An improved protocol for the ruthenium(pybox)-catalyzed asymmetric alkene epoxidation

Article abstract of DOI:10.1016/j.tetlet.2003.08.016

A considerable rate enhancement in the ruthenium-catalyzed asymmetric epoxidation of olefins in the presence of PhI(OAc)₂ is reported. By the addition of H₂O, the rate of the reaction was increased by two orders of magnitude. Reactions of both aliphatic and aromatic olefins were realized for the first time and enantioselectivities up to 71% ee were obtained. In addition an in situ generation of ruthenium pybox catalysts for faster screening of oxidation catalysts was also developed.

Full text of DOI:10.1016/j.tetlet.2003.08.016

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7479–7483
An improved protocol for the ruthenium(pybox)-catalyzed
asymmetric alkene epoxidation
Man Kin Tse, Santosh Bhor, Markus Klawonn, Christian Do¨bler and Matthias Beller*
Leibniz-Institut fu¨r Organische Katalyse an der Universita¨t Rostock e.V. (IfOK), Buchbinderstraße 5-6, D-18055 Rostock,
Germany
Received 29 July 2003; revised 7 August 2003; accepted 7 August 2003
Abstract—A considerable rate enhancement in the ruthenium-catalyzed asymmetric epoxidation of olefins in the presence of
PhI(OAc)2 is reported. By the addition of H2O, the rate of the reaction was increased by two orders of magnitude. Reactions of
both aliphatic and aromatic olefins were realized for the first time and enantioselectivities up to 71% ee were obtained. In addition
an in situ generation of ruthenium pybox catalysts for faster screening of oxidation catalysts was also developed.
© 2003 Published by Elsevier Ltd.
Chiral non-racemic epoxides are interesting building
blocks for fine chemical production and the pharma-
ceutical industry.1 Clearly, asymmetric epoxidation of
olefins is a powerful way to obtain these compounds.
The most important developments of enantioselective
oxidation reactions include the titanium-catalyzed
epoxidation (Sharpless AE) of allylic alcohols and the
manganese–salen-catalyzed epoxidation of unfunction-
alized olefins (Jacobsen–Katsuki AE).1,2 Based on our
previous work in asymmetric dihydroxylation reac-
tions,3 we have been interested recently in developing
improved asymmetric epoxidation catalysts. We
focused our attention primarily on Ru catalysts because
optically active Ru complexes are less well studied
compared with Mn–salen type compounds and they
tolerate a broader variety of ligand types.4,5
Our first attempts to increase the reaction rate by
doubling the concentration of the oxidizing agent,
PhI(OAc)2, resulted in comparable yields but lower
enantioselectivity (Table 1, entry 1 and 2). We assumed
that the water content present in the reaction mixture
reduced the enantioselectivity. However, when carefully
dried anhydrous toluene was used as the solvent, the
conversion was only 12% after 67 h (Table 1, entry 3)!
Surprisingly, when 1 equiv. of H2O was added to the
reaction mixture, the reaction time is reduced to 3.5 h
with 70–80% yield and 46% ee (Table 1, entry 4). This
suggests that water plays a crucial role in this reaction,
possibly due to the enabling of the oxidation of the
Initially we were attracted by Nishiyama’s Ru-
(pyridinebisoxazoline)(pyridinedicarboxylic acid)-cata-
lyzed asymmetric epoxidation of trans-stilbene (Fig. 1,
Scheme 1) because of the easy accessibility of
pyridinebisoxazoline (pybox) ligands from natural
occurring amino acids.5b
Unfortunately, the previously reported work revealed
that this system had several drawbacks such as low
reactivity (96 h were needed for full conversion) and the
limited scope of the catalyst. So far successful epoxida-
tions have only been achieved using trans-stilbene as
the substrate.
Figure 1. Structure of Ru(pybox)(pyridinedicarboxylic acid).
Scheme 1. Nishiyama’s epoxidation of trans-stilbene.5b
* Corresponding author. Tel.: +49-(0)381-4669313; fax: +49-(0)381-
4669324; e-mail: matthias.beller@ifok.uni-rostock.de
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.08.016

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M. K. Tse et al. / Tetrahedron Letters 44 (2003) 7479–7483
Table 1. Effect of solvent and water on the Ru-catalyzed asymmetric epoxidation of trans-stilbene using PhI(OAc)2 as the
oxidanta
Entry
Ratiob
Solvent
Time (h)
Conv.c (%)
GC Yield (%)
eed (%)
1
2
3
4
5
6
7
8
1:3:0
1:6:0
1:6:0
1:6:6
1:6:3
1:3:3
1:3:6
1:1:1
1:6:6
1:6:6
1:6:6
Toluene
Toluene
Anhyd. toluene
Anhyd. toluene
Anhyd. toluene
Anhyd. toluene
Anhyd. toluene
Anhyd. toluene
96
<63
67
3.5
3
26
5.5
25
25
2
97
100
12
100
100
100
82
55
99
100
100
80
80
11
70–80
80
83
63
53
25
63e
53
n.d.f
46
43–59
49
29
71
9
10
11
THF/anhyd. toluene 4:6
1,4-Dioxane/anhyd. toluene 4:6
tBuOH/anhyd. toluene 4:6
n.d.f
59
60
84
1
57
a To a solution of Ru(S,S-iPr2-pybox)(pydic) (14.2 mg, 0.025 mmol), trans-stilbene (90 mg, 0.5 mmol) and (nBuOCH2CH2O)2 or dodecane (100
mL, internal standard) in the appropriate solvent (10 mL) at room temperature, PhI(OAc)2 was added. After stirring for 10 min., H2O was added.
The reaction was then monitored by GC-FID.
b Ratio of trans-stilbene:PhI(OAc)2:H2O.
c Conversion of trans-stilbene.
d Determined by HPLC, the major enantiomer of trans-stilbene oxide had (1S,2S) configuration.5b
e Ref. 5b.
f Not determined.
18-electron Ru(S,S-iPr2-pybox)(pydic) by ligand disso-
ciation.6 As shown in Table 1, decreasing the amount of
water had an insignificant effect to the reaction when
excess oxidizing agent was used (Table 1, entry 5).
Moreover, in the presence of an excess amount of
water, the reaction ceased and the ee is reduced (Table
1, entries 6 and 7). Hence, a stoichiometric amount of
water with respect to oxidant was used. To our delight,
the ee of the reaction increased up to 71% at low
concentration of PhI(OAc)2 (Table 1, entry 8).
position of the carboxylic acid groups resulted in the
total loss of reactivity and ee (Table 2, entries 2 and 6).
The internal nitrogen atom of the co-ligand is also
important. Both weakly coordinating thiophene and
non-coordinating CꢀH derivatives manifested to be
inferior (Table 2, entries 9 and 10). 2,6-Di(hydroxy-
methyl)pyridine revealed to be a viable co-ligand candi-
date, possibly due to the formation of 2,6-pyridinedi-
carboxylic acid by oxidation (Table 2, entry 4).7 On the
other hand, commercially available 2,6-pyridinebisoxa-
zolines showed very good reactivities (Table 2, entries
i
Due to the strong influence of water on the reaction
rate and selectivity, the effects of polar co-solvent have
been further investigated. We found that a solvent
1, 11 and 12). Here, the Pr-substituted pybox gave the
best enantioselectivity, while the phenyl-substituted
derivative showed the best reactivity. The trans-phenyl
group a to the oxygen of the oxazoline ring of S,S-
Me2-S,S-Ph2-pybox induced a minor but reversed enan-
tioselectivity (Table 2, entry 11). Further investigation
of chiral ligands was then directed to pybox derivatives
containing more bulky aryl groups and also to ligands
which contain cis-substituents on both 4- and 5-posi-
tions of the oxazoline group.
t
mixture of BuOH and toluene gave superior results
(Table 1, entry 11) compared to toluene. The reaction
finished in 1 h with 84% yield and 57% ee, which is
approximately 100 times faster than the original system.
By using this mixed solvent system, an in situ genera-
tion method for the active catalyst was also developed.
This procedure is especially important in order to test
new chiral pybox ligands and different pyridinedicar-
boxylate (pydic)-type co-ligands. In general, the Ru
catalyst can easily be generated by heating [Ru(p-
cymene)Cl2]2 with S,S-iPr2-pybox, 2,6-pyridinedicar-
Next, we demonstrated that the Ru(S,S-iPr2-
pybox)(pydic) catalyst could be also applied to other
olefinic substrates (Table 3).8 These reactions consti-
tuted the first examples of ruthenium(pybox)-catalyzed
epoxidations other than that of trans-stilbene. The
highest activity was observed towards 1,2-disubstituted
and tri-substituted aromatic alkenes (Table 3, entries 1,
2, 5). For terminal and 1,1-disubstituted aromatic
olefins, unspecific decomposition of the catalyst
occurred at room temperature and gave low yields of
epoxides. However, the reactions of these substrates in
tamyl alcohol as the solvent at 0°C gave good yields of
the corresponding epoxides (Table 3, entries 3 and 4).
Aliphatic olefins also yielded the corresponding epoxide
t
t
boxylic acid (H2pydic) and Et3N in BuOH or amyl
alcohol at 65°C under Ar for 1 h (Table 2). The model
reaction of trans-stilbene to trans-stilbene oxide went
well giving 67% yield with 60% ee in 2–3 h (Table 2,
entry 1). Next, 3 different commercially available pybox
ligands, 6 tri- or tetradentate N- or O-donating ligands
and 27 acid co-ligands have been screened efficiently by
this method. Selected results are shown in Table 2. On
one hand, successful variations of the structure of the
acid co-ligand were relatively limited. Changing the
dicarboxylic acid to a mono-acid or scrambling the

M. K. Tse et al. / Tetrahedron Letters 44 (2003) 7479–7483
7481
Table 2. Influence of ligands on the Ru-catalyzed asymmetric epoxidation of trans-stilbenea)

7482
M. K. Tse et al. / Tetrahedron Letters 44 (2003) 7479–7483
Table 3. Scope and limitations of the Ru-catalyzed asymmetric epoxidation of olefinsa)
t
products in notable amounts in amyl alcohol at room
temperature (Table 3, entries 7 and 8). While the reac-
tions gave significant enantioselectivity for trans-stil-
bene (Table 3, entry 1), only poor ee’s were found with
other olefins.
2. For reviews, see: (a) Johnson, R. A.; Sharpless, K. B. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New
York, 1993; pp. 153–158; (b) Jacobsen; E. N.; Wu, M. H.
In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, 1999;
pp. 649–693; (c) Katsuki, T. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York,
2000; pp. 287–325; (d) Katsuki, T. Adv. Synth. Catal. 2002,
344, 131–147.
In summary, a large rate enhancement of the rutheni-
um(pybox)-catalyzed asymmetric epoxidation of olefins
has been demonstrated by adding water. The scope of
this epoxidation catalyst was enlarged to terminal, 1,1-
disubstituted, trisubstituted and aliphatic olefins.
3. (a) Do¨bler, C.; Mehltretter, G. M.; Beller, M. Angew.
Chem., Int. Ed. 1999, 38, 3026–3028; (b) Do¨bler, C.;
Mehltretter, G. M.; Sundermeier, U.; Beller, M. J. Am.
Chem. Soc. 2000, 122, 10289–10297; (c) Do¨bler, C.;
Mehltretter, G. M.; Sundermeier, U.; Beller, M. J.
Organomet. Chem. 2001, 621, 70–76; (d) Do¨bler, C.;
Mehltretter, G. M.; Sundermeier, U.; Beller, M.; Eckert,
M.; Militzer, H.-C. Tetrahedron Lett. 2001, 42, 8447–8449;
(e) Sundermeier, U.; Do¨bler, C.; Mehltretter, G. M.; Bau-
mann, W.; Beller, M. Chirality 2003, 15, 127–134; (f)
Mehltretter, G. M.; Eckert, M.; Bhor, S.; Klawonn, M.;
Do¨bler, C.; Militzer, H.-C.; Beller, M. Synthesis 2003,
295–301.
Further studies towards the mechanism of this reaction
and ligand modifications to obtain higher ee’s are cur-
rently under investigation.
Acknowledgements
M.K.T. thanks the Alexander-von-Humboldt-Stiftung
for granting him a AvH-fellowship. This work has been
financed by the State of Mecklenburg-Western Pom-
merania and the Bundesministerium fu¨r Bildung und
Forschung (BMBF) and Bayer AG. We thank Dr. W.
Ma¨gerlein and Dr. H.-C. Millitzer (Bayer AG) for
general discussions.
4. For an excellent review, see: Barf, G. A.; Sheldon, R. A. J.
Mol. Catal. 1995, 102, 23–39.
5. For recent achievements in Ru-based asymmetric epoxida-
tion, see: (a) Kureshy, R. I.; Kahn, N. H.; Abdi, S. H. R.;
Bhatt, K. N. Tetrahedron: Asymmetry 1993, 4, 1693–1701;
(b) Nishiyama, H.; Shimada, T.; Itoh, H.; Sugiyama, H.;
Motoyama, Y. Chem. Commun. 1997, 1863–1864; (c) End,
N.; Pfaltz, A. Chem. Commun. 1999, 589–590; (d) Gross,
Z.; Ini, S. Org. Lett. 1999, 1, 2077–2080 and references
therein; (f) Stoop, R. M.; Bachmann, S.; Valentini, M.;
Mezzetti, A. Organometallics 2000, 19, 4117–4126; (e)
Pezet, F.; A¨ıt-Haddou, H.; Daran, J.-C.; Sadaki, I.; Bal-
avoine, G. G. A. Chem. Commun. 2002, 510–511.
6. Ribe, S.; Wipf, P. Chem. Commun. 2001, 299–307.
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Nishiyama, H. Chem. Lett. 2002, 284–285.
References
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M. K. Tse et al. / Tetrahedron Letters 44 (2003) 7479–7483
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8. General procedure: In a typical experiment (Table 3, entry
2), trans-b-methylstyrene (0.5 mmol), dodecane (100 mL),
PhI(OAc)2 (1.5 mmol) and Ru(S,S-iPr2-pybox)(pydic)5b (5
mol%) were dissolved in anhydrous toluene (6 mL) and
tBuOH (4 mL) at room temperature. After 10 min., H2O
(1.5 mmol) was added. The reaction was monitored by
GC-FID. trans-b-Methylstyrene oxide was identified by
comparison with the authentic sample by GC-FID
(HP5890 series; column: HP5 (crosslinked 5% PH ME
Siloxane, 30 m, 0.25 mm, 0.25 mm). All products were also
confirmed by GC–MS and NMR data. After the reaction,
the reaction mixture was quenched by saturated Na2SO3
solution (10 mL) and extracted with CH2Cl2 (2×10 mL).
After removal of solvent under reduced pressure, the prod-
ucts were dissolved in n-hexane, filtered and analyzed by
HPLC.