Investigations on the iron-catalyzed asymmetric sulfide oxidation

Article abstract of DOI:10.1002/chem.200400857

The development of an enantioselective sulfide oxidation involving a chiral iron catalyst and aqueous hydrogen peroxide as oxidant is described. In the presence of a simple carboxylic acid, or a carboxylate salt, the reaction affords sulfoxides with remarkable enantioselectivities (up to 96% ee) in moderate to good yields. The influence of the structure of the additive on the reaction outcome is reported. In the sulfoxide-to-sulfone oxidation a kinetic resolution (with s = 4.8) occurs, which, however, plays only a negligible role in the overall enantioselective process. Furthermore, a positive nonlinear relationship between the ee of the product and that of the catalyst has been found. On the basis of these observations, a possible catalyst structure is proposed.

Full text of DOI:10.1002/chem.200400857

Investigations on the Iron-Catalyzed Asymmetric Sulfide Oxidation
[
a]
Julien Legros and Carsten Bolm*
Abstract: The development of an enan-
tioselective sulfide oxidation involving
a chiral iron catalyst and aqueous hy-
drogen peroxide as oxidant is de-
scribed. In the presence of a simple
carboxylic acid, or a carboxylate salt,
the reaction affords sulfoxides with re-
markable enantioselectivities (up to
The influence of the structure of the
additive on the reaction outcome is re-
ported. In the sulfoxide-to-sulfone oxi-
dation a kinetic resolution (with s=
4.8) occurs, which, however, plays only
a negligible role in the overall enantio-
selective process. Furthermore, a posi-
tive nonlinear relationship between the
ee of the product and that of the cata-
lyst has been found. On the basis of
these observations, a possible catalyst
structure is proposed.
Keywords: asymmetric amplifica-
tion · asymmetric catalysis · iron ·
oxidation · sulfoxide
96% ee) in moderate to good yields.
[7f–h]
Introduction
(eemax =40%).
Consequently, finding an efficient iron-
catalyzed asymmetric sulfoxidation reaction, which proceeds
under mild reaction conditions, still remains an attractive
goal. In this context, we recently reported on a novel iron-
catalyzed asymmetric sulfide oxidation that fulfils most of
the requirements and affords sulfoxides with up to 90%
Chiral sulfoxides find increasing use as auxiliaries in asym-
[1]
metric synthesis and ligands in enantioselective catalysis,
and recently, they have been shown to promote asymmetric
[2]
allylation reactions. Moreover, a number of pharmaceuti-
cally important drugs contain asymmetric sulfinyl moie-
[8]
ee. It proceeds under very simple reactions conditions (at
room temperature in a capped flask) and utilizes (ꢀ4 mol%
of) a readily available chiral iron complex, generated in situ
[1a,3]
ties.
The development of processes for the preparation
of chiral sulfoxides with high enantiomeric purity is there-
fore a prime target. Among all methods described so far,
the asymmetric oxidation of sulfides by metal catalysts is
one of the most attractive routes to optically active sulfox-
[9]
from [Fe(acac) ] and a Schiff base ligand of type 1. Fur-
3
thermore, inexpensive and safe 35% aqueous hydrogen per-
[10]
oxide serves as terminal oxidant (Scheme 1).
[4]
ides. In this line, titanium, manganese and vanadium com-
[4,5]
plexes have been widely applied.
Conversely, catalysts
based on nontoxic and inexpensive iron is relatively under-
[6]
represented in the field, and the few systems developed so
[7]
far fail in terms of efficiency and practicability. Most of
them involve structurally complex iron porphyrines, and io-
dosylbenzene or alkyl hydroperoxides as terminal oxidant,
and, most importantly, the enantioselectivities are only mod-
[7a–e]
erate (<55% ee).
The iron complex [Fe O(pb) (H O) ]-
2 4 2 2
(
ClO4)4 (pb=(À)-4,5-pinene-2,2’-bipyridine) was reported
by Fontecave et al. as catalyst for the sulfide oxidation with
H O , but the enantioselectivity remained rather low
Scheme 1.
2
2
[
a] Dr. J. Legros, Prof. Dr. C. Bolm
Institut fꢀr Organische Chemie
Rheinisch-Westfꢁlische Technische Hochschule
Professor-Pirlet-Strasse 1, 52056 Aachen (Germany)
Fax : (+49)241-809-2391
A limitation of the reported iron catalysis stemmed from
the fact that under the conditions required for achieving
high enantioselectivities, large amounts of unreacted sub-
strates remained, limiting the sulfoxide yields (ꢀ44%). In a
subsequent communication we then disclosed that the effi-
E-mail: carsten.bolm@oc.rwth-aachen.de
1086
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/chem.200400857
Chem. Eur. J. 2005, 11, 1086 – 1092

FULL PAPER
ciency of the process (in terms of both enantioselectivity
[11]
and yield) could greatly be improved by using additives.
We now detail the influence of the additive structure on the
reaction course and describe further investigations revealing
specific features of this novel iron-catalyzed process.
Results and Discussion
The use of additives is a common and convenient method
for the efficiency enhancement of metal-catalyzed reac-
[12]
tions. They facilitate catalyst tuning without re-designing
the ligand, and very often their value is under-appreciated.
Unfortunately, the process of discovering which additive has
to be used clearly requires trial and error and can commonly
not be predicted. In asymmetric sulfoxidation, this strategy
has already been applied. For example, Maruyama and
Naruta used 1-methylimidazole in catalyses with iron por-
Figure 1. Effect of benzoic acid (AH1) on the ee (measured on the crude;
~
) and yield (NMR yield;
with 35% H (1.2 equiv) catalyzed by [Fe(acac)
4 mol%).
&
) of (S)-3a in the asymmetric oxidation of 2a
2
O
2
3
] (2 mol%) and (S)-1a
(
the one with benzoic acid (AH1)] was observed. In contrast,
use of para-substituted electron rich derivatives AH6
[7b,c]
[9]
phyrins,
and in Bolmꢃs vanadium-catalyzed process,
Katsuki et al. added methanol in order to improve the enan-
tioselectivity (without affecting the catalyst turnover and
(pMe N) and AH7 (pMeO) led to very good results, afford-
2
ing 3a with 80% ee in 68 and 66% yield, respectively. Steri-
cally hindered acids AH10–12 gave good results (74–79%
ee) as well. Nonconjugated acids [acetic acid (AH1) and
phenylacetic acid (AH14)] have also been assessed and
showed improvements with respect to the initial conditions,
but the enantioselectivity remained inferior (70% ee).
Chiral acids, (R)- and (S)-mandelic acid (AH15 and AH16)
and their corresponding methyl derivatives (AH17 and
AH18) were totally ineffective.
Next, benzoic acid derivative AH7 was studied in combi-
nation with catalysts based on other Schiff bases (Table 1).
A positive effect was also observed with Schiff base 1b (en-
tries 3 and 4) leading to major improvements in yield and
enantioselectivity, very close to the ones obtained with 1a.
Only a modest increase of the enantioselectivity was ob-
served with 1c (entries 5 and 6). Schiff base 1d derived
from valinol had no effect on both yield and ee (entries 7
and 8).
[9e]
yield). Our attempts to use those additives in the iron-cat-
alyzed reaction shown in Scheme 1 led to clearly negative
effects. In epoxidation reactions with H O catalyzed by iron
2
2
II
complex [Fe (mep)(CH CN) ](SbF ) (mep=N,N’-dimethyl-
3
2
6 2
N,N’-bis(2-pyridylmethyl)-ethane, 1,2-diamine) Jacobsen re-
cently found that the presence of sub-stoichiometric
amounts of a carboxylic acid stabilized the catalytic system
making it more well-behaved improving its efficiency. Con-
sequently, even with a reduced catalyst loading and an in-
creased H O addition rate (from dropwise to rapid addi-
2
2
[13]
tion) higher epoxide yields were achieved. These results
suggested an investigation of the iron-catalyzed sulfoxida-
tion (Scheme 1) with benzoic acid (AH1) as additive. Thioa-
nisole (2a) was selected as substrate, and the catalyses were
performed with (S)-1a as ligand under the previously opti-
mized reaction conditions. The effect of the acid on the be-
havior of the catalyst system was remarkable. It appeared to
be entirely dependent on the additive quantity, and the best
enantioselectivity was obtained with an AH1/[Fe(acac)3]
ratio of 0.5:1. Under those conditions, the ee of the corre-
sponding sulfoxide 3a increased from 59% (no additive) to
The halogen atoms on the aromatic ring (I, 1a; Br, 1b)
and the tert-butyl group (stemming from tert-leucinol) in the
imino alcohol side chain of the ligand have a tremendous in-
fluence on the reaction outcome. Whereas we have no ra-
tional explanation for this “halogen effect” at this time, it is
interesting to note that 1a is also optimal in the related va-
73% (Figure 1). Gratifyingly, the yield of 3a was also higher
than before (56% versus 41% without the additive). In-
[9d]
creasing the AH1/[Fe(acac) ] ratio to 10:1 had almost no
nadium-catalyzed sulfoxidation process. Conversely, Schiff
3
[14]
effect on the yield of the sulfoxide (71%), but lowered the
ee of 3a to only 9%.
The electronic and steric properties of the additive were
easily fine-tuned by using various commercially available
substituted benzoic acids. This screening, which was done
under optimized conditions (with 0.5 equivalents of the ad-
base 1b is much less efficient in this latter system.
Next, we once more focussed our attention on the addi-
tive structure. The fact, that electron rich carboxylic acids
(AH6, AH7) led to the best results suggested that the addi-
tive acted as a co-ligand and that its chelating property and
not its acidity was the essential point. It was therefore hy-
pothesized that a carboxylate salt should further increase
the efficiency of the reaction. Lithium, sodium, potassium,
cesium and tetrabutylammonium 4-methoxybenzoates
ditive relative to [Fe(acac) ]), was extended to the use of
3
nonaromatic additives (Figure 2).
The reaction outcome was highly dependent on the
nature and the position of the substituents on the aryl ring.
(ALi7, ANa7, AK7, ACs7 and ABu N7, respectively) were
4
With electron-withdrawing groups (NO , AH2–AH4; I,
thus assessed in the oxidation of 2a by using Schiff base 1a
2
AH5), a decrease of the catalysis efficiency [compared with
as ligand (Table 2). Confirming our assumption we found
Chem. Eur. J. 2005, 11, 1086 – 1092
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ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1087

C. Bolm and J. Legros
out the additive, almost all sulf-
oxides were now obtained in
[8]
more than 55% yield.
In
terms of asymmetric induction
the best results were obtained
with phenyl methyl sulfide (2a)
and para-substituted derivatives
thereof, where all sulfoxides
had ee values above 90%
(
eemax =96%). The oxidations
of more challenging substrates
like phenyl ethyl sulfide (3b:
8
2% ee, 56% yield) and phenyl
benzyl sulfide (3c: 79% ee,
3% yield) proceeded remarka-
7
bly well too. For the last sub-
strate, the improvement due to
the additive was particularly
impressive (no additive: 27%
ee, 44% yield). It is worth to
note also that, without any ad-
ditive, only sulfoxide 3h was
previously obtained with an ee
superior to 80%. Interestingly,
with vinyl- and allyl phenyl sul-
fides (2m and 2n, respectively),
the reaction was highly chemo-
selective affording only sulfox-
ides 3m and 3n with good
enantioselectivities (>70% ee).
Figure 2. Influence of various carboxylic acids (AH1–AH18; 1 mol%) on the yield (NMR yield; clear, front)
and the ee (measured on the crude; dark, back) of (S)-3a in the asymmetric oxidation of 2a with 35% H
1.2 equiv) catalyzed by [Fe(acac) ] (2 mol%) and (S)-1a (4 mol%).
2
O
2
(
3
Table 1. Catalytic enantioselective oxidation of 2a with H
chiral iron complex in presence of AH7.
2
O
2
and a
2 2 3
Table 2. Catalytic enantioselective oxidation of 2a with H O , [Fe(acac) ]
and Schiff base 1a, in presence of AX7.
[
a]
[a]
[
b]
[c]
Entry
Ligand (S)-1
AH7
Yield 3a [%]
ee 3a [%]
Entry
AX7 (X=)
Yield of 3a
ee of 3a
[%]
[
b]
[c]
[
%]
1
2
3
4
5
6
7
8
1a
–
+
–
36
63
30
53
27
27
50
53
59
80
55
80
26
43
22
24
1
2
3
4
5
6
H
Li
Na
K
Cs
4
Bu N
63
63
67
64
65
57
80
90
90
88
87
82
1b
1c
1d
+
–
+
–
+
[
a]–[c] As in Table 1.
[
(
a] Reaction conditions: [Fe(acac)
3
]
(0.02 mmol), (S)-1 (0.04 mmol),
AH7; 0.01 mmol), 2a (1 mmol) and aqueous H (35%; 1.2 mmol) in
Cl at room temperature for 16 h. [b] Yield of isolated product.
c] The enantiomer ratios were determined by HPLC using a chiral sta-
2 2
O
CH
[
2
2
An oxidation of the double bond was not observed. As a
general feature, the reaction proceeded with high enantiose-
lectivity for a wide variety of monoaryl sulfides. Assessment
of other substrate types gave, for the moment, unsatisfactory
tionary phase. 3a had (S) configuration in all cases.
[15]
that all the metal salts (entries 2–5) gave improved results
with enantioselectivities of up to 90% ee for ALi7 and
ANa7 (entries 2 and 3, respectively). The yields of 3a were
comparable in all reactions.
The substrate scope was then studied under optimized
conditions (Table 3).
results (e.g. Bn-S(O)-Me 3o: 23% ee, 64% yield).
Kinetic resolution: The fact that each time, when the reac-
tion afforded a sulfoxide with high ee (ꢁ80%), a significant
amount of sulfone (9–16%; see Table 3) was detected in the
crude product mixture, suggested the existence of a kinetic
[16]
For all substrates assessed the presence of AH7 and ALi7
greatly improved both enantioselectivity and yield. Whereas
resolution process during the course of the reaction.
In
order to investigate this aspect an experiment was per-
formed under standard asymmetric sulfide oxidation condi-
44% was the best yield under the previous conditions with-
1088
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Chem. Eur. J. 2005, 11, 1086 – 1092

Asymmetric Oxidation
FULL PAPER
Table 3. Catalytic enantioselective oxidation of sulfides 2 with H
an additive.
2
O
2
and a chiral iron complex in presence of yield of 3a was 70%, and the
product had 80% ee. At this
[
a]
stage 9% of sulfone 4a were
found. Thus, the ee of 3a re-
mained almost constant during
Entry
1
Sulfide 2
R’
Sulfoxide 3
with additive
the reaction course (78Æ2%),
independent of the formation of
3a and 4a. Consequently, it can
be concluded that under the ex-
perimental conditions applied
no additive
R
Yield
%]
ee
[%]
AX7
Yield
[%]
ee
[%]
[
b]
[c]
[b]
[c,d]
[
Ph
Ph
Ph
Ph
Me
Me
Et
2a
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
36
n.p.
30
59
n.p.
44
ALi7
ALi7
ALi7
AH7
ALi7
ALi7
ALi7
AH7
ALi7
ALi7
ALi7
ALi7
AH7
ALi7
ALi7
ALi7
63
64
56
73
78
66
59
60
36
48
50
44
67
34
63
64
90
3a
3a
[
e]
[f]
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
88
82
79
92
86
94
92
96
66
70
77
95
75
71
23
3b for the sulfide oxidation, the ki-
Bn
40
27
3c
3d
3e
3 f
3g
netic resolution plays only a
negligible role and that the ob-
served enantioselectivity origi-
nates (almost exclusively) from
4-MeC
4-MeOC
4-BrC
4-ClC
4-NO
2-BrC
2-MeOC
6
H
4
Me
Me
Me
Me
Me
Me
Me
Me
Me
n.p.
n.p.
41
n.p.
n.p.
78
6
H
4
6
H
4
6
H
4
32
65
2
C
6
H
4
21
90
3h the asymmetric sulfide oxidation
0
1
2
3
4
5
6
6
H
4
n.p.
n.p.
n.p.
44
n.p.
n.p.
n.p.
70
3i
3j
3k
3l
itself. Apparently, the kinetic
6
H
4
resolution does not significantly
mesityl
2-naphthyl
Ph
[19]
affect the ee of the sulfoxide.
CH=CH
CH CH=CH
Me
2
n.p.
n.p.
n.p.
n.p.
n.p.
n.p.
3m
Ph
Bn
2
2
3n Nonlinear effect: The search for
3o
nonlinear effects (NLE) in a
[
a] Reaction conditions: [Fe(acac)
3
] (0.02 mmol), Schiff base (S)-1a (0.04 mmol), AH7 or ALi7 (0.01 mmol), given system has become
a
useful probe for analyzing the
nature of the catalytic species
involved in an asymmetric proc-
sulfide 2 (1 mmol) and aqueous H
isolated product. [c] The enantiomer ratios were determined by HPLC analysis of the isolated product by
using a chiral stationary phase. See Experimental Section. [d] Each time the reaction afforded sulfoxide 3 with
>
2
2 2 2
O (35%; 1.2 mmol) in CH Cl at room temperature for 16 h. [b] Yield of
80% ee, 9–16% of sulfone 4 was detected. [e] Reaction performed with (R)-1a. [f] Experiment not per-
[20]
formed (n.p.).
ess. With the intention to get
tions using racemic sulfoxide 3a as substrate, Schiff base
[17]
(
S)-1a as ligand and AH7 as additive (Scheme 2).
Scheme 2.
Figure 3. Kinetics of the enantioselective oxidation of thioanisole 2a with
3
(
5% H
S)-1a (4 mol%) and AH7 (1 mol%). The NMR conversion of 2a (ꢄ)
into sulfoxide 3a (
) and sulfone 4a (~) and the ee of 3a (*) are repre-
2 2 3
O (1.2 equiv) catalyzed by [Fe(acac) ] (2 mol%), Schiff base
After 16 h reaction time the conversion of sulfoxide 3a to
sulfone 4a was low (15%), and a large quantity of 3a could
be recovered. The ee of 11% for recovered 3a (in favor for
the S-configured sulfoxide) revealed that the sulfoxide-to-
sulfone oxidation was indeed enantioselective (with k >k ).
&
sented according to time.
R
S
[18]
Even though the stereoselectivity factor (s)
was rather
small (4.8), we decided to study the time dependence of the
asymmetric process in more detail. By determining the con-
version of thioanisole (2a), the formation of sulfoxide 3a,
the enantiomer ratio of 3a, and the formation of sulfone 4a
with time, we hoped to shine light on the importance of the
kinetic resolution for the overall oxidative process
a deeper insight into the features of the iron-catalyzed sul-
foxidation, and in order to understand the role of the addi-
tive, we investigated the impact of the ee of the ligand [here
(S)-1a] on the enantioselectivity in the formation of the sulf-
oxide, with and without AH7 (Figure 4).
In both cases, a positive nonlinear effect was found.
Whereas the NLE was less pronounced without additive, it
was more significant when the reaction was performed in
the presence of AH7. At the present stage the observed
asymmetric amplification is difficult to interpret, but it clear-
(
Figure 3).
After 0.5 h reaction time, sulfoxide 3a was formed in
11% yield (as determined by NMR) having an ee of 78%.
No sulfone 4a was detected as this stage. After 16 h, the
Chem. Eur. J. 2005, 11, 1086 – 1092
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1089

C. Bolm and J. Legros
uct. An asymmetric amplification was observed, which is in
accord with our previous hypothesis of the presence of a
possible catalytically active species containing two chiral li-
gands. We are currently trying to isolate and characterize
such intermediates and explore further improvements of the
experimental conditions.
Experimental Section
1
13
General methods: H and C NMR spectra were obtained on a Varian
Gemini 300 or Innova 400 spectrometer. In all measurements CDCl was
3
used as solvent. Chemical shifts d are given in ppm relative to TMS as in-
ternal standard. Optical rotations were measured on a Perkin–Elmer PE-
Figure 4. Dependence of the enantioselectivity in the oxidation of 2a to
give 3a with 35% aq. H catalyzed by [Fe(acac) ] and (S)-1a on the ee
of the ligand, in the absence (~) and in the presence of AH7 (*). For
2
41 apparatus. The enantiomer ratios of sulfoxides 3 were determined by
2
O
2
3
chiral HPLC (Gynkotek apparatus; UV detector UVD 170S (l 254 nm);
[
24]
2
08C).
Absolute configurations were assigned by comparison of the
comparison, the broken lines indicate a possible linear relationship.
sign of the specific rotations with literature data. When it was necessary,
samples of racemic sulfoxides were prepared, according to the litera-
[
25]
ture. All the reactions were performed at room temperature under air.
ly indicates that more than one ligand is involved in the ster-
eochemistry-determining step of the catalytic process.
From the great interest in functional enzyme models,
which mimic non-heme metalloproteins, especially methane
monooxygenase (MMO), a large number of complexes with
Materials: All chemicals were used as provided without further purifica-
tion. Iron(iii) acetylacetonate was purchased from Aldrich, 35% aqueous
hydrogen peroxide from Acros, and 3,5-diiodosalicylaldehyde from Lan-
caster. (S)- and (R)-tert-Leucine were provided by Degussa and reduced
[
26]
to tert-leucinol according to the literature.
Monitoring of the reactions: The conversion of phenyl methyl sulfide
thioanisole) (2a) to phenyl methyl sulfoxide (3a) and phenyl methyl sul-
[21]
a (m-oxo)(m-carboxylato)diiron core have emerged. Some
(
of them have been demonstrated to be capable of oxidizing
fone (4a) was measured by integration of the methyl group signals in the
[13,22]
1
substrates with various terminal oxidants.
In the light of
H NMR spectra of the corresponding compounds on the crude product
mixture: Ph-S-Me, 2.5 ppm; Ph-S(O)-Me, 2.7 ppm; Ph-S(O
.1 ppm.
2
)-Me,
these reports and taking into account that in the sulfide oxi-
dation described here, the best results were obtained with
half an equivalent of carboxylic acid (and/or carboxylate
salt) relative to iron, and that a positive NLE was observed,
it can be suggested that in the reaction medium containing
3
[
9d]
(
S)-(À)-2-(N-3,5-Diiodosalicyliden)amino-3,3-dimethyl-1-butanol (1a):
A solution of (S)-tert-leucinol (313 mg, 2.7 mmol) in ethanol (2 mL) was
added to a suspension of 3,5-diiodosalicylaldehyde (1 g, 2.7 mmol) in eth-
anol (4 mL), and the resulting deep-yellow mixture was kept under stir-
ring. After 16 h, the solvent was evaporated, and the residue was recrys-
[
Fe(acac) ], the ligand (1a) and ArCOOX, a monocarboxy-
3
tallized in cyclohexane to afford 1a as yellow needles (65–75% yield).
late-bridged diiron(iii) complex is generated, which resem-
bles a key intermediate in the catalytic cycle of the oxidative
process. Isolation and characterization of such complex,
and/or in situ studies are now required to confirm this hy-
pothesis. Until now, however, all attempts to isolate relevant
1
M.p. 163–1648C; [a]
9
D
=À16.6 (c=1.0 in acetone); H NMR: d=0.93 (s,
H), 3.01 (dd, J=9.6, 2.9 Hz, 1H), 3.62 (dd, J=11.4, 9.7 Hz, 1H), 3.94
(
dd, J=11.3, 2.4 Hz, 1H), 4.40 (brs, 1H), 7.45 (d, J=2.2 Hz, 1H), 7.96
1
3
(d, J=2.0 Hz, 1H), 8.02 (s, 1H), 14.59 (brs, 1H); C NMR: d=26.8,
2.9, 61.8, 75.6, 77.9, 93.2, 116.7, 141.2, 150.0, 164.7, 167.2.
General procedure for asymmetric oxidation of sulfides: [Fe(acac)
7.1 mg, 0.02 mmol) and Schiff base (S)-1a (18.9 mg, 0.04 mmol) were
3
[23]
3
]
intermediates of such kind remained unsuccessful.
(
dissolved in dichloromethane (0.7 mL), and the clear red solution was
stirred until it turned clear brown (15 min). This solution was then added
to a suspension of 4-methoxybenzoic acid AH7 (1.5 mg, 0.01 mmol) [or
of the corresponding lithium salt ALi7 (1.6 mg, 0.01 mmol) in dichloro-
methane (0.5 mL) in a 10 mL flask, and the resulting mixture was stirred
for 10 min. A solution of sulfide 2 (1 mmol) in dichloromethane (0.8 mL)
was then added to the previous solution, followed by the dropwise addi-
Conclusion
Highly enantioselective oxidations of prochiral sulfides
giving synthetically valuable sulfoxides can be performed
under simple reaction conditions using a readily available in
situ iron catalyst (ꢀ4 mol%) and aqueous hydrogen perox-
ide. In the presence of small quantities of a carboxylic acid
or a carboxylate salt (1 mol%), optically active sulfoxides
with excellent enantioselectivities (up to 96% ee) are ob-
tained in moderate to good yields (up to 78%). The simplic-
ity of the reaction protocol (aerobic conditions at ambient
temperature) and the high ee values of the products render
this process attractive and make it an interesting alternative
to the existing methodology. Our studies reveal that the
enantioselectivity directly originates for the asymmetric sul-
fide oxidation and that the overoxidation to the correspond-
ing sulfones has almost no influence on the ee of the prod-
tion of aqueous H
reaction mixture was slowly stirred at room temperature (approximately
50 rpm). After 16 h, the aqueous layer was separated, and the organic
layer was dried over MgSO , filtered, and the solvent was removed in
2 2
O (35%; 1.2 mmol). The flask was capped, and the
1
4
vacuo. The product was then purified by flash chromatography on silica
gel (pentane/diethyl ether 1:2, then ethyl acetate).
(
S)-(À)-Phenyl methyl sulfoxide (3a): Reaction was performed with
ALi7. Purification by silica gel chromatography afforded the product as a
colorless oil (88 mg, 63%, 90% ee). [a]
=À130.1 (c=1.7 in acetone);
lit: [a] =+130 (c=1.7 in acetone) for (R), 89% ee; H NMR: d=2.72
(R)=26.5 min, t (S)=
D
[27] 1
D
(
3
s, 3H), 7.52 (m, 3H), 7.65 (m, 2H); HPLC: t
1.2 min (Chiralcel OD; flow rate, 0.5 mLmin ; heptane/iPrOH 9:1).
r
r
À1
(
S)-(À)-Phenyl ethyl sulfoxide (3b): Reaction was performed with ALi7.
Purification by silica gel chromatography afforded the product as a color-
less oil (87 mg, 56%, 82% ee). [a]
D
=À169.1 (c=1.4 in EtOH); lit:
1090
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org Chem. Eur. J. 2005, 11, 1086 – 1092

Asymmetric Oxidation
FULL PAPER
[
28] 1
[
a]
D
=À143.1 (c=1.4 in EtOH) for (S), 74% ee;
H NMR: d=1.20 (t,
(S)-(À)-2-Naphthyl methyl sulfoxide (3l): Reaction was performed with
AH7. Purification by silica gel chromatography afforded the product as a
J=7.4 Hz, 3H), 2.84 (m, 2H), 7.52 (m, 3H), 7.62 (m, 2H); HPLC: t
r
À1
(
R)=22.0 min, t
heptane/iPrOH 9:1).
S)-(À)-Phenyl benzyl sulfoxide (3c): Reaction was performed with
AH7. Purification by silica gel chromatography afforded the product as a
white solid (158 mg, 73%, 79% ee). [a]
=À169.8 (c=1.0 in acetone);
lit: [a] H NMR: d=4.00
=À91.0 (c=1.0 in acetone) for (S), 36% ee;
d, J=12.6 Hz, 1H), 4.10 (d, J=12.6 Hz, 1H), 6.99 (m, 2H), 7.26 (m,
r
(S)=27.2 min (Chiralcel OD; flow rate, 0.5 mLmin
;
white solid (127 mg, 67%, 95% ee). [a]
[a] =+127 (c=2.0 in CHCl ) for (R), 90% ee;
H), 7.60 (m, 3H), 7.93 (m, 2H), 7.99 (d, J=8.8 Hz, 1H), 8.22 (s, 1H);
HPLC: t (R)=37.2 min, t (S)=40.8 min (Chiralcel OD; flow rate,
.5 mLmin ; heptane/iPrOH 9:1).
S)-(À)-Phenyl vinyl sulfoxide (3m): Reaction was performed with ALi7.
Purification by silica gel chromatography afforded the product as a
yellow oil (52 mg, 34%, 75% ee). [a]
D
=À133.1 (c=2.0 in CHCl
3
); lit:
H NMR: d=2.80 (s,
[
30] 1
D
3
3
(
r
r
À1
0
D
[
29] 1
(
D
(
3
D
=À160 (c=0.5 in acetone); lit:
[29] 1
H), 7.41 (m, 5H); HPLC: t
r
(R)=28.8 min, t
r
(S)=36.1 min (Chiralcel
OD; flow rate, 0.5 mLmin ; heptane/iPrOH 9:1).
À1
[a] =À120 (c=1.0 in acetone) for (S), 39% ee;
H NMR: d=5.91 (d,
D
J=9.6 Hz, 1H), 6.21 (d, J=16.1 Hz, 1H), 6.60 (dd, J=9.6 Hz, J=
(
S)-(À)-4-Tolyl methyl sulfoxide (3d): Reaction was performed with
ALi7. Purification by silica gel chromatography afforded the product as a
white solid (120 mg, 78%, 92% ee). [a]
=À126.9 (c=2.0 in acetone);
lit: [a] =+132 (c=2.0 in acetone) for (R), 91% ee; H NMR: d=2.42
s, 3H), 2.71 (s, 3H), 7.33 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H);
HPLC: t (R)=24.0 min, t (S)=26.2 min (Chiralcel OD; flow rate,
.5 mLmin ; heptane/iPrOH 9:1).
S)-(À)-4-Methoxyphenyl methyl sulfoxide (3e): Reaction was performed
with ALi7. Purification by silica gel chromatography afforded the prod-
uct as a pale yellow oil (112 mg, 66%, 86% ee). [a]
=À129.7 (c=2.0 in
CHCl ); lit: [a] ) for (S), 86% ee; H NMR:
=À102 (c=2.0 in CHCl
d=2.71 (s, 3H), 3.86 (s, 3H), 7.04 (d, J=8.9 Hz, 2H), 7.60 (d, J=8.9 Hz,
1
r r
6.4 Hz, 1H), 7.51 (m, 3H), 7.63 (m, 2H); HPLC: t (S)=21.5 min, t
À1
(
8
R)=31.1 min (Chiralcel OB; flow rate, 0.5 mLmin ; heptane/iPrOH
:2).
S)-(À)-Phenyl allyl sulfoxide (3n): Reaction was performed with ALi7.
Purification by silica gel chromatography afforded the product as a
yellow oil (104 mg, 63%, 71% ee). [a]
D
[
27] 1
D
(
(
r
r
À1
D
=À143 (c=1.0 in acetone); lit:
=À107 (c=1.0 in acetone) for (S) 61% ee; H NMR: d=3.55 (m,
H), 5.20 (d, J=16.8 Hz, 1H), 5.34 (d, J=10.1 Hz, 1H), 5.66 (m, 1H),
0
[29] 1
[
a]
D
(
2
7
.52 (m, 3H), 7.60 (m, 2H); HPLC: t
r
(S)=19.6 min, t
r
(R)=34.4 min
À1
D
(
Chiralcel OB; flow rate, 0.5 mLmin ; heptane/iPrOH 8:2).
[
27] 1
3
D
3
(
+)-Benzyl methyl sulfoxide (3o): Reaction was performed with ALi7.
Purification by silica gel chromatography afforded the product (99 mg,
2
0
H); HPLC: t
.5 mLmin ; heptane/iPrOH 7:3).
r
(S)=50.0 min, t
r
(R)=92.1 min (Chiralcel OB; flow rate,
6
4%, 23% ee). [a]
D
[30] 1
=+21 (c=1.9 in EtOH); lit: [a]
D
=À33.6 (c=3.0 in
H NMR: d=2.47 (s, 3H), 3.92 (d, J=12.8 Hz, 1H),
(+)=22.8 min, t
À1
EtOH), 58% ee;
(
S)-(À)-4-Bromophenyl methyl sulfoxide (3 f): Reaction was performed
with ALi7. Purification by silica gel chromatography afforded the prod-
uct as a white solid (130 mg, 59%, 94% ee). [a]
=À97.5 (c=1.8 in ace-
tone); lit: [a] =+77 (c=1.8 in acetone) for (R), 80% ee; H NMR:
4
.08 (d, J=12.6 Hz, 1H), 7.35 (m, 5H); HPLC: t
r
r
(À)=
À1
28.4 min (Chiralcel OB; flow rate, 0.5 mLmin ; heptane/iPrOH 8:2).
D
[
27] 1
D
d=2.65 (s, 3H), 7.46 (d, J=8.7 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H); HPLC:
À1
t
r
(S)=25.8 min, t
heptane/iPrOH 8:2).
S)-(À)-4-Chlorophenyl methyl sulfoxide (3g): Reaction was performed
with AH7. Purification by silica gel chromatography afforded the product
as a colorless oil (92 mg, 60%, 92% ee). [a]
=À109.7 (c=2.0 in ace-
tone); lit: [a] =+97 (c=2.0 in acetone) for (R), 78% ee; H NMR:
r
(R)=35.9 min (Chiralcel OB; flow rate, 0.5 mLmin
;
(
Acknowledgement
D
We are grateful to the Fonds der Chemischen Industrie and to the Deut-
sche Forschungsgemeinschaft (DFG) within the SFB 380 “Asymmetric
Synthesis by Chemical and Biological Methods” for financial support.
We also thank the Alexander von Humboldt Foundation for a postdoc-
toral fellowship (J.L.). Degussa is acknowledged for generous gifts of (S)-
and (R)-tert-leucine, and Dr. J. R. Dehli is thanked for fruitful discus-
sions.
[
27] 1
D
d=2.73 (s, 3H), 7.52 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H); HPLC:
À1
t
r
(S)=19.9 min, t
heptane/iPrOH 8:2)
S)-(À)-4-Nitrophenyl methyl sulfoxide (3h): Reaction was performed
with ALi7. Purification by silica gel chromatography afforded the prod-
uct as a white solid (66 mg, 36%, 96% ee). [a]
=À128.5 (c=0.75 in
CHCl ); lit: [a] =+156.9 (c=0.75 in CHCl ) for (R), 99.3% ee;
H NMR: d=2.80 (s, 3H), 7.85, (d, J=8.9 Hz, 2H), 8.40 (d, J=8.9 Hz,
r
(R)=30.0 min (Chiralcel OB; flow rate, 0.5 mLmin
;
(
D
[
30]
3
D
3
1
[
1] For reviews on the use of chiral sulfoxides, see: a) I. Fernꢅndez, N.
Khiar, Chem. Rev. 2003, 103, 3651–3705; b) M. C. CarreÇo, Chem.
Rev. 1995, 95, 1717–1760.
2
0
H); HPLC: t
.5 mLmin ; heptane/iPrOH 7:3).
r
(R)=42.9 min, t
r
(S)=47.5 min (Chiralcel OJ; flow rate,
À1
(
À)-2-Bromophenyl methyl sulfoxide (3i): Reaction was performed with
[2] a) A. Massa, A. V. Malkov, P. Kocovsky, A. Scettri, Tetrahedron
Lett. 2003, 44, 7179–7181; b) S. Kobayashi, C. Ogawa, H. Konishi,
M. Sugiura, J. Am. Chem. Soc. 2003, 125, 6610–6611.
[3] One of the most sold drugs in the world (with total sales in 2002 of
US$ 6.6 Billion) is the chiral sulfoxide Omeprazole. Its enantioselec-
tive synthesis involves an asymmetric sulfide oxidation. a) For a
summary of recent developments and data, see: A. M. Rouhi,
Chem. Eng. News 2003, 81(19), 56–61; b) for a general overview on
asymmetric syntheses of biologically active chiral sulfoxides, see: J.
Legros, J. R. Dehli, C. Bolm, Adv. Synth. Catal. in press.
ALi7. Purification by silica gel chromatography afforded the product as a
yellow oil (105 mg, 48%, 66% ee). [a]
D
=À174.9 (c=1.3 in CHCl
3
);
1
H NMR: d=2.83 (s, 3H), 7.38 (m, 1H), 7.59 (m, 2H), 7.95 (m, 1H);
(À)=19.3 min, t (+)=28.9 min (Chiralcel OB; flow rate,
.5 mLmin ; heptane/iPrOH 8:2).
S)-(À)-2-Methoxyphenyl methyl sulfoxide (3j): Reaction was performed
with ALi7. Purification by silica gel chromatography afforded the prod-
uct as a yellow oil (85 mg, 50%, 70% ee). [a]
=À36.0 (c=0.9 in ace-
tone); lit: [a] =+318.6 (c=1.0 in acetone) for (R), 98% ee; H NMR:
d=2.79 (s, 3H), 3.89 (s, 3H), 6.94 (d, J=8.3 Hz, 1H), 7.20 (d, J=7.5 Hz,
HPLC: t
0
r
r
À1
(
D
[
31] 1
D
[
4] Reviews on asymmetric sulfoxidations: a) H. B. Kagan, T. Luukas in
Transition Metals for Organic Synthesis (Eds.: M. Beller, C. Bolm),
Wiley-VCH, Weinheim, 1998, pp. 361–373; b) H. B. Kagan in Cata-
lytic Asymmetric Synthesis (Ed.: I. Ojima), 2nd ed., Wiley-VCH,
New York, 2000, pp. 327–356; c) C. Bolm, K. MuÇiz, J. P. Hilde-
brand in Comprehensive Asymmetric Catalysis (Eds.: E. N. Jacobsen,
A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999, pp. 697–713.
1
3
H), 7.46 (m, 1H), 7.82 (m, 1H); HPLC: t
6.15 min (Chiralcel OB; flow rate, 0.5 mLmin ; heptane/iPrOH 8:2).
r
À1
(S)=19.1 min, t
r
(R)=
(
S)-(À)-Mesityl methyl sulfoxide (3k): Reaction was performed with
ALi7. Purification by silica gel chromatography afforded the product as a
yellow oil (80 mg, 44%, 77% ee). [a]
D
=À180 (c=0.9 in acetone); lit:
=À241 (c=1.0 in acetone) for (S), 98% ee; H NMR: d=2.29 (s,
H), 2.55 (s, 6H), 2.89 (s, 3H), 6.88 (s, 2H); HPLC: t (R)=17.3 min, t
[
32] 1
[
a]
D
[5] Recently, niobium and tungsten complexes have also been involved
in asymmetric sulfoxidation reactions: a) Nb: T. Miyazaki, T. Katsu-
ki, Synlett 2003, 1046–1048; b) W: V. V. Takur, A. Sudalai, Tetrahe-
dron: Asymmetry 2003, 14, 407–410.
3
(
9
r
r
À1
S)=26.9 min (Chiralcel OD; flow rate, 0.5 mLmin ; heptane/iPrOH
:1).
Chem. Eur. J. 2005, 11, 1086 – 1092
www.chemeurj.org
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1091

C. Bolm and J. Legros
[
[
6] For a general review on the use of iron catalysts in organic synthesis,
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25% ee, measured by optical rotation).
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Top. Stereochem. 1988, 18, 249–330.
[17] It was previously demonstrated that in the absence of any additive,
the oxidation of sulfoxide to sulfone occurred in a non-enantioselec-
tive manner (see ref. [8]).
6
217–6254.
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[
19] For examples of asymmetric oxidations of sulfides followed by ki-
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into the sulfones, see ref. [4a].
[
20] For comprehensive reviews on NLE in asymmetric catalysis, see:
a) C. Bolm in Advanced Asymmetric Catalysis (Ed.: G. R. Stephen-
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3
8, 1261–1268; h) Y. Mekmouche, H. Hummel, R. Y. N. Ho, L.
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998, 110, 3088–3127; Angew. Chem. Int. Ed. 1998, 37, 2922–2959;
[
[
8] J. Legros, C. Bolm, Angew. Chem. 2003, 115, 5645–5647; Angew.
Chem. Int. Ed. 2003, 42, 5487–5489.
9] Schiff bases of this type have also been used in vanadium-catalyzed
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e) H. B. Kagan, Synlett 2001, 888–899.
[
21] For a review on models for non-heme carboxylate-bridged diiron
metalloproteins, see: E. Y. Tshuva, S. J. Lippard, Chem. Rev. 2004,
asymmetric sulfide oxidations with H
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S. J. F. Macdonald, G. Priem, R. F. W. Jackson, Synlett 2002, 1055–
2 2
O : a) C. Bolm, F. Bienewald,
1
04, 987–1012.
1
[
22] For reviews on non-heme iron catalysts in oxidation, see: a) M. Fon-
tecave, S. Mꢆnage, C. Duboc-Toia, Coord. Chem. Rev. 1998, 178–
1
1
80, 1555–1572; b) M. Costas, K. Chen, L. Que Jr., Coord. Chem.
Rev. 2000, 200–202, 517–544.
1
1
2
1
2
060; e) C. Ohta, H. Shimizu, A. Kondo, T. Katsuki, Synlett 2002,
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[
23] For a recent mechanistic study on iron-catalyzed epoxidations with
combinations of acetic acid and hydrogen peroxide, see: M. Fujita,
L. Que Jr., Adv. Synth. Catal. 2004, 346, 190–194.
[
24] The ee values given in the experimental section were determined on
the isolated product after chromatography on silica gel. All the frac-
tions containing sulfoxide were mixed before the ee measurement.
See: P. Diter, S. Taudien, O. Samuel, H. B. Kagan, J. Org. Chem.
[
10] For overviews on the use of hydrogen peroxide in oxidation reac-
tions, see: a) Catalytic Oxidations with Hydrogen Peroxide as Oxi-
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Jones, Applications of Hydrogen Peroxides and Derivatives, Royal
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1
994, 59, 370–373.
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[
[
[
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[
12] a) For an interesting list of additives used in metal-catalyzed epoxi-
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[
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[
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[
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23, 7194–7195.
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[
14] a) The vanadium-catalyzed asymmetric oxidations of 2a with Schiff
bases 1a and 1b gave 3b with 90% (see ref. [9d]) and 60% ee, re-
spectively. J. Legros, C. Bolm, unpublished results; b) see also: D. A.
Cogan, G. Liu, K. Kim, B. J. Backes, J. A. Ellman, J. Am. Chem.
Soc. 1998, 120, 8011–8019.
Received: August 19, 2004
Published online: December 22, 2004
1092
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 1086 – 1092