Addition of bis-sulfinyl anions to ketones: Stereoselective synthesis of allylic alcohols through Evans-Mislow rearrangement based domino reactions

Article abstract of DOI:10.1055/s-2007-966070

Enantiopure cyclic allylic alcohols were obtained from cyclic ketones and bis-sulfoxides through a domino reaction mixing anionic and concerted elementary steps. Total transfer of chirality was achieved, presumably through cooperative effects of both sulf

Full text of DOI:10.1055/s-2007-966070

PAPER
2273
Addition of Bis-sulfinyl Anions to Ketones: Stereoselective Synthesis of Allylic
Alcohols through Evans–Mislow Rearrangement Based Domino Reactions
E
nantioselecti
r
axy-methyln
Université Pierre et Marie Curie-Paris 6, Laboratoire de chimie organique (UMR CNRS 7611), Institut de chimie moléculaire (FR 2769),
4 place Jussieu, C. 229, 75005 Paris, France
Fax +33(1)44277360; E-mail: lacote@ccr.jussieu.fr; E-mail: louis.fensterbank@upmc.fr; E-mail: max.malacria@upmc.fr
Received 2 February 2007
This paper is dedicated to our mentor, colleague, and friend Paul A. Wender on the occasion of his 60th birthday.
stereochemical outcome arises from a diastereoselective
Abstract: Enantiopure cyclic allylic alcohols were obtained from
protonation after the double bond migration. Nonetheless,
cyclic ketones and bis-sulfoxides through a domino reaction mixing
the control of the allylic center was not optimal. Llera and
co-workers introduced enantiopure bis-sulfoxides as part-
anionic and concerted elementary steps. Total transfer of chirality
was achieved, presumably through cooperative effects of both sul-
foxides units. Depending on the ring size, both sulfinyl groups ners for the SPAC reaction, but in this particular case the
diastereoselectivity was poor.4 Following our interest in
could be converted, giving C2-symmetric bis-allylic alcohols.
bis-sulfoxides,5 we wondered whether introducing strain
Key words: alkenation, carbanion, pericyclic reaction, sulfoxide,
sulfur
into the Knoevenagel adducts would help the diastereose-
lectivity. We, thus, decided to focus on ketones instead of
aldehydes in the hope that this would make Llera’s ap-
proach stereoselective;4,6 we report herein the results.
The Evans–Mislow rearrangement is an extremely effec-
tive and rapid way to access allylic alcohols.1 Thanks to its
pericyclic mechanism, very high control of the double
bond geometry is possible and both carbon-to-carbon and
sulfur-to-carbon chirality transfer are possible. Thus, the
reaction has attracted considerable interest, notably for
synthetic purposes. More complex domino reactions that
use the Evans–Mislow rearrangement have been devised.
The sulfoxide piperidine aldehyde condensation (SPAC)
process is of particular interest (Scheme 1).2
O
O
S
O
S
S
p-Tol
p-Tol
+
7
HO
p-Tol
5
6a
(+H2O)
O
O
S
O
S
O
S
O
S
p-Tol
S
p-Tol
p-Tol
O
p-Tol
p-Tol
O
S
OH
p-TolS
N
H
+
EWG
R
CHO
*
Ar
MeCN
R
EWG
1
4
one-pot
O
O
O
Ar
O
Ar
p-Tol
S
S
S
S
p-Tol
R
EWG
R
EWG
2
3
Scheme 2
Scheme 1
Bis-sulfoxide 5 was first reacted with cyclohexanone and
piperidine, but to no avail (Table 1, entry 1). Thus, 5 was
deprotonated at –40 °C with butyllithium, then treated
with cyclohexanone; when the reaction was allowed to
warm to room temperature, two new products were ob-
tained. The desired product 6a was isolated in 30% yield
together with 7, the product of the thiolation of 5, in 45%
yield. This validated our approach, as the expected cas-
cade was still taking place (Scheme 2).
In this sequence, an easily accessible a-cyano, b-oxo, or
a-methoxycarbonyl sulfoxide 1 can be transformed into a
functionalized allylic alcohol 4 through a process featur-
ing a Knoevenagel reaction, followed by base-triggered
double bond migration, sigmatropic rearrangement, and
final collapse of the sulfenate from 3. Moderate enantio-
meric excesses were obtained upon starting from enan-
tiopure sulfoxides.3 The authors proposed that the
SYNTHESIS 2007, No. 15, pp 2273–2278
x
x.
x
x
.
2
0
0
7
Advanced online publication: 11.05.2007
DOI: 10.1055/s-2007-966070; Art ID: C00707SS
© Georg Thieme Verlag Stuttgart · New York

2274
F. Brebion et al.
PAPER
Table 1 Reaction of Bis-sulfoxides with Base and a Ketone
O
S
O
S
1. base
2. ketone
O
S
O
S
p-Tol
+
p-Tol
6a–c
p-Tol
thiophile
p-Tol
Sp-Tol
5
7
Entry
1
Base
Ketone
Thiophile
–
Product
Yield (%)
ds
–
Yield (%) of 7
a
piperidine
–
–
O
O
O
O
O
O
2
3
4
5
6
7
8
9
BuLi
BuLi
BuLi
LDA
BuLi
BuLi
BuLi
BuLi
–
6a
6a
6a
6a
6a
6b
6b
6c
30
33b
28
31
65
5c
100:0
100:0
100:0
100:0
100:0
–
45
50b
46
45
–
–
P(OEt)3
i-Pr2NH
PhSLi
–
45
–
O
PhSLi
PhSLi
61
42
100:0
4.45:1
O
–
t-Bu
O
a
O
10
BuLi
PhSLi
–
–
–
11
12
BuLi
BuLi
PhSLi
PhSLi
9
60
–
–
–
–
O
d
–
O
a No reaction.
b Crude yield (1,4-dimethoxybenzene as internal standard).
c Allyl sulfoxide 8 (37%) was also obtained.
d Degradation.
However, one half of the starting bis-sulfoxide was react- these improved conditions, we could isolate a much high-
ing as a thiophile, shifting the Evans–Mislow rearrange- er yield of 6a (65%, one diastereomer), and no 7 (Table 1,
ment toward the allylic alcohol at the expense of the entry 6).
overall yield. Despite this problem, the diastereoselectiv-
With these conditions in hand, we endeavored to examine
ity was high, since we did not observe any trace of a minor
the scope of the reaction. Reaction with cyclopentanone
diastereomer, a noticeable improvement over previous
was similar to that of cyclohexanone (Table 1, entry 8).
work. This reaction suffered some reproducibility issues
Yet, allyl sulfoxide 8 (Figure 1) was also observed in
some cases. It arises from the migration of the double
bond in the final hydroxy sulfoxide 6b (Figure 1). 4-tert-
Butylcyclohexanone not surprisingly delivered 6c, albeit
(approx. 5–10% variation in the yield of 6a). Upon work-
ing with an internal standard, we showed that this was not
due to degradation of 6a during the purification step
(Table 1, compare entries 2 and 3). Hence, our hypothesis
the yields were slightly lower and the diastereoselectivity
was that the anion of 6a is not stable. To avoid this degra-
was not optimal (Table 1, entry 9). This is most certainly
due to the anchoring tert-butyl group. Logically, further
reduction of the ring size was detrimental (Table 1, entry
dation, we decreased the reaction time. A quick screening
of different thiophiles indicated that the lithium salt of
thiophenol was optimal (Table 1, entries 4–6). Using
11); the reaction stopped after the initial addition of the
Synthesis 2007, No. 15, 2273–2278 © Thieme Stuttgart · New York

PAPER
Enantioselective Hydroxymethylation
2275
bis-sulfinyl anion to cyclobutanone giving 9; upon dehy-
dration of 9,5a vinyl bis-sulfoxide 10 was isolated, albeit in
low yield (31%), and it did not react further. This nonethe-
less provides an entry into hetero-substituted strained
alkylidenecyclobutanes. An increase in the ring size also
resulted in efficiency loss (yield and selectivity) of the
synthetic process (37% yield for cycloheptanone, 81:19
ds). The use of acyclic ketones, such as pentan-3-one, led
only to degradation (Table 1, entry 12), while steric con-
gestion on the cyclic ketone blocked the initial addition
(Table 1, entry 10).
O
S
O
S
O
S
p-Tol
HO
p-Tol
p-Tol
HO
HO
t-Bu
6c
Figure 2
6a
6b
O
ylene. Intermediate A would be favored because B would
develop a nonbonding interaction between the tolyl group
of the reacting sulfoxide and the cycloalkene ring
(Scheme 4). In this regard, the two sulfinyl units would
have a coordinated role reminiscent of a cog wheel.
O
S
O
O
S
O
p-Tol
S
p-Tol
S
S
p-Tol
p-Tol
p-Tol
HO
HO
8
9
10
H
Ar
Figure 1
H
Ar
O
O
O
Ar
S
S
S
S
The absolute configuration of the newly created stereo-
genic center on 6a was established by chemical derivati-
zation (Scheme 3). 2-{[(R)-4-Tolylsulfinyl]methyl-
ene}cyclohexanol 6a was converted into 2-acetoxycyclo-
hexanone 11, which was obtained enantiomerically pure.
Optical rotation measurement ([a]D25) of 11 correlated to
the S absolute configuration.7
H
Ar
H
O
H
H
B
A
O
S
O
S
p-Tol
p-Tol
O
S
HO
OH
O
1. Ac2O, DMAP, py
2. O3, then Me2S
p-Tol
HO
AcO
6a
46% (two steps)
Scheme 4
6a
(S)-11
er > 99:1 (GC)
As stated before, we observed that vinyl sulfoxide 6b
slowly rearranged to allyl sulfoxide 8. This is in line with
reported rates of double bond migration from an exocyclic
position toward the inside position.8 It would eventually
lead to a loss of the stereochemical purity at the sulfur at-
om, however, the epimerization rate is relatively slow
(half life of >1 d in THF at 30 °C) and this process can be
halted at lower temperatures (no epimerization after more
than two years in the freezer!). Configurationally stable
allyl sulfoxides are rare, but not unprecedented.9 We de-
cided to run a second Evans–Mislow rearrangement on
diastereomerically pure 8 (Scheme 5).
Scheme 3
X-ray diffraction analysis of crystals grown from 6b indi-
cated that the absolute configuration was identical to that
of 6a (Figure 2). It also established the E configuration for
the double bond.
The origin of the stereoselectivity is difficult to assess. We
propose the following model: In both transition states A
and B, the spectator sulfinyl group would lock the system
by occupying the pseudoequatorial position and adopting
a staggered conformation putting the sterically demand-
ing tolyl group furthest away from the cyclic allylic meth-
Synthesis 2007, No. 15, 2273–2278 © Thieme Stuttgart · New York

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F. Brebion et al.
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All reactions were performed under an argon or N2 atmosphere in
anhyd solvents and dried flask. TLC was performed on Merck silica
gel 60 F 254 and developed with either a UV lamp (l = 254 nm) or
p-anisaldehyde soln. Column chromatography was performed with
silica gel Merck Geduran SI (40–63 nm) and using Still’s method.
Solvents were systematically distilled prior to used. IR spectra were
recorded on a Perkin-Elmer 1420 or a Bruker Tensor 27 ATR dia-
mond PIKE spectrophotometer. NMR spectra were recorded at r.t.,
either at 200 MHz (1H) or 50 MHz (13C) on a AC200 Bruker spec-
trometer, or at 400 MHz (1H) or 100 MHz (13C) on an ARX400 and
an AVANCE 400 Bruker spectrometers. The reference for 1H NMR
was residual solvent signal (d 7.26 for CDCl3) and for 13C NMR it
was the solvent central peak (d 77.0 for CDCl3). Elemental analysis
were performed by the Service Régional de Microanalyse de l’Uni-
versité Pierre et Marie Curie or by ICSN (CNRS, Gif-sur-Yvette,
France). MS were performed by the Laboratoire Structure et Fonc-
tion de Molécules Bioactives (CNRS, UMR 7613, FR 2769, Paris,
France). Melting points were obtained on a Reichert apparatus and
are uncorrected. Chiral GC was run using a column CP-Chirasil-
DEX CB (25 m), FID and N2 as carrier gas.
O
S
p-Tol
(EtO)3P
OH
HO
HO
MeOH, ∆
8
Ac2O, DMAP
OAc
OAc
+
AcO
AcO
py, r.t.
82%, two steps
12
13
12/13 = 94:6
Scheme 5
When submitted to triethyl phosphite in refluxing metha-
nol, allyl sulfoxide 8 gave a bis-allyl alcohol that could
not be separated from a minor impurity. The crude prod-
uct was, thus, acylated to give diastereomeric diacetates
12 and 13 in 82% yield in a ratio of 94:6. The major prod-
uct of the reaction 12 was optically active, thus it is the C2-
symmetric isomer. Because the absolute configuration of
the first stereogenic center has been shown to be S, we de-
duced the newly created center also to be S. This double
Evans–Mislow could not be extended to the cyclohexyl-
idene series; the migration of the exo-double bond to the
intracyclic position could not be achieved. Nonetheless,
the reaction in the cyclopentane series is very interesting
since chiral bis-allylic alcohols can be obtained with good
enantiomeric ratios and these can be further functional-
ized, via p-allyl palladium intermediates, for example.
Addition of Bis-sulfoxides to Ketones with Lithium Benzene-
thiolate as Thiophile; General Procedure
Bis-sulfoxide 5 was heated overnight in vacuo at 80 °C prior to use.
To a soln of 5 (1 equiv) and PhSH (3 equiv) in THF (6 mL/mmol of
5) at –40 °C was added 2.5 M BuLi in hexanes (4.1 equiv). After 1
h, the distilled ketone (3 equiv) was added dropwise. The mixture
was then warmed to the relevant temperature (–20 °C for 6b, r.t. for
6a and 6c) until completion (for 6a and 6c, the reaction was stopped
after 1 h; degradation was observed when the reaction time was in-
creased), then quenched with aq sat. NH4Cl. The aqueous layer was
extracted with CH2Cl2 and the combined organics were washed
with brine and dried (MgSO4), filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography.
(S)-2-{[(R)-4-Tolylsulfinyl]methylene}cyclohexanol (6a)
Following the general procedure from 5 (585 mg, 2.00 mmol) and
cyclohexanone (0.62 mL, 3 equiv), chromatography (PE–EtOAc,
70:30 to 0:100) afforded 6a as a white solid; yield: 325 mg (65%);
mp 156–158 °C.
O
Ar
Ar
S
HO
S
12
13
O
OH
D
C
[a]D20 –144.0 (c 1.15, CHCl3).
IR (neat): 3332, 3041, 2940, 1620, 1492, 1445, 1080, 814 cm–1.
Scheme 6
1H NMR (400 MHz, CDCl3): d = 1.44–1.59 (m, 3 H, CH2CH2),
1.75–1.88 (m, 2 H, CH2CH2), 2.02–2.11 (m, 2 H, CH2CH2,
CHHC=), 2.36 (s, 3 H, p-Tol), 3.24–3.28 (m, 1 H, CHHC=), 4.02–
4.05 (m, 1 H, CHOH), 6.34 (s, 1 H, =CH), 7.24 (d, J = 8.1 Hz, 2 H,
arom), 7.42 (d, J = 8.1 Hz, 2 H, arom).
13C NMR (100 MHz, CDCl3): d = 21.4 (p-Tol), 24.0 (CH2), 27.3
(CH2), 29.3 (CH2), 36.7 (CH2), 72.2 (CHOH), 124.8 (CH arom),
126.6 (=CH), 129.9 (CH arom), 140.8 (C arom), 141.2 (C arom),
158.2 (=C).
The high diastereoselectivity achieved during the reaction
can be attributed to the matching directing effects of the
stereogenic sulfur and the already installed hydroxy group
(Scheme 6). Indeed, a nonbonding interaction between
the aryl group and the hydroxy moiety develops on transi-
tion state D. This behavior is similar to that observed by
Hoffman with congested allyl cyclopentenyl sulfoxides.10
To conclude, we have shown that enantiopure bis-sulfox-
ides are good starting materials for the preparation of
chiral cyclic allyl alcohols from cyclic ketones. The key
element that renders the process highly stereoselective is
the increased steric hindrance on the carbonyl group. By
playing on the cycle strain, one can direct the reaction to-
ward either no allylic sigmatropy (cyclobutane case), sin-
gle Evans–Mislow rearrangement (cyclohexane family),
or double Evans–Mislow rearrangement (cyclopentane
series). Work to exploit this reaction, as well as the full
potential of bis-sulfoxides in synthesis is under way and
will be reported in due course.
(S)-2-{[(R)-4-Tolylsulfinyl]methylene}cyclopentanol (6b)
Following the general procedure from 5 (1.75 g, 6.00 mmol) and cy-
clopentanone (1.59 mL, 3 equiv), chromatography (CH2Cl2–
EtOAc, 75:25 to 10:90) and crystallization (CH2Cl2–EtOAc) af-
forded 6b as a white crystalline solid; yield: 873 mg (61%); mp
125–130 °C (dec).
[a]D20 –142.5 (c 1.2, CH2Cl2).
IR (neat): 3283, 3053, 2983, 1645, 1597, 1081, 810, 790 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.62–1.69 (m, 2 H, CH2CH2),
1.91–1.95 (m, 1 H, CH2CH2), 2.05–2.10 (m, 1 H, CH2CH2), 2.40 (s,
3 H, p-Tol), 2.54–2.62 (m, 1 H, =CCHH), 2.90–2.95 (m, 1 H,
=CCHH), 4.40 (br s, 1 H, CHOH), 6.42 (br s, 1 H, =CH), 7.29 (d,
J = 8.4 Hz, 2 H, arom), 7.49 (d, J = 8.4 Hz, 2 H, arom).
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Enantioselective Hydroxymethylation
2277
13C NMR (100 MHz, CDCl3): d = 21.0 (=CCH2CH2), 21.6 (p-Tol),
28.5 (=CCH2), 34.3 [=CCH(OH)CH2], 75.8 (CHOH), 124.5 (CH
arom), 127.9 (=CH), 130.3 (CH arom), 141.1 (C arom), 141.5 (C
arom), 161.0 (=C).
137.4 (C arom), 138.1 (C arom), 139.0 (C arom), 142.8 (C arom),
146.6 (C arom).
Anal. Calcd for C22H22O2S3: C,63.73; H, 5.35. Found: C, 63.67; H,
5.36.
(2S,4RS)-4-tert-Butyl-2-{[(R)-4-tolylsulfinyl]methylene}cyclo-
hexanol (6c)
Following the general procedure from 5 (585 mg, 2.00 mmol) and
4-tert-butylcyclohexanone (925 mg, 3 equiv), in THF (doubled con-
centration, 3 mL/mmol of 5), chromatography (CH2Cl2–EtOAc,
80:20 to 10:90) delivered 6c as two diastereomers in order of elu-
tion: minor (42 mg, 7%) and major (215 mg, 35%).
(S)-2-[(4-Tolylsulfinyl)methyl]cyclopent-2-enol (8)
White solid; mp 95–96 °C.
[a]D20 +266.0 (c 1.1, CHCl3).
IR (neat): 3284, 3053, 2966, 1595, 1071, 1010, 811 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.77–1.84 (m, 1 H, CH2CH2),
2.22–2.31 (m, 2 H, CH2CH2), 2.39 (s, 3 H, p-Tol), 2.47–2.52 (m, 1
H, CH2CH2), 3.57 (B of AB, J = 13.0 Hz, 1 H, CHHS), 3.79 (A of
AB, J = 13.0 Hz, 1 H, CHHS), 4.63 (br s, 1 H, CHOH), 5.87 (s, 1
H, =CH), 7.30 (d, J = 8.1 Hz, 2 H, arom), 7.52 (d, J = 8.1 Hz, 2 H,
arom).
1H NMR (400 MHz, THF-d8): d = 1.65–1.71 (m, 1 H, CH2CH2),
2.16–2.24 (m, 2 H, CH2CH2), 2.37–2.43 (m, 1 H, CH2CH2), 2.43 (s,
3 H, p-Tol), 3.47 (B of AB, J = 12.9 Hz, 1 H, CHHS), 3.74 (A of
AB, J = 12.9 Hz, 1 H, CHHS), 4.58 (br s, 1 H, CHOH), 5.67 (s, 1
H, =CH), 7.37 (d, J = 7.8 Hz, 2 H, arom), 7.56 (d, J = 7.8 Hz, 2 H,
arom).
1H NMR (400 MHz, CD3OD): d = 1.68–1.74 (m, 1 H, CH2CH2),
2.20–2.31 (m, 2 H, CH2CH2), 2.41–2.46 (m, 1 H, CH2CH2), 2.46 (s,
3 H, p-Tol), 3.73–3.80 (AB, 2 H, CH2S), 4.55 (br s, 1 H, CHOH),
5.75 (br s, 1 H, =CH), 7.44 (d, J = 8.1 Hz, 2 H, arom), 7.60 (d, J =
8.1 Hz, 2 H, arom).
13C NMR (100 MHz, CDCl3): d = 21.7 (p-Tol), 30.6 (CH2CH2),
34.0 (CH2CH2), 58.1 (CH2S), 77.8 (CHOH), 124.4 (CH arom),
130.1 (CH arom), 136.4 (=C), 136.9 (=CH), 140.3 (C arom), 142.1
(C arom).
Minor diastereomer
Colorless liquid.
[a]D20 –100.0 (c 0.8, CHCl3).
IR (neat): 3324, 2951, 2866, 1625, 1082, 801 cm–1.
1H NMR (400 MHz, CDCl3):
d = 0.84–0.86 [m, 1 H,
CH(OH)CHH], 0.87 (s, 9 H, CMe3), 1.23–1.36 [m, 3 H,
CHHCH2C=, CHCMe3, CH(OH)CHH], 1.91–1.97 (m, 1 H,
CHHC), 2.21–2.25 (m, 1 H, CHHCH2C=), 2.38 (s, 3 H, p-Tol),
3.38–3.43 (m, 1 H, CHHC=), 4.05–4.12 (m, 1 H, CHOH), 6.38 (s,
1 H, =CH), 7.25 (d, J = 8.1 Hz, 2 H, arom), 7.44 (d, J = 8.1 Hz, 2 H,
arom).
13C NMR (100 MHz, CDCl3): d = 21.6 (p-Tol), 27.8 [C(CH3)3], 28.3
[CH(OH)CH2], 29.3 (CH2C=), 32.6 (CMe3), 38.6 (CH2CH2C=),
46.8 (CHCMe3), 72.9 (CHOH), 124.5 (CH arom), 126.8 (HC=),
130.2 (CH arom), 141.1 (C arom), 141.8 (C arom), 157.5 (C=).
HRMS: m/z [M + Na]+ calcd for C18H26O2NaS: 329.1551; found:
329.1561.
Major diastereomer
White solid; mp 131–133 °C.
[a]D20 –102.0 (c 1.15, CHCl3).
IR (neat): 3330, 2948, 1630, 1394, 1083, 1012, 797 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.86 (s, 9 H, CMe3), 0.93–1.11 (m,
1 H, CHHCH2C=), 1.18–1.27 [m, 1 H, CH(OH)CHH], 1.78 (tt, J =
12.6, 3.1 Hz, 1 H, CHCMe3), 2.01–2.10 [m, 2 H, CH(OH)CHH,
CHHCH2C=], 2.41 (s, 3 H, p-Tol), 2.59–2.69 (m, 1 H, CHHC=),
3.12 (dt, J = 13.6, 3.0 Hz, 1 H, CHHC=), 4.27 (br s, 1 H, CHO), 6.10
(d, J = 1.5 Hz, 1 H, =CH), 7.32 (d, J = 8.1 Hz, 2 H, arom), 7.47 (d,
J = 8.1 Hz, 2 H, arom).
1-{Bis[(S)-4-Tolylsulfinyl]methyl}cyclobutan-1-ol (9)
Following the general procedure from 5, bis-sulfinyl alcohol 9 was
isolated as a white solid; yield: 60%; mp 128–130 °C.
[a]D20 +83.5 (c 1.1, CHCl3).
IR (neat): 3420, 2980, 2920, 1080, 1050 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.60–1.83 (m, 1 H, CH2), 2.04–
2.27 (m, 5 H, CH2), 2.34 (s, 3 H, p-Tol), 2.46 (s, 3 H, p-Tol), 3.77
(s, 1 H, CHS), 4.81 (br s, 1 H, OH), 6.88 (d, J = 8.2 Hz, 2 H, arom),
7.15 (d, J = 8.2 Hz, 2 H, arom), 7.38 (d, J = 8.2 Hz, 2 H, arom), 7.58
(d, J = 8.2 Hz, 2 H, arom).
13C NMR (50 MHz, CDCl3): d = 15.4 (CH2), 21.3 (p-Tol), 21.5 (p-
Tol), 35.8 (CH2), 36.5 (CH2), 79.1 (C-OH), 93.4 (CHS), 123.9 (CH
arom), 124.8 (CH arom), 130.0 (CH arom), 130.3 (CH arom), 138.9
(C arom), 139.8 (C arom), 141.3 (C arom), 142.4 (C arom).
13C NMR (100 MHz, CDCl3): d = 21.6 (p-Tol), 26.2 (CH2C=), 27.7
[C(CH3)3], 28.7 (CH2CH2C=), 32.2 (CMe3), 35.5 [CH(OH)CH2],
40.4 (CHCMe3), 72.2 (CHOH), 124.3 (CH arom), 129.7 (=CH),
130.3 (CH arom), 141.3 (C arom), 156.4 (=C).
HRMS: m/z [M + Na]+ calcd for C18H26O2NaS: 329.1551; found:
329.1557.
Anal. Calcd for C19H22O3S2: C, 62.95; H, 6.12. Found: C, 62.95; H,
6.41.
{Bis[(S)-4-Tolylsulfinyl]methylene}cyclobutane (10)
To a soln of 9 (100 mg, 0.28 mmol, 1 equiv) in MeCN (2 mL) at r.t.
were added N-cyclohexyl-N¢-[2-(4-methylmorpholino)ethyl]carbo-
diimide p-toluenesulfonate salt (176 mg, 0.41 mmol, 1.5 equiv) and
a catalytic amount of CuCl2 (0.1 equiv). The reaction was heated at
70 °C for 14 h. After cooling, the mixture was diluted with CH2Cl2
and filtered over a short pad of Celite and silica gel, and concentrat-
ed in vacuo to give bis-sulfoxide 10 as a white solid; yield: 31%; mp
112–114 °C.
[a]D20 –135.0 (c 1.3, CHCl3).
IR (neat): 1470, 1080, 1050 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.18 (quint, J = 7.9 Hz, 2 H,
=CCH2CH2), 2.36 (s, 6 H, p-Tol), 2.90–3.17 (m, 2 H, =CCH2),
3.20–3.36 (m, 2 H, =CCH2), 7.14 (s, 8 H, arom).
Bis[(S)-4-Tolylsulfinyl]methyl 4-Tolyl Sulfide (7)
Following the general procedure, 7 was eluted as a byproduct (less
polar fraction) as a white solid; mp 76–78 °C.
[a]D20 +44.0 (c 1.05, CHCl3).
IR (neat): 3000, 1600, 1490, 810 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.16 (s, 3 H, p-Tol), 2.42 (s, 3 H,
p-Tol), 2.43 (s, 3 H, p-Tol), 4.51 (s, 1 H, CHS3), 6.06 (d, J = 8.1 Hz,
2 H, arom), 6.55 (d, J = 8.1 Hz, 2 H, arom), 7.26 (d, J = 8.0 Hz, 2
H, arom), 7.31 (d, J = 8.1 Hz, 2 H, arom), 7.58 (d, J = 8.0 Hz, 2 H,
arom), 7.70 (d, J = 8.1 Hz, 2 H, arom).
13C NMR (100 MHz, CDCl3): d = 21.4 (p-Tol), 21.9 (p-Tol), 104.5
(CHS3), 125.9 (CH arom), 127.1 (CH arom), 128.5 (C arom), 129.8
(CH arom), 130.1 (CH arom), 130.2 (CH arom), 133.0 (CH arom),
Synthesis 2007, No. 15, 2273–2278 © Thieme Stuttgart · New York

2278
F. Brebion et al.
PAPER
13C NMR (50 MHz, CDCl3): d = 18.3 (=CCH2CH2), 21.3 (p-Tol),
33.2 (=CCH2), 124.6 (CH arom), 129.6 (CH arom), 139.0 (=C),
141.2 (=C), 167.5 (=CS2).
The structure of 13 (minor diastereomer) was confirmed by GC-MS
and by a characteristic 1H NMR signal (400 MHz, CDCl3): d = 2.09
(s, 3 H, OAc).
Anal. Calcd for C19H20O2S2: C, 66.24; H, 5.85. Found: C, 65.94; H,
6.04.
Acknowledgment
(S)-1-Acetoxy-2-{[(R)-4-tolylsulfinyl]methylene}cyclohexane
(Acetylated 6a)
We thank Dr. Mihaela Gulea (CNRS, Caen, France) for fruitful dis-
cussions. Financial support from CNRS, UPMC and IUF is grate-
fully acknowledged.
To a soln of 6a (142 mg, 0.56 mmol, 1 equiv) in pyridine (1 mL)
were added at r.t. Ac2O (0.11 mL, 1.13 mmol, 2 equiv) and DMAP
(7 mg, 0.056 mmol, 0.1 equiv). After 1 h, the mixture was diluted
with Et2O and washed with 1 M HCl and brine. The organic layer
was dried (MgSO4) and concentrated in vacuo to give acetylated 6a
as a pale yellow solid; yield: 66%; mp 56–58 °C.
[a]D25 –169.0 (c 1.1, CHCl3).
IR (neat): 2940, 2840, 1730, 1625, 1445, 1370, 1240, 1080 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.45–1.60 (m, 3 H, CH2), 1.78–
1.86 (m, 2 H, CH2), 1.95 (s, 3 H, Ac), 1.95–2.05 (m, 1 H, CH2),
2.14–2.20 (m, 1 H, =CCHH), 2.32 (s, 3 H, p-Tol), 3.24–3.27 (m, 1
H, =CHH), 5.15–5.20 (m, 1 H, CHO), 6.07 (s, 1 H, =CH), 7.23 (d,
J = 8.1 Hz, 2 H, arom), 7.38 (d, J = 8.1 Hz, 2 H, arom).
13C NMR (100 MHz, CDCl3): d = 21.2 (Me), 21.5 (Me), 23.7 (CH2),
27.0 (CH2), 29.8 (CH2), 33.6 (CH2), 73.4 (CHO), 124.2 (CH arom),
128.7 (=CH), 130.2 (CH arom), 141.2 (C arom), 141.5 (C arom),
151.3 (=C), 169.8 (C=O).
References
(1) (a) Bickart, P.; Carson, F. W.; Jacobus, J.; Miller, E. G.;
Mislow, K. J. Am. Chem. Soc. 1968, 90, 4869. (b) Evans,
D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147.
(c) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1979, 18,
563. For rearrangements involving sulfoxides, see:
(d) Braverman, S. In The Chemistry of Sulphones and
Sulphoxides; Patai, S.; Rappoport, Z.; Stirling, C. J. M., Eds.;
John Wiley: London, 1988, 717 . For [2,3] sigmatropic
rearrangements, see: (e) Ritter, K. In Houben–Weyl, 4th ed.,
Vol. E 21; Helmchen, G.; Hoffmann, R. W.; Mulzer, J.;
Schaumann, E., Eds.; Thieme: Stuttgart, 1996, 4971.
(2) (a) Tanikaga, R.; Nozaki, Y.; Tamura, T.; Kaji, A. Synthesis
1983, 134. (b) Ono, T.; Tamaoka, T.; Yuasa, Y.; Matsuda,
T.; Nokami, J.; Wakabayashi, S. J. Am. Chem. Soc. 1984,
106, 7890. (c) Nokami, J.; Kataoka, K.; Shiraishi, K.;
Osafune, M.; Hussain, I.; Sumida, S.-I. J. Org. Chem. 2001,
66, 1228. (d) Trost, B. M.; Grese, T. A. J. Org. Chem. 1991,
56, 3189.
Anal. Calcd for C16H20O3S: C, 65.72; H, 6.89. Found: C, 65.64; H,
6.97.
(S)-2-Acetoxycyclohexanone [(S)-11]
(3) (a) Burgess, K.; Henderson, I. Tetrahedron Lett. 1989, 30,
3633. For a different and more selective cascade, see:
(b) Arce, E.; Carreño, M. C.; Cid, M. B.; Garcìa Ruano, J. L.
J. Org. Chem. 1994, 59, 3421. (c) Carreño, M. C.; Cid, M.
B.; Garcìa Ruano, J. L. Tetrahedron: Asymmetry 1996, 7,
2151.
Ozone was added to a cold (–78 °C) soln of acetylated 6a (50 mg,
0.17 mmol, 1 equiv) in CH2Cl2 (4 mL) until a persistent blue color
appeared. Excess ozone was removed with a N2 flow. Me2S (0.2
mL, 2.55 mmol, 15 equiv) was added. The mixture was slowly
warmed to r.t., then washed with brine and dried (MgSO4). The
crude cyclohexanone was purified by flash chromatography, giving
(S)-11 as a pale yellow oil; yield: 60%; >99% ee (GC). Spectral data
were identical to those described in the literature.11
(4) Guerrero-de la Rosa, V.; Ordoñez, M.; Alcudia, F.; Llera, J.
M. Tetrahedron Lett. 1995, 36, 4889.
(5) (a) Delouvrié, B.; Nájera, F.; Fensterbank, L.; Malacria, M.
J. Organomet. Chem. 2002, 643–644, 130. (b) Brebion, F.;
Vitale, M.; Fensterbank, L.; Malacria, M. Tetrahedron:
Asymmetry 2003, 14, 2889. (c) Brebion, F.; Delouvrié, B.;
Nájera, F.; Fensterbank, L.; Malacria, M.; Vaissermann, J.
Angew. Chem. Int. Ed. 2003, 42, 5342. (d) Brebion, F.;
Goddard, J.-P.; Fensterbank, L.; Malacria, M. Synthesis
2005, 2449. (e) Brebion, F.; Goddard, J.-P.; Gomez, C.;
Fensterbank, L.; Malacria, M. Synlett 2006, 713.
(6) Additions of the anion derived from Aggarwal’s cyclic bis-
sulfoxide to not to sterically demanding ketones led to the
corresponding bis-sulfinyl alcohols, without further
reaction: Aggarwal, V. K.; Franklin, R.; Maddock, J.; Evans,
G. R.; Thomas, A.; Mahon, M. F.; Molloy, K. C.; Rice, M.
J. J. Org. Chem. 1995, 60, 2174.
(7) Sugimura, T.; Iguchi, H.; Tsuchida, R.; Tai, A.; Nishiyama,
N.; Hakushi, T. Tetrahedron: Asymmetry 1998, 9, 1007.
(8) The properties of alkene carbenium ions and carbanions:
Richey, H. G. J. In The Chemistry of Alkenes, Vol. 2;
Zabicky, J., Ed.; John Wiley: London, 1970, 39.
(9) (a) Annunziata, R.; Cinquini, M.; Cozzi, F.; Farina, S.;
Montanari, V. Tetrahedron 1987, 43, 1013. (b) Koprowski,
M.; Krawczyk, E.; Skowroñska, A.; McPartlin, M.; Choi,
N.; Radojevic, S. Tetrahedron 2001, 57, 1105. (c) Zohar,
E.; Stanger, A.; Marek, I. Synlett 2005, 2239.
[a]D25 –70.0 (c 0.8, MeOH).
(1S,3S)-1,3-Diacetoxy-2-methylenecyclopentane (12)
A soln of allyl sulfoxide 8 (275 mg, 1.16 mmol) and P(OEt)3 (1.0
mL, 5.82 mmol, 5 equiv) in MeOH (22 mL) was heated at reflux for
5 h. The mixture was concentrated, and the crude material was dis-
solved in pyridine (16 mL) and Ac2O (0.44 mL, 4 equiv) and DMAP
(9 mg, 0.06 equiv) were added at 0 °C. The mixture was stirred at
r.t. for 2.5 h, then diluted with CH2Cl2 and washed with aq 1 M HCl
and brine. The organic layer was dried (MgSO4), filtered, and con-
centrated in vacuo. The residue was purified by chromatography
(silica gel, pentane–EtOAc, 95:5 to 50:50) to afford pure 12 as a col-
orless oil. (134 mg) and a mixture of 12 and 13 (56 mg, ratio 12/13
~3.4:1); overall yield: 82%.
[a]D20 +19.0 (c 1.2, CHCl3).
IR (neat): 2979, 1732, 1372, 1224, 1019 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.61–1.68 (m, 2 H, CH2), 2.00 (s,
6 H, OAc), 2.12–2.19 (m, 2 H, CH2), 5.37 (br s, 2 H, =CH2), 5.50–
5.54 (m, 2 H, CHO).
13C NMR (100 MHz, CDCl3): d = 21.4 (CH3C=O), 30.0 (CH2), 74.6
(CH-OAc), 116.5 (=CH2), 148.8 (=C), 170.8 (C=O).
HRMS: m/z [M + Na]+ calcd for C10H14NaO4: 221.0790; found:
221.0828.
(10) Hoffmann, R. W.; Goldmann, S.; Gerlach, R.; Maak, N.
Chem. Ber. 1980, 113, 845.
(11) Harada, T.; Wada, I.; Oku, A. J. Org. Chem. 1989, 54, 2599.
Synthesis 2007, No. 15, 2273–2278 © Thieme Stuttgart · New York