Selective sulfoxidation with hydrogen peroxide catalysed by a titanium catalyst

Abstract

A moisture-tolerant cyclopentadienyl–silsesquioxane titanium complex efficiently catalyses the selective oxidation of various types of sulfides to either sulfoxides (TOFs up to 32 530 h⁻¹) or sulfones with H₂O₂ (30% in water) under mild conditions.

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Introduction

The development of highly efficient catalytic systems for the oxidation of sulfides is of much current interest because the final products, sulfoxides and sulfones are important intermediates for the synthesis of chemically and biologically significant molecules¹ and also in the context of desulfurisation of fuels.²

The use of an environmentally benign oxidant such as H₂O₂ represents an important goal in oxidation reactions since it is non-toxic, cheap and forms water as the only by-product.³ Furthermore, the selective synthesis of sulfoxides over the fully oxidised sulfones represents another important challenge.

In recent years, some homogeneous H₂O₂-based catalytic systems mediated by transition metals for the oxidation of sulfides have been reported in the literature.^4,5 However, most of them present disadvantages, such as the use of excess oxidant, low chemoselectivity, and limited applicability. Notable among these are the efficient catalytic systems based on Ti,⁶ V,⁷ and Fe⁸ using equimolecular amounts of H₂O₂.

Recently, we disclosed the excellent performance of robust cyclopentadienyl–silsesquioxane titanium complexes in olefin epoxidation using H₂O₂ as the oxidant.⁹ For the first time, we demonstrated the applicability of H₂O₂ as the oxidant in reactions catalysed by titanium silsesquioxanes. Encouraged by these exciting results, we decided to explore further their catalytic activity in oxidation processes. Herein, we report an efficient method for the selective oxidation of sulfides to either sulfoxides or sulfones under green conditions using H₂O₂ as the oxidant and methanol as solvent with the titanium complex [Ti{η⁵-C₅H₄SiMe₂OPh₇Si₇O₁₁-κ²O₂}Cl] (1) (Fig. 1). To the best of our knowledge, this is the first report on the oxidation of sulfides by titanium silsesquioxane complexes using aqueous H₂O₂ as the primary oxidant. So far, the use of titanium silsesquioxanes in oxidation reactions has been limited to catalytic epoxidation of olefins.^10–14

Fig. 1 Titanium cyclopentadienyl–silsesquioxane complex (1).

Results and discussion

We first investigated the oxidation of methylphenylsulfide (thioanisole) as a model substrate to explore the potential of 1 as a sulfoxidation catalyst and optimise the reaction conditions. Such oxidation was initially performed in methanol using a 0.5 mol% loading of 1 and 1 equiv. of H₂O₂ (30% in water) at ambient temperature. We were pleased to find that thioanisole was quantitatively and chemoselectively oxidised to methylphenylsulfoxide in 5 min (Table 1, entry 1). The reaction mixture was examined after 24 h, confirming that no overoxidation process to its corresponding sulfone occurred. In addition, blank experiments confirmed that no reaction took place in the absence of the catalyst.

Table 1 Selective sulfoxidation of thioanisole to methylphenylsulfoxide catalysed by 1^a

Entry	Cat. (mol%)	% Yield^b	TOF^c
a All reactions were carried out with 0.54 mmol of thioanisole and 1 equiv. of H2O2 (30% aqueous solution) in MeOH at ambient temperature in 5 min. b Yield determined by ^1H NMR spectroscopy using mesitylene (0.26 mmol) as the internal standard. c TOFs (turnover frequencies) calculated at 5 min of reaction.
1	0.5	>99	2385
2	0.25	>99	4771
3	0.1	58	6987
4	0.01	27	32 530

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The catalyst loading could be lowered to 0.01 mol% (Table 1, entry 4) without appreciable deterioration of the effectiveness of the catalyst, achieving turnover frequency (TOF) values up to 32 530 h⁻¹. These TOF numbers are among the highest reported for titanium-catalysed reactions.⁶

We investigated the reuse and the selectivity of the catalyst by adding to the reaction mixture new charges of substrate and oxidant in a ratio of 1 : 1. Interestingly, the catalyst was reused for up to 14 cycles without any loss in its activity and selectivity. The total turnover attained was 2800. No sulfone was present in the reaction mixture after being stirred for ca. 6 h, indicating the remarkable chemoselectivity and stability of our catalyst under these reaction conditions.

To explore the scope of 1 as a sulfoxidation catalyst, we studied the oxidation of a wide variety of substrates with aqueous hydrogen peroxide under the optimised reaction conditions found for thioanisole (0.25 mol% of 1, 1 equiv. of H₂O₂, in methanol, and at room temperature). As summarised in Table 2, various aryl-alkyl (Table 2, entries 1–6) and dialkyl sulfides (Table 2, entries 7–9) were selectively oxidised in excellent yields (85–98%) within short reaction times (5–60 min). It is worth emphasising the high tolerance displayed by 1 toward sensitive functional groups such as C=C, OH, OMe, N₂O, COOEt and COOH. However, when using this protocol for oxidation of thiophene derivatives (benzothiophene and dibenzothiophene), the corresponding sulfones were formed along with the sulfoxides almost simultaneously. The low selectivity observed with diaryl sulfides is a general behaviour in electrophilic oxidation.¹⁵

Table 2 Selective oxidation of sulfides to sulfoxides catalysed by 1^a

Entry	Substrate	t (min)	% Yield^b
a All reactions were carried out with 0.54 mmol of the substrate and 1 equiv. of H2O2 (30% aqueous solution) in MeOH at ambient temperature using 0.25 mol% of the catalyst. b Isolated yields.
1		5	98
2		5	87
3		5	88
4		60	98
5		30	88
6		30	97
7		5	98
8		15	85
9		15	87

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Based on these results, we decided to pursue the oxidation of sulfides to sulfones by increasing the substrate : oxidant molar ratio. Thus, when the oxidation of thioanisole was performed in methanol using 0.5 mol% loading of 1 and 2 equiv. of H₂O₂ (30% in water) at room temperature, a mixture of the sulfoxide and sulfone was observed. Nevertheless, we were delighted to find that a slight increment of the oxidant amount up to 2.3 equiv. and a reaction temperature of 50 °C led to quantitative oxidation of thioanisole to methylphenylsulfone in a reasonable short reaction time (>99% yield in 3 h, Table 3, entry 1). Remarkably, a quasi-equivalent amount of H₂O₂ was sufficient to achieve the 99% yield of sulfone, indicating the high efficiency of this oxidation. The effect of the catalyst amount on the reaction rate was evaluated in methanol; decreasing the amount of the catalyst to 0.25 and 0.1 mol% significantly slowed down the oxidation process (Table 3, entries 2 and 3, respectively). The oxidation in different solvents under the optimum reaction conditions was also investigated. As shown in Table 3, methanol and acetonitrile yielded quantitative methylphenylsulfone in 3 h, while lower yields were obtained in dichloromethane and acetone (Table 3, entries 1, 4, 5, and 6, respectively).

Table 3 Optimisation of reaction conditions for oxidation of thioanisole to methylphenylsulfone catalysed by 1^a

Entry	Cat. (mol%)	% Yield^b	Solvent
a All reactions were carried out with 0.54 mmol of thioanisole and 2.3 equiv. of H2O2 (30% aqueous solution) in MeOH in 3 h at 50 °C. b Yield determined by ^1H NMR spectroscopy using mesitylene (0.26 mmol) as the internal standard. c Reaction time: 5 h.
1	0.5	>99	MeOH
2	0.25	76	MeOH
3	0.1	53	MeOH
4	0.5	>99	NCMe
5^c	0.5	56	CH2Cl2
6^c	0.5	60	Acetone

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Further, we explored the scope of the oxidation of sulfides to sulfones with a wide variety of substrates under the optimised reaction conditions using 0.5 mol% of catalyst 1 and 2.3 equiv. of H₂O₂ in methanol at 50 °C. Various alkyl-aryl (Table 4, entries 1–7), dialkyl (Table 4, entries 8–10), and diaryl (Table 4, entries 11–13) sulfides were oxidised quantitatively to their corresponding sulfones with high efficiency within relatively short periods of time. Results are summarised in Table 4. Significantly, challenging compounds such as benzothiophene (BTP) and dibenzothiophene (DBT) were also oxidised to their corresponding sulfones in quantitative yields (Table 4, entries 12 and 13), although a higher amount of catalyst was required for these substrates (2 mol% of 1).

Table 4 Selective oxidation of sulfides to sulfones catalysed by 1^a

Entry	Substrate	t (h)	% Yield^b
a All reactions were carried out with 0.54 mmol of the substrate and 2.3 equiv. of H2O2 (30% aqueous solution) with 0.5 mol% of catalyst 1 in MeOH at 50 °C. b Yield determined by ^1H NMR spectroscopy using mesitylene (0.26 mmol) as the internal standard. The numbers in parentheses are isolated yields. c Yield determined by GC analysis, reactions done with 2 mol% of catalyst 1. The numbers in parentheses are isolated yields.
1		3	>99 (98)
2		3	>99 (70)
3		3	>99 (85)
4		5	>99 (84)
5		3	>99 (85)
6		0.5	>99 (95)
7		3	>99 (72)
8		3	>99 (98)
9		3	>99 (97)
10		3	>99 (91)
11		5	>99 (60)^c
12		5	>99 (56)^c
13		5	>99 (70)^c

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The generally accepted mechanism for titanium-based oxidation catalysts involves the formation of a peroxo-titanium active species, in which the peroxo group is η² coordinated to the metal centre.⁶ In order to gain insight into the species formed during the course of the reaction, catalyst 1 was treated with a 10-fold excess of H₂O₂ (30% in water) in acetonitrile at ambient temperature, and the reaction was followed by MS-ESI. The MS-ESI spectrum of 1 displays an intense peak at m/z 1096.8 corresponding to the titanium ion [C₄₉H₄₅O₁₂Si₈Ti]⁺, [M-Cl]⁺. Immediately after addition of H₂O₂, a new intense peak at m/z 1146.9 appeared in the mass spectrum while the peak at 1096.8 completely disappeared from the spectrum. The peak at m/z 1146.9 displayed the characteristic pattern arising from the natural abundance of titanium isotopes and it was assigned to the aquo peroxo-titanium species [M(O–O)(H₂O)]⁺, which might be the catalytically active species.† The MS-ESI experiments were performed in acetonitrile instead of methanol (the solvent used in the catalytic assays) due to the poor solubility of the titanium species in methanol. Recently, Licini and Zonta have reported an elegant mechanistic study of the oxidation of sulfides with H₂O₂ in methanol using a titanium(IV) aminotriphenolate complex.¹⁶ Based on kinetic experiments and theoretical calculations, they proved the fundamental role of methanol in the activation of H₂O₂ in sulfoxidation. In order to clarify if MeOH could coordinate to the titanium centre of 1, we decided to study the stability of 1 in methanol by preparing a solution of 1 in deuterated chloroform, adding some drops of methanol, and monitoring the sample by NMR spectroscopy. We observed that complex 1 was maintained intact after 24 h in methanol at room temperature. Complex 1 also exhibited remarkable stability towards water; wet methanol solutions of 1 could be kept for 48 h without exhibiting any decomposition. These observations corroborate that methanol does not coordinate to complex 1. The use of methanol does not seem to accelerate the oxidation reaction, since similar activity of catalyst 1 was found when the reactions were performed in acetonitrile (Table 3, entries 1 and 4, respectively).

Conclusions

In summary, the titanium complex 1 acts as a highly efficient catalyst for the chemoselective oxidation of sulfides either to sulfoxides or to sulfones with near-stoichiometric amount of aqueous H₂O₂. This method represents the first example of a titanium silsesquioxane complex catalysing the oxidation of sulfides under environmentally friendly (H₂O₂/methanol) and mild conditions. It is worth noting that catalyst 1 showed remarkable stability towards water, being reused for up to 14 cycles without appreciable loss in its activity. We are currently investigating the potential of this type of catalyst in other oxidation processes with hydrogen peroxide.

Experimental section

Materials and methods

The compound Ti(η⁵-C₅H₄SiMe₂Cl)Cl₃ was synthesised according to the method described in the literature.¹⁷ All other reagents were used as received from commercial suppliers without further purification. All manipulations were carried out under a nitrogen atmosphere using standard Schlenk techniques and solvents were purified from appropriate drying agents. Deuterated solvents were degassed and stored over molecular sieves. ¹H, ¹³C, and ²⁹Si NMR spectra were recorded on a Bruker Avance III 400 MHz. Electrospray mass spectra (MS-ESI) were recorded on a Micromass Quattro LC instrument; nitrogen was employed as drying and nebulising gas.

Synthesis of Ti(η⁵-C₅H₄SiMe₂OPh₇Si₇O₁₁-κ²O₂)Cl (1). A solution of NEt₃ (0.40 mL, 2.88 mmol) in CH₂Cl₂ (25 mL) was added to a mixture of Ti(η⁵-C₅H₄SiMe₂Cl)Cl₃ (0.3 g, 0.96 mmol) and Ph₇Si₇O₉(OH)₃ (0.89 g, 0.96 mmol) and finely mashed. The reaction mixture was heated at 70 °C and stirred for 3 days. The resultant suspension was cooled down to room temperature and the ammonium salt was removed by filtration. The filtrate was concentrated under vacuum and the residue was extracted into toluene (5 × 15 mL). The toluene solution was concentrated (35 mL) and cooled at −20 °C to give 1 as a pale yellow solid. Yield: 1.03 g (95%). ¹H NMR (CDCl₃, 400 MHz): δ 0.43 (s, 6H; SiMe₂O), 6.89, 6.97 (m, 2 × 2H; C₅H₄), 7.33, 7.41, 7.66 (m, 14H, 7H, 14H; Ph). ¹³C NMR (CDCl₃): δ 0.9 (SiMe₂O), 123.8, 124.1, 125.8, 125.9, 126.6, 126.9, 127.7, 127.8, 127.9, 128.0, 128.2, 128.5, 128.9, 129.1, 130.2, 130.4, 130.43, 130.5, 130.6, 130.7, 131.6, 131.9 (C₅H₄ and C₆H₅). ²⁹Si NMR (CDCl₃): δ −6.7 (SiMe₂O), −70.3, −69.4, −67.3, −66.5, −65.8. Anal. calc for C₄₉H₄₅ClO₁₂Si₈Ti (1133.92): C, 51.86; H, 3.97. Found: C, 51.83; H, 4.01. MS (ESI-TOF): m/z [M-Cl]⁺ calc for C₄₉H₄₅O₁₂Si₈Ti, 1097.0; found: 1096.8 [M-Cl]⁺.

Catalytic oxidation of sulfides to sulfoxides

To a stirred mixture of catalyst, sulfide (0.54 mmol), and mesitylene (0.26 mmol, 37 μl) in MeOH (1.25 mL), 1 equiv. of H₂O₂ (30% aqueous solution, 60 μl) was added. The course of the reaction was monitored by ¹H NMR or analyzed by GC. In the latter case, aliquots of 0.1 mL were taken at regular intervals, treated with MnO₂ in 0.4 mL of CH₂Cl₂, and filtered over Celite previously to be analysed. The products were characterized by ¹H and ¹³C NMR spectroscopy.

Catalytic oxidation of sulfides to sulfones

A procedure similar to that described for sulfoxides was adopted by using 2.3 equiv. of H₂O₂ (30% aqueous solution, 140 μl) and heating to 50 °C.

To isolate the final sulfone or sulfoxide, the above-mentioned reactions were performed without mesitylene and kept until completion of the reaction. The final mixture was treated with MnO₂ in 2 mL of CH₂Cl₂, filtered over a Celite pad, and volatile liquids were removed under vacuum to afford the corresponding sulfone or sulfoxide. The data produced were identified by comparison of the NMR spectra with the reported data.¹⁸

Acknowledgements

We gratefully acknowledge financial support from FCT of Portugal, POCI 2010 and FEDER through projects PTDC/QEQ-QIN/0565/2012, CRUP and the Ministerio de Educación y Ciencia for Bilateral Action Program. We thank FCT for REDE/1517/RMN/2005. M.V. thanks the University of Alcalá for a fellowship. C. M. Almeida is acknowledged for providing data from Mass Spectrometry Services at ITQB.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: NMR and MS-ESI spectra of the compounds. See DOI: 10.1039/c4cy00965g

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