Iron-Catalyzed Asymmetric Sulfide Oxidation with Aqueous Hydrogen Peroxide

Article abstract of DOI:10.1002/anie.200352635

An iron in the fire: Iron-based catalysts promote the asymmetric oxidation of alkyl aryl sulfides to the corresponding sulfoxides with up to 90% ee (see scheme). Simple hydrogen peroxide (30% in water) serves as the terminal oxidant.

Full text of DOI:10.1002/anie.200352635

Angewandte
Chemie
however, the latter points become more dominant and aspects
such as the simplicity of the process and the availability and
toxicity of the reactants play a very significant role.[1] With
respect to metal-catalyzed asymmetric oxidation reactions,
this means that the choice of metal and terminal oxidant is of
primary concern.[2] Along these lines, we now report an iron-
catalyzed asymmetric sulfide oxidation, which provides
optically active sulfoxides with up to 90% ee.[3] The catalysis
proceeds under very simple reaction conditions (room
temperature in a capped flask) and utilizes a readily available
chiral iron complex (44 mol%) as well as inexpensive and
safe 30% aqueous hydrogen peroxide (Scheme 1).[4]
Scheme 1. Iron-catalyzed asymmetric oxidation of sulfides to
sulfoxides.
Enantioselective oxidation of sulfides with titanium,
manganese, and vanadium complexes has been widely
studied.[5,6] Conversely, iron is relatively underrepresented
in this field, and the few systems developed so far fail in terms
of efficiency and practicability.[5] Most involve structurally
complex iron porphyrins and iodosylbenzene[7a–d] or alkyl
hydroperoxides[7e] as terminal oxidant, and the enantioselec-
tivities are only moderate (< 55% ee).[8] The iron complex
[Fe2O(pb)4(H2O)2](ClO4)4] (pb = (À )-4,5-pinene-2,2’-bipyri-
dine) as a catalyst for sulfide oxidations with H2O2 was
reported by Fontecave and co-workers but, unfortunately, the
enantioselectivity remained rather low (max. 40% ee).[9]
We have now found that sulfides can rapidly be oxidized
to give chiral sulfoxides (max. 90% ee) by using an iron
catalyst formed in situ from [Fe(acac)3] and a Schiff base of
type 1 (Scheme 1).[10] The process is synthetically interesting
for the following reasons: 1) The oxidation can be performed
without particular precautions as the presence of water and
air does not affect the outcome. 2) Aqueous hydrogen
peroxide (30%, 1.2 equiv) is the most efficient oxidizing
agent.[11] 3) Iron is abundant and relatively nontoxic in
comparison to other transition metals, and [Fe(acac)3] is
commercially available and inexpensive. 4) Ligands of type 1
are easily prepared from the corresponding aminoalcohol and
salicylaldehyde derivatives. Already the first screening with
simple ligands revealed that products with high enantioselec-
tivities could be obtained (Table 1). Further ligand adjust-
ments for specific target structures appear to be possible.
The influence of the structure of the ligand on the
enantioselectivity of the reaction was studied in the oxidation
Iron-Catalyzed Oxidations
Iron-Catalyzed Asymmetric Sulfide Oxidation
with Aqueous Hydrogen Peroxide**
Julien Legros and Carsten Bolm*
Dedicated to Dr. Jean-Pierre BØguØ
on the occasion of his 65th birthday
Research concerning new catalytic asymmetric reactions is
often focused on the efficiency of the chemical transformation
itself (i.e. yield and enantioselectivity) and less so on the
practicability of the process and on environmental as well as
economic issues. In the development of practical syntheses,
[*] Prof. Dr. C. Bolm, Dr. J. Legros
Institut für Organische Chemie
Rheinisch-Westfälische Technische Hochschule Aachen
Professor-Pirlet-Strasse 1, 52056 Aachen (Germany)
Fax: (+49)241-809-2391
E-mail: carsten.bolm@oc.rwth-aachen.de
[**] We are grateful to the Fonds der Chemischen Industrie and to the
Deutsche Forschungsgemeinschaft (DFG) within the SFB 380
“Asymmetric Synthesis by Chemical and Biological Methods” for
financial support. We thank the Alexander von Humboldt Founda-
tion for a postdoctoral fellowship (J.L.).
Angew. Chem. Int. Ed. 2003, 42, 5487 –5489
DOI: 10.1002/anie.200352635
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5487

Communications
Table 1: Catalytic enantioselective oxidation of sulfides with H2O2 and a
the catalysts and to determine which iron species is respon-
sible for the observed enantioselectivity.
chiral iron complex.[a]
Entry Ligand Sulfide 2
Sulfoxide Yield [%][b] ee [%][c] Config.[d]
1
2
3
4
5
1a
1b
1c
1d
1e
Ph-S-Me
(2a)
Ph-S-Me
(2a)
Ph-S-Me
(2a)
Ph-S-Me
(2a)
Ph-S-Me
(2a)
Ph-S-Me
(2a)
Ph-S-Et (2b) 3b
Ph-S-Bn (2c) 3c
p-ClPh-S-Me 3d
(2d)
p-BrPh-S-Me 3e
(2e)
3a
3a
3a
3a
3a
3a
27
15
27
30
36
40
26
13
23
55
59
51
(S)-(À)
(S)-(À)
(S)-(À)
(S)-(À)
(S)-(À)
(S)-(À)
Experimental Section
[Fe(acac)3] (7.1 mg, 0.02 mmol) and ligand 1 (0.04 mmol) were
dissolved in dichloromethane (1 mL) in a 10-mL flask, and the clear
red solution was stirred until it turned brown (15 min). A solution of
the sulfide (1 mmol) in dichloromethane (1 mL) was then added,
followed by the dropwise addition of aqueous H2O2 (30%; 1.2 mmol).
The flask was then capped and the reaction mixture was slowly stirred
at room temperature (approximately 150 rpm). After 16 h, the
aqueous layer was separated, and the organic layer was dried over
MgSO4, filtered, and the solvent removed in vacuo. The product was
then purified by flash chromatography on silica gel (pentane/diethyl
ether 1:1, then ethyl acetate). The enantiomeric excesses were
determined by HPLC on chiral stationary phases (Gynkotek appa-
ratus; UV detector UVD 170S (254 nm); 208C; flow rate
0.5 mLminÀ1 unless indicated otherwise). Retention times [min]:
(R)-3a 26.6, (S)-3a 31.7 (Chiralcel OD, heptane/iPrOH 9:1); (R)-3b
20.5, (S)-3b 25.7 (Chiralcel OD, heptane/iPrOH 9:1); (R)-3c 31.3,
(S)-3c 38.7 (Chiralcel OD, heptane/iPrOH 9:1); (S)-3d 23.2, (R)-3d
34.3 (Chiralcel OD, heptane/iPrOH 9:1); (S)-3e 26.1, (R)-3e 35.0
(Chiralcel OB-H, heptane/iPrOH 8:2, flow rate 0.4 mLminÀ1); (R)-3 f
44.2, (S)-3 f 49.7 (Chiralcel OJ, heptane/iPrOH 7:3); (+)-3g 38.9, (À )-
3g 43.5 (Chiralcel OD, heptane/iPrOH 9:1; optical rotation measured
in CHCl3).
6[e] 1e
7
8
9
1e
1e
1e
30
40
32
44
27
65
(S)-(À)
(S)-(À)
(S)-(À)
10
11
12
1e
1e
1e
41
21
44
78
90
70
(S)-(À)
(S)-(À)
(À)
p-NO2Ph-S- 3 f
Me (2 f)
2-Naphthyl- 3g
S-Me (2g)
[a] Reaction conditions: [Fe(acac)3] (0.02 mmol), ligand (0.04 mmol),
sulfide (1 mmol), aqueous H2O2 (30%; 1.2 mmol), CH2Cl2. [b] Yield of
isolated product. [c] The enantiomer ratios were determined by HPLC on
a chiral stationary phase. [d] The absolute configurations were assigned
by comparing optical rotations and HPLC elution orders with known
literature data. [e] Urea–H2O2 adduct (UHP, 1.2 mmol) was used instead
of aqueous H2O2.
Received: August 12, 2003 [Z52635]
Keywords: asymmetric catalysis · iron · oxidation · peroxides ·
.
sulfoxides
[1] a) R. A. Sheldon, Chem. Tech. 1994, 24, 38 – 47; b) see also: C.
Bolm, O. Beckmann, O. A. G. Dabard, Angew. Chem. 1999, 111,
957 – 959; Angew. Chem. Int. Ed. 1999, 38, 907 – 909.
of thioanisole (2a) (Table 1, entries 1–5). The highest enan-
tioselectivities were obtained with ligands derived from (S)-
tert-leucinol. In contrast to large substituents such as tert-butyl
(less than 23% ee for ligands 1b and 1c) on the aryl moiety,
halogen atoms such as Br or I (ligands 1d and 1e[10d]) increase
the enantioselectivity significantly (55 and 59% ee, respec-
tively; Table 1, entries 4 and 5).
[2] For a recent comparative assessment of asymmetric oxidations,
see: C. Bonini, G. Righi, Tetrahedron 2002, 58, 4981 – 5021.
[3] Efficient asymmetric sulfide oxidations are required in various
processes towards pharmaceutically relevant molecules. One of
the most important is the synthesis of the chiral sulfoxide,
omeprazole, which is one of the most sold drugs in the world
(sales in 2002: US$6.6 billion). For a summary of recent
developments and data, see: A. M. Rouhi, Chem. Eng. News
2003, 81(19), 56 – 61.
[4] For overviews on the use of H2O2 in oxidation reactions, see:
a) Catalytic Oxidations with Hydrogen Peroxide as Oxidant (Ed.:
G. Strukul), Kluwer Academic, Dordrecht, 1992; b) C. W. Jones,
Applications of Hydrogen Peroxide and Derivatives, Royal
Society of Chemistry, Cambridge, 1999; c) B. S. Lane, K.
Burgess, Chem. Rev. 2003, 103, 2457 – 2473.
[5] 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 Catalytic Asymmetric
Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley-VCH, New York, 2000,
pp. 327 – 356; c) C. Bolm, K. Muꢀiz, J. Hildebrand in Compre-
hensive Asymmetric Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H.
Yamamoto), Springer, Berlin, 1999, pp. 697 – 713.
[6] Recently, niobium and tungsten complexes have also been
involved in asymmetric sulfoxidation reactions: a) Nb: T.
Miyazaki, T. Katsuki, Synlett 2003, 1046 – 1048; b) W: V. V.
Takur, A. Sudalai, Tetrahedron: Asymmetry 2003, 14, 407 – 410.
[7] a) J. T. Groves, P. Viski, J. Org. Chem. 1990, 55, 3628 – 3634; b) Y.
Naruta, F. Tani, K. Maruyama, J. Chem. Soc. Chem. Commun.
1990, 1378 – 1380; c) Y. Naruta, F. Tani, K. Maruyama, Tetrahe-
The chiral iron/H2O2 system affords products with partic-
ularly high ee values in the oxidation of aryl methyl sulfides
(59–90% ee). Under the conditions described, no sulfones are
formed, which indicates that the enantioselectivities are a
direct result of the asymmetric sulfide oxidation and not of a
kinetic resolution by overoxidation of the resulting sulfox-
ide.[12] A limitation of the reported catalysis stems from the
fact that under the reaction conditions optimized to achieve
high enantioselectivities, significant amounts of the substrates
remain and the yields do not exceed 44%. All attempts to
reach higher sulfide conversions (by increasing the catalyst
loading and/or the amount of oxidant,[12] slow addition of the
oxidant, or performing the reaction under homogeneous
conditions[13]) afforded sulfoxides with lower ee values.
The results described herein, albeit not as good as those
already reported with chiral complexes of other metals,[5]
constitute the basis for a promising new approach and a
major step in the ascent of iron-catalyzed asymmetric
oxidation in general, and sulfoxidation in particular. Inves-
tigations are currently underway to improve the efficiency of
5488
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Chemie
dron: Asymmetry 1991, 2, 533 – 542; d) L.-C. Chiang, K. Konishi,
T. Aida, S. Inoue, J. Chem. Soc. Chem. Commun. 1992, 254 – 256;
e) Q. L. Zhou, K. C. Chen, Z. H. Zhu, J. Mol. Catal. 1992, 72,
59– 65.
[8] For an exception, see references [7b,c]. In these cases, Naruta
et al. reported that the oxidation of methyl pentafluorophenyl
sulfide gave a product with 73% ee.
[9] a) C. Duboc-Toia, S. MØnage, C. Lambeaux, M. Fontecave,
Tetrahedron Lett. 1997, 38, 3727 – 3730; b) Y. Mekmouche, H.
Hummel, R. Y. N. Ho, L. Que, V. Schünemann, F. Thomas, A. X.
Trautwein, C. Lebrun, K. Gorgy, J.-C. LeprÞtre, M.-N. Collomb,
A. Deronzier, M. Fontecave, S. MØnage, Chem. Eur. J. 2002, 8,
1196 – 1204.
[10] Such ligands have also been used in vanadium-catalyzed
asymmetric sulfide oxidations; see: a) C. Bolm, F. Bienewald,
Angew. Chem. 1995, 107, 2883 – 2885; Angew. Chem. Int. Ed.
Engl. 1995, 34, 2640 – 2642; b) C. Bolm, G. Schlingloff, F.
Bienewald, J. Mol. Catal. A 1997, 117, 347 – 350; c) C. Bolm, F.
Bienewald, Synlett 1998, 1327 – 1328; d) B. Pelotier, M. S. Anson,
I. B. Campbell, S. J. F. Macdonald, G. Priem, R. F. W. Jackson,
Synlett 2002, 1055 – 1060; e) S. A. Blum, R. G. Bergman, J. A.
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Ellman, Org. Lett. 2003, 5, 1317 – 1320; g) for a review, see: C.
Bolm, Coord. Chem. Rev. 2003, 237, 245 – 256, and references
therein.
[11] Urea–H2O2 adduct (UHP) also gives satisfactory results.
[12] After a reaction time of 16 h, a potassium iodide test revealed
that no more oxidant was present in the reaction medium. In the
presence of a large excess of H2O2, complete conversion of
sulfide into racemic sulfoxide and sulfone was observed. In
independent experiments, it was demonstrated that the sulfoxide
to sulfone oxidation proceeded in
manner.
a non-enantioselective
[13] Attempts to substitute dichloromethane with other solvents such
as acetonitrile, acetone, toluene, or tert-butyl methyl ether were
unsuccessful.
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