Vanadium catalyzed enantioselective oxidation of sulfides: Easy transformation of bis(arylthio)alkanes into C2 symmetric chiral sulfoxides

Article abstract of DOI:10.1016/S0957-4166(99)00374-2

A facile and selective method for the title transformation is described. The two-phase oxidation of bis-sulfides with hydrogen peroxide catalyzed by vanadium complex of chiral Schiff base leads to the corresponding chiral mono- and bis-sulfoxides. In the

Full text of DOI:10.1016/S0957-4166(99)00374-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3457–3461
Vanadium catalyzed enantioselective oxidation of sulfides: easy
transformation of bis(arylthio)alkanes into C2 symmetric chiral
sulfoxides
Jacek Skarz˙ewski,∗ Elz˙bieta Ostrycharz and Renata Siedlecka
Institute of Organic Chemistry, Biochemistry and Biotechnology, Wrocław University of Technology, 50-370 Wrocław, Poland
Received 21 July 1999; accepted 23 August 1999
Abstract
A facile and selective method for the title transformation is described. The two-phase oxidation of bis-sulfides
with hydrogen peroxide catalyzed by vanadium complex of chiral Schiff base leads to the corresponding chiral
mono- and bis-sulfoxides. In the case of 1,2-bis(arylthio)ethanes the respective optically active bis-sulfoxides are
formed in up to over 95% e.e. © 1999 Elsevier Science Ltd. All rights reserved.
Optically active sulfoxides constitute the class of highly valuable chiral auxiliaries and reagents
in asymmetric synthesis.1 The most attractive method for their preparation is the enantioselective
oxidation of the easily available prochiral sulfides.2 Procedures based on the modified Katsuki–Sharpless
epoxidation reagents3 and the oxaziridines of Davis4 are often used for this important transformation.
However, there is still much interest in the development of a new, simple and truly catalytic oxidizing
system. In 1995 Bolm and Bienewald described successful enantioselective oxidations catalyzed by
the in situ formed vanadyl complex of the substituted salicylidene derivatives of (S)-tert-leucinol (1.5
mol%) and 30% hydrogen peroxide used as a stoichiometric oxidant.5 They have found that in the
case of oxidation of thioanisole 3-tert-butyl-5-nitrosalicylidene derivative 1a was the most effective
chiral inducer, while the 3,5-di-tert-butylsalicylidene ligand 1b was the best suited for the oxidation
of dithioacetals and dithioketals, e.g. 2-phenyl-1,3-dithiane was converted to the respective trans-
monosulfoxide in 85% e.e.6 These two chiral ligands have been chosen from the collection of 44 Schiff
bases examined.7 Another highly successful ligand was obtained from the axially chiral 1-naphthyl-
2-hydroxy-3-naphthylaldehyde and (S)-tert-leucinol: it gave some improvement in the oxidation of
thioanisole (78% e.e. at 0°C and 71% e.e. at 25°C),8 but this seems to result rather from the decrease
of reaction temperature than from the structural changes.
These results encouraged us to report our findings.9 We scrutinized other simple chiral Schiff bases
and discovered that the ligand 1c obtained from D- or L-valinol and 3-phenyl-5-nitrosalicylaldehyde
∗
Corresponding author. E-mail: skarzewski@kchf.ch.pwr.wroc.pl
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00374-2

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performed under the same oxidation conditions at least as well as the previously reported ones. Moreover,
this catalyst may be considered as a more versatile one because both its enantiomers are easily available
and it gives relatively good enantiomeric excess in both model reactions. Also, the derivative 1d gave
good results, while the ligands 1e–h were worse. It seems that the particular set of substituents on 1c
gives a ligand that fits better to the oxidation transition state. As was reported,5,6,8 the chirality transfer
occurred generating the same configuration at the sulfur atom as in the catalyst, i.e. (S)-sulfoxide was
formed using the ligands derived from L-valinol, and (R)-sulfoxide was obtained with that of D-valinol.
Chiral synthetic building blocks of C2 symmetry10 containing sulfoxide functions are particularly
promising for the construction of various important compounds and several oxidative procedures are
viable for their preparation by oxidation of sulfides. The oxidation of two prochiral centers present in a
bis-sulfide molecule may lead to two diastereoisomeric products, namely a meso form and a chiral, C2
symmetric bis-sulfoxide can be expected. To the best of our knowledge, the only reported enantioselective
oxidations of substrates of this type were those of bis-methylthiobenzenes11 and its cyclic analog12
using the Modena version of the Katsuki–Sharpless oxidant. Recently, we have investigated the catalytic

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oxidation of 1,x-bis(phenylthio)alkanes to the respective mono- and bis-sulfoxides;13 however, only the
meso bis-sulfoxides were formed selectively. When we oxidized the bis-sulfide 2a with 1.2 equiv. of
cumyl hydrogen peroxide in the presence of 2:1:1 equiv. of (+)-DET, Ti(Oi-Pr)4 and H2O, respectively,
at −20°C, racemic mono-sulfoxide 3a (93%) and meso-bis-sulfoxide 4a (6%) were obtained.
Now, we extend the application of the new catalytic system elaborating a selective procedure for the
oxidation of 1,2-bis(arylthio)alkanes 2 and ortho-bis(phenylthiomethyl)benzene to the corresponding
chiral bis-sulfoxides 4. We examined several ligands for this oxidation, and again 1c was chosen as the
most suitable one.
Although mixtures containing mono- and bis-sulfoxides were usually obtained, flash chromatography
gave complete separation. All the obtained chiral bis-sulfoxides (see below) are configurationally stable
and can be separated from the respective meso-forms, while the recrystallization of mono-sulfoxides 3
leads to gradual racemization. The e.e. values reported refer to the obtained chiral major-4 or 3 (1H NMR,
300 MHz, CCl4 solution in the presence of Eu(hfc)3, ∆δ(enantiomers) ca. 0.2 ppm for ortho hydrogens of
the arylsulfinyl group). Several recrystallizations of the chromatographed 4 gave material of the highest
specific rotation and no minor enantiomer could be detected by NMR with the chiral shift reagent. The
absolute configuration of (+)-(R,R)-4e has already been proved14 by chemical correlation.
If the reaction was carried out with one equivalent of H2O2 the only products were mono- and bis-
sulfoxides (no sulfonosulfoxide) in comparable yields and the stereochemical results were not much
different from those expected for the same reactivity (enantioselectivity) at both centers. The same
enantioselectivity in the oxidation of the prochiral sulfur atom in 2 and 3 requires, for the ratio of major
enantiomer of 3:ent-3 being x:1, that the ratio of stereoisomers for 4 is x2:2x:1 for major-4:meso-4:ent-4,
respectively. Thus the ratio of meso-4:dl 4 is 2x/x2+1 and this value is available from the NMR spectrum
of crude 4. When we correlated by the least squares method the calculated enantioselectivities for both
oxidation steps vs the observed specific rotations of the crude samples of 3 and 4, two lines resulted
and the extrapolated [α]D values for 100% e.e. were in acceptable agreement with the observed ones
(Fig. 1). Additionally, in order to test the possibility of autocatalytic enantioselective oxidation (NLE)15
we ran the reaction with 2c using the catalytic amount of enantiomerically pure 4c (>95% e.e.) instead of
chiral ligand 1c. However, in this case, the products obtained were completely racemic. All these suggest
that the stereoselectivity enhancement for the formation of bis-sulfoxides is due to the known statistical
effects.16
In order to learn about the scope and limitations of the catalytic oxidation we examined
the reaction of several different 1,2-bis(arylthio)ethanes, 1,3-bis(phenylthio)propane and ortho-
bis(phenylthiomethyl)benzene. The oxidizing species are clearly electrophilic, so the more electron-rich
system is easier to oxidize and in these cases the catalyzed enantioselective reaction leads to the
highest yield and e.e., and the reverse is true for the electron-poor arylsulfinyl group 2d. Interestingly, a

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Figure 1. Plot of the measured [α]D values (CHCl3, 25°C) vs the calculated e.e.s for 3a and 4a obtained under various reaction
conditions
three-carbon-atom bridge in the case of 2f, in spite of the high yield and d.e. observed in the oxidation,
causes much lower e.e. values for 4f. This result suggests low stereoselectivity in the first oxidation step.
Probably, in this case, the first sulfoxide function is involved in the second oxidation step giving the high
d.e. value.
Work on synthetic applications of the thus prepared chiral bis-sulfoxides is underway. We have already
found that 4c in the presence of methyllithium (THF, −30°C) underwent elimination and the respective
chiral vinyl sulfoxide (ca. 75% e.e.) was formed.
In conclusion, the method described in this paper offers a convenient route to some C2 symmetric
chiral bis-sulfoxides obtained in good d.e. and often excellent e.e. from the easily available bis-sulfides.
Acknowledgements
We thank the Committee for Scientific Research (Warsaw) for financial support (KBN Grant 3 T09A
028 12).

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