The search for exceptions in the highly enantioselective titanium catalysed oxidation of aryl benzyl sulfides

Article abstract of DOI:10.1016/j.tet.2015.05.036

After the discovery of a few cases of lower enantioselectivity in the oxidation of aryl benzyl sulfides with hydroperoxides in the presence of a complex between titanium isopropoxide and (S, S)-hydrobenzoin, a screening of the oxidation of new substrates that are related to the structures that gave low ee values, was performed. From this screening, we confirmed that only a few sulfides remain as exceptions within a framework of exceptionally high stereoselectivity of the oxidation reaction. Moreover, the exceptions are clearly identified and are connected to particular coordinating moieties present on the aryl groups.

Full text of DOI:10.1016/j.tet.2015.05.036

Tetrahedron 71 (2015) 4810e4816
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Tetrahedron
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The search for exceptions in the highly enantioselective titanium
catalysed oxidation of aryl benzyl sulfides
Maria Annunziata M. Capozzi a, Giancarlo Terraneo b, Gabriella Cavallo b,
,
Cosimo Cardellicchio c
*
a
ꢀ
Dipartimento di Chimica, Universita di Bari, via Orabona 4, 70125 Bari, Italy
b Dipartimento di Chimica, Materiali e Ingegneria Chimica ‘Giulio Natta’, Politecnico di Milano, via Mancinelli 7, 20131 Milan, Italy
c
ꢀ
CNR ICCOM, Dipartimento di Chimica, Universita di Bari, via Orabona 4, 70125 Bari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
After the discovery of a few cases of lower enantioselectivity in the oxidation of aryl benzyl sulfides with
hydroperoxides in the presence of a complex between titanium isopropoxide and (S, S)-hydrobenzoin,
a screening of the oxidation of new substrates that are related to the structures that gave low ee values,
was performed. From this screening, we confirmed that only a few sulfides remain as exceptions within
a framework of exceptionally high stereoselectivity of the oxidation reaction. Moreover, the exceptions
are clearly identified and are connected to particular coordinating moieties present on the aryl groups.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 27 January 2015
Received in revised form 24 April 2015
Accepted 11 May 2015
Available online 20 May 2015
Keywords:
Titanium
Hydrobenzoin
Sulfoxide
X-ray diffraction
CD spectra
1. Introduction
enantioselective oxidation of aryl benzyl sulfides.4,8e12 The corre-
sponding sulfoxides were obtained with good yields (57e92%, with
The synthesis of enantiopure sulfoxides, relevant intermediates
in asymmetric organic synthesis and very useful in medicinal
chemistry,1 is an interesting research topic, as witnessed by the
numerous recent literature papers.1 In the past years, our work
focused on different enantioselective oxidation reactions of
sulfides.2e4 Some of the sulfoxides that were obtained with this
route were also transformed into other useful sulfinyl compounds
with our strategy based upon a displacement of carbanionic leaving
groups, resulting in a carbon for carbon substitution.2e5 A large
chemical library of enantiopure sulfoxides was synthesised by us by
using these two strategies.5 Our more recent research6e12 has fo-
cused on the application of the asymmetric sulfide oxidation re-
action with tert-butyl hydroperoxide as the oxidant in the presence
of a catalytic amount of a 1:2 complex between titanium i-prop-
oxide and (S, S)- or (R, R)-hydrobenzoin, a chiral ligand that is
employed in many enantioselective processes.13
a single exception) and high ee values (81e>98% ee). In a favour-
able stereochemical framework, these high ee values can be in-
creased with a crystallisation step, thus allowing us to obtain
a large number of enantiopure aryl benzyl sulfoxides.8,9 This high
asymmetric induction pattern is invariantly obtained regardless of
the presence of a variety of substituents (such as halogen atoms,
methoxy, nitro, carbomethoxy and even bulky aryl or alkyl groups)
on both the phenyl moieties on the starting sulfides.8,9 In a sub-
sequent step of our research,9,10 some fluorinated aryl benzyl sul-
fides were oxidised with the formation of the corresponding
sulfoxides always in an enantiopure form (>98% ee value) and even
with higher average isolated yields (81e96%) with respect to the
non-fluorinated starting materials. A theoretical calculation was
able to account for the high enantioselectivity of the oxidation
process, both for non-fluorinated8 and for fluorinated substrates.10
Surprisingly,10 after the synthesis of several enantiopure aryl
benzyl sulfoxides, the oxidation of 2,3,4,5,6-pentafluorobenzyl
pentafluorophenyl sulfide emerged as an exception. The ee value
of the obtained sulfoxide lowered to 61% ee, whereas the isolated
yield dropped to 19%.10 Nevertheless, our theoretical mechanism
was able to account also for this unsatisfactory result. The rationale
for this uncommon reaction path was found in a different approach
mode of the sulfide to be oxidised towards the titanium complex,
After the application of this oxidation protocol to the asym-
metric synthesis of valuable intermediates, such as Sulindac alkyl
esters,6 or
b
-keto-sulfoxides,7 we turned our attention to the
* Corresponding author. Tel.: þ39 080 5442077; fax: þ39 080 5539596; e-mail
address: cardellicchio@ba.iccom.cnr.it (C. Cardellicchio).
http://dx.doi.org/10.1016/j.tet.2015.05.036
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

M.A.M. Capozzi et al. / Tetrahedron 71 (2015) 4810e4816
4811
an approach that was stabilised by weak interactions involving the
fluorine atoms.10
absence of small amounts of water.4e8 In all the oxidation reactions
collected in Table 1, the corresponding sulfone is generally absent,
or present in low amounts (<5%). This evidence is useful to exclude
a further enrichment of the ee values through kinetic resolution
during the over-oxidation of the sulfoxide to sulfone.9
At this point, we considered it of interest to single out further
exceptions of this stereochemical framework, to better define scope
and limitations of the procedure. On the basis of the results of our
calculations, the investigation addressed the modifications of the
approach modes of the sulfide to the titanium catalyst, due, for
example, to coordinating moieties present on the phenyl groups of
the substrates.
The present research started with the oxidation of 2,3,4,5,6-
pentafluorobenzyl sulfides 1a14e3a that have methyl, nitroeor
methoxy-groups in the para-position of the phenyl groups. This
choice was determined by the partial similarity of these substrates
with the problematic 2,3,4,5,6-pentafluorobenzyl penta-
fluorophenyl sulfide. However, good yields (65e84%, Table 1, en-
tries 1e3) of the corresponding enantiopure (>98% ee) sulfoxides
1b14-3b were obtained. Taking into account all the aryl 2,3,4,5,6-
pentafluorobenzyl sulfides that were oxidised in the pre-
vious9,10,12 and in the present work, the only exception to the
synthesis of an enantiopure sulfoxide remains the cited 2,3,4,5,6-
pentafluorobenzyl pentafluorophenyl sulfide. A further exception,
limited to the lowering of the yield, in a framework of generally
high isolated yields (80e96%) can be considered the oxidation of 4-
methoxyphenyl pentafluorobenzyl sulfide 3a (Table 1, entry 3), in
which the yield decreases to 65%.
We performed a first series of tests,11 studying the oxidation of
aminophenyl or pyridyl benzyl sulfides, i.e. aryl benzyl sulfides
bearing coordinating nitrogen moieties, different from the nitro-
group previously investigated.8 Actually, a decrease of the ee
values of the produced sulfoxides was observed for the amino-
phenyl benzyl sulfide (43% ee value) and the 4-pyridyl benzyl sul-
fide (21% ee value).11 Another oxidation test was performed with
2,4-dichlorophenyl 2,3,4,5,6-pentafluorobenzyl sulfide,12 that is
a highly halogenated substrate similar to the 2,3,4,5,6,-penta-
fluorobenzyl pentafluorophenyl sulfide. However, in this case, the
usual high yields (91 and 96%, according to different reaction
conditions) of the enantiopure 2,4-dichlorophenyl 2,3,4,5,6-
pentafluorobenzyl sulfoxide (>98% ee value) were obtained.12
At this point, we decided to perform a further screening of the
oxidation of other aryl benzyl sulfides that could have different
approach modes to the titanium catalyst, thus leading to other
exceptions to the highly favourable stereochemical outcome de-
scribed so far.
A further series of oxidation was performed focusing on pen-
tafluorophenyl sulfides 4a and 5a (Table 1, entries 4 and 5), in which
the complete fluorination was reserved only to the aryl moiety, as
occurs, for example, in the case of the very successful oxidation of
simple benzyl pentafluorophenyl sulfide.10 Actually, in the oxida-
tion of the 2,4-dichlorobenzyl pentafluorophenyl sulfide 4a, we
observed (Table 1, entry 4) only a slight decrease both of the iso-
lated yield (72%) of sulfoxide 4b and of the enantioselectivity of the
process (88% ee value), in comparison with the very high ee values
of the other reactions performed with fluorinated substrates.
However, the crystallisation of sulfoxide 4b allowed us to obtain it
in an enantiopure form (>98% ee). At this point, we considered it of
interest to test for the first time an iodinated sulfide as a reaction
substrate. With this aim, 4-iodobenzyl pentafluorophenyl sulfide
5a was chosen. In this case, we observed a good isolated yield (81%)
of sulfoxide 5b, but having only a 73% ee value. The crystallisation
step was able to increase the ee value only to 85% (Table 1, entry 5).
The effect of the iodine atom of the benzyl phenyl group
prompted us to consider other oxidation reactions of iodinated
sulfides that had not been investigated previously. Therefore, we
decided to test for the first time some iodinated non-fluorinated
aryl benzyl sulfides. In a first run, we chose to react p-tolyl 4-
iodobenzyl sulfide 6a15 and 4-bromophenyl 4-iodobenzyl sulfide
7a16 (Table 1, entries 6 and 7). Good isolated yields (84% and 95%
respectively) of the corresponding sulfoxides 6b15 and 7b16 were
obtained having the usual high enantiomeric enrichment value (95
and>98% ee respectively). Sulfoxide 6b was also obtained in an
enantiopure form after crystallisation (Table 1, entry 6). At this
stage we considered it of interest to compare the results obtained
for 4-bromophenyl 4-iodobenzyl sulfoxide 7b with the oxidation of
4-bromophenyl 4-bromobenzyl sulfide 8a16 (Table 1, entry 8). Only
a slight decrease of the ee value was measured (93% ee) that was
soon balanced by a crystallisation step that allowed us to obtain the
enantiopure 8b16 (Table 1, entry 8). For a better comparison, we also
reported in Table 1 the oxidation of the unsubstituted benzyl
phenyl sulfide 9a,17 to give sulfoxide 9b,18 that had not been pre-
viously oxidised with our protocol, and the oxidation of benzyl 4-
bromophenyl sulfide 10a,4 that was reported at the beginning of
our investigation on this procedure. The inspection of the data re-
ported in entries 6e10 of Table 1 can be considered homogeneous
(84e95% isolated yields; 93- >98% ee values) upon varying the
halogen atom in the para-position of both the aryl rings. Thus, the
unusual decrease of the ee value observed for the oxidation of
sulfide 5a should be due only to a combined effect of both the io-
dine atom on the benzyl group and the pentafluophenyl moiety.
2. Results and discussion
2.1. Enantioselective synthesis of aryl benzyl sulfoxides
Aryl benzyl sulfides 1ae12a were asymmetrically oxidised on
a 1 mmol scale to the corresponding sulfoxides 1be12b with tert-
butyl hydroperoxide in the presence of 5% of a 1:2 complex formed
in situ by mixing titanium i-propoxide and (S, S)-hydrobenzoin
(Table 1).
As can be deduced from the experimental section, the operating
procedure of this asymmetric oxidation reaction is simple and
convenient, because it is just a ‘mix-and-wait’ procedure, without
utilising complicated manipulations. In this respect, it is worth
mentioning that our protocol is also insensitive to the presence or
Table 1
Enantioselective oxidation of aryl sulfides by TBHP in the presence of a titanium/(S,
S)-hydrobenzoin complex
TBHP, n-hexane, rt
2
1
Ar
2
+
Ar
1
Ar
S
Ar
S
-
5% Ti(O-i-Pr) / (S, S)-hydrobenzoin
4
O
Entry Sulfide Ar1
Ar2
Sulfoxide Yield %a ee (%)b
1
2
3
4
5
6
7
8
1a
2a
3a
4a
5a
6a
7a
8a
4-Me-C6H4
4-O2NeC6H4
4-MeO-C6H4
C6F5
C6F5
C6F5
C6F5
(R)-1b
(R)-2b
(R)-3b
84
80
65
72
81
84
95
80
87
>98
>98
>98
2,4-Cl2C6H3 (R)-4b
88 (>98)c
73 (85)c
95 (>98)c
>98
C6F5
4-I-C6H4
4-I-C6H4
4-I-C6H4
4-Br-C6H4
C6H5
(R)-5b
(R)-6b
(R)-7b
(R)-8b
(R)-9b
4-MeC6H4
4-Br-C6H4
4-Br-C6H4
C6H5
4-Br-C6H4
2-HOOC-C6H4
93 (>98)c
>98
9
9a
10
11
12
10a
11a
12a
C6H5
C6H5
(R)-10bd 85d
>98d
d
(R)-11b
(R)-12b
d
2-HOH2CeC6H4 C6H5
74
29
a
Yields refer to pure isolated products.
Determined by HPLC.
After crystallisation.
b
c
d
Data already reported in Ref. 4.

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M.A.M. Capozzi et al. / Tetrahedron 71 (2015) 4810e4816
As a final test, taking into account the effect of the amino-group
occurs for this type of compounds.12 Thus, we decided to use chi-
roptical spectroscopy, a technique that we have demonstrated to
provide sound attribution of configuration for this class of com-
pounds with both recent theoretical and experimental in-
vestigations.9,21,22 Actually, we found for sulfoxides 3be5b the
classical Mislow pattern23 for the (R)-configuration of sulfoxides
(minimum at lower wavelengths and maximum at higher wave-
lengths in the range 200e300 nm). Fig. 1 shows the CD spectra of
close to the reaction centre,11 we decided to investigate the effect of
the hydroxyl groups of a carboxylic acid or of an alcohol, in the
ortho-position of the phenyl group, very close to the sulfur atom to
be oxidised. To this end, we tested (2-benzylsulfanyl)benzoic acid
11a19 and (2-benzylsulfanyl)benzoic alcohol 12a20 (Table 1, entry 11
and 12). We observed that only very small quantities of sulfide 11a
were oxidised under the usual reaction conditions. Therefore, the
reaction was not investigated further.
It is reasonable to believe that this inertia was due to the pres-
ence of the free carboxylic group, since the corresponding methyl
(2-benzylsulfanyl)benzoate 13a (i.e., the same sulfide, but having
the carboxyl group protected as an ester) was easily oxidised with
the formation of the enantiopure 13b in our previous in-
vestigation.8 On the other hand, sulfide 12a was oxidised to the
corresponding sulfoxide 12b20 with a good yield (74%) but with
a low enantiomeric purity (29% ee value). According to our hy-
pothesis, the presence of the hydroxyl moiety very close to the
sulfur atom to be oxidised changes the coordination mode of the
sulfide to the titanium catalyst, thus causing the decrease of the ee
value of the sulfoxide 12b, in the same way that occurred for the
cited oxidation of an aminophenyl sulfide.11
2.2. Transformation of an enantiopure aryl benzyl sulfoxide
From the results reported above, it appears that, in spite of our
efforts, the extent of the exceptions reaches a small level. Fur-
thermore, the synthesised enantiopure sulfinyl compounds are so
numerous that the request of a single sulfoxide belonging to the
deviating samples could be overcome by using an indirect ap-
proach. For example, sulfoxide 12b is an interesting structure.20
Since the asymmetric oxidation of sulfide 12a is not satisfactory
(Table 1, entry 12), we reasoned that the previously synthesised
methyl (R)-2-(benzylsulfinyl)benzoate 13b8 is a direct precursor
both of the acid 11b and of the alcohol 12b (Scheme 1).
Fig. 1. 190e500 nm CD spectra (in acetonitrile) of (R)-4-methoxyphenyl 2,3,4,5,6-
pentafluorobenzyl sulfoxide 3b.
3b. Thus, the (R)-configuration, can be safely attributed to this
product.
As far as 4-nitrophenyl 2,3,4,5,6-pentafluorobenzyl sulfoxide 2b
and of pentafluorophenyl 2, 4-dichlorobenzyl sulfoxide 4b are
concerned (see Fig. S1, Supplementary Data), the lowest wave-
length section of the CD spectra is more complex than usual, but
similar to the pattern of, for example, the homologous non-
fluorinated (R)-benzyl 4- nitrophenyl sulfoxide.21
O
Ph
O
Ph
S
S
DIBAL-H, -30°C
toluene
COOMe
CH2OH
Also in this case, the attribution of the (R)-configuration can be
considered safe. An analogous pattern was found in the case of 4-
iodobenzyl pentafluorophenyl sulfoxide 5b (85% ee value) whose
CD spectrum in the 200e300 nm range was depicted in the
Supplementary Data section (Fig. S2).
13b
12b
Scheme 1. Synthesis of alcohol 12b by reducing ester 13b.
Thus, we chose to transform ester 13b into alcohol 12b. After
a preliminary screening of the reaction conditions, we reacted
enantiopure (R)-13b with DIBAL-H in toluene at ꢀ30 ꢁC (Scheme 1).
We soon obtained enantiopure (R)-12b sulfoxide (69% yield), as
checked by chiral HPLC (see Experimental Section).
2.3.2. X-ray diffraction experiments. On the other hand, single
crystals of 6b, 7b, 8b, obtained in the conditions outlined in the
Experimental Section, together with those of the already reported
(R)-10b,4 were found to be suitable for X-ray diffraction experi-
ments. The expected (R)-configuration for all the analysed sulfox-
ides was confirmed by anomalous-dispersion effects in diffraction
measurements (Table S1, Supplementary Data).
2.3. Configuration assignments
The crystal structures of sulfoxides 6be8b and 10b share strong
similarities. Specifically, in molecule 10b the crystal packing is
mainly driven by two hydrogen bonds occurring between the sul-
finyl oxygen atom, which behaves as bidentate electron density
donor site, and two hydrogen atoms, one of the methylene group
and one ortho-hydrogen of the benzyl phenyl group belonging to
a translated molecule along the (ꢀ1,0,0) direction (Fig. 2).
2.3.1. CD spectra. According to a rule that up to now has found
always confirmation,4,6e12 when (S, S)-hydrobenzoin was used as
a ligand of the titanium, (R)-aryl benzyl sulfoxides were obtained.
The rule is immediately confirmed by the comparison of the optical
rotatory values in the cases of sulfoxides 1b14 and 9b,18 that were
reported in the literature. The configuration of (R)-12b was attrib-
uted from the configuration of (R)-13b, since the reduction step
does not involve the stereogenic centre at the sulfur atom (Scheme
1).
Similar hydrogen bonding patterns are also present in the other
structures. In iodinated sulfoxides 6b and 7b, the oxygen atom
works either as bidentate electron density donor site, as occurs in
10b, and as tridentate hydrogen bond acceptor interacting with an
additional methylene hydrogen atom of adjacent molecule, while
As far as fluorinated sulfoxide 2be5b are concerned, it was not
possible to obtain crystals suitable for the X-ray analysis, as often

M.A.M. Capozzi et al. / Tetrahedron 71 (2015) 4810e4816
4813
the strong tendency of sulfinyl oxygen atom to interact with weak
acidic hydrogen atoms. Interestingly, a different hydrogen bond
motif is also present in iodinated sulfoxides 6b and 7b. The sulfur
atom behaves as electron density donor site toward an ortho-hy-
ꢁ
drogen atom of the benzyl residue (S$$$H distances are: 2.96 A in
ꢁ
6b and 2.98 A in 7b, respectively).
Another common supramolecular motif that further stabilises
the crystal packing of all systems is the interaction between some
aryl hydrogen atoms and the
CH/
interactions24 occur in a T-shape fashion (Fig. 3), meaning
that the hydrogen atoms enter quasi-perpendicular to the -cloud
p systems of the aryl moieties. These
p
p
of the benzene ring (see also Supplementary Data, Table S2).
It is interesting to note that the presence of halogen atoms with
a large polarisable electron density distribution such as bromine
and iodide, namely good halogen bonding donors,25 might give rise
to the possible formation of halogen bonding interactions.26
However, only in sulfoxide 10b the bromine atom weakly in-
teracts with the
p system of benzyl phenyl ring (see Supplementary
Data, Table S2). This suggests that the ability of the halogen atoms
in this sulfoxide series to work as electron density acceptor site is
quite poor and not sufficient to interfere in the formation of the
hydrogen bond pattern.
3. Conclusions
The asymmetric oxidation of aryl benzyl sulfides with hydro-
peroxides in the presence of a complex between titanium and (S, S)-
hydrobenzoin is a simple and straightforward route for the syn-
thesis of more than thirty valuable enantiopure sulfoxides.4,8e10,12
This highly valuable stereochemical profile was explained with
a theoretical mechanism that was able to account also for the single
reaction that constitutes the exception to this framework, and to
suggest other possible special cases.
After further screenings, the exceptions that have been observed
are sporadic and connected to sulfides bearing nitrogen co-
ordinating groups or hydroxyl moiety on the starting sulfides, be-
cause these groups can alter the proper coordination mode of the
sulfide to the metal, as drawn in our theoretical model. Two further
exceptions are connected with the presence of two penta-
fluorophenyl moieties on the starting sulfide and, to a lower extent,
to the presence of one pentafluorophenyl group together with an
Fig. 2. Hydrogen bonding pattern in 10b. Hydrogen bonds are pictured in black dotted
lines. Colour code: C gray; H white; O red; S yellow and Br light brown.
in 8b the hydrogen atoms involved in the hydrogen bond contacts
come from two methylene units of two different molecules.
In the analysed structures, the hydrogen bond donor-acceptor
ꢁ
ꢁ
distances (O/H) are in the range of 2.263 Ae2.717 A while the
angles CeH/O are in the range of 169ꢁe141ꢁ (see Supplementary
Data, Table S2, for selected distances and angles). The reported
geometrical parameters classify these supramolecular contacts as
medium-weak hydrogen bonds. However, their systematic occur-
rence suggests how the S]O$$$H synthon promotes and stabilises
the formation of the aryl benzyl sulfoxide crystals. Recently,12 these
hydrogen bond patterns were observed in some crystal structures
of similar sulfoxide derivatives and their presence clearly highlights
Fig. 3. Ball and stick representation of a dimeric system in 10b (left). Ball and stick representation of three molecules of sulfoxide 5b assembled via hydrogen bonds and CeH/
p
contact (right). Hydrogen bonds, halogen bonds and CeH/p interactions are pictured in black dotted lines. Colour code: C gray; H white; O red; S yellow; Br light brown and I
purple.

4814
M.A.M. Capozzi et al. / Tetrahedron 71 (2015) 4810e4816
iodine atom. However, taking into account first the high number of
enantiopure sulfoxides that were synthesised against the few cases
of a lower enantioselectivity, and secondly the fact that these few
cases seem to be predictable on the basis of the present and the
past research, we can arrive to the conclusion that nowadays this
oxidation protocol is the best synthetic route to synthesise a large
number of enantiopure aryl benzyl sulfoxides that, when subjected
to our carbanionic leaving group strategy, should lead to a cascade
of sulfoxides.
147.8 (dm, 1JCF 246 Hz, CAr), 141.7 (dm, 1JCF 256 Hz, CAr), 137.5 (dm,
1JCF 256 Hz, CAr),134.8 (CAr),134.4 (CAr),133.0 (CAr),131.3 (CAr),129.7
(CAr), 127.3 (CAr), 107.8 (m, CAr), 36.3 (CH2S). 19F NMR (565 MHz,
CDCl3) ꢀ132.1 (m), ꢀ151.8 (tm, 3JFF¼21 Hz), ꢀ161.1 (m). IR (KBr)
n/
cmꢀ1 2941, 1655, 1514, 1477, 1097, 974, 860.
4.5. 4-Iodobenzyl pentafluorophenyl sulfide (5a)
Transparent oil/white solids. Kugelrohr oven temp 115e120 ꢁC,
p¼0.1 mbar; mp 71e72 ꢁC. Found: C, 37.30; H 1.52. C13H6F5IS re-
quires C, 37.52; H, 1.45%.1H NMR (500 MHz, CDCl3) dH 7.63e7.56
(2H, m, HAr), 7.01e6.94 (2H, m, HAr), 3.99 (2H, s, CH2S). 13C NMR
4. Experimental section
1
1
Chemicals were used as received. Elemental analyses were
performed on a CHNSeO Elemental Analyzer. NMR spectra were
recorded on a 1H-500 MHz and 13C-125 MHz spectrometer. 19F
spectra were recorded at 565 MHz by using trichlorofluoromethane
as an internal standard. Only the absolute value of each coupling
constant was reported. Crystallographic data for the structures in
this paper have been deposited with the Cambridge Crystallo-
graphic Data Center as supplementary publications. CCDC numbers
1031517-1031520. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ
UK (fax: þ44 (0)1223 336033 or e-mail deposit@ccdc.cam.ac.uk).
Sulfides 1ae9a were synthesised by reacting at 50 ꢁC for 3 h in
acetone the corresponding benzyl bromides with the sodium salt of
commercially available thiols on a 6 mmol scale. They were purified
by distillation, but solidify on standing.
(125 MHz, CDCl3) dC 147.5 (dm, JCF 244 Hz, CAr), 141.3 (dm, JCF
1
252 Hz, CAr), 137.7, 137.5 (dm, JCF 251 Hz, CAr), 136.0 (CAr), 130.5
(CAr), 107.9 (m, CAr), 93.4 (I-CAr), 38.4 (CH2S). 19F NMR (566 MHz,
CDCl3) ꢀ132.7 (m), ꢀ152.4 (tm, 3JFF¼21 Hz), ꢀ161.3 (m). IR (KBr)
n/
cmꢀ1 2963, 1639, 1517, 1479, 1092, 977, 861.
4.6. 4-Iodobenzyl p-tolyl sulfide (6a)
Transparent oil/white solids. Kugelrohr oven temp 150e154 ꢁC,
p¼0.1 mbar; mp 94e95 ꢁC (lit.15 mp 93 ꢁC).
4.7. 4-Bromophenyl 4-iodobenzyl sulfide (7a)
White solids. Mp 126e128 ꢁC (n-hexane/acetone 1:1) (lit.16 mp
118 ꢁC).
4.1. 2,3,4,5,6-Pentafluorobenzyl p-tolyl sulfide (1a)
4.8. 4-Bromobenzyl 4-bromophenyl sulfide (8a)
Transparent oil/white solids. Kugelrohr oven temp 93e96 ꢁC,
p¼0.1 mbar; mp 65e66 ꢁC (lit.14 mp 64e66 ꢁC).
Transparent oil/white solids. Kugelrohr oven temp 170e175 ꢁC,
p¼0.1 mbar; mp 114e116 ꢁC (lit.16 mp 101 ꢁC).
4.2. 4-Nitrophenyl 2,3,4,5,6-pentafluorobenzyl sulfide (2a)
4.9. Benzyl phenyl sulfide (9a)
Transparent yellowish oil/white solids. Kugelrohr oven temp
160e165 ꢁC, p¼0.1 mbar; mp 77e78 ꢁC. Found: C, 46.21; H, 1.92; N,
4.50. C13H6F5NO2S requires C, 46.57; H, 1.80; N, 4.18%. 1H NMR
(500 MHz, CDCl3) dH 8.19e8.15 (2H, m, HAr), 7.49e7.45 (2H, m, HAr),
Transparent oil/white solids. Kugelrohr oven temp 125e130 ꢁC,
p¼0.1 mbar; mp 42e43 ꢁC (lit.17 bp 171e193 ꢁC at 12 Torr).
(2-Benzylsulfanyl)benzoic acid (11a)19 and benzyl 2-
hydroxymethylphenyl sulfide (12a)20 were synthesised according
to literature protocol. Racemic sulfoxides 1be12b (used in the
setting up of the chiral HPLC separation) were synthesised by
standard mCPBA oxidation.
4
4.26 (2H, t, JHF 1.1 Hz, CH2S). 13C NMR (125 MHz, CDCl3) dC 146.4
(CAr), 145.1 (dm, 1JCF 250 Hz, CAr), 144.1 (CAr), 140.9 (dm, 1JCF 255 Hz,
C
C
Ar), 137.6 (dm, 1JCF 253 Hz, CAr), 129.1 (CAr), 124.1 (CAr), 110.8 (m,
Ar), 25.0 (CH2S). 19F NMR (565 MHz, CDCl3) ꢀ142.4 (dm,
3
3JFF¼21 Hz), ꢀ154.2 (tm, JFF¼21 Hz), ꢀ161.5 (m). IR (KBr)
n
/cmꢀ1
4.10. Enantioselective oxidation of aryl benzyl sulfide. Rep-
resentative procedure
2946, 1654, 1522, 1498, 1340, 986, 836.
4.3. 4-Methoxyphenyl 2,3,4,5,6-pentafluorobenzyl sulfide (3a)
A solution of Ti(O-i-Pr)4 (0.014 g, 0.05 mmol) in 4 mL of n-
hexane was added to a solution of (S, S)-hydrobenzoin (0.021 g,
0.1 mmol) in 8 mL of n-hexane under a nitrogen atmosphere. The
mixture was stirred for 1 h at room temperature. A solution of aryl
benzyl sulfide (1 mmol) (as an alternative, a suspension of low
soluble sulfides) in 8 mL of n-hexane was added at this stage, and
the mixture was stirred for 30 min. After this time, 0.14 mL of
a commercial 80% solution of tert-butyl hydroperoxide (in di-tert-
butyl peroxide/water 3:2) (1.1 mmol) was added and the stirring
was continued for 2 days at room temperature. Finally, the solvent
was removed in vacuo and the residue was subjected to column
chromatography (petroleum ether/ethyl acetate 4:1).
Transparent oil/white solids. Kugelrohr oven temp 95e98 ꢁC,
p¼0.1 mbar; mp 51e52 ꢁC. Found: C, 52.34; H, 3.08. C14H9F5OS
requires C, 52.50; H, 2.83%.1H NMR (500 MHz, CDCl3) dH 7.31e7.27
(2H, m, HAr), 6.83e6.79 (2H, m, HAr), 3.97 (2H, t, 4JHF 1.2 Hz, CH2S),
3.80 (3H, s, OCH3). 13C NMR (125 MHz, CDCl3) dC 160.3 (O-CAr),144.8
(dm, 1JCF 252 Hz, CAr), 140.1 (dm, 1JCF 253 Hz, CAr), 137.3 (dm, 1JCF
252 Hz, CAr), 135.9 (CAr), 123.6 (CAr), 114.6 (CAr), 112.8 (CAr, m), 55.3
(OCH3), 28.3 (CH2S). 19F NMR (565 MHz, CDCl3) ꢀ143.4 (dm,
3
3JFF¼21 Hz), ꢀ156.4 (tm, JFF¼21 Hz), ꢀ162.9 (m). IR (KBr)
n
/cmꢀ1
2936, 1654, 1522, 1506, 986, 830.
4.4. 2,4-Dichlorobenzyl pentafluorophenyl sulfide (4a)
4.11. (R)-2,3,4,5,6-Pentafluorobenzyl p-tolyl sulfoxide (1b)
White solids. Mp 138e140 ꢁC (from ethanol), (lit.14 mp
Transparent oil/white solids. Kugelrohr oven temp 150e155 ꢁC,
p¼0.1 mbar; mp 54e55 ꢁC. Found: C, 43.71; H, 1.44. C13H5Cl2F5S
requires C, 43.48; H, 1.40%.1H NMR (500 MHz, CDCl3) dH 7.37 (1H, d,
4JHH 2.0 Hz, HAr), 7.15 (1H, dd, 3JHH 8.2 Hz, 4JHH 2.0 Hz, HAr), 7.09 (1H,
d, 3JHH 8.2 Hz, HAr), 4.12 (2H, s, CH2S). 13C NMR (125 MHz, CDCl3) dC
117e122 ꢁC for the (S)-sulfoxide having a 45% ee). ½a 2D5
þ185.3 (c 0.8
ꢂ
in CHCl3) (lit.14
½
a 2D5
ꢂ
ꢀ75.8 (c 1.0 in CH2Cl2) for the (S)-sulfoxide
having a 45% ee). The ee values was measured by HPLC (Column:
Chiralpak IA. Eluent: n-hexane/i-propanol 90:10).

M.A.M. Capozzi et al. / Tetrahedron 71 (2015) 4810e4816
4815
4.12. (R)-4-Nitrophenyl 2,3,4,5,6-pentafluorobenzyl sulfoxide
(2b)
Crystal data for C14H13IOS, M¼356.20, Monoclinic, a¼7.6569(4)
3
ꢁ ꢁ ꢁ
ꢁ
ꢁ
A, b¼5.6310(4) A, c¼16.2048(8) A,
b
¼101.407(2) , V¼684.88(7) A ,
T¼103(2) K, space group P21, Z¼2,
m
(MoK
a
)¼2.472 mmꢀ1, 20,262
White solids. Mp 174e176 ꢁC (from ethyl acetate). ½a 2D5
ꢂ
þ241.4 (c
reflections measured, 2437 independent reflections (Rint¼0.0361).
0.35 in CH3CN). The ee value was measured by HPLC (Column:
Chiralcel OD-H. Eluent: hexane/i-propanol 70:30). Found: C, 44.36;
H, 1.73; N, 4.26. C13H6F5NO3S requires C, 44.45; H, 1.72; N, 3.99%. 1H
NMR (500 MHz, CDCl3) dH 8.43e8.37 (2H, m, HAr), 7.76e7.70 (2H, m,
The final R1 values were 0.0333 (I>2s
(I)). The final wR(F2) values
were 0.0706 (I>2s(I)). The final R1 values were 0.0385 (all data).
The final wR(F2) values were 0.0722 (all data). The goodness of fit on
F2 was 1.054. CCDC number CCDC 1031518.
H
Ar), 4.33 (1H, dt, 2JHH 13.4 Hz, 4JHF 1.2 Hz, CH2SO), 4.13 (1H, dt, 2JHH
4
13.4 Hz, JHF 1.2 Hz, CH2SO). 13C NMR (125 MHz, CDCl3) dC 149.9
(CAr), 149.8 (CAr), 145.5 (dm, 1JCF 251 Hz, CAr), 141.4 (dm, 1JCF 257 Hz,
4.17. (R)-4-Bromophenyl 4-iodobenzyl sulfoxide (7b)
Ar), 137.4 (dm, 1JCF 254 Hz, CAr), 125.2 (CAr), 124.4 (CAr), 103.0 (m,
White crystals. Mp 196e197 ꢁC (from ethanol/n-hexane 1:1),
C
C
Ar), 50.0 (CH2SO). 19F NMR (565 MHz, CDCl3) ꢀ140.4 (dm,
(lit.16 mp 171 ꢁC for the racemic sulfoxide). ½a 2D5
þ113.5 (c 1.0 in
ꢂ
3
3JFF¼21 Hz), ꢀ151.3 (tm, JFF¼21 Hz), ꢀ160.9 (m). IR (KBr)
n
/cmꢀ1
CHCl3). The ee value was measured by HPLC (Column: Chiralcel OD-
2934, 1654, 1524, 1502, 1344, 1046, 988, 852.
H. Eluent: n-hexane/i-propanol 70:30).
Crystal data for
C
13H10BrIOS, M¼421.08, Monoclinic,
¼101.72(2)ꢁ,
ꢁ
ꢁ ꢁ
4.13. (R)-4-Methoxyphenyl 2,3,4,5,6-pentafluorobenzyl sulf-
oxide (3b)
a¼7.6772(16) A, b¼5.6108(12) A, c¼16.313(3) A,
b
3
ꢁ
V¼688.0(2) A , T¼103(2) K, space group P21, Z¼2,
m(MoKa)¼
5.363 mmꢀ1, 5163 reflections measured, 2366 independent re-
flections (Rint¼0.0582). The final R1 values were 0.0380 (I>2 (I)).
(I)). The final R1 values
White solids. Mp 131e133 ꢁC (from n-hexane/acetone 9:1). ½a 2D5
þ166.4 (c 0.7 in CHCl3). The ee value was measured by HPLC (Col-
umn: Chiralcel OD-H. Eluent: n-hexane/i-propanol 70:30). Found:
C, 50.25; H, 2.90. C14H9F5O2S requires C, 50.00; H, 2.70%. 1H NMR
(500 MHz, CDCl3) dH 7.46e7.42 (2H, m, HAr), 7.02e6.98 (2H, m, HAr),
ꢂ
s
The final wR(F2) values were 0.0806 (I>2
s
were 0.0468 (all data). The final wR(F2) values were 0.0840 (all
data). The goodness of fit on F2 was 1.001. CCDC number CCDC
1031520.
2
4
2
4.14 (1H, dt, JHH 13.0 Hz, JHF 1.2 Hz, CH2SO), 4.09 (1H, dt, JHH
13.0 Hz, 4JHF 1.2 Hz, CH2SO), 3.87 (3H, s, OCH3). 13C NMR (125 MHz,
CDCl3) dC 162.7 (O-CAr), 145.4 (dm, 1JCF 250 Hz, CAr), 141.1 (dm, 1JCF
4.18. (R)-4-Bromobenzyl 4-bromophenyl sulfoxide (8b)
White crystals. Mp 163e165 ꢁC (from n-hexane/acetone 3:2),
1
256 Hz, CAr), 137.4 (dm, JCF 252 Hz, CAr), 133.1 (CAr), 125.9 (CAr),
114.8 (CAr), 104.4 (m. CAr), 55.6 (OCH3), 50.3 (CH2SO). 19F NMR
(lit.16 mp 145e146 ꢁC for the racemic sulfoxide). ½a 2D5
þ127.9 (c 0.8
ꢂ
(565 MHz, CDCl3) ꢀ140.7 (m), ꢀ153.1 (tm, 3JFF¼21 Hz), ꢀ161.9 (m).
in CHCl3). The ee value was measured by HPLC (Column: Chiralcel
IR (KBr) n
/cmꢀ1 2944, 1654, 1522, 1490, 986, 818.
OD-H. Eluent: n-hexane/i-propanol 90:10).
Crystal data for
C
13H10Br2OS, M¼374.09, Monoclinic,
4.14. (R)-2,4-Dichlorobenzyl pentafluorophenyl sulfoxide (4b)
¼103.898(3)ꢁ,
ꢁ
ꢁ ꢁ
a¼7.7288(6) A, b¼5.6057(5) A, c¼16.0226(12) A,
b
3
ꢁ
V¼673.86(9) A , T¼103(2) K, space group P21, Z¼2,
m(MoKa)¼
White solids. Mp 94e96 ꢁC (from ethanol). ½a 2D5
þ8.14 (c 0.5 in
ꢂ
6.150 mmꢀ1, 12,164 reflections measured, 2249 independent re-
flections (Rint¼0.0439). The final R1 values were 0.0414 (I>2 (I)).
(I)). The final R1 values
CHCl3). The ee value was measured by HPLC (Column: Chiralcel OD-
s
H. Eluent: n-hexane/i-propanol 70:30). Found: C, 41.64; H, 1.47.
The final wR(F2) values were 0.0802 (I>2
s
C
13H5Cl2F5OS requires C, 41.62; H, 1.34%. 1H NMR (500 MHz, CDCl3)
were 0.0603 (all data). The final wR(F2) values were 0.0904 (all
data). The goodness of fit on F2 was 1.078. CCDC number CCDC
1031519.
dH 7.44e7.42 (1H, m, HAr), 7.27e7.24 (2H, m, HAr), 4.73e4.68 (2H, m,
CH2SO). 13C NMR (125 MHz, CDCl3) dC 145.4 (dm, 1JCF 252 Hz, CAr),
143.8 (dm, 1JCF 262 Hz, CAr), 137.5 (dm, 1JCF 254 Hz, CAr), 136.1 (CAr),
135.3 (CAr), 133.1 (CAr), 129.9 (CAr), 127.8 (CAr), 125.5 (CAr), 116.7 (m,
4.19. (R)-Benzyl phenyl sulfoxide (9b)
C
Ar), 57.5 (CH2SO). 19F NMR (565 MHz, CDCl3) ꢀ139.0 (m), ꢀ146.2
(tm, 3JFF¼21 Hz), ꢀ158.8 (m). IR (KBr)
n
/cmꢀ1 2927,1638,1518,1482,
White solids. Mp 134e136 ꢁC (from n-hexane/ethyl acetate 3:2).
1069, 976, 820.
(lit.18 mp 138e139 ꢁC for a sulfoxide having a 91% ee). ½a 2D5
þ96.5 (c
ꢂ
1.1 in CHCl3). (lit.18
½
a 2D5
ꢂ
ꢀ135.9 (c 0.49 in acetone) for the (S)
4.15. (R)-4-Iodobenzyl pentafluorophenyl sulfoxide (5b)
sulfoxide having a 91% ee).
4.20. (R)-Benzyl p-bromophenyl sulfoxide (10b)4
Crystal data for C13H11BrOS, M¼295.19, Orthorhombic,
White solids. Mp 180e181 ꢁC (from acetone/n-hexane 1:1). ½a 2D5
ꢀ19.3 (c 0.3 in CHCl3). The ee value was measured by HPLC (Col-
umn: Whelk-O1. Eluent: hexane/i-propanol 70:30). Found: C,
35.95; H, 1.68. C13H6F5IOS requires C, 36.13; H, 1.40%. 1H NMR
(500 MHz, CDCl3) dH 7.71e7.64 (2H, m, HAr), 6.98e6.91 (2H, m, HAr),
4.60 (1H, d, 2JHH 12.7 Hz, CH2SO), 4.43 (1H, d, 2JHH¼12.7 Hz, CH2SO).
13C NMR (125 MHz, CDCl3) dC 145.2 (dm, 1JCF 255 Hz, CAr),143.8 (dm,
1JCF 251 Hz, CAr), 138.4 (CAr), 137.7 (dm, 1JCF 255 Hz, CAr), 131.6 (CAr),
128.1 (CAr), 116.6 (CAr), 95.3 (I-CAr), 59.7 (CH2SO). 19F NMR
ꢂ
3
ꢁ
ꢁ
ꢁ
ꢁ
a¼5.6665(8) A, b¼12.081(2) A, c¼17.219(3) A, V¼1178.8(3) A ,
T¼93(2) K, space group P212121, Z¼4,
m
(MoK
a
)¼3.638 mmꢀ1,19,480
reflections measured, 2404 independent reflections (Rint¼0.1146).
The final R1 values were 0.0402 (I>2s
(I)). The final wR(F2) values
were 0.0744 (I>2s(I)). The final R1 values were 0.0555 (all data).
The final wR(F2) values were 0.0790 (all data). The goodness of fit on
F2 was 1.029. CCDC number CCDC 1031517.
(565 MHz, CDCl3) ꢀ138.8 (m), ꢀ146.1 (m), ꢀ158.7 (m). IR (KBr)
n/
cmꢀ1 2920, 1638, 1519, 1488, 1058, 982, 834.
4.16. (R)-4-Iodobenzyl p-tolyl sulfoxide (6b)
4.21. (R)-Benzyl 2-hydroxymethylphenyl sulfoxide (12b)
White crystals. Mp>210 ꢁC (from n-hexane/acetone 2:3), (lit.15
Enantiopure sulfoxide 12b was obtained by standard DIBAL-H
reduction of (R)-benzyl 2-carboxymethylphenyl sulfoxide 13b in
toluene at ꢀ30 ꢁC. Yield: 69%. White solids. Mp 139e141 ꢁC (from n-
hexane/ethyl acetate 3:2). (Lit.20 mp 101.5e102.5 ꢁC for a racemic
mp 174 ꢁC for the racemic sulfoxide). ½a 2D5
þ108.6 (c 0.8 in CHCl3).
ꢂ
The ee value was measured by HPLC (Column: Chiralcel OD-H. El-
uent: n-hexane/i-propanol 90:10).

4816
M.A.M. Capozzi et al. / Tetrahedron 71 (2015) 4810e4816
4. Capozzi, M. A. M.; Cardellicchio, C.; Naso, F.; Rosito, V. J. Org. Chem. 2002, 67,
sample). ½a 2D5
ꢂ
þ124.9 (c 0.4 in CHCl3). The ee value was controlled
7289e7294.
by HPLC (Column: Whelk-O1. Eluent: hexane/i-propanol 70:30).
5. Capozzi, M. A. M.; Cardellicchio, C.; Naso, F. Eur. J. Org. Chem. 2004, 1855e1863.
6. Naso, F.; Cardellicchio, C.; Affortunato, F.; Capozzi, M. A. M. Tetrahedron:
Asymmetry 2006, 17, 3226e3229.
7. Cardellicchio, C.; Hassan Omar, O.; Naso, F.; Capozzi, M. A. M.; Capitelli, F.;
Bertolasi, V. Tetrahedron: Asymmetry 2006, 17, 223e229.
8. Naso, F.; Capozzi, M. A. M.; Bottoni, A.; Calvaresi, M.; Bertolasi, V.; Capitelli, F.;
Cardellicchio, C. Chem.dEur. J. 2009, 15, 13417e13426.
9. Capozzi, M. A. M.; Centrone, C.; Fracchiolla, G.; Naso, F.; Cardellicchio, C. Eur. J.
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Acknowledgements
Dr. Roberto Berardozzi and Dr. Nicola Di Masi are gratefully ac-
knowledged for the acquisition of the CD and 19F NMR spectra re-
spectively. Thanks are due to CINMPIS consortium and to ‘Phoebus’
Project ‘Tecnologie plastiche per la realizzazione di celle solari e
sorgenti organiche per illuminazione ad elevata efficienza, uni-
10. Capozzi, M. A. M.; Capitelli, F.; Bottoni, A.; Calvaresi, M.; Cardellicchio, C.
ChemCatChem 2013, 5, 210e219.
11. Capozzi, M. A. M.; Fracchiolla, G.; Cardellicchio, C. J. Sulf. Chem. 2013, 34,
646e650.
12. Capozzi, M. A. M.; Capitelli, F.; Cardellicchio, C. Cryst. Growth Des. 2014, 14,
5442e5451.
ꢀ
formita e brillanza’ in the framework of the Reti di Laboratori
Pubblici di Ricerca.
13. Okano, K. Tetrahedron 2011, 67, 2483e2512.
14. Santoni, G.; Mba, M.; Bonchio, M.; Nugent, W. A.; Zonta, C.; Licini, G. Chem.
dEur. J. 2010, 16, 645e654.
Supplementary data
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Supplementary data (CD spectra of sulfoxides 2b, 4b and 5b.
Crystallographic Tables. 1H and 13C NMR spectra of already reported
compounds.) associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2015.05.036. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
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