This journal is c The Royal Society of Chemistry 2011 Chem. Commun., 2011, 47, 6957–6959 6957

Cite this: Chem. Commun., 2011, 47, 6957–6959

First enantioselective iron-porphyrin-catalyzed sulfide oxidation with

aqueous hydrogen peroxidewzPaul Le Maux and Gerard Simonneaux*

Received 23rd March 2011, Accepted 21st April 2011

DOI: 10.1039/c1cc11675d

The asymmetric oxidation of sulfides by H2O2 to give optically

active sulfoxides (ee up to 90%) was carried out in methanol and

water using chiral water-soluble iron porphyrins as catalysts.

The selective oxidation of sulfides to sulfoxides has attracted

much attention over the years after the pioneering work

of Kagan et al.1 and Modena et al.2 Sulfoxides constitute

chiral synthons in organic synthesis for the preparation of

biologically active compounds.3 They also serve as chiral

auxiliaries.4 Among all methods described so far,5 the

asymmetric oxidation of sulfides by metal catalysts is one of

the most attractive routes to optically active sulfoxides,3,4,6

and quite recently, even nontoxic and inexpensive iron

complexes have been developed successfully, using hydrogen

peroxide as an oxidant.7–10 Metalloporphyrins, widely studied

as models of hemes or cytochrome P-450, have been known to

exhibit the catalytic activity for monooxygenation, proceeding

via the formation of a high valency metal–oxygen complex

intermediate. However the asymmetric oxidation of sulfides

catalysed by chiral iron porphyrin is still unprecedented when

the oxidant is hydrogen peroxide. This is quite surprising

since the first metalloporphyrin-catalyzed oxygenation with

hydrogen peroxide reported the formation of sulfoxide from

sulfide11 and the enzymatic oxidation of sulfides to optically

active sulfoxides catalysed by peroxidases12–15 and other heme

proteins4 have been reported.

There are previously reported asymmetric homogeneous

iron-porphyrin-catalyzed sulfide oxidations in the literature

with iodosylbenzene as an oxidant.16–21 Many iron porphyrin–

H2O2 systems have been studied to get information on the

mechanism and nature of the active intermediates.22–25 The

two main obstacles when using hydrogen peroxide are the

high activity of many first-row transition metals in its

decomposition thereof, the so-called catalase reaction26 and

the catalyst destruction by hydroxyl radicals readily released

by homolytic H2O2 decomposition.

A chiral water-soluble iron Halterman porphyrin, due to the

presence of four sulfonate groups at the para-position,

was previously reported by our group and used for chiral

recognition of amino acids27 and catalytic carbene transfer in

water.28 Herein we report its use for catalytic asymmetric

sulfoxidation in polar solvents (water or methanol) by 35%

aqueous hydrogen peroxide (Scheme 1).

The starting point of the work described here was the

introduction of four sulfonate groups into an optically active

porphyrin with the aim of preparing water soluble porphyrins.

We choose a C2-symmetric group which contains two

norbornane groups fused to the central benzene ring, previously

reported by Halterman and Jan.29 The resulting metallo-

porphyrin28 after iron insertion (Fig. 1) is an electron-rich

iron(III) porphyrin which may tend to favour O–O homolysis

of hydroperoxide.22 Since it has been reported many times30,31

that solvent alcohols coordinate to the iron(III) porphyrin to

facilitate the heterolytic cleavage of the oxygen–oxygen bond,

we first use methanol as a solvent to favour the heterolytic

cleavage.

Oxidation of methyl phenyl sulfide was first examined with

this solvent at room temperature and lower temperatures.

The reaction is fast at room temperature though slight

over-oxidation to sulfones was observed (5%) and the

Fig. 1 Structure of the iron catalysts.

Scheme 1 Oxidation of sulfides by hydrogen peroxide.

Ingenierie Chimique et Molecules pour le Vivant, UMR CNRS 6226,Campus de Beaulieu, Universite de Rennes 1, 35042 Rennes, France.E-mail: gerard.simonneaux@univ-rennes1.fr;Fax: +33 (0)223235637; Tel: +33 (0)223236285w Electronic supplementary information (ESI) available: Experimentaldetails, chromatograms and visible spectra. See DOI: 10.1039/c1cc11675dz Dedicated to Professor Didier Astruc on the occasion of his 65thbirthday.

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6958 Chem. Commun., 2011, 47, 6957–6959 This journal is c The Royal Society of Chemistry 2011

corresponding sulfoxide was obtained with 71% ee. At �20 1C,

the ee increases to 84% whereas the yield is still maintained

after 1 hour. We next examined the oxidation of other alkyl

aryl sulfides with 1 as the catalyst under identical conditions.

Similar levels of yields and enantioselectivities were obtained.

The enantioselectivities were high (between 78 and 90%) at

�20 1C, the best results being obtained with alkyl aryl sulfides

bearing electron-withdrawing groups onto the phenyl ring. It

is also interesting to note that ee is low when the phenyl group

is replaced by benzyl. The results are summarized in Table 1.

Our goal was not only to optimize this particular reaction,

but to use it as an indicator of the mechanism of oxygen atom

transfer. Because the sulfoxide yield depends on the efficiency

of the oxygen-atom transfer, and the degree of asymmetry

induction depends on the chirality of the catalyst, we can infer

the state of the catalyst from its catalytic activity in various

media. Furthermore, the enzymatic oxidation of sulfides to

sulfoxides in water by heme peroxidases is an important

process from both the mechanistic32–34 and synthetic point

of view allowing to get optically active sulfoxides with high

enantiomeric excess.12 Consequently, a systematic investigation

of the effect of the water content on the oxidation of methyl

phenyl sulfide at room temperature was first undertaken. The

results are summarized in Table 2, showing an interesting

phenomenon for the different combination of methanol/water.

Indeed, the results show that the yield of sulfoxide and the

enantioselectivity in its formation are relatively correlated.

Even when a large amount of water is added, the yields and

ees are still maintained and correct. With pure water (pH 7)

however, both chemical yields and ees are very poor, 18% and

15%, respectively. Low solubility of the aromatic sulfides in

pure water can decrease the rate of the catalysed oxidation.

Since the contribution of the non-catalyzed reaction is weak

(o1%), the reason for low enantioselectivity may come

from porphyrin degradation. Gas apparition and catalytic

destruction were also observed in the latter case. Hydroxyl

and hydroperoxyl radicals are shown to form in homolytic

cleavage, and thus these species may be involved in porphyrin

degradation and the production of dioxygen.35,36

We next explore the effect of alcohol solvents on the

catalytic sulfoxidation of sulfide by the chiral iron porphyrin

1 and H2O2. The results in Table 3 show that the yields and ees

of methyl phenyl sulfoxide were markedly influenced by

alcohol solvents; the yields and ees were high in methanol

and ethanol, whereas only small amount of sulfoxide (ee: 41%)

was yielded with isopropyl alcohol. In the latter case, however,

it was necessary to add 50% of water to solubilize the catalyst

and, accordingly we note both a decrease of the yield and

ee (vide supra). It should be also noted that it has been demon-

strated previously that alcohols bind to metalloporphyrins as

axial ligands, and one of the effects of the alcohol solvents on

the catalyst activity results from the coordination of alcohols

as axial ligands. Steric effects may also be observed for

branched alcohols, such as iso-propanol which may be too

large to fit inside the encumbered chiral metalloporphyrin but

the weak solubility of 1 in this alcohol prevents a definitive

interpretation.

The fact that in some cases there is a slight amount of

sulfone may suggest the existence of a kinetic resolution

process during the course of the reaction. In order to investigate

this aspect an experiment was performed under standard

Table 1 Asymmetric oxidation of sulfides catalyzed by the FeClHaltS–H2O2 system

a

Entry T/1CConversionb

(%)SO : SO2

ratiob (%)Eec (%)(Config)d

1 X = H 20 100 98 : 2 71 (S)-(�)2 H 0 100 96 : 4 81 (S)-(�)3 H �20 100 95 : 5 84 (S)-(�)4 He 20 40 95 : 5 34 (S)-(�)5 p-Me 20 100 81 : 19 65 (S)-(�)6 p-Me 0 100 95 : 5 77 (S)-(�)7 p-Me �20 87 95 : 5 79 (S)-(�)8 p-OMe 20 100 76 : 24 61 (S)-(�)9 p-OMe 0 100 93 : 7 68 (S)-(�)10 p-OMe �20 95 94 : 6 76 (S)-(�)11 p-NO2 20 99 93 : 7 74 (S)-(�)12 p-NO2 0 94 94 : 6 82 (S)-(�)13 p-NO2 �20 90 95 : 5 85 (S)-(�)14 p-Br 20 99 88 : 12 72 (S)-(�)15 p-Br 0 99 93 : 7 82 (S)-(�)16 p-Br �20 82 94 : 6 82 (S)-(�)17 o-Br 20 100 97 : 3 74 (S)-(�)18 o-Br 0 98 98 : 2 82 (S)-(�)19 o-Br �20 98 98 : 2 87 (S)-(�)20 MeSCH2C6H4 20 100 83 : 17 o121 MeSCH2C6H4 0 98 91 : 9 2 (S)-(�)a Reaction conditions: a mixture containing catalyst 1 (1 mmol), sulfide

(100 mmol) and H2O2 (120 mmol) in 1 ml distilled CH3OH under argon

was stirred for 1 h. b Determined by GC on the crude reaction

mixture. c Determined by HPLC on a chiral phase. d The configura-

tions were determined on the basis of the optical rotatory. e Reaction

conditions: a mixture containing catalyst 2 (1 mmol), thioanisole

(100 mmol) and H2O2 (120 mmol) in a 1 ml distilled CH3OH :CH2Cl2mixture (1 : 1) under argon was stirred for 1 h.

Table 2 Asymmetric oxidation of thioanisole by the Fe HaltS–H2O2

system in the presence of watera

EntryMeOH :H2O(%)

Conversionb

(%)SO : SO2 ratio

b

(%)Eec

(%)

1 100 : 0 100 98 : 2 712 70 : 30 100 97 : 3 633 50 : 50 79 97 : 3 564 30 : 70 55 98 : 2 505 0 : 100 18 99 : 1 15

a Reaction conditions: a mixture containing catalyst 1 (1 mmol),

thioanisole (100 mmol) and H2O2 (120 mmol) in 1 ml distilled CH3OH

under argon was stirred at 20 1C for 1 h. b Determined by GC on the

crude reaction mixture. c Determined by HPLC on a chiral phase.

Table 3 Solvent effect on asymmetric oxidation of thioanisole by theFeCl HaltS–H2O2 system

a

Entry T/1C SolventConversionb

(%)SO : SO2

ratiob (%)Eec

(%)

1 20 MeOH 100 98 : 2 712 20 EtOH 100 97 : 3 703 20 IprOHd 30 100 : 0 43

a Reaction conditions: a mixture containing catalyst 1 (1 mmol),

thioanisole (100 mmol) and H2O2 (120 mmol) in a 1 ml solvent under

argon was stirred for 1 h at room temperature. b Determined by GC

on the crude reaction mixture. c Determined by HPLC on a chiral

phase. d 50% of water was added.

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This journal is c The Royal Society of Chemistry 2011 Chem. Commun., 2011, 47, 6957–6959 6959

asymmetric sulfide oxidation conditions using racemic sulf-

oxide as a substrate. After 1 hour reaction time, the conversion

of sulfoxide to sulfone was 30%. The ee of 10% for recovered

sulfoxide (in favor for the S-configured sulfoxide) revealed that

the sulfoxidation was indeed enantioselective. However, the

importance of the kinetic resolution under the experimental

conditions applied for the sulfide oxidation (very low amount

of sulfone) is very weak and consequently, the observed

enantioselectivity originates from the sulfide oxidation itself.

Even though the degradation of the catalyst is weak after 1

hour (o10% decrease of the Soret band, see ESIw), we decidedto study the time dependence of the asymmetric process in

more detail. Actually, most of the sulfoxidations are ended up

after 15 min.

Generally, in protic solvents which can act as a proton

donor, such as methanol and ethanol, the role of a cocatalyst

is not important, as shown by the unnecessary presence of a

cocatalyst with the iron system as reported by Traylor et al.37

Nevertheless, we noted a longer reaction time for complete

conversion of thioanisole after addition of 10 equivalents of

2-methylimidazole at room temperature with a slight increase

of the ee value: from 71% to 75%. All the results are

summarized in Table 4. As a possible explanation, imidazole

binds the iron center more strongly than methanol and may

decrease the rate of H2O2 consumption.

In conclusion, this investigation of H2O2 asymmetric oxidation

of sulfides in a protic solvent shows the practicability of the

process (absence of excess of oxidant and substrate, small

reaction time, room temperature reaction. . .) even though the

chiral catalyst does not bear a robust porphyrin ligand.

A protection of the oxoiron(IV) cation radical intermediate

from the two norbornane groups fused to the central benzene

ring is suggested since a similar reaction catalysed by

FeClTPPS yields to the destruction of the porphyrin ring.35

Ongoing work includes investigations of an extended range of

substrates, particularly those of pharmaceutical importance,

further optimization of the reaction medium and chiral

catalysts, and more experiments to precise the role of the

chirality in the mechanism.

Notes and references

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2 F. Di Furia, G. Modena and R. Seraglia, Synthesis, 1984, 325.3 J. Legros, J. R. Dehli and C. Bolm, Adv. Synth. Catal., 2005, 347,19.

4 I. Fernandez and N. Khiar, Chem. Rev., 2003, 103, 3651.5 K. Kaczorowska, Z. Kolarska, K. Mitka and P. Kowalski, Tetra-hedron, 2005, 61, 8315.

6 M. C. Carreno, G. H. Hernandez-Torres, M. Ribagorda andA. Urbano, Chem. Commun., 2009, 6129.

7 J. Legros and C. Bolm, Angew. Chem., Int. Ed., 2004, 43, 4225.8 J. Legros and C. Bolm, Chem.–Eur. J., 2005, 11, 1086.9 H. Egami and T. Katsuki, J. Am. Chem. Soc., 2007, 129, 8940.10 H. Egami and T. Katsuki, Synlett, 2008, 1543.11 S. Oae, Y. Watanabe and K. Fujimori, Tetrahedron Lett., 1982, 23,

1189.12 S. Colonna, N. Gaggero, G. Carrea and P. Pasta, J. Chem. Soc.,

Chem. Commun., 1992, 357.13 R. Z. Harris, S. L. Newmyer and P. R. Ortiz de Montellano,

J. Biol. Chem., 1993, 268, 1637.14 M. P. J. van Deurzen, F. van Rantwijk and R. A. Sheldon,

Tetrahedron, 1997, 53, 13183.15 E. N. Kadnikova and N. M. Kostic, J. Org. Chem., 2003, 68, 2600.16 J. T. Groves and P. Viski, J. Org. Chem., 1990, 55, 3628.17 Y. Naruta, F. Tani and K. Maruyama, J. Chem. Soc., Chem.

Commun., 1990, 1378.18 Y. Naruta, F. Tani and K. Maruyama, Tetrahedron: Asymmetry,

1991, 2, 533.19 L. C. Chiang, K. Konishi, T. Aida and S. Inoue, J. Chem. Soc.,

Chem. Commun., 1992, 254.20 S. Inoue, T. Aida and K. Konoshi, J. Mol. Catal., 1992, 74, 121.21 Y. Ferrand, R. Daviaud, P. Le Maux and G. Simonneaux, Tetra-

hedron: Asymmetry, 2006, 17, 952.22 B. Meunier, Chem. Rev., 1992, 92, 1411.23 W. Nam, H. J. Han, S.-Y. Oh, Y. J. Lee, M.-H. Choi, S.-Y. Han,

C. Kim, S. K. Woo and W. Shin, J. Am. Chem. Soc., 2000, 122,8677.

24 E. Baciocchi, M. F. Gerini, O. Lanzalunga, A. Lapi and M. GraziaLo Piparo, Org. Biomol. Chem., 2003, 1, 422.

25 M. Wolak and R. van Eldik, Chem.–Eur. J., 2007, 13, 4873.26 I. W. C. E. Arends, Angew. Chem., Int. Ed., 2006, 45, 6250.27 I. Nicolas, S. Chevance, P. L. Maux and G. Simonneaux, Tetra-

hedron: Asymmetry, 2010, 21, 1788.28 I. Nicolas, P. Le Maux and G. Simonneaux, Tetrahedron Lett.,

2008, 49, 5793.29 R. L. Halterman and S. T. Jan, J. Org. Chem., 1991, 56, 5253.30 T. G. Traylor and F. Xu, J. Am. Chem. Soc., 1990, 112, 178.31 W. Nam, S.-Y. Oh, Y. J. Sun, J. Kim, W.-K. Kim, S. K. Woo and

W. Shin, J. Org. Chem., 2003, 68, 7903.32 E. Baciocchi, O. Lanzalunga, S. Malandrucco, M. Ioele and

S. Steenken, J. Am. Chem. Soc., 1996, 118, 8973.33 Y. Goto, T. Matsui, S.-i. Ozaki, Y. Watanabe and S. Fukuzumi,

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Table 4 Asymmetric oxidation of thioanisole by the FeCl HaltS–H2O2 system in the presence of 2-methylimidazolea

Entry T/1C2-Methylimidazole/mmol

Conversionb

(%)SO : SO2

ratiob (%)Eec

(%)

1 20 — 100 98 : 2 712 20 10 100 91 : 9 753 0 — 100 96 : 4 784 0 10 99 91 : 9 845 �20 — 100 95 : 5 826 �20 10 99 92 : 8 85.57d �20 10 61 92 : 8 90

a Reaction conditions: a mixture containing catalyst 1 (1 mmol),

2-methylimidazole (10 mmol) sulfide (100 mmol) and H2O2 (120 mmol)

in 1 ml distilled CH3OH under argon was stirred for 1 h. b Determined

by GC on the crude reaction mixture. c Determined by HPLC on a

chiral phase. d With 2-bromothioanisole.

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