Introduction

Sulfoxides are important fragments in organic synthesis1,2,3,4 and biologically active molecules5, including commercialized medicines6,7 and antiseptics8. Oxidation of thioethers into sulfoxides was the most straightforward pathway for the synthesis of sulfoxides9,10,11. Several methods in this field were developed during the past decades, including hydrogen peroxide oxidation12,13,14, metal complexes-catalyzed oxidation15,16,17,18,19,20, organocatalytic oxidation21, photo oxidation22,23,24,25,26,27, etc. However, stoichiometric external organic or inorganic oxidants were generally required in those reactions. Thus, a large amount of environmentally unfavorable wastes were generated during the production of sulfoxides. Another issue of those methods were the low selectivity between sulfoxides and over-oxidized by-product sulfones in many cases14. Although some catalytic system showed high selectivity, but the catalyst was too expensive to practical applications15,17. With the consideration of “Green Chemistry”, an environmentally friendly, energy-saving, atom-economical, and highly selective oxidation from thioethers to sulfoxides is required.

Visible light has attracted wide attentions with its clean and abundant advantages. Outstanding works by MacMillan et al. showed the utilizations of visible light in organic reactions28. Two typical pathways normally proceeded in visible light catalysis: electron transfer and energy transfer. Ru or Ir complexes29,30,31,32,33 and some heteroatom-containing metal-free organic dyes34,35,36, which trend to grab or donate an electron in its excited state, are often used as the electron transfer catalyst. On the other hand, some rigid and conjugated organic compounds37,38,39, which can absorb visible light photon but are not capable of grabbing or donating electrons, could be used as energy transfer catalyst. Selective oxidations of thioethers into sulfoxides catalyzed by visible light photo catalysts have been widely studied24,25,26,27. Those reactions could also be classified to electron transfer process and energy transfer process as mentioned above (Fig. 1). In electron transfer process, superoxide ion (O2−) was the key oxidative intermediate27. Recently, Chao and Zhao reported a visible light-induced photo oxidation of thioethers using a dinuclear Ru-Cu complex as the catalyst23. While in energy transfer process, oxygen was directly excited to its singlet state (1O2) which served as the predominant oxidative species25. Notably, Vitamin B2 Derivative could achieve this reaction via both electron transfer process and energy transfer process22. Although visible light-induced selective oxidations of thioethers into sulfoxides under aerobic conditions have been reported, these reactions normally required expensive photo-catalysts with relatively high loading. Reactions with higher efficiency and lower cost were still required. Based on our continuous interest in photo oxidation reactions40,41,42, we decided to investigate whether thioxanthone derivatives would be an effective energy transfer catalyst in thioethers oxidation. Herein, we wish to report our recent results on visible light sensitizer-catalyzed aerobically selective oxidation of thioethers into sulfoxides.

Figure 1
figure 1

Photo oxidation of thioethers into sulfoxides.

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Results and Discussion

Optimization and scope investigation

In the beginning, methyl phenyl thioether (2a) was chosen as the model substrate. The initial attempt was conducted under oxygen atmosphere at rt using 5 mol% of thioxanthone (1a) as the catalyst, toluene as the solvent and purple LED as the light source. A 7% NMR yield of methyl phenyl sulfoxide (3a) was formed with 55% of 2a recovered (entry 1, Table 1). The low recovery was mainly caused by the loss during the process of rotary evaporation, since the boiling point of 2a was low. Encouraged by the initial result, a screening of solvents was carried out. Only trace amount of 3a was afforded when THF or CH3NO2 was used as the solvent (entries 2 and 3, Table 1). When cyclohexane, CH2Cl2, ethyl acetate (EA) or acetone was tested, the yield of 3a was slightly increased (entries 4–7, Table 1). A dramatic improvement of the yield was observed using CH3CN as the solvent (entry 8, Table 1). But on the other hand, over oxidized product, methyl phenyl sulfone (4a), was also generated in a 4% NMR yield. The reaction in CH3OH gave an excellent yield of 3a with increased selectivity of 3a/4a (entry 9, Table 1). Thus, CH3OH was chosen as the best solvent. Next, modifications of thioxanthone derivatives were conducted aiming at promoting efficiency and selectivity. Thioxanthone derivatives were synthesized by the coupling of iodine compound with thiosalicylic acid followed by Friedel-Crafts reaction43. Reaction employing 2-chloro-thioxanthone (1b) showed better selectivity but lower yield (entry 10, Table 1). When 4-phenyl-thioxanthone (1c) was used as the catalyst, the reaction gave a 99% NMR yield of 3a with the ratio of 3a:4a being more than 99:1 (entry 11, Table 1). Then methoxy group was attached at 2-position of thioxanthone, but showed lower efficiency than 1c (entry 12, Table 1). 1,4-Dihydroxy-thioxanthone (1e) was proved to be unfeasible in this transformation probably due to its low solubility (entry 13, Table 1). Thus, 1c was chosen as the best catalyst. To our delight, decreasing the amount of 1c till 0.1 mol% still gave excellent yield and selectivity (entries 14 and 15, Table 1). Further reducing the amount of 1c to 0.01 mol% led to a sharply decreased yield (entry 16, Table 1). Finally, a series of control experiments were carried out indicating both catalyst and light was necessary for this reaction (entries 17 and 18, Table 1). Furthermore, considering the thermal effect caused by the purple LED light, the reaction was carried out at 50 °C without light. The result validated that no reaction took place at all even heated (entry 19, Table 1). Thus, Condition A (0.1 mol% of 1c, CH3OH, purple LED, air atmosphere, and rt) was chosen as the optimized condition for further studies.

Table 1 Optimization of the reaction conditionsa.
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With the optimized reaction condition in hand, the scope of this oxidation was examined carefully. Some typical results are summarized in Fig. 2. Firstly, the electron effect of the aryl group in methyl aryl thioether was studied (3a–k). Excellent to good yields were obtained for methyl o-, m- or p-methoxyphenyl thioether (3b–d). Methyl 4-methylphenyl sulfoxide (3e) was formed in good yield from the corresponding reactant. In cases of substrates with halogen atom, excellent yields were obtained (3f–h). Substrates with strong electron withdrawing groups, like formyl (3i), methoxy carbonyl (3j), and nitrile (3k), were also tolerant in this reaction. When naphthyl ring was used instead of phenyl ring, a 94% isolated yield of methyl 2-naphthyl sulfoxide (3l) was generated. Secondly, we focused on the influence of alkyl group. Ethyl (3m) or cyclopropyl (3n) were applied instead of methyl. The corresponding yields were nice. Thirdly, diaryl thioether was also tolerant in this reaction, giving the corresponding sulfoxide (3o) in excellent yield and selectivity. Finally, aliphatic thioethers were examined. Di-n-butyl thioether led to an excellent yield of 3p, while tetrahydro-2H-thiopyran and tetrahydrothiophene resulted in slightly lower yields of 3q and 3r, respectively. Scale-up reaction was also conducted using 2o (Fig. 3) under Condition A. 95% of 3o was afforded. This result showed the potential in organic synthesis.

Figure 2
figure 2

Photo oxidation under Condition Aa. aAll reactions were carried out using 2 (1 mmol) and 1c (0.1 mol%) in CH3OH (5 mL) irradiated by a purple LED light at rt under air atomsphere. Isolated yield was reported.

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Figure 3
figure 3

Gram scale synthesis of 3o.

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Mechanism studies

To gain insight into the reaction mechanism, singlet oxygen quencher 1,4-diazabicyclo[2.2.2]octane (4)44 and superoxide radical anion quencher N-tert-Butyl-1-phenylmethanimine oxide (5)45,46 were added into the reaction system (Fig. 4), respectively. Severe inhibitions were observed in both cases. These results clearly indicated that both singlet oxygen and superoxide radical anion were likely involved in this transformation.

Figure 4
figure 4

Quenching experiments.

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Based on the experiment results above and literature precedents24,26,27, a possible mechanism was proposed as shown in Fig. 5. 1c was excited upon the visible light irradiation and then sensitized oxygen to its singlet state24 which is more oxidative than normal triplet oxygen. Singlet oxygen could grab one electron from the lone pair electron of thioether 2, forming thioether radical cation 6 and superoxide radical anion27. Then 6 could react with superoxide radical anion to give intermediate 727. 7 and another molecule of 2 further furnished 3 as the final product27.

Figure 5
figure 5

Proposed mechanism.

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Conclusions

In conclusion, we developed a visible light sensitizer-catalyzed highly selective oxidation from thioethers into sulfoxides under aerobic condition. This reaction employed visible light as limitless energy source and 4-phenyl-9H-thioxanthen-9-one (1c) as metal-free catalyst with the loading as low as 0.1 mol%. This reaction showed high efficiency and selectivity with broad functional group tolerance. Gram-scale reaction could also be achieved under optimized conditions in nice yield and excellent selectivity. Mechanism studies indicated that both singlet oxygen and superoxide radical anion were likely involved in this transformation via energy transfer between visible light sensitizer and oxygen. Further applications of this reaction are in progress in our group.

Methods

Synthesis of methyl phenyl sulfoxide (3a)

A solution of 1c (10 mg, 0.03 mmol) in CH3OH (100 mL) was prepared prior to use. 2a (124 mg, 1.0 mmol), 1c (3 mL, 0.1 mg/mL, 0.001 mmol), and CH3OH (2 mL) were added to a schlenk bottle which was equipped with a magnetic stirrer. The mixture was irradiated by a purple LED at rt under air atmosphere. The photoreaction was completed after 5 hours as monitored by TLC (eluent: petroleum ether/ethyl acetate = 10/1). The solvent was removed and the residue was purified by flash column chromatography on silica gel (eluent: petroleum ether→petroleum ether/ethyl acetate = 20/1→10/1→1/1) to afford 3a18 as a solid (130 mg, 93%); 1H NMR (400 MHz, CDCl3) δ 7.68–7.63 (m, 2 H), 7.57–7.47 (m, 3 H), 2.72 (s, 3 H).