Oxidative kinetic resolution of alkyl aryl sulfoxides

Article abstract of DOI:10.1055/s-2006-958409

Kinetic resolution is observed in the oxidation of racemic alkyl aryl sulfoxides using a combination of VO(acac)₂ and ligand 1 in chloroform at 0 °C, conditions previously described for asymmetric oxidation of prochiral sulfides. Kinetic resolution is also observed in toluene as the solvent, although higher temperatures are required. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-958409

3540
CLUSTER
Oxidative Kinetic Resolution of Alkyl Aryl Sulfoxides
O
xidativ
r
e
Kinetic
a
Resolution
j
of
A
lkyl
Ar
M
yl Sulfoxides ohammadpoor-Baltork, Mathias Hill, Lorenzo Caggiano,* Richard F. W. Jackson*
Department of Chemistry, Dainton Building, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
Fax +44(114)2229303; E-mail: r.f.w.jackson@sheffield.ac.uk
Received 30 August 2006
A key breakthrough was the discovery that use of the
diiodo ligand 1 in chloroform affords the highest levels of
enantioselectivity in the vanadium-catalyzed oxidation of
alkyl aryl sulfides using hydrogen peroxide as the oxi-
Abstract: Kinetic resolution is observed in the oxidation of racemic
alkyl aryl sulfoxides using a combination of VO(acac)2 and ligand
1 in chloroform at 0 °C, conditions previously described for asym-
metric oxidation of prochiral sulfides. Kinetic resolution is also
observed in toluene as the solvent, although higher temperatures are dant.28 During these investigations, it was discovered that
required.
the excellent enantioselectivities observed were due to a
combination of two processes, namely enantioselective
Key words: asymmetric catalysis, oxidation, kinetic resolution,
sulfoxides, Schiff bases
oxidation and kinetic resolution.28
Asymmetric oxidation of a prochiral sulfide with con-
comitant kinetic resolution of the resultant mixture of
sulfoxides to give the corresponding sulfone has been well
documented for similar systems.18–20,22,29–32 Indeed a
process for asymmetric sulfur oxidation using vanadium
and readily available ligands, which delivers sulfoxides
with high ee and moderate yields through a combination
of asymmetric oxidation and kinetic resolution, has been
reported.33 More recently, kinetic resolution using vanadi-
um in combination with ligand 1 has been employed in the
enantioselective preparation of aryl benzyl sulfoxides.34
Enantiomerically enriched chiral sulfoxides have attract-
ed much interest, due to their synthetic utility as chiral
auxiliaries in synthetic transformations1–3 and the pres-
ence of this structural motif in biologically active pharma-
ceutical compounds.4
There exist several methods for the preparation of chiral
sulfoxides, the most common of which employs asym-
metric oxidation of the corresponding prochiral sulfide.
This transformation has been achieved with chiral
oxidants (including chiral oxaziridines5 and hydro-
peroxides6,7), enzymes8,9 and by the use of chiral metal
complexes,1,4,10–12 which has generated the most interest
following the initial reports by Kagan13,14 and Modena15
using modified Sharpless reagents. Chiral complexes of
titanium,16 manganese,17,18 iron,19 and molybdenum20
have all been described, and one of the most widely
studied metal-based sulfoxidation systems uses
vanadium21 in combination with various chiral ligands in-
cluding salan22 and Schiff base ligands (1, Figure 1),
initially reported by Bolm and Bienewald.23–25 Following
a substantial amount of development undertaken by a
number of groups, the ligand 1 was identified as optimal
for the process.26,27
In order to understand better the significance of the kinetic
resolution process in our optimized preparation of alkyl
aryl sulfoxides {1.5 mol% 1, 1.0 mol% [VO(acac)2],
CHCl3, 0 °C}27,28 and also to establish the role of the
solvent, a study of the efficiency of kinetic resolution (as
measured by the stereoselectivity S-factor)35 for a variety
of substrates was undertaken. The necessary racemic
sulfoxide substrates and sulfone standards were prepared
by oxidation of the corresponding sulfides using a slight
modification of the Mn(II)-mediated oxidation procedure,
reported by Nájera.36 In an ideal kinetic resolution of a
racemic sulfoxide, 0.5 equivalent of H2O2 is required.
With a view to establishing the best compromise between
high ee and isolated yield of the sulfoxide, 0.6 equivalent
of H2O2 was chosen. The results of the study are shown in
Scheme 1 and Table 1.
I
I
Conversions were determined by HPLC analysis (with
detection at 252 nm), which necessitated a careful calibra-
tion using mixtures of known composition (determined by
I
I
N
OH
N
OH
1
weight, and checked by H NMR) for each sulfoxide
OH
OH
(R)-1
(S)-1
O
O
S
O
O
ligand 1 (1.5 mol%)
VO(acac)2 (1.0 mol%)
S
S
Figure 1 Schiff base ligands
R
R
R
H2O2 (0.6 equiv)
CHCl3 or toluene, 20 h
X
X
X
enantioenriched
sulfoxide
racemic
sulfoxide
SYNLETT 2006, No. 20, pp 3540–3544
1
8
.1
2
.2
0
0
6
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-958409; Art ID: Y01006ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Kinetic resolution of racemic sulfoxides

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Oxidative Kinetic Resolution of Alkyl Aryl Sulfoxides
3541
Table 1 Kinetic Resolution of Racemic Sulfoxides in Chloroforma
Entry
1
Sulfoxide
Temp (°C) Sulfoxide/sulfone
Yield (%)c
Sulfoxide ee (%)
80–81 (R)
79 (S)
S
PhSOMe
22
0
39:61
45:55
46:54
46:54
46:54
41:59
42:58
43:57
47:53
43:57
44:56
42:58
65:35
75:25
51:49
41:59e
7.5
2b
3
PhSOMe
10.5
13–14
21
4-BrC6H4SOMe
4-BrC6H4SOMe
4-ClC6H4SOMe
4-ClC6H4SOMe
4-MeC6H4SOMe
4-MeC6H4SOMe
4-MeOC6H4SOMe
4-MeOC6H4SOMe
PhSOEt
22
0
82 2 (R)
89 (R)
4c
5
43
40
43
88 (R)c
91 (R)c
87 (R)c
22
0
75 (R)
10
6c
7
92 (R)
15
22
0
84 2 (R)
88 (R)
10.5
13.5
8c
9
22
0
90 2 (R)
98 1 (R)
84 1 (R)
90 3 (R)
49 1 (R)
29 2 (R)
70 2 (R)
97–98 (R)
24
28
2
5
10
11
12
13
14
15
16
22
0
12–13
17
PhSOEt
4-NO2C6H4SOMe
4-NO2C6H4SOMe
2-NaphthSOMe
2-NaphthSOMe
22
0
>30d
>30d
13
22
0
17–18
a Reactions performed with (R)-1 (1.5 mol%), VO(acac)2 (1.0 mol%) and H2O2 (0.6 equiv; 30% in H2O) in CHCl3, except where indicated.
b Ligand (S)-1 was used.
c Reaction performed on 3-mmol scale, yield and ee are that of isolated sulfoxide after column chromatography.
d The analytical conditions did not provide baseline separation of the components, so there is some uncertainty over the precise S factor.
e The reason for the higher conversion at 0 °C in this case is not clear, although variations in H2O2 concentration are most likely.
substrate and sulfone product. The ratio of response fac- this temperature. This observation would nicely account
tors for each sulfoxide substrate and sulfone product var- for the lower enantioselectivity and also higher isolated
ied considerably depending on the aromatic substituent,37 yield of sulfoxide previously reported in the asymmetric
a not unexpected result given the distinct absorption oxidation of the corresponding 4-nitrothioanisole deriva-
maxima exhibited by these compounds.38,39
tive (88% yield, 87% ee cf. 4-MeOC6H4SMe 71% yield,
99.5% ee) at 0 °C.28 In this case, the kinetic resolution is
not able to operate efficiently as the sulfoxide, the initial
product of the asymmetric oxidation, precipitates from so-
lution. Therefore the enantiomeric excess observed is due
mainly to the asymmetric oxidation, and is not amplified
by the kinetic resolution process.
Previous work had shown that the choice of solvent and
temperature dramatically influences the efficiency of the
vanadium-catalyzed oxidative kinetic resolution of
methyl phenyl sulfoxide. Improved stereoselectivity
factors were previously observed at 20 °C (S = 5.8) com-
pared to 0 °C (S = 1.1) for methyl phenyl sulfoxide in
dichloromethane, whilst in chloroform the kinetic resolu- The reactions were in all cases performed open to the
tion was more efficient at 0 °C (S = 11.6) than at 20 °C atmosphere, using commercial chloroform without fur-
(S = 7.7) for the same substrate using 0.5 equivalent of ther purification.40 Although it had been shown that
H2O2.28 The same trend is also observed in chloroform chloroform was optimum for asymmetric sulfur oxidation
with other substrates using 0.6 equivalent H2O2, as shown using VO(acac)2 and ligand 1, an investigation of the
in Table 1. Each reaction was repeated at least three times. effects of using toluene as a co-solvent/solvent in the
Use of larger amounts of H2O2 will lead to higher ee, at the kinetic resolution of 4-bromophenyl methyl sulfoxide was
cost of lower sulfoxide recovery (e.g. entry 16, Table 1).
carried out (Table 2).
It is interesting to note that under the same reaction condi- When the kinetic resolution reaction was performed in a
tions, the 4-nitro derivative gave poorer conversions at mixture of chloroform and toluene, or just toluene, high
room temperature and especially at 0 °C (entries 13 and levels of selectivity were obtained at 22 °C comparable to
14, Table 1). The most likely reason for poor conversion those using chloroform. As toluene is preferred to chloro-
at 0 °C is the observed low solubility of the sulfoxide at form for reactions on an industrial scale,41 a study of the
Synlett 2006, No. 20, 3540–3544 © Thieme Stuttgart · New York

3542
I. Mohammadpoor-Baltork et al.
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Table 2 Effect of Toluene in the Kinetic Resolution Reactiona
Entry
Sulfoxide
Solvent ratio
Sulfoxide/sulfone
Sulfoxide ee (%)
S
CHCl3/toluene
Entry 3, Table 1b
4-BrC6H4SOMe
4-BrC6H4SOMe
4-BrC6H4SOMe
100:0
50:50
0:100
46:54
46:54
46:54
82 2 (R)
85–86 (S)
86 2 (S)
13–14
17
1
2
15
1
a Reactions performed with (S)-1 (1.5 mol%), VO(acac)2 (1.0 mol%) and H2O2 (0.6 equiv; 30% in H2O) at 22 °C.
b Ligand (R)-1 was used.
Table 3 Kinetic Resolution of Racemic Sulfoxides in Toluenea
Entry
Sulfoxide
Temp (°C)
Sulfoxide/sulfone
46:54
Sulfoxide ee (%)
86 2 (S)
S
Entry 2, Table 2
4-BrC6H4SOMe
4-BrC6H4SOMe
4-ClC6H4SOMe
4-ClC6H4SOMe
PhSOMe
22
45
22
45
22
45
22
45
15
15
1
1
1
2
3
4
5
6
7
46:54
83 1 (S)
55:45
5
1
44:56
78 (S)
9
41:59
3
3
1
PhSOMe
42:58
61 (S)
5
4-MeC6H4SOMe
4-MeC6H4SOMe
48:52
3
1
1
41:59
79 (S)
8
a All reactions were performed with ligand (S)-1 (1.5 mol%), VO(acac)2 (1.0 mol%) and H2O2 (0.6 equiv; 30% in H2O) in toluene.
efficiency and selectivity of the vanadium–Schiff base tions employed [(R)-1 (1.5 mol%), VO(acac)2 (1.0 mol%)
ligand system in toluene was performed and the results are and H2O2 (1.2 equiv) in toluene at 0 °C] the kinetic reso-
reported in Table 3.
lution effect does not occur and that the selectivity ob-
served is due solely to the asymmetric oxidation reaction.
This observation does raise the possibility that an efficient
asymmetric oxidation of alkyl aryl sulfides may be
achievable in toluene by careful choice of reaction condi-
tions to allow kinetic resolution of the product sulfoxide.
The results in Table 3 show that although high levels of
stereoselectivity were observed in the oxidative kinetic
resolution of 4-bromophenyl methyl sulfoxide in toluene
at room temperature (entry 2, Table 2), other substrates
gave almost racemic products under the same reaction
conditions (entries 2, 4 and 6, Table 3). When the reaction In conclusion, kinetic resolution of the product sulfoxides
was performed at 0 °C (results not shown), although con- has been shown to be a general phenomenon during the
version to the sulfone occurred, no selectivity was ob- asymmetric oxidation of alkyl aryl sulfides with H2O2
served for the substrates listed in Table 3. When the using a combination of VO(acac)2 and ligand 1 as catalyst.
reactions were conducted at elevated temperatures (45 Where this process cannot occur readily (e.g. 4-nitro-
°C), however, an increase in selectivity was observed for phenyl methyl sulfide), lower levels of enantiomeric ex-
4-chlorophenyl-, 4-tolyl- and phenyl methyl sulfoxide cess are obtained in the asymmetric oxidation. The kinetic
compared to that obtained at room temperature (entries 3, resolution of aryl methyl sulfoxides using this system can
5 and 7, Table 3). Although higher temperatures gave in- also occur in toluene, suggesting that it may be applicable
creased selectivities for these substrates, the S-factors are on a larger scale.
lower than those in chloroform at either room temperature
or 0 °C. However, oxidative kinetic resolution of 4-bro-
mophenyl methyl sulfoxide in toluene, at either 22 °C or
45 °C, gave synthetically useful selectivity, similar to that
in chloroform.
General Procedure for the Synthesis of Racemic Sulfoxides
Using the procedure reported by Nájera,36 but at a concentration
more than ten times greater than that reported on a 1-mmol scale,43
an aq solution of H2O2 (30% in H2O, 50 mmol) was added to a
stirred solution of the alkyl aryl sulfide (10 mmol) and MnSO4·H2O
(20 mg, 1 mol%) in MeCN (20 mL) at r.t. The reaction mixture was
stirred for 24 h until TLC analysis (EtOAc–PE 40–60 °C, 1:3)
During the optimization of the asymmetric oxidation of
phenyl methyl sulfide, in which chloroform gave the best
results, use of toluene as a solvent gave the sulfoxide with
modest selectivity (53% ee cf. 97% ee in CHCl3).42 The indicated complete conversion, and the reaction was then quenched
with solid Na2S2O3. The solvent was evaporated under reduced
results in Table 3 suggest that under the reaction condi-
Synlett 2006, No. 20, 3540–3544 © Thieme Stuttgart · New York

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Oxidative Kinetic Resolution of Alkyl Aryl Sulfoxides
3543
pressure, H2O (10 mL) added and the mixture extracted with EtOAc
(3 × 40 mL). The organic extracts were combined, dried over
MgSO4, filtered and the solvent evaporated under reduced pressure
to afford the crude mixture which was purified by column chroma-
tography (silica gel; EtOAc–PE 40–60 °C, 1:2) to give the corre-
sponding alkyl aryl sulfoxide as a white crystalline solid (yield 65–
95%).
References and Notes
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General Procedure for the Synthesis of Sulfones
Using the procedure reported by Nájera,36 but at a concentration
significantly greater than that reported on a 1-mmol scale,43 an aq
solution of H2O2 (30% in H2O, 25 mmol) and an aq solution of
NaHCO3 (0.2 M, 50 mL) was added to a stirred solution of the alkyl
aryl sulfide (5 mmol) and MnSO4·H2O (10 mg, 1 mol%) in MeCN
(25 mL) at r.t. The reaction mixture was stirred for 24 h until TLC
analysis (EtOAc–PE 40–60 °C, 1:3) indicated complete conversion,
and the reaction was then quenched with solid Na2S2O3. The solvent
was evaporated under reduced pressure, H2O (10 mL) added and the
mixture extracted with EtOAc (3 × 30 mL). The organic extracts
were combined, dried over MgSO4, filtered and the solvent evapo-
rated under reduced pressure to afford, without the need for further
purification, the corresponding alkyl aryl sulfone as a white crystal-
line solid (yield 70–95%).
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General Procedure for the Kinetic Resolution of Racemic
Sulfoxides at Room Temperature and 0 °C (0.5-mmol Scale)
A solution of VO(acac)2 in CHCl3 (0.02 M, 250 mL, 0.005 mmol)
was added to a solution of the ligand (R)- or (S)-1 in CHCl3 (0.03
M, 250 mL, 0.0075 mmol) at r.t. and stirred open to the air for 30
min. The racemic sulfoxide (0.5 mmol) in CHCl3 (0.5 mL) was add-
ed and the mixture stirred for a further 30 min.
Reaction at r.t. (22 °C): a solution of H2O2 (30% in H2O, 31 mL, 0.6
equiv, 0.3 mmol) was added and the reaction mixture stirred at r.t.
for 20 h.
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Reaction at 0 °C: the mixture was then cooled to 0 °C with the aid
of a cryostat, H2O2 (30% in H2O, 31 mL, 0.6 equiv, 0.3 mmol) added
and the reaction mixture stirred at 0 °C for 20 h.
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Samples (15 mL) were removed after 20 h and diluted with 20% i-
PrOH–heptane for analysis by HPLC, using a Daicel Chiralpak AS
column, with detection at 252 nm.
General Procedure for the Kinetic Resolution of Racemic
Sulfoxides at 0 °C (3-mmol Scale, Entries 4, 6 and 8, Table 1)
To a stirred solution of the ligand (R)-1 (21.3 mg, 0.045 mmol) in
CHCl3 (3 mL) was added VO(acac)2 (7.95 mg, 0.03 mmol). The
yellow solution quickly turned darker as it was stirred open to air at
r.t. for 30 min. The sulfoxide (3 mmol) was added in one portion,
followed by CHCl3 (3 mL). The reaction mixture was cooled to
0 °C with the aid of a cryostat, and H2O2 (30% in H2O, 185 mL, 0.6
equiv, 1.8 mmol) was added dropwise. The reaction mixture was
then left to stir at 0 °C for 20 h. Solid Na2SO3 (1 g) was added to the
reaction mixture at 0 °C and a sample of the crude mixture taken for
HPLC analysis. The crude mixture was purified directly by column
chromatography [EtOAc–PE (40–60 °C)] to give the corresponding
alkyl aryl sulfoxide and sulfone.
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Acknowledgment
We thank the Department of Chemistry at Isfahan University,
Isfahan 81746-73441, Iran for sabbatical leave granted to Prof. I.
Mohammadpoor-Baltork and the Erasmus exchange with the Uni-
versität Hamburg, for supporting M. Hill. We thank Dr. C. Drago
for his substantial contributions to the earlier research on which the
work described in this paper is based, E.-J. Walker for preparation
of starting materials and HPLC calibration of the substrates used,
and Degussa AG for generous gifts of (S)- and (R)-tert-leucine.
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Synlett 2006, No. 20, 3540–3544 © Thieme Stuttgart · New York

3544
I. Mohammadpoor-Baltork et al.
CLUSTER
CHCl3 gave very similar results to those observed using
either unpurified CHCl3 or dried CHCl3 with 1 mol% of 2 M
HCl. Interestingly, however, the addition of 0.5 mol% of i-
PrOH gave moderate conversion (35%) to the sulfone and
racemic sulfoxide.
(36) Alonso, D. A.; Nájera, C.; Varea, M. Tetrahedron Lett.
2002, 43, 3459.
(37) The ratios of response factors for each sulfoxide and sulfone
at 252 nm were determined as follows: R = Me; Ar = Ph
(9.9), p-BrC6H4 (7.5), p-ClC6H4 (16.5), p-Tol (12.7), p-
MeOC6H4 (1.8), p-NO2C6H4 (0.56), 2-Naphth (4.9): R = Et,
Ar = Ph (10.0).
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Green Chem. 2004, 6, 418.
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1995, 1287.
(39) Rosini, C.; Donnoli, M. I.; Superchi, S. Chem. Eur. J. 2001,
7, 72.
(40) HPLC-grade chloroform was purchased from Fisher
Scientific, stabilized with amylene (100 ppm). Since CHCl3
can also be stabilized with a small amount of alcohols, and
may contain HCl, we investigated the effects of these
additives in the kinetic resolution reaction. Using dried
(42) Drago, C. PhD Thesis; University of Sheffield: UK, 2005.
(43) In our experience, use of 23 mL of solvent per mmol of
substrate as originally reported results in slow reactions and
much poorer yields, a problem that can be overcome by
drastically reducing the amount of solvent. Alonso and
Nájera have made similar observations when conducting
larger-scale reactions: Alonso D. A. and Nájera, C., personal
communication from Alonso, D. A., August 2006.
Synlett 2006, No. 20, 3540–3544 © Thieme Stuttgart · New York