Efficient electrophilic and nucleophilic epoxidations utilizing a sulfonylperoxy radical and peroxysulfate species

Article abstract of DOI:10.1002/hc.10078

Reaction of superoxide anion radical (O₂^-. with o-nitrobenzenesulfonyl chloride yields a o-nitrobenzenesulfonyl peroxy radical with strong oxidizing ability, which is capable of oxidizing aryl methylene moieties to aryl ketones and relatively electron-rich alkenes regioselectively to epoxides. The oxidizing species is tentatively attributed to the o-nitrobenzenesulfonyl peroxy radical of structure 1. Tetrabutylammonium peroxydisulfate (TBA)₂S₂O₈, 2) was prepared by the reaction of tetrabutylammonium hydrogen sulfate with potassium peroxydisulfate. The epoxidation of enals and enones, such as α,β-unsaturated aldehydes or ketones, was efficiently achieved with 2 in the presence of hydrogen peroxide and base in acetonitrile or in methanol at 25°C. A base-sensitive substrate, such as cinnamaldehyde, could be successfully epoxidized under mild reaction conditions and in short reaction time.

Full text of DOI:10.1002/hc.10078

Heteroatom Chemistry
Volume 13, Number 5, 2002
Efficient Electrophilic and Nucleophilic
Epoxidations Utilizing a Sulfonylperoxy Radical
and Peroxysulfate Species
Min Young Park, Seung Gak Yang, and Yong Hae Kim
Center for Molecular Design and Synthesis, Department of Chemistry, Korea Advanced Institute
of Science and Technology, Taejon 305-701, South Korea
Received 22 June 2001; revised 5 April 2002
INTRODUCTION
ABSTRACT: Reaction of superoxide anion radical
(O2 ) with o-nitrobenzenesulfonyl chloride yields a
o-nitrobenzenesulfonyl peroxy radical with strong ox-
idizing ability, which is capable of oxidizing aryl
methylene moieties to aryl ketones and relatively
electron-rich alkenes regioselectively to epoxides. The
oxidizing species is tentatively attributed to the
o-nitrobenzenesulfonyl peroxy radical of structure 1.
Intensive research interests [1] in the physical prop-
erties and chemical reactivities of the superoxide ion
have stimulated the development of organic synthe-
ses using the superoxide anion as a key reagent. Only
a few studies of the oxidation of sulfur compounds,
such as thiols [2], thiouracils [3], disulfides [4], and
sulfur halides [5], have been reported.
Tetrabutylammonium peroxydisulfate ((TBA)2 S O8, 2)
Earlier, a peroxysulfonate intermediate was pos-
tulated by Berger [6] to be the key reagent in alkaline
autoxidation of thiols to sulfonates. The superoxide
anion radical (O2 ) displays three basic modes of
operation, a base, an anion, and a radical, but in
general, it is a very weak oxidizing agent. In order
to increase the usefulness of O2 , it has been ex-
amined in reactions with various substrates such as
disulfides, sulfinyl chlorides, and sulfonyl chlorides.
o-Nitrobenzenesulfonyl chloride was found to be the
most interesting and useful substrate, and it was re-
acted with O2 in MeCN at ca. 30 C to form the
o-nitrobenzenesulfonyl peroxy radical 1, which is
stable enough for use in organic syntheses at low
temperatures [7] (Scheme 1).
2
was prepared by the reaction of tetrabutylammo-
nium hydrogen sulfate with potassium peroxydisul-
fate. The epoxidation of enals and enones, such
as , -unsaturated aldehydes or ketones, was effi-
ciently achieved with 2 in the presence of hydro-
gen peroxide and base in acetonitrile or in methanol
at 25 C. A base-sensitive substrate, such as cin-
namaldehyde, could be successfully epoxidized un-
der mild reaction conditions and in short reaction
C
time.
2002 Wiley Periodicals, Inc. Heteroatom Chem
13:431–436, 2002; Published online in Wiley Interscience
(www.interscience.wiley.com). DOI 10.1002/hc.10078
The epoxidation of electron-deficient olefins
such as ␣,␤-unsaturated ketones or aldehydes has
been an important target for the functionalizations
of ketones or aldehydes in organic synthesis. In
contrast to the electrophilic epoxidation of alkenes,
generally epoxidation of electron-deficient olefins re-
quires the use of a nucleophilic oxidant employed un-
der the alkaline condition. A number of epoxidations
of electron-deficient olefins have been developed us-
ing tert-butyl peroxide [8], hydrogen peroxide [9],
Dedicated to Prof. Shigeru Oae on the occasion of this memorial
symposium.
Correspondence to: Yong Hae Kim; e-mail: kimyh@sorak.kaist.
ac.kr.
Contract grant sponsor: KOSEF.
Contract grant number: R03-2001-00033.
Contract grant sponsor: School of Molecular Science of MOE.
2002 Wiley Periodicals, Inc.
c
431

432 Park, Yang, and Kim
SCHEME 1
peroxide-ammonium fluoride [10], sodium perbo-
rate [11], or dioxirane [12] under strong alkaline con-
ditions. However, in general, the known methods for
the epoxidations require a relatively long reaction
time and the yields are varied depending upon the
substrates and reaction conditions. We have been
interested in the epoxidation of electron-deficient
olefins, such as ␣,␤-unsaturated ketones, utilizing a
peroxysulfonate. In our earlier work [13], attempts
to epoxidize the electron-deficient double bond by
use of a sulfonyl peroxy intermediate under alkaline
conditions failed. Now, the sulfonyl peroxy interme-
diate 1 turned out to be a sulfonyl peroxy radical,
which showed a strong electrophilic oxidizing ability
to epoxidize a double bond of a chain or ring com-
pound regioselectively.
SCHEME 3
rate constants for the oxidative decarboxylation of
various substituted phenylacetates relative to pheny-
lacetate were found to decrease with decreasing elec-
tron density at the benzylic carbon. Radical 1 shows
an electrophilic oxidation ability toward arylacetic
acids that can be correlated by the Hammett’s equa-
tion, Hammett’s
[15].
The ␣-C H bonds of benzylic ethers, in various
substrates having benzylic ether groups, were also
found to be oxidized by 1, and gave the correspond-
ing benzylic esters in good yields [16] (Scheme 4).
These reactions can be rationalized by invoking the
radical process with 1. In order to measure the ef-
fects of p-substituents on the oxidation of benzylic
ethers, competitive oxidations of p-substituted ben-
zylic propyl ethers with 1 were carried out. The re-
+
value being 0.408 (␥ = 0.9996)
RESULTS AND DISCUSSION
Benzylic methylene moieties were oxidized by 1 to
give ketones in high yields under mild conditions
[14] (Scheme 2). In order to confirm the radical
character of 1 and to extend its utility, oxidations of
arylacetic acids have been achieved to give the cor-
responding ketones or aldehydes and alcohols (see
Scheme 3) [15]. Competitive decarboxylation reac-
tions between phenylacetic acid and p-substituted
phenyl acetic acids were carried out. The ratios of
sults could be correlated by Hammett’s equation us-
+
ing
rather than constants of substituents in the
+
aromatic ring and with a value of
=
0.57 (r =
0.99). This + value indicates that 1 is an electrophilic
+
species and the value of
is comparable to the
+
( 0.65) for benzylic hydrogen abstraction from
dibenzylic ethers by the benzoyloxyl radicals [17].
It may be possible that the intermediate 1 is
converted to the anion 10 by a one-electron trans-
fer from O2 under alkaline conditions (Scheme 5).
Thus, if 10 exists, nucleophilic epoxidations of ␣,␤-
unsaturated carbonyl compounds with 10 would be
expected. However, electrophilic epoxidations on
SCHEME 2
SCHEME 4

Efficient Electrophilic and Nucleophilic Epoxidations Utilizing a Sulfonylperoxy Radical and Peroxysulfate Species 433
SCHEME 7
SCHEME 5
ing K-region arene oxides by treatment with 1. An-
thracene was oxidized to anthraquinone under the
same conditions. It is interesting that various arenes
were readily oxidized to their oxides under mild con-
ditions. Such arene oxides are important metabo-
lites formed in vivo from processes catalyzed by
monooxygenase [20, Y. H. Kim, K. S. Kim, and B. C.
Jung, unpublished data.] (Scheme 9).
Metabolic degradation of polyaromatic hydro-
carbons is believed to be caused by oxidation by a cer-
tain activated oxygen, namely by an enzyme present
in all aerobic organisms and also soil bacteria [20].
2-Methylnaphthalene is oxidized to phthalic acid, to-
gether with other unidentified products by 1 under
mild conditions (Y. H. Kim, K. S. Kim, and B. C. Jung,
unpublished data.) (Scheme 10). The oxidation is
considered to be initiated via epoxidation of an aro-
matic ring, followed by fragmentations to carbonyl
compound. It is intriguing that the aromatic ring can
be readily destroyed at low temperature because de-
struction of the aromatic ring usually requires a high
energy process under drastic conditions.
Biomimetic oxidation of triacetylated inosine
to triacetylated xanthosine was carried out with 1.
The oxidation appears to be initiated via the forma-
tion of an aziridine, followed by conversion into the
monooxygenated product (Scheme 11).
In our earlier work [21] we reported that various
␣,␤-unsaturated ketones reacted with 2 in the pres-
ence of H2O2 and NaOH in CH3CN at 25 C to give
the corresponding epoxides in excellent yields. The
yields of epoxidation were generally varied depend-
ing on the reaction conditions as shown in Table 1.
The best solvent used is acetonitrile or methanol
(entries 4, 8, and 9 in Table 1) which may be at-
tributed to the increase of the solubility of base in
the polar solvents. Among a variety of bases, better
results were obtained by the use of sodium hydroxide
(95% in acetonitrile, entry 4, and 98% in methanol,
the other double bonds of L-carvone, and ␣- and
␤-ionone occurred as shown in Scheme 6. From
these results it appears that, the sulfonylperoxy rad-
ical intermediate 1, and not the anion type 10, is
involved in these reactions.
Highly strained acenaphthalene was smoothly
epoxidized in quantitative yields at 30 C in acetoni-
trile by the use of 1 (Scheme 7). Acenaphthalene ox-
ide is known to be unstable under acidic conditions,
but more stable under basic conditions [18]. Thus,
acenaphthalene oxide could be isolated in higher
yield by the use of 1 as the oxidant than that obtained
by other known methods [19], perhaps because of the
stability of the product under basic conditions. Here,
the sulfonyl peroxy intermediate is likely to be more
of the character of a radical rather than an anion.
When cis-stilbene was reacted with 1 at 30 C in
MeCN, a mixture of trans- (70%) and cis-oxide (30%)
was obtained (Scheme 8). If the peroxy intermediate
1 is anionic, stereospecific epoxidation of cis-stilbene
to cis-epoxide may occur.
Arene oxides and their subsequent metabolites
have been implicated as the intermediates which are
responsible for the carcinogenicity and mutagenicity
of polyaromatic hydrocarbons, and there has been a
considerable interest both in the related chemical re-
actions and in understanding how they are formed
physiologically. Polyaromatic compounds, such as
phenanthrene and pyrene, which are inert to super-
oxide itself, were readily oxidized to the correspond-
SCHEME 6
SCHEME 8

434 Park, Yang, and Kim
TABLE 1 Ketones Under Various Conditions
2/H2O2/Base
4a
→ 5a
solvent
Entry
2/H2O2 (equiv)
Base (equiv)
Solvent
Time (min)
Yield a (%)
1
2
3
4
5
6
7
8
9
1/1
1/–
–/1
1/1
1/1
1/1
1/1
1/1
0.5/0.5
K2CO3 (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (0.5)
CH3CN
CH3CN
CH3CN
CH3CN
Benzene
CH2Cl2
CHCl3
60
60
60
30
60
60
60
5
50
Trace
30
95
10
65
73
98
90
MeOH
MeOH
10
aIsolated yield.
entry 8). When potassium carbonate was used as a
base, the yield was low (50% in acetonitrile, entry 1).
An equimolar amount of H2O2 and NaOH in the ab-
sence of 2 resulted in a low yield under the same con-
ditions (30%, entry 3). In the absence of H2O2, trace
amount of epoxide was isolated (entry 2). When 0.5
equiv of each 2, H2O2, and NaOH (entry 9) were used,
the epoxide was obtained in about 90% yield. This
result indicates that 0.5 equiv of each 2 and HOO
form a stoichiometric amount of 3 with respect to
the substrate, as shown in Scheme 12.
SCHEME 9
The epoxidation of various electron-deficient
olefins was carried out in acetonitrile solvent using 1
equiv each of 2 and H2O2 in the presence of 1 equiv
of NaOH at 25 C. Cyclic enones and a chain double
bond of an ␣,␤-unsaturated carbonyl group can be
smoothly epoxidized. The results obtained are shown
in Table 2.
Concerning the epoxidation mechanism, the
epoxidations appears to be initiated by the formation
of peroxysulfate anion 3 by the attack of HOO on
2. The 1,4-addition of 3 to ␣,␤-unsaturated ketones
or aldehydes may produce the epoxide products, to-
gether with tetrabutylammonium sulfate 6, as shown
in Scheme 13.
SCHEME 10
Tetrabutylammonium sulfate 6 was actually iso-
lated in 80% yield. There are two competitive routes
for the epoxidation of an enone: one is epoxidation
by 3 and the other one is epoxidation by HOO . The
main epoxidaion route by 3 can be rationalized by
the following results. Equivalent amounts of 2, H2O2,
and NaOH gave the best yields (entry 4, 8, and 9 in
Table 1). Equivalent amounts of H2O2 and NaOH
in the absence of 2 resulted in a low yield (entry
3 in Table 1) under the same reaction conditions.
The peroxydisulfate 2 without using H2O2 afforded
a trace amount of epoxide (entry 2 in Table 1). The
SCHEME 11

Efficient Electrophilic and Nucleophilic Epoxidations Utilizing a Sulfonylperoxy Radical and Peroxysulfate Species 435
SCHEME 13 Possible mechanism for epoxidation.
by nucleophilic epoxidations with tetrabutylammo-
nium peroxysulfate anion 3. Furthermore, acetal,
ketal, and thioether moieties have been found to be
inert to 2 in the furanylation and pyranylation of
alcohols [22] and in the oxidation of alcohols. The
present epoxidation may provide a practically effi-
cient method for epoxidations of electron-deficient
carbonyl compounds under mild conditions contain-
ing various functional groups.
SCHEME 12
EXPERIMENTAL
stronger nucleophilicity of HOO over HO may be
the reason for the formation of 3 more easily. Such
a peroxysulfate 3 has neither been isolated nor con-
firmed. However, judging from the above results, the
new epoxidation should involve such a tetrabutylam-
monium peroxysulfate 3, which shows a strong nu-
cleophilic oxidizing ability.
In conclusion, o-nitrobenzenesulfonylperoxy ra-
dical, intermediate 1, which shows strong oxidizing
ability, oxidized benzyl ethers to the corresponding
benzyl esters in situ at 35 C in acetonitrile in excel-
lent yields, and relatively electron rich alkenes were
regioselectively epoxidized in good yields. However,
cyclic and acyclic ␣,␤-unsaturated ketones were
smoothly oxidized to the corresponding epoxides
Electrophilic Epoxydation with 1
In a general procedure, a solution of 2-nitrobenzen-
esulfonyl chloride (220 mg, 1 mmol) and L-carvone
(90 mg, 0.6 mmol; 2 ml CH3CN) was added to a heter-
ogeneous solution of potassium superoxide (222 mg,
3 mmol; 1 ml CH3CN) at ca. 35 C maintained under
a dry argon atmosphere. After having been stirred for
ca. 4 h at ca. 35 C, the reaction mixture was con-
centrated and then extracted with CHCl3; concen-
tration of the CHCl3 layer gave highly pure epoxide
(78 mg, 87%). Further purification by preparative
TLC afforded pure epoxide (74.8 mg, 83%).
Nucleophilic Epoxidation with 2
The following experimental procedure is represen-
tative. 2-Cyclohexen-1-one (98 mg, 1 mmol) was dis-
solved in anhydrous acetonitrile (1 ml). The solution
of 2 (667 mg, 1 mmol) and sodium hydroxide (40 mg,
1 mmol) in anhydrous acetonitrile (4 ml) was added
and then hydrogen peroxide (50% w/w, 0.052 ml,
1 mmol) was slowly added to the reaction mixture.
After having been stirred for 0.5 h at 25 C with mon-
itoring of the reaction by TLC, the reaction mixture
was extracted with methylene chloride (30 ml 3),
washed with water, dried over anhydrous MgSO4,
and concentrated in vacuo to give a crude product
TABLE 2 Epoxidation of , -Unsaturated Carbonyl Com-
pounds in Acetonitrile at 25 Ca
Entry
Substrate
Time (min)
Product
Yield b (%)
1
2
3
4
5
6
4a
4d
4e
4f
4g
4h
30
150
30
30
30
5a
5d
5e
5f
5g
5h
95
88
95
85
95
92
120
aThe ratio of 2:4: H2O2/NaOH = 1:1:1:1.
bIsolated yield.

436 Park, Yang, and Kim
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