A study of factors affecting enantioselectivity in the oxidation of aryl benzyl sulfides in the presence of chiral titanium catalysts

Article abstract of DOI:10.1002/ejoc.201100310

A series of experiments was performed to test a theoretical model that we have recently proposed to explain the highly enantioselective oxidation of aryl benzyl sulfides with tert-butyl hydroperoxide in the presence of a complex between titanium and (S,S)

Full text of DOI:10.1002/ejoc.201100310

FULL PAPER
DOI: 10.1002/ejoc.201100310
A Study of Factors Affecting Enantioselectivity in the Oxidation of Aryl
Benzyl Sulfides in the Presence of Chiral Titanium Catalysts
Maria Annunziata M. Capozzi,[a] Caterina Centrone,[b][‡] Giuseppe Fracchiolla,[c]
Francesco Naso,[b][‡‡] and Cosimo Cardellicchio*[d]
Dedicated to Professor Saverio Florio in the occasion of his 70th birthday
Keywords: Oxidation / Titanium / Reaction mechanisms / Enantioselectivity / Circular dichroism
A series of experiments was performed to test a theoretical
model that we have recently proposed to explain the highly
enantioselective oxidation of aryl benzyl sulfides with tert-
butyl hydroperoxide in the presence of a complex between
titanium and (S,S)- or (R,R)-hydrobenzoin. The studied varia-
tions involved the sulfides, the ligands, and the order of ad-
dition of reactants. The reaction path predicted by our model
was confirmed in every experiment. In particular, aryl benzyl
sulfides behaved as the ideal substrate for this type of asym-
metric oxidation, which yields synthetically useful, enantio-
pure aryl benzyl sulfoxides in a straightforward manner.
not easily produced by other methods, through a straight-
forward displacement reaction with Grignard reagents.[9]
The most successful asymmetric oxidation reactions in-
volving sulfides[7,8] are based upon an achiral oxidant (hy-
droperoxides or hydrogen peroxide) in the presence of a chi-
ral metal catalyst. Among the various metal catalysts,[7,8]
titanium complexes play a special role. Indeed, since their
first use[10] they have become common and are also em-
ployed in industrial protocols.[7,8]
For many years, titanium catalyst chemistry in the oxi-
dation of sulfides has focused mainly on the synthetic as-
pects, whereas mechanistic investigations have seldom been
reported.[11–13] However, in 2009, three similar studies[6,14,15]
on titanium-catalyzed enantioselective oxidation of sulfides
were published, two of them[6,15] also considered theoretical
aspects.
Introduction
In the last half-century, enantiopure sulfoxides have been
employed as useful starting materials in many asymmetric
syntheses.[1–3] Some sulfoxides are very important on their
own right,[4] for instance, the anti-ulcer agent (S)-omepra-
zole.[5,6] Indeed, this drug is nowadays one of the best-sell-
ing drugs, and it is produced on a multi-ton-per-year
scale.[6] Among the various strategies that have been em-
ployed to produce optically active sulfoxides,[1–3] special
interest has focused on the enantioselective oxidation of sul-
fides,[7,8] in a procedure that is also preferentially employed
in the industrial synthesis of bioactive target molecules.[7,8]
Furthermore, in our previous work[9] we have shown that
the enantioselective oxidation is a valuable strategy for pre-
paring sulfoxides bearing carbanionic leaving groups; this
approach opens a route to many other sulfoxides that are
Szabó et al. examined the asymmetric synthesis of (S)-
omeprazole with tert-butyl hydroperoxide (TBHP), in the
presence of a titanium/tartrate complex.[6] It was pointed
out that, in contrast to Sharpless-like catalysts, the active
complex should contain a single titanium atom. Formation
of a similar complex was reported to be favored by the ad-
dition of water,[6] which is absent in the Sharpless enantiose-
lective epoxidation. When the investigation on the oxidation
was extended to small molecules that are structurally re-
lated to the omeprazole sulfide, such as alkyl imidazolyl
sulfides, high enantioselectivity (Ͼ94% ee) was frequently
observed.[6] In particular, the imidazole ring was found to
[a] Dipartimento di Scienze Agroambientali, Chimica e Difesa
Vegetale, Università di Foggia,
Via Napoli 25, 71100 Foggia, Italy
[b] Dipartimento di Chimica, Università di Bari,
Via Orabona 4, 70125 Bari, Italy
[c] Dipartimento Farmaco-Chimico, Università di Bari,
Via Orabona 4, 70125 Bari, Italy
[d] CNR ICCOM, Dipartimento di Chimica,
Via Orabona 4, 70125 Bari, Italy
Fax: +39-0805-539596
E-mail: cardellicchio@ba.iccom.cnr.it
[‡] Present address: CNR National Nanotechnology Laboratory,
Via Arnesano Km 5, 73100 Lecce, Italy
[‡‡]Present address: SYNCHIMIA srl c/o Dipartimento di
Chimica,
be a crucial feature for successful asymmetric synthesis.[6]
A
Via Orabona 4, 70125 Bari, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100310.
DFT calculation was performed on these small molecules
to outline a plausible mechanism, which was confirmed by
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C. Cardellicchio et al.
FULL PAPER
detection of the proposed reaction intermediates with reaction to the presence or absence of added
APCI- and ESI-MS. Both the calculation and the spectro- water[13,15,17–18] could be considered as further confirmation
metric measurements suggested that a titanium peroxo spe- that a catalyst based upon a single titanium atom is acting.
cies was formed first, which then reacted with the sulfide. Our model also predicts that the tetrahedral complex be-
This substrate coordinates to the titanium center through tween titanium and hydrobenzoin is approached first by the
one of the nitrogen atoms of the imidazole moiety.[6]
sulfide, and then by the oxidant, thus yielding an octahedral
A synthetic work on the molecules mentioned above was titanium complex.
reported by Jiang et al.,[14] in which omeprazole sulfide and
The reaction paths leading to the (R)- or to the (S)-sulf-
other similar 1H-benzimidazolyl pyridinylmethyl sulfides oxide were calculated, assuming that the (S,S)-hydroben-
were oxidized with TBHP in the presence of a complex be- zoin was used as a ligand of the metal. The octahedral com-
tween titanium and hydrobenzoin, or hydrobenzoin-like di- plex leading to the (R)-sulfoxide was found to be more
ols, which are easily available chiral auxiliaries in asymmet- stable than its counterpart, and thus it should be formed
ric synthesis.[16] Enantiopure (S)-omeprazole was obtained preferentially. The detailed reaction path was described in
when (1R,2R)-1,2-bis(2-bromophenyl)ethane-1,2-diol was our previous paper.[15] For the sake of brevity, it will suffice
used as a ligand of the titanium.[14]
to report here (Figure 1) a simplified form of the pro-(R)-
Our contribution to the same topic was represented by a octahedral complex before the oxygen transfer from the hy-
combined theoretical and experimental investigation[15] of droperoxide to the sulfide. First, strong hydrogen bonding
the highly enantioselective TBHP oxidation of aryl benzyl was found between the acidic hydrogen atom of the TBHP
sulfides in the presence of a complex between titanium and and one oxygen atom of a hydrobenzoin molecule. This in-
hydrobenzoin.[16] In the contribution, we described our teraction assists the deprotonation of the oxidant.[15]
most recent research on the application of this oxidation
protocol.[13,15,17,18] In the experiments performed, we oxid-
ized many aryl benzyl sulfides, in which different substitu-
ents were present on both phenyl rings.[15] We found that
high enantiomeric purities (95Ǟ98% ee), with only some
exceptions for which slightly lower enantioselectivities (81–
88% ee) were obtained, were achieved, regardless of the na-
ture and the position of the substituents.[15]
From a theoretical point of view, the oxidation of the
prototypal benzyl phenyl sulfide was investigated with DFT
MPWB1K functionals.[15] The calculated reaction profile
explained the high enantioselectivity of the reaction by de-
Figure 1. A simplified form of the pro-(R) titanium complex before
oxygen transfer from the hydroperoxide to the sulfide.
scribing the stabilizing interactions of the various molecular
aggregates.[15] For example, weak π interactions[19] were
Furthermore, a CH-π interaction, which is a type of in-
found to play a crucial role because no atom capable of
binding to the titanium center, such as nitrogen or oxygen,
is present in the starting sulfide. High computational power
was necessary to calculate these interactions. In this respect,
our model was the first example of an investigation into the
enantioselectivity of an asymmetric oxidation of sulfides
performed on the whole reacting molecular assembly. In
fact, taking into account the many theoretical calculations
performed on the asymmetric syntheses,[20,21] only a few[6,11]
were devoted to the study of titanium-catalyzed oxidation
of sulfides, and these studies were only carried out on a
simplified form of the reaction.
teraction that is also of increasing interest in recent works
dealing with crystal engineering[22–24] and in asymmetric
synthesis,[25–26] was found between a hydrogen of one hy-
drobenzoin and the phenyl group (Figure 1). Other weaker
interactions involving the π aryl group are present in the
rear part of the complete structure, as indicated in Fig-
ure 1.[15] The absence of these stabilizing interactions in the
octahedral complex leading to the other enantiomer of the
sulfoxide accounted for the higher stability of the pro-(R)
molecular intermediate and, thus, for the prevalent forma-
tion of the (R)-sulfoxide.[15]
To achieve a higher degree of confidence in our theoreti-
cal model, we planned a series of experiments that are de-
scribed below. In contrast to our previous works, we used
n-hexane as reaction solvent because it is more environmen-
tally benign than carbon tetrachloride, although the latter
would ensure higher yields.[13,17–18] The configurations of
the synthesized sulfoxides were established with the aid of
CD spectra.
Here, we wish to report the results of experiments that
were performed to test the theoretical model.
Results and Discussion
Since 2002, on the basis of the NMR spectra of the reac-
tion mixture, we had hypothesized[13] that a simple tetrahe-
dral complex between titanium and two molecules of the
ligand is formed in solution when titanium tetraisopropox-
ide and hydrobenzoin are mixed. Furthermore, also accord-
Enantioselective Oxidation of the Sulfides
Because the interactions involving the aryl π systems of
ing to the results of Szabò et al.,[6] the insensitivity of our the ligand and of the sulfide should play a crucial role in
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Oxidation of Aryl Benzyl Sulfides
our model, we decided to run the oxidation of benzyl p- two days at room temperature (Table 1, entry 2), we ob-
bromophenyl sulfide 1a[13] with TBHP in the presence of a served the formation of (R)-benzyl p-bromophenyl sulfox-
complex between titanium and commercially available ide (1b) with 91% ee in 58% isolated yield, together with
(R,R)-1,2-dicyclohexyl-1,2-ethanediol, which is a chiral diol sulfone 1c (25%). Furthermore, when the (R,R)-1,2-dicyclo-
similar to the hydrobenzoin in which the phenyl groups are hexyl-1,2-ethanediol was used as a ligand of the titanium,
substituted by the cyclohexyl rings. Thus, according to the sulfoxide 1b synthesized in this reaction had the (R)-config-
theoretical model, the enantioselection of the reaction uration, which is in contrast to the results obtained by using
should be different due to the absence of the aromatic moi- our procedure in which the (S)-sulfoxide was obtained when
ety. When our standard reaction conditions (room tempera- the (R,R)-hydrobenzoin was used as a ligand of the tita-
ture, two days reaction time) were employed, we observed nium. We interpret these results as suggesting that the use
the formation of large amounts of sulfone 1c,[13] which was of a ligand similar to the hydrobenzoin but void of aryl
not produced to such an extent when hydrobenzoin was groups, drives the reaction toward a different mechanism
used as a chiral ligand of the titanium.[13] The formation of that is characterized by a lower enantioselectivity, provided
this sulfone is a clear indication that a different mechanism that over-oxidation to the sulfone is inhibited. Actually, the
is operating when a cycloaliphatic diol is used. In fact, it is reaction would appear to be more similar to the hydroper-
known that in many enantioselective oxidation procedures[7] oxide oxidation of alkyl aryl sulfides reported by Imamoto
the same catalyst is able to over-oxidize the sulfoxide, which and Yamanoi,[28] in which a complex between titanium and
is produced with moderate enantioselectivity, to the sulfone. 2,2,5,5-tetramethyl-3,4-hexanediol, i.e., a 1,2-di-tert-butyl-
This kinetic resolution process may increase the final enan- 1,2-ethanediol, was used. With the (S,S)-form of this diol
tiomeric purity of the sulfoxide if the minor enantiomer is as a ligand of titanium, a kinetic resolution increased the
preferentially oxidized. Clearly, the final isolated yield of moderate ee values of the produced sulfoxide that presented
sulfoxide is reduced with respect to that obtained with a the (S)-configuration.[28]
highly enantioselective mono-oxidation process because
part of it is oxidized further to the sulfone.
In a further experiment, we used our standard system
[TBHP in the presence of a complex between titanium and
As reported in similar cases,[18,27] we then decided to (S,S)-hydrobenzoin] to oxidize aryl benzyl sulfides in which
measure the ee values of this reaction while inhibiting the bulky substituents (aryl groups or alkyl chains) are present
kinetic resolution step (Table 1, entry 1). This inhibition on the phenyl ring bound to the sulfur atom. Indeed, our
could be accomplished by lowering the temperature to 0 °C model requires that substituents located on this phenyl ring
and reducing the reaction time to 7 h.[18,27] Under these should not affect the enantioselectivity to a large extent be-
conditions, we observed the formation of sulfoxide 1b with cause there is enough space around the same ring for their
48% ee in 43% isolated yield. Sulfide 1a (54%) was reco- accommodation, even if they are bulky.
vered from the reaction mixture. On the other hand, when
We therefore synthesized sulfides 2a–4a in which a long
over-oxidation to the sulfone was allowed to continue for carbon chain (n-hexyl), an aryl moiety (p-tolyl), or a bulky
Table 1. Enantioselective oxidation of aryl sulfides by TBHP in the presence of a chiral titanium complex.
Entry
Sulfide
R
Ar
n
Ligand
T
Sulfoxide
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
1a
1a
2a
3a
4a
5a
6a
7a
7a
8a
9a
9a
10a
10a
4-Br
4-Br
4-n-Hex
4-pTol
4-tBu
2-tBu
4-Br
2-Br
2-Br
4-Br
4-Br
Ph
Ph
Ph
Ph
Ph
Ph
C6F5
C6F5
C6F5
Ph
Ph
Ph
Ph
Ph
1
1
1
1
1
1
1
1
1
0
2
2
3
3
(R,R)-DCY[c]
(R,R)-DCY[c]
(S,S)-HB[e]
(S,S)-HB[e]
(S,S)-HB[e]
(S,S)-HB[e]
(S,S)-HB[e]
(S,S)-HB[e]
(R,R)-HB[e]
(S,S)-HB[e]
(S,S)-HB[e]
(S,S)-HB[e]
(S,S)-HB[e]
(S,S)-HB[e]
0 °C[d]
r. t.
r. t.
r. t.
r. t.
r. t.
r. t.
r. t.
r. t.
(R)-1b
(R)-1b
(R)-2b
(R)-3b
(R)-4b
(R)-5b
(R)-6b
(R)-7b
(S)-7b
8b[f]
(R)-9b
(R)-9b
(R)-10b
(R)-10b
43
58
53
68
66
98
81
96
97
45
51
49
68
46
48
91
Ͼ98
Ͼ98
Ͼ98
94
Ͼ98
Ͼ98
Ͼ98
6
9
10
11
12
13
14
r. t.
0 °C[d]
r. t.
52
4-Br
4-Br
4-Br
90 (Ͼ98)[g]
62
0 °C[d]
r. t.
Ͼ98
[a] Isolated product. [b] Determined by HPLC. [c] DCY = 1,2-dicyclohexyl-1,2-ethanediol. [d] 7 h reaction time (see text). [e] HB =
hydrobenzoin. [f] Configuration not determined. [g] After crystallization.
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C. Cardellicchio et al.
FULL PAPER
substituent (tert-butyl) were used to replace the bromine sulfone was inhibited by performing the reaction at 0 °C for
atom of sulfide 1a in the para-position. When sulfides 2a– 7 h, (R)-10b was obtained with 62% ee (Table 1, entry 13).
4a were oxidized with our oxidation procedure, no decrease On the other hand, performing the reaction at room tem-
in the enantiomeric purity was observed and the usual perature for two days allowed the preparation of enantio-
enantiopure aryl benzyl sulfoxides 2b–4b with the (R)-con- pure (R)-10b with 46% yield (Table 1, entry 14).
figuration were obtained (Ͼ98% ee, Table 1, entries 3–5).
Summing up, the results of these experiments suggest
Only a slight decrease in the enantioselection (94% ee, that only the over-oxidation step is able to produce sulfox-
Table 1, entry 6) was observed in the oxidation of sulfide ides with high ee values (but with necessarily lower yields)
5a, in which the bulky tert-butyl group was placed in the when the optimal situation occurring in the benzyl structure
ortho-position of the phenyl moiety connected to the sulfur is changed either by increasing or decreasing the distance
atom to be oxidized. In summary, the results presented between the sulfur atom and the second phenyl ring.
above (Table 1, entries 3–6) fits well with our theoretical
model and are not compatible with a mechanism in which
the space around the phenyl ring plays a critical role as, for
instance, should occur for a mechanism in which the sulfide
enters into a catalytic hollow.
Enantioselective Oxidation of Sulfide 1a; Inverse Addition
Changing the order of addition of the reagents[5,6] with
In a further set of experiments, p-bromophenyl or o-bro- respect to the original procedures[10] is one of the experi-
mophenyl pentafluorophenyl sulfide 6a and 7a were used in mental modifications that have been reported to increase
our oxidation system to investigate whether the presence of the enantioselectivity in the synthesis of (S)-omeprazole.[5,6]
the fluorine atoms on the benzyl aryl group could alter the Other reactions also appear to be sensitive to variations in
enantioselectivity of the process. As a result, the usual high the order of addition of reagents. For instance, in the asym-
isolated yields (81–96%, Table 1, entries 7–8) were ob- metric addition of diethylzinc to benzaldeyde in the pres-
tained, and the produced sulfoxides (R)-6b and (R)-7b were ence of a chiral ligand, the reaction rate and the ee values
practically enantiopure (Ͼ98% ee). The oxidation of sulfide of the products differed significantly when the order of ad-
7a was repeated in the presence of a complex between tita- dition of reagents was changed.[29]
nium and (R,R)-hydrobenzoin. Sulfoxide 7b was obtained
with (S)-configuration (Table 1, entry 9).
In our standard procedure, the sulfide was added first
to the titanium/hydrobenzoin complex, and the addition of
In the final series of experiments (Table 1, entries 10–14), TBHP was made subsequently. The energetic profile that
the same oxidation procedure was used with aryl sulfides in was calculated in our theoretical model was based upon this
which the distance between the second phenyl group and sequence, which involves initial approach of the sulfide and
the sulfur atom is different, a situation that occurs in the then of the oxidant to the metal complex.
o-bromophenyl phenyl sulfide 8a (Table 1, entry 10), in p-
At this stage, we decided to drastically change our estab-
bromophenyl 2-phenylethyl sulfide 9a, or in p-bromophenyl lished protocol by performing reactions in which the oxi-
3-phenylpropyl sulfide 10a. In these molecules, no methyl- dant was added to the complex between titanium and (S,S)-
ene group (sulfide 8a), or two or three methylene groups, hydrobenzoin; the addition of the benzyl p-bromophenyl
respectively (sulfides 9a and 10a), separate the second sulfide 1a was then made at a later stage. Under these con-
phenyl group from the sulfur atom. According to our ditions, we observed the production of enantiopure sulfox-
model,[15] the oxidation of sulfides 8a–10a should have a ide (R)-1b after a two days reaction time, as observed in
lower enantioselectivity because only the aryl benzyl sul- the standard procedure, but we also observed the unusual
fides have the right distance to allow weak interactions to formation of a relatively large amount (20%) of the corre-
be operating in the molecular assemblies depicted in Fig- sponding sulfone 1c. A possible explanation for this result
ure 1.
is that the change in the sequence of mixing the reaction
The experimental results confirmed our hypothesis components leads to the formation of a different reacting
(Table 1, entries 10–14). Indeed, in the case of the oxidation species.
of o-bromophenyl phenyl sulfide 8a (Table 1, entry 10), the
To assess the validity of this hypothesis, the “inverse ad-
ee values dropped to 6%. In the oxidation of sulfides 9a dition” reaction was repeated and the amounts of sulfide
and 10a, we observed the formation of large amounts (25– 1a, (R)- and (S)-1b sulfoxides, and sulfone 1c were mea-
30%) of the corresponding sulfone. Thus, as reported in sured during reaction time, with special focus on the early
Table 1, entry 1, we decided to measure the enantio- stages of the process. The results are summarized in Table 2.
selectivities of these reactions without the over-oxidation by
After 15 min, a 16% yield of sulfoxide 1b with an ee
performing the reaction at 0 °C for 7 h. Under these condi- value of 63% was formed (Table 2, entry 1). This represents
tions, a value of 52% ee was measured for the formation of a significant difference with respect to the results obtained
sulfoxide (R)-9b (Table 1, entry 11). When the reaction was in other reactions in which high enantiomeric purity sulfox-
performed at room temperature for two days, sulfoxide (R)- ide 1b was present from the early stages of the reaction.[13]
9b was obtained with 90% ee in 49% yield (Table 1, entry Sulfone 1c was not detected in the reaction mixture after
12). This sulfoxide could be recrystallized to prepare 15 min but appeared only after 30 min (Table 2, entry 2).
enantiopure (R)-9b. The same sequence was repeated for The ee value increased moderately to 67 and 68% after 45
the oxidation of sulfide 10a. When the over-oxidation to and 60 min, respectively, with a simultaneous slight increase
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Oxidation of Aryl Benzyl Sulfides
Table 2. Percentage of sulfide 1a, sulfoxide 1b, and sulfone 1c in ferences were observed when electron-withdrawing groups
the enantioselective oxidation of sulfide 1a performed following the
or substituents in the ortho-position irrespective of their
inverse addition procedure.
electronic effect were present on the phenyl group.[32] How-
Entry Time
[min]
1a[a] 1b[a] 1c[a] ee[b]
(R)-1b[b] (S)-1b[b]
ever, by performing TDDFT calculations, we have been able
to make a full and fairly accurate prediction of all the CD
spectra of the (R)-aryl benzyl sulfoxides.[32] On the basis of
these predictions, and also taking into account all the re-
ported CD spectra of the (R)-alkyl aryl sulfoxides,[30–31] the
attribution of configuration of the aryl benzyl sulfoxides
and related molecules by CD spectra can now be considered
safe.
[c]
1
2
3
4
5
6
7
15
30
45
60
75
300
1740
84
78
70
60
53
23
8
16
20
27
36
41
59
72
–
2
3
4
63
63
67
68
76
Ͼ98
Ͼ98
13.0
16.3
22.5
30.2
36.0
59.0
72.0
3.0
3.7
4.5
5.8
5.0
6
[c]
18
20
–
[c]
–
In the present work, sulfoxides 2b–5b and 9b–10b show
the reported typical pattern, with the negative band in the
narrow interval 219–225 nm, and the positive band in the
interval 254–267 nm (see Figures 2, 3, and 4). Sulfoxides 2b,
4b, 9b, and 10b display the behavior expected for alkyl aryl
sulfoxides (Figure 2).
[a] Determined by HPLC and NMR analyses. [b] Determined by
HPLC analysis. [c] Not detectable.
in the amount of sulfone (Table 2, entries 3–4). The amount
of sulfoxide (S)-1b, an enantiomer that is not formed in
the standard procedure, reached its maximum after 60 min
(5.8%) and decreased subsequently (Table 2, entries 5–7)
until it disappeared from the reaction mixture after 5 h
(Table 2, entry 6). We are inclined to think that the disap-
pearance of (S)-1b sulfoxide from the reaction mixture is
due to a contemporary kinetic resolution process, as shown
by the formation of a relatively large amount of sulfone 1c
(18% after 5 h, Table 2, entry 6). In fact, once the (S)-iso-
mer had disappeared from the reaction mixture, only a
small increase in the amount of sulfone 1c (20%) was ob-
served after 29 h (Table 2, entry 7) and the expected (R)-
sulfoxide was the main product.
From these results, we tentatively infer that the addition
of TBHP to the itanium/hydrobenzoin complex causes tran-
sitory formation of a different catalytic species that does
not follow the reaction path modeled by us. Thus, this cata-
lyst oxidizes the incoming sulfide with lower enantio-
selectivity, yielding a sulfoxide with a reduced ee value
(63%) after 15–30 min. After this preliminary oxidation, a
new and more efficient oxidizing catalyst is formed in the
reaction mixture. This more efficient species, which could
be the same catalyst usually acting in our standard oxi-
dation procedures and that should follow our theoretical
model, is able both to remove, through a kinetic resolution
process, the minor amount of (S)-1b that is formed in the
earlier stages, and to ensure the usual high level of enantio-
selectivity that is observed in the reaction.
Figure 2. CD spectra of sulfoxides (R)-2b, (R)-4b, (R)-9b, and (R)-
10b.
Determination of Configuration of Sulfoxides; CD Spectra
As stated in the introductory section, because it was not
possible to obtain suitable crystals for an X-ray dif-
fractometric analysis, determination of the configuration of
Figure 3. CD spectra of sulfoxides (R)-3b and (R)-5b.
Sulfoxide 3b, with a biphenylyl structure, has a further
the sulfur stereogenic center of the synthesized sulfoxides negative band centered at 242 nm, with the positive band
was based upon CD spectra. The first CD spectrum of (R)- shifted to 279 nm (Figure 3). Sulfoxide 5b, in which the
benzyl p-tolyl sulfoxide was recorded by Stirling,[30] and a bulky tert-butyl group is present in the ortho-position of the
similar pattern was reported by Mislow et al.[31] for (R)- phenyl group, differs from the others and has a small band
alkyl aryl sulfoxides. In our recent experimental and theo- centered at 234 nm (Figure 3).
retical work on (R)-aryl benzyl sulfoxides,[32] we found the
Fluorinated molecules 6b and 7b (Figure 4) show nega-
same pattern reported in the literature,[30–31] i.e., a moder- tive bands at 230 and 233 nm, respectively, but the ortho-
ately intense positive band around 250–260 nm and a nega- substituted sulfoxide 7b has a further negative band at
tive band around 220–230 nm.[32] The most significant dif- 211 nm (Figure 4). The enantiomeric sulfoxide 7b, obtained
Eur. J. Org. Chem. 2011, 4327–4334
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4331

C. Cardellicchio et al.
FULL PAPER
and, eventually, stereochemical consequences. A useful by-
product of our investigation is the observation that origi-
nally low ee values can be increased by a post-reaction con-
version (i.e., over-oxidation) in which a kinetic resolution
occurs.
In conclusion, independent of the nature, position, and
dimensions of the substituents, aryl benzyl sulfoxides can
be readily obtained in optically pure form. This represents
an important result because, as shown in our previous
work,[9] these compounds can be easily transformed into a
variety of other sulfoxides in a highly enantioselective man-
ner.
Figure 4. CD spectra of fluorinated sulfoxides (R)-6b and (R)-7b.
Experimental Section
General: Chemicals were purchased from Sigma–Aldrich and were
used as received. n-Hexane employed in the enantioselective oxi-
dation protocol was distilled from 4 Å molecular sieves prior to
use. NMR spectra were recorded with a Bruker AM500 spectrome-
ter. HPLC analyses were performed with an Agilent 1100 chroma-
tograph, equipped with a DAD detector. Elemental analyses were
performed with a Carlo Erba CHNS-O EA1108 Elemental Ana-
lyzer. CD spectra were recorded in acetonitrile solution with a Ja-
in the reaction performed in the presence of a titanium
complex with the (R,R)-hydrobenzoin (Table 1, entry 9),
shows the expected inverted CD spectrum (see Figure S3 in
the Supporting Information).
Because the patterns of these CD spectra are expected
both from experimental[30,31] and theoretical points of
view[32] for sulfoxides having the (R)-configuration,[30–32]
this configuration could also be assigned to compounds 2b– sco J-810 spectropolarimeter.
7b and 9b–10b.
Sulfides 2a (78% yield) and 3a (76% yield) were synthesized by
reacting benzyl p-bromophenyl sulfide (1a) with n-hexyl- or p-tolyl-
magnesium bromide, respectively, in diethyl ether in the presence
of 3 mol-% [NiCl2(dppe)].[33]
Having settled the configuration of the produced sulfox-
ides, it is worth noting that the rule[13,15,17,18] predicting that
(R)-sulfoxides are always obtained when (S,S)-hydroben-
zoin is used as a ligand of the titanium is followed once
again.
Benzyl 4-(n-Hexyl)phenyl Sulfide (2a): Kugelrohr oven temp. was
157–160 °C; p = 0.1 mbar. 1H NMR (500 MHz, CDCl3): δ = 7.28–
7.25 (m, 5 H, ArH), 7.24–7.21 (m, 2 H, ArH), 7.08–7.05 (m, 2 H,
ArH), 4.08 (s, 2 H, CH2S), 2.58–2.53 (m, 2 H, CH2), 1.60–1.54 (m,
2 H, CH2), 1.34–1.25 (m, 6 H, CH2), 0.90–0.85 (m, 3 H, CH3) ppm.
13C NMR (125 MHz, CDCl3): δ = 141.6 (CAr), 137.7 (CAr), 132.7
(CAr), 130.5 (CAr), 128.9 (CAr), 128.8 (CAr), 128.4 (CAr), 127.0
(CAr), 39.7 (CH2S), 35.5 (CH2), 31.7 (CH2), 31.3 (CH2), 28.9
(CH2), 22.6 (CH2), 14.1 (CH3) ppm. C19H24S (284.46): calcd. C
80.22, H 8.50; found C 80.12, H 8.83.
Conclusions
The enantioselective oxidation of aryl benzyl sulfide with
TBHP in the presence of a chiral titanium/hydrobenzoin
complex is a straightforward procedure that yields aryl
benzyl sulfoxides with high enantiomeric purity with a very
easy work-up. To explain the observed enantioselectivity,
we had proposed a theoretical model in which interactions
involving the π aryl systems play a central role. The model
is now fully confirmed by the set of experiments reported
herein. Aryl benzyl sulfides always behave as the ideal sub-
strates for our oxidation system, and the departure from
these structures always has negative stereochemical conse-
quences. In fact, a ligand that is void of aryl groups yielded
a lower enantioselectivity and the oxidation was ac-
complished through a different reaction pathway. A similar
result was also found to be valid when different substrates
(e.g., diaryl sulfides or aryl alkyl sulfides) were oxidized,
thus emphasizing the importance of the appropriate geome-
try predicted by our model. The importance of the crucial
CH-π interactions responsible for the stereochemical prefer-
ence appears to be of a type that has so far been underesti-
mated. It seems clear that future work will uncover other
examples in which such a type of interaction will determine
the choice of reaction pathway. Another feature of interest
discussed above is the observation that changes in the se-
Benzyl 4Ј-Methylbiphenylyl Sulfide (3a): M.p. 148–149 °C (etha-
1
nol). H NMR (500 MHz, CDCl3): δ = 7.55–7.43 (m, 4 H, ArH),
7.41–7.21 (m, 9 H, ArH), 4.15 (s, 2 H, CH2S), 2.39 (s, 3 H,
CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 139.2 (CAr), 137.5
(CAr), 137.4 (CAr), 137.2 (CAr), 135.0 (CAr), 130.1 (CAr), 129.5
(CAr), 128.8 (CAr), 128.5 (CAr), 127.3 (CAr), 127.2 (CAr), 126.7
(CAr), 39.1 (CH2S), 21.1 (CH3) ppm. C20H18S (290.42): calcd. C
82.71, H 6.25; found C 82.65, H 6.58.
Sulfides 4a–7a and 9a–10a were synthesized by reacting the corre-
sponding benzyl bromides with the sodium salt of commercially
available thiols.
Benzyl 4-tert-Butylphenyl Sulfide (4a):[34] Kugelrohr oven temp. was
125–128 °C; p = 0.1 mbar.
Benzyl 2-tert-Butylphenyl Sulfide (5a): Kugelrohr oven temp. was
120–125 °C; p = 0.1 mbar. 1H NMR (500 MHz, CDCl3): δ = 7.48–
7.45 (m, 1 H, ArH), 7.42–7.39 (m, 1 H, ArH), 7.36–7.24 (m, 5 H,
ArH), 7.20–7.14 (m, 2 H, ArH), 4.16 (s, 2 H, CH2S), 1.49 (s, 9 H,
CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 149.9 (CAr), 137.1
(CAr), 135.7 (CAr), 132.9 (CAr), 129.1 (CAr), 128.5 (CAr), 127.2
(CAr), 126.5 (CAr), 126.4 (CAr), 126.3 (CAr), 41.4 (CH2S), 36.5 (C),
30.4 (CH3) ppm. C17H20S (256.41): calcd. C 79.63, H 7.86; found
quence of addition of the reactants may have mechanistic C 79.81, H 7.66.
4332
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4327–4334

Oxidation of Aryl Benzyl Sulfides
4-Bromophenyl Pentafluorophenylmethyl Sulfide (6a): Kugelrohr
oven temp. was 107–110 °C; p = 0.1 mbar. 1H NMR (500 MHz,
CDCl3): δ = 7.46–7.37 (m, 2 H, ArH), 7.29–7.18 (m, 2 H, ArH),
4.07 (s, 2 H, CH2S) ppm. 13C NMR (125 MHz, CDCl3): δ = 144.8
CH2SO), 2.43 (s, 3 H, CH3) ppm. 13C NMR (125 MHz, CDCl3): δ
= 144.1 (CAr), 141.0 (CAr), 138.1 (CAr), 136.8 (CAr), 130.4 (CAr),
129.7 (CAr), 129.1 (CAr), 128.5 (CAr), 128.3 (CAr), 127.3 (CAr),
127.0 (CAr), 125.0 (CAr), 63.6 (CH2SO), 21.1 (CH3) ppm.
1
1
(app. d, J = 249 Hz, CAr), 140.5 (app. d, J = 254 Hz, CAr), 137.4 C20H18OS (306.42): calcd. C 78.39, H 5.92; found C 78.17, H 5.61.
(app. d, 1J = 254 Hz, CAr), 134.1 (CAr), 132.7 (CAr), 132.2 (CAr),
(R)-Benzyl 4-tert-Butylphenyl Sulfoxide (4b):[38] M.p. 121–122 °C
122.5 (CAr), 112.0 (m, CAr), 27.0 (CH2S) ppm. C13H6BrF5S
(n-hexane/ethyl acetate, 9:1). [α]2D5 = +94.4 (c = 0.85, CHCl3) {lit.[38]
(369.14): calcd. C 42.30, H 1.64; found C 42.11, H 1.80.
[α]2D5 = +22.3 (c = 1.5, acetone) for sulfoxide with 10% ee}. The ee
2-Bromophenyl Pentafluorophenylmethyl Sulfide (7a): Kugelrohr
oven temp. was 108–111 °C; p = 0.1 mbar. 1H NMR (500 MHz,
CDCl3): δ = 7.61 (dd, J = 1.4, J = 7.9 Hz, 1 H, ArH), 7.38 (dd,
value was measured by HPLC (column: Chiralcel OD-H; eluent:
n-hexane/2-propanol, 70:30).
4
3
(R)-Benzyl 2-tert-Butylphenyl Sulfoxide (5b): [α]2D5 = +236.7 (c =
1.6, CHCl3) for sulfoxide with 94% ee. The ee value was measured
by HPLC (column: Whelk-O1; eluent: n-hexane/2-propanol, 80:20).
1H NMR (500 MHz, CDCl3): δ = 8.12–8.08 (m, 1 H, ArH), 7.45–
7.41 (m, 3 H, ArH), 7.35–7.31 (m, 3 H, ArH), 7.25–7.20 (m, 2 H,
3
4
3
3
4J = 1.6, J = 7.7 Hz, 1 H, ArH), 7.25 (ddd, J = 1.4, J = 7.4, J
4
3
3
= 7.7 Hz, 1 H, ArH), 7.16 (ddd, J = 1.6, J = 7.4, J = 7.9 Hz, 1
H, ArH), 4.14 (s, 2 H, CH2S) ppm. 13C NMR (125 MHz, CDCl3):
δ = 145.0 (app. d, 1J = 245 Hz, CAr), 140.6 (app. d, 1J = 254 Hz,
C
Ar), 137.4 (app. d, 1J = 253 Hz, CAr), 134.6 (CAr), 133.5 (CAr),
2
2
ArH), 4.12 (d, J = 13.0 Hz, 1 H, CH2SO), 3.92 (d, J = 13.0 Hz,
1 H, CH2SO), 1.43 (s, 9 H, CH3) ppm. 13C NMR (125 MHz,
CDCl3): δ = 148.4 (CAr), 144.2 (CAr), 131.3 (CAr), 131.2 (CAr),
130.2 (CAr), 128.7 (CAr), 128.4 (CAr), 127.4 (CAr), 126.9 (CAr),
126.1 (CAr), 64.3 (CH2SO), 36.5 (C), 32.3 (CH3) ppm. C17H20OS
(272.40): calcd. C 74.95, H 7.40; found C 75.10, H 7.20.
133.4 (CAr), 129.4 (CAr), 127.9 (CAr), 127.7 (CAr), 111.5 (m, CAr),
25.9 (CH2S) ppm. C13H6BrF5S (369.14): calcd. C 42.30, H 1.64;
found C 42.39, H 1.90.
2-Bromophenyl Phenyl Sulfide (8a):[35] Prepared by reacting iodo-
benzene and 2-bromothiophenol in the presence of potassium car-
bonate and copper iodide in NMP according to a reported pro-
cedure.[36] Kugelrohr oven temp. was 117–122 °C; p = 0.1 mbar.
Yield: 60%.
(R)-4-Bromophenyl Pentafluorophenylmethyl Sulfoxide (6b): M.p.
165–166 °C (ethanol). [α]2D5 = +191.4 (c = 0.6, CHCl3). The ee value
was measured by HPLC (column: Chiralcel OD-H; eluent: n-hex-
ane/2-propanol, 70:30). 1H NMR (500 MHz, CDCl3): δ = 7.68–
7.65 (m, 2 H, ArH), 7.41–7.38 (m, 2 H, ArH), 4.20 (d, 2J = 13.1 Hz,
1 H, CH2SO), 4.09 (d, 2J = 13.1 Hz, 1 H, CH2SO) ppm. 13C NMR
(125 MHz, CDCl3): δ = 145.5 (app. d, 1J = 250 Hz, CAr), 141.6
(CAr), 141.2 (app. d, 1J = 257 Hz, CAr), 137.4 (app. d, 1J = 255 Hz,
4-Bromophenyl 2-Phenylethyl Sulfide (9a): Kugelrohr oven temp.
1
was 130–132 °C; p = 0.01 mbar. H NMR (500 MHz, CDCl3): δ =
7.38–7.33 (m, 2 H, ArH), 7.28–7.22 (m, 2 H, ArH), 7.20–7.11 (m,
5 H, ArH), 3.12–3.07 (m, 2 H, CH2), 2.88–2.83 (m, 2 H, CH2) ppm.
13C NMR (125 MHz, CDCl3): δ = 139.9 (CAr), 135.6 (CAr), 131.9
(CAr), 130.6 (CAr), 128.5 (CAr), 128.4 (CAr), 126.5 (CAr), 119.7
CAr), 132.6 (CAr), 126.7 (CAr), 125.5 (CAr), 103.9 (m, CAr), 50.2
(CAr), 35.4 (CH2), 35.1 (CH2) ppm. C14H13BrS (293.22): calcd. C (CH2SO) ppm. C13H6BrF5OS (385.14): calcd. C 40.54, H 1.57;
57.35, H 4.47; found C 57.17, H 4.86.
found C 40.78, H 1.59.
4-Bromophenyl 3-Phenylpropyl Sulfide (10a):[37] M.p. 56–58 °C (eth-
anol).
(R)-2-Bromophenyl Pentafluorophenylmethyl Sulfoxide (7b): M.p.
190–192 °C (n-hexane/ethyl acetate, 1:1). [α]2D5 = +366.9 (c = 0.8,
CHCl3).
Racemic Sulfoxides 2b–10b: These compounds were used to set up
the chiral HPLC conditions and were synthesized by standard m-
chloroperoxybenzoic acid (MCPBA) mediated oxidation. Enantio-
enriched sulfoxides 2b–10b were produced by TBHP-oxidation ac-
cording to our protocol[13,15,17–18] in n-hexane, in the presence of
5 mol-% titanium/hydrobenzoin catalyst. The ee value for sulfoxide
1b[13] was measured by HPLC (column: Chiralcel OD-H; eluent: n-
hexane/2-propanol, 90:10).
(S)-2-Bromophenyl Pentafluorophenylmethyl Sulfoxide (7b): M.p.
190–192 °C (n-hexane/ethyl acetate, 1:1). [α]2D5 = –360.0 (c = 0.7,
CHCl3). The ee value was measured by HPLC (column: Chiralcel
OD-H; eluent: n-hexane/2-propanol, 90:10). 1H NMR (500 MHz,
4
3
CDCl3): δ = 7.61 (dd, J = 1.0, J = 7.8 Hz, 1 H, ArH), 7.53 (dd,
4J = 1.9, J = 7.8 Hz, 1 H, ArH), 7.50 (ddd, J = 1.0, J = 7.2, J
3
4
3
3
4
3
3
= 7.8 Hz, 1 H, ArH), 7.42 (ddd, J = 1.9, J = 7.2, J = 7.8 Hz, 1
H, ArH), 4.46 (d, 2J = 13.2 Hz, 1 H, CH2SO), 4.26 (d, 2J = 13.2 Hz,
1 H, CH2SO) ppm. 13C NMR (125 MHz, CDCl3): δ = 147.8
(app. d, 1J = 251 Hz, CAr), 141.9 (CAr), 141.1 (app. d, 1J = 255 Hz,
CAr), 137.2 (app. d, 1J = 253 Hz, CAr), 133.0 (CAr), 132.9 (CAr),
128.3 (CAr), 126.4 (CAr), 119.0 (CAr), 103.8 (m, CAr), 46.9
(CH2SO) ppm. C13H6BrF5OS (385.14): calcd. C 40.54, H 1.57;
found C 40.71, H 1.73.
(R)-Benzyl 4-(n-Hexyl)phenyl Sulfoxide (2b): M.p. 80–82 °C (n-hex-
ane). [α]2D5 = +74.4 (c = 1.0, CHCl3). The ee value was measured
by HPLC (column: Whelk-O1. Eluent: n-hexane/2-propanol,
80:20). 1H NMR (500 MHz, CDCl3): δ = 7.31–7.21 (m, 7 H, ArH),
7.00–6.96 (m, 2 H, ArH), 4.09 (d, 2J = 12.5 Hz, 1 H, CH2SO), 3.97
(d, 2J = 12.5 Hz, 1 H, CH2SO), 2.66–2.62 (m, 2 H, CH2), 1.64–
1.55 (m, 2 H, CH2), 1.34–1.27 (m, 6 H, CH2), 0.91–0.86 (m, 3 H,
CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 146.7 (CAr), 139.7
(CAr), 130.3 (CAr), 129.4 (CAr), 128.9 (CAr), 128.4 (CAr), 128.1
(CAr), 124.5 (CAr), 63.7 (CH2SO), 35.8 (CH2), 31.6 (CH2), 31.2
(CH2), 28.7 (CH2), 22.6 (CH2), 14.1 (CH3) ppm. C19H24OS
(300.46): calcd. C 75.95, H 8.05; found C 75.74, H 7.73.
2-Bromophenyl Phenyl Sulfoxide (8b):[35] M.p. 53–54 °C. The ee
value was measured by HPLC (column: Chiralpak IA; eluent: n-
hexane/2-propanol, 97:3).
(R)-4-Bromophenyl 2-Phenylethyl Sulfoxide (9b): M.p. 68–70 °C (n-
hexane/ethanol, 95:5). [α]2D5 = +88.7 (c = 0.6, CHCl3). The ee value
was measured by HPLC (column: Whelk-O1; eluent: n-hexane/2-
(R)-Benzyl 4Ј-Methylbiphenylyl Sulfoxide (3b): M.p. 190–192 °C
(ethanol/ethyl acetate, 7:3). [α]2D5 = +100.9 (c = 0.8, CHCl3). The ee
value was measured by HPLC (column: Chiralcel OD-H. Eluent:
n-hexane/2-propanol, 70:30). 1H NMR (500 MHz, CDCl3): δ =
7.70–7.59 (m, 2 H, ArH), 7.54–7.47 (m, 2 H, ArH), 7.46–7.40 (m,
1
propanol, 80:20). H NMR (500 MHz, CDCl3): δ = 7.68–7.64 (m,
2 H, ArH), 7.52–7.49 (m, 2 H, ArH), 7.32–7.27 (m, 2 H, ArH),
7.25–7.21 (m, 1 H, ArH), 7.19–7.16 (m, 2 H, ArH), 3.14–2.98 (m,
3 H, CH2SO and CHH), 2.92–2.85 (m, 1 H, CHH) ppm. 13C NMR
2 H, ArH), 7.34–7.20 (m, 5 H, ArH), 7.06–7.01 (m, 2 H, ArH), (125 MHz, CDCl3): δ = 142.6 (CAr), 138.4 (CAr), 132.5 (CAr), 128.8
4.15 (d, 2J = 12.7 Hz, 1 H, CH2SO), 4.03 (d, 2J = 12.7 Hz, 1 H,
(CAr), 128.5 (CAr), 126.8 (CAr), 125.6 (CAr), 125.5 (CAr), 58.2
Eur. J. Org. Chem. 2011, 4327–4334
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[13] M. A. M. Capozzi, C. Cardellicchio, F. Naso, V. Rosito, J. Org.
Chem. 2002, 67, 7289–7294.
[14] B. Jiang, X.-L. Zhao, J.-J. Dong, W.-J. Wang, Eur. J. Org.
Chem. 2009, 987–991.
[15] F. Naso, M. A. M. Capozzi, A. Bottoni, M. Calvaresi, V.
Bertolasi, F. Capitelli, C. Cardellicchio, Chem. Eur. J. 2009, 15,
13417–13420.
(CH2SO), 28.0 (CH2) ppm. C14H13BrOS (309.22): calcd. C 54.38,
H 4.24; found C 54.17, H 3.96.
(R)-4-Bromophenyl 3-Phenylpropyl Sulfoxide (10b): M.p. 74–76 °C
(n-hexane/diethyl ether, 95:5). [α]2D5 = +124.8 (c = 1.0, CHCl3). The
ee value was measured by HPLC (column: Whelk-O1; eluent: n-
hexane/2-propanol, 80:20). 1H NMR (500 MHz, CDCl3): δ = 7.66–
7.62 (m, 2 H, ArH), 7.47–7.42 (m, 2 H, ArH), 7.30–7.18 (m, 3 H,
ArH), 7.15–7.11 (m, 2 H, ArH), 2.83–2.69 (m, 4 H, CH2), 2.15–
2.04 (m, 1 H, CH2), 1.98–1.88 (m, 1 H, CH2) ppm. 13C NMR
(125 MHz, CDCl3): δ = 142.8 (CAr), 140.2 (CAr), 132.4 (CAr), 128.5
(CAr), 128.4 (CAr), 126.3 (CAr), 125.6 (CAr), 125.3 (CAr), 56.1
(CH2SO), 34.4 (CH2), 23.4 (CH2) ppm. C15H15BrOS (323.25):
calcd. C 55.73, H 4.68; found C 55.65, H 4.54.
[16] K. Okano, Tetrahedron 2011, 67, 2483–2512.
[17]
C. Cardellicchio, O. Hassan Omar, F. Naso, M. A. M. Capozzi,
F. Capitelli, V. Bertolasi, Tetrahedron: Asymmetry 2006, 17,
223–229.
[18]
[19]
F. Naso, C. Cardellicchio, F. Affortunato, M. A. M. Capozzi,
Tetrahedron: Asymmetry 2006, 17, 3226–3229.
E. A. Meyer, R. K. Castellano, F. Diederich, Angew. Chem. Int.
Ed. 2003, 42, 1210–1250.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, overlay of CD spectra of sulfoxides
(R)-7b and (S)-7b and further NMR spectra.
[20] D. Balcells, F. Maseras, New J. Chem. 2007, 31, 333–343.
[21]
[22]
N. Fey, Dalton Trans. 2010, 39, 296–310.
W. B. Jennings, B. M. Farrell, J. F. Malone, Acc. Chem. Res.
2001, 34, 885–894.
[23]
[24]
M. Nishio, CrystEngComm 2004, 6, 130–158.
M. Nishio, Y. Umezawa, K. Honda, S. Tsuboyama, H. Suez-
awa, CrystEngComm 2009, 11, 1757–1788.
M. Nishio, Tetrahedron 2005, 61, 6923–6950.
Acknowledgments
[25]
The work was financially supported in part by the Ministero
dell’Università e della Ricerca (MIUR), Rome (PRIN project, ster-
eoselezione in sintesi organica: metodologie e applicazioni) and by
the University of Bari. We thank Luca Nigro and Massimo Fiore
for preliminary oxidation experiments.
[26] M. Yamakawa, I. Yamada, R. Noyori, Angew. Chem. Int. Ed.
2001, 40, 2818–2821.
[27] X. Jia, X. Li, L. Xu, Y. Li, Q. Shi, T. T.-L. Au-Yeung, C. W.
Yip, X. Yao, A. S. C. Chan, Adv. Synth. Catal. 2004, 346, 723–
726.
[28] Y. Yamanoi, T. Imamoto, J. Org. Chem. 1997, 62, 8560–8564.
[29] K. Akasura, T. Yamamoto, S. Inoue, S. Osanai, D. K. Konde-
pudi, T. Yamaguchi, Chem. Phys. Lett. 2005, 406, 312–317.
[30] C. J. M. Stirling, J. Chem. Soc. 1963, 5741–5745.
[31] K. Mislow, M. M. Green, P. Laur, J. T. Melillo, T. Simmons,
A. L. Ternay Jr., J. Am. Chem. Soc. 1965, 87, 1958–1976.
[32] G. Pescitelli, S. Di Pietro, C. Cardellicchio, M. A. M. Capozzi,
L. Di Bari, J. Org. Chem. 2010, 75, 1143–1154.
[33] a) K. Tamio, K. Sumitami, M. Kumada, J. Am. Chem. Soc.
1972, 94, 4374–4377; b) F. Naso, G. Marchese, Carbon–carbon
bond formation involving organic halides and transition metal
compounds, in: The Chemistry of Functional Group, Supplement
D (Eds: S. Patai, Z. Rappoport), Wiley, New York, 1988, pp.
1353–1449.
[1] M. Mikołajczyk, J. Drabowicz, P. Kiełbasin´ski, Chiral Sulfur
Reagents. Application in Asymmetric and Stereoselective Syn-
thesis, CRC Press, Boca Raton, 1997.
[2] I. Fernandez, N. Khiar, Chem. Rev. 2003, 103, 3651–3705.
[3] E. Wojaczyn´ska, J. Wojaczyn´ski, Chem. Rev. 2010, 110, 4303–
4356.
[4] R. Bentley, Chem. Soc. Rev. 2005, 34, 609–624.
[5] H. Cotton, T. Elebring, M. Larsson, L. Li, H. Sorensen, S.
von Unge, Tetrahedron: Asymmetry 2000, 11, 3819–3825.
[6] M. Seenivasaperumal, H.-J. Federsel, K. J. Szabó, Adv. Synth.
Catal. 2009, 351, 903–919.
[7] K. P. Volcho, N. F. Salakhutdinov, Russ. Chem. Rev. 2009, 78,
457–464.
[8] J. Legros, J. R. Dehli, C. Bolm, Adv. Synth. Catal. 2005, 347,
19–31.
[9] M. A. M. Capozzi, C. Cardellicchio, F. Naso, Eur. J. Org.
Chem. 2004, 1855–1863.
[10] P. Pitchen, E. Duñach, M. N. Deshmukh, H. B. Kagan, J. Am.
Chem. Soc. 1984, 106, 8188–8193; F. Di Furia, G. Modena, R.
Seraglia, Synthesis 1984, 325–327.
[34] Y.-J. Wu, H. He, Synlett 2003, 1789–1790.
[35] A. Szadkowska, A. Makal, K. Wozniak, R. Kadyrov, K. Grela,
´
Organometallics 2009, 28, 2693–2700.
[36] E. Sperotto, G. P. M. van Klink, J. G. de Vries, G. van Koten,
J. Org. Chem. 2008, 73, 5625–5628.
[37] K. Nishide, T. Miyamoto, K. Kumar, S.-I. Ohsugi, N. Node,
Tetrahedron Lett. 2002, 43, 8569–8573.
[11] K. A. Jørgensen, J. Chem. Soc. Perkin Trans. 2 1994, 117–124.
[12] G. Pescitelli, L. Di Bari, P. Salvadori, Organometallics 2004, 23,
4223–4229; G. Pescitelli, L. Di Bari, P. Salvadori, J. Organomet.
Chem. 2006, 691, 2311–2318.
[38] T. Sugimoto, T. Kokubo, J. Miyazaki, S. Tanimoto, M. Okano,
J. Chem. Soc., Chem. Commun. 1979, 402–404.
Received: March 4, 2011
Published Online: June 7, 2011
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