Highly active, immobilized ruthenium catalysts for oxidation of alcohols to aldehydes and ketones. Preparation and use in both batch and flow systems

Article abstract of DOI:10.1021/ja051246c

A novel, highly active immobilized ruthenium catalyst, which can be successfully used in oxidation of alcohols to aldehydes and ketones, has been developed. In contrast to most immobilized catalysts, the Ru catalyst has activity that is higher than that of the original nonimmobilized catalyst. In a batch system, the Ru catalyst was recovered and reused several times without loss of activity. The catalyst was also applied to a flow system, In which excellent conversions and yields were demonstrated. No leaching of Ru was observed in both cases.

Full text of DOI:10.1021/ja051246c

Published on Web 06/07/2005
Highly Active, Immobilized Ruthenium Catalysts for Oxidation
of Alcohols to Aldehydes and Ketones. Preparation and Use
in Both Batch and Flow Systems
Sh uj Kobayashi,* Hiroyuki Miyamura, Ryo Akiyama, and Tasuku Ishida
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
The HFRE DiVision, ERATO, Japan Science and Technology Agency (JST), Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
Received February 27, 2005; E-mail: skobayas@mol.f.u-tokyo.ac.jp
Abstract: A novel, highly active immobilized ruthenium catalyst, which can be successfully used in oxidation
of alcohols to aldehydes and ketones, has been developed. In contrast to most immobilized catalysts, the
Ru catalyst has activity that is higher than that of the original nonimmobilized catalyst. In a batch system,
the Ru catalyst was recovered and reused several times without loss of activity. The catalyst was also
applied to a flow system, in which excellent conversions and yields were demonstrated. No leaching of Ru
was observed in both cases.
Introduction
several metal-based oxidizing reagents have been developed,
in many cases, stoichiometric amounts of metal oxidants, and
Immobilized catalysts are of interest primarily for two reasons.
First, they are crucial for achieving environmentally benign
chemical synthesis, the catalysts are readily recovered and
reused, and total waste is decreased. Second, immobilized
catalysts play a key role for combinatorial library generation,
synthetic procedures are simplified using immobilized catalysts,
and their application to automation is facile. However, many
immobilized catalysts have been developed, but many of them
thus large amounts of metal containing wastes, are needed. In
this aspect, oxidation of alcohols using a catalytic amount of a
1
5
metal reagent is very attractive. Although several successful
examples of catalytic oxidation of alcohols have been devel-
1
d,2
6
oped, highly active immobilized catalysts that can be used in
7
both batch and flow systems are limited.
1
are less active than the original nonimmobilized catalysts.
Moreover, few examples are known for immobilized catalysts
that have high activity and can be used in both batch and flow
3
systems. In this paper, we describe novel immobilized ruthe-
nium catalysts, which have high activity for the oxidation of
alcohols to aldehydes and ketones in both batch and flow
systems.
Recently, we have developed novel immobilization methods
for metal catalysts, microencapsulation and polymer incarcerated
methods, which are based on electronic interactions between
Results and Discussion
Oxidation of alcohols to aldehydes and ketones is one of the
4
most important transformations in organic synthesis. While
(
5) (a) Sheldon, R.; Kochi, J. K. Metal-Catalyzed Oxidations of Organic
Compounds; Academic Press: New York, 1981. (b) Madin, A. In
ComprehensiVe Organic Chemistry; Trost, B. M., Fleming, I., Ley, S. V.,
Eds.; Pergamon: Oxford, U.K., 1991; Vol. 7, p 251. (c) Parshall, G. W.;
Ittel, S. D. Homogeneous Catalysis, 2nd ed.; John Wiley & Sons: New
York, 1992.
(
1) (a) Gladysz, J. A. Chem. ReV. 2002, 102, 3215. (b) McNamara, C. A.;
Dixon, M. J.; Bradley, M. Chem. ReV. 2002, 102, 3275. (c) Polymeric
Materials in Organic Synthesis and Catalysis; Buchmeiser, M. R., Ed.;
Wiley-VCH: Weinheim, Germany, 2003. (d) Kobayashi, S.; Akiyama, R.
Chem. Commun. 2003, 449. (e) Anastas, P. T.; Warner, J. C. Green
Chemistry: Theory and Practice; Oxford University Press: New York,
(6) Review: Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach,
A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, I.; Taylor, S. J. J.
Chem. Soc., Perkin Trans. 1 2000, 3815.
1
998.
(2) (a) Lee, A.; Ley, S. V. Org. Biomol. Chem. 2003, 1, 3263. (b) Dolle, R. E.
J. Comb. Chem. 2004, 6, 623.
(7) Review: (a) Mallat, T.; Baiker, A. Chem. ReV. 2004, 104, 3037. See also:
(b) Yamaguchi, K.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J.
Am. Chem. Soc. 2000, 122, 7144. (c) Yamaguchi, K.; Mizuno, N. Chem.s
Eur. J. 2003, 9, 4353. (d) Langer, P. J. Prakt. Chem. 2000, 342, 728. (e)
Bleloch, A.; Johnson, F. G.; Ley, S. V.; Price, A. J.; Shephard, D. S.;
Thomas, A. W. Chem. Commun. 1999, 1907. (f) Mori, K.; Hara, T.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2003, 125, 11460.
(g) Motokura, K.; Nishimura, D.; Mori, K.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. J. Am. Chem. Soc. 2004, 126, 5662. (h) Zhang, Y.; Fei, J.; Yu,
Y.; Zheng, X. Catal. Commun. 2004, 5, 643 and references cited therein.
While molecular oxygen is regarded as an environmentally friendly oxidant,
applications are sometimes limited due to safety reasons. In addition, the
use of molecular oxygen in combinatorial flow systems is rare.
(
3) Reviews: (a) Jas, G.; Kirschning, A. Chem.sEur. J. 2003, 9, 5708. (b)
Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew. Chem., Int. Ed.
2
001, 40, 650. See also: (c) Kirschning, A.; Altwicker, C.; Dr a¨ ger, G.;
Harders, J.; Hoffmann, N.; Hoffmann, U.; Sch o¨ nfeld, H.; Solodenko, W.;
Kunz, U. Angew. Chem., Int. Ed. 2001, 40, 3995. (d) Solodenko, W.; Wen,
H.; Leue, S.; Stuhlmann, F.; Sourkouni-Argirusi, G.; Jas, G.; Sch o¨ nfeld,
H.; Kunz, I. U.; Kirschning, A. Eur. J. Org. Chem. 2004, 3601.
4) (a) Hill, C. L. In AdVances in Oxygenated Processes; Baumstark, A. L.,
Ed.; JAI Press: London, 1988; Vol. 1, p 1. (b) Hundlucky, M. Oxidations
in Organic Chemistry; ACS Monograph Series; American Chemical
Society: Washington, DC, 1990.
(
10.1021/ja051246c CCC: $30.25 © 2005 American Chemical Society
J. AM. CHEM. SOC. 2005, 127, 9251-9254
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9251

A R T I C L E S
Kobayashi et al.
Table 2. PI-Ru Catalyzed Oxidation of Various Substratesa
Table 1. Effect of Solvents and Additives
a
b
Yield /% [leaching (%)]
entry
PI−Ru (mol %)
solvent
first
second
third
1
2
3
4
5
6
7
15
15
15
15
15
15
5
toluene
THF
DMF
CH3CN
CH2Cl2
acetone
acetone
acetone
33 [nd]
31 [nd]
57 [6.8]
41 [nd]
48 [nd]
61 [nd]
64 [nd]
28 [nd]
27 [2.4]
50 [nd]
48 [nd]
45 [nd]
70 [nd]
72 [nd]
19 [nd]
31 [nd]
48 [nd]
42 [nd]
56 [nd]
73 [nd]
65 [nd]
92 [nd]
c
8
5
quant [nd]
96 [nd]
a
b
Yields were determined by GC analysis. Leachings were measured
c
by XRF analysis; nd ) not detected. 500 mg/mmol of MS 4A was used.
metals and benzene rings of polystyrene derivatives and are
8
successful in immobilizing highly active catalysts. We decided
to use these methods for immobilization and chose dichlorotris-
(
triphenylphosphine)ruthenium (RuCl2(PPh3)3) as a starting
9
catalyst because we thought that the three PPh3 groups of
8
a
RuCl2(PPh3)3 would be eliminated during immobilization to
create a more Lewis acidic, less hindered active catalyst.
Epoxide-containing copolymer (1) was dissolved in tetrahydro-
furan (THF) at room temperature, and RuCl2(PPh3)3 was added
to this solution. Hexane was then added to form microcap-
sules,1
d,10
which were filtered, washed, and dried. The micro-
capsules were next heated at 120 °C for 3.5 h to afford polymer
incarcerated Ru (PI-Ru (2)). PI-Ru (2) was preliminarily
oxidized using 5 equiv of N-methylmorpholine-N-oxide (NMO)
in acetone/2-propanol (1/9) at room temperature for 12 h before
being subjected to oxidation reactions.11
PI-Ru (3) thus prepared was initially examined in the
oxidation of dodecanol using NMO as a co-oxidant in a batch
system (Table 1). Several solvents were tested, and it was found
that the oxidation proceeded smoothly in acetone to afford
dodecanol in good yield using 15 mol % of PI-Ru at 30 °C
for 2 h (entry 6). The catalyst was recovered quantitatively by
simple filtration and reused three times without loss of activity.
In addition, no leaching of Ru was detected by fluorescence
X-ray (XRF) analysis. When the catalyst loading was reduced
to 5 mol %, similar results were obtained. Finally, the yield
was dramatically improved by adding molecular sieves (MS)
a
500 mg/mmol of MS 4A was used. The leaching of Ru to the reaction
mixture was measured by XRF and ICP analyses. No peaks for Ru were
b
detected in all entries (<0.5 ppm). Yields were determined by GC analysis.
c RuCl (PPh ) (5 mol %) was used instead of PI-Ru. d Isolated yield.e The
2
3 3
f
reaction was performed for 0.5 h. The product is shown in parentheses.
g
8
6% yield using PI-Ru (1 mol %) for 4 h; 89% yield using PI-Ru (0.5
mol %) for 15 h. TPAP (5 mol %) in acetonitrile was used instead of
PI-Ru. Enantiomeric excess of the product was determined by chiral
HPLC analysis.
h
i
alcohols also worked well (entries 9 and 10), and a 1,4-
dihydroxy compound gave the corresponding lactone directly
entry 8). For optically active aldehydes having a stereogenic
center at the 2-position, it is well-known that partial racemization
occurs during oxidation and that a racemic aldehyde is formed
in many cases. Indeed, when optically pure alcohol 4 (>99%
ee) was oxidized using RuCl2(PPh)3, the corresponding aldehyde
(
5
was obtained in 77% yield with 81% ee. While a somewhat
better result was obtained using tetra-n-propylammonium per-
4
A (entry 8). Molecular sieves would remove water that is
generated during the oxidation and would prevent deactivation
of the catalyst as well as further oxidation of the aldehyde to
the corresponding carboxylic acid.
Under the optimized conditions, several alcohols were
oxidized, and the results are summarized in Table 2. Primary
and secondary, aliphatic and aromatic, and even allylic alcohols
were oxidized smoothly in the presence of PI-Ru (3) to afford
the corresponding carbonyl compounds in high yields (entries
1
2
ruthenate (TPAP) (66% yield, 91% ee), PI-Ru (3) was
excellent so that the desired aldehyde was obtained in 84% yield
with almost no racemization (97% ee). We assume that the
polymer serves to reduce the basicity of the reaction mixture
to prevent the partial racemization of the aldehyde.
PI-Ru was then applied to a flow system. Flow systems are
now very important not only in industries but also in high-
throughput organic synthesis related to combinatorial library
1
-7). It should be noted that the yields were better than those
3
generation. Whereas many immobilized catalysts have been
developed, those that can be applied to flow systems are limited.
using the parent metal source, RuCl2(PPh)3. Heterocyclic
Our flow system was set up as shown in Scheme 1. PI-Ru and
MgSO4 were placed into a column, and an acetone solution
of an alcohol and NMO was passed through the column. Under
(
8) (a) Akiyama, R.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3412. (b)
Okamoto, K.; Akiyama, R.; Kobayashi, S. J. Org. Chem. 2004, 69, 2871.
9) (a) Sharpless, K. B.; Akashi, K.; Oshima, K. Tetrahedron Lett. 1976, 17,
1
3
(
2
503. See also: (b) Naota, T.; Takaya, H.; Murahashi, S.-I. Chem. ReV.
1
998, 98, 2599.
(
(
10) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1998, 120, 2985.
11) Details are shown in the Experimental Section (Supporting Information).
(12) Review: Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
9252 J. AM. CHEM. SOC.
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VOL. 127, NO. 25, 2005

Ru Catalysts for Oxidation of Alcohols
A R T I C L E S
Table 3. PI-Ru Catalyzed Oxidation Reaction Using Flow System
time (h)b
0−1.05
1.05−2.10
2.10
−3.15
3.15
−4.20
4.20
−5.25
5.25
−6.30
6.30
−7.35
7.35−8.40
c
conversion (%)
yield (%)
>99
94
>99
92
>99
87
>99
>99
99
95
98
88
96
89
94
92
c
a
1
.99 mg/mL of benzyl alcohol and 6.94 mg/mL of NMO acetone solution were passed through a column containing 40.3 mg of PI-Ru (loading level
c
is 0.312 mmol/g) with MgSO4. Flow rate was 0.08 mL/min. Conversion and yield was calculated based on the total starting material as an average of 1.05
h.
sulfone in 96% yield (eq 2).17 Diphenyl sulfide gave diphenyl
sulfone in 99% yield under the same reaction conditions (eq
Scheme 1
3
). The system was also used for the oxidation of diphenyl-
acetylene, and benzyl was obtained in good yield under mild
reaction conditions (eq 4). It is noted that, in all cases, the Ru
catalyst was recovered by simple filtration and reused without
loss of activity. Moreover, no leaching of Ru was observed in
all cases.
Table 4. Elemental Analysis of PI-Ru
Ru (mmol/g)a
Cl (mmol/g)
[equiv]
P (mmol/g)
[equiv]
[
equiv]
microcapsules before
cross-linking
PI-Ru (2)
0.29
[1.0]
0.31
0.64
[2.2]
0.66
[2.1]
0.66
[2.3]
0.31
[1.1]
0.14
[0.5]
0.08
[0.3]
[
1.0]
0.29
1.0]
PI-Ru (3)
[
a
Observed by XRF analysis.
the conditions shown in the scheme, the substrate mixture came
in contact with the catalyst in the column for approximately 20
min. After passing through the column, the alcohol was
1
4
converted to the aldehyde almost quantitatively (Table 3). It
is noted that high conversions and yields were kept even after
1
5
8
h continuous flow, and that no leaching of Ru was
1
1
observed. Applications to a large-scale synthesis as well as
combinatorial chemistry using this flow system are underway.
16
At this stage, we have information on the structure of PI-
Ru. In our initial plan, the three PPh3 groups of RuCl2(PPh3)3
would be eliminated during immobilization to create a more
active catalyst. For the activity of the newly created immobilized
catalyst (RI-Ru (3)), higher activity of PI-Ru (3) compared
with that of RuCl2(PPh3)3 was demonstrated in several cases.
Elemental analyses of PI-Ru (3) support our working hypoth-
esis (Table 4). We analyzed a Ru catalyst just after micro-
encapsulation (before cross-linking), PI-Ru before activation
For the use of PI-Ru in other oxidation reactions, we have
briefly examined the oxidation of sulfides and an acetylene
derivative (eqs 1-4). In the presence of PI-Ru (5 mol %) and
MS 4A, thioanisole was treated with NMO in acetonitrile at
room temperature for 15 h to afford methyl phenyl sulfoxide
in 76% yield (eq 1). On the other hand, methyl phenyl sulfone
was obtained in high yield using (diacetoxyiodo)benzene (PhI-
(OAc)2) as a co-oxidant. Thus, thioanisole was treated with PhI-
(OAc)2 in the presence of PI-Ru (5 mol %) in acetone/water
(10/1) at room temperature for 15 min to afford methyl phenyl
(PI-Ru (2)), and PI-Ru after activation (PI-Ru (3)). In all
cases, the same levels of Ru loadings were observed, and 2
equiv of chlorine to Ru was detected. More importantly, almost
all of the PPh3 was removed during the preparation of PI-Ru
(3). Analyses by EXAFS also support this structure, but more
experiments are needed to further clarify the precise structure
of PI-Ru.
(
13) We tested MS 4A and MgSO
4
in both batch and flow systems, and MS
was better for the flow
4
A was better for the batch system, while MgSO
4
system. Although the precise reason is not clear at this stage, the rate
difference of the absorption of water may explain the results.
(
14) After the column, the solution was passed through a short silica gel pad to
afford the almost pure aldehyde (>98%). See Experimental Section
(Supporting Information).
(
15) We did not continue the flow system experiment after 8.40 h due to an
experimental reason.
Conclusion
(
16) While polymer-supported perruthenate was used for oxidation of alcohols
in a batch system, its catalytic activity was lower than that of PI-Ru. See:
We have developed a novel, highly active immobilized
ruthenium catalyst, which can be successfully used in oxidation
(a) Hinzen, B.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1997, 1907. On
the other hand, stoichiometric use of an immobilized co-oxidant for
oxidation of alcohols in both batch and flow systems was reported. (b)
Br u¨ njes, M.; Sourkouni-Argirusi, G.; Kirschning, A. AdV. Synth. Catal.
(17) Greater than 99% yield using PI-Ru (1 mol %) for 2 h; 95% yield using
PI-Ru (0.5 mol %) for 15 h.
2
003, 345, 635. See also ref 3.
J. AM. CHEM. SOC.
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VOL. 127, NO. 25, 2005 9253

A R T I C L E S
Kobayashi et al.
of alcohols to aldehydes and ketones. In contrast to most
immobilized catalysts, the Ru catalyst has activity that is higher
than that of the original nonimmobilized catalyst. In a batch
system, the Ru catalyst was recovered and reused several times
without loss of activity. The catalyst was also applied to a flow
system, in which excellent conversions and yields were dem-
onstrated. No leaching of Ru was observed in both cases. Further
investigations to develop other reactions using PI-Ru as well
as to clarify the precise structure of the PI-Ru catalyst are now
in progress.
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Japan Society of
the Promotion of Science (JSPS).
Supporting Information Available: Experimental Section.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA051246C
9254 J. AM. CHEM. SOC.
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VOL. 127, NO. 25, 2005