Practical and environmentally friendly epoxidation of olefins using Oxone

Article abstract of DOI:10.1021/op025511f

A practical and efficient epoxidation of aromatic olefins using Oxone in a two-phase system (ethyl acetate - water) is described. The reported method is suitable for large-scale synthesis and does not require phase transfer catalyst (PTC) or pH control.

Full text of DOI:10.1021/op025511f

Organic Process Research & Development 2002, 6, 405−406
Practical and Environmentally Friendly Epoxidation of Olefins Using Oxone
Norio Hashimoto* and Atsushi Kanda
Chemical DeVelopment Laboratories, Fujisawa Pharmaceutical Co. Ltd., Kashima, 2-1-6, Yodogawa-ku,
Osaka, 532-8514, Japan
Abstract:
A practical and efficient epoxidation of aromatic olefins using
Oxone in a two-phase system (ethyl acetate-water) is described.
The reported method is suitable for large-scale synthesis and
does not require phase transfer catalyst (PTC) or pH control.
Introduction
Dioxiranes are highly clean and powerful oxidants and
1
have been applied to a variety of oxidations. Recently Shi
and co-workers reported a new method for epoxidation using
trifluoroacetone in aqueous acetonitrile as solvent and
hydrogen peroxide2 in place of Oxone (potassium peroxo-
monosulphate) generally used as dioxiranes generator.
Though this method is practical and does not need large
amounts of potassium carbonate to neutralize the conse-
quently formed potassium hydrogen sulfate, several prob-
lematic features are still evident from the standpoint of large-
scale manufactureability. For example, aqueous acetonitrile
generally does not readily dissolve aromatic olefins due to
their poor solubilities. A more fundamental problem is that
toxic and rather expensive acetonitrile is unavoidable as an
oxidizing mediator2b to ensure high conversion. Recycling
of acetonitrile is also difficult mainly due to boiling point
which is almost the same as that of water. In the last two
decades, two-phase systems have been investigated in order
to overcome these problems.3 These procedures in general
Figure 1. Biphasic dioxirane epoxidation.
Table 1. Concentration of acetone in aqueous phase (20 °C)
a,b
ethyl dichloro-
dichloro-
a
organic solvents acetate methane methane & PTC toluene
b
distribution in
aqueous phase
62%
32%
33%
70%
a
4 4
In the presence of n-Bu NHSO
(0.1 equiv). b Water, solvent, sodium
bicarbonate (5 equiv), and acetone (10 equiv) stirred at room temperature.
Results and Discussion
We selected Oxone as an oxidant since this reagent is
stable and commercially available in large quantities. First
we evaluated phase transfer catalysts. DMDO (dimethyl
dioxirane) is generated in situ from Oxone and a parent
ketone, typically acetone. We envisaged that DMDO is more
lipophilic than acetone, and thus it might be present in the
organic phase even in the absence of a PTC.
a-e
3d,4,5
used n-Bu4NHSO4 as the phase transfer catalyst (PTC).
As a result, a tedious dropwise addition of base solution over
a long time period under strict pH control was needed to
avoid the oxidation of the PTC. From environmental and
economical viewpoints, we sought a more practical and
efficient procedure using an alternative solvent. Herein we
report a practical and environmentally friendly epoxidation
procedure using Oxone in a two-phase system (Figure 1).
As shown in Table 1, the concentration of acetone in the
aqueous phase before the addition of Oxone is highest in
toluene as the organic solvent. These results indicated that
the concentration of DMDO in the aqueous phase would be
highest in the two-phase system of toluene-water from a
kinetic consideration. On the basis of this study, the improved
methodology for the DMDO epoxidation was first applied
to the epoxidation of indene. As shown in Table 2 (entry 1),
6
*
Corresponding author. Telephone: +81-6-6390-1183. Fax: +81-6-6390-
Oxone oxidized the PTC into n-Bu4NHSO5 (Trost’s salt ),
4
419. E-mail: norio_hasimoto@po.fujisawa.co.jp.
easily soluble in organic phase, to cause a background
reaction. Further investigation showed the possibility that
the reaction might give the expected products in excellent
yields even in the absence of PTC (entry 3). We believed
that DMDO is present in both of the two phases. Toluene
resulted in lower yields against our expectation (entry 7).
The affinity of DMDO for the organic solvent is presumably
crucial for this reaction. To our surprise, ethyl acetate showed
(
(
1) Curci, R.; Dinoi, A.; Rubino, M. Pure Appl. Chem. 1995, 67, 811-822.
2) (a) A pioneer of the asymmetric epoxidation using a fructose-derived ketone.
Yong, T.; Wang, Z.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806-9807.
(
b) Shu, L.; Shi, Y. J. Org. Chem. 2000, 65, 8807-8810.
3) (a) Curci, R.; Fiorentino, M.; Troisi, L. J. Org. Chem. 1980, 45, 4758-
760. (b) Curci, R.; Cicala, G.; Fiorentino, M.; Laricchiuta, O. J. Org.
Chem. 1982, 47, 2670-2673. (c) Murray, R.; Jeyaraman, R. J. Org. Chem.
985, 50, 2847-2853. (d) Denmark, S.; Forbes, D.; Hays, D.; DePue, J.;
(
4
1
Wilde, R. J. Org. Chem. 1995, 60, 1391-1407. (e) Curci, R.; D’Accolti,
L.; Fiorentino, M.; Rosa, A. Tetrahedron Lett. 1995, 36, 5831-5834.
4) Denmark, S.; Wu, Z. J. Org. Chem. 1998, 63, 2810-2811.
(
(
5) Yang, D.; Jiao, G.; Yip, Y.; Wong, M. J. Org. Chem. 1999, 64, 1635-
1
639.
(6) Trost, B.; Braslau, R. J. Org. Chem. 1988, 53, 532-537.
1
0.1021/op025511f CCC: $22.00 © 2002 American Chemical Society
Vol. 6, No. 4, 2002 / Organic Process Research & Development
•
405
Published on Web 06/05/2002

Table 2. DMDO epoxidation of indene in a two-phase
system
usefulness of this methodology for large-scale synthesis;
addition of excess sodium bicarbonate in the aqueous phase
followed by addition of aqueous Oxone solution over a few
hours without pH control gave the desired product in
excellent yield. Using this methodology, several olefins were
successfully converted into epoxides (Table 3). Low reactiv-
ity of substrates (entries 1, 7) due to steric hindrance, or
electron-withdrawing substituents led to DMDO decomposi-
acetone Oxone PTCa conversion
entry organic solvent (equiv) (equiv) (equiv)
(%)b
1
2
3
4
5
6
7
dichloromethane
dichloromethane
dichloromethane
ethyl acetate
ethyl acetate
ethyl acetate
toluene
0
10
10
10
10
10
10
2.0
2.0
2.0
2.0
1.2
1.2
2.0
0.1
0.1
0
0
0
0
0
6.4
99.8
90.8
96.4
76.5
80.2
78.1
c
8
tion to methyl acetate, resulting in a low yield (entry 1a).
d
An important feature of the reaction to ensure high yields is
the longer the time taken for the addition of the aqueous
Oxone solution, the higher the yield obtained (entry 1c).
Other olefins were oxidized in good yields (entries 2-6).
e
a
added. Calculated by quantitative HPLC analysis. c 74.3%
4 4
n-Bu NHSO
d
b
of isolated yield. Aqueous Oxone solution added over 2 h. e 19.8% of starting
material recovered.
Conclusions
Table 3. Convenient biphasic epoxidation using Oxone (2.0
An environmentally friendly and totally practical two-
phase epoxidation using Oxone and ethyl acetate was
successfully performed without PTC. Further application of
this process to other oxidative reactions including an asym-
metric epoxidation is under investigation.
equiv) and ethyl acetate
Typical Procedure
To a 300-mL three-necked flask were added sodium
bicarbonate (3.55 g, 0.0423mol), water (40 mL), acetone
(
5
4.90 g, 0.0846mol), ethyl acetate (40 mL), and 1,2-dehydro-
-benzyloxytetralin (2.00 g, 0.00846mol) and were stirred
vigorously. An aqueous Oxone solution (Oxone 5.20 g,
0
2
.00846mol, water 36 mL) was added dropwise over 1 h at
0 to 25 °C. The reaction mixture was stirred for an
additional 1 h. The organic layer was separated and washed
with 20% (w/v) aqueous sodium chloride (20 mL) and then
evaporated. The residue was purified by silica gel chro-
matograpy (silica gel 57 g, n-hexane:ethyl acetate (15:1-
1
0:1), eluant) to give 1,2-dehydro-5-benzyloxytetralin oxide
1
(
1.96 g, 0.00777 mol, 91.8% yield) as a white solid. H NMR
CDCl , 200 MHz): 1.15-1.79 (m, 1H), 2.28-2.44 (m, 2H),
.05-3.13 (m, 1H), 3.73 (m, 1H), 3.84 (d, 1H, J ) 4.2),
.06 (s, 2H), 6.92 (d, 1H, J ) 8.0), 7.03-7.41 (m, 7H). Mass
(
3
5
3
a
Calculated by quantitative HPLC analysis. b Aqueous Oxone solution added
c
over 2 h. In other entries, Oxone was added over 1 h. Calculated by NMR
analysis after purification.
9
16 2
(TIC, m/z): 253 (M + 1). Anal. Calcd for C17H O : C, 80.93;
H, 6.39. Found: C, 80.18; H, 6.25
the highest conversion of olefin to epoxide even in the
absence of PTC (entry 4).
Acknowledgment
Dichloromethane is one of the most unfavorable organic
solvents for large-scale synthesis from an environmental
viewpoint, and exchanging dichloromethane for an alternative
solvent is a crucial issue for a pharmaceutical company. As
shown in entry 4, the best result was obtained using ethyl
acetate as solvent. Thus, this result could expand the
applications of DMDO for many kinds of oxidative reactions
on a large scale. Efficient conversion of active oxygen is
also worth mentioning: 67% of the active oxygen in Oxone
was consumed efficiently, owing to the high affinity of
DMDO for ethyl acetate, even in the absence of PTC (entry
We especially thank Dr. Masaharu Ichihara and Dr.
Atsuhiko Zanka, Chemical Development Laboratories,
Fujisawa Pharmaceutical Co. Ltd., for their interest and
helpful discussions on this work.
Received for review January 27, 2002.
OP025511F
(
7) Yang, D.; Jiao, G.; Yip, Y.; Wong, M. J. Org. Chem. 1999, 64, 1635-
1639.
(
(
8) Adam, W.; Curci, R.; Edwards, J. Acc. Chem. Res. 1989, 22, 205-211.
9) Two methyne protons of chalcone epoxide were identified completely with
the following chemical shifts and coupling constants: (4.08 ppm, 1H, J )
6). To our knowledge, 32% was the highest recorded
conversion in the case of epoxidations using a two-phase
1
.85 Hz), (4.29 ppm, 1H, J ) 1.85 Hz) Bako, B.; Czinege, E.; Bako, T.;
system.3 The simplicity of this reaction highlights the
c
Czugler, M.; Toke, L. Tetrahedron: Asymmetry 1999, 10, 4539-4551.
406
•
Vol. 6, No. 4, 2002 / Organic Process Research & Development