WO3-30% H2O2-cinchona alkaloids: A new heterogeneous catalytic system for the asymmetric oxidation of sulfides and the kinetic resolution of racemic sulfoxides

Article abstract of DOI:10.1016/S0957-4166(02)00865-0

WO₃-catalyzed asymmetric oxidation of thioethers and kinetic resolution of sulfoxides with 30% aq. H₂O₂ in the presence of cinchona alkaloids under heterogeneous conditions affords chiral sulfoxides in high yields with moderate to good enantioselectivities.

Full text of DOI:10.1016/S0957-4166(02)00865-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 407–410
WO3–30% H2O2–cinchona alkaloids: a new heterogeneous
catalytic system for the asymmetric oxidation of sulfides and the
kinetic resolution of racemic sulfoxides
Vinay V. Thakur and A. Sudalai*
Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411008, India
Received 18 November 2002; accepted 17 December 2002
Abstract—WO3-catalyzed asymmetric oxidation of thioethers and kinetic resolution of sulfoxides with 30% aq. H2O2 in the
presence of cinchona alkaloids under heterogeneous conditions affords chiral sulfoxides in high yields with moderate to good
enantioselectivities. © 2003 Elsevier Science Ltd. All rights reserved.
Chiral sulfoxides have emerged as versatile building
blocks and chiral auxiliaries in the synthesis of pharma-
ceutical products.1 The asymmetric oxidation of prochi-
ral sulfides with chiral metal complexes has become one
of the most effective routes to obtain these chiral
sulfoxides.2 Chiral metal complexes such as Ti-diol/–
BINOL,3 V, Ti and Mn–salen4 and V–Schiff bases5 are
mainly used as homogeneous catalysts in combination
with either alkyl hydroperoxides or expensive chiral
hydroperoxides as terminal oxidants, for asymmetric
sulfoxidation, often in stochiometric amounts. In recent
years, kinetic resolution of racemic sulfoxides6 has
emerged as a promising method to obtain optically
pure sulfoxides, as racemic sulfoxides are readily pre-
pared by direct oxidative methods. Although several
modified procedures have been reported for both asym-
metric sulfoxidations and kinetic resolutions, scant
attention has been given to the heterogeneous version
of these reactions involving the use of less expensive
commercially avialable metal catalysts and chiral lig-
ands.7 The use of heterogeneous catalysts under ambi-
ent conditions offers several advantages compared with
their homogeneous counterparts e. g. ease of recovery
and recycling and enhanced stability. Further use of aq.
H2O2 is highly desirable from the viewpoints of atom
economy and ecological considerations.
In this communication, we wish to report a new hetero-
geneous catalytic system (WO3–30% H2O2) which
efficiently catalyzes both the asymmetric oxidation of
variety of thioethers and kinetic resolution of racemic
sulfoxides in the presence of cinchona alkaloids such as
hydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether
[(DHQD)2–PYR] to produce optically active sulfoxides
in high yields and with good enantioselectivities
(Schemes 1 and 2).
Table 1 shows the results from the asymmetric oxida-
tions of phenyl benzyl sulphide with 30% H2O2 in the
presence of a catalytic amount of WO3 and cinchona
alkaloids and it was found that (DHQD)2–PYR in
THF gave the best result (70% yield; 53% ee). Among
the solvents screened (CH3OH, CH2Cl2, CHCl3,
CH3CN, etc.), THF proved to be the best choice while
water and acetic acid were found to be detrimental to
the selectivity of the sulfoxidation. Among the various
oxidants employed, 30% H2O2 as well as H2O2–urea
complex were found to be effective oxidants, giving
excellent yields of sulfoxides with moderate enantiose-
lectivities. After initial optimization studies, combina-
tion of WO3 (5 mol%), chiral cinchona alkaloid (10
mol%) and aq. 30% H2O2 (1.1 equiv.) in THF proved
to be the best catalytic system for the asymmetric
oxidation of aryl alkyl sulfides.
* Corresponding author. Tel.: +91-020-5893300; fax: +91-20-5893359;
e-mail: sudalai@dalton.ncl.res.in
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00865-0

408
V. V. Thakur, A. Sudalai / Tetrahedron: Asymmetry 14 (2003) 407–410
Scheme 1. Reagents and conditions: (i) WO3 (5 mol%), (DHQD)2–PYR (10 mol%), aq. 30% H2O2 (1.1 equiv.), THF, 0°C.
It is evident from Table 2† that a variety of aryl alkyl
sulfides 1 underwent oxidation under the reaction con-
ditions to yield the corresponding optically active sul-
foxides 2 in 78–90% yields and 35–65% ee. Sulfides
possessing benzyl as the R group showed better enan-
tioselectivity than other alkyl groups. Increasing the
loading of the ligand (50 mol%) did not have any
significant effect on the enantioselectivity of the
reactions.
optical purity of the recovered sulfoxide with (R)-
configuration increased to 90% ee.
Mechanistically, it is believed that the electrophilicity of
the peroxide oxygen of H2O2 is increased by the
oxometal (MꢀO) group coordinated by the chiral lig-
and, L* 6 so that the asymmetric sulfoxidation of
thioethers proceeds readily to give chiral sulfoxides in
high yields.
It was also of interest to subject various racemic sulfox-
ides to WO3-catalyzed kinetic resolution in the presence
of (DHQD)2–PYR as ligand, the results of which are
presented in Table 3.† Kinetic resolutions were per-
formed at 25°C to afford optically active sulfoxides 4 in
25–44% yield and 44–90% ee along with the corre-
sponding sulfones 5 (Scheme 2).
As shown in Fig. 1, when the conversion of racemic
sulfoxide to sulfone reached 75% for 18 h, the observed
The present methodology was applied to the enantiose-
lective sulfoxidation of 79 to produce antiulcer drug
(R)-Lansoprazole 8 in 84% yield and 88% ee (Scheme
3).‡
In conclusion, the asymmetric oxidation of thioethers
as well as kinetic resolution of sulfoxides with 30%
H2O2 catalyzed by a stable, recyclable and commer-
cially avialable solid WO3 catalyst provides a simple
and effective procedure for the preparation of chiral
sulfoxides in good enantiomeric purity.
† Typical experimental procedure: A 25 ml round-bottomed flask was
charged with WO3 (0.012 g, 0.05 mmol), (DHQD)2–PYR (0.088 g,
0.1 mmol) and sulfide or racemic sulfoxide (1 mmol) in THF (2 ml).
To this reaction mixture was added 30% H2O2 (0.12 ml, 1.1 mmol)
at a given temperature. The reaction mixture was further stirred for
the specified time. The catalyst was filtered off and the filtrate was
diluted with EtOAc (10 ml). The organic layer was washed with
water, brine and dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude reaction mixture was purified by
column chromatography using petroleum ether and EtOAc as elu-
ents to afford optically active sulfoxides.
‡ (R)-(+)-Lansoprazole 8: yield 84%; mp 162–165°C (dec.); [h]D25
=
+250.60 (c 0.5, acetone); HPLC: 88% ee, Chiralcel OD-H, u=254
nm, hexane:2-propanol (9:1), 0.5 ml/min. Retention time: (R)-enan-
tiomer=18.4 min, (S)-enantiomer=21.3 min. IR (Nujol, cm−1):
3200, 3053, 2950, 2852, 1658, 1559, 1444, 1379, 1267, 1263, 1163,
1037, 1110, 973, 858, 746, 576; 1H NMR (CDCl3): l 2.18 (s, 3H),
4.35 (q, J=8.14 Hz, 2H), 4.81 (d, J=6.30 Hz, 2H), 6.64 (d, J=6.30
Hz, 1H), 7.27–7.66 (m, 5H), 8.32 (d, J=6.31 Hz, 1H); 13C NMR
(CDCl3): l 11.08, 30.19, 61.11, 66.25 (q), 107.27, 116.61, 124.66,
148.88, 150.54, 153.52, 163.07; MS m/z (rel. int.): 369 (M+, 26), 353
(20), 308 (4), 320 (60), 252 (16), 238 (83), 204 (40), 165 (56), 150
(32), 137 (51), 122 (72), 106 (82), 90 (73), 77 (50), 65 (76), 52 (100).
Anal. calcd for C16H14F3N3SO2: C, 52.03; H, 3.82; N, 11.38; S,
8.68. Found: C, 52.02; H, 3.72; N, 11.31; S, 8.73%.
Scheme 2. Reagents and conditions: (i) WO3 (5 mol%),
(DHQD)2–PYR (10 mol%), aq. 30% H2O2 (1.1 equiv.), THF,
25°C.

V. V. Thakur, A. Sudalai / Tetrahedron: Asymmetry 14 (2003) 407–410
409
Table 1. WO3-catalyzed asymmetric oxidation of phenyl benzyl sulfide by aq. H2O2 in the presence of cinchona alkaloidsa
Sr. No.
Chiral ligand
Solvent
Temp. (°C)
Time (h)
Yieldb (%)
% eec
1
2
3
4
5
6
7
(−)-Quinine
(−)-Quinine
(−)-Quinine
DHQDd
CH3CN
THF
THF
CH3CN
CH2Cl2–H2O
THF
0
25
0
48
4
27
46
8
83
62
88
79
86
70
63
29 (R)
34 (R)
41 (R)
27 (R)
13 (R)
53 (R)h
22 (R)
0
NBCCe
25
25
25
(DHQD)2–PYRf
(DHQD)2–PHALg
5
8
THF
a Reaction conditions: WO3 (5 mol%), (DHQD)2–PYR (10 mol%), aq. 30% H2O2 (1.1 equiv.), THF.
b Isolated yield after column chromatography.
c Ee based on comparison of [h]D values reported in literature,3,8 as well as by chiral HPLC analysis using Chiralcel OD-H column (conditions:
u=254 nm, hexane:2-propanol (9:1), 0.5 ml/min).
d Dihydroquinidine.
e N-Benzyl cinchoninium chloride.
f Hydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether.
g Hydroquinidine 1,4-phthalazinediyl diether.
h WO3 was recovered and recycled at least five times, showing essentially the same conversion and enantioselectivity.
Table 2. Asymmetric oxidation of prochiral sulfides by aq. H2O2 catalyzed by WO3–cinchona alkaloids at 0°Ca
Sr. No.
1
Ar
Ph
R
Chiral ligand
Time (h)
Yieldb (%)
% eec
Me
Me
(DHQD)2–PYR
(DHQ)2–PYRd
(DHQD)2–PYR
(DHQD)2–PYR
(DHQD)2–PYR
(DHQD)2–PYR
(DHQD)2–PYR
(DHQD)2–PYR
(DHQ)2–PYR
49
46
44
44
40
36
24
44
32
46
34
88
83
82
83
90
78
88
81
87
86
85
59 (R)
55 (S)
51 (R)
45 (R)
35 (R)
46 (R)
61 (R)
44 (R)
52 (S)
43 (R)
65 (R)e
Et
iPr
nBu
C6H11
CH2Ph
Me
Me
Et
2
p-Tolyl
(DHQD)2–PYR
(DHQD)2–PYR
CH2Ph
a Reaction conditions: WO3 (5 mol%), (DHQD)2–PYR (10 mol%), aq. 30% H2O2 (1.1 equiv.), THF, 0°C.
b Isolated yield after column chromatography.
c Ee based on comparison of [h]D values reported in the literature, as well as by chiral HPLC analysis using Chiralcel OD-H column (conditions:
u=254 nm, hexane:2-propanol (9:1), 0.5 ml/min).
d Hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether.
e WO3 was recovered by simple filteration and recycled at least five times, essentially showing the same conversion and enantioselectivity.
Table 3. WO3-catalyzed kinetic resolution of aryl alkyl sulfoxides in presence of (DHQD)2–PYR at 25°Ca
Sr. No.
Ar
R
Time (h)
Yieldb (%)
Sulfone 5
% eec of 4
Sulfoxide 4
1
Ph
Me
12
10
12
10
13
20
16
14
12
18
40
39
32
44
35
31
29
33
28
25
55
52
60
48
62
57
66
67
66
72
69
66
60
44
71
82
67
58
62
90
Et
iPr
nBu
C6H11
C6H5CH2
Me
2
p-Tolyl
Et
iPr
C6H5CH2
a Reaction conditions: WO3 (5 mol%), (DHQD)2–PYR (10 mol%), aq. 30% H2O2 (1.1 equiv.), THF.
b Isolated yield after column chromatography.
c Ee based on comparison of [h]D values reported in literature, as well as by chiral HPLC analysis using Chiralcel OD-H column (conditions:
u=254 nm, hexane:2-propanol (9:1), 0.5 ml/min).

410
V. V. Thakur, A. Sudalai / Tetrahedron: Asymmetry 14 (2003) 407–410
2. (a) Solladie, G. Synthesis 1981, 185; (b) Anderson, K. K.
In Chemistry of Sulfones and Sulfoxides; Patai, S.; Rappo-
port, Z.; Stirling, C. J., Eds.; John Wiley & Sons:
Chichester, UK, 1988; Chapter 3, pp. 55–94; (c) Posner, G.
H. In Chemistry of Sulfones and Sulfoxides; Patai, S.;
Rappoport, Z.; Stirling, C. J., Eds.; John Wiley & Sons:
Chichester, UK, 1988; Chapter 16, pp. 823–849; (d) Bar-
bachyn, J. D.; Johnson, C. R. In Asymmetric Synthesis;
Morrison, J. D.; Scott, J. W., Eds.; Acadamic Press: New
York, 1983; Vol. 4, pp. 227–261; (e) Kagan, H. B.;
Rebiere, F. Synlett 1990, 643; (f) Posner, G. H. Acc. Chem.
Res. 1987, 20, 72; (g) Mikolaczyk, M.; Drabowicz, J. Top.
Stereochem. 1982, 13, 333; (h) Kagan, H. B. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed. Asymmetric Oxida-
tion of Sulfides; VCH: Weinheim, 1993; pp. 203–226; (i)
Noyori, R. In Asymmetric Catalysis in Organic Synthesis;
Wiley-Interscience: New York, 1994.
3. (a) Furia, D. F.; Modena, G.; Seraglia, R. Synthesis 1984,
325; (b) Pitchen, P.; Dunach, E.; Deshmukh, M. N.;
Kagan, H. B. J. Am. Chem. Soc. 1984, 106, 8188.
4. (a) Palucki, M.; Hanson, P.; Jacobson, E. N. Tetrahedron
Lett. 1992, 33, 7111; (b) Noda, K.; Hosoya, N.; Yanai, K.;
Irie, R.; Katsuki, T. Tetrahedron Lett. 1994, 35, 1887; (c)
Nakajima, K.; Kijima, M.; Fujita, J. Chem. Lett. 1986,
1483; (d) Bolm, C.; Bienewald, F. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2883; (e) Adam, W.; Korb, M. N.;
Roschmann, K. J.; Moller, C. R. S. J. Org. Chem. 1998,
63, 3423.
Figure 1. Kinetic resolution of p-tolyl benzyl sulfoxide.
5. Vetter, A. H.; Berkessel, A. Tetrahedron Lett. 1998, 39,
1741.
Scheme 3. Reagents and conditions: (i) WO3 (5 mol%),
(DHQD)2–PYR (10 mol%), aq. 30% H2O2 (1.1 equiv.), THF,
0°C, 50 h.
6. (a) Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S.
J. Org. Chem. 1993, 58, 7624; (b) Nagata, T.; Imagawa,
K.; Yamada, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn.
1995, 68, 3241; (c) Lattanzi, A.; Bonadies, F.; Senatore,
A.; Soriente, A.; Scettri, A. Tetrahedron: Asymmetry 1997,
8, 2473; (d) Noda, K.; Hosoya, N.; Irie, R.; Yamashita,
Y.; Katsuki, T. Tetrahedron 1994, 50, 9609.
Acknowledgements
7. Choudary, B. M.; Rani, S. S.; Rao, Y. V. S. Stud. Surf.
V.V.T. thanks the CSIR, New Delhi, for the award of
Senior Research Fellowship. The authors would also
like to thank Dr. S. Devotta, Head, PD Division, for
his constant encouragement and help.
Sci. Catal. 1993, 75, 1247.
8. (a) Mikolajczyk, M.; Drabowicz, J. J. Am. Chem. Soc.
1978, 100, 2510; (b) Mislow, K.; Green, M. M.; Laur, P.;
Melillo, J. T.; Simmons, T.; Temay, A. L., Jr. J. Am.
Chem. Soc. 1965, 87, 1958; (c) Mislow, K.; Jacobus, J. J.
Am. Chem. Soc. 1967, 89, 5228; (d) Komori, T.; Nonaka,
T. J. Am. Chem. Soc. 1984, 106, 2656; (e) Brunel, J. M.;
Diter, P.; Duetsch, M.; Kagan, H. B. J. Org. Chem. 1995,
60, 8086.
References
1. (a) Mata, E. G. Phosphorus Sulfur Silicon 1996, 117, 231;
(b) Kagan, H. B.; Rebiere, F.; Samuel, O. Phosphorus
Sulfur Silicon 1991, 58, 89; (c) Carreno, M. C. Chem. Rev.
1995, 95, 1717.
9. Nohana, A. Eur. Pat. Appl. 174, 726; Chem. Abstr. 105,
133883.