Nucleophilic additions to alkylidene bis(sulfoxides)-stereoelectronic effects in vinyl sulfoxides

Article abstract of DOI:10.1002/chem.200701847

Conjugate additions of nucleophiles (e.g. enolates, amines and malonate anions) to bis(p-tolylsulfinyl)alkenes, alkylidene-1,3-dithiane-1,3-dioxides and alkylidene-1,3-dithiolane-1,3-dioxides have recently been published. Reasons for different selectiviti

Full text of DOI:10.1002/chem.200701847

FULL PAPER
DOI: 10.1002/chem.200701847
Nucleophilic Additions to Alkylidene Bis(sulfoxides)—Stereoelectronic
Effects in Vinyl Sulfoxides
Tobias Wedel,[a] Timo Gehring,[a] Joachim Podlech,*[a] Elena Kordel,[b]
Angela Bihlmeier,[b] and Wim Klopper*[b]
Dedicated to Professor Dr. Dr. h. c. Dieter Seebach on the occasion of his 70th birthday
Abstract: Conjugate additions of nucle-
ophiles (e.g. enolates, amines and mal-
onate anions) to bis(p-tolylsulfinyl)al-
kenes, alkylidene-1,3-dithiane-1,3-diox-
ides and alkylidene-1,3-dithiolane-1,3-
dioxides have recently been published.
Reasons for different selectivities and
reaction rates will be discussed by con-
sideration of steric and electronic ef-
fects. The preferred mode of attack can
be explained by stereoelectronic effects
(hyperconjugation) in the primarily
carbanion, which is stabilized by
n!S-O-s* interaction with an antiperi-
planar S=O group. Calculation of the
transition states [BP86/aug-TZVP] for
the addition of acetone enolate to the
dithiane-derived alkylidene bis(sulfox-
ide) revealed that 6.6–7.3 kJmolꢀ1
more energy is needed for an attack
leading to a less-stabilized carbanion.
Two axial S=O groups in dithiolane-de-
rived alkylidene bis(sulfoxides) lead to
Keywords: density functional calcu-
lations · diastereoselectivity · nucle-
ophilic addition · stereoelectronic
effects · sulfur heterocycles
a
higher reactivity towards nucleo-
philes.
Introduction
yl compounds, much less is published or commonly known
about sulfoxides and especially about vinyl-substituted sulf-
oxides.[4] During the examination of nucleophilic additions
to dithiane-derived alkylidene bis(sulfoxides),[5,6] we were
confronted with some fundamental questions which have
hardly been addressed in the literature.
A multitude of information has been published on the addi-
tion of nucleophiles to carbonyl compounds and a,b-unsatu-
rated carbonyl compounds. The frontier orbitals in these re-
actions are well known to every chemist[1] and special modes
of attack, like the Zimmerman–Traxler transition state, can
be handled by 3rd year students.[2] Even very sophisticated
stereoelectronic effects are—though possibly not commonly
known—at least understood by specialists in this field.[3]
While sulfoxides behave in some aspects similarly to carbon-
Alkylidene bis(sulfoxides)[4] have repeatedly been used in
organic synthesis due to their electron-deficient double
bond.[8] Since non-symmetrically substituted sulfoxides are
chiral and configurationally stable, these reactions can be
led diastereoselectively. Aggarwal and co-workers very suc-
cessfully used dithiane- and dithiolane-derived bis(sulfox-
ides) of type 2 and 3 in epoxidations, cyclopropanations, and
cycloadditions (Figure 1).[9] The cleavage of the auxiliary, for
instance with the Pummerer reaction, releases a carbonyl
group.[4,9b,10] Fensterbank, Malacria, and co-workers reported
on nucleophilic additions to ditolyl-substituted alkylidene
bis(sulfoxides) 1 (Figure 1) and observed excellent selectivi-
ties and a high reactivity in the addition of C-, N-, and O-
nucleophiles.[11,12] They argued that a steric hindrance arising
from the p-stacked tolyl groups is responsible for these se-
lectivities. We found that dithiane-derived substrates 2 gave
somewhat poorer selectivities and are not as reactive. For
example, a nucleophilic attack of secondary amines is ach-
ieved only with a high excess (amine used as solvent), with
[a] Dr. T. Wedel, Dipl.-Chem. Dipl.-Math. T. Gehring,
Prof. Dr. J. Podlech
Institut für Organische Chemie, Universität Karlsruhe (TH)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax: ( +49)721-608-7652
E-mail: joachim.podlech@ioc.uka.de
[b] Dr. E. Kordel, Dipl.-Chem. A. Bihlmeier, Prof. Dr. W. Klopper
Institut für Physikalische Chemie, Lehrstuhl für Theoretische Chemie
Universität Karlsruhe (TH)
Engesserstrasse 15, 76131 Karlsruhe (Germany)
Fax: ( +49)721-608-3319
E-mail: klopper@chem-bio.uni-karlsruhe.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2008, 14, 4631 – 4639
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4631

son olefination and subsequent enantio- and diastereoselec-
tive S-oxidation. Addition of enolates to bis(sulfoxide) 2a
proceeded with selectivities better than 85:15 and with close
to quantitative yields,[5] in which a single recrystallization
gave pure products (Scheme 1). Yields and selectivities were
Figure 1. Alkylidene bis(sulfoxides) and their crystal structures.[7] top;[11a]
middle;[5] bottom.[6]
a significantly lower rate and with a poor yield. Neverthe-
less, steric hindrance should be essentially the same in 2 as
in substrates 1. In contrast, we observed a significantly
higher reactivity in additions to dithiolane-derived alkyli-
dene bis(sulfoxides) 3. Addition of piperidine as a secondary
amine proceeded fast, even at ꢀ788C and with only a slight
excess of the amine.[6] Though substrates 1–3 are quite simi-
lar on a first glance, they behave very differently in terms of
reactivity and selectivity.
To understand and to be able to influence the stereo-
chemical outcome in the nucleophilic addition to vinyl sulf-
oxides, it seems to be essential to know about the stereo-
electronic effects arising from the S=O double bond. These
effects compete with possible steric effects or with a puta-
tive pre-complexation as present in the Zimmerman–Traxler
transition state. Though stereoelectronic effects of sulfoxides
have occasionally been investigated,[13,14] much less is known
about orbital interactions in vinyl sulfoxides.[15] The systems
used up to now were either not in a fixed (or otherwise un-
ambiguously known) conformation and thus did not allow a
concise treatment[11,16] or were present together with inter-
fering carbonyl groups,[8a,17] which did not allow an inde-
pendent examination of the sulfoxideꢁs influence. Herein we
discuss stereoelectronic effects in the reactions of vinyl sulf-
oxides.
Scheme 1. Nucleophilic attack to dithiane-derived substrates 2. [a] Puri-
fied major isomer. [b] Mixture of isomers. [c] Isomers could not be sepa-
rated. LDA=lithium diisopropylamide.
similar when allylamine was added, though the resulting dia-
stereoisomers (78:22) were not separable, either by chroma-
tography or by crystallization. The attack is assumed to pro-
ceed generally from the Re side. Evidence for this comes
from X-ray crystallographic analyses.[5]
In a mechanistic investigation on diastereoselectivities,
the conformational space and its population by preferred
conformations is of special importance. In the open-chain
bis(sulfoxides) 1 several conformations should be consid-
ered, even though it has been claimed that the p-stacked
conformation 1-A is solely relevant in nucleophilic additions
(Scheme 2).[11a] Dithiane-derived bis(sulfoxide) 2 is less flexi-
ble. At least for bulky substituents (R=Ph), only conforma-
tion 2a-A is significantly populated because of allylic strain
Results and Discussion
Dithiane-derived alkylidene bis(sulfoxides): Dithiane-de-
rived alkylidene bis(sulfoxides) were prepared by slight
modification of a procedure presented by Aggarwal et al.[18]
They were obtained in two steps from 1,3-dithiane by Peter-
Scheme 2. Conformations in alkylidene bis(sulfoxides).
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Nucleophilic Additions
FULL PAPER
(A1,3 strain)[19] and a (admittedly weak) hydrogen bond be-
tween the equatorial S=O oxygen and the vinylic hydro-
gen.[20] We calculated that the energy of conformation 2a-B
(R=Ph) is about 15.9 kJmolꢀ1 higher than for conformation
2a-A [BP86/aug-TZVP]. The Curtin–Hammett principle
allows for energy-rich conformations in mechanistic path-
ways;[21] nevertheless, conformation 2a-B will not be consid-
ered in the further discussions when a bulky phenyl group
(R=Ph) is present in the molecule.
Several reasons might be responsible for the observed dia-
stereoselectivity in this reaction. A prerequisite for an ap-
propriate consideration of possible steric reasons is a suffi-
cient knowledge of the assumable trajectory. Nucleophilic
additions to Michael-type systems proceed very similar[22] to
additions to carbonyl double bonds in which the trajectory
angle (O=C···Nu) has been determined by Bürgi, Dunitz,
and Shefter to be about 1098.[23] Consequently, in conjugated
systems, an approaching nucleophile should be far away
from steric influences beyond the electron-deficient double
bond as present in alkylidene bis(sulfoxides) 1–3.
Scheme 3. Carbanion formation through nucleophilic attack to alkylidene
bis(sulfoxides).
Besides this steric reasoning, diastereoselectivities might
be ruled by a pre-complexation of the incoming nucleophile
through the S=O oxygen. This seems not to be very likely in
the reactions discussed here, since no influence of the coun-
terion was observed by us in the addition of enolates. Even
enolates released from silyl enol ethers with tetrabutylam-
monium fluoride (TBAF) were added with virtually identi-
cal selectivities.[5] Pre-complexation in the addition of cup-
rates is widely accepted in additions to a,b-unsaturated car-
bonyl compounds.[24] Nevertheless, the addition of cuprates
to tolyl-substituted substrates 1 proceeded antiperiplanar to
the axial S=O group,[11a] making a pre-complexation of the
incoming cuprate very unlikely.[25]
bonding angle from 1208 to about 1098 force the former al-
kylidene group towards the incoming nucleophile
(Scheme 3). This structural change should lead to a signifi-
cant increase in steric repulsion if the nucleophile ap-
proaches from the Si side (! 10-B). This effect would in
fact favor an attack from the unhindered Re side, although
it becomes operative only in an advanced state of the reac-
tion (compare the structures of the transition states in
Figure 3).
A second effect should have an even higher impact on se-
lectivities during nucleophilic attack. An evolved axial lone
pair is stabilized through antiperiplanar S=O bonds.[30] Con-
trary to a-carbonyl carbanions, which are stabilized through
ꢀ
The primary product in a conjugate addition of nucleo-
philes is a stabilized carbanion where the reasons for the
stabilization should already work during the reaction and
thus should have an impact on the nature of the transition
state. While in a classical Michael addition (i.e., addition to
an a,b-unsaturated carbonyl) a planar enolate is formed in
which the negative charge and the counterion are predomi-
nantly located at the oxygen, this is not necessarily valid for
vinyl sulfoxides (Scheme 3). The structure of a-sulfinyl car-
banions has occasionally been studied. While NMR spectro-
scopic investigations suggested a planar structure (compare
to the putative structure 10-C),[26] more meaningful X-ray
crystallographic analyses proved that the carbon atom is sig-
nificantly pyramidalized when no further stabilizing substitu-
ent (e.g., an a-phenyl group) is present. The counterion is
usually located in the vicinity of the carbon atom.[27] The
high kinetic acidity of a-sulfinyl alkanes gives further evi-
dence for a pyramidalized structure of the respective anions.
No re-hybridization and thus no overcoming of an intrinsic
barrier is necessary.[28,29]
interaction with the p* orbital, here, it is an S O s* orbital
in an appropriate orientation which leads to interaction and
thus to stabilization of the n orbital by hyperconjugation
(Figure 2, top row). A comparable interaction is not possible
Figure 2. Stereoelectronic effects in sulfinyl carbanions.
for an equatorial lone pair (though it should be stabilized to
some extent through an antiperiplanar C S s* orbital[13b,31]).
ꢀ
The simultaneous formation of an antiperiplanar carba-
nionic lone pair by attack of a nucleophile should have far-
reaching consequences. The concomitant change in hybridi-
zation at the a-carbon and consequently the change of the
A similar, though less favorable interaction should be possi-
ble with a synperiplanar S=O bond (see below), but it
should be negligible for clinal oriented S=O bonds.
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J. Podlech, W. Klopper et al.
This reasoning is strongly supported by calculations per-
formed by us. The negatively charged disulfinyl-substituted
carbon in 10 is perspicuously pyramidalized with an angular
sum[32] of 338.48 proving that an n!S-O-s* interaction is
working to a significant extent. Calculations of the transition
states of the competing diastereotopic modes of attack
showed that this stabilizing interaction is already evident
during the reaction. The transition state emerging from Re
attack of the acetone enolate is 7.3 kJmolꢀ1 lower than that
of a Si attack (Figure 3, Table 1). On the other hand, enolate
Figure 4. Sulfinylmethyl sulfides and axially chiral bis(sulfoxides).
vestigations revealed that the S=O bond is in a sterically
and stereoelectronically favored equatorial position.[35] Ob-
viously, the electron-withdrawing tendency of a sulfinyl
group is not sufficiently active when the S=O bond is not
co-planar with the evolving carbanionic lone pair.
If this reasoning applies, the presence of two S=O bonds
antiperiplanar to an evolving lone pair should have an even
higher impact. Reactivity of the alkylidene bis(sulfoxides)
should increase and the diastereoselectivities should be even
better. This might be a valid scenario in the reaction of bis-
(tolylsulfinyl)-substituted substrates 1. Though X-ray crystal-
lographic analysis suggests the presence of conformation 1-
A with only one S=O group axial in the crystal (Figure 1),
conformation 1-B containing two axial S=O groups should
be more reactive and thus might be susceptible towards the
addition of nucleophiles (Scheme 2). Further evidence for
the commanding influence of the axial S=O groups could
possibly be supplied through the reaction outcome with sub-
strate 14. Unfortunately, up to now, no synthesis, either of
the parent bis(sulfoxide) 14 or of its conformationally con-
strained derivative 15, is known. The sulfinyl-sulfone 16
(R=Ph) bearing two axial S=O bonds could be prepared
for comparison by oxidation of bis(sulfoxide) 2a.[14] It react-
ed much faster with enolates than the parent bis(sulfoxide)
2a, though the formation of 2:1 adducts (two equivalents of
the sulfone reacted with one equivalent of the enolate in
spite of a substantial steric hindrance for the second
attack[36]) led to non-separable mixtures, which made a de-
termination of the productꢁs configurations impossible.
The poor and even inverted selectivity in the addition of
the acetophenone enolate to ethylidene-1,3-dithiane-1,3-di-
oxide (2b-A) can be explained by comparison of calculated
transition-state energies (Scheme 1 and Scheme 4).[33] An
attack from the top is again favored over an attack from the
bottom (6.6 kJmolꢀ1). Nevertheless, here we have to consid-
er a reaction of the high-energy isomer 2b-B, which is only
10.6 kJmolꢀ1 less stable and thus significantly populated.
Reaction of this conformer leads to permuted diastereoiso-
mers, in which attack from the top again is 6.6 kJmolꢀ1 less
expensive than attack from the bottom. The activation barri-
er for the ring-flipping between conformers 2-A and 2-B
was measured for the parent alkylidene bis(sulfoxide) 2c
Figure 3. Calculated transitions states for attack of acetone enolate to al-
kylidene bis(sulfoxide) 2a.[7]
Table 1. Energy differences between transition states and ground states
of the reactants.
Entry
Transition
state
Mode of attack[a]
Transition state
energy [kJmolꢀ1
[b]
]
1
2
3
4
11-A
11-A
11-B
11-B
Re (top)
Si (bottom)
Re (bottom)
Si (top)
43.4
50.7
46.1
50.3
[a] Orientation of acceptor 11 as depicted in Scheme 3 and Figure 3.
[b] BP86/aug-TZVP.
addition to the high-energy conformer 2a-B is preferred
from the Re side (i.e. from the bottom). The activation bar-
rier for the Si attack to 2a-B was calculated to be
4.2 kJmolꢀ1 higher than that of the Re attack.[33] Obviously
the n!S-O-s* interaction here is exceeded by other effects.
Detailed inspection of the transition state geometries re-
vealed that in the more favored transition state 11-B, Re the
enolate is closer to the acceptor (229.6 pm) than in transi-
tion state 11-B, Si (234.1 pm). Furthermore, in 11-B, Re the
phenylꢁs ortho proton is closer to the equatorial oxygen
(218.7 pm) than in transition state 11-B, Si (247.4 pm), possi-
bly allowing a weak but significantly stabilizing hydrogen
bond. Nucleophilic attack to methyl-substituted alkylidene
bis(sulfoxide) 2b as a system without perturbing steric ef-
fects is discussed below.
While nucleophilic additions to sulfinylmethyl sulfides 12
are possible in open-chain substrates,[34] the cyclic, confor-
mationally constrained substrate 13 (R=Ph)[14] does not
react with enolates at all (Figure 4). NMR spectroscopic in-
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Nucleophilic Additions
FULL PAPER
cantly contributes to the transition states energy difference
between attack from the top and attack from the bottom,
but it has to be kept in mind that this is only one stereoelec-
tronic effect in a plethora of interactions which stabilize a
molecule. The interaction of the alkylidene p bond with the
equatorial S=O s* orbital is worth less than 4 kJmolꢀ1 for
all considered transition states. Evidently, this is a negligible
hyperconjugation.
Dithiolane-derived Alkylidene bis(sulfoxides): In the corre-
sponding dithiolane derived alkylidene bis(sulfoxides) 3
both the S=O groups are approximately co-planar and
stretching in antipodal directions (Figure 1).[6] These com-
pounds are significantly more reactive than dithiane derived
substrates 2 which caused some problems during the workup
process. Chromatography with dichloromethane and metha-
nol on silica gel led to a distinct addition of methanol to the
electron deficient double bond. We assume that not only the
antiperiplanar S=O group but also—though possibly less ef-
fective—the synperiplanar S=O group stabilizes the carba-
nionic lone pair (Figure 5). Due to this stabilization in both
Scheme 4. Nucleophilic attacks to substrates bearing
a small methyl
group (Nuꢀ =acetone enolate). All values were calculated (BP86/aug-
TZVP) except for the activation barrier for the conformational inter-
change between 2b-A and 2b-B which was measured by NMR spectros-
copy for the parent compound 2c.
Figure 5. Conceivable structures of carbanions formed during nucleophil-
ic attack to bis(sulfoxides) 3.
(R=H)[37] by determination of the coalescence in deuterat-
ed methanol at 500 MHz.[38,33] The coalescence temperature
was found to be ꢀ678C, corresponding to a free energy of
activation of 40 kJmolꢀ1 and an activation barrier of
52 kJmolꢀ1 at this temperature.[39,40,41] It is reasonable to
assume that this value is similar for the methyl-substituted
substrate 2b. These findings explain that none of the diaste-
reoisomers is formed preferentially with this substrate. In-
vestigations with conformationally locked substrates, for ex-
ample 5-tert-butyl-substituted 17, which should give further
evidence for this explanation, are in progress.
directions, a sp2 hybridization of the carbanion can no
longer be excluded. As a matter of fact, the angular sum of
the primarily formed carbanion was calculated to be 359.68,
the 2-substituent forms an angle of only 78 with the plane
spanned by S1, C2, and S3.
The addition of the acetophenone enolate to phenyl-sub-
stituted bis(sulfoxide) 3a led to only one diastereomer
(ꢁ98:2, Scheme 5, Table 2), in which a top approach is pre-
A generally applied tool for the quantification of hyper-
conjugative interactions is the natural bond orbital method
(NBO) developed by Weinhold and co-workers,[42,43] trans-
forming the canonical delocalized Hartree–Fock molecular
orbitals (MOs) into localized hybrid orbitals (NBOs). The
interactions between filled and antibonding orbitals quantify
the energetic contribution of a distinct hyperconjugation.
We calculated selected energy contributions of these deloc-
alizations by deletion of the corresponding off-diagonal ele-
ments of the Fock matrixin the NBO basis. [33] These calcula-
tions were performed for transition states 18. The energy
contribution for the interaction of the alkylidene p bond
(donor) with the axial S=O s* orbital (acceptor) are 41.9
(18-B, Si) and 41.5 kJmolꢀ1 (18-A, Re), respectively, when
attack of the enolate comes from the top (as depicted in
Figure 3). They are only 25.4 (18-B, Re) and 25.9 kJmolꢀ1
(18-A, Si), respectively, when the enolate approaches from
the lower side. Apparently, this hyperconjugation signifi-
Scheme 5. Addition of nucleophiles to dithiolane-derived bis(sulfoxides)
3.
ferred (orientation of the substrate as seen in Scheme 5).
This could be proven by two X-ray crystallographic analyses
of the addition products.[6] The further tested piperidine and
the malonate anion added to the bissulfoxide 3a with high
yields and selectivities (Table 2, entries 2 and 3). This find-
ing again proved the high reactivity of the herein presented
substrates. Whereas the dithiane derived compound 2a (R=
Ph) gave only a poor 20% yield when reacted for 48 h in pi-
peridine as the solvent, bis(sulfoxide) 3a cleanly gave the
adduct 20 with only two equivalents of piperidine at ꢀ788C
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J. Podlech, W. Klopper et al.
Table 2. Nucleophilic attack to dithiolane-derived substrates 3.
Conclusion
Entry
Bis(sulfoxide)
Nucleophile
Product
Yield [%]
d.r.
A sulfoxide is an electron-withdrawing functional group es-
tablishing electrophilic properties in its vicinity. From the
stereochemistry in the addition of nucleophiles to vinyl sulf-
oxides and from theoretical investigations we concluded
that a stabilizing stereoelectronic effect works favorably
when a donor orbital (e.g. a lone pair) is antiperiplanar to
an S=O group. This innovative finding should be an impor-
tant foundation for the development of stereoselective reac-
tions involving sulfoxides and related compounds.
1
3a, R=Ph
19
80
ꢁ98:2
2
3a, R=Ph
20
quant.
92:8
3
4
3a, R=Ph
3b, R=Me
21
22
92
81
94:6
55:45[a]
[a] Isomers could not be separated.
for 30 min (Table 2, entry 2). With a smaller methyl group
present in the bis(sulfoxide), selectivity of an enolate addi-
tion virtually vanished to 55:45.
Experimental Section
Computational methods: Quantum-chemical calculations were performed
with the program package TURBOMOLE[44] using the DFT level of
theory in combination with the RI-J approximation,[45] the BP function-
al,[46] and an aug-TZVP basis set (a TZVP basis set,[47] augmented with
diffusive s, p, d, and f functions from Dunningꢁs aug-cc-pVTZ basis[48]).
The geometries of the starting materials, transition states and products
were optimized at the BP86/aug-TZVP level and their nature was con-
firmed by vibrational analyses. To recover the influence of the solvent we
used the COSMO module employing an infinite e and optimized radii.[49]
The NBO 3.1 program[42,43] was used as interfaced to the Gaussian 03
program package.[50]
Since these substrates (3) are quasi-C2 symmetric, both
trajectories of a nucleophilic attack should be favored
through similar stereoelectronic effects. Nevertheless, with a
bulky phenyl substituent present in the substrate attack is
highly selective leading predominantly to one diastereoiso-
mer. Our preliminary rational for this observation is that a
second effect due to steric constrains becomes dominant.
With respect to the plane of the double bond, four trajecto-
ries are possible (Scheme 6): attack 1) from the top right, 2)
General: The synthesis of compounds 2a,[5] 2c,[37] 3a,[6] 5–7,[5] 13,[14] 16,[14]
and 19[6] was published elsewhere. Tetrahydrofuran (THF) was distilled
over a sodium benzophenone ketyl radical and CH2Cl2 was distilled over
CaH2. All moisture-sensitive reactions were carried out in oxygen-free
argon using oven-dried glassware and a vacuum line. Flash column chro-
matography[51] was carried out using Merck silica gel 60 (230–400 mesh)
and thin layer chromatography was carried out using commercially avail-
1
able Merck F254 pre-coated sheets. H and 13C NMR spectra were record-
ed on a Bruker Cryospek WM-250, AM-400 and DRX 500. Chemical
shifts are given in ppm downfield of tetramethylsilane. 13C NMR spectra
were recorded with broad band proton decoupling and were assigned
using DEPT experiments. Melting points were measured on a Büchi ap-
paratus and were not corrected. IR spectra were recorded on a Bruker
IFS-88 spectrometer. Elemental analyses were performed on a Heraeus,
CHN-O-rapid. Electrical ionization and high resolution mass spectra
were recorded on a Finnigan MAT-90. Optical rotations were recorded
on a Perkin Elmer 241 polarimeter and specific optical rotations [a]D are
given in units of 10ꢀ1 degcm2 gꢀ1
(R,R)-2-Ethylidene-1,3-dithiane-1,3-dioxide (2b): The procedure is a
.
Scheme 6. Nucleophilic attack to dithiolane-derived alkylidene bis(sulfox-
ides). See text for details.
A
slightly modified procedure from Aggarwal et al.[18] 1,3-Dithiane (2.40 g,
20.0 mmol) was suspended in THF (60 mL) under argon with stirring.
The suspension was cooled to ꢀ788C and nBuLi (2.5m solution in
hexane, 8.3 mL, 21 mmol) was added over 15 min. The solution was al-
lowed to warm to 08C over 1 h. The solution was re-cooled to ꢀ788C
and TMS-Cl (2.64 mL, 20.8 mmol) dissolved in THF (80 mL) was added
within 15 min. The solution was allowed to warm to room temperature
over a period of 1 h. The solution was re-cooled to ꢀ788C and nBuLi
(2.5m solution in hexane, 8.3 mL, 21 mmol) was added within 15 min.
The solution was allowed to warm to 08C within 1 h. The solution was
re-cooled to ꢀ788C and freshly distilled ethanal (916 mg, 20.8 mmol) dis-
solved in THF (8 mL) was added within 15 min. The solution was
warmed to room temperature overnight. The solution was poured in a sa-
turated NH4Cl solution (60 mL), extracted with ethyl acetate (3”60 mL),
dried (Na2SO4) and the solvents were removed under reduced pressure.
Purification via bulb-to-bulb distillation (bath temperature of up to
1208C, 1.5”10ꢀ2 mbar) afforded the desired crude ketene dithioacetal as
a pale viscous oil (2.9 g).
from the top left, 3) from the bottom right and 4) from the
bottom left. Attacks 1 and 4 are possibly hindered through
the axial oxygen atoms since these are much closer to the
assumed trajectory than in substrates 2. Attacks from the
right (1 and 3) should be less favorable because of the inter-
fering substituent R. This hindrance is negligible with a
small methyl group giving rise to a poor selectivity (55:45)
but becomes dominant with a bulky phenyl group allowing
an attack only from direction 2, which would explain the ob-
served selectivity of 98:2.
(+)-Diethyl tartrate (4.12 g, 40 mmol, traces of water were removed by
azeotropic distillation with toluene) and freshly distilled Ti(OiPr)4
A
4636
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4631 – 4639

Nucleophilic Additions
FULL PAPER
(3.0 mL, 10 mmol) were dissolved in CH2Cl2 (90 mL) at room tempera-
ture under argon and stirred for 30 min. The solution became yellow. The
crude ketene dithioacetal (prepared as described above) was dissolved in
CH2Cl2 (12 mL) and added to the reaction mixture, which was then
cooled to ꢀ458C and stirred for 2 h. Cumene hydroperoxide (80%;
15 mL, 80 mmol) in CH2Cl2 (8 mL) was added over a period of 1 h, while
the solution was allowed to warm to ꢀ208C. The mixture was stored for
24 h in a freezer (about ꢀ238C). Distilled water (7.2 mL, 0.4 mol) was
added and the reaction mixture was stirred vigorously for 1 h. The result-
ing gel was placed in an ultrasonic bath for 1 h to afford a filterable sus-
pension, which was suction-filtered through a large sintered glass funnel
filled with celite (1.5 cm height). The celite pad was washed with CH2Cl2
(ꢂ10”5 mL). The filtrate was then stirred for 1 h with a mixture of 2n
NaOH (60 mL) and brine (32 mL). The organic layer was separated,
dried (Na2SO4), and evaporated to leave about 18 g of an oily material.
Pure bis(sulfoxide) 2b was obtained by chromatography (SiO2, CH2Cl2/
MeOH 50:1) (2.35 g, 13.2 mmol, 66% over three steps) as a yellowish
(71), 72 (100), 71 (84); HRMS (EI) calcd for C5H8O2S2: 163.9966, found
163.9964.
(3R,1’R,3’R)-3-(1,3-Dioxo-1,3-dithian-2-yl)-1-phenyl-1-butanone
NaHMDS (2m solution in hexane, 600 mL, 1.2. mmol) was added at
ꢀ788C to solution of acetophenone (168 mg, 1.4 mmol) in THF
(8):
a
(10 mL). After 45 min at ꢀ788C, this mixture was transferred via a can-
nula to a ꢀ788C solution of bis(sulfoxide) 2b (178 mg, 1 mmol) in THF
(15 mL). The reaction mixture was stirred for 5 h and was then quenched
by addition of MeOH (0.5 mL) at ꢀ788C. The solution was poured into a
saturated NH4Cl solution (25 mL), extracted with ethyl acetate (3”
15 mL), dried (Na2SO4), and the solvent was removed under reduced
pressure. A slurry of the hardly soluble residue and SiO2 (2 g) in CH2Cl2
was carefully evaporated and the remnant was filled on top of a loaded
column (SiO2). Chromatography (CH2Cl2/MeOH 20:1) yielded a mixture
of isomers (266 mg, 0.891 mmol, 89%) which were recrystallized twice
(50 mL MeOH) to give diastereomerically pure 8 as colorless prisms
(80 mg, 0.268 mmol, 27%): m.p. 2248C (decomp); [a]2D0 =ꢀ23.2 (c=0.19
wax: softening range about 40 8C; Rf =0.16 (CH2Cl2/acetone 2:1); [a]D20
=
1
3
in CHCl3); H NMR (500 MHz, [D6]DMSO): d=1.28 (d, J=7.1 Hz, 3H;
4-H), 2.24–2.29 (m, 1H; 5’-Heq), 2.51–2.2.61 (m, 1H), 3.00–3.11 (m, 3H),
3.21–3.26 (m, 1H), 3.34–3.39 (m, 2H; 3’-H2), 3.44–3.61 (m, 1H; 4’-Heq),
3.97 (d, 3J=3.9 Hz, 1H; 2’-H), 7.53–7.77 (m, 2H; arom.), 7.65–7.68 (m,
1H; arom.), 8.99–8.01 ppm (m, 2H; arom.); 13C NMR (125 MHz,
[D6]DMSO): d=15.7 (t), 17.1 (q), 27.7 (d), 42.8 (t), 46.3 (t), 53.3 (t), 76.9
(d), 128.4 (d, 2 C), 129.3 (d, 2 C), 133.8 (d), 137.0 (s), 198.3 ppm (s); IR
(DRIFT): n˜ =2979 (m), 1684 (s), 1362 (m), 1225 (m), 1030 (s, S=O), 775
(m), 695 cmꢀ1 (m); elemental analysis calcd (%) for C14H18O3S2: C 56.35,
H 6.08; found: C 56.33, H 6.26.
+4.0 (c=1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=2.16 (d, 3J=
7.3 Hz, 3H; CH3), 2.38 (ddddd, 2J=15.9 Hz, 3J=5.4 Hz, 3J=3.9 Hz, 3J=
3.1 Hz, 3J=2.7 Hz, 1H; 5-Heq), 2.67 (ddd, 2J=14.1 Hz, 3J=12.9 Hz, 3J=
3.1 Hz, 1H; 6-Hax), 2.80 (ddd, 3J=13.2 Hz, 2J=11.9 Hz, 3J=2.7 Hz, 1H;
4-Hax), 3.09 (ddddd, 2J=15.9 Hz, 3J=13.2 Hz, 3J=12.9 Hz, 3J=2.7 Hz,
3J=2.4 Hz, 1H; 5-Hax), 3.23 (dddd, 2J=14.1 Hz, 3J=3.9 Hz, 3J=2.7 Hz,
4J=1.3 Hz, 1H; 6-Heq), 3.63 (dddd, 2J=11.9 Hz, 3J=5.4 Hz, 3J=2.4 Hz,
4J=1.3 Hz, 1H; 4-Heq), 6.76 ppm (q, 3J=7.3 Hz, 1H; =CH); 13C NMR
(100 MHz, CDCl3): d=14.8 (t), 15.0 (q), 48.6 (t), 55.2 (t), 136.6 (d),
144.7 ppm (s); IR (DRIFT): n˜ =2920 (s), 1740 (s), 1433 (m), 1050 (s, S=
O), 867 cmꢀ1 (m); MS (EI, 608C): m/z (%): 178 (12) [M+], 130 (100)
[(MꢀSO)+], 106 (19), 104 (19), 90 (19), 89 (22), 72 (38), 71 (38), 57 (41),
43 (67); HRMS (EI) calcd for C6H10O2S2: 178.0122, found 178.0126.
(1R,3R,1’R)- and (1R,3R,1’S)-2-[Phenyl(prop-2-en-1-ylamino)methyl]-
1,3-dithiane-1,3-dioxide (9a,b): A solution of bis(sulfoxide) 2a (60 mg,
0.25 mmol) and allyl amine (100 mL, 1.33 mmol) in CH2Cl2 (1 mL) were
stirred at room temperature for 24 h. Volatile components were removed
in vacuo and the residue was purified by chromatography on SiO2
(CH2Cl2/MeOH 10:1) to yield 9 (77 mg, 0.25 mmol, 99%) as a mixture of
A
(4.72 g, 50.0 mmol) was added dropwise at 08C to propionyl chloride
(4.62 g, 50.0 mmol) and stirred for 30 min at this temperature. Perchloric
acid (70%, 5.2 mL, 60 mmol) was carefully added dropwise. An exother-
mic reaction started after 0.5–5 min. The mixture was stirred for 30 min
at room temperature, then cooled to 08C and freshly distilled Ac2O
(35 mL) was carefully added dropwise. The dithiolanylium salt was pre-
cipitated with anhydrous Et2O (80 mL) and filtrated under argon. The
red needles were washed with Et2O (3”30 mL) and dissolved in anhy-
drous MeCN (50 mL). Et3N was added until the red color disappeared
and the solvents were removed at reduced pressure. The resulting oil was
dissolved in saturated aqueous NH4Cl solution (70 mL) and the solution
was extracted with EtOAc (3”30 mL). The combined organic layers
were dried (Na2SO4 and K2CO3), the solvents were removed and the resi-
due was distilled by bulb-to-bulb distillation yielding 2-ethylidene-1,3-di-
thiolane (2.90 g, 22.0 mmol, 44%) as a yellowish oil. Spectroscopic data
were in full agreement with published information.[52]
1
isomers (78:22). Major isomer 9a: H NMR (400 MHz, CDCl3): d=2.25–
2
3
3
2.33 (m, 1H; 5’-Heq), 2.51 (ddd, J=14.4 Hz, J=12.3 Hz, J=3.5 Hz, 1H;
3
2
3
6’-Hax), 2.87 (ddd, J=12.3 Hz, J=11.9 Hz, J=2.3 Hz, 1H; 4’-Hax), 2.93–
3.07 (m, partly covered, 4H; 5’-Hax, CH2NH), 3.27 (dddd, 2J=14.4 Hz,
3J=5.1 Hz, 3J=2.3 Hz, 4J=1.2 Hz, 1H; 6’-Heq,), 3.31 (d, 3J=4.0 Hz, 1H;
2’-H), 3.61 (dddd, J=11.9 Hz, J=5.8 Hz, J=2.4 Hz, J=1.2 Hz, 1H; 4’-
eq), 4.84 (mbr, 1H; 1-H), 5.01 (dddd, J=10.2 Hz, J=1.4 Hz, J=1.4 Hz,
2
3
3
4
3
4
4
H
2J=1.4 Hz, 1H;=CHaHb), 5.07 (dddd, 3J=17.2 Hz, 4J=1.8 Hz, 4J=
1.5 Hz, 2J=1.4 Hz, 1H;=CHaHb), 5.82 (dddd, 3J=17.2 Hz, 3J=10.2 Hz,
3J=6.3 Hz, 3J=5.4 Hz, 1H; -CH=CH2), 7.26–7.46 ppm (m, 5H; arom.);
13C NMR (100 MHz, CDCl3): d=14.4 (t), 46.0 (t), 49.7 (t), 50.5 (t), 58.4
(d), 80.6 (d), 116.4 (t), 127.7 (d, 2 C), 128.2 (d), 129.0 (d, 2 C), 136.0 (d),
137.9 ppm (s). Minor isomer 9b (selected data): 1H NMR (400 MHz,
CDCl3): d=2.60 (ddd, 2J=14.6 Hz, 3J=12.2 Hz, 3J=3.5 Hz, 1H; 6’-H),
3.55 (dddd, 2J=12.9 Hz, 3J=6.3 Hz, 3J=2.9 Hz, 4J=1.1 Hz, 1H; 4’-Heq),
3.38 (d, 3J=8.4 Hz, 1H; 2’-H), 4.70 (d, 3J=8.4 Hz, 1H; 1-H), 5.76 ppm
(dddd, 3J=17.2 Hz, 3J=10.3 Hz, 3J=6.9 Hz, 3J=5.0 Hz, 1H; -CH=CH2);
13C NMR (100 MHz, CDCl3): d=14.2 (t), 45.6 (t), 49.5 (t), 50.9 (t), 62.4
(d), 79.6 (d), 116.5 (t), 128.5 (d, 2 C), 128.7 (d), 129.0 (d, 2 C), 136.0 (d),
137.9 ppm (s); IR (DRIFT): n˜ =3335 (s, NH), 3069 (m), 2901 (s), 1643
(m), 1421 (m), 1027 (s, S=O), 917 (m), 871 cmꢀ1 (m); MS (EI, 1108C):
m/z (%): 297 (10) [M+], 280 (20), 242 (56), 206 (21), 192 (59), 175 (29),
146 (100), 134 (55), 118 (25), 102 (26), 91 (37), 77 (18), 56 (14), 41 (34);
HRMS (EI) calcd for C14H19NO2S2: 297.0857, found 297.0853.
(+)-Diethyl tartrate (9.1 g, 44 mmol, traces of water were removed by
azeotropic distillation with toluene) and freshly distilled Ti(OiPr)4
N
(3.13 g, 11.0 mmol) were dissolved at room temperature under argon in
anhydrous CH2Cl2 (5 mL per mmol) and stirred for 30 min. 2-Ethylidene-
1,3-dithiolane (2.90 g, 22.0 mmol) in CH2Cl2 (22 mL) was added, and the
mixture was cooled to ꢀ408C and stirred for 2 h. Cumene hydroperoxide
(technical grade, 80%, 16.7 g, 88.0 mmol) in CH2Cl2 (9 mL) was added
within 1 h. The solution was warmed to ꢀ208C and stored for 15 h in a
freezer (<ꢀ208C). H2O (8 mL) was added, and the mixture was stirred
vigorously for 1 h at room temperature. The slurry was kept for 1 h in an
ultrasonic bath, and the resulting suspension was filtered through a sinter
glass (G2) covered with a celite pad (1.5 cm). The filter cake was washed
repeatedly with small amounts of CH2Cl2. The solvents were removed
and chromatography on SiO2 (CH2Cl2/acetone 2:1) yielded bis(sulfoxide)
3b (1.80 g, 11.0 mmol, 50%) as a yellowish highly viscous oil, which sol-
idified upon standing. Rf =0.18 (CH2Cl2/acetone 2:1); [a]2D0 =ꢀ82.8 (c=
1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=2.42 (d, 3J=7.2 Hz, 3H;
(1’R,1’’R,3’’R)-1-[(1,3-Dioxo-1,3-dithiolan-2-yl)phenylmethyl]piperidine
(20): Freshly distilled piperidine (40 mL, 34 mg, 0.40 mmol) was added at
ꢀ788C to the bis(sulfoxide) 3a (45 mg, 0.20 mmol) in THF (2 mL). The
mixture was stirred for 30 min at ꢀ788C (monitored by TLC) and al-
lowed to warm to room temperature over 30 min. Excess piperidine was
removed by rotary evaporation using azeotropic distillation with benzene
(2”10 mL) and the residue was dissolved in CH2Cl2 (ca. 400 mL). Hexane
(10 mL) was added and the precipitate, colorless crystals (mixture of iso-
mers 20, 92:8), was collected by filtration (62 mg, 0.20 mmol, quant.):
1H NMR (500 MHz, CDCl3, major isomer): d=1.30–1.35 (m, 2H; CH2),
1.53–1.60 (m, 2H; CH2), 1.62–1.69 (m, 2H; CH2), 2.25–2.33 (m, 2H;
3
CH3), 3.61–3.83 (m, 4H; 4-H2, 5-H2), 7.44 ppm (q, J=7.2 Hz, 3H; =CH);
13C NMR (100 MHz, CDCl3): d=18.9 (q), 50.6 (t), 50.7 (t), 151.3 (d),
157.7 ppm (s); IR (film): n˜ =2980 (m), 1610 (m), 1399 (m), 1017 cmꢀ1 (s,
S=O); MS (EI, 258C): m/z (%): 164 (80) [M+], 136 (74), 108 (80), 87
Chem. Eur. J. 2008, 14, 4631 – 4639
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4637

J. Podlech, W. Klopper et al.
CH2), 2.58–2.61 (m, 2H; CH2), 3.58 (dddd, 2J=13.7 Hz, 3J=4.1 Hz, 3J=
1.4 Hz, 5J=1.0 Hz, 1H), 3.65 (ddd, 3J=13.8 Hz, 2J=13.5 Hz, 3J=4.1 Hz,
1H), 3.75 (ddd, 2J=13.5 Hz, 3J=4.3 Hz, 3J=1.4 Hz, 1H), 3.85 (ddd, 3J=
13.8 Hz, 2J=13.7 Hz, 3J=4.3 Hz, 1H), 4.58 (d, 3J=13.6 Hz, 1H; CH),
4.11 (d, 3J=13.6 Hz, 1H; CH), 7.28–7.30, 7.40–7.48 ppm (2 m, 5H; Ph);
1H NMR (500 MHz, CDCl3, minor isomer, selected data): d=4.08 (d,
3J=13.4 Hz, 1H), 4.49 ppm (d, 3J=13.3 Hz, 1H); 13C NMR (125 MHz,
CDCl3, major isomer): d=24.3 (t), 26.3 (t), 49.6 (t), 50.3 (bt), 51.2 (t),
95.9 (d), 128.6 (d), 129.2 (d), 130.7 (d), 132.6 ppm (s); IR (DRIFT): n˜ =
2935 (m), 1028 cmꢀ1 (s, S=O); MS (FAB): m/z (%): 312 (100) [M+];
HRMS (FAB) calcd for C15H22NO2S2: 312.1092, found: 312.1098; elemen-
tal analysis calcd (%) for C15H21NO2S2: C 57.84, H 6.80, N 4.50; found: C
57.46, H 6.84, N 4.54.
105 (100) [C7H5O+], 77 (50), 57 (14), 43 (14); HRMS (EI) calcd for
C13H16O3S2: 284.0541, found 284.0535; elemental analysis calcd (%) for
C13H16O3S2: C 54.90, H 5.67; found C 54.68, H 5.74.
Acknowledgements
We are deeply indebted to Dr. Wolfgang U. Frey (University of Stuttgart)
for the X-ray crystal structure analyses. We thank Prof. Dr. E. Juaristi
(Mexico) for inspiring discussions and Pia Lang for her help in measuring
activation barriers with NMR spectrosocpy. This work was supported by
the Deutsche Forschungsgemeinschaft, in part through the Center for
Functional Nanostructures (CFN, Project No. C3.3). It has been further
supported by a grant from the Ministry of Science, Research and the
Arts of Baden-Württemberg (Az: 7713.14–300).
Dimethyl (1’R,1’’R,3’’R)-2-[(1,3-Dioxo-1,3-dithiolan-2-yl)phenylmethyl]-
malonate (21): Dimethyl malonate (228 mL, 264 mg, 2.00 mmol) was
added at 08C to a slurry of NaH (suspension in mineral oil, 60%,
80.0 mg, 2.00 mmol) in THF (5 mL) and the mixture was stirred for 1 h
at 08C, cooled to ꢀ788C and transferred via a cannula to a pre-cooled
solution of 3a (113 mg, 1.00 mmol) in THF (10 mL). The reaction was
quenched after 5 min with MeOH (ꢂ0.5 mL) and the mixture was
poured into a saturated aqueous NH4Cl solution, extracted with ethyl
acetate (2”20 mL) and CH2Cl2 (2”20 mL), and dried (Na2SO4, K2CO3).
After removal of the solvents in vacuo the diastereomeric ratio was de-
termined to be 94:6 (1H NMR, integration of the signals for 2’’-H). The
residue was purified by MPLC on SiO2 (CH2Cl2/MeOH 50:1) to yield a
mixture of isomers 20 (164 mg, 0.458 mmol, 92%) as a colorless solid:
Major isomer 21a: Rf =0.26 (CH2Cl2/acetone 2:1); 1H NMR (400 MHz,
CDCl3): d=3.48–3.53 (m, 2H; 4-H2 or 5-H2), 3.65 (s, 3H; Me), 3.70 (s,
3H; Me), 3.79–3.86 (m, 2H; 4-H2 or 5-H2), 4.12 (dd, 3J=10.1 Hz, 3J=
5.8 Hz, 1H; 1’-H), 4.20 (d, 3J=5.8 Hz, 1H; 2-H), 4.68 (d, 3J=10.1 Hz,
1H; 2’’-H), 7.30–7.39, 7.42–7.45 ppm (2 m, 5H; Ph); 13C NMR (100 MHz,
CDCl3): d=40.1 (d), 50.7 (t), 52.1 (t), 52.8 (q), 52.9 (q), 55.1 (d), 94.7 (d),
128.7 (d), 128.9 (d), 129.3 (d), 136.6 (s), 167.6 (s), 167.7 ppm (s); IR
(DRIFT): n˜ =1749 (s, C=O), 1438 (m), 1154 (m), 1030 cmꢀ1 (s, S=O); MS
(EI, 1608C): m/z (%): 358 (13) [M+], 327 (13), 326 (19), 298 (28), 234
(33), 233 (32), 232 (24), 222 (100), 218 (26), 205 (21), 202 (27), 198 (13),
190 (13), 189 (10), 175 (44), 173 (32), 163 (19), 162 (64), 135 (12), 134
(47), 131 (17), 121 (28), 116 (10), 115 (43), 108 (89), 43 (14); HRMS (EI)
calcd for C15H18O6S2: 358.0544, found: 358.0540; Elemental analysis calcd
(%) for C15H18O6S2: C 50.26, H 5.06; found: C 50.30, H 5.21. Minor
[1] I. Fleming, Frontier orbitals and organic chemical reactions, Wiley,
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[4] a) M. Mikołajczyk, J. Drabowicz, P. Kiełbasinski, Chiral Sulfur Re-
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[6] T. Wedel, J. Podlech, Synlett 2006, 2043–2046.
[7] Color figures are given in the Supporting Information.
[8] a) G. H. Posner in Asymmetric Synthesis, Stereodifferentiating Addi-
tion Reactions, Part A, (Ed.: J. D. Morrison) Vol. 2, Academic Press,
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1986, 42, 2919–2929.
[9] a) V. K. Aggarwal, J. Drabowicz, R. S. Grainger, Z. Gültekin, M.
Lightowler, P. L. Spargo, J. Org. Chem. 1995, 60, 4962–4963;
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Spargo, J. Chem. Soc. Perkin Trans. 1 1998, 2771–2781; c) V. K. Ag-
garwal, J. K. Barrell, J. M. Worrall, R. Alexander, J. Org. Chem.
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P. Goddard, C. Gomez, L. Fensterbank, M. Malacria, Synlett 2006,
713–716.
1
3
isomer 21b, selected data: H NMR (400 MHz, CDCl3): d=4.58 (dd, J=
4
11.9 Hz, J=1.4 Hz, 1H; 2“-H) ppm.
(3R,1’R,3’R)-3-(1,3-Dioxo-1,3-dithiolan-2-yl)-1-phenylbutan-1-one (22):
NaHMDS (2m in hexane, 600 mL, 1.20 mmol) was added at ꢀ788C to a
solution of acetophenone (168 mg, 1.40 mmol) in THF (10 mL). After
stirring for 45 min, this solution was transferred via a cannula to a pre-
cooled (ꢀ788C) solution of 3b (164 mg, 1 mmol) in THF (15 mL per
mmol). The reaction was quenched after 10 min with MeOH (ca. 0.5 mL)
and the mixture was added to a saturated aqueous NH4Cl solution
(20 mL per mmol), extracted with EtOAc (2”20 mL) and CH2Cl2 (2”
20 mL), and dried (Na2SO4, K2CO3). The solvents were removed in
vacuo. The diastereomeric ratio was determined by 1H NMR spectrosco-
py (d.r. 55:45, integration of the signals of the S,S-acetalic hydrogens).
The remnant was separated and purified by MPLC (SiO2, CH2Cl2/MeOH
50:1) afforded 22 (231 mg, 0.812 mmol, 81%) as a non-separable mixture
of isomers: Rf =0.26 (CH2Cl2/acetone 2:1); 1H NMR (400 MHz, CDCl3,
mixture of isomers): d=1.41 (d, 3J=6.6 Hz, 3H; 4-H3, major), 1.49 (d,
3J=6.8 Hz, 3H; 4-H3, minor), 2.99–3.17 (m, 2H; 3-H, both), 3.26 (dd,
[12] a) F. Brebion, M. Vitale, L. Fensterbank, M. Malacria, Tetrahedron:
Asymmetry 2003, 14, 2889–2896; b) B. DelouvriØ, F. Nµjera, L. Fen-
sterbank, M. Malacria, J. Organomet. Chem. 2002, 643–644, 130–
135.
3
2
3
2J=17.0 Hz, J=7.6 Hz, 1H; 2-CHaHb, minor), 3.29 (dd, J=17.4 Hz, J=
7.8 Hz, 1H; 2-CHaHb, major), 3.46 (dd, 2J=17.0 Hz, 3J=4.6 Hz, 1H; 2-
HaHb, minor), 3.64 (dd, 2J=17.4 Hz, 3J=4.0 Hz, 1H; 2-HaHb, major),
3.63–3.86 (m, 9H; 4’-H2, 5’-H2, both, 2’-H, major), 3.95 (dd, 3J=8.8 Hz,
4J=1.1 Hz, 1H; 2’-H, minor), 7.46–7.51, 7.57–7.61, 7.97–7.10 ppm (3 m,
5H; Ph, both); 13C NMR (100 MHz, CDCl3, mixture of isomers): d=19.3
(q), 20.4 (q), 26.7 (d), 27.5 (d), 43.5 (t), 43.7 (t), 51.3 (t), 51.45 (t), 51.54
(t), 97.6 (d), 97.9 (d), 128.1 (d), 128.2 (d), 128.7 (d), 128.7 (d), 133.5 (d),
136.5 (s), 136.6 (s), 197.4 (s) 197.6 ppm (s); IR (DRIFT): n˜ =2078 (m),
1681 (s, C=O), 1447 (m), 1223 (m), 1029 cmꢀ1 (s, S=O); MS (EI, 1608C):
m/z (%): 284 (3) [M+], 267 (11), 159 (18), 148 (10), 145 (10), 108 (45),
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ꢀ
[14] We revealed stereoelectronic effects of sulfoxides by measuring C
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4638
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4631 – 4639

Nucleophilic Additions
FULL PAPER
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ꢀ
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Received: November 23, 2007
Published online: March 28, 2008
Chem. Eur. J. 2008, 14, 4631 – 4639
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4639