Asymmetric transfer hydrogenation of aromatic ketones in water using a polymer-supported chiral catalyst containing a hydrophilic pendant group

Article abstract of DOI:10.1002/adsc.200800362

Hydrophilic polymers having pendant groups of carboxylates or sulfonates have been used as a polymer support for chiral 1,2-diamine monosulfonamides. The polymeric chiral complex prepared from the polymer-supported chiral ligand with ruthenium dichloride·p-cymene was used in the asymmetric transfer hydrogenation of prochiral ketones in water. The balance between hydrophilicity and hydrophobicity of the polymer support influenced both the reactivity and the enantioselectivity of the reaction in water. The chiral polymeric complex having a quaternary ammonium salt structure as the pendant group worked well in water. In most cases the polymer-supported catalyst having a quaternary ammonium sulfonate pendant group showed superior enantioselectivity compared to the corresponding non-supported model catalyst in the solution system. The polymeric catalysts can be reused without loss of catalytic activity.

Full text of DOI:10.1002/adsc.200800362

FULL PAPERS
DOI: 10.1002/adsc.200800362
Asymmetric Transfer Hydrogenation of Aromatic Ketones in
Water using a Polymer-Supported Chiral Catalyst Containing a
Hydrophilic Pendant Group
Yukihiro Arakawa,a Atsuko Chiba,a Naoki Haraguchi,a and Shinichi Itsunoa,*
a
Department of Materials Science, Toyohashi University of Technology, Tempaku-cho, 441-8580 Toyohashi, Japan
Fax : (+81)-0532-44-6813; e-mail: itsuno@tutms.tut.ac.jp
Received: June 11, 2008; Revised: July 28, 2008; Published online: September 9, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800362.
Abstract: Hydrophilic polymers having pendant group worked well in water. In most cases the poly-
groups of carboxylates or sulfonates have been used mer-supported catalyst having a quaternary ammoni-
as a polymer support for chiral 1,2-diamine monosul- um sulfonate pendant group showed superior enan-
fonamides. The polymeric chiral complex prepared tioselectivity compared to the corresponding non-
from the polymer-supported chiral ligand with ruthe- supported model catalyst in the solution system. The
nium dichloride·p-cymene was used in the asymmet- polymeric catalysts can be reused without loss of cat-
ric transfer hydrogenation of prochiral ketones in alytic activity.
water. The balance between hydrophilicity and hy-
drophobicity of the polymer support influenced both
the reactivity and the enantioselectivity of the reac- Keywords: aqueous-phase catalysis; asymmetric cat-
tion in water. The chiral polymeric complex having a alysis; hydrogen transfer; immobilization; ketones;
quaternary ammonium salt structure as the pendant polymers
Introduction
mainly due to their easy separation and recycle use
after the reaction. Although a considerable number of
Organic reactions in water have attracted much atten- papers on the immobilization of chiral catalyst to po-
tion and a great number of asymmetric reactions have lymer has been published so far,[3] only a limited num-
been performed in water.[1] Most in vivo organic reac- bers of reports on polymer-supported chiral catalysts
tions occur in an aqueous environment, and are effi- that can be used in water have appeared.[4–13]
ciently catalyzed by enzymes. The amphiphilic proper-
The combination of the ꢀaqueous systemꢁ and the
ty of enzymes may be one of the most important ꢀrecyclable catalytic systemꢁ would provide an ideal
issues to promote such organic reactions in an aque- chemical process for environmentally friendly asym-
ous environment. Hydrophobic substrates are effi- metric synthesis. The first example of this combina-
ciently incorporated into a hydrophobic pocket of the tion was demonstrated by Andersson et al.[4] They de-
enzyme, where the reaction smoothly occurs. Howev- veloped a water-soluble poly(acrylic acid salt)-sup-
er, the use of water as a reaction media in usual or- ported (2S,4S)-4-diphenylphosphino-2-(diphenylphos-
ganic synthesis is sometimes seriously restricted since phinomethyl)pyrrolidine (PPM)-rhodium(II) complex,
most organic compounds are less soluble in water and which was used for the asymmetric hydrogenation of
hydrolytic degradation of reagents or catalysts inhibits prochiral olefins in water. Poly(ethylene glycol) is an-
the reaction. Many efforts to overcome such draw- other type of typical water-soluble polymer, which has
backs have been investigated in the past several years, been used as polymer support for various kinds of
and a number of efficient chiral catalysts for enantio- asymmetric reactions including transfer hydrogena-
selective reactions in aqueous media has been devel-
ACHTREUNG
oped.[2]
On the other hand, from the viewpoint of efficiency functionalities only on the end group of the polymer
in organic synthesis, polymer-supported chiral cata- chain, resulting in a very low level of catalyst loading.
lysts are extremely useful for asymmetric reactions, Water-soluble polymers are not always necessary as
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Yukihiro Arakawa et al.
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supporting polymers for the organic reactions in the
Asymmetric transfer hydrogenation of prochiral ke-
aqueous phase. In order to produce a suitable micro- tones is one of the most powerful methodologies for
environment for organic reactions in water, the am- the production of optically active secondary alco-
phiphilic property of the polymer support would be hols.[14] Among the various chiral catalysts reported
rather essential. The important work of this area has for the asymmetric transfer hydrogenation, the most
been undertaken by Uozumi et al. with amphiphilic significant to date is the Ru(II) complex with optically
PS-PEG [polystyrene-poly(ethylene glycol)] resin- active N-toluenesulfonyl-1,2-diphenylethylenediamine
supported chiral palladium complexes, which have (TsDPEN) developed by the Ikariya and Noyori
been successfully used for asymmetric p-allylic substi- groups.[15] Some polymeric versions of the catalysts
tution reactions in water.[6] Hayashi et al. also report- were also developed for the same reaction.[16] The
ed on asymmetric 1,4-addition using a similar type of first example of the polymer-supported 1,2-diamine
PS-PEG resin-supported chiral rhodium catalyst in monosulfonamide as a chiral ligand of an asymmetric
water.[7] Hydrophobic substrate molecules would transfer hydrogenation catalyst was reported by Lem-
make a strong interaction with the PS matrix of the aire and co-workers in 1997.[16a] They synthesized the
catalyst in water, where reaction smoothly occurs with polystyrene-supported chiral monosulfonamide by
the catalytic moiety located in the vicinity of the sub- radical polymerization of (S,S)-12 with styrene and di-
strate. Another type of amphiphilic polymer is the vinylbenzene in CH2Cl2. The corresponding polymeric
poly(2-oxazoline)s.[8] Polymer-supported catalysts chiral Ru(II) complex in 2-propanol/triethylamine
based on poly(oxazoline)s are an important example gave 84% ee with 23% yield after two days at 708C.
of a polymeric catalyst that can be used in aqueous
In the past several years, the effectiveness of the
media. Nuyken et al. prepared a poly(2-oxazoline) use of water as the sole solvent for the asymmetric
block copolymer-supported PPM-rhodium complex transfer hydrogenation has been proved.[17,18] Polymer-
for the asymmetric hydrogenation of prochiral olefins ic chiral catalysts immobilized on PEG[5a] or silica[19]
in water.[9] More recently, Weberskirch et al. demon- have also been prepared and used for the same reac-
strated that the same type of amphiphilic block copo- tion in water. However, polystyrene-based polymers
lymer-supported CoACHTERNGU(III)ACHRTE(UGN salen) complex can be em- have not been used because of their high hydropho-
ployed for the hydrolytic kinetic resolution of epox- bicity. We have designed a novel amphiphilic polymer
ides in water.[10] Polystyrene-supported proline deriva- support that consists of cross-linked polystyrene
tives are also considered to be amphiphilic polymers having carboxylate and sulfonate derivatives as hy-
which were used as the organocatalyst for asymmetric drophilic pendant groups. A chiral catalyst attached
aldol reactions in water.[11] A different approach to to these amphiphilic polymers may be efficiently used
polymeric chiral catalysts in water is the use of the in aqueous media. We have found that the amphiphil-
microencapsulation technique using hydrophobic ic polystyrene-supported chiral 1,2-diamine monosul-
polystyrene. Kobayashi developed a microencapsulat- fonamides were excellent chiral ligands for asymmet-
ed osmium catalyst by means of cross-linked polystyr- ric transfer hydrogenation catalysts.[13] Although intro-
ene and used it for the asymmetric dihydroxylation of duction of the sulfonate moiety into reagents and cat-
olefins
with
phthalazine
bis-dihydroquinidine alysts is a typical way to facilitate the reaction in
[(DHQD)2PHAL] in water.[12]
aqueous media,[20] to the best of our knowledge, there
We have introduced a novel type of amphiphilic po- has been no report on the use of sulfonated polymer-
lymer support that consists of a polystyrene main supported chiral catalysts in water. In this article, we
chain and a quaternary ammonium sulfonate as its describe the details of our study on the asymmetric
side chain.[13] We have found that such an amphiphilic transfer hydrogenation of aromatic ketones by using
polymer support behaved efficiently to provide a suit- the amphiphilic polymer-supported chiral catalyst in
able microenvironment for asymmetric reactions. The water.
purpose of this study focuses on the development of
the polymer support that can be efficiently used in
water. In order to understand the suitability of the po- Results and Discussion
lymer support in aqueous media we have prepared
various kinds of amphiphilic polymer supports having Preparation of Novel Polymer-Supported Chiral 1,2-
hydrophilic pendant groups such as carboxylates and Diamine Monosulfonamides
sulfonates. Enantiopure 1,2-diamine monosulfon-
ACHTREUNGamide as a chiral ligand was immobilized on to such As shown in Figure 1 we have prepared various kinds
an amphiphilic polymer support for use in asymmetric of cross-linked polymer-supported 1,2-diamine mono-
reactions. We chose the asymmetric transfer hydroge- sulfonamides (R,R)-1–9. We first prepared enantio-
nation of prochiral ketones as a model reaction to pure 1,2-diamine monosulfonamide monomer (R,R)-
evaluate the amphiphilic polymeric catalysts.
12 from (R,R)-1,2-diphenylethylenediamine (R,R)-10
and p-styrenesulfonyl chloride 11 (Scheme 1). Radical
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Asymmetric Transfer Hydrogenation of Aromatic Ketones in Water
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Scheme 2. Preparation of cross-linked polystyrene-supported
chiral 1,2-diamine monosulfonamide (R,R)-1.
ant groups in the polymeric chiral ligands (Figure 1).
These polymers were easily obtained by radical poly-
merization in good yield.
Polymer-supported chiral ligands (R,R)-2–4 con-
taining carboxylate derivatives were synthesized as
shown in Scheme 3. Under radical polymerization
Figure 1. Polymer-supported chiral 1,2-diamine monosulfon-
amides.
ACHTREUNG
polymerization of this chiral monomer with styrene in
the presence of divinylbenzene (DVB) as cross-link-
ing agent in DMF gave the insoluble polymer-sup-
ported chiral 1,2-diamine monosulfonamide (R,R)-1
(Scheme 2). The polymer (R,R)-1 was well swollen in
a good solvent for polystyrene such as DMF, THF
and toluene. In contrast, the same polymer (R,R)-1
was completely shrunk in water as expected from its
highly hydrophobic character owing to the polystyr-
ene main chain structure. This type of polymer would
not be suitable for use in aqueous media due to the
highly hydrophobicity. Since organic reactions in
Scheme 3. Preparation of carboxylated polymer-supported
chiral 1,2-diamine monosulfonamides (R,R)-2–4.
water are one of the important means of organic syn- conditions in DMF, terpolymerization of (R,R)-12,
thesis that meet green chemistry conditions, it is desir- DVB and 13 gave (R,R)-2 in quantitative yield. Treat-
able to develop some amphiphilic polymer supports ment of (R,R)-2 with Na2CO3 in water afforded the
which can be efficiently used in aqueous media. In sodium carboxylate pendant structure in (R,R)-3. Re-
order to investigate the effect of their amphiphilic action of 4-vinylbenzoic acid 13 with Na2CO3 fol-
properties on the asymmetric reaction in water, we in- lowed by an exchange reaction of sodium 4-vinylben-
troduced novel polymer support structures including zoate
with
benzyltributylammonium
chloride
carboxylate (R,R)-2–4, alkanesulfonate (R,R)-5–7 and (BTBAC) gave the quaternary ammonium salt mono-
arenesulfonate (R,R)-8, 9 as achiral hydrophilic pend- mer 14. This monomer was then polymerized with
Scheme 1. Synthesis of chiral 1,2-diamine monosulfonamide monomer (R,R)-12.
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(R,R)-12 in the presence of DVB to give the amphi- shows the preparation of (R,R)-9 having an aromatic
philic cross-linked polymeric chiral ligand (R,R)-4. quaternary ammonium sulfonate pendant group by
The synthesis of polymers (R,R)-5–7 having alkane- terpolymerization of (R,R)-12, DVB and quaternary
sulfonate pendant groups is shown in Scheme 4. Ac- ammonium sulfonate monomer 18 derived from 17.
rylamide monomer 15 having an alkanesulfonic acid In contrast to the polystyrene-supported chiral ligand
moiety was copolymerized with (R,R)-12 and DVB to (R,R)-1, these amphiphilic polymers were all swollen
in water.
Asymmetric Transfer Hydrogenation of
Acetophenone in Water
One of the most efficient catalysts for the asymmetric
transfer hydrogenation of prochiral ketones is the
Ru(II) complex of TsDPEN developed by Ikariya
et al.[15] The reaction usually occurs under mild reac-
tion conditions using 2-propanol or formic acid deriv-
atives as a hydrogen source. Since the chiral Ru(II)
complex is tolerant of water, it is possible to use the
complex in aqueous systems. Xiao et al. demonstrated
the asymmetric hydrogenation of ketones with aque-
ous HCOONa and the Ru-TsDPEN complex.[17,18] We
have tested our amphiphilic polymers containing
TsDPEN moieties for the asymmetric transfer hydro-
genation in water. According to Ikariyaꢁs procedure
the polymer-supported chiral 1,2-diamine monosulfo-
Scheme 4. Preparation of sulfonated polymer-supported
chiral 1,2-diamine monosulfonamides (R,R)-5–7.
namide was treated with [RuCl
2ACHTRE(UNG p-cymene)]2 in water
at 408C for 1 h. The obtained polymeric complex
give (R,R)-5, which was converted into (R,R)-6 by showed an orange color which is typical of the Ru(II)
treatment with Na2CO3 in water. The reaction of 15 complex. Although the polymer is insoluble due to its
1
with BTBAC gave the quaternary ammonium salt cross-linked structure, we took the H NMR spectra
monomer 16 of the sulfonate which was copolymer- of the polymers. The gel-phase NMR of the cross-
ized with (R,R)-12 and DVB to give (R,R)-7 linked polymers showed differences between the
(Scheme 4). Polymer-supported chiral ligands (R,R)-8 states before and after complexation. For example,
and 9 having an arenesulfonate pendant group were after complexation, proton peaks attributed to p-
also prepared as shown in Scheme 5. Terpolymeriza- cymene were detected. We used these polymeric
tion of (R,R)-12, DVB and sodium styrenesulfonate chiral complexes for the asymmetric transfer hydroge-
monomer 17 in DMF gave (R,R)-8. Scheme 5 also nation of acetophenone.
Because of the hydrophobic character of aromatic
ketones using the non-supported Ru(II)-TsDPEN
complex, vigorous stirring is necessaryfor the reaction
to proceed in water. Under such conditions the corre-
sponding enantioenriched secondary alcohol 20 was
obtained in 52% conversion with 94% ee (Table 1,
entry 1).[2g] A very low conversion (6%) was attained
when the reaction was conducted in water without
stirring (entry 2). When the Ru(II) complex prepared
from polystyrene-supported chiral ligand (R,R)-1 was
used, only a miserable conversion was obtained after
longer reaction times as expected from the strong hy-
drophobicity of the polymeric catalyst (Table 1,
entry 5). Vigorous stirring gave no positive effect in
the case of hydrophobic (R,R)-1. In order to reduce
the hydrophobic property of the polystyrene support,
we have introduced the carboxylic acid moiety in the
side chain of the polystyrene support. Preparation of
Scheme 5. Preparation of aromatic sulfonated polymer-sup-
ported chiral 1,2-diamine monosulfonamides (R,R)-8 and 9. chiral polymers (R,R)-2–4 containing a carboxylate
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Table 1. Asymmetric transfer hydrogenation of acetophenone 19 in water.[a]
Entry
Ligand
Polymer-support[b]
Temperature [8C]
Time [h]
Conversion[c] [%]
ee[d] [%]
Configuration
1[e]
2[f]
3[g]
4[h]
5
6
7
8
9
10
11
12
13
14
15
16[f]
17[i]
18[j]
TsDPEN
TsDPEN
TsDPEN
TsDPEN
A
R
E
N
A
U
U
U
ACHTREUNG
ACHTREUNG
G
G
R
U
–
–
–
–
28
32
40
40
40
40
40
40
40
40
40
40
18
40
18
32
40
40
1
2
52
6
30
84
7
94
94
94
95
86
–
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
24
0.5
17
43
20
20
2
polystyrene
H
Na
Q
H
Na
Q
Na
Na
Q
1
2
–
50
23
34
100
92
10
100
100
38
66
54
96
92
92
96
91
91
98
98
98
95
97
2
2
15
15
3
18
2
Q
Q
Q
Q
26
24
[a]
Unless otherwise noted reactions were carried out using 1 mmol of 19, 5 equiv. of HCOONa, and an S/C ratio of 100 in
2 mL of water.
[b]
H: polymer having free acid pendant group. Na: polymer having Na salt pendant group. Q: polymer having quaternary
ammonium salt pendant group.
Determined by GC analysis.
[c]
[d]
[e]
[f]
Determined by HPLC with Chiralcel OD.
Ref.[2g]
Reaction was performed without stirring.
Reaction was performed using sodium benzoate as an additive.[h] Reaction was performed using benzyltributylammonium
[g]
p-toluenesulfonate as an additive. [TsDPEN]:ACHTREU[NG Additive]=1:9.
Reaction was carried out using a 0.1M solution of acetophenone in 2-propanol. Acetophenone:Ru:ligand:KOH=
100:1.0:1.5:20.
S/C=1000.
[i]
[j]
structure is shown in Scheme 3. We have examined ammonium salt of benzoic acid as pendant group im-
these carboxylated polymer-supported chiral ligands proved the reactivity in the same reaction (entry 8).
[(R,R)-2–4] for the same reaction in water. Although By using (R,R)-4, (R)-phenylethanol was obtained in
(R,R)-2 was smoothly suspended in water, almost no 50% yield with 96% ee.
reaction occurred (entry 6). Even when a more hydro-
Next we examined the alkanesulfonic acid deriva-
philic polymer-supported chiral ligand [(R,R)-3] pos- tives as a hydrophilic pendant group of the polymer
sessing the sodium salt structure in the side chain was support. The use of the polymeric catalysts derived
used, the polymeric catalyst remained completely in- from this type of polymeric chiral ligands [(R,R)-5–7]
active in water (entry 7). In the model reaction using gave higher yields as compared to those from car-
the TsDPEN-derived complex, we found that the re- boxylated polymers (entries 9–11). In this type of po-
action was strongly hindered when sodium benzoate lymer again that with the quaternary ammonium salt
was added to the reaction mixture. The yield of the of the sulfonate as a pendant group [(R,R)-7] gave
alcohol decreased to 30% even after longer reaction the best result with quantitative conversion and high
time (24 h) at higher temperature (408C) in the pres- level of enantioselectivity, 96% ee (entry 11). We then
ence of sodium benzoate (entry 3), although the examined the polymeric chiral ligands (R,R)-8 and 9
reason for the retarding effect is not clear at this containing aromatic sulfonate derivatives as a pend-
moment. On the other hand, the use of the polymer- ant group on the polymer support. Even higher con-
supported chiral ligand (R,R)-4 having the quaternary version was obtained when the catalyst was derived
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from a sodium sulfonate polymer (entry 12). How- sentially required for the reaction with TsDPEN.
ACHTREUNGever, on lowering the reaction temperature to 188C Even with no stirring some reaction did occur in 2 h
an appreciable decrease of the conversion was ob- to give the chiral alcohol with 98% ee (entry 16),
served (entry 13) with the (R,R)-8 derived catalyst. while the use of TsDPEN gave only 6% conversion
Further higher enantioselectivity (98% ee) with quan- without stirring (entry 2), as mentioned before. These
titative conversion was attained by using the quater- data obtained using the polymeric catalyst obviously
nary ammonium salt of the aromatic sulfonated poly- showed that both the reactivity and the enantioselec-
mer support (R,R)-9h (entry 14). It is also noted that tivity using the catalyst derived from the quaternary
both the enantioselectivity and conversion obtained ammonium sulfonate polymer (R,R)-9h were higher
with this polymeric catalyst are obviously higher than than those obtained from the corresponding low mo-
those obtained from the low molecular weight catalyst lecular weight counterpart catalyst derived from
derived from TsDPEN in water. The polymeric cata- TsDPEN in solution system. When 2-propanol was
lyst could be easily separated from the reaction mix- used as hydrogen source instead of an aqueous solu-
ture due to its insolubility and reused for the follow- tion of sodium formate, a longer reaction time was re-
ing reaction. We have confirmed that at least five re- quired with a decrease of the enantioselectivity to
cycle uses were possible without any loss of catalytic some extent (entry 17). This result also revealed that
activity of the polymeric catalyst. Under the reaction the quaternary ammonium salt polymers are especial-
conditions of entry 14 using the catalyst derived from ly effective in water.
(R,R)-9h we obtained 20 in quantitative yield with 98,
In order to understand the effect of catalyst load-
97, 97, 97, and 97% ees for five recycling experiments. ing, degree of cross-linking, and the content of quater-
Lowering the temperature did not severely influence nary ammonium pendant groups on the asymmetric
the reactivity as appeared in the case of the quaterna- transfer hydrogenation reaction, we have prepared
ry ammonium salt polymer-support (R,R)-9h (en- various kinds of sulfonated polymer-supported chiral
tries 14, 15). More interestingly, in spite of heteroge- 1,2-diamine monosulfonamides (R,R)-9 as shown in
neous conditions using (R,R)-9h, the reaction smooth- Table 2. These polymer-supported chiral ligands
ly proceeded without vigorous stirring which was es- (R,R)-9 with different composition (l: chiral ligand,
Table 2. Effect of the chiral ligand loading and the cross-linking degree on the enantioselective transfer hydrogenation of
acetophenone 19 in water.[a]
Entry
Polymeric chiral ligand
Time [h]
Conversion[b] [%]
ee[c] [%]
Configuration
l
m
n
1
2
3
4
5
6
7
8
9
9a
9b
9c
9d
9e
9f
9g
9h
9i
0.01
0.10
0.30
0.50
0.10
0.10
0.10
0.10
0.10
0
0
0
0
0.01
0.03
0.05
0.10
0.20
0.99
0.90
0.70
0.50
0.89
0.87
0.85
0.80
0.70
10
3
72
98
98
97
97
98
98
98
98
97
R
R
R
R
R
R
R
R
R
100
100
100
100
100
100
100
100
15
17
20
20
20
3
20
[a]
Reactions were carried out at 408C using 1 mmol of 19, 5 equiv. of HCOONa, and an S/C ratio of 100 in 2 mL of water.
Determined by GC analysis.
Determined by HPLC with Chiralcel OD.
[b]
[c]
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Asymmetric Transfer Hydrogenation of Aromatic Ketones in Water
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m: cross-linking agent, n: sulfonated monomer) were water (entry 2). Instead of benzyltributylammonium
applied to the reduction of 19 (Table 2). The influence salt, a longer tetraalkyl quaternary ammonium salt
of the catalyst loading (1%, 10%, 30% and 50%) was (R,R)-21 was also effective for the reaction (entry 3).
first investigated. In all cases, 97–98% enantioselectiv- The high enantioselectivity with quantitative conver-
ities were constantly observed (entries 1–4). However, sion was achieved even when the quaternary phos-
the composition (l, m, n) in the polymer influenced phonium salt of the sulfonate pendant group was em-
the reactivity of the polymeric catalyst. The balance ployed (entries 4 and 5). It should be noted that, re-
between hydrophilicity and hydrophobicity of the po- gardless of the kind of X, a quaternarized structure
lymer-support would be the most important factor to obviously plays a very important role in the polymer
control the reactivity. The best composition was found support providing excellent performance in water.
to be l=0.10, m=0.10, n=0.80 (entry 8). The degree
Next, we have examined the effect of transition
of cross-linking sometimes severely affects on the re- metal precursors other than Ru(II) in the same reac-
activity of the polymeric catalyst. We have used poly- tion using the polymeric chiral catalyst derived from
meric catalysts having different cross-linking degrees (R,R)-9b (Table 4). Almost the same activity was ob-
(entries 5–9). Interestingly, the reaction still smoothly served with the catalyst prepared from [RhCl2Cp*]2
occurred on using highly cross-linked polymer 9i.
while the catalyst prepared from [IrCl2Cp*]2 de-
Since the significant performance in the asymmetric creased both reactivity and enantioselectivity.
catalysis was achieved when polymer (R,R)-9 having
quaternary ammonium sulfonate pendant groups was
Table 4. Effect of other transition metal precursors on the enan-
used, we next investigated the effect of the counter
cation X in the achiral sulfonate pendant group on
the same reaction (Table 3). A series of polymer-sup-
ported chiral ligands (R,R)-8b, 9b, 21–23 containing
various kinds of cations were synthesized through co-
polymerization of (R,R)-12 and the corresponding sul-
fonate monomers (Table 3). When sodium sulfonated
polymer (R,R)-8b was used, the reaction stopped
before reaching completion (Table 3, entry 1). Since
the polymer was unusually swollen in water, this
would cause the insufficient stirring. The catalyst de-
rived from (R,R)-9b [X=NBn(Bu)3], as well as the
cross-linked one, gave the corresponding chiral alco-
hol 20 in 98% ee with quantitative conversion in
tioselective transfer hydrogenation of acetophenone 19 using
polymeric catalyst derived from (R,R)-9b in water.[a]
Entry Metal pre-
cursor
Time Conversion[b] ee[c] Configuration
[h]
[%]
[%]
1
A
(p-
3
100
98
R
2
3
C
99
77
98
89
R
R
4
[a]
Reactions were carried out at 408C using 1 mmol of 19,
5 equiv. of HCOONa, and an S/C ratio of 100 in 2 mL of
water.
Determined by GC analysis.
Determined by HPLC with Chiralcel OD.
[b]
[c]
Table 3. Effect of sulfonate structure on the enantioselective transfer hydrogenation of acetophenone 19 in water.[a]
Entry
Ligand
Time [h]
Conversion[b] [%]
ee[c] [%]
Configuration
1
2
3
4
5
U
15
3
10
11
10
97
92
98
98
98
97
R
R
R
R
R
100
100
100
100
[a]
Reactions were carried out at 408C using 1 mmol of 19, 5 equiv. of HCOONa, and an S/C ratio of 100 in 2 mL of water.
Determined by GC analysis.
Determined by HPLC with Chiracel OD.
[b]
[c]
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Yukihiro Arakawa et al.
FULL PAPERS
Asymmetric Transfer Hydrogenation of Various
Aromatic Ketones in Water
content of quaternary ammonium salt and its struc-
ture. In this paper, we exemplified the asymmetric
transfer hydrogenation of various aromatic ketones in
Encouraged by the results mentioned above, the order to emphasize the effectiveness of the amphi-
asymmetric transfer hydrogenations of various kinds philic polymers containing the quaternary ammonium
of aromatic ketones by using the sulfonated polystyr- salt structure as pendant group of the support poly-
ene-supported chiral catalyst (R,R)-9 containing the mers. By using the polymeric catalyst prepared from
quaternary ammonium salt pendant group were inves- polymer 9, the enantioselective reduction of aromatic
tigated (Table 5). Since the polymeric catalysts pre- ketones was achieved in water to give optically active
pared from (R,R)-9b and (R,R)-9h showed the same secondary alcohols with up to 99% ee. Moreover, the
catalytic activity in the case of acetophenone reduc- catalyst was recycled several times without loss of the
tion (entries 1 and 2), we can evaluate the aromatic catalytic activity. We are currently investigating the
ketone reduction by using these polymers. Most of usefulness of the novel amphiphilic polymer support
the aromatic ketones tested were smoothly converted in other asymmetric reactions in water.
into the corresponding optically active secondary al-
cohols with excellent enantioselectivities of up to
99% ee using the polymeric catalysts in water. Inter-
estingly, in all cases the enantioselectivities obtained
Experimental Section
with the polymeric catalysts were superior to those in
the model reaction[18o] using the catalyst derived from
TsDPEN as shown in Table 5. To the best of our
knowledge, there have been only a few reports of
polymeric chiral catalysts that provided a higher
enantioselectivity than those obtained from their low
molecular weight counterparts.
Preparation of Aromatic Sulfonated Polymer-Sup-
ported Chiral 1,2-Diamine Monosulfonamides
(R,R)-9
A glass ampoule equipped with a magnetic stirring bar was
charged with DMF (0.78 g), (R,R)-12 (71.9 mg, 0.19 mmol),
18 (0.70 g, 1.52 mmol), divinylbenzene (25.0 mg, 0.19 mmol),
and AIBN (6.5 mg, 40.0 mmol). The ampoule was sealed
after three freeze-thaw cycles under liquid nitrogen. Copoly-
merization was carried out at 608C for 60 h. The ampoule
was opened and the resulting mixture was poured into
ether. The obtained polymer was collected on a glass filter
and washed with THF and methanol and dried under
Conclusions
In conclusion, we have successfully synthesized novel
polymer-supported chiral 1,2-diamine monosulfon-
ACHTREUNGamides containing a hydrophilic functional group such
as carboxylate and sulfonate. We have found that the
chiral polymeric ligand having a pendant group of
quaternary ammonium salt structure was highly suita-
ble for the use in water. The amphiphilic property of
the support polymers can be easily controlled by the
1
vacuum; yield: 94%. H NMR (400 MHz, DMSO-d6, T MS):
d=0.6–1.8 (br; CH2, CH), 2.8–3.3 (br; CH2), 4.3–4.8 (br;
CH2 of benzyl), 6.8–7.2 (br; Ar-H of sulfonamide), 6.0–7.9
(br; Ar-H); 13C NMR (100 MHz, DMSO-d6, T MS):d=13.4,
18–20, 22–24, 56–62, 125–134; IR (KBr): n=1333 cmÀ1 (SO2
of sulfonamide); anal. calcd. for C24.8H36NO2.6S0.9: C 71.15%,
H 8.67%, N 3.35%, S 6.89%; found: C 71.08%, H 8.61%, N
3.29%, S 6.86%.
Table 5. Enantioselective transfer hydrogenation of various aromatic ketones using polymeric catalyst derived from (R,R)-9
in water.[a]
Entry Ketone
Polymeric ligand Time [h] Conversion[b] [%]
ee [%][c]
Configuration
polymer TsDPEN[d]
1
2
3
4
5
6
7
8
9
Acetophenone
Acetophenone
Propiophenone
1-Acetonaphthone
1-Indanone
4-Chloroacetophenone
2-Chloroacetophenone
2-Methoxyacetophenone
2-Trifluoromethylacetophenone
U
3
3
2
13
22
2
22
3
100
100
91
98
98
96
97
(94)
(94)
(86)
(87)
(95)
(91)
(89)
(72)
(20)
R
R
R
R
R
R
R
R
R
97
100[e]
90
98
99
100
79
46
99[f]
91[f]
60[f]
45
[a]
[b]
[c]
[d]
[e]
[f]
Reactions were carried out using 1 mmol of ketone, 5 equiv. of HCOONa, and an S/C of 100 in 2 mL of water.
Determined by GC analysis, unless otherwise noted.
Determined by HPLC with Chiralcel OD, unless otherwise noted.
Data obtained from the literature (ref.[18o]) by using TsDPEN-derived catalyst.
1
Determined by H NMR.
Determined by GC with b-DEX 120.
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Asymmetric Transfer Hydrogenation of Aromatic Ketones in Water
FULL PAPERS
(Ed.: J. C. Salamone), CRC Press, Boca Raton, 1996,
Vol. 10, pp 8078–8087; c) T. J. Dickerson, N. N. Read,
K. D. Janda, Chem. Rev. 2002, 102, 3325–3344; d) A. S.
Chan, Q. H. Fan, Y. M. Li, Chem. Rev. 2002, 102,
3385–3466; e) N. E. Leadbeater, M. Marco, Chem. Rev.
2002, 102, 3217–3274.
General Procedure for Asymmetric Transfer
Hydrogenation
ACHTREUNG[RuCl2ACHTREUNG(p-cymene)]2 (3.0 mg, 0.005 mmol) and the polymer-
supported chiral 1,2-diamine sulfonamide (0.012 mmol)
were added in water (2 mL). After the mixture had been de-
gassed and stirred at 408C for 1 h under an argon atmos-
phere, sodium formate (340 mg, 5 mmol) was introduced.
Ketone (1 mmol) was then added and the mixture was
stirred at 408C for a certain period of time. After cooling to
room temperature, the organic compounds were extracted
twice with ether. The conversion and enantioselectivity were
determined by GC and HPLC analysis, respectively. The
aqueous phase was extracted from the reaction vessel, and a
0.3M aqueous solution of benzyltributylammonium chloride
(2 mL) was added to the remaining polymeric Ru catalyst
and stirred for 3 min. The polymeric Ru catalyst was then
reused by adding the same amount of sodium formate and
ketone again.
[4] a) T. Malmstrçm, C. Andersson, Chem. Commun. 1996,
1135–1136; b) T. Malmstrçm, C. Andersson, J. Mol.
Catal. 1999, 139, 259–270.
[5] a) X. G. Li, X. F. Wu, W. P. Chen, F. E. Hancock, F.
King, J. Xiao, Org. Lett. 2004, 6, 3321–3324; b) M. Be-
naglia, M. Cinquini, F. Cozzi, G. Celentano, Org.
Biomol. Chem. 2004, 2, 3401–3407; c) X. Wang, L. Yin,
T. Yang, Y. Wang, Tetrahedron: Asymmetry 2007, 18,
108–114.
[6] a) Y. Uozumi, H. Danjo, T. Hayashi, Tetrahedron Lett.
1998, 39, 8303–8306; b) Y. Uozumi, K. Shibatomi, J.
Am. Chem. Soc. 2001, 123, 2919–2920; c) Y. Uozumi,
H. Tanaka, K. Shibatomi, Org. Lett. 2004, 6, 281–283;
d) Y. Kobayashi, D. Tanaka, H. Danjo, Y. Uozumi,
Adv. Synth. Catal. 2006, 348, 1561–1566; e) Y. Uozumi,
M. Kimura, Tetrahedron: Asymmetry 2006, 17, 161–
166; f) Y. Uozumi, T. Suzuka, J. Org. Chem. 2006, 71,
8644–8646.
Supporting Information
Experimental procedures, characterization, and spectra for
compounds 1–9, 12, 14, 16, 18, 21–23 are available as Sup-
porting Information.
[7] Y. Otomaru, T. Senda, T. Hayashi, Org. Lett. 2004, 6,
3357–3359.
[8] T. Saegusa, Makromol. Chem. Macromol. Symp., 1988,
13/14, 111; T. Saegusa, Y. Chujo, Makromol. Chem.
Macromol. Symp., 1990, 33, 31; S. Kobayashi, Prog.
Polym. Sci. 1990, 15, 751–823.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Sci-
entific Research from the Ministry of Education, Science,
Sports and Culture of Japan.
[9] M. T. Zarka, O. Nuyken, R. Weberskirch, Chem. Eur. J.
2003, 9, 3228–3234.
[10] B. M. Rossbach, K. Leopold, R. Weberskirch, Angew.
Chem. Int. Ed. 2006, 45, 1309–1312.
[11] a) D. Font, C. Jimeno, M. A. Pericꢃs, Org. Lett. 2006, 8,
4653–4655; b) F. Giacalone, M. Gruttadauria, A. M.
Marculescu, R. Noto, Tetrahedron Lett. 2007, 48, 255–
259.
[12] T. Ishida, R. Akiyama, S. Kobayashi, Adv. Synth. Catal.
2005, 347, 1189–1192.
References
[1] Aqueous Phase OrganometallicCatalysis , 2nd edn.,
(Eds.: B. Cornils, W. A. Herrmann), Wiley-VCH, Wein-
heim, 2004.
[13] Y. Arakawa, N. Haraguchi, S. Itsuno, Tetrahedron Lett.
[2] a) S. Itsuno, Y. Arakawa, N. Haraguchi, J. Soc. Rubber
Industry 2006, 79, 448–454; b) K. Manabe, S. Kobaya-
shi, Chem. Eur. J. 2002, 8, 4095–4101; c) D. Sinou, Adv.
Synth. Catal. 2002, 344, 221–237; d) U. M. Lindstrçm,
Chem. Rev. 2002, 102, 2751–2772; e) C-J. Li, Chem.
Rev. 2005, 105, 3095–3166; f) T. Hamada, K. Manabe,
S. Kobayashi, J. Am. Chem. Soc. 2004, 126, 7768–7769;
g) F. Wang, H. Liu, L. Cun, J. Zhu, J. Deng, Y. Jiang, J.
Org. Chem. 2005, 70, 9424–9429; h) A. Scarso, G. Stru-
kul, Adv. Synth. Catal. 2005, 347, 1227–1234; i) R. S.
Dickins, S. Gaillard, S. P. Hughes, A. Badari, Chirality
2005, 17, 357–363; j) M. Boudou, C. Ogawa, S. Ko-
bayashi, Adv. Synth. Catal. 2006, 348, 2585–2589; k) Y.
Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushi-
ma, M. Shoji, Angew. Chem. Int. Ed. 2006, 45, 958–
961; l) J. Liu, B. Liu, X. Jia, X. Li, A. S. C. Chan, Tetra-
hedron: Asymmetry 2007, 18, 396–399; m) H. Egami,
T. Katsuki, J. Am. Chem. Soc. 2007, 129, 8940–8941.
[3] Reviews on asymmetric reaction using polymer-sup-
ported catalyst, see: a) S. Itsuno, N. Haraguchi, Y. Ara-
kawa, Recent Res. Dev. Org. Chem. 2005, 9, 27–47;
b) S. Itsuno, in: Polymeric Materials Encyclopedia,
2006, 47, 3239–3243.
[14] S. Gladiali, E. Alberico, Chem. Soc. Rev. 2006, 35, 237–
248.
[15] S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R.
Noyori, J. Am. Chem. Soc. 1995, 117, 7562–7563.
[16] Asymmetric transfer hydrogenation of ketones in or-
ganic solvent by using polymer-supported chiral cata-
lyst, see: a) R. terHalle, E. Schulz, M. Lemaire, Synlett
1997, 1257–1258; b) D. J. Bayston, C. B. Travers,
M. E. C. Polywka, Tetrahedron: Asymmetry 1998, 9,
2015–2018; c) X. Li, W. Chen, W. Hems, F. King, J.
Xiao, Tetrahedron Lett. 2004, 45, 951–953; d) P. N. Liu,
P. M. Gu, F. Wang, Y. Q. Tu, Org. Lett. 2004, 6, 169–
172.
[17] Reviews on asymmetric transfer hydrogenation in
water, see: a) X. Wu, X. Li, A. Zanotti-Gerosa, A.
Pettman, J. Liu, A. J. Mills, J. Xiao, Chem. Eur. J. 2008,
14, 2209–2222; b) X. Wu, J. Xiao, Chem. Commun.
2007, 2449–2466.
[18] Asymmetric transfer hydrogenation of ketones in
water, see: a) X. Wu, J. Liu, D. Di Tommaso, J. A. Iggo,
Adv. Synth. Catal. 2008, 350, 2295 – 2304
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2303

Yukihiro Arakawa et al.
FULL PAPERS
C. R. A. Catlow, J. Bacsa, J. Xiao, Chem. Eur. J. 2008,
article online in advance of print; b) J. Liu, Y. Zhou, Y.
Wu, X. Li, A. S. C. Chan, Tetrahedron: Asymmetry
2008, 19, 832–837; c) E. Alza, A. Bastero, S. Jansat,
M. A. Pericas, Tetrahedron: Asymmetry 2008, 19, 374–
378; d) N. A. Cortez, G. Aguirre, M. Parra-Hake, R.
Somanathan, Tetrahedron: Asymmetry 2008, 19, 1304–
1309; e) N. A. Cortez, G. Aguirre, M. Parra-Hake, R.
Somanathan, Tetrahedron Lett. 2007, 48, 4335–4338;
f) J. Canivet, G. Suss-Fink, Green Chem. 2007, 9, 391–
397; g) L. Li, J. S. Wu, F. Fang, J. Liao, H. Zhang, C. X.
Lian, J. Zhu, J. G. Deng, Green Chem. 2007, 9, 23–25;
h) H. Q. Yang, J. Li, J. Yang, Z. M. Liu, Q. H. Yang, C.
Li, Chem. Commun. 2007, 1086–1088; i) J. S. Wu, F.
Wang, Y. P. Ma, X. C. Cui, L. F. Cun, J. Zhu, J. G.
Deng, B. L. Yu, Chem. Commun. 2006, 1766–1768;
j) Y. Xing, J. S. Chen, Z. R. Dong, Y. Y. Li, J. X. Gao,
Tetrahedron Lett. 2006, 47, 4501–4503; k) D. S. Ma-
tharu, D. J. Morris, G. J. Klarkson, M. Wills, Chem.
Commun. 2006, 3232–3234; l) B. Z. Li, J. S. Chen,
Z. R. Dong, Y. Y. Li, Q. B. Li, J. X. Gao, J. Mol. Catal.
2006, 258, 113–117; m) L. Jiang, T. F. Wu, Y. C. Chen,
J. Zhu, J. G. Deng, Org. Biomol. Chem. 2006, 4, 3319–
3324; n) J. C. Mao, B. S. Wan, S. Wu, S. W. Lu, Tetrahe-
dron Lett. 2006, 43, 7341–7344; o) X. Wu, X. Li, W.
Hems, F. King, J. Xiao, Org. Biomol. Chem. 2004, 2,
1818–1821; p) Y. Ma, H. Liu, L. Chen, X. Cui, J. Zhu,
J. Deng, Org. Lett. 2003, 5, 2103–2106; q) H. Y. Rhyoo,
H. J. Park, W. H. Suh, Y. K. Chung, Tetrahedron Lett.
2002, 43, 269–272; r) H. Y. Rhyoo, H. J. Park, Y. K.
Chung, Chem. Commun. 2001, 2064–2065; s) C.
Bubert, J. Blacker, S. M. Brown, J. Crosby, S. Fitzjohn,
J. P. Muxworthy, T. Thorpe, J. M. J. Williams, Tetrahe-
dron Lett. 2001, 42, 4037–4039.
[19] a) P. N. Liu, J. G. Deng, Y. Q. Tu, S. H. Wang, Chem.
Commun. 2004, 2070–2071; b) P. N. Liu, P. M. Gu, J. G.
Deng, Y. Q. Tu, Y. P. Ma, Eur. J. Org. Chem. 2005,
3221–3227.
[20] B. Cornils, E. G. Kuntz, J. Organomet. Chem. 1995, 502,
177–186.
2304
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