Influence of an ortho-sulfinyl group on the configurational stability of α-lithiated aryloxiranes: deuteration of tolylsulfinyl styrene oxides

Article abstract of DOI:10.1016/j.tet.2008.10.021

The influence of the p-tolylsulfinyl group, located at ortho-, meta-, and para-position, on the regio- and stereoselectivity of the deuteration reactions of substituted styrene oxides has been investigated. The sulfinyl group at an ortho-position reduces

Full text of DOI:10.1016/j.tet.2008.10.021

Tetrahedron 65 (2009) 383–388
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Influence of an ortho-sulfinyl group on the configurational stability of
a-lithiated
aryloxiranes: deuteration of tolylsulfinyl styrene oxides
,
a
a
a
Vito Capriati a, Saverio Florio a , Renzo Luisi , Antonio Salomone , Maria Giovanna Tocco ,
*
b
b,
b
*
´
´
´
Ana M. Martın Castro , Jose Luis Garcıa Ruano , Esther Torrente
a
`
Dipartimento Farmaco-Chimico, Universita di Bari, Consorzio Interuniversitario Nazionale Metodologie e Processi Innovativi di Sintesi C.I.N.M.P.I.S,
Via Edoardo Orabona 4, I-70125 Bari, Italy
b
´
`
Departamento de Qu´ımica Organica (C-I), Universidad Autonoma, Cantoblanco, 28049 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The influence of the p-tolylsulfinyl group, located at ortho-, meta-, and para-position, on the regio- and
Received 1 August 2008
Received in revised form
19 September 2008
Accepted 9 October 2008
Available online 14 October 2008
stereoselectivity of the deuteration reactions of substituted styrene oxides has been investigated. The
sulfinyl group at an ortho-position reduces the configurational stability of
a-lithiated styrene oxides,
whereas meta- and para-sulfinyl derivatives completely control the regioselectivity only yielding deu-
terated products at the aromatic ring due to its strong ortho-director effect.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Lithiation
Phenyl sulfinyl styrene oxide
Configurational stability
1. Introduction
illustrating the influence of the sulfinyl group on the configura-
tional stability of a-lithiated aryloxiranes.
It is well-known that
a-lithiated aryloxiranes (obtained by
lithiation of styrene oxides) are configurationally stable in-
termediates,1 whose reactions with electrophiles take place with
complete retention of configuration at the benzylic carbon. How-
ever, reactions with prochiral electrophiles, such as aldehydes, af-
ford mixtures of epimers at the hydroxylic carbon,2 thus limiting
the scope of the use of these carbanions in asymmetric synthesis.
The high efficiency of the ortho-sulfinyl group in the stereo-
selectivity control of the reactions of benzylic carbanions with
electrophiles is also well documented.3 More precisely, the
reactions of ortho-sulfinyl benzyl carbanions with prochiral elec-
trophiles, such as imines4 or aldehydes,5 proceeded with high
levels of stereoselectivity. This fact suggested that the presence of
2. Results and discussion
Diastereoisomeric 2-p-tolylsulfinyl styrene oxides (S,Ss)-2a and
(R,Ss)-3a were prepared by the reaction of optically active (S)-2-p-
tolylsulfinyl benzaldehyde 16a,b with dimethylsulfonium methylide
in DMSO (Corey–Chaykovsky’s epoxidation)6c at room temperature
(10 min) (80% yield, dr 2a/3a: 56/44) (Scheme 1). Although better
dr values (66/34 and 71/29) were obtained when reactions were
conducted in DMSO/THF at lower temperatures (0 or ꢀ40 ꢁC, re-
spectively) for longer reaction times (2 or 10 h), the yields were also
lower (49–68%, see Section 4). Diastereoisomer 2a could be isolated
from the mixture of 2a and 3a in 92% de by crystallization (Et2O/
hexane). The absolute configuration of 2a was proved to be S,Ss by
desulfinylation with n-BuLi (50% yield) and comparison of the
resulting styrene oxide with commercially available (S)-styrene
oxide (Scheme 1).
a sulfinyl group at the ortho-position of
a-lithiated aryloxiranes
could enhance the stereoselectivity of their reactions with prochiral
electrophiles. As the first step of this research we describe herein
the synthesis of optically pure 2-p-tolylsulfinyl styrene oxides and
the results obtained in their lithiation/deuteration sequences,
The synthesis of optically pure (R,Ss)-2-p-tolylsulfinyl styrene
oxide 3a was achieved when (R)-2-bromostyrene oxide 4 (obtained
by hydrolytic kinetic resolution7 of racemic 2-bromostyrene oxide8
(ꢂ)-4 using an R,R-salen cobalt complex) was successively
subjected to bromine–lithium exchange with t-BuLi/THF and sul-
finylated with (S)-(ꢀ)-menthyl-p-toluenesulfinate (48% yield, dr
98/2) (Scheme 2).
* Corresponding authors. Tel.: þ39 080 5442749; fax: þ39 080 5442539 (S.F.).
Tel.: þ34 914974701; fax: þ34 914973966 (J.L.G.R.).
E-mail addresses: florio@farmchim.uniba.it (S. Florio), joseluis.garcia.ruano@
´
uam.es (J.L. Garcıa Ruano).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.021

384
V. Capriati et al. / Tetrahedron 65 (2009) 383–388
Table 1
Deprotonation/reprotonation of 2a/3a mixtures with LDA/MeOH
O
O
H
H
LDA, time
(S)
(R)
+
O
O
THF, –98 °C
S
S
Tolyl
Tolyl
2a
3a
O
O
Li
Li
MeOH
(R)
(S)
2a+3a
O
O
S
S
Tolyl
Tolyl
(S,SS)-2a-Li
(R,SS)-3a-Li
Scheme 1.
dr 2a/3a before
Time (min)
dr 2a/3a after
deprotonationa,b
reprotonationa,c
86/14
56/44
56/44
37/63
10
10
30
30
76/24
76/24
76/24
76/24
HKR
O
(R,R)-(Salen)-Co·OAc
H
0.55 eq H2O
30 %
a
Calculated by 1H NMR of the crude reaction mixture.
Br
( )-4
b
c
Starting value of dr for different reaction mixtures before deprotonation.
Final value of dr after reprotonation.
pure (R,Ss)-3a (dr 96/4, er>98/2) and (S,Ss)-2a (dr 98/2, er>98/2),
the same final ratio [dr (S,Ss)-2a/(R,Ss)-3a about 70/30] was
obtained regardless of the reaction times (entries 3, 4, and 6, Table
3), thus suggesting a relatively fast deprotonation reaction. The
extent of the deuteration in the final products seems to be time-
dependent. However, looking at the deuterium incorporated into
(S,Ss)-2a-D and (R,Ss)-3a-D, it can be seen that their ratios are
opposite to those observed in the final mixtures; specifically,
diastereoisomer (R,Ss)-3a is deuterated to a further extent than
O
O
1) t-BuLi/THF
H
H
2) (–)-menthyl-(S)-
p-toluenesulfinate
48%
(R)
(R)
O
Br
S
Tolyl
(R)-4
ee > 98 %
(R,SS)-3a
ee > 98 %
Scheme 2.
Table 2
With epoxides 2a and 3a in hand we investigated their lith-
Lithiation/deuteration sequence of mixtures of (S,Ss)-2a and (R,Ss)-3a
iation. A deprotonation/reprotonation sequence, run on different
diastereoisomeric mixtures [dr (S,Ss)-2a/(R,Ss)-3a¼37/63–86/14]
with LDA/THF showed that, after acidic quenching, the final mix-
tures had the same composition [dr (S,Ss)-2a/(R,Ss)-3a¼76/24] re-
gardless of the composition of the starting mixture (see Table 1).
This result suggests that an epimerization probably occurs
during the lithiation step. There are two possible sites where the
epimerization might occur: the benzylic stereocenter of the epox-
ide and the sulfur atom. Both hypotheses should be demonstrated
1) base, time
THF, –98 °C
2) MeOD
(S,SS)-2a
(R,SS)-3a
+
O
D
(S)
O
D
(R)
+
O
O
S
S
Tolyl
Tolyl
because precedent reports showed that either a-lithiated styrene
(R,SS)-3a-D
(S,SS)-2a-D
oxide2 or chiral sulfoxides3 is configurationally stable under the
reaction conditions which had been used. In order to prove that
a
-lithiation actually takes place with LDA, the deprotonation/deu-
Entry Base
dr 2a/3a before T (min) D%b dr 2a/3a after dr 2a-D/3a-Da
deprotonation
teration sequence was investigated using several diastereoisomeric
mixtures of varied composition and quenching the reaction mix-
ture with MeOD (Table 2).
the reactiona,c
1
2
3b
4
5
6
7
8
LDA
LDA
LDA
LDA
LDA
LDA
65/35
65/35
4/96
15
60
60
5
50
21
20
11
30
38
56
50
70/30
76/24
80/20
79/21
70/30
70/30
60/40
73/27
39/61
32/68
40/60
34/66
25/75
33/67
46/54
47/53
Here again, regardless of the diastereoisomeric composition of
the starting mixture, almost the same final ratio [dr (S,Ss)-2a/(R,Ss)-
3a¼70/30–80/20] was obtained (entries 1–6, Table 2). Interestingly,
by 1H NMR spectroscopy it could be seen that the deuterium was
incorporated at the benzylic position of the epoxide.9 From the
results collected in Table 2 some remarkable comments can be done
considering the reaction time, the composition of the starting di-
astereoisomeric mixture, the extent of the deuteration, and the
ratio of the deuterated epoxides. Starting from almost optically
4/96
50/50d
98/2
5
15
15
60
LTMP 50/50
LTMP 4/96
a
Calculated by 1H NMR of the crude reaction mixture.
b
c
Calculated by MS-ESI or 1H NMR spectra of the crude reaction mixture.
This ratio takes into consideration the contribution deriving from deuteration.
0.55 equiv of LDA were used.
d

V. Capriati et al. / Tetrahedron 65 (2009) 383–388
385
Table 3
Lithiation of (S,Ss)-2a and (R,Ss)-3a in the presence of excess [N-D1]DIPA
(S,SS)-2a + (R,SS)-3a
+ LDA + [N-D1]DIPA
(S,SS)-2a-Li
+ [N-H]DIPA + [N-D1]DIPA
(R,SS)-3a-Li
(S,SS)-2a-D + (R,SS)-3a-D
[N-H]DIPA + LDA
MeOH
(S,SS)-2a + (R,SS)-3a
Entry
BuLi (equiv)a
[N-D1]DIPA
dr 2a/3a before
deprotonation
D %b
dr 2a/3a after
dr 2a-D/3a-Db
(equiv)a
the reactionb,c
1
2
1.5
1.5
1.8
4.0
56/44
56/44
20
56
73/27
83/17
70/30
80/20
a
Equivalents to be referred to the starting mixture of epoxides (2aþ3a).
Calculated by 1H NMR of the crude reaction mixture.
This ratio takes into consideration the contribution deriving from deuteration.
b
c
(S,Ss)-2a. By a HPLC analysis and by comparison with a racemic
mixture of 2a and 3a, it was also demonstrated that the change of
diastereoisomeric ratio did not affect the enantiomeric ratio of the
diastereoisomers so proving that the sulfur atom did not undergo
any loss of configurational integrity. Therefore, it may be concluded
that the above epimerization does not involve the sulfur stereo-
center; instead, it has to be ascribed to the lithiation at the benzylic
center of the epoxide. This means that the latter is configurationally
unstable under the conditions used and two equilibrating di-
astereoisomeric lithiated intermediates (S,Ss)-2a-Li and (R,Ss)-3a-
Li (see Table 1) should be present in the reaction mixture. More-
over, from the deuteration experiments, it is also evident that the
final ratio of (S,Ss)-2a-D/(R,Ss)-3a-D could be correlated to the ratio
of the rapidly equilibrating lithiated species and the different and
opposite ratio of (S,Ss)-2a/(R,Ss)-3a in the final mixtures suggests
that an equilibrium between the starting epoxide and the lithiated
intermediate, in the presence of LDA, may be playing a role (Eq. 1).
tetramethylpiperidide (LTMP) (pKa TMP¼37.3 in THF)11 comparable
results were obtained (entries 7 and 8, Table 2): indeed, lithiation of
different mixtures of (S,Ss)-2a and (R,Ss)-3a followed by deutera-
tion with MeOD furnished a similar ratio for the final epoxides
(S,Ss)-2a/(R,Ss)-3a, the epoxide (S,Ss)-2a still being the main
product. On the other hand, the (S,Ss)-2a-D/(R,Ss)-3a-D ratio was
slightly less shifted toward 3a-D. It is interesting to observe that in
the case of lithiation performed in the presence of an excess of [N-
D1]DIPA, 2a/3a and 2a-D/3a-D ratio are almost the same after
quenching of the reaction mixture with MeOH (entries 1 and 2,
Table 3). This is because, [N-D1]DIPA being the only deuterium
source, a hydrogen or a deuterium could be picked up with the
same probability from [N-H]DIPA or [N-D1]DIPA, respectively, by
the equilibrating anions, 2a-Li and 3a-Li. However, as aggregation
undoubtly plays a significant role on lithiation other than shifts and
basicities, until the association of these lithiated epoxides will be
well understood, the interpretation of the above equilibria must be
made with caution.
(S,SS)-2a + LDA
In order to confirm the influence of the sulfinyl group on the
configurational stability of the a-carbon of the styrene oxide, the
(R,SS)-3a-Li + DIPA
(S,SS)-2a-Li
ð1Þ
role of such a group at meta- and para-position has been in-
vestigated. The needed meta- and para-sulfinyl styrene oxides
were then prepared starting from 3- and 4-bromostyrenes, which
were oxidized to the corresponding oxides (90% yield, m-CPBA,
CH2Cl2). 3-Bromostyrene oxide (ꢂ)-57a was subjected to hydrolytic
kinetic resolution [HKR, (R,R)-(Salen)-Co$OAc] to give (R)-3-bro-
mostyrene oxide (R)-5 (31% yield, ee 96%), which was successively
treated first with t-BuLi and then with (S)-(ꢀ)-menthyl-p-tolue-
nesulfinate leading to the formation of (R,Ss)-2-[3-(p-tolyl)sulfi-
nyl]styrene oxide 6 [40% overall yield, dr (R,Ss)-6/(R,Rs)-6¼70/30,
(R,Ss)-6 96% ee] (Scheme 3).12 Epoxide 6 was first treated with LDA
(1.5 equiv, THF, ꢀ98 ꢁC) and then with MeOD to furnish epoxide 6-
D (76% D, 96% ee), deuterated only at C-2 of the phenyl ring. No
(R,SS)-3a + LDA
To demonstrate such an equilibrium, a mixture of (S,Ss)-2a and
(R,Ss)-3a (dr¼56/44) was treated in two separate experiments with
1.5 equiv of LDA, prepared from 1.5 equiv of BuLi and either 1.8 or
4.0 equiv of [N-D1]diisopropylamine ([N-D1]DIPA,10 that is, with 0.3
and 2.5 excess [N-D1]DIPA, respectively (entries 1 and 2, Table 3)).
After quenching of the reaction mixture with MeOH, 1H NMR
spectroscopic analysis of the crude showed a conspicuous in-
corporation of deuterium (up to 56%, entry 2, Table 3) at the ben-
zylic position of epoxides 2a and 3a (whose relative ratio reflected
roughly those previously found, see Table 2) so supporting the
hypothesis that an equilibrium between ‘neutral’ and lithiated di-
astereoisomeric epoxides may be really under way.
Regardless of the aggregation states and complexation phe-
nomena, it is reasonable to assume that the pKa of the protons to be
removed in (S,Ss)-2a and (R,Ss)-3a are very close to the pKa of DIPA
(35.7 in THF)11 and that the final ratio (S,Ss)-2a/(R,Ss)-3a and the
different composition of the deuterated epoxides (S,Ss)-2a-D/
(R,Ss)-3a-D may be mainly the result of a difference of the ther-
modynamic acidity in the protonated species. That is, under the
above equilibrating conditions, should only the relative free ener-
gies of the reactants and products (which are the two di-
astereomeric epoxides 2a and 3a) be crucial in determining the
position of the equilibrium. (S,Ss)-2a is probably slightly less acidic
than (R,Ss)-3a, which is deprotonated faster, so giving a higher
concentration of (R,Ss)-3a-Li, which is finally trapped as (R,Ss)-3a-
D. Using the more basic and sterically demanding lithium
a-deuteration was observed. The complete regioselectivity ob-
served in this reaction can be explained by the ortho-directing
effect of the sulfinyl group and the oxiranic oxygen. The lithiation/
deuteration sequence of the diastereoisomeric mixture of 4-sul-
finyl styrene oxide (ꢂ)-8, prepared from racemic 4-bromostyrene
oxide (ꢂ)-7 upon Br–Li exchange followed by sulfinylation (40%),
was also studied. Lithiation (LDA, 30 min, ꢀ98 ꢁC or ꢀ78 ꢁC) of 8
followed by deuteration (MeOD) only produced deuterated epox-
ide 8-D (48% D at ꢀ98 ꢁC, 35% D at ꢀ78 ꢁC) as it is indicated in
Scheme 3. The complete regioselectivity observed in this reaction
is not unexpected on the basis of the strong ortho-directing effect
of the sulfinyl group.13
These results led us to conclude that the sulfinyl group affects
the stereochemistry of the
from the ortho-position. The ‘negative’ influence of the sulfinyl
group on the configurational stability of the -lithiated aryloxiranes
a-lithiation of styrene oxides exclusively
a

386
V. Capriati et al. / Tetrahedron 65 (2009) 383–388
O
O
H
O
H
O
H
HKR
H
1) LDA, THF
–98 °C
(R,R)-(Salen)-Co·OAc
1) t-BuLi/THF
(R)
(R)
(R)
0.55 eq. H2O
31%
2) (–)-menthyl-(S)-
p-toluenesulfinate
2) MeOD
D
O
O
Br
Br
S
S
40%
( )-5
(R)-5
Tolyl
Tolyl
(R,SS)-6 (96% ee)
(R,SS)-6-D
76% D, 96% ee
1) LDA, THF
O
O
H
O
H
–98 °C
H
1) t-BuLi/THF
D
2) MeOD
2) (–)-menthyl-(S)-
p-toluenesulfinate
Br
Tolyl
Tolyl
S
S
40%
( )-7
( )-8
( )-8-D
48% D
O
O
Scheme 3.
distribution analysis. Conformers were then grouped into families
on the basis of relevant torsion angle values. The best representa-
tive of each family was submitted to a PM3 semi-empirical geom-
etry optimization and, in order to introduce electron correlation in
the computation of the energetics, we performed, on the best
conformer of each analog, single-point calculations using the
density functional theory (DFT) at the B3LYP/6-311þG(df,p)//PM3
level of theory.15 Diastereoisomer (S,Ss)-2a resulted to be thermo-
dynamically more stable than (R,Ss)-3a of 1.9 kcal/mol.
In order to improve the stereoselectivity and simultaneously
support the previously indicated model, we prepared dimethylox-
iranes 11a and 12a, following the sequence depicted in Scheme 5.
The incorporation of two methyl groups at the oxirane ring might
affect the relative stability of their carbanions, 11a-Li and 12a-Li
(Scheme 4), and also that of 11a and 12a.
Compounds 11a and 12a were prepared as a 1/1 mixture by
epoxidation of 2-bromophenyl 1,1-dimethylethylene16 9 and sub-
sequent sulfinylation of 10 with (ꢀ)-menthyl-(S)-p-toluenesulfi-
nate. After their chromatographic separation, configurational
assignment was made by NMR spectroscopy (see Section 4). A 50/
50 mixture of 11a and 12a was treated with LDA in THF at ꢀ98 ꢁC
for 10 min (an intense dark brown color indicates the formation of
the carbanion) and then protonated with methanol at the same
temperature. The resulting product is formed by an 86/14 di-
astereoisomeric mixture of 11a and 12a. When pure 11a or 12a
were the starting materials, the composition of the reaction mix-
ture was identical, which indicated that equilibration of the carb-
anions was taking place. It is noteworthy that the relative
configuration of the major product 11a is identical to that of 3a
obtained as the minor product in the reaction on the non-meth-
ylated oxirane. Similarly, experiences of deuteration provided
analogous results. The deuteration degree was lower (20%) than for
2a or 3a. Starting from pure 11a or 12a, the non-deuterated com-
pounds also appeared as an 86/14 mixture of both. Similar ab initio
calculations, at the same DFT level as in the case of 2a and 3a,
demonstrated that (R,Ss)-11a is, in this case, thermodynamically
more stable than (S,Ss)-12a in about 0.8 kcal/mol.
Tolyl
R
Tolyl
R
S
S
O
O
(R)
(R)
H
Li
H
O
O
R
R
R = H: (R,SS)-3a-Li
R = Me: (R,SS)-11a-Li
R = H: (R,SS)-3a
R = Me: (R,SS)-11a
Tolyl
Tolyl
S
S
O
O
(S)
(S)
H
Li
H
O
O
R
R
R
R
R = H: (S,SS)-2a-Li
R = Me: (S,SS)-12a-Li
R = H: (S,SS)-2a
R = Me: (S,SS)-12a
Scheme 4.
2a-Li and 3a-Li (Scheme 4) could be explained by assuming that the
coordination of the sulfinyl oxygen to the lithium would lengthen
the C–Li bond in such a way to lower the inversion barrier so
promoting a quick equilibration between the above lithiated spe-
cies.14 Their protonation from the less hindered face afforded 2a
and 3a, respectively. The predominance of 2a in the reaction mix-
ture would suggest that its stability may be higher than that of 3a.
To verify this, preliminarily, equilibrium geometries were calcu-
lated for each diastereomer starting with a systematic conformer
H
H
O
O
O
m-CPBA
CH2Cl2
80%
1) PhLi/THF
+
2) (–)-methyl-(S)-
-p-toluensulfinate
60%
Br
O
Br
S
O
S
Tolyl
Tolyl
9
10
(R,SS)-11a
(S,SS)-12a
Scheme 5.

V. Capriati et al. / Tetrahedron 65 (2009) 383–388
387
3. Conclusion
4.2.2. Preparation of (R,Ss)-3a, (ꢂ)-8, and (R,Ss)-6: general
procedure
In conclusion, we have investigated the lithiation reaction of
sulfinyl-substituted styrene oxides revealing that, from the ortho-
position, the sulfinyl group causes epimerization at the benzylic
carbon of the epoxide. To the best of our knowledge, this should be
the first case in which an optically active styrene oxide undergoes
racemization upon lithiation, which can be rationalized by the in-
fluence of the sulfinyl group.
A solution of (R)-ortho-, (ꢂ)-meta- or (R)-para-bromostyrene
oxide (0.7 mmol, 140 mg) in THF (1 mL) was added to a stirred
precooled solution (ꢀ78 ꢁC, dry ice/acetone bath) of t-BuLi
(1.4 mmol, 750 mL of a 1.7 M solution in pentane) in THF (4 mL)
under Ar. After 15 min at this temperature, the resulting mixture
was added via cannula to a precooled (ꢀ78 ꢁC) solution of (S)-
(ꢀ)-menthyl-p-toluenesulfinate (1 mmol, 295 mg) and TMEDA
(1 mmol, 149 mL) in THF (4 mL) under Ar, stirred for an additional
time of 15 min, quenched with saturated aq NH4Cl, and extracted
with AcOEt (3ꢃ5 mL). The solvent was removed under reduced
pressure and the crude residue purified by flash chromatography
4. Experimental
4.1. General information
(silica gel; hexane/AcOEt 1/1). (R,Ss)-3a: 50% yield, colorless oil, dr
20
98/2, [
a
]
D
ꢀ189.6 (c 0.9, CHCl3); 1H NMR (500 MHz, CDCl3)
d 2.37
Tetrahydrofuran (THF) was freshly distilled under a nitrogen
atmosphere over sodium/benzophenone ketyl. Petroleum ether
refers to the 40–60 ꢁC boiling fraction. N,N,N0,N0-Tetramethylethy-
lenediamine (TMEDA) was distilled over finely powdered calcium
hydride. For the 1H and 13C NMR spectra (1H NMR 300, 400,
500 MHz; 13C NMR 75, 100, 125, 150 MHz), CDCl3 was used as the
solvent if not specified otherwise. MS-ESI analyses were performed
on LC/MSD trap system VL. Melting points were uncorrected. Op-
tical rotation was measured with a polarimeter using a cell of 1 dm
path length, the concentration (c) is expressed in g/100 mL. Enan-
tiomeric purity assay was ascertained by HPLC employing a Daicel
Chiralcel OD-H column (250ꢃ4.6 mm). Analytical thin layer chro-
matography (TLC) was carried out on precoated 0.25 mm thick
plates of Kieselgel 60 F254; visualization was accomplished by UV
light (254 nm) or by spraying a solution of 5% (w/v) ammonium
molybdate and 0.2% (w/v) cerium(III) sulfate in 100 mL 17.6% (w/v)
aq sulfuric acid and heating to 200 ꢁC for some time until blue spots
appear. All reactions involving air-sensitive reagents were per-
formed under argon in oven-dried glassware using syringe-septum
cap technique.
(s, 3H), 2.60 (dd, J¼2.9, 5.9 Hz, 1H), 3.04 (dd, J¼3.9, 5.9 Hz, 1H), 4.23
(dd, J¼2.9, 3.9 Hz, 1H), 7.26 (d, J¼7.9 Hz, 2H), 7.33 (d, J¼6.9 Hz, 1H),
7.44–7.48 (m, 2H), 7.50 (d, J¼7.9 Hz, 2H), 7.89 (d, J¼6.9 Hz, 1H); 13C
NMR (125 MHz)
d 21.3, 48.8, 51.8, 125.3, 125.4, 128.9, 130.0, 131.6,
136.2, 141.1, 141.6, 143.6; FTIR (neat): 3055, 2990, 1594, 1492, 1191,
1083, 986, 877 cmꢀ1; MS (ESI): 281 [MþNa]þ; HRMS (ESI) Calcd for
C15H15O2S: 259.0787. Found: 259.0792. (ꢂ)-8: 40% yield, oil, in-
separable mixture of diastereoisomers, dr 50/50; 1H NMR
(400 MHz, CDCl3)
d
2.23 (s, 3H), 2.69 (2ꢃdd, J¼2.6, 4.4 Hz, 1H), 3.10
(d, J¼2.6, 4.4 Hz, 1H), 3.83 (dd, J¼2.6, 4.0 Hz, 1H), 7.22 (d, J¼8.4 Hz,
2H), 7.32 (d, J¼8.4 Hz, 2H), 7.49 (d, J¼8.4 Hz, 2H), 7.58 (d, J¼8.4 Hz,
2H); 13C NMR (100 MHz)
d 21.3, 51.3, 51.6, 124.72, 124.74, 124.76,
124.8, 126.2, 129.9, 140.81, 140.82, 141.61, 141.64, 142.2, 145.5; FTIR
(neat): 3051, 2922, 1492, 1087, 1046, 877, 834, 810 cmꢀ1; MS (ESI):
281 [MþNa]þ. (R,Ss)-6 and (R,Rs)-6: 40% overall yield, colorless oil,
inseparable mixture of diastereoisomers by column chromatogra-
phy, dr 70/30 in favor of (R,Ss)-6 (evaluated by 13C NMR), 96% ee
(HPLC, Daicel Chiralcel OD-H column: n-hexane/i-PrOH 90/10, flow
1.0 mL/min [tR(R,Ss)¼21.0 min, tR(S,Ss)¼25.0 min); 1H NMR
(400 MHz, CDCl3) (major)
d
2.37 (s, 3H), 2.75 (dd, J¼2.2, 5.5 Hz, 1H),
3.14 (dd, J¼4.0, 5.5 Hz, 1H), 3.87 (dd, J¼2.2, 4.0 Hz, 1H), 7.26 (d,
J¼8.1 Hz, 2H), 7.32 (d, J¼7.3 Hz, 1H), 7.42 (t, J¼7.7 Hz, 1H), 7.52–7.54
4.2. Experimental procedures
(m, 3H), 7.59 (s, 1H); 13C NMR (150 MHz)
d 21.2, 51.2, 51.7, 121.4,
124.2, 124.8, 127.6, 129.2, 129.9, 139.3, 141.6, 142.1, 146.2; FTIR
(neat): 3052, 2922, 1597, 1493, 1476, 1088, 1047, 884, 811 cmꢀ1; MS
(ESI): 281 [MþNa]þ.
4.2.1. Preparation of diastereoisomeric mixture of 2a and 3a
A solution of (S)-2-p-tolylsulfinyl benzaldehyde 1 (244 mg,
1 mmol) in 1 mL of DMSO was slowly added to a stirred solution of
Me3SI (612 mg, 3 mmol) and NaH (60% oil dispersion, 120 mg,
3 mmol, previously washed three times with hexane) in DMSO
(3 mL) under Ar. After 10 min at room temperature, the resulting
mixture was diluted with 6 mL of water and extracted with AcOEt
(3ꢃ3 mL). The combined organic phases were washed with brine
(3ꢃ3 mL) and the solvent removed under reduced pressure. The
crude residue was purified by flash chromatography (silica gel;
hexane/AcOEt 1/1) to give 206 mg of sulfinyl styrene oxides 2aþ3a
(80% yield, dr 56/44). Employing a 1/1 DMSO/THF mixture at 0 or
ꢀ40 ꢁC, a dr 66/34 (68% overall yield) or 71/29 (49% overall yield) of
2a/3a was obtained, respectively. Compound 2a was separated
4.2.3. Preparation of (ꢂ)-10: general procedure
To
a
solution of 2-bromophenyl 1,1-dimethylethylene 913
(1.0 mmol, 210 mg) in 10 mL of anhydrous dichloromethane, cooled
at 0 ꢁC, was slowly added 70% m-CPBA (1.5 mmol, 365 mg) and the
reaction mixture was stirred overnight at room temperature. Then,
it was quenched with satd NaHSO3 (10 mL). The organic layer was
washed with satd NaHCO3 (10 mL) and the aqueous layers were
extracted with CH2Cl2 (3ꢃ15 mL). Collected organic layers were
dried over Na2SO4 and evaporated in vacuo. The residue was pu-
rified by flash chromatography (silica gel, hexane/AcOEt 6/1).
(ꢂ)-10: 86% yield, colorless oil; 1H NMR (300 MHz, CDCl3)
d 1.01 (s,
from a 56/44 diastereoisomeric mixture by crystallization (ether/
hexane, dr 2a/3a: 96/4). (S,Ss)-2a: 47% yield; waxy solid, [
3H), 1.54 (s, 3H), 3.86 (s, 1H), 7.17–7.12 (m, 1H), 7.31–7.28 (m, 2H),
20
a
]
7.52 (d, J¼8.0 Hz, 1H); 13C NMR (75 MHz)
d 18.2, 24.2, 61.1, 65.0,
D
ꢀ105.7 (c 1, CHCl3, 98% ee); 1H NMR (400 MHz, CDCl3)
d
2.36 (s, 3H),
122.1, 127.1, 128.4, 128.8, 131.8, 136.7. MS (ESI): 227 [MþH]þ; HRMS
2.38 (dd, J¼2.8, 5.5 Hz, 1H), 2.96 (dd, J¼4.0, 5.5 Hz, 1H), 4.18 (dd,
J¼2.8, 4.0 Hz, 1H), 7.24 (d, J¼8.1 Hz, 2H), 7.30 (dd, J¼1.5, 7.7 Hz, 1H),
7.43–7.54 (m, 2H), 7.48 (d, J¼8.1 Hz, 2H), 8.06 (dd, J¼1.5, 7.7 Hz,1H);
(ESI) Calcd for C10H12OBr: 227.0055. Found: 227.0066.
4.2.4. Preparation of (R,Ss)-11a and (S,Ss)-12a: general procedure
To a precooled solution (ꢀ78 ꢁC, dry ice/acetone bath) of ortho-
bromo 2,2-dimethylstyrene oxide 10 (1 mmol, 322 mg) in THF
13C NMR (100 MHz)
d 21.4, 48.2, 50.4, 124.2, 124.7, 125.8, 128.9,
130.0, 131.2, 135.7, 141.8, 141.9, 143.6; FTIR (KBr): 3055, 2990, 1594,
1492, 1191, 1083, 986, 877 cmꢀ1; MS (ESI): 281 [MþNa]þ; HRMS
(ESI) Calcd for C15H15O2S: 259.0787. Found: 259.0790.
Diastereoisomeric excess evaluated via HPLC on a Daicel Chiralcel
OD-H column: n-hexane/i-PrOH 60/40, flow 0.2 mL/min [tR(S,S-
2a)¼60.1 min, tR(R,S-3a)¼65.2 min].
(6 mL) was added a solution of PhLi (1.56 mmol, 870 mL of a solution
1.8 M in cyclohexane/ether). After 30 min at this temperature, the
resulting mixture was added via cannula to a precooled solution
(ꢀ78 ꢁC) of (S)-(ꢀ)-menthyl-p-toluenesulfinate (1 mmol, 295 mg)
in 4 mL of THF under Ar, stirred for an additional time of 15 min,

388
V. Capriati et al. / Tetrahedron 65 (2009) 383–388
quenched with saturated solution aq NH4Cl, and extracted with
CH2Cl2. The solvent was removed under reduced pressure and the
Applicazioni’ supported by the MIUR (Rome), by the University of
Bari, and by the Interuniversities Consortium CINMPIS.
crude residue was purified by flash chromatography (silica gel,
We thank DGITYC (Grant CTQ2006-06741/BQU) for financial
20
´
hexane/AcOEt 4/1). (R,Ss)-11a: 30% yield, colorless oil, [
1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
2.37 (m, 3H), 3.94 (s,1H), 7.26–7.22 (m, 2H), 7.36–7.32 (m,1H), 7.57–
7.43 (m, 4H), 8.12 (m, 1H); 13C NMR (75 MHz)
17.2, 21.4, 24.1, 61.6,
a
]
ꢀ71.1 (c
support. One of us (E.T.) thanks Ministerio de Educacion y Ciencia
D
´
d
0.53 (s, 3H), 1.26 (s, 3H),
(Spain) for a predoctoral fellowship, and the Universidad Autonoma
de Madrid for financial support of a predoctoral stay.
d
62.1, 124.1, 127.0, 127.1, 128.7, 129.9, 130.5, 134.3, 141.5, 142.2, 142.5.
FTIR (KBr): 3055, 2923, 1594, 1495, 1492, 1178, 1089, 916 cmꢀ1 MS
(ESI): 287 [MþH]þ; HRMS (ESI) Calcd for C17H19O2S: 287.1092.
References and notes
20
Found: 287.1100. (S,Ss)-12a: 30% yield, colorless oil, [
a
]
D
ꢀ23.5 (c
`
1. (a) Capriati, V.; Florio, S.; Luisi, R. Synlett 2005, 1359; (b) Chemla, F.; Vrancken, E.
1.2, CHCl3); 1H NMR (300 MHz, CDCl3)
2.37 (m, 3H), 3.84 (s, 1H), 7.28–7.22 (m, 2H), 7.55–7.42 (m, 4H),
7.67–7.64 (m, 1H), 7.94–7.91 (m, 1H); 13C NMR (75 MHz)
18.2, 21.3,
24.0, 61.2, 61.4, 124.8, 125.7, 127.5, 129.1, 129.9, 130.7, 135.2, 141.5,
142.3; FTIR (KBr): 3055, 2940,1594,1493,1178,1083, 916, 877 cmꢀ1
d 0.90 (s, 3H), 1.43 (s, 3H),
In The Chemistry of Organolithium Compounds; Rappoport, Z., Marek, I., Eds.;
John Wiley and Sons: New York, NY, 2004; Vol. 2, Chapter 18, p 1165; (c)
Capriati, V.; Florio, S.; Luisi, R. Chem. Rev. 2008, 108, 1918.
d
2. Capriati, V.; Florio, S.; Luisi, R.; Salomone, A. Org. Lett. 2002, 4, 2445.
´
˜
3. Garcıa Ruano, J. L.; Carreno, M. C.; Toledo, M. A.; Aguirre, J. M.; Aranda, M. T.;
.
Fischer, J. Angew. Chem., Int. Ed. 2000, 39, 2736.
´
´
´
4. (a) Garcıa Ruano, J. L.; Aleman, J.; Soriano, J. F. Org. Lett. 2003, 5, 677; (b) Garcıa
Ruano, J. L.; Alema´n, J. Org. Lett. 2003, 5, 4513; (c) Garcı´a Ruano, J. L.; Alema´n, J.;
Cid, M. B. Synthesis 2006, 687; (d) Arroyo, Y.; Meana, A.; Rodrı´guez, J. F.; Santos,
M.; Sanz-Tejedor, M. A.; Garcı´a Ruano, J. L. J. Org. Chem. 2005, 70, 3914; (e)
Arroyo, Y.; Rodrı´guez, J. F.; Santos, M.; Sanz-Tejedor, M. A.; Garcı´a Ruano, J. L.
HRMS (ESI) Calcd for C17H19O2S: 287.1092. Found: 287.1102.
The absolute configuration of the stereogenic center of oxiranes
11a and 12a was assigned by comparison with the chemical shift
(1H NMR and 13C NMR) of 2a and 3a on the signal corresponding to
the benzylic position (C–H).
´
´
J. Org. Chem. 2007, 72, 1035; (f) Garcıa Ruano, J. L.; Aleman, J.; Alonso, I.; Parra,
A.; Marcos, V.; Aguirre, J. Chem.dEur. J. 2007, 13, 6179.
´
5. Garcıa Ruano, J. L.; Aranda, M. T.; Aguirre, J. M. Tetrahedron 2004, 60, 5383.
6. (a) Lai, C.-Y.; Mak, E. Y.; Chan, Y.; Sau, Y.-K.; Zhang, Q.-F.; Lo, M. F.; Willians, I. D.;
Leung, W.-H. Inorg. Chem. 2003, 42, 5863; (b) Garcı´a Ruano, J. L.; Martı´n Castro,
4.2.5. Lithiation/deuteration reaction of 2a, 3a, 6, (ꢂ)-8, 11a, and
12a: general procedure
´
A. M.; Tato, F.; Cardenas, D. J. Tetrahedron: Asymmetry 2005, 16, 1963; (c) Corey,
A solution of sulfinyl styrene oxides 2a, 3a, 6, 8, 11a, or 12a
(0.2 mmol) in THF (1 mL) was added to a stirred solution of
0.3 mmol of LDA (generated by reaction of 1.8 equiv of DIPA and
1.5 equiv of n-BuLi 2.5 M in hexanes) in THF (3 mL) at ꢀ98 ꢁC (liquid
nitrogen/methanol bath) under Ar. After 10–60 min at this tem-
E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
7. (a) Jin, H.; Li, Z.; Dong, X.-W. Org. Biomol. Chem. 2004, 2, 408; (b) Schaus, S. E.;
Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 1307; (c) Keith, J. M.; Larrow, J. F.; Jacobsen, E.
N. Adv. Synth. Catal. 2001, 343, 5; (d) Brandes, B. D.; Jacobsen, E. N. Tetrahedron:
Asymmetry 1997, 8, 3927; (e) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen,
E. N. Science 1997, 277, 936.
8. Akgu¨ n, E.; Glinski, M. B.; Dhawan, K. L.; Durst, T. J. J. Org. Chem. 1981, 46, 1165.
9. As reported (see Ref. 2), for the lithiation of styrene oxide to occur, an orga-
nolithium such as s-BuLi was needed whereas LDA did not work.
10. [N-D1]DIPA was prepared as reported: Newcomb, M.; Reeder, R. J. Org. Chem.
1980, 45, 1489.
perature, the resulting mixture was quenched with 200 mL of
CH3OD, diluted with brine, and extracted with AcOEt (3ꢃ5 mL). The
solvent was removed under reduced pressure and the crude resi-
due purified by flash chromatography (silica gel, hexane/AcOEt 1/
20
20
1). (R)-5: [
a
]
D
ꢀ8.3 (c 1, CHCl3, 96% ee), lit. 7a; (S)-5: [
a]
þ4.0 (c
D
11. Fraser, R. R.; Bresse, M.; Mansour, T. S. J. Chem. Soc., Chem. Commun. 1983, 620.
12. Upon the treatment with t-BuLi/(S)-(ꢀ)-menthyl-p-toluenesulfinate, a partial
racemization at the sulfur atom occurred. However, epoxide (R,SS)-6 resulted to
be 96% enantiomerically enriched.
1.1, CHCl3, 35% ee,); (ꢂ)-5 separated on a Daicel Chiralcel column: n-
hexane/i-PrOH 99.5/0.5, flow 1.0 mL/min, tR[(R)-5]¼9.9 min, tR[(S)-
20
5]¼10.6 min. (R)-4: [
a
]
ꢀ62.5 (c 1, CHCl3, 96% ee), lit. 6a; (S)-4:
D
13. (a) Whisler, M. C.; NacNeil, S. L.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed.
20
[
a]
þ68.7 (c 1.1, CHCl3, 99% ee,); (ꢂ)-4 separated on a Daicel
D
´
2004, 43, 2206; (b) Le Fur, N.; Mojovic, L.; Ple, N.; Turck, A.; Reboul, V.; Metzner,
P. J. Org. Chem. 2006, 71, 2609.
Chiralcel column: n-hexane/i-PrOH 99.5/0.5, flow 1.0 mL/min,
tR[(R)-4]¼6.8 min, tR[(S)-4]¼7.2 min.
14. As far as the configurational inversion at the a-lithiated benzylic-type carbon
atom is concerned, an ion pair or a SE2-like rear-side attack of a lithium cation
or a ‘conveyer-belt’ delivery mechanism may be playing a role, as reported:
Schlosser, M. Organoalkali Chemistry In Organometallics in Synthesis: A Manual;
Schlosser, M., Ed.; Wiley & Sons: 2004; p 52.
Acknowledgements
15. All calculations were performed by SPARTAN, Version 07; Wavefunction: Irvine,
CA (USA), 2007.
16. Lin, M.-Y.; Das, A.; Liu, R.-S. J. Am. Chem. Soc. 2006, 128, 9340.
This work was carried out under the framework of the National
Project ‘Stereoselezione in Sintesi Organica: Metodologie ed