Highly selective sulfoxidation of allylic and vinylic sulfides by hydrogen peroxide using a flavin as catalyst

Article abstract of DOI:10.1021/jo034273z

A highly chemoselective oxidation of allylic and vinylic sulfides to the corresponding sulfoxides has been developed using flavin 1 as the oxidation catalyst and hydrogen peroxide as the terminal oxidant. The sulfoxides were formed in good to excellent yields in a highly selective manner even when an excess of the oxidant was used. Sulfone formation was completely suppressed to <0.5% (in one single case 1.5% sulfone was detected). No epoxidation of double bonds or interference with other functional groups was observed under the reaction conditions. The general applicability was demonstrated by the selective oxidation of various allylic and vinylic sulfides having different electronic properties. A number of functionalities including hydroxy, acetoxy, amino, silyloxy, and formyl groups are tolerated under these mild reaction conditions.

Full text of DOI:10.1021/jo034273z

High ly Selective Su lfoxid a tion of Allylic a n d Vin ylic Su lfid es by
Hyd r ogen P er oxid e Usin g a F la vin a s Ca ta lyst
Auri A. Linde´n, Lars Kru¨ger,*,† and J an-E. Ba¨ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden
jeb@organ.su.se
Received March 3, 2003
A highly chemoselective oxidation of allylic and vinylic sulfides to the corresponding sulfoxides
has been developed using flavin 1 as the oxidation catalyst and hydrogen peroxide as the terminal
oxidant. The sulfoxides were formed in good to excellent yields in a highly selective manner even
when an excess of the oxidant was used. Sulfone formation was completely suppressed to <0.5%
(in one single case 1.5% sulfone was detected). No epoxidation of double bonds or interference with
other functional groups was observed under the reaction conditions. The general applicability was
demonstrated by the selective oxidation of various allylic and vinylic sulfides having different
electronic properties. A number of functionalities including hydroxy, acetoxy, amino, silyloxy, and
formyl groups are tolerated under these mild reaction conditions.
In tr od u ction
some methods have been developed for selective oxidation
to sulfoxides,6 further improvement of this chemoselective
reaction is desirable. A variety of the existing methods
have the disadvantage of being expensive, using toxic
chemicals, or suffering from moderate selectivity. In
particular, for the oxidation of sulfides containing double
bonds only one thorough investigation with regard to the
scope of substrates has been published.7 Recently, Koo
and co-workers reported on the oxidation of allylic
sulfides using a trirutile-type solid oxide catalyst.8 Sev-
eral allylic sulfides were oxidized to the corresponding
sulfoxides without formation of epoxides. Sulfone forma-
tion, however, could in none of the cases be completely
avoided, even when equimolar amounts of the oxidant
were used.
Organosulfur compounds are versatile intermediates
in organic synthesis and useful for the preparation of
biologically and medically important products.1 In par-
ticular, sulfoxides and sulfones have been extensively
used for carbon-carbon bond forming reactions,2 rear-
rangements,3 and eliminations.4 When different func-
tional groups are present in a molecule, it can be difficult
to transform one of them without interfering with the
other. It is therefore of great interest to chemoselectively
synthesize these compounds. Organic sulfides having a
nucleophilic double bond present in the molecule are
examples of such compounds. The sulfur moiety can
easily be oxidized by electrophilic oxidants, but special
conditions are required to chemoselectively obtain sul-
foxides without sulfone formation or epoxidation of the
double bond.
These results prompted us to examine the use of a
biomimetic flavin system, previously developed in our
There is a significant difference in the nucleophilicity
of the sulfide compared to the sulfoxide,5 and although
(5) Bonchio, M.; Conte, V.; De Conciliis, M. A.; Di Furia, F.;
Ballistreri, F. P.; Tomaselli, G. A.; Toscana, R. M. J . Org. Chem. 1995,
60, 4475-4480.
* Corresponding author.
† Current address: Karo Bio AB, Novum, SE-14157 Huddinge,
Sweden. E-mail: lars.krueger@karobio.se.
(6) For examples, see: (a) Trost, B. M.; Curran, D. P. Tetrahedron
Lett. 1981, 22, 1287-1290. (b) Ali, M. H.; Stevens, W. C. Synthesis
1997, 764-768. (c) Batigalhia, F.; Zaldini-Hernandes, M.; Ferreira,
A. G.; Malvestiti, I.; Cass, Q. B. Tetrahedron 2001, 57, 9669-9676.
(d) Sua´rez, A. R.; Rossi, L. I.; Martin, S. E. Tetrahedron Lett. 1995,
36, 1201-1204. (e) Ravikumar, K. S.; Be´gue´, J .-P.; Bonnet-Delpon, D.
Tetrahedron Lett. 1998, 39, 3141-3144. (f) Fraile, J . M.; Garc´ıa, J . I.;
La´zaro, B.; Mayoral, J . A. J . Chem. Soc., Chem. Commun. 1998, 1807-
1808. (g) Iranpoor, N.; Firouzabadi, H.; Pourali, A.-R. Tetrahedron
2002, 58, 5179-5184. (h) Raghavan, P. S.; Ramaswamy, V.; Upadhya,
T. T.; Sudalai, A.; Ramaswamy, A. V.; Sivasanker, S. J . Mol. Catal., A
1997, 122, 75-80. (i) Martin, S. E.; Rossi, L. I. Tetrahedron Lett. 2001,
42, 7147-7151. (j) Orito, K.; Hatakeyama, T.; Takeo, M.; Suginome,
H. Synthesis 1995, 1357-1358. (k) Breton, G. W.; Fields, J . D.; Kropp,
P. J . Tetrahedron Lett. 1995, 36, 3825-3828. (l) Arterburn, J . B.;
Nelson, S. L. J . Org. Chem. 1996, 61, 2260-2261.
(1) General Reviews: (a) Metzner, P.; Thuillier, A. Sulfur Reagents
in Organic Synthesis; Academic Press: London, 1994. (b) Drabowicz,
J .; Kielbasinski, P.; Mikolajczyk, M. In The chemistry of sulphones and
sulphoxides; Patai, S., Rappoport, Z., Stirling, C., Eds.; Wiley: Chich-
ester, U.K., 1988; pp 233-378. (c) Gundermann, K.-D.; Hu¨mke, K. In
Methoden der Organischen Chemie (Houben-Weyl) Organische Schwefel-
Verbindungen; Klamann, D., Ed.; Thieme: Stuttgart, New York, 1985;
Vol. E11, Teil 1. (d) Page, P. C. B., Ed. Organosulfur Chemistry I;
Springer: Berlin, 1999. (e) Page, P. C. B., Ed. Organosulfur Chemistry
II; Springer: Berlin, 1999.
(2) Solladie, G. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6, p 148.
(3) (a) Tang, R.; Mislow, K. J . Am. Chem. Soc. 1970, 92, 2100. (b)
Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147. (c) De
Lucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40, 157. (d)
Braverman, S. In The chemistry of sulphones and sulphoxides; Patai,
S., Rappoport, Z., Stirling, C., Eds.; Wiley: Chichester, U.K., 1988; pp
717-758.
(7) For the sulfoxidation of some terminally unsaturated sulfides,
see: (a) Ravikumar, K. S.; Be´gue´, J .-P.; Bonnet-Delpon, D. Tetrahedron
Lett. 1998, 39, 3141-3144. (b) Ravikumar, K. S.; Zhang, Y. M.; Be´gue´,
J .-P.; Bonnet-Delpon, D. Eur. J . Org. Chem. 1998, 2937-2940.
(8) Choi, S.; Yang, J .-D.; J i, M.; Choi, H.; Kee, M.; Ahn, K.-H.; Byeon,
S.-H.; Baik, W.; Koo, S. J . Org. Chem. 2001, 66, 8192-8198.
(4) (a) Hofmann, J . E.; Wallace, T. L.; Schriesheim, A. J . Am. Chem.
Soc. 1964, 86, 1561. (b) De Groot, A.; J ansen, B. J . M.; Reuvers, J . T.
A.; Tedjo, E. M. Tetrahedron Lett. 1981, 22, 4137.
10.1021/jo034273z CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/02/2003
5890
J . Org. Chem. 2003, 68, 5890-5896

Sulfoxidation of Allylic and Vinylic Sulfides
CHART 1
SCHEME 2
Resu lts a n d Discu ssion
Oxid a tion of Va r iou s Allylic Su lfid es w ith Dif-
fer en t Electr on ic P r op er ties. To use hydrogen perox-
ide as terminal oxidant for the selective sulfoxidation of
allylic substrates, suitable reaction conditions have to be
found. Hydrogen peroxide is known to be a nucleophilic
oxidant; therefore, it is not surprising that the uncata-
lyzed reaction of hydrogen peroxide with sulfides is very
slow.9b To selectively oxidize sulfides to their correspond-
ing sulfoxides, the hydroperoxide has to be moderately
electrophilic to prevent further oxidation of the sulfoxide
to a sulfone or interfere with double bonds present in the
molecule.
SCHEME 1
The catalytic cycle (Scheme 1)9b is initiated by the
generation of the electrophilic and reactive hydroperoxide
intermediate 211 from 1 and molecular oxygen. The
hydroperoxide 2 transfers an oxygen atom to the sulfide
to give sulfoxide and hydroxyflavin intermediate 4.
Elimination of OH- from 4 produces the aromatic 1,4-
diazine 5. The latter intermediate becomes the catalytic
species that activates and reacts with hydrogen peroxide
to give the flavin hydroperoxide 2. The advantage of the
N,N,N-1,3,5-trialkylated flavin system (Scheme 1) over
the N,N,N-3,5,10-trialkylated analogues often used is
that the elimination of OH- from 4 to give 5 is favored
due to aromatization.
Using the electron-rich phenyl prenyl sulfide (3) as a
model compound, we adopted a previously established
procedure for the sulfoxidation of saturated sulfides.9b
Only a small amount of flavin catalyst 1 was employed
(2 mol %), and a minor excess of the oxidant H2O2 (1.5
equiv) was used. Methanol was chosen as the solvent,
and no inert conditions such as dry solvent or argon
atmosphere were required. With this catalytic system
sulfide 3 was oxidized to sulfoxide 4 in 92% isolated yield
with remarkable selectivity (>99.5%) with respect to both
the sulfur moiety and the double bond; neither sulfone
nor epoxide formation could be detected (Scheme 2). It
was not necessary to strictly control the amount of
hydrogen peroxide to avoid overoxidation, which shows
that the flavin system is highly selective for sulfoxidation.
To demonstrate the generality and scope of this
methodology, a variety of allylic sulfides containing
various functional groups were oxidized to the corre-
sponding sulfoxides under these reaction conditions
(Table 1). Allyl phenyl sulfide (5) and geranyl phenyl
sulfide (7) were oxidized to the corresponding sulfoxides
in high yields (Table 1, entries 2 and 3). No overoxidation
products or epoxides were formed in either case. In
particular for 7 this is noteworthy since it has two
trisubstituted and therefore very nucleophilic double
bonds. Also the even more electron-rich double bonds in
sulfides 9, 11, 13, and 15 were not attacked under the
group,9 in the sulfoxidation of allylic and some vinylic
sulfides without overoxidation to sulfone or epoxide
formation. The same system has been used in studies on
heteroatom oxidations by our group.9 On the basis of the
results obtained for oxidation of tertiary amines to amine
oxides,9a a triple catalytic system for the dihydroxylation
of olefins using hydrogen peroxide as the terminal
oxidant has been developed.10 The N,N,N-1,3,5-trialkyl-
ated flavin 1 serves as a catalyst precursor which is
activated by molecular oxygen to give hydroperoxy flavin
2 (Chart 1). Hydroperoxide 2 transfers its electrophilic
oxygen to the substrate, and is readily reoxidized by
hydrogen peroxide to maintain the catalytic cycle (Scheme
1).
Herein, we report a mild procedure for the highly
chemoselective sulfoxidation of various allylic and some
vinylic sulfides using environmentally benign hydrogen
peroxide as terminal oxidant. An advantage with the
present system is that the hydrogen peroxide can be kept
at a low concentration by slow addition, leading to even
milder conditions.
(9) (a) Bergstad, K.; Ba¨ckvall, J .-E. J . Org. Chem. 1998, 63, 6650-
6655. (b) Minidis, A. B. E.; Ba¨ckvall, J .-E. Chem.sEur. J . 2001, 7, 297-
302.
(10) (a) Bergstad, K.; J onsson, S. Y.; Ba¨ckvall, J .-E. J . Am. Chem.
Soc. 1999, 121, 10424-10425. (b) J onsson, S. Y.; Adolfsson, H.;
Ba¨ckvall, J .-E. Org. Lett. 2001, 3, 3463-3466. (c) J onsson, S. Y.;
Fa¨rnegårdh, K.; Ba¨ckvall, J .-E. J . Am. Chem. Soc. 2001, 123, 1365-
1371.
(11) One reviewer considered participation of a dioxirane intermedi-
ate as an alternative mechanism. Such a mechanism seems less likely
in our case.
J . Org. Chem, Vol. 68, No. 15, 2003 5891

Linde´n et al.
TABLE 1. Oxid a tion of Va r iou s Allylic Su lfid es w ith th e
dium dithionite destroyed the product formed, and
therefore, an alternative workup was used (see the Ex-
perimental Section). Sulfide 17, synthesized from trans-
1-acetoxy-4-chloro-2-cyclohexene,12 was oxidized to a 1:1
diastereomeric mixture of the corresponding sulfoxides
18. Compounds 19 and 21 containing unsubstituted cy-
cloalkene moieties were as well cleanly transformed to
sulfoxides 20 and 22, respectively. In the case of 21 the
yield could be slightly increased by using 2 equiv of
hydrogen peroxide and 0.04 equiv of the catalyst and
running the reaction overnight.
F la vin Ca ta lyst-H2O2 System a
Phenyl propargyl sulfide (23) (Table 1, entry 11) was
transformed to sulfoxide 24 by the flavin catalytic system,
although a slightly lower yield (75%) was obtained. Also
in this case no other oxidation products could be detected.
As expected, electron-rich allylic sulfides were oxidized
faster than their electron-deficient counterparts. The
oxidation of diprenyl sulfide (25) under standard condi-
tions gave a high yield of sulfoxide contaminated with
small amounts of the corresponding sulfone as a side
product, the sulfoxide-to-sulfone ratio being 98:2. Lower-
ing the temperature to 0 °C improved the sulfoxide-to-
sulfone ratio to 98.5:1.5. It is noteworthy that a catalyst
loading of only 1 mol % was enough to perform the reac-
tion equally well. On the other hand, sulfide 27, having
an R,â-unsaturated carbonyl moiety and being less
electron-rich on the sulfur, needed modified conditions
to be oxidized. Running the reaction overnight employing
0.04 equiv of 1 and 4 equiv of hydrogen peroxide gave
77% isolated yield without the formation of sulfone,
whereas using the standard conditions gave 65% sulfox-
ide 28 after 3 h. It is noteworthy that no epoxide was
formed, although the double bond is more electrophilic
and might be susceptible to hydrogen peroxide attack.
Since amines also can be oxidized to their correspond-
ing N-oxides using the catalytic flavin system,9b it was
of interest to investigate how sulfide 29 acts under these
reaction conditions. It is well-known that tertiary amines
react faster than secondary amines, but the competitive
behavior of a tertiary amine vs a thioether using flavins
has not been studied so far. The sole product in the
catalytic oxidation of 29 was sulfoxide 30, which was
obtained in 86% isolated yield after 3 h. No N-oxide could
be detected when the reaction was followed by NMR
spectroscopy.
Oxid a tion of Vin ylic Su lfid es to th e Cor r esp on d -
in g Su lfoxid es. Attempts to apply the developed condi-
tions to vinylic substrates proved to be moderately
successful using 2 mol % flavin 1. When phenyl vinyl
sulfide (31) was allowed to react with hydrogen peroxide
under the standard conditions (Table 2, entry 1), after 3
h only 24% of the sulfide was converted to sulfoxide. With
the use of 0.04 equiv of 1 and 4 equiv of hydrogen
peroxide an isolated yield of 60% was obtained.
1,3-Dienic systems influence the flavin-catalyzed pro-
cess even more. The oxidation of sulfides 31 and 33 led
to conversions of only 11% and 12%, respectively, after 3
h under standard conditions. Also in these cases an
increase of the amounts of catalyst and oxidant yielded
sulfoxides in better yields as exemplified by oxidation of
31 to 32 (Table 2, entry 1). Using the H2O2‚urea complex
a
Unless otherwise noted, the reactions were performed using
0.018 equiv of 1 in MeOH at rt. Reaction times vary from 2.5 to 3
b
h. The reaction was run overnight. c The reaction was run with
d
0.04 equiv of 1. The reaction was run at 0 °C; 1.5% sulfone was
formed.
reaction condition (Table 1, entries 4-7). Comparing sul-
fides 9 and 11, the position of the electron-donating
methyl group on the double bond does not affect their
reactivity toward oxidation. The sulfide 13 tolerated the
condition applied, but quenching the reaction with so-
(12) Ba¨ckvall, J .-E.; Nystro¨m, J . E.; Nordberg, R. E. J . Am. Chem.
Soc. 1985, 107, 3676-3686.
5892 J . Org. Chem., Vol. 68, No. 15, 2003

Sulfoxidation of Allylic and Vinylic Sulfides
TABLE 2. Oxid a tion of Vin ylic Su lfid es w ith th e F la vin
Ca ta lyst-H2O2 System
tional groups are tolerated in the sulfoxidation of allylic
sulfides, including tertiary amines, which demonstrates
the mildness of the procedure. In all cases allylic sulfox-
ides were obtained in high to excellent yields under mild
reaction conditions and short reaction times, whereas
vinylic substrates require a slightly modified procedure.
Exp er im en ta l Section
Gen er a l Meth od s. 1H (400 or 300 MHz) and 13C (100 or
75 MHz) NMR spectra were recorded in CDCl3 using residual
solvent as internal standard. Chemical shifts (δ) are reported
in parts per million, and coupling constants (J ) are given in
hertz. IR spectra were obtained using an FT-IR instrument,
and the samples were examined as neat films on NaCl plates.
Only the strongest/structurally most important peaks (cm-1
)
are listed. Mass spectra were recorded using a GC-MS
instrument with a 15 m × 0.32 mm column. Silica gel 60 (240-
400 mesh) was used for flash chromatography, and analytical
thin-layer chromatography was performed on precoated silica
gel 60-F254 plates. Unless otherwise noted, all chemicals were
obtained from commercial suppliers and used without further
purification. All reactions were performed at room temperature
unless otherwise noted. Phenyl sulfide compounds were pre-
pared by the reaction of the corresponding halides (either
chloride or bromide) with thiophenol in acetone in the presence
of K2CO3, and diprenyl sulfide (25) was prepared by the
reaction of prenyl bromide with Na2S‚xH2O in EtOH.
a
The reactions were performed using 0.02 equiv of 1 in MeOH
b
at rt. Reaction times vary from 2.5 to 3 h. nd ) not determined.
c The reaction was run for 24 h using 0.04 equiv of 1. The reaction
d
was run for 48 h using 0.04 equiv of 1 and H2O2‚urea complex.
e The reaction was run at 35 °C.
as the oxidant source for the oxidation of the vinylic
sulfides (Table 2, entries 2 and 3) gave better results,
presumably because of better solubility and increased
stability of the oxidant.
Su lfid e 9.14,15 To a solution of triethylaluminum (2.71 g,
23.8 mmol, 1.0 M solution in hexanes, 23.8 mL) was added
dropwise at 0 °C a solution of thiophenol (3.6 mL, 35.7 mmol)
in benzene (12 mL). After the mixture was stirred for 30 min
at room temperature 1-methyl-1-vinyloxirane (1 g, 11.9 mmol)
was added over 35 min. Aqueous workup with cold diluted
hydrochloric acid followed by column chromatography (pen-
tane/EtOAc, 85:15) afforded 98% sulfide 9 (2.26 mg, 11.6 mmol)
as a mixture of Z- and E-isomers in a ratio of 8:2 and 98%
Due to the longer reaction times (and elevated tem-
perature in the case of 35) the vinylic sulfoxides could
react further, once formed, which serves as an explana-
tion for the somewhat lower yields. In addition, the flavin
hydroperoxide might decompose if the sulfide reacts too
slowly.13 Nevertheless, the chemoselectivity of the cata-
lytic process was not affected by the changed conditions.
Neither sulfone nor epoxide formation was observed.
Frontal orbital theory can be used to explain the different
behavior of this class of compounds. Compared to that
of allylic sulfides, the HOMO of the vinylic sulfides is,
due to conjugation with the double bond, significantly
lowered. Therefore, the high chemoselectivity observed
in the case of allylic sulfides, which is explained by a good
orbital overlap of the LUMO of the hydroperoxy flavin 2
and the HOMO of the allylic sulfides, is decreased in
going to vinylic sulfides. This effect is even more pro-
nounced for the 1,3-dienic sulfides where the electrons
are delocalized over the whole unsaturated system.
(Diphenyl sulfide, in which the electrons are delocalized
over two aromatic rings, gave only 13% conversion under
standard conditions.) The high chemoselectivity of the
flavin-catalyzed sulfoxidation, associated with a moderate
reactivity of the flavin hydroperoxide, leads to a slow
conversion with these less reactive vinylic substrates.
1
yield. The following are data for the Z-isomer. H NMR (300
MHz, CDCl3): δ 7.41-7.19 (m, 5 H), 5.50-5.42 (m, 1 H), 3.94
(s, 2 H), 3.57-3.54 (dd, J ) 8.0, 0.8 Hz, 2 H), 1.79 (app m, 3
H). 13C NMR (75 MHz, CDCl3): δ 139.1, 135.7, 131.6, 129.0,
127.1, 122.9, 61.9, 32.4, 21.4. The following are data for the
1
E-isomer. H NMR (300 MHz, CDCl3): δ 7.41-7.19 (m, 5 H),
5.62-5.55 (m, 1 H), 3.99 (s, 2 H), 3.60-3.57 (m, 2 H), 1.61 (br
s, 3 H). 13C NMR (75 MHz, CDCl3): δ 139.7, 136.4, 130.2,
128.9, 126.5, 120.6, 68.3, 31.8, 13.7.
Su lfid e 11.16 A mixture of (E)- and (Z)-4-acetoxy-2-methyl-
2-butenyl phenyl sulfide (15) (0.230 mg, 0.97 mmol) was
allowed to react with a 2 M solution of NaOH (160 mg, 4 mmol
in 2 mL of H2O) in ethanol. After 1 h 15 mL of brine was added
and the mixture washed with 3 × 15 mL of dichloromethane.
The combined organic phases were dried over MgSO4, filtered,
and evaporated. Flash chromatography with pentane/EtOAc
(2:1) gave a mixture of E/Z-isomers (E:Z ) 3.4:1) of sulfide 11
(150 mg, 0.77 mmol) in 77% yield as a colorless oil. The
following are data for the E-isomer. 1H NMR (400 MHz,
CDCl3): δ 7.44-7.18 (m, 5H), 5.44-5.40 (m, overlap with
Z-isomer signal, 1H), 4.08 (d, J ) 7.0 Hz, 2H), 3.50 (s, 2H),
1.8 (d, J ) 0.4 Hz, 3H). The following are data for the Z-isomer.
1H NMR (400 MHz, CDCl3): δ 7.44-7.18 (m, 5H), 5.52-5.48
(m, overlap with E-isomer signal, 1H), 3.80 (d, J ) 7.0 Hz,
2H), 3.51 (s, 2H), 1.89 (br d, J ) 1.2 Hz, 3H).
Con clu sion
We have shown that a flavin-catalyzed oxidation with
hydrogen peroxide as the terminal oxidant can be used
in a highly efficient and chemoselective sulfoxidation of
various allylic and vinylic sulfides. A number of func-
Su lfid e 13.8 To a stirred solution of sulfide 9 (194 mg, 1
mmol) and imidazole (204 mg, 3 mmol) in DMF (2.5 mL) was
added tert-butyldimethylsilyl chloride (226 mg, 1.5 mmol).
(13) (a) Mager, H. I. X.; Berends, W. Tetrahedron 1976, 32, 2303-
2312. (b) Smith, S. B.; Bruice, T. C. J . Am. Chem. Soc. 1975, 97, 2875-
2881. (c) Venkataram, U. V.; Bruice, T. C. J . Chem. Soc., Chem.
Commun. 1984, 899-900. (d) Bruice, T. C.; Miller, A. J . Chem. Soc.,
Chem. Commun. 1980, 693-694. (e) Iwata, M.; Bruice, T. C.; Carrell,
H. L.; Glusker, J . P. J . Am. Chem. Soc. 1980, 102, 5036-5044.
(14) Mori, I.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron 1984,
40, 4013-4018.
(15) Yasuda, A.; Takahashi, M.; Takaya, H. Tetrahedron Lett. 1981,
22, 2413-2416.
(16) Moiseenkov, A. M.; Veselovsky, V. V.; Makarova, Z. G.; Zhulin,
V. M.; Smit, W. A. Tetrahedron Lett. 1984, 25, 5929-5932.
J . Org. Chem, Vol. 68, No. 15, 2003 5893

Linde´n et al.
After 22 h the reaction mixture was poured into 5 mL of water,
and the resulting mixture was extracted with 2 × 15 mL of
chloroform. The combined organic layers were dried over Na2-
SO4. Sulfide 13 (284 mg, 0.96 mmol) was obtained as a mixture
of E- and Z-isomers in a ratio of 1:2.6 in 96% yield. The
following are data for the Z-isomer. 1H NMR (300 MHz,
CDCl3): δ 7.36-7.15 (m, overlap with E-isomer signal), 5.41-
5.33 (m, 1H), 4.0 (s, overlap with E-isomer signal, 2H), 3.58
(d, overlap with E-isomer signal, J ) 10 Hz, 2H), 1.74 (br s,
3H), 0.89 (s, overlap with E-isomer signal, 9H), 0.05 (s, 6H).
ether and washed with 5 mL of water and 5 mL of brine. The
organic phase was dried over Na2SO4. Filtration through silica
afforded 1.54 g (91%) of the product as a mixture of E- and
Z-isomers (pale yellow oil). The following are data for the E-
+ Z-isomers. GC-MS: m/z 212 [M]+ (77), 214 [M]+ (29), 177
[M - Cl]+ (16), 176 [M - HCl]•+ (20), 110 [C6H5S]•+ (100). The
following are data for the Z-isomer. 1H NMR (400 MHz,
CDCl3): δ 7.37-7.19 (m, 5H), 5.55-5.50 (m, 1H), 3.88 (s, 2H),
3.58-3.55 (dd, J ) 0.9, 8.1 Hz, 2H), 1.84 (app q, J ) 0.9, 1.5,
1.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 135.7, 135.4, 130.8,
129.0, 126.7, 125.5, 42.8, 32.1, 21.7. The following are data
for the E-isomer. 1H NMR (400 MHz, CDCl3): δ 7.37-7.19 (m,
5H), 5.70-5.40 (m, 1H), 3.98 (s, 2H), 3.52 (d, overlap with the
Z-isomer signal, 2H), 1.64 (app t, J ) 0.9, 0,6 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 135.7, 135.4, 130.9, 129.0, 126.8,
125.6, 51.6, 32.3, 14.3.
1
The following are data for the E-isomer. H NMR (300 MHz,
CDCl3): δ 7.36-7.15 (m, overlap with Z-isomer signal, 5H),
5.62-5.54 (m, 1H), 3.99 (s, overlap with Z-isomer signal, 2H),
3.58 (d, overlap with Z-isomer signal, 2H), 1.55 (br s, 3H), 0.89
(s, overlap with Z-isomer signal, 9H), 0.04 (s, 6H).
Su lfid e 15. This sulfide was prepared from 4-acetoxy-1-
chloro-2-methyl-2-butene12 and thiophenol using the procedure
described in ref 17 for reaction with 4-acetoxy-1-chloro-2-
butene. Sulfide 15 (435 mg, 1.84 mmol) was obtained as a
mixture of E- and Z-isomers in a ratio of 3.6:1 in 96% yield.
Su lfid e 29. A mixture of 4-chloro-3-methyl-2-butenyl phenyl
sulfide (851.5 mg, 4 mmol), diethylamine (8.36 mL, 80 mmol),
potassium carbonate (1.9 g, 14.4 mmol), and sodium iodide (0.5
g, 3.3 mmol) in acetonitrile was stirred at room temperature
for 2 h. The solvent was removed under reduced pressure, and
the residue was diluted with 50 mL of saturated aqueous
sodium carbonate solution and washed with 3 × 70 mL of
dichloromethane. The combined organic layers were dried over
Na2SO4, and the solvent was removed in vacuo. Sulfide 29
(106.2 mg, 0.43 mmol) (yellow oil) was obtained as a mixture
of E- and Z-isomers in a ratio of 4:1 in 85% yield. The following
are data for the E- + Z-isomers. GC-MS: m/z 250 [M + H]+
(15), 249 [M]+ (9), 234 [M - CH3]+ (31), 178 [M - N(C2H5)2 +
H]•+ (18), 177 [M - N(C2H5)2]+ (88), 176 [M - HN(C2H5)2]•+
(100), 140 [M - C6H5S]+ (42), 135 [C6H5SC2H2]+ (33), 110
[C6H5S]•+ (6), 86 [(C2H5)2NCH2]+ (25), 72 [(C2H5)N(C2H4)]+ (32).
1
The following are data for the E-isomer. H NMR (400 MHz,
CDCl3): δ 7.34-7.20 (m, overlap with Z-isomer signal, 5H),
5.4-5.35 (m, 1H), 4.52 (d, J ) 6.8 Hz, 2H), 3.5 (s, 2H), 2.01 (s,
3H), 1.83 (br m, 3H). The following are data for the Z-isomer.
1H NMR (400 MHz, CDCl3): δ 7.4-7.17 (m, overlap E-isomer
signal, 5H), 5.44-5.4 (m, 1H), 4.25 (d, J ) 7.2 Hz, 2H), 3.55
(s, 2H), 1.99 (s, 3H), 1.9 (br m, 3H). The sulfide was character-
ized by hydrolysis to the known16 alcohol 11.
Su lfid e 17. cis-1-Acetoxy-4-chlorocyclo-2-hexene12 (698 mg,
4 mmol) was allowed to react with thiophenol (0.62 mL, 6
mmol) and K2CO3 (1.10 g, 8 mmol) in 20 mL of refluxing
acetone overnight. Water was added, and the mixture was
extracted with diethyl ether. The combined organic layers were
washed with brine, dried over MgSO4, and filtered. After
removal of the solvent in vacuo the residue was purified by
flash chromatography (pentane/EtOAc, 90:10) to give sulfide
17 (800 mg, 3.2 mmol) in 81% yield as a pale yellow oil. GC-
MS: m/z 248 [M]+ (2), 189 [M - AcO]+ (15), 188 [M - AcOH]+
(47), 139 [M - C6H5S]+ (18), 110 [C6H5SH]+ (49), 79 (100), 77
1
The following are data for the Z-isomer. H NMR (300 MHz,
CDCl3): δ 7.36-7.32 (m, 2H), 7.30-7.23 (m, 2H), 7.21-7.15
(m, 1H), 5.49-5.43 (m, 1H), 3.65-3.62 (d, J ) 7.7 Hz, 2H),
2.88 (br s, 2H), 2.42-2.35 (q, J ) 7.2 Hz, 4H), 1.75 (d, J ) 1.2
Hz, 3H), 1.01-0.96 (t, J ) 7.0, 6H). 13C NMR (100 MHz,
CDCl3): δ 138.7, 136.8, 130.0, 128.9, 126.2, 122.8, 53.7, 46.9,
31.8, 23.0, 11.9. The following are data for the E-isomer. 1H
NMR (300 MHz, CDCl3): δ 7.36-7.32 (m, 2H), 7.30-7.23 (m,
2H), 7.21-7.15 (m, 1H), 5.49-5.43 (m, 1H), 3.60-3.57 (d, J )
7.2, 2H), 2.86 (br s, 2H), 2.41-2.34 (q, J ) 7.2 Hz, 4H), 1.61
(br s, 3H), 0.97-0.92 (t, J ) 7.2, 6H). 13C NMR (100 MHz,
CDCl3): δ 136.8, 130.2, 128.8, 126.3, 122.8, 61.7, 46.6, 32.1,
15.1, 11.5.
Gen er a l P r oced u r e for th e Ch em oselective Oxid a tion
of Allylic Su lfid es to th e Cor r esp on d in g Su lfoxid es
Usin g th e F la vin -H2O2 System . To a stirred solution of the
allylic sulfide (0.5 mmol) in methanol (1.5 mL) at room
temperature was added flavin 1 (2.7 mg, 0.01 mmol, 2 mol %,
if not indicated differently). After 1 min under air atmosphere
30% aqueous hydrogen peroxide (0.75 mmol, 1.5 equiv) was
added to the solution in one portion, leading to a color change
from red to yellow. The resulting mixture was stirred at room
temperature for the specified amount of time, and sodium
dithionite was added. Workup method A: Water (20 mL) was
added, and the mixture was extracted with 3 × 15 mL of
dichloromethane. The combined organic layers were washed
with brine, dried over MgSO4 and filtered. Workup method B:
The reaction mixture was diluted with 40 mL of diethyl ether,
and the organic phase was washed with 3 × 20 mL of water.
The organic layer was dried over Na2SO4 and filtered. After
removal of the solvent in vacuo the residue was purified by
flash chromatography.
[C6H5]+ (52). IR (film): 3035, 2949, 1732, 1242, 739, 692 cm-1
.
1H NMR (300 MHz, CDCl3): δ 7.50-7.35 (m, 2H), 7.34-7.20
(m, 3H), 6.00 (dd, J ) 10.2, 3.9, 1H), 5.81 (ddd, J ) 10.2, 3.9,
1.5 Hz, 1H), 5.26-5.18 (m, 1H), 3.88-3.80 (m, 1H), 2.25-2.06
(m, 2H), 2.03 (s, 3H), 1.80-1.64 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ 170.4, 134.6, 132.1, 131.9, 128.9, 127.8, 127.2, 66.9,
43.3, 25.6, 25.1, 21.2.
P r op a r gyl P h en yl Su lfid e (23).8,18 Sodium hydroxide (1.5
g, 37.5 mmol) and thiophenol (2.3 mL, 22.5 mmol) were stirred
in water (20 mL) for 25 min, after which the reaction mixture
was cooled to 0 °C and propargyl bromide (3.35 g, 80% solution
in toluene, 22.5 mmol) in benzene (25 mL) was added dropwise.
Tetrabutylammonium bromide (0.73 g, 2.25 mmol) was added,
and the mixture was stirred vigorously for 2.5 h. The organic
phase was separated, washed with water (2 × 12 mL) and then
brine (12 mL), and dried over MgSO4, and solvents were
removed in vacuo. Sulfide 23 was obtained in 90% yield (2.99
g) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.50-7.24
(m, 5H), 3.6 (d, J ) 2.8 Hz, 2H), 2.25 (t, J ) 2.8 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 135.4, 130.5, 129.4, 127.4, 80.3,
72.0, 23.0.
4-Ch lor o-3-m eth yl-2-bu ten yl P h en yl Su lfid e (37). To a
stirred solution of 4-hydroxy-3-methyl-2-butenyl phenyl sul-
fide14,15 (9) (194 mg, 1 mmol) in 3 mL of dry dichloromethane
was added triethylamine (279 µL, 2 mmol). The solution was
cooled in an ice bath, after which methanesulfonyl chloride
(155 µL, 2 mmol) was added dropwise. The solution was stirred
overnight at room temperature. The reaction mixture was
concentrated in vacuo and the residue diluted with diethyl
Oxid a tion of P h en yl P r en yl Su lfid e (3):8 Su lfoxid e 4.8,19
The reaction time was 2.5 h. Workup was made according to
method B. Flash chromatography with pentane/EtOAc (3:1)
afforded sulfoxide 4 (82 mg, 0.46 mmol) in 92% yield as a
colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.60-7.57 (m, 2H),
7.50-7.46 (m, 3H), 5.10-5.03 (m, 1H), 3.56-3.48 (m, 2H), 1.71
(17) Ba¨ckvall, J .-E.; Selle´n, M.; Nystro¨m, J .-E. Acta Chem. Scand.
1988, B42, 397-402.
(18) Donkerwood, J . G.; Gordon, A. R.; J ohnstone, C.; Kerr, W. J .;
Lange, U. Tetrahedron 1996, 52, 7391-7420.
(19) Binns, M. R.; Haynes, R. K.; Katsifis, A. G.; Schober, P. A.;
Vonwiller, S. C. J . Am. Chem. Soc. 1988, 110, 5411-5423.
5894 J . Org. Chem., Vol. 68, No. 15, 2003

Sulfoxidation of Allylic and Vinylic Sulfides
(s, 3H), 1.40 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 143.6,
142.4, 131.1, 129.0, 124.5, 111.2, 56.8, 26.0, 18.1.
3.53 (m, 2H), 1.25 (s, 3H), 0.86 (s, 9H), 0.02 (d, J ) 0.9 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 144.5, 143.4, 131.2, 129.1,
124.5, 112.2, 61.8, 55.8, 25.9, 21.4, 18.5, -5.25.
Oxid a tion of Allyl P h en yl Su lfid e (5):20 Su lfoxid e 6.6b,21
The reaction time was 2.5 h. Workup was made according to
method A. Flash chromatography with pentane/EtOAc (1:4)
afforded sulfoxide 6 (74 mg, 0.44 mmol) in 88% yield as a
colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.62-7.56 (m, 2H),
7.54-7.44 (m, 3H), 5.61 (ddt, J ) 17.2, 9.6, 7.6 Hz, 1H), 5.32
(ddd, J ) 9.6, 1.2, 1.2 Hz, 1H), 5.18 (ddd, J ) 17.2, 1.2, 1.2
Hz, 1H), 3.53 (dd, J ) 12.8, 7.6 Hz, 1H), 3.46 (dd, J ) 12.8,
7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 142.9, 131.0, 128.9,
125.2, 124.2, 123.8, 60.8.
Oxid a tion of 15: Su lfoxid e 16.16 The reaction time was
3 h and 20 min. Workup was made according to method A.
Flash chromatography with pentane/EtOAc (1:1) afforded the
E- and Z-isomers (5.4:1) of sulfoxide 16 in 96% yield as a white
powder. The following are data for the E-isomer. 1H NMR (300
MHz, CDCl3): δ 7.62-7.47 (m, 5H), 5.39-5.33 (m, 1H), 4.62-
4.48 (m, 2H), 3.51 and 3.39 (AB pattern, J AB ) 16.6 Hz, 2H),
2.03 (s, 3H), 1.78 (br m, 3H). The following are data for the
1
Z-isomer. H NMR (300 MHz, CDCl3): δ 7.65-7.49 (m, 5H),
Oxid a tion of Ger a n yl P h en yl Su lfid e (7):8 Su lfoxid e
8.8 The reaction time was 3 h. Workup was made according to
method B. Flash chromatography with pentane/EtOAc (65:35)
afforded an isomeric mixture of sulfoxide 8 (101 mg, 0.38
mmol) in 76% yield as a pale yellow oil. The following are data
for isomer A. 1H NMR (300 MHz, CDCl3): δ 7.64-7.56 (m,
2H), 7.52-7.44 (m, 3H), 5.09-5.00 (m, 2H), 3.64-3.44 (m, 2H),
2.02 (br s, 4H), 1.68 (s, 3H), 1.59 (s, 3H), 1.43 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 145.9, 132.1, 131.1, 129.9, 124.6, 123.8,
110.9, 56.7, 39.9, 26.5, 25.8, 17.8, 16.6. The following are data
for isomer B. 1H NMR (300 MHz, CDCl3): δ 7.64-7.56 (m,
2H), 7.52-7.44 (m, 3H), 5.09-5.00 (m, 2H), 3.64-3.44 (m, 2H),
1.97-1.89 (m, 4H), 1.74 (d, J ) 1.2 Hz, 3H), 1.67 (d, J ) 0.8
Hz, 3H), 1.62 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 145.6,
143.6, 131.1, 129.1, 124.5, 123.8, 110.9, 56.7, 32.3, 26.5, 23.7,
17.8, 16.6.
Oxid a tion of Su lfid e 9: Su lfoxid e 10.8 The reaction time
was 2 h. Workup was made according to method B. Flash
chromatography with pentane/EtOAc (1:1) afforded E- and
Z-isomers (1:2.6) of sulfoxide 10 (80.5 mg, 0.38 mmol) in 77%
yield as a yellow oil. The following are data for the Z-isomer.
1H NMR (300 MHz, CDCl3): δ 7.61-7.58 (m, 2H), 7.56-7.46
(m, 3H), 5.45-5.37 (m, 1H), 4.0 (s, 2H), 3.62-3.58 (m, 2H),
1.44 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 148.5, 145.3, 131.3,
129.2, 124.5, 110.9, 67.6, 55.9, 14.0. The following are data
for the E-isomer. 1H NMR (300 MHz, CDCl3): δ 7.61-7.58 (m,
2H), 7.56-7.46 (m, 3H), 5.02-4.98 (m, 1H), 3.97 (s, 2H), 3.77-
3.70 (m, 2H), 1.87 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 145.3,
143.2, 131.3, 129.2, 124.3, 112.7, 61.5, 54.8, 22.7.
5.69-5.63 (m, 1H), 4.38-4.24 (m, 1H), 3.71 and 3.54 (AB
pattern, J AB ) 16.8 Hz, 2H), 2.0 (s, 3H), 1.8 (br s, 3H).
Oxid a tion of Su lfid e 17: Su lfoxid e 18. The reaction time
was 3.5 h. Workup was made according to method A. Flash
chromatograph with pentane/EtOAc (1:1) afforded sulfoxide
18 (106 mg, 0.40 mmol) in 80% yield as a pale yellow oil in a
nonseparable diastereomeric mixture of 1:1. A 20% yield of
4-acetoxy-2-cyclohexenyl phenyl sulfide (17) (30 mg, 0.10
mmol) could be recovered. The following are data for diaster-
eomers A + B: GC-MS: m/z 250 [M - CH2]+ (37), 125 [C6H5-
SO]+ (100), 109 [C6H5S]+ (12), 77 [C6H5]+ (49). IR (film): 3066,
2930, 1732, 1243, 748, 690 cm-1. The following are data for
diastereomer A. 1H NMR (400 MHz, CDCl3): δ 7.65-7.60 (m,
2H), 7.53-7.48 (m, 3H), 6.00 (ddd, J ) 10.4, 4.0, 1.6 Hz, 1H),
5.47 (ddd, J ) 10.4, 4.0, 0.8 Hz, 1H), 5.24-5.16 (m, 1H), 3.38-
3.32 (m, 1H), 2.28-1.70 (m, 7H). 13C NMR (100 MHz, CDCl3):
δ 170.3, 141.7, 132.5, 131.5, 129.1, 125.1, 124.7, 66.0, 62.2, 25.2,
21.1, 17.6. The following are data for diastereomer B. 1H NMR
(400 MHz, CDCl3): δ 7.64-7.58 (m, 2H), 7.54-7.48 (m, 3H),
6.08 (ddd, J ) 10.0, 3.2, 2.0 Hz, 1H), 5.82 (ddd, J ) 10.0, 3.2,
1.2 Hz, 1H), 5.25-5.16 (m, 1H), 3.46-3.38 (m, 1H), 2.28-1.55
(m, 7H). 13C NMR (100 MHz, CDCl3): δ 170.3, 141.6, 133.2,
131.3, 129.0, 125.1, 124.1, 66.8, 60.8, 25.9, 19.9, 17.6.
Oxid a tion of 2-Cycloh exen yl P h en yl Su lfid e (19):23
Su lfoxid e 20.24 The reaction time was 2.5 h. Workup was
made according to method A. Flash chromatography with
pentane/EtOAc (1:4) afforded sulfoxide 20 (88 mg, 0.42 mmol)
in 84% yield as a yellow oil in a nonseparable diastereomeric
mixture of 55:45. The following are data for the first diaster-
eomer. 1H NMR (400 MHz, CDCl3): δ 7.64-7.54 (m, 2H),
7.49-7.42 (m, 3H), 6.11-6.05 (m, 1H), 5.61-5.54 (m, 1H),
3.35-3.28 (m, 1H), 2.34-1.40 (m, 6H). 13C NMR (100 MHz,
CDCl3): δ 142.1, 135.1, 130.8, 128.8, 124.7, 119.3, 61.3, 24.5,
23.2, 19.8. The following are data for the second diastereomer.
1H NMR (400 MHz, CDCl3): δ 7.64-7.54 (m, 2H), 7.49-7.42
(m, 3H), 5.99-5.93 (m, 1H), 5.15-5.08 (m, 1H), 3.27-3.21 (m,
1H), 2.34-1.40 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 142.1,
135.1, 131.1, 128.7, 125.1, 119.9, 62.9, 24.8, 21.3, 18.8.
Oxid a t ion of 2-Cyclooct en yl P h en yl Su lfid e (21):25
Su lfoxid e 22.26 Sulfide 21 (109 mg, 0.50 mmol) was reacted
with 30% aqueous hydrogen peroxide solution (112 µL, 1.00
mmol) using flavin 1 (5.4 mg, 0.02 mmol) as catalyst for 2.5 h
at room temperature. Workup was made according to method
A. Flash chromatography with pentane/EtOAc (65:35) afforded
sulfoxide 22 (102 mg, 0.43 mmol) in 86% yield as a pale yellow
oil in a nonseparable diastereomeric mixture of 78:22. The
following are data for the first diastereomer. 1H NMR (300
MHz, CDCl3): δ 7.65-7.40 (m, 5H), 5.76-5.68 (m, 1H), 5.54-
5.65 (m, 1H), 3.60-3.48 (m, 1H), 2.10-1.18 (m, 10H). 13C NMR
(100 MHz, CDCl3): δ 142.4, 134.0, 130.9, 128.8, 124.9, 123.4,
63.3, 28.6, 28.2, 26.4, 26.1, 24.9. The following are data for
the second diastereomer. 1H NMR (300 MHz, CDCl3): δ 7.65-
7.40 (m, 5H), 5.84-5.72 (m, 1H), 5.48-5.40 (m, 1H), 3.70-
Oxid a tion of Su lfid e 11:16 Su lfoxid e 12.22 The reaction
time was 3 h and 20 min. Workup was made according to
method A. Flash chromatography with pentane/EtOAc (4:1)
afforded the E- and Z-isomers (4:1) of sulfoxide 12 in 74% yield
1
as a colorless oil. The following are data for the E-isomer. H
NMR (300 MHz, CDCl3): δ 7.62-7.47 (m, 5H), 5.50-5.46 (m,
1H), 4.16-4.12 (m, 2H), 3.48 and 3.39 (AB pattern, J AB ) 12.4,
2H), 2.16 (br s, 1H), 1.8 (br s, 3H). The following are data for
the Z-isomer. 1H NMR (300 MHz, CDCl3): δ 7.67-7.44 (m,
5H), 6.05-5.0 (m, 1H), 3.97 (br m, 2H), 3.76 and 3.42 (AB
pattern, J AB ) 17 Hz, 2H), 2.55 (br s, 1H), 1.71 (br s, 3H).
Oxid a tion of Su lfid e 13: Su lfoxid e 14.8 The reaction time
was 3 h. Workup was made according to method B without
quenching. Flash chromatography with pentane/EtOAc (5:1)
afforded the E- and Z-isomers (1:3.3) of sulfoxide 14 (135 mg,
0.43 mmol) in 87% yield as a yellow oil. The following are data
for the Z-isomer. 1H NMR (300 MHz, CDCl3): δ 7.62-7.55 (m,
2H), 7.51-7.44 (m, 3H), 5.37-5.31 (m, 1H), 3.97 (s, 2H), 3.68-
3.53 (m, 2H), 1.39 (s, 3H), 0.86 (s, 9H), 0.035 (d, J ) 1.5 Hz).
13C NMR (75 MHz, CDCl3): δ 145.3, 144.5, 131.1, 129.0, 124.6,
110.0, 67.7, 56.2, 25.9, 21.4, 13.8, -5.33. The following are data
for the E-isomer. 1H NMR (300 MHz, CDCl3): δ 7.62-7.55 (m,
2H), 7.51-7.44 (m, 3H), 5.18-5.09 (m, 1H), 3.84 (s, 2H), 3.68-
(20) Arnau, N.; Moreno-Man˜as, M.; Pleixats, R. Tetrahedron 1993,
49, 11019-11028.
(23) Hopkins, P. B.; Fuchs, P. L. J . Org. Chem. 1978, 43, 1208-
1217.
(24) Hua, D. H.; Venkataraman, S.; Chan-Yu-King, R.; Paukstelis,
J . V. J . Am. Chem. Soc. 1988, 110, 4741-4748.
(25) Hardinger, S. A.; Fuchs, P. L. J . Org. Chem. 1987, 52, 2739-
2749.
(21) Antoniak, D. J .; Ridley, D. D.; Smal, M. A. Aust. J . Chem. 1980,
33, 2635-2651.
(22) (a) Nederlof, P. J . R.; Moolenar, M. J .; de Waard, E. R.;
Huisman, H. O. Tetrahedron Lett. 1976, 36, 3175-3178. (b) van der
Laan, R.; Moolenaar, M. J .; de Koning, H.; Huisman, H. O. Recl. Trav.
Chim. Pays-Bas 1985, 104, 220-225.
(26) Whitesell, J . K.; Carpenter, J . F.; Yaser, H. K.; Machajewski,
T. J . Am. Chem. Soc. 1990, 112, 7653-7659.
J . Org. Chem, Vol. 68, No. 15, 2003 5895

Linde´n et al.
3.56 (m, 1H), 2.10-1.18 (m, 10H). 13C NMR (100 MHz,
CDCl3): δ 142.2, 133.5, 130.6, 128.7, 124.4, 121.6, 61.9, 30.3,
28.2, 26.5, 26.1, 25.3.
yellow. The resulting mixture was stirred at room temperature
or 35 °C for the specified amount of time and quenched by
addition of sodium dithionite (0.2 g, 1.1 mmol). Water (20 mL)
was added, and the mixture was extracted with 3 × 15 mL of
dichloromethane. The combined organic layers were washed
with brine, dried over MgSO4, and filtered. After removal of
the solvent in vacuo the residue was purified by flash chro-
matography.
Oxid a tion of Vin yl P h en yl Su lfid e (31):30 P r ep a r a tion
of Su lfoxid e 32.6b Sulfide 31 (68 mg, 0.50 mmol), 30% aqueous
hydrogen peroxide (224 µL, 2.00 mmol), and flavin 1 (5.4 mg,
0.02 mmol) were reacted for 24 h at room temperature. Flash
chromatography with pentane/EtOAc (1:1) afforded sulfoxide
32 (45 mg, 0.30 mmol) in 60% yield as a yellow oil. A 14%
yield of 31 (10 mg, 0.07 mmol) could be recovered. 1H NMR
(400 MHz, CDCl3): δ 7.63-7.56 (m, 2H), 7.52-7.44 (m, 3H),
6.67 (dd, J ) 16.4, 9.6 Hz, 1H), 6.17 (d, J ) 16.4, 1H), 5.87 (d,
J ) 9.6, 1H). 13C NMR (100 MHz, CDCl3): δ 143.1, 142.9,
131.2, 129.4, 124.5, 120.6.
Oxid a tion of P r op a r gyl P h en yl Su lfid e (23): Su lfoxid e
24.27 The reaction time was 21 h. Workup was made according
to method B. Flash chromatography with pentane/EtOAc (9:
1) afforded sulfoxide 24 (61.8 mg, 0.38 mmol) in 76% yield as
a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.72-7.69 (m,
2H), 7.55-7.51 (m, 3H), 3.70-3.57 (dq, AB pattern, J AB ) 19.4
Hz, J 4 ) 2.8 Hz, 2H), 2.33 (t, J ) 2.8 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 143.0, 131.9, 129.2, 124.6, 76.5, 72.9, 47.9.
Oxid a tion of Dip r en yl Su lfid e(25):28 Su lfoxid e 26.8 The
reaction time was 2.5 h at 0 °C. Workup was made according
to method A. Flash chromatography with pentane/EtOAc (1:
4) afforded sulfoxide 26 (79 mg, 0.425 mmol) in 85% yield as
a colorless oil. 1H NMR (400 MHz, CDCl3): δ 5.27-5.18 (m,
2H), 3.45-3.30 (m, 4H), 1.77 (s, 6H), 1.68 (s, 6H). 13C NMR
(100 MHz, CDCl3): δ 141.2, 111.4, 49.8, 25.9, 18.4.
Oxid a tion of Su lfid e 27:29 Su lfoxid e 28.8 Sulfide 27 (96
mg, 0.50 mmol) was reacted with 30% aqueous hydrogen
peroxide solution (112 µL, 1.00 mmol) using flavin 1 (5.4 mg,
0.02 mmol) as catalyst for 3 h at room temperature. Workup
was made according to method A. Flash chromatography with
pentane/EtOAc (1:1) afforded sulfoxide 28 (81 mg, 0.385 mmol)
in 77% yield as a yellow oil. 1H NMR (300 MHz, CDCl3): δ
9.35 (s, 1H), 7.60-7.52 (m, 2H), 7.52-7.44 (m, 3H), 6.37 (dt, J
) 8.1, 1.5 Hz, 1H), 3.92 (dd, J ) 12.9, 8.1 Hz, 1H), 3.71 (dd, J
) 12.9, 8.1 Hz, 1H), 3.53 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 193.6, 145.1, 142.3, 138.0, 131.5, 129.2, 123.9, 55.6, 9.4.
Oxid a tion of Su lfid e 29: Su lfoxid e 30. The reaction time
was 3.5 h. Workup was made according to method B. Flash
chromatography with pentane/EtOAc (4:1) afforded sulfoxide
30 (97 mg, 0.37 mmol) in 86% yield as a yellow oil. The
following are data for the Z- + E-isomers. MS: m/z calcd for
Oxid a tion of 3-Meth yl-2-p h en ylth io-1,3-bu ta d ien e (33):
31
Su lfoxid e 34.31 Sulfide 33 (88 mg, 0.50 mmol), urea
hydrogen peroxide addition complex (475 mg, 5.00 mmol), and
flavin 1 (5.4 mg, 0.02 mmol) were reacted for 48 h at room
temperature. Flash chromatography with pentane/EtOAc (1:
1) afforded sulfoxide 34 (51 mg, 0.265 mmol) in 53% yield as
a yellow oil. A 16% yield of 33 (14 mg, 0.08 mmol) could be
1
recovered. H NMR (300 MHz, CDCl3): δ 7.66-7.58 (m, 2H),
7.47-7.36 (m, 3H), 6.18 (s, 1H), 5.80 (s, 1H), 5.21 (s, 1H), 5.05
(s, 1H), 1.78 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 153.6, 143.7,
137.5, 131.2, 129.0, 125.6, 116.2, 114.8, 22.1.
Oxid a t ion of 1-(1-P h en ylt h iovin yl)cycloh exen e (35):
31
Su lfoxid e 36.31 Sulfide 35 (108 mg, 0.50 mmol), urea
hydrogen peroxide addition complex (475 mg, 5.00 mmol), and
flavin 1 (6.8 mg, 0.025 mmol) were reacted for 48 h at 35 °C.
Flash chromatography with pentane/EtOAc (4:1) afforded
sulfoxide 36 (70 mg, 0.30 mmol) in 60% yield as a yellow oil.
C
15H24NSO (M+ + H) 266.1573, found 266.1585. The following
are data for the Z-isomer. 1H NMR (400 MHz, CDCl3): δ 7.61-
7.58 (m, 2H), 7.51-7.47 (m, 3H), 5.30-5.23 (m, 1H), 3.64-
3.57 (m, 2H), 2.84 (s, 2H), 2.38-2.33 (q, J ) 7.2 Hz, 4H), 1.44
(app s, 3H), 0.93 (t, J ) 7.2 Hz, 6H). 13C NMR (100 MHz,
CDCl3): δ 144.5, 143.6, 131.1, 129.1, 124.6, 112.5, 61.7, 56.4,
46.7, 23.5, 11.8. The following are data for the E-isomer. 1H
NMR (400 MHz, CDCl3): δ 7.61-7.58 (m, 2H), 7.51-7.47 (m,
3H), 5.30-5.23 (br m, 1H), 3.69-3.65 (m, 2H), 2.72-2.71 (d,
J ) 4 Hz, 2H), 2.35-2.29 (q, J ) 7.2 Hz, 4H), 1.76 (app s, 3H),
0.96-0.92 (t, J ) 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
144.6, 143.7, 131.1, 129.1, 124.6, 114.3, 56.1, 54.1, 46.8, 15.4,
11.9.
1
A 26% yield of 35 (30 mg, 0.13 mmol) could be recovered. H
NMR (400 MHz, CDCl3): δ 7.66-7.58 (m, 2H), 7.46-7.36 (m,
3H), 6.02 (s, 1H), 6.00-5.96 (m, 1H), 5.65 (s, 1H), 1.40-2.30
(m, 8H). 13C NMR (100 MHz, CDCl3): δ 154.4, 144.1, 131.5,
131.0, 129.1, 128.9, 125.5, 112.2, 27.7, 25.3, 22.2, 21.6.
Ack n ow led gm en t. This research is supported by
the Swedish Research Council for Engineering Sciences,
the Royal Swedish Academy of Sciences, a Marie Curie
Fellowship of the European Community program “Im-
proving Human Research Potential and the Socio-
Economic Knowledge” under Contract Number HPMF-
CT-2000-00770.
Gen er a l P r oced u r e for th e Ch em oselective Oxid a tion
of Vin ylic Su lfid es to th e Cor r esp on d in g Su lfoxid es
Usin g th e F la vin -H2O2 System . To a stirred solution of the
vinylic sulfide (0.5 mmol) in methanol (1.5 mL) at room
temperature was added flavin 1 (5.4 mg, 0.02 mmol, if not
indicated differently). After 1 min under air atmosphere the
specified amount of hydrogen peroxide was added to the
solution in one portion, leading to a color change from red to
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 17, 18, 24, 26, and 28-30. This material
is available free of charge via the Internet at http:pubs.acs.org.
J O034273Z
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