Highly enantioselective iron-catalyzed sulfide oxidation with aqueous hydrogen peroxide under simple reaction conditions

Article abstract of DOI:10.1002/anie.200460236

An attractive alternative to the currently existing methods for the metal-catalyzed oxidation of sulfides to sulfoxides is asymmetric iron-catalyzed oxidation with hydrogen peroxide as the terminal oxidant (see scheme). In the presence of a benzoic acid derivative, this simple process provides sulfoxides with up to 96% ee in moderate to good yields (up to 78%).

Full text of DOI:10.1002/anie.200460236

Angewandte
Chemie
Asymmetric Oxidations
Highly Enantioselective Iron-Catalyzed Sulfide
Oxidation with Aqueous Hydrogen Peroxide
under Simple Reaction Conditions**
Julien Legros and Carsten Bolm*
Iron is one of the most abundant metals in the universe.[1] It is
inexpensive, environmentally benign, and relatively nontoxic
in comparison to other metals. For oxidation reactions the
application of iron catalysts[2] in combination with aqueous
hydrogen peroxide[3] would be most desirable. Asymmetric
oxidations could then be achieved by the use of chiral iron
complexes. In this context we recently reported a new
enantioselective sulfide oxidation,[4–6] which provides opti-
cally active sulfoxides with up to 90% ee.[7] The catalysis
proceeds under very simple reaction conditions (at room
temperature in a capped flask) and utilizes a readily available
iron complex generated in situ from [Fe(acac)3] and Schiff
base 3.[8] Inexpensive and safe 30–35% aqueous hydrogen
peroxide serves as terminal oxidant (Scheme 1).
Although the asymmetric induction in this iron-catalyzed
sulfoxidation was remarkable, the practicability of the process
was limited owing to the low conversion of 1. Thus, under the
conditions required for high enantioselectivities, large
amounts of unconverted sulfides remained, and the best
yield of sulfoxide 2 was only 44%. We now report on a
significant improvement in this iron-catalyzed sulfide oxida-
tion, leading to both higher enantioselectivities (up to
96% ee) and better yields (up to 78%).
[*] Dr. J. Legros, Prof. Dr. C. Bolm
Institut für Organische Chemie der RWTH 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.). Degussa is acknowledged
for gifts of (S)- and (R)-tert-leucine. J.-C. Frison and Dr. Y. Yuan are
thanked for fruitful discussions.
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DOI: 10.1002/anie.200460236
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4225

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Next, several other carboxylic acids (AH2–AH6), which
varied in their electronic and steric properties, were applied
(Scheme 2). Apparently, the nature of the carboxylic acid and
the position of its substituents has a major effect on the sulfide
Scheme 1. Iron-catalyzed enantioselective sulfoxidation.
The use of additives is a common and convenient method
for the enhancement of the efficiency of metal-catalyzed
reactions,[9] as it allows the fine-tuning of the catalyst system
without redesigning the ligand.[10] Recently, Jacobsen and co-
workers reported the beneficial effects of the presence of
substoichiometric amounts of a carboxylic acid in epoxidation
reactions with H2O2 and the iron complex [FeII(mep)-
(CH3CN)2](SbF6)2 (mep = N,N’-dimethyl-N,N’-bis(2-pyridyl-
methyl)-ethylene 1,2-diamine).[11] Motivated by these obser-
vations we began to investigate the influence of benzoic acid
(AH1) on the enantioselectivity and the yield of methyl
phenyl sulfoxide (2a) obtained in the iron-catalyzed oxida-
tion of methyl phenyl sulfide (1a). As shown in Figure 1 the
Scheme 2. Effect of various carboxylic acids (AH1–AH6, 1 mol%) on
the yield (determined by NMR spectroscopic analysis) and the ee value
(measured on the crude product) of (S)-2a obtained in the asymmetric
oxidation of 1a with H2O2 (35%; 1.2 equiv) catalyzed by [Fe(acac)3]
(2 mol%) and (S)-3 (4 mol%).
oxidation. Thus, use of acids with electron-withdrawing
substituents (NO2: AH2; I: AH3) led to a decrease in the
efficiency of the catalysis (relative to the reaction with
benzoic acid, AH1). In contrast, electron-rich benzoic acids
AH4 and AH5 (with p-MeO-phenyl and mesityl groups) gave
very good results and afforded 2a with 80 and 79% ee,
respectively. The yields were slightly better as well (56% for
AH1, 66% for AH4, and 68% for AH5). Also the presence of
acetic acid (AH6) resulted in an improvement (with respect
to the original conditions), giving 2a with 68% ee.
The fact that the electron-rich carboxylic acids AH4 and
AH5 led to the best results suggested that the additives acted
as coligands, and that the essential characteristic was their
chelating properties, not their acidity. Carboxylate salts were
therefore expected to increase the efficiency of the reaction
further. To our delight we found that this hypothesis was
correct. Thus, the use of lithium 4-methoxybenzoate (ALi4) in
the oxidation of thioanisole 1a resulted in the formation of
sulfoxide 2a with 90% ee (Table 1, entry 1).[12] As shown in
Table 1, the effect of the carboxylate in the oxidation of other
substrates was similar.
Figure 1. Effect of benzoic acid (AH1) on the ee value (”; measured by
&
HPLC on the crude product) and the yield ( ; determined by NMR
spectroscopic analysis) of (S)-2a obtained in the asymmetric oxidation
of 1a with H2O2 (35%; 1.2 equiv) catalyzed by [Fe(acac)3] (2 mol%)
and (S)-3 (4 mol%).
Relative to the original protocol (without any additive),
both the enantioselectivity and the yield increased when the
sulfide oxidation was performed in the presence of either acid
AH4 or carboxylate ALi4. In most cases the latter additive
proved to be superior with respect to the former. The best
results were observed with para-substituted substrates
(Table 1, entries 11, 15, 17 and 21), leading to sulfoxides
with > 92% ee (eemax = 96%) in moderate to good yields (up
to 78%). Remarkable enantioselectivities were also attained
in the oxidation of more-challenging substrates such as phenyl
ethyl sulfide (1b) and phenyl benzyl sulfide (1c), which gave
the corresponding sulfoxides with 82 and 79% ee, respectively
effect of the acid was remarkable. Its presence improved both
the asymmetric induction as well as the yield. The best
enantioselectivity was obtained with an AH1/[Fe(acac)3] ratio
of 0.5:1. Under those conditions (see footnote in Figure 1),
the enantiomeric excess of sulfoxide 2a increased from
59% ee (no additive) to 73% ee. Furthermore, the yield of
2a rose from 41% (no additive) to 56%. The use of larger
quantities of benzoic acid afforded 2a with lower ee values,
albeit in good yield [for example, an AH1/[Fe(acac)3] ratio of
10:1 gave 2a with 9% ee in 71% yield)].
4226
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Chemie
Table 1: Catalytic enantioselective oxidation of sulfides 1 to sulfoxides 2 with H2O2 and a chiral iron
In summary, we developed an
complex in the presence of an additive.[a]
asymmetric iron-catalyzed sulfide
oxidation with hydrogen peroxide
as terminal oxidant, which pro-
vides sulfoxides with up to
96% ee in moderate to good
yields (up to 78%). The simplicity
of the process (room temperature,
aerobic atmosphere) and the high
enantioselectivities render this
process an attractive alternative to
the currently existing methods for
metal-catalyzed asymmetric sulfide
oxidations.
Entry
Config.
of 3
1
Additive
2
Yield
[%][b]
ee
Config.
[%][c,d]
of 2[e]
1
2
3
(S)
(R)
(R)
Ph-S-Me (1a)
Ph-S-Me (1a)
Ph-S-Me (1a)
ALi4
AH4
ALi4
2a
2a
2a
63
61
64
90
77
88
(S)-(À)
(R)-(+)
(R)-(+)
4
5
6
(S)
(S)
(S)
Ph-S-Et (1b)
Ph-S-Et (1b)
Ph-S-Et (1b)
–
AH4
ALi4
2b
2b
2b
30
51
56
44
71
82
(S)-(À)
(S)-(À)
(S)-(À)
7
8
9
(S)
(S)
(S)
Ph-S-Bn (1c)
Ph-S-Bn (1c)
Ph-S-Bn (1c)
–
AH4
ALi4
2c
2c
2c
40
73
64
27
79
78
(S)-(À)
(S)-(À)
(S)-(À)
Experimental Section
[Fe(acac)3] (7.1 mg, 0.02 mmol) and
ligand
dissolved
3
(18.9 mg, 0.04 mmol) were
in dichloromethane
10
11
(S)
(S)
4-MeC6H4-S-Me (1d)
4-MeC6H4-S-Me (1d)
AH4
ALi4
2d
2d
68
78
78
92
(S)-(À)
(S)-(À)
(0.7 mL), and the clear red solution
was stirred until it turned clear brown
(15 min). This solution was then trans-
ferred into a 10-mL flask containing a
suspension of either 4-methoxybenzoic
acid (AH4; 1.5 mg, 0.01 mmol) or lith-
ium salt ALi4 (1.6 mg, 0.01 mmol) in
dichloromethane (0.5 mL), and the
resulting mixture was stirred for
10 min. A solution of the sulfide 1
(1 mmol) in dichloromethane (0.8 mL)
was then added to the previous solu-
tion, followed by the dropwise addition
of aqueous H2O2 (35%; 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, the organic layer was dried
over MgSO4, filtered, and the solvent
was removed in vacuo. The product was
then purified by chromatography on
silica gel (pentane/Et2O 1:2, then ethyl
acetate). The ee values were deter-
mined by HPLC on a chiral stationary
phase (Gynkotek apparatus; UV detec-
tor UVD 170S (254 nm); 208C; flow
rate 0.5 mLminÀ1). Retention times
[min]: (R)-2a 26.5, (S)-2a 31.2 (Chir-
alcel OD; heptane/iPrOH, 9:1); (R)-2b
12
(S)
2-BrC6H4-S-Me (1e)
ALi4
2e
48
66
(À)
13
14
15
(S)
(S)
(S)
4-BrC6H4-S-Me (1 f)
4-BrC6H4-S-Me (1 f)
4-BrC6H4-S-Me (1 f)
–
AH4
ALi4
2 f
2 f
2 f
41
55
59
78
91
94
(S)-(À)
(S)-(À)
(S)-(À)
16
17
18
(S)
(S)
(S)
4-ClC6H4-S-Me (1 g)
4-ClC6H4-S-Me (1 g)
4-ClC6H4-S-Me (1 g)
–
AH4
ALi4
2g
2g
2g
32
60
53
65
92
92
(S)-(À)
(S)-(À)
(S)-(À)
19
20
21
(S)
(S)
(S)
4-NO2C6H4-S-Me (1h)
4-NO2C6H4-S-Me (1h)
4-NO2C6H4-S-Me (1h)
–
AH4
ALi4
2h
2h
2h
21
41
36
90
91
96
(S)-(À)
(S)-(À)
(S)-(À)
22
23
24
(S)
(S)
(S)
2-Naphthyl-S-Me (1i)
2-Naphthyl-S-Me (1i)
2-Naphthyl-S-Me (1i)
–
AH4
ALi4
2i
2i
2i
44
67
63
70
95
93
(S)-(À)
(S)-(À)
(S)-(À)
25
(S)
PhCH2-S-Me (1j)
ALi4
2j
64
23
(+)
[a] Reaction conditions: [Fe(acac)3] (0.02 mmol), ligand 1 (0.04 mmol), AH4 or ALi4 (0.01 mmol),
sulfide (1 mmol) and aqueous H2O2 (35%; 1.2 mmol) in CH2Cl2 at room temperature for 16 h. [b] After
column chromatography. [c] The ee values were measured on the isolated product and determined by
HPLC analysis on a chiral stationary phase. [d] In cases in which the ee value was ꢀ90%, the formation
of sulfone (10–15%) was observed; see also comment in reference [13]. [e] The absolute configurations
were assigned by comparing optical rotations and/or HPLC elution order with known literature data.
(Table 1, entries 6 and 8). The last result is particularly
22.0, (S)-2b 27.2 (Chiralcel OD; heptane/iPrOH, 9:1); (R)-2c 28.8,
(S)-2c 36.1 (Chiralcel OD; heptane/iPrOH, 9:1); (R)-2d 24.0, (S)-2d
26.2 min (Chiralcel OD; heptane/iPrOH, 9:1); (À)-2e 19.3, (+)-2e
28.9 (Chiralcel OB; heptane/iPrOH, 8:2); (S)-2 f 25.8, (R)-2 f 35.9
(Chiralcel OB; flow rate, heptane/iPrOH, 8:2); (S)-2 g 19.9, (R)-2 g
30.0 (Chiralcel OB; heptane/iPrOH, 8:2); (R)-2h 42.9, (S)-2h 47.5
(Chiralcel OJ; heptane/iPrOH, 7:3); (R)-2i 37.2, (S)-2i 40.8 (Chir-
alcel OD; heptane/iPrOH, 9:1); (+)-2j = 22.8, (À)-2j = 28.4 (Chir-
alcel OB; heptane/iPrOH, 8:2).
impressive, as the product was obtained with only 27% ee in
the absence of an additive. Furthermore, the yield of 2c
increased from 44% (no additive) to 73% (with AH4).[13]
Although it is difficult to provide a mechanistic rational
for the observed improvements at the present stage, the fact
that the best results were obtained with 0.5 equivalents of the
carboxylic acid (and/or the carboxylate salt) relative to iron
suggests that monocarboxylate-bridged diiron(iii) complexes
similar to those investigated as functional models able to
mimic non-heme metalloproteins[2,14] could be involved.
Attempts to isolate and to characterize those species
formed in situ under the conditions described herein are
currently in progress.
Received: April 6, 2004 [Z460236]
Keywords: asymmetric catalysis · iron · oxidation · peroxides ·
.
sulfoxides
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H. Grꢀger, M. Shibasaki, Angew. Chem. 1999, 111, 1672 – 1680;
Angew. Chem. Int. Ed. 1999, 38, 1570 – 1577.
[1] F. A. Cotton, G. Wilkinson, Anorganische Chemie, 4th ed.,
Verlag Chemie, Weinheim, 1982, p. 767.
[10] This strategy has already been demonstrated in asymmetric
sulfoxidations: Maruyama and co-workers used 1-methylimida-
zole with iron porphyrin catalysts,[6b,c] and Katsuki and co-
workers added methanol to Bolmꢁs vanadium catalyst (C. Ohta,
H. Shimizu, A. Kondo, T. Katsuki, Synlett 2002, 161 – 163). In
both cases improvements in enantioselectivities were observed,
whereas turnovers and yields did not increase. The use of those
additives in the iron-catalyzed reaction shown in Scheme 1 had a
negative effect.
[11] M. C. White, A. G. Doyle, E. N. Jacobsen, J. Am. Chem. Soc.
2001, 123, 7194 – 7195.
[12] Sodium, potassium, cesium and tetrabutyl ammonium salts have
also been assessed in the oxidation of 2a: ANa4, 90% ee; AK4,
88% ee; ACs4, 87% ee; ABu4N4, 82% ee.
[2] For reviews on non-heme iron catalysts in oxidation reactions,
see: a) M. Fontecave, S. MØnage, C. Duboc-Toia, Coord. Chem.
Rev. 1998, 178–180, 1555 – 1572; b) M. Costas, K. Chen, L.
Que, Jr., Coord. Chem. Rev. 2000, 200–202, 517 – 544, and
references therein.
[3] For overviews on the use of hydrogen peroxide 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 Peroxides and
Derivatives, Royal Society of Chemistry, Cambridge, 1999;
c) B. S. Lane, K. Burgess, Chem. Rev. 2003, 103, 2457 – 2473;
d) R. Noyori, M. Aoki, K. Sato, Chem. Commun. 2003, 1977 –
1986.
[13] In oxidations that give sulfoxides with high ee values (ꢀ 90%)
significant amounts of sulfone (ca. 15%) were detected in the
crude product. Preliminary studies revealed the existence of a
kinetic resolution process that enhances the inherent ee value of
the sulfoxide. This behavior contrasts that found in the original
process (without an additive[7]). Details of these findings will be
reported in due course.
[14] For a review on models for non-heme carboxylate-bridged diiron
metalloproteins, see: E. Y. Tshuva, S. J. Lippard, Chem. Rev.
2004, 104, 987 – 1012, and references therein.
[4] For reviews on asymmetric sulfoxidations, see: 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. Muæiz, J. P. Hildebrand in Comprehensive Asymmetric
Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, Berlin, 1999, pp. 697 – 713; d) for a recent review on
chiral sulfoxides, see: I. Fernµndez, N. Khiar, Chem. Rev. 2003,
103, 3651 – 3705.
[5] One of the most widely sold drugs in the world (with total sales
in 2002 of US$ 6.6 billion) is the chiral sulfoxide omeprazole. Its
enantioselective synthesis involves an asymmetric sulfide oxida-
tion. For a summary of recent developments and data, see: A. M.
Rouhi, Chem. Eng. News 2003, 81(19), 56 – 61.
[6] For other iron-catalyzed sulfoxidations, see: 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, Tetrahedron: 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; f) C.
Duboc-Toia, S. MØnage, C. Lambeaux, M. Fontecave, Tetrahe-
dron Lett. 1997, 38, 3727 – 3730; g) C. Duboc-Toia, S. MØnage,
R. Y. N. Ho, L. Que, Jr., M. Fontecave, Inorg. Chem. 1999, 38,
1261 – 1268; h) Y. Mekmouche, H. Hummel, R. Y. N. Ho, L.
Que, Jr., 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.
[7] J. Legros, C. Bolm, Angew. Chem. 2003, 115, 5645 – 5647; Angew.
Chem. Int. Ed. 2003, 42, 5487 – 5489.
[8] Schiff bases of this type have also been used in vanadium-
catalyzed asymmetric sulfide oxidations with H2O2. Most
interestingly, the same ligand 3 (derived from 3,5-di-iodosalicy-
ladehyde) that is optimal for the V-catalyzed asymmetric sulfur
oxidation is also optimal in the iron-promoted process. For the
vanadium-catalyzed reaction, 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, 34, 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. Berg-
man, J. A. Ellman, J. Org. Chem. 2003, 68, 150 – 155; f) D. J.
Weix, J. A. Ellman, Org. Lett. 2003, 5, 1317 – 1320; g) for a
review, see: C. Bolm, Coord. Chem. Rev. 2003, 237, 245 – 256,
and references therein.
[9] For an interesting list of additives used in metal-catalyzed
epoxidation with hydrogen peroxide, see reference [3c]; for a
general review on additive effects in catalysis, see: E. M. Vogl,
4228
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