Convenient method for epoxidation of alkenes using aqueous hydrogen peroxide

Article abstract of DOI:10.1021/ol047604i

(Chemical Equation Presented) The complex [Ru(tpy)(pydic)] (1a) is an active catalyst for epoxidation of alkenes by aqueous 30% hydrogen peroxide in tertiary alcohols. The protocol is simple to operate and gives the corresponding epoxides in good to excellent yields. Chiral enantiopure [Ru(tpy*)(pydic) ] complexes have been synthesized and successfully applied in this procedure.

Full text of DOI:10.1021/ol047604i

ORGANIC
LETTERS
2005
Vol. 7, No. 6
987-990
Convenient Method for Epoxidation of
Alkenes Using Aqueous Hydrogen
Peroxide
Man Kin Tse,† Markus Klawonn,† Santosh Bhor,† Christian Do
Gopinathan Anilkumar,† Herbert Hugl,‡ Wolfgang Magerlein,‡ and
Matthias Beller*,†
1
bler,†
1
Leibniz Institut fu¨r Organische Katalyse (IfOK) an der UniVersita¨t Rostock e.V.,
Buchbinderstrasse 5-6, D-18055 Rostock, Germany, and LANXESS Deutschland
GmbH, BU Fine Chemicals, D-51369 LeVerkusen, Germany
matthias.beller@ifok.uni-rostock.de
Received November 22, 2004
ABSTRACT
The complex [Ru(tpy)(pydic)] (1a) is an active catalyst for epoxidation of alkenes by aqueous 30% hydrogen peroxide in tertiary alcohols. The
protocol is simple to operate and gives the corresponding epoxides in good to excellent yields. Chiral enantiopure [Ru(tpy*)(pydic)] complexes
have been synthesized and successfully applied in this procedure.
Oxidation reactions of olefins to give epoxides are of major
importance for organic synthesis. Nowadays, especially
asymmetric epoxidation reactions1 and the use of environ-
mentally benign oxidants2 are the focus of methodological
developments. Apart from molecular oxygen,3 hydrogen
peroxide is an ecologically sustainable, “green” oxidant.4 It
can reach up to 47% atom efficiency in epoxidation reactions
and generates only water as a byproduct. Moreover, it is
economical and readily available.5
Traditionally, epoxides are synthesized by reaction of
olefins with peroxoacids generated from hydrogen peroxide
and acids or acid derivatives.6 A drawback of this convenient
(3) For some examples of transition metal-catalyzed oxidations using
molecular oxygen, see: (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) Groves, J. T.; Quinn, R. J. Am.
Chem. Soc. 1985, 107, 5790-5792. (e) Paeng, I. R.; Nakamoto, K. J. Am.
Chem. Soc. 1990, 112, 3289-3297. (f) Montanari, F., Casella, L., Eds.
Metalloporphyrin Catalyzed Oxidations; Kluwer: Dordrecht, 1994. (g)
Marko´, I. E.; Giles, P. R.; Tsukazaki, M.; Chelle´-Regnant, I.; Urch, C. J.;
Brown, S. M. J. Am. Chem. Soc. 1997, 119, 12661-12662. (h) Peterson,
K. P.; Larock, R. C. J. Org. Chem. 1998, 63, 3185-3189. (i) Coleman, K.
S.; Lorber, C. Y.; Osborn, J. A. Eur. J. Inorg. Chem. 1998, 1673-1675. (j)
Christoffers, J. J. Org. Chem. 1999, 64, 7668-7669.
† Leibniz Institut fu¨r Organische Katalyse.
‡ BU Fine Chemicals.
(1) Selected reviews: (a) Shi, Y. Acc. Chem. Res. 2004, 37, 488-496.
(b) Gerlach, A.; Geller, T. AdV. Synth. Catal. 2004, 346, 1247-1249. (c)
Yang, D. Acc. Chem. Res. 2004, 37, 497-505. (d) Abdi, S. H. R.; Kureshy,
R. I.; Khan, N. H.; Jasra, R. V. Catal. SurVeys Asia 2004, 8, 187-197.
(2) (a) Fioroni, G.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Green Chem.
2003, 5, 425-428. (b) Beckman, E. J. Green Chem. 2003, 5, 332-336. (c)
Srinivas, K. A.; Kumar, A.; Chauhan, S. M. S. Chem. Commun. 2002,
2456-2457. (d) Liang, J.; Tang, Q. H.; Meng, G. Y.; Wu, H. L.; Zhang,
Q. H.; Wang, Y. Chem. Lett. 2004, 33, 1140-1141.
(4) Jones, C. W. Applications of Hydrogen Peroxide and DeriVatiVes;
Royal Society of Chemistry: Cambridge, 1999.
(5) Kroschwitz, J. I., Howe-Grant, M., Eds.; Kirk-Othmer Encyclopedia
of Chemical Technology, 4th ed.: John Wiley & Sons: New York, 1995;
Vol. 13, p 961.
10.1021/ol047604i CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/17/2005

method is the limited use for acid-labile olefins or epoxides
and the generation of significant amounts of waste (salts).
To control the selectivity of epoxidation reactions and to
overcome the aforementioned problems, transition metal-
catalyzed oxidations using hydrogen peroxide have been
developed.7 Among them, probably the most general method
to epoxidize alkenes in neutral conditions is the well-known
methyltrioxorhenium (MTO) system.8 Nevertheless, from a
practical point of view, the development of more active and
productive catalysts for stereoselective and racemic oxidation
reactions using H2O2 is an important and challenging goal
in oxidation chemistry.
benign tertiary alcohol with 30% aqueous hydrogen peroxide
as the oxidant as well as the initial attempt for its asymmetric
version.
Recently, we became interested in the use of ruthenium
catalysts9 for olefin epoxidations.10 For example, we were
able to make optically active ruthenium (pyridine-bisoxazo-
line)(2,6-pyridinedicarboxylate) complexes [Ru(pybox)-
(pydic)]9c (2) to become more practical oxidation catalysts
by adding a defined amount of water to the reaction
mixture.11 This also led to the development of novel
enantioselective epoxidation protocols applying alkyl per-
oxides12 and hydrogen peroxide13 as oxidants in the presence
of ruthenium pybox and pyboxazine complexes.
Figure 1.
Complex 1a was introduced by Nishiyama et al. for
epoxidation of alkenes.9c The original protocol in dichlo-
romethane used 5 mol % 1a with oxidants such as PhI(OAc)2,
oxygen/tBuCHO, and BuOOH. Unfortunately, the catalyst
t
showed only low activity (the reaction took 72 h to complete)
and no general substrate variations were demonstrated.
In our recent work on catalytic asymmetric epoxidations,13
we were able to employ tert-amyl alcohol as the solvent and
30% aqueous hydrogen peroxide as the oxidant. In a
prototypical reaction, â-methyl styrene was used as the
substrate. To our delight, complex 1a showed, under the same
conditions and in comparison to 2-4, a significantly
increased reactivity and stability.
Even at 0.01 mol % catalyst loading with 0.1 mol % of
both terpyridine (tpy) and pyridine-2,6-dicarboxylic acid (H2-
pydic), conversions of 93 and 88% were observed, which
corresponds to a TON of 8800. At a ruthenium content of
as low as 0.001 mol %, there was still an observable activity
(Table 1).
Figure 1 shows 3 of over 50 ruthenium complexes we have
synthesized and applied in asymmetric epoxidations. Despite
the advantages of these catalytic systems such as (enantio)-
selectivity, generality, and tunability, we looked for more
active and robust complexes that would diminish the catalyst
loading (5 mol %), which is typically needed for the [Ru-
(pybox)(pydic)] protocol, and allow at the same time for
epoxidation of a broader substrate range. Here, we report
for the first time a general epoxidation protocol that uses
[Ru(terpyridine)(2,6-pyridinedicarboxylate)] (1a) and is car-
ried out under mild neutral conditions in an environmentally
(6) Examples using peracids for olefin epoxidation without metal
catalyst: (a) Crawford, K.; Rautenstrauch, V.; Uijttewaal, A. Synlett 2001,
1127-1128. (b) Wahren, U.; Sprung, I.; Schulze, K.; Findeisen, M.;
Buchbauer, G.; Tetrahedron Lett. 1999, 40, 5991-5992. (c) Kelly, D. R.;
Nally, J. Tetrahedron Lett. 1999, 40, 3251-3254.
(7) (a) Bregeault, J. M. Dalton Trans. 2003, 3289-3302. (b) Lukasiewicz,
M.; Pielichowski, J. Przem. Chem. 2002, 81, 509-514.
Table 1. Influence of Catalyst Loadinga
(8) (a) Herrmann, W. A.; Fischer, R. W.; Marz, D. W. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 1638-1641. (b) Rudolf, J.; Reddy, K. L.; Chiang,
J. P.; Sharpless, K. B. J. Am. Chem. Soc. 1997, 119, 6189-6190. (c)
Hermann, W. A.; Kratzer, R. M.; Ding, H.; Thiel, W. R.; Glas, H. J.
Organomet. Chem. 1998, 555, 293-295.
catalyst loading
(mol %)
conversionb
(%)
yieldb
(%)
entry
TON
1
2
3
4
5
1
0.1
0.01
0.01
0.001
100
100
22
93c
14c
96
95
18
88c
8c
96
950
1800
8800
8000
(9) For an excellent review using Ru complexes for epoxidation reactions,
see: (a) Barf, G. A.; Sheldon, R. A. J. Mol. Catal. A 1995, 102, 23-39.
For recent achievements in Ru-based asymmetric epoxidation, see: (b)
Kureshy, R. I.; Khan, N. H.; Abdi, S. H. R.; Bhatt, K. N. Tetrahedron:
Asymmetry 1993, 4, 1693-1701. (c) Nishiyama, H.; Shimada, T.; Itoh, H.;
Sugiyama, H.; Motoyama, Y. Chem. Commun. 1997, 1863-1864. (d) End,
N.; Pfaltz, A. Chem. Commun. 1998, 589-590. (e) 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. (g) Pezet, F.; A¨ıt-Haddou, H.; Daran, J.-C.; Sadaki, I.; Balavoine, G.
G. A. Chem. Commun. 2002, 510-511. For recent examples using Ru salen
complexes, see: (h) Takeda, T.; Irie, R.; Shinoda, Y.; Katsuki, T. Synlett
1999, 1157-1159. (i) Nakata, K.; Takeda, T.; Mihara, J.; Hamada, T.; Irie,
R.; Katsuki, T. Chem. Eur. J. 2001, 7, 3776-3782.
a Reaction conditions: In a 25 mL Schlenk tube, the catalyst 1a was
stirred at room temperature in tert-amyl alcohol (9 mL) for 10 min. â-Methyl
styrene (0.5 mmol) and dodecane (GC internal standard, 100 µL) were
added. To this reaction mixture was added a solution of hydrogen peroxide
(170 µL, 1.5 mmol) in tert-amyl alcohol (830 µL) over a period of 12 h
via a syringe pump. b Determined by comparison with authentic samples
on GC-FID. c At the outset, 0.1 mol % tpy and 0.1 mol % H2pydic were
added.
(10) Klawonn, M.; Tse, M. K.; Bhor, S.; Do¨bler, C.; Beller, M. J. Mol.
Catal. A 2004, 218, 13-19.
(11) Tse, M. K.; Bhor, S.; Klawonn, M.; Do¨bler, C.; Beller, M.
Tetrahedron Lett. 2003, 44, 7479-7483.
The continuous addition of H2O2 by a syringe pump was
proven to be a reliable method to avoid nonproductive
decomposition of the oxidant. Interestingly, also an addition
of all the oxidant at once gave good results in most cases,
(12) Bhor, S.; Tse, M. K.; Klawonn, M.; Do¨bler, C.; Beller, M.;
Ma¨gerlein, W. AdV. Synth. Catal. 2004, 346, 263-267.
(13) Tse, M. K.; Do¨bler, C.; Bhor, S.; Klawonn, M.; Ma¨gerlein, W.;
Hugl, H.; Beller, M. Angew. Chem., Int. Ed. 2004, 43, 5255-5260.
988
Org. Lett., Vol. 7, No. 6, 2005

especially with electron-rich substrates such as â-methyl
styrene or 1-phenylcyclohexene. Nevertheless, we persisted
with the continuous addition to allow for a more general
method. From the data in Table 1, the beneficial effect of
additional ligands suggests that the development of an in
situ-type reaction is possible. Thus, by simply adding some
ruthenium source and the ligands separately, the additional
preparation of 1a can be avoided. In Table 2, the feasibility
a
Table 3. Epoxidation of Various Alkenes with H2O2
Table 2. Epoxidation Using an in situ Catalyst Systema
tpy
H2pydic conversionb yieldb selectivity
entry (mol %)
(mol %)
(%)
(%)
(%)
1c
25
5
2c
3c
4c
5d
6d
7d
8d
0.5
0.5
0.5
0.5
<2
21
37
<40
72
93
0.5
0.5
29
40
32
12
42
45
<2
24
35
<20
57
78
0.5
0.5
a Reaction conditions: In a 25 mL Schlenk tube, the ruthenium source,
tpy, and pydic were stirred at room temperature in tert-amyl alcohol (9
mL) for 10 min. â-Methyl styrene (0.5 mmol) and dodecane (GC internal
standard, 100 µL) were added. To this reaction mixture was added a solution
of hydrogen peroxide (170 µL, 1.5 mmol) in tert-amyl alcohol (830 µL)
over a period of 12 h Via a syringe pump. b Determined by comparison
with authentic samples on GC-FID. c Performed with 0.0025 mmol
RuCl3‚nH2O as the Ru source. d Performed with 0.00125 mmol [Ru(p-
cymene)Cl2]2 as the Ru source.
of such a concept is demonstrated using two readily available
ruthenium sources, RuCl3‚nH2O and [Ru(p-cymene)Cl2]2,
along with tpy and H2pydic at 0.5 mol % each (Table 2,
compare Table 1, entry 3).
No epoxide was observed without any added ligand and
with only terpyridine. H2pydic as the sole ligand showed
some reactivity; however, the selectivity toward the desired
product was lower than that in the case when both ligands
were applied. The differences between the two ruthenium
sources were insignificant. These results suggest that both
ligands are necessary for obtaining a high epoxide selectivity.
H2pydic is mainly responsible for the reactivity and tpy for
the selectivity.
Since the yields in the in situ systems are somewhat lower
compared to that obtained by the application of the pre-made
1a, we used the protocol described in Table 1 as the standard
procedure.
As shown in Table 3, a large number of different alkenes
were epoxidized in good to excellent yields. All substitution
patterns of aromatic olefins such as monosubstituted, 1,1-
disubstituted, 1,2-cis/trans-substituted, 1,1,2-trisubstituted,
and finally tetrasubstituted alkenes gave the corresponding
epoxides. The compatibility of this protocol with functional
groups such as -OH-, -OR-, -OTBDMS-, halogen-,
acetal-, and nitrogen-containing compounds is noteworthy
(Table 3). In cases of less reactive substrates (entries 15 and
26), neither increasing the concentration of 1a to 1 mol %
nor conducting the reaction at 50 °C resulted in higher
a Reaction conditions: In a 25 mL Schlenk tube, the catalyst 1a (0.0025
mmol) was stirred at room temperature in tert-amyl alcohol (9 mL) for 10
min. Alkene (0.5 mmol) and dodecane (GC internal standard, 100 µL) were
added. To this reaction mixture was added a solution of hydrogen peroxide
(170 µL, 1.5 mmol) in tert-amyl alcohol (830 µL) over a period of 12 h
Via a syringe pump. b Determined by comparing with authentic samples
on GC-FID. c Performed with 0.05 mmol [Ru(tBu3-tpy)(pydic)] 1b as the
1
catalyst. d Isolated yield. e Determined by H NMR.
Org. Lett., Vol. 7, No. 6, 2005
989

epoxide yields (>50%). We thought that this may be due to
the insufficient solubility of 1a at higher concentration (1
mol %) and the increased decomposition of the hydrogen
peroxide at elevated temperature. A solution to this problem
was found in the application of a more soluble ruthenium
terpyridine complex [Ru(tBu3-tpy)(pydic)] 1b. It is interesting
to note that the reaction conditions could be easily scaled
up to 10 mmol in a 10-fold substrate concentration smoothly.14
Of all epoxidation procedures using hydrogen peroxide
in neutral conditions known in the literature, our protocol
compares best to the MTO-system. Advantageously, our
system runs in environmentally benign solvents and the
catalyst is more easily prepared compared to methyltrioxo-
rhenium.
literature.15 All complexes 5-8 were synthesized under
similar conditions as 1 and 2 (see Supporting Information).
With our model substrate â,â-dimethyl styrene, excellent
yields were reached for 5, 6, and 8 applied at a comparably
low concentration of 0.5 mol %. For 6, a moderate enantio-
selectivity of 54% ee (Table 4) was achieved.
Table 4. Epoxidation of â,â-Dimethyl Styrenea
entry
catalyst
conversionb (%)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
100
100
53
93
96
45
96
-15
+54d
+24d
-29
100
a Reaction conditions: In a 25 mL Schlenk tube, the catalyst was stirred
at room temperature in tert-amyl alcohol (9 mL) for 10 min. Olefin (0.5
mmol) and dodecane (GC internal standard, 100 µL) were added. To this
reaction mixture was added a solution of 30% hydrogen peroxide (170 µL,
1.5 mmol) in tert-amyl alcohol (830 µL) over a period of 12 h Via a syringe
pump. b Determined by comparison with authentic samples on GC-FID.
c Determined by HPLC. d (R)-(+)-1-Phenyl-2-methyl-1-propene oxide was
the major enantiomer.
In summary, we have developed a ruthenium-catalyzed
epoxidation protocol that runs under mild conditions in an
environmetally friendly manner. In general, highly selective
epoxidation of aromatic and branched aliphatic alkenes is
achieved at low catalyst loading, and moderate enantio-
selectivity was obtained for the asymmetric protocol. Further
work using other ruthenium terpyridine pydic complexes for
epoxidation is currently in progress.
Acknowledgment. This work has been supported by the
State of Mecklenburg-Western Pommerania and the
Bundesministerium fu¨r Bildung und Forschung (BMBF). We
thank Mrs. C. Mewes, Mrs. H. Baudisch, Mrs. A. Lehmann,
and Mrs. S. Buchholz (all IfOK) for their excellent technical
and analytical support. Dr. A. Ko¨ckritz (ACA) is thanked
for general discussions.
Figure 2.
Due to the excellent performance of 1a in racemic
epoxidations we started to explore an enantioselective
procedure by variation of the terpyridine ligand. The ligands
were prepared according to a reaction scheme known in the
Supporting Information Available: Synthesis and char-
acterization of all complexes, experimental procedures, and
characterization data for all epoxides. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) 1-Phenyl-2-cyclohexene (9.5 mmol) and [Ru(tpy)(pydic)] (1a, 0.05
mmol, 0.5 mol %) were dissolved by stirring in tert-amyl alcohol (20 mL).
To this mixture was added 30% aqueous hydrogen peroxide (3.04 mL) Via
syringe pump over 12 h. After quenching the reaction (30 mL of 10%
aqueous Na2SO3 solution), extraction (three times with 20 mL of ethyl
acetate), and purification (column chromatography, Merck silica gel 60,
hexane to hexane/ethyl acetate 95:5 as the gradient eluent), 1.37 g (83%
yield with respect to 1-phenyl-2-cyclohexene) of the epoxide remained.
OL047604I
(15) (a) Ziegler, M.; Monney, V.; Stoeckli-Evans, H.; Von Zelewsky,
A.; Sasaki, I.; Dupic, G.; Daran, J. C.; Balavoine, G. G. A. J. Chem. Soc.,
Dalton Trans. 1999, 667-675. (b) Kwong, H.-L.; Lee, W.-S. Tetrahe-
dron: Asymmetry 2000, 11, 2299-2308.
990
Org. Lett., Vol. 7, No. 6, 2005