常見的硫醚氧化制備砜的方法

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砜類化合物在天然產(chǎn)物及醫(yī)藥中間體中非常常見。雖然有很多方法合成砜，但最常見的方法是直接由硫醚或亞砜氧化得到。實(shí)現(xiàn)這一轉(zhuǎn)化的常見的氧化劑有：H2O2, mCPBA, , NaClO, KMnO4，氧氣等。將硫醚氧化成亞砜的反應(yīng)速度要比將硫醚氧化成砜的反應(yīng)速度快很多，所以硫醚更容易被氧化到亞砜的階段，要氧化得到砜通常需要在催化劑存在下氧化才能實(shí)現(xiàn)。

一、H2O2

H2O2是氧化制備砜的最常用的氧化劑。反應(yīng)后副產(chǎn)物是水，不引入其他雜質(zhì)，產(chǎn)物容易分離。但是要氧化硫醚得到砜，需要加入其他催化劑 ，如Ti, Mo, Fe, V, W, Re, Ru, Sc, Zr和Mn等，另外還有有機(jī)催化劑，如Cyanuric chloride (CC)，六氯環(huán)三磷腈等。

【J. Org. Chem.1993, 58, 1672】

【J. Org. Chem.2007, 72, 9924-9935】

a Sulfide (0.5 mmol), 50% H2O2, and WO3/MCM-48 (5.0 wt %, 2-3

nm, 1.0 mol %) in MeOH (2.0 mL). b Condition A: 1.1 equiv of H2O2, 25

°C, 4 h. Condition B: 3.0 equiv of H2O2, 60 °C, 12 h. c Average NMR

yields of two runs based on an internal standard (anisole), and the numbers in parentheses are isolated yields.

【Org. Lett. 2005, 7, 5015–5018】

General Procedure for the Preparation of Sulfones. To the mixture of sulfide (1 mmol) and TAPC (0.1 mmol, 0.035 g) was added 30% H2O2 (2 mmol, 0.2 mL). The mixture was stirred at room temperature for the appropriate period of time until the complete consumption of starting material as observed by TLC. After the completion of the reaction,H2O(10 mL) was added to the reaction mixture. The residue was then extracted with EtOAc (45 mL), and the combined extracts were dried (MgSO4). The filtrate was evaporated and the corresponding sulfone was obtained as the only product (Table 1). An identical procedure was employed using sulfoxide (1 mmol) 30%H2O2 (1 mmol, 0.1 mL) and TAPC (0.1 mmol, 0.035 g), for the oxidation of sulfoxides to sulfones

【J. Org. Chem. 2010, 75, 6208–6213】

General procedure for the oxidation of sulfides to sulfoxides

In a 25ml round-bottom flask, to a solution of sulfide (1 mmol) in THF (4 ml), 35% H2O2 (1 equivalent) and CC (0.4 mmol) were added successively and the mixture was stirred magnetically at r.t. for the time indicated in Table 2. The progress of the reaction was monitored

by TLC. After completion of the reaction, solid CA precipitate was filtered and washed with diethyl ether. The filtrate was neutralized by adding (10%) NaHCO3. The product was extracted with diethyl ether (3 × 5 ml) and the combined extracts were dried (Na2SO4). The solvent was removed under reduced pressure to give the corresponding pure sulfoxide. Further purification was achieved by short-column chromatography on silica gel with EtOAc/n-hexane (1:2) as the eluent.

General procedure for the oxidation of sulfides to sulfones

In a 25ml round-bottom flask, to a solution of sulfide (1 mmol) in THF (6 ml), 35% H2O2 (2.5 equivalents) and CC (1 mmol) were added successively and the mixture was stirred magnetically at r.t. for the time indicated in Table 2. The progress of the reaction was monitored by TLC. After completion of the reaction, solid CA precipitate was filtered and washed with diethyl ether. The combined filtrates were neutralized by adding (10%) NaHCO3. The product was extracted with diethyl ether (3 × 5 ml) and the combined extracts were dried (Na2SO4). Evaporation of the solvent under reduced pressure gave the corresponding pure sulfone in most cases. Further purification was achieved by recrystallization from EtOH.

【Journal of Sulfur Chemistry, 2011, 32, 435-441 】

Typical procedure. UHP (12 mol) was introduced to the solution of the trifluoroacetic anhydride (9 mmol) in acetonitrile (10 cm3) and the resulting solution was mixed at room temperature for 20 min. The substrate 1 (3 mmol for dialkyl-, and 1.5 mmol for alkyl-aryl or diary1 sulfides) was then added with stimng. The progress of the reaction was followed by TLC (silica gel; hexane-acetone 3:l). After completion of oxidation water (10 cm3) was added to the reaction mixture. The aqueous phase was extracted with dichloromethane (3x7 cm3), and the combined organic layer was washed with water (2x7 cm3). The combined extracts were then dried over sodium sulfate, filtered an concentrated in vacuo. Flash silica gel chromatography of the residue with dichloromethane-ethyl acetate 10: 1 as eluent gave of pure sulfones 2 (cf. Table 1).

【Synthetic Communications (1999), 29(13), 2235-2239】

General procedure for the preparation of sulfonesTo the mixture of sulfide (1 mmol) and 30% H2O2 (4 mmol, 0.4 ml) in acetonitrile (5 ml), TiCl4 (1 mmol, 0.11 ml) was added. The mixture was stirred at room temperature for an appropriate period of time (Table 3). A white solid (TiO2) immediately precipitated. After the complete Downloaded by [Florida State University] at 04:14 26 September 2014 162 K. Bahrami et al. consumption of the starting material as observed by TLC, the reaction mixture was filtered to give TiO2. The filtrate was poured into water (10 ml). The residue was then extracted with EtOAc (4 × 5 ml) and the combined extracts were dried (MgSO4). The filtrate was evaporated and the corresponding sulfone was obtained as the only product. In the case of sulfones 3, 7, 9, and 10, the crude product after evaporation of the solvent was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate as eluent (90:10).

【Journal of Sulfur Chemistry, 2012, 33, 155-163 】

硫酸錳【Synlett 2006, 20, 540–3544；DOI: 10.1055/s-2006-958409】

二、過氧酸

【Synlett 2005, 20, 3067-3070 】

A solution of (R)-2-((4-phenylbutan-2-yl)thio)pyrimidine (1.595 g, 6.53 mmol) (1a) in dichloromethane (13.1 mL) at 0 °C was treated with 3-chloroperoxybenzoic acid, 77% 10 max. (3.38 g, 13.7 mmol). Bath was removed and mixture allowed to warm to ambient temperature and stir until thioether and sulfoxide were consumed by LC/MS analysis (1h). Mixture was quenched with 10% sodium thiosulfate/saturated bicarbonate solution. Diluted with ethyl acetate and washed with saturated aqueous bicarbonate solution. Organics dried over sodium sulfate and concentrated. The residue was absorbed onto a plug of silica gel and purified 15 by chromatography through a Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 30-100% ethyl acetate in heptanes, to provide (R)-2-((4-phenylbutan-2- yl)sulfonyl)pyrimidine (1.57 g, 5.68 mmol, 87 % yield) as a colorless oil.

【Org. Lett. 2014, 16, 6248–6251】

三、高價(jià)鹵素氧化劑

此類氧化劑常見的有：次氯酸鈉，高碘酸鈉，H5IO6，醋酸碘苯等。但是為了完全氧化得到砜，反應(yīng)中通常也會(huì)加入催化劑。

General Procedure for the Imide-Catalyzed Oxidation of Sulfide: Oxidation of Diphenyl Sulfide 1 (Table 1, Entry 3). To a solution of 1 (10.00 g, 53.69 mmol) and cyanuric acid (0.69 g, 5.37 mmol) in toluene (100 mL) was added 10% (w/w) aqueous NaOCl (119.90 g, 161.07 mmol), and the mixture was stirred for 3 h at ambient temperature. Ethyl acetate (200 mL) and sodium sulfite (6.77 g, 53.69 mmol) were added to the reaction mixture, and the whole mixture was stirred for 0.5 h at ambient temperature. After being separated, the organic layer was washed with aqueous NaOH solution (0.3 M, 100 mL) and concentrated in vacuo. The resulting residue was crystallized in ethanol to afford 2 (11.35 g, 98%).

【J. Org. Chem. 2010, 75, 4629–4631】

氧化鋁固載的RuCl3催化下，高碘酸鈉氧化硫醚制備砜。

Preparation of the Solid-Supported Reagent

RuCl3–Al2O3 reagent was prepared by stirring a mixture of RuCl3 (10 mg) and anhydrous γ-alumina (Al2O3; 2 g) in anhydrous acetone (10 mL), overnight in a round-bottom flask followed by removal of acetone under vacuum.

Oxidation of Diphenylsulphide to Diphenyl Sulfone; General Procedure

Basic γ-alumina (2 g) and sodium metaperiodate (3 mmol) were placed in a small, round-bottom flask. The basic γ-alumina added above provided support to the metaperiodate. To the well-stirred mixture, H2O (1 mL) was added followed by Ru–Al2O3 catalyst (20 mg, 0.0005 mmol RuCl3). After 2–3 min, DMC (6 mL) was added followed by a solution of diphenylsulphide (1 mmol) in DMC (2 mL). The reaction mixture was stirred at r.t. and the progress of the reaction was monitored by thin-layer chromatography (TLC). When the reaction was complete (ca. 2 h), the mixture was filtered, the solid was rinsed with EtOAc (3 × 6 mL), and the combined filtrate was washed with brine and dried over anhydrous Na2SO4. Evaporation of the organic solvent gave the crude product, which was purified by column chromatography over silica gel (petroleum ether–EtOAc, 75:25) to provide the corresponding sulfone.

【Synthesis2016, 48, 429–436】

【J. Org. Chem.2003, 68, 5388-5391】

四、OXONE

OXONE空氣中相對(duì)穩(wěn)定，價(jià)格經(jīng)濟(jì)。OXONE氧化制備砜具有較高的選擇性，控制好當(dāng)量，雙鍵和羥基都不受影響。在氧化鋁或硅膠催化下OXONE氧化制備砜，可以通過控制當(dāng)量得到亞砜和砜【Synlett (1992), (3), 235-236 】。

In a typical experimental procedure, thioanisole (10 mmol) was dissolved in methanol (40 ml) and cooled to 0℃. To this was added a solution of 49.5% KHSO5 (30 mmoles) in water (40 ml). The resulting cloudy slurry was stirred for 4h at room temperature, diluted with water, and extracted with chloroform (3X). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give a quantitative recovery of methyl phenyl sulfone as a white solid. Solid sulfones were purified by simple recrystalization.

【Tetrahedron Lett.1981, 22, 1287-1290】

(1R, 5 R)-2-Benzenesulfonyl-5-methyl-cyclohex-2-enol (24). A solution of ketone 28 (45 g, 206 mmol) and CeCl3?7H2O (106 g, 284 mmol) in MeOH (500 ml ) was cooled to 0?C. Under mechanical stirring, 10.6 g (279 mmol) of NaBH4 was added in small portions. When the reaction was complete by TLC, H2O was slowly added until no further bubbling was observed, then a total of 500 ml of H2O was added. The solution was then extracted with CH2Cl2 (3 × 300 mL). If the solution forms an emulsion, 10-20 mL of aqueous 5% HCl can be added which will clear the solution and break any emulsion. The combined organic layers were dried over Na2SO4, and concentrated via rotary evaporation to afford 43 g analytically pure compound, which was used directly for next oxidation step. It was dissolved in MeOH (800 mL) and THF (200 mL), and cooled to 0?C, under mechanical stirring, a solution of 380 g (600 mmol) of Oxone in H2O (800 mL) was added in portions. The cooling bath was removed after half of the Oxone solution was added, and the reaction was stirred for further 24 h at room temperature, then 300 mL of CH2Cl2 was added, the layers were separated, and the aqueous layer was further extracted with CH2Cl2 (4 × 300 mL). The combined organic layers were dried over Na2SO4, and concentrated via rotary evaporation to give 46.9 g (95%) of an analytically pure white solid.

【Org. Lett. 2002, 4, 3571–3574】

Preparation of Silica gel Supported Caro’s Acid To an ice cooled 98% sulfuric acid (4.7 g) is added in small portions potassium persulfate (4.5 g) with stirring; to this is added crushed ice (13 g) and the temperature is kept below 15℃. Silica gel (5 g, Kieselgel 60G, 70–230 mm) is then added in portions to the mixture and stirred for 4 h in ice-water bath. The mixture is filtered under suction and dried in a desiccator to give a white free flowing powder.

Preparation of Benzyl Phenyl Sulfone As a Typical Procedure Caro’s acid-silica gel (1.8 g, Caro’s acid content 3 mmol),1 is slowly added to a solution of benzyl phenyl sulfide (200 mg, 1 mmol) in acetonitrile (10 ml). The resulting mixture was stirred magnetically for 5 h at 40℃. The progress of reaction is monitored by T.L.C. (eluent: n-hexane/ether; 1 : 1). On completion of the reaction, the mixture is filtered. Evaporation of the solvent gave the crude product which was recrystallized from ethanol-water to afford the pure benzyl phenyl sulfone (225 mg, 97%); 【Synthetic Communications, 2002, 32, 847–850 】

五、其他方法

KMnO4氧化制備砜

Oxidation of Diphenylsulfide in Acetonitrile: A Typical Procedure

Diphenyl sulfide (0.16 g, 1.0 mmol) was dissolved in 25mL of CH3CN and placed in a round-bottomed flask. Finely ground KMnO4 (1.0 g, 6.3 mmol) was added in small portions over a period of 15 min. The mixture was stirred vigorously at room temperature for 22 h. The product was filtered through a celite pad and the residue washed successively with CH3CN (2 x 10 mL). The filtrate was treated with three to four drops of NH2-NH2 . 2HCl in order to reduce any residual oxidant. After filtering and evaporating the solvent, pure diphenyl sulfone (0.21 g, 0.98 mmol, 98%)。

【Synthetic Communications (2005), 35(4), 571-580】

流動(dòng)化學(xué)條件下，利用臭氧氧化硫醚制備砜。

【Org. Lett., 2011, 13, 984-987】

In a typical reaction, sulfdes (2 mmol), n-butylaldehyde (6 mmol), NHPI (5 mol%) and DCE (3 g) were placed into a three-necked round bottom fask (10 mL) ftted with an oxygen balloon and a magnetic stir bar. The reaction mixture was stirred at 40 °C for 24–36 h and monitored by GC.

【Catal Lett 2022, 152, 1131–1139】