Catalytic asymmetric oxidation of 1H-benzimidazolyl pyridinylmethyl sulfides with cumene hydroperoxide catalyzed by a titanium complex with (S,S)-N,N′-dibenzyl tartramide ligand

Article abstract of DOI:10.1016/j.tetasy.2012.03.017

A chiral titanium complex, formed in situ from Ti(Oi-Pr)₄, (S,S)-N,N′-dibenzyl tartramide and water was found to serve as an efficient catalyst for the asymmetric oxidations of 1H-benzimidazolyl pyridinylmethyl sulfides with cumene hydroperoxide (CHP) in the absence of a base. Several proton pump inhibitors (PPIs), such as esomeprazole, lansoprazole, rabeprazole and pantoprazole were obtained in high yield (up to 92%) and excellent enantiomeric excess (up to 96%).

Full text of DOI:10.1016/j.tetasy.2012.03.017

Tetrahedron: Asymmetry 23 (2012) 457–460
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Catalytic asymmetric oxidation of 1H-benzimidazolyl pyridinylmethyl
sulfides with cumene hydroperoxide catalyzed by a titanium complex
0
with (S,S)-N,N -dibenzyl tartramide ligand
Guoyong Che , Jing Xiang a,c, Tian Tian a,c, Qingfei Huang , Linfeng Cun , Jian Liao , Qiwei Wang ,
a,c
a
a
a
a
a
a,b,
⇑
Jin Zhu , Jingen Deng
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Graduate School of the Chinese Academy of Sciences, Beijing 100049, China
a
b
c
a r t i c l e i n f o
a b s t r a c t
0
Article history:
Received 17 February 2012
Accepted 29 March 2012
A chiral titanium complex, formed in situ from Ti(Oi-Pr) , (S,S)-N,N -dibenzyl tartramide and water was
4
found to serve as an efficient catalyst for the asymmetric oxidations of 1H-benzimidazolyl pyridinylm-
ethyl sulfides with cumene hydroperoxide (CHP) in the absence of a base. Several proton pump inhibitors
(PPIs), such as esomeprazole, lansoprazole, rabeprazole and pantoprazole were obtained in high yield (up
to 92%) and excellent enantiomeric excess (up to 96%).
Ó 2012 Elsevier Ltd. All rights reserved.
1
. Introduction
hydroperoxide in the absence of a base catalyzed by a chiral
0
titanium complex, formed in situ from Ti(Oi-Pr)
4
, (S,S)-N,N -diben-
Optically active sulfoxides have been widely used as chiral aux-
zyl tartramide (DbzTA) and water.
iliaries in a variety of highly diastereoselective carbon–carbon bond
forming reactions, and have also exhibited a broad range of biolog-
ical properties, especially as blockbuster gastric proton pump inhib-
2
. Results and discussions
The corresponding tartramide ligands derived from commer-
1
itors (PPIs). Consequently, much effort has been directed toward
the development of enantioselective sulfoxidation.2 Among these
chiral complexes of transition metals used in the synthesis of opti-
cally active sulfoxides, the chiral titanium complex has proven to be
a powerful catalyst in generating optically active PPI on a large-
scale.5 Early in 1984, Kagan6 and Modena7 employed modified
Sharpless reagents for enantioselective sulfoxidation. Subsequently,
Unge8 used Kagan’s conditions for the oxidation of pyrmetazol,
although only racemic omeprazole was generated. However, when
–4
cially available DET were conveniently prepared using a classical
ammonolysis method. Next, using pyrmetazol as the template sub-
strate, we investigated these different tartramide ligands in order
to improve the enantioselectivity of the sulfoxidation. The catalyst
was prepared in situ by treatment of titanium tetraisopropoxide
with the corresponding tartramide ligands at 80 °C for 1 h. As sum-
marized in Table 1, the primary amide 4 exhibited sluggish reactiv-
ity and poor enantioselectivity (28% ee) (entry 1). A remarkable
improvement in enantioselectivity was observed for all secondary
amides 5a–j compared with primary amide 4 (entries 2–11 vs 1). It
was found that the ee value increased with the length of the side
chains on the nitrogen atom (entries 2–4); 5c bearing two n-propyl
groups gave 92% ee despite slightly poorer reactivity than 5b (entry
0
N,N -diisopropylethylamine (DIPEA) was used in Kagan’s system,
esomeprazole could be synthesized efficiently.9 Later, a tungsten
(
3
VI) oxide (WO )-cinchona alkaloid system was found to effectively
catalyze the oxidation of lansoprazole sulfide, to afford (R)-lansop-
razole with 88% ee in 84% yield.10 More recently, 1H-benzimidazolyl
pyridinylmethyl sulfoxides were prepared with up to 98% ee using
3
vs 4). However, a further increase in the size of the substituent on
4
Jiang’s system, which used a combination of tert-butyl hydroperox-
the nitrogen atom resulted in a decrease in enantioselectivity and
reactivity for 5d–f (entries 5–7 and 11), especially for 5e and 5f,
respectively, with a bulky isobutyl group and a bulky isopropyl
group. Compound 5g bearing two benzene groups was unsuccess-
ful in affording a satisfactory ee value (entry 8), while 5i (DbzTA)
possessing two benzyl groups provided the desired esomeprazole
with excellent enantioselectivity (96% ee) (entry 10), along with
trace amounts of overoxidized sulfone. It is noteworthy that the
4
ide (TBHP), Ti(Oi-Pr) , (1R,2R)-1,2-bis(2-bromophenyl)-ethane-1,2-
diol and water.
Herein we report a new procedure for the asymmetric oxidation
of 1H-benzimidazolyl pyridinylmethyl sulfides with cumene
⇑
Corresponding author.
E-mail address: jgdeng@cioc.ac.cn (J. Deng).
0
957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.03.017

4
58
G. Che et al. / Tetrahedron: Asymmetry 23 (2012) 457–460
Table 1
Asymmetric oxidation of pyrmetazol using Ti-complexes with different tartramides
a
H3CO
O
N
OCH3
OCH3
S
N
H
H3CO
OCH3
N
N
Ti(Oi-Pr)4/ L*/H2O (1/2/1)
S
esomeprazole 2
N
H
CHP, toluene
N
H3CO
O
S
N
pyrmetazol 1
N
H
O
N
3
O
O
R1
NH
R3
N
R2
R3
O
O
O
O
O
O
O
HN
R1
H2N
NH2
N
O
R2
HO
OH
HO
OH
HO
OH
HO
OH
2
3
4
5a
1
1
6a R ,R = CH3
R
= CH3
7
2
3
5
b R = CH2CH3
6b R ,R = (-CH2CH2-)2
1
5
5
5
5
5
5
5
5
c R = CH CH CH
2
2
3
1
d R = CH2CH2CH2CH3
1
e R = CH CH(CH )
2
3 2
1
f R = CH(CH3)2
1
g R = phenyl
1
h R = 2-furanmethyl
1
i R = benzyl
1
j R = cyclohexyl
Entry
Ligand
Eeb (%)
Ratioc (%)
SO
2
3
SO 2
S 1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
4
28 (S)
71 (S)
91 (S)
92 (S)
89 (S)
84 (S)
52 (S)
39 (S)
90 (S)
96 (S)
57 (S)
24 (R)
37 (R)
16 (S)
0
0
0
0
0
0
0
0
0
0.3
0
0
0
2.3
9.7
5.9
90.3
94.1
49.0
53.4
68.9
87.9
91.6
39.3
51.2
19.0
84.1
73.9
64.3
55.1
5a
5b
5c
5d
5e
5f
5g
5h
5i
51.0
46.6
31.1
12.1
8.4
60.7
48.8
80.7
15.9
26.1
35.7
42.5
0
1
2
3
4
5j
6a
6b
7
d
a
Unless otherwise noted, the reaction was carried out with 10 mmol of pyrmetazol in 20 mL of toluene at 30 °C for 2 h and the activation temperature of catalyst was 80 °C,
sulfide/ligand/Ti(Oi-Pr) /H O/CHP (80% in cumene) = 1.0:0.6:0.3:0.3:1.0.
4
2
b
Determined by chiral HPLC analysis.
Determined by HPLC analysis.
The activation temperature of the catalyst was 54 °C.
c
d
and 13). The above findings prompted us to examine (S,S)-DET 7
under standard conditions without Hünig’s base (entry 14). This
Table 2
8
Effect of the amount of water in the asymmetric sulfioxidationa
frequently used ligand displayed a significantly inferior enantiose-
lectivity compared to all of the tartramides (16% ee). This clearly
indicated that when DIPEA was used in Astrazeneca’s procedure
for the preparation of esomeprazole, it had a significant effect with
regards to achieving excellent enantioselectivity. Moreover, Kagan
has demonstrated that the dielectric constant of the solvent had an
importance influence on the enantioselectivity in the asymmetric
Entry
(H
2
O/Ti) (mol/mol)
Eeb (%)
Ratioc (%)
SO
2
3
SO 2
S 1
1
2
3
4
5
0
68
96
96
96
94
0.9
0.2
0.3
0.3
0.2
19.2
60.2
70.1
80.7
84.1
79.8
39.6
29.6
19.0
15.7
0.5
0.7
1
1.5
1
1
oxidation of sulfides. Therefore, we investigated the effect of sol-
vent on the enantioselectivity in the presence of ligand 5i and
a
Unless otherwise noted, all reactions were carried out with sulfide/5i/Ti(Oi-
4
/CHP (80% in cumene) = 1.0:0.6:0.3:1.0 in toluene at 30 °C for 2 h and the
Pr)
2 2 3
found that other solvents, such as CH Cl , CHCl , and EtOAc, gave
activation temperature of the catalyst was 80 °C. Compound 5i was employed as the
ligand.
poor results compared with toluene.
b
Determined by chiral HPLC analysis.
Kagan has previously reported that the addition of water has a
positive impact on the enantioselectivity in the case of the asym-
c
Determined by HPLC analysis.
6
metric oxidation of sulfides. Consequently, we investigated the
effect of water in the asymmetric oxidation of pyrmetazol in the
presence of 5i and the results are shown in Table 2. When the mo-
lar ratio of water with titanium tetraisopropoxide was varied from
tertiary amides 6a and 6b showed reverse asymmetric induction in
contrast to the primary amide and the secondary amide (entries 12

G. Che et al. / Tetrahedron: Asymmetry 23 (2012) 457–460
459
Table 3
Further optimization of the reaction conditions for the asymmetric oxidation of pyrmetazol
a
Entry
Catalystb (mol %)
CHPc (mol %)
Temp (°C)
Time (h)
Eed (%)
Ratioe (%)
SO
2
3
SO 2
S 1
1
2
3
4
5
30
30
20
30
30
100
200
200
200
200
30
30
30
20
40
2
1
1
1
1
96
95
94
95
92
0.3
0.4
0.2
0.4
0.7
80.7
94.1
85.8
77.0
96.7
19.0
5.5
14.0
22.6
2.6
a
b
c
Unless otherwise noted, all reactions were carried out with 5i/Ti(Oi-Pr)
The molar ratio of the catalyst and pyrmetazol.
The molar ratio of CHP and pyrmetazol.
Determined by chiral HPLC analysis.
Determined by HPLC analysis.
4 2
/H O = 2:1:1 in toluene while the activation temperature of the catalyst was 80 °C.
d
e
Table 4
detected when the reaction was carried out with 1–2 equiv of oxi-
dant. Lowering the load of the catalyst to 20 mol % resulted in a de-
crease in the reactivity while the enantioselectivity was almost
unaffected (entry 3). In general, the reaction temperature had a sig-
nificant influence on the enantioselectivity and the amount of the
sulfoxide. When the reaction temperature was lowered to 20 °C,
the enantioselectivity was unchanged but the yield of the sulfoxide
was reduced from 94.1% to 77.0% (entries 4 vs 2). When the reaction
temperature was increased to 40 °C, the enantioselectivity de-
creased to 92% ee although the yield of the sulfoxide increased to
a
Asymmetric oxidation of pyrmetazol involving different bases
Entry
Base
Eeb (%)
Ratioc (%)
SO
2
3
SO 2
S 1
1
2
3
4
5
6
—
TEA
95
94
94
94
91
73
0.4
0.4
0.4
3.3
3.1
3.5
94.1
88.6
93.1
93.4
90.0
35.5
5.5
11.0
6.5
3.3
6.9
DIPEA
N,N-Dimethylaniline
NaHCO
Na CO
3
2
3
60.9
a
4 2
Unless otherwise noted, all reactions were carried out with 5i/Ti(Oi-Pr) /H O/
9
6.7% (entry 6). Therefore, the following studies were conducted
Base = 2:1:1:1 in toluene and the activation temperature of the catalyst was 80 °C.
b
at 30 °C in the presence of 30 mol % of catalyst.
Determined by chiral HPLC analysis.
Determined by HPLC analysis.
c
As described by Szabó et al., Hünig’s base plays a critical role in
the asymmetric induction, which could coordinate with the
titanium center and consequently be involved in the oxidation pro-
1
2
0
.5 to 1.0, this transformation occurred with the best enantioselec-
cess. Thus we investigated the effect of the base on the enantiose-
lectivity, with the results summarized in Table 4. It can be seen that
both organic bases (entries 2–4) or inorganic bases (entries 5–6) had
a marginal influence on the enantioselectivity and on the amount of
the sulfoxide, thus indicating that the base did not have any positive
effect on our oxidation system.
tivity (96% ee) (entry 2 and 3) and the sulfoxide increased with the
growing amount of water (entry 2 vs 3). Anidentical molar ratio of
water with titanium tetraisopropoxide was found to be the best
choice for achieving excellent catalytic efficiency.
We next focused our efforts on investigating the factors influenc-
ing the selectivity of the asymmetric oxidation of pyrmetazol, such
as the amount of oxidant, the amount of titanium complex, and the
temperature in the presence of 5i (Table 3). A higher conversion was
obtained when 2 equivalents of oxidant were used (entries 2) while
no other remarkable differences in the enantioselectivity were
With the optimized conditions [30 mol % of Ti(Oi-Pr) , 60 mol %
4
of 5i, 30 mol % water, 200 mol % of CHP in toluene at 30 °C] in hand,
we consequently explored the substrate scope of this newly devel-
oped system. As listed in Table 5, other proton pump inhibitors
were obtained in high yield and with excellent enantioselectivities.
Table 5
a
Enantioselective oxidation of 1H-benzimidazolyl pyridinylmethyl sulfides
R5
R5
R4
R6
R4
R6
i
O
S
H
N
Ti(O Pr)4 / 5i / H2O
S
N
N
CHP, toluene
N
N
R7
HN
R7
8
9
a R ,R = H, R5 = OCH CF , R = CH3
4
7
6
9a lansoprazole
9b rabeprazole
8
8
8
2
3
4
7
5
6
b R , R = H, R =OCH2CH2CH2OCH3, R = CH3
9
c pantoprazole
4
5
6
7
c R = H, R ,R = OCH , R = OCHF2
3
Entry
Sulfide (g)
Time (h)
Yieldb (%)
Eec (%)
Configurationd
1
2
3
4
1 (10.0)
1
1
1
2
92
89
87
85
95
94
94
96
(S)
(S)
(S)
(S)
8a (50.0)
8b (3.43)
8c (3.57)
a
Unless otherwise noted, all reactions were carried out with 8/5i/Ti(Oi-Pr)
/H
4 2
O/CHP (80% in cumene) = 1.0:0.6:0.3:0.3:2.0 in toluene at 30 °C, according to the sequence in
the Experimental.
b
Isolated yield.
Enantiomeric excess was determined by HPLC analysis.
Absolute configuration was assigned by comparison of the specific rotation and the retention time of the HPLC analysis reported in the literature.
c
d
3,13

4
60
G. Che et al. / Tetrahedron: Asymmetry 23 (2012) 457–460
ꢂ1
Esomeprazole 1 was obtained in 95% ee and 92% yield on a 10 g
scale (entry 1), while lansoprazole 9a was furnished with 94% ee
and 89% yield even when amplified to a 50 gram scale (entry 2).
Rabeprazole 9b was afforded with 94% ee and 87% yield (entry
column, n-hexane/i-PrOH (85:15), 1.0 mL min , UV 254 nm, tma-
jor = 18.7 min, tminor = 24.3 min.
4.2.2. Lansoprazole 9a3
1
3
). Pantoprazole 9c was obtained with 96% ee and 85% yield (entry
Obtained as a foam-like solid in 89% yield and 94% ee. H NMR
(300 MHz, DMSO-d ): d 13.6 (br s, 1H), 8.28(d, J = 5.6 Hz, 1H), 7.65
6
0
4
). The above results clearly indicated that the (S,S)-N,N -dibenzyl
tartramide/titanium catalytic system shows good potential for
the synthesis of PPIs with a 1H-benzimidazolyl pyridinylmethyl
sulfoxide skeleton.
(br s, 2H), 7.30 (m, 2H), 7.09 (d, J = 5.6 Hz, 1H), 4.90 (q, J = 8.7 Hz,
2H), 4.83 and 4.75 (AB-system, J = 13.7 Hz, 2H), 2.17 (s, 3H).
2
5
½
a
ꢁ
¼ ꢂ199:7 (c 1.0, acetone). The ee was determined by HPLC
D
on Kromasil KR100-5CHI-TBB column, n-hexane/i-PrOH/acetic
ꢂ1
acid/TEA (90:10:0.1:0.2), 1.5 mL min , UV 284 nm, tmajor = 8.3 -
3
. Conclusion
min, tminor = 10.4 min.
In conclusion, we have reported a novel efficient catalytic sys-
4
.2.3. Rabeprazole 9b3
Obtained as an oil in 87% yield and 94% ee. H NMR (300 MHz,
DMSO-d ): d 13.59 (br s, 1H), 8.21 (d, J = 5.4 Hz, 1H), 7.65 (br s, 2H),
.30 (m, 2H), 6.95(d, J = 5.4 Hz, 1H), 4.80 and 4.72 (AB-system,
J = 13.5 Hz, 2H), 4.05 (t, J = 6.1 Hz, 2H), 3.46 (t, J = 6.1 Hz, 2H),
tem for the asymmetric oxidation of 1H-benzimidazolyl pyridi-
nylmethyl sulfides in the absence of a base and the desired
product being obtained with excellent enantioselectivity. Further
work on the reaction mechanism and amplification of these reac-
tions are currently underway in our laboratory.
1
6
7
2
5
3
.23 (s, 3H), 2.14 (s, 3H), 2.00 (m, 2H). ½
CHCl ). The ee was determined by HPLC on Chiralpak AD-H col-
umn, i-PrOH, 0.6 mL min
major = 10.5 min.
a
ꢁ
¼ ꢂ135:0 (c 0.05,
D
3
ꢂ1
4
4
. Experimental
.1. General
,
UV 292 nm, tminor = 9.5 min;
t
4
.2.4. Pantoprazole 9c3
Obtained as an off-white solid in 85% yield and 96% ee. H NMR
1
1
H NMR spectra were recorded at 300 MHz. Chemical shifts (d)
1
are reported in ppm relative to DMSO (d = 2.49 ppm) for H NMR
spectroscopy. Coupling constants (J) are given in Hz. The optical
rotation was determined with a Perkin–Elmer 341 polarimeter.
Enantiomeric excess, and the ratio of the sulfide, sulfoxide, and sul-
fone were determined by HPLC analysis. Toluene was freshly dis-
(300 MHz, DMSO-d ): d 13.8 (br s, 1H), 8.16 (d, J = 5.5 Hz, 1H), 7.68
(d, J = 8.3 Hz, 1H), 7.45 (s, 1H) , 7.25 (t, J = 74.3 Hz, 1H), 7.14–7.17
(m, 1H), 7.10 (d, J = 5.5 Hz, 1H), 4.67 and 4.73 (AB-system,
6
2
D
5
J = 13.0 Hz, 2H), 3.90 (s, 3H), 3.77 (s, 3H). ½
aꢁ
¼ ꢂ95:5 (c 0.3,
MeOH). The ee was determined by HPLC on Chiralpak AD-H col-
ꢂ1
tilled over sodium benzophenone ketyl under
a
nitrogen
umn, n-hexane/i-PrOH(85:15), 1.0 mL min , UV 254 nm, tmi-
atmosphere prior to its use. Ti(Oi-Pr) was distilled under a nitro-
4
= 29.9 min; tmajor = 40.2 min.
nor
gen atmosphere prior to use. Chiral tartaric amides were prepared
according to the literature procedures.14
Acknowledgments
We gratefully acknowledge the National Nature Science Foun-
dation of China (Grant No. 21172152), the National Basic Research
Program of China (973 Program, No. 2010CB833300) and the Sich-
uan University for their financial support.
4
.2. General experimental procedures
In a typical experiment, Ti(Oi-Pr)
to a solution of (S,S)-DBzTA 5i (1.969 g, 6 mmol) and pyrmetazol
3.29 g, 10 mmol) in toluene (20 mL) at 80 °C. The solution was
4
(0.9 mL, 3 mmol) was added
(
Reference
stirred for 60 min., after which water (54 mg, 3 mmol) was added
to the mixture, and the solution was stirred for another 60 min.
Next, the temperature was adjusted to 30 °C, after which cumene
hydroperoxide (80 %, 3.6 mL, 20 mmol) was slowly added. After
1.
(a) Rouhi, A. M. Chem. Eng. News. 2003, 81, 56; (b) Fernandez, I.; Khiar, N. Chem.
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T.; Kawano, Y.; Kawano, Y.; Uchida, M. Tetrahedron: Asymmetry 1997, 8, 3707;
(d) Carlsson, E.; Lindberg, P.; Unge, S. V. Chem. Br. 2002, 38, 42.
1
h at 30 °C, the solution was added to aqueous sodium hydroxide
2
3
.
.
Urbano, A. Angew. Chem., Int. Ed. 2003, 42, 3986.
Carreno, M. C.; Hernandez-Torres, G.; Ribagorda, M.; Urbano, A. Chem. Commun.
(
1.2 g NaOH in 20 mL water), stirred for 1 h, and extracted with
water (20 mL ꢀ 3). The aqueous phase was adjusted to pH 8 with
2009, 6129.
acetic acid, separated, and extracted with dichloromethane
4. Jiang, B.; Zhao, X. L.; Dong, J. J.; Wang, W. J. Eur. J. Org. Chem. 2009, 987.
5
6
.
.
Legros, J.; Dehli, J. R.; Bolm, C. Adv. Synth. Catal. 2005, 347, 19.
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(
20 mL ꢀ 3). The combined organic solutions were dried over
anhydrous Na SO , filtered, and the solvent was removed in vacuo.
2
4
1
06, 8188.
7. DiFuria, F.; Modena, G.; Seraglia, R. Synthesis 1984, 325.
The residue was purified by chromatography on silica gel with
ethyl acetate/petroleum ether (2:1) as the eluent to afford the
sulfoxide.
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Larsson, E. M.; Stenhede, U. J.; Sörensen, H.; von Unge, S.; Cotton, H. K. Patent
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1
0. Thakur, V. V.; Sudalai, A. Tetrahedron: Asymmetry 2003, 14, 407.
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Appl Chem. 1911, 1985, 57.
4
.2.1. Esomeprazole 23,8,14
Obtained as an oil in 92% yield and 95% ee. H NMR (300 MHz,
DMSO-d ): d 8.15 (s, 1H), 7.53(d, J = 8.9 Hz, 1H), 7.08 (s, 1H), 6.90
dd, J = 2.3 Hz, 8.9 Hz, 1H), 4.75 and 4.66 (AB-system, J = 13.6 Hz,
1
1
1
1
2. Seenivasaperumal, M.; Federsel, H. J.; Szabó, K. J. Adv. Synth. Catal. 2009, 351,
6
903.
(
2
3. Deng, J. G.; Chi, Y. X.; Fu, F. M.; Cui, X.; Yu, K. B.; Zhu, J.; Jiang, Y. Z. Tetrahedron:
Asymmetry 2000, 11, 1729.
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25
H), 3.78 (s, 3H), 3.65 (s, 3H), 2.15(s, 6H). ½
a
ꢁ
¼ ꢂ152:0 (c 0.1,
D
CHCl ). The ee was determined by HPLC on Chiralpak AD-H
3