Biocatalytic Oxidation of Sulfides to Sulfones

Introduction

Sulfones have been widely used in organic synthesis to synthesize many popular and complicated molecules.¹They constitute key skeletal framework of many natural products as well as pharmaceuticals and have attracted considerable attention because of their important biological properties.² A few medicinally privileged compounds containing sulfone as the structural motif are shown in Figure 1.  Many compounds containing sulfonyl group are known to exhibit antibiotic, antitumor, antidepressant, antiresorptive and anticancer properties.^3-5

Figure 1: A few medicinally important Sulfones. Click here to View figure

Synthesis of sulfoxides or sulfone has attracted a great deal of attention from the researchers. They are used to stabilize intermediates like α-radicals,⁶ α-anions⁷etc. They have been also used as cationic synthons in many known reactions.⁸There are many reagents available which can carry out the complete oxidation of sulfides to sulfoxides and sulfones.^9,10 There are manyconventional oxidants available like NaBO₃,¹¹ NaClO₄,¹²Ca(ClO)₂,¹³ H₅IO₆/[Mn^IV-Mn^IV-(µ-O)₃L₂](PF₆)₂,¹⁴ KHSO₅,¹⁵ HNO₃,¹⁶(NH₄)₂Ce(NO₃)₆,¹⁷ NaIO₄,¹⁸ MnO₂,¹⁹ KMnO₄,²⁰ RuO₄,²¹ CF₃CO₃H,²² dimethyldioxirane,^23,24 t-C₄H₉O₂H,²⁵ 4-Methyl morpholine is used with OsO₄,²⁶ 3-ClC₆H₄CO₃H²⁷ and [(n-C₄H₉)₄N]-HSO₅²⁸ which resultin oxidation. The major drawback of most of the above mentioned reagents is that they were not effective for medium- to large-scale synthesis. The major factors which contribute to this are low content of effective oxygen available which would cause the desired oxidation, high cost of production and formation of unwanted side products which is not industry friendly. Singlet oxygen²⁹ or molecular oxygen combined with reagents like CH₃CH(CH₃)CHO³⁰ or CH₃CH(CH₃)CH₂CHO and Co(acac)₂³¹ have also been  widely employed. It has been observed that aqueous hydrogen peroxide having a concentration of 60% is a versatile reagent as it forms negligible side products, is industry friendly and can be transported easily.³² These added advantages have led to the development of various H₂O₂ basedoxidation methods, which primarily uses tungsten (W) as catalyst systems such as H₂WO₄,³³[C₅H₅N(n-C₁₆H₃₃)]₃PO₄-[W(O)(O₂)₂]₄,³⁴ Na₂WO₄+[(n-C₄H₉)₄N]Cl,³⁵ as well as CH₃ReO₃,³⁶ CH₃ReO₃,³⁷ 2-NO₂C₆H₄SeO₂H³⁸and hemoglobin.³⁹

The oxidation of various sulfides was carried out using a mixture containing 30% H₂O₂ and a buffer solution of NaHCO₃ in the presence of a catalyst MnSO₄.H₂O.⁴⁰A number of sulfides which contained different functional groups were subjected to oxidation (Table 1). Aromatic sulfides such as diphenyl sulfide showed complete oxidation without the use of any catalyst using both solvents acetonitrile and DMF (Table 1, Entries 1-3). The use of benzyl phenyl sulfide as a substrate to carry out the oxidation showed that acetonitrile was the best solvent for the reaction (Table 1, Entries 4 and 5). The oxidation of  p-anisyl methyl sulfide showed that the rate of the reaction was much faster in DMF than CH₃CN without the use of any catalyst. (Table 1, Entries 6-9).

Table 1: Chemical Oxidation of Various Sulfides.

Entry	Sulfide	H2O2	Solvent	Time (h)	Yield (%)
1	PhSPh	3	CH3CN	0.25	100(94)
2	PhSPh	3	DMF	0.25	100(94)
3	PhSPh	2b	CH3CN	0.25	100
4	PhSCH2Ph	5	DMF	24	55
5	PhSCH2Ph	5	CH3CN	0.25	100 (99)
6	4-OMeC6H4SMe	5	DMF	0.25	100 (70)
7	4-OMeC6H4SMe	5 b	DMF	0.25	100
8	4-OMeC6H4SMe	3.5	CH3CN	24	63
9	4-OMeC6H4SMe	3.5 b	CH3CN	24	98
10	PhSCH2CH2OH	5	DMF	0.25	72
11	PhSCH2CH2OH	5	CH3CN	0.25	100 (88)
12	PhSCH2CH2OTHP	5	DMF	0.25	80
13	PhSCH2CH2OTHP	5	CH3CN	0.25	100 (85)
14	PhSCH2CH2OTBDMS	5	DMF	0.25	72 c
15	PhSCH2CH2OTBDMS	5	CH3CN	0.25	100 (86)
16	3,5-(CF3) 2C6H3SCH2CH2OH	5	CH3CN	0.25	100 d
17	PhSCH2CO2CH2Ph	5	DMF	0.25	80 e
18	PhSCH2CO2CH2Ph	5	CH3CN	0.25	100 d
19	3-CF3C6H4SCO2CH2Ph	5	CH3CN	24	100 (93)
20	PhSCH=CH2	5	CH3CN	0.25	100 (80)
21	PhSCH2CH=CH2	5	CH3CN	0.25	95
22	(CH2= CH CH2)2S	5	CH3CN	0.25	100 (94)
23	PhCH2 SCH2CH=CH2	5	CH3CN	0.25	100 (90)
24	PhSCH2CH=C(CH3)2	5	DMF	0.25	100 (87)
25	PhSCH2CH=C(CH3)CH=C(CH3)2	5	CH3CN	0.25	100

The rate of conversion rate has been determined by spectroscopic analysis. In brackets are mentioned isolated yields after working up the reaction

There has been no use of the catalyst for the reaction.

It clearly shows sulfoxide yield in the reaction.

Only sulfoxide was formed as the oxidation product. No sulfone formation occurred.

The yield of the sulfoxide as by-product was only 20%.

However, many other examples showed acetonitrile as a better solvent to get complete oxidation product sulfone (Table 1, Entries 10-18). It was observed that both vinyl and allyl containing sulfides were completely oxidized to the corresponding sulfones (Table 1, Entries 20-23).

Another strange observation was that even reactive tri-substituted olefin containing moieties were quite inert under these strong oxidation conditions and produced the completely oxidized sulfone (Table 1, Entries 24 and 25).

Alonso et al. have demonstrated the best oxidation of various sulfides to their corresponding sulfoxides or sulfones. The oxidant that was used was 30% hydrogen peroxide without the use of any solvent.⁴¹

Materials and Methods

During the initial screening of microorganisms, it was noticed that a number of strains of microorganisms, were able to oxidize simple sulfides like butyl phenyl sulfide and benzyl phenyl sulfide. It was observed that the desired sulfoxide was either not obtained or obtained only as a minor product. In order to select a strain of micro-organisms which would cause complete oxidation of sulfide to sulfone required extensive screening of a library of microorganisms. To begin with, small molecules containing sulfides like butyl phenyl sulfide was chosen as a substrate to oxidize using different strains of micro-organisms. The bacterial cultures chosen after the initial screening were grown in a medium containing Peptone (0.5%), beef extract (0.2%), yeast extract (0.1%) and Sodium Chloride (0.5%) at a pH 7.0-7.5 for 18-24 h. The medium used for selected strains of Fungi was Peptone M (0.2%), beef extract (0.2%) and KH₂PO₄ (0.2%) at a pH of 6.0-6.5 for 48-72 h.⁴² The bacterial or fungal cells were isolated by centrifugation, followed by their washing with phosphate buffer having a pH 7.0 The cells were subjected to a bio-catalytic reaction using 2 mg of butyl phenyl sulfide at 200 rpm in a shaker for 12 h. The supernatant was extracted with 4 mL of organic solvent (ethyl acetate). The standard reagents butyl phenyl sulfoxide and sulfone were prepared by chemical oxidation with reagents like m-chloroperbenzoic acid and oxone^® respectively. The bio-catalyzed butyl phenyl sulfoxide prepared was analyzed using Thin Layer Chromatography (TLC) by running parallel standard samples of sulfoxide and sulfone. The final confirmation of sulfone was done by ¹H-NMR spectroscopy. The same reaction was repeated at a larger scale using 4 g of bacterial or fungal cells and 20 mM substrate concentration.

Approximately 20% of the strains tested (400 bacterial and 200 fungal) showed the formation of sulfone with conversion rate varying from 3-100% based on TLC analysis. A number of strains (such as BNI0011N, BNI0047N, BNI0025N, BNI0018N, BNI0029N and BNI0044N) isolated from sea water and grown in the presence of 5% NaCl produced sulfone at 10-60% conversion rate. Two strains designated as PF7 and PF9 were selected for further studies.

Results and Discussion

Two fungal Strains PF7 and PF9 have been previously described in connection with enantioselective oxidation of β-keto esters.⁴²The identification of the strains has already been reported as Aspergillus ochraceus and Penicillium funiculosum, respectively by MTCC, IMTECH. The strains have been given accession numbers MTCC 5245 and MTCC 5246. Aspergillus ochraceus and Penicillium funiculosum were grown in fungal medium as described in the experimental section. The mycelia were isolated by filtration and the cells were suspended in phosphate buffer at pH 7.0 at a concentration of 0.5 g/mL and incubated with 2 mg of butyl phenyl sulfide (3) at 200 rpm at 30 ^oC for 12 h. The supernatant was separated by centrifugation and extracted with ethyl acetate. The formation of the sulfone 7 was confirmed by ¹H NMR for which the biotransformation was repeated at 50 mg scale using 20 mM substrate concentration and 6 g washed cells. The product was assigned structures sulfone based on its ¹H NMR spectral data which showed presence of methyl group as triplet (J = 7.27 Hz) at δ 0.89, two of the methylene protons as multiplet at δ 1.35-1.45 and δ 1.64-1.79 and the methylene attached to sulfur atom at δ 3.00 as triplet (J = 7.99 Hz). The aromatic protons appeared as multiplet at δ 7.51-7.88. The NMR spectral data was different from NMR data of sulfoxide prepared by oxidation with m-chloroperbenzoic acid. The CH₂SO methylene group in sulfoxide resonated at δ 2.73 as triplet (J = 7.1Hz), approximately 0.27 ppm upfield and aromatic protons resonated at δ 7.43-7.60 approximately 0.15 ppm upfield compared to the biocatalyzed product. The ¹H NMR spectral data, however, corresponded well with ¹H NMR data of standard sample of sulfone prepared by oxidation of sulfides with oxone^®.

Similarly, Aspergillus ochraceus and Penicillium funiculosum catalyzed oxidation of methyl phenyl sulfide (1), ethyl phenyl sulfide (2) and4-Chlorothioanisole (4) produced corresponding sulfones 5, 6 and 8(Scheme 1). In all these examples, the product was different from corresponding standard sulfoxide prepared by oxidation with m-chloroperbenzoic acid. In all cases, the proton attached to the α-carbon atom of the biocatalyzed product showed 0.25-0.31 ppm downfield shift and aromatic protons 0.10-0.16 ppm downfield shift compared to standard sulfoxide. NMR spectral data of sulfones corresponded with the standard sample of sulfone prepared by oxidation of the corresponding sulfides with oxone^®.

Scheme 1: Aspergillus ochraceus and Penicillium funiculosum catalyzed oxidation of methyl phenyl sulfide yield = 90 – 95%. Click here to View scheme

Methyl 3-(phenylthio) propionate (9), prepared by conjugate addition of thiophenol on methyl acrylate on biocatalyzed reaction with Aspergillus ochraceus and Penicillium Funiculosum failed to give the desired sulfoxide 10 or sulfone 11, but TLC showed complete consumption of starting material and formation of a high polarity compound. The NMR spectral data of the isolated product showed absence of ester methyl protons, instead a broad singlet was present at δ 11.12. The aromatic protons resonated at δ 7.13-7.33 as multiplet and methylene protons as a triplet (J = 7.47 Hz) each at δ 2.62 and δ 3.10. The product was therefore assigned the structure 12 (Scheme 2). No sulfoxide or sulfone of ester, 9 or acid, 12 could be isolated from the reaction mixture.

Scheme 2: sulfoxide or sulfone of ester, 9 or acid, 12 could be isolated from the reaction mixture. Click here to View scheme

4-phenyl-4-(phenylsulfonyl)butan-2-one 15 also failed to produce any sulfoxide or sulfone, but instead gave a product, which was identified as trans-cinnamic acid 17 based on ¹H NMR spectral data. In all probabilities the trans-cinnamic acid was produced via oxidation of sulfide to either sulfoxide or sulfone (16).But neither sulfoxide nor sulfone could be isolated from the reaction mixture. Oxidation of 15 with H₂O₂ or oxone^® also resulted in the formation of 17, which indicated lability of the sulfoxide/sulfone under the reaction conditions (Scheme 3).

Scheme 3: which indicated lability of the sulfoxide/sulfone under the reaction conditions. Click here to View scheme

Conclusion

Two strains of fungi, Aspergillus ochraceus MTCC 5245 and Penicillium funiculosum MTCC 5246 have been identified which oxidize alkyl aryl sulfides to corresponding sulfones in high yield. The method is environmentally benign as it requires no organic solvents and can be carried under mild reaction conditions. However, methyl 3-(phenylthio)propionate(9) failed to give desired sulfone 11, instead only the hydrolysis of the ester functionality occurred to give acid, 12. Oxidation of 4-phenyl-4-(phenylsulfonyl)butan-2-one (15) occurred, but sulfoxide/sulfone readily eliminated under the reaction conditions to give trans-cinnamic acid (17). In a similar way, Aspergillus ochraceus and Penicillium funiculosum catalyzed oxidation of substrates such as methyl phenyl sulfide, ethyl phenyl sulfide and4-Chlorothioanisole produced corresponding sulfones. In all these examples, the product was different from corresponding standard sulfoxide prepared by oxidation with m-chloroperbenzoic acid. In all cases, the proton attached to the α-carbon atom of the biocatalyzed product showed 0.25-0.31 ppm downfield shift and aromatic protons 0.10-0.16 ppm downfield shift compared to standard sulfoxide. NMR spectral data of sulfones corresponded with the standard sample of sulfone prepared by oxidation of the corresponding sulfides with oxone^®.

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