Bimetallic titanium complex catalyzed enantioselective oxidation of thioethers using aqueous H2O2 as a terminal oxidant

Article abstract of DOI:10.1039/c5ra06528c

A series of dimeric amino alcohol derived Schiff bases with various chiral amino alcohols and their corresponding bimetallic titanium complex were generated in situ. Thereafter with the in situ generated complexes, the asymmetric oxidation of prochiral aryl alkyl sulfides has been investigated using aqueous H₂O₂ as a terminal oxidant. During the study we found that the use of methanol or tert-butanol as an additive improved the catalytic activity in terms of both conversion and enantioselectivity. Moreover we observed a co-operative effect of the two reactive units of the bimetallic complex, which results in high reactivity as well as enantioselectivity compared to the corresponding monomeric complex. With this improved catalytic system several aryl alkyl sulfides and 1,3-dithianes were oxidised to the corresponding sulfoxides with good to high enantioselectivity (ee 78-99%) and conversion (70-99%). Unlike the monomer, oxidation of substrates like benzyl phenyl sulfide was achieved with high enantioselectivity as well as high yield.

Full text of DOI:10.1039/c5ra06528c

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: P. K. Bera, N.
Gupta, S. H. R. Abdi, N. H. Khan, R. I. Kureshy and H. C. Bajaj, RSC Adv., 2015, DOI: 10.1039/C5RA06528C.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

View Article Online
DOI: 10.1039/C5RA06528C
Page 1 of 8
RSC Advances
Journal Name
RSCPublishing
ARTICLE
Bimetallic titanium complex catalyzed enantioselective
oxidation of thioethers using aqueous H2O2 as terminal
oxidant
Cite this: DOI: 10.1039/x0xx00000x
Prasanta Kumar Bera,a Naveen Gupta,a, b Sayed H. R. Abdi,* a, b Noor-ul H.
Khan,a, b Rukhsana I. Kureshy,a, b Hari C. Bajaja, b
,
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
A series of dimeric amino alcohol derived Schiff bases with various chiral amino alcohols and
their corresponding bimetallic titanium complex were generated in situ. Thereafter with the in
situ generated complexes, the asymmetric oxidation of prochiral aryl alkyl sulfides has been
investigated using aqueous H2O2 as a terminal oxidant. During the study we found that the use
of methanol or tert-butanol as an additive improve the catalytic activity in terms of both
conversion and enantioselectivity. Moreover we observed co-operative effect of the two
reactive unit of bimetallic complex, which results high reactivity as well as enantioselectivity
compared to the corresponding monomeric complex. With this improved catalytic system
several aryl alkyl sulfides and 1,3-dithianes were oxidised to corresponding sulfoxides with
good to high enantioselectivity (ee 78-99%) and conversion (70-99%). Unlike monomer,
Oxidation of substrates like benzyl phenyl sulfide were achieved with high enantioselectivity
as well as high yield.
www.rsc.org/
parallel study, chiral amino alcohol derived Schiff base ligands
and salen ligands were successfully used for enantioselective
sulfoxidation reaction especially with vanadium10 and iron11
Introduction
The enantioselective oxidation of prochiral sulfides is a current
focus of asymmetric organic oxidative transformations due to
its increasing application as chiral auxiliaries,1 ligands,2
organo-catalysts3 and in pharmaceutical industries as drug and
intermediate for the synthesis of biologically active
compounds.4 During the last few decades motivated by the
reports of Kagan5 and Modena6 on asymmetric sulfoxidation
using modified Sharpless catalytic system, this reaction has
been studied extensively7 using various transition metal based
catalysts such as titanium, vanadium, iron, copper, manganese
etc. as well as with organo catalyst. After the discovery of first
catalytic protocol using titanium isopropoxide (Ti(Oi-Pr)4) as
titanium source, (R,R)-DET as ligand and tert-butyl
hydroperoxide as oxidant, the following research based on
titanium catalyst mainly focused on the use of various chiral
diol type ligand as a substituent of DET to improve the
enantioselectivity of the products.8 These Ti-diol systems
mostly worked well with tert-butyl hydrogen peroxide (TBHP)
and cumene hydroperoxide (CHP) as oxidant but not with the
aqueous hydrogen peroxide. Instead of using chiral Ti-complex,
several chiral hydroperoxides were also employed for the
asymmetric induction to the sulfoxides as well as oxidant in
presence of catalytic amount of titanium isopropoxide.9 In
and titanium12 complexes. Bryliakov et al.12c for the first time
demonstrated catalytic system with chiral amino alcohol
derived Schiff base as ligand and Ti(Oi-Pr)4 as metal source.
However only 43% ee was obtained with chiral 1-amino-2-
indanol derived Schiff base ligand using environment benign
and economically favorable aqueous H2O2 as an oxidant. Later
on the same group developed catalytic system using in situ
generated Ti-salan complex12e-12g which provided better
enantioselectivity (98.5% ee) due to the successive oxidative
kinetic resolution of the sulfoxide, formed in asymmetric
oxidation of sulfides. This catalytic protocol particularly
worked well for the oxidation of aryl benzyl sulfides. In case of
aryl alkyl sulfides poor enantioselectivity was observed and the
low selectivity significantly reduce the overall yield of the
desired product. Sun et al. screened a series of amino alcohol
derived Schiff base ligand12h for the enantioselective oxidation
of aryl methyl sulfide and achieved moderate but still better
enantioselectivity (40-73% ee). In this context, taking the
challenge to developed Titanium-amino alcohol derived Schiff
base ligand mediated catalytic protocol, our group have
developed Ti-mediated asymmetric sulfoxidation12i procedure
in 2011 using a family of 1,2-diphenyl amino alcohol derived
This journal is © The Royal Society of Chemistry 2013
J. Name., 2013, 00, 1-3 | 1

View Article Online
RSC Advances
DOI: 10.1039/C5RA06P52a8gCe 2 of 8
ARTICLE
Journal Name
Schiff bases as ligand. The study revealed the steric and
electronic effect of the ligands on the outcome of the reaction.
Herein we synthesized a series of dimeric ligands derived from
different chiral amino alcohols and used them to generate
bimetallic titanium complex in situ for the asymmetric
sulfoxidation using aqueous H2O2 as oxidant. This study
showed the co-operative effect of the two reacting unit of
dimeric complex to increase the reactivity of the system as well
as the enantioselectivity of the product. Besides this the use of
methanol or tert-butanol as an additive was found to be
beneficial to improve the enantioselectivity.
Results and discussion
In our previous report12i we identified 2-amino-1,2-diphenyl
ethanol as efficient chiral auxiliary for Ti-mediated asymmetric
sulfoxidation and the most attention was given to find out the
effect of substituents on the salicylaldehyde moiety. The study
revealed the importance of tert-butyl group at 3 position of the
salicylaldehyde moiety for better enantioinduction to the
product. In recent years, dimeric or polymeric complexes are
getting more attention because of the higher catalytic efficiency
dut to co-operative effective of reactive centers. Keeping these
Fig. 1 Structure of the amino alcohol derived dimeric Schiff base
ligands.
Table
1 Ligand screening experiments for the asymmetric
sulfoxidation of methyl phenyl sulfidea
in mind we have selected a bis-aldehyde (
group at 3 position of the salicylaldehyde part. Thereafter a
family of dimeric amino alcohol derived Schiff base (L1-L7
A) having tert-butyl
)
were synthesized by the condensation of bis-aldehyde (
a variety of chiral amino alcohols (Scheme 1).
A) with
Entry Ligand
Conversionb
(%)
Selectivityb
(%)
eec
(%)
Config.d
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
78
93
94
93
90
73
91
92
94
90
85
91
92
93
60
10
38
25
41
3
R(+)
S(-)
S(-)
S(-)
R(+)
S(-)
S(-)
Scheme 1 Synthesis of amino alcohol derived dimeric chiral ligands
L1 L7
(
-
)
Next in ligand screening experiments, we have generated
bimetallic titanium complexes (see supporting information) in
situ by reacting dimeric ligands (L1-L7, Fig. 1) with Ti(Oi-Pr)4
in dry DCM under an inert atmosphere (N2) at room
temperature (RT). These in situ generated complexes were then
used as catalysts for the enantioselective oxidation of methyl
phenyl sulfide with aqueous H2O2 as an oxidant. In most of the
cases we observed high conversions (73-95%) and chemo-
selectivity (85-94%) for the desired products (Table 1).
However, the best enantioselectivity achieved was 60% ee
(Table 1, entry 1) with the catalyst generated from the ligand
L1 having chirality originated from 2-amino-1,2-
diphenylethanol. Ligands derived from (S)-phenyl alaninol
4
a
Reaction condition: 0.5 mmol C6H5SCH3, 2.5 mol% Ti(Oi-Pr)4 with respect
to substrate. Ti:ligand (L1-L7) = 1:1.25 (the ratio was calculated based on the
monomeric unit of ligands), 1.2 equiv. 30% aqueous H2O2 in 2 ml of dry
DCM at RT for 3.5h. Determined by H NMR measurement of sulfide,
sulfoxide and sulfone relative concentration. Determined by HPLC with a
Daicel Chiralcel OD column, flow rate = 0.5 ml/min. hexane/i-PrOH = 8/2
(v/v). The absolute configuration were assigned by comparing HPLC
elution orders and sign of optical rotations with literature data.
b
1
c
d
enantioenduction in the product and the same product
configuration but with low ee (3-4%) was observed in case of
ligands (L6 and L7) having di-phenyl substitution at α-position
of amino alcohol, though these ligands were derived from R-
amino alcohols. This observation clearly indicate that the
substitution at α-position of amino alcohol moiety had a
significant impact on the enantioselectivity as well as on dual
stereo control properties of the catalytic system.13 Thus based
on the ligand screening experiments, ligand L1 was selected to
optimize other catalytic reaction parameters.
(
L3), (S)-valinol (L4) and (1S,2R)-1-amino-2-indanol (L5)
provided moderate (38, 25 and 41% ee respectively; Table 1,
entries 3, 4 and 5) result. However, L2, L6 and L7 gave inferior
results in term of both yield and enantioselectivity (Table 1,
entries 2, 6 and 7). It is worthy to mention that catalysts
generated from the ligands (L2, L3 and L4) having (S)-amino
alcohol without any substitution at α-position induce (S)-
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

View Article Online
DOI: 10.1039/C5RA06528C
Page 3 of 8
Journal Name
RSC Advances
ARTICLE
Table 3 Optimization of catalyst loading and metal to ligand ratioa
In the course to optimize the reaction condition, other
chlorinated solvents and several green solvents viz., MeOH,
EtOH, EtOAc, 1,4-dioxan and DMC were employed for this
reaction. In order to rule out the issue of patchy complexation
in different solvents, the catalyst was first generated by the
reaction of L1 with Ti(Oi-Pr)4 in DCM. Thereafter the DCM
was evaporated under reduced pressure and the catalytic run
was carried out in different solvents (Table 2, entries 2-9).
Though the conversion and selectivity of these solvents were
comparable or even better in some cases, but the
enantioselectivity (up to 49% ee for EtOH) were well below the
ee (60%) obtained with DCM as solvent. Thereafter other
alternative oxidants such as UHP, CHP, and TBHP were also
screened (entries 10-12), but none of these provided
comparable result with H2O2 as oxidant.
Entry
Catalyst
loading
(mol %)
2
Ti:L
ratio
Conversionb Selectivityb
eec
(%)
(%)
(%)
1
2
3
4
5
6
7
1:1.25
1:1.25
1:1.25
1:1.25
1:1
68
76
78
82
72
78
74
93
94
93
89
86
91
88
53
60
65
66
56
61
62
2.5
3
3.5
3
3
1:1.15
1:2
Table 2 Investigation of solvent for asymmetric sulfoxidationa
3
a
Reaction condition: 0.5 mmol C6H5SCH3, Ti(Oi-Pr)4, ligand L1(the ratio
was calculated based on the monomeric unit of ligands), 1.2 equiv. 30%
aqueous H2O2 in 2 ml of dry DCM at RT for 3.5h. b Determined by 1H NMR
c
measurement of sulfide, sulfoxide and sulfone relative concentration.
Determined by HPLC with a Daicel Chiralcel OD column, flow rate = 0.5
ml/min. hexane/i-PrOH = 8/2 (v/v).
Entry
Solvent
Oxidant
Conv.b (%) Select.b (%)
eec (%)
1
2
3
4
5
6
7
DCM
CHCl3
DCE
CCl4
MeOH
EtOH
EtOAc
1,4-
Dioxan
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
78
71
76
68
71
69
83
93
91
89
85
94
97
90
60
35
42
11
32
49
45
When dealing with the in situ generated catalysis, the use of
exact 1:1 ratio of titanium and ligand may cause incomplete
consumption of Ti(Oi-Pr)4 and the excess ligand cause the
formation of multiple Ti-complexes.12c Therefore, the metal to
ligand ratio was varied taking 3 mol% of Ti(Oi-Pr)4, (Table 3,
entries 5-7). On increasing the Ti to ligand ratio from 1:1 to
1:1.2, slight increase in conversion and enantioselectivity was
observed which went up to 65% ee at a Ti to ligand ratio of
1:1.25 (Table 3, entry 3). However, a further increase in this
ratio caused decreased in the enantioselectivity (ee, 62%; Table
3, entry 7).
8
H2O2
91
75
43
9
DMC
H2O2
UHP
CHP
89
83
68
71
92
88
88
91
23
49
8
10
11
12
DCM
DCM
DCM
TBHP
5
a Reaction condition: 0.5 mmol C6H5SCH3, 2.5 mol% Ti(Oi-Pr)4, with respect
to substrate, ligand L1, Ti:ligand = 1:1.25 (the ratio was calculated based on
the monomeric unit of ligand), 1.2 equiv. 30% aqueous H2O2 in 2 ml of dry
The asymmetric sulfoxidation with in situ generated
bimetallic titanium complex reflects the significant
b
1
solvent at RT for 3.5h. Determined by H NMR measurement of sulfide, improvement in the reactivity as well as enantioselectivity over
sulfoxide and sulfone relative concentration. Determined by HPLC with a
the monometallic complex.12i The bimetallic catalytic system
c
Daicel Chiralcel OD column, flow rate = 0.5 ml/min. hexane/i-PrOH = 8/2
(v/v).
took only 3.5h to complete the reaction, whereas in case of
monomeric system the reaction time was 10h. To get a deeper
insight into the matter, we have tested the nonlinear effect
(NLE) of the present bimetallic titanium system (Fig. 2) and
observed a positive NLE of this catalytic system. At the present
stage, the precise reason for this implication in reactivity and
enantioselectivity in not known but based on Figure 2 a
possible cooperative effect in bimetallic complex cannot be
ruled out.
Katsuki et al.10b reported an enhancement in
enantioselectivity when methanol was used as an additive in the
asymmetric sulfoxidation reaction with vanadium catalyst.
Furthermore, in titanium complex based sulfoxidation it was
suggested that methanol acts as a coordinating solvent to
generate the active catalyst.12a and 12b
Next we performed catalytic reactions by taking different
catalyst loadings as well as metal to ligand ratios which was
calculated based on monomeric unit of the ligand (Table 3). On
decreasing the catalyst loading from 2.5 mol% to 2 mol%
keeping the metal to ligand ratio 1:1.25 (calculated based on the
monomeric unit of ligand), both yield and enantioselectivity
decreased to 53% (Table 3, entry 1), whereas it increased
slightly on increasing the catalyst loading to 3 mol% (Table 3,
entry 3, ee 65%). A further increase in the catalyst loading does
not improve the enantioselectivity, but a marginal increase in
the conversion and decrease in chemo-selectivity (Table 3,
entry 4) was observed.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3

View Article Online
RSC Advances
DOI: 10.1039/C5RA06P52a8gCe 4 of 8
ARTICLE
Journal Name
gave slightly higher ee, we have selected methanol as additive
100
90
80
70
60
50
40
30
20
10
0
for this catalytic system because we noticed inferior ee in
alcohols as solvent and for the same mol% of additive,
methanol has significantly less volume (≤2) compared to t-
butanol, which allow us to check broad range of additive
loading without significant solvent effect on the result.
It is well known in the literature that some of the titanium
based catalytic system essentially needs water as an additive to
generate oxo bridge titanium complex as an effective catalyst in
situ.12d However in current case we observed a significant
improvement in the reaction rate using 2.2 equivalent of H2O as
an additive at post-complexation step but at the same time it
caused lower enantioinduction (Fig. 3, (a)). Fortunately the use
of methanol together with H2O catalyzed the reaction at higher
reaction rate retaining the enantioselectivity as observed with
methanol alone (Fig. 3, (b)).
0
20
40
60
80
100
ee of (1S,2R)-L1
Fig. 2 Positive NLE in the oxidation of C6H5SCH3 with in situ
generated bimetallic Ti-catalyst from dimeric ligand L1
.
Taking a clue from this report, a series of non-chiral as well as
chiral alcohols (50 mol% with respect to substrate) such as
methanol, ethanol, 2-propanol, tert-butanol menthol and 2-
napthol were screened as additive with the in situ generated Ti-
complex (Table 4). As it turned out to be, the use of an alcohol
except 2-napthol (Table 4, entry 7), proved to be beneficial in
improving the conversion as well as enantioselectivity, but in
case of acetone we observed a drop in enantioselectivity (Table
4, entry 8).
100
(b)
(b)
(a)
90
80
70
60
50
40
30
(a)
Table 4 Effect of additive on catalytic oxidation of methyl phenyl
sulfide a
Conversion
Conversion
ee
ee
15
30
45
60
75
Minutes
Entry
Additive
Conversionb
(%)
Selectivityb eec (%)
(%)
Fig. 3 Effect of H2O (a) and CH3OH with H2O (b) as additive on
catalytic oxidation of C6H5SCH3 with dimeric Ti-complex catalyzed
asymmetric sulfoxidation.
(50 mol%)
1
2
3
4
5
6
7
8
MeOH
EtOH
88
86
90
91
92
92
80
79
88
88
87
89
91
90
91
86
75
73
67
75
70
73
58
52
IPA
For more refinement in the enantioselectivity, catalytic
activity was examined at lower temperature using methanol as
an additive (Table 5). On decreasing the reaction temperature
the enantioselectivity gradually increased to 85% (entries 1-5)
t-BuOH
Menthol (R/S)
Menthol (L)
2-Napthol
Acetone
o
and selectivity increased to 95% at 0 C but the conversion
decreased to 83%. Further decrease in the reaction temperature
caused a sharp drop in the conversion without any improvement
in the enantioselectivity (Table 5, entry 5). The excellent
selectivity for the desired product clearly indicate the negligible
contribution of kinetic resolution of sulfoxide to increase of the
enantiomeric excess of the product at lower temperature. Next
a
Reaction condition: 0.5 mmol C6H5SCH3, 3 mol % Ti(Oi-Pr)4, ligand L1,
Ti:ligand = 1:1.25 (the ratio was calculated based on the monomeric unit of
b
ligand), 1.2 equiv. 30% aqueous H2O2 in 2 ml of dry DCM at RT for 3.5h.
Determined by 1H NMR measurement of sulfide, sulfoxide and sulfone
c
relative concentration. Determined by HPLC with a Daicel Chiralcel OD
column, flow rate = 0.5 ml/min. hexane/i-PrOH = 8/2 (v/v).
the amount of additive also checked at
0
oC. The
enantioselectivity as well as conversion increased with the
increase in the amount of additive up to 40 µl (Table 5, entries
6) and attained the maximum value of 91%.
Having optimized the reaction condition with the ligand L1
and MeOH as an additive, the scope of substrate variation was
investigated and the results are shown in Table 6. All the
sulfides were oxidized to sulfoxides smoothly, with high
In the case of methanol and tert-butanol (Table 4, entries 1 and
4) the enantioselectivity increased to 75% from 65% at RT. To
know the effect of chiral alcohols on enantioselectivity both
racemic as well as chiral menthol were used as an additive
(Table 4, entries 5 and 6), but a marginal difference in
enantioselectivity was observed. Though t-butanol as additive
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

View Article Online
DOI: 10.1039/C5RA06528C
Page 5 of 8
Journal Name
RSC Advances
ARTICLE
enantioselectivity (up to 99%), conversion (up to 95%) and enantioselectivity (78-95% ee). It is worthy to mention that the
chemo-selectivity for all the substrates (89-95%).
catalyst get precipitated out on excess addition of hexane to the
concentrated reaction mixture. But unfortunately the activity of
the recovered catalyst dropped significantly.
Table 5 Effect of temperature and methanol as an additive for the
asymmetric sulfoxidationa
Table 6 Catalytic asymmetric sulfoxidation with in situ generated
L1-Ti complex using H2O2 as oxidanta
Entry
Additive
amount
(µl)
Temperature
(oC)
Conversionb
(%)
Selectivityb
(%)
eec
(%)
1d
2
10
10
10
10
10
20
40
60
25 (RT)
96
90
87
83
72
95
95
96
88
94
96
95
97
96
95
95
75
81
84
85
85
88
91
87
Entry
Sulfide
Conv.b
(%)
Select.b (%)
eec
(%)
Config.d
10
5
3
1
2
3
95
94
93
94
91
90
91
94
82
R(+)
R(+)
R(+)
4
0
5
-5
0
5d
6d
7 d
0
0
a
4
5
88
87
95
93
84
91
R(+)
R(+)
Reaction condition: 0.5 mmol C6H5SCH3, 3 mol % Ti(Oi-Pr)4, ligand L1,
Ti:ligand = 1:1.15, additive (methanol), 30% aqueous H2O2 in 2 ml of dry
DCM for 1h. Determined by H NMR measurement of sulfide, sulfoxide
and sulfone relative concentration. Determined by HPLC with a Daicel
Chiralcel OD column, flow rate = 0.5 ml/min. hexane/i-PrOH = 8/2 (v/v).
b
1
c
d
The reaction was continued for 1.5h.
6
7
88
70
94
92
95
99
R(+)
R(+)
The catalytic results were found to be more or less, independent
of the substituents present on the phenyl group of methyl
phenyl sulfide. For the substrates with electron donating group
or without any electron withdrawing group oxidized with little
higher conversion (Table 6, entries 1-3, 10 and 11) compare to
those having electron with drawing substituent (entries 4-9).
The enantioselectivity of the catalytic system did not follow
any regular trend for aryl methyl sulfides. For the electron rich
para substituted methyl phenyl sulfide viz. para Me (ee 94%),
withdrawing para Br (ee 95%), and NO2 (ee 98%) (entries 2, 6
and 7) the enantioselectivity were better as compare to the
methyl phenyl sulfide. On the other hand substrate with
electron donating para OMe (ee 82%), withdrawing F (ee 84%)
(entries 3 and 4) provided comparatively low enantioselectivity.
Unlike the electron withdrawing Br group at para position, we
observed a significant decrease in enantioselectivity (entry 9) in
case of Br (ee 86%) at meta position whereas in case of Cl the
ee value (91%) remained same (entry 8). Most of the reported
catalytic system reported a drop in enantioselectivity when the
methyl group was replaced by other bulkier alkyl or benzyl
group. Hence we have used ethyl phenyl sulfide (entry 10, ee
78%) and benzyl phenyl sulfide (entry 11, ee 79%) as
8
9
85
89
93
93
90
91
91
85
78
R(+)
R(+)
R(+)
10
11
12
91
89
79
84
R(+)
(1S,2S)
(+)
>99 (93)
>99:1 (dr)e
13
14
15
>99 (94)
>99 (94)
>99 (92)
>99:1 (dr)e
>99:1 (dr)e
>98:2 (dr)e
78
95
84
(+)
(+)
(+)
a
Reaction condition: 0.5 mmol sulfide, 3 mol % Ti(Oi-Pr)4, ligand L1,
Ti:ligand = 1:1.15, 40 µl MeOH (additive), 1.2 equiv. 30% aqueous H2O2 in
substrates.
This
catalyst
system
provided
better
2 ml of dry DCM for 1.5 h at 0 oC. b Determined by 1H NMR measurement of
enantioinduction in both the cases, especially a significant
improvement in the ee was observed for the product obtained
with benzyl phenyl sulfide over the monometallic titanium
complex.12i Furthermore we explore the efficiency of this
catalytic system for cyclic dithioacetals (Table 6, entries 12-
15). Excellent conversion (>99%) was observed for all
substrate with electron donating Me and withdrawing Cl or F
group at para position of phenyl ring with moderate to high
c
sulfide, sulfoxide and sulfone relative concentration. Determined by HPLC
with a Daicel Chiralcel OD column, flow rate = 0.5 ml/min. hexane/i-PrOH =
d
8/2 (v/v). The absolute configuration were assigned by comparing HPLC
e
elution order and sign of optical rotations with literature data. Determined
by 1H NMR analysis.13, 14 The values given in parenthesis are isolated yield of
the product.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

View Article Online
RSC Advances
DOI: 10.1039/C5RA06P52a8gCe 6 of 8
ARTICLE
Journal Name
2H, J = 2 Hz), 5.01 (d, 2H, J = 6.5 Hz), 4.43 (d, 2H, J = 6.5
Experimental
Hz), 3.73 (s, 2H), 1.40 (s, 18H) ppm; 13C NMR (125 MHz,
CDCl3): δ = 166.6, 158.5, 140.1, 139.4, 137.2, 130.5, 130.2,
129.6, 128.6, 128.1, 128.0, 127.9, 127.2, 118.3, 80.1, 78.3,
40.2, 34.8, 29.3 ppm; Anal. Calcd. for C51H54N2O4: C, 80.71;
H, 7.17; N, 3.69; Found C, 80.61; H, 7.02; N 3.81; TOF-MS
(ESI+): m/z Calcd. for [C51H54N2O4] 758.41, Found 759.73
[M+H]+ and 760.64 [M+2H]+.
General
All the sulfides, 30% aqueous H2O2 were purchased and used
as received. The solvents were dried and stored over activated
molecular sieve under nitrogen atmosphere.1H NMR and 13C
NMR spectra of ligands were obtained from Bruker-Avance-
DPX-200 (200 MHz) or 500 MHz spectrometer at ambient
temperature using TMS as internal standard. TOF mass of the
ligands and intermediates were determined on a Micromass Q-
TOF-micro instrument. The enantiomeric excess of sulfoxides
were determined by chiral Shimadzu-HPLC with SPD-M10A-
VP and SPD-M20A UV detector and PDR-Chiral Lnc.
advanced Laser Polarimeter (PDR-CLALP), using chiral Daicel
Chiralcel columns with 2-propanol/hexane mixture as eluent of
the reaction mixture. Absolute configurations of chiral
sulfoxides were determined by comparing the sign of optical
rotation (obtained from PDR-CLALP) and elution order with
the literature. Conversion and selectivity were determined by
integrating the methyl proton signal of sulfide, sulfoxide and
1
L2: Yellow solid; yield: 96 %; H NMR (500 MHz, CDCl3): δ
= 13.70 (s, 2H), 8.28 (s, 2H), 7.21 (s, 2H), 6.91 (s, 2H), 3.91
(dd, 2H, J = 11.5 Hz, 3 Hz), 3.85 (s, 2H), 3.72 (dd, 2H, J = 11
Hz, 9.5 Hz), 2.89 (dd, 2H, J = 9.5 Hz, 2.5 Hz), 1.43 (s, 18H),
0.96 (s, 18H) ppm; 13C NMR (125 MHz, CDCl3):δ =166.7,
158.8, 137.4, 130.4, 130.3, 129.6, 118.3, 81.3, 62.5, 40.5, 34.8,
33.2, 29.4, 27.1 ppm; Anal. Calcd. for C35H54N2O4: C, 74.16;
H, 9.60; N, 4.94; Found C, 74.30; H, 9.52; N, 4.86; TOF-MS
(ESI+): m/z Calcd. for [C35H54N2O4] 566.41, Found 567.62
[M+H]+and 568.56 [M+2H]+.
L3: Yellow solid; Yield 97%; 1H NMR (500 MHz, CDCl3): δ =
13.66 (s, 1H), 8.30 (s, 2H), 7.20 (d, 2H, J = 2 Hz), 6.90 (d, 2H,
J = 2 Hz), 3.86, (s, 2H), 3.84-3.74 (m, 4H), 3.02-2.98 (m, 2H),
1.96-1.89 (m, 2H), 1.43 (s, 18H), 0.94 (dd, 12H, J = 6.5 Hz, 5.5
Hz) ppm; 13C NMR (125 MHz, CDCl3): δ = 166.7, 158.7,
137.4, 130.4, 130.4, 129.5, 118.3, 77.8, 64.6, 40.5, 34.8, 30.1,
29.4, 19.8, 18.8 ppm; Anal. Calcd. for C33H50N2O4: C, 73.57;
H, 9.35; N, 5.20; Found, C, 73.45; H, 9.26; N, 5.04; TOF-MS
(ESI+): m/z Calcd. for [C33H50N2O4] 538.38, Found 539.50
[M+H]+ and 540.53 [M+2H]+.
1
sulfone in H NMR spectra of the crude reaction mixture, but
for phenyl ethyl sulfoxide, phenyl benzyl sulfoxide and 1,3-
dithianes products were isolated.
Typical experimental procedure for the enantioselective
sulfoxidation reaction
To a stirring solution of ligands L1 (9.38 μmol) in dry DCM (2
ml), Ti(Oi-Pr)4 (15 μmol) was added and stirred for 2h at RT
under N2 atmosphere. Thereafter 2.2 equiv. H2O, 40 µl MeOH
and 0.5 mmol of substrate were added in sequence to the
reaction mixture keeping 20 min. of interval after each addition.
1
L4: Yellow solid; Yield 95%; H NMR (500 MHz, CDCl3): δ =
13.62, (br, 2H), 8.05 (s, 2H), 7.24-7.21 (m, 4H), 7.17-7.12 (m,
8H), 6.72 (s, 2H), 3.78 (s, 2H), 3.76-3.71 (m, 4H), 3.46 (br,
2H), 2.96-2.83 (m, 4H), 1.42 (s, 18H) ppm; 13C NMR (125
MHz, CDCl3): δ = 166.7, 158.6, 137.9, 137.3, 130.4, 130.3,
129.5, 129.4, 128.4, 126.4, 118.2, 73.1, 65.7, 40.3, 39.1, 34.8,
29.4 ppm; Anal. Calcd. for C41H50N2O4: C, 77.57; H, 7.94; N,
4.41; Found, C, 77.68; H, 7.82; N, 4.32; TOF-MS (ESI+): m/z
Calcd. for [C41H50N2O4] 634.38, Found 635.62 [M+H]+ and
636.58 [M+2H]+.
L5: Yellow solid; Yield: 90 %; 1H NMR (500 MHz, CDCl3): δ
= 13.16 (s, 2H), 8.55 (s, 2H), 7.32-7.27 (m, 4H), 7.23-7.21 (m,
4H), 7.17 (d, 2H, J = 7.5 Hz), 6.94 (d, 2H, J = 2 Hz), 4.77 (d,
2H, J = 5.5 Hz), 4.67 (q, 2H, J = 5.5 Hz), 3.89 (s, 2H), 3.24 (dd,
2H, J = 16 Hz, 6 Hz), 3.12 (dd, 2H, J = 16 Hz, 5 Hz), 1.40 (s,
18H) ppm; 13C NMR (125 MHz, CDCl3): δ = 167.8, 158.6,
140.8, 140.8, 137.6, 131.0, 130.6, 129.9, 128.6, 127.0, 125.5,
124.9, 118.4, 75.7, 75.2, 40.4, 39.7, 34.8, 29.3 ppm; Anal.
Calcd. for C41H46N2O4: C, 78.06; H, 7.35; N, 4.44; Found C,
78.20; H, 7.50; N, 4.53; TOF-MS (ESI+): m/z Calcd. for
[C41H46N2O4] 630.35, Found 631.48 [M+H]+ and 632.52
[M+2H]+.
o
Finally the reaction mixture was cooled to 0 C and 1.2 equiv.
aqueous hydrogen peroxide (30%) was added at once. After
1.5h of stirring at 200 rpm, the organic layer was washed three
times with water (1 ml  3), the product was purified by
column chromatography with silica gel and hexane/ethyl
acetate solvent mixture as an eluent.
Synthesis of amino alcohol derived Schiff base ligands L1-L7
The starting bis-aldehyde 5,5'-methylenebis(3-(tert-butyl)-2-
hydroxybenzaldehyde),
synthesized according to our previously reported procedure in
the literature.15
A for the preparation of ligands was
To a stirring solution of
A (1 mmol) in dry methanol solid
chiral amino alcohol (1 mmol) was added and the reaction
mixture was stirred for 24h. The color of the reaction mixture
gradually changed to yellow with the progress of the reaction.
The progress of the reaction was checked on TLC and after the
complete consumption of the bis-aldehyde (A), the solvent was
evaporated to have the chiral dimeric ligand as yellow solid.
L6: Yellow solid; Yield: 90 %; 1H NMR (500 MHz, CDCl3): δ
= 13.13 (br, 2H), 8.09 (s, 2H), 7.66 (d, 4H, J = 7.5 Hz), 7.52 (d,
4H, J = 7.5 Hz), 7.28-7.24 (m, 4H), 7.20-7.14 (m, 6H), 7.06 (s,
2H), 7.02 (t, 2H, J = 7.5 Hz), 6.69 (s, 2H), 4.07 (s, 2H), 3.76 (s,
2H), 2.96 (s, 2H), 1.37 (s, 18H) ppm; 13C NMR (125 MHz,
CDCl3): δ = 167.5, 158.3, 147.6, 144.8, 137.1, 130.5, 130.0,
Characterization data of the dineric ligands
1
L1: Yellow solid; Yield 95%; H NMR (500 MHz, CDCl3): δ =
13.46 (s, 2H), 7.99 (s, 2H), 7.34 (d, 8H, J = 4 Hz), 7.30-7.28
(m, 2H), 7.23-7.19 (m, 10H), 7.08 (d, 2H, J = 2Hz), 6.61 (d,
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

View Article Online
DOI: 10.1039/C5RA06528C
Page 7 of 8
Journal Name
RSC Advances
ARTICLE
129.6, 128.1, 127.9, 126.6, 126.3, 126.1, 125.7, 118.0, 83.4, Tel: +91-0278-2567760, Fax: +91-0278-2566970; E-mail:
80.6, 40.2, 36.3, 34.8, 29.6, 29.3 ppm; Anal. Calcd. for shrabdi@csmcri.org
C59H70N2O4: C, 81.34; H, 8.10; N, 3.22; Found C, 81.49; H, Electronic Supplementary Information (ESI) available:
8.21; N, 3.42; TOF-MS (ESI+): m/z Calcd. for [C59H70N2O4] [Characterization data, HPLC chromatograms of products and
870.53, Found 871.64 [M+H]+ and 872.71 [M+2H]+.
1H NMR, 13C NMR spectra of ligands are described herein].
L7: Yellow solid; Yield: 90 %;1H NMR (500 MHz, CDCl3): δ See DOI: 10.1039/b000000x/
= 12.96 (s, 2H), 8.31 (s, 2H), 7.53 (d, 4H, J = 8Hz), 7.49 (d,
4H, J = 8 Hz), 7.31 (t, 4H, J = 8Hz), 7.25-7.19 (m, 6H), 7.14-
7.12 (m, 4H), 7.77 (s, 2H), 4.50 (q, 2H, J = 6.5 Hz), 3.80 (s,
2H), 1.36 (s, 18H), 1.22 (d, 16H, 6.5 Hz) ppm; 13C NMR (125
MHz, CDCl3): δ = 166.2, 158.2, 145.7, 144.2, 137.3, 130.5,
130.3, 129.6, 128.2, 126.8, 126.3, 126.0, 118.4, 79.6, 70.2,
40.3, 34.8, 29.3, 17.6 ppm; Anal. Calcd. for C53H58N2O4:C,
80.88; H, 7.43; N, 3.56; Found C, 79.03; H, 7.58; N, 3.73;
TOF-MS (ESI+): m/z Calcd. for [C53H58N2O4] 786.44, Found
786.81 [M+H]+ and 788.70 [M+2H]+.
1
J. Legros, J. R.Dehli and C. Bolm, Adv. Synth. Catal., 2005,
347, 19-31.
R. Bentley, Chem. Soc. Rev., 2005, 34, 609-624.
(a) I. Fernández and N. Khiar, Chem. Rev., 2003, 103, 3651-
3706; (b) M. Mellah, A. Voituriez and E. Schulz, Chem.
Rev., 2007, 107, 5133-5209.
(a) A. Massa, A. V.Malkov, P. Kocovsky and A. Scettri,
Tetrahedron Lett., 2003, 44, 7179-7181; (b) S. Kobayashi,
C. Ogawa, H. Konishi and M. Sugiura, J. Am. Chem. Soc.,
2003, 125, 6610-6611.
2
3
4
5
6
7
P. Pitchen, E. Daunach, M. N. Deshmukh and H. B. Kagan,
J. Am. Chem. Soc., 1984, 106, 8188-8193.
F. Di Furia, G. Modena and R. Seraglia, Synthesis, 1984,
325-326.
(a) G. E. O’Mahony, P. Kelly, S. E. Lawrence and A. R.
Maguire, ARKIVOC (i) 2011, 1-110; (b) H. Srour, P. L.
Maux, S. Chevance and G. Simonneaux, Coord. Chem.
Rev., 2013, 257, 3030-3050.
(a) N. Komatsu, Y. Nishibayashi, T. Sugita and S. Uemura,
Tetrahedron Lett., 1992, 33, 5391-5394; (b) C. Bolm and
O. A. G. Dabard, Synlett, 1999, 360-362; (c) Y. Yamanoi
and T. Imamoto, J. Org. Chem., 1997, 62, 8560-8564; (d)
S. Superchi and C. Rosini, Tetrahedron: Asymmetry, 1997,
Conclusions
In conclusion we have established a highly efficient catalytic
system based on in situ generated bimetallic Ti-complex of
dimeric amino alcohol derived Schiff base using aqueous H2O2
as an oxidant. This study revealed the use of water and
methanol together as additive to boost the catalytic activity as
well as enantioselectivity. The separation of the product is very
easy for this system as the catalyst get precipitated out from the
reaction mixture on the addition of hexane. This catalyst
showed better enantioselectivity (up to 99%) with very good
conversion (up to 95%) and selectivity (up to 95%) for the
desired sulfoxide as compared to the corresponding monomeric
catalyst within significantly shorter reaction time. Additionally
this catalytic protocol efficiently oxidized aldehyde-derived
1,3-dithianes with excellent conversion and good to high
enantioselectivity (up to 95%). To the best of our knowledge,
this modified procedure provided the best result for the
Titanium-amino alcohol derived Schiff base ligand mediated
asymmetric oxidation of aryl alkyl sulfides.
8
8
, 349-352; (e) S. TBHP-Superchi, P. Scafato, L. Restaino
and C. Rosini, Chirality, 2008, 20, 592-596.
9
(a) W. Adam, M. N. Korb, K. J. Roschmann and C. R.
Saha-Moeller, J. Org. Chem., 1998, 63, 3423-3428; (b) A.
Scettri, F. Bonadies and A. Lattanzi, Tetrahedron:
Asymmetry, 1996,
7, 629-632; (c) A. Lattanzi and A.
Scettri, J. Organomet. Chem., 2006, 691, 2072-2082; (d)
A. Lattanzi, P. Iannece and A. Scettri, Tetrahedron:
Asymmetry, 2004, 15, 1779-1785.
Acknowledgements
10 (a) C. Bolm and F. Bienewald, Angew. Chem. Int. Ed. Engl.,
1995, 34, 2640-2642; (b) C. Ohta, H. Shimizu, A. Kondo,
T. Katsuki, Synlett, 2002, 161-163; (b) Q. Zeng, H. Wang,
T. Wang, Y. Cai, W. Weng and Y. Zhao, Adv. Synth.
Catal., 2005, 347, 1933-1936; (c) Q. Zeng, H. Wang, W.
Weng, W. Lin, Y. Gao, X. Huanga and Y. Zhao, New J.
Chem., 2005, 29, 1125-1127; (d) P. Kelly, S. E. Lawrence
and A. R. Maguire, Eur. J. Org. Chem., 2006, 4500-4509;
(e) I. Lippolda, J. Becherb, D. Klemmb and W. Plass, J.
Mol. Catal. A: Chem., 2009, 299, 12-17; (f) Y. Wu, J. Liu,
X. Li, and A. S. C. Chan, Eur. J. Org. Chem., 2009, 2607-
2610; (g) Y. Wang, M. Wang, Y. Wang, X. Wang, L.
Wang and L. Sun, J. Catal., 2010, 273, 177-181; (h) P.
Adꢀo, M. L. Kuznetsov, S. Barroso, A. M. Martins, F.
Avecilla and J. C. Pessoa, Inorg. Chem., 2012, 51, 11430-
11449; (i) A. E. Aydin, Tetrahedron: Asymmetry, 2013,
24, 444-448.
CSIR-CSMCRI Communication No.: CSIR-CSMCRI
187/2014.
Authors are thankful to UGC, DST and CSIR Network Project
on Catalysis for financial assistance, and also thankful to
“Analytical Discipline and Centralized Instrument Facility” for
providing instrumental facilities.
–
Notes and references
a Discipline of Inorganic Materials and Catalysis, CSIR-Central
Salt and Marine Chemicals Research Institute (CSIR-
CSMCRI), Council of Scientific & Industrial Research (CSIR),
b
G. B. Marg, Bhavnagar, 364002, Gujarat, India. Academy of
Scientific and Innovative Research (AcSIR), CSIR-Central Salt
and Marine Chemicals Research Institute (CSIR-CSMCRI),
Council of Scientific & Industrial Research (CSIR), G. B.
Marg, Bhavnagar, 364002, Gujarat, India.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 7

View Article Online
RSC Advances
DOI: 10.1039/C5RA06P52a8gCe 8 of 8
ARTICLE
Journal Name
11 (a) J. Legros and C. Bolm, Angew. Chem. Int. Ed., 2004, 43
,
4225-4228; (b) J. Legros and C. Bolm, Chem. Eur. J.,
2005, 11, 1086-1092; (c) H. Egami and T. Katsuki, J. Am.
Chem. Soc., 2007, 129, 8940-8941; (d) C. Mukherjee, A.
Stammler, H. Bögge, and T. Glaser, Chem. Eur. J., 2010,
16, 10137-10149; (e) S. Liaoa and B. List, Adv. Synth.
Catal., 2012, 354, 2363-2367; (f) K. A. Stingl, K. M. Weiß
and S. B. Tsogoeva, Tetrahedron, 2012, 68, 8493-8501;
(g) P. K. Bera, P. Kumari, S. H. R. Abdi, N. H. Khan, R. I.
Kureshy, P. S. Subramanian and Hari C. Bajaj, RSC Adv.,
2014,
4, 61550-61556.
12 (a) B. Saito and T. Katsuki, Tetrahedron Lett., 2001, 42
,
3873-3876; (b) B. Saito and T. Katsuki, Tetrahedron Lett.,
2001, 42, 8333-8336; (c) K. P. Bryliakov and E. P. Talsi, J.
Mol. Catal. A: Chem., 2007, 264, 280-287; (d) P. Adão, F.
Avecilla, M. Bonchio, M. Carraro, J. C. Pessoa and I.
Correia, Eur. J. Inorg. Chem., 2010, 5568-5578; (e) K. P.
Bryliakov and E. P. Talsi, Eur. J. Org. Chem., 2008, 3369-
3376; (f) K. P. Bryliakov and E. P. Talsi, Eur. J. Org.
Chem., 2011, 4693-4698; (g) E. P. Talsi and K. P.
Bryliakov, Appl. Organometal. Chem., 2013, 27, 239-244;
(h) Y. Wang, M. Wang, L. Wang, Y. Wang, X. Wang and
L. Sun, Appl. Organometal. Chem., 2011, 25, 325-330; (i)
P. K. Bera, D. Ghosh, S. H. R. Abdi, N. H. Khan, R. I.
Kureshy, H. C. Bajaj, J. Mol. Catal. A: Chem., 2012, 361
,
36-44; (j) S. Barman, S. Patil, and C. J. Levy, Chem. Lett.,
2012, 41, 974-975; (k) C. Zhu, X. Chen, Z. Yang, X. Du,
Y. Liu and Yong Cui, Chem. Commun., 2013, 49, 7120-
7122; (l) W. Xuan, C. Ye, M. Zhang, Z. Chen and Y. Cui,
Chem. Sci., 2013,
13 (a) J. Escorihuela, M. I. Burgueteb and S. V. Luis, Chem.
Soc. Rev., 2013, 42, 5595 5617; (b) W. Q. Wu, Q. Peng, D.
4, 3154-3159.
‐
X. Dong, X. L. Hou and Y. D. Wu, J. Am. Chem. Soc.,
2008, 130, 9717-9725.
14 P. C. Bulman Page, R. D. Wilkes, E. S. Namwindwa and
M. J. Witty, Tetrahedron, 1996, 52, 2125-2154.
15 R. I. Kureshy, K. J. Prathap, S. Agrawal, N. H. Khan, S. H.
R. Abdi and R. V. Jasra, Eur. J. Org. Chem., 2008, 3118-
3128.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012