Asymmetric Transfer Hydrogenation in Thermomorphic Microemulsions Based on Ionic Liquids

Article abstract of DOI:10.1021/acs.oprd.9b00150

A thermomorphic ionic-liquid-based microemulsion system was successfully applied for the Ru-catalyzed asymmetric transfer hydrogenation of ketones. On the basis of the temperature-dependent multiphase behavior of the targeted microemulsion, simple product separation as well as catalyst recycling could be realized. The use of water-soluble ligands improved the immobilization of the catalyst in the microemulsion phase and significantly decreased the catalyst leaching into the organic layer upon extraction of the product. Eventually, the optimized microemulsion system could be applied to a wide range of aromatic ketones that were reduced with good isolated yields (up to 98%) and enantioselectivities (up to 97%), while aliphatic ketones were less successful.

Full text of DOI:10.1021/acs.oprd.9b00150

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Full Paper
Asymmetric transfer hydrogenation in thermomorphic
microemulsions based on ionic liquids
Mahtab Hejazifar, Ádám Pálvölgyi, Jacqueline Bitai, Olga Lanaridi, and Katharina Bica-Schröder
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00150 • Publication Date (Web): 02 Jul 2019
Downloaded from http://pubs.acs.org on July 2, 2019
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Asymmetric transfer hydrogenation in thermomorphic
microemulsions based on ionic liquids
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Mahtab Hejazifara , Ádám Márk Pálvölgyia, Jacqueline Bitaia, Olga A. Lanaridia and Katharina
Bica-Schrödera*
a
Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9/163, 1060 Vienna,
Austria
*
Corresponding
author
Katharina
Schröder
(née
K.
Bica).
Email:
katharina.schroeder@tuwien.ac.at, Tel: +43 1 58801 163601.
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TOC graphic
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Microemulsion layer
Aqueous layer
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Coolin
g
Heating
OH
Starting material
O
Product
Ru-cat/chiral ligand
HCOONa
Catalyst
Salts
Catalyst
H-Donor
Catalyst regeneration
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Abstract
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A thermomorphic ionic liquid based microemulsion system was successfully applied for the Ru-
catalyzed asymmetric transfer hydrogenation of ketones. Based on the temperature-dependent
multiphase behaviour of the targeted microemulsion, simple product separation as well as catalyst
recycling could be realized. The use of water-soluble ligands improved the immobilization of the
catalyst in the microemulsion phase and significantly decreased the catalyst leaching into the
organic layer upon extraction of the product. Eventually, the optimized microemulsion system
could be applied to a wide range of aromatic ketones that were reduced with good isolated yields
(up to 98 %) and enantioselectivities (up to 97%), while aliphatic ketones were less successful.
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Keywords
microemulsion, ionic liquid, asymmetric transfer hydrogenation, multiphase catalysis
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Introduction
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Chiral secondary alcohols are important and invaluable intermediates for the preparation of
pharmaceuticals and fine chemicals. One of the most versatile and powerful methods for their
synthesis is the asymmetric reduction of ketones.1 Among the wide field of asymmetric reduction
methods, asymmetric transfer hydrogenations have emerged as particularly powerful and practical
tool due to its operational simplicity combined with high reaction rates and enantioselectivity.2 The
use of a simple organic compound as hydrogen donor in transfer hydrogenation has several
advantages over the use of molecular hydrogen since it avoids risks and constraints associated with
hydrogen gas, but also the necessity for pressurized vessels and other specialized equipment.3 A
number of different donor molecules can be employed as hydrogen source in transfer
hydrogenations, including organic molecules such as formic acid and its salts, as well as primary
and secondary alcohols.4,5,6
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Apart from the hydrogen donor, the appropriate choice of transition metal catalyst and reaction
conditions are crucial for achieving the desired chemo-or stereoselectivity under mild conditions
in asymmetric transfer hydrogenations.3 Over the last three decades, considerable attention has
been dedicated to the use of ruthenium-based complexes developed by Noyori and co-workers. 4,7,8
Reported already in 1995, the highly active and selective (pre-) catalyst, a TsDPEN-coordinated
(TsDPEN = N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine) Ru(II) complex (Ru-TsDPEN)
can be considered as benchmark system for the asymmetric transfer hydrogenation of aromatic
ketones (Scheme 1). This breakthrough has inspired intense research in the area asymmetric
transfer hydrogenations that is growing steadily in the past years.2,7
Recently, considerable effort has been dedicated to asymmetric transfer hydrogenations in aqueous
reaction media. With the rising awareness for sustainable chemistry, water as solvents is often
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considered as safe, economical, nontoxic and benign reaction media compared to typical organic
solvents.1,2,9 The classical drawbacks of homogeneous catalysis, such as the difficult separation of
product and catalyst or the tricky recycling of the catalyst can be overcome in an elegant liquid-
liquid biphasic approach, relying on water as catalyst-carrying phase that can be simply separated
from the insoluble products.10 Moreover, water is a particularly attractive and valuable solvent for
transfer hydrogenations, as it enables the use of sodium formate as the most easily available,
inexpensive and non-reversible hydrogen source.9,10,11,12 However, the use of water as reaction
media in asymmetric transition-metal catalysis is still challenging, as many metal catalysts are
unstable towards hydrolysis.1 Moreover, the low solubility of many transition metal catalysts in
water is a limiting factor. To solve this issue a number of water-soluble ligands and catalysts have
been developed for asymmetric transfer hydrogenations of ketones in aqueous media, providing
the desired secondary alcohols in high yield and enantioselectivity.1,2,7 Several strategies have been
pursued to improve the water-solubility of the TsDPEN structural motive, including the
modification with anionic groups in case of aryl sulfonated systems (e.g.: (R,R)-1, (R,R)-2), the
functionalization with cationic groups such as trialkylammonium moieties, but also development
of polyethylene glycol-supported TsDPEN systems.13,14,15,16,17 Recently, we reported the synthesis
of ion-tagged chiral ligands for asymmetric synthesis in water or ionic liquids, including the use
for highly selective and efficient asymmetric transfer hydrogenation of aliphatic or aromatic
ketones and imines in aqueous media.18,19,20
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SO3Na
NaO3S
5
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H2N
NHTs
H2N
NH2
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1
TsDPEN
(R,R)-
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SO3Na
NaO3S
H2N
NHTs
2
(R,R)-
Scheme 1. Structure of N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (TsDPEN) and water-
soluble ligands (R,R-1) and (R,R-2) used in this work.
While ligand modifications with ionic groups or polymers can overcome the limited solubility of
conventional transition metals catalysts, the solubility of hydrophobic reactants such as higher
ketones in water remains an issue in liquid-liquid biphasic catalysis.21 Microemulsions provide an
attractive solution to overcome this problem, as they can simultaneously dissolve hydrophobic and
hydrophilic reactants. In general, microemulsions are defined as thermodynamically stable,
isotropic and optically transparent solutions composed of two intrinsically immiscible solvents in
the presence of one or more amphiphiles.22,23,24 The simultaneous dissolution of hydrophobic and
hydrophilic solutes is a key advantage of microemulsions and resulted in wide application for
catalytic reactions and processes.24,25 Moreover, the phase behaviour and separation can be
precisely tuned by temperature variation, which provides a particularly attractive tool for
multiphase catalysis. A thermomorphic microemulsion (ME) system as depicted in Figure 1. can
overcome potential mass transfer limitations since catalysis occurs in one homogeneous liquid
phase, while simultaneously enabling an effective separation of catalyst and products due to
temperature induced phase separation.26,27
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Figure 1. Thermomorphic asymmetric transfer hydrogenation in microemulsion.
So far, only few examples on transfer hydrogenation in microemulsions were reported.22,28
Batarseh et al. investigated the transfer hydrogenation of various unsaturated substrates by
cyclohexene and similar water-insoluble hydrogen donors in aqueous microemulsion at 100-140 °C,
relying mostly on fatty alcohol polyethylene glycol ethers as non-ionic surfactant.28 The influence
of surfactant was also a key aspect in a study by Schwarze et al. in 2015, addressing the transfer
hydrogenation of 4-acetylbiphenyl with 2-propanol as the hydrogen donor, Rh/TPPTS as catalyst
and K2CO3 as base.22 A strong influence of the surfactant on the catalytic activity was observed, as
TX-100 showed about 10% higher conversions compared to fatty alcohol polyethylene glycol
ethers in a three phase n-heptane/water/surfactant/2-propanol microemulsion system, although
higher concentrations of TX-100 led to a decrease in activity. As a consequence, the authors
emphasized that the initial selection of an appropriate surfactant that primarily supports the
catalytic reaction and, in addition, gives the best performance in the separation step is of crucial
importance. Considering that substrate, product and their variable concentrations significantly
influence the phase behaviour and shift the phase boundaries to other temperatures, it is obvious
that the selection and application of a reliable surfactant system in microemulsions is not an easy
task.
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Recently, we addressed the role of surface-active ionic liquids composed of both surface-active
cations and anions for the formation of stable microemulsions with n-heptane and water, allowing
for tuneable surfactant structure with precise control over its composition.24 Ionic liquids with long
alkyl chains of typically 8 carbon atoms or more show amphiphilic behaviour, which renders them
ideally suited for the development of microemulsions with potential advantages of conventional
surfactants that are often sold as mixtures with variable composition. In our previous work, we
reported the design of surface-active ionic liquids ([C12mim][(iC8)2PO2] (3) and
[C12dmim][(iC8)2PO2]) (4) (Scheme 2) that are able to form stable microemulsions with n-heptane
and water as novel reaction media for thermomorphic palladium-catalysed cross-coupling reactions.
High reactivity was observed even at low catalyst loadings, while the temperature-dependent phase
behaviour allowed simple product separation and successful catalyst recycling through
thermomorphic catalysis.24
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N
N
R
O
P
O
R = H: [C12mim][(iC8)2PO2]
R = CH3: [C12dmim][(iC8)2PO2]
3
4
Scheme 2. Surface active ionic liquids used for the formation of microemulsions.
In here, we expand our research towards ruthenium-catalysed asymmetric transfer hydrogenation
of ketones, aiming to overcome solubility issues of a hydrophobic substrates and a hydrophilic
hydrogen donor in a targeted microemulsion system while simultaneously facilitating product
separation and catalyst recovery.
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Results and Discussion
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Studies on phase behaviour for the reduction of acetophenone
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The reduction of acetophenone (5) to 1-phenylethanol (6) was selected as the model reaction to
evaluate the application of ionic liquid based microemulsion systems as reaction media for
asymmetric transfer hydrogenation (Scheme 3).
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O
OH
[RuCl(p-cymene)((R,R)-TsDPEN)]
HCOONa, Ar
IL:n-heptane:H2O
5
6
Scheme 3. Asymmetric transfer hydrogenation of acetophenone (5) in ionic liquid based
microemulsion systems.
As already stated by Schwarze et al. in 2015, the composition of the microemulsion system is of
crucial importance for thermomorphic catalysis with microemulsion systems.22 Detailed
investigations on the phase behaviour of water-n-heptane-[C12mim][(iC8)2PO2] (3) mixtures at
25 °C were reported in our previous paper, showing that all four types of Winsor microemulsion
systems are present.24 Specifically, Winsor type I systems are formed at small concentrations of
surfactant as biphasic system (2) of a oil-in-water (o/w) microemulsions with excess oil.
Alternatively, the surfactant rich water-in-oil (w/o) microemulsion may co-exist with the
surfactant-poor aqueous phase (2, Winsor type II). Type III corresponds to a three-phase system
(3) where the ionic liquid-rich middle-phase co-exists with both excess water and oil, while
Winsor type IV is a single phase (1) isotropic solution which forms upon addition of higher
surfactant concentrations.29 However, the presence of additives and a variable substrate/product
ratio inevitably affects the phase behaviour, which is of particular importance for the chosen
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transfer hydrogenation, as the formed alcohol might act as a co-surfactant in the microemulsion. In
order to identify a suitable composition of the ionic liquid-based microemulsion system that would
allow separating the product in a three-phase system, phase diagrams were studied at different
substrate/product ratios (see Figure 2 and ESI Figures S1-S7). Consequently, the phase behaviour
of n-heptane/water mixtures at equal mass fraction (α = 0.5) in the presence of HCOONa,
acetophenone and 1-phenylethanol with variable ionic liquid [C12mim][(iC8)2PO2] (3) content was
studied at different temperatures. The compositions of these microemulsions is typically
characterised by parameters α and γ:
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푚oil
훼 =
(푚oil + 푚water
)
푚IL
훾 =
(푚oil + 푚water + 푚IL)
The isotropic phase was determined by titration of the n-heptane/water mixture with α = 0.5 and
variable surfactant content γ for [C12mim][(iC8)2PO2] (3) at different temperatures, according to the
studies on phase behavior by Nowothnick et al.25 After adding a defined amount of ionic liquid,
the mixture was stirred and equilibrated at the indicated temperatures for an appropriate time until
clear phases were observed. Figure 2 depicts the temperature-dependent phase diagram with
acetophenone/1-phenylethanol in a ratio 1:1, corresponding to 50% conversion and with pure 1-
phenylethanol to simulate complete conversion. In general, at lower temperatures and higher
amount of ionic liquid a triphasic area (3) with a surfactant-rich middle-phase (Winsor III) is
observed, while at higher temperatures and lower amount of ionic liquid, two phases (2) are
formed where the microemulsion system coexists with excess water (Winsor II).24 As expected,
the increasing amount of 1-phenylethanol is affecting the phase behaviour, resulting in a
considerably smaller triphasic area. As can be seen from figure 2, at least 0.3 g of ionic liquid 3
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(corresponding to γ = 0.15) are required for the existence of a triphasic system at room temperature,
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and hence for the isolation of the product via simple phase separation.
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Figure 2. Phase diagram of (●) HCOONa (2 mmol), acetophenone (0.25 mmol), 1-phenylethanol
(0.25 mmol), at equal mass fraction of water (2 g) and heptane (2 g) (α =0.5). (▪) HCOONa (2
mmol), 1-phenylethanol (0.5 mmol), at equal mass fraction of water and heptane (α =0.5).
Optimization of the asymmetric transfer hydrogenation of acetophenone (5)
After initially studying the phase behaviour, the reduction of acetophenone (5) to 1-phenylethanol
(6) was further evaluated at variable water/n-heptane/ionic liquid ratio and variable temperatures
to optimize the reaction conditions (Table 1). In the attempt to minimize the volume of the organic
solvent n-heptane as much as possible we initially studied the effect of n-heptane on the asymmetric
transfer hydrogenation, keeping the ionic liquid ratio fixed at 0.3 g as initially established in the
phase behavior studies. As can be seen from Table 1, a reduction of the n-heptane ratio from α =
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0.5 to α = 0 was beneficial, and yields increased from 47% to 98%, while the excellent
enantioselectivity was maintained (entries 1-6). Main similar results are reported by Li et. al, who
demonstrated that the presence of the organic solvents resulted in a much slower reaction.30
However, keeping the consecutive work-up in mind, we choose an n-heptane/water ratio of 0.5 g/2
g (corresponding to α = 0.2) as optimum amount of organic solvent. A reduction of the ionic liquid
ratio was not beneficial: apart from problems that would be occurring during phase separation, a
decrease in ionic liquid reduced the yield to 86% (entries 5, 7-9).
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Table 1. Optimization of the asymmetric transfer hydrogenation of acetophenone (5) catalyzed by
[RuCl(p-cymene)((R,R)-TsDPEN)], performed with [C12mim][(iC8)2PO2] (3).
Weight Ratio
Temp.
[°C]
Yieldb
[%]
eec,d
[%]
Entrya
α
γ
IL/heptane/H2O
1
2
0.3/2.5/2
0.3/2/2
0.56 0.06
0.50 0.07
0.43 0.08
0.33 0.09
0.20 0.11
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47
66
72
89
95
98
91
86
86
58
74
84
97
91
92 (R)
94 (R)
94 (R)
91 (R)
92 (R)
92 (R)
93 (R)
94 (R)
94 (R)
94 (R)
95 (R)
93 (R)
93 (R)
93 (R)
3
0.3/1.5/2
0.3/1/2
4
5
0.3/0.5/2
0.3/0/2
6
0
0.13
7
0.25/0.5/2
0.2/0.5/2
0.15/0.5/2
0.3/1.5/2
0.3/1.5/2
0.3/1.5/2
0.3/1.5/2
0.3/1.5/2
0.20 0.09
0.20 0.07
0.20 0.06
0.43 0.08
0.43 0.08
0.43 0.08
0.43 0.08
0.43 0.08
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0.3/0.5/0.5
0.3/0.5/1
0.3/0.5/1.5
0.3/0.5/2
0.0/0.5/2
0.50 0.23
0.33 0.17
0.25 0.13
0.20 0.11
0.20 0.00
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83
94
98
99e
96
94 (R)
94 (R)
93 (R)
95 (R)
90 (R)
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a Performed with 0.5 mmol acetophenone, 2 mmol HCOONa, and 0.005 mmol
(0.5 mol%) [RuCl(p-cymene)((R,R)-TsDPEN)] for 20 h, unless otherwise
indicated. b Yield determined via HPLC using phenol as internal standard. c The
enantiomeric excess was determined via HPLC using a DAICEL Chiracel IB
d
column. Absolute configuration was determined via measurement of optical
rotation values and comparison with literature data. e Turnover frequency was
370 h-1.
Further studies on the effect of temperature showed that a lower yield can be compensated with
increasing temperature (entries 10-14).28,30 The excellent enantioselectivity was maintained even
at a temperature of 70 °C, which is in accordance with our previous observations.20 The results for
entries 15-18 suggest that the addition of an appropriate amount of water (i.e. decreasing  while
keeping the ionic liquid amount constant at 0.3 g) is beneficial to increase the yield of the reaction.
A similar effect of water is reported by Wang et al.31 Eventually, at optimum reaction conditions
(ionic liquid 3/n-heptane/water 0.3/0.5/2 g, 0.5 mmol acetophenone, 2 mmol HCOONa, 0.005
mmol (0.5 mol%) [RuCl(p-cymene)((R,R)-TsDPEN)], 20 h at 60 °C) excellent yield and
enantiomeric excess ≥ 95% were obtained. It is interesting to note that the asymmetric transfer
hydrogenation proceeds also quite well without the presence of ionic liquid. Even in a biphasic
system composed of water and n-heptane (2 g/0.5 g), high yields and enantioselectivity were
obtained (Table 1, entry 19). However, kinetic studies of the asymmetric transfer hydrogenation of
acetophenone shows that the reaction rate in the microemulsion formed upon addition of ionic
liquid 3 is higher than in the conventional biphasic system (ESI Fig. S7) and a turnover frequency
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of 370 h-1 could be achieved under optimized conditions. The nanometer-sized oil or water droplets
in microemulsions provide highly dynamic nanoreactors, with the interface disintegrating and
reforming on a time scale of milliseconds, which can promote favorable reaction kinetics.32
9
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While the variation of parameters could optimize yield and selectivity, several problems existed
for work-up and potential recycling of catalyst. After running the reaction at optimized conditions,
the product was separated from the three-phase system formed. While the direct separation of
product was possible, for convenience of handling on small scale, a mixture of n-heptane/diethyl
ether (1:1, 2 ml) was added to facilitate phase separation and product extraction in the three-phase
system. However, extensive leaching of the catalyst into the organic phase was observed by using
[RuCl(p-cymene)((R,R)-TsDPEN)], which could be easily seen from the colorization of the organic
phase (Fig. 3, left).
Figure 3. Phase distribution and leaching of catalyst into the oil phase in case of using (a) [RuCl(p-
cymene)((R,R)-TsDPEN)], (b) [RuCl(p-cymene)((R,R)-2)]. Lower phase: aqueous layer,
middle phase: catalyst containing surfactant-rich middle layer, upper phase: organic layer
with product.
To overcome the problems of catalyst leaching which would inevitably result in product
contamination and limited recyclability, we replaced the TsDPEN ligand with its water-soluble
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derivative (R,R)-2 (Scheme 1). The chiral water-soluble sulfonated product (R,R)-1 was prepared
via treatment of commercially available (R,R)-DPEN with oleum according to the published
methods, resulting in a mixture of different isomers.9,33 After purification of the crude sample by
preparative HPLC, the major product, the bis-meta-sulfonated ligand was isolated in 76% yield.
The desired mono-N-tosylated derivative (R,R)-2 was obtained by subsequent tosylation in 62%
yield.9 The water-soluble ruthenium catalyst [RuCl(p-cymene)((R,R)-2)] was prepared by reacting
[RuCl2(p-cymene)]2 with (R,R)-2 at 40 °C for one hour in aqueous media. As can be seen in Figure
3 (right), after running the reaction under similar conditions with [RuCl(p-cymene)((R,R)-2)] the
organic phase remained colourless, suggesting that the ion-tagged ruthenium catalyst is efficiently
immobilized in the surfactant-rich middle layer through additional interactions with the charged
ionic liquid species, and that there is no significant catalyst leaching into the organic layer.
In order to quantify the effect of the ligand structure on the ruthenium leaching, ICP-OES
measurements have been carried out from the corresponding n-heptane phases after the reaction.
While 30 ppm of ruthenium were found in the n-heptane phase in case of the unmodified [RuCl(p-
cymene)((R,R)-TsDPEN)], only 2 ppm of ruthenium could be detected by switching to the ion-
tagged and more hydrophilic [RuCl(p-cymene)((R,R)-2)], resulting in a significant
improvement on the immobilization of the catalyst and confirming the previous qualitative
results. Regarding to the catalytic activity of the [RuCl(p-cymene)((R,R)-2)] - as is shown in
Table 2 - the obtained result were similar to those with the [RuCl(p-cymene)((R,R)-TsDPEN)]
under optimized condition. However, slightly longer reaction time of 24 h was required when using
the hydrophilic ligand (R,R)-2 eventually giving the product in excellent isolated yield and
enantioselectivity. Almost identical behaviour was found when using the ionic liquid
[C12dmim][(iC8)2PO2] (4) instead of [C12mim][(iC8)2PO2] (3), indicating that acidic proton in
position 2 of the imidazolium is not involved in the process.
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Table 2. ATH of acetophenone (5) in different microemulsion systems.
5
6
7
eed,e
[%]
Entrya Ionic liquid
Catalyst
Con./Yieldb,c[%]
8
9
[RuCl(p-cymene)((R,R)-
1
2
3
4
3
3
4
4
99 (99)
99 (98)
99 (99)
98 (96)
95 (R)
94 (R)
93 (R)
94 (R)
TsDPEN)]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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38
39
40
41
42
43
44
45
46
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49
50
51
52
53
54
55
56
57
58
59
60
[RuCl(p-cymene)((R,R)-2)]
[RuCl(p-cymene)((R,R)-
TsDPEN)]
[RuCl(p-cymene)((R,R)-2)]
a Performed with ionic liquid/n-heptane/water 0.3/0.5/2 g, 0.5 mmol acetophenone, 2
mmol HCOONa, 0.005 mmol (0.5 mol%) catalyst at 60 °C for 24 h. Conversion
b
c
determined via HPLC using phenol as internal standard. Isolated yields after flash
d
column chromatograph given in brackets. The enantiomeric excess was determined
e
via HPLC using a DAICEL Chiracel IB column. Absolute configuration was
determined via measurement of optical rotation values and comparison with literature
data.
We subsequently investigated the substrate scope for a wider range of ketones and imines under
the previously optimized conditions. While the ATH of 4’-methylacetophenone (Table 3, entry 2),
gave similarly high ee of 97 % compared to the reduction of acetophenone, other substituted
aromatic ketones (Table 3, entries 1, 3-5) gave lower enantioselectivities (84-88 % ee). High
enantioselectivity was also observed for the ATH of a -ketoester, whereas lower yield and
selectivity was found for the corresponding -analogue compound (Table 3, entries 6 and 7). This
difference between the two type of ketoesters might be explained with the strong functional group
chelation of the β-ester carbonyl with the chiral ligand, further stabilizing the diastereomeric
transition states thus leading to an overall higher enantiocontrol and higher reaction rate. In case of
(E)-chalcone, double reduction was observed, resulting in 1,3-diphenylpropan-1-ol as major
product (Table 3, entry 8). These results have been in good agreement with the previous reports.10
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As to be expected from literature data, the reduction of aliphatic ketones is considerably more
difficult and resulted in poor yield and enantioselectivity or no conversion at all (entries 9 and
7
8
9
10).34,35,36,37 This can be based on the lack of -CH interaction that play a key role in the
휋
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enantiocontrol when using ruthenium- or rhodium-arene catalysts for the reduction of aromatic
ketones.37
Apart from the reduction of ketones, Noyori-type complexes can be equally effective in the ATH
of imines.38,39 Unlike the ATH reactions of ketones, these kind of transfer hydrogenations proceed
via an ionic mechanism in which acidic activation of the imine starting materials is required.40,41
Therefore the azeotropic mixture of formic acid and triethylamine (5:2 molar ratio) rather than
sodium formate is used as a powerful and non-reversible hydrogen source.40,42 The microemulsion
system shown in here was also suitable for the reduction of imines (Table 3, entries 11-14).
However, since the applied conditions were optimized for the reduction of ketones rather than
imines, it is not surprising that yields remain low for all imine evaluated in here.
Table 3. Scope and limitations of ATH with a variety of ketones and imines, using ionic liquid
based microemulsions.
Isolated
Entrya
Substrate
eec,d [%]
87 (R)
yieldb [%]
O
1
2
3
91
Cl
O
85
81
97 (R)
O
86 (R)
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O
4
5
4
68
88 (R)
O
6
7
O
5
6
7
8
65
84 (R)
94 (R)
64 (S)
55 (R)
8
9
10
11
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O
O
O
O
O
73
48
64
O
O
O
9
49
38 f (S)
O
10
< 1 c
n.d.
< 1 c
10 c
n.d.
N
11
12
N
26 (R)
P(O)Ph2
N
13
14
27
15
15 (R)
42 (R)
P(O)Ph2
N
a
Performed with IL 3/n-heptane/water 0.6/1/4 g, 1 mmol substrate, 4
mmol HCOONa, 0.01 mmol (0.5 mol%) [RuCl(p-cymene)((R,R)-2)]
for 20 h at 60 °C. b Isolated yield after flash column chromatography. c
d
Yield determined by GC analysis. The enantiomeric excess was
determined by chiral HPLC analysis. Absolute configuration was
determined via measurement of optical rotation values and comparison
with literature data. f Determined by 19F{1H} NMR after derivatization
with (S)-Mosher’s acid chloride.
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The recovery of the catalytic system was also tested by carrying out consecutive cycles with the
water soluble catalyst [RuCl(p-cymene)((R,R)-2)]in the optimized microemulsion system. After
complete conversion of acetophenone, the product was carefully extracted from the microemulsion,
while the catalyst remained immobilized in the intermediate phase. The vial was loaded with fresh
acetophenone and 2.0 equiv. HCOOH to regenerate HCOONa. In general, catalytic activity with
high enantioselectivity could be maintained for 3 cycles, although a decrease in conversion was
observed in each recycling cycle (Table 4). The water soluble ligand (R,R)-2 was more suitable
for recycling with ([C12mim][(iC8)2PO2] (3) and[C12dmim][(iC8)2PO2]) (4), as higher conversions
were observed compared with the result obtained from the TsDPEN-ligand reactions (e.g.: Table
4, entries 1-3 vs 4-6). This can be associated with the prevention of leaching when the sulphonated
ligand (R,R)-2 was used.
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59
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As we observed during the recycling experiments, the colour of the solution changes from orange
to dark brown indicates decomposition of the catalyst (Figure 3). In fact, recent studies by Hall et
al. on the ruthenium-catalyzed transfer hydrogenation of acetophenone with isopropanol/KOH
identified different pathways for the deactivation of the active hydride species, identifying the loss
of the arene ligand as key step in the formation of ruthenium nanoparticles as ultimate degradation
product.43 Comparable results were also reported by several other research groups, indicating that
the stability of the catalytic system rather than the immobilization of the complex is the limiting
factor in these recycling experiments.12,44,45
Table 4. Catalyst recycling in the ATH of acetophenone in the presence of ionic liquids
[C12mim][(iC8)2PO2] (3) and [C12dmim][(iC8)2PO2] (4).
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Ionic
liquid
Entrya
Catalyst
Run
Con.b [%]
eec,d [%]
6
7
8
9
1
2
1
2
3
1
2
3
1
2
3
1
2
3
99
62
40
99
67
46
99
48
16
98
62
39
95 (R)
92 (R)
91 (R)
94 (R)
93 (R)
92 (R)
94 (R)
86 (R)
59 (R)
94 (R)
88 (R)
66 (R)
[RuCl(p-cymene)((R,R)-
3
3
4
TsDPEN)]
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11
12
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58
59
60
3
4
5
[RuCl(p-cymene)((R,R)-2)]
6
7
[RuCl(p-cymene)((R,R)-
8
TsDPEN)]
9
10
11
12
[RuCl(p-cymene)((R,R)-2)]
4
a Performed with IL/n-heptane/water 0.6/1/4 g, 1 mmol acetophenone, 4 mmol HCOONa, 0.01
mmol (0.5 mol%) catalyst for 20 h at 60 °C. b Conversion determined via HPLC using phenol as
c
internal standard. The enantiomeric excess values were determined via chiral HPLC using a
DAICEL Chiracel IB column. Absolute configuration was determined via measurement of
optical rotation values and comparison with literature data.
d
Conclusion
Herein, we showed that microemulsions based on the surface-active ionic liquids
([C12mim][(iC8)2PO2] (3) and [C12dmim][(iC8)2PO2]) (4) can be successfully applied for Ru-
catalyzed asymmetric transfer hydrogenation of acetophenone. High yields and enantioselectivities
were observed under optimized conditions in case of aromatic ketones. Moreover, the temperature-
dependent phase behavior of the microemulsion allowed for high reactivity in combination with
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facile product separation. The optimized microemulsion system could be applied to a wide range
of aromatic ketones that were reduced with good isolated yields and selectivities, while aliphatic
ketones were less successful.
9
10
11
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Furthermore, it was shown that the use of a water soluble ligand ((R,R)-2) can improve
immobilization of the catalyst in the intermediate phase and decrease the leaching in the organic
phase, meanwhile the excellent conversion and enantioselectivity was also maintained in case of
the reduction of acetophenone. However, only moderate results were obtained when studying
recycling and reuse of the catalyst due to decomposition, indication that there are still limitations
when applying ionic liquid based microemulsion system in the asymmetric transfer hydrogenation.
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Experimental Section
5
6
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8
Materials and Methods
9
All reagents were purchased from commercial suppliers and used without further purification
unless otherwise noted. Ionic liquids ([C12mim][(iC8)2PO2] (3) and ([C12dmim][(iC8)2PO2] (4) were
prepared according to previously reported procedures and dried for at least 24-48 h at room
temperature or 50 °C and 0.01 mbar before use.46,24 Melting points were measured on an automated
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1
13
19
melting point system OPTI MELT of Stanford Research Systems. H NMR, C NMR and F
NMR spectra were recorded on a Bruker Advance UltraShield 400 (400 MHz) spectrometer and
chemical shifts (δ) are reported in ppm, using tetramethylsilane as internal standard. Coupling
constants (J) are reported in Hertz (Hz). The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, quin. = quintett, sex. = sextet, m =
multiplet, brs = broad singlet. HPLC analysis for determination of yield and conversion were
performed on a Jasco HPLC unit equipped with a PDA detector and a C18 column (Maisch
ReproSil 100, 250 × 4.6 mm, 5 µm) at 30 °C, using acetonitrile and water (ACN: H2O 30:70 + 0.1
trifluoroethanoic acid) as the mobile phase at flow rate of 0.8 cm3 min-1. The detection was at 210
nm. Phenol was used as internal standard and calibration curves were prepared in the range from
2.0-0.01 mg cm-3 for starting material and product. The enantiomeric excess values were
determined via HPLC analysis on a DAIONEX UPLC that was equipped with a photodiode array
(PDA) plus detector (190–360 nm), using a DAICEL IB or AS-H column (250×4.60 mm, 5 µm),
mixtures of n-heptane/iPrOH or n-hexane/EtOH as solvent, and flow rate of 0.7-1 mL min–1.
Reversed phase flash chromatography was performed on a Grace Reveleris X2 preparative system
using Phenomenex Luna C18 column (250×21.2 mm, 10 µm) at a flow rate of 15 mL min-1. Optical
rotation was measured on an Anton Paar MCP500 polarimeter at the specified conditions and the
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concentrations are stated in g/100 mL. ICP-OES measurements were carried out on a radial ICP-
OES spectrometer (Thermo iCAP 6500, Thermo Scientific, USA) by using a V-groove nebulizer
(Thermo Scientific, USA) at 1400 W and argon as plasma gas. The flow of the nebulizer gas,
cooling gas and auxiliary gas were 0.5 L min-1, 12 L min-1 and 0.8 L min-1, respectively. A solution
of 5% n-octanol in conostan was used for the sample dilution. Signal intensities measured at the
wavelength of 267.876 nm were used for the quantification of ruthenium, while emission lines
240.272 and 266.161 were used for monitoring and quality control during the measurements.
Calibration curves for the quantification of ruthenium were prepared from a stock solution of
Noyoris catalyst [RuCl(p-cymene)((R,R)-TsDPEN)] in 1-octanol in a range of 0.5-3.5 ppm. To
correct for potential instrument drifts as well as non-spectral interferences indium has been added
to all standard and sample solutions; for quantification the obtained ruthenium signals were
normalized using the indium response measured at the wavelength of 230.606 nm.
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Phase diagrams
The phase behaviour of water-n-heptane-[C12mim][(iC8)2PO2] (3) in the presence of HCOONa,
acetophenone (5) and 1-phenylethanol (6) at different temperatures were determined by visual
inspection titration of the mixture with [C12mim][(iC8)2PO2] (3) at different temperatures. After
adding a certain amount of ionic liquid, the mixture was stirred magnetically and left to equilibrate
in a thermostated heating block. After visual assessment of phase behaviour, new ionic liquid was
added and the procedure was repeated until clear phases were obtained.
Synthesis of (R,R)-2: 9,33
A round-bottomed flask charged with 10 mL of oleum (65%) was cooled down to 0 °C using an
ice bath. (R,R)-DPEN (1 g, 4.7 mmol) was added batchwise. The mixture was stirred for 24 h at
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0 °C to room temperature. The viscous mixture was poured onto 100 g of crushed ice with vigorous
stirring. After the pH value of the solution was adjusted to 9 with solid NaOH, the aqueous phase
was washed with DCM. After removal of the water under reduced pressure, a yellow solid was
obtained. The crude product was re-dissolved in 50 mL of CH3OH and the insoluble compound
was removed by filtration. The product was purified by RP chromatography and 1.6 g (yield: 76%)
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of white solid (R,R)-1 was obtained. M.p. >280 °C (decomposition);
ퟐퟎ +36.13 (c= 1.1, H2O);
[훂]퐃
1H NMR (400 MHz; D2O) δ: 5.15 (2H, s, 2 x CHNH2), 7.27 (2H, d, J = 7.84 Hz, H-arom), 7.39
(2H, t, J = 7.86 Hz, H-arom), 7.66 (2H, s, H-arom), 7.71 (2H, d, J = 7.81 Hz, H-arom).
Compound (R,R)-1 (1.5 g, 3.3 mmol) and Na2CO3 (1.4 g, 13.2 mmol) were dissolved in 20 mL of
H2O, then a THF solution (20 mL) of TsCl (759 mg, 3.9 mmol) was added to the aqueous solution
dropwise with vigorously stirring at 0 °C. Once the addition was completed, the resulting mixture
was warmed up to 40 °C and stirred for 24 h. This was followed by washing the aqueous layer with
Et2O and removal of the water under reduced pressure. The residue was re-dissolved in 50 mL of
CH3OH, followed by the removal of the insoluble compound by filtration. After concentration
under reduced pressure, the resulting solid was purified by RP chromatography and 1.2 g (yield:
62%) colourless solid product (R,R-2) was obtained. M.p. 240-249 °C;
ퟐퟎ+320.23 (c= 1.01,
[훂]퐃
H2O); 1H NMR (400 MHz; D2O) δ: 1.95 (3H, s, CH3), 4.57 (1H, d, J = 8.9 Hz, CHNH2), 4.64
(1H, d, J = 9.1 Hz, CHNH), 6.58 (1H, d, J = 7.8 Hz, H-arom), 6.68 (1H, d, J = 7.1 Hz, H-arom)
6.75 (2H, d, J = 8.3 Hz, H-arom), 7.44-7.46 (1H, m, H-arom), 7.12-7.20 (6H, m, H-arom), 7.56
(1H, s, H-arom). 13C NMR (100 MHz; CDCl3) δ: 20.4 (CH3), 58.3 (CHNH2), 60.6 (CHNH),
123.8 (C-arom), 124.2 (C-arom), 125.0 (C-arom), 126.1 (C-arom), 126.5 (C-arom), 126.6 (C-arom),
128.4 (C-arom), 129.0 (C-arom), 129.5 (C-arom), 129.8 (C-arom), 130.5 (C-arom), 131.1 (C-arom),
133.1 (C-arom), 134.4 (C-arom), 134.6 (C-arom), 142.7 (C-arom), 143.3 (C-arom), 144.8 (C-arom).
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Synthesis of 1-methyl-3,4-dihydroisoquinoline (Table 3, entry 11): 47
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Freshly distilled 2-phenylethylamine (1 eq., 12.3 mmol) was dissolved in anhydrous pyridine (1.02
eq. 1.1 mL), and acetic anhydride (1.04 eq. 12.8 mmol, 1.22 mL) was slowly added with a syringe.
The reaction mixture was stirred at 90 °C for 2 h and subsequently allowed to room temperature.
Then the mixture was poured onto 25 g ice and stirred for 5 min before 11 mL HCl were added.
The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were
subsequently washed with saturated NaHCO3 solution, dried over Na2SO4 and the solvent was
removed under reduced pressure. N-Phenethylacetamide was obtained as a light yellow solid (1.51
g, 75%) and could be used without further purification. In a round bottom flask P2O5 (1.25 eq.,
10.2 mmol, 2.90 g) and POCl3 (3.75 eq., 30.6 mmol, 2.86 mL) were mixed in 50 mL o-xylene. N-
Phenethylacetamide (1 equiv., 8.1 mmol, 1.33 g) was added and the mixture was refluxed for 20
h. After cooling to room temperature, the mixture was neutralized with 2 M NaOH. The phases
were separated and the aqueous phase was extracted with Et2O. The combined organic phases were
dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was
purified via Kugelrohr distillation (0.4 mbar, 75 to 100°C). 1-methyl-3,4-dihydroisoquinoline was
obtained as a colourless liquid (948 mg, 54%). 1H NMR (400 MHz; CDCl3) δ: 2.33 (3H, s, CH3),
2.62 (2H, t, J = 7.1 Hz, CCH), 3.60 (2H, t, J = 6.1 Hz, NCH2), 7.08-7.24 (4H, m, H-arom).
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Synthesis of 1-phenyl-3,4-dihydroisoquinoline (Table 3, entry 12): 48
1-Phenyl-1,2,3,4-tetrahydroisoquinoline (3 mmol, 628 mg) was dissolved in 12.5 mL DMF and
stirred at 100 °C. After complete reaction, the solvent was removed from the crude reaction mixture
under reduced pressure. The crude product was purified via column chromatography and 1-phenyl-
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3,4-dihydroisoquinoline was obtained as colourless solid (94%). 1H NMR (400 MHz; CDCl3) δ:
2.80 (2H, t, J = 7.1 Hz, CCH), 3.85 (2H, t, J = 7.4 Hz, NCH2), 7.28-7.63 (9H, m, H-arom).
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General procedure for the preparation of N-diphenylphosphinoyl ketoimines (Table 3,
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entries 13,14): 49
N-Diphenylphosphinoyl ketoimines were prepared according to the published method: To a stirred
solution of NH2OH · HCl (26 mmol, 1.81 g) and NaOAc (26 mmol, 2.13 g) in EtOH/H2O (1/1, 16
mL), ketone (18 mmol) was added and heated to reflux. After complete conversion the mixture
was cooled to -10 °C and left to crystallize for 24 h. The solid was filtered and washed with water.
The product was dried and used directly for the next step. To a stirred solution of the corresponding
oxime (9.6 mmol) and triethylamine (9.6 mmol) in petroleum ether/CH2Cl2 (1/1, 30 mL), a solution
of chlorodiphenylphosphine (10 mmol) in CH2Cl2 (5 mL) was added over 30 min at -45 °C. The
mixture was stirred for 1 h at room temperature before evaporating the solvent. The residue was
dissolved in CH2Cl2, washed with sat. NaHCO3, brine, dried over Na2SO4 and concentrated. The
residue was purified by flash column chromatography using AcOEt/petroleum ether (1/1) as eluent.
The product was further purified by recrystallization from CH2Cl2/hexane.
P,P-Diphenyl-N-[(1E)-1-phenylethylidene]phosphinic amide:
1H NMR (400 MHz; CDCl3) δ: 2.37 (3H, s, CH3), 7.18-7.47 (11H, m, H-arom), 7.51-7.87 (4H,
m, H-arom).
N-Diphenylphosphoryl-1-naphthalen-2-ylethanimine:
1H NMR (400 MHz; CDCl3) δ: 3.03 (3H, s, CH3), 7.26-7.51 (10H, m, H-arom), 7.53-7.98 (7H,
m, H-arom).
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General procedure for parameter optimization
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A mixture of RuCl(p-cymene)[(R,R)-TsDPEN] (3.18 mg, 0.005 mmol), [C12mim][(iC8)2PO2] (0.3
g), sodium formate (136 mg, 2 mmol), degassed water (2 g), n-heptane (0.5 g) and acetophenone
(60.08 mg, 0.5 mmol) was stirred in an oil bath at 60 °C under argon atmosphere for 20 h. The
reaction mixture was diluted with MeOH to a total volume of 50 cm3 to obtain a homogenous
solution. A sample (200 µl) was taken, diluted with MeOH (800 µl), and an internal standard (200
µl of phenol in MeOH stock solution) was added. The sample was thoroughly mixed, filtered over
a syringe filter (0.2 µm) and analysed by Jasco HPLC. The enantiomeric excess values were
determined by analysed via chiral HPLC. This strategy was also assessed to study kinetic behaviour.
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General procedure for product isolation
A mixture of [Ru(p-cymene)Cl2]2 (1.53 mg, 0.0025 mmol), (R,R)-2 (3.62 mg, 0.006 mmol) and
degassed water (2 g) was stirred at 40 °C under argon atmosphere for 1 h. After cooling to room
temperature, ionic liquid ([C12mim][(iC8)2PO2] (3) or [C12dmim][(iC8)2PO2]) (4) (0.3 g), sodium
formate (136 mg, 2 mmol), n-heptane (0.5 g) and ketone (0.5 mmol) were subsequently added and
the reaction mixture was reacted at 60 °C for 24 h. After cooling to room temperature, the three-
phase reaction mixture was extracted with degassed n-heptane/diethyl ether (1;1, 2 ml) four times.
The combined extracts were concentrated in vacuum to afford the desired products that were further
purified via flash column chromatography over silica.
Recycling strategy for the asymmetric transfer hydrogenation of acetophenone
After the extraction of product, the residual microemulsion and aqueous phases containing the
catalyst, ligand and ionic liquid were reused by adding formic acid (2 eq.) to regenerate sodium
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formate. Fresh acetophenone was added into the aqueous solution and the next cycle of the reaction
was started under the same conditions.
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(R)-2-Phenylethanol: 50
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1H NMR (400 MHz; CDCl3) δ: 1.38 (3H, d, J = 6.5 Hz, CH3), 2.89 (1H, s, OH), 4.73 (1H, q, J =
6.4 Hz, CH3CH), 7.19-7.28 (5H, m, H-arom). Determination of enantiomeric excess: DAICEL
Chiracel IB column, n-hexane/i-PrOH, 98.5/1.5 V/V, 1.0 mL min–1, 25ºC, UV 254 nm: tR (R) =
14.8 min, tR (S) = 16.7 min (95% ee).
(R)-1-(4-Chlorophenyl)ethanol: 50
1H NMR (400 MHz; CDCl3) δ: 1.41 (3H, d, CH3, J = 6.3 Hz), 3.16 (1H, s, OH), 4.77 (1H, q, J =
6.4 Hz CH3CH), 7.25 (4H, qvin., H-arom). Determination of enantiomeric excess: DAICEL
Chiracel IB column, n-hexane/i-PrOH, 98.5/1.5 V/V, 1.0 mL min–1, 25ºC, UV 254 nm: tR (R) =
15.5 min, tR (S) = 14.8 min (87% ee).
(R)-1-(p-Tolyl)ethanol: 50
1H NMR (400 MHz; CDCl3) δ: 1.50 (3H, d, J = 6.4 Hz, CH3), 2.39 (3H, s, CCH3), 2.66 (1H, s,
OH), 4.83 (1H, q, J = 6.4 Hz, CH3CH), 7.17-7.30 (4H, m, H-arom). Determination of
enantiomeric excess: DAICEL Chiracel IB column, n-hexane/i-PrOH, 98.5/1.5 V/V, 1.0 mL
min–1, 25ºC, UV 254 nm: tR (R) = 18.4 min, tR (S) = 16.3 min (97% ee).
(R)-1-(1’-Naphtyl)ethanol: 51
1H NMR (400 MHz; CDCl3) δ: 1.50 (3H, d, J = 6.7 Hz, CH3), 2.23 (1H, s, OH), 5.45 (1H, q, J =
6.4 Hz, CH3CH), 7.18-7.96 (7H, m, H-arom). Determination of enantiomeric excess: DAICEL
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Chiracel IB column, n-heptane/i-PrOH, 93/7 V/V, 1.0 mL min–1, 25ºC, UV 254 nm: tR (R) = 12.1
min, tR (S) = 9.3 min (86% ee).
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(R)-1-(4-Methoxyphenyl)ethanol: 50
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1H NMR (400 MHz; CDCl3) δ: 1.33 (3H, d, J = 6.3 Hz, CH3), 2.53 (1H, s, OH), 3.67 (3H, s, CH3),
4.67 (1H, q, J = 6.5 Hz, CH3CH), 6.74 (2H, d, J = 8.7 Hz, H-arom), 7.15 (2H, d, H-arom, J = 8.6
Hz). Determination of enantiomeric excess: DAICEL Chiracel IB column, n-hexane/i-PrOH,
98.5/1.5 V/V, 1.0 mL min–1, 25ºC, UV 254 nm: tR (R) = 21.6 min, tR (S) = 23.3 min (88% ee).
(R)-1-Phenylpropan-1-ol: 50
1H NMR (400 MHz; CDCl3) δ/ppm: 0.85 (3H, d, J = 7.3 Hz, CH3), 1.67-1.77 (3H, m, OH,
CH3CH2), 4.52 (1H, t, J = 6.2 Hz, CH2CHC), 7.18-7.29 (5H, m, H-arom). Determination of
enantiomeric excess: DAICEL Chiracel IB column, n-hexane/i-PrOH, 98.5/1.5 V/V,
1.0 mL min-1, 25ºC, UV 254 nm: tR (R) = 11.6 min, tR (S) = 12.8 min (84% ee).
(R)-Methyl 3-hydroxy-3-phenylpropanoate: 52
1H NMR (400 MHz; CDCl3) δ: 1.25 (3H, t, J = 7.1 Hz, CH3,), 2.71 (2H, q, J = 8.0 Hz, CH3CH2),
3.41 (1H, s, OH), 4.15 (2H, q, J = 14.0 Hz, CHCH2), 5.11 (1H, q, J = 5.2 Hz, CH), 7.30-7.37 (5H,
m, H-arom). Determination of enantiomeric excess: AS-H column, n-heptane/i-PrOH 98/2 V/V,
of 0.7 mL min–1, 25ºC, UV 254 nm: tR (R) = 17.8 min, tR (S) = 19.1 min (94% ee).
(S)-Ethyl 2-hydroxy-2-phenylacetate: 53
1H NMR (400 MHz; CDCl3) δ: 1.14 (3H, t, J = 7.1 Hz, CH3), 3.40 (1H, s, OH), 4.09-4.17 (2H,
m, CH3CH2), 5.07 (1H, s, CH), 7.24-7.33 (5H, m, H-arom). Determination of enantiomeric
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