Asymmetric oxidation of sulfides with H2O2 catalyzed by titanium complexes of Schiff bases bearing a dicumenyl salicylidenyl unit

Article abstract of DOI:10.1002/aoc.1762

The sterically hindered Schiff bases (L³-L⁵), prepared from 3,5-dicumenyl salicylaldehyde and chiral amino alcohols, were used in combination with Ti(OiPr)₄ for asymmetric oxidation of aryl methyl sulfides with H₂O₂ as terminal oxidant. Among the ligands L³-L⁵, L⁴ with a tert-butyl group in the chiral carbon of the amino alcohol moiety gave the best result with 89% yield and 73% ee for the sulfoxidation of thioanisole under optimal conditions [with 1 mol% of Ti(OiPr)₄ in a molar ratio of 100:1:1.2:120 for sulfide:Ti(OiPr)₄:ligand:H₂O₂ in CH ₂Cl₂ at 0 °C for 3 h]. The reaction afforded good yield (84%) with a moderate enantioselectivity (62% ee) even with a lower catalyst loading from 1.0 to 0.5 mol%. The oxidations of methyl 4-bromophenyl sulfide and methyl 4-methoxyphenyl sulfide with H₂O₂ catalyzed by the Ti(OiPr)₄-L⁴ system gave 79-84% yields and 54-59% ee of the corresponding sulfoxides in CH₂Cl₂ at 20 °C. The chiral induction capability of the cumenyl-modified sterically hindered Schiff bases for sulfoxidation was compared with the conventional Schiff bases bearing tert-butyl groups at the 3,5-positions of the salicylidenyl unit.

Full text of DOI:10.1002/aoc.1762

Full Paper
Received: 21 September 2010
Revised: 4 November 2010
Accepted: 10 November 2010
Published online in Wiley Online Library: 9 February 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1762
Asymmetric oxidation of sulfides with H2O2
catalyzed by titanium complexes of Schiff
bases bearing a dicumenyl salicylidenyl unit
Ying Wanga, Mei Wanga∗, Lin Wanga, Yu Wanga, Xiuna Wanga
and Licheng Suna,b∗ ∗
The sterically hindered Schiff bases (L3 –L5), prepared from 3,5-dicumenyl salicylaldehyde and chiral amino alcohols, were
used in combination with Ti(OiPr)4 for asymmetric oxidation of aryl methyl sulfides with H2O2 as terminal oxidant. Among
the ligands L3 –L5, L4 with a tert-butyl group in the chiral carbon of the amino alcohol moiety gave the best result with 89%
yield and 73% ee for the sulfoxidation of thioanisole under optimal conditions [with 1 mol% of Ti(OiPr)4 in a molar ratio
of 100 : 1 : 1.2 : 120 for sulfide : Ti(OiPr)4 : ligand : H2O2 in CH2Cl2 at 0 ◦C for 3 h]. The reaction afforded good yield (84%) with
a moderate enantioselectivity (62% ee) even with a lower catalyst loading from 1.0 to 0.5 mol%. The oxidations of methyl
4-bromophenyl sulfide and methyl 4-methoxyphenyl sulfide with H2O2 catalyzed by the Ti(OiPr)4 –L4 system gave 79–84%
yieldsand54–59%eeofthecorrespondingsulfoxidesinCH2Cl2 at20 ◦C. Thechiralinductioncapabilityofthecumenyl-modified
sterically hindered Schiff bases for sulfoxidation was compared with the conventional Schiff bases bearing tert-butyl groups at
c
the 3,5-positions of the salicylidenyl unit. Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: asymmetric catalysis; chiral sulfoxides; dicumenyl salicylaldehyde; Schiff bases; titanium
Introduction
the systems: (1) good-to-high enantioselectivity; (2) the simplicity,
convenient preparation and easy modification of chiral Schiff base
ligands; (3) the utilization of cheap and environmentally benign
terminal oxidant (H2O2); and (4) the facile reaction conditions
and easy workup.[13a] However, vanadium-based catalysts are not
desirable from the environmental point of view. Catalyst systems
based on nontoxic metals such as titanium and iron with ‘green’
oxidant H2O2 are of particular interest. Bolm and co-workers
reported that the iron-based catalyst system of Fe(acac)3-Schiff
bases could catalyze the oxidation of sulfides using H2O2 as
oxidant in the presence of certain acids or carboxylates, giving
sulfoxides in 36–78% yields and 66–96% ee.[14c] The other iron-
based catalyst is an Fe(salan) complex bearing additional chiral
centers in aromatic rings, which displayed enantioselectivity up to
96% ee with 72–90% yields for sulfoxidation of sulfides with H2O2
in water. Synthesis of such salan ligands with additional elements
Enantiopuresulfoxidesareusefulauxiliariesandsynthonsinasym-
metric synthesis.[1] In recent years, chiral sulfoxides are finding
increasing use as bioactive ingredients in the pharmaceutical in-
dustrybecauseofthespecialbiologicalpropertyofthechiraldrugs
containing a sulfinyl group with a defined configuration.[2] The
most challenging approach to enantiopure sulfoxides is transition
metal-catalyzed asymmetric oxidation of sulfides. In 1984, Kagan
and Modena independently discovered that prochiral sulfides
could be effectively oxidized to chiral sulfoxides with good-to-
high enantioselectivity by modified Sharpless catalytic systems
comprising Ti(OiPr)4 –chiral tartrate–alkyl hydroperoxide.[3] This
method has been successfully used in preparation of the drug es-
omeprazole, the active ingredient in AstraZeneca’s antiulcer drug
Nexium.[4] The disadvantages of this method are the sensitivity
of the titanium-based catalyst system to moisture, low turnover
numbers (4–16 mol% of the catalyst required), low chemoselec-
tivity, and the use of expensive and toxic aryl hydroperoxides such
as cumene hydroperoxide (CHP) as oxidants.[5] Development of
more active, highly chemo- and enantioselective, robust, cheap
and environmentally benign catalyst systems has been one of the
attractive topics in the field of asymmetric catalysis in the past
two decades. Various catalyst systems for asymmetric oxidation of
∗
Correspondence to: Mei Wang, State Key Laboratory of Fine Chemicals, DUT-
KTH Joint Education and Research Center on Molecular Devices, Dalian
University of Technology (DUT), Dalian 116012, P. R. China.
E-mail: symbueno@dlut.edu.cn
∗∗
Licheng Sun, State Key Laboratory of Fine Chemicals, Dalian University of
Technology, Zhongshan Road 158-46, Dalian 116012, P. R. China.
E-mail: lichengs@kth.se
sulfideshavebeenreported, suchasTi-BINOL,[6] -salen,[7] -salan,[8]
-
C2-symmetric diol[9] and -Schiff base,[10] Zr-trialkanol amine,[11]
Mn-salen,[12] V-[13] and Fe-Schiff base,[14] Al-salan[15] and organic
catalysts.[16] In recent years, the research in this field has mainly
focused on the titanium- and vanadium-based catalyst systems.
Bolm’s catalyst systems of VO(acac)2-Schiff bases have been
extensively studied since 1995 because of the advantages of
a
StateKeyLaboratoryofFineChemicals, DUT-KTHJointEducationandResearch
Center on Molecular Devices, Dalian University of Technology (DUT), Dalian
116012, P. R. China
b
Department of Chemistry, Royal Institute of Technology (KTH), 10044
Stockholm, Sweden
c
Appl. Organometal. Chem. 2011, 25, 325–330
Copyright ꢀ 2011 John Wiley & Sons, Ltd.

Y. Wang et al.
Figure 2. The structures of the Schiff base ligands L3 –L7.
Figure 1. Efficient iodo-functionalized chiral Schiff bases used in Bolm’s
catalyst systems.
Table 1. Titanium-catalyzed oxidation of thioanisole with different
oxidantsa
O
chirality is difficult.[17a] With easily prepared salen ligands, the
enantioselectivity of the iron-based catalyst systems decreased to
64% ee.[17b]
[Ti(Oi-Pr)4]/L4
S
S
Ph
CH3
oxidant, CH2Cl2, 20 °C
Ph
CH3
Entry Oxidant Time (h) Yield (%)b Ee (%)c,d Configuration
Conventional titanium-based catalyst systems need alkyl or
aryl hydroperoxides as terminal oxidants to form sulfoxides in
high enantioselectivity. The first example of the titanium-based
systemsusingH2O2 asoxidantforasymmetricoxidationof sulfides
wasreportedbyPasiniin1986, whichgavealowenantioselectivity
(<20% ee).[7a] Similarly, low enantioselectivity (10% ee) was
obtained even with a mononuclear titanium salen complex
bearing additional elements of chirality in the salen ligand,
while the corresponding di-µ-oxo binuclear titanium complex in
combinationwithacomplicatedsalenligandcontainingadditional
chiral elements displayed good-to-high enantioselectivity (up to
99% ee) and 78–92% yields of chiral sulfoxides for the oxidation
of aryl methyl sulfides with H2O2.[7b] Furthermore, Ti(OiPr)4
in combination with the N-salicylidene-L-aminoalcohol-derived
Schiff bases, which were usually adopted in vanadium-based
Bolm’s catalyst systems, proved to be highly active for oxidation
of sulfides with H2O2.[10] These titanium-based catalyst systems
displayed good chemoselectivity (up to 97%) but only low-to-
moderate enantioselectivities, up to 60% ee for oxidation of
benzyl phenyl sulfide and 42% ee for aryl methyl sulfide. Although
it was found that the catalyst systems comprising VO(acac)2
and iodo-functionalized chiral Schiff bases (L1 and L2, Fig. 1)
displayed considerably improved enantioselectivity in asymmetric
oxidation of sulfides as compared with other analogous Schiff
bases,[18] theracemicsulfoxideswereobtainedfromtheoxidations
of thioanisole (this work) and methyl 4-nitrophenyl sulfide[10]
catalyzed by Ti(OiPr)4 –L1 and–L2 systems with H2O2 as oxidant.
The results indicate that introduction of halogen atoms with
1
2
3
4
H2O2
2
10
1
89
89
84
–
66
−3
21
–
S
R
S
tBuOOH
mCPBA
PhIO
24
a Reaction conditions: Ti(OiPr)4 (0.01 mmol), L4 (0.012 mmol),
thioanisole (1.0 mmol), oxidant (1.2 mmol), CH2Cl2 (2 ml), 20 ◦C.
b Isolated yield, calculated based on the adding amount of the
sulfide. c Determined by HPLC with Daicel Chiralcel OD-H column,
V(hexane)–V(iPrOH) = 9:1.
d The absolute configuration was assigned by comparing optical
rotations and HPLC elution orders with literature data.
Ti(OiPr)4 on the asymmetric oxidation of sulfides. Preliminary
results show that the catalyst systems of Ti(OiPr)4 and Schiff bases
bearing cumenylsubstituentswithH2O2 asoxidantdisplayedhigh
activity [using 0.5–1 mol% Ti(OiPr)4] for oxidation of thioanisole
with enantioselectivity up to 73% ee under optimal conditions.
The enantioselectivity of sulfoxides comes dominantly from the
sulfide oxidation instead of the kinetic resolution in sulfoxide
overoxidation, resulting in high chemoselectivity. The asymmetric
induction effect of Schiff bases L3 –L5 was compared with that of
the widely used Schiff bases L6 and L7 (Fig. 2).
some stereoelectric effect to the aromatic ring of Schiff bases, Results and Discussion
the strategy used for enhancement of the enantioselectivity
of vanadium-based catalysts, does not work for the Ti(OiPr)4-
tridentate Schiff base systems.
We first explored the performance of the Ti(OiPr)4 –L4 catalyst
system for asymmetric oxidation of thioanisole using different
oxidants in a molar ratio of 1 : 1.2 : 100 : 120 for Ti(OiPr)4 –Schiff
base ligand–thioanisole–oxidant in CH2Cl2 at 20 ◦C. The catalytic
results are given in Table 1. Each catalytic reaction was repeated
at least twice. Thioanisole cannot be oxidized by PhIO in the
Ti(OiPr)4 –L4 system. With tBuOOH as oxidant, methyl phenyl
sulfoxide was obtained in good yield after 10 h reaction, but it
is nearly racemic. The Ti(OiPr)4 –L4 system displayed a relatively
high activity with mCPBA as oxidant. The oxidation of thioanisole
completed at 20 ◦C in 1 h, giving the corresponding sulfoxide in
84% yield with a low enantioselectivity (21% ee). Aqueous H2O2
(30%) emerges as a good performing oxidant for the titanium-
catalyzed asymmetric oxidation of thioanisole, which afforded
methyl phenyl sulfoxide in 89% yield and 66% ee (Table 1, entry
1). The dominant enantiomer is in S configuration. Aqueous H2O2
To find Schiff base ligands with good enantioselectivity
for titanium-catalyzed sulfoxidations with H2O2, we prepared
three sterically hindered chiral Schiff bases L3 –L5 (Fig. 2) from
condensation reactions of 3,5-dicumenylsalicylaldehyde with
chiral amino alcohols. Except for L4,[19] L3 and L5 have not
been reported in the literature. These Schiff bases were used
for the asymmetric oxidation of prochiral sulfides for the first
time. We found that the enantioselectivity of sulfide oxidations
with Ti(OiPr)4-Schiff base systems could be improved by using
these sterically hindered chiral Schiff bases. We screened the
catalytic behaviors of L3 –L5 in combination with Ti(OiPr)4 for
asymmetric oxidation of aryl methyl sulfides and explored the
influences of terminal oxidants, solvents, temperature, the ratio
of Ti(OiPr)4 to Schiff base ligands and the loading amount of
c
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Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 325–330

Asymmetric oxidation of sulfides with H2O2
Table 2. Influence of temperature on the titanium-catalyzed asym-
Table 3. Influence of solvents on the titanium-catalyzed asymmetric
metric oxidation of thioanisolea
oxidation of thioanisolea
O
O
[Ti(Oi-Pr)4]/L4
[Ti(Oi-Pr)4]/L4
S
S
..
..
S
Ph
S
CH3
Ph
CH3
H2O2, CH2Cl2
Ph
H2O2, solvent
Ph
CH3
ee (%)c,d
CH3
Entry Solvent Temperature (◦C) Time (h) Yield (%)b ee (%)c,d
Entry
Temperature (◦C)
Time (h)
Yield (%)b
1
2
3
20
0
2
3
3
89
89
88
66
73
70
1
CH2Cl2
CHCl3
CCl4
0
0
3
3
3
3
3
3
3
2
2
2
2
2
2
89
75
37
64
88
87
95
89
87
85
71
96
87
73
57
57
58
41
47
44
66
63
39
64
31
47
2
−10
3
0
4
Toluene
THF
0
a Reaction conditions: Ti(OiPr)4 (0.01 mmol), L4 (0.012 mmol),
thioanisole (1.0 mmol), aqueous H2O2 (30%, 1.2 mmol), CH2Cl2 (2 ml).
b Isolated yield. c See footnote c in Table 1.
5
0
6
CH3CN
CH3OH
CH2Cl2
CH2Cl2
THF
0
d The major enantiomers obtained from all entries are in the S
configuration.
7
0
8
20
20
20
20
20
20
9e
10
11e
12
13e
(30%) was used as terminal oxidant in the following catalytic
reactions.
THF
CH3OH
CH3OH
Table 2 shows the influence of temperature on the oxidation
of thioanisole catalyzed by the Ti(OiPr)4 –L4 system with H2O2 in
CH2Cl2. The GC analysis showed that the oxidation of thioanisole
was close to the end in 1 h at room temperature and in 3 h at 0 ◦C
(Figs S1 and S2, see Supporting Information). When the reaction
temperature was decreased from room temperature to 0 ◦C, the
enantioselectivity of the sulfoxide was increased from 66 to 73%
ee (entry 1 vs 2). Further decrease in the temperature to −10 ◦C
did not apparently affect the yield and the enantioselectivity of
the sulfoxide (entry 2 vs 3).
The GC analysis of the resulting solution from entry 2 in Table 2
shows that the reaction reaches equilibrium at 0 ◦C after 3 h
and a small amount (ca 10%) of thioanisole is still left in the
solution (Figs S2 and S4). Methyl phenyl sulfoxide is the dominant
product detected by GC analysis. The peak at 10–11 min in the
GC spectrum Fig. S3 for methyl phenyl sulfone, formed from the
sulfoxidation of thioanisole catalyzed by VO(acac)2 –Schiff base
ligand, is hardly observed in Fig. S4. Further studies on the kinetic
resolution of racemic methyl phenyl sulfoxide show that methyl
phenyl sulfoxide can be oxidized to the corresponding sulfone
by the Ti(OiPr)4 –L4 system with H2O2 in CH2Cl2 at 20 ◦C, but
the reaction has no enantioselectivity. The results indicate that
this titanium-based catalyst system has high chemoselectivity and
thatthegoodenantioselectivityoftheTi(OiPr)4 –L4 systemdirectly
comes from the asymmetric oxidation of thioanisole instead of
the kinetic resolution by overoxidation of the initially formed
sulfoxide.
Next, the influence of solvents on the asymmetric oxidation
of thioanisole catalyzed by the Ti(OiPr)4 –L4 system was explored
with H2O2 as oxidant at 0 ◦C for 3 h (Table 3). Compared with the
less hydrophilic solvents such as toluene, CCl4, CHCl3 and CH2Cl2,
the solvents with strong polarity and miscible with water such as
THF, CH3CN and CH3OH gave better yields (87–95%) but lower
enantioselectivity(41–47%ee).Wealsofoundthatslowadditionof
H2O2 to the THF or CH3OH solution could apparently improve the
enantioselectivity (entry 11 vs 10, 64 vs 39% ee in THF; entry 13 vs
12,47 vs31%eeinCH3OH),buttheyieldsweredecreasedby10%or
so.Incontrast,slowadditionofH2O2 tothesolventshardlymiscible
with water, such as CH2Cl2, did not influence the ee value and the
yield of methyl phenyl sulfoxide (entry 9 vs 8). Presumably, the
better solubility of aqueous H2O2 in THF, CH3CN and CH3OH could
a Reaction conditions: Ti(OiPr)4 (0.01 mmol), L4 (0.012 mmol),
thioanisole (1.0 mmol), aqueous H2O2 (30%, 1.2 mmol), solvent (2 ml).
b Isolated yield. c See footnote c in Table 1. d See footnote d in Table 2.
e Slow addition of H2O2 (1.2 mmol for 30 min).
facilitatetheformationofanoxidizedactivetitaniumspeciesbythe
simple reaction of Ti(OiPr)4 with H2O2 without participation of the
chiral ligand,[13b,20] leading to a decrease in the enantioselectivity
of sulfoxide. Indeed, in the absence of Schiff bases, Ti(OiPr)4 can
catalyze the oxidation of thioanisole with H2O2 in CH2Cl2 at 0 ◦C
to the corresponding racemic sulfoxide. Slow addition of H2O2
may depress the formation of the active achiral titanium species in
water-miscible solvents. Considering both enantioselectivity and
yield, dichloromethane is the best solvent among all the tested
solvents for the titanium-catalyzed asymmetric oxidation of aryl
methyl sulfides. The oxidation of thioanisole with H2O2 in CH2Cl2
at 0 ◦C affords 89% yield of methyl phenyl sulfoxide with 73% ee.
The influence of the molar ratio of Ti(OiPr)4 to the Schiff base
ligand was also explored for asymmetric oxidation of thioanisole.
When the molar ratio of ligand to Ti(OiPr)4 was changed from 1 : 1
to 1.2 : 1, the yield of the sulfoxide was raised from 82 to 89% and
the enantioselectivity from 70 to 73% ee (entry 2 vs 1 in Table 4).
Further increase in the ratio of ligand to Ti(OiPr)4 to 1.5 : 1 and 2 : 1
ledtoadecreaseintheyieldandenantioselectivityofthesulfoxide
(entries 3 and 4). These results are identical with the previous
report that titanium species containing more than one ligand per
titanium can hardly be responsible for asymmetric oxidations and
therefore,increasingtheratioofligandtoTi(OiPr)4 (over1.25)leads
to lower conversions and enantioselectivity.[10] With a low loading
ofTi(OiPr)4 (0.5 mol%),theoxidationofthioanisolestillgaveagood
yield and enantioselectivity of methyl phenyl sulfoxide (entry 5,
84% yield and 62% ee) in the optimal molar ratio of 1.2 : 1 for ligand
to Ti(OiPr)4 with H2O2 as oxidant in CH2Cl2 at 0 ◦C for 3 h. The
result shows that this titanium-based catalyst system has a high
activityascomparedwiththeconventionaltitanium-basedsystem
of Ti(OiPr)4 –chiral tartrate–alkyl hydroperoxide, which requires
4–16 mol% catalyst loading for effective oxidation of sulfides.[3–5]
Increase of the Ti(OiPr)4 loading to 2.0 mol% could not give better
c
Appl. Organometal. Chem. 2011, 25, 325–330
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Y. Wang et al.
Table 4. Influences of the molar ratio of Ti(OiPr)4 –L4 and the loading
Table 5. Effects of Schiff base ligands on the titanium-catalyzed
asymmetric oxidation of aryl methyl sulfidesa
amount of the catalyst on the asymmetric oxidation of thioanisolea
O
O
[Ti(Oi-Pr)4]/L4
S
[Ti(Oi-Pr)4]/L
S
..
S
Ar
CH3
S
Ph
CH3
H2O2, CH2Cl2, 0 °C
Ar
H2O2, CH2Cl2, 0 °C, 3 h
Ph
CH3
ee (%)c,d
CH3
Entry
Ligand
Ar
Yield (%)b
Ti(OiPr)4 –L4
(molar ratio)
Entry
Ti(OiPr)4 (mol%)
Yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
8f
9f
L1
L2
L3
L4
L5
L6
L7
L4
L4
4-NO2C6H4
43 (3 h)
Racemice
Racemic
57
Ph
66 (24 h)
1
2
3
4
5
6
1
1 : 1
82
89
82
79
84
85
70
73
69
68
62
64
Ph
91
89
83
71
90
84
79
1
1 : 1.2
1 : 1.5
1 : 2
Ph
Ph
73
1
46
1
Ph
40
0.5
2
1 : 1.2
1 : 1.2
Ph
48
4-BrC6H4
4-CH3OC6H4
54g
a Reaction conditions: Ti(OiPr)4 (0.01 mmol) except for entries 5 and
6, L4, thioanisole (1.0 mmol), aqueous H2O2 (30%, 1.2 mmol), CH2Cl2
(2 ml), 0 ◦C, 3 h. b Isolated yield. c See footnote c in Table 1.d See
footnote d in Table 2.
59g
a Reaction conditions: Ti(OiPr)4 (0.01 mmol), ligand (0.012 mmol), aryl
methyl sulfide (1.0 mmol), aqueous H2O2 (30%, 1.2 mmol), CH2Cl2
(2 ml), 0 ◦C, 3 h. b Isolated yield. c See footnote c i◦n Table 1. d See
footnote d in Table 2. e Bryliakov and Talsi.[10] f At 20 C. g Determined
by HPLC with Daicel Chiralcel OB-H column, V(hexane)–V(iPrOH) = 8:2
for entry 8 and 5 : 5 for entry 9.
yield and ee value of the sulfoxide (entry 6). On the basis of
the results obtained from all catalytic experiments, the optimal
conditions for the titanium-catalyzed asymmetric oxidation of
sulfides with H2O2 are in the molar ratio of 100 : 1 : 1.2 : 120 for
sulfide–Ti(OiPr)4 –ligand–H2O2 with a 1 mol% loading of Ti(OiPr)4
in CH2Cl2 at 0 ◦C.
of methyl 4-bromophenyl sulfide and methyl 4-methoxylphenyl
sulfide (entries 8 and 9). Compared with the enantioselectivities
(29–42% ee) obtained by Ti(OiPr)4 –L1 and–L2 systems for
the asymmetric oxidation of methyl 4-bromophenyl sulfide
reported in the literature,[10] the Schiff base L4 containing two
cumenyl substituents has a better asymmetric induction effect for
asymmetric oxidation of aryl methyl sulfides.
It was found that the iodo and bromo substituents at the 3,
5-positions of the salicylidenyl moiety of the Schiff base displayed
quite different effects on the vanadium- and titanium-catalyzed
asymmetric oxidations of sulfides. Ligands L1 and L2 containing
the iodo substituent(s) gave high enantioselectivities (90–97% ee)
for the vanadium-catalyzed oxidation of thioanisole with H2O2
in CH2Cl2 or CHCl3,[18] while racemic methyl phenyl sulfoxide
was obtained from the same reaction under similar conditions
catalyzed by Ti(OiPr)4 –L1 and–L2 (entries 1 and 2 in Table 5). The
effect of the bulky cumenyl groups in the Schiff base ligands on
the titanium-catalyzed asymmetric oxidation of sulfides can be
illustrated by comparing the catalytic results of the two subsets
(L3 vs L6 and L4 vs L7) with the same R group in the chiral
amino alcohol moiety. The oxidation of thioanisole using titanium
catalysts in combination with the Schiff bases L3 and L4 containing
two cumenyl groups at the 3,5-positions of the salicylidenyl unit
gave high yields (89–91%) with 57% and 73% ee (entries 3 and
4), respectively, which are apparently higher than those (40% and
48% ee) obtained from the titanium catalyst systems with ligands
L6 and L7 bearing two tert-butyl groups (entries 6 and 7). For
the Schiff bases L3, L4 and L5, with different R groups in the
chiral carbon of the amino alcohol moiety, the enantioselectivity
of the sulfoxide considerably reduced with decrease in the size
Conclusions
In conclusion, Schiff bases L3 –L5, easily prepared from 3,
5-dicumenyl salicylaldehyde and chiral amino alcohols, are
effective ligands for the titanium-catalyzed asymmetric oxidation
of aryl methyl sulfides using H2O2 as terminal oxidant. The
Ti(OiPr)4 –L (L=L3, L4 and L5) systems exhibited high activity
with low loading of the titanium catalyst (0.5–1.0 mol%) and also
high chemoselectivity to sulfoxides (up to 91% isolated yield).
Compared with the widely used Schiff bases L1 and L2 derived
from 3,5-di-tert-butyl salicylaldehyde and chiral amino alcohols, L3
and L4 in combination with Ti(OiPr)4 displayed apparently higher
enantioselectivity [up to 73% ee for (S)-methyl phenyl sulfoxide],
which results dominantly from the direct asymmetric oxidation of
sulfides.
of the R group (entries 3–5): L4 (R = tert-butyl, 73% ee) >L3 Experimental
(R = isopropyl, 57% ee) >L5 (R = benzyl, 46% ee). The results
Materials and Instruments
show that the large steric effect of the bulky substituents, both
at the 3,5-positions of the salicylidenyl unit and in the chiral
carbon of the amino alcohol moiety, can apparently improve the
enantioselectivity of the titanium-catalyzed sulfide oxidation with
H2O2 as oxidant.
All aryl methyl sulfides were purchased from Aldrich and chiral
amino acids (S)-tert-leucine, (S)-valine and (S)-phenylalanine from
Aldrich and GL Biochem (Shanghai) Ltd. 2,4-Dicumenylphenol
was purchased from Aladdin and Ti(OiPr)4 from Alfa Aesar.
Other starting compounds of reagent grade were obtained from
local suppliers and used as received. Chiral amino alcohols were
prepared by reduction of corresponding amino acids according to
the literature procedures.[21]
Asymmetric oxidations of other aryl methyl sulfides were
also explored using the Ti(OiPr)4 –L4 system with H2O2 as
terminal oxidant in CH2Cl2 at 0 ◦C. Good yields with moderate
enantioselectivities (54–59% ee) were obtained for oxidations
c
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Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 325–330

Asymmetric oxidation of sulfides with H2O2
(S)-2-[N-{3,5-Bis(α,α-dimethylbenzyl)salicylidene}amino]-3-methyl-
1-butanol (L3)
◦
Yellow solid, 37% yield, m.p.: 45–46 C, [α] = −21.3◦ (c = 0.05,
23
589
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 0.83 [d, J = 6.0 Hz, 3H,
HC(CH3)2], 0.90 [d, J = 6.0 Hz, 3H, HC(CH3)2], 1.64, 1.70 [2s, 12H,
PhC(CH3)2], 1.78–1.85 [m, 1H, HC(CH3)2], 2.88–2.92 (m, 1H, C N-
CH), 3.68 (m, 1H, CHHOH), 3.77 (m, 1H, CHHOH), 7.05 (d, J = 2.4 Hz,
1H, ArH), 7.13 (t, J = 6.8 Hz, 1H, ArH), 7.18–7.24 (m, 5H, ArH),
7.28–7.29 (m, 4H, ArH), 7.33 (d, J = 2.4 Hz, 1H, ArH), 8.25 (s,
1H, HC N), 13.06 (s, 1H, ArOH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 19.2, 19.3 [2C, HC(CH3)2], 28.8, 30.1, 30.3, 30.9 [4C, PhC(CH3)2],
31.1 [HC(CH3)2], 42.3, 42.5 [2C, PhC(CH3)2], 64.5 (CH2OH), 78.2
(C N–CH), 125.2, 125.5, 126.8, 127.9, 129.5, 129.6, 136.2, 139.8,
150.7, 150.8 (17C, C6H5, C6H2), 157.9 (CPh –OH), 166.7 (HC N)
ppm. IR (KBr): ν = 3420, 2964, 2931, 2872, 1630, 1599, 1493, 1462,
1442, 1382, 1362, 1278, 764, 699 cm−1. ESI-MS: m/z = 444.2 [M +
H]+.
Scheme 1. Synthetic route for Schiff bases L3 –L5.
The 1H NMR spectra were obtained on an Unity Inova 400NMR
spectrometer with TMS as internal standard. Mass spectra were
performed by electrospray ionization (ESI) on an HP 1100 MSD
instrument. IR spectra were performed on a Jasco FT/IR 430
infrared spectrometer. Optical rotations at 589 nm were measured
with a Jasco P-1010 digital polarimeter.
(S)-2-[N-{3,5-Bis(α,α-dimethylbenzyl)salicylidene}amino]-3,
3-dimethyl-1-butanol (L4)
◦
Yellow solid, 35% yield, mp: 53–54 C, [α] = −23.2◦ (c = 0.05,
23
589
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 0.88 [s, 9H, C(CH3)3],
1.62, 1.69 [2s, 12H, PhC(CH3)2], 2.84 (m, 1H, C N-CH), 3.64 (m,
1H, CHHOH), 3.82 (m, 1H, CHHOH), 7.05 (d, J = 2.4 Hz, 1H, ArH),
7.13 (t, J = 7.0 Hz, 1H, ArH), 7.18–7.23 (m, 5H, ArH), 7.28–7.30
(m, 4H, ArH), 7.33 (d, J = 2.4 Hz, 1H, ArH), 8.24 (s, 1H, HC N),
13.05 (s, 1H, ArOH) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.2 [3C,
C(CH3)3], 30.3, 30.6, 31.0, 31.2 [4C, PhC(CH3)2], 33.3 [C(CH3)3], 42.3,
42.5 [2C, PhC(CH3)2], 62.5 (CH2OH), 81.7 (C N–CH), 125.2, 125.9,
126.9, 127.9, 128.2, 129.5, 136.1, 139.8, 150.6, 150.7 (17C, C6H5,
C6H2), 157.9 (CPh –OH), 166.9 (HC N) ppm. IR (KBr): ν = 3436,
2965, 2870, 1630, 1599, 1493, 1460, 1441, 1396, 1382, 1362, 764,
699 cm−1. ESI-MS: m/z = 458.3 [M + H]+.
Synthesis of Schiff Bases
Ligands L6 and L7 were prepared according to literature
procedures.[10] Schiff bases L3 –L5 were prepared in two steps:
formylation of 2,4-dicumenylphenol and condensation of 3,
5-dicumenylsalicylaldehyde with chiral amino alcohols, as shown
in Scheme 1.
Preparation of 3,5-Dicumenylsalicylaldehyde[22]
2,4-Dicumenylphenol (13.2 g, 0.04 mol) was added to the solution
of Mg(OCH3)2 (2.6 g, 0.03 mol) in methanol (30 ml) under an
N2 atmosphere. The mixture was heated to reflux and half of
the methanol was distilled out. After the resulting solution was
cooled to room temperature, 30 ml of toluene was added to the
solutionandthelow-boilingfractionswereremovedbydistillation.
Paraformaldehyde (4.32 g, 0.14 mol) was added portion wise in 1 h
at 95 ◦C. The mixture was stirred at 95 ◦C for 2 h and the solution
turned to orange. Dilute sulfuric acid (45 ml, 10%) was slowly
added to the solution after it was cooled to room temperature.
The mixture was stirred at 35 ◦C for 2 h, and then poured to a
separatory funnel and stand overnight. The aqueous layer was
extracted with toluene (3 × 30 ml) and the collected organic
layer was washed with brine and dried over anhydrous MgSO4.
Solvents were removed under reduced pressure. The product was
purified by flash chromatography on silica gel with petroleum
ether–CH2Cl2 (1 : 1, v/v) as eluent. The oily product (yield: 65%)
was used directly in the next step synthesis.
(S)-2-[N-{3,5-Bis(α,α-dimethylbenzyl)salicylidene}amino]-3-phenyl-
1-propanol (L5)
Yellow solid, 39% yield, mp: 64–65 ◦C, [α]23 = −128.9◦ (c = 0.05,
589
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.66, 1.68 [2s, 12H,
PhC(CH3)2], 2.78 (m, 1H, CHHPh), 2.84 (m, 1H, CHHPh), 3.40 (m,
1H, C N-CH), 3.68 (m, 2H, CH2OH), 6.93 (s, 1H, ArH), 7.05 (d,
J = 7.6 Hz, 2H, ArH), 7.14–7.20 (m, 7H, ArH), 7.24–7.31 (m, 6H,
ArH), 7.35 (d, J = 2.4 Hz, 1H, ArH), 8.06 (s, 1H, HC N), 13.07 (s,
1H, ArOH) ppm. 13C NMR (100 MHz, CDCl3): δ = 29.3, 29.5, 29.8,
31.0 [4C, PhC(CH3)2], 39.1 (PhCH2), 42.2, 42.5 [2C, PhC(CH3)2], 65.6
(CH2OH), 73.3 (C N–CH), 125.2, 125.7, 125.8, 126.4, 126.8, 128.0,
128.1, 128.2, 128.5, 129.3, 129.5, 136.1, 138.0, 139.8, 150.7 (23C,
C6H5, C6H2), 157.7 (CPh –OH), 166.8 (HC N). IR (KBr): ν = 3440,
2964, 2927, 2870, 1629, 1493, 1441, 1382, 1361, 764, 699 cm−1
ESI-MS: m/z = 492.3 [M + H]+.
.
General Procedure for the Asymmetric Oxidation of Aryl
Methyl Sulfides
General Procedure for the Preparation of L3 –L5
3,5-Dicumenylsalicylaldehyde (1.0 mmol) and a chiral amino
alcohol (1.2 mmol) were dissolved in dry methanol (20–50 ml)
under nitrogen atmosphere. The solution was refluxed for 4 h.
Afterwards solvent was removed under reduced pressure to give
a crude product, which was purified by flash chromatography
on silica gel with ether–CH2Cl2 (4 : 1, v/v) and then CH2Cl2 as
eluents.
Compound Ti(OiPr)4 (2.8 mg, 0.01 mmol) and a Schiff base ligand
(0.012 mmol) were dissolved in solvent (1 ml). The mixture turned
frompaleyellowtobrilliantyellowandstirredatroomtemperature
for 30 min. A solution of the sulfide (1.0 mmol) in the selected
solvent (1 ml) was added with stirring, followed by addition of
an aqueous H2O2 (30%, 1.2 mmol) at 0 ◦C. After the mixture was
stirred at 0 ◦C for 3 h, the resulting solution was extracted with
c
Appl. Organometal. Chem. 2011, 25, 325–330
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
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Y. Wang et al.
CH2Cl2. The organic layer was washed with brine and dried over
Na2SO4. Filtration and evaporation gave a residue, which was
purified by flash chromatography on silica gel with petroleum
ether–ethyl acetate (3 : 2, v/v) and then ethyl acetate as eluents.
The pure sulfoxide was obtained after removal of solvent by
rotary evaporation. Enantiomeric excesses (ee) of sulfoxides were
determined by HPLC analysis using chiral columns (Daicel Chiracel
OD-H, 25×0.46 cm i.d. and Daicel Chiracel OB-H, 25×0.46 cm i.d.).
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We are grateful to the National Natural Science Foundation of
China (grant no. 20973032), the Program for Changjiang Scholars
and Innovative Research Team in University (IRT0711) and the K&A
Wallenberg Foundation of Sweden for financial support of this
work.
Supporting information
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Supporting information may be found in the online version of this
article.
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Appl. Organometal. Chem. 2011, 25, 325–330