Efficient epoxidation of alkenes with aqueous hydrogen peroxide catalyzed by methyltrioxorhenium and 3-cyanopyridine

Article abstract of DOI:10.1021/jo005623+

The epoxidation of alkenes with 30% aqueous hydrogen peroxide is catalyzed efficiently by methyltrioxorhenium (MTO) in the presence of pyridine additives. The addition of 1-10 mol % of 3-cyanopyridine increases the system's efficiency for terminal and trans-disubstituted alkenes resulting in high isolated yields of the corresponding epoxides. The system allows for epoxidation of alkenes with various functional groups. Alkenes leading to acid-sensitive products are efficiently epoxidized using a mixture of pyridine and 3-cyanopyridine as additives. This method is operationally very simple and uses an environmentally benign oxidant. The effects of different pyridine additives on the alkene conversion and the catalyst lifetime are discussed.

Full text of DOI:10.1021/jo005623+

J . Org. Chem. 2000, 65, 8651-8658
8651
Efficien t Ep oxid a tion of Alk en es w ith Aqu eou s Hyd r ogen
P er oxid e Ca ta lyzed by Meth yltr ioxor h en iu m a n d 3-Cya n op yr id in e
,
†
‡
§
|
Hans Adolfsson,* Christophe Cop e´ ret, J ay P. Chiang, and Andrei K. Yudin
Department of Chemistry and the Skaggs Institute of Chemical Biology, The Scripps Research Institute,
1
0550 North Torrey Pines Road, La J olla, California 90237
hansa@organ.su.se
Received August 25, 2000
The epoxidation of alkenes with 30% aqueous hydrogen peroxide is catalyzed efficiently by
methyltrioxorhenium (MTO) in the presence of pyridine additives. The addition of 1-10 mol % of
3
-cyanopyridine increases the system’s efficiency for terminal and trans-disubstituted alkenes
resulting in high isolated yields of the corresponding epoxides. The system allows for epoxidation
of alkenes with various functional groups. Alkenes leading to acid-sensitive products are efficiently
epoxidized using a mixture of pyridine and 3-cyanopyridine as additives. This method is
operationally very simple and uses an environmentally benign oxidant. The effects of different
pyridine additives on the alkene conversion and the catalyst lifetime are discussed.
In tr od u ction
efficiency of the process. This field has been extensively
studied, but there are only a few systems that show good
applicability and reliability. Currently, one of the more
Three-membered ring systems containing one hetero-
atom, e.g., epoxides and aziridines, serve as important
building blocks for a wide variety of chemical compounds.
The search for and development of efficient and selective
methods for the preparation of epoxides is therefore of
high importance. Although base-promoted dehydrochlo-
rination of chlorohydrins is one of the most employed
methods, the direct oxidation of alkenes represents the
most cost-effective and elegant method for the production
of epoxides. The major advantage of direct epoxidation
using various environmentally benign oxygen sources
such as hydrogen peroxide, alkyl hydroperoxides, or most
desireful, molecular oxygen, is the limited amount of
byproducts formed from the oxidant. Whereas dehydro-
chlorinations always produce equimolar amounts of
hydrogen chloride, the only byproduct formed in hydrogen
peroxide mediated epoxidations is water. Various per-
acids commonly used to transform alkenes to epoxides
also suffer from the same disadvantage of producing
equimolar amounts of byproducts, namely the parent
acids, and thus need to be buffered to prevent epoxide
ring opening via acidic activation.
2
successful transition metal catalyzed epoxidations uses
aqueous hydrogen peroxide as oxidant in the presence
of sodium tungstate as the catalyst. This system was
3
originally found by Payne and Williams in 1959. Ven-
turello et al. improved the system by addition of phos-
4
phoric acid and quaternary ammonium salts, and more
recently, Noyori et al. found that changing the additives
to (aminomethyl)phosphonic acid and methyltrioctylam-
monium hydrogensulfate further enhanced the sodium
5
tungstate catalyzed epoxidation of alkenes. With this
method it is possible to epoxidize a wide variety of
alkenes; however, sensitive epoxides undergo ring-open-
ing reactions due to the inherent Lewis acidity of the
system. The industrially used process based on a het-
erogeneous titanium substituted silicate (TS-1) catalyst
introduced by Enichem represents another efficient
catalytic epoxidation system using hydrogen peroxide as
6
oxidant. This system shows high preference for epoxi-
dation of small unbranched terminal alkenes, but recent
developments in this area, by taking into account the size
of the zeolite pores, have increased the range of sub-
Despite numerous procedures described in the litera-
ture there is still a lack of a highly efficient, general, and,
most important, neutral method for epoxidation of al-
strates working in this system.7
(2) For a recent review on transition metal catalyzed epoxidation
1
kenes. The problem with most of the current methods
reactions, see: Sheldon, R. A. In Applied Homogeneous Catalysis with
Organometallic compounds; Cornils, B., Herrmann, W. A., Eds.;
VCH: Weinheim, 1996.
is the inherent acidity (Br o¨ nsted or Lewis), which may
lead to ring cleavage of the formed epoxides. Although
some alkenes react directly with a variety of oxidants,
the use of transition-metal catalysts often increases the
(3) Payne, G. B.; Williams, P. H. J . Org. Chem. 1959, 24, 54.
(4) (a) Venturello, G.; Alneri, E.; Ricci, M. J . Org. Chem. 1983, 48,
831. (b) Venturello, C.; D′Aloisio, R. J . Org. Chem. 1988, 53, 1553.
3
See also: (c) Prandi, J .; Kagan, H. B.; Mimoun, H. Tetrahedron Lett.
986, 27, 2617. For W-based heteropoly acid-catalyzed epoxidation,
1
†
To whom correspondence should be addressed. Present address:
see: (d) Ishii, Y.; Yamawaki, K.; Ura, T.; Yamada, H.; Yoshida, T.;
Ogawa, M. J . Org. Chem. 1988, 53, 3587.
Department of Organic Chemistry, Stockholm University, Stockholm,
Sweden.
(5) (a) Sato, K.; Aoki, M.; Ogawa, M.; Hashimoto, T.; Noyori, R. J .
Org. Chem. 1996, 61, 8310. (b) Sato, K.; Aoki, M.; Ogawa, M.;
Hashimoto, T.; Panyella, D.; Noyori, R. Bull Soc. Chem. J pn. 1997,
70, 905.
(6) (a) Enichem; Taramasso, M.; Perego, G.; Notari, B. US 4.410.501,
1983. (b) Notari, B. Catal. Today 1993, 18, 163. (c) Notari, B. Stud.
Surf. Sci. Catal. 1987, 37, 413.
‡
Present address: Laboratoire COMS - CNRS/CPE UMR 9986,
Villeuerbanne, France.
§
Present address: Coelacanth Corp., East Windsor, NJ 08520.
Present address: Department of Chemistry, University of Toronto,
|
Toronto, Canada.
(1) For a general overview on epoxidation of alkenes, see: Strukul,
G. In Catalytic Oxidation with Hydrogen Peroxide as Oxidant; Kluwer
Academic Publishers: New York, 1992.
(7) Murugavel, R.; Roesky, H. W. Angew. Chem., Int. Ed. Engl. 1997,
36, 477 and references therein.
1
0.1021/jo005623+ CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/18/2000

8
652 J . Org. Chem., Vol. 65, No. 25, 2000
Adolfsson et al.
oxidation systems15 led to the discovery that pyridine had
a beneficial influence on the rate of the MTO-catalyzed
epoxidation of cyclooctene.8 This discovery also allowed
the introduction of the relatively safe and environmen-
tally friendly 30% aqueous hydrogen peroxide as oxidant.
With the addition of pyridine, epoxidations could be
performed in a biphasic water-organic solvent system,
selectively giving epoxides in high yields with a low
catalyst loading. The addition of pyridine promotes an
increase in the rate of the reaction and protects the
formed epoxide from possible ring-opening reactions,
catalyzed by the Lewis acidic metal center. This system
turned out to be most effective for more electron-rich
systems such as tetra-, tri-, and cis-disubstituted alkenes.
Trans-disubstituted and terminal alkenes react slower
with electrophilic oxygen-transfer reagents and thus
required prolonged reaction times to reach acceptable
conversion. The addition of 3-cyanopyridine instead of
pyridine to the epoxidation system resulted in high
conversion of terminal alkenes to their corresponding
epoxides.8b Herrmann et al. introduced pyrazole as an
Sch em e 1
a
We have previously reported on the effects of various
heterocyclic additives, i.e., pyridine and pyridine deriva-
tives, in the methyltrioxorhenium (MTO)-catalyzed ep-
8
oxidation of alkenes with aqueous hydrogen peroxide.
MTO was originally introduced as a catalyst for alkene
epoxidation by Herrmann et al. in 1991.9,10
Despite the fact that this organometallic compound on
first glance may seem to be unstable under oxidation
reaction conditions, it has proven to be an excellent
catalyst for a variety of oxidative processes. In the
original MTO process for epoxidation of alkenes, the use
of aqueous-free hydrogen peroxide in tert-butyl alcohol
was essential for a successful outcome of the reaction.
However, the Lewis acidity of the catalyst restricted the
1
1
system to alkenes leading to less acid-sensitive ep-
oxides.12 The use of the hydrogen peroxide-urea complex
1
6
additive promoting efficient epoxidation of alkenes. This
system has properties similar to the pyridine systems and
a comparison of which amine additive to choose depend-
as the terminal oxidant somewhat improved the sub-
strate scope of the system, though at the cost of lower
reactivity.13
8
c
ing on the nature of the substrate was recently published.
There are two peroxo complexes formed in the reaction
between MTO and hydrogen peroxide, the monoperoxo
and the bisperoxo complexes as shown in Scheme 1.
Espenson and co-workers have shown that with excess
of hydrogen peroxide the bisperoxo-complex is the most
abundant; however, both peroxo intermediates can take
part in the oxygen-transfer step.14
Herein we report a comprehensive study of the MTO-
catalyzed epoxidation of alkenes with aqueous hydrogen
peroxide in the presence of pyridine additives.
Resu lts a n d Discu ssion
Ep oxid a tion Con d ition s. The inability of the simple
pyridine system to fully convert terminal alkenes into
their corresponding epoxides led us to search for other
additives that could enhance the catalytic process. Sty-
rene, representing a terminal alkene and a progenitor
for a very acid-sensitive epoxide, was chosen as the model
substrate for this investigation. Screening the reaction
with different functionalized pyridines showed that
heterocycles containing electron-releasing substituents,
thus having a higher basicity, such as 4-tert-butyl- and
Our continuing search for ligand-accelerated catalytic
(8) (a) Rudolph, J .; Reddy, K. L.; Chiang, J . P.; Sharpless, K. B. J .
Am. Chem. Soc. 1997, 62, 6189. (b) Cop e´ ret, C.; Adolfsson, H.;
Sharpless, K. B. Chem. Commun. 1997, 1565. (c) Adolfsson, H.;
Converso, A.; Sharpless, K. B. Tetrahedron Lett. 1999, 40, 3991.
(9) (a) Hoechst AG.; Herrmann, W. A.; Marz, D. W.; Kuchler, J . G.;
Weichselbaumer, G.; Fischer, R. W. DE 3.902.357, 1989. (b) Herrmann,
W. A.; Fischer, R. W.; Marz, D. W. Angew. Chem. 1991, 103, 1706;
Angew. Chem., Int. Ed. Engl. 1991, 30, 1638. (c) Herrmann, W. A.;
Fischer, R. W.; Rauch, M. U.; Scherer, W. J . Mol. Catal. 1994, 86, 243.
(
d) Crocco, G. L.; Shum, W. P.; Zajacek, J . G.; Kesling, H. S., J r. ARCO
Chemical Technology. US 5.166.372, 1992.
10) For the original preparation of MTO, see; Beattie, I. R.; J ones,
P. J . Inorg. Chem. 1979, 18, 2318.
11) The versatility of MTO as an oxidation catalyst is covered in
two recent review articles: (a) Espenson, J . H. Chem. Commun. 1999,
4
-methoxypyridine did protect the formed epoxide from
(
ring cleavage but had a negative effect on the catalyst
lifetime, leading to lower conversion. On the other hand,
pyridine derivatives with electron-withdrawing substit-
uents (less basic) and particularly the meta-substituted
ones, 3-cyanopyridine, 3-fluoropyridine, methyl nicotinate
and nicotinic acid, allowed the reaction to reach high
conversion. The disadvantage, though, was the inability
of these additives to protect the epoxide from the occur-
rence of various side reactions, resulting in product
mixtures of benzaldehyde, benzoic acid, phenyl-1,2-
ethylene glycol, and only trace amounts of the epoxide
(
4
2
79. (b) Owens, G. S.; Arias, J .; Abu-Omar, M. M. Catalysis Today
000, 55, 317. For original oxidation references, see the following.
Amines: (c) Murray, R. W.; Iyanar, K.; Chen, J .; Wearing, J . T.
Tetrahedron Lett. 1995, 36, 6415. (d) Zhu, Z.; Espenson J . H. J . Org.
Chem. 1995, 60, 1326. (e) Murray, R. W.; Iyanar, K.; Chen, J .; Wearing,
J . T. Tetrahedron Lett. 1996, 37, 805. (f) Goti, A.; Nannelli, L.
Tetrahedron Lett. 1996, 37, 6025. (g) Murray, R. W.; Iyanar, K.; Chen,
J .; Wearing, J . T. J . Org. Chem. 1996, 61, 8099. (h) Yamazaki, S. Bull.
Soc. Chem. J pn. 1997, 70, 877. Sulfides: (i) Adam, W.; Mitchell, C.
M.; Saha-M o¨ ller, C. R. Tetrahedron 1994, 50, 13121. (j) Vasell, K. A.;
Espenson, J . H. Inorg. Chem. 1994, 33, 5491. Phosphines: (k) Abu-
Omar, M. M.; Espenson, J . H. J . Am. Chem. Soc. 1995, 117, 272.
Alkynes: (l) Zhu, Z.; Espenson, J . H. J . Org. Chem. 1995, 60, 7728.
Phenols. (m) Adam, W.; Herrmann, W. A.; Lin, J .; Saha-M o¨ ller, C. R.
J . Org. Chem. 1994, 59, 8281. Arenes: (n) Adam, W.; Herrmann, W.
A.; Lin, J .; Saha-M o¨ ller, C. R. Fisher, R. W.; Correia, J . D. G. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2475. Oxygen insertion in C-H
bonds: See ref 11c. Baeyer-Villiger oxidation: (o) Herrmann, W. A.;
Fischer, R. W.; Correia, J . D. G. J . Mol. Catal. 1994, 94, 213.
(Table 1).
Table 1 also shows the influence of the pyridines on
1
the H NMR chemical shift of the methyl group in MTO.
The change in chemical shift serves as a guide to how
strongly the additives coordinate to the rhenium center
and reflects the Lewis base strength of the pyridines. The
addition of more basic pyridines substantially decrease
the chemical shift of MTO, which would indicate a strong
(12) MTO has, due to its high Lewis acidity, successfully been
employed as the catalyst for Diels Alder reactions; see: Zhu, Z.;
Espenson, J . H. J . Am. Chem. Soc. 1997, 119, 3507.
(13) (a) Adam, W.; Mitchell, C. M. Angew. Chem. 1996, 108, 578;
Angew. Chem., Int. Ed. Engl. 1996, 35, 533. (b) Boelow, T. R.; Spilling,
C. S. Tetrahedron Lett. 1996, 37, 2717.
(15) (a) Berrisford, D. J .; Bolm, C.; Sharpless, K. B. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1059. (b) Meunier, B. Bull. Soc. Chim. Fr.
1986, 578.
(14) (a) Al-Ajlouni, A. M.; Espenson, J . H. J . Am. Chem. Soc. 1995,
1
17, 9243. (b) Pestovsky, O.; van Eldik, R.; Huston, P.; Espenson, J .
H. J . Chem. Soc., Dalton Trans. 2 1995, 133. (c) Al-Ajlouni, A. M.;
Espenson, J . H. J . Org. Chem. 1996, 61, 3969.
(16) Herrmann, W. A.; Kratzer, R. M.; Ding, H.; Thiel, W. R.; Glas,
H. J . Organomet. Chem. 1998, 555, 293.

Efficient Epoxidation of Alkenes
J . Org. Chem., Vol. 65, No. 25, 2000 8653
Ta ble 1. In flu en ce of P yr id in e Ad d itives on th e
Ep oxid a tion of Styr en e w ith Aqu eou s Hyd r ogen
P er oxid e Ca ta lyzed by MTO
chemical
shift
yield of
conversionb epoxide
a
additive
no additive
pKa
δ (-∆δ))
(%)
(%)
2.62
100
99
100
100
95
98
85
93
94
62
70
14
58
63
69
63
5
3
1
2
3
4
3
3
-cyanopyridine
-cyanopyridine
-cyanopyridine
-chloropyridine
-fluoropyridine
-0.26 2.62 (0)
1.45 2.40 (0.22)
1.9
2.81 2.22 (0.4)
2.97 2.22 (0.4)
2.65 2.62 (0)
3.25 2.13 (0.51)
3.26 2.18 (0.44)
4.87 2.46 (0.16)
5.17 1.85 (0.77)
5.97 2.59 (0.03)
5.60 1.85 (0.77)
6.03 1.84 (0.78)
5.99 1.70 (0.92)
6.62 1.79 (0.83)
2.42 (0.2)
7
87
97
13
86
90
62
70
14
58
63
69
63
methyl picolinate
methyl nicotinate
methyl isonicotinate
quinoline
pyridine
2
3
4
4
4
-picoline
-picoline
-picoline
-tert-butylpyridine
-methoxypyridine
a
F igu r e 1. Influence of different additives on the epoxidation
of 1-decene with 30% aqueous hydrogen peroxide (2 equiv)
catalyzed by MTO (0.5 mol %) in dichloromethane at 24 °C.
The 1H NMR chemical shift of the methyl group in MTO in
the presence of 10 equiv of pyridine additives in CD2Cl2 at 25 °C.
The numbers in parentheses are the differences between the
chemical shift for MTO and the observed chemical shift upon
tion only late in the process at high alkene conversion.
Employing 3-cyanopyridine N-oxide as an additive re-
sulted in overall much lower reaction rate, which can
explain the decrease in reaction rate observed at high
alkene conversion when 3-cyanopyridine is used as
additive.18 We have recently investigated the scope of this
system, and a number of pyridines were successfully
transformed in high yields to their corresponding N-
oxides.19
b
addition of the pyridines. Reactions were run using 30% aqueous
H2O2, styrene, additive, and MeReO3 in a 400:200:20:1 molar ratio
at 24 °C for 17 h. Alkene concentration: 1.3 M in CH2Cl2. The
conversion of styrene was determined by GC analysis with respect
to internal standard.
coordination to rhenium.17 This effectively blocks the
Lewis acidic metal center from epoxide coordination
which in term is leading to better epoxide protection. The
less basic pyridines have no or little influence on the
chemical shift and can therefore be assumed to have a
much weaker coordination to the metal, a situation
leading to a decreased yield of epoxide. In summary,
these results showed that highly basic additives protect
the epoxide but are detrimental to the catalyst lifetime,
decomposing MTO into a perrhenic acid pyridine adduct
and methanol (eq 1). Less basic additives, however,
allowed higher conversion at the cost of lower selectivity.
In conclusion, terminal alkenes can efficiently be
epoxidized in high yields as a result of changing the
additive to 3-cyanopyridine. The conditions are sum-
marized in eq 2. For alkenes leading to more sensitive
epoxides, a mixture of pyridine and 3-cyanopyridine (10
mol %, respectively) as additives was successfully em-
ployed to give epoxides in high yield.20
The enhanced yields obtained employing 3-cyanopyri-
dine as an additive led us to further investigate the use
of this additive for the epoxidation of higher substituted
alkenes. First we examined trans-disubstituted alkenes,
which typically required longer reaction times using the
parent pyridine as an additive. Performing the MTO-
catalyzed epoxidation of trans-3-decene in the presence
of pyridine (12 mol %) and 3-cyanopyridine (10 mol %),
respectively, showed that using the functionalized pyri-
dine resulted in full conversion of the olefin after 7 h
whereas the reaction containing pyridine required >20
h. The substantially shorter reaction time observed with
H O
2
2
CH ReO
8 HOReO ‚2py + CH OH (1)
3 3
3
3
pyridine
Employing these observations in the epoxidation of
-decene, a substrate giving an epoxide less sensitive for
1
nucleophilic ring cleavage than styrene oxide, resulted
in a system where the addition of 10 mol % 3-cyanopy-
ridine effectively gave full conversion of the alkene in only
1
7 h. Figure 1 shows that 3-cyanopyridine turned out to
be, as in the previous study of styrene epoxidation, the
additive of choice and that the reaction with no additive
surprisingly led to higher conversion of the alkene than
in the case where pyridine was added.
It is worth noting that the epoxidation of 1-decene
containing 3-cyanopyridine was very fast up to about 85-
9
0% conversion, when the rate suddenly substantially
3
-cyanopyridine as the additive led us to further inves-
decreased. In the following workup of the reaction a white
precipitate was isolated and characterized as 3-cyanopy-
ridine N-oxide. In fact, MTO has previously been used
as a catalyst for the oxidation of amines to nitrones and
in one example pyridine to its N-oxide.1 However, the
oxidation of this additive did compete with the epoxida-
tigate how various factors as amount of catalyst, amount
of additive and the alkene concentration influence the
1c
(18) The epoxidation of 1-decene with 30% aqueous hydrogen
peroxide catalyzed by MTO containing 3-cyanopyridine N-oxide (10 mol
%) as additive shows a first-order kinetics for the alkene.
(
19) Cop e´ ret, C.; Adolfsson, H.; Khuong, T.-A. V.; Yudin, A. K.;
(17) Complexation constants have been determined for the reaction
Sharpless, K. B. J . Org. Chem. 1998, 63, 1742.
between a number of pyridines and MTO; see: Wang, W.-D.; Espenson,
J . H. J . Am. Chem. Soc. 1998, 120, 11335.
(20) For the scope of the MTO-catalyzed epoxidation of terminal
alkenes in the presence of 3-cyanopyridine, see ref 8b.

8
654 J . Org. Chem., Vol. 65, No. 25, 2000
Adolfsson et al.
F igu r e 2. Reaction profiles for the epoxidation of trans-3-decene with 30% aqueous hydrogen peroxide catalyzed by MTO (0.3
mol %) in the presence of various amounts of (a) 3-cyanopyridine and (b) pyridine, respectively.
F igu r e 3. Plots showing the influence of varying the amount additive in the epoxidation of trans-3-decene with 30% aqueous
hydrogen peroxide (2 equiv) catalyzed by MTO (0.3 mol %) at ambient temperature: (a) 1 mol % additive, reaction time 4 h; (b)
1
0 mol % additive, 8 h.
MTO-catalyzed epoxidation of trans-substituted alkenes
with aqueous hydrogen peroxide.
the lower amount of the additive. Thus, full conversion
of trans-3-decene was obtained after only 4 h using 1 mol
% of 3-cyanopyridine (Figure 2a).
We initially focused on the amount of catalyst required
for achieving full conversion. When the reaction condi-
tions from the above epoxidation of terminal alkenes were
used, i.e., 10 mol % of 3-cyanopyridine, 2 equiv of 30%
aqueous hydrogen peroxide at an alkene concentration
of 2 M in dichloromethane, varying the amount of MTO
showed that the minimum catalyst loading necessary for
full conversion of trans-3-decene to trans-3,4-epoxydecane
was 0.3 mol % compared to 0.5 mol % required in the
pyridine system.
We then focused our attention upon the additive and
more so upon the importance of electronic and steric
effects from various pyridine additives on the epoxidation
of trans-3-decene. Figure 2 shows the reaction profiles
for the epoxidation of trans-3-decene with aqueous hy-
drogen peroxide catalyzed with 0.3 mol % MTO in the
presence of various amounts of 3-cyanopyridine and
pyridine, respectively. Interestingly, the lower amount
of 3-cyanopyridine resulted in higher conversion in
shorter time while the opposite is true for pyridine where
the catalytic activity completely is lost after 1 h using
To further investigate the importance of the additives,
we extended the study using the following substituted
pyridines: 2-, 3-, and 4-cyanopyridine, the methyl esters
of picolinic, nicotinic, and isonicotinic acid, the parent
pyridine, and 2-, 3-, and 4-picoline. The reaction without
any additive was also included for comparison. Thus,
screening the epoxidation reaction using exactly the same
conditions in each case, i.e., 0.3 mol % MTO, 2 equiv of
30% aqueous hydrogen peroxide at an alkene concentra-
tion of 2 M in dichloromethane, and varying only the
amount and substituent of the pyridine additive gave the
following results: Using 1 mol % of additive showed that
the cyanopyridines, independently on the position of
substitution, gave high conversion of the alkene within
only a short time (Figure 3a), whereas all the other
additives in the study typically showed low conversion.
It is worth pointing out that 3-cyanopyridine still was
the best of the additives.
Increasing the amount of additives successively from
1 mol % to 10 mol % resulted in longer reaction times

Efficient Epoxidation of Alkenes
5-8 h) to reach full conversion (3-cyanopyridine). The
J . Org. Chem., Vol. 65, No. 25, 2000 8655
(
reaction mixtures containing 10 mol % of additives
showed very small differences and went almost to comple-
tion within 8 h, the exceptions being the 2-substituted
pyridines, methyl picolinate, and 2-picoline, where the
former effectively slows down the reaction and the latter
completely inhibits the epoxidation of the alkene. In
conclusion, the additive of choice for trans-disubstituted
alkenes turned out to be, as in the case of epoxidation of
terminal alkenes, 3-cyanopyridine, with the big difference
that only 1 mol % additive was required for full conver-
sion in a short time.
The alkene concentration was also demonstrated to be
of importance, and an increase of the concentration of
trans-3-decene from 2 to 3 M with respect to the organic
solvent, using 0.3 mol % MTO, 10 mol % 3-cyanopyridine,
and 2 equiv of 30% aqueous hydrogen peroxide, dramati-
cally shortened the reaction time to only 3 h. For best
results in general, however, alkene concentrations of 2
M is recommended, due to the potential change of
reaction medium (low polarity) obtained when higher
concentrations are used. It is worth pointing out that
transition metal catalyzed oxygen transfer reaction typi-
cally works better when the amount hydrocarbon solvents
is kept at a low level, due to decreased solvation of the
active catalysts.21 The optimized conditions for epoxida-
tion of trans-disubstituted alkenes are summarized in eq
F igu r e 4. Effect of different stirring rates in the biphasic
epoxidation of cyclooctene with aqueous hydrogen peroxide
catalyzed by MTO with or without pyridine additive.
Sch em e 2
3
.
Employing 3-cyanopyridine as the additive for the
epoxidation of cis-disubstituted or other more electron-
rich alkenes (tri- or tetrasubstituted alkenes) did not
result in any improvements compared to when the parent
pyridine was added. In fact, lower reaction rates and less
product protection was typically observed; thus, for faster
reacting alkenes (more electron-rich substrates) the
system containing 12 mol % pyridine gives the best
results in terms of conversion and selectivity.
Th e Role of th e Ad d itive. Addition of pyridine or
pyridine derivatives to the MTO-catalyzed epoxidation
of alkenes clearly have an improving effect, both in
increasing the rate of the reaction and protecting the
formed epoxide from Lewis acid mediated nucleophilic
ring-opening reactions. The origin of the rate-improving
effect is still not fully understood, but several observa-
tions of the reaction indicates that the pyridine or
pyridine derivatives play an important role as phase-
transfer catalysts, transporting the peroxo complexes of
MTO from the aqueous layer into the organic phase. This
serving the reaction profile obtained when the epoxida-
tion reaction is performed with different stirring rates
(Figure 4).
In the epoxidation of cyclooctene with 30% aqueous
hydrogen peroxide catalyzed by MTO (0.3 mol %) with a
stirring rate at 200 rpm we observed a dramatic increase
in conversion of the alkene when pyridine was added
compared to the reaction without any additive. This effect
was even more pronounced when the rate of stirring was
increased to 700 rpm. On the negative side, the more
basic pyridines also display a clearly detrimental effect
on the catalyst lifetime (Scheme 2).
MTO is known to be stable under acidic conditions but
when treated with base under oxidative aqueous condi-
tions, the formation of perrhenic acid and methanol is
an important side reaction.22 Even a weak base like water
can act destructively on the catalyst, forming a perrhenic
acid-base adduct, which under these conditions is a
2
3
completely inactive oxygen-transfer catalyst. This ex-
plains why the system containing pyridine as the sole
additive is only able to successfully epoxidize electron-
rich and thereby faster reacting alkenes, since these
can easily be observed from the bright yellow color of the
peroxo complexes of MTO,17 that in the absence of any
additive is only observed in the aqueous layer, whereas
upon addition of pyridine or a pyridine derivative, the
yellow peroxo complexes are transported into the organic
phase. Further evidence indicating that the pyridine
additives act as phase-transfer agents comes from ob-
(22) (a) Abu-Omar, M. M.; Hansen, P. J .; Espenson, J . H. J . Am.
Chem. Soc. 1996, 118, 4966. (b) Yudin, A. K.; Sharpless, K. B.
Unpublished results.
(
23) Inorganic rhenium compounds are inactive as oxidation cata-
(
21) The use of saturated hydrocarbon solvents in metal catalyzed
lysts in the presence of aqueous hydrogen peroxide. This problem can,
however, be overcome using bistrimethylsilyl peroxide (BTSP) as the
terminal oxidant; see: (a) Yudin, A. K.; Sharpless K. B. J . Am. Chem.
Soc. 1997, 119, 11536. (b) Coper e´ t, C.; Adolfsson, H.; Chiang, J . P.;
Yudin, A. K.; Sharpless, K. B. Tetrahedron Lett. 1998, 39, 761.
oxidations reactions is known to dramatically change the catalyst
composition and thereby decreasing the catalytic activity; see: Wod-
dard, S. S.; Finn, M. G.; Sharpless, K. B. J . Am. Chem. Soc. 1991,
1
13, 106.

8
656 J . Org. Chem., Vol. 65, No. 25, 2000
Ta ble 2. Rela tive In itia l Ra tes of Alk en e Ep oxid a tion a
Adolfsson et al.
a
Reactions were run using 30% aqueous H2O2, alkene, and MeReO3 in a 2000:1000:3 molar ratio at 24 °C with stirring at 700 rpm.
Amounts of additive as noted above. Alkene concentration: 2 M in CH2Cl2. The initial rates were determined by GC analysis of the
conversion for each alkene, respectively, and the relative rates were calculated from the observed rate constants with the initial rate for
1
-decene without additive normalized to 1. The numbers in parentheses are the relative initial rates for each additive, respectively.
reactions are fast enough to occur before a considerable
amount of the catalyst is decomposed. 3-Cyanopyridine,
however, being less basic than the parent pyridine, has
a less detrimental effect on the catalyst lifetime and can
therefore serve as an additive for slower reacting alkenes.
In a recent study, Espenson and Wang investigated the
effects of pyridine on the equilibrium and kinetics in the
MTO/aqueous hydrogen peroxide system.17 The observed
results indicated that the accelerating effect obtained
upon addition of pyridine is strongly connected to the
Br o¨ nsted basicity of the heterocycle. Thus, the presence
of pyridine increases the concentration of the mono-
Epoxidation of cis- and trans-disubstituted alkenes is
stereospecific and gives the corresponding epoxides with
retention of configuration. The relative initial rate be-
tween cis- and trans-alkenes (Z/E ) 2:1) are somewhat
higher than the ratio observed when m-chloroperbenzoic
acid is used as the oxidation reagent (3-octene, Z/E ) 1.2:
5
b
1). This is in sharp contrast to dimethyldioxirane (3-
25
hexene, Z/E ) 8.3:1) and the sodium tungstate system
5
b
developed by Noyori et al. (3-octene, Z/E ) 7.3:1) which
show a much higher reactivity toward cis-alkenes. The
situation changes dramatically when using 10 mol % of
3-cyanopyridine as the additive. Relative initial rates for
this system show a much smaller difference between
terminal and disubstituted alkenes, which in terms
explains the observed reactivity of this system where
reactions performed on terminal alkenes with 3-cyan-
opyridine as the additive works better than when the
unfunctionalized pyridine is added. There is practically
no difference in initial rates between cis- and trans-
disubstituted alkenes for the system containing 3-cyan-
opyridine (Z/E ) 1:1.2), and in contrast to the pyridine
system, the trans-alkenes react slightly faster. Interest-
ingly, with the exception of terminal alkenes, the system
containing 1 mol % of 3-cyanopyridine shows higher
initial reactivity toward each class of alkenes compared
to when 10 mol % of the additive is present. The similar
relative initial rates observed for the systems containing
pyridine and 1 mol % 3-cyanopyridine indicate that the
latter could be the additive of choice also for more
substituted alkenes. In our hands, however, the simple
pyridine system performs with full satisfaction in epoxi-
dations of alkenes other than terminal- and trans-
disubstituted ones.
-
hydrogen peroxide anion (HOO ), which results in a
faster formation of the peroxo-complexes of MTO. The
-
higher concentration of HOO is also increasing the rate
of MTO decomposition. The latter is in agreement with
the fact that, in the presence of the less basic 3-cyan-
opyridine, the lifetime of the catalyst seems to be
considerable longer. The isolation of 3-cyanopyridine
N-oxide after the epoxidation reaction speaks clearly
against the possibility that the additive is involved in a
oxygen transfer process similar to the Payne epoxida-
tion.24 The latter reaction would lead to the formation
3
-pyridinecarboxamide or its N-oxide. The Payne epoxi-
dation also requires a stoichiometric amount of the
nitrile.
Ca ta lytic P er for m a n ce. High initial rates are of
great significance in a system where catalyst decomposi-
tion is an important side reaction competing with the
reaction path leading to product. Thus, lower conversion
can be expected for slow reacting substrates since longer
reaction times results in more catalyst deactivation. This
is indeed true for the MTO catalyzed epoxidation of
alkenes where the lifetime of the catalyst certainly is
limited, especially under basic reaction conditions (vide
supra). The differences between the two epoxidation
systems discussed above (pyridine and 3-cyanopyridine
as additives respectively) are clearly visualized when
comparing the relative initial rates these systems show
for alkenes with various substitution patterns. As shown
in Table 2, the pyridine system shows a reactivity toward
the alkenes following the expected order for electrophilic
epoxidations, where a rate increase is expected when the
electron density of the substrates increases.
Scop e a n d Lim ita tion s. With the optimized condi-
tions in hand, we then investigated the catalytic activity
of the above system containing 1 mol % of 3-cyanopyri-
dine as additive on various trans-disubstituted alkenes.
As listed in Table 3 this epoxidation method shows high
applicability on a wide variety of substrates. Linear as
well as the sterically more demanding branched alkenes
are all epoxidized in good yields (entry 1-4) and in
shorter reaction times compared to the previously re-
ported pyridine containing system. Severe steric hin-
drance in positions next to the alkene did not dramati-
(24) Payne, G. B. Tetrahedron 1962, 18, 763.
(25) Baumstark, A. L.; Vasquez, P. C. J . Org. Chem. 1988, 53, 3437.

Efficient Epoxidation of Alkenes
J . Org. Chem., Vol. 65, No. 25, 2000 8657
Ta ble 3. Ep oxid a tion of tr a n s-Alk en es w ith Hyd r ogen P er oxid e, Ca ta lyzed by Meth yltr ioxor h en iu m in th e P r esen ce of
-cya n op yr id in ea
3
a
0% aqueous H2O2 (2 equiv) used unless otherwise noted. b Isolated yield. c 50% aqueous H2O2 (2 equiv).
3
Ta ble 4. Ep oxid a tion of P h en yl-Su bstitu ted tr a n s-Alk en es w ith Hyd r ogen P er oxid e, Ca ta lyzed by Meth yltr ioxor h en iu m
in th e P r esen ce of 3-Cya n op yr id in e a n d P yr id in ea
a
0% aqueous H2O2 (2 equiv) used in all entries. b Isolated yield. c Conversion to epoxide, no diol was detected. No further conversion
3
after 20 h.
cally affect either the yield or the reaction time. This is
to be compared to the epoxidation of trans-2,5-dimethyl-
cocktail is not clear, but performing reactions on phenyl-
substituted alkenes using only one of the additives results
in lower yields of epoxides (cf. Table 1; epoxidation of
styrene). For high selectivity in epoxidations of the
alkenes in Table 4 the following requirements need to
met: (1) the MTO catalyst must be stabilized against
decomposition, and (2) the products need to be protected
against ring opening. The cocktail provides a combination
which satisfy these criterea. Electron-poor alkenes as
ethyl cinnamate did not perform well under these epoxi-
dation conditions (entry 5).
3
-hexene catalyzed by MTO (0.5 mol %) and pyridine (12
mol %) where only 68% was obtained after 17 h. Func-
tional groups as alcohols or esters do not interfere with
the epoxidation reaction and good yields were obtained
with allylic and homoallylic 1-hexanols, in this case with
a catalyst amount of only 0.2 mol % (entry 5 and 6). High
yields were also obtained in the epoxidation of noncon-
jugated unsaturated esters (entry 7 and 8). Alkenes
yielding epoxides more sensitive to nucleophilic ring
opening, e.g., phenyl-substituted alkenes, required a
mixture of 3-cyanopyridine and pyridine (10 and 5-10
mol % respectively) for a successful outcome of the
reaction. These results are presented in Table 4. The
yield of trans-stilbene was significantly increased using
the mixture of pyridines compared to the system contain-
ing only pyridine as the additive8 (entry 2). The epoxi-
dation of cinnamyl acetate with 0.5 mol % MTO and 12
mol % pyridine resulted in 54% conversion, whereas
using the cocktail (3-cyanopyridine and pyridine) and
only 0.3 mol % catalyst gave a significantly higher yield
Con clu sion s
We have shown that changing the additive from
pyridine to 3-cyanopyridine in the MTO-catalyzed epoxi-
dation of alkenes with the environmental friendly oxidant
aqueous hydrogen peroxide has several beneficial effects.
Epoxidation of terminal alkenes can efficiently be ac-
complished in high yields using 10 mol % 3-cyanopyridine
and 0.5 mol % catalyst. Trans-disubstituted alkenes were
successfully epoxidized using only 0.3 mol % catalyst and
1-2 mol % 3-cyanopyridine. Alkenes leading to acid-
a
(entry 4). The role of the two pyridines used in the

8
658 J . Org. Chem., Vol. 65, No. 25, 2000
Adolfsson et al.
The reaction mixture was stirred for 6 h when MnO was
added in portions. When no more oxygen gas evolution was
observed, the phases were separated and the aqueous layer
sensitive epoxides were oxidized in high yields using a
cocktail consisting of pyridine and 3-cyanopyridine. Py-
ridine is, however, still the additive of choice for epoxi-
dation of more electron-rich alkenes. The epoxidation
system shows high tolerance toward functional groups
in the substrates. The role of the additives in the system
can to a great extent be explained by phase-transfer
effects, where the pyridine additives take part in the
transfer of the active peroxospecies of MTO into the
organic solvent. Basic additives were shown to be very
deleterious to the lifetime of the catalyst, presumable due
2
was washed with CH
phases were dried with Na
2
Cl
2
(2 × 20 mL). The combined organic
2
SO (s), and the solvent was
4
removed under reduced pressure. The obtained crude was
distilled under vacuum to yield 1.53 g (98%) of trans-3,4-
epoxydecane.
St a n d a r d P r oced u r e for E p oxid a t ion of P h en yl-
Su bstitu ted Alk en es Exem p lified for tr a n s-Stilben e. To
a 250 mL Erlenmeyer flask were added trans-stilbene (54.07
g, 300 mmol), 3-cyanopyridine (3.12 g, 30 mmol), pyridine (2.37
g, 30 mmol), MTO (374 mg, 1.5 mmol), and 50 mL of CH Cl .
2 2
The flask was placed in a water bath (24 °C), and 30% aqueous
hydrogen peroxide (68 mL, 600 mmol) was added. The reaction
-
to the formation of higher concentrations of HOO . The
obtained enhancement of the system using 3-cyanopyri-
dine as an additive can partly be explained by its lower
mixture was stirred for 17 h when MnO
2
was added in
pK
a
, which in term is leading to a slower decomposition
portions. When no more oxygen gas evolution was observed,
the phases were separated and the aqueous layer was washed
rate of the catalyst.
with CH
dried with Na
2
Cl
2
(2 × 200 mL). The combined organic phases were
Exp er im en ta l Section
2
SO (s), and the solvent was removed under
4
reduced pressure. The obtained crude was recrystallized from
ethanol to yield 54.16 g (92%) of trans-stilbene oxide: mp 68-
70 °C (65-67 °C).
All reagents and solvents were purchased and used without
further purification. All reactions were carried out at ambient
temperature (24 °C, water bath) under air.
P r oced u r e for th e Rela tive In itia l Ra te Deter m in a -
tion . In a 20 mL scintillation vial were added alkene (10
mmol), MTO (0.03 mmol), additive, cyclooctane or dodecane
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM 28384), the National Science
Foundation (CHE 9521152), the W. M. Keck Founda-
tion, the Skaggs Institute for Chemical Biology, and the
Scripps Research Institute for financial support to the
Sharpless laboratory. Professor K. Barry Sharpless is
greatly acknowledged for his support and all the inspir-
ing discussions. We also thank Dr. J oachim Rudolph for
the initial discovery of the pyridine effect on the MTO
epoxidation system. H.A. and C.C. are grateful to the
Swedish Natural Science Research Council and the
Association des Amis des Sciences for postdoctoral
fellowships, respectively.
2 2
(100 µl) as internal standard, and CH Cl to give a 2.0 M
concentration of the alkene in the organic solvent. The stirring
was set to 700 rpm, temperature regulated to 24 °C (water
2 2
bath), and 2 mL of aqueous H O (20 mmol) was added. The
reaction was monitored by taking aliquots (40 µL) at different
time intervals (initially every 30 s for the faster reacting
alkenes). The samples were quenched by addition of the
aliquots to MnO
2
, diluted with ethyl acetate (2 mL), and dried
with Na SO . The samples were analyzed by GC, and the
2
4
initial rates were determined from the conversion of alkene
versus time plots by comparing the slopes of the straight lines
obtained.
Sta n d a r d P r oced u r e for Ep oxid a tion of Tr a n s-Disu b-
stitu ted Alk en es Exem p lified for tr a n s-3-Decen e. To a
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic char-
acterization of the products and plots for relative initial rate
determinations. This material is available free of charge via
the Internet at http://pubs.acs.org.
2
0 mL scintillation vial were added trans-3-decene (1.40 g, 10
mmol), 3-cyanopyridine (0.2 mL 1 M in CH Cl , 0.2 mmol),
MTO (0.3 mL 0.1 M in CH Cl , 0.03 mmol), and 1.6 mL of CH
Cl . The flask was placed in a water bath (24 °C), and 30%
aqueous hydrogen peroxide (2.26 mL, 20 mmol) was added.
2
2
2
2
2
-
2
J O005623+