Epoxidation of olefins by β-bromoalkoxydimethylsulfonium ylides

Article abstract of DOI:10.1016/j.tetlet.2010.10.068

Olefins can be converted to their respective epoxides in a one-pot procedure by dissolving the olefin in anhydrous DMSO, adding NBS to the reaction mixture to generate a β-bromoalkoxydimethylsulfonium ylide, and then adding DBU to the reaction mixture. A large variety of alkenes were successfully epoxi-dized with yields largely dependent on the structure of the alkene. Most importantly, the facial selectivity of this one-pot process is the opposite of that observed when using traditional epoxidizing reagents. Electron-poor alkenes are not epoxidized under these conditions.

Full text of DOI:10.1016/j.tetlet.2010.10.068

Tetrahedron Letters 51 (2010) 6830–6834
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Epoxidation of olefins by b-bromoalkoxydimethylsulfonium ylides
George Majetich , Joel Shimkus , Yang Li à
⇑
Department of Chemistry, University of Georgia, Athens, Georgia 30602, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2010
Revised 8 October 2010
Accepted 12 October 2010
Available online 29 October 2010
Olefins can be converted to their respective epoxides in a one-pot procedure by dissolving the olefin in
anhydrous DMSO, adding NBS to the reaction mixture to generate a b-bromoalkoxydimethylsulfonium
ylide, and then adding DBU to the reaction mixture. A large variety of alkenes were successfully epoxi-
dized with yields largely dependent on the structure of the alkene. Most importantly, the facial selectivity
of this one-pot process is the opposite of that observed when using traditional epoxidizing reagents. Elec-
tron-poor alkenes are not epoxidized under these conditions.
Ó 2010 Published by Elsevier Ltd.
In 1967, Dalton et al.1 and van Tamelen and Sharpless2 reported
the preparation of bromohydrins from alkenes using NBS in moist
DMSO.3 The proposed mechanism of this reaction is shown in
Scheme 1. In the initial step, alkene 1 reacts with NBS to produce
a bromonium ion intermediate (cf. 1), which opens in trans fashion
either through attack by water to directly generate bromohydrin 3,
or by attack of DMSO to form b-bromodimethylalkoxysulfonium
ion ii. In the latter case, the presence of water in the reaction mix-
ture cleaves the O–S bond to form bromohydrin 3, and subsequent
treatment of 3 with base generates alkoxide iii, which produces
epoxide 4. In contrast to peroxyacids, which epoxidize the less
R
R
R
peroxyacid
R = alkyl
O
O
R
4
Swern
1
2
Br
R
R
oxidation
-H+
R = alkyl
- Br
O
NBS
condi-
HO
O
H
tions
Br
Br
R
R
_
R
S
Nuc =
H2O
Br
base
+
Br
O
+
(vi)
Br
- H+
OH
R
CH3
S
CH3
S
(i)
3
(iii)
Cl
Cl-
Nuc
+
O
_
Cl
loss of
R
H2O
O
Nuc =
+
S
addition
DMSO
to (v)
R = Ph (6)
= CH3 (8)
(v)
R
R
R = Ph (vii)
R
Br
base
and
ylide
form-
ation
Br
O
= CH3 (ix)
O
Br
O
Cl
O
5
(ii)
(iv)
S
7
_
S
CH3SCH2
R
_
R
CH3
CH2
S
S
Scheme 1. Known strategies and proposed epoxidation strategy via
moalkoxydimethylsulfonium ylide.
a
b-bro-
O
O
TEA
Cl
Cl
⇑
Corresponding author. Tel./fax: +1 706 542 1966.
E-mail address: Majetich@chem.uga.edu (G. Majetich).
R = Ph (viii)
= CH3 (x)
R = Ph
= CH3
Taken in part from the Ph.D. Dissertation of Joel Shimkus, University of Georgia,
Athens, GA (2009).
à
Taken in part from the Ph.D. Dissertation of Yang Li, University of Georgia, Athens,
Scheme 2. Known haloalkoxydimethylsulfonium ylides which give oxidation
GA (2006).
products.
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.10.068

G. Majetich et al. / Tetrahedron Letters 51 (2010) 6830–6834
6831
hindered face of the double bond (cf. 2), the mechanism of bro-
mohydrin formation produces an epoxide on the more hindered
face of the double bond.
O
Br
i) NBS/
DMSO
i) NBS/
DMSO
ii) Et3N or
i-Pr2NEt or
DABCO
OH
C6H5
ii) DBU or
C6H5
C6H5
10
DMSO is an excellent solvent for the elimination of aryl sulfo-
nates4 and halogens5 through solvolysis to prepare alkenes. We
speculated that using DMSO as the solvent in a bromohydrin reac-
tion might cause the elimination of methylmethylenesulfonium
ion v from ylide iv to generate in situ alkoxide iii. We expected that
intramolecular epoxide formation would be faster than bimolecu-
lar methylthioether formation6 (cf. 5). In addition, because bro-
mide is a poor nucleophile in DMSO, we predicted that the
nascent epoxide would be stable. These speculations have been
realized and the results of this study are the focus of this Letter.7
NaOCH3 or
dimsyl anion
ort-BuOK
9
Scheme 3. Optimization studies.
a base to the solution of the b-bromoalkoxydimethylsulfonium
ylide intermediate produces styrene oxide (9) in good yield
(Scheme 3).
Five major variables were considered to optimize this epoxida-
tion process: (1) the amount of NBS needed, (2) the amount and
choice of base needed, (3) the optimum reaction temperature, (4)
the time required for dimethylalkoxysulfonium salt formation,
and (5) the time required for epoxide formation. Simple tests
established that iodine, NCS, and NIS were not effective as halogen
sources and that 1.5 equiv of NBS and 2.0 equiv of base were opti-
mal. Amine bases, such as triethylamine, Hünig’s base, or DABCO
gave good yields of bromohydrin 10, while bases, such as sodium
methoxide, potassium t-butyl oxide, or dimsyl anion favored sty-
rene oxide formation, but in moderate yield. DBU, a hindered
amine base, gave the best yields of the epoxide and thus became
our preferred base. Early trials showed little change in the reaction
Halohydrins are routinely oxidized to
a
-halo ketones8 using
Swern’s conditions via an ylide, such as vi (Scheme 2).9 Nakai
and Kurono found that treating cyclohexene oxide with thioani-
sole-chlorine complex 6 generates intermediates vii and ylide viii,
which produces
chlorodimethylsulfonium chloride (8) to convert cyclohexene
oxide into
-chloroketone 7 (cf. ix and ylide x).11 Each of the reac-
a
-chloroketone 7.10 Alternatively, Olah et al. used
a
tions shown in Scheme 2 proceeds through a dimethyloxysulfoni-
um ylide with a leaving group vicinal to the sulfonium ylide, but
produced ketones and not epoxides. Nevertheless, in contrast to
these known oxidations, we found that treatment of styrene
dissolved in dry DMSO with NBS, followed by the addition of
Table 1
Epoxidation of aliphatic mono- and disubstituted olefins
O
i) 1.5 equiv NBS/ DMSO, t1 at 10 ºC
ii) 2.0 equiv DBU, t2 at 10 ºC
R
2
R
2
R
1
R
1
Entry
Compd
R1
R2
t1/t2 (min)
Product
Isolated yield (%)
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
11
13
15
17
19
21
23
(E)-25
(E)-27
(E)-29
(Z)-31
Cycloheptene (33)
Cyclooctene (35)
C6H13
C8H17
H
H
H
H
H
H
H
C3H7
C2H5
i-Pr
CH3
20/30
20/30
25/30
20/30
20/30
20/30
20/30
25/25
25/35
25/30
25/30
10/25
15/25
12
14
16
18
20
22
24
trans-26
trans-28
trans-30
cis-32
Cycloheptene oxide (34)
Cyclooctene oxide (36)
70
66
59
60
63
60
68
75
50a
70
75
79
50
C
10H21
PhCH2CH2
3,4-(CH3O)2C6H3CH2
CH3COCH2CH2
HOCH2(C7H14
C3H7
t-Bu
i-Pr
C5H11
)
(9)
(10)
(11)
(12)
(13)
a
Compound is volatile under isolation conditions.
Table 2
Epoxidation of styrenyl olefins
R1
R1
O
i) 1.5 equiv NBS/ DMSO, t1 at 10 ºC
ii) 2.0 equiv DBU, t2 at 10 ºC
R2
R2
Ph
Ph
Entry
Compd
R1
R2
t1/t2 (min)
Product
Isolated yield (%)
(14)
(15)
(16)
(17)
(18)
Styrene
37
39
41
H
H
CH3
H
H
Ph
H
30/30
20/—a
30/30
60/30
25/30
9
38
a
77
76
-Methylstyrene oxide (40)
70
CH3
b-Methylstyrene oxide (42)
Indene oxide (44)
50b
51c
Indene (43)
a
b
c
NaH was used as the base; reaction was worked up upon consumption of alkene.
Polymerizes in DMSO.
Compound is volatile under isolation conditions.

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G. Majetich et al. / Tetrahedron Letters 51 (2010) 6830–6834
Table 3
Epoxidation of aliphatic tri- and tetrasubstituted olefinsa,b
Entry
(19)
Compd
t1/t2 (min)
Product(s)
Isolated yield (%)
45c
R
1 = R2 = R3 = C2H5 (45)
20/20
(46)
(47)
+
(20)
25/30
O
Br
(49) 38%
62
c
(48) 15%
(21)
(22)
1-Methylcyclohexene (50)
1-Methylcycloheptene (52)
35/30
35/30
1,2-Epoxy-1-methyl-cyclohexane (51)
1,2-Epoxy-1-methyl-cyclohexane (53)
75
(55)
(54)
(23)
(24)
35/30
35/30
73
O
O
76d
OH
(56)
(57)
OH
O
O
O
O
(58)
+
(25)
35/30
O
(60) 41%
(59)
35%
O
O
(26)
(27)
25/30
35/30
58
(61)
(62)
H
H
O
O
58
(64)
(63)
a
b
c
1.5 equiv NBS/DMSO, t1 at 10 °C.
2.0 equiv DBU, t2 at 0 °C.
Compound is volatile under isolation conditions.
d
Produced a mixture of diastereomers.
yield as the temperature was varied, thus a reaction temperature of
10 °C (above the freezing point of DMSO) was set as a standard
parameter. Surprisingly, the dimethylalkoxysulfonium salt could
be detected by TLC analysis, which allowed us to monitor the reac-
tions for the formation of the sulfonium salt (ꢀ30 min) and for its
collapse once the DBU was added (ꢀ30 min).
were studied, the influence of the sulfur-bound substituents is
not a concern. However, several sulfonium ylide-based oxidations
demonstrate substrate dependencies. Albright and Goldman found
that sterically hindered axial steroidal alcohols gave oxidation
products, whereas the equatorial isomers favored methylthiom-
ethyl ether formation.14 Since these substrates lack a vicinal
leaving group, epoxidation could not be observed. Swern and co-
workers also found that sterically-hindered alcohols oxidized more
rapidly and gave better results than less hindered substrates.7a,9
They postulated that the less hindered alcohols would allow the di-
rect attack of the sulfur atom by the TEA expelling the correspond-
ing alkoxide and increasing ether formation and that increasing the
bulkiness of the base would lead to more ylide formation improv-
ing the oxidation yield. Unfortunately, neither of these specula-
tions proved valid.
Sulfonium ylide-based reactions are solvent dependent. Corey
and Kim noted that while alcohols are cleanly oxidized in toluene,
thioether formation becomes competitive in CH2Cl2 and dominant
in CH2Cl2/DMSO.15 Most halohydrin oxidations use Swern’s condi-
tions in CH2Cl2.8 Interestingly, addition of CH2Cl2 as a co-solvent to
our one-pot DMSO/DBU-based epoxidation protocol caused car-
bonyl formation to occur at the expense of epoxidation. Clearly,
the concentration of DMSO present in the reaction determines
whether the sulfonium ylide forms a carbonyl group or produces
an epoxide.
With these basic parameters in hand, a series of aliphatic mono-,
di-, tri-, and tetrasubstituted olefins, as well as styrenyl olefins
and conjugated dienes, were epoxidized. The results of these epox-
idations are summarized in Tables 1–4.12 In general, the epoxida-
tion of alkenes occurs in good yield using this one-pot protocol.
Mono- and disubstituted olefins react in a straightforward manner
(Table 1) and the geometry of the double bond is maintained dur-
ing epoxidation (cf. (Z)-27, entry 9). Styrenyl substrates gave good
yields of reaction products with the exception of 41, which in our
hands decomposes in DMSO (Table 2). Bulky groups proximal to
the double bond favor dibromide formation. For example, the for-
mation of bromide 45 is due either to elimination from the dibro-
mide or unreacted bromonium ion, both
a result of the
considerable steric bulk of the system. As expected, cis-carene (54)
gave only epoxidation from the more hindered face (Table 3).13
Ketal 60 arises from intramolecular attack of the bromonium ion
by the carbonyl, followed by addition of the resulting alkoxide
anion to the activated carbonyl.
Electron-poor olefins were inert under these conditions (cf. 67
and 69), whereas isolated double bonds were selectively epoxi-
dized in good yield (Table 4). In substrates having two or more
alkenes (cf. 71, 73, and 75) the most electron-rich double bond
reacted preferentially in each case. Substrates containing isolated
double bonds and conjugated dienes, such as myrcene (81)
and ocimene (84) epoxidized exclusively the isolated double
bond.
In summary, the epoxidation of olefins via b-bromodimethyl-
alkoxysulfonium ions is general for a wide range of substrates. This
procedure is economical, convenient, and provides an alternative
approach for cases where using peroxide oxidants may be
incompatible or the opposite facial selectivity is desired. We have
concluded that the combination of DBU in DMSO favors the irre-
versible collapse of the sulfonium ylide resulting in epoxide forma-
tion and are investigating whether this process can be applicable
for asymmetric epoxidation by using chiral sulfoxides16 or chiral
NBS equivalents.17
Three factors influence the sulfonium ylide’s reactivity: the nat-
ure of the sulfur-bound substituents, substrate structural effects,
and the solvent used. Since only alkoxydimethylsulfonium ylides

G. Majetich et al. / Tetrahedron Letters 51 (2010) 6830–6834
6833
Table 4
Competitive epoxidation of isolated double bonds in various systemsa,b
Entry
Compd
t1/t2 (min)
Product(s)
Isolated yield (%)
88
O
(28)
25/30
(65)
(66)
O
O
O
O
(29)
(30)
30/30
30/30
74
H
O
H
O
E/ Z= 1:1 (68)e
(67)
O
O
70
60
(70)c
(69)
(71)
O
H3CO
(31)
(32)
25/30
30/30
(72)
H3CO
HO
Geraniol (73)
Nerol (75)
60e
O
(74)
OH
OH
(33)c
30/30
O
+
+
(77)e,f
O
O
(76) 65%
O
O
O
(34)
(35)
30/30
30/30
(78)
(79) 69%d
(80)c
O
O
O
17%e
+
+
(81)
(82) 50%c,e
(83)
O
O
1:2 (E):(Z)
(84)
(36)
30/30
O
(85) 56%d
(86) 47%d
a
b
c
1.5 equiv NBS/DMSO, t1 at 10 °C.
2.0 equiv DBU, t2 at 0 °C.
Only 1.0 equiv NBS used.
Yield based on recovered starting material.
A mixture of diastereomers were produced.
Obtained when 1.5 equiv NBS was used.
d
e
f
E.; Moffat, J. G. J. Am. Chem. Soc. 1965, 87, 5670–5678; (d) Fenselau, A. H.;
Moffat, J. G. J. Am. Chem. Soc. 1966, 88, 1762–1765.
Acknowledgment
7. For more comprehensive reviews of the alkoxysulfonium ion literature, see: (a)
Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185; (b) Natus, G.; Goethals, E. J.
Bull. Soc. Chim. Belg. 1965, 74, 450–452; (c) Epstein, W. W.; Sweat, F. W. Chem.
Rev. 1967, 67, 247–260.
We thank the NSF for support of this research (CHE-05064846).
Supplementary data
8. For the oxidation of fluoro, chloro, and bromohydrin, see: Fluorine: (a)
Thaisrivongs, S.; Pals, D. T.; Kati, W. M.; Turner, S. R.; Thomasco, L. M. J. Med.
Chem. 1985, 28, 1555–1558; (b) Myers, A. G.; Barbay, J. K. Org. Lett. 2001, 3,
425–428; (c) Wong, A.; Munos, J. W.; Devasthali, V.; Johnson, K. A.; Liu, H.-W.
Org. Lett 2004, 6, 3625–3628; Chlorine: (d) Satoh, T.; Sugimoto, A.; Yamakawa,
K. Chem. Pharm. Bull. 1989, 37, 184–186; (e) Satoh, T.; Motohashi, S.; Kimura, S.;
Tokutake, N.; Yamakawa, K. Tetrahedron Lett. 1993, 34, 4823–4826; (f) Miura,
M.; Toriyama, M.; Motohashi, S. Synth. Commun. 2006, 36, 259–264; Bromine:
(g) Noyori, R.; Nishizawa, M.; Shimizu, F.; Hayakawa, Y.; Maruoka, K.;
Hashimoto, S.; Yamamoto, H.; Nozaki, H. J. Am. Chem. Soc. 1979, 101, 220–
222.
Supplementary data (detailed experimentals as well as 1H and
13C NMR data have been provided for all substrates listed in Tables
1–4) associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2010.10.068.
References and notes
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was stirred for 30 min. The reaction was quenched at 10 °C with 3 mL of brine,

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G. Majetich et al. / Tetrahedron Letters 51 (2010) 6830–6834
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