Ti-Salan catalyzed asymmetric sulfoxidation of pyridylmethylthiobenzimidazoles to optically pure proton pump inhibitors

Article abstract of DOI:10.1016/j.cattod.2016.03.006

The asymmetric sulfoxidation of two pyridylmethylthiobenzimidazoles to anti-ulcer drugs of the PPI family (S)-omeprazole and (R)-lansoprazole with hydrogen peroxide, mediated by a series of chiral titanium(IV) salan complexes is reported. High sulfoxide yields (up to?>95%) and enantioselectivities (up to 94% ee) have been achieved. The introduction of electron-withdrawing substituents leads to less active and less enantioselective catalysts. Like for the previously reported Ti-salalen catalyzed sulfoxidations, the temperature dependence of the sulfoxidation enantioselectivity in the presence of Ti-salan complexes is nonmonotonic, demonstrating isoinversion behavior with decreasing temperature. The oxidation is likely rate-limited by the formation of the active (presumably peroxotitanium(IV)) species, followed by a faster oxygen transfer to the substrate.

Full text of DOI:10.1016/j.cattod.2016.03.006

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Ti-Salan catalyzed asymmetric sulfoxidation of
pyridylmethylthiobenzimidazoles to optically pure proton pump
inhibitors
Evgenii P. Talsia,b, Konstantin P. Bryliakova,b,∗
a Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russia
b Boreskov Institute of Catalysis, Pr. Lavrentieva 5, Novosibirsk 630090, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric sulfoxidation of two pyridylmethylthiobenzimidazoles to anti-ulcer drugs of the PPI
family (S)-omeprazole and (R)-lansoprazole with hydrogen peroxide, mediated by a series of chiral tita-
nium(IV) salan complexes is reported. High sulfoxide yields (up to >95%) and enantioselectivities (up to
94% ee) have been achieved. The introduction of electron-withdrawing substituents leads to less active
and less enantioselective catalysts. Like for the previously reported Ti-salalen catalyzed sulfoxidations,
the temperature dependence of the sulfoxidation enantioselectivity in the presence of Ti-salan com-
plexes is nonmonotonic, demonstrating isoinversion behavior with decreasing temperature. The oxidation
is likely rate-limited by the formation of the active (presumably peroxotitanium(IV)) species, followed
by a faster oxygen transfer to the substrate.
Received 15 October 2015
Received in revised form 10 March 2016
Accepted 14 March 2016
Available online xxx
Keywords:
Asymmetric oxidation
Esomeprazole
Hydrogen peroxide
Isoinversion
Mechanism
© 2016 Elsevier B.V. All rights reserved.
Titanium
Salan
1. Introduction
omeprazole is by now manufactured via the von Unge process,
which requires high catalyst loadings (30 mol % of Ti, 60 mol % of
After the milestone emergence of the Kagan-Modena catalyst
system, capable of conducting the highly enantioselective oxida-
tion of thioethers to sulfoxides with alkylhydroperoxides [1–3],
transition-metal catalyzed sulfoxidations have made a substantial
progress [4–16], with one of the major trends being the devel-
opment of environmentally benign catalyst systems relying on
“green” hydrogen peroxide as the terminal oxidant [17–27]. In spite
of extensive studies, some drawbacks persisted, i.e., until recently
there were no simple and highly enantioselective catalyst systems
able to oxidize thioethers, bearing two bulky substituents at the
sulfur atom, with H2O2.
From a practical perspective, simple, efficient and environ-
mentally benign catalyst systems are highly challenging. At the
moment, the industry continues exploiting the Kagan-Modena
type systems possessing serious technical and environmental
drawbacks [28]. In particular, the blockbuster anti-ulcer drug (S)-
optically pure diethyltartrate), aromatic solvent (toluene), Hünig’s
base (30 mol %) as additive, nonconstant temperature profile,
high-molecular-weight oxidant (cumene hydroperoxide) produc-
ing high-MW byproduct, and the need in precise moisture control
(by adding calculated amounts of water) [29–31]. Recently, we have
reported a family of chiral titanium(IV) salalen (dihydrosalen) com-
plexes, capable of mediating the asymmetric synthesis of anti-ulcer
drugs of the PPI (Proton Pump Inhibitors) family, (S)-omeprazole
and (R)-lansoprazole, by the highly enantioselective (up to 96% ee)
oxidation of the corresponding pyridylmethylthiobenzimidazole
precursors with H2O2 [32]. Isoinversion behavior has been docu-
mented for the oxidation of the thioether precursors, resulting in
maximum enantioselectivity at 274 7 K. The reason of this isoin-
version behavior was identified as the existence of two alternative
reaction pathways, one prevailing at low temperature and the other
at high temperatures [32].
From the technical standpoint, preparation and purification of
chiral salalen ligands is a tedious procedure, which typically results
in low yields and requires a thorough separation. In contrast to
salalen ligands, salan ones can be readily prepared from the cor-
responding chiral salens in good yields [33–36]. Previously, we
showed that Ti-salan complexes can serve as highly enantiose-
∗
Corresponding author at: Boreskov Institute of Catalysis, Pr. Lavrentieva 5,
Novosibirsk 630090, Russia, and Novosibirsk State University, Pirogova 2, Novosi-
birsk 630090, Russia.
E-mail address: bryliako@catalysis.ru (K.P. Bryliakov).
http://dx.doi.org/10.1016/j.cattod.2016.03.006
0920-5861/© 2016 Elsevier B.V. All rights reserved.
Please cite this article in press as: E.P. Talsi, K.P. Bryliakov, Ti-Salan catalyzed asymmetric sulfoxidation of pyridylmethylthiobenzimi-
dazoles to optically pure proton pump inhibitors, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.03.006

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H
H
H
N
H
H
N
N
N
N
N
X
OH HO
X
X
OH HO
X
X
OH HO
X
Y
Y
11
12
13 X= H
1 X= Ac
6 X= H, Y= Cl
7 X= H, Y= Me
X= Ac
X= Br
2
3
4
X= Br
X= H
X= Me
8
9
X= H, Y= OMe
X= H, Y= Ph
14 X= OMe
5 X= OMe
10
X= OMe, Y= OMe
H
H
NH HN
OH HO
N
N
O
1. Ti(OiPr)4
Ti
CH2Cl2
2. H2O
R2
R2
R2
O
R2
O
R1
R1
R1
R1
2
Ti-1 Ti-10 (salan)
...
Ti-11...Ti-14 (salalen)
N
N
N
S
N
S
N
H
N
H
O
O
O
OMS
CF3
LPS
Scheme 1. Chiral salan and salalen ligands, Ti(IV) complexes and sulfide precursors considered in this work.
lective catalysts for the oxidation of alkyl aryl sulfides [34–36].
It is thus tempting to test the catalytic reactivity of Ti-salan cata-
lysts toward the asymmetric oxidation of the industrially attractive
pyridylmethylthiobenzimidazoles.
In this contribution, we present the asymmetric oxidation of
sulfide precursors of (S)-omeprazole and (R)-lansoprazole with
H2O2 on a series of Ti-salan complexes. The catalysts demonstrate
high chemo- and enantioselectivity, and nonmonotonic depen-
dence of the enantioselectivity upon the reaction temperature. The
mechanistic peculiarities of Ti-salan catalyzed sulfoxidations are
discussed.
measured on Shimadzu LC-20HPLC chromatograph equipped with
Daicel Chiralpack AD-H chiral column (250 × 4.6 mm) as described
in Ref. [32]. Chiral HPLC measurements were performed at least
in duplicate (until concordant results were obtained), except for
kinetic measurements. The resulting ee measurement uncertainty
did not exceed 0.5% for ees falling in the range 80–94% and did
not exceed 1.0% for ees < 80%. For HPLC separation details see
Supporting information for Refs. [32,34,35].
2.2. Standard procedure for small-scale catalytic sulfoxidation
Sulfide (OMS or LPS, 100 ␮mol) and the Ti-salalen catalyst
(1.1 ␮mol) were dissolved in the solvent (typically: EtOAc, 6.0 mL),
the mixture was thermostatted at desired temperature (typically
0 ◦C, or −20 to +20 ◦C for variable-temperature measurements),
and 30% aqueous hydrogen peroxide (0.105 mmol of H2O2) was
then introduced in one portion. Stirring (500 rpm) was continued
at that temperature (typically 24 h). For low-temperature exper-
iments, the reaction times were about 30 h at −10 ◦C and up to
10 days at −20 ◦C.
2. Experimental
2.1. General methods
H2O2 was used as commercial analytical grade 30% aqueous
solution. Silica gel 60 (0.063–0.200 mm) for column chromatogra-
phy was purchased from Panreac. All other chemicals were Aldrich,
AlfaAesar, or Acros commercial reagents. Ti-salan complexes Ti-
1. . .Ti-10 [33] and Ti-salalen complexes Ti-11. . .Ti-14 [32] were
prepared as previously described.
To analyze the reaction outcome, 20 ␮L aliquots of the reaction
mixture were taken to a vial and immediately carefully evaporated
to dryness with a stream of compressed air during ca. 15–20 s. The
remaining solid was dissolved in 0.20 mL of 1% Et3N solution in
Enantiomeric excess values and absolute configurations of sul-
foxides, as well as the proportion of sulfide/sulfoxide/sulfone were
Please cite this article in press as: E.P. Talsi, K.P. Bryliakov, Ti-Salan catalyzed asymmetric sulfoxidation of pyridylmethylthiobenzimi-
dazoles to optically pure proton pump inhibitors, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.03.006

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Table 1
Enantioselective oxidation of OMS and LPS with H2O2 in the presence of Ti-salan and Ti-salalen catalystsa.
No
Catalyst
Substrate
Solvent
T [◦C]
Conversion
Sulfoxide yield [%]b
ee [%] (config.)b
1
2
3
4
5
6
7
8
(R,R)-Ti-1c
(R,R)-Ti-2
(S,S)-Ti-3
(R,R)-Ti-4
(R,R)-Ti-5
(S,S)-Ti-6
OMS
OMS
OMS
OMS
OMS
OMS
OMS
OMS
OMS
OMS
OMS
OMS
OMS
OMS
LPS
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
CH2Cl2
CH2Cl2
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
+21
−20
+10
−10
0
90.0
84.0
91.5
94.5
97.0
64.5
75.0
98.5
84.0
95.0
14.0
44.0
97.0
98.0
97.5
99.0
94.0
98.5
98.0
100.0
89.0
81.5
97.0
88.0
99.9
99.7
77.5
81.5
88.5
91.5
93.5
59.0
70.5
90.0
76.5
89.0
13.5
42.5
94.5
94.0
95.0
96.0
91.0
93.0
92.5
96.0
87.0
78.5
91.0
83.5
94.0
96.0
48.0 (R)
66.5 (R)
90.5 (S)
90.5 (R)
91.5 (R)
26.5 (S)
59.0 (S)
71.5 (R)
52.5 (R)
87.0 (R)
50.0 (R)
75.5 (R)
94.5 (R)
94.5 (R)
91.5 (S)
93.5 (R)
88.0 (R)
92.5 (R)
82.5 (S)
96.0 (R)
89.5 (S)
83.0 (S)
88.0 (R)
84.0 (R)
93.5 (S)
94.0 (S)
(S,S)-Ti-7
(R,R)-Ti-8d
(R,R)-Ti-9
(R,R)-Ti-10
(R,R)-Ti-11e
(R,R)-Ti-12e
(R,R)-Ti-13e
(R,R)-Ti-14e
(S,S)-Ti-3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
(R,R)-Ti-13e
(R,R)-Ti-5
(R,R)-Ti-14e
(S,S)-Ti-3
LPS
LPS
LPS
OMS
OMS
LPS
(R,R)-Ti-13e
(S,S)-Ti-3f
(S,S)-Ti-3g
(R,R)-Ti-5h
(R,R)-Ti-5i
(S,S)-Ti-3j
(S,S)-Ti-3j
LPS
OMS
OMS
OMS
LPS
0
a
[H2O2]/[substrate]/[catalyst] = 105 ␮mol:100 ␮mol:1.1 ꢀmol, the oxidant was added in one portion and the mixture was stirred for 24 h.
b
c
d
e
f
Sulfoxide yield and ee determined by chiral HPLC analysis.
Reaction time 30 h.
[H2O2]/[substrate]/[catalyst] = 110 ␮mol:100 ␮mol:2 ꢀmol.
From Ref. [32].
Reaction time 6 h.
Reaction time 10 days.
Reaction time 14 h.
Reaction time 30 h.
2.2 mol % of the catalyst.
g
h
i
j
isopropyl alcohol, and the contents of residual sulfide, (R)- and
(S)-sulfoxide, and sulfone, were analyzed by chiral HPLC as noted
above.
duction of electron-acceptors attenuates the catalytic activity
and deteriorates the chemo- and enantioselectivity of Ti-salan
complexes (entries 1–5); (2) unlike the case of olefin epoxida-
tion [33], the presence of o-substituents at the 3-Ph rings leads to
less chemo- and enantioselective catalysts (entries 6–10). Eventu-
ally, catalysts Ti-3, Ti-4, Ti-5, exhibited very similar performances,
with the enantioselectivities approaching 91.5% ee (entries 3, 4,
5). Under similar conditions, Ti-salan catalysts showed somewhat
lower enantioselectivities as compared to their Ti-salalen proto-
types (cf. entries 1–3, 5 and 11–14 for OMS oxidations amd entries
15, 16, and 17, for LPS oxidations).
2.3. Kinetic measurements
Kinetic measurements were conducted at 0 ◦C in EtOAc as under
standard conditions (see above), but 20 ␮L aliquots were taken
every 30 min. The aliquots were immediately evaporated with com-
pressed air, dissolved in 0.2 mL of 1% Et3N solution in isopropyl
alcohol and analyzed by chiral HPLC to provide relative amounts of
the sulfide, sulfoxides ((R)- and (S)-), and sulfone, and the sulfoxide
ee for each point.
For Ti-salalen catalysts, the replacement of EtOAc with CH2Cl2
increased the sulfoxide yield and ee (cf. enties 13 and 20) [32]. For
Ti-salan catalysts, a similar solvent changeover had opposite effect
(cf. entries 3 and 19).
3. Results and discussion
We have examined the effect of concentration on the oxidation
of OMS on catalyst Ti-3. Reduction of the reaction volume (2–4
times as compared to the “normal” conditions as applied in Table 1)
resulted in a significant deterioration of the ee (Fig. 2A). At the same
time, a two-fold dilution did not result in a comparable gain in
the enantioselectivity. Interestingly, increasing the catalyst load-
ing (when keeping the same initial concentration of OMS) sharply
improved the optical purity of the resulting (S)-omeprazole (Fig. 2B,
Table 1, entries 3 and 25, and Table S1, SI), approaching 94% ee at
a catalyst loading of >2.5 mol %. The observed dependence is very
intriguing; although the reason of the sharp enhancement of the
ee when increasing the catalyst loading from 1.0 to 1.5–2.5 mol %
remains unclear, the catalyst system seems to hold a good prac-
tical potential for enantioselectivity improvement. A similar rise
of enantioselectivity with rising catalyst loading has been docu-
mented for the oxidation of LPS (Table 1, cf. entries 15 and 26).
3.1. Enantioselective oxidation of OMS and LPS with H2O2 on
various titanium(IV) salan complexes
Recently, we studied the enantioselective epoxidation of olefins
with H2O2 on chiral titanium(IV) salan complexes and found that
the epoxidation enantioselectivity only depended on the steric
demand of the 3,3ꢀ-aryl moieties, while electron-donating and
withdrawing groups (at the 5,5ꢀ-positions) only affected the epoxi-
dation rate [33]. We have tested a series of those Ti-salan complexes
(Ti-1. . .Ti-10, Scheme 1) as catalysts for the oxidation of OMS and
LPS (sulfide precursors of omeprazole and lansoprazole, respec-
tively). The reactions were conducted in ethyl acetate which
previously showed good results in Ti-salalen catalyzed sulfoxida-
tions [32]. The obtained data are collected in Table 1. By analyzing
them, one can make some preliminary conclusions: (1) the intro-
Please cite this article in press as: E.P. Talsi, K.P. Bryliakov, Ti-Salan catalyzed asymmetric sulfoxidation of pyridylmethylthiobenzimi-
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A
A
20
18
16
“normal”
conditions
14
12
10
8
6
0,00
0,01
0,02
0,03
0,04
0,05
0,06
0,07
[OMS]0, M
B
94
93
92
91
90
B
“normal”
conditions
0,5
1,0
1,5
2,0
2,5
3,0
Fig. 2. Kinetic plots for the oxidation of OMS with H2O2 in the presence of
Ti-3 (EtOAc, 0 ◦C, [S]0 = [H2O2]0 = 1.67·10−2 M, [S]0:[cat] = 50)—(A): concentrations
of OMS—(black) and omeprazole (sum of (R)- and (S)-enantiomers)—blue; (S)-
omeprazole optical purity (ee)—red. [S]0/[S] vs. time plot for the OMS concentration
after 110 min (B), and its non-linear fit (dash line). 50% conversion of OMS was
achieved within 130 min. (For interpretation of the references to colour in this figure
legend, the reader is referred to the web version of this article).
Ti-3 loading, mol. %
Fig. 1. Concentration dependence of the enantiomeric ratio (er) in the oxidation
of OMS to (S)-omeprazole on Ti-3 (A). Dependence of the enantiomeric excess (ee)
of the same reaction on the catalyst loading (B). “Normal” conditions are those in
footnotes for Table 1.
1,0
0,8
0,6
0,4
3.2. Monitoring the kinetics of sulfoxidation of OMS and LPS
Monitoring the kinetics of the oxidation of OMS on the Ti-salan
catalysts revealed some features as distinct from the behavior of
the Ti-salalen based systems [32]. First of all, the Ti-salan catalyst
systems displayed shorter induction periods (not longer than 1 h,
Fig. 2 and Figs. S1-S7, SI) [37]. Secondly, there was no steady-state
regime for any of the catalysts considered, the reaction decelera-
tion being apparent almost from the beginning. In contrast to the
Ti-salalen systems (for which the enantioselectivity monotonously
increased), the oxidation enantioselectivities quickly approached a
maximum at <50% conversions and further gradually declined by a
few per cent (Fig. 2A and S1-S5, SI) [38].
1
0,2
2
0,0
3
4
Interestingly, kinetic analysis revealed that the reactions cat-
alyzed by Ti-1. . .Ti-4 exhibited apparent ∼2nd order in the sulfide
concentration (Fig. 2B and Figs. S2-S4 of the SI) [39]. When
interpretingthe aboveresults, one has to take into accountthat stoi-
chiometric amounts of OMS and H2O2 were loaded at the beginning
of the reaction, whose concentrations are equal and decrease in par-
allel during the oxidation. Within a two-step kinetic model, with
rate-limiting formation of the active titanium(IV) peroxo species
[40–42] (see SI), one could assume that the rate-limiting step
may be assisted by another molecule of H2O2, thus explaining the
observed ∼2nd reaction order on the substrate.
0
100
200
300
400
500
600
t, min
Fig. 3. Kinetics of oxidation of OMS with H2O2 on Ti-3 (EtOAc,
0 ◦C,
[S]0 = 1.67·10−2 M,
[S]0:[cat] = 50):
[H2O2]0:[S]0 = 1:1—(1),
[H2O2]0:[S]0 = 1.33:1—(2), [H2O2]0:[S]0 = 2:1—(3), [H2O2]0:[S]0 = 3:1—(4).
with H2O2 is relatively fast and may not be correctly taken as the
rate-limiting step.
Increasing the amount of H2O2 accelerated the reaction (Fig. 3)
and altered the observed reaction order. In particular, when excess
of H2O2 was used, the observed reaction order decreased to <1
(33% excess of H2O2: n = 0.88; 100% excess of H2O2: n = 0.60). More-
over, under the conditions of high excess of H2O2, there was no
On the other hand, the oxidation of OMS on catalyst Ti-5 exhib-
ited an apparent ca. 1st order (Fig. S1, SI), which may indicate that
for Ti-5, the mechanism is more complex, such that the interaction
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3,2
3,1
3,0
2,9
2,8
2,7
2,6
2,5
2,4
2,3
A
273 K
3.3
3.4
3.5
3.6
3.7
3.8
3.9
4.0
1000/T
Fig. 5. Modified Eyring plot for the oxidation of OMS on catalyst Ti-5. er − enan-
tiomeric ratio (100 + ee)/(100-ee).
B
Fig. 4. Kinetic plots for the oxidation of OMS with H2O2 on Ti-3 (EtOAc,
0
◦C, [S]0 = 1.67·10−2 M, [S]0:[cat] = 50, [H2O2]0:[S]0 = 2)—(A): concentrations of
OMS—(black) and omeprazole (sum of (R)- and (S)-enantiomers) − blue; (S)-
omeprazole optical purity—red. [S]0/[S] vs. time plot for the OMS concentration after
50 min (B) and its nonlinear fit (dash line). 50% conversion of OMS was achieved
within 90 min. (For interpretation of the references to colour in this figure legend,
the reader is referred to the web version of this article).
Scheme 2. Proposed reaction schemes for sulfoxidation in the presence of water. L
is solvent or vacancy.
enantioselectivity decrease, the latter remaining in the range
93.0. . .93.5% ee (Fig. 4 and S6). At high conversions (>90%), the
reactions visibly decelerated owing to nearly complete sulfide con-
sumption (Fig. 3).
+20 ◦C (Fig. 5 and S8, SI) demonstrated a maximum at ca. 273 K,
indicating isoinversion behavior similar to that exhibited by Ti-
salalen sulfoxidation catalysts [32].
Noticeably, while the oxidation of OMS was relatively fast with
catalysts Ti-3, Ti-4, Ti-5 (ensuring 50% conversion within 70 min
(Ti-4) or 130 min (Ti-3)), catalysts Ti-1 and Ti-2 with electron-
withdrawing substituents showed much lower reaction rates (with
50% conversions achieved at 230 min (Ti-1) or 300 min (Ti-2), see
Figs. S1-S5 of the SI). Apparently, the presence of electron-acceptors
at the ligand core must lead to a more electrophilic (and hence more
reactive) oxidizing species, which requires a higher activation bar-
rier for the rate-limiting formation of the active oxidant (cf. Ref.
[32]), which stage is followed by relatively fast oxygen transfer to
the sulfide. Earlier, we came to the same conclusions when dis-
cussing the oxidation of benzyl phenyl sulfide in the presence of
ent-Ti-1 [36].
The origin of the isoinversion behavior was previously dis-
cussed in terms of the changeover of the oxidation mechanism
[32]. In particular, it was proposed that at high temperature,
a
water-coordinated titanium-salalen peroxo complex is the
major oxygen-transferring intermediate. At low temperatures
(<273 K), water freezes out, thus leading to a water-free interme-
diate, responsible for the less-enantioselective oxidation pathway
(Scheme 2). DFT calculations witness that water-coordinated inter-
mediate is ca. 7 kcal/mol lower in energy than EtOAc-coordinate
one [43], thus suggesting that the latter can only predominate
under water-deficient conditions, i.e., below the melting point of
H2O. We believe that a similar situation is the case for Ti-salan
based catalysts.
3.3. Temperature dependence of sulfoxidation enantioselectivity
4. Conclusions
For Ti-salalen catalysts Ti-13 an Ti-14, the optimum temper-
ature range was 273. . .283 K, while performing the reaction at
higher or lower temperature resulted in significant depletion of the
enantiomeric excess [32]. Similarly, the Ti-salan catalysts demon-
strated reduced enantioselectivity at temperatures below or above
273 K (cf. entries 15, 21, 22 for Ti-3 and 5, 23, 24 for Ti-5 in Table 1).
Modified Eyring plots (Ln(enantiomeric ratio) vs. T−1) for oxidations
of OMS and LPS performed in the temperature range −20 up to
Titanium(IV) salan complexes have been shown to catalyze
the asymmetric sulfoxidation of two pyridylmethylthiobenzimi-
dazoles to anti-ulcer drugs of the PPI family (S)-omeprazole and
(R)-lansoprazole with aqueous H2O2. High sulfoxide yields (up
to >95%) and enantioselectivities (up to 94% ee) have been achieved.
These values are similar to those demonstrated by the commercial
von Unge’s system; additional advantages of the Ti-salan systems
are the simplicity of manipulations, cheap and environmen-
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tally benign oxidant and non-aromatic solvent, and low catalyst
loading (1–2 mol %). The introduction of electron-withdrawing sub-
stituents leads to less active and less enantioselective catalysts.
Analysis of the oxidation kinetics suggests that the reaction is most
likely rate-limited by formation of the active (presumably per-
oxotitanium(IV)) species, followed by a faster oxygen transfer to
the substrate. The temperature dependence of the sulfoxidation
enantioselectivity in the presence of Ti-salan complexes is non-
monotonic, demonstrating isoinversion behavior with a maximum
at ca. 273 K, which temperature may be recommended for prepar-
ative catalytic reactions.
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Acknowledgment
[28] I.e. low TOF and TON, high catalyst loading (up to 30 mol.%, see Ref. 29),
complexity (the active sites are generated in situ by mixing individual
components), low atom economy, the need in additives and in precise
moisture control, the use of hazardous oxidants, etc.: K. P. Bryliakov,
Mini-Reviews Org. Chem. 11 (2014) 87–96.
The present work was supported by the Russian Scientific Foun-
dation, grant 14-13-00158.
Appendix A. Supplementary data
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Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.cattod.2016.03.
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Please cite this article in press as: E.P. Talsi, K.P. Bryliakov, Ti-Salan catalyzed asymmetric sulfoxidation of pyridylmethylthiobenzimi-
dazoles to optically pure proton pump inhibitors, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.03.006