl ketone with TONs up to 1000000 affording the corresponding chiral alcohols in ee’s up to >99% (W. Li et al., 2009). Among them, the catalyst precursor C5 was found to be the most efficient, since decreasing the catalyst loading from 0.01 mol% to a ppm level had only a small impact on ee in the hydrogenation of acetophenone (99.8→98% ee), though high conversions necessitated longer reaction times (Fig. 3).


Figure 3.

Highly active ruthenium catalysts

The discovery of new classes of hydrogenation catalysts that deviate from the Noyori-type C1 may represent a good opportunity to reduce every type of ketone substrate with high reactivity and selectivity. Indeed, while the conventional [BINAP-Ru-(1,2-diamine)] catalysts have shown poor reactivity and enantio-selectivity in the hydrogenation of sterically congested tert-alkyl ketones, a reduction using the BINAP/(α-picolylamine)-based Ru complex C6 in a ratio S/C as high as 100000 provided the corresponding tert-alkyl carbinols from ketones 14–18 in a high enantiomeric purity (Fig. 4) and proved to be chemoselective for enone 16 and also active for the highly hindered β-keto ester 18 (Ohkuma et al., 2005).

Interestingly, a combined amine-benzimidazole ligand in the complex C7 influenced the reverse enantioselection from that typically observed in the AH of ring-substituted acetophenones and allowed the reduction to proceed in nonprotic solvents (toluene/t-BuOH 9:1) with S/C 1000 to 50000 giving (S)-alcohols in 82-99% ee (Fig. 4) (Y. Li et al., 2009).


Figure 4.

AH of sterically congested and poorly reactive ketones

AH using non-phosphine-based catalysts is attractive due to the toxicity of the catalyst precursors and the product contamination when Noyori-type catalysts are used. However, the efficiency of the π-allyl Ru precursor in combination with the phosphorous-free pyridyl-containing ligand L1 did not exceed that of the original [BINAP-Ru-diamine] complexes (Fig. 4) (Huang et al., 2006). Interestingly, this new catalyst system catalyzes the hydrogenation of 1-indanone only in the absence of a base.

The most efficient AH catalysts tend to mimic that of Noyori as its excellent enantioselectivity is proposed to be a result of the synergistic effect of chiral phosphane and chiral amine ligands. Nevertheless, commercially available achiral diphosphanes (DPPF, DPEphos) in conjunction with rigid chiral biisoindoline-based diamines have been applied in the Ru-catalyzed AH of (hetero)aromatic ketones, affording excellent enantioselectivities (up to 99% ee) with an S/C up to 100000 (Zhu et al., 2011).

Since ketones coordinate more weakly to metals than olefins, many Rh-phosphane complexes show no activity for hydrogenation of simple ketones. However, the highly enantioselective direct hydrogenation of simple ketones 19−24 using an in-situ-prepared catalyst from simple precursors, [Rh(COD)Cl]2 and the rigid chiral biphosphane ligand L2 promoted by 2,6-lutidine (2,6-dimethylpyridine) and KBr has been reported (Fig. 5) (Q. Jiang et al., 1998). With this catalyst system, the hydrogenation of acetophenone was sluggish and gave only 57% ee of (S)-1-phenylethanol, whereas the presence of additives dramatically accelerated the reaction and enhanced the enantioselectivity (95% ee). While with aryl(heteroaryl) ketones (19 and 20) high ee’s were observed, more importantly, this hydrogenation procedure proved to be satisfactorily enantioselective for several alkyl-methyl ketones (21–23), even those bearing unbranched alkyl groups (24), which in principle represent the toughest problem for asymmetric reduction.

The complex prepared from [Rh(COD)OCOCF3)]2 and the amide-phosphine-phosphinite ligand L3 catalyzed the AH of trifluoromethyl ketones 25 giving almost quantitative yields of the corresponding alcohols in 83-97% ee (Kuroki et al., 2001). Interestingly, this Rh-catalyst showed preferential activity and stereoselectivity for fluorinated ketone substrates since acetophenone gave only a 2% yield of 1-phenylethanol in 8% ee.


Figure 5.

Rh-catalyzed AH of simple and fluorinated ketones

The hydrogenation of ketones catalyzed by chiral iridium complexes has been well studied and developed because iridium is less expensive than rhodium (Malacea et al., 2010). Generally, Ir(I) or Ir(III) complexes with chiral diamines, diphosphines or a combination of both, very similar to those in Ru-catalyzed hydrogenation, have been successfully employed in the AH of various aromatic ketones and β-keto esters. On the other hand, chiral Ir(I) complexes bearing N-heterocyclic carbenes as ligands proved to be far less efficient (Diez & Nagel, 2009). Although complexes of [Ir(COD)Cl]2 and planar-chiral ferrocenyl phosphine-thioethers (e.g, L4) (Le Roux et al., 2007) or spiro aminophosphine ligands (e.g., L5) (J.-B. Xie et al., 2010) efficiently catalyze the AH of acetophenone-type substrates and more importantly exo-cyclic α,β-unsaturated ketones 26, chiral Ir-complexes with phosphorous-nitrogen ligands tend to lose their activity under hydrogenation conditions. The introduction of an additional coordination group in the bidentate spiro aminophosphine ligand L6 led to a very stable and efficient catalyst for the AH of simple ketones 27, affording the chiral alcohols 28 in up to 99.9% ee (Fig. 6) (J.-H. Xie et al., 2011). For example, acetophenone was reduced with a 2 10-5 mol% catalyst loading to give (S)-1-phenylethanol in 98% ee, reaching a TON of 4.55 106 and a TOF of 1.26 104 h-1.


Figure 6.

Ir-catalyzed AH

With its origin in Meerwein-Pondorf-Verley reduction, and later developed in its asymmetric version, the transfer hydrogenation of ketones has emerged as an operationally simpler and significantly safer alternative to catalytic H2-hydrogenation as there is no need for special vessels and high pressures (Ikariya & Blacker, 2007; Palmer & Wills 1999). Moreover, chemo-, regio- and stereoselectivity can often be different from that of AH. In the ATH process, the transition-metal catalyst is able to abstract a hydride and a proton from the hydrogen donor and deliver them to the carbonyl moiety of the ketone. Suitable catalysts for ATH are typically complexes of homochiral ligands with Ru, Rh or Ir, whilst i-PrOH/base (hydroxide or alkoxyide) or formic acid/triethylamine (FA/TEA, 5:2 azeotrope) are the most common hydrogen donors usually being the solvents at the same time. A major drawback of using i-PrOH is the reaction reversibility, giving limited conversions and affecting the enantiomeric purity of the products after long reaction times. The use of formic acid can overcome these drawbacks, although only a narrow range of catalysts that tolerate formic acid is available.

In parallel with the discovery of efficient ruthenium catalysts for AH, Noyori and co-workers found a prototype of chiral (arene)Ru(II) catalysts of type C8 bearing N-sulfonated 1,2-diamines (e.g., TsDPEN = N-(p-toluenesulfonyl)-1,2-diphenyl-ethylenediamine) or amino alcohols such as chiral ligands for the highly enantio-selective ATH of (hetero)aromatic ketones in i-PrOH/KOH or in FA/TEA (Fig. 7) (Fujii et al., 1996; Hashiguchi et al., 1995; Takehara et al., 1996). After this milestone discovery a large number of related or novel ligands and catalysts for ATH have been developed that display a broad substrate scope and provide optically active alcohols in a high enantiomeric purity (Baratta & Rigo, 2008; Everaere et al., 2003; Gladiali et al., 2006).

The stereochemically rigid β-amino alcohols L7 or L8 work very well as ligands for Ru-catalyzed ATH in basic i-PrOH, outperforming N-(p-toluenesulfonyl)-1,2-diamines in some cases, but in general these types of ligands appear to be incompatible with a FA/TEA reduction system (Fig. 7) (Palmer et al., 1997; Alonso et al., 1998).

An in-situ-prepared complex from [RuCl2(benzene)]2 and ‘’roofed’’ cis-diamine ligand L9, which is both conformationally rigid and sterically congested, functions as an excellent catalyst for ATH with the FA/TEA of aryl ketones, including sterically bulky ketones (Matsunaga et al., 2005).

It was first disclosed by Noyori, that a N-H moiety is necessary for an efficient transfer of hydrogen from the metal hydride. However, the Ru complex with the oxazolyl-pyridyl-benzimidazole-based NNN ligand L10 featuring no N-H functionality exhibited a high catalytic activity in the ATH of different acetophenones (Fig. 7) (Ye et al., 2011).

Another type of ligands lacking a basic NH group like L11 are based on a combination of N-boc-protected α-amino acids and a sugar amino alcohol unit and have shown a high enantioselectivity (typically >99 ee) in the Ru-catalyzed ATH of aryl ketones, where the enantioselectivity is exclusively controlled by the sugar moiety (Coll et al., 2011). It was found that the addition of LiCl for the ATH in a i-PrOH/THF mixture catalyzed by Ru complexes bearing N-boc-protected -amino acid hydroxyamide L12 significantly enhanced the activity and selectivity, hence suggesting a non-classical bimetallic hydrogen-transfer mechanism (Fig. 7) (Wettergren et al., 2009).

The combination of [RuCl2(p-cymene)]2 and the chiral BINOL-derived diphosphonite ligand L13 constitutes yet another Ru catalyst system solely composed of P-ligands for the efficient ATH (i-PrOH/t-BuOK) of alkyl-aryl and alkyl-alkyl ketones, although the ee’s were lower for the latter (Fig. 7) (Reetz & Li, 2006). In contrast, H2-hydrogenation is less successful when using this system.


Figure 7.

Selected ligands for ATH

There is a continuing search for stable catalysts that would not degrade easily during the hydrogenation process, thus making it possible to execute as many as possible catalytic cycles. In this respect, the covalent linkage from the diamine to the η6-arene unit in the ‘’tethered’’ catalysts C9 provide extra stability and a significant increase in rate relative to the ‘’unthetered’’ catalyst in some cases (Fig. 8) (Cheung et al., 2007). With these catalysts, ring-substituted acetophenones, -chloroacetopehones, dialkyl ketones and ketopyridines were converted to the corresponding chiral alcohols in FA/TEA, mostly near to room temperature.

It has been shown that the Rh complex with the ‘’achiral’’ but tropos benzophenone-derived ligand L14 and a chiral diamine activator (e.g., L3) affords higher enantioselectivities in the ATH of acetophenones and 1-acetylnaphthalene than those obtained by the enantiopure BINAP counterpart (Fig. 8) (Mikami et al., 2006). Cyclometalated Ru(II), Rh(III) and Ir(III) complexes C10−C12 being easily prepared from commercial ligands, have shown a satisfactory catalytic activity and a high-to-very high enantioselectivity (ee’s up to 98%) in the ATH of different ketones (cyclic ketone, aryl-alkyl ketone, 2-acetylfuran, cyclopropyl-phenyl ketone) (Fig. 8) (Pannetier et al., 2011). The complexes C11 and C12 were not isolated but used in situ.

The unique phenomenon of an enhancement of the enantioselectivity by using the chiral bulky alcohol (S)-1-(9-anthracenyl)ethanol as an additive in the ATH of 4’-phenylacetophenone as well as in the H2-hydrogenation of several acetophenone derivatives with the catalyst C13 was recently demonstrated (Fig. 8) (Ito et al., 2012).


Figure 8.

ATH catalyst systems

2.2. Hydrogenation and transfer hydrogenation employing other transition metals

Although Ru(II) complexes have enzyme-like properties reaching high TONs and TOFs, many times near to room temperature, and deliver the secondary alcohols in near-quantitative ee’s, the limited availability of precious metals, their high price and their toxicity reduce their attractiveness for future use. In this respect the development of catalysts with similar properties to replace platinum-group metals is very desirable from both the economic and environmental points of view. In fact, iron is cheap and ubiquitous, and its traces in final products are not as serious a problem as traces of ruthenium, for example (Morris, 2009).

The first hydrogenation of ketones catalyzed by a well-defined iron catalyst was effected with an iron hydride Shvo-type complex C14 (Casey & Guan, 2007), while later on Morris and co-workers succeeded in the ATH of simple ketones catalyzed by iron complexes containing chiral PNNP tetradentate ligands, attaining ee values up to 99% in the best cases (Mikhailine et al., 2009; Sues et al., 2011). For example, acetophenone was reduced to (S)-1-phenylethanol in 82% ee and a TOF as high as 3.6∙103 h-1 with the pre-catalyst C15, while installing the sterically more hindered P-ligand in the complex C16 even increased the activity (2.6∙104 h-1) and enantioselectivity (90% ee) at the beginning of the reaction (Fig. 9).

An asymmetric Shvo-type iron complex C17 was found to be a very poor catalyst for the transfer hydrogenation of acetophenone with FA/TEA, since after 48 hours only a 40% conversion and a 25% ee were observed (Hopewell et al., 2012).

Enantioselective, copper-catalyzed homogenous H2-hydrogenation was introduced by Shimizu and co-workers, who used a catalyst system based on [Cu(NO3){P(3,5-Xylyl)3}2], (R)-SEGPHOS (L15) or (S,S)-BDPP (L16), and t-BuONa for the reduction of (hetero)aryl ketones, affording good yields and ee’s up to 92% (Shimizu et al., 2007, 2009). A range of aryl, alkyl, cyclic, heterocyclic, and aliphatic ketones were hydrogenated under 50 bar of H2 with a combination of inexpensive Cu(OAc)2 and monodentate binaphthophosphepine ligand L17 (Junge et al., 2011). On the other hand, Cu(OTf)2 with the bisoxazoline ligand L18 mimics alcohol dehydrogenase and catalyzes the ATH of α-ketoesters with Hantzsch esters as hydrogen donors (Fig. 10) (J. W. Yang & List, 2006).


Figure 9.

Selected iron catalysts

Owing to the stronger bonding of Os compared to Ru, robust and thermally stable complexes can be obtained, which is important for achieving highly productive catalysts. Os(II) CNN pincer complexes C18 exhibited a high catalytic activity and productivity in both the AH (5 atm H2/t-BuOK) and ATH (i-PrOH/i-PrONa) of ketones (Baratta et al., 2008). Enantioselectivities up to 98% ee are possible with a remarkably low catalyst loading (0.005-0.02 mol%). More active and productive [OsCl2(diphosphane)(diamine)] complexes like C19, resembling those of Noyori, catalyzed the AH of alkyl-aryl, tert-butyl and cyclic ketones with S/C ratios of 10000–100000 and TOFs up to 104 h-1 (Baratta et al., 2010) (Fig. 10).


Figure 10.

Ligands for Cu-mediated hydrogenation and Os-complexes

2.3. Hydrogenation and transfer hydrogenation in water and ionic liquids

As a consequence of the increasing demand for ‘’greener’’ laboratory and industrial applications, the development of water-operating catalytic systems for the asymmetric hydrogenation of ketones has been of great interest (Wu & Xiao, 2007). The main disadvantage, however, is the low solubility of the homogenous metal catalysts and most of the organic substrates when going from organic to aqueous media, which may be reflected in a reduced activity and selectivity. To circumvent this, either hydrophilic, often charged, functionalities can be introduced to ligands to render the catalysts water-soluble, or different surfactants can be added in order to solvate the reaction partners, although in some cases water-insoluble catalysts can deliver a superior activity and selectivity.

Water-soluble Ru, Ir or Rh catalysts were prepared in situ using modified Noyori-type ligands L19 and enabled the ATH in i-PrOH in the presence of water (Bubert et al., 2001, Thorpe et al., 2001), while Chung and co-workers communicated the first examples of the ATH of aromatic ketones with HCO2Na in neat water catalyzed by [RuCl2(p-cymene)]2 together with the (S)-proline amide ligand L20 attaining ee’s comparable with those in a homogenous solution (Rhyoo et al., 2001). The latter catalyst system appeared to be quite stable, since it could be recycled six times with little loss of performance. Similarly, an in-situ-prepared catalytic complex from the proline-functionalized ligand L21 and [RuCl2(p-cymene)]2 in a 1:1 ratio showed good activity for the aqueous ATH of acetophenone-type ketones as well as bicyclic ketones (Manville et al., 2011). Due to its difficult purification, the ligand L22 was replaced by another water-soluble ligand L23, and its complex with [C5Me5RhCl2]2 was active for the ATH of α-bromomethylaromatic ketones, besides ring-substituted acetophenones, and bicyclic ketones (L. Li et al., 2007). The tethered Rh complex C20 reported by Wills acts as a very productive catalyst for aqueous-reduction as it continues to turnover a reaction at low loadings, even at 0.01 mol%, typically associated with the best H2-hydrogenation catalysts, without any decrease in the enantioselectivity (Matharu et al., 2006). The chiral aqua Ir(III)-complex C21 bearing non-sulfonated diamine was shown to be very flexible in the ATH of -cyano- and -nitroacetophenones as the reaction can be conducted at pH 2 (formic acid) as well as at pH 5.5 (HCO2Na) in a water-methanol system without affecting the selectivity (Vázquez-Villa et al., 2011) (Fig. 11).


Figure 11.

Selected ligands and complexes for aqueous hydrogenation

Surfactants are often added as co-solvents to obtain a sufficient solubility of the reactants, products and metal catalysts, thus retaining the activity and selectivity of the hydrogenation process. The ATH of ketones, particularly -bromomethyl aromatic ketones, was successfully performed with HCO2Na by employing the unmodified and hydrophobic Ru-, Rh- and Ir-TsDPEN complexes C22 and C23 in the presence of single-tailed, cationic and anionic surfactants and to form micelles and vesicles (Fig. 11) (Wang et al., 2005). It is notable that catalysts embedded in these micro-reactors can be separated from the organic phase and reused for at least six times without any loss of activity and enantioselectivity.

In recent years ionic liquids (ILs) have attracted an increasing interest because of their non-volatility, non-flammability and low toxicity. Additionally, ILs are capable of immobilizing homogenous catalysts and facilitating the recycling of catalysts. Ideally, organic products can be easily separated by extraction with a less polar solvent and the IL phase containing catalyst can be reused. Such an immobilization of catalysts also promises to prevent the leaching of toxic metals into the organic products, which is especially desirable in the production of pharmaceutical intermediates.

Various aromatic ketones were reduced with FA/TEA in an ionic liquid L25 at 40 °C, catalyzed by an in-situ-generated catalyst from [RuCl2(p-cymene)]2 and the ionic chiral aminosulfonamide ligand L24, affording good-to-excellent conversions and ee values (Fig. 12) (Zhou et al., 2011). The catalytic system could be recovered and reused three times with a slight loss of enantioselectivity from 97% to 94% ee for the reduction of acetophenone. In contrast, the catalyst activity showed a remarkable drop with each cycle, and therefore the reaction times had to be prolonged for high conversions.

While for the AH of β-alkyl β-ketoesters high enantioselectivities can be attained by using the Ru-BINAP system, for the analogous β-aryl ketoesters much more inferior ee values were obtained (Noyori et al., 1987). However, the highly enantioselective hydrogenation of a wide range of β-aryl ketoesters 29 in the homogenous ionic liquid L26/methanol system was possible with Ru catalysts bearing 4,4’-substituted BINAP ligands L27 (Fig. 12) (Hu et al., 2004a). The catalysts were recycled and reused four times, but there was a remarkable deterioration in the conversion rates and ee values, which were more pronounced with the ligand R = SiMe3.


Figure 12.

Hydrogenation in ionic liquids

2.4. Mechanistic considerations

Homogenous hydrogenation and transfer hydrogenation may be mechanistically closely related because both reactions involve a metal hydride species under catalytic conditions, thus sharing a multistep pathway of hydride transfer to the ketone, i.e., the hydridic route, which can operate in the inner or outer coordination sphere of the catalyst metal center (Clapham et al., 2004). Applied only to the transfer hydrogenation, direct hydrogen transfer (Meerwein-Ponndorf-Verly reaction) from the metal alkoxyide to the ketone without the involvement of metal hydrides proceeding through a six-membered transition state has also been proposed, and is typical for non-transition metals (e.g., Al) (deGraauw et al., 1994).

Noyori and co-workers proposed metal-ligand bifunctional catalysis for their Ru catalysts containing chiral phosphine-amine ligands and for (arene)Ru-diamine catalysts, which consequently resulted in a widely accepted mechanism to be responsible for the highly enantio-selective hydrogenation and transfer hydrogenation of prochiral ketones (Noyori et al., 2001, 2005). The actual catalysts, Ru-hydrides 31 or 34, are usually created in a basic alcoholic solution (under H2 or not) at the beginning of the catalytic reaction from the Ru precursors 30 or 33. Note that only the trans-RuH2 31 is a very active catalyst. A key feature of bifunctional catalysts is that the N-H unit of a diamine ligand forms a hydrogen bond with carbonyl oxygen, thus stabilizing the six-membered pericyclic transition state (TS1 or TS1’) and hence facilitating the hydride transfer from Ru-H, which adds to the carbonyl carbon concurrently with a transfer of the acidic proton from N-H to the carbonyl oxygen. This concerted process results in the formation of an alcohol product and Ru-amido species (32 or 35). The hydride intermediate (31 or 34) is then regenerated either by the addition of molecular hydrogen or by the reverse hydrogen transfer from a dihydrogen source (e.g., i-PrOH) to the formal 16-electron Ru-amido intermediate (32 or 35). The latter step is considered to be a rate-limiting step. The overall process is occurring outside the coordination sphere of the metal without the interacting of the ketone or alcohol with the metal center. This is known as an outer-sphere mechanism. It is depicted in Fig. 13 for the hydrogenation with molecular hydrogen catalyzed by the diphosphine-Ru-diamine system (a) and for transfer hydrogenation catalyzed by the (arene)Ru-diamine complex (b) in its simplified representation.


Figure 13.

Outer-sphere hydridic route for bifunctional catalysts

Depending on transition-metal catalysts, an ionic mechanism has also been proposed where the proton and hydride transfer occur in separate steps (Bullock, 2004).

The active species in catalytic cycles, Ru-hydride (31 or 34) and Ru-amido complexes (32 or 35), have not only been detected but also isolated in some cases (Abdur-Rashid et al., 2001, 2002; Haack et al 1997).

The absolute configuration of the alcohol product in AH is determined in the six-membered transition state resulting from the reaction of a chiral diphosphine-diamine-RuH2 complex with a prochiral ketone (Noyori et al., 2005). Because the enantiofaces of the ketone are differentiated on the molecular surface of the saturated RuH2 complex, a suitable combination of the catalyst and substrate is necessary for high efficiency. The prochiral ketone (e.g., acetophenone) approaches in such a ways as to minimize the non-bonded repulsion between the phosphine Ar group and the phenyl ring of the ketone, and to maximize the electronic NH/π attraction (Fig 14 (a)).

The stereoselectivity in the hydrogenation of prochiral aryl ketones catalyzed by (arene)Ru(II) complexes (mostly in ATH) has been ascribed not only to the chiral environment originating from the amine ligand, but also to the contribution of the arene ligand to the stabilization of the transition state through the CH/π interaction (Fig 14 (b)) (Yamakawa et al., 2001). This interaction as well as the NH/π interaction occurring in the transition states with diphosphine-Ru-(1,2-diamine) systems may explain why aryl ketones usually give better ee values than simple unfunctionalized alkyl-alkyl ketones.

Depending on the ligands attached to the metal center (M = transition metal) the inner-sphere mechanisms, in which monohydride or dihydride species are involved, can operate in H2-hydrogenation and transfer hydrogenation (Clapham et al., 2004, Samec et al., 2006; Wylie et al., 2011). In contrast to the outer-sphere mechanism, here the ketone and alcohol interact with the metal center.


Figure 14.

Enantiodifferentiation in the bifunctional-catalyzed hydrogenation of acetophenone

3. Heterogeneous hydrogenation

For the heterogeneous, asymmetric, catalytic reduction of the C=O functionality, there are two types of heterogeneous catalysts. One is chirally modified supported metals, and the other is the immobilized homogeneous catalyst on a variety of organic and inorganic polymeric materials. There are also two major reasons for preparing and studying heterogeneous catalysts: firstly, and most importantly, the better and advanced separation and handling properties, and, secondly, the potential to create catalytic positions with an improved catalytic performance. The ultimate heterogeneous catalyst can easily be renewed, reused without of loss of activity and selectivity, which are at least as good or even better than those of the homogeneous analogue.

3.1. Immobilized chiral complexes

The immobilization of a homogeneous metal coordination complex is a useful strategy in the preparation of new hydrogenation catalysts. Much effort has been devoted to the preparation of such heterogenized complexes over the past decade due to their ease of separation from the reaction mixture and the desired minimal product contamination caused by metal leaching, as well as to their efficient recyclability without any significant loss of activity. Preferably, Rh, Ir, and Ru complexes have been employed in the hydrogenations of carbonyl functionality (Corma et al., 2006). Chemically different supports have been used for the immobilization of various homogeneous complexes, including polymeric organic and inorganic supports (Saluzzo et al., 2002; Bergbreiter, 2002; Fan et al., 2002). Due to their chemical nature, organic polymeric supports have some drawbacks concerning reduced stability that affects the reusability of the catalysts, mainly due to their swelling and deformation (Bräse et al., 2003; Dickerson et al., 2002). Supports of an inorganic nature are more suitable owing to their physical properties, chemical inertness and stability (with respect to swelling and deformation) in organic solvents. The above-mentioned properties of the inorganic supports will facilitate the applications of the materials in reactions carried at higher temperatures and their use in continuous-flow reactions. In the past decade a lot of research effort has been devoted to the development of adequate procedures to attach homogenous catalysts onto inorganic supports (Merckle & Blümel, 2005; Crosman et al., 2005; Corma et al., 2005; Jones et al., 2005; Melero et al., 2007). Immobilization via covalent bonds is undoubtedly the most convenient, but on the other hand, it is the most challenging method for immobilization to perform on such supports (Jones et al., 2005; Steiner et al., 2004; Pugin et al., 2002; Sandree et al., 2001). For example, micelle templated silicas (MTS) featuring a unique porous distribution and high thermal and mechanical stabilities can be easily functionalized by the direct grafting of the functional organo-silane groups on their surfaces (McMorn & Hutchings, 2004; Heckel & Seebach, 2002; Bigi et al., 2002, Clark & Macquarrie, 1998; Tada & Iwasawa, 2006). On the other hand, polar solvents such as water or alcohols and high temperatures during the catalytic procedure can promote the hydrolysis of the grafted moieties.

The heterogenized catalysts can potentially combine the advantages of both homogenous and heterogeneous systems. In 2003, Hu and coworkers developed a novel chiral porous solid catalyst based on zirconium phosphonates for the practically useful enantio-selective hydrogenation of unfunctionalized aromatic ketones (Fig. 15) (Hu et al., 2003a).


Figure 15.

Schematic presentation of chiral porous Zr-phosphonate-Ru-(R)-C24 in Ru-(R)-C25 heterogeneous catalysts

With the built-in Ru-BINAP-DPEN moieties, porous solids of Ru-(R)-C24 and Ru-(R)-C25 exhibited high activity and enantioselectivity in the hydrogenation of aromatic ketones (Table 1). Acetophenone was hydrogenated, producing 1-phenylethanol with a complete conversion and 96.3% ee in i-PrOH with a 0.1 mol% loading of Ru-(R)-C24. This level of enantioselectivity is higher than that observed for the parent Ru-BINAP-DPEN homogeneous catalyst, which gives ~80% ee for the hydrogenation of acetophenone (Ohkuma et al., 1995a; Doucet et al., 1998). As indicated in table 1, the Ru-(R)-C24 immobilized catalyst has also been tested to catalyze the hydrogenation of other aromatic ketones resulting in the formation of the corresponding alcohols with the same high enantioselectivity (90.6-99.0% ee) and complete consumption of the starting ketone. Although the Ru-(R)-C25 catalyst is also highly active for the hydrogenation of aromatic ketones, the enantoselectivity is modest and similar to that of the parent Ru-BINAP-DPEN homogeneous catalyst. The authors believe that the modest enantioselectivities observed for the Ru-(R)-C25 catalyst originate in the substituent effects on the BINAP ligand. Furthermore, the catalysts were successfully reused without any deterioration of the enantioselectivity in eight cycles. The activities did not decrease for the first six cycles, but began to drop during the seventh run (95% conversion), reaching 85% of conversion in the eighth cycle. Furthermore, the Ru(II) catalysts of type Ru-(R)-C24 and Ru-(R)-C25 having dimethylformamide as a ligand instead of 1,2-diphenylethylenediamine were developed and used for the heterogeneous AH of β-keto esters with ee values from 91.7 up to 95.0 % with the same enantio enrichment as is the case in the parent homogenous BINAP-Ru catalyst. The substrates, β-aryl-substituted β-keto esters, are hydrogenated with the same modest ee values (69.6 % ee) as observed when using the homogenous BINAP-Ru analogue (Noyori & Takaya, 1990). The introduced catalysts can be readily recycled and reused (Hu et al., 2003b). Structurally similar Ru(II) catalysts with phosphonic-acid-substituted BINAP were prepared and afterwards immobilized on magnetite nanoparticles prepared by the thermal decomposition method (MNP-C26, Fig. 15) or by the coprecipitation method (NMP-C27, Fig. 15) (Hu et al., 2005). The catalysts were tested for the heterogeneous asymmetric hydrogenation of aromatic ketones showing a remarkably high activity and enantioselectivity (Table 1).

Substrate 36Ru-(R)-C24; ee (%)Ru-(R)-C25; ee (%)MNP-C26; ee (%)MNP-C27; ee (%)
Ar = Ph, R = Me96.379.087.681.7
Ar = 2-naphtyl, R = Me97.182.187.682.0
Ar = 4-tBu-Ph, R = Me99.291.595.191.1
Ar = 4-MeO-Ph, R = Me96.079.987.677.7
Ar = 4-Cl-Ph, R = Me94.959.376.670.6
Ar = 4-Me-Ph, R = Me97.079.587.980.5
Ar = Ph, R = Et93.183.988.986.3
Ar = Ph, R = cyclo-Pr90.6
Ar = 1-naphtyl, R = Me99.295.8

Table 1.

Heterogeneous hydrogenation of the aromatic ketones using Ru(II) catalyst

Heterogeneous chiral Ru(II)-TsDPEN-derived catalysts based on Noyori’s (1S,2S)- or (1R,2R)-N-p-tosylsulfonyl)-1,2-diphenylethylenediamine (TsDPEN) were successfully immobilized onto amorphous silica gel and silica mesopores of MCM-41 and SBA-15 using an easily accessible approach (P.-N. Liu et al., 2004a, 2004b, 2005). The immobilized catalysts demonstrated high catalytic activities and enantioselectivities (up to >99% ee, 38a-38l) (Fig. 16) for the heterogeneous ATH of different ketones. In particular, the catalyst could be recovered and reused in multiple consecutive runs (up to 10 uses) with a completely maintained enantioselectivity.


Figure 16.

Heterogeneous RuII mesoporous silica-supported catalysts

Additionally, Li and coworkers (J. Li et al., 2009) developed a Ru(II)-TsDPEN-derived catalyst that was immobilized in a magnetic siliceous mesocellular foam material. The heterogeneous catalyst showed comparable activities and enantioselectivities (ee 89-97%) with the parent catalyst Ru(II)-TsDPEN in the ATH of imines and simple aromatic ketones. Polymer-supported-TsDPEN ligands combined with [RuCl2(p-cymene)]2 have been shown to exhibit high activities (93-98%) and enantioselectivities (86-97% ee) for the heterogeneous ATH of aromatic ketones, which are suitable intermediates for the synthesis of (S)-fluoxetine with a 75% yield and a 97% ee (Y. Li et al., 2005).


Figure 17.

Ir and Ru mesoporous silica-supported catalysts

Chiral Ru and Ir, mesoporous, silica-supported catalysts were introduced by Liu and coworkers (G. Liu et al., 2008a, 2008b). The Ir-C28-SBA-(R,R)-DPEN catalyst was investigated using a series of aromatic ketones as substrates (Fig. 17). In general, high conversions (95-99 %) and an excellent enantioselectivity, producing the corresponding R enantiomers, were observed by applying 40 atm of H2 at 50 oC and 0.4 mol% of catalyst loading. The catalyst was recovered and reused several times without considerably affecting the ee values. The analogous Ru catalyst, Ru-C29-SBA-(R,R)-DPEN, also displays a high catalytic activity and enantioselectivity under similar reaction conditions (Fig. 17) for the ATH of aromatic ketones.

Two magnetic chiral Ir and Rh catalysts were prepared via directly post-grafting 1,2-diphenylethylenediamine and 1,2-cyclohexanediamine-derived organic silica onto silica-coated iron oxide nanoparticles (G. Liu et al., 2011). The synthesis was followed by a complexation with Ir(III) or Rh(III) complexes. High catalytic activities (up to 99% conversion) and enantioselectivities (up to 92% ee) were obtained in the ATH reaction, reducing the aromatic ketones in an aqueous medium (Fig. 18). Both catalysts could be recovered by magnetic separation and be reused ten times without significantly affecting their catalytic activities and enantioselectivities.


Figure 18.

Magnetic Ir and Rh chiral catalysts

The mesoporous SBA-15 anchored 9-amino epi-cinchonine-[Ir(COD)Cl]2 complex shows good activity and moderate enantio-selectivity (45-78% ee) in the ATH reaction of substituted acetophenones (Shen et al., 2010).

The chiral RuCl2-diphosphine-diamine complex with siloxy functionality was successfully immobilized on mesoporous silica nanospheres with three-dimensional channels (Fig. 19) (Mihalcik & Lin, 2008). Upon activation with t-BuOK, the catalysts C32-C36 can be used for the AH of aromatic ketones; however, C32-C36 exhibit lower enantioselectivities than their parent homogeneous catalysts. The highest ee value of 82% was observed for the hydrogenation of 2-acetonaphthone using C33 as a catalyst. A similar drop in enantio-selectivities has been noticed for many asymmetric catalysts immobilized on bulk mesoporous silica (Song & Lee, 2002). Catalysts of the type C32-C34 were also examined in a dynamic kinetic resolution of -branched aryl aldehydes. The highest ee value of 97% was obtained using 0.1 mol% of the C33 catalyst and 700 psi of H2 pressure on 3-methyl-2-phenylbutanal as a substrate.


Figure 19.

Chiral RuCl2-diphosphine-diamine complexes immobilized on mesoporous silica nanospheres

Differently substituted Rh complexes were anchored on an Al2O3 support and applied for the enantioselective C=O hydrogenation with reasonable activity and enantioselectivities with ees up to 80% (Zsigmond et al., 2008). Due to the fact that an immobilized catalyst did not show a superior enantio-selectivity compared to its homogenous counterparts, the major advantage of the catalyst’s immobilization is the possibility to recycle the catalysts.

The immobilization of the rhodium complexes [Rh((R)-BINAP)(COD)]CF3SO3, [Rh((S)-BINAP)(COD)]ClO4thf, and [Rh((S,S)-chiraphos)(NOR)]ClO4, and the ruthenium complexes [Ru((R)-BINAP)(PPh3)Cl2] and [Ru((R)-BINAP)Cl3] in a thin film of silica-supported ionic liquid enhanced the enantioselectivity of the parent catalyst. As the model reaction, the stereo-selective hydrogenation of acetophenone as a non-chelating prochiral ketone was studied. The enantioselectivities in a moderate range (up to 74%) were observed (Fow et al., 2008). Furthermore, a mesoporous material-supported ionic liquid phase was used as a carrier medium to immobilize the chiral ruthenium complex composed of a chiral 1,2-diamine and an achiral monophosphine (Lou et al., 2010). All the prepared catalysts were active in the hydrogenation of simple aromatic ketones enabling an enantioselectivity from 45 up to 78% ee.

Furthermore, a series of polystyrene-supported TsDPEN ligands were prepared in one step and converted to the corresponding Ru(II) complexes by a treatment with [RuCl2(p-cymene)]2 in dichloromethane at 40 oC for an hour (Marcos et al., 2011). The so-prepared polystyrene-based Ru(II)-catalytic resins showed a low conversion (37%, 48 h, 40 oC) of acetophenone to the corresponding (R)-alcohol (85% ee) in the ATH (HCO2H/Et3N = 5/2) in water. The more promising results were obtained in dichloromethane, where (R)-1-phenylethanol was produced in 99% conversion and with 97% ee. The catalytic resin could be recycled three times without any significant loss of conversion and enantioselectivity, but further recycling shows a major drop in performance of the catalytic resin. A modified tethered Rh(III)-p-toluenesulfonyl-1,2-diphenylethylenediamine (Rh-TsDPEN) complex immobilized on polymeric supports (amino-functionalized polyethylene microparticles) was used in kinetic and up-scaling experiments on the ATH of acetophenone in water. A second-order model describes the enantioselective conversion of acetophenone to phenylethanol and mainly the solution pH was found to play a pivotal role for the activity and reusability of the catalyst (Dimroth et al., 2011). Polyethylene glycol (PEG) supported chiral ligands have also been developed and examined in the Ru-catalyzed ATH of prochiral aromatic ketones in water using HCO2Na as the hydrogen source. Xiao et al. introduced a PTsDPEN ligand that has two PEG chains (PEG-2000) on the meta-position of the TsDPEN’s phenyl groups. Comparing the results of the Ru-TsDPEN catalyst in water, the PEG Ru(II) catalyst in the ATH of various aromatic ketones by HCO2Na in water gave faster rates and a good reusability (X. Li et al., 2004a, 2004b). As an alternative for attaching a PEG chain onto the TsDPEN-tipe ligands, a medium-length PEG chain (PEG-750) at the para-position of the aryl sulfonate group was introduced (J. Liu et al., 2008). The corresponding Ru-PEG-BsDPEN catalyst displays a high activity, reusability and enantioselectivity (up to 99% ee) in the ATH in water.

A series of dendrimers and hybrid dendrimers based on Noyori-Ikariya’s TsDPEN ligand were prepared and the application of their Ru(II) complexes in the ATH of acetophenones was studied. A high catalytic activity and completely maintained enantio-selectivity (acetophenone, 93.4-98.2% ee; 4-bromoacetophenone, 90.1-92.7% ee; 1-(naphthalen-2-yl)ethanone, 92.8-95.1% ee; 1,2-diphenylethanone, 93.9% ee) were observed. Higher-generation core-functionalized dendritic catalysts could be recovered through solvent precipitation and reused several times without any major loss of activity and enantio-selectivity (Y.-C. Chen et al., 2001, 2002, 2005; W. Liu et al., 2004). Hydrophobic Fréchet-type dendritic chiral 1,2-diaminocyclohexane-Rh(III) complexes have also been tested for ATH in water (Jiang et al., 2006). Excellent conversions (70-99%) and enantioselectivity, acetophenone (96% ee), 4-chloroacetophenone (93% ee), 4-methoxyacetophenone (94% ee), 1-tetralone (97% ee), 2-acetylpyridine (91% ee), 2-acetyltiophene (96% ee), ethyl 2-oxo-2-phenylacetate (72% ee), and (E)-4-phenylbut-3-en-2-one (52% ee) were obtained.

3.2. “Self-supported” and solid-supported heterogeneous catalysts

Among various approaches for homogeneous catalyst immobilization, the “self-supported” strategy exhibits some relevant characteristics, such us easy preparation, good stability, high density of catalytically active sites, and high stereocontrol performance, as well as simple recovery (Dai, 2004; Ding et al., 2007). Self-supported Noyori-type catalysts C37-C40 for the AH of ketones by the programmed assembly of bridged diphosphine and diamine ligands with Ru(II) ions were developed (Fig. 20) (Liang et al., 2005; Liang et al., 2006). The enantioselectivity of the hydrogenation of the aromatic ketones under the catalysis of the self-supported catalyst C40 was in some cases significantly higher than the ee values obtained in the homogeneous catalysis. However, it is expected that the enantioselectivities achieved in the hydrogenation of ketones with the catalysts C37 and C38 composed of chirally flexible biphenylphosphine ligands are lower than those of the C39 and C40 constructed with chiral BINAP-containing ligands. This might be explained using Mikami’s mechanistic considerations obtained by an 1H NMR study of the monomeric complex of DM-BIPHEP/RuCl2/(S,S)-DPEN (Mikami et al., 1999). Furthermore, this type of catalyst can be readily recovered and reused with the retention of enantioselectivity and reactivity.

A very interesting example is the asymmetric synthesis of the chiral alcohol function that makes use of the strength of ion pairing in ionic liquids (Schulz et al., 2007). The hydrogenation of substrate 46 using H2 (60 bar) at 60 oC in the presence of the heterogeneous, achiral catalyst Ru/C in an ethanolic solution, gave the corresponding hydroxyl-functionalized ionic liquid in a quantitative yield and up to 80% ee (Fig. 21). The degree of enantioselectivity is dependent on the concentration of the substrate 46 in ethanol during the transformation. The higher the concentration of 46, the higher the ee value of the hydrogenated cation that was observed. This behavior can be explained by considering the ion-pair separating effect of the ethanol solvent.


Figure 20.

Self-supported Noyori-type catalysts C37-C40 for the AH of ketones


Figure 21.

Enantio-selective hydrogenation of a keto-functionalized ionic liquid

Importing chirality to a catalytic active metal surface by the adsorption of a chiral organic molecule (often referred to as a chiral modifier) seems to be one of the promising strategies to obtain new chiral heterogeneous catalytic systems. In the hydrogenation of C=O function, chirality-modified supported metal catalysts represent a promising approach with synthetic potential. Orito et al. introduced the strategy of a cinchona-alkaloid-modified platinum catalyst system in 1979 (Orito et al., 1979). Following the early work of Blaser et al. (Studer et al., 1999, 2000, 2003; Blaser et al., 2000), Baiker et al. (Heinz et al., 1995, von Arx et al., 2002), and others, the methodology developed in the sense of the substrate scope, and on the other hand, extensive efforts were carried out to get more insight into understanding the mechanistic aspects of the transformation. The method was found to have excellent performance in the hydrogenation of activated ketones (Fig. 22).

The modifiers derived from CD and quinine (QN) lead to an excess of (R)-ethyl lactate, whereas the CN and QD derivatives preferentially lead to the S enantiomer. It has been shown that substituted aliphatic and aromatic -keto ethers are suitable substrates for the enantioselective hydrogenation catalyzed by cinchona-modified Pt catalysts and both kinetic and dynamic kinetic resolution is possible (Studer et al., 2002). For conversions less than 50%, ee’s of up to 98% were observed when starting with racemic substrates (kinetic resolution). Strong acceleration of the reaction was noticed in the presence of KOH, but without of the enantiomeric excess. In order to get dynamic kinetic resolution the OH ions had to be immobilized on a solid ion-exchange resin enabling ee’s of more than 80%.

A systematic structure-selectivity study of the hydrogenation of activated ketones catalyzed by a modified Pt-catalyst revealed a high substrate specificity of the catalytic system. Relatively small structural changes in the substrate or modifier can strongly affect the enantio-selectivity and often in the opposite manner, especially when comparing reactions in toluene and AcOH (Exner et al., 2003). Fluorinated β-diketones can be enantioselectively hydrogenated on cinchona-alkaloids-modified Pt/Al2O3 catalysts. Methyl, ethyl, and isopropyl 4,4,4-trifluoroacetoacetates were hydrogenated in the presence of MeOCD-modified Pt/Al2O3 catalysts, producing the corresponding alcohols in 93-96% ee (van Arx et al., 2002).

Synthetically obtained (R,R)-pantoyl-naphtylethylamine ((R,R)-PNEA) provides 93% ee in the hydrogenation of 1,1,1-trifluoro-2,4-pentanedione and 85% ee in the case of 1,1,1-trifluoro-5,5-dimethyl-2,4-hexanedione (Diezi et al., 2005a, 2005b, Hess et al., 2004). A thorough investigation concerning the origin of the chemo- and enantioselectivity in the hydrogenation of diketones on platinum revealed that the structures of ammonium ion-enolate-type ion pairs formed between the modifier and 1,3-diketones are different in solution and on the surface of the metal. The chemoselectivity is attributed to the selective interaction of the protonated amine group of the modifier to the absorbed activated keto-carbonyl function and prevention of the interaction of the non-activated carbonyl group with the metal surface (Diezi et al., 2006). Results on the enantioselective hydrogenation of -fluoroketones, a group of activated ketones on chiral platinum-alumina surface have shown that the Orito reaction is also suitable for the preparation of the corresponding chiral -fluoroalcohols. The enantioselectivity of 92% was achieved in the hydrogenation of 2,2,2-trifluoroacetophenone under optimized reaction conditions using a CD-modified Pt catalyst (von Arx et al., 2001a). However, the enantioselectivities obtained on other -fluorinated ketones were only moderate (Varga et al., 2004; Felföldi et al., 2004; Szöri et al., 2009).


Figure 22.

Enantio-selective hydrogenation of activated ketones.

A supported (SiO2) iridium catalyst, which is stabilized by PPh3 and modified by a chiral diamine, derived from cinchona alkaloids, exhibits a high activity and high enantioselectivity for the hydrogenation for the simple aromatic ketones (Fig. 23). The addition of different bases (t-BuOK, LiOH, NaOH, or KOH) improves both the activity and the enantioselectivity of the reaction (Jiang et al., 2008). A similar ruthenium catalyst (Ru/γ-Al2O3) was also developed and a broad range of aromatic ketones over this catalyst can be hydrogenated (Jiang et al. 2010).


Figure 23.

Enantioselective hydrogenation of activated ketones.

A series of silica (SiO2) supported iridium catalysts stabilized by cinchona alkaloids were also prepared and applied in the heterogeneous asymmetric hydrogenation of acetophenone. Cinchona alkaloids display a substantial capability to stabilize and disperse the Ir particles. A synergistic effect between the (1S,2S)-DPEN (modifier) and the CD (stabilizer) significantly accelerates the activity as well as the enantioselectivity (up to 79% ee) on acetophenone (Yang et al. 2009).

Besides improving the cinchonidine-platinum catalyst system, extensive efforts have been made in developing a reliable mechanistic interpretation. To understand the adsorption behavior of the modifier and reactant, their conformation, and their intra-molecular interactions at solid-liquid interface, an in-situ attenuated, total-reflection, infrared study has been performed. The adsorption of cinchonidine on the Pt/Al2O3 in the presence of a solvent and H2 is strongly concentration dependent. The quinolone moiety of the modifier is responsible for the absorption on the Pt surface (Ferri & Bürgi, 2001).


Figure 24.

Schematic representation of the adsorption mode of CD on the metal surface and interactions between the half-hydrogenated state of the activated ketone and the basic quinuclidine-N atom of the chiral modifier.

An inversion of the enantioselectivity occurs in the asymmetric hydrogenation of the activated ketones by changing the solvent composition, including water and acid additives (von Arx et al., 2001b; Bartók et al., 2002). Hydrogenation of the ethyl pyruvate over Pt/Al2O3 (Huck et al., 2003a) and 4-methoxy-6-methyl-2-pyrone over Pd/TiO2 (Huck et al., 2003b), an equimolar mixture of cinchona alkaloids CD and QD resulted in ee’s similar to those obtained with CD alone, while QD gave a high ee of the opposite enantiomers. This was explained by different adsorption strengths and absorption modes of the modifier (Fig. 24). Furthermore, cinchona ether homologues can give opposite enantiomers through maintaining the same absolute configuration of the parent alkaloid. In the hydrogenation of ketopantolactone the CD alkaloid produced (R)-pantolactone in 79% ee, whereas O-phenylcinchonidine (PhOCD) gave S-enantiomere in 52% ee. It seems that the OH group of CD is not involved in the substrate-modifier interaction during the hydrogenation process, which is also confirmed by the fact that O-methyl-CD and O-ethyl-CD gave the same enantiomer in excess than CD. The inversion of enantioselectivity is explained by the change in the chiral pocket experienced by the incoming reactant and the change is related to the conformational behavior of the absorbed alkaloid and the steric effects of the ether group. PhOCD can generate conformations whose adsorption energy is decreased with respect to the parent CD. An equally important change is also the alteration of the chiral pocket obtained upon absorption of the modifier (Fig. 24). These changes are enough to induce the inversion of enantio-selectivity (Bonalumi et al., 2005; Vargas et al., 2006, 2007). The aspects of the interaction of different modifiers, MeOCD, t-MeSiOCD (Bonalumi et al., 2007), (R)-iCN (Schmidt et al., 2008), and tryptophan and tryptophan-based di end tripeptides (Mondelli et al., 2009) with a metal surface have also been studied experimentally (using TEM, XPS, and ATR-IR spectroscopy) and theoretically (DFT calculations). Furthermore, it has been shown that the rate of hydrogenation and enantioselectivity outcome depends on the shape and terrace sites (Pt{100}or {111}) of the nanoparticles. Both the rate and the ee increased in the hydrogenation of ethyl pyruvate and ketopantolactone when Pt {111} nanoparticles were modified using CD or QN as the chiral modifiers (Schmidt et al., 2009).

4. Conclusions

This chapter discusses the transition-metal-catalyzed, asymmetric, homogenous and heterogeneous hydrogenation of prochiral ketones, not so much focusing on the reactions providing valuable chiral alcohols, but rather it gives prominent and interesting examples of the ketone substrates and catalyst systems that are found in the recent literature. Despite the tremendous effort being made in the catalytic, asymmetric hydrogenation of prochiral ketones, approaching the enzymatic performance in some cases, there is still much potential for the continued development of these reactions. Concerning the environmental and economic issues, the introduction of non-toxic, cheap, and at the same time efficient and universal catalyst systems, being able to operate under mild conditions in a highly selective manner and for a broad range of substrates, remains a challenge for future research. Additionally, more rational catalyst designs are possible with better mechanistic understandings of the catalytic cycles in catalytic AH and ATH reactions.


The Ministry of Higher Education, Science and Technology of the Republic of Slovenia, the Slovenian Research Agency (P1-0230-0103), EN→FIST Centre of Excellence, and Krka, Pharmaceutical company, d.d. are gratefully acknowledged for their financial support.


1 - K. Abdur-Rashid, M. Faatz, A. J. Lough, R. H. Morris, 2001Catalytic Cycle for the Asymmetric Hydrogenation of Prochiral Ketones to Chiral Alcohols: Direct Hydride and Proton Transfer from Chiral Catalysts trans-Ru(H)2(diphosphine)(diamine) to Ketones and Direct Addition of Dihydrogen to the Resulting Hydridoamido Complexes. Journal of the American Chemical Society, 12330August 2001), 747374740002-7863
2 - K. Abdur-Rashid, S. E. Clapham, A. Hadzovic, J. N. Harvey, A. J. Lough, R. H. Morris, 2002Mechanism of the Hydrogenation of Ketones Catalyzed by trans-Dihydrido(diamine)ruthenium(II) Complexes. Journal of the American Chemical Society, 12450December 2002), 15104151180002-7863
3 - D. A. Alonso, D. Guijarro, P. Pinho, O. Temme, P. G. Andersson, 1998S,3R,4R)-2-Azanorbornylmethanol, an Efficient Ligand for Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Ketones. The Journal of Organic Chemistry, 638April 1998), 274927510022-3263
4 - N. Arai, T. Ohkuma, 2010Reduction of Carbonyl Groups: Hydrogenation, In: Science of Synthesis: Stereoselective Synthesis 2, G.A Molander, (Ed.), 957Thieme, 978-3-13154-121-5Stuttgart, Germany
5 - K. Balázsik, K. Szöri, K. Felföldi, B. Török, M. Bartók, (2000). Asymmetric synthesis of alkyl 5-oxotetrahydrofuran-2-carboxylates by enantioselective hydrogenation of dialkyl 2-oxoglutarates over cinchona modified Pt/Al2O3 catalysts. Chemical Communications, 17 555556 , 1359-7345
6 - W. Baratta, M. Ballico, G. Chelucci, K. Siega, P. Rigo, 2008Osmium(II) CNN Pincer Complexes as Efficient Catalysts for Both Asymmetric Transfer and H2 Hydrogenation of Ketones. Angewandte Chemie International Edition, 4723May 2008), 436243651433-7851
7 - W. Baratta, P. Rigo, 2008Pyridin-2-yl)methanamine-Based Ruthenium Catalysts for Fast Transfer Hydrogenation of Carbonyl Compounds in 2-Propanol. European Journal of Inorganic Chemistry, 26September 2008), 404140531099-0682
8 - W. Baratta, C. Barbato, S. Magnolia, K. Siega, P. Rigo, 2010Chiral and Nonchiral [OsX2(diphosphane)(diamine)] (X: Cl, OCH2CF3) Complexes for Fast Hydrogenation of Carbonyl Compounds, Chemistry-A European Journal, 1610March 2010), 320132061521-3765
9 - M. Bartók, M. Sutyinszki, K. Felföldi, Gy. Szöllősi, 2002Unexpected change of the sense of the enantioselective hydrogenation of ethyl pyruvate catalyzed by a Pt- alumina-cinchona alkaloid system. Chemical Communications, 10113011311359-7345
10 - D. E. Bergbreiter, 2002Using Soluble Polymers To Recover Catalysts and LigandsChemical Reviews10210August 2002), 334533840009-2665
11 - F. Bigi, L. Moroni, R. Maggi, G. Sartori, 2002Heterogeneous Enantioselective Epoxidation of Olefins Catalysed by Unsymmetrical (salen)Mn(III) Complexes Supported on Amorphous or MCM-41 Silica Through a New Triazine-Based Linker. Chemical Communications, 77167171359-7345
12 - H. U. Blaser, H. P. Jalett, 1993Enantioselective Hydrogenation of α-Ketoacids Using Platinum Catalysts Modified With Cinchona Alkaloids. Studies in Surface Science and Catalysis, 78139146978-0-44489-063-4
13 - H. U. Blaser, H. P. Jalett, W. Lottenbach, M. Studer, 2000Heterogeneous Enantioselective Hydrogenation of Ethyl Pyruvate Catalyzed by Cinchona- Modified Pt Catalysts: Effect of Modifier Structure. Journal of the American Chemical Society12251December 2000), 12675126820002-7863
14 - N. Bonalumi, A. Vargas, D. Ferri, T. Bürgi, T. Mallat, A. Baiker, 2005Competition at Chiral Metal Surfaces: Fundamental Aspects of the Inversion of Enantioselectivity in Hydrogenations on Platinum.Journal of the American Chemical Society12723June 2005), 846784770002-7863
15 - N. Bonalumi, A. Vargas, D. Ferri, A. Baiker, 2007Chirally Modified Platinum Generated by Adsorption of Cinchonidine Ether Derivatives: Towards Uncovering the Chiral SitesChemistry- A European Journal, 1333November 2007), 923692440143-4193X
16 - S. Bräse, F. Lauterwasser, R. E. Ziegert, 2003Recent Advances in Asymmetric C-C and C- Heteroatom Bond Forming Reactions using Polymer-Bound Catalysts.Advanced Synthesis & Catalysis3458August 2003), 8699291615-4169
17 - C. Bubert, J. Blacker, S. M. Brown, J. Crosby, S. Fitzjohn, J. P. Muxworthy, T. Thorpe, J. M. J. Williams, 2001Synthesis of water-soluble aminosulfonamide ligands and their application in enantioselective transfer hydrogenationTetrahedron Letters4224June 2001), 403740390040-4039
18 - R. M. Bullock, (2004, Ionic. Catalytic, Chemistry. Hydrogenations-A, Journal. European, Vol.1, No.1, . May, 2004, 2366237 . pp, I. S. S. , 1521-3765
19 - T. Bürgi, A. Baiker, 2004Heterogeneous Enantioselective Hydrogenation over Cinchona Alkaloid Modified Platinum: Mechanistic Insights into a Complex Reaction.Accounts of Chemical Research3711November 2004), 9099170001-4842
20 - C. P. Casey, H. Guan, 2007An Efficient and Chemoselective Iron Catalyst for the Hydrogenation of Ketones.Journal of the American Chemical Society12918May 2007), 581658170002-7863
21 - Y. Chen, C. , T. Wu, F. , J. Deng, G. , H. Liu, J. Jiang, Z. , M. C. K. Choi, A. S. C. Chan, 2001Dendriticcatalysts for asymmetric transfer hydrogenation.Chemical Communications, 16148814891359-7345
22 - Y. Chen, C. , T. Wu, F. , J. Deng, G. , H. Liu, X. Cui, J. Zhu, Y. Jiang, Z. , M. C. K. Choi, A. S. C. Chan, 2002Multiple Dendritic Catalysts for Asymmetric Transfer Hydrogenation.The Journal of Organic Chemistry6715Juliy 2002), 530153060022-3263
23 - C. Chen, R. A. Reamer, J. R. Chilenski, C. J. Mc Williams, 2003Highly Enantioselective Hydrogenation of Aromatic-Heteroaromatic Ketones.Organic Letters526December 2003), 503950421523-7060
24 - Y. Chen, C. , T. Wu, F. , L. Jiang, J. Deng, G. , H. Liu, J. Zhu, Y. Jiang, Z. , 2005Synthesis of Dendritic Catalysts and Application in Asymmetric Transfer Hydrogenation.The Journal of Organic Chemistry703February 2005), 100610100022-3263
25 - F. K. Cheung, C. Lin, F. Minissi, A. L. Crivillé, M. A. Graham, D. J. Fox, M. Wills, 2007An Investigation into the Tether Length and Substitution Pattern of Arene-Substituted Complexes for Asymmetric Transfer Hydrogenation of Ketones.Organic Letters922October 2007), 465946621523-7060
26 - S. E. Clapham, A. Hadzovic, R. H. Morris, 2004Mechanism of the H2-hydrogenation and transfer hydrogenation of polar bonds catalyzed by ruthenium hydride complexes. Coordination Chemistry Reviews24821-24December 2004), 220122370010-8545
27 - J. H. Clark, D. J. Macquarrie, 1998Catalysis of Liquid Phase Organic Reactions Using Chemically Modified Mesoporous Inorganic SolidsChemical Communications88538601359-7345
28 - M. Coll, O. Pàmies, H. Adolfsson, M. Diéguez, 2011Carbohydrate-based pseudo-dipeptides: new ligands for the highly enantioselective Ru-catalyzed transfer hydrogenation reaction. Chemical Communications, 474412188121901359-7345
29 - A. Corma, D. Das, H. García, A. Leyva, 2005A Periodic Mesoporous Organosilica Containing a Carbapalladacycle Complex as Heterogeneous Catalyst for Suzuki Cross-CouplingJournal of Catalysis2292January 2005), 3223310021-9517
30 - A. Corma, H. Garcia, 2006Silica-Bond Homogenous Catalysts as Recoverable and Reusable Catalysts in organic Synthesis. Advanced Synthesis & Catalysis, 34812-13August 2006), 139114121615-4169
31 - A. Crosman, W. F. Hoelderich, 2005Enantioselective Hydrogenation Over Immobilized Rhodium Diphosphine Complexes on Aluminated SBA-15Journal of Catalysis2321May 2005), 43500021-9517
32 - L. Dai, X. , 2004Chiral Metal-Organic Assemblies-A New Approach to Immobilizing Homogeneous Asymmetric CatalystsAngewandte Chemie International Edition4343November 2004), 572657291433-7851
33 - C. F. de Graauw, J. A. Peters, H. van Bekkum, J. Huskens, 1994Meerwein-Ponndorf-Verley Reductions and Oppenauer Oxidations: An Integrated ApproachSynthesis10September 1994), 100710170039-7881
34 - T. J. Dickerson, N. N. Reed, K. D. Janda, 2002Soluble Polymers as Scaffolds for Recoverable Catalysts and Reagents.Chemical Reviews10210September 2002), 332533440009-2665
35 - C. Diez, U. Nagel, 2010Chiral iridium(I) bis(NHC) complexes as catalysts for asymmetric transfer hydrogenation. Applied Organometallic Chemistry, 247July 2010), 5095161099-0739
36 - S. Diezi, M. Hess, E. Orglmeister, T. Mallat, A. Baiker, 2005Chemo and enantioselective hydrogenation of fluorinated ketones on platinum modified with (R)-1-(1-naphthyl)ethylamine derivatives. Journal of Molecular Catalysis A: Chemical, 2391-2September 2005), 49561381-1169
37 - S. Diezi, M. Hess, E. Orglmeister, T. Mallat, A. Baiker, 2005An efficient synthetic chiral modifier for platinumCatalysis Letters1023-4August 2005), 1211250101-1372X
38 - S. Diezi, D. Ferri, A. Vargas, T. Mallat, A. Baiker, 2006The Origin of Chemo- and Enantioselectivity in the Hydrogenation of Diketones on Platinum.Journal of the American Chemical Society12812March 2006), 404840570002-7863
39 - J. Dimroth, U. Schedler, J. Keilitz, R. Haag, R. Schomäcker, 2011New Polymer- Supported Catalysts for the Asymmetric Transfer Hydrogenation of Acetophenone in Water-Kinetic and Mechanistic Investigations.Advanced Synthesis & Catalysis3538May 2011), 133513441615-4169
40 - K. Ding, Z. Wang, L. Shi, 2007Self-supported chiral catalysts for heterogeneous enantioselective reactionsPure and Applied Chemistry799153115400033-4545
41 - H. Doucet, T. Ohkuma, K. Murata, T. Yokozawa, M. Kozawa, E. Katayama, A. F. England, T. Ikariya, R. Noyori, 1998trans-[RuCl2(phosphane)2(1,2-diamine)] and Chiral trans-[RuCl2(diphosphane)(1,2-diamine)]: Shelf-Stable Precatalysts for the Rapid, Productive, and Stereoselective Hydrogenation of Ketones. Angewandte Chemie International Edition, 3712July 1998), 170317070000-1433
42 - C. Exner, A. Pfaltz, M. Studer, H. Blaser, U. , 2003Heterogeneous Enantioselective Hydrogenation of Activated Ketones Catalyzed by Modified Pt-Catalysts: A Systematic Structure-Selectivity StudyAdvanced Synthesis & Catalysis345November 2003), 11125312601615-4169
43 - K. Everaere, A. Mortreux, J. Carpentier, F. , 2003Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation of Carbonyl Compounds with 2-Propanol and Ephedrine-Type Ligands. Advanced Synthesis & Catalysis, 3451-2January 2003), 67771615-4169
44 - Q. Fan, H. , Y. Li, M. , A. S. C. Chan, 2002Recoverable Catalysts for Asymmetric Organic SynthesisChemical Reviews10210September 2002), 338534650009-2665
45 - K. Felföldi, T. Varga, P. Forgó, M. Bartók, 2004Enantioselective Hydrogenation of Trifluoromethylcyclohexyl Ketone on Cinchona Alkaloid Modified Pt-Alumina CatalystCatalysis Letters971-2August 2004), 65700101-1372X
46 - D. Ferri, T. Bürgi, 2001An in Situ Attenuated Total Reflection Infrared Study of a Chiral Catalytic Solid−Liquid Interface: Cinchonidine Adsorption on Pt. Journal of the American Chemical Society, 12348December 2001), 12074120840002-7863
47 - K. L. Fow, S. Jaenicke, T. E. Müller, C. Sievers, 2008Enhanced enantioselectivity of chiral hydrogenation catalysts after immobilisation in thin films of ionic liquidJournal of Molecular Catalysis A: Chemical2792January 2008), 2392471381-1169
48 - A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya, R. Noyori, 1996Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation of Ketones Using a Formic Acid−Triethylamine Mixture. Journal of the American Chemical Society, 11810March 1996), 252125220002-7863
49 - S. Gladiali, E. Alberico, 2006Asymmetric transfer hydrogenation: chiral ligands and applicationsChemical Society Reviews353March 2006), 2262360306-0012
50 - K. Haack, J. , S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori, 1997The Catalyst Precursor, Catalyst, and Intermediate in the RuII-Promoted Asymmetric Hydrogen Transfer between Alcohols and KetonesAngewandte Chemie International Edition in English363February 1997), 2852881433-7851
51 - S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R. Noyori, 1995Asymmetric Transfer Hydrogenation of Aromatic Ketones Catalyzed by Chiral Ruthenium(II) Complexes. Journal of the American Chemical Society, 11728July 1995), 756275630002-7863
52 - A. Heckel, D. Seebach, 2002Preparation and Characterization of TADDOLs Immobilized on Hydrophobic Controlled-Pore-Glass Silica Gel and Their Use in Enantioselective Heterogeneous CatalysisChemistry- A European Journal, 83January 2002), 5595721521-3765
53 - T. Heinz, G. Wang, A. Pfaltz, B. Minder, M. Schürch, T. Mallat, A. Baiker, 1995Naphtyl)ethylamine and Derivatives Thereof as Chiral Modifiers in the Enantioselective Hydrogenation of Ethyl Pyruvate over Pt-Alumina. Journal of the Chemical Society, Chemical Communications, No. 142114221359-7345
54 - R. Hess, S. Diezi, T. Mallat, A. Baiker, 2004Chemo- and enantioselective hydrogenation of the activated keto group of fluorinated β-diketones. Tetrahedron: Asymmetry, 152January 2004), 2512570957-4166
55 - J. P. Hopewell, J. E. D. Martins, T. C. Johnson, J. Godfrey, M. Wills, 2012Developing asymmetric iron and ruthenium-based cyclone complexes; complex factors influence the asymmetric induction in the transfer hydrogenation of ketonesOrganic & Biomolecular Chemistry101January 2012), 134145ISSN
56 - A. Hu, H. L. Ngo, W. Lin, (2003). Chiral Porous Hybrid for Practical Heterogeneous Asymmetric Hydrogenation of aromatic ketones. Journal of the American Chemical Society, 125 38 (September 2003) 1149011491 , 0002-7863
57 - A. Hu, H. L. Ngo, W. Lin, 2003Chiral, Porous, Hybrid Solids for Highly Enantioselective Heterogeneous Asymmetric Hydrogenation of β-Keto Esters. Angewandte Chemie International Edition, 439December 2003), 600060031433-7851
58 - A. Hu, H. L. Ngo, W. Lin, 2004Remarkable 4,4′-Substituent Effects on Binap: Highly Enantioselective Ru Catalysts for Asymmetric Hydrogenation of β-Aryl Ketoesters and Their Immobilization in Room-Temperature Ionic Liquids. Angewandte Chemie International Edition, 4319May 2004), 250125041433-7851
59 - A. Hu, T. G. Yee, W. Lin, 2005Magnetically Recoverable Chiral Catalysts Immobilized on Magnetite Nanoparticles for Asymmetric Hydrogenation of Aromatic Ketones.Journal of the American Chemical Society12736September 2005), 12486124870002-7863
60 - W. Huck, R. , T. Mallat, A. Baiker, 2003Non-Linear Effect of Modifier Composition on Enantioselectivity in Asymmetric Hydrogenation over Platinum MetalsAdvanced Synthesis & Catalysis3451-2January 2003), 2552601615-4169
61 - W. Huck, R. , T. Bürgi, T. Mallat, A. Baike, 2003Asymmetric hydrogenation on platinum:nonlinear effect of coadsorbed cinchona alkaloids on enantiodifferentiation.Journal of Catalysis2161-2May-June 2003), 2762870021-9517
62 - H. Huang, T. Okuno, K. Tsuda, M. Yoshimura, M. Kitamura, 2006Enantioselective Hydrogenation of Aromatic Ketones Catalyzed by Ru Complexes of Goodwin−Lions-type sp2N/sp3N Hybrid Ligands R-BINAN-R’-Py. Journal of the American Chemical Society, 12827July 2006), 871687170002-7863
63 - T. Ikariya, A. J. Blacker, 2007Asymmetric Transfer Hydrogenation of Ketones with Bifunctional Transition Metal-Based Molecular Catalysts.Accounts of Chemical Research4012December 2007), 130013080001-4842
64 - J. Ito, T. Teshima, H. Nishiyama, 2012Enhancement of enantioselectivity by alcohol additives in asymmetric hydrogenation with bis(oxazolinyl)phenyl ruthenium catalysts. Chemical Communications, 488110511071359-7345
65 - Q. Jiang, Y. Jiang, D. Xiao, P. Cao, X. Zhang, 1998Highly Enantioselective Hydrogenation of Simple Ketones Catalyzed by a Rh-PennPhos ComplexAngewandte ChemieInternational Edition, 378May 1998), 110011031433-7851
66 - L. Jiang, T. Wu, F. , Y. Chen, C. , J. Zhu, J. Deng, G. , 2006Asymmetric transfer hydrogenation catalysed by hydrophobic dendritic DACH-rhodium complex in waterOrganic & Biomolecular Chemistry417331933241477-0520
67 - H. Jiang, C. Yang, C. Li, H. Fu, H. Chen, R. Li, X. Li, 2008Heterogeneous Enantioselective Hydrogenation of Aromatic Ketones Catalyzed by Cinchona- and Phosphine-Modified Iridium CatalystsAngewandte Chemie International Edition, 4748November 2008), 924092441433-7851
68 - H. Jiang, H. Chen, R. Li, 2010Cinchona-modified Ru catalysts for enantioselective heterogeneous hydrogenation of aromatic ketonesCatalysis Communications117March 2010), 5845871566-7367
69 - C. W. Jones, M. W. Mc Kittrick, J. V. Nguyen, K. Yu, 2005Design of silica-tethered metal complexes for polymerization catalysisTopics in Catalysis341-467761022-5528
70 - K. Junge, B. Wendt, D. Addis, S. Zhou, S. Das, S. Fleischer, M. Beller, 2011Copper-Catalyzed Enantioselective Hydrogenation of KetonesChemistry- A European Journal, 171January 2011), 1011051521-3765
71 - F. D. Klingler, 2007Asymmetric Hydrogenation of Prochiral Amino Ketones to Amino Alcohols for Pharmaceutical Use.Accounts of Chemical Research4012December 2007), 136713760001-4842
72 - Y. Kuroki, Y. Sakamaki, K. Iseki, 2001Enantioselective Rhodium(I)-Catalyzed Hydrogenation of Trifluoromethyl Ketones. Organic Letters, 33January 2001), 4574591523-7060
73 - N. Künzle, A. Szabo, M. Schürch, G. Wang, 1998Enantioselective hydrogenation of a cyclic imidoketone over chirally modified Pt/Al2O3Chemical Communications13137713781359-7345
74 - C. Le Blond, J. Wang, J. Liu, A. T. Andrews, Y. Sun, K. , 1999Highly Enantioselective Heterogeneously Catalyzed Hydrogenation of α-Ketoesters under Mild Conditions. Journal of the American Chemical Society, 12120May 1999), 492049210002-7863
75 - E. Le Roux, R. Malacea, E. Manoury, R. Poli, L. Gonsalvi, M. Peruzzini, (2007). Highly Efficient Asymmetric Hydrogenation of Alkyl Aryl Ketones Catalyzed by Iridium Complexes with Chiral Planar Ferrocenyl Phosphino-Thioether.Advanced Synthesis & Catalysis, 349 3 (February 2007), 309313 , 1615-4169
76 - X. Li, W. Chen, W. Hems, F. King, J. Xiao, 2004Asymmetric transfer hydrogenation of ketones with a polymer-supported chiral diamineTetrahedron Letters455January 2004), 9519530040-4039
77 - X. Li, X. Wu, W. Chen, F. E. Hancock, K. King, J. Xiao, 2004Asymmetric Transfer Hydrogenation in Water with a Supported Noyori-Ikariya Catalyst.Organic Letters619September 2004), 332133241523-7060
78 - Y. Li, Z. Li, F. Li, Q. Wang, F. Tao, 2005Preparation of polymer-supported Ru-TsDPEN catalysts and use for enantioselective synthesis of (S)-fluoxetine. Organic & Biomolecular Chemistry, 314251325181477-0520
79 - Y. Li, K. Ding, C. A. Sandoval, 2009Hybrid NH2-Benzimidazole Ligands for Efficient Ru-Catalyzed Asymmetric Hydrogenation of Aryl KetonesOrganic Letters114Februar 2009), 9079101523-7060
80 - L. Li, J. Wu, F. Wang, J. Liao, H. Zhang, C. Lian, J. Zhu, J. Deng, 2007Asymmetric transfer hydrogenation of ketones and imines with novel water-soluble chiral diamine as ligand in neat waterGreen Chemistry9123251463-9262
81 - J. Li, Y. Zhang, D. Han, Q. Gao, C. Li, 2009Asymmetric transfer hydrogenation using recoverable ruthenium catalyst immobilized into magnetic mesoporous silicaJournal of Molecular Catalysis A: Chemical298February 2009), 31351381-1169
82 - W. Li, X. Sun, L. Zhou, G. Hou, S. Yu, X. Zhang, 2009Highly Efficient and Highly Enantioselective Asymmetric Hydrogenation of Ketones with TunesPhos/1,2-Diamine-Ruthenium(II) ComplexesThe Journal of Organic Chemistry743Februar 2009), 139713990022-3263
83 - Y. Liang, Q. Jing, X. Li, L. Shi, K. Ding, 2005Programmed Assembly of Two Different Ligands with Metallic Ions: Generation of Self-Supported Noyori-type Catalysts for Heterogeneous Asymmetric Hydrogenation of Ketones.Journal of the American Chemical Society12721769476950002-7863
84 - Y. Liang, Z. Wang, K. Ding, 2006Generation of Self-Supported Noyori-Type Catalysts Using Achiral Bridged-BIPHEP for Heterogeneous Asymmetric Hydrogenation of KetonesAdvanced Synthesis & Catalysis34812-13August 2006), 153315381615-4169
85 - P. Liu, N. , P. Gu, M. , F. Wang, Y. Tu, Q. , 2004Efficient Heterogeneous Asymmetric Transfer Hydrogenation of Ketones Using Highly Recyclable and Accessible Silica- Immobilized Ru-TsDPEN CatalystsOrganic Letters62January 2004), 1691721523-7060
86 - P. Liu, N. , P. Gu, M. , J. G. Deng, Y. Tu, Q. , Ma Y. , P. , 2005Efficient Heterogeneous Asymmetric Transfer Hydrogenation Catalyzed by Recyclable Silica-Supported Ruthenium ComplexesEuropean Journal of Organic Chemistry15August 2005), 322132270143-4193X
87 - P. Liu, N. , J. G. Deng, Y. Tu, Q. , S. H. Wang, 2004Highly efficient and recyclable heterogeneous asymmetric transfer hydrogenation of ketones in waterChemical Communications18207020711359-7345
88 - W. Liu, X. Cui, L. Cun, J. Zhu, J. Deng, 2004Tunable dendritic ligands of chiral 1,2- diamine and their application in asymmetric transfer hydrogenation. TetrahedronAsymmetry, 1615August 2005), 252525300957-4166
89 - J. Liu, Y. Zhou, Y. Wu, X. Li, A. S. C. Chan, 2008Asymmetric transfer hydrogenation of ketones with a polyethylene glycol bound Ru catalyst in waterTetrahedronAsymmetry, 197April 2008), 8328370957-4166
90 - G. Liu, M. Yao, F. Zhang, Y. Gao, H. Li, 2008Facile synthesis of a mesoporous silica- supported catalyst for Ru-catalyzed transfer hydrogenation of ketones. Chemical Communications33473491359-7345
91 - G. Liu, M. Yao, J. Wang, X. Lu, M. Liu, F. Zhang, H. Li, 2008Enantioselective Hydrogenation of Aromatic Ketones Catalyzed by a Mesoporous Silica-Supported Iridium CatalystAdvanced Synthesis & Catalysis, 35010July 2008), 146414681615-4169
92 - G. Liu, H. Gu, Y. Sun, J. Long, Y. Xu, H. Li, 2011Magnetically Recoverable Nanoparticles: Highly Efficient Catalysts for Asymmetric Transfer Hydrogenation of Aromatic Ketones in Aqueous MediumAdvanced Synthesis & Catalysis3538May 2011) 131713241615-4169
93 - L. Lou, L. , Y. Dong, K. Yu, S. Jiang, Y. Song, S. Cao, S. Liu, 2010Chiral Ru complex immobilized on mesoporous materials by ionic liquids as heterogeneous catalysts for hydrogenation of aromatic ketonesJournal of Molecular Catalysis A: Chemical3331-2December 2010), 20271381-1169
94 - R. Malacea, R. Poli, E. Manoury, (2010, hydrosilylation. Asymmetric, hydrogenation. transfer, of. hydrogenation, catalyzed. ketones, iridium. by, complexes, Coordination Chemistry Reviews2545-6March 2010), 7297520010-8545
95 - C. V. Manville, G. Docherty, R. Padda, M. Wills, 2011Application of Proline-Functionalised 1,2-Diphenylethane-1,2-diamine (DPEN) in Asymmetric Transfer Hydrogenation of KetonesEuropean Journal of Organic Chemistry34December 2011), 689369011099-0690
96 - R. Marcos, C. Jimeno, M. A. Pericàs, 2011Polystyrene-Supported Enantiopure 1,2- Diamines: Development of a Most Practical Catalyst for the Asymmetric Transfer Hydrogenation of Ketones. Advanced Synthesis & Catalysis, 3538May 2011) 134513521615-4169
97 - D. S. Matharu, D. J. Morris, G. J. Clarkson, M. Wills, 2006An outstanding catalyst for asymmetric transfer hydrogenation in aqueous solution and formic acid/triethylamineChemical Communications30323232341359-7345
98 - K. Matsumura, N. Arai, K. Hori, T. Saito, N. Sayo, T. Ohkuma, 2011Chiral Ruthenabicyclic Complexes: Precatalysts for Rapid, Enantioselective, and Wide-Scope Hydrogenation of KetonesJournal of the American Chemical Society13328July 2011), 10696106990002-7863
99 - H. Matsunaga, T. Ishizuka, T. Kunieda, 2005Highly efficient asymmetric transfer hydrogenation of ketones catalyzed by ‘roofed’ cis-diamine-Ru(II) complex. Tetrahedron Letters, 4621May 2005), 364536480040-4039
100 - P. Mc Morn, G. J. Hutchings, 2004Heterogeneous Enantioselective Catalysts: Strategies for the Immobilisation of Homogeneous CatalystsChemical Society Reviews3321081220306-0012
101 - C. Merckle, J. Blümel, 2005Improved Rhodium Hydrogenation Catalysts Immobilized on SilicaTopics in Catalysis341-45151022-5528
102 - J. A. Melero, J. Iglesias, J. M. Arsuaga, J. Sainz-Pardo, P. Frutos, S. Blazquez, 2007Synthesis and Catalytic Activity of Organic-Inorganic Hybrid Ti-SBA-15 MaterialsJournal of Materials Chemistry17November 2006), 3373850959-9428
103 - D. J. Mihalcik, W. Lin, 2008Mesoporous Silica Nanosphere Supported Ruthenium Catalysts for Asymmetric HydrogenationAngewandte Chemie International Edition, 4733622962321521-3773
104 - K. Mikami, T. Korenaga, M. Terada, T. Ohkuma, T. Pham, R. Noyori, 1999Conformationally Flexible Biphenyl-phosphane Ligands for Ru-Catalyzed Enantioselective HydrogenationAngewandte Chemie International Edition384February, 1999), 4954971521-3773
105 - K. Mikami, K. Wakabayashi, Y. Yusa, K. Aikawa, 2006Achiral benzophenone ligand-rhodium complex with chiral diamine activator for high enantiocontrol in asymmetric transfer hydrogenationChemical Communications22June 2006), 236523671359-7345
106 - A. Mikhailine, A. J. Lough, R. H. Morris, 2009Efficient Asymmetric Transfer Hydrogenation of Ketones Catalyzed by an Iron Complex Containing a P−N−N−P Tetradentate Ligand Formed by Template Synthesis. Journal of the American Chemical Society, 1314February 2009), 139413950002-7863
107 - C. Mondelli, A. Vargas, G. Santarossa, A. Baiker, 2008Fundamental Aspects of the Chiral Modification of Platinum with Peptides: Asymmetric Induction in Hydrogenation of Activated KetonesThe Journal of Physical Chemistry C11334Avgust 2009), 15246152591932-7447
108 - R. H. Morris, 2009Asymmetric hydrogenation, transfer hydrogenation and hydrosilylation of ketones catalyzed by iron complexes. Chemical Society Reviews, 388August 2009), 228222910306-0012
109 - R. Noyori, T. Ohkuma, M. Kitamura, H. Takaya, N. Sayo, H. Kumobayashi, S. Akutagawa, (1987). Asymmetric hydrogenation of beta-keto carboxylic esters. A practical, purely chemical access to beta-hydroxy esters in high enantiomeric purity. Journal of the American Chemical Society, 109 19 (September 1987), 58565858 , 0002-7863
110 - R. Noyori, H. Takaya, 1990BINAP: an efficient chiral element for asymmetric catalysisAccounts of Chemical Research2310October 1990), 3453500001-4842
111 - R. Noyori, T. Ohkuma, 2001Asymmetric Catalysis by Architectural and Functional Molecular Engineering: Practical Chemo- and Stereoselective Hydrogenation of KetonesAngewandte Chemie, International Edition, 401January 2001), pp. 1433-7851
112 - R. Noyori, M. Yamakawa, S. Hashiguchi, 2001Metal-Ligand Bifunctional Catalysis: A Nonclassical Mechanism for Asymmetric Hydrogen Transfer between Alcohols and Carbpnyl Compounds. The Journal of Organic Chemistry, 6624November 2001), 793179440022-3263
113 - R. Noyori, C. A. Sandoval, K. Muñiz, T. Ohkuma, 2005Metal-ligand bifunctional catalysis for asymmetric hydrogenation. Philosophical Transactions of The Royal Society A, 3631829April 2005), 9019120136-4503X
114 - T. Ohkuma, H. Ooka, T. Ikariya, R. Noyori, 1995Preferential hydrogenation of aldehydes and ketonesJournal of the American Chemical Society11741October 1995), 10417104180002-7863
115 - T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori, 1995Practical Enantioselective Hydrogenation of Aromatic KetonesJournal of the American Chemical Society1179March 1995), 267526760002-7863
116 - T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa, K. Murata, E. Katayama, T. Yokozawa, T. Ikariya, R. Noyori, 1998Asymmetric Hydrogenation of Alkenyl, Cyclopropyl, and Aryl Ketones. RuCl2(xylbinap)(1,2-diamine) as a Precatalyst Exhibiting a Wide ScopeJournal of the American Chemical Society12054December 1998), 13529135300002-7863
117 - T. Ohkuma, M. Koizumi, M. Yoshida, R. Noyori, 2000General Asymmetric Hydrogenation of Hetero-aromatic KetonesOrganic Letters212May 2000), 174917511523-7060
118 - T. Ohkuma, M. Koizumi, K. Muñiz, G. Hilt, C. Kabuto, R. Noyori, 2002trans-RuH(η1-BH4)(binap)(1,2-diamine): A Catalyst for Asymmetric Hydrogenation of Simple Ketones under Base-Free Conditions. Journal of the American Chemical Society, 12423June 2002), 650865090002-7863
119 - T. Ohkuma, C. A. Sandoval, R. Srinivasan, Q. Lin, Y. Wei, K. Muñiz, R. Noyori, 2005Asymmetric Hydrogenation of tert-Alkyl Ketones. Journal of the American Chemical Society, 12723June 2005), 828882890002-7863
120 - T. Ohkuma, 2010Asymmetric hydrogenation of ketones: Tactics to achieve high reactivity, enantioselectivity, and wide scopeProceedings of the Japan AcademySeries B, 863March 2010), 2022190386-2208
121 - Y. Orito, S. Imai, S. Niwa, 1979Asymmetric hydrogenation of methyl pyruvate using a platinum-carbon catalyst modified with cinchonidine. Nippon Kagaku Kaishi, 8111811200369-4577
122 - M. J. Palmer, M. Wills, 1990Asymmetric transfer hydrogenation of C=O and C=N bondsTetrahedron: Asymmetry1011June 1999), 204520610957-4166
123 - M. Palmer, T. Walsgrove, M. Wills, 1997R,2S)-(+)-cis-1-Amino-2-indanol: An Effective Ligand for Asymmetric Catalysis of Transfer Hydrogenations of Ketones. The Journal of Organic Chemistry, 6215July 1997), 522652280022-3263
124 - N. Pannetier, J. Sortais, B. , J. Issenhuth, T. , L. Barloy, C. Sirlin, A. Holuigue, L. Lefort, L. Panella, J. G. de Vries, M. Pfeffer, 2011Cyclometalated Complexes of Ruthenium, Rhodium and Iridium as Catalysts for Transfer Hydrogenation of Ketones and IminesAdvanced Synthesis & Catalysis35314-15October 2011), 284428521615-4169
125 - B. Pugin, H. Landert, F. Spindler, H. R. Blaser, 2002More than 100,000 Turnovers with Immobilized Ir-Diphosphine Catalysts in an Enantioselective Imine HydrogenationAdvanced Synthesis & Catalysis3449October 2002), 9749791615-4169
126 - M. T. Reetz, X. Li, 2006An Efficient Catalyst System for the Asymmetric Transfer Hydrogenation of Ketones: Remarkably Broad Substrate Scope.Journal of the American Chemical Society1284February 2006), 104410450002-7863
127 - H. Y. Rhyoo, H. Park, J. , Y. K. Chung, 2001The first Ru(II)-catalysed asymmetric hydrogen transfer reduction of aromatic ketones in aqueous media. Chemical Communications, 20206420651359-7345
128 - C. Saluzzo, M. Lemaire, 2002Homogeneous-Supported Catalysts for Enantioselective Hydrogenation and Hydrogen Transfer ReductionAdvanced Synthesis & Catalysis3449October 2002), 9159281615-4169
129 - J. S. M. Samec, J. Bäckvall, E. , P. G. Andersson, P. Brandt, 2006Mechanistic aspects of transition metal-catalyzed hydrogen transfer reactionsChemical Society Reviews353March 2006), 2372480306-0012
130 - A. J. Sandree, J. N. H. Reek, P. C. J. Kamer, P. W. N. M. van Leeuwen, 2001A Silica-Supported, Switchable, and Recyclable Hydroformylation−Hydrogenation Catalyst. Journal of the American Chemical Society, 12336September 2011) 846884760002-7863
131 - P. S. Schulz, N. Müller, A. Bösmann, P. Wasserscheid, 2007Effective Chirality Transfer in Ionic Liquids through Ion-Pairing EffectsAngewandte ChemieInternational Edition, 468February 2007), 129312951433-7851
132 - M. Schürch, N. Künzle, T. Mallat, A. Baiker, 1998Enantioselective Hydrogenation of Ketopantolactone: Effect of Stereospecific Product Crystallization during ReactionJournal of Catalysis1762June 1998), 5695710021-9517
133 - E. Schmidt, D. Ferri, A. Vargas, A. Baiker, 2008Chiral Modification of Rh and Pt Surfaces: Effect of Rotational Flexibility of Cinchona-Type Modifiers on Their Adsorption BehaviorThe Journal of Physical Chemistry C11210March 2008), 345340181932-7447
134 - E. Schmidt, D. Ferri, A. Vargas, T. Mallat, A. Baiker, 2009Shape-Selective Enantioselective Hydrogenation on Pt NanoparticlesJournal of the American Chemical Society13134September 2009), 12358123670002-7863
135 - Y. Shen, Q. Chen, L. Lou, L. , K. Yu, F. Ding, S. Liu, 2010Asymmetric Transfer Hydrogenation of Aromatic Ketones Catalyzed by SBA-15 Supported Ir(I) Complex Under Mild Conditions. Catalysis Letters, 1371-2June 2010), 1041090101-1372X
136 - H. Shimizu, D. Igarashi, W. Kuriyama, Y. Yusa, N. Sayo, T. Saito, 2007Asymmetric Hydrogenation of Aryl Ketones Mediated by a Copper Catalyst.Organic Letters99April 2007), 165516571523-7060
137 - H. Shimizu, T. Nagano, N. Sayo, T. Saito, T. Ohshima, K. Mashima, 2009Asymmetric Hydrogenation of Heteroaromatic Ketones and Cyclic and Acyclic Enones Mediated by Cu(I)-Chiral Diphosphine Catalysts. Synlett, 2009, 19December 2009), 314331460936-5214
138 - T. Shiomi, H. Nishiyama, 2007Intermolecular Asymmetric Reductive Aldol Reaction of Ketones as Acceptors Promoted by Chiral Rh(Phebox) Catalyst. Organic Letters, 99April 2007), 165516571523-7060
139 - C. E. Song, S. Lee, 2002Supported Chiral Catalysts on Inorganic Materials.Chemical Reviews10210August 2002), 349535240009-2665
140 - I. Steiner, R. Aufdenblatten, A. Togni, H. U. Blaser, B. Pugin, 2004Novel silica gel supported chiral biaryl-diphosphine ligands for enantioselective hydrogenation Tetrahedron: Asymmetry, 1514July 2004) 230723110957-4166
141 - M. Studer, S. Burkhardt, H. Blaser, U. , 1999Enantioselective hydrogenation of α-keto acetals with cinchona modified Pt catalyst. Chemical Communications, 17172717281359-7345
142 - M. Studer, S. Burkhardt, A. F. Indolese, H. Blaser, U. , 2000Enantio- and chemoselective reduction of 2,4-diketo acid derivatives with cinchona modified Pt-catalyst-Synthesis of (R)-2-hydroxy-4-phenylbutyric acid ethyl esterChemical Communications14132713281359-7345
143 - M. Studer, H. Blaser, U. , S. Burkhardt, 2002Hydrogenation of α-Keto Ethers: Dynamic Kinetic Resolution with a Heterogeneous Modified Catalyst and a Heterogeneous Base. Advanced Synthesis & Catalysis, 3445July 2002), 5115151615-4169
144 - M. Studer, H. Blaser, U. , C. Exner, 2003Enantioselective Hydrogenation Using Heterogeneous Modified Catalysts: An UpdateAdvanced Synthesis & Catalysis3451-2January 2003), 45651615-4169
145 - P. E. Sues, A. J. Lough, R. H. Morris, 2011Stereoelectronic Factors in Iron Catalysis: Synthesis and Characterization of Aryl-Substituted Iron(II) Carbonyl P-N-N-P Complexes and Their Use in the Asymmetric Transfer Hydrogenation of Ketones. Organometallics, 3016August 2011), 441844310276-7333
146 - M. Sutyinszki, K. Szöri, K. Felföldi, M. Bartók, 2002Enantioselectivity in the asymmetric synthesis of a useful chiral building block by heterogeneous method: Enantioselective hydrogenation of ethyl-benzoylformate over cinchona modified Pt/Al2O3 catalysts in the acetic acid. Catalysis Communications, 33March 2002), 1251271566-7367
147 - K. Szőri, M. Sutyinszki, K. Felfőldi, M. Bartók, 2002Heterogeneous asymmetric reactions: Part 28. Efficient and practical method for the preparation of (R)- and (S)- α-hydroxy esters by the enantioselective heterogeneous catalytic hydrogenation of α-ketoesters. Applied Catalysis A: General, 2371-2November 2002), 2752800092-6860X
148 - K. Szőri, K. Balázsik, S. Cserényi, G. Szőllősi, M. Bartók, 2009Inversion of enantioselectivity in the 2,2,2-trifluoroacetophenone hydrogenation over Pt- alumina catalyst modified by cinchona alkaloids. Applied Catalysis A: General, 3621-2June 2009), 1781840092-6860X
149 - M. Tada, Y. Iwasawa, 2006Advanced chemical design with supported metal complexes for selective catalysisChemical Communications27283328441359-7345
150 - J. Takehara, S. Hashiguchi, A. Fujii, S. Inoue, T. Ikariya, R. Noyori, 1996Amino alcohol effects on the ruthenium(II)-catalysed asymmetric transfer hydrogenation of ketones in propan-2-ol. Chemical Communications, 3Februar 1996), 2332341359-7345
151 - T. Thorpe, J. Blacker, S. M. Brown, C. Bubert, J. Crosby, S. Fitzjohn, J. P. Muxworthy, J. M. J. Williams, 2001Efficient rhodium and iridium-catalysed asymmetric transfer hydrogenation using water-soluble aminosulfonamide ligandsTetrahedron Letters4224June 2001), 404140430040-4039
152 - B. Török, K. Balázsik, M. Bartók, K. Felföldi, M. Bartók, 1999New synthesis of a useful C3 chiral building block by a heterogeneous method: enantioselective hydrogenation of pyruvaldehyde dimethyl acetal over cinchona modified Pt/Al2O3 catalysts.Chemical Communications17172517261359-7345
153 - B. Török, K. Felföldi, G. Szakonyi, K. Balázsik, M. Bartók, 1998Enantiodifferentiation in asymmetric sonochemical hydrogenationsCatalysis Letters521-2June 1998), 81840101-1372X
154 - T. Varga, K. Felföldi, P. Forgó, M. Bartók, 2004Heterogeneous asymmetric reactions: Part 38. Enantioselective hydrogenation of fluoroketones on Pt-alumina catalyst. Journal of Molecular Catalysis A: Chemical, 2162July 2004), 1811871381-1169
155 - A. Vargas, N. Bonalumi, D. Ferri, A. Baiker, 2006Solvent-Induced Conformational Changes of O-Phenyl-cinchonidine: A Theoretical and VCD Spectroscopy Study.The Journal of Physical ChemistryA, 1103January 2006), 110611171089-5639
156 - A. Vargas, D. Ferri, N. Bonalumi, T. Mallat, A. Baiker, 2007Controlling the Sense of Enantioselection on Surfaces by Conformational Changes of Adsorbed ModifiersAngewandte Chemie International Edition4621May 2007), 390539081521-3773
157 - H. Vázquez-Villa, S. Reber, M. A. Ariger, E. M. Carreira, 2011Iridium Diamine Catalyst for the Asymmetric Transfer Hydrogenation of KetonesAngewandte Chemie International Edition, 5038September 2011), 897989811433-7851
158 - Arx. M. von, T. Mallat, A. Baiker, 2001Platinum-catalyzed enantioselective hydrogenation of aryl-substituted trifluoroacetophenonesTetrahedronAsymmetry, 1222December 2001), 308930940957-4166
159 - Arx. M. von, T. Mallat, A. Baiker, 2002Asymmetric Hydrogenation of Activated Ketones on Platinum: Relevant and Spectator SpeciesTopics in Catalysis191March 2002), 75871022-5528
160 - Arx. M. von, T. Mallat, A. Baiker, 2001Inversion of Enantioselectivity during the Platinum-Catalyzed Hydrogenation of an Activated KetoneAngewandte Chemie International Edition4012June 2001), 230223051521-3773
161 - Arx. M. von, T. Mallat, A. Baiker, 2002Highly Efficient Platinum-Catalyzed Enantioselective Hydrogenation of Trifluoroacetoacetates in Acidic SolventsCatalysis Letters781-4March 2002), 2672710101-1372X
162 - F. Wang, H. Liu, L. Cun, J. Zhu, J. Deng, Y. Jiang, 2005Asymmetric Transfer Hydrogenation of Ketones Catalyzed by Hydrophobic Metal−Amido Complexes in Aqueous Micelles and Vesicles. The Journal of Organic Chemistry, 7023November 2005), 942494290022-3263
163 - X. Wu, J. Xiao, 2007Aqueous-phase asymmetric transfer hydrogenation of ketones- a greener approach to chiral alcohols. Chemical Communications, 24June 2007), 244924661359-7345
164 - W. N. O. Wylie, A. J. Lough, R. H. Morris, 2011Mechanistic Investigation of the Hydrogenation of Ketones Catalyzed by a Ruthenium(II) Complex Featuring an N-Heterocyclic Carbene with a Tethered Primary Amine Donor: Evidence for an Inner Sphere Mechanism. Organometallics, 305March 2011), 123612520276-7333
165 - J. Wettergren, E. Buitrago, P. Ryberg, H. Adolfsson, 2009Mechanistic Investigations into the Asymmetric Transfer Hydrogenation of Ketones Catalyzed by Pseudo-Dipeptide Ruthenium ComplexesChemistry- A European Journal, 1523June 2009), 570957181521-3765
166 - J. Xie, B. , J. Xie, H. , X. Liu, Y. , W. Kong, L. , S. Li, Q. Zhou, L. , 2010Highly Enantioselective Hydrogenation of α-Arylmethylene Cycloalkanones Catalyzed by Iridium Complexes of Chiral Spiro Aminophosphine Ligands. Journal of the American Chemical Society, 13213April 2010), 453845390002-7863
167 - J. Xie, H. , X. Liu, Y. , J. Xie, B. , L. Wang, X. , Q. Zhou, L. , 2011An Additional Coordination Group Leads to Extremely Efficient Chiral Iridium Catalysts for Asymmetric Hydrogenation of KetonesAngewandte ChemieInternational Edition, 5032August 2011), 732973321433-7851
168 - M. Yamakawa, I. Yamada, R. Noyori, 2001CH/π Attraction: The Origin of Enantioselectivity in Transfer Hydrogenation of Aromatic Carbonyl Compounds Catalyzed by Chiral η6-Arene-Ruthenium(II) Complexes. Angewandte Chemie International Edition, 4015August 2001), 281828211433-7851
169 - J. W. Yang, B. List, 2006Catalytic Asymmetric Transfer Hydrogenation of α-Ketoesters with Hantzsch Esters. Organic Letters, 824November 2006), 565356551523-7060
170 - C. Yang, H. Jiang, J. Feng, H. Fu, R. Li, H. Chen, X. Li, 2009Asymmetric hydrogenation of acetophenone catalyzed by cinchonidine stabilized Ir/SiO2Journal of Molecular CatalysisA: Chemical, 3001-2March 2009), 981021381-1169
171 - W. Ye, M. Zhao, W. Du, Q. Jiang, K. Wu, P. Wu, Z. Yu, 2011Highly Active Ruthenium(II) Complex Catalysts Bearing an Unsymmetrical NNN Ligand in the (Asymmetric) Transfer Hydrogenation of Ketones. Chemistry- A European Journal, 1717April 2011), 473747411521-3765
172 - Z. Zhou, Y. Sun, A. Zhang, 2011Asymmetric transfer hydrogenation of prochiral ketones catalyzed by aminosulfonamide-ruthenium complexes in ionic liquidCentral European Journal of Chemistry91February 2011), 1751791895-1066
173 - Q. Zhu, D. Shi, C. Xia, H. Huang, 2011Ruthenium Catalysts Containing Rigid Chiral Diamines and Achiral Diphosphanes for Highly Enantioselective Hydrogenation of Aromatic KetonesChemistry- A European Journal, 1728July 2011), 776077631521-3765
174 - Á. Zsigmond, S. Undrala, F. Notheisz, Á. Szöllősy, J. Bakos, 2008The effect of substituents of immobilized Rh complexes on the asymmetric hydrogenation of acetophenone derivatives. Central European Journal of Chemistry, 64December 2008), 5495541895-1066