Enantioselective synthesis of benzyl tert-butyl sulfoxides

Article abstract of DOI:10.1002/ejoc.201101059

Enantiomerically pure benzyl sulfoxides are effective tools for the formation of new C-C bonds with control of configuration at new stereogenic centres. The reaction of enantioenriched tert-butyl tert-butanethiosulfinate with benzyllithium derivatives, ob

Full text of DOI:10.1002/ejoc.201101059

FULL PAPER
DOI: 10.1002/ejoc.201101059
Enantioselective Synthesis of Benzyl tert-Butyl Sulfoxides
Majid Khalil Syed[a] and Mike Casey*[a]
Keywords: Synthetic methods / Lithiation / Grignard reaction / Nucleophilic substitution / Enantioselectivity / Sulfoxides
Enantiomerically pure benzyl sulfoxides are effective tools
for the formation of new C–C bonds with control of configu-
ration at new stereogenic centres. The reaction of enantioen-
riched tert-butyl tert-butanethiosulfinate with benzyllithium
derivatives, obtained by deprotonation of the corresponding
toluene derivatives, gave a wide variety of benzyl tert-butyl
sulfoxides with complete inversion of configuration. The
benzyl sulfoxides were deprotonated in situ, and addition of
the electrophiles gave α-substituted products with good dia-
stereoselectivity.
tive synthesis of benzyl tert-butyl sulfoxides. The prepara-
tion of this class of sulfoxides through the asymmetric
oxidation of sulfides has been studied, and very good re-
sults have been obtained using chiral reagents,[14] but cata-
lytic asymmetric oxidation resulted in modest enantio-
selectivity.[15] We briefly investigated asymmetric oxidation
using vanadium[16] and titanium[17] catalysis, but the results
were not promising and therefore were not pursued.
The second major method for asymmetric synthesis of
sulfoxides is by the reaction of organometals with enan-
tioenriched sulfinic acid derivatives.[1,3] Benzyl tert-butyl
sulfoxide has been made with excellent enantioselectivity
from sulfinates derived from chiral auxiliaries,[18,19] but we
favored a catalytic approach. In Ellman’s highly influential
work in this area, a simple and efficient method was re-
ported for the catalytic asymmetric oxidation of tert-butyl
Introduction
Enantiopure sulfoxides are widely used as intermediates
in asymmetric synthesis
[1,2]
and are attracting growing
interest as chiral catalysts and ligands.[3,4] A large number
also show biological activity, and some are important
drugs.[1,5] Many of their applications in asymmetric synthe-
sis stem from the fact that sulfoxides readily undergo α-
deprotonation, and the resulting anions can be treated with
a wide range of electrophiles to give products with high
stereoselectivity at the newly created stereogenic cen-
ters.[1,2,6] There are several synthetically useful methods to
remove the sulfinyl group subsequent to the α-substitu-
tion,[7–9] and therefore, it may be regarded as a chiral auxil-
iary for carbanions. Earlier, we showed that sulfoxide-stabi-
lized carbanions undergo efficient regioselective conjugate
addition to α,β-unsaturated esters and ketones, generally re-
sulting in excellent diastereoselectivity (Scheme 1).[10,11] As
expected, the nonacidic group on the sulfoxide, referred to
as the “spectator group” (R1 in Scheme 1), has a pro-
nounced effect on the yield and diastereoselectivity in these
reactions.[1,2,6,10–12] Reactions of benzyl sulfoxides with a
tert-butyl spectator group yielded particularly good results,
and the potential of this methodology was showcased in a
very short formal total synthesis of (Ϯ)-podophyllotoxin.[13]
disulfide to form a highly enantioenriched thiosulfinate
[20]
ester 1
which was then used as an intermediate for
the asymmetric synthesis of tert-butyl sulfoxides
2
(Scheme 2).[21]
Scheme 2. Enantioselective synthesis of sulfoxides 2 through thio-
sulfinate 1[21] and sulfinate 3.[22]
Scheme 1. Diastereoselective conjugate additions of sulfoxides.
Having developed this strategy using racemic sulfoxides,
we needed to find an efficient method for the enantioselec-
The Ellman group also showed that highly enantioen-
riched tert-butanesulfinate esters 3 are readily obtained by
reaction of tert-butanesulfinyl chloride with benzyl alcohols
in the presence of chiral sulfinyl transfer catalysts.[22] Sim-
ilar results were also reported by Shibata.[23] However, we
could find no reference to the reaction of these sulfinate
[a] School of Chemistry & Chemical Biology, University College
Dublin,
Belfield, Dublin 4, Ireland
Fax: +353-17161178
E-mail: mike.casey@ucd.ie
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M. K. Syed, M. Casey
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or thiosulfinate esters with benzylmagnesium halides, apart However, it failed in some cases, therefore, we attempted to
from a mention in a footnote.[24] We now report that the find an alternative that might be more successful for the
reaction of benzylmagnesium halides with thiosulfinate 1 preparation of heavily oxygenated benzylic sulfoxides.
can give sulfoxides, though it is limited in scope. However,
We investigated using the more reactive benzyllithium de-
the reaction of benzyllithium derivatives with the thiosulfin- rivatives. As in the case of benzylmagnesium compounds,
ate can generate a wide array of benzyl tert-butyl sulfoxides the generation of benzyllithium derivatives is often compli-
with good yields and high enantioselectivities.
cated by competing Wurtz coupling, but preparation has
been accomplished by the reductive lithiation of benzyl
methyl ethers.[26,27] At first, we applied Azzena’s method to
obtain (3,4,5-trimethoxybenzyl)lithium (5)[28] through the
reductive cleavage of 3,4,5-trimethoxybenzyl methyl ether
with Li metal and catalytic naphthalene (Scheme 3). How-
ever, addition of sulfinate ester 3a to the reaction mixture
gave only small amounts of the substituted benzyl tert-butyl
sulfoxide 4c, possibly because of the instability of sulfinate
ester 3a under the strongly reducing environment of this
reaction.
Results and Discussion
The enantioselective synthesis of sulfoxides by treating
enantioenriched sulfinic acid derivatives with Grignard rea-
gents is a long-established reaction,[1] therefore, we investi-
gated it as a possible strategy for the preparation of benzyl
tert-butyl sulfoxides. The formation of benzylmagnesium
halides is often accompanied by Wurtz coupling, so we used
an excess amount of activated magnesium, prepared by
Brown’s method,[25] to minimize this side reaction. By care-
fully choosing the reaction conditions, three benzylic Grig-
nard reagents were obtained relatively cleanly, but the at-
tempted preparation of [(4-bromophenyl)methyl]magne-
sium bromide predominantly resulted in the coupled prod-
uct under all the conditions studied. Addition of (R)-thio-
sulfinate[20] to the Grignard reagents in THF (tetra-
hydrofuran) at –30 °C gave sulfoxides 4 with essentially
complete inversion of configuration (Table 1). Substantial
reduction in the enantiopurity was found when higher tem-
peratures were used and when the order of addition was
reversed. This indicates that the racemization of (R)-thio-
sulfinate 1, by the thiolate byproduct produced in the reac-
tion, can become competitive with sulfoxide formation if
the conditions are not carefully controlled.
Scheme 3. Attempted formation of sulfoxide using benzyllithium
formed by reductive lithiation.
In contrast, we found that benzyllithium, generated by
treating toluene with butyllithium and TMEDA
(N,N,NЈ,NЈ-tetramethyl-1,2-ethylenediamine) at 20 °C,[29]
reacted smoothly with racemic sulfinate ester 3a and with
racemic thiosulfinate ester 1 at low temperature to form
benzyl tert-butyl sulfoxide 4b (Scheme 4). Initially,
1.3 equiv. of BuLi was used, but the yield of sulfoxide 4b
was low and a substantial amount of sulfinate ester 3a was
recovered. It seemed likely that the benzyllithium was being
consumed by the deprotonation of 4b under the strongly
basic conditions. This hypothesis was confirmed by the ad-
dition of benzaldehyde to the reaction mixture which re-
sulted in the formation of an adduct in good yield by trap-
ping the lithiated benzyl sulfoxide (see Table 3). When a
twofold excess amount of benzyllithium was employed, rea-
sonable yields of sulfoxide 4b were obtained. As thiosulfin-
ate ester 1 gave slightly better yields and cleaner reaction
mixtures, and it was easier to prepare by catalytic asymmet-
ric oxidation of tert-butyl disulfide,[20] we focused on it in-
stead of sulfinate ester 3a.
Table 1. Reaction of thiosulfinate 1 with benzylmagnesium halides.
Product
Rn
X
% ee (R)-1[a]
% Yield
% ee 4[a,b]
4a
4b
4c
3,4-OCH2O
H
3,4,5-(OMe)3 Cl
Br
Br
96
92
90
50
60
0
94 (S)
92 (S)
–
[a] Measured by HPLC using a CHIRALPAK AS-H column.
[b] The configurations of sulfoxides 4 were determined as described
in Table 2.
Although the unsubstituted Grignard reagent and the
3,4-methylenedioxy-substituted analog gave moderate
yields of sulfoxide by this method, the 3,4,5-trimethoxy de-
rivative did not react with the thiosulfinate, even at room
temperature (Table 1). This preliminary study showed that
the reaction of benzylic Grignard reagents with the thiosulf-
inate is a viable and convenient method for the enantiose-
lective synthesis of sulfoxides, and no doubt it could be ex-
Scheme 4. Formation of sulfoxide using benzyllithium formed by
deprotonation.
Although this method worked well for the preparation of
tended to the preparation of many additional examples. the unsubstituted benzyl sulfoxide 4b, the literature sug-
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Enantioselective Synthesis of Benzyl tert-Butyl Sulfoxides
gested that it could not be used for a wide range of substi- using different electrophiles,[31] and in addition, these re-
tuted toluene derivatives. Superbasic mixtures of organo- sults show that acceptable yields can be obtained with an
lithium derivatives and/or lithium dialkylamides together alkoxy group in the para position. It is not surprising that
with alkali metal alkoxides can be used for the α-lithiation the presence of electron-withdrawing substituents facilitated
of a broad range of toluene derivatives.[30] Recently, O’Shea the deprotonation and resulted in good yields of sulfoxides
and co-workers used
a superbasic mixture formed 4h and 4i. For 4-cyanotoluene, the deprotonation was car-
from BuLi, tBuOK, and 2,2,6,6-tetramethylpiperidine ried out using preformed LTMP and tBuOK to avoid the
(TMPH),[31] and we adopted a similar procedure. We found competing addition of BuLi to the nitrile.
that the benzyllithium derivatives generated in this way do
Table 2. Enantioselective synthesis of benzyl tert-butyl sulfoxides.
react with the thiosulfinate 1, but attack occurs at both sul-
fur atoms (Scheme 5). Reaction at the expected sulfur(IV)
site gave the desired sulfoxides 4 in moderate yields, but the
competing reaction at the sulfur(II) atom gave benzyl tert-
butyl sulfides 6. Significant amounts of dithioacetals 7 and
dithioacetal monosulfoxides 8 were also formed. When the
unsubstituted benzyl sulfide 6 was formed, by reaction of
di-tert-butyl disulfide with excess benzyllithium, formed
from toluene as shown in Scheme 5, and sulfinate 1 was
added, side products 7 and 8 were formed. However, depro-
tonation of sulfoxide 4b using benzyllithium followed by
reaction with either di-tert-butyl disulfide or thiosulfinate 1
only resulted in unchanged sulfoxide. These control experi- 4e
ments demonstrate that dithioacetals 7 and 8 were formed
Product R1
R2
H
R3
H
R4
H
% ee 1[a] % Yield
% ee 4[a,b]
4b
4c
4d
H
H
H
Ͼ98
92
60
47
Ͼ98 (S)
91 (S)
97 (S)
Ͼ98 (S)
92 (S)
91 (S)
96 (S)
88 (S)
OMe OMe OMe
OMe OMe
H
OMe
H
H
H
H
H
H
H
97
52
OMe
H
H
H
OMe
H
CN
Ͼ98
92
75
70
4f
4g
H
92
33
in situ by deprotonation of sulfides 6 at the benzylic posi-
tion and subsequent reaction with the thiosulfinate ester 1.
4h
H
F
H
97
90
76
4i
H
80 [c]
[a] Measured by HPLC using a CHIRALPAK AS-H column.
[b] The configuration of sulfoxide 4b was determined by compari-
son of the specific rotation with the literature value (ref.[15]). The
configurations of the other sulfoxides were assigned by analogy,
supported by the observation that the minor enantiomer eluted first
from the CHIRALPAK® AS-H column in every case, except for
sulfoxide 4i. [c] Preformed LTMP (lithium 2,2,6,6-tetramethylpip-
eridide) was used for lithiation.
Attempts to form the 3,4-methylenedioxy derivative by
this method failed, as selective deprotonation of the toluene
could not be achieved.[32,33] Numerous experiments using
a variety of bases gave complex mixtures, indicating that
deprotonation occurred mostly at the acetal carbon to give
Scheme 5. Reaction of thiosulfinate 1 with benzyllithium deriva-
tives.
Optimization revealed that conducting the reactions at products suggestive of carbenoid intermediates.[34] Because
low concentration (approximately 0.1 m) gave homogeneous methylenedioxyphenyl groups are common in lignan struc-
mixtures and resulted in higher yields of sulfoxides 4 with tures, we decided to persevere, but instead to pursue the
less side-product formation. It should be noted that the de- formation of the requisite benzyllithium derivative by tin–
sired sulfoxides are easily separated from the side products lithium exchange.[35] The benzyltributylstannane 9 was
by chromatography.
formed in a standard way,[36] and tin–lithium exchange, fol-
The reaction of the benzyllithium derivatives, prepared lowed by addition of the thiosulfinate 1 (Ͼ98% ee), success-
from the corresponding toluene derivatives using this opti- fully furnished the sulfoxide 4a (57%, Ͼ98% ee) (Scheme 6).
mized method, with enantioenriched thiosulfinate ester (R)- To the best of our knowledge, this is the first report of
1, obtained using Ellman’s procedure,[20] gave a range of the efficient formation of a methylenedioxy-substituted
enantioenriched sulfoxides 4b–i (Table 2). The thiosulfinate benzyllithium derivative.
precursor 1 was obtained in 86%ee, and recrystallization at
As described earlier, the in situ deprotonation of the
low temperature gave samples with up to 99%ee.[20] The benzyl sulfoxides by a second equivalent of benzyllithium
substitution reactions occurred with complete inversion of occurs under the reaction conditions, and this suggests the
configuration at the sulfur atom and gave moderate to good possibility of the one-pot formation for α-substituted prod-
yields of the benzyl tert-butyl sulfoxides bearing a range of ucts with one or two additional stereocenters. Initially,
substituents. Table 2 shows that one, two, or three alkoxy using methyl cinnamate as the electrophile, we found that
substituents, needed for application to lignan syntheses, 2.4 equiv. of BuLi and 2.6 equiv. of tBuOK were necessary
were tolerated. The yields for the ortho- and meta-substi- to generate an excess of benzyllithium and provide a good
tuted compounds are very similar to those found by O’Shea yield of conjugate adduct, but as a mixture of two dia-
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M. K. Syed, M. Casey
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the isolated yield of the major diastereomer of methylated
product 10d was highest employing the original method of
2.6 equiv. of tBuOK. The results for these one-pot reactions
compare favorably with those obtained by formation of the
sulfoxide followed by a separate reaction with the electro-
philes.[10,11,38,39] In contrast to these results, we found that
when benzylic sulfoxides are formed using Grignard rea-
gents under the conditions described earlier, in situ depro-
tonation does not occur. Thus, the ability to form highly
enantioenriched α-substituted sulfoxides in a one-pot pro-
cedure is a new and unique feature of the benzyllithium
method. As far as we are aware, this is the first report of a
method that allows formation and α-substitution of enanti-
oenriched sulfoxides in one operation.
Scheme 6. Enantioselective synthesis of methylenedioxy-substituted
benzyl tert-butyl sulfoxide.
stereomers. In the case of methyl crotonate, the product of
two consecutive conjugate additions was obtained, even af-
ter short reaction times. These results are in striking con-
trast to the efficient stereoselective conjugate additions ob-
served using lithiated sulfoxides generated by deprotonation
with LDA (lithium diisopropylamide)[11] and again high-
light the marked effect of the potassium alkoxide additive.
Optimization of the reaction conditions revealed that reduc-
ing the amount of tBuOK to 0.8 equiv. gave much better
results (Table 3). Clean conjugate addition with high dia-
stereoselectivity (no more than traces of products that
might have been diastereomers were evident in the 1H
NMR spectra of the crude mixtures) was observed with
methyl crotonate and methyl cinnamate, but at the expense
of slightly lower yields, possibly because of the less efficient
generation of the benzyllithium derivative. Conjugate ad-
duct 10a was obtained in high ee (90%, Ͼ98% after
recrystallization), thus proving that highly enantioenriched
α-substituted sulfoxides could be formed in this way, and
the remaining one-pot reactions were carried out using the
racemic thiosulfinate. When benzaldehyde was used as elec-
trophile, the two diastereomeric adducts 10c and 10cЈ were
obtained in a 3.5:1 ratio.[37] In the case of iodomethane,[38]
Conclusions
These results show that a wide variety of benzyl tert-but-
yl sulfoxides can be obtained with high enantioselectivity
by deprotonation of toluene derivatives using superbasic
conditions and the in situ reaction of the benzyllithium de-
rivatives with tert-butyl tert-butanethiosulfinate. A unique
aspect of this method is that complex α-substituted sulfox-
ides can be formed with high stereoselectivity in a one-pot
procedure by addition of electrophiles to the reaction mix-
tures. Using benzylmagnesium halides also gives sulfoxides,
but this method, although very convenient, is more limited
in scope. These new methods should prove useful for the
asymmetric synthesis of natural products, especially lignans,
and work in this area is well advanced.
Experimental Section
General: All reagents were purchased from commercial suppliers
and used as obtained, unless otherwise stated. All reactions were
carried out under a nitrogen atmosphere in oven- or flame-dried
glassware, and all moisture-sensitive liquids and solutions were
transferred through a syringe or cannula. Methyl crotonate and
benzaldehyde were used after distillation. TMEDA and 2,2,6,6-tet-
ramethylpiperidine (TMPH) were distilled from CaH2 prior to use.
(R)-(+)-thiosulfinate ester 1[20] and racemic sulfinate ester 3[22] were
prepared by reported methods. Magnesium turnings were mechani-
cally activated for 3–4 d in a Schlenk tube using Brown’s method.[25]
The concentration of the butyllithium solution in hexane was deter-
mined by titration with diphenylacetic acid in THF before use.[39]
Flash column chromatography was performed using silica 60 (40–
63 microns). Assignments of the signals in the 1H NMR spectra
were supported by gCOSY (gradient COSY) and HSQCAD (het-
eronuclear single bond coherence adiabatic) spectra. For HPLC
analyses, a CHIRALPAK AS-H column was used, and detection
was achieved with UV analysis at 3 wavelengths, 210.8, 230.8, and
254.8 nm. Mass spectrometry data were obtained using electro-
spray ionization (ESI), and high resolution mass spectra were col-
lected with a TOF (time-of-flight) spectrometer.
Table 3. One-pot formation of α-substituted benzyl sulfoxides 10.
General Procedure A. Enantioselective Synthesis of Benzyl Sulfox-
ides Using Grignard Reagents: To a flask (25 mL) containing acti-
vated magnesium turnings (74 mg, 3.08 mmol, 4 equiv.) was added
a solution of benzylic halide (1.69 mmol, 2.2 equiv.) in THF
(5 mL). The reaction mixture was stirred vigorously at room tem-
[a] The ee of thiosulfinate used was 96%, and the ee of the product
10a was 90% (analysis by HPLC using a CHIRALPAK AS-H col-
umn). [b] Stereochemistry assigned according to ref.[37] [c] The reac-
tion mixture was warmed to –20 °C after addition of electrophile.
[d] Stereochemistry assigned according to ref.[38]
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Enantioselective Synthesis of Benzyl tert-Butyl Sulfoxides
perature for 2 h before it was filtered through a syringe into another
flask (25 mL) and cooled to –30 °C. A solution of (R)-(+)-thiosulf-
inate ester 1 (150 mg, 0.77 mmol) in dry THF (5 mL) was added
very slowly through a cannula, and the mixture was stirred for
50 min. The reaction was quenched with water (7 mL), and the
mixture was extracted with CH2Cl2 (3ϫ15 mL). The combined or-
ganic layers were dried with MgSO4 and concentrated to dryness.
Purification by silica gel chromatography afforded the pure benzyl
sulfoxide.
THF, 2.68 mL, 2.68 mmol, 2.60 equiv.) was added dropwise fol-
lowed by the addition of 2,2,6,6-tetramethylpiperidine (0.43 mL,
2.52 mmol, 2.45 equiv.). After 35 min, a solution of (R)-(+)-thiosul-
finate ester 1 (200 mg, 1.03 mmol) in THF (3 mL) was added over
a period of 5 to 8 min. The reaction mixture was stirred for another
35 min before quenching with the addition of saturated NaHCO3
(5 mL). The mixture was then allowed to warm to room temp.
Water (7 mL) was added, and the product was extracted with
EtOAc (3ϫ15 mL). The combined extracts were dried with magne-
sium sulfate and concentrated to dryness. Purification by silica gel
chromatography afforded pure benzyl sulfoxides 4b–4h.
(S)-tert-Butyl (1,3-Benzodioxol-5-yl)methyl Sulfoxide (4a): Applying
general procedure A and using 5-bromomethyl-1,3-benzodioxole
(363 mg, 1.69 mmol) as the substrate yielded sulfoxide 4a (93 mg,
50%) as a white solid after chromatography (pentane/EtOAc, 1:1);
m.p. 141–143 °C (heptane). 1H NMR (400 MHz, CDCl3): δ = 1.31
[s, 9 H, C(CH3)3], 3.53 (d, J = 12.8 Hz, 1 H, CH2Ar), 3.75 (d, J =
(S)-Benzyl tert-Butyl Sulfoxide (4b): Applying general procedure B
and using toluene (0.28 mL) as the substrate yielded sulfoxide 4b
(122 mg, 60%) as a white solid after chromatography (pentane/
EtOAc 3:2). [α]D = –191.1 (c = 1, CHCl3), ref.[15] [α]D = –128 (c =
12.8 Hz, 1 H, CH2Ar), 5.95 (s, 2 H, O-CH2-O), 6.79 (apparent s, 2 0.6, CHCl3). HPLC (CHIRALPAK AS-H column; heptane/EtOH,
H, Ar), 6.83 (apparent s, 1 H, Ar) ppm. 13C NMR (101 MHz, 90:10; 1.0 mL/min), tR (minor enantiomer) = 8.46 min, tR (major
CDCl3): δ = 23.0 (CH3), 52.7 (CH2), 53.5 (C), 101.1 (CH2), 108.5
enantiomer) = 13.31 min, Ͼ98%ee.
(CH), 110.1 (CH), 123.4 (CH), 125.4 (C), 147.5 (C), 147.9 (C) ppm.
(S)-tert-Butyl (3,4,5-Trimethoxyphenyl)methyl Sulfoxide (4c): Ap-
plying general procedure B and using 3,4,5-trimethoxytoluene
(0.44 mL) as the substrate yielded sulfoxide 4c (138 mg, 47%) as a
white solid after chromatography (pentane/EtOAc, 3:7); m.p. 101–
103 °C (heptane). [α]D = –242.7 (c = 1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.34 [s, 9 H, C(CH3)3], 3.56 (d, J = 12.8 Hz,
1 H, CH2Ar), 3.74 (d, J = 12.8 Hz, 1 H, CH2Ar), 3.84 (s, 3 H,
OMe), 3.87 (s, 6 H, 2 OMe), 6.57 (s, 2 H, Ar) ppm. 13C NMR
(101 MHz, CDCl3): δ = 23.1 (CH3), 53.1 (CH2), 53.6 (C), 56.1
(CH3), 60.8 (CH3), 106.9 (CH), 127.4 (C), 137.8 (C), 153.4
IR (KBr): ν = 827, 1028, 1249, 2980 cm–1. MS (ESI): m/z = 241.1
˜
[M + H]+. HRMS: calcd. for C12H17O3S [M + H]+ 241.0898; found
241.0895. HPLC (CHIRALPAK AS-H column; heptane/EtOH,
90:10; 1.0 mL/min): tR (minor enantiomer) = 18.86 min, tR (major
enantiomer) = 22.86 min, 94%ee. C12H16O3S (240.32): calcd. C
59.97, H 6.71; found C 59.76, H 6.57.
(S)-Benzyl tert-Butyl Sulfoxide (4b): Applying general procedure A
and using benzyl bromide (289 mg, 1.69 mmol) as the substrate
yielded sulfoxide 4b (92 mg, 60%) as a white solid after chromatog-
raphy (pentane/EtOAc, 3:2). 1H NMR (400 MHz, CDCl3): δ = 1.33
[s, 9 H, C(CH3)3], 3.63 (d, J = 12.9 Hz, 1 H, CH2Ar), 3.83 (d, J =
12.9 Hz, 1 H, CH2Ar), 7.29–7.39 (m, 5 H, Ar) ppm. 13C NMR
(101 MHz, CDCl3): δ = 23.2 (CH3), 53.1 (CH2), 53.8 (C), 128.1
(CH), 129.1 (CH), 130.1 (CH), 132.1 (C) ppm. MS (ESI): m/z =
197.3 [M + H]+. HRMS: calcd. for C11H17OS [M + H]+ 197.1000;
found 197.0999. HPLC (CHIRALPAK AS-H column; heptane/
EtOH, 90:10; 1.0 mL/min): tR (minor enantiomer) = 8.43 min, tR
(major enantiomer) = 12.64 min, 92%ee.
(C) ppm. IR (KBr): ν = 780, 1039, 1122, 2835, 2998 cm–1. MS
˜
(ESI): m/z = 287.4 [M + H]+. HRMS: calcd. for C14H23O4S [M +
H]+ 287.1317; found 287.1315. HPLC (CHIRALPAK AS-H col-
umn; heptane/EtOH, 90:10; 1.0 mL/min): tR (minor enantiomer) =
10.47 min, tR (major enantiomer) = 13.95 min, 91%ee. C14H22O4S
(286.39): calcd. C 58.71, H 7.74; found C 58.68, H 7.76.
(S)-tert-Butyl (3,4-Dimethoxyphenyl)methyl Sulfoxide (4d): Apply-
ing general procedure B and using 3,4-dimethoxytoluene (0.38 mL)
as the substrate yielded sulfoxide 4d (138 mg, 52%) as a white solid
after chromatography (pentane/EtOAc, 3:7); m.p. 136–139 °C (hep-
Synthesis of (؎)-Benzyl tert-Butyl Sulfoxide (4b) Using Benzyllith-
ium Obtained from an Organolithium Amine Complex: A solution
of BuLi (2.5 m in hexane, 0.85 mL, 2.14 mmol, 2.0 equiv.) was
1
tane). [α]D = –209.9 (c = 1, CHCl3). H NMR (400 MHz, CDCl3):
δ = 1.33 [s, 9 H, C(CH3)3], 3.58 (d, J = 12.9 Hz, 1 H, CH2Ar), 3.78
added to tetramethylethylenediamine (0.33 mL, 2.24 mmol, (d, J = 12.9 Hz, 1 H, CH2Ar), 3.88 (s, 3 H, OMe), 3.90 (s, 3 H,
2.1 equiv.) at room temperature under nitrogen, and the mixture
was stirred for 10 min before dry toluene (1.14 mL, 10.7 mmol,
10 equiv.) was added. After 30 min, the mixture was transferred
through a syringe to a solution of racemic sulfinate ester 3a
OMe), 6.80–6.94 (m, 3 H, Ar) ppm. 13C NMR (101 MHz, CDCl3):
δ = 23.1 (CH3), 52.5 (CH2), 53.5 (C), 55.91 (CH3), 55.93 (CH3),
111.3 (CH), 112.8 (CH), 122.2 (CH), 124.3 (C), 148.9 (C), 149.1
(C) ppm. IR (KBr): ν = 766, 1037, 1261, 1518, 2961 cm–1. MS
˜
(300 mg, 1.07 mmol, 1 equiv.) in dry THF (7 mL) at –78 °C. The (ESI): m/z = 257.4 [M + H]+. HRMS: calcd. for C13H21O3S [M +
reaction mixture was stirred for 30 min before the addition of satu-
rated NaHCO3 (5 mL), and it was then allowed to warm to room
temp. Water (5 mL) was added, and the product was extracted into
EtOAc (3ϫ15 mL). The combined organic extracts were dried with
magnesium sulfate and concentrated to dryness. Purification by sil-
ica gel chromatography (pentane/EtOAc, 3:2) afforded pure benzyl
sulfoxide 4b (127 mg, 61%) as a white solid. Applying the same
procedure using racemic thiosulfinate ester 1 (207 mg, 1.07 mmol)
as the electrophile yielded sulfoxide 4b (136 mg, 65%) as a white
solid.
H]+ 257.1211; found 257.1199. HPLC (CHIRALPAK AS-H col-
umn; heptane/EtOH, 90:10; 1.0 mL/min): tR (minor enantiomer) =
13.72 min, tR (major enantiomer) = 15.89 min, 97%ee. C13H20O3S
(256.36): calcd. C 60.91, H 7.86; found C 60.50, H 7.78.
(S)-tert-Butyl (2-Methoxyphenyl)methyl Sulfoxide (4e): Applying
general procedure B and using 2-methoxytoluene (0.33 mL) as the
substrate yielded sulfoxide 4e (175 mg, 75%) as a white solid after
chromatography (pentane/EtOAc, 1:1); m.p. 80–82 °C (heptane).
[α]D = –259.2 (c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
1.25 [s, 9 H, C(CH3)3], 3.30 (d, J = 12.5 Hz, 1 H, CH2Ar), 4.13 (d,
J = 12.5 Hz, 1 H, CH2Ar), 3.75 (s, 3 H, OMe), 6.77–6.90 (m, 2 H,
Ar), 7.18–7.29 (m, 2 H, Ar) ppm. 13C NMR (101 MHz, CDCl3): δ
= 22.8 (CH3), 48.3 (CH2), 53.5 (C), 55.4 (CH3), 110.4 (CH), 120.6
(C), 120.7 (CH), 129.3 (CH), 131.8 (CH), 157.3 (C) ppm. IR (KBr):
General Procedure B. Enantioselective Synthesis of Benzyl Sulfox-
ides Using Benzyllithium Derivatives Generated from a Superbasic
Mixture: To
a stirred solution of the toluene (2.68 mmol,
2.60 equiv.) at –78 °C in THF (26 mL) was added dropwise a solu-
tion of BuLi (2.0 m in hexane, 1.2 mL, 2.47 mmol, 2.4 equiv.), and
the mixture was stirred for 5 min. A solution of tBuOK (1.0 m in
ν = 750, 1099, 1250, 2959, 3063 cm–1. MS (ESI): m/z = 227.4 [M
˜
+ H]+. HRMS: calcd. for C12H19O2S [M + H]+ 227.1106; found
Eur. J. Org. Chem. 2011, 7207–7214
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7211

M. K. Syed, M. Casey
FULL PAPER
227.1112. HPLC (CHIRALPAK AS-H column; heptane/EtOH,
90:10; 1.0 mL/min): tR (minor enantiomer) = 8.71 min, tR (major
enantiomer) = 9.73 min, Ͼ98%ee. C12H18O2S (226.33): calcd. C
63.68, H 8.02; found C 63.63, H 8.01.
stirred for 35 min and then quenched by the addition of saturated
NaHCO3 (5 mL). The mixture was warmed to room temp. Water
(7 mL) was added, and the product was extracted with EtOAc
(3ϫ15 mL). The combined extracts were dried with magnesium
sulfate and concentrated to dryness. Purification by silica gel
chromatography afforded the pure benzyl sulfoxide 4i (183 mg,
80%) as a white solid after chromatography (pentane/EtOAc, 3:2);
m.p. 109–111 °C (heptane). [α]D = –257.1 (c = 1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.35 [s, 9 H, C(CH3)3], 3.65 (d, J = 12.6 Hz,
1 H, CH2Ar), 3.83 (d, J = 12.6 Hz, 1 H, CH2Ar), 7.44–7.50 (m, 2
H, Ar), 7.63–7.69 (m, 2 H, Ar) ppm. 13C NMR (101 MHz, CDCl3):
δ = 22.9 (CH3), 52.4 (CH2), 54.2 (C), 111.9 (C), 118.5 (C), 130.8
(S)-tert-Butyl (3-Methoxyphenyl)methyl Sulfoxide (4f): Applying
general procedure B and using 3-methoxytoluene (0.33 mL) as the
substrate yielded sulfoxide 4f (164 mg, 70%) as a white solid after
chromatography (pentane/EtOAc, 1:1); m.p. 93–95 °C (heptane).
[α]D = –192.7 (c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
1.32 [s, 9 H, C(CH3)3], 3.60 (d, J = 12.8 Hz, 1 H, CH2Ar), 3.80 (d,
J = 12.8 Hz, 1 H, CH2Ar), 3.81 (s, 3 H, OMe), 6.83–6.95 (m, 3 H,
Ar), 7.24–7.29 (m, 1 H, Ar) ppm. 13C NMR (101 MHz, CDCl3): δ
= 22.0 (CH3), 52.0 (CH2), 52.7 (C), 54.2 (CH3), 112.8 (CH), 114.2
(CH), 121.2 (CH), 128.8 (CH), 132.4 (C), 158.8 (C) ppm. IR (KBr):
(CH), 132.4 (CH), 137.7 (C) ppm. IR (KBr): ν = 540, 1034, 2229,
˜
2963, 3035 cm–1. MS (ESI): m/z = 222.1 [M + H]+. HRMS: calcd.
for C12H16NOS [M + H]+ 222.0953; found 222.0949. HPLC (CHI-
RALPAK AS-H column; heptane/EtOH, 90:10; 1.0 mL/min): tR
ν = 794, 1049, 1154, 1267, 2961 cm–1. MS (ESI): m/z = 227.4 [M
˜
+ H]+. HRMS: calcd. for C12H19O2S [M + H]+ 227.1106; found
227.1108. HPLC (CHIRALPAK AS-H column; heptane/EtOH,
85:15; 1.0 mL/min): tR (minor enantiomer) = 8.77 min, tR (major
enantiomer) = 11.78 min, 92%ee. C12H18O2S (226.33): calcd. C
63.68, H 8.02; found C 63.84, H 8.06.
(major enantiomer)
= 24.62 min, tR (minor enantiomer) =
29.38 min, 88%ee.
(tert-Butylsulfinyl)(tert-butylthio)methylbenzene (8): To a stirred
solution of toluene (0.26 mol, 2.46 mmol, 2.2 equiv.) at –78 °C in
THF (8 mL) was added dropwise a solution of BuLi (2.0 m in hex-
ane, 1.0 mL, 2.24 mmol, 2.0 equiv.), and the mixture was stirred for
5 min. A solution of tBuOK (1.0 m in THF, 2.24 mL, 2.24 mmol,
2.0 equiv.) was added dropwise followed by the addition of 2,2,6,6-
tetramethylpiperidine (0.37 mL, 2.24 mmol, 2.0 equiv.). After
30 min, a solution of tert-butyl disulfide (200 mg, 1.12 mmol) in
THF (3 mL) was added dropwise. After 35 min, a solution of race-
mic thiosulfinate ester 1 (217 mg, 1.12 mmol) in THF (3 mL) was
added over a period of 6 min. The reaction mixture was stirred for
35 min followed by the addition of saturated NaHCO3 (5 mL), and
the mixture was allowed warm to room temperature. Water (5 mL)
was added, and the product was extracted with EtOAc (3ϫ15 mL).
The combined extracts were dried with magnesium sulfate and con-
centrated to dryness. Purification by silica gel chromatography
(pentane/EtOAc, 3:1) afforded the following: (i) an inseparable
mixture of (tert-butylthio)methylbenzene and bis(tert-butylthio)-
methylbenzene[40] and (ii) a mixture of diastereomeric dithioacetal
(S)-tert-Butyl (4-Methoxyphenyl)methyl Sulfoxide (4g): Applying
general procedure B and using 4-methoxytoluene (0.33 mL) as the
substrate yielded sulfoxide 4g (70 mg, 33%) as a white solid after
chromatography (pentane/EtOAc, 1:1); m.p. 124–126 °C (heptane).
[α]D = –232.5 (c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
1.31 [s, 9 H, C(CH3)3], 3.58 (d, J = 12.9 Hz, 1 H, CH2Ar), 3.79 (d,
J = 12.9 Hz, 1 H, CH2Ar), 3.80 (s, 3 H, OMe), 6.86–6.92 (m, 2 H,
Ar), 7.22–7.29 (m, 2 H, Ar) ppm. 13C NMR (101 MHz, CDCl3): δ
= 23.0 (CH3), 52.1 (CH2), 53.4 (C), 55.2 (CH3), 114.3 (CH), 123.7
(C), 131.1 (CH), 159.4 (C) ppm. IR (KBr): ν = 794, 1049, 1267,
˜
1582, 2961 cm–1. MS (ESI): m/z = 227.4 [M + H]+. HRMS: calcd.
for C12H19O2S [M + H]+ 227.1106; found 227.1106. HPLC (CHI-
RALPAK AS-H column; heptane/EtOH, 90:10; 1.0 mL/min): tR
(minor enantiomer)
= 12.46 min, tR (major enantiomer) =
15.78 min, 91%ee. C12H18O2S (226.33): calcd. C 63.68, H 8.02;
found C 63.38, H 8.03.
1
(S)-tert-Butyl (3-Fluorophenyl)methyl Sulfoxide (4h): Applying ge-
neral procedure B and using 3-fluorotoluene (0.28 mL) as the sub-
strate yielded sulfoxide 4h (168 mg, 76%) as a white solid after
chromatography (pentane/EtOAc, 1:1); m.p. 69–71 °C (heptane).
[α]D = –287.2 (c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
1.33 [s, 9 H, C(CH3)3], 3.59 (d, J = 12.8 Hz, 1 H, CH2Ar), 3.80 (d,
J = 12.8 Hz, 1 H, CH2Ar), 6.97–7.16 (m, 3 H, Ar), 7.27–7.36 (m,
1 H, Ar) ppm. 13C NMR (101 MHz, CDCl3): δ = 22.9 (CH3), 52.4
(d, J = 2 Hz, CH2), 53.8 (C), 114.8 (d, J = 21 Hz, CH), 116.9 (d,
J = 21 Hz, CH), 125.7 (d, J = 3 Hz, CH), 130.2 (d, J = 8.3 Hz,
CH), 134.4 (d, J = 7.8 Hz, C), 162.8 (d, J = 246.8 Hz, C) ppm. IR
monosulfoxides 8 as a white solid. H NMR (400 MHz, CDCl3): δ
= 1.12 [s, 9 H, C(CH3)3], 1.20 [s, 9 H, C(CH3)3], 1.31 [s, 9 H,
C(CH3)3], 1.36 [s, 9 H, C(CH3)3], 4.83 (s, 1 H, CHAr), 4.88 (s, 1
H, CHAr), 7.26–7.44 (m, 10 H, Ar) ppm. 13C NMR (101 MHz,
CDCl3): δ = 23.9 (CH3), 24.0 (CH3), 31.2 (CH3), 31.9 (CH3), 46.0
(C), 46.1 (C), 56.6 (C), 56.8 (C), 61.4 (CH), 65.5 (CH), 109.9 (C),
128.2 (CH), 128.2 (CH), 128.3 (CH), 128.4 (CH), 128.9 (CH), 129.7
(CH), 138.4 (C) ppm. IR (KBr): ν = 702, 1039, 1156, 1367, 1455,
˜
2956, 3029 cm–1. HRMS: calcd. for C15H24OS2 [M + H]+ 307.1166;
found 307.1154.
(1,3-Benzodioxo-5-ylmethyl)tributylstannane (9): To a two-necked
flask (25 mL) containing magnesium turnings (210 mg, 8.36 mmol)
was added a solution of tributyltin chloride (0.98 mL, 3.60 mmol)
in THF (5 mL), and the mixture was heated to 60 °C. After 10 min,
(KBr): ν = 786, 1034, 1258, 2976, 3056 cm–1. MS (ESI): m/z = 215.3
˜
[M + H]+. HRMS: calcd. for C11H16FOS [M + H]+ 215.0906;
found 215.0907. HPLC (CHIRALPAK AS-H column; heptane/
EtOH, 85:15; 1.0 mL/min): tR (minor enantiomer) = 6.62 min, tR
(major enantiomer) = 11.57 min, 96%ee.
a
solution of 3,4-methylenedioxybenzyl bromide (500 mg,
2.34 mmol) in THF (5 mL) was added dropwise through a syringe.
The reaction mixture was stirred for an additional 3 h, and then it
(S)-tert-Butyl (4-Cyanophenyl)methyl Sulfoxide (4i): To a stirred
solution of 2,2,6,6-tetramethylpiperidine (0.43 mL, 2.52 mmol, was cooled in an ice bath and quenched with water (8 mL). The
2.45 equiv.) in THF (20 mL) at –78 °C was added dropwise a solu-
tion of BuLi (2.0 m in hexane, 1.2 mL, 2.47 mmol, 2.4 equiv.) fol-
lowed by the addition of a solution of tBuOK (1.0 m in THF,
mixture was extracted with Et2O (3ϫ15 mL). The combined ex-
tracts were washed with 5% HCl, water, and brine and then dried
with anhydrous Na2SO4. The resulting mixture was concentrated
2.68 mL, 2.68 mmol, 2.60 equiv.). After 5 min, a solution of 4- in vacuo to complete dryness. Purification by silica gel chromatog-
methylbenzonitrile (0.31 g, 2.68 mmol, 2.60 equiv.) in THF (5 mL)
was added dropwise, and the mixture was stirred for 35 min. A
solution of thiosulfinate ester 1 (200 mg, 1.03 mmol) in THF
(3 mL) was added over a period of 8 min. The reaction mixture was
raphy (pentane/Et2O, 9.8:0.2) afforded (1,3-benzodioxo-5-ylmeth-
yl)tributylstannane (9[41], 877 mg, 88%) as a colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 0.77–0.90 (m, 15 H, CH3-CH2), 1.20–1.31
(m, 6 H, CH2), 1.36–1.47 (m, 6 H, CH2), 2.23 (s, 2 H, CH2Ar),
7212
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7207–7214

Enantioselective Synthesis of Benzyl tert-Butyl Sulfoxides
5.86 (s, 2 H, O-CH2-O), 6.42 (dd, J = 1.6, 7.9 Hz, 1 H, Ar), 6.49 chromatography (pentane/EtOAc, 1:1). 1H NMR (400 MHz,
(d, J = 1.4 Hz, 1 H, Ar), 6.63 (d, J = 7.9 Hz, 1 H, Ar) ppm. 13C CDCl3): δ = 1.04 [s, 9 H, C(CH3)3], 2.71 (dd, J = 11.6, 15.6 Hz, 1
NMR (101 MHz, CDCl3): δ = 9.2 (CH2), 13.6 (CH3), 17.7 (CH2), H, H2), 3.19 (dd, J = 4.2, 15.6 Hz, 1 H, H2), 3.49 (s, 3 H, CO-
27.2 (CH2), 29.0 (CH2), 100.3 (CH2), 107.6 (CH), 108.1 (CH), 119.1
(CH), 137.4 (C), 143.4 (C), 147.4 (C) ppm.
OCH3), 3.99 (d, J = 3.4 Hz, 1 H, H4), 4.15–4.26 (m, 1 H, H3) 6.82–
7.32 (m, 10 H, Ar) ppm. 13C NMR (101 MHz, CDCl3): δ = 23.6
(CH3), 34.7 (CH2), 41.5 (CH), 51.5 (CH3), 56.0 (C), 66.0 (CH),
126.9 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 128.6 (CH), 130.3
(CH), 133.8 (C), 140.0 (C), 171.7 (C) ppm. MS (ESI): m/z = 359.1
[M + H]+. HRMS: calcd. for C21H27O3S [M + H]+ 359.1681; found
359.1677.
Enantioselective Synthesis of (S)-tert-Butyl (1,3-Benzodioxol-5-yl)-
methyl Sulfoxide (4a) Using Benzyllithium Obtained by Tin–Lithium
Exchange: To a stirred solution of the benzyltributylstannane 9
(0.56 g, 1.33 mmol, 2.60 equiv.) in THF (15 mL) at –78 °C was
added dropwise a solution of BuLi (2.0 m in hexane, 0.59 mL,
1.18 mmol, 2.3 equiv.). After 35 min, a solution of (R)-(+)-thiosulf-
inate ester 1 (100 mg, 0.51 mmol) in THF (4 mL) was added over
a period of 8 min. The reaction mixture was stirred for another
35 min followed by the addition of saturated NaHCO3 (5 mL). The
reaction mixture was then warmed to room temp. Water (5 mL)
was added, and the product was extracted with EtOAc (3ϫ15 mL).
The combined organic extracts were dried with magnesium sulfate
and concentrated to dryness. Purification by silica gel chromatog-
raphy (1:1 pentane/EtOAc) afforded sulfoxide 4a (69 mg, 57%) as
a white solid. [α]D = –230.1 (c = 1, CHCl3). HPLC (CHIRALPAK
AS-H column; heptane/EtOH, 90:10; 1.0 mL/min): tR (major en-
antiomer) = 23.21 min, Ͼ98%ee.
rac-(SS,1S,2S)-2-(tert-Butylsulfinyl)-1,2-diphenylethanol (10c) and
rac-(SS,1R,2S)-2-(tert-Butylsulfinyl)-1,2-diphenylethanol (10cЈ): Ap-
plying general procedure C and using benzaldehyde (0.14 mL,
1.38 mmol, 0.9 equiv.) as the electrophile yielded α-substituted
product 10c (200 mg, 42%) and 10cЈ (60 mg, 12%) as white solids
after chromatography (pentane/EtOAc, 1:1). Data for 10c: 1H
NMR (400 MHz, CDCl3): δ = 1.22 [s, 9 H, C(CH3)3], 4.09 [d, J =
9.4 Hz, 1 H, CHS(O)], 5.38 [d, J = 9.4 Hz, 1 H, PhCH(OH)], 6.14
(br. s, 1 H, OH), 6.92–7.20 (m, 10 H, Ar) ppm. 13C NMR
(101 MHz, CDCl3): δ = 23.3 (CH3), 56.6 (C), 66.7 (CH), 77.7 (CH),
127.0 (CH), 127.5 (CH), 127.7 (CH), 128.5 (CH), 129.5 (CH), 134.3
(C), 140.1 (C) ppm. IR (KBr): ν = 706, 985, 1047, 3033, 3324 cm–1.
˜
MS (ESI): m/z = 303.4 [M + H]+. HRMS: calcd. for C18H23O2S
[M + H]+ 303.1419; found 303.1432. Data for 10cЈ: 1H NMR
(400 MHz, CDCl3): δ = 1.11 [s, 9 H, C(CH3)3], 3.98 [d, J = 2.5 Hz,
1 H, CHS(O)], 4.53 (d, J = 5.2 Hz, 0.5 H, OH), 4.55 (d, J = 5.2 Hz,
0.5 H, OH), 5.67 [br. dd, J = 2.5, 5.2 Hz, 1 H, PhCH(OH)], 6.97–
7.27 (m, 10 H, Ar) ppm. 13C NMR (101 MHz, CDCl3): δ = 23.5
(CH3), 55.4 (C), 67.7 (CH), 72.3 (CH), 126.5 (CH), 127.2 (CH),
127.7 (CH), 127.9 (CH), 128.0 (CH), 130.7 (CH), 132.7 (C), 140.5
General Procedure C. Formation of α-Substituted Benzyl Sulfoxides
(10a–10c): To a stirred solution of toluene (0.46 mL, 4.31 mmol,
2.8 equiv.) at –78 °C in THF (40 mL) was added dropwise a solu-
tion of BuLi (2.0 m in hexane, 1.8 mL, 3.69 mmol, 2.4 equiv.), and
the mixture was stirred for 5 min. A solution of tBuOK (1.0 m in
THF, 1.22 mL, 1.22 mmol, 0.8 equiv.) was added dropwise followed
by the addition of 2,2,6,6-tetramethylpiperidine (0.63 mL,
3.77 mmol, 2.45 equiv.). After 60 min, a solution of thiosulfinate
ester 1 (300 mg, 1.54 mmol) in THF (3 mL) was added over a
period of 5 to 8 min. The reaction mixture was stirred for an ad-
ditional 45 min, and then the electrophile (1.38 mmol, 0.9 equiv.)
was added. After 15 min, the reaction was quenched by the ad-
dition of saturated NaHCO3 (7 mL), and the mixture was warmed
to room temp. Water (10 mL) was added, and the product was ex-
tracted with EtOAc (3ϫ20 mL). The combined extracts were dried
with magnesium sulfate and concentrated to dryness. Purification
by silica gel chromatography afforded α-substituted benzyl sulfox-
ides 10a–10c.
(C) ppm. IR (KBr): ν = 703, 1017, 1056, 2956, 3304 cm–1. MS
˜
(ESI): m/z = 303.4 [M + H]+. HRMS: calcd. for C18H23O2S [M +
H]+ 303.1419; found 303.1412.
rac-(SS,1R)-tert-Butyl 1-Phenylethyl Sulfoxide (10d) and rac-
(SS,1S)-tert-Butyl 1-Phenylethyl Sulfoxide (10dЈ): To a stirred solu-
tion of toluene (0.46 mL, 4.31 mmol, 2.8 equiv.) in THF (40 mL)
at –78 °C was added dropwise a solution of BuLi (2.0 m in hexane,
1.8 mL, 3.69 mmol, 2.4 equiv.), and the mixture was stirred for
5 min. A solution of tBuOK (1.0 m in THF, 4.0 mL, 4.0 mmol,
2.6 equiv.) was added dropwise followed by the addition of 2,2,6,6-
tetramethylpiperidine (0.63 mL, 3.77 mmol, 2.45 equiv.). After
35 min, racemic thiosulfinate ester 1 (300 mg, 1.54 mmol) in THF
(3 mL) was added over a period of 6 min. The reaction mixture
was stirred for 35 min. Iodomethane (0.1 mL, 1.84 mmol,
1.2 equiv.) was added, and the reaction mixture was warmed to
–25 °C. After 1 h, saturated NaHCO3 (7 mL) was added, and the
reaction mixture was warmed to room temp. Water (10 mL) was
added, and the product was extracted with EtOAc (3ϫ20 mL). The
combined organic extracts were dried with magnesium sulfate and
concentrated to dryness. Purification by silica gel chromatography
(pentane/EtOAc, 1:1) afforded α-methylbenzyl sulfoxide 10d
(160 mg, 50%) and 10dЈ (50 mg, 15%) as white solids. Data for
Methyl (SS,3S,4R)-4-(tert-Butylsulfinyl)-3-methyl-4-phenylbutano-
ate (10a): Applying general procedure C and using (R)-(+)-thiosulf-
inate ester (96%ee) with methyl crotonate (0.14 mL, 1.38 mmol,
0.9 equiv.) as the electrophile yielded conjugate adduct 10a
(230 mg, 50%) as a clear oil after silica gel chromatography (pen-
tane/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3): δ = 1.03–1.07 (ob-
scured d, 3 H, CH3), 1.06 [s, 9 H, C(CH3)3], 2.02 (dd, J = 4.2,
15.0 Hz, 1 H, H2), 2.91 (dd, J = 3.5, 15.0 Hz, 1 H, H2), 2.94–3.09
(m, 1 H, H3), 3.65 (s, 3 H, COOCH3), 3.85 (d, J = 4.0 Hz, 1 H,
H4), 7.19–7.39 (m, 5 H, Ar) ppm. 13C NMR (101 MHz, CDCl3): δ
= 17.9 (CH3), 23.6 (CH3), 30.7 (CH), 36.9 (CH2), 51.5 (CH3), 55.6
(C), 65.3 (CH), 128.0 (CH), 128.6 (CH), 129.8 (CH), 134.5 (C),
172.6 (C) ppm. MS (ESI): m/z = 297.2 [M + H]+. HRMS: calcd.
for C16H25O3S [M + H]+ 297.1524; found 297.1539. HPLC (CHI-
RALPAK AS-H column; heptane/EtOH, 90:10; 1.0 mL/min): tR
(minor enantiomer) = 5.63 min, tR (major enantiomer) = 7.77 min,
90%ee.
1
10d: H NMR (400 MHz, CDCl3): δ = 1.13 [s, 9 H, C(CH3)3], 1.64
(d, J = 7.2 Hz, 3 H), 3.89 (q, J = 7.2 Hz, 1 H), 7.25–7.37 (m, 5 H,
Ar) ppm. 13C NMR (101 MHz, CDCl3): δ = 17.8 (CH3), 23.6
(CH3), 55.1 (C), 56.9 (CH), 127.7 (CH), 128.0 (CH), 128.9 (CH),
139.8 (C) ppm. HRMS: calcd. for C12H19OS [M + H]+ 211.1157;
1
found 211.1163. Data for 10dЈ: H NMR (400 MHz, CDCl3): δ =
rac-Methyl (SS,3R,4R)-4-(tert-Butylsulfinyl)-3,4-diphenylbutanoate
(10b): Applying general procedure C and using methyl cinnamate
(224 mg, 1.38 mmol, 0.9 equiv.) as the electrophile yielded conju-
gate adduct 10b (230 mg, 41%) as a clear oil after silica gel
1.10 [s, 9 H, C(CH3)3], 1.73 (d, J = 7.3 Hz, 3 H), 3.84 (q, J =
7.3 Hz, 1 H), 7.27–7.39 (m, 5 H, Ar) ppm. 13C NMR (101 MHz,
CDCl3): δ = 19.5 (CH3), 23.5 (CH3), 54.8 (C), 55.1 (CH), 127.8
(CH), 128.3 (CH), 129.0 (CH), 137.3 (C) ppm.
Eur. J. Org. Chem. 2011, 7207–7214
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7213

M. K. Syed, M. Casey
FULL PAPER
[21] D. A. Cogan, G. Liu, K. Kim, B. J. Backes, J. A. Ellman, J.
Am. Chem. Soc. 1998, 120, 8011–8019.
Acknowledgments
[22] H. M. Peltier, J. W. Evans, J. A. Ellman, Org. Lett. 2005, 7,
1733–1736.
[23] N. Shibata, M. Matsunaga, T. Fukuzumi, S. Nakamura, T.
Toru, Synlett 2005, 1699–1702.
We wish to acknowledge generous financial support from Univer-
sity College Dublin.
[24] C. Ferrer, A. Riera, X. Verdaguer, Organometallics 2009, 28,
4571–4576.
[25] K. V. Baker, J. M. Brown, N. Hughes, A. J. Skarnulis, A. Sex-
ton, J. Org. Chem. 1991, 56, 698–703.
[26] H. Gilman, H. McNinch, D. Wittenberg, J. Org. Chem. 1958,
23, 2044–2045.
[1] I. Fernández, N. Khiar, Chem. Rev. 2003, 103, 3651–3706.
[2] H. Pellissier, Tetrahedron 2006, 62, 5559–5601.
[3] M. Mellah, A. Voituriez, E. Schulz, Chem. Rev. 2007, 107,
5133–5209.
[4] V. D. Sio, M. R. Acocella, R. Villano, A. Scettri, Tetrahedron:
Asymmetry 2010, 21, 1432–1435.
[27] U. Azzena, S. Carta, G. Melloni, A. Sechi, Tetrahedron 1997,
[5] E. Wojaczyn´ska, J. Wojaczyn´ski, Chem. Rev. 2010, 110, 4303–
53, 16205–16212.
4356.
[28] U. Azzena, G. Dettori, I. Mascia, L. Pisano, M. Pittalis, Tetra-
hedron 2007, 63, 11998–12006.
[29] C. D. Broaddus, J. Org. Chem. 1970, 35, 10–15.
[30] M. Schlosser, in: Organometallics in Synthesis A Manual (Ed.:
M. Schlosser), John Wiley & Sons, Chichester, 2004, pp. 1–352.
[31] P. Fleming, D. F. O’Shea, J. Am. Chem. Soc. 2011, 133, 1698–
1701.
[6] A. J. Walker, Tetrahedron: Asymmetry 1992, 3, 961–998.
[7] M. Casey, A. C. Manage, P. J. Murphy, Tetrahedron Lett. 1992,
33, 965–968.
[8] M. Casey, R. S. Gairns, A. J. Walker, Synlett 2000, 1725–1728.
[9] Z. Appelbe, M. Casey, C. M. Keaveney, C. J. Kelly, Synlett
2002, 1404–1408.
[10] M. Casey, A. C. Manage, L. Nezhat, Tetrahedron Lett. 1988,
[32] A. C. Ranade, R. S. Mali, S. R. Bhide, S. R. Mehta, Synthesis
1976, 123.
29, 5821–5824.
[11] M. Casey, A. C. Manage, R. S. Gairns, Tetrahedron Lett. 1989,
30, 6919–6922.
[12] M. Casey, R. S. Gairns, G. M. Geraghty, C. J. Kelly, P. J. Mur-
phy, A. J. Walker, Synlett 2000, 1721–1724.
[13] M. Casey, C. M. Keaveney, Chem. Commun. 2004, 184–185.
[14] F. A. Davis, R. T. Reddy, W. Han, P. J. Carroll, J. Am. Chem.
Soc. 1992, 114, 1428–1437.
[33] S. Grasso, G. De Sarro, A. De Sarro, N. Micale, M. Zappala,
G. Puja, M. Baraldi, C. De Micheli, J. Med. Chem. 2000, 43,
2851–2859.
[34] W. Gensler, J. Stouffer, J. Org. Chem. 1958, 23, 908–910.
[35] H. Gilman, S. Rosenberg, J. Org. Chem. 1959, 24, 2063–2064.
[36] J. E. Deline, R. B. Miller, Tetrahedron Lett. 1998, 39, 1721–
1724.
[15] P. Kelly, S. E. Lawrence, A. R. Maguire, Eur. J. Org. Chem.
2006, 4500–4509.
[16] C. Drago, L. Caggiano, R. F. W. Jackson, Angew. Chem. 2005,
117, 7387–7389; Angew. Chem. Int. Ed. 2005, 44, 7221–7223.
[17] M. A. M. Capozzi, C. Cardellicchio, F. Naso, V. Rosito, J. Org.
Chem. 2002, 67, 7289–7294.
[18] F. Rebiere, O. Samuel, L. Ricard, H. B. Kagan, J. Org. Chem.
1991, 56, 5991–5999.
[19] J. Drabowicz, B. Bujnicki, P. Biscarini, M. Mikolajczyk, Tetra-
hedron: Asymmetry 1999, 10, 3177–3187.
[20] D. J. Weix, J. A. Ellman, Org. Lett. 2003, 5, 1317–1320.
[37] S. G. Pyne, G. Boche, J. Org. Chem. 1989, 54, 2663–2667.
[38] Y. Kodama, K. Nishihata, M. Nishio, Y. Litaka, J. Chem. Soc.
Perkin Trans. 2 1976, 1490–1495.
[39] W. G. Kofron, L. M. Baclawski, J. Org. Chem. 1976, 41, 1879–
1880.
[40] F. G. Bordwell, G. E. Drucker, G. J. McCullum, J. Org. Chem.
1982, 47, 2504–2510.
[41] J. Zhang, S. Didierlaurent, M. Fortin, D. Lefrancois, E. Uridat,
J. P. Vevert, Bioorg. Med. Chem. Lett. 2000, 10, 1351–1355.
Received: July 20, 2011
Published Online: October 18, 2011
7214
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7207–7214