Novel biomimetic iron-catalysts for environmentally benign epoxidations of olefins

Article abstract of DOI:10.1016/j.tetlet.2007.07.006

A new selective and easily manageable epoxidation method is presented using an inexpensive and efficient FeCl₃·6H₂O and imidazole derivatives as catalysts. Aqueous hydrogen peroxide as an environmentally benign oxidant is utilized. This novel Fe/imidazole system gives moderate to excellent yields toward aromatic mono-, di-, and tri-substituted olefins.

Full text of DOI:10.1016/j.tetlet.2007.07.006

Tetrahedron Letters 48 (2007) 6339–6342
Novel biomimetic iron-catalysts for environmentally benign
epoxidations of olefins
Kristin Schro¨der,a Xiaofeng Tong,a Bianca Bitterlich,a Man Kin Tse,a,b
Feyissa Gadissa Gelalcha,a Angelika Brucknerc and Matthias Bellera,b,
*
¨
aLeibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Albert-Einstein-Strasse 29a, D-18059 Rostock, Germany
bUniversity of Rostock, Center for Life Science Automation (CELISCA), Friedrich-Barnewitz-Strasse 8, D-18119 Rostock, Germany
cLeibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Richard-Willsta¨tter-Strasse 12, D-12489 Berlin, Germany
Received 24 May 2007; revised 29 June 2007; accepted 4 July 2007
Available online 7 July 2007
Abstract—A new selective and easily manageable epoxidation method is presented using an inexpensive and efficient FeCl3Æ6H2O
and imidazole derivatives as catalysts. Aqueous hydrogen peroxide as an environmentally benign oxidant is utilized. This novel
Fe/imidazole system gives moderate to excellent yields toward aromatic mono-, di-, and tri-substituted olefins.
Ó 2007 Elsevier Ltd. All rights reserved.
Epoxides play an important role in industry as inter-
mediates for the production of fine chemicals as well
as pharmaceuticals. With respect to environmental and
economical considerations, the applied oxidant deter-
mines to a significant extent the value of the system.1
Thus, the combination of hydrogen peroxide with a
non-toxic and inexpensive metal source constitutes an
ideal system for epoxidation reactions, especially in li-
quid phase processes in industry.2,3 Among the various
metals iron is the most abundant metal in nature and
is indispensable in nearly all organisms.4 Many biologi-
cal systems such as hemoglobin, myoglobin, cytochrome
oxygenases, and non-heme oxygenases are iron contain-
ing enzymes or co-enzymes.5,6
Imidazole derivates play a fundamental role as ligands
or base in enzymes.13 For instance, the imidazole part
of histidine often acts as a ligand in metalloenzymes,
for example, hemoglobin.14 With regard to epoxidations
it is noteworthy that 1-sulfonylated imidazoles and
hydrogen peroxide are known as powerful oxidant in
stoichiometric amount for the reactions.15 Besides, imi-
dazoles and pyrazoles are widely employed as additives
in epoxidation systems, such as iron16 and manganese17
porphyrins, manganese salen complexes,18 methyltri-
oxorhenium,19 and manganese schiff bases.20
Recently, we demonstrated that a combination of FeCl3Æ
6H2O, pyridine-2,6-dicarboxylic acid (H2pydic) and an
organic base like pyrrolidine catalyzes the epoxidation
of trans-stilbene with 30% H2O2 to trans-stilbene oxide
in high yield within 1 h.11 Key to the success of this reac-
tion is the use of pyridine-2,6-dicarboxylic acid as
ligand. By studying the effect of the organic base in more
detail, we found that a combination of FeCl3Æ6H2O with
simple imidazole without any pyridine-2,6-dicarboxylic
acid gave also trans-stilbene oxide in 38% yield with
90% selectivity (Table 1, entry 1).21 Further investiga-
tions showed that the activity and selectivity of the cat-
alytic system can be improved by varying the imidazole
ligands (Table 1).
Due to its low cost and biological relevance there is an
increasing interest to use iron complexes as catalysts
for a wide range of reactions.7 In this respect, recently
we developed iron catalysts for C–C-coupling reac-
tions,8 transfer hydrogenations9 as well as epoxida-
tions.10,11 Based on the latter work, we report here a
novel biomimetic FeCl3/imidazole-system for epoxida-
tions of olefins using aqueous hydrogen peroxide as
the oxidant.12
Keywords: Iron; Epoxidation; Imidazole; Hydrogen peroxide.
*
The influence of the substitution pattern of the imidazo-
le ligands reveals some interesting aspects. Substitution
Corresponding author. Tel.: +49 (0)381 1281 0; fax: +49 (0)381 1281
5000; e-mail: matthias.beller@catalysis.de
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.006

6340
K. Schro¨der et al. / Tetrahedron Letters 48 (2007) 6339–6342
Table 1. Reactivity of different imidazole derivatives
ties for the effectiveness of these imidazole ligands might
be the participation of a carbene type ligand in the
reaction system due to their outstanding r-donor
strength.22
5 mol % FeCl3 6H2O,
10 mol % imidazole derivative
O
2 equiv. H2O2, tert-amyl alcohol,
r.t., 1 h addition
However, replacement of the imidazole derivative with
1,3-dimesityl-2,3-dihydro-1H-imidazol-2-ide gave no
conversion at all. Besides, in the presence of the radical
trap TEMPO (2,2,6,6-tetramethyl-piperidine-1-oxyl;
1.5 equiv), the reaction showed insignificant conversion
and yield. This suggests the participation of a radical
in the catalytic cycle in this epoxidation system. Control
experiments indicated that all the components are essen-
tial for the activity and selectivity. Indeed, in the pres-
ence of 10 mol % of 5-Cl-1-MeIm without FeCl3Æ6H2O
no product formation is observed. On the other hand
5 mol % of FeCl3Æ6H2O without 5-Cl-1-MeIm gave only
5% yield. These results exclude the possibility of
organocatalysis.
Entry
1
Imidazole
derivative
Conv.a,b
(%)
Yieldb
(%)
Selectivityc
(%)
N
43
47
83
38
39
80
90
83
97
N
H
N
2
N
Bn
N
3
N
Cl
Br
N
N
Further optimization showed that a higher yield (84%
yield and 99% selectivity) can be reached when 3 equiv
of 30% hydrogen peroxide is used.23 The yield was main-
tained with a slight drop of selectivity when 4 equiv of
hydrogen peroxide was added. Applying a higher
amount of the ligand 5-Cl-1-MeIm gave slightly better
results. Hence, with 15 mol % of 5-Cl-1-MeIm and
5 mol % FeCl3Æ6H2O, the product yield reached 86%
with 97% selectivity. No further significant improvement
is observed with higher ligand loading.
4
5
69
40
69
39
100
99
N
N
Bu
N
6
7
5
4
90
93
N
H
N
Next, various olefins were applied to the reaction under
the optimized reaction conditions (3 equiv H2O2,
5 mol % FeCl3Æ6H2O, and 15 mol % 5-Cl-1-MeIm)
(Table 2).
39
36
N
H
Br
N
8
5
5
87
N
In the presence of Fe/imidazole catalyst mono-, di-, and
tri-substituted olefins can be epoxidized in moderate to
excellent yield with high selectivity (Table 2). Compared
with our previously reported first generation iron cata-
lyst, this reaction system improved both the yield
and selectivity especially for trisubstituted olefins.11
For example, epoxidation of (cyclohexylidenemethyl)-
benzene gave 25% yield with 64% selectivity in the
new protocol (Table 2, entry 3) while the old system
gave only 11% yield with 39% selectivity. Furthermore,
all halogen-substituted styrenes gave improved selectiv-
ity compared to the first generation catalysts (up to
91%).
Bn
a Reaction conditions: in
a 25 mL Schlenk tube, FeCl3Æ6H2O
(0.025 mmol), imidazole derivative (0.05 mmol), tert-amyl alcohol
(9 mL), trans-stilbene (0.5 mmol) and dodecane (GC internal stan-
dard, 100 lL) were added in sequence at rt in air. To this mixture, a
solution of 30% H2O2 (115 lL, 1.0 mmol) in tert-amyl alcohol
(885 lL) was added over a period of 1 h at rt by a syringe pump.
b Conversion and yield were determined by GC analysis.
c Selectivity refers to the ratio of yield to conversion in percentage.
at the 2-position of the imidazole gave inferior results
(Table 1, entries 1, 2, 6, and 8). Furthermore, N-substi-
tution of the 5-bromoimidazole led to a higher yield and
conversion (Table 1, entries 4 and 7). In addition, 5-
halo-N-methylimidazoles enhanced the yield signifi-
cantly. In fact 5-chloro-1-methylimidazole (Table 1,
entry 3) gave the best result (80% yield; 97% selectivity).
It is noteworthy that 5-chloro-1-methylimidazole (5-Cl-
1-MeIm) is a near-optimal imidazole activity enhancing
additive with balanced steric and electronic factors in an
iron–porphyrin system.16
In conclusion, we have developed a novel, biomimetic
and easily manageable epoxidation reaction. For the
first time it is possible to perform epoxidations with
hydrogen peroxide in the presence of simple Fe/imid-
azole catalysts. Compared to our previous catalyst
system the newly developed iron catalyst does not need
any pyridine-2,6-dicarboxylic acid and gave improved
yield and selectivity for more difficult tri-substituted
olefins and styrenes.24 Efforts to examine the reaction
mechanism and to realize an asymmetric version of this
reaction are going on in our group.
Next, we tried to find out more about the mechanism
of this novel epoxidation catalyst. One of the possibili-

K. Schro¨der et al. / Tetrahedron Letters 48 (2007) 6339–6342
Table 2. Scope and limitations of the reaction25
6341
O
5 mol % FeCl3 6H2O, 15 mol % 5-chloro-1-methylimdazole
3 equiv. H2O2, tert-amyl alcohol, r.t., 1 h addition
R2
R2
Ar1
Ar1
R3
R3
Entry
1
Substrates
Conv.a,b (%)
Yieldb (%)
Selectivityc (%)
92
87
94
88
2
46
41
3
4
39
34
25
64
71
24d
5
6
52
74
36
70
68
95
7
90
79
88
Cl
Br
8
9
91
73
74
82
62
67
90
86
91
F
Cl
10
Cl
11
55
46
84
a Reaction conditions: in a 25 mL Schlenk tube, FeCl3Æ6H2O (0.025 mmol), 5-chloro-1-methylimidazole (0.075 mmol), tert-amyl alcohol (9 mL),
trans-stilbene (0.5 mmol) and dodecane (GC internal standard, 100 lL) were added in sequence at rt in air. To this mixture, a solution of 30% H2O2
(170 lL, 1.5 mmol) in tert-amyl alcohol (830 lL) was added over a period of 1 h at rt by a syringe pump.
b Conversion and yield were determined by GC analysis.
c Selectivity refers to the ratio of yield to conversion in percentage.
d Additionally 3% trans-stilbene oxid and trans-stilbene were observed.
Acknowledgments
(BMBF) and the Deutsche Forschungsgemeinschaft
(SPP 1118 and Leibniz-prize) for financial support.
Dr. Xiaofeng Tong thanks the Alexander-von-Hum-
boldt-Stiftung. Mrs. M. Heyken, Mr. H.-M. Kaiser,
We thank the State of Mecklenburg-Western Pommera-
nia, the Federal Ministry of Education and Research

6342
K. Schro¨der et al. / Tetrahedron Letters 48 (2007) 6339–6342
11. (a) Bitterlich, B.; Anilkumar, G.; Gelalcha, F. G.; Spilker,
B.; Grotevendt, A.; Jackstell, R.; Tse, M. K.; Beller, M.
Chem. Asian J. 2007, 2, 521–529; (b) Anilkumar, G.;
Bitterlich, B.; Gelalcha, F. G.; Tse, M. K.; Beller, M.
Chem. Commun. 2007, 289–291.
Mr. I. Zenz, Dr. Feng Shi and Dr. B. Spilker (LIKAT)
are acknowledged for their valuable support in the
laboratory.
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23. Aqueous H2O2 (30%) from Merck was used as received.
The peroxide content varied from 33% to 40% as deter-
mined by titration.
24. Side-products are rearrangement products of the corre-
sponding epoxide.
25. Most of the substrates and epoxides for GC–FID
calibration are commercially available. The others were
synthesized according to literature methods and deter-
mined by NMR and GC–MS. In addition, authentic
samples of the commercial products were analyzed by
GC–MS and GC–FID.