Vanadium-catalyzed sulfur oxidation/kinetic resolution in the synthesis of enantiomerically pure alkyl aryl sulfoxides

Article abstract of DOI:10.1002/anie.200503046

(Chemical Equation Presented) The importance of the mix: The use of chloroform as solvent, the ligand (R)-2 and [VO(acac)₂] as catalyst, and H₂O₂ as oxidant promotes the highly enantioselective oxidation of simple alkyl aryl sulfides 1 to give alkyl aryl sulfoxides (R)-3 (see scheme). The success of this process partly derives from an efficient kinetic resolution of the product sulfoxides.

Full text of DOI:10.1002/anie.200503046

Angewandte
Chemie
Asymmetric Catalysis
DOI: 10.1002/anie.200503046
Vanadium-Catalyzed Sulfur Oxidation/Kinetic
Resolution in the Synthesis of Enantiomerically
Pure Alkyl Aryl Sulfoxides**
Carmelo Drago, Lorenzo Caggiano, and
Richard F. W. Jackson*
Chiral sulfoxides are an important class of compounds that
find increasing use as chiral auxiliaries in asymmetric syn-
thesis.[1,2] Current interest also reflects the existence of
products with biological properties containing a sulfinyl
group with a defined configuration.[3]
Scheme 1. Vanadium-catalyzed asymmetric oxidation ofalkyl aryl
sulfides.
Several methods for the asymmetric oxidation of prochi-
ral sulfides have been reported, including the use of chiral
oxidants, such as chiral oxaziridines,[4] chiral hydroperox-
ides,[5] and enzymes.[6,7] The majority of investigations have
concentrated on the use of chiral metal complexes[1,3,8–11]
following the initial reports by Kagan and co-workers[12,13]
and Modena and co-workers[14] on the use of variously
modified Sharpless reagents for this reaction.
with a view to understanding the nature of the active catalytic
species better.[23] The nature of the active species is still not
completely established, but while spectroscopic studies indi-
cate the presence of a vanadium(v)oxomonoperoxo spe-
cies,[24] recent calculations suggest that the active species may
be a vanadium(v)oxohydroperoxide.[25] Recently, the use of
analogous salan ligands has been reported to give high levels
of enantioselectivity (95% ee) in the oxidation of methyl
phenyl sulfide, but lower levels of enantioselectivity were
observed with other substrates.[26]
Anson and co-workers screened a variety of chiral Schiff
base ligands, and found that the 3,5-diiodo ligand (S)-2, in
combination with [VO(acac)2] gave excellent results in the
catalytic asymmetric sulfoxidation of alkyl aryl sulfides with
hydrogen peroxide, again in dichloromethane at 08C.[27] For
example, methyl phenyl sulfide was oxidized to (S)-methyl
phenyl sulfoxide (81%, 90% ee). Recently, Bolm and co-
workers reported that a combination of this ligand with iron is
also very effective for the asymmetric oxidation of prochiral
sulfides,[28,29] especially in the presence of substituted benzoic
acids and with the corresponding lithium salts as addi-
tives.[30,31]
In all asymmetric oxidations of prochiral sulfides to
sulfoxides, the possibility of subsequent kinetic resolution of
the product sulfoxide by oxidation to the corresponding
sulfone exists. Uemura and co-workers had demonstrated the
viability of this process as long ago as 1993; they observed
stereoselectivity factors of 7.4–8.5 for kinetic resolutions[32]
using a catalyst prepared from Ti(OiPr)4, 2,2’-dihydroxy-1,1’-
binaphthyl (binol), and H2O.[33] A more recent example
makes use of a catalyst derived from WO3 and cinchona
alkaloids for the kinetic resolution of alkyl aryl sulfoxides
using hydrogen peroxide.[34] The process developed by
Uemura and co-workers[33,35] has been exploited by Scettri
and co-workers (using furyl hydroperoxides as the oxidant)[36]
and more recently by Chan and co-workers (using tert-
butylhydroperoxide as the oxidant).[37] Specifically, Chan and
co-workers described a process in which an initial oxidation at
08C (at which temperature the enantioselectivity is optimum)
and then at 258C (where the kinetic resolution is most
efficient) allowed the isolation of sulfoxides in reasonable
One of the most widely studied metal-based systems has
been that discovered by Bolm and Bienewald,[15,16] who
employed a combination of Schiff bases 1 derived from chiral
amino alcohols and [VO(acac)2] (1.0 mol%; acac = acetyl-
acetanoate), with aqueous hydrogen peroxide as the oxidant,
in a two-phase system using dichloromethane as the solvent at
208C (Scheme 1). The advantages of the system developed by
Bolm et al. include high activity, the very simple reaction
conditions, and the use of hydrogen peroxide as the oxidant.
The only drawback associated with the initial ligands tested
was that the levels of enantiomeric excess were good, rather
than excellent. Other research groups sought to optimize the
system, by variation of the aromatic aldehyde,[17–19] the amino
alcohol,[20] and the manner of addition of hydrogen perox-
ide,[21] and in many cases it is striking that the best outcome
was usually obtained when the reaction was conducted in
dichloromethane at 08C. Avery nice application of the system
developed by Bolm et al. was the asymmetric oxidation of di-
tert-butyl disulfide, reported by Ellman and co-workers,[22]
who have since reported the results of spectroscopic studies
[*] C. Drago, Dr. L. Caggiano, Prof. Dr. R. F. W. Jackson
Department ofChemistry
Dainton Building
University of Sheffield
Sheffield, S37HF (UK)
Fax: (+44)114-273-8673
E-mail: r.f.w.jackson@shef.ac.uk
[**] This work was supported by the Commission ofthe European Union
(IHP Network HPRN-CT-2000-00014) through a studentship (to
C.D.), supported by GSK. We thank Dr. Chiara Monti for preliminary
studies on the kinetic resolution ofalkyl aryl sulof xides, Dr. M. S.
Anson and Dr. S. J. F. Macdonald for helpful discussions, and
Degussa AG (Dr. D. Reichert and Dr. Krahnert) for a generous gift of
(R)-tert-leucinol.
Angew. Chem. Int. Ed. 2005, 44, 7221 –7223
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7221

Communications
yields and excellent ee values (65% and 99.9% ee in the case
tolyl sulfoxide (4b, 41% of a maximum of 50%, 98.0% ee), as
well as sulfone 5b (Scheme 3).
of methyl para-tolyl sulfoxide, the best so far published).[37]
However, it appears that no significant kinetic resolution in
the oxidation of sulfoxides has so far been reported in studies
in which chiral vanadium(iv)–Schiff base complexes were
used. Nevertheless, such an effect has been reported in the
case of vanadium–salan systems (selectivity factor S = 7.3 for
the resolution of methyl phenyl sulfoxide) when larger
amounts of catalyst (5 mol%) were used.[26]
Scheme 3. Kinetic resolution ofmethyl para-tolyl sulfoxide.
In an initial experiment it was confirmed that there was no
significant kinetic resolution in the oxidation of racemic
methyl phenyl sulfoxide using 3,5-diiodo ligand (R)-2 (pre-
pared from (R)-tert-leucinol, which has recently become
commercially available) in combination with [VO(acac)2] and
hydrogen peroxide in dichloromethane at 08C (S = 1.1).
However, a significant effect was observed (S = 5.8) when
the kinetic resolution was carried out at 208C. A tandem
catalytic approach to the asymmetric oxidation of methyl
phenyl sulfoxide using a combination of (R)-2 with [VO-
(acac)2] in dichloromethane was developed: an initial oxida-
tion step at 08C followed by the addition of further oxidant to
the same reaction vessel and warming to 208C allowed the
isolation of (R)-methyl phenyl sulfoxide (44%, 97.3% ee;
Scheme 2). While this was an interesting result, the modest
yield meant that it was not ideal from a preparative
perspective.
The observation that the optimum temperature for the
kinetic resolution of racemic sulfoxides with the catalyst
derived from (R)-2 and [VO(acac)2] in chloroform was 08C
(the optimum temperature for most previous asymmetric
oxidations of prochiral sulfides using chiral vanadium(iv)–
Schiff base complexes) suggested that these conditions might
also be extremely effective for the enantioselective prepara-
tion of alkyl aryl sulfoxides. This indeed proved to be the case,
and Table 1 shows results from the oxidation of a range of
Table 1: Asymmetric oxidation ofalkyl aryl sulfides 3 in chloroform using
ligand (R)-2 with [VO(acac)2] and H2O2 (1.2 equiv).
Ar
R
Product
Yield [%][a]
ee [%][b]
Ph
Me
Me
Me
Me
Me
Me
Me
Pr
(R)-4a
(R)-4b
(R)-4c
(R)-4d
(R)-4e
(R)-4 f
(R)-4g
(R)-4h
(R)-4i
70
70
73
88
72
71
79
86
76
96.7
>99.5
>99.5
86.9
96.9
99.5
95.5
98.3
97.4
Given the striking effect of temperature on the efficiency
of the kinetic resolution, it seemed appropriate to explore the
influence of the solvent. After substantial solvent screening in
the oxidation of racemic methyl phenyl sulfoxide (4a) using
(R)-2 and [VO(acac)2] as the catalyst, and hydrogen peroxide
as oxidant (0.5 equiv), it was found that the use of chloroform
as the solvent[38] resulted in an improved kinetic resolution
effect at 208C (S = 7.7). No other solvent that was screened
gave comparable results. The kinetic resolution in chloroform
was more efficient at 08C (S = 11.6). The highest value so far
reported (S = 28) was obtained when the kinetic resolution of
4-MeC6H4
2-naphthyl
4-NO2C6H4
4-ClC6H4
4-MeOC6H4
4-BrC6H4
Ph
Ph
Et
[a] Yield ofisolated product. Reactions were conducted on a 1.5 mmol
scale. [b] Determined by HPLC ofthe purifed products on a chiral
stationary phase using a DAICEL Chiralpak AS column.
alkyl aryl sulfides to give the (R)-alkyl aryl sulfoxides
(Scheme 4). In each case, the corresponding sulfone 5
was also observed, thus indicating that, as expected,
some kinetic resolution had taken place. The only
unsatisfactory result was the oxidation of methyl para-
nitrophenyl sulfide (3d), which gave the product 4d in
only 86.9% ee.
These encouraging results on
a small scale
prompted an investigation into scaling the reaction
up. Oxidation of methyl phenyl sulfide (3a) with
60.0 mmol of substrate under the same reaction
conditions (albeit with an increase in the reaction
time from 16 h to 48 h) allowed the isolation of (R)-
Scheme 2. Oxidation/kinetic resolution process for the preparation of (R)-methyl phenyl
sulfoxide (4a).
racemic methyl para-tolyl sulfoxide (4b) at 08C was inves-
tigated (Scettri and co-workers reported S = 23 by using a
stoichiometric process).[36] This kinetic resolution could be
adapted for preparative use (with 0.6 equiv of hydrogen
peroxide), which allowed the isolation of (R)-methyl para-
Scheme 4. Optimized asymmetric oxidation ofalkyl aryl sulifdes.
7222
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 7221 –7223

Angewandte
Chemie
[6] E. G. Mata, Phosphorus Sulfur Relat. Elem. 1996, 117, 231 – 286.
methyl phenyl sulfoxide (4a; 87%, 93% ee). The oxidation
was also performed on the same scale using methyl para-tolyl
sulfide (3b), to give (R)-methyl para-tolyl sulfoxide (4b;
82%, > 99.5% ee after one recrystallization from Et2O/
hexane), and methyl para-bromophenyl sulfide (3g), to
give (R)-methyl para-bromophenyl sulfoxide (4g; 77%,
> 99.5% ee after one recrystallization from Et2O/hexane).
In these latter two cases, the efficiency of the process was even
higher than that observed on a small scale.
The combination of very high ee values with high yield,
the consequence of an efficient initial asymmetric oxidation
followed by an efficient kinetic resolution process, makes this
system very practical for the catalytic asymmetric oxidation of
simple alkyl aryl sulfides. Both enantiomers of ligand 2 are
easily prepared on a multigram scale from commercially
available precursors, and the ligands may be stored at room
temperature on the open bench without any special precau-
tions.
[7] D. R. Boyd, N. D. Sharma, S. A. Haughey, M. A. Kennedy, B. T.
McMurray, G. N. Sheldrake, C. C. R. Allen, H. Dalton, K.
Sproule, J. Chem. Soc. Perkin Trans. 1 1998, 1929 – 1933.
[8] K. Kaczorowska, Z. Kolarska, K. Mitka, P. Kowalski, Tetrahe-
dron 2005, 61, 8315 – 8327.
[9] H. B. Kagan, T. O. Luukas, in Transition Metals for Organic
Synthesis, Vol. 2, 2nd ed. (Eds.: M. Beller, C. Bolm), Wiley-
VCH, Weinheim, 2004, pp. 479 – 495.
[10] K. P. Volcho, N. F. Salakhutdinov, A. G. Tolstikov, Russ. J. Org.
Chem. 2003, 39, 1537 – 1552.
[11] C. Bolm, Coord. Chem. Rev. 2003, 237, 245 – 256.
[12] P. Pitchen, E. Duæach, M. N. Deshmukh, H. B. Kagan, J. Am.
Chem. Soc. 1984, 106, 8188 – 8193.
[13] P. Pitchen, H. B. Kagan, Tetrahedron Lett. 1984, 25, 1049 – 1052.
[14] F. DiFuria, G. Modena, R. Seraglia, Synthesis 1984, 325 – 326.
[15] C. Bolm, F. Bienewald, Angew. Chem. 1995, 107, 2883 – 2885;
Angew. Chem. Int. Ed. Engl. 1995, 34, 2640 – 2642.
[16] C. Bolm, G. Schlingloff, F. Bienewald, J. Mol. Catal. A 1997, 117,
347 – 350.
[17] A. H. Vetter, A. Berkessel, Tetrahedron Lett. 1998, 39, 1741 –
1744.
[18] J. Skarzewski, E. Ostrycharz, R. Siedlecka, Tetrahedron: Asym-
metry 1999, 10, 3457 – 3461.
[19] Y. C. Jeong, S. Choi, Y. D. Hwang, K. H. Ahn, Tetrahedron Lett.
2004, 45, 9249 – 9252.
[20] C. Ohta, T. Katsuki, Tetrahedron Lett. 2001, 42, 3885 – 3888.
[21] N. N. Karpyshev, O. D. Yakovleva, E. P. Talsi, K. P. Bryliakov,
O. V. Tolstikova, A. G. Tolstikov, J. Mol. Catal. A 2000, 157, 91 –
95.
[22] D. A. Cogan, G. C. Liu, K. J. Kim, B. J. Backes, J. A. Ellman, J.
Am. Chem. Soc. 1998, 120, 8011 – 8019.
[23] S. A. Blum, R. G. Bergman, J. A. Ellman, J. Org. Chem. 2003, 68,
150 – 155.
[24] K. P. Bryliakov, N. N. Karpyshev, S. A. Fominsky, A. G. Tolsti-
kov, E. P. Talsi, J. Mol. Catal. A 2001, 171, 73 – 80.
[25] D. Balcells, F. Maseras, G. Ujaque, J. Am. Chem. Soc. 2005, 127,
3624 – 3634.
[26] J. T. Sun, C. J. Zhu, Z. Y. Dai, M. H. Yang, Y. Pan, H. W. Hu, J.
Org. Chem. 2004, 69, 8500 – 8503.
[27] B. Pelotier, M. S. Anson, I. B. Campbell, S. J. F. Macdonald, G.
Priem, R. F. W. Jackson, Synlett 2002, 1055 – 1060.
[28] J. Legros, C. Bolm, Angew. Chem. 2003, 115, 5645 – 5647; Angew.
Chem. Int. Ed. 2003, 42, 5487 – 5489.
Experimental Section
Typical large-scale asymmetric oxidation procedure for the prepara-
tion of (R)-4b: A solution of [VO(acac)2] (159.0 mg, 0.60 mmol) in
chloroform (15 mL) was added to a solution of (R)-2 (425.8 mg,
0.90 mmol) in chloroform (15 mL) and the reaction mixture was
stirred for 2 h. A solution of 3b (8.29 g, 60.0 mmol) in chloroform
(30 mL) was added and the reaction mixture stirred for 30 min at
room temperature before cooling it to 08C. After 30 min, 30% H2O2
(7.36 mL, 72.0 mmol) was added to the reaction mixture, which was
stirred vigorously at 08C for 48 h. Samples (1–2 mL) were then
removed at different times and diluted with 20% isopropanol/
heptane for analysis by HPLC. The reaction was quenched with 10%
Na2S2O3 solution (200 mL) and the mixture extracted with chloro-
form (3 ” 100 mL). The extracts were combined, washed with brine
(3 ” 100 mL), and dried (MgSO4). Finally, the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography (EtOAc/petroleum ether 50:50). The purified prod-
uct was dissolved in the minimum amount of hot diethyl ether, and
hexane was added until the solution became turbid. The solution was
then gently warmed to give a clear solution, which was allowed to cool
to room temperature and then kept at À158C overnight to give the
product sulfoxide as needles. The crystalline solid was then filtered
and washed with cooled (À158C) hexane to (R)-4b (7.60 g, 82%),
ee > 99.5% (determined by HPLC on a Daicel Chiralpak AS column,
with 15% isopropanol in heptane, and a flow rate of 1.0 mLminÀ1),
[a]D20 = 151 (c = 1.0, acetone); [(Lit.[39] (R)-4b; ee 95%); [a]2D0 = 142
(c = 1.5, acetone)].
[29] A. Korte, J. Legros, C. Bolm, Synlett 2004, 2397 – 2399.
[30] J. Legros, C. Bolm, Angew. Chem. 2004, 116, 4321 – 4324; Angew.
Chem. Int. Ed. 2004, 43, 4225 – 4228.
[31] J. Legros, C. Bolm, Chem. Eur. J. 2005, 11, 1086 – 1092.
[32] All stereoselectivity factors were calculated using the equation
developed by Kagan and Fiaud.[40]
[33] N. Komatsu, M. Hashizume, T. Sugita, S. Uemura, J. Org. Chem.
1993, 58, 7624 – 7626.
[34] V. V. Thakur, A. Sudalai, Tetrahedron: Asymmetry 2003, 14,
407 – 410.
Received: August 26, 2005
Published online: October 17, 2005
[35] N. Komatsu, M. Hashizume, T. Sugita, S. Uemura, J. Org. Chem.
1993, 58, 4529 – 4533.
[36] A. Massa, F. R. Siniscalchi, V. Bugatti, A. Lattanzi, A. Scettri,
Tetrahedron: Asymmetry 2002, 13, 1277 – 1283.
[37] X. Jia, X. Li, L. Xu, Y. Li, Q. Shi, T. Au-Yeung, C. Yip, X. Yao, A.
Chan, Adv. Synth. Catal. 2004, 346, 723 – 726.
Keywords: asymmetric catalysis · kinetic resolution · oxidation ·
sulfoxides · vanadium
.
[1] I. Fernµndez, N. Khiar, Chem. Rev. 2003, 103, 3651 – 3705.
[2] M. C. Carreæo, Chem. Rev. 1995, 95, 1717 – 1760.
[3] J. Legros, J. R. Dehli, C. Bolm, Adv. Synth. Catal. 2005, 347, 19 –
31.
[4] F. A. Davis, R. T. Reddy, W. Han, P. J. Carroll, J. Am. Chem. Soc.
1992, 114, 1428 – 1437.
[38] Chloroform had been used by Ellman and co-workers in the
oxidation of di-tert-butyl disulfide,[22] and by Zhu and co-
workers[26] in oxidations of alkyl aryl sulfides catalyzed by
vanadium–salan complexes.
[39] A. Lattanzi, F. Bonadies, A. Senatore, A. Soriente, A. Scettri,
Tetrahedron: Asymmetry 1997, 8, 2473 – 2478.
[5] W. Adam, M. N. Korb, K. J. Roschmann, C. R. Saha-Möller, J.
Org. Chem. 1998, 63, 3423 – 3428.
[40] H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18, 249.
Angew. Chem. Int. Ed. 2005, 44, 7221 –7223
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7223