Catalytic enantioselective oxidation of bulky alkyl aryl thioethers with H2O2 over titanium-salan catalysts

Article abstract of DOI:10.1002/ejoc.201100557

A simple and efficient catalytic procedure for the oxidation of bulky (preferably aryl benzyl substituted) thioethers with hydrogen peroxide in good to high yields and enantioselectivities (up to 98.5%ee) is reported. The high optical yields are achieved in a tandem stereoconvergent enantioselective oxidation and kinetic resolution process. A reasonable balance between the sulfoxide yield and enantioselectivity could be found by varying the concentration and temperature. An improved synthesis of the titanium-salan catalysts for the preparation of a more stereoselective catalyst is reported.

Full text of DOI:10.1002/ejoc.201100557

FULL PAPER
DOI: 10.1002/ejoc.201100557
Catalytic Enantioselective Oxidation of Bulky Alkyl Aryl Thioethers with
H2O2 over Titanium–Salan Catalysts
Konstantin P. Bryliakov*[a] and Evgenii P. Talsi[a]
Keywords: Asymmetric catalysis / Oxidation / Sulfur / Titanium / Peroxides
A simple and efficient catalytic procedure for the oxidation
of bulky (preferably aryl benzyl substituted) thioethers with
balance between the sulfoxide yield and enantioselectivity
could be found by varying the concentration and tempera-
hydrogen peroxide in good to high yields and enantio- ture. An improved synthesis of the titanium–salan catalysts
selectivities (up to 98.5%ee) is reported. The high optical for the preparation of a more stereoselective catalyst is re-
yields are achieved in a tandem stereoconvergent enantiose- ported.
lective oxidation and kinetic resolution process. A reasonable
However, while the above systems efficiently catalyze the
Introduction
oxidation of simple model substrates (like methyl aryl sulf-
ides), their capability to oxidize thioethers with bulky sub-
stituents at both sulfur atoms has not been proven. More-
over, even the replacement of the SMe group with SEt in
some cases led to a substantial drop in sulfoxide yield and
enantioselectivity.[6e,7a,7e,8] To date, while many sulfide pre-
cursors of biologically active chiral sulfoxides bear rather
bulky substituents at the sulfur atom,[3c–3e] the search for
environmentally benign and efficient catalyst systems for
the asymmetric oxidation of bulky sulfides remains a chal-
lenge.
The discovery of selective and efficient catalyst systems
for asymmetric sulfoxidations is a crucial task of catalytic
chemistry, taking into account the importance of chiral
sulfoxides for stereoselective synthetic applications and
pharmaceutical industry.[1] Since the milestone works of
Kagan[2a,2b] and of Modena,[2c] who reported enantioselec-
tive sulfoxidations with alkyl hydroperoxides over titanium–
tartrate catalysts, a good deal of catalytic systems for asym-
metric sulfoxidations have appeared, and they have been pe-
riodically overviewed.[3]
In 2008, we announced a titanium(IV)–salan based cata-
lyst system for the enantioselective oxidation of thioethers
and kinetic resolution of sulfoxides.[10] Herewith, an opti-
mized catalytic procedure for the enantioselective oxidation
of several aryl benzyl and other sulfides to sulfoxides is re-
ported. The role of electronic factors on the catalyst per-
formance has been probed. A proper selection of concentra-
tion and temperature conditions has reduced over-oxidation
to sulfone, yielding sulfoxides in 75–87% yield with up to
98.5%ee. To the best of our knowledge, these values are
among the highest ever reported for the transition-metal-
catalyzed enantioselective oxidation of benzyl aryl sulfides
with H2O2. A modified procedure for the synthesis of tita-
nium–salan complexes is reported, providing catalysts with
improved performance.
To date, quite a number of metal-based catalyst systems
are known, but very few of them have been applied for the
practical synthesis of optically pure sulfoxides.[4] Common
drawbacks preventing manufacturing applications are low
turnover numbers, insufficient stereoselectivities, the use of
relatively toxic metals, and harmful waste-producing oxi-
dants (like alkyl hydroperoxides). The significance of envi-
ronmental factors will increase in the future, in line with
toughening ecological requirements worldwide.
The use of molecular oxygen as an oxidant for prepara-
tive asymmetric sulfoxidations has not been achieved.[5] On
the contrary, various catalyst systems are known that suc-
cessfully use hydrogen peroxide as a cheap and environmen-
tally benign terminal oxidant. Some notable examples of
promising systems are the Bolm-type vanadium–[6a–6d] and
iron–Schiff base[6e–6g] complexes and Katsuki’s iron–
salen[7a,7b] and aluminum–salalen[7c–7g] systems.
Results and Discussion
[a] Department of Physical Methods of Catalytic Research,
Boreskov Institute of Catalysis
We found that a reported catalyst preparation[10] actually
yielded a mixture of titanium-containing species. Fortu-
nately, the reaction mixture could be readily separated, and
the active component could be purified on the basis of the
different solubilities of the resulting species in nonpolar sol-
Pr. Lavrentieva 5, Novosibirsk 630090, Russian Federation
Fax: +7-383-3308056
E-mail: bryliako@catalysis.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100557.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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K. P. Bryliakov, E. P. Talsi
FULL PAPER
vents (for details see the Experimental Section). Hereafter, examined. The results plotted in Figure 1 indicate that ef-
all catalytic results are given for the purified active cata- ficient kinetic resolution is crucial for achieving high enan-
lyst.[11] Earlier, we reported that catalysts with phenyl sub- tiomeric excess of the sulfoxide, the latter approaching 98–
stituents in the 3-position of the salicyl rings of the ligand 99% at oxidant/substrate ratios over 1.3–1.4. Another im-
demonstrated higher chemo- and enantioselectivities than portant observation is that the highest yield of the desired
those without or with various 3-alkyl substituents.[10] In this product, the (R)-sulfoxide,[13] is attained at relatively low
work, we examined the electronic effect of substituents in [H2O2]/substrate ratios of ca. 1.1, and a further increase in
the 5-position. Complexes 1–4 were prepared and purified, the amount of the oxidant reduces the yield of the (R)-sulf-
and their catalytic properties in the oxidation of several oxide as a result of pronounced over-oxidation to the sul-
sterically demanding sulfides have been tested (Scheme 1).
fone (Figure 1). Therefore, it would be unreasonable to use
Scheme 1. Titanium(IV) complexes 1–4.
First of all, we explored the effect of temperature, con-
centration, and substrate/catalyst ratio by using enantio-
meric complexes 1 and 2 (Table 1). It was found that sulfide
selectivity and asymmetric induction increased with
decreasing sulfide concentration (Table 1, Entries 1–4). An
increase in catalyst loading from 0.5 to 1.0 mol-% did not
clearly lead to higher enantioselectivity (Table 1, Entries 2,
3, 5–7);[12] however, in further experiments we used 1.0 mol-
% catalyst loading to guarantee acceptable reaction times.
The best results (in terms of sulfide selectivity and enantio-
meric excess) were obtained when the reaction temperature
was reduced to –10 °C (Table 1, Entries 8 and 9). Unexpec-
tedly, further cooling to –20 °C led to poorer ee values and
required longer reaction times (Table 1, Entries 10 and 11),
so further experimentation was conducted at –10 °C.
Figure 1. Sulfide conversion (᭿); yields of sulfoxide (᭹), (R)-sulfox-
ide (᭛), and sulfone (᭡); and enantiomeric excess (᭢) vs. H2O2/
sulfide ratio. (a) Catalyst 1 and substrate PhSCH2Ph and (b) cata-
For a proper choice of reaction conditions, the oxidation
of two bulky sulfides at various oxidant/substrate ratios was lyst 1 and substrate 2-naphthylSCH2Ph.
Table 1. Asymmetric oxidation of benzyl phenyl sulfide.[a]
Entry
Catalyst[b]
Substrate conc.
T
[°C]
Conversion
[%]
Sulfoxide/sulfone
yield [%]
ee [%]
(config.)
[mm]
1
2
3
4
5
6
7
8
2 (0.5)[c]
2 (0.5)[c]
2 (1.0)[c]
2 (1.0)[c]
2 (0.5)
100
25
25
12.5
10
10
10
10
10
10
0
0
0
0
0
0
0
–10
–10
–20
–20
84.5
86.5
85.1
87.5
94.1
94.2
93.8
96.7
94.8
96.4
94.2
74.7/9.8
77.0/9.5
77.5/7.6
83.4 (S)
92.0 (S)
90.6 (S)
93.2 (S)
92.7 (S)
94.1 (S)
92.3 (R)
93.6 (R)
94.7 (R)
90.0 (R)
89.8 (S)
79.9/7.6
81.6/12.5
80.6/13.6
79.9/13.9
83.5/13.2
81.3/13.5
82.4/14.0
82.6/11.6
2 (1.0)
1 (0.5)
1(1.0)
9
10
11
2(1.0)
1 (1.0)[d]
2 (1.0)[d]
10
[a] Reactions performed in CH2Cl2, oxidant/substrate = 1.1 mol/mol, reaction time 16 h. [b] Catalyst loading (mol-%) given in parentheses.
[c] Oxidant/substrate = 0.95 mol/mol. [d] Reaction time 2 d.
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Eur. J. Org. Chem. 2011, 4693–4698

Oxidation of Thioethers with H2O2 over Titanium–Salan Catalysts
a large excess of the oxidant (over 10%). On the other hand, enantioselectivities were attained with benzyl phenyl sulfide
in cases when resolution of the enantiomers of the sulfox- and its homologues and derivatives (Table 2, Entries 5–8).
ides offers difficulties, one could increase the H2O2/sub- While impressive optical yields have been documented for
strate ratio to 1.3–1.4 to obtain the sulfoxide in Ͼ98%ee. benzyl phenyl sulfide itself (Table 2, Entry 5), introduction
The results of enantioselective oxidation of several thio- of a weakly electron-donating methyl group into the phenyl
ethers are presented in Table 2.
ring of the substrate led to slightly lower enantioselection
Catalysts of type 1–4 display poor ee values in the oxi- (Table 2, Entry 6). The substrate with a strong electron-
dation of methyl aryl sulfides (Table 2, Entries 1, 2, 9). The withdrawing NO2 group was oxidized with higher ee and
enantioselectivity is much higher when methyl is substituted lower chemoselectivity. Titanium–salan catalysts are poorly
for a bulkier alkyl group like isopropyl or cyclohexyl selective for the oxidation of disulfides: along with the
(Table 2, Entries 3 and 4). However, the highest chemo- and major monosulfoxide, significant amounts of disulfides
Table 2. Asymmetric oxidation of various sulfides.
[a] Sulfide initial concentration 10 mm, reaction time 16 h. [b] Catalyst loading (mol-%) given in parentheses. [c] The yield of (R)-sulfoxide
was calculated as in ref.[13] [d] Reaction time 40 h. [e] Conversions measured after 16 and 24 h were found to be identical. [f] Yield of
monoxide/chiral dioxide/meso-dioxide given.
Eur. J. Org. Chem. 2011, 4693–4698
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4695

K. P. Bryliakov, E. P. Talsi
FULL PAPER
were detected in the oxidation of 1,2-bis(phenylthio)- sults were only reported by Ahn and co-workers who used
ethane (Table 2, Entry 10). Bolm’s catalytic protocol, with specially designed sterically
Introduction of an electron-withdrawing Br substituent hindered Schiff base ligands possessing additional elements
in the salicylidene ring gave less stereoselective catalyst 3 of chirality.[9d] The enantioselective sulfoxidation is ac-
(Table 2, Entries 5 and 6); furthermore, 3 displayed much companied by a stereoconvergent kinetic resolution process.
lower reactivity, so that the reaction required 40 h even with The role of kinetic resolution is critical, as the sulfoxidation
a higher (1.5 mol-%) catalyst loading. On the other hand, stage itself, at low conversion levels, allows sulfoxides to
introduction of a weakly electron-donating methyl groups be formed with only ca. 85–87%ee, and the optical purity
into the 5-position of the salicylidene ring of the ligand (i.e., substantially rises at high conversions. The electronic struc-
catalyst 4) led to lower chemo- and enantioselectivities of tures of complexes 1 and 2 are optimal for the sulfoxid-
sulfoxidation (Table 2, Entries 5–8), apparently associated ations; introduction of electron-donating substituents re-
with higher catalyst reactivity caused by additional electron duces the catalyst selectivity and turnover number, whereas
density.
electron-withdrawing ones reduce the reactivity, and the
Remarkably, lower conversions (compared to catalyst 1) enantioselectivity drops in both cases. Methylene chloride
were observed in all cases for catalyst 4 (this is especially was used as the reaction solvent, which could be easily dis-
true for p-NO2PhSCH2Ph; for the latter, conversions mea- tilled from the reaction mixture and recycled repeatedly. For
sured after 16 and 24 h were found to be identical and quite the preparation of the titanium–salan catalyst, a new syn-
low, 44.5%). A likely reason for that is faster deactivation of thetic procedure was developed that allows the isolation of
catalyst 4 and, hence, a lower turnover number is realized. the active catalyst component in a chemically pure form,
The oxidations are scalable; one such example is de- and the catalysts prepared thereby display higher chemo-
scribed in the Experimental Section. Benzyl p-tolyl sulfide and stereoselectivity. Practical applications of the presented
(0.5 mmol) was oxidized to the corresponding sulfoxide in systems are foreseen.
80.9% yield with 92.0%ee. After column workup and
recrystallization, the sulfoxide was isolated in 69.4% yield
with 98.1%ee (the latter was further increased to 99.7%
after additional recrystallization).
Experimental Section
General Methods: H2O2 was used as analytical grade 30% aqueous
solution. Silica gel 60 (0.063–0.200 mm) for column chromatog-
raphy was purchased from Panreac. CH3CN for syntheses was
dried with 4 Å molecular sieves and stored under an atmosphere
Of particular interest is the structure of the titanium–
salan precatalyst. Katsuki and co-workers reported a bis(μ-
oxo) binuclear structure for the titanium–salan precatalysts
used in the enantioselective epoxidation of alkenes.[14] How- of argon. Hexane and dichloromethane for catalysts preparation
were dried with 4 Å molecular sieves. All other chemicals were Ald-
rich, AlfaAesar, or Acros commercial reagents. Chiral salan ligands
were prepared according to common procedures.[10] Details of the
syntheses of other reagents are described in the Supporting Infor-
mation. 1H and 13C NMR spectra were measured with a Bruker
Avance 400 at 400.13 and 100.613 MHz, respectively, in 5 mm cy-
lindrical tubes. Chemical shifts were referenced to internal reference
TMS, with positive values in the low-field direction. Peak assign-
ment in the 1H and 13C spectra of titanium–salan complexes has
been performed based on homo- (1H–1H) and heteronuclear (13C–
ever, our synthetic procedure is different in that we do not
add any water into the reaction mixture, and a special sepa-
ration procedure is applied to isolate the desired active cata-
lyst. In principle, one could expect the formation of mono-
nuclear titanium–salan complexes similar to those charac-
terized by Walsh and co-workers,[15] but this did not occur
in our case. On the contrary, while mononuclear titanium–
salan species of the type [LTi(OiPr)2] (L = salan ligand)
were formed in solution of L/Ti(OiPr)4 (1:1), both NMR
and X-ray data evidenced the binuclear structure of catalyst 1H) correlated spectra.
2 [LTi(μ-O)2TiL]·xS (S = Et2O or iPrOH, x = 1.2–2.0), iso-
lated as a solid from this mixture. The other solid fraction
Representative Procedure for the Preparation of Ti–Salan Catalysts:
Ti(OiPr)4 (0.27 mmol) and the (S,S)-salan ligand (0.27 mmol) were
separated before the isolation of the active catalyst
stirred in dry CH2Cl2 (1 mL) for 15 min and then all volatiles were
(“crop 1”) is probably a mixture of oligomeric species (for removed in vacuo. The residue was redissolved in CH2Cl2 (1 mL),
and the volatiles were removed in vacuo again. The residue was
dissolved in CH2Cl2 (1 mL), diluted with hexane (10 mL), and al-
lowed to evaporate slowly (during 16 h) to a volume of 5 mL. The
solid precipitate (“crop 1”) was filtered off, and the filtrate was
evaporated over 10 h to yield desired [LTi(μ-O)2TiL] complex 2
(97 mg, “crop 2”). For X-ray measurements, 2 was recrystallized
from diethyl ether at –10 °C.
details see the Supporting Information and the Experimen-
tal Section).
Conclusions
In conclusion, we have developed a simple and efficient
synthetic protocol for the catalytic enantioselective oxi-
dation of bulky thioethers with cheap and environmentally
benign hydrogen peroxide; aryl benzyl sulfides emerged as
the most appropriate substrates. Chiral sulfoxides were ob-
tained in 75–87% yield with up to 98.5%ee, which are
among the highest values for catalytic sulfoxidations of aryl
General Oxidation Procedure: Sulfide (0.1 mmol) was added to the
Ti–salan catalyst (1 μmol) dissolved in the appropriate volume of
CH2Cl2 (ca. 10 mL). The mixture was thermostatted at the desired
temperature (ca. –10 °C), and an appropriate volume of aqueous
hydrogen peroxide (30%) was then added in one portion. Stirring
was continued at the desired temperature for 16–40 h. The reaction
progress was periodically monitored by TLC (EtOAc/hexane). Af-
benzyl sulfides with H2O2 reported so far; comparable re- ter the reaction was complete, a 1-mL aliquot of the mixture was
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Eur. J. Org. Chem. 2011, 4693–4698

Oxidation of Thioethers with H2O2 over Titanium–Salan Catalysts
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salen-based catalyst system for aerobic sulfoxidations; however,
high (5 mol-%) catalyst loadings, the high cost of the catalyst,
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The only exception is the vanadium–Schiff base system, which
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taken and quickly evaporated in a stream of air. The residue was
dissolved in CCl4 (0.6 mL) or CDCl3/CCl4, and the composition
of products was analyzed by 1H NMR spectroscopy (for NMR
spectroscopic data see Supporting Information and ref.[10]). For En-
tries 1–4 and 9 (Table 2), the enantiomeric excess values were mea-
sured by 1H NMR with Eu(hfc)3 chiral shift reagent in CCl4 or
CDCl3/CCl4 as reported in ref.[10] and the references cited therein.
For Entries 5–8 and 10 (Table 2), crude reaction mixtures were sep-
arated on a short column (SiO2, hexane/acetone), and the enantio-
meric excess of the sulfoxides were measured with a Shimadzu LC-
20 HPLC chromatograph with chiral columns. Benzyl phenyl sulf-
[2]
[3]
oxide: Chiralcel OD-H, hexane/iPrOH
254 nm, tR = 13.7 (R), 16.7 (S) min. Benzyl p-tolyl sulfoxide: Chi-
ralpak AD-H, hexane/iPrOH = 90:10, 1.0 mL/min, 227 nm, tR
= 90:10, 1.0 mL/min,
=
11.2 (R), 12.4 (S) min. Benzyl p-nitrophenyl sulfoxide: Chiralcel
OD-H, hexane/iPrOH = 85:15, 1.0 mL/min, 254 nm, tR = 34.0 (R),
38.4 (S) min. Benzyl 2-naphthyl sulfoxide: Chiralpak AD-H, hex-
ane/iPrOH = 80:10, 1.0 mL/min, 227 nm, tR = 17.5 (R), 19.6
(S) min. 1-Phenylsulfinyl-2-phenylthioethane: Chiralcel OD-H,
hexane/iPrOH = 90:10, 1.0 mL/min, 254 nm, tR = 16.3 (R), 19.5
(S) min. The absolute configurations of the sulfoxides were estab-
lished by comparison of the Eu(hfc)3-shifted NMR patterns of the
sulfoxides with those of the sulfoxides with known absolute config-
uration (as described in ref.[16h]).
[4]
[5]
[6]
Preparative Oxidation: Benzyl p-tolyl sulfide (0.5 mmol, 107.0 mg)
was added to the Ti–salan catalyst (ca. 5 μmol, 6.0 mg) dissolved
in CH2Cl2 (50 mL). The mixture was thermostatted at –10 °C, and
30% aqueous hydrogen peroxide (60 μL, 1.2 equiv.) was then added
in one portion. Stirring was continued at the desired temperature
for 18 h. A 0.4 mL aliquot was taken; volatiles were removed in a
stream of air, and the residue was dissolved in CCl4 (0.6 mL) for
NMR analysis. 1H NMR spectroscopy revealed 3.8% of unreacted
sulfide, 80.9% of sulfoxide, and 15.3% of sulfone. All volatiles were
removed in a vacuum. The solid residue was separated on a short
SiO2 column, to yield 86.6 mg (75.3%) of the crude sulfoxide hav-
ing optical purity 92.0%ee. The latter was dissolved in acetone/
hexane (1:1, 50 mL) and allowed to evaporate slowly (during 3 d)
at room temperature to ca. 15–20 mL and then stored at –20 °C
overnight. The crystals were filtered off and dried in air. Yield of
(R)-sulfoxide after recrystallization was 79.8 mg (69.4%), and op-
tical purity 98.1%ee. One more recrystallization at –20 °C yielded
69.4 mg of (R)-sulfoxide with 99.7% ee.
[7]
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic procedures, spectroscopic data, additional catalytic
data, and structure of the binuclear titanium catalyst.
Acknowledgments
[8]
[9]
This work was supported by the Russian Foundation for Basic Re-
search for the financial support of this work, grant 09-03-00087.
The authors thank Mr. Bernhard Weibert (University of Konstanz)
for the X-ray measurements.
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The term “active catalyst” might be somewhat confusing here,
as the admixtures have also been found to be capable of cata-
lyzing asymmetric sulfoxidation, albeit with lower chemo- and
enantioselectivity (see the Supporting Information).
Eur. J. Org. Chem. 2011, 4693–4698
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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K. P. Bryliakov, E. P. Talsi
FULL PAPER
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Received: April 20, 2011
Published Online: June 21, 2011
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Eur. J. Org. Chem. 2011, 4693–4698