Remarkably mild and simple preparation of sulfenate anions from β-sulfinylesters: A new route to enantioenriched sulfoxides

Article abstract of DOI:10.1021/jo0478003

(Chemical Equation Presented) A general, efficient, and experimentally simple method for the generation of sulfenate salts has been developed using β-sulfmylesters as substrates. The process is based on a retro-Michael reaction, initiated by deprotonation at low temperature. Upon treatment with alkyl halides, the liberated sulfenates are subsequently converted into sulfoxides in good to excellent yield. Extension of the methodology to an unprecedented access to nonracemic sulfoxides by introduction of an enantiopure ligand, (-)-sparteine, is also described.

Full text of DOI:10.1021/jo0478003

SCHEME 1. Arenesulfenates by Thiolate
Oxidation
Remarkably Mild and Simple Preparation
of Sulfenate Anions from â-Sulfinylesters:
A New Route to Enantioenriched
Sulfoxides
Caroline Caupe`ne, Ce´dric Boudou,
Ste´phane Perrio,* and Patrick Metzner
SCHEME 2. Sulfenates from â-Sulfinylesters
Laboratoire de Chimie Mole´culaire et Thio-organique
(UMR CNRS 6507), ENSICaen-Universite´ de Caen
Basse-Normandie, 6 Boulevard du Mare´chal Juin,
14050 Caen, France
stephane.perrio@ensicaen.fr
Received December 16, 2004
with a wide range of thiophenols. However, application
of the methodology to the preparation of alkanesulfenates
was unsuccessful. Under similar conditions, instead of
the desired monooxidation product, the sulfinate salt
(RSO2Li) was isolated as a consequence of an unwanted
double-oxidation reaction.3
Other reported approaches1 to sulfenate anions involve
transformations of sulfenate esters, sulfines, or sulfox-
ides, but very few are efficient with a broad spectrum of
applicability.4 As a consequence, new methods for the
generation of sulfenates are needed, the ideal strategy
being one that proceeds efficiently in both the aryl and
alkyl series. We reasoned that â-sulfinylesters 1 could
be suitable precursors5 through a base-promoted retro-
Michael reaction (Scheme 2). On the basis of pKa values,6
proton abstraction should occur regioselectively R to the
carbonyl group; the enolate thus formed should then be
susceptible to fragmentation with concomitant liberation
of the sulfenate salt and an acrylate byproduct.7-9 In this
A general, efficient, and experimentally simple method for
the generation of sulfenate salts has been developed using
â-sulfinylesters as substrates. The process is based on a
retro-Michael reaction, initiated by deprotonation at low
temperature. Upon treatment with alkyl halides, the liber-
ated sulfenates are subsequently converted into sulfoxides
in good to excellent yield. Extension of the methodology to
an unprecedented access to nonracemic sulfoxides by intro-
duction of an enantiopure ligand, (-)-sparteine, is also
described.
(3) Despite having screened a range of oxaziridines with varying
structural characteristics, we have thus far been unable to identify a
suitable reagent for this reaction.
Sulfenate salts RSO- are not common sulfur nucleo-
philes for the organic chemist, the major contributing
factor being a lack of efficient methods for their genera-
tion.1 However, these anions are very attractive as
precursors of sulfenic acids, sulfoxides, sulfenate esters,
sulfenamides, and thiols. Furthermore, interest in
sulfenates has recently been heightened by their identi-
fication as key intermediates in some bioorganic trans-
formations.1
(4) For the most relevant contributions: Schwan introduced methyl
â-sulfinylacrylate esters as a convenient source of sulfenate anions with
an addition/elimination methodology. (a) O’Donnell, J. S.; Schwan, A.
L. Tetrahedron Lett. 2003, 44, 6293-6296. Tanaka reported the
formation of zinc sulfenates by oxidative addition of 1-alkynyl sulfox-
ides with a Pd(0) catalyst followed by transmetalation with Et2Zn. (b)
Maezaki, N.; Yagi, S.; Ohsawa, S.; Ohishi, H.; Tanaka, T. Tetrahedron
2003, 59, 9895-9906. (c) Maezaki, N.; Yagi, S.; Maeda, J.; Yoshigami,
R.; Tanaka, T. Heterocycles 2004, 62, 263-277. (d) Maezaki, N.; Yagi,
S.; Yoshigami, R.; Maeda, J.; Suzuki, T.; Ohsawa, S.; Tsukamoto, K.;
Tanaka, T. J. Org. Chem. 2003, 68, 5550-5558.
(5) According to literature precedents, the synthesis of 1 can be
achieved in only two steps from the appropriate thiol. See for
example: (a) Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2003, 59,
2417-2421. (b) Greenhalgh, R. P. Synlett 1992, 235-236.
(6) The pKa value (in DMSO) of a proton R to a sulfoxide group is
33-36, compared with around 30 for a proton R to an ester carbonyl.
(7) Concomitant liberation of an alkene and a sulfenate salt was
recently reported with a secondary R-lithiosulfinyl carbanion through
a tandem zinc homologation-â-elimination reaction, but the authors
focused only on the olefin product. Abramovitch, A.; Varghese, J. P.;
Marek, I. Org. Lett. 2004, 6, 621-623.
As part of our research2 into the oxidation of thiolates
with N-sulfonyloxaziridines, we have previously reported
an original and efficient approach to arenesulfenate
anions2a,b and introduced an unusual N-sulfonyloxaziri-
dine derived from pinacolone as the ideal reagent (Scheme
1). Subsequent S-alkylation with aliphatic halides led to
sulfoxides in good to excellent yield. The mild conditions
we developed (-78 °C) allowed the reaction to be quite
general with high chemoselectivity and compatibility
(8) Reaction with analogous compounds incorporating sulfide or
sulfone functionalities has already been examined by other groups and
provided an elegant and highly efficient access to thiolate and sulfinate
anions, respectively: (a) Becht, J.-M.; Wagner, A.; Mioskowski, C. J.
Org. Chem. 2003, 68, 5758-5761. (b) Becht, J.-M.; Wagner, A.;
Mioskowski, C. Tetrahedron Lett. 2004, 45, 7031-7033. (c) Baskin, J.
M.; Wang, Z. Tetrahedron Lett. 2002, 43, 8479-8483.
* To whom correspondence should be addressed. Phone: int code
+23145-2884. Fax: int code +23145-2877.
(1) For a recent review including chemical and biological aspects of
sulfenates: O’Donnell, J. S.; Schwan, A. L. J. Sulfur Chem. 2004, 25,
183-211.
(2) (a) Sandrinelli, F.; Perrio, S.; Beslin, P. J. Org. Chem. 1997, 62,
8626-8627. (b) Sandrinelli, F.; Perrio, S.; Averbuch-Pouchot, M.-T. Org.
Lett. 2002, 4, 3619-3622. (c) Sandrinelli, F.; Fontaine, G.; Perrio, S.;
Beslin, P. J. Org. Chem. 2004, 69, 6916-6919. (d) Sandrinelli, F.;
Perrio, S.; Beslin, P. Org. Lett. 1999, 1, 1177-1180.
(9) Substrates 1 have been reported to undergo a facile thermolysis
to the corresponding sulfenic acid, which was efficiently trapped in
situ with an activated alkene or alkyne: (a) Bilokin, Y. V.; Melman,
A.; Niddam, V.; Benhamu´, B.; Bachi, M. D. Tetrahedron 2000, 56,
2425-2437. (b) Melwig, J. Y.; Jullien, Y.; Curci, M.; Mieloszynski, J.
10.1021/jo0478003 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/22/2005
2812
J. Org. Chem. 2005, 70, 2812-2815

TABLE 2. Sulfoxides 2 via Sulfenates According to
Scheme 2
SCHEME 3. Preparation of â-Sulfinylesters
isolated yielda
entry substrate
R1
R2 R3X product
(%)
1
2
3
4
5
6
7
1b
1c
1d
1e
1f
1g
1h
2-MeOC6H4 Et MeI
2,6-Me2C6H3 Et BnBr
2b
2c
2d
2e
2f
2g
2h
80 (13)
68
TABLE 1. Influence of the Base and Solvent with 1a (R1
) 4-MeC6H4 and R2 ) Et) According to Scheme 2
Me
Me BnBr
Et BnBr
Et BnBr
68
entry
base
NaHMDSb THF
NaH THF
KHMDSc THF
solvent R3X sulfoxide isolated yielda (%)
n-Bu
Bn
95
57b
76
1
2
3
4
5
6
7
8
9
BnBr
BnBr
BnBr
2a1
2a1
2a1
2a1
2a1
2a1
2a1
2a2
2a3
91
cyclo-C6H11 Et BnBr
t-Bu Et BnBr
77
79
82
79
KHMDSc toluene BnBr
a Isolated yield of sulfenate ester 3b is shown in parentheses.
LDAd
THF
THF
THF
THF
THF
BnBr
BnBr
BnBr
MeI
83
b Yield was 56% with NaHMDS in THF.
BuLi
65
t-BuOKe
t-BuOKe
t-BuOKe
77
83 (15)
88 (5)
3 and 4). Use of methyl and ethyl iodides as alternative
electrophiles with the t-BuOK/THF conditions likewise
led to the corresponding sulfoxides 2a2 and 2a3 in yields
of g83% (entries 8 and 9). Contamination with sulfenate
esters 3a2 and 3a3 was observed this time, but only to a
small degree (<15%).13 Both S-and O-alkylation products
were readily separated by purification on a silica gel
column. The overall yield for the alkylation was 98 and
93%, respectively, again demonstrating the efficiency of
the intermediate sulfenate formation.
To investigate the scope of the reaction, a range of
sulfinyl esters 1 with various aromatic and aliphatic R1
substituents were then examined using t-BuOK as a base
and THF as the solvent.14 In all cases, the corresponding
arene- and alkanesulfenates were formed, with alkylation
affording the corresponding sulfoxides 2 in good to
excellent yield (Table 2). Furthermore, there appears to
be no restrictions on structure in the aliphatic series, as
primary (entries 3-5), secondary (entry 6), and tertiary
(entry 7) sulfenates were efficiently generated. As already
reported above, sulfenic ester 3b was obtained as a side
product when methyl iodide was used as the electrophile
(entry 1).
Having developed a general and efficient access to
sulfenate anions with wide experimental tolerances, we
felt it had the potential for further development, its use
in asymmetric synthesis being of particular interest.
Sulfenates being prochiral, a stereogenic sulfur center
is produced upon alkylation. Any control over the result-
ing stereochemistry arises through a discrimination
between the two sulfur lone pairs of the sulfenate.
However, use of these sulfur nucleophiles in this area
has received scant attention. Diastereoselective ap-
proaches with lithium sulfenates already possessing a
chiral center have been reported,2b,4a,15 and high asym-
metric inductions, with diastereomeric ratios of up to 98:
2, were accomplished upon reaction with alkyl halides.
In addition, an asymmetric sulfinylzincation of alkynoates
has been investigated by Tanaka et al, whose best
diastereoselectivity (92:8) was obtained using an isoborneol
EtI
a Isolated yields of sulfenate esters 3 (if produced) are shown
in parentheses. b 2 M solution in THF. c 0.5 M in toluene .
d Freshly prepared by reaction of BuLi with i-Pr2NH. e 1 M
solution in THF.
Note, we present the results obtained with this approach,
and the generated sulfenates were all converted into
sulfoxides 2 by treatment with alkyl halides. We also
describe an asymmetric variant on this theme in which
enantioselective alkylation of the prochiral sulfenates
affords enantioenriched sulfoxides.
We began by investigating 3-p-tolylsulfinylpropionic
acid ethyl ester 1a (R1 ) 4-MeC6H4 and R2 ) Et, Scheme
3) as the substrate. Reaction of 4-methylthiophenol with
ethyl acrylate in the presence of a catalytic amount of
K2CO3 gave thioether 4a in 92% yield. Subsequent
oxidation with NaIO4 in a methanol/water solution af-
forded the desired sulfoxide in 75% yield.10 Conveniently,
the intermediate sulfide 4a was used in its crude form
and the final sulfoxide 1a purified by a rapid filtration
on silica gel. The synthesis was routinely performed on
a 20 g scale without loss of efficiency.
The validity of our concept was then examined using
our prototype compound 1a and a variety of bases and
solvents. The sulfoxide 1a was treated at low tempera-
ture (-78 °C) with stoichiometric amounts of bases,
including NaHMDS, NaH, KHMDS, LDA, BuLi, and
t-BuOK.11 After 20 min, benzyl bromide was added to
trap the eventual sulfenate anion formed. The results
obtained are listed in Table 1. In all cases, the anticipated
benzyl sulfoxide 2a1 was produced and isolated in a good
to excellent yield (65-91%, entries 1-7). Examination
of the crude product revealed the absence of sulfenic
ester, which might arise through a competing O-alkyla-
tion of the ambident sulfenate.12 Variation of the solvent
employed is also possible, sulfoxide 2a1 being formed with
the same efficiency in THF and toluene (compare entries
L.; Paquer, D. Phosphorus Sulfur 1996, 118, 105-111. (c) Tsukurimi-
chi, E.; Yoshimura, T.; Yoshizawa, M.; Itakura, H.; Shimasaki, C.
Phosphorus Sulfur 1989, 46, 113-120. (d) Crich, D.; Lim L. B. L. J.
Chem. Res., Synop. 1987, 353. (e) Bachi, M. D.; Gross, A. J. Org. Chem.
1982, 47, 897-898. (f) Shelton, J. R.; Davis, K. E. Int. J. Sulfur Chem.
1973, 8, 205-216.
(13) Alkylation with the soft alkyl halide still takes place predomi-
nantly at the soft sulfur center of the sulfenates. Use of NaHMDS as
a base in THF and methyl iodide as the electrophile led to sulfenate
ester 2a2 in 9% yield. In contrast, only a 3.5% yield of 2a2 was obtained
with n-BuLi.
(14) Commercial 1 M t-BuOK solution in THF was preferred over
the other bases previously on account of its ease of handling, liberation
of the water-soluble tert-butyl alcohol, and isolation of cleaner crude
products according to their 1H NMR spectra.
(10) If the temperature is rigorously controlled (<0 °C), no sulfone
is detected.
(11) Sulfinylester 1a survived base workup with saturated Na2CO3
or K2CO3 and 1 N NaOH solutions.
(12) (a) Hogg, D. R.; Robertson, A. J. Chem. Soc., Perkin Trans. 1
1979, 1125-1128. (b) Kobayashi, M.; Toriyabe, K. Sulfur Lett. 1985,
3, 117-122.
(15) (a) Blake, A. J.; Westaway, S. M.; Simpkins, N. S. Synlett 1997,
919-920. (b) Blake, A. J.; Cooke, P. A.; Kendall, J. D.; Simpkins, N.
S.; Westaway, S. M. J. Chem. Soc., Perkin Trans. 1 2000, 153-163.
J. Org. Chem, Vol. 70, No. 7, 2005 2813

TABLE 3. Solvent Effect in the (-)-Sparteine-Mediated
Alkylation of a Sulfenate Generated from 1a (R1
)
4-MeC6H4 and R2 ) Et) at -40 °C According to Scheme 2
entry R3X sulfoxide solvent yield (%)a ee (%) configuration
1
2
3
4
5
6
7
MeI
MeI
MeI
MeI
MeI
MeI
BnBr
2a2
2a2
2a2
2a2
2a2
2a2
2a1
THF
42
47
59
4
44
54
59
0
0
Et2O
cumene
pentane
TMTHF
toluene
toluene
0
0
5
23
17
S
S
S
a Alkylation time was set at 4 h.
derivative.4b With regard to enantioselective approaches,
Kobayashi achieved a modest transfer of chirality (23%
ee) in the alkylation of anthraquinone-1-sulfenate with
an enantiopure sulfonium salt.16
FIGURE 1. Effect of temperature on the (-)-sparteine-
mediated alkylation of the sulfenate anion of 1a (R1
)
4-MeC6H4) with methyl iodide (R3X ) MeI, 1 equiv) in toluene
for 4 h according to Scheme 2.
We envisaged an alternative and conceptually different
approach based on an external ligand-controlled enan-
tioselective alkylation. By introduction of an enantiopure
coordinating ligand, both lone pairs on sulfur become
diastereotopic, and we can expect that one will react
preferentially to give an enantioenriched sulfoxide.17 This
could provide an original and convergent route to non-
racemic sulfoxides, the traditional strategies being asym-
metric oxidations of prochiral sulfides or Andersen-type
reactions.18 As a preliminary study, we chose for our
purposes (-)-sparteine, a tetracyclic lupine alkaloid with
broad applications in asymmetric synthesis, when as-
sociated to a lithium cation.19 The influence of solvent
and temperature was examined using the p-tolyl-
substituted sulfinyl ester 1a.
disappointing in terms of enantioselectivity, they indi-
cated clearly that the presence of the chiral bidentate
ligand does not adversely affect sulfenate formation and
the subsequent alkylation. A lack of enantioselectivity
was also observed in pentane in which the yield was a
mere 4% due to the poor solubility of the reactants (entry
4). A slight enantiomeric excess of 5% in favor of the (S)-
enantiomer was observed in 2,2,5,5-tetramethyltetrahy-
drofuran as a solvent (entry 5). Gratifyingly, a significant
improvement with a 23% ee for the (S)-configuration
product and a 54% yield was obtained in toluene (entry
6).22 Use of benzyl bromide (1 equiv) as an alternative
electrophile under similar conditions led to sulfoxide 2a1
in 17% ee (AD-H column), likewise with the (S)-stereo-
chemistry and 59% yield.22
With toluene having been identified as the best solvent,
the influence of the temperature over a range from -78
to -20 °C was next examined. This parameter was found
to play a crucial role in both the conversion and the
enantioselectivity, as can be seen from Figure 1. The
isolated yield of sulfoxide 2a2 increases almost linearly
with the temperature. Whereas a poor yield of 14% was
obtained at -78 °C, an increase to 69% was observed at
-20 °C, though with an enantioselectivity of only 9%. A
nonclassical temperature effect, explained by the prin-
ciple of isoinversion23 introduced by Scharf et al., was
observed for the enantioselectivity, the highest enantio-
meric excess (29%) being obtained at -45 °C for the (S)-
enantiomer.
The chiral lithium base was prepared at room temper-
ature by reaction of equimolar amounts of n-BuLi and
(-)-sparteine and then added to a cooled solution (-40
°C) of â-sulfinylester 1a in one of the six solvents listed
in Table 3. Methyl iodide (1 equiv) is then added, with
the alkylation time arbitrarily set at 4 h. After hydrolysis
and purification by column chromatography,20 the enan-
tiomeric excesses were determined by enantioselective
stationary phase HPLC (OB-H column). Use of THF,
diethyl ether, and cumene led to the formation of the
anticipated sulfoxide 2a2 in 42-59% yield, but in racemic
form21 (entries 1-3). Even though these results were
In summary, we have developed a practical and highly
efficient route to versatile sulfenate salts through a base-
promoted retro-Michael reaction of â-sulfinylesters. Sub-
sequent alkylation at the sulfur center with alkyl halides
led to sulfoxides in good to excellent yield. Use of a 1:1
(16) Kobayashi, M.; Manabe, K.; Umemura, K.; Matsuyama, H.
Sulfur Lett. 1987, 6, 19-24.
(17) Asymmetric dehydration of sulfenic acid t-BuSOH in the
presence of enantiopure amines led to thiosulfinate t-BuS(O)St-Bu with
an optimal ee of 26%. Drabowicz, J.; Lyzwa, P.; Mikolajczyk, M.
Phosphorus Sulfur 1983, 16, 267-270.
(22) Stereochemistry assignment can be found in Supporting Infor-
mation.
(18) Ferna´ndez, I.; Khiar, N. Chem. Rev. 2003, 103, 3651-3705.
(19) (a) Organolithiums in Enantioselective Synthesis, Topics in
Organometallic Chemistry, Hodgson, D. M., Ed.; Springer: Berlin,
2003; Vol. 5. (b) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 2282-2316. (c) Clayden, J. Organolithiums: Selectivity for
Synthesis; Baldwin, J. E., Williams, R. M., Eds; Pergamon Press:
Oxford, 2002; Vol. 23.
(23) (a) Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P.
Angew. Chem., Int. Ed. Engl. 1991, 30, 477-515. (b) Gypser, A.;
Norrby, P.-O. J. Chem Soc., Perkin Trans. 2 1997, 939-943. (c)
Cainelli, G.; Giacomini, D.; Galletti, P. J. Chem. Soc., Chem. Commun.
1999, 567-572. (d) Nowaczyk, S.; Alayrac, C.; Metzner, P.; Averbuch-
Pouchot, M.-T. J. Org. Chem. 2002, 67, 6852-6855. (e) He´nin, F.;
Le´tinois, S.; Muzart, J. Tetrahedron: Asymmetry 2000, 11, 2037-2044.
(f) Enders, D.; Ullrich, E. C. Tetrahedron: Asymmetry 2000, 11, 3861-
3865. (g) Pardigon, O.; Tenaglia, A.; Buono, G. J. Mol. Catal. A: Chem.
2003, 196, 157-164.
(20) No sulfenic ester was detected this time.
(21) THF and Et2O probably compete with the (-)-sparteine as a
lithium ligand.
2814 J. Org. Chem., Vol. 70, No. 7, 2005

1-Methylsulfinyl-4-methylbenzene 2a2.25b Obtained as the
major alkylation product from â-sulfinylester 1a (R1 ) 4-MeC6H4,
R2 ) Et, 245 mg, 1.02 mmol) and methyl iodide as the
electrophile. Yield 83% (131 mg, 0.85 mmol). White solid. Mp
43-44 °C, cyclohexane (lit.25a 42-43 °C). TLC (heptane/AcOEt,
50:50) Rf ) 0.08. 1H NMR (250 MHz, CDCl3): δ 2.42 (s, 3H),
2.70 (s, 3H), 7.26-7.31 (m, 2H), 7.52-7.56 (m, 2H). 13C NMR
(62.9 MHz, CDCl3): δ 21.8, 44.4, 123.9, 130.4, 141.9, 142.9. IR
(KBr, cm-1): ν 2928, 1592, 1490, 1046. MS (EI) m/z 154 (M+,
99), 139 (100), 138 (42), 91 (29), 77 (46), 65 (27), 63 (19). The
corresponding sulfenic ester 3a2 resulting from the competing
O-alkylation of the intermediate sulfenate was also produced.
4-Methylbenzenesulfenic Acid Methyl Ester 3a2.25c Yield
15% (23 mg, 0,15 mmol). Colorless oil. TLC (CH2Cl2) Rf ) 0.32.
1H NMR (250 MHz, CDCl3): δ 2.44 (s, 3H), 3.03 (s, 3H), 7.35
(dapp, J ) 8.0 Hz, 2H), 7.80-7.83 (m, 2H). 13C NMR (62.9 MHz,
CDCl3): δ 21.8, 44.7, 127.5, 130.1, 137.9, 144.8. IR (NaCl, cm-1):
ν 3010, 2959, 2926, 2854, 1320, 1299, 1287, 1144, 1090. MS
(EI) m/z 155 (MH+, 86), 154 (M+, 33), 139 (11), 107 (75), 91 (100),
77 (4), 65 (28).
n-BuLi/(-)-sparteine combination allowed an asymmetric
extension of the methodology, with p-tolyl methyl and
p-tolyl benzyl sulfoxides produced in 29 and 17% ee,
respectively. Though this novel route to enantiomerically
enriched sulfoxides is not as yet competitive with the
classical repertoire, our preliminary results described
herein demonstrate unambiguously the synthetic utility
of this concept. An additional feature of this approach is
the formation of the sulfoxide by asymmetric creation of
the carbon-sulfur bond, in contrast to the sulfur-oxygen
one by the more conventional oxidation reaction. Our
immediate goal is to improve the enantioselectivity
through optimization of the external ligand and inves-
tigation of other substrates. Current work is also focused
on rationalization of the asymmetric induction, and a
model will be reported in due course.24
Experimental Section
Typical Procedure for Enantioenrichied Sulfoxides 2
with n-BuLi/(-)-Sparteine as a Base: Alkylation of the
Intermediate Sulfenate at -45 °C. n-BuLi (770 µL of a 1.43
M solution in hexanes, 1.1 mmol, 1.1 equiv) was added at room
temperature to a solution of (-)-sparteine (234 mg, 1 mmol, 1
equiv) in toluene (2 mL). After being stirred for 15 min, the
resulting complex was added dropwise to a solution of â-sulfi-
nylester 1a (240 mg, 1 mmol, 1 equiv) in toluene (5 mL)
previously cooled at -45 °C. The reaction mixture was stirred
at -45 °C for 30 min, treated with methyl iodide (65 µL, 1 mmol,
1 equiv), stirred at this temperature for 4 h, and quenched with
a saturated aqueous NH4Cl solution (20 mL). The resulting
mixture was extracted with ethyl acetate (3 × 25 mL). The
combined organic layers were successively washed with a
saturated aqueous NH4Cl solution (20 mL) and a saturated
aqueous NaCl solution (10 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The resulting solid was
then purified on silica gel eluting with diethyl ether to afford
enantioenriched sulfoxide 2a2 as a white solid (62 mg, 40%, 29%
ee).
Typical Procedure for the Preparation of Racemic
Sulfoxides 2 with t-BuOK as a Base. A solution of â-sulfi-
nylester 1 (1.0 mmol, 1 equiv) in dry THF (5 mL) was cooled to
-78 °C, and t-BuOK (1.1 mL of a 1 M solution in THF, 1.1 mmol,
1.1 equiv) was added. After the mixture was stirred at -78 °C
for 20 min, the alkyl halide (1.2 mmol, 1.2 equiv) was added.
The reaction mixture was stirred at -78 °C for 1 h 30 and then
allowed to warm to room temperature for 18 h. After concentra-
tion in a vacuum, EtOAc (15 mL) was added and the organic
layer was washed with water (15 mL). The aqueous layer was
extracted with EtOAc (3 × 15 mL). The organic layers were
combined, washed with saturated aqueous NaCl (50 mL), dried
over MgSO4, filtered, and evaporated to dryness. The resulting
crude product was then purified by column chromatography to
afford anticipated racemic sulfoxide 2. Use methyl or ethyl
iodides as the electrophile also produced sulfenate ester 3 (O-
alkylation product), which was readily separated from the major
sulfoxide (S-alkylation product).
1-Benzylsulfinyl-4-methylbenzene 2a1.25a Obtained from
â-sulfinylester 1a (R1 ) 4-MeC6H4, R2 ) Et, 240 mg, 1.00 mmol)
with benzyl bromide as the electrophile. Yield 77% (176 mg, 0.77
mmol). White solid. Mp 139-140 °C (lit.25a 140-141 °C). TLC
(CH2Cl2/AcOEt, 80:20) Rf ) 0.43. 1H NMR (250 MHz, CDCl3):
δ 2.39 (s, 3H), 3.97 and 4.09 (AB, J ) 12.5, 2H), 6.97-7.01 (m,
2H), 7.20-7.89 (m, 7H). 13C NMR (62.9 MHz, CDCl3): δ 21.4,
63.7, 124.5, 128.2, 128.4, 129.4, 129.6, 130.4, 139.7, 141.6. IR
(KBr, cm-1): ν 3058, 3032, 2960, 2910, 1033. MS (CI, isobutane)
m/z 271 [(M + C3H5+), 2], 269 [(M + C3H3+), 2], 231 (MH+, 100),
215 (6).
Acknowledgment. We gratefully acknowledge fi-
nancial support from the “Ministe`re de la Recherche et
des Nouvelles Technologies”, CNRS (Centre National de
la Recherche Scientifique), the “Re´gion Basse-Nor-
mandie”, and the European Union (FEDER funding).
We also thank Florian Gourmel (University of Caen) for
the synthesis of advanced materials.
(24) There is a lack of literature information on lithium sulfenates
in solution. As a consequence, the proposition of an unambiguous
transition state model is not straightforward.
(25) (a) Kise, M.; Oae, S. Bull. Chem. Soc. Jpn. 1970, 43, 1426-
1430. (b) Kim, S. S.; Nehru, K.; Kim, S. S.; Kim, D. W.; Jung, H. C.
Synthesis 2002, 17, 2484-2486. (c) Yoshimura, T.; Hamada, K.;
Yamazaki, S.; Shimasaki, C.; Ono, S.; Tsukurimishi, E. Bull. Chem.
Soc. Jpn. 1995, 68, 211-218.
Supporting Information Available: General methods of
the Experimental Section, stereochemistry assignment for (S)-
2a1 and (S)-2a2, and full spectroscopic data for 1-4. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO0478003
J. Org. Chem, Vol. 70, No. 7, 2005 2815